Antibody which specifically binds to human crth2

Abstract

There is provided an anti-human CRTH2 antibody which has desired activity by recognizing and binding to a specific human CRTH2; the antibody fragment; DNA which encodes the amino acid sequence of the antibody; a vector which comprises the DNA; hybridomas and antibody producing cells which produce the antibody; a method of producing the antibody; a composition which comprises the antibody or the antibody fragment; a treatment method and a diagnostic method of an allergic disease, an autoimmune disease, a disease accompanied by at least one of increase and hyperergasia of eosinophils; a disease accompanied by at least one of increase and hyperergasia of Th2 cells using the antibody or the antibody fragment; and a medicine and a diagnostic agent which comprise the antibody or the antibody fragment.

What is claimed is: 
     
         1 . An antibody or the antibody fragment thereof which recognizes at least one of 192th glycine and 194th aspartic acid in the amino acid sequence of human CRTH2 represented by SEQ ID NO: 2 and binds thereto. 
     
     
         2 . The antibody or the antibody fragment thereof according to  claim 1 , wherein the antibody recognizes at least one amino acid residue selected from the group consisting of 12th proline, 13th isoleucine, 14th leucine, 15th glutamic acid, 177th aspartic acid, 178th glycine, 179th arginine, 180th isoleucine, 181th methionine, 182nd cysteine, 183rd tyrosine, 184th tyrosine, 185th asparagine, 186th valine, 187th leucine, 188th leucine, 189th leucine, 195th arginine, 196th aspartic acid, 197th alanine, and 198th threonine in the amino acid sequence of human CRTH2 represented by SEQ ID NO: 2 and binds thereto. 
     
     
         3 . The antibody or the antibody fragment thereof according to  claim 1 , wherein the antibody recognizes at least one amino acid residue selected from the group consisting of the following (a) to (g):
 (a) 12th proline, 14th leucine, and 15th glutamic acid in the amino acid sequence of human CRTH2 represented by SEQ ID NO: 2;   (b) 177th aspartic acid, 178th glycine, and 179th arginine in the amino acid sequence of human CRTH2 represented by SEQ ID NO: 2;   (c) 180th isoleucine and 181st methionine in the amino acid sequence of human CRTH2 represented by SEQ ID NO: 2;   (d): 183rd tyrosine, 184th tyrosine, and 185th asparagine in the amino acid sequence of human CRTH2 represented by SEQ ID NO: 2;   (e) 187th leucine, 188th leucine, and 189th leucine in the amino acid sequence of human CRTH2 represented by SEQ ID NO: 2;   (f) 195th arginine in the amino acid sequence of human CRTH2 represented by SEQ ID NO: 2; and   (g) 196th aspartic acid and 198th threonine in the amino acid sequence of human CRTH2 represented by SEQ ID NO: 2.   
     
     
         4 . The antibody or the antibody fragment thereof according to  claim 1 , wherein the antibody is any one selected from the group consisting of the following (a) to (d):
 (a) an antibody in which complementarity determining regions (hereinafter, abbreviated as CDR) 1 to 3 of an antibody heavy chain variable region (hereinafter, abbreviated as VH) comprise amino acid sequences represented by SEQ ID NOS: 20 to 22, respectively, and CDRs 1 to 3 of an antibody light chain variable regions (hereinafter, abbreviated as VL) comprise amino acid sequences represented by SEQ ID NOS: 23 to 25, respectively;   (b) an antibody which comprises VH comprising the amino acid sequence represented by SEQ ID NO: 49 or the amino acid sequence obtained by introducing at least one modification selected from modifications of substituting 18th leucine with methionine, 77th asparagine with serine, 93th valine with threonine, and 117th threonine with valine in the amino acid sequence represented by SEQ ID NO: 49 and VL comprising the amino acid sequence represented by SEQ ID NO: 33 or the amino acid sequence obtained by at least one modification selected from modifications of substituting 2nd isoleucine with valine, 4th methionine with leucine, 15th proline with leucine, and 85th alanine with proline in the amino acid sequence represented by SEQ ID NO: 33;   (c) an antibody which comprises VH comprising any one of the amino acid sequences represented by SEQ ID NOS: 49, 51, 53, 55, 57, and 59 and VL comprising any one of the amino acid sequences represented by SEQ ID NOS: 33, 35, 37, 39, 41, 43, 45, and 47; and   (d) an antibody which comprises VH comprising the amino acid sequence represented by SEQ ID NO: 17 and VL comprising the amino acid sequence represented by SEQ ID NO: 19.   
     
     
         5 . The antibody or the antibody fragment thereof according to  claim 1 , wherein the antibody has at least one characteristic selected from the group consisting of the following (a) to (h):
 (a) reactivity of the antibody against human CRTH2 does not decrease in the presence of a ligand of human CRTH2;   (b) neutralizing activity is not shown by the antibody;   (c) antibody-dependent cell-mediated cytotoxicity (ADCC) is shown by the antibody;   (d) a reaction of the antibody with at least one of mast cells and Th1 cells does not occur;   (e) a reaction of the antibody with at least one selected from eosinophils, basophils, Th2 cells, and type 2 innate lymphoid cells (ILC2) occurs;   (f) agonist activity is not shown by the antibody;   (g) a signal caused by the ligand of human CRTH2 is not enhanced by the antibody; and   (h) reactivity of the antibody against human CRTH2 in an activated or inactivated state does not changed.   
     
     
         6 . The antibody or the antibody fragment thereof according to  claim 1 , wherein the antibody comprises a human Fc region. 
     
     
         7 . The antibody or the antibody fragment thereof according to  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         8 . The antibody or the antibody fragment thereof according to  claim 1 , wherein the antibody is a recombinant antibody. 
     
     
         9 . The recombinant antibody or the antibody fragment thereof according to  claim 8 , wherein the recombinant antibody is any one recombinant antibody selected from a human chimeric antibody, a human CDR-grafted antibody, and a human antibody. 
     
     
         10 . The antibody or the antibody fragment thereof according to  claim 1 , wherein the antibody is an antibody which binds to monkey CRTH2. 
     
     
         11 . The antibody fragment according to  claim 1 , wherein the antibody fragment is any one selected from Fab, Fab′, F(ab′) 2 , scFv, diabody, dsFv, and peptide including CDR. 
     
     
         12 . A hybridoma which generates the antibody or the antibody fragment thereof according to  claim 1 . 
     
     
         13 . A DNA which encodes the antibody or the antibody fragment thereof according to  claim 1 . 
     
     
         14 . A recombinant vector which comprises the DNA according to  claim 13 . 
     
     
         15 . A transformant which is obtained by introducing the recombinant vector according to  claim 14  into a host cell. 
     
     
         16 . A method of producing an antibody or the antibody fragment thereof, comprising:
 culturing the hybridomas according to  claim 12  in a culture medium;   producing and accumulating the antibody or the antibody fragment thereof in a culture; and   collecting the antibody or the antibody fragment thereof from the culture.   
     
     
         17 . A method of producing an antibody or the antibody fragment thereof, comprising:
 culturing the transformant according to  claim 15  in a culture medium;   producing and accumulating the antibody or the antibody fragment thereof in a culture; and   collecting the antibody or the antibody fragment thereof from the culture.   
     
     
         18 . A method of treating a disease associated with human CRTH2 comprising:
 administrating an effective amount of the antibody or the antibody fragment thereof according to  claim 1 .   
     
     
         19 . A method of diagnosing a disease associated with human CRTH2 using the antibody or the antibody fragment thereof according to  claim 1 . 
     
     
         20 . The method according to  claim 18 , wherein the disease associated with human CRTH2 is an allergic disease; an autoimmune disease; a disease accompanied by at least one of increase and hyperergasia of eosinophils; a disease accompanied by at least one of increase and hyperergasia of Th2 cells; or a disease accompanied by at least one of increase and hyperergasia of ILC2.