Anti-factor xii / xiia antibodies and uses thereof
A fully human monoclonal antibody targeting FXII and FXIIa addresses the need for effective FXII inhibition, providing a therapeutic solution for thrombosis-related diseases by neutralizing its activity.
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- REGENERON PHARMACEUTICALS INC
- Filing Date
- 2026-06-08
- Publication Date
- 2026-07-17
AI Technical Summary
Current treatments for diseases associated with thrombosis lack effective means to inhibit or neutralize the activity of the factor XII (FXII) protein, which plays a crucial role in the initiation of blood coagulation.
A fully human monoclonal antibody that binds to FXII and its activated form (FXIIa) is developed to inhibit or neutralize its activity, providing a therapeutic approach for treating or preventing thrombotic conditions.
The antibody effectively inhibits FXII activity, offering a targeted treatment for thrombosis-related diseases by neutralizing its function and potentially reducing thrombotic events.
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Abstract
Description
This invention provides a monoclonal antibody that binds to the factor XII (FXII) protein and a method of using the same. In various embodiments of the invention, the antibody is a fully human antibody that binds to FXII and its activated form (FXIIa). In some embodiments, the antibody of the invention can be used to inhibit or neutralize the activity of FXII, thereby providing a means for the treatment or prevention of diseases, symptoms, or conditions associated with thrombosis in humans. Abstract
Claims
CLAIMSWhat is claimed is:
1. An antibody, or antigen-binding fragment thereof, that binds to human Factor XII (FXI I) , wherein the antibody, or antigen-binding fragment thereof, comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR); and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR), wherein the HCDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24, the HCR2 has an amino acid sequence selected from SEQ ID NOs: 6 and 26, and the HCDR3 has an amino acid sequence selected from SEQ ID NOs: 8 and 28, wherein the LCDR1 has an amino acid sequence selected from SEQ ID NOs: 12 and 32, the LCR2 has an amino acid sequence of SEQ ID NO: 14, and the LCDR3 has an amino acid sequence selected from SEQ ID NOs: 16 and 34.
2. The antibody, or antigen binding portion thereof, of claim 1 , wherein:(a) the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 4;(b) the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 6;(c) the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 8;(d) the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 12;(e) the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 14; and(f) the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 16; or wherein:(a) the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 24;(b) the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 26;(c) the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 28;(d) the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 32;(e) the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 14; and(f) the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 34.
3. The antibody, or antigen binding portion thereof, of any one of the previous claims, wherein:the heavy chain variable region comprises a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 2 and the light chain variable region comprises a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 10; or the heavy chain variable region comprises a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 22 and the light chain variable region comprises a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 30.
4. The antibody, or antigen binding portion thereof, of any one of the previous claims, wherein: the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 2 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 10; or the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 22 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 30.
5. The antibody, or antigen-binding portion thereof, of any one of the previous claims, comprising a heavy chain (HC) and a light chain (LC), wherein: the heavy chain comprises a sequence having at least 90% identity to SEQ ID NO: 18, and the light chain comprises a sequence having at least 90% identity to SEQ ID NO: 20; the heavy chain comprises a sequence having at least 90% identity to SEQ ID NO: 36, and the light chain comprises a sequence having at least 90% identity to SEQ ID NO: 38; or the heavy chain comprises a sequence having at lest 90% identity to SEQ ID NO: 40, and the light chain comprises a sequence having at least 90% identity to SEQ ID NO: 20.
6. The antibody, or antigen-binding portion thereof, of any one of the previous claims, comprising a heavy chain (HC) and a light chain (LC), wherein: the heavy chain comprises a sequence of SEQ ID NO: 18, and the light chain comprises a sequence of SEQ ID NO: 20; or the heavy chain comprises a sequence of SEQ ID NO: 36, and the light chain comprises a sequence of SEQ ID NO: 38.
7. The antibody, or antigen-binding portion thereof, of any one of claims 1-5, comprising a heavy chain (HC) and a light chain (LC), wherein: the heavy chain comprises a sequence of SEQ ID NO: 40, and the light chain comprises a sequence of SEQ ID NO: 20.
8. An antibody, or antigen-binding fragment thereof, that binds to human FXII / FXIIa, wherein the antibody, or antigen-binding fragment thereof, comprises three heavy chain CDRs (HCDR1 , HCDR2 and HCDR3) contained within a HCVR and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) contained within a LCVR;(a) wherein the HCVR comprises an amino acid sequence having at least 90% identity SEQ ID NO: 2; and wherein the LCVR comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 10; or(b) wherein the HCVR comprises an amino acid sequence having at least 90% identity SEQ ID NO: 22; and wherein the LCVR comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 30.
9. The antibody, or antigen-binding fragment thereof, of claim 8,(a) wherein the HCVR comprises an amino acid sequence having at least 95% identity SEQ ID NO: 2; and wherein the LCVR comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 10; or(b) wherein the HCVR comprises an amino acid sequence having at least 95% identity SEQ ID NO: 22; and wherein the LCVR comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 30.
10. The antibody, or antigen-binding fragment thereof, of claim 8 or claim 9,(a) wherein the HCVR comprises an amino acid sequence having no more than 12 amino acid substitutions in SEQ ID NO: 2; and wherein the LCVR comprises an amino acid sequence having no more than 12 amino acid substitutions in SEQ ID NO: 10; or(b) wherein the HCVR comprises an amino acid sequence having no more than 12 amino acid substitutions in SEQ ID NO: 22; and wherein the LCVR comprises an amino acid sequence having no more than 12 amino acid substitutions in SEQ ID NO: 30.
11. The antibody, or antigen-binding fragment thereof, of any one of claims 8-10,(a) wherein the HCVR comprises an amino acid sequence of SEQ ID NO: 2; and wherein the LCVR comprises an amino acid sequence of SEQ ID NO: 10; or(b) wherein the HCVR comprises an amino acid sequence of SEQ ID NO: 22; and wherein the LCVR comprises an amino acid sequence of SEQ ID NO: 30.
12. The antibody, or antigen-binding fragment thereof, of any one of claims 8-11 , wherein:(a) the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 4;(b) the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 6;(c) the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 8;(d) the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 12;(e) the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 14; and(f) the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 16; or wherein:(a) the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 24;(b) the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 26;(c) the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 28;(d) the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 32;(e) the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 14; and(f) the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 34.
13. The antibody, or antigen-binding fragment thereof, of any one of claims 8-12, comprising a heavy chain (HC) and a light chain (LC), wherein: the heavy chain comprises a sequence of SEQ ID NO: 18, and the light chain comprises a sequence of SEQ ID NO: 20; or the heavy chain comprises a sequence of SEQ ID NO: 36, and the light chain comprises a sequence of SEQ ID NO: 38.
14. The antibody, or antigen-binding fragment thereof, of any one of claims 8-12, comprising a heavy chain (HC) and a light chain (LC), wherein: the heavy chain comprises a sequence of SEQ ID NO: 40, and the light chain comprises a sequence of SEQ ID NO: 20.
15. An antibody, or antigen-binding fragment thereof, that binds to human Factor XI I (FXI I) , wherein the antibody, or antigen-binding fragment thereof, comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR); and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR), wherein(a) the HCDR1 comprises an amino acid sequence G-F-T-F-S-S-Y-A (SEQ ID NO: 4);(b) the HCDR2 comprises an amino acid sequence l-G-G-S-G-G-N-T (SEQ ID NO: 6);(c) the HCDR3 comprises an amino acid sequence A-S-F-l-P-A-A-l-R-G-G-D-W-l-D-P (SEQ ID NO: 8);(d) the LCDR1 comprises an amino acid sequence Q-G-l-R-N-Y (SEQ ID NO: 12);(e) the LCDR2 comprises an amino acid sequence A-A-S (SEQ ID NO: 14); and(f) the LCDR3 comprises an amino acid sequence Q-Y-Y-N-S-A-P-L-T (SEQ ID NO: 16).
16. An antibody, or antigen-binding fragment thereof, that binds to Factor XII (FXI I) , wherein the antibody, or antigen-binding fragment thereof, comprises three heavy chain complementarity determining regions (CDRs) (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR); and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR), wherein(a) the HCDR1 comprises an amino acid sequence G-D-S-V-S-S-N-S-A-A (SEQ ID NO: 24);(b) the HCDR2 comprises an amino acid sequence T-Y-Y-R-S-K-W-Y-N (SEQ ID NO: 26);(c) the HCDR3 comprises an amino acid sequence A-R-E-V-S-G-R-Y-N-W-F-D-S (SEQ ID NO: 28);(d) the LCDR1 comprises an amino acid sequence Q-T-l-N-S-Y (SEQ ID NO: 32);(e) the LCDR2 comprises an amino acid sequence A-A-S (SEQ ID NO: 14); and(f) the LCDR3 comprises an amino acid sequence Q-Q-N-Y-R-T-F-T (SEQ ID NO: 34).
17. The antibody, or antigen-binding fragment thereof, of any one of the previous claims, comprising an Fc domain comprising one or more mutations that alter Fc region function.
18. The antibody, or antigen-binding fragment thereof, of claim 15, wherein the Fc domain comprises a mutation in the CH2 or a CH3 region that increase FcyR binding activity.
19. The antibody, or antigen-binding fragment thereof, of claim 17 or claim 18, wherein the Fc domain comprises at least one mutation in one or more amino acids selected from the group consisting of amino acids at positions 248, 250, 252, 254, 256. 257, 307, 311, 376, 380, 428, 433 and 434.
20. The antibody, or antigen-binding fragment thereof, of claim 19, wherein the Fc domain comprises at least one mutation in one or more amino acids at positions 252, 254 and 256.
21. The antibody, or antigen-binding fragment thereof, of claim 19 or claim 20, wherein the at least one mutation in the Fc domain comprises: mutating position 252 to Y mutating position 254 to T; and / or mutating position 256 to E.
22. The antibody, or antigen-binding fragment thereof, of any one of claims 17-21, wherein the at least one mutation in the Fc domain increases the half-life of the antibody, or antigen-binding fragment thereof, in blood plasma compared to an antibody, or an antigenbinding fragment thereof, without the mutation.
23. The antibody, or antigen-binding fragment thereof, of claim 22, wherein the half-life is increased by at least 1.2-fold, preferably at least 1.5-fold, compared to an antibody, or an antigen-binding fragment thereof, without the mutation.
24. The antibody, or antigen-binding fragment thereof, of any one of the previous claims, comprising a modified glycosylation pattern, wherein the modification increases antibody dependent cellular cytotoxicity (ADCC) function and / or alters complement dependent cytotoxicity (CDC) activity.
25. The antibody, or antigen-binding fragment thereof, of any one of the previous claims, wherein the antibody or antigen-binding fragment thereof, is a monoclonal antibody, a bispecific antibody, a multi-specific antibody, or an antigen-binding fragment thereof.
26. The antibody, or antigen-binding fragment thereof, of claim 25, wherein the multispecific antibody binds different epitopes of FXII or contains antigen-binding domains specific for FXII and one or more additional target polypeptides.
27. The antibody, or antigen-binding fragment thereof, of any one of the previous claims, comprising one or more of the following characteristics:(a) is a fully human monoclonal antibody;(b) binds to activated Factor XI I (FXIIa, FXIIab);(c) binds to FXII with a dissociation constant (KD) of less than 1.5nM at 25 °C;(d) binds to FXII with a KD of less than 17nM at 37 °C;(e) binds to FXIIa with a KD of less than 5nM, preferably less than 0.9nM, at 25 °C;(f) binds to FXIIa with a KD of less than 6.5nM, preferably less than 2.5nM, at 37 °C;(g) binds to FXIIab with a KD of less than 5nM, preferably less than 0.7nM, at 25 °C;(h) blocks thrombin generation by intrinsic pathway at a concentration of less than 250nM; and(I) blocks thrombin generation by intrinsic pathway without blocking thrombin generation by extrinsic pathway; or any combinations thereof of (a)-(l).
28. The antibody, or the antigen binding fragment thereof, of any one of the previous claims, wherein the antibody is a humanized antibody or a chimeric antibody.
29. The antibody, or the antigen binding fragment thereof, of any one of the previous claims, wherein the antibody, or the antigen binding fragment thereof is chemically or biologically conjugated to a therapeutic moiety.
30. The antibody, or the antigen binding fragment thereof, of claim 29, wherein the conjugated moiety comprises a radioactive agent, a cytokine, an interferon, a target or reporter moiety, an enzyme, a second different antibody, a peptide or protein, or a therapeutic agent.
31. An antibody or antigen-binding fragment thereof that competes for binding to Factor XII with an antibody or antigen-binding fragment thereof of any one of the previous claims.
32. An antibody or antigen-binding fragment thereof that binds to the same epitope as an antibody or antigen-binding fragment thereof of any one of the previous claims.
33. A pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof that binds to Factor Xll / Xlla according to any one of the previous claims and a pharmaceutically acceptable carrier or diluent.
34. An isolated polynucleotide molecule comprising a polynucleotide sequence that encodes a HCVR of the antibody or antigen-binding fragment thereof, as set forth in any one of claims 1-32.
35. An isolated polynucleotide molecule comprising a polynucleotide sequence that encodes a LCVR of the antibody or antigen-binding fragment thereof, as set forth in any one of claims 1-32.
36. A vector comprising the polynucleotide sequence of claim 34, the polynucleotide sequence of claim 35, or both the polynucleotide sequences of claim 34 and claim 35.
37. A cell expressing the vector of claim 36.
38. A method of producing an anti-FXI l / FXI la antibody or antigen-binding fragment thereof, comprising growing the cell of claim 37 under conditions permitting production of the antibody or antigen-binding fragment thereof, and recovering the antibody or fragment so produced.
39. The method of claim 38, further comprising formulating the antibody or antigenbinding fragment thereof as a pharmaceutical composition comprising an acceptable carrier.
40. A method of preventing the formation of a thrombus or treating a subject at risk of thrombus formation, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment thereof of any one of claims 1-32 to a subject in need thereof.
41. The method of claim 40, wherein the subject has a disease, disorder or condition selected from the group consisting of venous thrombosis, arterial thrombosis, device thrombosis, thromboembolism, hereditary angioedema, stroke, thrombophilia, cardiac ischemia, atherosclerotic plaque rupture, use of mechanical valve prostheses, use of bloodcontacting medical devices, use of blood-contacting extracorporeal circuits, venous thromboembolism, pulmonary embolism, deep vein thrombosis, portal vein thrombosis, Budd-Chiari syndrome, Paget-Schroetter disease, renal vein thrombosis, cerebral venous sinus thrombosis, jugular vein thrombosis, cavernous sinus thrombosis, hepatic artery thrombosis, limb ischemia and myocardial infarction.
42. The method of claims 40 or 41 , wherein the pharmaceutical composition is administered prophylactically or therapeutically to the subject in need thereof.
43. The method of any one of claims 40-42, wherein the pharmaceutical composition is administered in combination with a second therapeutic agent.
44. The method of claim 43, wherein the second therapeutic agent is selected from the group consisting of an anti-coagulant, a direct thrombin inhibitor, a thrombolytic drug, a fibrinolytic drug, an anti-platelet drug, an anti-inflammatory drug, an anti-hypertensive drug, a second anti-FXII antibody, a lipid-lowering drug, mechanical clot retrieval, catheter-guided thrombolysis, compression stockings, and surgery.
45. The method of any one of claims 40-44, wherein the pharmaceutical composition is administered subcutaneously, intravenously, intradermally, intraperitoneally, or intramuscularly.
46. The method of any one of claims 40-45, wherein the pharmaceutical composition is administered at a dose of about 0.1 mg / kg of body weight to about 100 mg / kg of body weight of the subject.
47. The method of any one of claims 40-46, wherein the pharmaceutical composition is administered at one or more doses comprising between about 10 mg to about 600 mg to the subject.
48. The method of any one of claims 40-47, wherein the pharmaceutical composition is administered for more than one dose, wherein the subsequent doses are approximately the same or less than that of the initial dose, wherein the subsequent dose are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.49 A method of preventing the formation of a thrombus or treating a subject at risk of thrombus formation, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment thereof of any one of claims 1-32 prior to, concurrent with, or after one or more additional therapeutic agents to a subject in need thereof.
50. The method of claim 49, wherein the one or more additional therapeutic agents are selected from an anti-coagulant, a thrombin inhibitor, a thrombolytic drug, an anti-plateletdrug, an antihypertensive, an immunosuppressive agent, a fibrinolytic agent, a cholesterol- lowering agent, an anti-inflammatory drug, a second anti-FXII antibody, mechanical clot retrieval, catheter-guided thrombolysis and surgery.
51. A method of diagnosing or detecting a FXII-associated-disease or disorder, the method comprising contacting a sample of a subject with one or more antibodies or antigenbinding fragment thereof of any one of claims 1-32, wherein the antibody or antigen-binding fragment thereof is detectably labeled.