Two-step radio-immunotargeting of renal-cell carcinoma xenografts in nude mice with anti-renal-cell-carcinoma X anti-DTPA bispecific monoclonal antibodies

Abstract

The specificity of antibodies offers unique opportunities to target tumors with radionuclides. However, due to the slow clearance of radiolabeled antibody, relatively high background is observed in non-target organs. Pre- targeting protocols using bispecific monoclonal antibodies (bsMAbs) and radiolabeled chelates may overcome this problem. We have evaluated the anti- renal-cell-carcinoma (RCC) x anti-DTPA bsMAb G250 x DTIn1 for 2-step targeting of RCC tumors in nude mice. Tumor uptake of 111In-DTPA was similar up to a 3-day interval between bsMAb and 111In-DTPA injections and decreased thereafter. The effect of G250 x DTIn1 protein dose was studied. High tumor uptake was seen at 1 to 4 μg, whereas at higher doses uptake decreased. Tumor was saturated with 15 μg bsMAb. At the saturating bsHAb dose the 111In-DTPA amount was varied. High tumor uptake was observed at a 10-fold molar excess 111In-DTPA, whereas at higher excess uptake decreased. After priming with 15 μg bsMAb and targeting with a 10-fold molar excess 111In-DTPA, the biodistribution of 111In-DTPA was studied for 1 to 48 hr after injection. Good tumor retention of 111In-DTPA was observed, while the radiolabel cleared rapidly from the blood. Consequently, tumor-to- blood ratios increased with time to 500 at 24 hr after injection. In conclusion, RCC xenografts can be targeted efficiently using G250 x DTIn1 and 111In-DTPA. However, this requires careful tuning of bsMAb protein dose and 111In-DTPA dose. Using the optimal protein dose and 111In-DTPA dose, high 111In-DTPA tumor uptake and tumor to-blood ratios can be obtained, thus providing good perspectives for diagnostic and therapeutic use in humans.