title: The role of monoclonal antibody affinity in tumor immunotherapy evaluated in in vivo models for minimal residual disease.
abstract: To evaluate the role of affinity in monoclonal antibody (mAb)-mediated treatment of carcinomas, we compared the antibodies 17-1A and 323/A3 that bind with different affinities overlapping epitopes on the epithelial adhesion molecule Ep-CAM. This comparison was performed in several models for minimal residual disease in mice grafted with Ep-CAM transfected B16 melanoma cells originating from C57BL/6 mice. These cells were either grafted subcutaneously or injected intravenously into nude BALB/c mice, or grafted subcutaneously in immunocompetent C57BL/6 mice. In the BALB/c subcutaneous model, significant therapeutic results (p < 0.05) compared with the control mAb were obtained with both mAbs 17-1A and 323/A3. However, when treating lung metastases in nude BALB/c mice that had developed after intravenous injection of the B16/Ep-CAM tumor cells, only the high-affinity 323/A3 mAb could significantly (p < 0.05) reduce the number of metastases that appeared. In syngeneic C57BL/6 mice grafted subcutaneously with B16/ Ep-CAM cells, a single 323/A3 or 17-1A mAb injection had no effect, in contrast to that observed for the nude BALB/c mouse model. However, multiple injections of the 323/A3 mAb significantly (p < 0.005) reduced the mean tumor volume, although they did not prevent tumor development. The results show that in vivo antibody-mediated effector cell activation and subsequent tumor cell elimination is determined by mAb affinity and target antigen density. Therefore, treatment of minimal residual disease with high-affinity mAb 323/ A3 is expected to improve the clinical results obtained with mAb 17-1A.
authors.affiliation: Department of Pathology, Leiden University Hospital, The Netherlands.
authors.forename: M P
authors.initials: MP
authors.lastname: Velders
authors.forename: C M
authors.initials: CM
authors.lastname: van Rhijn
authors.forename: I M
authors.initials: IM
authors.lastname: Cornelissen
authors.forename: G N
authors.initials: GN
authors.lastname: van Muijen
authors.forename: I H
authors.initials: IH
authors.lastname: Briaire
authors.forename: M
authors.initials: M
authors.lastname: Dohlsten
authors.forename: G J
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: S O
authors.initials: SO
authors.lastname: Warnaar
authors.forename: S V
authors.initials: SV
authors.lastname: Litvinov
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000915:Antibody Affinity / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018365:Neoplasm, Residual / Q000628:therapy*; D012878:Skin Neoplasms / Q000628:therapy; D014162:Transfection / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal