Anti-coagulation factor XI antibodies
Antibodies that bind the apple 3 domain of human coagulation Factor XI and inhibit activation of FXI by coagulation factor XIIa as well as activation of FIX by FXIa are described.
1. A method for therapeutic or prophylactic treatment of a thromboembolic disorder or disease in a subject comprising:
administering to the subject an effective amount of an antibody or antigen binding fragment comprising:
six complimentary determining regions (CDRs) of an anti-FXI antibody of the αFXI-18623p family,
wherein the six CDRs comprise
(a) CDR1, CDR2, and CDR3 of the heavy chain (HC) having the amino acid sequence shown in SEQ ID NO:43; and
(b) CDR1, CDR2, and CDR3 of the light chain (LC) having the amino acid sequence shown in SEQ ID NO:31.
2. The method of claim 1 , wherein the antibody or antigen binding fragment comprises (a) a heavy chain complementarity determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, an HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and an HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10 and (b) a light chain complementarity determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, an LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and an LC-CDR 3 comprises having the amino acid sequence shown in SEQ ID NO:13.
3. The method of claim 2 , wherein the antibody or antigen binding fragment comprises an HC variable domain having the amino acid sequence shown in SEQ ID NO:28 or 29 and an LC variable domain having the amino acid sequence shown in SEQ ID NO:30.
4. The method of claim 1 , wherein the antibody comprises a HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
5. The method of claim 1 , wherein the antibody comprises a LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
6. The method of claim 1 , wherein the antibody or antigen binding fragment binds the apple 3 domain of coagulation factor XI (FXI) and inhibits activation of FXI and/or Factor XIa-mediated activation of Factor IX.
7. The method of claim 1 , wherein the antibody comprises:
(a) an HC having a constant domain and a variable domain wherein the variable domain comprises a heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, a HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and a HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10; and
(b) an LC having a constant domain and a variable domain wherein the variable domain comprises a light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:13.
8. The method of claim 7 , wherein the antibody comprises an HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
9. The method of claim 7 , wherein the antibody comprises an LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
10. The method of claim 1 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
11. The method of claim 1 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
12. The method of claim 1 , wherein the subject has end-stage renal disease (ESRD).
13. The method of claim 1 , wherein the thromboembolic disorder or disease is venous thromboembolism (VTE).
14. The method of claim 1 , wherein the therapeutic or prophylactic treatment of a thromboembolic disorder or disease in a subject is for Stroke Prevention in Atrial Fibrillation (SPAF).
15. The method of claim 1 , wherein the thromboembolic disorder or disease is medical device-related.
16. The method of claim 15 , wherein the medical device is a stent, endovascular stent graft, cardiac or venous catheter, continuous flow ventricular assist device (CF-LVAD), hemodialysis device, cardiopulmonary bypass device, Extracorporeal Membrane Oxygenation (ECMO) device, or ventricular assist device (VAD).
17. A method for therapeutic or prophylactic treatment of thromboembolic complications in a subject with end-stage renal disease (ESRD) comprising:
administering to the subject an effective amount of an antibody or antigen binding fragment comprising:
(i) six complimentary determining regions (CDRs) of an anti-FXI antibody of the aFXI-18623p family,
wherein the six CDRs comprise
(a) CDR1, CDR2, and CDR3 of the heavy chain (HC) having the amino acid sequence shown in SEQ ID NO:43; and
(b) CDR1, CDR2, and CDR3 of the light chain (LC) having the amino acid sequence shown in SEQ ID NO:31.
18. The method of claim 17 , wherein the antibody or antigen binding fragment comprises (a) a heavy chain complementarity determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, an HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and an HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10 and (b) a light chain complementarity determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, an LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and an LC-CDR 3 comprises having the amino acid sequence shown in SEQ ID NO:13.
19. The method of claim 18 , wherein the antibody or antigen binding fragment comprises an HC variable domain having the amino acid sequence shown in SEQ ID NO:28 or 29 and an LC variable domain having the amino acid sequence shown in SEQ ID NO:30.
20. The method of claim 17 , wherein the antibody comprises a HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
21. The method of claim 17 , wherein the antibody comprises a LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
22. The method of claim 17 , wherein the antibody or antigen binding fragment binds the apple 3 domain of coagulation factor XI (FXI) and inhibits activation of FXI and/or Factor XIa-mediated activation of Factor IX.
23. The method of claim 17 , wherein the antibody comprises:
(a) an HC having a constant domain and a variable domain wherein the variable domain comprises a heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, a HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and a HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10; and
(b) an LC having a constant domain and a variable domain wherein the variable domain comprises a light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:13.
24. The method of claim 23 , wherein the antibody comprises an HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
25. The method of claim 23 , wherein the antibody comprises an LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
26. The method of claim 17 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
27. The method of claim 17 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
28. A method for therapeutic or prophylactic treatment of a thromboembolic disorder or disease in a subject with end-stage renal disease (ESRD) comprising:
administering to the subject an effective amount of an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 or 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
29. A method for therapeutic or prophylactic treatment of treating or preventing venous thromboembolism (VTE) in a subject comprising:
administering to the subject an effective amount of an antibody or antigen binding fragment comprising:
six complimentary determining regions (CDRs) of an anti-FXI antibody of the αFXI-18623p family,
wherein the six CDRs comprise (a) CDR1, CDR2, and CDR3 of the heavy chain (HC) having the amino acid sequence shown in SEQ ID NO:43; and
(b) CDR1, CDR2, and CDR3 of the light chain (LC) having the amino acid sequence shown in SEQ ID NO:31.
30. The method of claim 29 , wherein the antibody or antigen binding fragment comprises (a) a heavy chain complementarity determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, an HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and an HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10 and (b) a light chain complementarity determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, an LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and an LC-CDR 3 comprises having the amino acid sequence shown in SEQ ID NO:13.
31. The method of claim 30 , wherein the antibody or antigen binding fragment comprises an HC variable domain having the amino acid sequence shown in SEQ ID NO:28 or 29 and an LC variable domain having the amino acid sequence shown in SEQ ID NO:30.
32. The method of claim 29 , wherein the antibody comprises a HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
33. The method of claim 29 , wherein the antibody comprises a LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
34. The method of claim 29 , wherein the antibody or antigen binding fragment binds the apple 3 domain of coagulation factor XI (FXI) and inhibits activation of FXI and/or Factor XIa-mediated activation of Factor IX.
35. The method of claim 29 , wherein the antibody comprises:
(a) an HC having a constant domain and a variable domain wherein the variable domain comprises a heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, a HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and a HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10; and
(b) an LC having a constant domain and a variable domain wherein the variable domain comprises a light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:13.
36. The method of claim 35 , wherein the antibody comprises an HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
37. The method of claim 35 , wherein the antibody comprises an LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
38. The method of claim 29 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
39. The method of claim 29 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
40. A method for therapeutic or prophylactic treatment of venous thromboembolism (VTE) in a subject comprising:
administering to the subject an effective amount of an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 or 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
41. A method for prophylaxis of venous thromboembolism (VTE) in orthopedic surgery in a subject comprising:
administering to the subject an effective amount of an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 or 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
42. A method for Stroke Prevention in Atrial Fibrillation (SPAF) in a subject comprising:
administering to the subject an effective amount of an antibody or antigen binding fragment comprising:
six complimentary determining regions (CDRs) of an anti-FXI antibody of the αFXI-18623p family,
wherein the six CDRs comprise
(a) CDR1, CDR2, and CDR3 of the heavy chain (HC) having the amino acid sequence shown in SEQ ID NO:43; and
(b) CDR1, CDR2, and CDR3 of the light chain (LC) having the amino acid sequence shown in SEQ ID NO:31.
43. The method of claim 42 , wherein the antibody or antigen binding fragment comprises (a) a heavy chain complementarity determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, an HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and an HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10 and (b) a light chain complementarity determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, an LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and an LC-CDR 3 comprises having the amino acid sequence shown in SEQ ID NO:13.
44. The method of claim 43 , wherein the antibody or antigen binding fragment comprises an HC variable domain having the amino acid sequence shown in SEQ ID NO:28 or 29 and an LC variable domain having the amino acid sequence shown in SEQ ID NO:30.
45. The method of claim 42 , wherein the antibody comprises a HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
46. The method of claim 42 , wherein the antibody comprises a LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
47. The method of claim 42 , wherein the antibody or antigen binding fragment binds the apple 3 domain of coagulation factor XI (FXI) and inhibits activation of FXI and/or Factor XIa-mediated activation of Factor IX.
48. The method of claim 42 , wherein the antibody comprises:
(a) an HC having a constant domain and a variable domain wherein the variable domain comprises a heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, a HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and a HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10; and
(b) an LC having a constant domain and a variable domain wherein the variable domain comprises a light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:13.
49. The method of claim 48 , wherein the antibody comprises an HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
50. The method of claim 48 , wherein the antibody comprises an LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
51. The method of claim 42 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
52. The method of claim 42 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
53. A method for Stroke Prevention in Atrial Fibrillation (SPAF) in a subject comprising:
administering to the subject an effective amount of an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 or 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
54. A method for therapeutic or prophylactic treatment of a medical device-related thromboembolic disorder or disease in a subject comprising:
administering to the subject an effective amount of an antibody or antigen binding fragment comprising:
six complimentary determining regions (CDRs) of an anti-FXI antibody of the αFXI-18623p family,
wherein the six CDRs comprise
(a) CDR1, CDR2, and CDR3 of the heavy chain (HC) having the amino acid sequence shown in SEQ ID NO:43; and
(b) CDR1, CDR2, and CDR3 of the light chain (LC) having the amino acid sequence shown in SEQ ID NO:31.
55. The method of claim 54 , wherein the antibody or antigen binding fragment comprises (a) a heavy chain complementarity determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, an HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and an HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10 and (b) a light chain complementarity determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, an LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and an LC-CDR 3 comprises having the amino acid sequence shown in SEQ ID NO:13.
56. The method of claim 55 , wherein the antibody or antigen binding fragment comprises an HC variable domain having the amino acid sequence shown in SEQ ID NO:28 or 29 and an LC variable domain having the amino acid sequence shown in SEQ ID NO:30.
57. The method of claim 54 , wherein the antibody comprises a HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
58. The method of claim 54 , wherein the antibody comprises a LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
59. The method of claim 54 , wherein the antibody or antigen binding fragment binds the apple 3 domain of coagulation factor XI (FXI) and inhibits activation of FXI and/or Factor XIa-mediated activation of Factor IX.
60. The method of claim 54 , wherein the antibody comprises:
(a) an HC having a constant domain and a variable domain wherein the variable domain comprises a heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, a HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and a HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10; and
(b) an LC having a constant domain and a variable domain wherein the variable domain comprises a light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:13.
61. The method of claim 60 , wherein the antibody comprises an HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
62. The method of claim 60 , wherein the antibody comprises an LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
63. The method of claim 54 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
64. The method of claim 54 , wherein the antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
65. The method of claim 54 , wherein the medical device is a stent, endovascular stent graft, cardiac or venous catheter, continuous flow ventricular assist device (CF-LVAD), hemodialysis device, cardiopulmonary bypass device, Extracorporeal Membrane Oxygenation (ECMO) device, or ventricular assist device (VAD).
66. A method for therapeutic or prophylactic treatment of a medical device-related thromboembolic disorder in a subject comprising:
administering to the subject an effective amount of an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 43 or 67 and a light chain having the amino acid sequence shown in SEQ ID NO:31.
67. The method of claim 66 , wherein the medical device is a stent, endovascular stent graft, cardiac or venous catheter, continuous flow ventricular assist device (CF-LVAD), hemodialysis device, cardiopulmonary bypass device, and Extracorporeal Membrane Oxygenation (ECMO) device, or ventricular assist device (VAD).