Extensive preclinical evaluation of lutetium-177-labeled PSMA-specific tracers for prostate cancer radionuclide therapy
Eline A. M. Ruigrok, Nicole van Vliet, Simone U. Dalm, Erik de Blois, Dik C. van Gent, Joost Haeck, Corrina de Ridder, Debra Stuurman, Mark Konijnenberg, Wytske M. van Weerden, Marion de Jong, Julie Nonnekens
Abstract
Abstract Purpose Various radiolabeled prostate-specific membrane antigen (PSMA)–targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues. Methods and results In vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC 50 values in the nanomolar range. Interestingly, [ 177 Lu]Lu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed [ 177 Lu]Lu-PSMA-617 to have the lowest binding to these healthy organs compared with [ 177 Lu]Lu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However, [ 177 Lu]Lu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio. Conclusion [ 177 Lu]Lu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with [ 177 Lu]Lu-PSMA-I&T and [ 177 Lu]Lu-JVZ-007. Based on our preclinical evaluation, [ 177 Lu]Lu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs.