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 competes for binding to PCSK9 with an antibody that comprises:
 a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 49; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 49; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 49; and   a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 23; a light chain CDR2 that a CDR2 in SEQ ID NO: 23; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 23.   
     
     
         38 . The isolated neutralizing antigen binding protein of  claim 37 , wherein the antigen binding protein is a LDLR competitive neutralizing antigen binding protein. 
     
     
         39 . The isolated neutralizing antigen binding protein of  claim 37 , wherein the antibody comprises all three of the following amino acid sequences: SEQ ID NO: 308, SEQ ID NO: 175, and SEQ ID NO: 180. 
     
     
         40 . The isolated neutralizing antigen binding protein of  claim 37 , wherein the antibody comprises all three of the following amino acid sequences: SEQ ID NO: 158, SEQ ID NO: 162, and SEQ ID NO: 395. 
     
     
         41 . The isolated neutralizing antigen binding protein of  claim 40 , wherein the antibody comprises all three of the following amino acid sequences: SEQ ID NO: 308, SEQ ID NO: 175, and SEQ ID NO: 180. 
     
     
         42 . The isolated neutralizing antigen binding protein of  claim 37 , wherein the antibody comprises all three of the following amino acid sequences: SEQ ID NO: 368, SEQ ID NO: 175, and SEQ ID NO: 180. 
     
     
         43 . The isolated neutralizing antigen binding protein of  claim 37 , wherein the antibody comprises: a CDR1 comprising SEQ ID NO: 158, a CDR2 comprising SEQ ID NO: 162, and a CDR3 comprising SEQ ID NO: 395. 
     
     
         44 . The isolated neutralizing antigen binding protein of  claim 37 , wherein each CDR is defined in accordance with the Kabat definition, the Chothia definition, the combination of the Kabat definition and the Chothia definition, the AbM definition, or the contact definition of CDR. 
     
     
         45 . The isolated neutralizing antigen binding protein of  claim 44 , wherein each CDR is defined in accordance with the CDR definition of Kabat. 
     
     
         46 . The isolated neutralizing antigen binding protein of  claim 44 , wherein each CDR is defined in accordance with the CDR definition of Chothia. 
     
     
         47 . The isolated neutralizing antigen binding protein of  claim 44 , wherein each CDR is defined in accordance with the combination of the Kabat definition and the Chothia definition. 
     
     
         48 . A pharmaceutical composition comprising at least one antigen binding protein according to  claim 37 , and a pharmaceutically acceptable excipient. 
     
     
         49 . An isolated neutralizing human monoclonal antibody that competes for binding to a PCSK9 protein with an antibody comprising:
 a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 49; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 49; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 49; and   a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 23; a light chain CDR2 that a CDR2 in SEQ ID NO: 23; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 23, wherein each CDR is defined in accordance with the CDR definition of Kabat.   
     
     
         50 . The isolated neutralizing human monoclonal antibody of  claim 49 , wherein the heavy chain polypeptide comprises SEQ ID NO: 49 and the light chain polypeptide comprises SEQ ID NO: 23. 
     
     
         51 . An antibody that competes for binding to a PCSK9 protein with an antibody that comprises:
 a heavy chain polypeptide comprising: the amino acid sequence of SEQ ID NO: 180; the amino acid sequence of SEQ ID NO: 175; and the amino acid sequence of SEQ ID NO: 308; and   a light chain polypeptide comprising: the amino acid sequence of SEQ ID NO: 395; the amino acid sequence of SEQ ID NO: 162; and the amino acid sequence of SEQ ID NO: 158.   
     
     
         52 . An isolated neutralizing human monoclonal antibody that competes for binding to a PCSK9 protein with an antibody comprising:
 a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 308 or a CDR1 in SEQ ID NO:368; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 175; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 180; and   a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 158; a light chain CDR2 that is a CDR2 in SEQ ID NO: 162; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 395.   
     
     
         53 . An isolated neutralizing human monoclonal antibody that competes for binding to a PCSK9 protein with an antibody that comprises:
 a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 49; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 49; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 49, wherein the heavy chain polypeptide comprises: the amino acid sequence of SEQ ID NO: 180; the amino acid sequence of SEQ ID NO: 175; and the amino acid sequence of SEQ ID NO: 308; and   a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 23; a light chain CDR2 that a CDR2 in SEQ ID NO: 23; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 23, wherein the light chain polypeptide comprises: the amino acid sequence of SEQ ID NO: 395; the amino acid sequence of SEQ ID NO: 162; and the amino acid sequence of SEQ ID NO: 158.   
     
     
         54 . An antigen binding protein that binds to an epitope on PCSK9 that is bound by an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 49 and a light chain variable region of SEQ ID NO: 23. 
     
     
         55 . The antigen binding protein of  claim 54 , wherein the antigen binding protein that binds to the same epitope is an antibody or a binding part thereof. 
     
     
         56 . The antigen binding protein of  claim 55 , wherein the antigen binding protein comprising the heavy chain variable region of SEQ ID NO: 49 and the light chain variable region of SEQ ID NO: 23 is an antibody. 
     
     
         57 . An antigen binding protein that binds to PSCK9, wherein, when bound to PCSK9 the antigen binding protein is positioned 5 angstroms or less from at least one of the following residues of PCSK9: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381. 
     
     
         58 . The antigen binding protein of  claim 57 , wherein the antigen binding protein is positioned 5 angstroms or less from at least two of the following residues of PCSK9: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381. 
     
     
         59 . The antigen binding protein of claim. 57, wherein the antigen binding protein is positioned 5 angstroms or less from at least four of the following residues of PCSK9: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381. 
     
     
         60 . The antigen binding protein of  claim 57 , wherein the antigen binding protein binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, and S381. 
     
     
         61 . An antigen binding protein that binds to PSCK9, wherein, when bound to PCSK9 the antigen binding protein is positioned 8 angstroms or less from at least one of the following residues of PCSK9: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, I368, G370, A371, S373, S376, or Q382. 
     
     
         62 . The antigen binding protein of  claim 61 , wherein the antigen binding protein binds to at least one of the following residues of PCSK9: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, I368, G370, A371, S373, S376, or Q382 
     
     
         63 . An antigen binding protein that binds to PSCK9, wherein, when bound to PCSK9 the antigen binding protein is positioned 8 angstroms or less from at least one of the following residues of PCSK9: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, I368, G370, A371, S373, S376, Q382, 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, G384, K69, D70, P71, S148, V149, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365, I368, I369, S372, S373, C378, F379, T385, S386, Q387, S153, S188, I189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, I154, T187, H193, E195, I196, M201, V202, C223, T228, 5235, G236, A239, G244, M247, I369, S372, C375, or C378. 
     
     
         64 . The antigen binding protein of  claim 63 , wherein the antigen binding protein binds to at least one of the following residues of PCSK9: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, I368, G370, A371, S373, S376, Q382, 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, G384, K69, D70, P71, S148, V149, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365, I368, I369, S372, S373, C378, F379, T385, S386, Q387, S153, S188, I189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, I154, T187, H193, E195, I196, M201, V202, C223, T228, S235, G236, A239, G244, M247, I369, S372, C375, or C378. 
     
     
         65 . The antigen binding protein of  claim 63 , wherein the antigen binding protein is an antibody or binding fragment thereof. 
     
     
         66 . An antigen binding protein that binds to PSCK9, wherein when bound to PCSK9 the antigen binding protein will bind to or within 30 angstroms of one or more of the following residues (numbering in reference to SEQ ID NO: 3): S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, I368, G370, A371, S373, S376, Q382, 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, G384, K69, D70, P71, S148, V149, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365, I368, I369, S372, S373, C378, F379, T385, S386, Q387, S153, S188, I189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, I154, T187, H193, E195, I196, M201, V202, C223, T228, 5235, G236, A239, G244, M247, I369, S372, C375, or C378. 
     
     
         67 . The antigen binding protein of  claim 66 , wherein the antigen binding protein will bind within 30 angstroms for at least 10 of the residues. 
     
     
         68 . An antigen binding protein that binds to PSCK9, wherein when bound to PCSK9 the antigen binding protein will bind to or within 30 angstroms of one or more of the following residues (numbering in reference to SEQ ID NO: 3): S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, I368, G370, A371, S373, S376, or Q382. 
     
     
         69 . The antigen binding protein of  claim 68 , wherein the antigen binding protein will bind within 30 angstroms for at least 10 of the residues. 
     
     
         70 . An antigen binding protein that binds to an epitope including residues 162-167 of SEQ ID NO: 1. 
     
     
         71 . An antigen binding protein that binds to an epitope including residues 123-132 of SEQ ID NO: 1. 
     
     
         72 . An antigen binding protein that binds to an epitope including residues 311-313 of SEQ ID NO: 1. 
     
     
         73 . An antigen binding protein that 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: 74 and a light chain variable region of SEQ ID NO: 5;   b) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 71 and a light chain variable region of SEQ ID NO: 9;   c) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 72 and a light chain variable region of SEQ ID NO: 10;   d) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 58 and a light chain variable region of SEQ ID NO: 15;   e) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 52 and a light chain variable region of SEQ ID NO: 16;   f) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 51 and a light chain variable region of SEQ ID NO: 17;   g) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 53 and a light chain variable region of SEQ ID NO: 18;   h) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 48 and a light chain variable region of SEQ ID NO: 19;   i) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 54 and a light chain variable region of SEQ ID NO: 20;   j) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 55 and a light chain variable region of SEQ ID NO: 21;   k) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 56 and a light chain variable region of SEQ ID NO: 22;   l) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 49 and a light chain variable region of SEQ ID NO: 23;   m) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 57 and a light chain variable region of SEQ ID NO: 24;   n) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 50 and a light chain variable region of SEQ ID NO: 26;   o) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 64 and a light chain variable region of SEQ ID NO: 30;   p) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 62 and a light chain variable region of SEQ ID NO: 31;   q) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 65 and a light chain variable region of SEQ ID NO: 33;   r) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 60 and a light chain variable region of SEQ ID NO: 46;   s) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 471 and a light chain variable region of SEQ ID NO: 473;   t) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 475 and a light chain variable region of SEQ ID NO: 477; or   u) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 87 and a light chain variable region of SEQ ID NO: 13.   
     
     
         74 . An antigen binding protein that 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: 74 and a light chain variable region of SEQ ID NO: 5;   b) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 71 and a light chain variable region of SEQ ID NO: 9;   c) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 72 and a light chain variable region of SEQ ID NO: 10;   d) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 58 and a light chain variable region of SEQ ID NO: 15;   e) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 52 and a light chain variable region of SEQ ID NO: 16;   f) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 51 and a light chain variable region of SEQ ID NO: 17;   g) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 53 and a light chain variable region of SEQ ID NO: 18;   h) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 48 and a light chain variable region of SEQ ID NO: 19;   i) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 54 and a light chain variable region of SEQ ID NO: 20;   j) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 55 and a light chain variable region of SEQ ID NO: 21;   k) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 56 and a light chain variable region of SEQ ID NO: 22;   l) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 49 and a light chain variable region of SEQ ID NO: 23;   m) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 57 and a light chain variable region of SEQ ID NO: 24;   n) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 50 and a light chain variable region of SEQ ID NO: 26;   o) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 64 and a light chain variable region of SEQ ID NO: 30;   p) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 62 and a light chain variable region of SEQ ID NO: 31;   q) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 65 and a light chain variable region of SEQ ID NO: 33;   r) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 60 and a light chain variable region of SEQ ID NO: 46;   s) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 471 and a light chain variable region of SEQ ID NO: 473;   t) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 475 and a light chain variable region of SEQ ID NO: 477; or   u) an antigen binding protein comprising a heavy chain variable region of SEQ ID NO: 87 and a light chain variable region of SEQ ID NO: 13.