Angiopoietin-2 specific binding agents

• US 20030124129A1
• Filed: 10/10/2002
• Published: 07/03/2003
• Est. Priority Date: 10/11/2001
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Oliner, Jonathan Daniel
• Granted Patent: US 7,521,053 B2
• Time in Patent Office: Days
• US Class Current: 424/155.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL

Abstract

Disclosed are specific binding agents, such as fully human antibodies, that bind to angiopoietin-2. Also disclosed are heavy chain fragments, light chain fragments, and CDRs of the antibodies, as well as methods of making and using the antibodies.

Claims

1. A specific binding agent comprising at least one peptide selected from the group consisting of:

SEQ ID NO. 1;

SEQ ID NO. 3;

SEQ ID NO. 5;

SEQ ID NO. 7;

SEQ ID NO. 9;

SEQ ID NO. 11;

SEQ ID NO. 13;

SEQ ID NO. 15;

SEQ ID NO. 17;

SEQ ID NO. 19;

SEQ ID NO. 21;

SEQ ID NO;

23;

SEQ ID NO. 25;

SEQ ID NO. 27;

SEQ ID NO. 29;

SEQ ID NO. 31;

SEQ ID NO. 33;

SEQ ID NO. 35;

SEQ ID NO. 37;

SEQ ID NO. 39;

SEQ ID NO. 41;

SEQ ID NO. 43;

SEQ ID NO. 45;

SEQ ID NO. 47;

SEQ ID NO. 49;

SEQ ID NO. 51;

SEQ ID NO. 53;

SEQ ID NO. 55;

SEQ ID NO. 57;

SEQ ID NO. 59;

SEQ ID NO. 61;

SEQ ID NO. 2;

SEQ ID NO. 12;

SEQ ID NO. 18;

SEQ ID NO. 20;

SEQ ID NO. 26;

SEQ ID NO. 28;

SEQ ID NO. 30;

SEQ ID NO. 32;

SEQ ID NO. 36;

SEQ ID NO. 44;

SEQ ID NO. 46;

SEQ ID NO. 48;

SEQ ID NO. 56;

SEQ ID NO. 62;

SEQ ID NO. 4;

SEQ ID NO. 6;

SEQ ID NO. 8;

SEQ ID NO. 10;

SEQ ID NO. 14;

SEQ ID NO. 16;

SEQ ID NO. 22;

SEQ ID NO. 24;

SEQ ID NO. 34;

SEQ ID NO. 38;

SEQ ID NO. 40;

SEQ ID NO. 42;

SEQ ID NO. 50;

SEQ ID NO. 52;

SEQ ID NO. 54;

SEQ ID NO. 58; and

SEQ ID NO. 60;

and fragments thereof.

2. The specific binding agent according to claim 1 that is an antibody.

3. The antibody of claim 2 that is a polyclonal, monoclonal, chimeric, humanized, or fully human antibody.

4. The antibody of claim 3 that is a single chain antibody.

5. A hybridoma that produces the monoclonal antibody according to claim 3.

6. A conjugate comprising a specific binding agent of claim 1.

7. A conjugate comprising an antibody of claim 2, 3, or 4.

8. A nucleic acid molecule encoding the specific binding agent of claim 1.

9. A nucleic acid molecule encoding the antibody of claim 2, 3, or 4.

10. A vector comprising the nucleic acid molecule of claim 8 or 9.

11. A host cell containing the vector according to claim 10.

12. A method of making a specific binding agent comprising:

(a) transforming a host cell with at least one nucleic acid molecule encoding the specific binding agent of claim 1;

(b) expressing the nucleic acid molecule in said host cell; and

(c) isolating said specific binding agent

13. A method of making an antibody comprising:

(a) transforming a host cell with at least one nucleic acid molecule encoding the antibody according to claim 2, 3, or 4;

(b) expressing the nucleic acid molecule in said host cell; and

(c) isolating said specific binding agent.

14. A method of inhibiting undesired angiogenesis in a mammal comprising administering a therapeutically effective amount of a specific binding agent according to claim 1.

15. A method of treating cancer in a mammal comprising administering a therapeutically effective amount of a specific binding agent according to claim 1.

16. A method of inhibiting undesired angiogenesis in a mammal comprising administering a therapeutically effective amount of an antibody according to claim 2, 3, or 4.

17. A method of treating cancer in a mammal comprising administering a therapeutically effective amount of antibody according to claim 2, 3, or 4.

18. A pharmaceutical composition comprising the specific binding agent of claim 1 and a pharmaceutically acceptable formulation agent.

19. A pharmaceutical composition comprising the antibody of claim 2, 3, or 4 and a pharmaceutically acceptable formulation agent.

20. A method of modulating or inhibiting angiopoietin-2 activity comprising administering the specific binding agent of claim 1.

21. A method of modulating or inhibiting angiopoietin-2 activity comprising administering the antibody of claim 2, 3, or 4.

22. A method of modulating at least one of vascular permeability or plasma leakage in a mammal comprising administering a therapeutically effective amount of the specific binding agent according to claim 1.

23. A method of treating at least one of ocular neovascular disease, obesity, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, inflammatory disorders, atherosclerosis, endometriosis, neoplastic disease, bone-related disease, or psoriasis in a mammal comprising administering a therapeutically effective amount of a specific binding agent according to claim 1.

24. A method of modulating at least one of vascular permeability or plasma leakage in a mammal comprising administering a therapeutically effective amount of the antibody according to claim 2, 3, or 4.

25. A method of treating at least one of ocular neovascular disease, obesity, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, inflammatory disorders, atherosclerosis, endometriosis, neoplastic disease, bone-related disease, or psoriasis in a mammal comprising administering a therapeutically effective amount of an antibody according to claim 2, 3, or 4.

26. A method of treating cancer in a mammal comprising administering a therapeutically effective amount of a specific binding agent according to claim 1 and a chemotherapeutic agent.

27. The method according to claim 26 wherein the specific binding agent and chemotherapeutic agent are not administered simultaneously.

28. A method of treating cancer in a mammal comprising administering a therapeutically effective amount of an antibody according to claim 2, 3, or 4 and a chemotherapeutic agent.

29. The method according to claim 26 wherein the specific binding agent and chemotherapeutic agent are not administered simultaneously.

34. A method of detecting the level of angiopoietin-2 in a biological sample comprising

(a) contacting a specific binding agent of claim 1 with said sample;

and

(b) determining the extent of binding of the specific binding agent to said sample.

35. A method of detecting the level of angiopoietin-2 in a biological sample comprising

(a) contacting an antibody of claim 20 with said sample;

and

(b) determining the extent of binding of the antibody to said sample.

30. A specific binding agent comprising CDR 1 of any of HC (SEQ ID NO. 1);

528 HC (SEQ ID NO.

     3);

531 HC (SEQ ID NO.

     5);

533 HC (SEQ ID NO.

     7);

535 HC (SEQ ID NO.

     9);

536 HC (SEQ ID NO.

     11);

537 HC (SEQ ID NO.

     13);

540 HC (SEQ ID NO.

     15);

543 HC (SEQ ID NO.

     17);

544 HC (SEQ ID NO.

     19);

545 HC (SEQ ID NO.

     21);

546 HC (SEQ ID NO.

     23);

551 HC (SEQ ID NO.

     25);

553 HC (SEQ ID NO.

     27);

555 HC (SEQ ID NO.

     29);

558 HC (SEQ ID NO.

     31);

559 HC (SEQ ID NO.

     33);

565 HC (SEQ ID NO.

     35);

F1-C6 HC (SEQ ID NO.

     37);

FB1-A7 HC (SEQ ID NO.

     39);

FD-B2 HC (SEQ ID NO.

     41);

FE-B7 HC (SEQ ID NO.

     43);

FJ-G11 HC (SEQ ID NO.

     45);

FK-E3 HC (SEQ ID NO.

     47);

G1D4 HC (SEQ ID NO.

     49);

GC1E8 HC (SEQ ID NO.

     51);

H1C12 HC (SEQ ID NO.

     53);

IA1-1E7 HC (SEQ ID NO.

     55);

IF-1C10 HC (SEQ ID NO.

     57);

IK-2E2 HC (SEQ ID NO.

     59);

IP-2C11 HC (SEQ ID NO.

     61);

526 kappa (SEQ ID NO.

     2);

536 kappa (SEQ ID NO.

     12);

543 kappa (SEQ ID NO.

     18);

544 kappa (SEQ ID NO.

     20);

551 kappa (SEQ ID NO.

     26);

553 kappa (SEQ ID NO.

     28);

555 kappa (SEQ ID NO.

     30);

558 kappa (SEQ ID NO.

     32);

565 kappa (SEQ ID NO.

     36);

FE-B7 kappa (SEQ ID NO.

     44);

FJ-G11 kappa (SEQ ID NO.

     46);

FK-E3 kappa (SEQ ID NO.

     48);

IA1-1E7 kappa (SEQ ID NO.

     56);

IP-2C11 kappa (SEQ ID NO.

     62);

528 lambda (SEQ ID NO.

     4);

531 lambda (SEQ ID NO.

     6);

533 lambda (SEQ ID NO.

     8);

535 lambda (SEQ ID NO.

     10);

537 lambda (SEQ ID NO.

     14);

540 lambda (SEQ ID NO.

     16);

545 lambda (SEQ ID NO.

     22);

546 lambda (SEQ ID NO.

     24);

559 lambda (SEQ ID NO.

     34);

F1-C6 lambda (SEQ ID NO.

     38);

FB1-A7 lambda (SEQ ID NO.

     40);

FD-B2 lambda (SEQ ID NO.

     42);

G1D4 lambda (SEQ ID NO.

     50);

GC1E8 lambda (SEQ ID NO.

     52);

H1C12 lambda (SEQ ID NO.

     54);

IF-IC 10 lambda (SEQ ID NO.

     58); and

IK-2E2 lambda (SEQ ID NO.

     60).

33. A nucleic acid molecule encoding the specific binding agent according to any of claims 30, 31, or 32.

31. A specific binding agent comprising CDR 2 of any of HC (SEQ ID NO. 1);

528 HC (SEQ ID NO.

     3);

531 HC (SEQ ID NO.

     5);

533 HC (SEQ ID NO.

     7);

535 HC (SEQ ID NO.

     9);

536 HC (SEQ ID NO.

     11);

537 HC (SEQ ID NO.

     13);

540 HC (SEQ ID NO.

     15);

543 HC (SEQ ID NO.

     17);

544 HC (SEQ ID NO.

     19);

545 HC (SEQ ID NO.

     21);

546 HC (SEQ ID NO.

     23);

551 HC (SEQ ID NO.

     25);

553 HC (SEQ ID NO.

     27);

555 HC (SEQ ID NO.

     29);

558 HC (SEQ ID NO.

     31);

559 HC (SEQ ID NO.

     33);

565 HC (SEQ ID NO.

     35);

F1-C6 HC (SEQ ID NO.

     37);

FB1-A7 HC (SEQ ID NO.

     39);

FD-B2 HC (SEQ ID NO.

     41);

FE-B7 HC (SEQ ID NO.

     43);

FJ-G11 HC (SEQ ID NO.

     45);

FK-E3 HC (SEQ ID NO.

     47);

G1D4 HC (SEQ ID NO.

     49);

GC1E8 HC (SEQ ID NO.

     51);

H1C12 HC (SEQ ID NO.

     53);

IA1-1E7 HC (SEQ ID NO.

     55);

IF-1C10 HC (SEQ ID NO.

     57);

IK-2E2 HC (SEQ ID NO.

     59);

IP-2C11 HC (SEQ ID NO.

     61);

526 kappa (SEQ ID NO.

     2);

536 kappa (SEQ ID NO.

     12);

543 kappa (SEQ ID NO.

     18);

544 kappa (SEQ ID NO.

     20);

551 kappa (SEQ ID NO.

     26);

553 kappa (SEQ ID NO.

     28);

555 kappa (SEQ ID NO.

     30);

558 kappa (SEQ ID NO.

     32);

565 kappa (SEQ ID NO.

     36);

FE-B7 kappa (SEQ ID NO.

     44);

FJ-G 11 kappa (SEQ ID NO.

     46);

FK-E3 kappa (SEQ ID NO.

     48);

IA1-1E7 kappa (SEQ ID NO.

     56);

IP-2C11 kappa (SEQ ID NO.

     62);

528 lambda (SEQ ID NO.

     4);

531 lambda (SEQ ID NO.

     6);

533 lambda (SEQ ID NO.

     8);

535 lambda (SEQ ID NO.

     10);

537 lambda (SEQ ID NO.

     14);

540 lambda (SEQ ID NO.

     16);

545 lambda (SEQ ID NO.

     22);

546 lambda (SEQ ID NO.

     24);

559 lambda (SEQ ID NO.

     34);

F1-C6 lambda (SEQ ID NO.

     38);

FBI-A7 lambda (SEQ ID NO.

     40);

FD-B2 lambda (SEQ ID NO.

     42);

G1D4 lambda (SEQ ID NO.

     50);

GC1E8 lambda (SEQ ID NO.

     52);

H1C12 lambda (SEQ ID NO.

     54);

IF-1C10 lambda (SEQ ID NO.

     58); and

IK-2E2 lambda (SEQ ID NO.

     60).

32. A specific binding agent comprising CDR 3 of any of HC (SEQ ID NO. 1);

528 HC (SEQ ID NO.

     3);

531 HC (SEQ ID NO.

     5);

533 HC (SEQ ID NO.

     7);

535 HC (SEQ ID NO.

     9);

536 HC (SEQ ID NO.

     11);

537 HC (SEQ ID NO.

     13);

540 HC (SEQ ID NO.

     15);

543 HC (SEQ ID NO.

     17);

544 HC (SEQ ID NO.

     19);

545 HC (SEQ ID NO.

     21);

546 HC (SEQ ID NO.

     23);

551 HC (SEQ ID NO.

     25);

553 HC (SEQ ID NO.

     27);

555 HC (SEQ ID NO.

     29);

558 HC (SEQ ID NO.

     31);

559 HC (SEQ ID NO.

     33);

565 HC (SEQ ID NO.

     35);

F1-C6 HC (SEQ ID NO.

     37);

FB1-A7 HC (SEQ ID NO.

     39);

FD-B2 HC (SEQ ID NO.

     41);

FE-B7 HC (SEQ ID NO.

     43);

FJ-G11 HC (SEQ ID NO.

     45);

FK-E3 HC (SEQ ID NO.

     47);

G1D4 HC (SEQ ID NO.

     49);

GC1E8 HC (SEQ ID NO.

     51);

H1C12 HC (SEQ ID NO.

     53);

IA1-1E7 HC (SEQ ID NO.

     55);

IF-1C10 HC (SEQ ID NO.

     57);

IK-2E2 HC (SEQ ID NO.

     59);

IP-2C11 HC (SEQ ID NO.

     61);

526 kappa (SEQ ID NO.

     2);

536 kappa (SEQ ID NO.

     12);

543 kappa (SEQ ID NO.

     18);

544 kappa (SEQ ID NO.

     20);

551 kappa (SEQ ID NO.

     26);

553 kappa (SEQ ID NO.

     28);

555 kappa (SEQ ID NO.

     30);

558 kappa (SEQ ID NO.

     32);

565 kappa (SEQ ID NO.

     36);

FE-B7 kappa (SEQ ID NO.

     44);

FJ-G11 kappa (SEQ ID NO.

     46);

FK-E3 kappa (SEQ ID NO.

     48);

IA1-1E7 kappa (SEQ ID NO.

     56);

IP-2C11 kappa (SEQ ID NO.

     62);

528 lambda (SEQ ID NO.

     4);

531 lambda (SEQ ID NO.

     6);

533 lambda (SEQ ID NO.

     8);

535 lambda (SEQ ID NO.

     10);

537 lambda (SEQ ID NO.

     14);

540 lambda (SEQ ID NO.

     16);

545 lambda (SEQ ID NO.

     22);

546 lambda (SEQ ID NO.

     24);

559 lambda (SEQ ID NO.

     34);

F1-C6 lambda (SEQ ID NO.

     38);

FB1-A7 lambda (SEQ ID NO.

     40);

FD-B2 lambda (SEQ ID NO.

     42);

G1D4 lambda (SEQ ID NO.

     50);

GC1E8 lambda (SEQ ID NO.

     52);

H1C12 lambda (SEQ ID NO.

     54);

IF-1C10 lambda (SEQ ID NO.

     58); and

IK-2E2 lambda (SEQ ID NO.

     60).

36. An antibody comprising a heavy chain and a light chain, said heavy chain comprising a heavy chain variable region selected from the group consisting of:

526 HC (SEQ ID NO.

     1);

528 HC (SEQ ID NO.

     3);

531 HC (SEQ ID NO.

     5);

533 HC (SEQ ID NO.

     7);

535 HC (SEQ ID NO.

     9);

536 HC (SEQ ID NO 0.11);

537 HC (SEQ ID NO.

     13);

540 HC (SEQ ID NO.

     15);

543 HC (SEQ ID NO.

     17);

544 HC (SEQ ID NO.

     19);

545 HC (SEQ ID NO.

     21);

546 HC (SEQ ID NO.

     23);

551 HC (SEQ ID NO.

     25);

553 HC (SEQ ID NO.

     27);

555 HC (SEQ ID NO.

     29);

558 HC (SEQ ID NO.

     31);

559 HC (SEQ ID NO.

     33);

565 HC (SEQ ID NO.

     35);

F1-C6 HC (SEQ ID NO.

     37);

FB1-A7 HC (SEQ ID NO.

     39);

FD-B2 HC (SEQ ID NO.

     41);

FE-B7 HC (SEQ ID NO.

     43);

FJ-G11 HC (SEQ ID NO.

     45);

FK-E3 HC (SEQ ID NO.

     47);

G1D4 HC (SEQ ID NO.

     49);

GC1E8 HC (SEQ ID NO.

     51);

H1C12 HC (SEQ ID NO.

     53);

IA1-1E7 HC (SEQ ID NO.

     55);

IF-1C10 HC (SEQ ID NO.

     57);

IK-2E2 HC (SEQ ID NO.

     59);

IP-2C11 HC (SEQ ID NO.

     61); and

antigen binding fragments thereof;

and said light chain comprising a light chain variable region selected from the group consisting of;

526 kappa (SEQ ID NO.

     2);

536 kappa (SEQ ID NO.

     12);

543 kappa (SEQ ID NO.

     18);

544 kappa (SEQ ID NO.

     20);

551 kappa (SEQ ID NO.

     26);

553 kappa (SEQ ID NO.

     28);

555 kappa (SEQ ID NO.

     30);

558 kappa (SEQ ID NO.

     32);

565 kappa (SEQ ID NO.

     36);

FE-B7 kappa (SEQ ID NO.

     44);

FJ-G11 kappa (SEQ ID NO.

     46);

FK-E3 kappa (SEQ ID NO.

     48);

IA1-1E7 kappa (SEQ ID NO.

     56);

IP-2C11 kappa (SEQ ID NO.

     62);

528 lambda (SEQ ID NO.

     4);

531 lambda (SEQ ID NO.

     6);

533 lambda (SEQ ID NO.

     8);

535 lambda (SEQ ID NO.

     10);

537 lambda (SEQ ID NO.

     14);

540 lambda (SEQ ID NO.

     16);

545 lambda (SEQ ID NO.

     22);

546 lambda (SEQ ID NO.

     24);

559 lambda (SEQ ID NO.

     34);

F1-C6 lambda (SEQ ID NO.

     38);

FB1-A7 lambda (SEQ ID NO.

     40);

FD-B2 lambda (SEQ ID NO.

     42);

G1D4 lambda (SEQ ID NO.

     50);

GC1E8 lambda (SEQ ID NO.

     52);

H1C12 lambda (SEQ ID NO.

     54);

IF-1C10 lambda (SEQ ID NO.

     58);

IK-2E2 lambda (SEQ ID NO.

     60);

and antigen binding fragments thereof.

37. A nucleic acid molecule encoding the antibody according to claim 36.