Human monoclonal antibody against a costimulatory signal transduction molecule ailim and pharmaceutical use thereof

Abstract

Immunization of human antibody-producing transgenic mice, which have been created using genetic engineering techniques, with AILIM molecule as an antigen resulted in various human monoclonal antibodies capable of binding to AILIM and capable of controlling a variety of biological reactions (for example, cell proliferation, cytokine production, immune cytolysis, cell death, induction of ADCC, etc.) associated with AILIM-mediated costimulatory signal (secondary signal) transduction. Furthermore, it has been revealed that the human monoclonal antibody is effective to treat and prevent various diseases associated with AILIM-mediated costimulatory signal transduction, being capable of inhibiting the onset and/or advancement of the diseases.

What is claimed is: 
     
         1 - 108 . (canceled) 
     
     
         109 . A method of treating or preventing rheumatoid arthritis, psoriasis, graft versus host disease, immunorejection associated with transplantation of tissues or organs, nephritis, or insulin dependent diabetes mellitus in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) a human monoclonal antibody or portion thereof that binds to human AILIM, wherein:
 (a) a V region DNA encoding a heavy chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin heavy chain V gene segment 1-02 or 3-13;   (b) a V region DNA encoding a light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment L5 or A27; or   (c) a V region DNA encoding a heavy chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin heavy chain V gene segment 1-02 or 3-13, and a V region DNA encoding a light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment L5 or A27.   
     
     
         110 . A method of treating or preventing rheumatoid arthritis, psoriasis, graft versus host disease, immunorejection associated with transplantation of tissues or organs, nephritis, or insulin dependent diabetes mellitus in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) a human monoclonal antibody or portion thereof that binds to human AILIM, wherein a heavy chain variable region of the human monoclonal antibody or portion thereof comprises an amino acid sequence selected from the group consisting of:
 (a) amino acids from position 20 through 117 of SEQ ID NO:28;   (b) amino acids from position 20 through 117 of SEQ ID NO:28 in which one to ten amino acid residues are deleted, substituted, or added;   (c) amino acids from position 20 through 116 of SEQ ID NO:32;   (d) amino acids from position 20 through 116 of SEQ ID NO:32 in which one to ten amino acid residues are deleted, substituted, or added;   (e) amino acids from position 20 through 116 of SEQ ID NO:36; and   (f) amino acids from position 20 through 116 of SEQ ID NO:36, in which one to ten amino acid residues are deleted, substituted, or added.   
     
     
         111 . A method of treating or preventing rheumatoid arthritis, psoriasis, graft versus host disease, immunorejection associated with transplantation of tissues or organs, nephritis, or insulin dependent diabetes mellitus in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) a human monoclonal antibody or portion thereof that binds to human AILIM, wherein a light chain variable region of the human monoclonal antibody or portion thereof comprises an amino acid sequence selected from the group consisting of:
 (a) amino acids from position 23 through 116 of SEQ ID NO:30;   (b) amino acids from position 23 through 116 of SEQ ID NO:30 in which one to ten amino acid residues are deleted, substituted, or added;   (c) amino acids from position 21 through 116 of SEQ ID NO:34;   (d) amino acids from position 21 through 116 of SEQ ID NO:34 in which one to ten amino acid residues are deleted, substituted, or added;   (e) amino acids from position 21 through 116 of SEQ ID NO:38; and   (f) amino acids from position 21 through 116 of SEQ ID NO:38 in which one to ten amino acid residues are deleted, substituted, or added.   
     
     
         112 . The method of  claim 109 , wherein a V region DNA encoding a heavy chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin heavy chain V gene segment 1-02 or 3-13. 
     
     
         113 . The method of  claim 109 , wherein a V region DNA encoding a light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment L5 or A27. 
     
     
         114 . The method of  claim 109 , wherein a V region DNA encoding a heavy chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin heavy chain V gene segment 1-02 or 3-13, and a V region DNA encoding a light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment L5 or A27. 
     
     
         115 . The method of  claim 114 , wherein the V region DNA encoding the heavy chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin heavy chain V gene segment 1-02, and the V region DNA encoding the light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment L5. 
     
     
         116 . The method of  claim 114 , wherein the V region DNA encoding the heavy chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin heavy chain V gene segment 3-13, and the V region DNA encoding the light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment A27. 
     
     
         117 . The method of  claim 110 , wherein a heavy chain polypeptide of the human monoclonal antibody or portion thereof comprises an amino acid sequence selected from the group consisting of:
 (a) amino acids from position 20 through 470 of SEQ ID NO:28, (b) amino acids from position 20 through 470 of SEQ ID NO:28 in which one to ten amino acid residues are deleted, substituted, or added,   (c) amino acids from position 20 through 470 of SEQ ID NO:32,   (d) amino acids from position 20 through 470 of SEQ ID NO:32 in which one to ten amino acid residues are deleted, substituted, or added,   (e) amino acids from position 20 through 470 of SEQ ID NO:36, and   (f) amino acids from position 20 through 470 of SEQ ID NO:36 in which one to ten amino acid residues are deleted, substituted, or added.   
     
     
         118 . The method of  claim 111 , wherein a light chain polypeptide of the human monoclonal antibody or portion thereof comprises an amino acid sequence selected from the group consisting of:
 (a) amino acids from position 23 through 236 of SEQ ID NO:30,   (b) amino acids from position 23 through 236 of SEQ ID NO:30 in which one to ten amino acid residues are deleted, substituted, or added,   (c) amino acids from position 21 through 236 of SEQ ID NO:34,   (d) amino acids from position 21 through 236 of SEQ ID NO:34 in which one to ten amino acid residues are deleted, substituted, or added,   (e) amino acids from position 21 through 236 of SEQ ID NO:38, and   (f) amino acids from position 21 through 236 of SEQ ID NO:38 in which one to ten amino acid residues are deleted, substituted, or added.   
     
     
         119 . The method of  claim 110 , wherein the human monoclonal antibody or portion thereof comprises:
 a heavy chain variable region comprising amino acid 20 through 117 according to SEQ ID NO:28, and   a light chain variable region comprising amino acid 23 through 116 according to SEQ ID NO:30.   
     
     
         120 . The method of  claim 117 , wherein the human monoclonal antibody or portion thereof comprises:
 a heavy chain polypeptide comprising amino acid 20 through 470 according to SEQ ID NO:28, and   a light chain polypeptide comprising amino acid 23 through 236 according to SEQ ID NO:30.   
     
     
         121 . The method of  claim 110 , wherein the human monoclonal antibody or portion thereof comprises:
 a heavy chain variable region comprising amino acid 20 through 116 according to SEQ ID NO:32, and   a light chain variable region comprising amino acid 21 through 116 according to SEQ ID NO:34.   
     
     
         122 . The method of  claim 117 , wherein the human monoclonal antibody or portion thereof comprises:
 a heavy chain polypeptide comprising amino acid 20 through 470 according to SEQ ID NO:32, and   a light chain polypeptide comprising amino acid 21 through 236 according to SEQ ID NO:34.   
     
     
         123 . The method of  claim 110 , wherein the human monoclonal antibody or portion thereof comprises:
 a heavy chain variable region comprising amino acid 20 through 116 according to SEQ ID NO:36, and   a light chain variable region comprising amino acid 21 through 116 according to SEQ ID NO:38.   
     
     
         124 . The method of  claim 117 , wherein the human monoclonal antibody or portion thereof comprises:
 a heavy chain polypeptide comprising amino acid 20 through 470 according to SEQ ID NO:36, and   a light chain polypeptide comprising amino acid 21 through 236 according to SEQ ID NO:38.   
     
     
         125 . The method of  claim 109 , wherein the V region DNA encoding the heavy chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin heavy chain V gene segment 1-02. 
     
     
         126 . The method of  claim 109 , wherein the V region DNA encoding the heavy chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin heavy chain V gene segment 3-13. 
     
     
         127 . The method of  claim 109 , wherein the V region DNA encoding the light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment L5. 
     
     
         128 . The method of  claim 109 , wherein the V region DNA encoding the light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment A27. 
     
     
         129 . The method of  claim 112 , wherein the V region DNA encoding the light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment L5. 
     
     
         130 . The method of  claim 112 , wherein the V region DNA encoding the light chain variable region of the human monoclonal antibody or portion thereof is from human immunoglobulin light chain V gene segment A27. 
     
     
         131 . The method of  claim 110 , wherein the heavy chain variable region of the human monoclonal antibody or portion thereof comprises amino acids from position 20 through 117 of SEQ ID NO:28. 
     
     
         132 . The method of  claim 110 , wherein the heavy chain variable region of the human monoclonal antibody or portion thereof comprises amino acids from position 20 through 116 of SEQ ID NO:32. 
     
     
         133 . The method of  claim 110 , wherein the heavy chain variable region of the human monoclonal antibody or portion thereof comprises amino acids from position 20 through 116 of SEQ ID NO:36. 
     
     
         134 . The method of  claim 117 , wherein the heavy chain polypeptide of the human monoclonal antibody or portion thereof comprises amino acids from position 20 through 470 of SEQ ID NO:28. 
     
     
         135 . The method of  claim 117 , wherein the heavy chain polypeptide of the human monoclonal antibody or portion thereof comprises amino acids from position 20 through 470 of SEQ ID NO:32. 
     
     
         136 . The method of  claim 117 , wherein the heavy chain polypeptide of the human monoclonal antibody or portion thereof comprises amino acids from position 20 through 470 of SEQ ID NO:36. 
     
     
         137 . The method of  claim 111 , wherein the light chain variable region of the human monoclonal antibody or portion thereof comprises amino acids from position 23 through 116 of SEQ ID NO:30. 
     
     
         138 . The method of  claim 111 , wherein the light chain variable region of the human monoclonal antibody or portion thereof comprises amino acids from position 21 through 116 of SEQ ID NO:34. 
     
     
         139 . The method of  claim 111 , wherein the light chain variable region of the human monoclonal antibody or portion thereof comprises amino acids from position 21 through 116 of SEQ ID NO:38. 
     
     
         140 . The method of  claim 118 , wherein the light chain polypeptide of the human monoclonal antibody or portion thereof comprises amino acids from position 23 through 236 of SEQ ID NO:30. 
     
     
         141 . The method of  claim 118 , wherein the light chain polypeptide of the human monoclonal antibody or portion thereof comprises amino acids from position 21 through 236 of SEQ ID NO:34. 
     
     
         142 . The method of  claim 118 , wherein the light chain polypeptide of the human monoclonal antibody or portion thereof comprises amino acids from position 21 through 236 of SEQ ID NO:38.