title: Light chain variants of an IgG3 anti-GD3 monoclonal antibody and the relationship among avidity, effector functions, tumor targeting, and antitumor activity.
abstract: R24 is an IgG3 mouse monoclonal antibody which recognizes the ganglioside GD3. Two variants of R24, in which one (V2-R24) or both (V1-R24) light chains were substituted by MOPC-21 light chains, were isolated and characterized. R24 had a 40-fold higher avidity for GD3 than either variant, suggesting that high avidity binding required the presence of two R24 light chains and, thus, divalency. R24 and both variants mediated antibody-dependent cellular cytotoxicity but antibody-dependent cellular cytotoxicity mediated by variants was weak compared to R24. The presence of at least one R24 light chain was required for complement-dependent cytotoxicity; complement-dependent cytotoxicity was mediated by R24 and weakly by V2-R24 but not by V1-R24. R24, but not V1-R24 or V2-R24, inhibited attachment of melanoma cells to plastic and activated T-lymphocytes, suggesting a threshold of avidity required for these biological effects. In a human melanoma xenograft model in nu/nu mice, radiolabeled R24, variants, and isotype-matched control monoclonal antibodies all appeared to localize in tumors (based on tumor:normal tissue ratios), but specific tumor targeting by R24 was generally 3- to 6-fold higher. R24 prevented melanoma outgrowth in nu/nu mice, while V2-R24 induced partial tumor protection. V1-R24 and the negative control monoclonal antibody did not inhibit tumor outgrowth. Antitumor activity of R24 corresponded to avidity and ability to mediate complement-dependent cytotoxicity in vitro.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
authors.forename: P B
authors.initials: PB
authors.lastname: Chapman
authors.forename: M
authors.initials: M
authors.lastname: Lonberg
authors.forename: A N
authors.initials: AN
authors.lastname: Houghton
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis* / Q000276:immunology / Q000493:pharmacokinetics; D000915:Antibody Affinity / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis* / Q000276:immunology / Q000493:pharmacokinetics; D007147:Immunoglobulin Light Chains / Q000032:analysis* / Q000276:immunology; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D005732:Gangliosides; D007074:Immunoglobulin G; D007147:Immunoglobulin Light Chains; C026226:ganglioside, GD3