Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (pcsk9)

Abstract

Antigen binding proteins that interact with Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) are described. Methods of treating hypercholesterolemia and other disorders by administering a pharmaceutically effective amount of an antigen binding protein to PCSK9 are described. Methods of detecting the amount of PCSK9 in a sample using an antigen binding protein to PCSK9 are described.

1 - 36 . (canceled) 
     
     
         37 . An isolated neutralizing antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the neutralizing antigen binding protein decreases the LDLR lowering effect of PCSK9 on LDLR, wherein the antigen binding protein is a LDLR non-competitive neutralizing antigen binding protein. 
     
     
         38 . The isolated neutralizing antigen binding protein of  claim 37 , wherein the antigen binding protein binds to PCSK9 with a K d  that is less than 100 pM. 
     
     
         39 . The isolated PCSK9 neutralizing antigen binding protein of  claim 37 , wherein the antigen binding protein binds specifically to the V domain of PCSK9 (amino acids 540-691 of SEQ ID NO: 3). 
     
     
         40 . The isolated PCSK9 neutralizing antigen binding protein of  claim 37 , wherein the antigen binding protein binds within amino acids 600-692 of SEQ ID NO: 3. 
     
     
         41 . The antigen binding protein of  claim 37 , wherein the antigen binding protein binds to human PCSK9 with an equilibrium dissociation constant (KD) of about 1000 pM or less. 
     
     
         42 . The antigen binding protein of  claim 37 , wherein the antigen binding protein binds to human PCSK9 with an equilibrium dissociation constant (KD) of about 100 pM or less. 
     
     
         43 . An isolated antigen binding protein that binds to PCSK9, wherein the antigen binding protein comprises:
 a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 74; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 74; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 74 and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 5; a light chain CDR2 that a CDR2 in SEQ ID NO: 5; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 5;   a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 69; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 69; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 69 and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 42; a light chain CDR2 that a CDR2 in SEQ ID NO: 42; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 42;   a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 91; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 91; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 91 and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 28; a light chain CDR2 that a CDR2 in SEQ ID NO: 28; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 28;   a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 89; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 89; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 89 and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 32; a light chain CDR2 that a CDR2 in SEQ ID NO: 32; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 32;   a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 81; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 81; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 81 and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 44; a light chain CDR2 that a CDR2 in SEQ ID NO: 44; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 44;   a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 85; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 85; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 85 and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 7; a light chain CDR2 that a CDR2 in SEQ ID NO: 7; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 7; or   a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 87; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 87; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 87 and a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 13; a light chain CDR2 that a CDR2 in SEQ ID NO: 13; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 13.   
     
     
         44 . The isolated antigen binding protein of  claim 43 ,
 wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 89; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 89; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 89 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 32; the light chain CDR2 that the CDR2 in SEQ ID NO: 32; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 32;   wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 81; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 81; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 81 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 44; the light chain CDR2 that the CDR2 in SEQ ID NO: 44; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 44;   wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 85; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 85; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 85 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 7; the light chain CDR2 that the CDR2 in SEQ ID NO: 7; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 7; or   wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 87; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 87; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 87 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 13; the light chain CDR2 that the CDR2 in SEQ ID NO: 13; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 13.   
     
     
         45 . The isolated antigen binding protein of  claim 43 , wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 89; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 89; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 89 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 32; the light chain CDR2 that the CDR2 in SEQ ID NO: 32; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 32. 
     
     
         46 . The isolated antigen binding protein of  claim 43 , wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 81; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 81; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 81 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 44; the light chain CDR2 that the CDR2 in SEQ ID NO: 44; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 44. 
     
     
         47 . The isolated antigen binding protein of  claim 43 , wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 85; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 85; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 85 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 7; the light chain CDR2 that the CDR2 in SEQ ID NO: 7; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 7. 
     
     
         48 . The isolated antigen binding protein of  claim 43 , wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 87; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 87; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 87 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 13; the light chain CDR2 that the CDR2 in SEQ ID NO: 13; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 13. 
     
     
         49 . The isolated antigen binding protein of  claim 43 ,
 wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 74; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 74; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 74 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 5; the light chain CDR2 that the CDR2 in SEQ ID NO: 5; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 5;   wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 69; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 69; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 69 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 42; the light chain CDR2 that the CDR2 in SEQ ID NO: 42; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 42;   wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 91; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 91; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 91 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 28; the light chain CDR2 that the CDR2 in SEQ ID NO: 28; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 28;   wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 89; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 89; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 89 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 32; the light chain CDR2 that the CDR2 in SEQ ID NO: 32; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 32; or   wherein the heavy chain polypeptide comprises the following complementarity determining regions (CDRs): the heavy chain CDR1 that is the CDR1 in SEQ ID NO: 81; the heavy chain CDR2 that is the CDR2 in SEQ ID NO: 81; the heavy chain CDR3 that is the CDR3 in SEQ ID NO: 81 and the light chain polypeptide comprises the following CDRs: the light chain CDR1 that is the CDR1 in SEQ ID NO: 44; the light chain CDR2 that the CDR2 in SEQ ID NO: 44; and the light chain CDR3 that is the CDR3 in SEQ ID NO: 44.   
     
     
         50 . The isolated antigen binding protein of  claim 43 , wherein the antigen binding protein is a neutralizing antigen binding protein. 
     
     
         51 . The isolated antigen binding protein of  claim 43 , wherein the antigen binding protein is a non-competitive antigen binding protein. 
     
     
         52 . The isolated antigen binding protein of  claim 51 , wherein the antigen binding protein is a neutralizing antigen binding protein. 
     
     
         53 . An isolated PCSK9 neutralizing antigen binding protein that binds within amino acids 600-692 of SEQ ID NO: 3. 
     
     
         54 . An isolated neutralizing antigen binding protein that competes for binding to PCSK9 with the antigen binding protein of any one or more of  claims 37 - 53 . 
     
     
         55 . A pharmaceutical composition comprising at least one antigen binding protein of one or more of  claims 37 - 54 ; and a pharmaceutically acceptable excipient. 
     
     
         56 . A method of lowering serum cholesterol level in a subject, said method comprising administering to a subject an effective amount of an isolated neutralizing antigen binding protein of any one of  claims 37 - 54 . 
     
     
         57 . The method of  claim 56 , further comprising administering a therapeutically effective amount of a statin to the subject. 
     
     
         58 . The method of  claim 57 , wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and any combination thereof.