Over-expression of tyrosine kinase cell surface receptors p185neu/c-erbB2 is associated with a variety of human tumor cell-types. Several monoclonal antibodies which specifically recognize these receptors and result in disruption of tumor cell growth have been characterized. However, the clinical use of these antibodies has been hindered by the human anti-mouse antibody (HAMA) response to these foreign proteins. Additionally, animal models which over-express these tyrosine kinase receptors have not been developed or well characterized. During the first three years of this proposal, Dr. Peterson will receive training in recombinant DNA techniques, computer modeling, and biochemical and immunological methods to develop small bioactive polypeptides which are specific to p185neu/c-erbB2 and EGFR. These compounds will then be compared to their parental antibodies for their ability to mediate alterations in tumor cell physiology and growth inhibition and to further elucidate mechanisms of receptor mediated cell transformation. Additionally, because of their smaller size, these bioactive polypeptides are likely to be less immunogenic and may potentially serve as diagnostic and therapeutical agents in the treatment of cancer. The second objective of this project will address the development of animal models which are needed for comparative studies of p185new/c-erB2 and EGFR mediated cell transformation and to evaluate the in vivo effectiveness of those compounds which were developed during the first three years of this project. In order to meet this objective, Dr. Peterson will learn and develop immunohistochemical staining techniques in order to analyze paraffin embedded and frozen animal tumor specimens for over-expression of p185neu/c-erbB2 and/or EGFR. During years four and five, a variety of tumor specimens from different species obtained from the Veterinary Hospital of the University of Pennsylvania (VHUP), University Laboratory Animal Resources(ULAR), and various pharmaceutical companies in the vicinity will be analyzed for over-expression of p185neu/cerbB2 and EGFR. Once a particular species which develops tumors of the specified type are identified, normal tissues of that species will be analyzed for receptor over-expression. Additionally, tumor localization, tissue distribution, and plasma clearance of the compounds will be analyzed initially in xenografted athymic mice, and later in animal models and VHUP cancer patients whose tumor cells are positive for over-express p185neu/c-erbB2 and/or EGFR. Ultimately, the results of this work will provide useful insights in the study of comparative oncology and may lead to the development of effective compounds for the diagnosis and treatment of cancer.
| Peterson, N C (1996) Recombinant antibodies: alternative strategies for developing and manipulating murine-derived monoclonal antibodies. Lab Anim Sci 46:8-14 |
