Agents that bind to nkg2a and pd-l1 and uses thereof

HK40135722APending Publication Date: 2026-07-31EXELIXIS INC
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Patent Information

Application Number
HK62026124035
Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-01-27
Filing Date
2026-05-27
Publication Date
2026-07-31

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Abstract

The present disclosure provides multispecific binding agents that bind to NKG2A and PD-L1 (e.g., multispecific antibodies such as bispecific antibodies) and uses thereof.
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Description

This disclosure provides multispecific binders (e.g., multispecific antibodies such as bispecific antibodies) that bind to NKG2A and PD-L1, and their uses. Abstract

Claims

WHAT IS CLAIMED IS:

1. A multispecific antibody or fragment thereof comprising a first binding domain that binds to NKG2A and a second binding domain that binds to PD-L1, wherein the first binding domain comprises any one or more of (i)-(iv): (i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:25 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:26; (ii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:46; (iii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:65; or (iv) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:

73.

2. The multispecific antibody or fragment thereof of claim 1, wherein the first binding domain comprises (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 7, 12, 13, and 18; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 19, and 24; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 9, 15, and 20; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 10, 16, and 21; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 11, and 22; and Page 206 of 225 NAI-1537263097(3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 17, and 23.

3. The multispecific antibody or fragment thereof of claim 1, wherein the first binding domain comprises any one or more of (i)-(vi): (i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:6; (ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:8, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:9; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:6; (iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:6; (iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:13, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:14, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:15; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:16, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:17; (v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:19, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:20; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:21, a VL CDR2 comprising Page 207 of 225 NAI-1537263097the amino acid sequence of SEQ ID NO:22, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:23; or (vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:24, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

6.

4. The multispecific antibody or fragment thereof of claim 1, wherein the first binding domain comprises (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 7, 12, 13, and 18; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 27, 32, 35, 39, and 44; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 33, 36, and 40; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 34, 37, and 41; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 11, and 42; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 38, and 43.

5. The multispecific antibody or fragment thereof of claim 1, wherein the first binding domain comprises any one or more of (i)-(vi): (i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:27, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:28; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:29, a VL CDR2 comprising Page 208 of 225 NAI-1537263097the amino acid sequence of SEQ ID NO:30, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:31; (ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:33; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:34, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:31; (iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:27, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:28; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:29, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:30, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:31; (iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:13, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:36; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:37, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:38; (v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:39, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:42, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:43; or (vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:44, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:28; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:29, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:30, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

31. Page 209 of 225 NAI-15372630976. The multispecific antibody or fragment thereof of claim 1, wherein the first binding domain comprises (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 47, 51, 54, 55, and 59; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 48, 52, 56, 60, and 63; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, 53, 57, and 61; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 10, 16, and 21; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 11, and 22; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 58, and 62.

7. The multispecific antibody or fragment thereof of claim 1, wherein the first binding domain comprises any one or more of (i)-(vi): (i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:47, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:49; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:50; (ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:53; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:50; (iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:54, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH Page 210 of 225 NAI-1537263097CDR3 comprising the amino acid sequence of SEQ ID NO:49; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:50; (iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:56, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:16, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:58; (v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:59, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:60, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:61; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:21, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:22, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:62; or (vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:47, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:49; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

50.

8. The multispecific antibody or fragment thereof of claim 1, wherein the first binding domain comprises (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 47, 51, 54, 55, and 59; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 48, 52, 56, 60, and 63; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, 53, 57, and 61; and (b) a VL region comprising: Page 211 of 225 NAI-1537263097(1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 68, 70, and 71; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 67, 69, and 72; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 58, and 62.

9. The multispecific antibody or fragment thereof of claim 1, wherein the first binding domain comprises any one or more of (i)-(vi): (i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:47, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:49; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:66, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:67, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:50; (ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:53; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:68, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:69, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:50; (iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:54, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:48, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:49; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:66, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:67, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:50; (iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:56, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:70, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:69, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:58; Page 212 of 225 NAI-1537263097(v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:59, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:60, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:61; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:71, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:72, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:62; or (vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:47, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:63, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:49; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:66, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:67, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

50.

10. The multispecific antibody or fragment thereof of any one of claims 1-9, wherein the first binding domain further comprises a framework 1 (FR1), a framework 2 (FR2), a framework 3 (FR3) and / or a framework 4 (FR4) sequence, optionally as set forth in any one of SEQ ID NOs: 25, 26, 45, 46, 64, 65, and 73.

11. The multispecific antibody or fragment thereof of any one of claims 1-10, wherein the first binding domain further comprises human framework sequences.

12. The multispecific antibody or fragment thereof of any one of claims 1-11, wherein the first binding domain comprises: (i) a VH comprising the amino acid sequence of SEQ ID NO:25 and a VL comprising the amino acid sequence of SEQ ID NO:26; (ii) a VH comprising the amino acid sequence of SEQ ID NO:45 and a VL comprising the amino acid sequence of SEQ ID NO:46; (iii) a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:65; or (iv) a VH comprising the amino acid sequence of SEQ ID NO:64 and a VL comprising the amino acid sequence of SEQ ID NO:

73.

13. The multispecific antibody or fragment thereof of any one of claims 1-12, wherein the second binding domain comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:98 and a VL CDR1, a Page 213 of 225 NAI-1537263097VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:99; wherein the first binding domain binds to a complex comprising NKG2A and CD94 or extracellular domains of each thereof; wherein the first binding domain does not bind to NKG2C, or a complex comprising NKG2C and CD94 or extracellular domains of each thereof; wherein the first binding domain also binds to cyno NKG2A; and / or wherein the first binding domain does not bind to cyno NKG2A.

14. A multispecific antibody or fragment thereof comprising a first binding domain that binds to NKG2A and a second binding domain that binds to PD-L1, wherein the second binding domain comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:98 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:

99. 15 The multispecific antibody or fragment thereof of claim 13 or 14, wherein the second binding domain comprises (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 7, 12, 13, and 18; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs:86, 89, 91, 94, and 97; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs:87, 90.92, and 95; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs:4, 10, 16, and 21; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs:5, 11, and 22; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs:88, 93, and 96. Page 214 of 225 NAI-153726309716. The multispecific antibody or fragment thereof of claim 13 or 14, wherein the second binding domain comprises any one or more of (i)-(vi): (i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:86, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:87; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:88; (ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:89, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:90; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:88; (iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:86, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:87; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:88; (iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:13, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:91, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:92; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:16, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:93; (v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:94, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:95; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:21, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:22, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:96; or (vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:97, a VH Page 215 of 225 NAI-1537263097CDR3 comprising the amino acid sequence of SEQ ID NO:87; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

88.

17. The multispecific antibody or fragment thereof of claim 13 or 14, wherein the second binding domain comprises VH region comprising the amino acid sequence of SEQ ID NO:98 and a VL region comprising the amino acid sequence of SEQ ID NO:

99.

18. The multispecific antibody or fragment thereof of any one of claims 1-17, wherein the multispecific antibody or fragment thereof comprises: (i) a first polypeptide comprising from N-terminus to C-terminus: a first VL, a first CH3, a first CH2, and a second CH3; (ii) a second polypeptide comprising from N-terminus to C-terminus: a first VH and a third CH3; (iii) a third polypeptide comprising from N-terminus to C-terminus: a second VL, a CL, a second CH2, and a fourth CH3; (iv) a fourth polypeptide comprising from N-terminus to C-terminus: a second VH and a CH1; wherein the first polypeptide and the second polypeptide form the second binding domain that binds to PD-L1, and the third polypeptide and the fourth polypeptide form the first binding domain that binds to NKG2A, wherein optionally: (1) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:118, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:121, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:122; (2) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:118, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:123, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:122; Page 216 of 225 NAI-1537263097(3) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:119, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:121, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:122; (4) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:118, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:125, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:126; (5) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:118, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:124, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:126; (6) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:119, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:125, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:126; (7) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:127, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:129, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:122; (8) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:127, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:130, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:122; (9) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:128, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set Page 217 of 225 NAI-1537263097forth in SEQ ID NO:129, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:122; (10) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:127, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:132, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:126; (11) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:127, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:131, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:126; or (12) the first polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:128, the second polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:120, the third polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:132, and the fourth polypeptide comprises the amino acid sequence as set forth in SEQ ID NO:

126.

19. The multispecific antibody or fragment thereof of any one of claims 1-18, wherein the multispecific antibody or fragment thereof further comprises a third binding domain.

20. The multispecific antibody or fragment thereof of claim 19, wherein the third binding domain binds to NKG2A.

21. The multispecific antibody or fragment thereof of claim 19, wherein the third binding domain is same as the first binding domain.

22. The multispecific antibody or fragment thereof of claim 20, wherein the multispecific antibody or fragment thereof comprises: (i) a first polypeptide comprising from N-terminus to C-terminus: a first VL, a first CH3, a first CH2, and a second CH3; (ii) a second polypeptide comprising from N-terminus to C-terminus: a first VH and a third CH3; Page 218 of 225 NAI-1537263097(iii) a third polypeptide comprising from N-terminus to C-terminus: a second VL, a first CL, a third VL, a second CL, a second CH2, and a fourth CH3, wherein the second VL and the third VL are the same, and the first CL and the second CL are the same; (iv) a fourth polypeptide comprising from N-terminus to C-terminus: a second VH and a first CH1; (v) a fifth polypeptide comprising from N-terminus to C-terminus: a third VH and a second CH1; wherein the second VH and the third VH are the same, and the first CH1 and the second CH1 are the same; and wherein the first polypeptide and the second polypeptide form the second binding domain that binds to PD-L1, the third polypeptide and the fourth polypeptide form the first binding domain that binds to NKG2A, and the third polypeptide and the fifth polypeptide form the third binding domain that binds to NKG2A.

23. The multispecific antibody or fragment thereof of claim 19, wherein the third binding domain binds to PD-L1.

24. The multispecific antibody or fragment thereof of claim 23, wherein the third binding domain is same as the second binding domain.

25. The multispecific antibody or fragment thereof of claim 23, wherein the multispecific antibody or fragment thereof comprises: (i) a first polypeptide comprising from N-terminus to C-terminus: a first VL, a first CH3, a second VL, a second CH3, a first CH2, and a third CH3, wherein the first VL and the second VL are the same, and the first CH3 and the second CH3 are the same; (ii) a second polypeptide comprising from N-terminus to C-terminus: a first VH and a fourth CH3; (iii) a third polypeptide comprising from N-terminus to C-terminus: a second VH and a fifth CH3; (iv) a fourth polypeptide comprising from N-terminus to C-terminus: a third VL, a first CL, a second CH2 and a sixth CH3; (v) a fifth polypeptide comprising from N-terminus to C-terminus: a third VH and a CH1; wherein the first VH and the second VH are the same, and the fourth CH3 and the fifth CH3 are the same; and Page 219 of 225 NAI-1537263097wherein the first polypeptide and the second polypeptide form the second binding domain that binds to PD-L1, the first polypeptide and the third polypeptide form the third binding domain that binds to PD-L1, and the fourth polypeptide and the fifth polypeptide form the first binding domain that binds to NKG2A.

26. A polynucleotide encoding the multispecific antibody or fragment thereof of any one of claims 1-25.

27. One or more vectors comprising one or more polynucleotides of claim 26 or a complementary polynucleotide thereto.

28. A cell comprising any one or more of: the multispecific antibody or fragment thereof of any one of claims 1-25, the polynucleotide of claim 26, or the one or more vectors of claim 27.

29. A pharmaceutical composition that comprises a pharmaceutically acceptable excipient and any one or more of: the multispecific antibody or fragment thereof of any one of claims 1-25, the polynucleotide of claim 26, the one or more vectors of claim 27, or the cell of claim 28.

30. A method of inhibiting interaction between HLA-E and NKG2A (or a complex comprising NKG2A and CD94 or extracellular domain of each thereof) and / or inhibiting interaction between PD-1 and PD-L1, comprising contacting the NKG2A (or the complex comprising NKG2A and CD94) and / or PD-L1 with the multispecific antibody or fragment thereof of any one of claims 1-25 or the pharmaceutical composition of claim 29.

31. The method of claim 30, wherein the NKG2A cell is expressed on an immune cell.

32. The method of claim 31, wherein the immune cell is an NK cell or a T cell, optionally wherein the T cell is a CD8+T cell.

33. The method of any one of claims 30-32, wherein the HLA-E is expressed on a cancer cell. Page 220 of 225 NAI-153726309734. A method of inhibiting interaction between PD-1 and PD-L1, comprising contacting the PD-L1 with the multispecific antibody or fragment thereof of any one of claims 1-25 or the pharmaceutical composition of claim 29.

35. The method of any one of claims 30-34, wherein the PD-L1 is on an immune cell or a cancer cell.

36. The method of any one of claims 30-35, wherein the PD-l is expressed on an immune cell, optionally an NK cell or a T cell, further optionally a CD8+T cell.

37. A method of preventing suppression of an immune cell or activating a response mediated by an immune cell, comprising contacting the immune cell with the multispecific antibody or fragment thereof of any one of claims 1-25 or the pharmaceutical composition of claim 29.

38. The method of claim 37, wherein the immune cell is an NK cell or a T cell.

39. The method of claim 38, wherein the T cell is a CD8+T cell.

40. The method of any one of claims 37-39, wherein the immune cell expresses NKG2A and / or PD-1.

41. The method of any one of clams 37-40, wherein the response mediated by the immune cell is an anti-tumor response, optionally wherein the tumor cell expresses HLA-E and / or PD-L1.

42. A method for treating a disease or disorder in a subject comprising administering to the subject the multispecific antibody or fragment thereof of any one of claims 1-25, or the pharmaceutical composition of claim 29.

43. The method of claim 42, wherein the disease or disorder is a cancer, optionally the cancer expresses HLA-E and / or PD-L1.

44. The method of claim 42, wherein the disease or disorder is an autoimmune and inflammatory disease.

45. The method of any one of claims 42-44, wherein the subject is a human subject. Page 221 of 225 NAI-153726309746. An antibody or fragment thereof that binds to PD-L1, comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:98 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:

99.

47. The antibody or fragment thereof of claim 46, comprising (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 7, 12, 13, and 18; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs:86, 89, 91, 94, and 97; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs:87, 90.92, and 95; and (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs:4, 10, 16, and 21; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs:5, 11, and 22; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs:88, 93, and 96.

48. The antibody or fragment thereof of claim 46 or 47, comprising any one or more of (i)-(vi): (i) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:86, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:87; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:88; (ii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:89, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:90; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:10, a VL CDR2 comprising Page 222 of 225 NAI-1537263097the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:88; (iii) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:86, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:87; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:88; (iv) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:13, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:91, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:92; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:16, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:93; (v) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:94, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:95; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:21, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:22, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:96; or (vi) a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:97, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:87; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

88.

49. The antibody or fragment thereof of any one of claims 46-48, wherein the VH region comprises the amino acid sequence of SEQ ID NO:98 and the VL region comprises the amino acid sequence of SEQ ID NO:

99.

50. A polynucleotide encoding the antibody or fragment thereof of any one of claims 46-49. Page 223 of 225 NAI-153726309751. One or more vectors comprising one or more polynucleotides of claim 50 or a complementary polynucleotide thereto.

52. A cell comprising any one or more of: the antibody or fragment thereof of any one of claims 46-49, the polynucleotide of claim 50, or the one or more vectors of claim 51.

53. A pharmaceutical composition that comprises a pharmaceutically acceptable excipient and any one or more of: the antibody or fragment thereof of any one of claims 46- 49, the polynucleotide of claim 50, the one or more vectors of claim 51, or the cell of claim 52.

54. A method of inhibiting interaction between PD-1 and PD-L1, comprising contacting the PD-L1 with the antibody or fragment thereof of any one of claims 46-49 or the pharmaceutical composition of claim 53.

55. A method of preventing suppression of an immune cell or activating a response mediated by an immune cell, comprising contacting the immune cell with the antibody or fragment thereof of any one of claims 46-49 or the pharmaceutical composition of claim 53.

56. A method for treating a disease or disorder in a subject comprising administering to the subject the antibody or fragment thereof of any one of claims 46-49 or the pharmaceutical composition of claim 53. Page 224 of 225 NAI-1537263097