Anti-PCSK9 antibodies
An human antibody or antigen-binding fragment of a human antibody that specifically binds and inhibits human proprotein convertase subtilisin/kexin type 9 (hPCSK9) characterized by the ability to reduce serum LDL cholesterol by 40-80% over a 24, 60 or 90 day period relative to predose levels, with little or no reduction in serum HDL cholesterol and/or with little or no measurable effect on liver function, as determined by ALT and AST measurements.
1. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising:
a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 76;
b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 78;
c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 80;
d) a light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 84;
e) a light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 86; and
f) a light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 88.
2. The antibody or antigen-binding fragment of an antibody of claim 1 , wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:755).
3. The antibody or antigen-binding fragment of an antibody of claim 1 , wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“hPCSK9(D374Y)”).
4. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:90; and a light chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:92.
5. The antibody or antigen-binding fragment of an antibody of claim 4 , wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:755).
6. The antibody or antigen-binding fragment of an antibody of claim 4 , wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“hPCSK9(D374Y)”).
7. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising:
a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO: 76;
b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO: 78;
c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO: 80;
d) a light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO: 84;
e) a light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO: 86; and
f) a light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO: 88.
8. The antibody or antigen-binding fragment of an antibody of claim 7 , wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:755).
9. The antibody or antigen-binding fragment of an antibody of claim 7 , wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“hPCSK9(D374Y)”).
10. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising a heavy chain variable region comprising an amino acid sequence that is at least 98% identical to SEQ ID NO:90; and a light chain variable region comprising an amino acid sequence that is at least 98% identical to SEQ ID NO:92.
11. The antibody or antigen-binding fragment of an antibody of claim 10 , wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:755).
12. The antibody or antigen-binding fragment of an antibody of claim 10 , wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“hPCSK9(D374Y)”).
13. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising:
a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO: 76;
b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO: 78;
c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO: 80;
d) a light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO: 84;
e) a light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO: 86; and
f) a light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO: 88.
14. The antibody or antigen-binding fragment of an antibody of claim 13 , wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:755).
15. The antibody or antigen-binding fragment of an antibody of claim 13 , wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“hPCSK9(D374Y)”).
16. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising a heavy chain variable region comprising an amino acid sequence that is at least 99% identical to SEQ ID NO:90; and a light chain variable region comprising an amino acid sequence that is at least 99% identical to SEQ ID NO:92.
17. The antibody or antigen-binding fragment of an antibody of claim 16 , wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:755).
18. The antibody or antigen-binding fragment of an antibody of claim 16 , wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“hPCSK9(D374Y)”).