Abstract ND09: Actinium-225 -PSMA-Trillium (BAY 3563254): Preclinical evaluation and clinical imaging study of a novel 225Ac-labeled PSMA-targeting small molecule triad for the treatment of mCRPC
Authors: Zitzmann-Kolbe Sabine , Hesterman Jacob , Cole Patricia E. , Salem Nicolas , Papple Alex , Jeffers Michael , Koca Goekben , Poethko Thorsten , Dostalek Miroslav , Hillier Shawn , Babich John W. 
Published: April 2024

With the approval of a PSMA-targeting small molecule labeled with the beta-emitter lutetium-177, PSMA is considered a clinically validated target for the treatment of mCRPC. Although effective, many patients treated with this therapeutic experience only transient clinical benefit, and G1/2 xerostomia is common due to salivary gland toxicity. Since the linear energy transfer and degree of induced DNA damage of alpha particles far exceeds that of beta particles, several investigational PSMA-targeting small molecules labeled with the alpha-emitter 225Ac have generated encouraging preliminary efficacy signals, but with severe xerostomia as a common dose-limiting toxicity. 225Ac-PSMA-Trillium is a novel PSMA-targeting radioligand consisting of a triad of important features: (1) a high-affinity PSMA inhibitor for specific tumor-targeting; (2) a customized albumin-binding domain designed to prolong plasma residence time and increase the therapeutic index by improving tumor uptake while reducing salivary gland uptake; and (3) a “macropa” chelator for efficient and stable radiolabeling with actinium-225. A series of compounds containing the same high-affinity PSMA-targeting moiety, but different chain lengths and albumin-binding domains, were evaluated to identify the optimal combination of features required to achieve the best therapeutic index. In vitro preclinical characterization was performed to test affinities for PSMA and albumin, compound stability and cell-killing potential in LNCaP and 22Rv1 CDX models as well as KuCaP-1 PDX model. Preclinical in vivo investigation of selected compounds showed increased plasma residence time, reduced uptake in normal organs, strong uptake and retention in PSMA-expressing tumors and robust anti-tumor activity. These analyses led to the selection of compounds for further evaluation in a Phase 0 imaging and PK study in mCRPC patients (NCT05773703). In this Phase 0 study, PSMA-Trillium compounds were labeled with indium-111 via a DOTA chelator and used as surrogates to facilitate longitudinal imaging. In patients, 111In-PSMA-Trillium demonstrated targeting to PSMA-expressing tumors as defined by PET/PSMA scans and a plasma residence time consistent with albumin-binding affinities. Importantly, 111In-PSMA-Trillium showed robust uptake and prolonged retention in tumors, and reduced uptake and relatively fast washout from salivary glands. Based on these preclinical data and clinical imaging results, a therapeutic first-in-human trial to evaluate 225Ac-PSMA-Trillium in patients with prostate cancer is anticipated to begin enrolling patients in the first half of 2024.

Citation Format: Sabine Zitzmann-Kolbe, Jacob Hesterman, Patricia E. Cole, Nicolas Salem, Alex Papple, Michael Jeffers, Goekben Koca, Thorsten Poethko, Miroslav Dostalek, Shawn Hillier, John W. Babich. Actinium-225 -PSMA-Trillium (BAY 3563254): Preclinical evaluation and clinical imaging study of a novel 225Ac-labeled PSMA-targeting small molecule triad for the treatment of mCRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND09.