Diagnosis and Treatment of Cancer Using Anti-Desmoglein-3 Antibodies

Abstract

Methods that involve detection of a DSG3 protein for diagnosing cancer are disclosed. In lung cancer, the expression of DSG3 was found to be enhanced at very high frequency at the gene level and protein level. Methods of the present invention can be carried out using an antibody that recognizes a DSG3 protein. Pharmaceutical compositions, cell growth inhibitors, and anticancer agents containing a DSG3-binding antibody as an active ingredient are also disclosed. Methods of inducing cell damage in DSG3-expressing cells and methods of suppressing proliferation of DSG3-expressing cells by contacting the DSG3-expressing cells with DSG3-binding antibodies are also disclosed.

1 . A pharmaceutical composition comprising as an active ingredient an antibody that binds to a DSG3 protein. 
     
     
         2 . A cell growth inhibitor comprising as an active ingredient an antibody that binds to a DSG3 protein. 
     
     
         3 . An anticancer agent comprising as an active ingredient an antibody that binds to a DSG3 protein. 
     
     
         4 . The anticancer agent of  claim 3 , wherein the antibody that binds to a DSG3 protein is an antibody that has cytotoxic activity. 
     
     
         5 . The anticancer agent of  claim 3 , wherein the antibody that binds to a DSG3 protein is an antibody described in any of (1) to (47) below:
 (1) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 2 as CDR1, the amino acid sequence of SEQ ID NO: 4 as CDR2, and the amino acid sequence of SEQ ID NO: 6 as CDR3;   (2) an antibody comprising the H chain of (1), wherein the H chain has the amino acid sequence of SEQ ID NO: 8 as CH;   (3) an antibody comprising the H chain of (1), wherein the H chain has the amino acid sequence of SEQ ID NO: 10 as CH;   (4) an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3;   (5) an antibody comprising the L chain of (4), wherein the L chain has the amino acid sequence of SEQ ID NO: 18 as CL;   (6) an antibody comprising the L chain of (4), wherein the L chain has the amino acid sequence of SEQ ID NO: 20 as CL;   (7) an antibody comprising the H chain of (1) and the L chain of (4);   (8) an antibody comprising the H chain of (2) and the L chain of (5);   (9) an antibody comprising the H chain of (3) and the L chain of (6);   (10) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 22 as CDR1, the amino acid sequence of SEQ ID NO: 24 as CDR2, and the amino acid sequence of SEQ ID NO: 26 as CDR3;   (11) an antibody comprising the H chain of (10), wherein the H chain has the amino acid sequence of SEQ ID NO: 28 as CH;   (12) an antibody comprising the H chain of (10), wherein the H chain has the amino acid sequence of SEQ ID NO: 10 as CH;   (13) an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 30 as CDR1, the amino acid sequence of SEQ ID NO: 32 as CDR2, and the amino acid sequence of SEQ ID NO: 34 as CDR3;   (14) an antibody comprising the L chain of (13), wherein the L chain has the amino acid sequence of SEQ ID NO: 36 as CL;   (15) an antibody comprising the L chain of (13), wherein the L chain has the amino acid sequence of SEQ ID NO: 20 as CL;   (16) an antibody comprising the H chain of (10) and the L chain of (13);   (17) an antibody comprising the H chain of (11) and the L chain of (14);   (18) an antibody comprising the H chain of (12) and the L chain of (15);   (19) an antibody comprising the H chain of (1) and the L chain of (13);   (20) an antibody comprising the H chain of (2) and the L chain of (14);   (21) an antibody comprising the H chain of (3) and the L chain of (15);   (22) an antibody comprising the H chain of (10) and the L chain of (4);   (23) an antibody comprising the H chain of (11) and the L chain of (5);   (24) an antibody comprising the H chain of (12) and the L chain of (6);   (25) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 81 as CDR1, the amino acid sequence of SEQ ID NO: 83 as CDR2, and the amino acid sequence of SEQ ID NO: 85 as CDR3;   (26) an antibody comprising the H chain of (25), wherein the H chain has the amino acid sequence of SEQ ID NO: 28 as CH;   (27) an antibody comprising the H chain of (25), wherein the H chain has the amino acid sequence of SEQ ID NO: 10 as CH;   (28) an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 87 as CDR1, the amino acid sequence of SEQ ID NO: 89 as CDR2, and the amino acid sequence of SEQ ID NO: 91 as CDR3;   (29) an antibody comprising the L chain of (28), wherein the L chain has the amino acid sequence of SEQ ID NO: 36 as CL;   (30) an antibody comprising the L chain of (28), wherein the L chain has the amino acid sequence of SEQ ID NO: 20 as CL;   (31) an antibody comprising the H chain of (25) and the L chain of (28);   (32) an antibody comprising the H chain of (26) and the L chain of (29);   (33) an antibody comprising the H chain of (27) and the L chain of (30);   (34) an antibody comprising the H chain of (1) and the L chain of (28);   (35) an antibody comprising the H chain of (2) and the L chain of (29);   (36) an antibody comprising the H chain of (3) and the L chain of (30);   (37) an antibody comprising the H chain of (10) and the L chain of (28);   (38) an antibody comprising the H chain of (11) and the L chain of (29);   (39) an antibody comprising the H chain of (12) and the L chain of (30);   (40) an antibody comprising the H chain of (25) and the L chain of (4);   (41) an antibody comprising the H chain of (26) and the L chain of (5);   (42) an antibody comprising the H chain of (27) and the L chain of (6);   (43) an antibody comprising the H chain of (25) and the L chain of (13);   (44) an antibody comprising the H chain of (26) and the L chain of (14);   (45) an antibody comprising the H chain of (27) and the L chain of (15);   (46) an antibody comprising one or more amino acid substitutions, deletions, additions, and/or insertions in the antibody of any of (1) to (45), which has equivalent activity as the antibody of any of (1) to (45); and   (47) an antibody that binds to the same DSG3 protein epitope as the antibody of any of (1) to (45).   
     
     
         6 . The anticancer agent of  claim 3 , wherein the cancer is selected from the group consisting of lung cancer, colon cancer, esophageal cancer, stomach cancer, pancreatic cancer, skin cancer, and uterine cancer. 
     
     
         7 . The anticancer agent of  claim 6 , wherein said lung cancer is non-small-cell lung cancer. 
     
     
         8 . A method of inducing cell damage in DSG3-expressing cells by contacting cells that express a DSG3 protein with an antibody that binds to the DSG3 protein. 
     
     
         9 . A method of suppressing growth of DSG3-expressing cells by contacting cells that express a DSG3 protein with an antibody that binds to the DSG3 protein. 
     
     
         10 . The method of  claim 8 , wherein the antibody that binds to the DSG3 protein has cytotoxic activity. 
     
     
         11 . The method of  claim 8 , wherein the antibody that binds to the DSG3 protein is an antibody of any of (1) to (47) below:
 (1) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 2 as CDR1, the amino acid sequence of SEQ ID NO: 4 as CDR2, and the amino acid sequence of SEQ ID NO: 6 as CDR3;   (2) an antibody comprising the H chain of (1), wherein the H chain has the amino acid sequence of SEQ ID NO: 8 as CH;   (3) an antibody comprising the H chain of (1), wherein the H chain has the amino acid sequence of SEQ ID NO: 10 as CH;   (4) an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3;   (5) an antibody comprising the L chain of (4), wherein the L chain has the amino acid sequence of SEQ ID NO: 18 as CL;   (6) an antibody comprising the L chain of (4), wherein the L chain has the amino acid sequence of SEQ ID NO: 20 as CL;   (7) an antibody comprising the H chain of (1) and the L chain of (4);   (8) an antibody comprising the H chain of (2) and the L chain of (5);   (9) an antibody comprising the H chain of (3) and the L chain of (6);   (10) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 22 as CDR1, the amino acid sequence of SEQ ID NO: 24 as CDR2, and the amino acid sequence of SEQ ID NO: 26 as CDR3;   (11) an antibody comprising the H chain of (10) having the amino acid sequence of SEQ ID NO: 28 as CH;   (12) an antibody comprising the H chain of (10) having the amino acid sequence of SEQ ID NO: 10 as CH;   (13) an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 30 as CDR1, the amino acid sequence of SEQ ID NO: 32 as CDR2, and the amino acid sequence of SEQ ID NO: 34 as CDR3;   (14) an antibody comprising the L chain of (13), wherein the L chain has the amino acid sequence of SEQ ID NO: 36 as CL;   (15) an antibody comprising the L chain of (13), wherein the L chain has the amino acid sequence of SEQ ID NO: 20 as CL;   (16) an antibody comprising the H chain of (10) and the L chain of (13);   (17) an antibody comprising the H chain of (11) and the L chain of (14);   (18) an antibody comprising the H chain of (12) and the L chain of (15);   (19) an antibody comprising the H chain of (1) and the L chain of (13);   (20) an antibody comprising the H chain of (2) and the L chain of (14);   (21) an antibody comprising the H chain of (3) and the L chain of (15);   (22) an antibody comprising the H chain of (10) and the L chain of (4);   (23) an antibody comprising the H chain of (11) and the L chain of (5);   (24) an antibody comprising the H chain of (12) and the L chain of (6);   (25) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 81 as CDR1, the amino acid sequence of SEQ ID NO: 83 as CDR2, and the amino acid sequence of SEQ ID NO: 85 as CDR3;   (26) an antibody comprising the H chain of (25), wherein the H chain has the amino acid sequence of SEQ ID NO: 28 as CH;   (27) an antibody comprising the H chain of (25), wherein the H chain has the amino acid sequence of SEQ ID NO: 10 as CH;   (28) an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 87 as CDR1, the amino acid sequence of SEQ ID NO: 89 as CDR2, and the amino acid sequence of SEQ ID NO: 91 as CDR3;   (29) an antibody comprising the L chain of (28), wherein the L chain has the amino acid sequence of SEQ ID NO: 36 as CL;   (30) an antibody comprising the L chain of (28), wherein the L chain has the amino acid sequence of SEQ ID NO: 20 as CL;   (31) an antibody comprising the H chain of (25) and the L chain of (28);   (32) an antibody comprising the H chain of (26) and the L chain of (29);   (33) an antibody comprising the H chain of (27) and the L chain of (30);   (34) an antibody comprising the H chain of (1) and the L chain of (28);   (35) an antibody comprising the H chain of (2) and the L chain of (29);   (36) an antibody comprising the H chain of (3) and the L chain of (30);   (37) an antibody comprising the H chain of (10) and the L chain of (28);   (38) an antibody comprising the H chain of (11) and the L chain of (29);   (39) an antibody comprising the H chain of (12) and the L chain of (30);   (40) an antibody comprising the H chain of (25) and the L chain of (4);   (41) an antibody comprising the H chain of (26) and the L chain of (5);   (42) an antibody comprising the H chain of (27) and the L chain of (6);   (43) an antibody comprising the H chain of (25) and the L chain of (13);   (44) an antibody comprising the H chain of (26) and the L chain of (14);   (45) an antibody comprising the H chain of (27) and the L chain of (15);   (46) an antibody comprising one or more amino acid substitutions, deletions, additions, and/or insertions in the antibody of any of (1) to (45), which has equivalent activity as the antibody of any of (1) to (45); and   (47) an antibody that binds to the same DSG3 protein epitope as the antibody of any of (1) to (45).   
     
     
         12 . The method of  claim 8 , wherein the cells that express a DSG3 protein are cancer cells. 
     
     
         13 . An antibody that binds to a DSG3 protein and has cytotoxic activity against cells that express a DSG3 protein. 
     
     
         14 . The antibody of  claim 13 , wherein the cytotoxic activity is ADCC activity. 
     
     
         15 . The antibody of  claim 13 , wherein the cytotoxic activity is CDC activity. 
     
     
         16 . The antibody of  claim 13 , wherein a low-molecular-weight chemotherapeutic agent or a toxic peptide is bound to the antibody. 
     
     
         17 . An antibody binding to a DSG3 protein, wherein a low-molecular-weight chemotherapeutic agent or a toxic peptide is bound to the antibody. 
     
     
         18 . The antibody of  claim 13 , wherein the antibody is an antibody of any of (1) to (47) below:
 (1) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 2 as CDR1, the amino acid sequence of SEQ ID NO: 4 as CDR2, and the amino acid sequence of SEQ ID NO: 6 as CDR3;   (2) an antibody comprising the H chain of (1), wherein the H chain has the amino acid sequence of SEQ ID NO: 8 as CH;   (3) an antibody comprising the H chain of (1), wherein the H chain has the amino acid sequence of SEQ ID NO: 10 as CH;   (4) an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 12 as CDR1, the amino acid sequence of SEQ ID NO: 14 as CDR2, and the amino acid sequence of SEQ ID NO: 16 as CDR3;   (5) an antibody comprising the L chain of (4) having the amino acid sequence of SEQ ID NO: 18 as CL;   (6) an antibody comprising the L chain of (4) having the amino acid sequence of SEQ ID NO: 20 as CL;   (7) an antibody comprising the H chain of (1) and the L chain of (4);   (8) an antibody comprising the H chain of (2) and the L chain of (5);   (9) an antibody comprising the H chain of (3) and the L chain of (6);   (10) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 22 as CDR1, the amino acid sequence of SEQ ID NO: 24 as CDR2, and the amino acid sequence of SEQ ID NO: 26 as CDR3;   (11) an antibody comprising the H chain of (10), wherein the H chain has the amino acid sequence of SEQ ID NO: 28 as CH;   (12) an antibody comprising the H chain of (10), wherein the H chain has the amino acid sequence of SEQ ID NO: 10 as CH;   (13) an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 30 as CDR1, the amino acid sequence of SEQ ID NO: 32 as CDR2, and the amino acid sequence of SEQ ID NO: 34 as CDR3;   (14) an antibody comprising the L chain of (13), wherein the L chain has the amino acid sequence of SEQ ID NO: 36 as CL;   (15) an antibody comprising the L chain of (13), wherein the L chain has the amino acid sequence of SEQ ID NO: 20 as CL;   (16) an antibody comprising the H chain of (10) and the L chain of (13);   (17) an antibody comprising the H chain of (11) and the L chain of (14);   (18) an antibody comprising the H chain of (12) and the L chain of (15);   (19) an antibody comprising the H chain of (1) and the L chain of (13);   (20) an antibody comprising the H chain of (2) and the L chain of (14);   (21) an antibody comprising the H chain of (3) and the L chain of (15);   (22) an antibody comprising the H chain of (10) and the L chain of (4);   (23) an antibody comprising the H chain of (11) and the L chain of (5);   (24) an antibody comprising the H chain of (12) and the L chain of (6);   (25) an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 81 as CDR1, the amino acid sequence of SEQ ID NO: 83 as CDR2, and the amino acid sequence of SEQ ID NO: 85 as CDR3;   (26) an antibody comprising the H chain of (25), wherein the H chain has the amino acid sequence of SEQ ID NO: 28 as CH;   (27) an antibody comprising the H chain of (25), wherein the H chain has the amino acid sequence of SEQ ID NO: 10 as CH;   (28) an antibody comprising an L chain having the amino acid sequence of SEQ ID NO: 87 as CDR1, the amino acid sequence of SEQ ID NO: 89 as CDR2, and the amino acid sequence of SEQ ID NO: 91 as CDR3;   (29) an antibody comprising the L chain of (28), wherein the L chain has the amino acid sequence of SEQ ID NO: 36 as CL;   (30) an antibody comprising the L chain of (28), wherein the L chain has the amino acid sequence of SEQ ID NO: 20 as CL;   (31) an antibody comprising the H chain of (25) and the L chain of (28);   (32) an antibody comprising the H chain of (26) and the L chain of (29);   (33) an antibody comprising the H chain of (27) and the L chain of (30);   (34) an antibody comprising the H chain of (1) and the L chain of (28);   (35) an antibody comprising the H chain of (2) and the L chain of (29);   (36) an antibody comprising the H chain of (3) and the L chain of (30);   (37) an antibody comprising the H chain of (10) and the L chain of (28);   (38) an antibody comprising the H chain of (11) and the L chain of (29);   (39) an antibody comprising the H chain of (12) and the L chain of (30);   (40) an antibody comprising the H chain of (25) and the L chain of (4);   (41) an antibody comprising the H chain of (26) and the L chain of (5);   (42) an antibody comprising the H chain of (27) and the L chain of (6);   (43) an antibody comprising the H chain of (25) and the L chain of (13);   (44) an antibody comprising the H chain of (26) and the L chain of (14);   (45) an antibody comprising the H chain of (27) and the L chain of (15);   (46) an antibody comprising one or more amino acid substitutions, deletions, additions, and/or insertions in the antibody of any of (1) to (45), which has equivalent activity as the antibody of any of (1) to (45); and   (47) an antibody that binds to the same DSG3 protein epitope as the antibody of any of (1) to (45).   
     
     
         19 . (canceled) 
     
     
         20 . A method of diagnosing cancer, comprising detecting a DSG3 protein using an antibody that binds to the DSG3 protein. 
     
     
         21 . A method of diagnosing cancer, comprising:
 (a) collecting a sample from a subject; and   (b) detecting a DSG3 protein contained in the collected sample using an antibody that binds to the DSG3 protein.   
     
     
         22 . The method of diagnosis of  claim 20 , wherein the antibody that binds to the DSG3 protein is labeled with a positron-emitting nuclide. 
     
     
         23 . The method of diagnosis of  claim 22 , wherein the positron-emitting nuclide is a nuclide selected from the group consisting of  11 C,  13 N,  15 O,  18 F,  45 Ti,  55 Co,  64 Cu,  66 Ga,  68 Ga,  76 Br,  89 Zr, and  124 I. 
     
     
         24 . A method of diagnosing cancer, comprising detecting expression of a gene encoding a DSG3 protein. 
     
     
         25 . The method of diagnosis of  claim 20 , wherein the cancer is selected from the group consisting of lung cancer, colon cancer, esophageal cancer, stomach cancer, pancreatic cancer, skin cancer, and uterine cancer. 
     
     
         26 . The method of diagnosis of  claim 25 , wherein said lung cancer is non-small-cell lung cancer. 
     
     
         27 .- 30 . (canceled) 
     
     
         31 . A method of suppressing cell growth, comprising the step of administering to a subject an antibody that binds to a DSG3 protein. 
     
     
         32 . A method of preventing or treating cancer, comprising the step of administering to a subject an antibody that binds to a DSG3 protein.