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. An antibody or antigen binding fragment comprising:
(i) at least the six complimentary determining regions (CDRs) of an anti-FXI antibody of the αFXI-18611p family,
wherein the antibody of the αFXI-18611p family comprises a heavy chain (HC) having the amino acid sequence shown in SEQ ID NO:33 or 35 and a light chain (LC) having the amino acid sequence shown in SEQ ID NO:26.
2. The antibody or antigen binding fragment of claim 1 , wherein the six CDRs of the αFXI-18611p family comprise;
HC CDR1 having the amino acid sequence set forth in SEQ ID NO:1, HC CDR2 having the amino acid sequence set forth in SEQ ID NO:2, and HC CDR3 having the amino acid sequence set forth in SEQ ID NO:3, LC-CDR1 having the amino acid sequence set forth in SEQ ID NO:5, LC CDR2 having the amino acid sequence set forth in SEQ ID NO:6, and LC CDR3 having the amino acid sequence set forth in SEQ ID NO:7.
3. The antibody or antigen binding fragment of claim 1 , wherein the antibody or antigen binding fragment comprises a HC variable domain comprising the amino acid sequence set forth in SEQ ID NO:21 or 22 and a LC variable domain comprising the amino acid sequence set forth in SEQ ID NO:25.
4. The antibody or antigen binding fragment of any one 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 any one 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 antibody fragment comprises:
(a) a heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO: 21 and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO:25; and
(b) a heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO:22 and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO:25.
7. The antibody or antigen binding fragment of claim 6 , wherein the antibody further comprises a HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, 19.
8. The antibody or antigen binding fragment of claim 6 , wherein the antibody further comprises a LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
9. 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.
10. 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 comprising a heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:1, a HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:2, and a HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:3; 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:5, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:6, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:7.
11. The antibody or antigen binding fragment of claim 10 , wherein the antibody comprises an HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.
12. The antibody or antigen binding fragment of claim 10 , wherein the antibody comprises an LC constant domain comprising the amino acid sequence shown in SEQ ID NO:20.
13. The antibody or antigen binding fragment of claim 1 , wherein the antibody comprises:
an HC having the amino acid sequence shown in SEQ ID NO: 33, 35, 45, 47, 69, or 71; and
an LC having the amino acid sequence shown in SEQ ID NO:26.
14. A composition comprising the antibody or antigen binding fragment of claim 1 and a pharmaceutically acceptable carrier or diluent.
15. An antibody or antibody fragment comprising a heavy chain variable domain (V H ) comprising the amino acid sequence shown in SEQ ID NO:21 or 22 and a light chain variable domain (V L ) comprising the amino acid sequence shown in SEQ ID NO:25.
16. The antibody or antibody fragment of claim 15 , 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.
17. A composition comprising the antibody or antibody fragment of claim 15 and a pharmaceutically acceptable carrier or diluent.