title: Paradoxical concentration effect of a homodimerizing antibody against a human non-small cell lung cancer cell line.
abstract: Drug dosing is commonly based on the dogma that, increasing the dose maximizes the therapeutic response until a dose level that is prohibitively toxic is reached. This doctrine also applies to antibody therapy, as several protocols have explored dose escalation. We have analyzed the effect of different amounts of a homophilic Herceptin targeting a human lung tumor cell line, and discovered that the normal dose-potency relationship does not apply. To study this paradoxical effect of antibody concentration on potency, we examined the molecular species of the homophilic Herceptin under different concentrations using size exclusion chromatography and gel electrophoresis. We also varied experimental conditions in FACS tumor targeting, such as concentration of antibody, membrane immobilization, temperature, and antibody homo/dimer immobilization. We observed that high concentrations of homophilic Herceptin reduce targeting, and also noted the tumor growth arrest in the xenograft mice after the tumor reached a critical size. The therapeutic window appears to be defined by tumor size and antibody concentration. Since the concentration of this homophilic antibody defines the optimum targeting window, our data suggest the therapeutic dose of antibody should be matched with the tumor burden.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. hkohl00@uky.edu
authors.forename: Heinz
authors.initials: H
authors.lastname: Kohler
authors.forename: Ann Jay
authors.initials: AJ
authors.lastname: Bryan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000737:chemistry / Q000276:immunology*; D000915:Antibody Affinity; D000951:Antigens, Neoplasm / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology*; D019281:Dimerization; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013696:Temperature; D000068878:Trastuzumab; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab