Antagonists of pcsk9

Abstract

Antagonists of human proprotein convertase subtilisin-kexin type 9 (“PCSK9”) are disclosed. The disclosed antagonists are effective in the inhibition of PCSK9 function and, accordingly, present desirable antagonists for the use in the treatment of conditions associated with PCSK9 activity. The present invention also discloses nucleic acid encoding said antagonists, vectors, host cells, and compositions comprising the antagonists. Methods of making PCSK9-specific antagonists as well as methods of using the antagonists for inhibiting or antagonizing PCSK9 function are also disclosed and form important additional aspects of the present disclosure.

1 - 38 . (canceled) 
     
     
         39 . An isolated PCSK9-specific antagonist antibody or antigen-binding fragment thereof that antagonizes PCSK9-mediated inhibition of cellular LDL uptake. 
     
     
         40 . The antibody or antigen-binding fragment thereof of  claim 39  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake and binds to human PCSK9 with an equilibrium dissociation constant (KD) of less than 1200 nM. 
     
     
         41 . The antibody or antigen-binding fragment thereof of  claim 40  that binds to human PCSK9 with a KD of less than 500 nM. 
     
     
         42 . The antibody or antigen-binding fragment thereof of  claim 40  that binds to human PCSK9 with a KD of less than 100 nM. 
     
     
         43 . The antibody or antigen-binding fragment thereof of  claim 40  that binds to human PCSK9 with a KD of less than 5 nM. 
     
     
         44 . The antibody or antigen-binding fragment thereof of  claim 39  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake at an IC50 of less than 500 nM. 
     
     
         45 . The antibody or antigen-binding fragment thereof of  claim 44  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake at an IC50 of less than 200 nM. 
     
     
         46 . The antibody or antigen-binding fragment thereof of  claim 44  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake at an IC50 of less than 100 nM. 
     
     
         47 . The antibody or antigen-binding fragment thereof of  claim 39  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake by at least 20%. 
     
     
         48 . The isolated antibody or antigen-binding fragment thereof of  claim 47  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake by at least 50%. 
     
     
         49 . The isolated antibody or antigen-binding fragment thereof of  claim 47  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake by at least 60%. 
     
     
         50 . The antibody or antigen-binding fragment thereof of  claim 39  which is a whole antibody. 
     
     
         51 . The antibody or antigen-binding fragment thereof of  claim 39  that comprises:
 (a) a heavy chain immunoglobulin variable region polypeptide comprising: 
 
       a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 81; 
       a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 83; 
       a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 85; and
 (b) a light chain immunoglobulin variable region polypeptide comprising: 
 
       a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:71; 
       a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 73; and 
       a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75. 
     
     
         52 . The antibody or antigen-binding fragment thereof of  claim 51  that binds to human PCSK9 with an equilibrium dissociation constant (KD) of less than 1200 nM. 
     
     
         53 . The antibody or antigen-binding fragment thereof of  claim 51  that binds to human PCSK9 with a KD of less than 500 nM. 
     
     
         54 . The antibody or antigen-binding fragment thereof of  claim 51  that binds to human PCSK9 with a KD of less than 100 nM. 
     
     
         55 . The antibody or antigen-binding fragment thereof of  claim 51  that binds to human PCSK9 with a KD of less than 5 nM. 
     
     
         56 . The antibody or antigen-binding fragment thereof of  claim 51  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake at an IC50 of less than 500 nM. 
     
     
         57 . The antibody or antigen-binding fragment thereof of  claim 51  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake at an IC50 of less than 200 nM. 
     
     
         58 . The antibody or antigen-binding fragment thereof of  claim 51  that antagonizes PCSK9-mediated inhibition of cellular LDL uptake at an IC50 of less than 100 nM. 
     
     
         59 . The antibody or antigen-binding fragment thereof of  claim 51  that antagonizes PCSK9-mediated inhibition of cellular uptake by at least 20%. 
     
     
         60 . The antibody or antigen-binding fragment thereof of  claim 51  which is a whole antibody. 
     
     
         61 . The antibody or antigen-binding fragment thereof of  claim 51  which comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 79 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 101. 
     
     
         62 . The antibody or antigen-binding fragment thereof of  claim 51  which comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 77 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 69. 
     
     
         63 . The antibody or antigen-binding fragment thereof of  claim 60  which comprises a heavy chain comprising a constant sequence comprising the amino acid sequence set forth in SEQ ID NO: 87. 
     
     
         64 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 39  and a pharmaceutically acceptable carrier. 
     
     
         65 . A method for inhibiting cellular low density lipoprotein uptake in a human patient comprising administering, to the patient, a therapeutically effective amount of the antibody or antigen-binding fragment thereof of  claim 39 . 
     
     
         66 . A composition comprising the antibody or antigen-binding fragment thereof of  claim 39  and a cholesterol absorption inhibitor. 
     
     
         67 . A composition comprising the antibody or antigen-binding fragment thereof of  claim 65  and a cholesterol synthesis inhibitor. 
     
     
         68 . The method of  claim 65  wherein the antibody or antigen-binding fragment thereof is administered to the patient in conjunction with a cholesterol absorption inhibitor. 
     
     
         69 . The method of  claim 65  wherein the antibody or antigen-binding fragment thereof is administered to the patient in conjunction with a cholesterol synthesis inhibitor.