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 . A method for treating or preventing a condition associated with an elevated serum cholesterol level in a patient, comprising administering to a patient in need thereof an effective amount of an antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the antigen binding protein competes for binding to PCSK9 with at least one of the following antigen binding proteins:
 a) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 79 and a light chain variable region of SEQ ID NO: 35;   b) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 80 and a light chain variable region of SEQ ID NO: 36;   c) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 76 and a light chain variable region of SEQ ID NO: 37;   d) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 77 and a light chain variable region of SEQ ID NO: 38;   e) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 78 and a light chain variable region of SEQ ID NO: 39;   f) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 83 and a light chain variable region of SEQ ID NO: 40;   g) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 67 and a light chain variable region of SEQ ID NO: 12;   h) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 483 and a light chain variable region of SEQ ID NO: 485;   i) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 459 and a light chain variable region of SEQ ID NO: 461; or   j) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 463 and a light chain variable region of SEQ ID NO: 465.   
     
     
         38 . The method of  claim 37 , wherein the antigen binding protein competes for binding to PCSK9 with at least one of:
 a) the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 67 and the light chain variable region of SEQ ID NO: 12;   b) the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 459 and the light chain variable region of SEQ ID NO: 461;   c) the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 483 and the light chain variable region of SEQ ID NO: 485; or   d) the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 463 and the light chain variable region of SEQ ID NO: 465.   
     
     
         39 . The method of  claim 37 , wherein the antigen binding protein competes for binding to PCSK9 with the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 67 and the light chain variable region of SEQ ID NO: 12. 
     
     
         40 . The method of  claim 37 , wherein the antigen binding protein competes for binding to PCSK9 with the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 459 and the light chain variable region of SEQ ID NO: 461. 
     
     
         41 . The method of  claim 37 , wherein the antigen binding protein competes for binding to PCSK9 with the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 463 and the light chain variable region of SEQ ID NO: 465. 
     
     
         42 . The method of  claim 37 , wherein the antigen binding protein competes for binding to PCSK9 with the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 483 and the light chain variable region of SEQ ID NO: 485. 
     
     
         43 . The method of  claim 37 , wherein the antigen binding protein that competes for binding is an antibody or a binding part thereof. 
     
     
         44 . A method for treating or preventing a condition associated with an elevated serum cholesterol level in a patient, comprising administering to a patient in need thereof an effective amount of an antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the antigen binding protein binds to an epitope on PCSK9 that is bound by at least one of the following antigen binding proteins:
 a) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 79 and a light chain variable region of SEQ ID NO: 35;   b) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 80 and a light chain variable region of SEQ ID NO: 36;   c) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 76 and a light chain variable region of SEQ ID NO: 37;   d) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 77 and a light chain variable region of SEQ ID NO: 38;   e) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 78 and a light chain variable region of SEQ ID NO: 39;   f) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 83 and a light chain variable region of SEQ ID NO: 40;   g) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 67 and a light chain variable region of SEQ ID NO: 12;   h) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 483 and a light chain variable region of SEQ ID NO: 485;   i) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 459 and a light chain variable region of SEQ ID NO: 461; or   j) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 463 and a light chain variable region of SEQ ID NO: 465.   
     
     
         45 . The method of  claim 44 , wherein the antigen binding protein binds to the epitope on PCSK9 that is bound by at least one of:
 a) the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 67 and the light chain variable region of SEQ ID NO: 12;   b) the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 483 and the light chain variable region of SEQ ID NO: 485;   c) the antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 459 and the light chain variable region of SEQ ID NO: 461; or   d) the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 463 and the light chain variable region of SEQ ID NO: 465.   
     
     
         46 . The method of  claim 45 , wherein the antigen binding protein binds to the epitope on PCSK9 that is bound by the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 67 and the light chain variable region of SEQ ID NO: 12. 
     
     
         47 . The method of  claim 45 , wherein the antigen binding protein binds to the epitope on PCSK9 that is bound by the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 459 and the light chain variable region of SEQ ID NO: 461. 
     
     
         48 . The method of  claim 45 , wherein the antigen binding protein binds to the epitope on PCSK9 that is bound by the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 463 and the light chain variable region of SEQ ID NO: 465. 
     
     
         49 . The method of  claim 45 , wherein the antigen binding protein binds to the epitope on PCSK9 that is bound by the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 483 and the light chain variable region of SEQ ID NO: 485. 
     
     
         50 . The method of  claim 44 , wherein the antigen binding protein that binds to the same epitope is an antibody or a binding part thereof. 
     
     
         51 . A method for treating or preventing a condition associated with an elevated serum cholesterol level in a patient, comprising administering to a patient in need thereof an effective amount of an antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the antigen binding protein binds to amino acids within amino acids 31-449 of PCSK9 of SEQ ID NO: 3. 
     
     
         52 . The method of  claim 51 , wherein the antigen binding protein binds to amino acids within amino acids 300-400. 
     
     
         53 . The method of  claim 51 , wherein the antigen binding protein is an antibody or a binding part thereof. 
     
     
         54 . A method for treating or preventing a condition associated with an elevated serum cholesterol level in a patient, comprising administering to a patient in need thereof an effective amount of an antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the antigen binding protein binds at least one of the following residues of PCSK9: D374, V380, 5381, D367, Q382, I369, S372, C378, F379, or S373 of SEQ ID NO: 3. 
     
     
         55 . The method of  claim 54 , wherein the antigen binding protein binds to at least one of the following residues: D374, V380, or S381. 
     
     
         56 . The method of  claim 54 , wherein the antigen binding protein binds to at least one of the following residues: D367 or Q382. 
     
     
         57 . The method of  claim 54 , wherein the antigen binding protein binds to at least one of the following residues: I369, S372, C378, or F379. 
     
     
         58 . The method of  claim 54 , wherein the antigen binding protein binds to S373 
     
     
         59 . The method of  claim 54 , wherein the antigen binding protein is an antibody or a binding part thereof. 
     
     
         60 . A method for treating or preventing a condition associated with an elevated serum cholesterol level in a patient, comprising administering to a patient in need thereof an effective amount of an antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the antigen binding protein blocks at least one of the following residues of PCSK9: D374, V380, 5381, D367, Q382, I369, S372, C378, F379, or S373 of SEQ ID NO: 3. 
     
     
         61 . The method of  claim 60 , wherein the antigen binding protein blocks at least one of the following residues: D374, V380, or S381. 
     
     
         62 . The method of  claim 60 , wherein the antigen binding protein blocks at least one of the following residues: D367 or Q382. 
     
     
         63 . The method of  claim 60 , wherein the antigen binding protein blocks at least one of the following residues: I369, S372, C378, or F379. 
     
     
         64 . The method of  claim 60 , wherein the antigen binding protein blocks S373. 
     
     
         65 . The method of  claim 60 , wherein the antigen binding protein is an antibody or a binding part thereof. 
     
     
         66 . A method for treating or preventing a condition associated with an elevated serum cholesterol level in a patient, comprising administering to a patient in need thereof an effective amount of an antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the antigen binding protein binds 5 angstroms or less from at least two of the following residues of PCSK9: W72, F150, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, or G384, wherein PCSK9 comprises the amino acid sequence of SEQ ID NO: 3. 
     
     
         67 . The method of  claim 66 , wherein the antigen binding protein is an antibody or a binding part thereof.