Pc33718e

Abstract

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.

It is claimed: 
     
         1 . An isolated antibody that comprises a PCSK9 binding region that competes with, or recognizes a first epitope of PCSK9 that overlaps with a second epitope that is recognized by, a monoclonal antibody selected from the group consisting of 5A10, which is produced by a hybridoma cell line deposited with the American Type Culture Collection and assigned accession number PTA-8986; 4A5, which is produced by a hybridoma cell line deposited with the American Type Culture Collection and assigned accession number PTA-8985; 6F6, which is produced by a hybridoma cell line deposited with the American Type Culture Collection and assigned accession number PTA-8984, and 7D4, which is produced by a hybridoma cell line deposited with the American Type Culture Collection and assigned accession number PTA-8983. 
     
     
         2 . An isolated antibody comprising a heavy chain variable region (VH) complementarity determining region one (CDR1) having the amino acid sequence shown in SEQ ID NO:59, 60 or 8, a VH CDR2 having the amino acid sequence shown in SEQ ID NO:61 or 9, and a VH CDR3 having the amino acid sequence shown in SEQ ID NO:10, and having one or more conservative amino acid substitutions in CDR1, CDR2, and/or CDR3, wherein the VH CDR1 comprises a substitution at amino acid position 8 of SEQ ID NO:59, the VH CDR2 comprises a substitution at one or more of amino acid positions 3, 4, 5, 6, and 7 of SEQ ID NO:9, and/or a VH CDR3 comprises a substitution at one or both of amino acid positions 7 and 9 of SEQ ID NO: 10; and a light chain variable region (VL) complementarity determining region one (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 a VL CDR3 having the amino acid sequence shown in SEQ ID NO:13, and having one or more conservative amino acid substitutions in CDR1, CDR2, and/or CDR3, wherein the VL CDR1 comprises a substitution at one or more amino acid positions 1, 2, 3, 4, 5, 6, 8, and 10 of SEQ ID NO:11, the VL CDR2 comprises a substitution at one or more amino acid positions 1, 4, 5, 6, and 7 of SEQ ID NO:12, and/or a VL CDR3 comprises a substitution at one or more amino acid positions 4, 5, 6, 7, 8, or 9 of SEQ ID NO:13. 
     
     
         3 . The antibody of  claim 2 , comprising a VH CDR1 having the amino acid sequence shown in SEQ ID NO:59, a VH CDR2 having the amino acid sequence shown in SEQ ID NO:65, 174, 175, 9, 176, or 185, and a VH CDR3 having the amino acid sequence shown in SEQ ID NO:45, 166, 167, 10, 168, 169, 170, 171, 172, or 10; and a VL CDR1 having the amino acid sequence shown in SEQ ID NO:30, a VL CDR2 having the amino acid sequence shown in SEQ ID NO:12, and a VL CDR3 having the amino acid sequence shown in SEQ ID NO:86, 134, 135, 31, 177, 179, 180, 13, 182, 183, 13, or 186. 
     
     
         4 . The antibody of  claim 3 , comprising a VH CDR1 having the amino acid sequence shown in SEQ ID NO:59, a VH CDR2 having the amino acid sequence shown in SEQ ID NO:9 or 185, 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:30, a VL CDR2 having the amino acid sequence shown in SEQ ID NO:12, and a VL CDR3 having the amino acid sequence shown in SEQ ID NO:13.