Anti-coagulation factor XI antibodies
View Patent ↗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. An antibody or antigen binding fragment comprising:
(i) 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. An antibody or antigen binding fragment comprising (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 having the amino acid sequence shown in SEQ ID NO:13.
3. The antibody or antigen binding fragment of claim 1 , 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 antibody or antigen binding fragment 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 antibody or antigen binding fragment of claim 1 , wherein the antibody comprises a LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
6. The antibody or antigen binding fragment 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 antibody or antigen binding fragment 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 antibody or antigen binding fragment 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 antibody or antigen binding fragment of claim 7 , wherein the antibody comprises an LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
10. A composition comprising the antibody or antigen binding fragment of claim 1 and a pharmaceutically acceptable carrier or diluent.
11. An antibody or antigen binding fragment that binds the apple 3 domain of coagulation factor XI (FXI) comprising a heavy chain variable domain (V H ) comprising the amino acid sequence shown in SEQ ID NO:29 and a light chain variable domain (V L ) comprising the amino acid sequence shown in SEQ ID NO:30.
12. The antibody or antigen binding fragment of claim 11 , wherein the antibody further comprises a heavy chain constant domain having the amino acid sequence shown in SEQ ID NO:16 or 17 and a light chain constant domain having the amino acid sequence shown in SEQ ID NO:20.
13. The antibody or antigen binding fragment of claim 11 , wherein the antibody further comprises a heavy chain constant domain of the IgG1 isotype that lacks N-glycosylation of the asparagine at position 297.
14. A composition comprising the antibody or antigen binding fragment of claim 11 and a pharmaceutically acceptable carrier or diluent.
15. An antibody that binds the apple 3 domain of coagulation factor XI (FXI) comprising 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.
16. A composition comprising an antibody that binds the apple 3 domain of coagulation factor XI (FXI) 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, and a pharmaceutically acceptable carrier or diluent.
17. An antibody that binds the apple 3 domain of coagulation factor XI (FXI) comprising 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.
18. A composition comprising an antibody that binds the apple 3 domain of coagulation factor XI (FXI) 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, and a pharmaceutically acceptable carrier or diluent.