title: Pretargeting of renal cell carcinoma: improved tumor targeting with a bivalent chelate.
abstract: Radiolabeled monoclonal antibodies (mAbs) can target tumors selectively. Sustained activity levels in nontarget tissues limit their application. Pretargeting approaches using bispecific mAbs (bsmAbs) or the biotinavidin interaction have been proposed to improve tumor:nontumor ratios. Pretargeting a tumor and subsequently administering the radioactivity as a low molecular weight ligand fundamentally changes the pharmacokinetics of the radiolabel. In previous studies, we have shown successful radioimmunotargeting of diethylenetriaminepentaacetic acid (DTPA) labeled with indium-111 to renal cell carcinoma (RCC) after pretargeting in nude mice. In this study, we aimed to optimize further a pretargeting strategy in nude mice with RCC xenografts based on a bispecific anti-RCC x anti-DTPA mAb. Using this two-step approach, we studied whether the use of a bivalent chelate ((111)In-diDTPA) could improve radioimmunotargeting. The (111)In-diDTPA dose greatly affected the uptake of the radiolabeled chelate in the tumor. At a low (111)In-diDTPA dose (< or = 7 pmol), tumor uptake of (111)In-diDTPA was very high [>50% injected dose (ID)/g, 1 h postinjection (p.i.)], whereas at higher doses (> or = 20 pmol), tumor uptake of (111)In-diDTPA decreased (<30% ID/g). With monovalent (111)In-DTPA uptake of the radiolabel in the tumor was much lower (<10% ID/g, 1 h p.i.). Furthermore, the bivalent chelate accreted rapidly in the tumor (78% ID/g, 4 h p.i.) and was virtually completely retained in the tumor during several days p.i. (92% ID/g, 72 h p.i.). Clearance of the (111)In-diDTPA from the blood and kidneys was rapid and complete without the need to clear the bsmAb from the blood, probably due to the relative lability of the univalent bsmAb-diDTPA complexes in the blood. As a result, with this two-step pretargeting approach tumor:blood ratios increased up to values as high as 3500 at 72 h p.i. High doses of diDTPA could be targeted preferentially to the tumor, indicating that this approach could also be used for radioimmunotherapy. Tumors could be imaged up to 1 week p.i. of 50 microCi of (111)In-diDTPA. Quantitative analysis of the images confirmed the biodistribution data and indicated that, at 20 h p.i., 50 +/- 15% of the whole-body activity was localized in the tumor. In conclusion, these studies indicate that the use of bivalent chelates can very effectively optimize two-step targeting of tumors with bsmAbs. Our data indicate that this approach could optimize radioimmunotherapy.
authors.affiliation: Department of Nuclear Medicine, University Hospital Nijmegen, The Netherlands. O.Boerman@nugen.azn.nl
authors.forename: O C
authors.initials: OC
authors.lastname: Boerman
authors.forename: M H
authors.initials: MH
authors.lastname: Kranenborg
authors.forename: E
authors.initials: E
authors.lastname: Oosterwijk
authors.forename: G L
authors.initials: GL
authors.lastname: Griffiths
authors.forename: W J
authors.initials: WJ
authors.lastname: McBride
authors.forename: W J
authors.initials: WJ
authors.lastname: Oyen
authors.forename: M
authors.initials: M
authors.lastname: de Weijert
authors.forename: J
authors.initials: J
authors.lastname: Oosterwijk-Wakka
authors.forename: H J
authors.initials: HJ
authors.lastname: Hansen
authors.forename: F H
authors.initials: FH
authors.lastname: Corstens
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000000981:diagnostic imaging*; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000000981:diagnostic imaging*; D051379:Mice; D008807:Mice, Inbred BALB C; D004369:Pentetic Acid / Q000493:pharmacokinetics; D016719:Radioimmunodetection; D014018:Tissue Distribution
chemical_list: D007205:Indium Radioisotopes; D004369:Pentetic Acid