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Radioimmunotherapy of A431 Xenografted Mice with Pretargeted B3 Antibody-Streptavidin and ⁹⁰Y-labeled 1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic Acid (DOTA)-Biotin

Nuclear Medicine Department of the Warren G. Magnuson Clinical Center [Z. Y., K. J. W., L. P., C. W. P., C. H. P., J. A. C.], Metabolism Branch [M. Z., T. A. W.], Radiation Oncology Branch [K. G., M. W. B.], and Laboratory of Molecular Biology [I. P.], National Cancer Institute, NIH, Bethesda, Maryland 20892, and NeoRx Corporation, Seattle, Washington 98119 [D. B. A., R. W. M., L. J. T., E. K. Y.]

We investigated the biodistribution of ⁸⁸Y/¹¹¹In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-biotin and therapy with ⁹⁰Y-labeled DOTA-biotin in tumor-bearing mice after B3-streptavidin antibody conjugate (B3-SA) pretargeting. B3 antibody, recognizing Lewis^y antigen, was conjugated to streptavidin (B3-SA). For pretargeting, 400 µg of the B3-SA was injected i.v. into mice bearing A431 tumor xenografts. After tumor localization of B3-SA, 100 µg of synthetic clearing agent was injected i.v. to clear the unbound B3-SA from the circulation. Four h later, 1 µg of radiolabeled DOTA-biotin was injected i.v. Radioimmunotherapy was performed with doses of 9.25 to 37 MBq of ⁹⁰Y-labeled DOTA-biotin. As a result, radiolabeled DOTA-biotin cleared rapidly. All of the normal tissues had <2.6% of the injected dose per gram, whereas tumor uptake reached 15% ID/g. The total tumor uptake of radioactivity remained similar for 96 h or longer. In the first study, the median survival of the control group was 8 days, whereas it increased to >163 days in the 37 MBq ⁹⁰Y group (P < 0.005). In a second therapy group, 7 of 10 mice receiving 37 MBq of ⁹⁰Y and B3-SA were cured, and remained healthy for >180 days after therapy, compared with control groups, with 29.2 days mean survival time (P < 0.001). Tumor pretargeting with B3-SA and radiolabeled DOTA-biotin has shown favorable, specific, and fast targeting that has resulted in good tumor responses and, thus, serves as a rationale for human studies with the B3-SA pretargeting approach.

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