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Center for Molecular Medicine and Immunology, Belleville, New Jersey

Requests for reprints: M. Jules Mattes, Garden State Cancer Center, Center for Molecular Medicine and Immunology, 520 Belleville Avenue, Belleville, NJ 07109. Phone: 973-844-7013; Fax: 973-844-7020. E-mail: mjmattes{at}gscancer.org

Antibodies conjugated to radionuclides emitting low-energy electrons, which include Auger electrons and some conversion electrons, were recently shown to efficiently kill cells bearing a high density of the antigen recognized. The primary purpose of this study was to determine if such killing could be obtained with anti–HER-2 antibodies conjugated to ¹¹¹In, using the chelator benzyl-diethylenetriaminepentaacetic acid, or ¹²⁵I. Target cells were the breast carcinoma SK-BR-3 and the ovarian carcinoma SK-OV-3.ip1. In preliminary experiments, antibody accumulation and catabolism during a 2- to 3-day incubation with antibody was investigated. The level of antibody uptake, in terms of molecules per cell, was high enough such that killing seemed feasible. With an ¹²⁵I label, but not an ¹¹¹In label, increasing the antibody concentration past a certain point caused a decrease in total antibody accumulation, which might be attributed to effects of antibody binding. To test for cytotoxicity, cells were incubated for 2 days with the labeled antibody, then assayed for colony-forming units with a limiting dilution assay. SK-BR-3 cells were strongly killed (3 logs) by antibody 21.1, and 100% kill was obtained by combining two noncompeting antibodies to HER-2 (21.1 and 4D5). SK-OV-3.ip.1 cells were more resistant to killing, but use of the two-antibody mixture produced a surviving fraction of 0.002. ¹¹¹In-labeled antibodies to other high-density antigens, epithelial glycoprotein-1 and epithelial glycoprotein-2, also killed these target cells. In contrast, unlabeled antibodies or a nonreactive-labeled antibody produced much less cytotoxicity. The same experiment with an ¹³¹I label (a ß-particle emitter) resulted in much greater levels of nonspecific cytotoxicity and essentially no specific cytotoxicity. This approach may be effective for therapy of micrometastases.

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² http://ubik.microbiol.washington.edu/computing/quality/jquality.htm

Received 12/17/04; revised 3/31/05; accepted 4/12/05.