title: Application and potential limitations of animal models utilized in the development of trastuzumab (Herceptin): a case study.
abstract: The preclinical and clinical development of trastuzumab, a humanized monoclonal antibody directed against a juxtamembrane epitope in the HER2 receptor ectodomain, relied heavily on the use of animal models to validate HER2 as a potential MAb target. The identification of HER2 (neu) as a proto-oncogene was first established in a carcinogen-induced brain tumor in the rat. Transgenic mouse technology led to an understanding of the role of HER2 in pathogenesis of breast cancer. Transfection studies of human HER2 cDNA into murine xenograft models further explored the role HER2 plays in tumor progression and metastasis. A murine subrenal capsule fresh human tumor explant assay was utilized to test efficacy of various murine monoclonal anti-HER2 antibodies, and the data were helpful in choosing the most efficacious for subsequent human engineering for clinical use. HER2-overexpressing xenograft models in athymic mice were used to test the efficacy of anti-HER2 antibodies, develop dose-response relationships, measure drug interactions between trastuzumab and chemotherapy, and optimize dosing schedules of chemotherapeutics combined with trastuzumab. In this work, we will highlight the utility of animal models exploited in the development of trastuzumab - noting not only their contribution to drug development but also their limitations in translation of preclinical data into the clinic. It is likely that the experience we gained in the case of preclinical animal models to study in vivo effects of trastuzumab have parallels in the development of other monoclonal antibodies since overcoming the species boundaries (i.e. cross-reactivity with antigenic determinant, development of cross-species neutralizing antibodies, and cross-species interaction with activating Fc receptors on immune effector cells) are major limitations in the design and interpretation of preclinical/translational experiments designed to fulfill various regulatory requirements prior to initiation of phase I human clinical trials.
authors.affiliation: University of California Los Angeles, David Geffen School of Medicine UCLA Center for the Health Sciences Los Angeles, CA, United States. mpegram@ucla.edu
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
authors.forename: Debbie
authors.initials: D
authors.lastname: Ngo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D009368:Neoplasm Transplantation; D000090063:Proto-Oncogene Mas; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D000068878:Trastuzumab