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[Cancer Research 64, 6200-6206, September 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

A Single Treatment of Yttrium-90-labeled CHX-A''–C6.5 Diabody Inhibits the Growth of Established Human Tumor Xenografts in Immunodeficient Mice

Gregory P. Adams1, Calvin C. Shaller1, Ekaterina Dadachova2, Heidi H. Simmons1, Eva M. Horak1, Abohawariat Tesfaye1, Andres J. P. Klein-Szanto1, James D. Marks3, Martin W. Brechbiel2 and Louis M. Weiner1

1 Divison of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania; 2 Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, Maryland; and 3 Department of Anesthesiology and Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California

Antitumor diabody molecules are noncovalent single-chain Fv dimers that recapitulate the divalent binding properties of native IgG antibodies. Diabodies are capable of substantial accumulation in tumor xenografts expressing relevant antigens in immunodeficient mouse models. With a Mr of approximately 55,000, diabodies are rapidly cleared from the circulation, resulting in tumor-to-blood ratios that significantly exceed those achieved early after the administration of monoclonal antibodies. We have evaluated the therapeutic potential of the ß-emitting isotope yttrium-90 (t1/2, 64 hours) conjugated to the C6.5K-A diabody that specifically targets the HER2/neu human tumor-associated antigen. We have found that a single intravenous dose of 150 µCi (200 µg) 90Y-CHX-A''–C6.5K-A diabody substantially inhibits the growth rates of established MDA-361/DYT2 human breast tumor xenografts in athymic nude mice. In contrast, 300 µCi (300 µg) 90Y-CHX-A''–C6.5K-A diabody resulted in only a minor delay in the growth of SK-OV-3 human ovarian cancer xenografts. The maximum tolerated dose was also dependent on the tumor xenograft model used. These studies indicate that genetically engineered antitumor diabody molecules can be used as effective vehicles for radioimmunotherapy.




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