US2013071410A1PendingUtilityA1

Human CGRP Receptor Binding Proteins

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Assignee: BOONE THOMAS CPriority: Dec 23, 2008Filed: Sep 12, 2012Published: Mar 21, 2013
Est. expiryDec 23, 2028(~2.4 yrs left)· nominal 20-yr term from priority
Inventors:Thomas C. BooneDavid W. BrankowColin GeggShaw-Fen Sylvia HuChadwick Terence KingHsieng Sen LuLicheng ShiCen Xu
A61P 3/10A61P 9/00A61P 25/06A61P 29/00A61P 25/00A61P 25/04C12N 15/63C07K 2317/32A61K 39/395C07K 2319/30A61K 39/3955C07K 2317/92C07K 2317/21C07K 16/2869C07K 2317/565C07K 2317/76A61K 2039/505C12N 5/10A61K 39/39533C07K 2317/56G01N 33/53A61K 2039/5156A61K 39/00C12N 15/00
60
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Claims

Abstract

Antigen binding proteins that bind to human CGRP receptor (CGRP R) are provided. Nucleic acids encoding the antigen binding protein, vectors, and cells encoding the same are also provided. The antigen binding proteins can inhibit binding of CGRP R to CGRP, and are useful in a number of CGRP R related, disorders including the treatment and/or prevention of migraine headaches.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . An isolated antigen-binding protein, wherein the isolated antigen binding protein selectively inhibits the human CGRP receptor. 
     
     
         2 . The isolated antigen binding protein of  claim 1 , wherein the isolated antigen binding protein selectively inhibits the human CGRP receptor with a selectivity ratio of 100 or more. 
     
     
         3 . The isolated antigen binding protein of  claim 2 , wherein the isolated antigen binding protein selectively inhibits the human CGRP receptor with a selectivity ratio of 500 or more. 
     
     
         4 . The isolated antigen binding protein of  claim 1 , wherein the isolated antigen binding protein specifically binds to human CGRP R with a K D ≦100 nM. 
     
     
         5 . The isolated antigen binding protein of  claim 4 , wherein the isolated antigen binding protein specifically binds to human CGRP R with a K D ≦10 nM as determined using a FACS binding assay. 
     
     
         6 . The isolated antigen binding protein of  claim 1 , wherein the isolated antigen binding protein has a Ki of less than 10 nM in a CGRP binding competition assay. 
     
     
         7 . The isolated. antigen binding protein of  claim 6 , wherein the isolated antigen binding protein has a Ki of less than 1 nM in a radiolabeled  12 I-CGRP binding competition assay to membranes from cells expressing human CGRP R. 
     
     
         8 . The isolated antigen-binding protein of  claim 1 , wherein the isolated antigen binding protein competes for binding to human CGRP R with a reference antibody, said reference antibody comprising (i) a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs:161, 163, 164, 166 and 168; and (ii) a light chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs: 140, 143, 146, 148 and 150. 
     
     
         9 . The isolated antigen binding protein of  claim 8 , wherein the reference antibody comprises (i) a heavy chain defined by a sequence selected from the group consisting of SEQ ID NOs:32, 34, 35, 37 and 39; and (ii) a light chain defined by a sequence selected from the group consisting of SEQ ID NOs: 15, 18, 21, 23 and 25. 
     
     
         10 . The isolated antigen binding protein of  claim 9 , wherein the reference antibody comprises a heavy chain and a light chain defined by one of the following pairs of sequences:
 SEQ ID NO: 32 and SEQ ID NO: 15;   SEQ ID NO: 34 and SEQ ID NO: 18;   SEQ ID NO: 35 and SEQ ID NO: 21;   SEQ ID NO: 37 and SEQ ID NO: 23; and   SEQ ID NO: 39 and SEQ ID NO: 25.   
     
     
         11 . An isolated antigen-binding protein comprising
 (A) one or more heavy chain complementary determining regions (CDRHs) selected from the group consisting of: (i) a CDRH1 having SEQ ID NO:134; (ii) a CDRH2 having SEQ ID NO:135; (iii) a CDRH3 having SEQ ID NO:136; and (iv) a CDRH of (i), (ii) or (iii) that contains one, two, three or four amino acid substitutions, deletions or insertions;   (B) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of: (i) a CDRL1 selected from the group consisting of SEQ ID NOs:107, 111 and 118; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 108, 112 and 119; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs: 109, 113 and 120; and optionally (iv) a CDRL of (i), (ii) and (iii) that contains one, two, three or four amino acid substitutions, deletions or insertions;   or (C) one or more heavy chain CDRHs of (A) and one or more light chain CDRLs of (B).   
     
     
         12 . The isolated antigen binding protein of  claim 11 , wherein the CDRHs are further selected from the group consisting of: (i) a CDRH1 having SEQ ID NO:131; (ii) a CDRH2 having SEQ ID NO:132; (iii) a CDRH3 having SEQ ID NO:133; and (iv) a CDRH of (i), (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions. 
     
     
         13 . The isolated antigen binding protein of  claim 12 , wherein the CDRHs are further selected from the group consisting of: (i) a CDRH1 selected from the group consisting of SEQ ID NO:76, 88, 100, 121, 125 and 128; (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 89, 101, 122, 124, 126, and 129; (iii) a CDRH3 selected from the group consisting of SEQ ID NO: 78, 90, 102, 123, 127, and 130; and (iv) a CDRH of (i), (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions. 
     
     
         14 . The isolated antigen binding protein of  claim 13 , wherein the CDRHs are further selected from the group consisting of: (i) a CDRH1 selected from the group consisting of SEQ ID NO: 73, 76, 79, 82, 85, 88, 92, 97, and 100; (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 74, 77, 80, 83, 86, 89, 91, 93, 95, 98, 101, and 129; (iii) a CDRH3 selected from the group consisting of SEQ ID NO: 75, 78, 81, 84, 87, 90, 96, 99, 102, and 123; and (iv) a CDRH of (i), (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions. 
     
     
         15 . The isolated antigen binding protein of  claim 11 , wherein the CDRLs are further selected from the group consisting of: (i) a CDRL1 selected from the group consisting of SEQ ID NOs:107, 111 and 115; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 108, 112 and 116; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs: 109, 113 and 117; and (iv) a CDRL of (i), (ii) and (iii) that contains one, two, three, or four amino acid substitutions, deletions or insertions. 
     
     
         16 . The isolated antigen binding protein of  claim 15 , wherein the CDRLs are further selected from the group consisting of: (i) a CDRL1 selected from the group consisting of SEQ ID NOs: 42, 45, 51, 57, 62, 69, 103, and 110; (ii) a CDRL2 selected, from the group consisting of SEQ ID NOs: 43, 52, 55, 58, 63, 70, 104, 108, and 114; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs: 44, 47, 53, 56, 59, 64, 105, and 106; and (iv) a CDRL of (i), (ii) and, (iii) that contains one, two or three amino acid substitutions, deletions or insertions. 
     
     
         17 . The isolated antigen binding protein of  claim 16 , wherein the CDRLs are further selected from the group consisting of: (i) a CDRL1 selected from the group consisting of SEQ ID NOs: 42, 45, 48, 51, 54, 57, 62, 65, 66, and 69; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 43, 46, 49, 52, 55, 58, 61, 63, 67, and 70; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs: 44, 47, 50, 53, 56, 59, 64, 68, 71, and 72; and (iv) a CDRL of (i), (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions. 
     
     
         18 . The isolated antigen binding protein of  claim 11 , wherein the isolated antigen-binding protein comprises at least one CDRH and at least one CDRL. 
     
     
         19 . The isolated antigen binding protein of  claim 18 , wherein the isolated antigen-binding protein comprises at least two CDRH and at least two CDRL. 
     
     
         20 . The isolated antigen binding protein of  claim 19 , wherein the isolated antigen-binding protein comprises a CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2 and a CDRL3. 
     
     
         21 . An isolated antigen-binding protein comprising a heavy chain variable region (V H ) sequence that has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:158-170. 
     
     
         22 . An isolated antigen-binding protein comprising a light chain variable region (V L ) sequence that has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:137-153. 
     
     
         23 . An isolated antigen-binding protein comprising a V H  sequence that has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 158, 159, and 162-172, and a V L  sequence that has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 137, 138, 140-145, 148-151, and 153-157. 
     
     
         24 . The isolated antigen binding protein of  claim 1 , wherein the isolated antigen-binding protein is selected from the group consisting of a monoclonal antibody, a Fab fragment, an Fab′ fragment, an F(ab′) 2  fragment, an FV fragment, a diabody, and a single chain antibody. 
     
     
         25 . The isolated antigen binding protein of  claim 24 , wherein the isolated antigen-binding protein is a monoclonal antibody selected from the group consisting of a fully human antibody, a humanized antibody and a chimeric antibody. 
     
     
         26 . The isolated antigen binding protein of  claim 25 , wherein the monoclonal antibody is an IgG1-, IgG2-, IgG3-, or IgG4-type antibody. 
     
     
         27 . The isolated antigen binding protein of  claim 26 , wherein the monoclonal antibody is an IgG1 or IgG2 antibody, 
     
     
         28 . An isolated nucleic acid polynucleotide that encodes an antigen-binding protein of  claim 1 . 
     
     
         29 . The isolated nucleic acid polynucleotide of  claim 28 , wherein the polynucleotide comprises a sequence that is 80% or more identical with a sequence selected from the group consisting of SEQ ID NOs:175, 176, 178, 179, 180, 181, 182, 183, 186, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209 and 210. 
     
     
         30 . The isolated nucleic acid polynucleotide of  claim 28 , wherein the polynucleotide comprises a sequence that is 80% or more identical with a sequence selected from the group consisting of SEQ ID NOs:224-258. 
     
     
         31 . The isolated nucleic acid polynucleotide of  claim 28 , wherein the polynucleotide comprises a sequence capable of hybridizing under stringent hybridization conditions with a sequence selected from the group consisting of SEQ ID NOs:224-258. 
     
     
         32 . An expression vector comprising an isolated polynucleotide of  claim 28 . 
     
     
         33 . A cell line transformed with expression vector of  claim 32 . 
     
     
         34 . A method of making an antigen-binding protein of  claim 1 , comprising preparing the antigen binding protein from a host cell that secretes the antigen-binding protein. 
     
     
         35 . The method of  claim 34 , wherein said antigen binding protein is generated using an immunogen comprising soluble CGRP receptor. 
     
     
         36 . The method of  claim 35 , wherein said soluble CGRP receptor is obtained by co-expressing and purifying an N-terminal extracellular domain (ECD) of human CRLR and an ECD of human RAMP1. 
     
     
         37 . The method of  claim 36 , wherein said ECD of human CRLR comprises SEQ ID NO: 6 and said ECD of RAMP1 comprises SEQ ID NO: 8. 
     
     
         38 . A pharmaceutical composition comprising an antigen binding protein of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         39 . A method for treating a condition associated with CGRP R in a patient, comprising administering to a patient an effective amount of an isolated antigen-binding protein of  claim 1 . 
     
     
         40 . The method of  claim 39 , wherein the condition is headache. 
     
     
         41 . The method of  claim 40 , wherein the condition is migraine. 
     
     
         42 . The method of  claim 41 , wherein the method comprises prophylactic treatment.

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