RADIOIMMUNOTHERAPY OF NUDE-MICE BEARING A HUMAN INTERLEUKIN-2 RECEPTOR ALPHA-EXPRESSING LYMPHOMA UTILIZING THE ALPHA-EMITTING RADIONUCLIDE-CONJUGATED MONOCLONAL-ANTIBODY BI-212-ANTI-TAC

The efficacy, specificity, and toxicity of bismuth (Bi-212) alpha part icle-mediated radioimmunotherapy was evaluated in nude mice bearing a murine lymphoma transfected with the human CD25 [human Tac; interleuki n 2 receptor alpha (IL-2R alpha)] gene, The therapeutic agent used was the tumor-specific humanized monoclonal antibody anti-Tac conjugated to Bi-212. The human IL-2R alpha-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 approxima tely 18,000 human IL-2R alpha molecules/cell. Following s.c. or i.p. i njection of 2 x 10(6) SP2/Tac cells into nude mice, rapidly growing tu mors developed in all animals after a mean of 10 and 13 days, respecti vely. The bifunctional chelate cyclohexyldiethylenetriaminepentaacetic acid was used to couple Bi-212 to the humanized anti-Tac monoclonal a ntibody. This immunoconjugate was shown to be stable in vivo. Specific ally, in pharmacokinetic studies in nude mice, the blood clearance pat terns of i.v. administered Bi-205/206-anti-Tac and coinjected I-125-an ti-Tac were comparable. The toxicity and therapeutic efficacy of Bi-21 2-anti-Tac were evaluated in nude mouse ascites or solid tumor models wherein SP2/Tac cells were administered either i.p. or s.c., respectiv ely. The i.p. administration of Bi-212-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 mu Ci prevented tumor occu rrence in 75% (95% confidence interval, 41-93%) of the animals. In the second model, i.v. treatment with Bi-212-anti-Tac 3 days following s. c. tumor inoculation also resulted in a prolongation of the period bef ore tumor development. However, prevention of tumor occurrence decreas ed to 30% (95% confidence interval, 11-60%). In both the i.p. and s.c. tumor trials, Bi-212-anti-Tac was significantly more effective for i. p. (P2 = 0.0128 50/100 mu Ci Bi-212-anti-Tac versus 50/100 mu Ci Mik b eta; P2 = 0.0142 150/200 mu Ci anti-Tac versus 150/200 mu Ci Mik beta) and for s.c. tumors (P2 = 0.0018 100 mu Ci anti-Tac versus 100 mu Ci Mik beta; P2 = 0.0042 200 mu Ci anti-Tac versus 200 mu Ci Mik beta 1) than the control antibody Mik beta 1 coupled to Bi-212 at comparable d ose levels. In contrast to the efficacy observed in the adjuvant setti ng, therapy of large, established s.c. SP-2/ Tac-expressing tumors wit h i.v. administered Bi-212-anti-Tac (at doses up to 200 mu Ci/animal) failed to induce tumor regression. Pharmacokinetic and tissue distribu tion studies of radiolabeled anti-Tac in this particular therapeutic s ituation provided an explanation for this observation. Only 5-6% of th e injected dose of radiolabeled antibody was present per g of tumor at 2 h following injection at a time when 75% of the administered Bi-212 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 specif ic antibody Bi-212/206-anti-Tac was not enriched in the tumor when com pared to the irrelevant monoclonal antibody Bi-205/206-Mik beta 1. Alt hough 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 postinjec tion with up to 15.6% injected dose present per g of tumor. The dose l imiting acute toxicity following i.v. administration of Bi-212 anti-Ta c was bone marrow suppression, which was observed at doses above 200 m u Ci. In summary, Bi-212-anti-Tac as a complete antibody may be of onl y limited value in the therapy of bulky solid tumors due to the short physical half-life of Bi-212 and the time required to achieve a useful tumor:normal tissue ratio of the radionuclide following administratio n of the radiolabeled antibody. However, this radionuclide may be usef ul in select situations such as adjuvant or intracavitary therapy, str ategies that target the vascular endothelial cells of tumors, or in th e treatment of leukemias.