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Radioimmunotherapy of Nude Mice Bearing a Human Interleukin 2 Receptor -expressing Lymphoma Utilizing the -emitting Radionuclide-conjugated Monoclonal Antibody ²¹²Bi-anti-Tac

Metabolism Branch [F. H., E. M. H., D. L. N., T. A. W.] and Inorganic and Radioimmune Chemistry Section [K. G., C. W., M. W. B., O. A. G.], Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892; Division for Monoclonal Antibodies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892 [R. W. K.]; and Protein Design Labs, Inc., Mountain View, California 94043 [J. T., S. A. K.]

The efficacy, specificity, and toxicity of bismuth (²¹²Bi) particle-mediated radioimmunotherapy was evaluated in nude mice bearing a murine lymphoma transfected with the human CD25 [human Tac; interleukin 2 receptor (IL-2R)] gene. The therapeutic agent used was the tumor-specific humanized monoclonal antibody anti-Tac conjugated to ²¹²Bi.

The human IL-2R-expressing cell line was produced by transfecting the gene encoding human Tac into the murine plasmacytoma cell line SP2/0. The resulting cell line, SP2/Tac, expressed approximately 18,000 human IL-2R molecules/cell. Following s.c. or i.p. injection of 2 x 10⁶ SP2/Tac cells into nude mice, rapidly growing tumors developed in all animals after a mean of 10 and 13 days, respectively. The bifunctional chelate cyclohexyldiethylenetriaminepentaacetic acid was used to couple ²¹²Bi to the humanized anti-Tac monoclonal antibody. This immunoconjugate was shown to be stable in vivo. Specifically, in pharmacokinetic studies in nude mice, the blood clearance patterns of i.v. administered ^205/206Bi-anti-Tac and coinjected ¹²⁵I-anti-Tac were comparable. The toxicity and therapeutic efficacy of ²¹²Bi-anti-Tac were evaluated in nude mouse ascites or solid tumor models wherein SP2/Tac cells were administered either i.p. or s.c., respectively. The i.p. administration of ²¹²Bi-anti-Tac, 3 days following i.p. tumor inoculation, led to a dose-dependent, significant prolongation of tumor-free survival. Doses of 150 or 200 µCi prevented tumor occurrence in 75% (95% confidence interval, 41–93%) of the animals. In the second model, i.v. treatment with ²¹²Bi-anti-Tac 3 days following s.c. tumor inoculation also resulted in a prolongation of the period before tumor development. However, prevention of tumor occurrence decreased to 30% (95% confidence interval, 11–60%). In both the i.p. and s.c. tumor trials, ²¹²Bi-anti-Tac was significantly more effective for i.p. (P2 = 0.0128 50/100 µCi ²¹²Bi-anti-Tac versus 50/100 µCi Mikß; P2 = 0.0142 150/200 µCi anti-Tac versus 150/200 µCi Mikß) and for s.c. tumors (P2 = 0.0018 100 µCi anti-Tac versus 100 µCi Mikß; P2 = 0.0042 200 µCi anti-Tac versus 200 µCi Mikß1) than the control antibody Mikß1 coupled to ²¹²Bi at comparable dose levels. In contrast to the efficacy observed in the adjuvant setting, therapy of large, established s.c. SP-2/Tac-expressing tumors with i.v. administered ²¹²Bi-anti-Tac (at doses up to 200 µCi/animal) failed to induce tumor regression. Pharmacokinetic and tissue distribution studies of radiolabeled anti-Tac in this particular therapeutic situation provided an explanation for this observation. Only 5–6% of the injected dose of radiolabeled antibody was present per g of tumor at 2 h following injection at a time when 75% of the administered ²¹²Bi radioactivity had decayed. Furthermore, at this time point, there was no greater uptake of Bi-anti-Tac into Tac-expressing tumors than was observed with Tac-nonexpressing variants of SP2/0. Finally, the specific antibody ^205/206Bi-anti-Tac was not enriched in the tumor when compared to the irrelevant monoclonal antibody ^205/206Bi-Mikß1. Although specific enrichment of radiolabeled Bi-anti-Tac was not seen at 2 h, such enrichment in the tumor was observed at 5 and 24 h postinjection with up to 15.6% injected dose present per g of tumor. The dose-limiting acute toxicity following i.v. administration of ²¹²Bi-anti-Tac was bone marrow suppression, which was observed at doses above 200 µCi.

In summary, ²¹²Bi-anti-Tac as a complete antibody may be of only limited value in the therapy of bulky solid tumors due to the short physical half-life of ²¹²Bi and the time required to achieve a useful tumor:normal tissue ratio of the radionuclide following administration of the radiolabeled antibody. However, this radionuclide may be useful in select situations such as adjuvant or intracavitary therapy, strategies that target the vascular endothelial cells of tumors, or in the treatment of leukemias.

¹ Present address: Innere Medizin I, Universitätskliniken des Saarlandes, D-66421 Homburg/Saar, Germany.

² To whom requests for reprints should be addressed, at Metabolic Branch, National Cancer Institute, Building 10, Room 4N115, NIH, Bethesda, MD 20892.

Received 12/13/93. Accepted 6/10/94.

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