PD-1 immune modulating agents
The present application provides anti-PD-1 antigen-binding proteins or a fragment thereof, as well as nucleic acids encoding anti-PD-1 antigen-binding proteins or CAR T cells expressing such antigen-binding protein or fragment. Also provided are methods of regulating T cells or treating patients using such constructs or cells.
1. A recombinant antigen-binding protein or antigen-binding fragment thereof, wherein the antigen is PD-1, comprising at least one of:
(A) an antigen binding region comprising an amino acid sequence that is at least 91% identical to SEQ ID NO: 53;
(B) an antigen binding region comprising a light chain variable region and a heavy chain variable region having amino acid sequences that are at least 80% identical to SEQ ID NO: 49 and at least 80% identical to SEQ ID NO:51, respectively; and
(C) an antigen binding region comprising
a light chain (LC) comprising LCCDR1, LCCDR2 and LCCDR3 having the amino acid sequences that are at least 80% identical to NIGSKS (SEQ ID NO: 34), YDS and at least 80% identical to QVWDSSSDYV (SEQ ID NO: 45), respectively, and a heavy chain (HC) comprising HCCDR1, HCCDR2 and HCCDR3 having amino acid sequences that are at least 80% identical to GFTFSSYA (SEQ ID NO: 46), at least 80% identical to ISGSGGST (SEQ ID NO. 47) and at least 80% identical to ARNYISMFDS (SEQ ID NO: 48), respectively.
2. The recombinant antigen-binding protein of claim 1 , wherein said protein is an antibody.
3. The recombinant antigen-binding protein of claim 2 , wherein the antibody is a human antibody.
4. The recombinant antigen-binding protein of claim 2 , wherein said antibody or antigen-binding fragment thereof is intact Ig, Fab, F(ab′) 2 , Fv, or scFv.
5. The antigen-binding protein of claim 1 , wherein said antigen-binding protein is a PD-1 antagonist.
6. The antigen-binding protein of claim 1 , wherein said antigen-binding protein is a chimeric antigen receptor.
7. A nucleic acid encoding an antigen-binding protein of claim 1 .
8. A vector comprising a nucleic acid of claim 7 .
9. A cell comprising a nucleic acid of claim 7 .
10. A cell comprising a vector of claim 8 .
11. An antigen-binding protein of claim 1 conjugated to a therapeutic agent.
12. The antigen-binding protein of claim 11 , wherein said therapeutic agent is a drug, toxin, radioisotope, protein, or peptide.
13. A pharmaceutical composition comprising an antigen-binding protein of claim 1 .
14. A pharmaceutical composition comprising a nucleic acid of claim 7 .
15. A pharmaceutical composition comprising a vector of claim 8 .
16. A pharmaceutical composition comprising a cell that expresses an antigen-binding protein of claim 14 .
17. A method of increasing a T cell response in a subject comprising administering to the subject a therapeutically effective amount of an antigen-binding protein or an antigen binding fragment thereof of claim 14 or a nucleic acid that encodes the antigen-binding protein or antigen binding fragment thereof.
18. The method of claim 17 , wherein the antigen-binding protein or antigen binding fragment thereof inhibits, reduces, modulates or abolishes signal transduction mediated by PD-1.
19. A vector comprising a first nucleic acid encoding the recombinant antigen-binding protein of claim 14 and a second nucleic acid encoding a chimeric antigen receptor, wherein said recombinant antigen-binding protein is not identical to said chimeric antigen receptor.
20. A cell comprising the vector of claim 19 .
21. A cell comprising a first nucleic acid encoding the recombinant antigen-binding protein of claim 14 and a second nucleic acid encoding a chimeric antigen receptor, wherein said recombinant antigen-binding protein is not identical to said chimeric antigen receptor.
22. A cell comprising a recombinant antigen-binding protein of claim 14 and a chimeric antigen receptor, wherein said recombinant antigen-binding protein is not identical to said chimeric antigen receptor.
23. A vector or a cell comprising a vector, wherein the vector comprises a polynucleotide that encodes the recombinant antigen-binding protein of claim 14 , wherein the recombinant antigen-binding protein is an antibody.
24. The vector or cell comprising the vector of claim 23 , wherein the recombinant antigen-binding protein is a human antibody.
25. The vector or cell comprising the vector of claim 23 , wherein the recombinant antigen-binding protein is an intact Ig, Fab, F(ab′) 2 , Fv, or scFv.
26. The vector or cell comprising the vector of claim 23 , wherein the recombinant antigen-binding protein is a PD-1 antagonist.
27. The vector or cell comprising the vector of claim 23 , wherein the recombinant antigen-binding protein is a secretable protein.
28. The vector or cell comprising the vector of claim 23 , wherein said vector further comprises a polynucleotide that encodes a chimeric antigen receptor and the chimeric antigen receptor specifically binds to CD19.
29. The vector or cell comprising the vector of claim 23 , wherein said vector further comprises a polynucleotide that encodes a chimeric antigen receptor and the chimeric antigen receptor comprises a transmembrane domain.
30. A pharmaceutical composition comprising the vector or cell comprising the vector of claim 23 .
31. A method of increasing a T cell response in a subject comprising administering to the subject a therapeutically effective amount of the vector of claim 23 , wherein the recombinant PD-1 antigen-binding protein is a PD-1 antagonist.
32. A method of increasing a T cell response in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises the vector of claim 23 .
33. The method of claim 32 , wherein the recombinant PD-1 antigen-binding protein inhibits, reduces, modulates or abolishes signal transduction mediated by PD-1.
34. A vector that encodes an antigen-binding protein of claim 14 and a chimeric antigen receptor or a cell comprising the vector, wherein at least one of the antigen-binding protein and chimeric antigen receptor is conjugated to a therapeutic agent.
35. The vector of claim 34 , wherein said therapeutic agent is a drug, toxin, radioisotope, protein, or peptide.
36. The recombinant antigen-binding protein of claim 14 , wherein the antigen is PD-1, comprising at least one of:
(A) an antigen binding region comprising the amino acid sequence of SEQ ID NO: 53;
(B) an antigen binding region comprising a light chain variable region and a heavy chain variable region having the amino acid sequences SEQ ID NO: 49 and SEQ ID NO:51, respectively; and
(C) an antigen binding region comprising
a light chain (LC) comprising LCCDR1, LCCDR2 and LCCDR3 having the amino acid sequences NIGSKS (SEQ ID NO: 34), YDS and QVWDSSSDYV (SEQ ID NO: 45), respectively, and a heavy chain (HC) comprising HCCDR1, HCCDR2 and HCCDR3 having amino acid sequences GFTFSSYA (SEQ ID NO: 46), ISGSGGST (SEQ ID NO. 47) and ARNYISMFDS (SEQ ID NO: 48).