title: Augmented lung adenocarcinoma cytotoxicity by the combination of a genetically modified anti-Lewis Y antibody and antibodies to complement regulatory proteins.
abstract: Complement-dependent cytotoxicity (CDC) mediated by a chimeric anti-Lewis Y monoclonal antibody (cH18A; human IgG1) was investigated in this study. Human lung adenocarcinoma cell lines (PC7, PC9, and PC14) were used as the target cells. PC7 and PC9 cells, expressed Lewis Y antigen and were lysed by cH18A as effectively as by the parent mouse anti-Lewis Y antibodies (mH18A) in a concentration-dependent manner. PC14 cells did not express Lewis Y antigen and were not lysed by either cH18A or mH18A. cH18A mediated CDC activity against PC7 and PC9 cells was enhanced by the combined use of monoclonal antibodies directed against CD46(MCP), CD55(DAF), and CD59. These molecules are complement-regulatory proteins which protect host cells from CDC. PC7 and PC9 cells, showed high levels of surface expression of these proteins, PC7 cells were more susceptible to cH18A-mediated CDC than PC9 cells. Use of multiple blocking antibodies to the complement-regulatory proteins produced more enhancement of cH18A-mediated CDC than a single antibody. Moreover, expression of CD55 and CD59 by PC7 and PC9 cells was decreased after treatment with PI-PLC, resulting in increased susceptibility to cH18A-mediated CDC. Although the reason is unknown, PC7 cells became more susceptible to CDC than PC9 cells after PI-PLC treatment even in the absence of cH18A. These data suggest that chimeric monoclonal antibodies can be used to induce CDC against lung adenocarcinoma, and that such CDC is potentiated by a variety of antibodies blocking compliment-regulatory proteins on the tumour cell surface.
authors.affiliation: Fourth Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Azuma
authors.forename: Y
authors.initials: Y
authors.lastname: Yamano
authors.forename: A
authors.initials: A
authors.lastname: Yoshimura
authors.forename: T
authors.initials: T
authors.lastname: Hibino
authors.forename: T
authors.initials: T
authors.lastname: Nishida
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: T
authors.initials: T
authors.lastname: Seya
authors.forename: R
authors.initials: R
authors.lastname: Kannagi
authors.forename: M
authors.initials: M
authors.lastname: Shibuya
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000276:immunology*; D018958:CD55 Antigens; D018957:CD59 Antigens; D002461:Cell Line, Transformed; D006801:Humans; D007983:Lewis Blood Group Antigens / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C497857:CD46 protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins