Isolated nucleic acid encoding an antibody which specifically binds to PCSK9 and a host cell that produces the antibody
The present invention provides antagonizing antibodies, antigen-binding portions thereof, and aptamers that bind to proprotein convertase subtilisin kexin type 9 (PCSK9). Also provided are antibodies directed to peptides, in which the antibodies bind to PCSK9. The invention further provides a method of obtaining such antibodies and antibody-encoding nucleic acid. The invention further relates to therapeutic methods for use of these antibodies and antigen-binding portions thereof to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease, including treatment of hypercholesterolemia.
1. A host cell that recombinantly produces an antibody which specifically binds to PCSK9, wherein the antibody comprises a heavy chain variable region (VH) comprising complementarity determining region one (CDR1), CDR2, and CDR3 of the amino acid sequence shown in SEQ ID NO: 54, and a light chain variable region (VL) comprising CDR1, CDR2, and CDR3 of the amino acid sequence shown in SEQ ID NO: 53.
2. The host cell of claim 1 , wherein the antibody comprises:
a VH complementarity determining region one (CDR1) having the amino acid sequence shown in SEQ ID NO:8, 59, or 60, a VH CDR2 having the amino acid sequence shown in SEQ ID NO:9 or 61, and a VH CDR3 having the amino acid sequence shown in SEQ ID NO:10; and
a VL CDR1 having the amino acid sequence shown in SEQ ID NO:11, a VL CDR2having the amino acid sequence shown in SEQ ID NO:12, and VL CDR3 having the amino acid sequence shown in SEQ ID NO:13.
3. The host cell of claim 2 , wherein the antibody comprises:
a VH region comprising the amino acid sequence shown in SEQ ID NO: 54 or a variant thereof with one or several amino acid substitutions in amino acids positions that are not within said CDRs; and
a VL region comprising the amino acid sequence shown in SEQ ID NO: 53 or a variant thereof with one or several amino acid substitutions in amino acids positions that are not within said CDRs.
4. The host cell of claim 3 , wherein the antibody further comprises an immunologically inert constant region.
5. The host cell of claim 4 , wherein the constant region is aglycosylated Fc.
6. The host cell of claim 4 , wherein the antibody has an isotype that is selected from the group consisting of IgG 2 , IgG 4 , IgG 2Δa , IgG 4Δb , IgG 4Δc , IgG 4 S228P, IgG 4Δb S228P and IgG 4Δc S228P.
7. The host cell of claim 3 , wherein the antibody comprises a light chain having the amino acid sequence shown in SEQ ID NO:14 and a heavy chain having the amino acid sequence shown in SEQ ID NO:15, with or without the C-terminal lysine of the amino acid sequence shown in SEQ ID NO: 15.
8. An isolated nucleic acid encoding an antibody which specifically binds to PCSK9, wherein the antibody comprises:
a heavy chain variable region (VH) comprising complementarity determining region one (CDR1), CDR2, and CDR3 of the amino acid sequence shown in SEQ ID NO: 54; and
a light chain variable region (VL) comprising CDR1, CDR2, and CDR3 of the amino acid sequence shown in SEQ ID NO: 53.
9. The isolated nucleic acid of claim 8 , wherein the antibody comprises:
a VH complementarity determining region one (CDR1) having the amino acid sequence shown in SEQ ID NO:8, 59, or 60, a VH CDR2 having the amino acid sequence shown in SEQ ID NO:9 or 61, and a VH CDR3 having the amino acid sequence shown in SEQ ID NO:10; and
a VL CDR1 having the amino acid sequence shown in SEQ ID NO:11, a VL CDR2 having the amino acid sequence shown in SEQ ID NO:12, and VL CDR3having the amino acid sequence shown in SEQ ID NO:13.
10. The isolated nucleic acid of claim 9 , wherein the antibody comprises:
a VH region comprising the amino acid sequence shown in SEQ ID NO: 54 or a variant thereof with one or several amino acid substitutions in amino acids positions that are not within said CDRs; and
a VL region comprising the amino acid sequence shown in SEQ ID NO: 53 or a variant thereof with one or several amino acid substitutions in amino acids positions that are not within said CDRs.
11. The isolated nucleic acid of claim 10 , wherein the antibody further comprises an immunologically inert constant region.
12. The isolated nucleic acid of claim 11 , wherein the constant region is aglycosylated Fc.
13. The isolated nucleic acid of claim 11 , wherein the antibody has an isotype that is selected from the group consisting of IgG 2 , IgG 4 , IgG 2Δa , IgG 4Δb , IgG 4Δc , IgG 4 S228P, IgG 4Δb S228P and IgG 4Δc S228P.
14. The isolated nucleic acid of claim 10 , wherein the antibody comprises a light chain having the amino acid sequence shown in SEQ ID NO:14and a heavy chain having the amino acid sequence shown in SEQ ID NO:15, with or without the C-terminal lysine of the amino acid sequence shown in SEQ ID NO: 15.