Abstract 6037: Copper-67 as a next-generation radioconjugate warhead for cancer therapy
Authors: Matt Harris, Kurt Gehlsen, Lachlan McInnes, Jason Lewis
Journal: Cancer Research (2024)

Abstract Background and Purpose: Antibody drug conjugates (ADCs) have shown promise as cancer treatments. However, the efficacy of ADCs has been limited in solid tumors and can come with significant toxicities. Radioconjugates utilize various radionuclides that are chelated and can be conjugated to small molecules, peptides and antibodies. We propose Targeted Copper Theranostics (TCTs) which use copper-64 to image tumors and beta-emitting copper-67 to irradiate and kill cancer cells using various molecular targets of oncological relevance. We have evaluated the efficacy of copper-67 based therapy in three formats; peptides, antibodies, and pre-targeting of antibody conjugates in relevant tumor mouse models. Benefits of copper-67 [half-life, 61.8 h; 100% β- energy in the range of 0.18-0.56 MeV] include high purity, high specific activity, manufacturing in a centralized distribution model at high yields on electron accelerators, and half-life suitable to various targeting formats. Copper-64 and copper-67 provide multiple logistical benefits relative to other radionuclides including Ga-68, F-18 and Lu-177. Methods: We evaluated three tumor-targeting moieties conjugated to a sarcophagine bifunctional chelator (SAR), including: a peptide dimer targeting prostate specific membrane antigen (SAR-bisPSMA); an antibody 5B1, targeting the PDAC-specific biomarker carbohydrate antigen-19-9 (CA19-9); and a Tz-TCO IDEEA huA33 antibody/sarcophagine tetrazine conjugate targeting transmembrane glycoprotein A33. Various doses were administered of [67Cu]Cu-SAR-bisPSMA in LNCAP xenografts; [67Cu]Cu-SAR-5B1 (~10 μg) in FC1245 Ft2Ab PDAC tumor-bearing C57BL/6 mice; and [67Cu]Cu-MeCOSAR-Tz in athymic nude mice bearing A33 antigen-expressing SW1222 human colorectal carcinoma xenografts 72 hours after administration of huA33-TCO. Results: Administration of either 7.5, 15 or 30 MBq of [67Cu]Cu-SAR-bisPSMA increased overall survival relative to the control group. Similarly, after administration of 4, 11, 18 MBq of [67Cu]Cu-5B1, treated groups enhanced overall survival to 32 days compared to control (14 days). Pre-targeting using ~18.5, 37.0 or 55.5 MBq or fractionated dosing of two 27.8 MBq doses of [67Cu]Cu-MeCOSAR-Tz showed efficient tumor growth reduction with enhanced overall survival for treated mice pre-administered huA33-TCO, from 68 days to &amp;gt;200 days (dose dependent) compared to control (21 days). Conclusion: We report the inhibition of tumor growth with minimal radiotoxicity and each format demonstrated significantly improved overall survival compared to controls. Collectively our results demonstrated that TCTs using the sarcophagine chelator with copper-67 are effective radioconjugates across multiple formats with an acceptable safety profile. Copper-67-based TCTs are being translated in multiple theranostic clinical trials in the USA and Australia. Citation Format: Matt Harris, Kurt Gehlsen, Lachlan McInnes, Jason Lewis. Copper-67 as a next-generation radioconjugate warhead for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6037.