Abstract 844: Preclinical activity of PSMA-TTC, a targeted alpha therapeutic in patient-derived prostate cancer models
Authors: Stefanie Hammer, Urs B. Hagemann, Sabine Zitzmann-Kolbe, Aasmund Larsen, Christine Ellingsen, Oliver von Ahsen, Jenny Karlsson, Roger M. Bjerke, Olav B. Ryan, Pascale Lejeune, Hartwig Hennekes, Alan Cuthbertson, Karl Ziegelbauer, Dominik Mumberg
Journal: Cancer Research (2018)

Abstract Targeted alpha therapy (TAT) agents deliver high linear energy transfer (LET) alpha-radiation selectively to tumors. The first TAT to be approved is radium-223 which prolongs overall survival in metastatic castration resistant prostate cancer (mCRPC) patients with symptomatic bone metastasis. Radium-223 shows a selective uptake in newly formed bone matrix such as bone metastasis and binds to hydroxyapatite. The PSMA targeted thorium-227 conjugate PSMA-TTC represents another TAT approach in mCRPC. It consists of a fully human PSMA IgG antibody covalently linked to the chelator moiety (3,2 HOPO). This antibody-chelator conjugate is radiolabeled with thorium-227, which decays with a half-life of 18.7 days to radium-223 via alpha-particle emission. Herein we describe tumor targeting and anti-tumor activity of PSMA-TTC in two PSMA positive patient derived xenograft (PDx) models of prostate cancer with different characteristics. In vivo biodistribution and anti-tumor efficacy were analyzed after i.v. injection of PSMA-TTC at radioactive doses from 75-500 kBq/kg and protein doses of either 0.14 or 0.43 mg/kg to tumor bearing mice. Initially, the PDx model KuCap1 (provided by Prof. O. Ogava, University of Kyoto, Japan), a prostate cancer model resistant to the second generation antiandrogen enzalutamide, was analyzed. In this model PSMA-TTC showed strong dose dependent tumor growth inhibition starting at a single dose of 75 kBq/kg. Moreover, after a single i.v. administration of PSMA-TTC at 300 kBq/kg 9 out of 10 mice (90%) showed either stable disease or tumor regression for at least 33 days after treatment. The observed activity was highly selective, as injection of a radiolabeled control conjugate at 300 kBq/kg showed only limited tumor growth inhibition. Next, PSMA-TTC was tested in the hormone- and enzalutamide-sensitive prostate cancer PDx model ST1273 (South Texas Accelerated Research Therapeutics, San Antonio, Texas). A single i.v. injection of PSMA-TTC resulted in significant tumor accumulation of thorium-227 for more than 3 weeks, whereas a radiolabeled isotype control conjugate did not show tumor uptake. In addition, single i.v. administration of PSMA-TTC showed strong dose dependent anti-tumor activity while limited tumor growth inhibition was observed for a radiolabeled isotype control conjugate. Single doses of either 250 or 500 kBq/kg resulted in a 100 % response rate 4 weeks after treatment, with all animals showing partial or even complete regression of tumor growth. No significant effects on body weight were detected compared to vehicle treated animals. In summary, PSMA-TTC shows strong anti-tumor activity in patient derived prostate cancer models which were either sensitive or resistant to standard of care drugs. These data warrant further clinical investigation of this targeted alpha pharmaceutical investigational agent. Citation Format: Stefanie Hammer, Urs B. Hagemann, Sabine Zitzmann-Kolbe, Aasmund Larsen, Christine Ellingsen, Oliver von Ahsen, Jenny Karlsson, Roger M. Bjerke, Olav B. Ryan, Pascale Lejeune, Hartwig Hennekes, Alan Cuthbertson, Karl Ziegelbauer, Dominik Mumberg. Preclinical activity of PSMA-TTC, a targeted alpha therapeutic in patient-derived prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 844.