Diagnosis and treatment of cancer using anti-itm2a antibody

Abstract

Disclosed is a monoclonal antibody binding to an ITM2A protein. This antibody is useful in the diagnosis, prevention, and treatment of cancer such as Ewing's sarcoma, T cell leukemia, T cell lymphoma, acute myeloid leukemia, B cell tumor, and multiple myeloma. The present invention also provides a pharmaceutical composition, a cell growth inhibitor, and an anticancer agent containing the antibody as an active ingredient, and a method for treating cancer, a method for predicting the efficacy of cancer treatment, and a method for determining the presence of cancer in a test subject using the antibody.

1 . A monoclonal antibody binding to a fragment of an ITM2A protein having the amino acid sequence represented by SEQ ID NO: 1. 
     
     
         2 . The antibody according to  claim 1 , wherein the fragment is a fragment consisting of amino acids 75 to 227 in the amino acid sequence represented by SEQ ID NO: 1. 
     
     
         3 . The antibody according to  claim 1 , wherein the antibody has a cytotoxic activity. 
     
     
         4 . The antibody according to  claim 3 , wherein the cytotoxic activity is an antibody-dependent cell-mediated cytotoxicity (ADCC) activity. 
     
     
         5 . The antibody according to  claim 3 , wherein the cytotoxic activity is a complement-dependent cytotoxicity (CDC) activity. 
     
     
         6 . The antibody according to  claim 1 , wherein the antibody is conjugated with a cytotoxic substance. 
     
     
         7 . The antibody according to  claim 6 , wherein the antibody has an internalization activity. 
     
     
         8 . The antibody according to  claim 1 , wherein the antibody inhibits cancer cell growth. 
     
     
         9 . The antibody according to  claim 8 , wherein the cancer cell is a Ewing's sarcoma cell. 
     
     
         10 . The antibody according to  claim 9 , wherein the Ewing's sarcoma cell is a cell having observable chromosomal translocation. 
     
     
         11 . The antibody according to  claim 10 , wherein the chromosomal translocation is t(11;22)(q24;q12). 
     
     
         12 . The antibody according to  claim 8 , wherein the cancer cell is a blood cancer cell. 
     
     
         13 . The antibody according to  claim 12 , wherein the blood cancer is any of T cell leukemia, T cell lymphoma, acute myeloid leukemia, B cell tumor, and multiple myeloma. 
     
     
         14 . An antibody described in any of the following (1) to (26):
 (1) an antibody comprising an H chain having the amino acid sequence represented by SEQ ID NO: 3 as CDR1, the amino acid sequence represented by SEQ ID NO: 4 as CDR2, and the amino acid sequence represented by SEQ ID NO: 5 as CDR3;   (2) an antibody comprising an L chain having the amino acid sequence represented by SEQ ID NO: 6 as CDR1, the amino acid sequence represented by SEQ ID NO: 7 as CDR2, and the amino acid sequence represented by SEQ ID NO: 8 as CDR3;   (3) an antibody comprising the H chain described in (1) and the L chain described in (2);   (4) an antibody comprising an H chain having the amino acid sequence represented by SEQ ID NO: 9 as CDR1, the amino acid sequence represented by SEQ ID NO: 10 as CDR2, and the amino acid sequence represented by SEQ ID NO: 11 as CDR3;   (5) an antibody comprising an L chain having the amino acid sequence represented by SEQ ID NO: 12 as CDR1, the amino acid sequence represented by SEQ ID NO: 13 as CDR2, and the amino acid sequence represented by SEQ ID NO: 14 as CDR3;   (6) an antibody comprising the H chain described in (4) and the L chain described in (5);   (7) an antibody comprising an H chain having the amino acid sequence represented by SEQ ID NO: 15 as CDR1, the amino acid sequence represented by SEQ ID NO: 16 as CDR2, and the amino acid sequence represented by SEQ ID NO: 17 as CDR3;   (8) an antibody comprising an L chain having the amino acid sequence represented by SEQ ID NO: 18 as CDR1, the amino acid sequence represented by SEQ ID NO: 19 as CDR2, and the amino acid sequence represented by SEQ ID NO: 20 as CDR3;   (9) an antibody comprising the H chain described in (7) and the L chain described in (8);   (10) an antibody comprising an H chain having the amino acid sequence represented by SEQ ID NO: 21 as CDR1, the amino acid sequence represented by SEQ ID NO: 22 as CDR2, and the amino acid sequence represented by SEQ ID NO: 23 as CDR3;   (11) an antibody comprising an L chain having the amino acid sequence represented by SEQ ID NO: 24 as CDR1, the amino acid sequence represented by SEQ ID NO: 25 as CDR2, and the amino acid sequence represented by SEQ ID NO: 26 as CDR3;   (12) an antibody comprising the H chain described in (10) and the L chain described in (11);   (13) the antibody described in any of (1) to (12) which is a chimeric antibody;   (14) the antibody described in any of (1) to (12) which is a humanized antibody;   (15) the antibody described in (1) or (3), comprising the amino acid sequence represented by SEQ ID NO: 28;   (16) the antibody described in (2) or (3), comprising the amino acid sequence represented by SEQ ID NO: 30;   (17) the antibody described in (4) or (6), comprising the amino acid sequence represented by SEQ ID NO: 32;   (18) the antibody described in (5) or (6), comprising the amino acid sequence represented by SEQ ID NO: 34;   (19) the antibody described in (7) or (9), comprising the amino acid sequence represented by SEQ ID NO: 36;   (20) the antibody described in (8) or (9), comprising the amino acid sequence represented by SEQ ID NO: 38;   (21) the antibody described in (10) or (12), comprising the amino acid sequence represented by SEQ ID NO: 40;   (22) the antibody described in (11) or (12), comprising the amino acid sequence represented by SEQ ID NO: 42;   (23) the antibody described in any of (15) to (22) which is a chimeric antibody;   (24) an antibody that has an amino acid sequence of an antibody described in any of (1) to (23) with a substitution, deletion, addition, and/or insertion of one or more amino acid(s) and has an activity equivalent to or a binding activity equivalent to that of the antibody;   (25) an antibody capable of binding to an epitope to which a second antibody binds, wherein the second antibody is the antibody described in any of (1) to (23); and   (26) an antibody capable of inhibiting the binding of a second antibody to an ITM2A protein fragment consisting of amino acids 75 to 227 in the amino acid sequence represented by SEQ ID NO: 1, wherein the second antibody is the antibody described in any of (1) to (23).   
     
     
         15 . The antibody according to  claim 1 , wherein the antibody has a human constant region. 
     
     
         16 . The antibody according to  claim 15 , wherein the antibody is a chimeric antibody, a humanized antibody, or a human antibody. 
     
     
         17 . The antibody according to  claim 1 , wherein the antibody is deficient in fucose added to its sugar chain or has a sugar chain having bisecting GlcNAc. 
     
     
         18 . A pharmaceutical composition comprising an antibody according to  claim 1  as an active ingredient. 
     
     
         19 . A cell growth inhibitor comprising an antibody according to  claim 1  as an active ingredient. 
     
     
         20 . An anticancer agent comprising an antibody according to  claim 1  as an active ingredient. 
     
     
         21 . The anticancer agent according to  claim 20 , wherein the cancer to be treated is Ewing's sarcoma. 
     
     
         22 . The anticancer agent according to  claim 21 , wherein the Ewing's sarcoma has observable chromosomal translocation. 
     
     
         23 . The anticancer agent according to  claim 22 , wherein the chromosomal translocation is t(11;22)(q24;q12). 
     
     
         24 . The anticancer agent according to  claim 20 , wherein the cancer cell is a blood cancer cell. 
     
     
         25 . The anticancer agent according to  claim 24 , wherein the blood cancer is any of T cell leukemia, T cell lymphoma, acute myeloid leukemia, B cell tumor, and multiple myeloma. 
     
     
         26 . A method for treating cancer, comprising administering an antibody according to  claim 1 . 
     
     
         27 . The method according to  claim 26 , wherein the cancer to be treated is Ewing's sarcoma. 
     
     
         28 . The method according to  claim 27 , wherein the Ewing's sarcoma has observable chromosomal translocation. 
     
     
         29 . The method according to  claim 28 , wherein the chromosomal translocation is t(11;22)(q24;q12). 
     
     
         30 . The method according to  claim 26 , wherein the cancer cell is a blood cancer cell. 
     
     
         31 . The method according to  claim 30 , wherein the blood cancer is any of T cell leukemia, T cell lymphoma, acute myeloid leukemia, B cell tumor, and multiple myeloma. 
     
     
         32 . A method for predicting the efficacy of cancer treatment by the administration of an antibody according to  claim 1 , comprising the step of detecting the expression level of an ITM2A in a biological sample collected from a test subject. 
     
     
         33 . The method according to  claim 32 , wherein an ITM2A protein in the sample collected from a test subject is detected. 
     
     
         34 . The method according to  claim 33 , wherein the detection of the ITM2A protein is performed using an antibody binding to the ITM2A protein. 
     
     
         35 . The method according to  claim 32 , wherein the cancer to be treated is Ewing's sarcoma. 
     
     
         36 . The method according to  claim 35 , wherein the Ewing's sarcoma has observable chromosomal translocation. 
     
     
         37 . The method according to  claim 36 , wherein the chromosomal translocation is t(11;22)(q24;q12). 
     
     
         38 . The method according to  claim 35 , wherein the cancer cell is a blood cancer cell. 
     
     
         39 . The method according to  claim 38 , wherein the blood cancer is any of T cell leukemia, T cell lymphoma, acute myeloid leukemia, B cell tumor, and multiple myeloma. 
     
     
         40 . A method for determining the presence of cancer in a test subject, comprising detecting an ITM2A protein in a sample collected from the test subject. 
     
     
         41 . A method for determining the presence of cancer in a test subject, comprising the following steps:
 (a) providing a sample collected from the test subject; and   (b) detecting an ITM2A protein contained in the sample of step (a) using an antibody binding to the ITM2A protein.   
     
     
         42 . A method for determining the presence of cancer in a test subject, comprising the following steps:
 (a) administering, to the test subject, a radioisotope-labeled antibody having a binding activity to an ITM2A protein; and   (b) detecting the accumulation of the radioisotope.   
     
     
         43 . The diagnosis method according to  claim 40 , wherein the cancer whose presence is to be determined is Ewing's sarcoma. 
     
     
         44 . The method according to  claim 43 , wherein the Ewing's sarcoma has observable chromosomal translocation. 
     
     
         45 . The method according to  claim 44 , wherein the chromosomal translocation is t(11;22)(q24;q12). 
     
     
         46 . The method according to  claim 40 , wherein the cancer is blood cancer. 
     
     
         47 . The method according to  claim 46 , wherein the blood cancer is any of T cell leukemia, T cell lymphoma, acute myeloid leukemia, B cell tumor, and multiple myeloma.