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Departments of Pediatrics [K. D.], Medicine [S. K. A., O. P.], and Biological Structure [S. K. A., O. P.], University of Washington, Seattle, Washington 98195; the Fred Hutchinson Cancer Research Center [K. D., O. P.], Seattle, Washington 98104; Geneatech, San Francisco, California [M. S., B. F., D. M.] 94080; and Department of Medicine, UCLA, Los Angeles, California 90024 [D. S.]
The HER-2/neu oncogene encodes a Mr 185,000 transmembrane phosphoglycoprotein which is overexpressed in 25–35% of breast and ovarian neoplasms and portends a poor prognosis. We have studied the feasibility of targeting this oncoprotein, designated p185, with radioiodinated murine monoclonal antibodies (muMABs) 4D5 and 7C2, which recognize distinct epitopes on its extracellular domain. The rates of internalization and catabolism of these antibodies were analyzed by cellular radioimmunoassay and electron microscopy. After binding to NIH3T3 HER-2/neu cells, which show high surface expression of p185, the muMABs were endocytosed via coated pits, routed to lysosomes, and degraded. Approximately 44% of 125I-4D5 and 39% of 125I-7C2 were catabolized by tumor cells after 24 h.
The biodistribution of radiolabeled 4D5 and 7C2 were evaluated in beige/nude mice bearing s.c. NIH3T3 HER-2/neu grafts. A high specificity of localization was seen with tumor:organ ratios of activity generally ranging from 5:1 to 30:1. However, the percentage injected dose of radioactivity per gram of tumor declined sharply from 25% at 24 h to 5% at 120 h postinjection. Treating the animals with 400–700 µCi 131I-4D5 caused a marked inhibition of tumor growth, although no mice were cured. Unlabeled 4D5 had no effect on tumor progression in this model, but administering 400–700 µCi of 131I-DA4-4, an isotype-matched irrelevant muMAB, resulted in an intermediate degree of growth retardation. Analysis of kinetic blood data and whole-body time-activity curves indicated that the irrelevant conjugate remained in the body 2–3 times longer than 131I-4D5. Radioiodinated anti-HER-2/neu muMABs are attractive agents for radioimmunodiagnosis and radioimmunotherapy of aggressive HER-2/neu-positive breast and ovarian carcinomas, but effective strategies for retarding intratumoral catabolism may be necessary to optimize their clinical utility.
1 This work was supported by Grants DE-FG06-88ER60719 from the Department of Energy, R01CA55596-01 from the NIH, and IN-26-32 from the American Cancer Society and a stipend from the RGK Foundation.
2 To whom requests for reprints should be addressed, at Mailstop RC-08, University of Washington Cancer Center, Seattle, WA 98195.
Received 6/21/91. Accepted 1/23/92.
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