Single-dose versus fractionated radioimmunotherapy of human colon carcinoma xenografts using I-131-labeled multivalent CC49 single-chain Fvs(1)

The prospects of radiolabeled antibodies in cancer detection and therapy re main promising. However, efforts to achieve cures, especially of solid tumo rs, with the systemic administration of radiolabeled monoclonal antibodies (MAbs) have met with limited success. Using genetic engineering techniques, MAbs have been tailored to improve the therapeutic index (tumor:normal tis sue ratio) in clinical radioimmunotherapy. In the present study, we investi gated the potential of tetravalent {[sc(Fv)(2)](2)} and divalent [sc(Fv)(2) ] single chain Fvs of MAb CC49 for therapy in athymic mice bearing s.c. LS- 174T human colon carcinoma xenografts. Mice received 1000 mu Ci of I-131-la beled [sc(Fv)(2)](2) or I-131-labeled sc(Fv)(2), either as a single injecti on on day 6 or as four injections (250 mu Ci each) on days 6, 7, 8, and 9; the day of tumor implantation was taken as day 0, The median survival for t he control group was 26 days. Comparisons of single and fractionated therap eutic regimens showed median survival as 32 (P < 0.001) and 53 days (P < 0. 0001), respectively for [sc(Fv)(2)](2) and 26 (P > 0.5) and 38 days (P < 0. 0001), respectively for sc(Fv)(2) when compared with the control groups. Th e time for the quadrupling of tumor volume for single and fractionated ther apeutic treatments were: 9.0 +/- 0.8 and 21.1 +/- 2.9 days respectively for sc(Fv)(2); 16.6 +/- 1.9 and 32.9 +/- 2.7 days respectively for [sc(Fv)(2)] (2); and 8.3 +/- 0.7 and 8.4 +/- 0.6 days respectively for the control grou p. No I-131-labeled systemic toxicity was observed in any treatment groups. The results show that radioimmunotherapy delivery for sc(Fv)(2) and [sc(Fv )(2)](2) in a fractionated schedule clearly presented a therapeutic advanta ge over single administration. The treatment group receiving tetravalent sc Fv showed a statistically significant prolonged survival with both single a nd fractionated administrations suggesting a promising prospect of this rea gent for cancer therapy and diagnosis in MAb-based radiopharmaceuticals.