Desmoglein 3 (hereinafter referred to as DSG3) was first identified as a glycoprotein having a molecular weight of 130 kDa by immunoprecipitation of keratinocyte extracts with an autoantibody obtained from the serum of patients affected by pemphigus vulgaris (hereinafter referred to as PV), which is an autoimmune blister-forming disease of the skin and mucosa, and was named the PV antigen (hereinafter referred to as PVA) (Non-patent Document 1 and J. Clin. Invest. 74, 313-320, 1984). Then, antibody molecules that react with the above-mentioned 130-kDa protein were isolated from the serum of PV patients by affinity purification. Next, an expression library was constructed using poly(A) RNA isolated from human keratinocytes and was screened using the isolated antibodies, and a cDNA encoding PVA was isolated. Based on analysis of the nucleotide sequence of the isolated cDNA, the PVA molecule was found to be highly homologous to the sequences of a group of molecules belonging to the cadherin gene superfamily which encodes intercellular adhesion factors (Non-patent Document 2).
Cadherin molecules are expressed in a wide variety of tissues and they are involved in cell adhesion in vivo. Within the cadherin group, a group of molecules are expressed in desmosomes, which are adhesion sites between cells on the cell membrane, and are called desmosomal cadherins or desmogleins. Keratinocytes, which were used for isolation and cloning of the DSG3 molecule (a member of the desmoglein family), are cells that occupy a large portion of the epidermis. They are tightly adhered to adjacent cells via desmosomes and the DSG3 molecule is considered to be involved in this adhesion. Anti-DSG3 autoantibodies present in PV patients' sera are thought to cause PV lesions by binding to the DSG3 molecule and inhibiting intercellular adhesion mediated by the DSG3 molecule.
As described above, PV lesions are induced by polyclonal anti-DSG3 autoantibodies present in PV patients' sera. Monoclonal anti-DSG3 antibodies that have the ability to induce PV-like lesions upon transplantation of hybridomas into mice have also been isolated (Non-patent Document 3), and they have been shown to have a cell-dissociating activity that inhibits cell adhesion of keratinocytes in the test tube as well (Non-patent Document 4). As described above, the cell-dissociating activity of anti-DSG3 antibodies observed in the test tube has been suggested to be the activity that induces PV lesions in vivo.
As described above, it is known that the DSG3 protein has an important function in keratinocyte adhesion, and that anti-DSG3 antibodies are involved in the development of PV lesions. However, involvement of the DSG3 protein in other diseases, or functions of anti-DSG3 antibodies other than the cell-dissociating activity have not been elucidated. In particular, connection of the DSG3 molecule with the development of cancer, especially lung cancer, and proliferation, invasion, metastasis, or transformation of lung cancer cells in mammals, in particular, humans, has not been elucidated.
Of the various types of cancers, lung cancer has the highest mortality rate in both men and women. The mortality rate of lung cancer in Japan has increased after 1950; as a result, the number of lung cancer deaths in 1998 was 50,871 individuals, which was approximately 18% of all malignant tumor deaths, and after 1993, the number of deaths has exceeded that of stomach cancer and is ranked number one among malignant tumors for men (Health and Welfare Statistics Association, Kokumin eisei no doko/kousei no shihyou (Trends of national health/indicators of welfare), 47, 52-53, 2000). Furthermore, on a global scale, approximately 3,000,000 people a year are dying of lung cancer. Basic histological types of lung cancer include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large cell carcinoma, and small cell carcinoma. Since the former four do not show large differences in prognosis or therapeutic strategy, they are collectively referred to as non-small cell lung cancer.
The number of non-small cell lung cancer cases accounts for 80% to 85% of the total number of lung cancer cases. Examples of the characteristics of non-small cell lung cancer are slow progression compared to small-cell cancers, and insufficient response to chemotherapy and radiation therapy. Therefore, when the tumor is localized, surgical resection is the number one choice, but the treatment outcome is very poor compared to other carcinomas such as stomach cancer at the same disease stage by TNM classification. While recent attempts have been actively pursued to improve the outcome by multimodal treatment, effective therapeutic methods that lead to complete remission have not been established. In non-small cell lung cancer, surgical therapy is considered for up to stage Ma, while in subsequent clinical disease stages, surgery is rarely applied, and chemotherapy and radiation therapy are the main therapies. SCC (squamous cell carcinoma related antigen), Cyfra (cytokeratin 19 fragment), CEA (carcinoembryonic antigen), and SLX (sialyl Lewis x-i antigen) are selected as markers for serodiagnosis, and they are used separately or in combination, but the positive rate for early stage cancers is still low, and development of diagnostic markers that will assure early-stage diagnosis of non-small cell lung cancer by serodiagnosis is anticipated (Shuyo maka no yomikata no jissai; haigan (Practical method for reading tumor markers; lung cancer) Rinsho to Kenkyu (Clinic and Research) 78, 35-40, 2001).
Small cell lung cancer tumors constitute approximately 15% to 20% of all lung cancers in Japan, and their speed of proliferation is fast compared to other lung cancers, but they are highly sensitive to anticancer agents and radiation therapy, and have significantly different clinical characteristics from those of adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and such. For small cell cancer, surgical therapy is considered only in stage Ia (tumor diameter is 20 mm or less, and no invasion or metastasis to lymph nodes and nearby organs is shown), and chemotherapy and radiation therapy are basically the main therapeutic methods employed. As diagnostic markers, NSE (neuron-specific enolase) and proGRP (pro gastrin-releasing peptide) are used as tumor markers with relatively high specificity to small cell cancer, and their positive rates are reported to be approximately 60% and 70%, respectively.
Although there are still no examples of application in clinical practice for lung cancers, the therapeutic response rate in breast cancer, lymphoma, and such is increasing, because targeted therapy using monoclonal antibodies against cancer-specific tumor antigens exhibits a mode of action different from conventional therapy which uses chemotherapeutic agents. In targeted therapy that uses the above-mentioned antibody pharmaceuticals, when the antibodies are functional and effective, their activities include: antibody-dependent cell-mediated cytotoxicity (ADCC) activity via effector cells; complement-dependent cytotoxicity (CDC) activity via complements; and cytotoxic activity as a result of construction of conjugate molecules with chemotherapeutic agents, toxic peptides, or radioactive chemical substances. Additional activities besides those mentioned above include, for example, agonistic activity in which the antibody itself catalyzes an agonistic effect on the antigenic molecule; and neutralizing activity that blocks signals for cell activation, proliferation, or the like. In order to apply molecular-targeting therapy that uses antibodies exhibiting activities such as those mentioned above in the treatment of lung cancer, which has low positive rate of diagnosis, low disease cure rate, and still has room for complete remission, identification of tumor-specific molecules expressed in lung cancer cells and production of antibodies that exhibit desirable activity by targeting such molecules are strongly anticipated.
Prior art literature information relating to the present invention is the following:    [Patent Document 1] WO 99/57149.    [Patent Document 2] WO 02/86443.    [Patent Document 3] WO 03/20769.    [Non-patent Document 1] J. Clin. Invest. 70, 281-288, 1982.    [Non-patent Document 2] Cell 67, 869-877, 1991.    [Non-patent Document 3] J. Immunology 170, 2170-2178, 2003.    [Non-patent Document 4] J. Invest. Dermatol., 124, 939-946, 2005.