title: The inhibitory effect of CD46, CD55, and CD59 on complement activation after immunotherapeutic treatment of cervical carcinoma cells with monoclonal antibodies or bispecific monoclonal antibodies.
abstract: The role of membrane-bound complement regulatory proteins (mCRP) in the protection of tumor cells in vivo against elimination by the immune system is still unknown. In this study the effect of expression of these mCRP by cervical cancer cells was investigated. In situ expression of mCRP was observed on cervical carcinomas, normal cervical epithelial cells, and the surrounding stroma. Deposition of C3 and C5b-9 was sporadically found on the tumor cells and the surrounding stroma. A low expression of CD46 was statistically significantly associated with deposition of C3. Comparable expression patterns were shown on primary cervical tumor cell suspensions. A relatively high deposition of C4c was found on these tumor cells, indicating classical pathway activation. Furthermore, it was demonstrated that CD55 and CD59 were the most potent inhibitors of C3 deposition and classical pathway-mediated lysis, respectively, on cervical cancer cell lines. The feasibility of increasing complement activation at the tumor cell membrane surface was demonstrated with an anti-HLA Class I*anti-CD55 bispecific mAb. The potential immunotherapeutic applicability was investigated with both anti-G250*anti-CD55 and anti-Ep-CAM*anti-CD55 bispecific mAbs. An approximate 2-fold increase in C3 deposition, compared with the parental anti-Ep-CAM mAb, was attained with an anti-Ep-CAM*anti-CD55 bispecific mAb when the tumor-associated antigen was expressed in sufficient amounts. These results demonstrate that when tumor-associated antigens are expressed in adequate amounts, bispecific mAbs in vivo may be potent immunotherapeutic agents to enhance an inflammatory reaction at the tumor site.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. K.Gelderman@lumc.nl
authors.forename: Kyra A
authors.initials: KA
authors.lastname: Gelderman
authors.forename: Vanessa T
authors.initials: VT
authors.lastname: Blok
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: Arko
authors.initials: A
authors.lastname: Gorter
mesh_terms: D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D018958:CD55 Antigens / Q000276:immunology*; D018957:CD59 Antigens / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000276:immunology; D003167:Complement Activation / Q000187:drug effects*; D003176:Complement C3 / Q000096:biosynthesis; D015938:Complement Membrane Attack Complex / Q000096:biosynthesis; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000276:immunology*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C497857:CD46 protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D015815:Cell Adhesion Molecules; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D000071858:Epithelial Cell Adhesion Molecule; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; C400566:antigen G250