Anti-PD-1 antibodies, antigen-binding portions thereof and checkpoint regulator antogonists comprising the same
Checkpoint regulator antagonists that bind specifically to TIGIT, PD-1 and/or PD-L1 are disclosed. Also disclosed are methods of making and using the checkpoint regulator inhibitors, including monospecific, bispecific and trispecific checkpoint regulator antagonists thereof.
1. An antibody, or an antigen-binding portion thereof, comprising:
(1) a heavy chain variable region, wherein the heavy chain variable region comprises three complementarity determining regions (HCDRs): HCDR1, HCDR2 and HCDR3,
wherein HCDR1 has an amino acid sequence selected from the group consisting of SEQ ID NOS:48, 51, 54, 56 and 59,
wherein HCDR2 has an amino acid sequence selected from the group consisting of SEQ ID NOS:49, 52, 57 and 60, and
wherein HCDR3 has an amino acid sequence selected from the group consisting of SEQ ID NOS:50, 53, 55, 58 and 61;
(2) a light chain variable region, wherein the light chain variable region comprises three complementarity determining regions (LCDRs): LCDR1, LCDR2 and LCDR3,
wherein LCDR1 has an amino acid sequence selected from the group consisting of SEQ ID NOS:62, 65, 68, 69, 70 and 73,
wherein LCDR2 has an amino acid sequence selected from the group consisting of SEQ ID NOS:63, 66, 71 and 74, and
wherein LCDR3 has an amino acid sequence selected from the group consisting of SEQ ID NOS:64, 67, 72 and 75,
wherein the antibody, or the antigen-binding portion thereof, binds specifically to human PD-1.
2. A bispecific checkpoint regulator antagonist, comprising:
an antigen binding domain comprising the antigen-binding portion of the antibody of claim 1 .
3. The bispecific checkpoint regulator antagonist of claim 2 , further comprising an antigen binding domain that binds specifically to human TIGIT.
4. The bispecific checkpoint regulator antagonist of claim 3 , wherein the antigen binding domain that binds specifically to human TWAT comprises:
(1) a heavy chain variable region, wherein the heavy chain variable region comprises three complementarity determining regions (HCDRs): HCDR1, HCDR2 and HCDR3,
wherein HCDR1 has an amino acid sequence selected from the group consisting of SEQ ID NOS:1, 6, 11, 15, 17, 20 and 23,
wherein HCDR2 has an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 7, 9, 12, 13, 16, 18, 21 and 24, and
wherein HCDR3 has an amino acid sequence selected from the group consisting of SEQ ID NOS: 3, 5, 8, 10, 14, 19, 22 and 25; and
(2) a light chain variable region, wherein the light chain variable region comprises three complementarity determining regions (LCDRs): LCDR1, LCDR2 and LCDR3,
wherein LCDR1 has an amino acid sequence selected from the group consisting of SEQ ID NOS:26, 29, 31, 33, 35, 39, 42 and 45,
wherein LCDR2 has an amino acid sequence selected from the group consisting of SEQ ID NOS:27, 30, 36, 37, 40, 43 and 46, and
wherein LCDR3 has an amino acid sequence selected from the group consisting of SEQ ID NOS:28, 32, 34, 38, 41, 44 and 47.
5. The bispecific checkpoint regulator antagonist of claim 4 , wherein the antigen binding domain that binds specifically to human TIGIT comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO:23, an HCDR2 comprising the amino acid sequence of SEQ ID NO:24, an HCDR3 comprising the amino acid sequence of SEQ ID NO:25, an LCDR1 comprising the amino acid sequence of SEQ ID NO:45, an LCDR2 comprising the amino acid sequence of SEQ ID NO:46, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:47.
6. The bispecific checkpoint regulator antagonist of claim 5 , wherein the antigen binding domain that binds specifically to human TIGIT comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:125 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:126.
7. A method for treating a cell proliferative disorder in a subject, comprising: administering to a subject in need thereof an effective amount of the bispecific checkpoint regulator antagonist of claim 2 .
8. The antibody, or an antigen-binding portion thereof, of claim 1 , wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:56, the HCDR2 comprises the amino acid sequence of SEQ ID NO:57, the HCDR3 comprises the amino acid sequence of SEQ ID NO:58, the LCDR1 comprises the amino acid sequence of SEQ ID NO:70, the LCDR2 comprises the amino acid sequence of SEQ ID NO:71, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 72.
9. The antibody, or an antigen-binding portion thereof, of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ. ID NO:135 and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:136.
10. A bispecific checkpoint regulator antagonist, comprising:
an antigen binding domain comprising the antigen-binding portion of the antibody of claim 8 .
11. The bispecific checkpoint regulator antagonist of claim 10 , further comprising an antigen binding domain that binds specifically to human TIGIT.
12. The bispecific checkpoint regulator antagonist of claim 11 , wherein the antigen binding domain that binds specifically to human TIGIT comprises:
(1) a heavy chain variable region, wherein the heavy chain variable region comprises three complementarity determining regions (HCDRs): HCDR1, HCDR2 and HCDR3,
wherein HCDR1has an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 6, 11, 15, 17, 20 and 23,
wherein HCDR2 has an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 7, 9, 12, 13, 16, 18, 21 and 24, and
wherein HCDR3 has an amino acid sequence selected from the group consisting of SEQ ID NOS:3, 5, 8, 10, 14, 19, 22 and 25; and
(2) a light chain variable region, wherein the light chain variable region comprises three complementarity determining regions (LCDRs): LCDR1, LCDR2 and LCDR3,
wherein LCDR1 has an amino acid sequence selected from the group consisting of SEQ ID NOS:26, 29, 31, 33, 35, 39, 42 and 45,
wherein LCD has an amino acid sequence selected from the group consisting of SEQ ID NOS:27, 30, 36, 37, 40, 43 and 46, and
wherein LCDR3 has an amino acid sequence selected from the group consisting of SEQ ID NOS:28, 32, 34, 38, 41, 44 and 47.
13. The bispecific checkpoint regulator antagonist of claim 12 , wherein the antigen binding domain that binds specifically to human TIGIT comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO:23, an HCDR2 comprising the amino acid sequence of SEQ ID NO:24, an HCDR3 comprising the amino acid sequence of SEQ ID NO:25, an LCDR1 comprising the amino acid sequence of SEQ ID NO:45, an LCDR2 comprising the amino acid sequence of SEQ ID NO:46, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:47.
14. The bispecific checkpoint regulator antagonist of claim 13 , wherein the antigen binding domain that binds specifically to human TIGIT comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:125 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:126.
15. A method for treating a cell proliferative disorder in a subject, comprising: administering to a subject in need thereof an effective amount of the bispecific checkpoint regulator antagonist of claim 10 .
16. An antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that comprises the amino acid sequence of SEQ ID NO:137 and a light chain variable region that comprises the ammo acid sequence of SEQ ID NO:138, wherein the antibody, or an antigen-binding portion thereof, binds to human PD-1.
17. The antibody, or an antigen-binding portion thereof, of claim 1 , wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:59, the HCDR2 comprises the amino acid sequence of SEQ ID NO:60, the HCDR3 comprises the amino acid sequence of SEQ ID NO:61, the LCDR1 comprises the amino acid sequence of SEQ ID NO:73, the LCDR2 comprises the amino acid sequence of SEQ ID NO:74, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:75.