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Improved Biodistribution of ¹²⁵I-labeled Anti-Tac Disulfide-stabilized Fv Fragment by Blocking Its Binding to the Subunit of the Interleukin 2 Receptor in the Circulation with Preinjected Humanized Anti-Tac IgG

Department of Nuclear Medicine [H. K., T. M. Y., D. D., M. K. K., B. F. S., N. L., C. H. P., J. A. C.], Warren G. Magnuson Clinical Center, and Laboratory of Molecular Biology, Division of Basic Sciences [K. O. W., I. P.] and Metabolism Branch, Division of Clinical Sciences, [T. A. W.], National Cancer Institute, NIH, Bethesda, Maryland 20892-1180

Animal studies using radiolabeled anti-Tac disulfide-stabilized Fv (dsFv) monoclonal antibody have shown formation of complexes in serum with the soluble subunit of the interleukin 2 receptor (sIL-2R). In this study, we improved the targeting of ¹²⁵I-labeled anti-Tac dsFv to receptor-positive tumors in the presence of circulating receptor by prein-jecting unlabeled humanized anti-Tac IgG antibody (HuTac IgG). We used mice bearing SP2/Tac tumor xenografts that express the IL-2R. A positive correlation was seen between tumor size and the concentration of circulating receptor. Tumor-bearing mice were injected with ¹²⁵I-labeled anti-Tac dsFv (400 ng), either alone or 15 min after injection of HuTac IgG. The ¹²⁵I-labeled anti-Tac dsFv formed high molecular weight complexes with the sIL-2R. The fraction of the dsFv present in the complexes increased as tumor size increased (greater sIL-2R levels). The fractions of dsFv in the complexes were 9.9- to 11.6-fold higher when sIL-2R was not blocked with preinjected HuTac IgG. The administration of a 12-fold molar excess of HuTac IgG over sIL-2R resulted in >80% of the ¹²⁵I activity present as the dsFv rather than in the complexes. Furthermore, the biodistribution of ¹²⁵I-labeled anti-Tac dsFv was improved by blocking its binding to sIL-2R by preinjecting HuTac IgG. Specifically, in the preinjected group, at 15 min postinjection, the ¹²⁵I-labeled anti-Tac dsFv levels in tumor increased to 10.8% compared to 5.6% injected dose per gram in the non-preinjected group. In summary, our studies showed that preinjection of HuTac IgG can block the formation of complexes of circulating sIL-2R and ¹²⁵I-labeled anti-Tac dsFv. This blockade is associated with faster blood clearance, higher tumor uptake, and greater tumor:nontumor ratios of the radiolabeled antibody fragment.

¹ To whom requests for reprints should be addressed, at Nuclear Medicine Department, Bldg. 10, Room IC496, NIH, 10 Center Drive, Bethesda, MD 20892-1180. Phone: (301) 496-5675; Fax: (301) 496-0114.

Received 10/23/96. Accepted 3/24/97.