title: Enhancement of the complement activating capacity of 17-1A mAb to overcome the effect of membrane-bound complement regulatory proteins on colorectal carcinoma.
abstract: Adjuvant immunotherapy with 17-1A mAb directed against colorectal carcinoma is found to be effective in patients. However, 52 % of the patients treated with mAb 17-1A showed recurrence within 7 years. This high recurrence rate might be due to inhibition of complement activation by membrane-bound complement regulatory proteins (mCRP). The effect of these complement regulatory proteins might be reduced by blocking mCRP, or be overcome by activating more complement at the tumor cell membrane. In this study the complement-activating capacity of the 17-1A mAb was enlarged by conjugating it to cobra venom factor (CVF) or C3b. The most important C3 regulatory protein, CD55, was blocked using a bispecific mAb directed against the 17-1A / Ep-CAM antigen and CD55. Up to a 13-fold increase in C3 deposition was observed due to 17-1A-CVF and 17-1A-C3b, as compared to 17-1A. CD55 was shown to partly inhibit complement activation by these conjugates. The effect of the bispecific anti-17-1A / Ep-CAM*anti-CD55 mAb was compared with 17-1A conjugates with CVF or C3, and bispecific mAb were shown to be equally or more efficient in complement activation than the 17-1A-CVF or 17-1A-C3b conjugates. Therefore, 17-1A conjugates and anti-17-1A / EpCAM*anti-CD55 bispecific mAb may be promising immunotherapeutic agents for patients with colorectal cancer.
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: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: Wouter
authors.initials: W
authors.lastname: Bruin
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: Arko
authors.initials: A
authors.lastname: Gorter
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D018958:CD55 Antigens / Q000096:biosynthesis / Q000276:immunology*; D018957:CD59 Antigens / Q000096:biosynthesis / Q000276:immunology*; D018938:Caco-2 Cells; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology*; D003179:Complement C3b / Q000276:immunology*; D004546:Elapid Venoms / Q000276:immunology*; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C497857:CD46 protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D015815:Cell Adhesion Molecules; D004546:Elapid Venoms; D000071858:Epithelial Cell Adhesion Molecule; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; C016310:cobra venom factor; D003179:Complement C3b