IP Library › Granted Patent US 8,735,553

Granted Patent B1

US 8,735,553 · App. 14/076,214 · Granted May 27, 2014

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.

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Quick Facts

Patent No.: US 8,735,553
App. No.: 14/076,214
Granted: May 27, 2014
Kind: B1

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 (629)

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)-(r) 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

mu317

GFSLT SYG VH

(a)

Kabat

SEQ ID NO: 11, res. 6-10

(b)

IMGT

SEQ ID NO: 11, res. 1-8

(c)

Comp.

SEQ ID NO: 11

mu317

KAS QSVSND VA

(d)

Kabat

SEQ ID NO: 14-

(e)

IMGT

SEQ ID NO: 14, res. 4-9

(f)

Comp.

SEQ ID NO: 14

317-4B6

GFSLT SYG VH

(g)

Kabat

SEQ ID NO: 11, res. 6-10

(h)

IMGT

SEQ ID NO: 11, res. 1-8

(i)

Comp.

SEQ ID NO: 11

317-4B6

KSS ESVSND VA

(j)

Kabat

SEQ ID NO: 34

(k)

IMGT

SEQ ID NO: 34, res. 4-9

(l)

Comp.

SEQ ID NO: 34

317-1H

GFSLT SYG VH

(m)

Kabat

SEQ ID NO: 11, res. 6-10

(n)

IMGT

SEQ ID NO: 11, res. 1-8

(o)

Comp.

SEQ ID NO: 11

317-4B2

GFSLT SYG VH

(p)

Kabat

SEQ ID NO: 11, res. 6-10

(q)

IMGT

SEQ ID NO: 11, res. 1-8

(r)

Comp.

SEQ ID NO: 11

Ab,

Chain

System

CDR2

mu317

V IWAGGST NYNSALMS

(a)

Kabat

SEQ ID NO: 12

(b)

IMGT

SEQ ID NO: 12, res. 2-8

(c)

Comp.

SEQ ID NO: 12

mu317

YAF HRFT

(d)

Kabat

SEQ ID NO: 15

(e)

IMGT

SEQ ID NO: 15, res. 1-3

(f)

Comp.

SEQ ID NO: 15

317-4B6

V IYADGST NYNPSLKS

(g)

Kabat

SEQ ID NO: 32

(h)

IMGT

SEQ ID NO: 32, res.2-8

(i)

Comp.

SEQ ID NO: 32

317-4B6

YAF HRFT

(j)

Kabat

SEQ ID NO: 15

(k)

IMGT

SEQ ID NO: 15, res.1-3

(l)

Comp.

SEQ ID NO: 15

317-1H

V IWAGGST NYNPSLKS

(m)

Kabat

SEQ ID NO: 59

(n)

IMGT

SEQ ID NO: 59, res. 2-8

(o)

Comp.

SEQ ID NO: 59

317-4B2

V IYAGGST NYNPSLKS

(p)

Kabat

SEQ ID NO: 60

(q)

IMGT

SEQ ID NO: 60, res.2-8

(r)

Comp.

SEQ ID NO: 60

Ab,

Chain

System

CDR3

mu317

AR AYGNYWYIDV

(a)

Kabat

SEQ ID NO: 13, res. 3-12

(b)

IMGT

SEQ ID NO: 13

(c)

Comp.

SEQ ID NO: 13

mu317

HQAYSSPYT

(d)

Kabat

SEQ ID NO: 16

(e)

IMGT

SEQ ID NO: 16

(f)

Comp.

SEQ ID NO: 16

317-4B6

AR AYGNYWYIDV

(g)

Kabat

SEQ ID NO: 13, res. 3-12

(h)

IMGT

SEQ ID NO: 13

(i)

Comp.

SEQ ID NO: 13

317-4B6

HQAYSSPYT

(j)

Kabat

SEQ ID NO: 16

(k)

IMGT

SEQ ID NO: 16

(l)

Comp.

SEQ ID NO: 16

317-1H

AR AYGNYWYIDV

(m)

Kabat

SEQ ID NO: 13, res. 3-12

(n)

IMGT

SEQ ID NO: 13

(o)

Comp.

SEQ ID NO: 13

317-4B2

AR AYGNYWYIDV

(p)

Kabat

SEQ ID NO: 13, res. 3-12

(q)

IMGT

SEQ ID NO: 13

(r)

Comp.

SEQ ID NO: 13.

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

mu317 HC

(a)

Kabat

SEQ ID NO: 11, res. 6-10

SEQ ID NO: 12

SEQ ID NO: 13, res. 3-12.

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

mu317 HC

(b)

IMGT

SEQ ID NO: 11, res. 1-8

SEQ ID NO: 12, res. 2-8

SEQ ID NO: 13.

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

mu317 HC

(c)

Comp.

SEQ ID NO: 11

SEQ ID NO: 12

SEQ ID NO: 13.

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

mu317 LC

(d)

Kabat

SEQ ID NO: 14

SEQ ID NO: 15

SEQ ID NO: 16.

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

mu317 LC

(e)

IMGT

SEQ ID NO: 14, res. 4-9

SEQ ID NO: 15, res. 1-3

SEQ ID NO: 16.

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

mu317 LC

(f)

Comp.

SEQ ID NO: 14

SEQ ID NO: 15

SEQ ID NO: 16.

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

317-4B6 HC

(g)

Kabat

SEQ ID

NO: 11,

NO: 32

NO: 13,

res. 6-10

res. 3-12.

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

317-4B6 HC

(h)

IMGT

SEQ ID

NO: 11,

NO: 32,

NO: 13.

res. 1-8

res.2-8

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

317-4B6 HC

(i)

Comp.

SEQ ID

NO: 11

NO: 32

NO: 13.

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

317-4B6 LC

(j)

Kabat

SEQ ID

NO: 34

NO: 15

NO: 16.

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

317-4B6 LC

(k)

IMGT

SEQ ID

NO: 34,

NO: 15,

NO: 16.

res. 4-9

res.1-3

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

317-4B6 LC

(l)

Comp.

SEQ ID

NO: 34

NO: 15

NO: 16.

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

317-1H HC

(m)

Kabat

SEQ ID

NO: 11,

NO: 59

NO: 13,

res. 6-10

res. 3-12.

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

317-1H HC

(n)

IMGT

SEQ ID

NO: 11,

NO: 59,

NO: 13.

res. 1-8

res. 2-8

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

317-1H HC

(o)

Comp.

SEQ ID

NO: 11

NO: 59

NO: 13.

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

Ab, Chain

System

CDR1

CDR2

CDR3

317-4B2 HC

(p)

Kabat

SEQ ID

NO: 11,

NO: 60

NO: 13,

res. 6-10

res. 3-12.

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

Ab, Chain

System

CDR1

CDR2

CDR3

317-4B2 HC

(q)

IMGT

SEQ ID

NO: 11,

NO: 60,

NO: 13.

res. 1-8

res.2-8

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

Ab, Chain

System

CDR1

CDR2

CDR3

317-4B2 HC

(r)

Comp.

SEQ ID

NO: 11

NO: 60

NO: 13.

20. 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 (j), (k) and (l).

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

Ab, Chain

CDR1

CDR2

CDR3

(c)

mu317 HC

SEQ ID

SEQ ID NO: 12

SEQ ID NO: 13

NO: 11

(f)

mu317 LC

SEQ ID

SEQ ID NO: 15

SEQ ID NO: 16

NO: 14

(i)

317-4B6 HC

SEQ ID

SEQ ID NO: 32

SEQ ID NO: 13

NO: 11

(l)

317-4B6 LC

SEQ ID

SEQ ID NO: 15

SEQ ID NO: 16

NO: 34

(o)

317-1H HC

SEQ ID

SEQ ID NO: 59

SEQ ID NO: 13

NO: 11

(r)

317-4B2 HC

SEQ ID

SEQ ID NO: 60

SEQ ID NO: 13.

NO: 11

22. 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:

mu317 H

(SEQ ID NOS: 4);

mu317 L

(SEQ ID NOS: 6);

317-4B6 H

(SEQ ID NOS: 24);

317-4B6 L

(SEQ ID NOS: 26);

317-4B2 H

(SEQ ID NOS: 43);

317-4B2 L

(SEQ ID NOS: 44);

317-4B5 H

(SEQ ID NOS: 45);

317-4B5 L

(SEQ ID NOS: 46);

317-1 H

(SEQ ID NOS: 48);

317-1 L

(SEQ ID NOS: 50);

317-3A1 L

(SEQ ID NOS: 64);

317-3C1 L

(SEQ ID NOS: 65);

317-3E1 L

(SEQ ID NOS: 66);

317-3F1 L

(SEQ ID NOS: 67);

317-3G1 L

(SEQ ID NOS: 68);

317-3H1 L

(SEQ ID NOS: 69);

317-3I1 L

(SEQ ID NOS: 70);

317-4B1 L

(SEQ ID NOS: 71);

317-4B3 L

(SEQ ID NOS: 72);

317-4B4 L

(SEQ ID NOS: 73); or

317-4A2 L

(SEQ ID NOS: 74).

23. 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:

mu317

(SEQ ID NOS: 4 and 6);

317-4B6

(SEQ ID NOS: 24 and 26)

317-4B2

(SEQ ID NOS: 43 and 44);

317-4B5

(SEQ ID NOS: 45 and 46);

317-1

(SEQ ID NOS: 48 and 50);

317-3A1

(SEQ ID NOS: 64 and 26);

317-3C1

(SEQ ID NOS: 65 and 26);

317-3E1

(SEQ ID NOS: 66 and 26);

317-3F1

(SEQ ID NOS: 67 and 26);

317-3G1

(SEQ ID NOS: 68 and 26);

317-3HI

(SEQ ID NOS: 69 and 26);

317-3I1

(SEQ ID NOS: 70 and 26);

317-4B1

(SEQ ID NOS: 71 and 26);

317-4B3

(SEQ ID NOS: 72 and 26);

317-4B4

(SEQ ID NOS: 73 and 26); or

317-4A2

(SEQ ID NOS: 74 and 26).

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

317-4B6 H (SEQ ID NOS:24) or 317-4B6 L (SEQ NOS:26).

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

317-4136 H (SEQ ID NOS:24) and 317-4B6 L (SEQ NOS:26).

26. An antibody antigen binding domain according to claim 1 which specifically binds PD1 residues: K45 and I93 (equivalent to K58 and I106 in SEQ ID NO 2).

27. 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.

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

29. A monoclonal IgG antibody comprising an antibody antigen binding domain according to claim 20 .

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

31. 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.

32. 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.

33. An IgG antibody comprising an antibody antigen binding domain according to claim 20 and an IgG4 heavy chain effector or constant domain comprising SEQ ID NO 87 or 88.

34. An IgG antibody comprising an antibody antigen binding domain according to claim 25 and an IgG4 heavy chain effector or constant domain comprising SEQ ID NO 87 or 88.

35. 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-I antagonism.

Assignments (5)

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 Dec 11, 2017

From: BEIGENE, LTD.

To: BEIGENE SWITZERLAND GMBH