Comparative evaluation of 225Ac-PSMA-Trillium with other 225Ac-PSMA-SMOL assets in a preclinical prostate cancer xenograft model
Presenter: Urs Hagemann, PhD Session: Targeted Radiopharmaceuticals and Combination Strategies in Cancer Therapy Time: 4/22/2026 9:00:00 AM → 4/22/2026 12:00:00 PM
Authors
Urs B. Hagemann 1 , Maria Spelling 1 , Shankari Nair 1 , Martin Kohs 1 , Meike Fehder 1 , Stefan Stargard 1 , Sabine Zitzmann-Kolbe 2 , Dmitry Zubov 1 , Ming Xu 1 1 Bayer AG, Berlin, Germany, 2 Life Molecular Imaging, Berlin, Germany
Abstract
Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein highly expressed on prostate cancer cells, making it an ideal target for novel prostate cancer therapies. Currently, there are several actinium-225 ( 225 Ac)-PSMA-targeting small molecules (SMOL) in clinical development for treating patients with metastatic castration-resistant prostate cancer. 225 Ac-PSMA-Trillium (BAY 3563254), is a novel PSMA-targeting molecule which comprises a highly specific PSMA-binding motif, an albumin-binding domain to optimize tumor uptake and retention, and a Macropa™ chelator complexed with the alpha-emitter 225 Ac. Here, we compared 225 Ac-PSMA-Trillium with three other 225 Ac-PSMA-SMOLs, i.e., 225 Ac-PSMA-617, 225 Ac-PSMA-R2 and 225 Ac-PSMA-I&T, which all utilize a DOTA chelator for complexing 225 Ac. All assets were synthesized and radiolabeled at Bayer AG. Binding to PSMA was confirmed using a surface plasmon resonance (SPR) assay . In vitro cytotoxicity in LNCaP cells was evaluated using CellTiterGlo®. The antitumor effects of 225 Ac-PSMA-SMOLs were investigated in male SCID mice with subcutaneous LNCaP tumors. Mice were randomized and treated with a single i.v injection of 225 Ac-PSMA-Trillium or the other 225 Ac-PSMA-SMOLs at different dose levels (100-400 kBq/kg, 375 kBq/nmol). Tumor growth and body weights were monitored for 4 weeks post injection. 225 Ac activity in various organs and tumors was measured using a high purity germanium detector or autoradiography. 177 Lu-PSMA-617 SPECT imaging was performed to evaluate tumor uptake. All PSMA-SMOLs exhibited strong binding affinity to recombinant PSMA as demonstrated by SPR. When radiolabeled with non-radioactive lanthanum as surrogate for 225 Ac, the target residence time of PSMA-SMOLs was weakened, except for PSMA-Trillium. All 225 Ac-labeled assets induced potent cytotoxicity in LNCaP cells in vitro. Radio-HPLC and iTLC confirmed the integrity and high radiochemical purity, respectively. 225 Ac-PSMA-Trillium at 400 kBq/kg showed higher tumor uptake compared to other 225 Ac-PSMA-SMOLs, homogeneous tumor accumulation 60 hours after injection, and fast clearance from the kidneys based on autoradiography. Furthermore, 225 Ac-PSMA-Trillium at all doses inhibited LNCaP tumor growth and decreased tumor weights in a dose-dependent manner, whereas the antitumor response was restricted to the higher doses for all other compounds. In summary, 225 Ac-PSMA-Trillium showed the highest tumor uptake and the strongest tumor growth inhibition with a clear dose response compared with the other 225 Ac-PSMA-SMOLs. These data support the clinical development of 225 Ac-PSMA-Trillium (NCT06217822).
Disclosure
U. B. Hagemann, Bayer AG Employment. M. Spelling, Bayer AG Employment. S. Nair, Bayer AG Employment. M. Kohs, Bayer Ag Employment, Stock. M. Fehder, Bayer AG Employment, Stock. S. Stargard, Bayer AG Employment, Stock. S. Zitzmann-Kolbe, Life Molecular Imaging Employment, Other, Previously an employee of Bayer AG. D. Zubov, Bayer AG Employment. M. Xu, Bayer AG Employment, Stock.
Cited in
Control: 2397 · Presentation Id: 3971 · Meeting 21436