FACTOR XI ANTIBODIES AND METHODS OF USE

• US 20190330372A1
• Filed: 12/21/2017
• Published: 10/31/2019
• Est. Priority Date: 12/23/2016
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: AIGNER, Maximillian, KOCH, Alexander Wolfgang, WALDHUBER, Markus
• Granted Patent: US 11,168,147 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07K 16/36 against blood coagulation factors
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present disclosure relates to monoclonal antibodies and antigen binding fragments thereof that bind to human Factor XI and activated Factor XI (“Factor XIa”), and pharmaceutical compositions and methods of treatment comprising the same.

Claims

1. An isolated anti-FXI antibody or antigen-binding fragment thereof that binds within the catalytic domain of FXI and/or FXIa comprising a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein

the HCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

3, 6, 7, and 9;

the HCDR2 comprises an amino acid sequence selected from the group consisting of;

(i) X1-I-X2-X3-X4-X5-X6-X7-T-X8-YADSVKG (SEQ ID NO;

     59), wherein X1 is any amino acid or is T or S, X2 is any amino acid or is D or E, X3 is any amino acid or is Y or S, X4 is any amino acid or is S, Y, or W, X5 is any amino acid or is S, D, or G, X6 is any amino acid or is Q, T, or D, X7 is any amino acid or is D or E, and X8 is any amino acid or is Y, H or D, wherein HCDR2 is not SEQ ID NO;

4,

(ii) X1-X2-X3-X4-X5-X6 (SEQ ID NO;

     60), wherein X1 is any amino acid or is E or D, X2 is any amino acid or is Y or S, X3 is any amino acid or is Y, S or W, X4 is any amino acid or is S, D, or G, X5 is any amino acid or is D, T, or Q, and X6 is any amino acid or is D or E, wherein HCDR2 is not SEQ ID NO;

8, and

(iii) I-X1-X2-X3-X4-X5-X6-T (SEQ ID NO;

     61), wherein X1 is any amino acid or is E or D, X2 is any amino acid or is Y or S, X3 is any amino acid or is S, Y, or W, X4 is any amino acid or is S, D, or G, X5 is any amino acid or is D, T, or Q, and X6 is any amino acid or is D or E, wherein HCDR2 is not SEQ ID NO;

10;

the HCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs;

5 and 11;

the LCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs;

16, 19, and 22;

the LCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs;

17 and 20; and

the LCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs;

18 and 21.

2. The antibody or antigen-binding fragment of claim 1, wherein

(i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:

3;

(ii) the HCDR2 comprises the amino acid sequence X1-I-X2-X3-X4-X5-X6-X7-T-X8-YADSVKG (SEQ ID NO;

     59), wherein X1 is any amino acid or is T or S, X2 is any amino acid or is D or E, X3 is any amino acid or is Y or S, X4 is any amino acid or is S, Y, or W, X5 is any amino acid or is S, D, or G, X6 is any amino acid or is Q, T, or D, X7 is any amino acid or is D or E, and X8 is any amino acid or is Y, H or D, and wherein HCDR2 is not SEQ ID NO;

4;

(iii) the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5;

(iv) the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16;

(v) the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17; and

(vi) the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18.

3. The antibody or antigen-binding fragment of claim 1, wherein

(i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:

6;

(ii) the HCDR2 comprises the amino acid sequence X1-I-X2-X3-X4-X5-X6-X7-T-X8-YADSVKG (SEQ ID NO;

     59), wherein X1 is any amino acid or is T or S, X2 is any amino acid or is D or E, X3 is any amino acid or is Y or S, X4 is any amino acid or is S, Y, or W, X5 is any amino acid or is S, D, or G, X6 is any amino acid or is Q, T, or D, X7 is any amino acid or is D or E, and X8 is any amino acid or is Y, H or D, and wherein HCDR2 is not SEQ ID NO;

4;

(iii) the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5;

(iv) the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16;

(v) the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17; and

(vi) the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18.

4. The antibody or antigen-binding fragment of claim 1, wherein

(i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:

7;

(ii) the HCDR2 comprises the amino acid sequence X1-X2-X3-X4-X5-X6 (SEQ ID NO;

     60), wherein X1 is any amino acid or is E or D, X2 is any amino acid or is Y or S, X3 is any amino acid or is Y, S or W, X4 is any amino acid or is S, D, or G, X5 is any amino acid or is D, T, or Q, and X6 is any amino acid or is D or E, and wherein HCDR2 is not SEQ ID NO;

8;

(iii) the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5;

(iv) the LCDR1 comprises the amino acid sequence of SEQ ID NO;

19;

(v) the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20; and

(vi) the LCDR3 comprises the amino acid sequence of SEQ ID NO;

21.

5. The antibody or antigen-binding fragment of claim 1, wherein

(i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:

9;

(ii) the HCDR2 comprises the amino acid sequence I-X1-X2-X3-X4-X5-X6-T of (SEQ ID NO;

     61), wherein X1 is any amino acid or is E or D, X2 is any amino acid or is Y or S, X3 is any amino acid or is S, Y, or W, X4 is any amino acid or is S, D, or G, X5 is any amino acid or is D, T, or Q, and X6 is any amino acid or is D or E, and wherein HCDR2 is not SEQ ID NO;

10;

(iii) the HCDR3 comprises the amino acid sequence of SEQ ID NO;

11;

(iv) the LCDR1 comprises the amino acid sequence of SEQ ID NO;

22;

(v) the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20; and

(vi) the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18.

34. The antibody or antigen-binding fragment of any one of claims 1-33, which is a monoclonal human antibody.

35. The antibody or antigen-binding fragment of any one of claims 1-33, which is a monoclonal humanized antibody.

36. The antibody or antigen-binding fragment of any one of claims 1-35, which is a human IgG1 isotype antibody.

37. The antibody or antigen-binding fragment of any one of claims 1-35, which is a human IgG2 or IgG4 isotype antibody.

38. The antibody or antigen-binding fragment of any one of claims 1-33, which is a single chain antibody, a Fab fragment, a Fv fragment, a F(ab′

)2 fragment, or a scFv fragment.

39. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof of any one of claims 1-38 and a pharmaceutically acceptable carrier.

40. A method of treating or managing or reducing the risk of a thromboembolic disorder comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment according to any one of claims 1-38.

41. The method of claim 40, wherein the subject is afflicated with, or is at risk of developing, one or more of stroke associated with atrial fibrillation and deep vein thrombosis.

42. The method of claim 40, wherein the subject is afflicated with, or at risk of developing, stroke associated with atrial fibrillation.

43. The method of claim 40, wherein the subject is afflicted with atrial fibrillation.

44. A method of preventing, treating or managing or reducing the risk of stroke comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment according to any one of claims 1-38.

45. The method of claim 44, wherein the subject is afflicted with atrial fibrillation.

46. A method of treating or managing or reducing the risk of a thromboembolic disorder comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an antibody or fragment according to any one of claims 1-38 in combination with one or more statin therapies.

47. A method of managing or reducing bleeding or bleeding risk in a subject treated or administered an anti-FXI antibody or antigen-biniding fragment of any one of claims 1-38, comprising the step of administering to the subject in need thereof, an anti-idiotype antibody or fragment thereof that specifically binds to the anti-FXI antibody and blocks the anti-FXI antibody from binding to FXI, and wherein the anti-idiotype antibody or fragment thereof reverses the anti-coagulant activity of the anti-FXI antibody.

48. The method of claim 47, wherein the anti-idiotype antibody or fragment thereof is administered to the subject once or twice to temporarily reverse the anti-coagulant effect of the anti-FXI antibody.

49. A method of managing or reducing bleeding or bleeding risk in a subject treated or administered an anti-FXI antibody or antigen-biniding fragment of any one of claims 1-38, said method comprises temporarily reversing of the anticoagulant effect for a sufficient time to manage the bleeding by one of the following:

(i) fluid replacement using colloids, crystalloids, human plasma or plasma proteins such as albumin;

(ii) transfusion with packed red blood or whole blood;

or (iii) administration of fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), activated PCC (APCC), such as, factor VIII inhibitor, and/or recombinant activated factor VII.

50. The method of any one of claims 40-46, comprising administering to the subject one or two dose of an anti-idiotype antibody or fragment thereof that specifically binds to the anti-FXI antibody and blocks the anti-FXI antibody from binding to FXI, and wherein the anti-idiotype antibody or fragment thereof reverses the anti-coagulant activity of the anti-FXI antibody.

51. The method of any one of claims 40-46, comprising temporarily reversing of the anticoagulant effect for a sufficient time to manage the bleeding by one of the following:

(i) fluid replacement using colloids, crystalloids, human plasma or plasma proteins such as albumin;

(ii) transfusion with packed red blood or whole blood;

or (iii) administration of fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), activated PCC (APCC), such as, factor VIII inhibitor, and/or recombinant activated factor VII.

52. A method for reversing the anticoagulant effect of an anti-FXI antibody or antigen-biniding fragment of any one of claims 1-38 in a patient being treated with the anti-FXI/FXIa antibody or antigen-binding fragment thereof, comprising administering an effective amount of an anti-idiotype antibody or fragment thereof that specifically binds to the anti-FXI antibody.

53. An anti-idiotype antibody or fragment thereof that specifically binds to the anti-FXI antibody of any one of claims 1-38, which blocks the anti-FXI antibody from binding to FXI, and wherein the anti-idiotype antibody or fragment thereof reverses the anti-coagulant activity of the anti-FXI antibody by at least 30% or by at least 40%.

54. A medicament comprising an antibody or antigen-binding fragment thereof according to any one of claims 1-38.

55. A polynucleotide comprising nucleic acid sequences encoding a VL, VH or a VL and VH of the antibody or antigen-binding fragment of any one of claims 1-38.

56. The polynucleotide of claim 55, which encodes a heavy chain, light chain, or a heavy chain and light chain of the antibody or antigen-binding fragment of any one of claims 1-38.

57. The polynucleotide of claim 55 comprising a nucleic acid sequence set forth in Table 2.

58. A vector comprising the polynucleotide according to any one of claims 55-57.

59. A host cell comprising the vector of claim 58.

60. The host cell of claim 59, which is a eukaryotic cell.

61. The host cell of claim 59, which is a mammalian cell.

62. A method of producing an anti-FXI/FXIa antibody or fragment thereof, comprising the step of culturing the host cell of any one of claims 59-61 under conditions suitable for expression of the anti-FXI/FXIa antibody or fragment thereof.

63. The method of claim 62, further comprising purifying the anti-FXI/FXIa antibody or fragment thereof.

64. A method to reduce the risk of stroke and/or systemic embolism in a patient with atrial fibrillation, comprising administering to the patient a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of claims 1-38.

65. The method of claim 64, wherein the patient has non-valvular atrial fibrillation.

66. The method of claim 64 or 65, wherein the patient has a demonstrated high risk of bleeding.

67. A method of reducing the risk of stroke and/or systemic embolism in a patient with chronic kidney disease, comprising administering to the patient a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of claims 1-38.

68. The method of claim 67, wherein patient has end stage renal disease (ESRD).

69. The method of claim 67, wherein the patient has ESRD and is undergoing dialysis.

70. The method of claim 69, wherein the patient has non-valvular atrial fibrillation.

71. The method of claim 70, wherein the patient has a demonstrated high risk of bleeding.

6. An isolated anti-FXI antibody or antigen-binding fragment thereof that binds within the catalytic domain of FXI and/or FXIa comprising (i) a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and (ii) a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein

the HCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

3, 6, 7, and 9;

the HCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs;

27, 28, 29, 38, 39, 40, 45, 46, and 47;

the HCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs;

5 and 11;

the LCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs;

16, 19, and 22;

the LCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs;

17 and 20; and

the LCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs;

18 and 21.

7. The antibody or antigen-binding fragment of claim 6, wherein

(i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:

3, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

45, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18;

(ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO;

6, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

45, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18;

(iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO;

7, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

46, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

19, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

21;

or

(iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO;

9, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

47, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

11, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

22, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18.

8. The antibody or antigen-binding fragment of claim 6, wherein

(i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:

3, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

38, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18;

(ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO;

6, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

38, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18;

(iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO;

7, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

39, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

19, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

21;

or

(iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO;

9, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

40, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

11, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

22, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18.

9. The antibody or antigen-binding fragment of claim 6, wherein

(i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:

3, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

27, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18;

(ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO;

6, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

27, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18;

(iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO;

7, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

28, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

19, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

21;

or

(iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO;

9, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

29, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

11, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

22, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18.

10. The antibody or antigen-binding fragment of claim 6, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:

3, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

27, 38, or 45, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18.

11. The antibody or antigen-binding fragment of claim 6, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:

6, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

27, 38, or 45, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

16, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

17, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18.

12. The antibody or antigen-binding fragment of claim 6, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:

7, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

28, 39, or 46, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

5, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

19, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

21.

13. The antibody or antigen-binding fragment of claim 6, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:

9, the HCDR2 comprises the amino acid sequence of SEQ ID NO;

29, 40, or 47, the HCDR3 comprises the amino acid sequence of SEQ ID NO;

11, the LCDR1 comprises the amino acid sequence of SEQ ID NO;

22, the LCDR2 comprises the amino acid sequence of SEQ ID NO;

20, and the LCDR3 comprises the amino acid sequence of SEQ ID NO;

18.

22. The antibody or antigen-binding fragment of claim 6, wherein the VH comprises the amino acid sequence of SEQ ID NOs:

30, 41, and 48; and

the VL comprises the amino acid sequence of SEQ ID NO;

34 or 55.

23. The antibody or antigen-binding fragment of claim 22, wherein the VH comprises the amino acid sequence of SEQ ID NO:

48 and the VL comprises the amino acid sequence of SEQ ID NO;

55.

24. The antibody or antigen-binding fragment of claim 22, wherein the VH comprises the amino acid sequence of SEQ ID NO:

48 and the VL comprises the amino acid sequence of SEQ ID NO;

34.

25. The antibody or antigen-binding fragment of claim 22, wherein the VH comprises the amino acid sequence of SEQ ID NO:

41 and the VL comprises the amino acid sequence of SEQ ID NO;

34.

26. The antibody or antigen-binding fragment of claim 22, wherein the VH comprises the amino acid sequence of SEQ ID NO:

30 and the VL comprises the amino acid sequence of SEQ ID NO;

34.

27. The antibody or antigen-binding fragment of claim 6, wherein the heavy chain comprises the amino acid sequence of SEQ ID NOs:

32, 43, 50, or 53; and

the light chain comprises the amino acid sequence of SEQ ID NO;

57 or 36.

28. The antibody or antigen-binding fragment of claim 22, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

53 and the light chain comprises the amino acid sequence of SEQ ID NO;

57.

29. The antibody or antigen-binding fragment of claim 22, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

50 and the light chain comprises the amino acid sequence of SEQ ID NO;

36.

30. The antibody or antigen-binding fragment of claim 22, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

43 and the light chain comprises the amino acid sequence of SEQ ID NO;

36.

31. The antibody or antigen-binding fragment of claim 22, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

32 and the light chain comprises the amino acid sequence of SEQ ID NO;

36.

32. The antibody or antigen-binding fragment of claim 6, wherein the VH comprises an amino acid sequence that is at least 90% identical to amino acid sequence of SEQ ID NOs:

30, 41, and 48;

the VL comprises an amino acid sequence that is at least 90% to the amino acid sequence of SEQ ID NO;

34 or 55, and wherein the VH does not comprise the amino acid sequence of SEQ ID NO;

12 and the VL does not comprise the amino acid sequence of SEQ ID NO;

23.

33. The antibody or antigen-binding fragment of claim 6, wherein the VH comprises an amino acid sequence that is at least 95% identical to amino acid sequence of SEQ ID NOs:

30, 41, and 48;

the VL comprises an amino acid sequence that is at least 95% to the amino acid sequence of SEQ ID NO;

34 or 55, and wherein the VH does not comprise the amino acid sequence of SEQ ID NO;

12 and the VL does not comprise the amino acid sequence of SEQ ID NO;

23.

14. An isolated anti-FXI antibody or antigen-binding fragment thereof that binds within the catalytic domain of FXI and/or FXIa comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises complementarity determining regions HCDR1, HCDR2, and HCDR3 selected from Table 2, and wherein the VL comprises complementarity determining regions LCDR1, LCDR2, and LCDR3 selected from Table 2.

15. The antibody or antigen-binding fragment of claim 14, wherein the VH comprises Combined HCDR1, HCDR2, and HCDR3 and the VL comprises Combined LCDR1, LCDR2, and LCDR3.

16. The antibody or antigen-binding fragment of claim 14, wherein the VH comprises Kabat HCDR1, HCDR2, and HCDR3 and the VL comprises Kabat LCDR1, LCDR2, and LCDR3.

17. The antibody or antigen-binding fragment of claim 14, wherein the VH comprises Chothia HCDR1, HCDR2, and HCDR3 and the VL comprises Chothia LCDR1, LCDR2, and LCDR3.

18. The antibody or antigen-binding fragment of claim 14, wherein the VH comprises IMGT HCDR1, HCDR2, and HCDR3 and the VL comprises IMGT LCDR1, LCDR2, and LCDR3.

19. An isolated anti-FXI antibody or antigen-binding fragment thereof that binds within the catalytic domain of FXI and/or FXIa comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises complementarity determining regions HCDR1, HCDR2, and HCDR3 of antibody AM1, and wherein the VL comprises complementarity determining regions LCDR1, LCDR2, and LCDR3 of antibody AM1.

20. An isolated anti-FXI antibody or antigen-binding fragment thereof that binds within the catalytic domain of FXI and/or FXIa comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises complementarity determining regions HCDR1, HCDR2, and HCDR3 of antibody AM2, and wherein the VL comprises complementarity determining regions LCDR1, LCDR2, and LCDR3 of antibody AM2.

21. An isolated anti-FXI antibody or antigen-binding fragment thereof that binds within the catalytic domain of FXI and/or FXIa comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises complementarity determining regions HCDR1, HCDR2, and HCDR3 of antibody AM3 or AM4, and wherein the VL comprises complementarity determining regions LCDR1, LCDR2, and LCDR3 of antibody AM3 or AM4.