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Improved Therapeutic Efficacy of a Monoclonal Antibody Radioiodinated Using N-Succinimidyl-3-(tri-n-butylstannyl)benzoate¹

Departments of Pathology [J. M. S., D. D. B., M. R. Z.] and Radiology [P. K. G., M. R. Z.] and the Preuss Brain Tumor Research Laboratory [D. D. B.], Duke University Medical Center, Durham, North Carolina 27710

Improvements in efficacy of radioimmunotherapy will require increased tumor uptake relative to normal tissue. We previously demonstrated that labeling the IgG2b glioma-reactive antitenascin monoclonal antibody 81C6 with ¹³¹I using N-succinimidyl-3-(tri-n-butylstannyl)benzoate (ATE) increased tumor uptake and tumor-to-normal tissue ratios and decreased deiodination compared with labeling using Iodo-Gen. The present study was conducted to determine whether ¹³¹I 81C6 labeled using ATE (81C6 ATE) would demonstrate a therapeutic advantage over ¹³¹I 81C6 labeled using Iodo-Gen (81C6 IOD) in treating s.c. D-54 MG human glioma xenografts in athymic mice. The subclass IgG2b MAb 45.6 labeled with ¹³¹I using ATE (45.6 ATE) was used as a control. Animals were injected with saline or 500 µCi of 45.6 ATE (23 µCi/µg), 81C6 ATE (26 µCi/µg), or 81C6 IOD (24 µCi/µg). With approximately 150 mm³ initial tumor volumes, growth delay for 81C6 ATE was significantly better by Wilcoxon rank sum analysis than saline (P = 0.0006 to 0.003), 45.6 ATE (P = 0.0006 to 0.002), and 81C6 IOD (P = 0.0008 to 0.007). Biodistribution data from similarly injected animals gave estimated radiation doses to tumor of 7723, 5200, and 1667 rad for 81C6 ATE, 81C6 IOD, and 45.6 ATE, respectively. In addition, 81C6 ATE administered at this dosage to animals with 50% larger initial tumors also improved tumor growth delay in comparison with 81C6 IOD given to animals with standard-size tumors. A similar experiment was conducted at 1000 µCi and, although radiation toxicity was noted in all labeled groups, two animals in the 81C6 ATE group had tumor regression for more than 240 days, and the other groups had no regressors. We conclude that the use of the ATE method may significantly improve the therapeutic efficacy of radioiodinated monoclonal antibodies.

¹ This work was supported by Research Grants CA 42324, CA 11898, and CA 14236 from the National Cancer Institute and by NS 20023 from the National Institute of Neurological Diseases and Stroke, NIH. J. M. S. is a recipient of a Howard Hughes Medical Institute Predoctoral Fellowship in Biological Sciences.

² To whom requests for reprints should be addressed, at Box 3808, Duke University Medical Center, Durham, NC 27710.

Received 2/19/91. Accepted 6/ 5/91.

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