Cancer stem cell-specific molecule

Abstract

An objective of the present invention is to obtain two types of substantively homogeneous cancer stem cell populations which can be characterized using the cell surface marker Lgr5, and to provide cancer therapeutics using an antibody against a cell membrane molecule specifically expressed in these cancer stem cells by identifying said cell membrane molecule. A further objective of the present invention is to provide, using an antibody against a cell membrane molecule specifically expressed in cancer stem cells, a reagent for detecting cancer stem cells, and a method for diagnosing and sorting cancer patients. The present inventors discovered that highly pure large intestine cancer stem cells (CSC) can be obtained in a large quantity, and identified the two types of conditions of large intestine CSCs distinguishable through Lgr5 expression. Moreover, the present inventors discovered that an antibody against a cell membrane molecule specifically expressed in said cancer stem cells can damage said cells.

1 . A pharmaceutical composition comprising as an active ingredient at least one antibody that binds to a protein of SEQ ID NOs: 1 to 8. 
     
     
         2 . The pharmaceutical composition of  claim 1 , which is an anti-cancer agent. 
     
     
         3 . The pharmaceutical composition of  claim 2 , which is an agent for inhibiting cancer recurrence. 
     
     
         4 . The pharmaceutical composition of  claim 2 , which is an agent for inhibiting cancer metastasis or an agent for postoperative adjuvant therapy. 
     
     
         5 . The pharmaceutical composition of  claim 4 , which is an agent for inhibiting cancer metastasis or an agent for postoperative adjuvant therapy against Lgr5-positive cancer, which comprises as an active ingredient at least one antibody that binds to a protein of SEQ ID NOs: 1 to 6. 
     
     
         6 . The pharmaceutical composition of  claim 2 , which is a therapeutic agent against drug-resistant cancer. 
     
     
         7 . The pharmaceutical composition of  claim 6 , which is a therapeutic agent against Lgr5-negative cancer, and which comprises as an active ingredient at least one antibody that binds to a protein of SEQ ID NOs: 1 to 8. 
     
     
         8 . The pharmaceutical composition of  claim 7  wherein the Lgr5-negative cancer is a drug-resistant cancer. 
     
     
         9 . The pharmaceutical composition of any one of  claims 2  to  8 , which is an agent for inhibiting cancer stem cell proliferation or an agent for disrupting cancer stem cells. 
     
     
         10 . The pharmaceutical composition of any one of  claims 2  to  9 , wherein the cancer is a solid cancer. 
     
     
         11 . The pharmaceutical composition of any one of  claims 2  to  10 , wherein the cancer is a digestive system cancer. 
     
     
         12 . The pharmaceutical composition of any one of  claims 2  to  11 , wherein the cancer is a colorectal cancer. 
     
     
         13 . The pharmaceutical composition of any one of  claims 1  to  12 , wherein the antibody is a monoclonal antibody. 
     
     
         14 . The pharmaceutical composition of any one of  claims 1  to  13 , wherein the antibody is a chimeric antibody, a humanized antibody, or a human antibody. 
     
     
         15 . The pharmaceutical composition of any one of  claims 1  to  14 , wherein the antibody is an antibody fragment. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the antibody is linked to a cytotoxic substance or a proliferation inhibitor. 
     
     
         17 . The pharmaceutical composition of any one of  claims 1  to  14 , wherein the antibody has a cytotoxic activity. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the cytotoxic activity is ADCC. 
     
     
         19 . The pharmaceutical composition of  claim 17  or  18 , which comprises an antibody with modified sugar chains whose sugar chain composition has been altered to increase the ratio of defucosylated antibody or to increase the ratio of antibody attached with bisecting N-acetylglucosamine. 
     
     
         20 . The pharmaceutical composition of  claim 17 , wherein the cytotoxic activity is CDC. 
     
     
         21 . The pharmaceutical composition of any one of  claims 1  to  20 , wherein the antibody has a neutralizing activity. 
     
     
         22 . The pharmaceutical composition of any one of  claims 2  to  21 , or a pharmaceutical composition comprising the polypeptide of SEQ ID NO: 9 or a polypeptide resulting from addition, deletion, and/or substitution of one or several amino acids in the polypeptide of SEQ ID NO: 9, which is to be used in combination with a chemotherapeutic agent simultaneously or after chemotherapeutic treatment. 
     
     
         23 . A reagent for detecting a cancer stem cell, which comprises as an active ingredient at least one antibody that binds to a protein of SEQ ID NOs: 1 to 8. 
     
     
         24 . The reagent of  claim 23 , wherein it is used in detecting an Lgr5-positive cancer stem cell, and wherein the antibody is at least one antibody that binds to a protein of SEQ ID NOs: 1 to 6. 
     
     
         25 . The reagent of  claim 23 , wherein it is used in detecting an Lgr5-negative cancer stem cell, and wherein the antibody is at least one antibody that binds to a protein of SEQ ID NOs: 1 to 8. 
     
     
         26 . A method for diagnosing cancer or selecting a cancer patient, wherein the method comprises, by using at least one antibody that binds to a protein of SEQ ID NOs: 1 to 8, detecting the presence of at least one of the proteins in a sample isolated from a cancer patient. 
     
     
         27 . The method of  claim 26 , wherein it is used in diagnosing Lgr5-positive cancer or selecting a cancer patient, and wherein the antibody is at least one antibody that binds to a protein of SEQ ID NOs: 1 to 6. 
     
     
         28 . The method of  claim 26 , wherein it is used in diagnosing Lgr5-negative cancer or selecting a cancer patient, and wherein the antibody is at least one antibody that binds to a protein of SEQ ID NOs: 1 to 8. 
     
     
         29 . A method for assessing the effectiveness of the pharmaceutical composition of any one of  claims 1  to  22 , wherein the method comprises detecting the presence of one or more of the proteins of SEQ ID NOs: 1 to 8 and/or polynucleotides encoding the proteins in a sample isolated from a subject administered with the pharmaceutical composition. 
     
     
         30 . The method of  claim 29 , which uses at least one antibody that binds to a protein of SEQ ID NOs: 1 to 8. 
     
     
         31 . The method of  claim 29 , which uses polynucleotides encoding the proteins of SEQ ID NOs: 1 to 8 and/or complementary strands thereof.