Anti-PD-1 antibody, antigen-binding fragment thereof and pharmaceutical use thereof

Patent metadata

Field	Value
Publication number	US-12428482-B2
Application number	US-202017427625-A
Country	US
Kind code	B2
Filing date	Jan 31, 2020
Priority date	Feb 3, 2019
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

Abstract

Provided are an anti-PD-1 antibody, an antigen-binding fragment thereof, and a pharmaceutical use thereof. Specifically, provided are a humanized anti-PD-1 antibody containing a specific CDR region and an antigen-binding fragment thereof, a pharmaceutical composition containing the anti-PD-1 antibody and the antigen-binding fragment thereof, and a used thereof as medicament. In particular, provided is a use of the humanized anti-PD-1 antibody in the preparation of the medicament for treating PD-1 associated diseases or disorders.

First claim

What is claimed is:

1. An anti-PD-1 antibody or antigen-binding fragment thereof, which comprises a heavy chain variable region and a light chain variable region, wherein the combination of the heavy chain variable region and the light chain variable region is selected from any one of the following (a) to (d):
(a) the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively, and
the light chain variable region comprising LCDR2 and LCDR3 as shown in SEQ ID NO: 12 and SEQ ID NO: 13, respectively, and LCDR1 as shown in SEQ ID NO: 11, 47, 48, 49, 50, 51 or 52;
(b) the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively, and
the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 17, SEQ ID NO: 12 and SEQ ID NO: 18, respectively;
(c) the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 21, SEQ ID NO: 22 and SEQ ID NO: 23, respectively, and
the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, respectively;
(d) the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively, and
the light chain variable region comprising LCDR2 and LCDR3 as shown in SEQ ID NO: 12 and SEQ ID NO: 13, respectively, and LCDR1 as shown in SEQ ID NO: 49.

2. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 1 , wherein the anti-PD-1 antibody or antigen-binding fragment thereof is a murine antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, or a humanized antibody or antigen-binding fragment thereof.

3. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 2 , wherein the anti-PD-1 antibody is a humanized antibody, said humanized antibody comprises a framework region from a human antibody or a framework region variant thereof, wherein:
the framework region variant has at most 11 amino acid back mutations in each of the light chain framework region and/or the heavy chain framework region of the human antibody,
wherein the framework region variant comprises mutation(s) selected from any one of the following (i) to (iii):
(i) 2G amino acid back mutation comprised in the light chain variable region, and/or
one or more amino acid back mutations selected from the group consisting of 27Y, 481, 67T, 69L, 82F and 93T comprised in the heavy chain variable region;
(ii) 2V amino acid back mutation comprised in the light chain variable region, and/or
one or more amino acid back mutations selected from the group consisting of 26D, 27F 30T, 38K, 43H, 481, 66K, 67A, 69L, 82F and 93T comprised in the heavy chain variable region; and
(iii) one or more amino acid back mutations selected from the group consisting of 42G, 44V and 71Y comprised in the light chain variable region, and/or
1K and/or 94S amino acid back mutations comprised in the heavy chain variable region; wherein the amino acid positions are numbered and determined according to the Kabat Criteria.

4. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 2 , the combination of the heavy chain variable region and the light chain variable region of the antibody is selected from any one of the following (a) to (f):
(a) a heavy chain variable region, the sequence of which is as shown in SEQ ID NO: 4 or has at least 90% sequence identity with SEQ ID NO: 4, and/or
a light chain variable region, the sequence of which is as shown in SEQ ID NO: 5 or has at least 90% sequence identity with SEQ ID NO: 5;
(b) a heavy chain variable region, the sequence of which is as shown in SEQ ID NO: 6 or has at least 90% sequence identity with SEQ ID NO: 6, and/or
a light chain variable region, the sequence of which is as shown in SEQ ID NO: 7 or has at least 90% sequence identity with SEQ ID NO: 7;
(c) a heavy chain variable region, the sequence of which is as shown in SEQ ID NO: 19 or has at least 90% sequence identity with SEQ ID NO: 19, and/or
a light chain variable region, the sequence of which is as shown in SEQ ID NO: 20 or has at least 90% sequence identity with SEQ ID NO: 20;
(d) a heavy chain variable region, the sequence of which is as shown in SEQ ID NO: 27, 30, 31 or 32, or has at least 90% sequence identity with SEQ ID NO: 27, 30, 31 or 32, and/or
a light chain variable region, the sequence of which is as shown in SEQ ID NO: 28, 29, 34, 35, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 or 64, or has at least 90% sequence identity with SEQ ID NO: 28, 29, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 or 64;
(e) a heavy chain variable region, the sequence of which is as shown in SEQ ID NO: 33, 36, 37, 38, 39 or 40, or has at least 90% sequence identity with SEQ ID NO: 33, 36, 37, 38, 39 or 40, and/or
a light chain variable region, the sequence of which is as shown in SEQ ID NO: 34, 35, or 55, or has at least 90% sequence identity with SEQ ID NO: 34, 35, or 55; and
(f) a heavy chain variable region, the sequence of which is as shown in SEQ ID NO: 41, 45 or 46, or has at least 90% sequence identity with SEQ ID NO: 41, 45 or 46, and/or
a light chain variable region, the sequence of which is as shown in SEQ ID NO: 42, 43 or 44, or has at least 90% sequence identity with SEQ ID NO: 42, 43 or 44.

5. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 2 , which comprises a heavy chain variable region, the sequence of which is as shown in SEQ ID NO: 27, and a light chain variable region, the sequence of which is as shown in SEQ ID NO: 55.

6. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody further comprises an antibody constant region.

7. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 6 , wherein the antibody comprises the heavy chain constant region as shown in SEQ ID NO: 72 or 79, and the light chain constant region as shown in SEQ ID NO: 73.

8. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 1 , wherein the anti-PD-1 antibody comprises: a light chain as shown in SEQ ID NO: 78 and a heavy chain as shown in SEQ ID NO: 77 or 82; or the anti-PD-1 antibody comprises a light chain as shown in SEQ ID NO: 75 and a heavy chain as shown in SEQ ID NO: 74, 76, 80 or 81.

9. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 1 , wherein the antigen-binding fragment is selected from the group consisting of Fab, Fab′, F (ab′) 2, single-chain antibody (scFv), dimerized V region (diabody) and disulfide bond stabilized V region (dsFv).

10. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody is a bispecific antibody, a multispecific antibody or an antibody fusion protein.

11. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 1 , which comprises a heavy chain variable region and a light chain variable region, wherein:
the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively, and
the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 49, SEQ ID NO: 12 and SEQ ID NO: 13, respectively.

12. The anti-PD-1 antibody or antigen-binding fragment thereof according to claim 1 , wherein the anti-PD-1 antibody comprises a light chain as shown in SEQ ID NO: 75 and a heavy chain as shown in SEQ ID NO: 74.

13. A pharmaceutical c

Assignees

• Jiangsu Hengrui Medicine Co
• Shanghai hengrui pharmaceutical co ltd

Inventors

• Gu Xiaoling
• Ye Xin
• Ge Hu
• Tao Weikang

Classifications

• C12N15/11

  DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity} · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title