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Pretargeting of renal cell carcinoma: improved tumor targeting with a bivalent chelate
O C Boerman1, M H Kranenborg, E Oosterwijk
1Department of Nuclear Medicine, University Hospital Nijmegen, The Netherlands. O.Boerman@nugen.azn.nl
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.
Insights
This study optimized pretargeting strategies for cancer imaging and therapy using bispecific monoclonal antibodies (bsmAbs) and a bivalent chelate, (111)In-diDTPA. The bivalent chelate significantly improved radiolabel accumulation in tumors, enhancing tumor-to-background ratios for improved radioimmunotherapy.
Area of Science:
- Oncology
- Radiochemistry
- Immunotherapy
Background:
- Radiolabeled monoclonal antibodies (mAbs) offer targeted tumor delivery but are limited by sustained off-target tissue activity.
- Pretargeting strategies, including bispecific mAbs (bsmAbs) and biotin-avidin systems, aim to enhance tumor-to-nontumor ratios.
- Previous work demonstrated successful radioimmunotargeting of indium-111 diethylenetriaminepentaacetic acid (DTPA) to renal cell carcinoma (RCC) in mice using pretargeting.
Purpose of the Study:
- To optimize a pretargeting strategy for renal cell carcinoma (RCC) xenografts in nude mice using a bispecific anti-RCC x anti-DTPA mAb.
- To evaluate the efficacy of a bivalent chelate, (111)In-diDTPA, in improving radioimmunotargeting compared to a monovalent chelate.
- To assess the impact of (111)In-diDTPA dose on tumor uptake and retention for potential radioimmunotherapy applications.
Main Methods:
- A two-step pretargeting approach was employed using a bispecific anti-RCC x anti-DTPA mAb in nude mice bearing RCC xenografts.
- The study investigated the effect of varying doses of bivalent (111)In-diDTPA and monovalent (111)In-DTPA on tumor uptake and biodistribution.
- Pharmacokinetic parameters, including tumor accretion, retention, and clearance from blood and kidneys, were quantified.
Main Results:
- Low doses of (111)In-diDTPA (< or = 7 pmol) resulted in very high tumor uptake (>50% injected dose/g) within 1 hour postinjection (p.i.).
- The bivalent chelate showed rapid tumor accretion (78% ID/g at 4 h p.i.) and sustained retention (92% ID/g at 72 h p.i.).
- High tumor:blood ratios (up to 3500 at 72 h p.i.) were achieved, with rapid clearance from non-target tissues.
Conclusions:
- The use of bivalent chelates significantly optimizes two-step tumor targeting with bispecific monoclonal antibodies (bsmAbs).
- This pretargeting strategy demonstrates potential for effective radioimmunotherapy due to preferential tumor targeting and high retention.
- Tumors could be effectively imaged up to one week postinjection, confirming the viability of this approach for diagnostic and therapeutic applications.