ENHANCEMENT OF CU-67-2IT-BAT-LYM-1 THERAPY IN MICE WITH HUMAN BURKITTS-LYMPHOMA (RAJI) USING INTERLEUKIN-2

BACKGROUND. Lymphomas have been shown to be responsive to I-131 immuno conjugates in studies conducted in mice and patients. We have observed that copper 67 (Cu-67)-labeled Lym-1 remains in lymphomatous tissue l onger than I-131-Lym-1 and, consequently, results in higher absorbed r adiation doses to tumors. In addition, recombinant interleukin-2 (rIL- 2) has been reported to increase tumor uptake of radiolabeled antibody . Therefore, we examined the efficacy of Cu-67-labeled Lym-1 and the a bility of rIL-2 to enhance this efficacy in athymic mice implanted wit h Raji xenografts. METHODS. 6[p-(bromoacetamido) benzyl]-1,4,8,11-tetr aazacyclotetradecane-N,N', N '',N'''-tetraacetic acid (BAT) was conjug ated to Lym-1 via 2-iminothiolane (2IT) to prepare 2IT-BAT-Lym-1, whic h was labeled with Cu-67. Mice with Raji xenografts were treated with 335-500 mu Ci (12.4-18.0 MBq) of Cu-67-2IT-BAT-Lym-1 with or without 4 8,000-144,000 IU of rIL-2 once or were treated b.i.d, for 5 days begin ning simultaneously with Cu-67-2IT-BAT-Lym-1. Mouse weight, blood coun ts, and mortality were monitored to assess toxicity, and tumor size wa s measured to assess efficacy. In addition, groups of mice were sacrif iced to assess the biodistribution of Cu-67-2IT- BAT-Lym-1 with and wi thout rIL-2. RESULTS. In mice treated with 335 mu Ci of Cu-67-2IT-BAT- Lym-1 alone, 28% of tumors were cured. When 48,000 IU of rIL-2 were ad ded, 50% were cured. The overall response rate was 50% for both regime ns. In mice treated with 400 mu Ci of Cu-67- 2IT-BAT-Lym-1 alone, 42% responded, all of which were cured. When 38,000 IU of rIL-2 were added , 77% of tumors responded, and 38% were cured. Larger or multiple dose s of rIL-2 did not result in additional therapeutic enhancement. The t umor uptake and radiation dose after Cu-67-2IT-BAT-Lym-1 were about tw o times greater when a single dose of rIL-2 was added: This may be the basis for enhanced therapeutic efficacy. Mortality was not altered fo r 335 mu Ci or 400 mu Ci doses of Cu-67-2IT-BAT-Lym-1 by rIL-2 nor wer e other toxicity parameters. Mortality was increased at 500 mu Ci by t he addition of rIL-2. CONCLUSIONS. Cu-67-2IT-BAT-Lym-1 provided a ther apeutic and frequently curative dose of radiation to tumored mice at t olerated doses. The therapeutic effectiveness of Cu-67-2IT-BAT-Lym-1 m ay have been enhanced by rIL-2. (C) 1997 American Cancer Society.