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 producing an antibody or antigen binding fragment comprising (i) six complementarity 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 CDR 3 of the light chain (LC) having the amino acid sequence shown in SEQ ID NO:31, the method comprising:
providing a host cell comprising a nucleic acid molecule encoding the heavy chain or antigen binding fragment thereof and a nucleic acid molecule encoding the light chain or antigen binding fragment thereof; and cultivating the host cell under conditions and a time sufficient to produce the antibody or antigen binding fragment.
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 1 D 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.