Abstract 5200: Preclinical pharmacology of the PSMA-targeted thorium-227 conjugate PSMA-TTC: a novel targeted alpha therapeutic for the treatment of prostate cancer

Abstract

Prostate-specific membrane antigen (PSMA, FOLH1) is a type II transmembrane glycoprotein of the M28 peptidase family that acts as a glutamate carboxypeptidase on various substrates. PSMA is well established as a target antigen in prostate cancer due to its high and specific overexpression on the surface of prostate cancer cells at all tumor stages, including metastatic and hormone-refractory disease. Several PSMA targeting antibodies and ligands are currently in clinical development or compassionate use therapeutically or as imaging agents. Targeted alpha therapy (TAT) has an established clinical profile with the successful transition of Ra223, an alpha-particle emitter, from bench to bedside in prostate cancer. Thorium-227 is the immediate precursor for Ra223 via alpha-particle emission. We herein describe the generation of a novel TAT, a high energy, alpha-particle emitting PSMA-targeted thorium-227 conjugate (PSMA-TTC). PSMA-TTC consists of a fully human PSMA targeting IgG1 antibody covalently linked via an amide bond to a chelator moiety (3,2 HOPO), enabling radiolabeling with thorium-227 (227Th). PSMA-TTC was prepared in high radiochemical yield and purity and tested for binding affinity to PSMA target (ELISA) as well as PSMA expressing cell lines (FACS). In vitro cytotoxicity experiments were carried out on prostate CA cell lines with different PSMA levels (from 3.000 to 150.000 mAbs bound/ cell). In vivo biodistribution and anti-tumor efficacy were analyzed after i.v. injection of 100-500 kBq/kg at protein doses of 0.14 mg/kg to mice bearing s.c. prostate cancer xenograft models. Additionally, anti-tumor efficacy was evaluated in a PSMA expressing orthotopic bone xenograft model (LNCaP-Luc) monitored by bioluminescence imaging, micro CT and x-ray. PSMA-TTC retains binding affinities to PSMA target and PSMA positive cancer cells similar to the PSMA antibody. Strong in vitro potency and selectivity of PSMA-TTC was shown on different PSMA positive cells. Biodistribution studies in C4-2 xenografts demonstrated specific tumor uptake of PSMA-TTC with a maximum of 50 % of ID/g at t = 72h post dose administration. Selective significant antitumor efficacy was shown for PSMA-TTC in s.c. prostate CA xenograft models with high (C4-2) and medium/low (22Rv1) PSMA protein levels at doses of 250 and 500 kBq/kg. Furthermore, statistically significant prevention of tumor growth was observed after treatment with PSMA-TTC at a dose of 100 kBq/kg in an orthotopic bone xenograft model (LNCaP-Luc). The promising preclinical antitumor activity of PSMA-TTC supports its development for the treatment of patients with metastatic prostate cancer. Citation Format: Stefanie Hammer, Aasmund Larssen, Christine Ellingsen, Solene Geraudie, Derek Grant, Baard Indrevoll, Oliver von Ahsen, Alexander Kristian, Urs B Hagemann, Jenny Karlsson, Roger M Bjerke, Olav B Ryan, Dominik Mumberg, Bertolt Kreft, Alan Cuthbertson. Preclinical pharmacology of the PSMA-targeted thorium-227 conjugate PSMA-TTC: a novel targeted alpha therapeutic for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5200. doi:10.1158/1538-7445.AM2017-5200

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

“…4). 80 Importantly, the accumulated dose per gram was comparable with that seen in the PSMA-TTC biodistribution studies, 65,[80][81][82] thus supporting the use of 89 Zr-HOPO-PSMA in guiding preclinical and clinical development of PSMA-TTC.…”

Targeted Radionuclide Therapy of Prostate Cancer—From Basic Research to Clinical Perspectives

“…However, in vivo experiments showed that a single course of the 213 Bi-J591 improved significantly median tumor-free survival and reduced PSA level in athymic nude mice bearing prostate cancer xenografts. These findings have subsequently prompted further preclinical in vitro and in vivo research with others α-particle-emitting radionuclides [187][188][189][190][191] ( Table 2).…”

Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model

“…In contrast, thorium-227 (half-life of 18.7 days), the parental radionuclide of radium-223, can be complexed to several chelator families including those of the 3,2-hydroxypyridinone (3,2-HOPO) class [5]. We have previously reported on several examples of targeted thorium-227 conjugates (TTCs) targeting a multitude of tumor-associated antigens including the HER2-TTC [6][7][8][9][10]. Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor that is part of the human epidermal growth factor receptor (EGFR) family [11].…”