Immunological reagents
This disclosure relates to binding agents with specificity for programmed cell death 1 (PD-1) and to methods for using the same to treat, prevent and/or ameliorate an infectious disease (e.g., human immunodeficiency virus (HIV)), cancer and/or autoimmunity. In addition, this disclosure identifies a novel binding patch (“P2”) on PD-1 that is linked with a previously unidentified functional activity of PD-1 that is distinct from the interaction site involved with either the PD-L1 or PD-L2 ligands. Furthermore, we demonstrate that antibodies that interact with this region of PD-1 are able to act as antagonists of PD-1 and that this antagonism is further enhanced with the addition of antibodies that act through the blockade of the PD-1/PD-L1/L2 interaction.
1. A humanized antibody that binds human PD-1 and comprises a combination of a heavy chain variable region (VH) and a light chain variable region (VL) selected from the group consisting of:
a VH comprising SEQ ID NO. 170 and a VL comprising SEQ ID NO: 178;
a VH comprising SEQ ID NO. 171 and a VL comprising SEQ ID NO: 179;
a VH comprising SEQ ID NO. 172 and a VL comprising SEQ ID NO: 180;
a VH comprising SEQ ID NO. 173 and a VL comprising SEQ ID NO: 181;
a VH comprising SEQ ID NO. 174 and a VL comprising SEQ ID NO: 182;
a VH comprising SEQ ID NO. 175 and a VL comprising SEQ ID NO: 183;
a VH comprising SEQ ID NO. 176 and a VL comprising SEQ ID NO: 184;
a VH comprising SEQ ID NO. 186 and a VL comprising SEQ ID NO: 195;
a VH comprising SEQ ID NO. 187 and a VL comprising SEQ ID NO: 196;
a VH comprising SEQ ID NO. 188 and a VL comprising SEQ ID NO: 197;
a VH comprising SEQ ID NO. 189 and a VL comprising SEQ ID NO: 198;
a VH comprising SEQ ID NO. 190 and a VL comprising SEQ ID NO: 199;
a VH comprising SEQ ID NO. 191 and a VL comprising SEQ ID NO: 200;
a VH comprising SEQ ID NO. 192 and a VL comprising SEQ ID NO: 201; and,
a VH comprising SEQ ID NO. 193 and a VL comprising SEQ ID NO: 202.
2. The humanized antibody of claim 1 comprising a VH comprising SEQ ID NO. 173 and a VL comprising SEQ ID NO: 181.
3. The humanized antibody of claim 1 comprising a VH comprising SEQ ID NO. 188 and a VL comprising SEQ ID NO: 197.
4. A composition comprising the humanized antibody of claim 1 and a pharmaceutically acceptable carrier.
5. A composition comprising the humanized antibody of claim 2 and a pharmaceutically acceptable carrier.
6. A composition comprising the humanized antibody of claim 3 and a pharmaceutically acceptable carrier.
7. The composition of claim 5 further comprising a humanized antibody comprising a VH comprising SEQ ID NO. 188 and a VL comprising SEQ ID NO: 197.
8. A method for binding PD-1 on a cell comprising contacting the cell with a humanized antibody of claim 1 , or a composition comprising the same.
9. A method for binding PD-1 on a cell comprising contacting the cell with a humanized antibody of claim 2 , or a composition comprising the same.
10. A method for binding PD-1 on a cell comprising contacting the cell with a humanized antibody of claim 3 , or a composition comprising the same.
11. A method for binding PD-1 on a cell comprising contacting the cell with a humanized antibody of claim 2 and a humanized antibody comprising a VH comprising SEQ ID NO. 188 and a VL comprising SEQ ID NO: 197, or a composition comprising the same.
12. The method of claim 8 that is a method for treating disease in a human.
13. The method of claim 12 wherein the disease is selected from the group consisting of cancer, autoimmunity, and infection.
14. The method of claim 12 wherein the disease is a cancer selected from the group consisting of breast, blood, colon, stomach, rectum, skeletal tissue, skin, brain, lung, bladder, kidney, ovary and liver cancer.
15. The method of claim 12 wherein the disease is an infection by human immunodeficiency virus (HIV).
16. The method of claim 9 that is a method for treating disease in a human.
17. The method of claim 16 wherein the disease is selected from the group consisting of cancer, autoimmunity, and infection.
18. The method of claim 16 wherein the disease is a cancer selected from the group consisting of breast, blood, colon, stomach, rectum, skeletal tissue, skin, brain, lung, bladder, kidney, ovary and liver cancer.
19. The method of claim 16 wherein the disease is an infection by human immunodeficiency virus (HIV).
20. The method of claim 10 that is a method for treating disease in a human.
21. The method of claim 20 wherein the disease is selected from the group consisting of cancer, autoimmunity, and infection.
22. The method of claim 20 wherein the disease is a cancer selected from the group consisting of breast, blood, colon, stomach, rectum, skeletal tissue, skin, brain, lung, bladder, kidney, ovary and liver cancer.
23. The method of claim 20 wherein the disease is an infection by human immunodeficiency virus (HIV).
24. The method of claim 11 that is a method for treating disease in a human.
25. The method of claim 24 wherein the disease is selected from the group consisting of cancer, autoimmunity, and infection.
26. The method of claim 24 wherein the disease is a cancer selected from the group consisting of breast, blood, colon, stomach, rectum, skeletal tissue, skin, brain, lung, bladder, kidney, ovary and liver cancer.
27. The method of claim 24 wherein the disease is an infection by human immunodeficiency virus (HIV).
28. An isolated polynucleotide encoding a humanized antibody of claim 1 .
29. An expression vector comprising a polynucleotide encoding a humanized antibody of claim 1 .
30. A host cell comprising an expression vector comprising a polynucleotide encoding a humanized antibody of claim 1 .