RADIOLABELED ANTIBODY TARGETING OF THE HER-2 NEU ONCOPROTEIN/

The HER-2/neu oncogene encodes a M(r) 185,000 transmembrane phosphogly coprotein which is overexpressed in 25-35% of breast and ovarian neopl asms and portends a poor prognosis. We have studied the feasibility of targeting this oncoprotein, designated p185, with radioiodinated muri ne monoclonal antibodies (muMABs) 4D5 and 7C2, which recognize distinc t epitopes on its extracellular domain. The rates of internalization a nd catabolism of these antibodies were analyzed by cellular radioimmun oassay and electron microscopy. After binding to NIH3T3 HER-2/neu cell s, which show high surface expression of p185, the muMABs were endocyt osed via coated pits, routed to lysosomes, and degraded. Approximately 44% of I-125-4D5 and 39% of I-125-7C2 were catabolized by tumor cells after 24 h. The biodistribution of radiolabeled 4D5 and 7C2 were eval uated in beige/nude mice bearing s.c. NIH3T3 HER-2/neu grafts. A high specificity of localization was seen with tumor:organ ratios of activi ty generally ranging from 5:1 to 30:1. However, the percentage injecte d 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- mu-Ci I-131-4D5 caused a marked inhibition of tumor growth, although n o mice were cured. Unlabeled 4D5 had no effect on tumor progression in this model, but administering 400-700-mu-Ci of I-131-DA44, an isotype -matched irrelevant muMAB, resulted in an intermediate degree of growt h retardation. Analysis of kinetic blood data and whole-body time-acti vity curves indicated that the irrelevant conjugate remained in the bo dy 2-3 times longer than I-131-4D5. Radioiodinated anti-HER-2/neu muMA Bs are attractive agents for radioimmunodiagnosis and radioimmunothera py of aggressive HER-2/neu-positive breast and ovarian carcinomas, but effective strategies for retarding intratumoral catabolism may be nec essary to optimize their clinical utility.