Trifunctional PSMA-targeting constructs for prostate cancer with unprecedented localization to LNCaP tumors

Treatment of late-stage prostate cancer by targeted radiotherapeutics such as131I-MIP-1095 and177Lu-PSMA-617 has shown encouraging early results. Lu-177 is preferred to I-131 in clinical settings, but targeted radioligand therapy (RLT) with177Lu-PSMA-617 has not reached its full potential due to insufficient dose delivery to the tumor. We recently developed a dual-targeting radioiodinated ligand, RPS-027, that targets PSMA and uses albumin binding to enable good tumor uptake and significantly reduced kidney uptake in a preclinical model. Further development of this ligand is limited by the inability to independently modify PSMA and albumin binding and the requirement of I-131 for therapeutic application. We therefore sought to devise a new class of trifunctional ligands for RLT with (1) a high-affinity PSMA-binding domain, (2) an albumin-binding group (ABG), and (3) a chelator for radiometals such as68Ga3+,177Lu3+and225Ac3+.

Ligands incorporating a triazolylphenylurea-containing PSMA-targeting group, an Nε-(2-(4-iodophenyl)acetyl)lysine ABG and the bifunctional chelator p-SCN-Bn-DOTA linked by a PEG-containing polymer containing 0,3,4,6,8 or 12 repeats were prepared. PSMA affinity was determined in LNCaP cells and uptake and tissue distribution was studied in mice bearing LNCaP tumor xenografts and compared to177Lu-PSMA-617. Imaging studies were performed up to 24 h post-injection (p.i.) using66Ga3+and biodistribution studies at 4 h, 24 h and 96 h p.i. with177Lu3+.

PSMA affinity was high (IC50 = 1-10 nM) and inversely proportional to the linker length. Tumor uptake correlated with binding affinity and was significantly greater than for177Lu-PSMA-617 over 96 h. The highest uptake was achieved with177Lu-RPS-063 (30.0 ± 6.9 %ID/g; 4 h p.i.). Kidney uptake was generally high, with the exception of the lowest affinity ligand177Lu-RPS-067. Each of the compounds showed slower blood clearance than177Lu-PSMA-617, with clearance proportional to linker length.

The high tumor uptake achieved with these trifunctional ligands predicts larger (up to 4×) doses delivered to the tumor than can be achieved with177Lu-PSMA-617. Although PSMA-mediated kidney uptake was also observed, the exceptional area under the curve (AUC) in the tumor warrants further investigation of these novel ligands as candidates for RLT.

European journal of nuclear medicine and molecular imaging. 2018 Apr 06 [Epub ahead of print]

James Kelly, Alejandro Amor-Coarasa, Shashikanth Ponnala, Anastasia Nikolopoulou, Clarence Williams, David Schlyer, Yize Zhao, Dohyun Kim, John W Babich

Division of Radiopharmaceutical Sciences and MI3, Department of Radiology, Weill Cornell Medicine, New York, NY, USA., Brookhaven National Laboratory, Upton, NY, USA., Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA., Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, USA., Division of Radiopharmaceutical Sciences and MI3, Department of Radiology, Weill Cornell Medicine, New York, NY, USA. .