title: 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 back-ground 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 micrograms, whereas at higher doses uptake decreased. Tumor was saturated with 15 micrograms bsMAb. At the saturating bsMAb 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 micrograms 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.
authors.affiliation: Department of Nuclear Medicine, University Hospital Nijmegen, The Netherlands. H.Kranenborg@nugen.azn.nl
authors.forename: M H
authors.initials: MH
authors.lastname: Kranenborg
authors.forename: O C
authors.initials: OC
authors.lastname: Boerman
authors.forename: J C
authors.initials: JC
authors.lastname: Oosterwijk-Wakka
authors.forename: M C
authors.initials: MC
authors.lastname: de Weijert
authors.forename: F H
authors.initials: FH
authors.lastname: Corstens
authors.forename: E
authors.initials: E
authors.lastname: Oosterwijk
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D004369:Pentetic Acid; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D018033:Antibodies, Bispecific; D007205:Indium Radioisotopes; D004369:Pentetic Acid