PD-1 single domain antibodies and therapeutic compositions thereof
Provided herein are binding polypeptides that specifically bind PD-1. More specifically, provided herein are fusion proteins, including multivalent and/or multispecific constructs and chimeric antigen receptors, that bind PD-1. Also provided are pharmaceutical compositions containing the polypeptides, nucleic acid molecules encoding the polypeptides and vectors and cells thereof, and methods of use and uses of the provided PD-1 binding polypeptides for treating diseases and conditions, such as cancer.
1. A method of stimulating or inducing an immune response in a subject, the method comprising administering, to a subject in need thereof, a PD-1-binding polypeptide construct, comprising at least one heavy chain only variable domain (PD-1 VHH domain) that specifically binds PD-1, wherein the at least one PD-1 VHH domain comprises a CDR1, CDR2 and CDR3 comprising:
the amino acid sequences set forth in SEQ ID NOS: 268, 278, and 283, respectively;
the amino acid sequences set forth in SEQ ID NOS: 272, 278, and 283, respectively; or
the amino acid sequences set forth in SEQ ID NOS: 273, 278, and 283, respectively.
2. The method of claim 1 , wherein the PD-1 binding polypeptide construct comprises one or more additional binding domains that binds to a target other than PD-1.
3. The method of claim 2 , wherein the one or more additional binding domains binds a co-stimulatory molecule.
4. The method of claim 3 , wherein the co-stimulatory molecule is 41BB, OX40, GITR, ICOS, or CD28.
5. The method of claim 2 , wherein the one or more additional binding domains binds an immune checkpoint other than PD1.
6. The method of claim 2 , wherein the one or more additional binding domains binds to an activating receptor on an immune cell.
7. The method of claim 2 , wherein the one or more additional binding domains binds to a tumor associated antigen (TAA).
8. The method of claim 1 , wherein the PD-1 VHH domain that specifically binds PD-1, blocks the interaction of PD-1 and PD-L1.
9. The method of claim 1 , wherein the polypeptide comprises an immunoglobulin Fc region.
10. The method of claim 1 , wherein the at least one PD-1 VHH domain comprises the sequence set forth in any of SEQ ID NOS: 251-267, or 284, or a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any of SEQ ID NOS: 251-267, or 284 and binds PD-1.
11. The method of claim 1 , wherein the at least one PD-1 VHH domain comprises a CDR1, CDR2 and CDR3 comprising the amino acid sequence set forth in SEQ ID NOS: 273, 278, and 283, respectively.
12. The method of claim 1 , wherein the at least one PD-1 VHH domain is an isolated single domain antibody.
13. A method of treating cancer in a subject with cancer, the method comprising administering, to the subject, a therapeutically effective amount of a PD-1-binding polypeptide construct, comprising at least one heavy chain only variable domain (PD-1 VHH domain) that specifically binds PD-1, wherein the at least one PD-1 VHH domain comprises a CDR1, CDR2 and CDR3 comprising:
the amino acid sequences set forth in SEQ ID NOS: 268, 278, and 283, respectively;
the amino acid sequences set forth in SEQ ID NOS: 272, 278, and 283, respectively; or
the amino acid sequences set forth in SEQ ID NOS: 273, 278, and 283, respectively.
14. The method of claim 13 , wherein the PD-1 binding polypeptide construct comprises one or more additional binding domain that binds to a target other than PD-1.
15. The method of claim 13 , wherein the polypeptide comprises an immunoglobulin Fc region.
16. The method of claim 13 , wherein the at least one PD-1 VHH domain comprises the sequence set forth in any of SEQ ID NOS: 251-267, or 284, or a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any of SEQ ID NOS: 251-267, or 284 and binds PD-1.
17. The method of claim 13 , wherein the at least one PD-1 VHH domain comprises CDR1, CDR2 and CDR3 comprising the amino acid sequence set forth in SEQ ID NOS: 273, 278, and 283, respectively.