Radiolabeled antibody targeting of the HER-2/neu oncoprotein
| Autor: | De Santes K, Slamon D, Sk, Anderson, Shepard M, Fendly B, Maneval D, Oliver Press |
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| Rok vydání: | 1992 |
| Předmět: |
Male
Ovarian Neoplasms Receptor ErbB-2 Antibodies Monoclonal Mice Nude Breast Neoplasms 3T3 Cells Protein-Tyrosine Kinases Radioimmunotherapy Transfection Iodine Radioisotopes Mice Cell Transformation Neoplastic Immunoglobulin G Proto-Oncogene Proteins Proto-Oncogenes Animals Autoradiography Female Tissue Distribution Microscopy Immunoelectron Neoplasm Transplantation |
| Zdroj: | Europe PubMed Central |
| ISSN: | 0008-5472 |
| Popis: | 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 muCi 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 muCi 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. |
| Databáze: | OpenAIRE |
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