IP Library › Granted Patent US 9,217,034

Granted Patent B2

US 9,217,034 · App. 14/194,797 · Granted Dec 22, 2015

Anti-PD1 antibodies and their use as therapeutics and diagnostics

Inventors: Kang Li (Beijing, CN); Tong Zhang (Beijing, CN); Jing Song (Beijing, CN); Lanlan Xu (Beijing, CN); Qi Liu (Beijing, CN); Hao Peng (Beijing, CN)

Assignee: BEIGENE, LTD.

C07K16/2803 A61K39/39591 C07K16/2818 A61K2039/505 C07K2317/24 C07K2317/34 C07K2317/52 C07K2317/55 C07K2317/565 C07K2317/567 C07K2317/569 C07K2317/70 C07K2317/71 C07K2317/76 C07K2317/92 C07K2317/94

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Quick Facts

Patent No.: US 9,217,034
App. No.: 14/194,797
Granted: Dec 22, 2015
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Provided are antibodies that specifically bind to Programmed Death-1 (PD1, Pdcd-1, or CD279) and inhibit PD1-mediated cellular signaling and activities in immune cells, antibodies binding to a set of amino acid residues required for its ligand binding, and uses of these antibodies to treat or diagnose cancer, infectious diseases or other pathological disorders modulated by PD1-mediated functions.

Claims (539)

1. An antibody antigen binding domain which specifically binds human PD-1, and comprises complementarity determining region (CDR) 1, CDR2 and CDR3, in a combination selected from (a)-(o) as follows, wherein the antibody (Ab), heavy chain (HC) or light chain (LC) and CDR nomenclature system (Kabat, IMGT or composite) from which the CDR combinations derive are shown in the first column, and residues in bold text are Kabat system, and residues underlined are IMGT system:

Ab,

Chain

System

CDR1

mu326

GYTFT NYG MN

(a)

Kabat

SEQ ID NO: 17, res. 6-10

(b)

IMGT

SEQ ID NO: 17, res. 1-8

(c)

Comp.

SEQ ID NO: 17

mu326

RAS ESVDNYGYSF MH

(d)

Kabat

SEQ ID NO: 20

(e)

IMGT

SEQ ID NO: 20, res. 4-13

(f)

Comp.

SEQ ID NO: 20

326-4A3

GYTFT NYG MN

(g)

Kabat

SEQ ID NO: 17, res. 6-10

(h)

IMGT

SEQ ID NO: 17, res. 1-8

(i)

Comp.

SEQ ID NO: 17

326-1

GYTFT NYG MN

(j)

Kabat

SEQ ID NO: 17, res. 6-10

(k)

IMGT

SEQ ID NO: 17, res. 1-8

(l)

Comp.

SEQ ID NO: 17

326-3B1

GYTFT NYG MN

(m)

Kabat

SEQ ID NO: 17, res. 6-10

(n)

IMGT

SEQ ID NO: 17, res. 1-8

(o)

Comp.

SEQ ID NO: 17

Ab,

Chain

System

CDR2

mu326

W INNNNGEP TYAEEFKG

(a)

Kabat

SEQ ID NO: 18

(b)

IMGT

SEQ ID NO: 18, res. 2-9

(c)

Comp.

SEQ ID NO: 18

mu326

RAS NLES

(d)

Kabat

SEQ ID NO: 21

(e)

IMGT

SEQ ID NO: 21, res. 1-3

(f)

Comp.

SEQ ID NO: 21

326-4A3

W INNNNAEP TYAQDFRG

(g)

Kabat

SEQ ID NO: 38

(h)

IMGT

SEQ ID NO: 38, res.2-9

(i)

Comp.

SEQ ID NO: 38

326-1

W INNNNGEP TYAQGFRG

(j)

Kabat

SEQ ID NO: 62

(k)

IMGT

SEQ ID NO: 62, res. 2-9

(l)

Comp.

SEQ ID NO: 62

326-3B1

W INNNNGEP TYAQDFRG

(m)

Kabat

SEQ ID NO: 63

(n)

IMGT

SEQ ID NO: 63, res. 2-9

(o)

Comp.

SEQ ID NO: 63

Ab,

Chain

System

CDR3

mu326

AR DVMDY

(a)

Kabat

SEQ ID NO: 19, res. 3-7

(b)

IMGT

SEQ ID NO: 19

(c)

Comp.

SEQ ID NO: 19

mu326

QQSKEYPT

(d)

Kabat

SEQ ID NO: 22

(e)

IMGT

SEQ ID NO: 22

(f)

Comp.

SEQ ID NO: 22

326-4A3

AR DVMDY

(g)

Kabat

SEQ ID NO: 19, res. 3-7

(h)

IMGT

SEQ ID NO: 19

(i)

Comp.

SEQ ID NO: 19

326-1

AR DVMDY

(j)

Kabat

SEQ ID NO: 19, res. 3-7

(k)

IMGT

SEQ ID NO: 19

(l)

Comp.

SEQ ID NO: 19

326-3B1

AR DVMDY

(m)

Kabat

SEQ ID NO: 19, res. 3-7

(n)

IMGT

SEQ ID NO: 19

(o)

Comp.

SEQ ID NO: 19.

2. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

mu326 HC

(a)

Kabat

SEQ ID NO: 17, res. 6-10

SEQ ID NO: 18

SEQ ID NO: 19, res. 3-7.

3. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

mu326 HC

(b)

IMGT

SEQ ID NO: 17, res. 1-8

SEQ ID NO: 18, res. 2-9

SEQ ID NO: 19.

4. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

mu326 HC

(c)

Comp.

SEQ ID NO: 17

SEQ ID NO: 18

SEQ ID NO: 19.

5. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

mu326 LC

(d)

Kabat

SEQ ID

NO: 20

NO: 21

NO: 22.

6. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

mu326 LC

(e)

IMGT

SEQ ID

NO: 20,

NO: 21,

NO: 22.

res. 4-13

res. 1-3

7. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

mu326 LC

(f)

Comp.

SEQ ID

NO: 20

NO: 21

NO: 22.

8. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

326-4A3 HC

(g)

Kabat

SEQ ID

NO: 17,

NO: 38

NO: 19,

res. 6-10

res. 3-7.

9. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

326-4A3 HC

(h)

IMGT

SEQ ID

NO: 17,

NO: 38,

NO: 19.

res. 1-8

res.2-9

10. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

326-4A3 HC

(i)

Comp.

SEQ ID

NO: 17

NO: 38

NO: 19.

11. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

326-1 HC

(j)

Kabat

SEQ ID

NO: 17,

NO: 62

NO: 19,

res. 6-10

res. 3-7.

12. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

326-1 HC

(k)

IMGT

SEQ ID

NO: 17,

NO: 62,

NO: 19.

res. 1-8

res. 2-9

13. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

326-1 HC

(l)

Comp.

SEQ ID

NO: 17

NO: 62

NO: 19.

14. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

326-3B1HC

(m)

Kabat

SEQ ID

NO: 17,

NO: 63

NO: 19,

res. 6-10

res. 3-7.

15. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

326-3B1HC

(n)

IMGT

SEQ ID

NO: 17,

NO: 63,

NO: 19.

res. 1-8

res. 2-9

16. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in combination as follows:

Ab, Chain

System

CDR1

CDR2

CDR3

326-3B1HC

(o)

Comp.

SEQ ID

NO: 17

NO: 63

NO: 19.

17. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) comprising a CDR1, CDR2 and CDR3 combination selected from (g), (h) and (i), and a light chain variable region (Vk) comprising a CDR1, CDR2 and CDR3 combination selected from (d), (e) and (f).

18. An antibody antigen binding domain according to claim 1 comprising CDR1, CDR2 and CDR3, in a combination selected from (c), (f), (i), (l), and (o), as follows:

Ab, Chain

CDR1

CDR2

CDR3

(c)

mu326

SEQ ID NO: 17

SEQ ID NO: 18

SEQ ID NO: 19

(f)

mu326

SEQ ID NO: 20

SEQ ID NO: 21

SEQ ID NO: 22

(i)

326-4A3

SEQ ID NO: 17

SEQ ID NO: 38

SEQ ID NO: 19

(l)

326-1

SEQ ID NO: 17

SEQ ID NO: 62

SEQ ID NO: 19

(o)

326-3B1

SEQ ID NO: 17

SEQ ID NO: 63

SEQ ID NO: 19.

19. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) or a light chain variable region (Vk), comprising a sequence selected from the group consisting of:

mu326 H

(SEQ ID NOS: 8);

mu326 L

(SEQ ID NOS: 10);

326-4A3 H

(SEQ ID NOS: 28);

326-4A3 L

(SEQ ID NOS: 30);

326-3B1 H

(SEQ ID NOS: 51);

326-3B1 L

(SEQ ID NOS: 52);

326-3G1 H

(SEQ ID NOS: 53);

326-3G1 L

(SEQ ID NOS: 54);

326-1 H

(SEQ ID NOS: 56);

326-1 L

(SEQ ID NOS: 58);

326-3A1 H

(SEQ ID NOS: 75);

326-3C1 H

(SEQ ID NOS: 76);

326-3D1 H

(SEQ ID NOS: 77);

326-3E1 H

(SEQ ID NOS: 78);

326-3F1 H

(SEQ ID NOS: 79);

326-3B N55D H

(SEQ ID NOS: 80);

326-4A1L

(SEQ ID NOS: 81); or

326-4A2L

(SEQ ID NOS: 82).

20. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) and a light chain variable region (Vk) comprising a sequence selected from the group consisting of:

mu326

(SEQ ID NOS: 8 and 10);

326-4A3

(SEQ ID NOS: 28 and 30);

326-3B1

(SEQ ID NOS: 51 and 52);

326-3G1

(SEQ ID NOS: 53 and 54);

326-1

(SEQ ID NOS: 56 and 58);

326-3A1

(SEQ ID NOS: 75 and 30);

326-3C1

(SEQ ID NOS: 76 and 30);

326-3D1

(SEQ ID NOS: 77 and 30);

326-3E1

(SEQ ID NOS: 78 and 30);

326-3F1

(SEQ ID NOS: 79 and 30);

326-3B N55D

(SEQ ID NOS: 80 and 30);

326-4A1

(SEQ ID NOS: 28 and 81); or

326-4A2

(SEQ ID NOS: 28 and 82).

21. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) or a light chain variable region (Vk) comprising:

326-4A3 H (SEQ ID NOS:28) or 326-4A3 L (SEQ ID NOS:30).

22. An antibody antigen binding domain according to claim 1 comprising a heavy chain variable region (Vh) and a light chain variable region (Vk) comprising:

326-4A3 H (SEQ ID NOS:28) and 326-4A3 L (SEQ ID NOS:30).

23. An antibody antigen binding domain according to claim 1 which specifically binds PD1 residues: I93, L95 and P97 (equivalent to I106, L108 and P110 in SEQ ID NO 2).

24. An antibody antigen binding domain according to claim 1 which induces IL-2 release in PD-1-transformed cells co-cultured with OS8/PD-L1 or OS8/PD-L2 cotransformed cells, and/or inhibits of IL-2 secretion in P3Z-transformed cells co-cultured with PD-L1- or PD-L2-transformed cells, wherein:

OS8 (SEQ ID NO:89) is a membrane-anchored chimeric Ab constructed by fusing the single chain variable fragment (scFv) of an anti-human CD3 mAb OKT3 to the C-terminal domain (113-220) of mouse CD8α; and

P3Z (SEQ ID NO:90) is a chimeric PD-1 receptor, constructed by fusing the extracellular and transmembrane domains of human PD-1 to the cytoplasmic domain of human CD3ζ chain.

25. A monoclonal IgG antibody comprising an antibody antigen binding domain according to claim 1 .

26. A monoclonal IgG antibody comprising an antibody antigen binding domain according to claim 17 .

27. A monoclonal IgG antibody comprising an antibody antigen binding domain according to claim 22 .

28. A monoclonal IgG antibody comprising an antibody antigen binding domain according to claim 1 and an IgG4 heavy chain effector or constant domain comprising any of SEQ ID NO:83-88.

29. An IgG antibody comprising an antibody antigen binding domain according to claim 1 and an IgG4 heavy chain effector or constant domain comprising SEQ ID NO 87 or 88.

30. An IgG antibody comprising an antibody antigen binding domain according to claim 17 and an IgG4 heavy chain effector or constant domain comprising SEQ ID NO 87 or 88.

31. An IgG antibody comprising an antibody antigen binding domain according to claim 22 and an IgG4 heavy chain effector or constant domain comprising SEQ ID NO 87 or 88.

32. A method of using an antibody antigen binding domain according to claim 1 comprising the step of administering the domain to a person determined to have cancer or a viral infection or to otherwise be in need of PD-1 antagonism.

Assignments (4)

CHANGE OF NAME Recorded Sep 23, 2025

From: BEIGENE SWITZERLAND GMBH

To: BEONE MEDICINES I GMBH

Reel/Frame 072872/0076 →

CHANGE OF ASSIGNEE ADDRESS Recorded Nov 4, 2021

From: BEIGENE SWITZERLAND GMBH

To: BEIGENE SWITZERLAND GMBH

Reel/Frame 058267/0358 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 28, 2018

From: BEIGENE, LTD.

To: BEIGENE SWITZERLAND GMBH