Abstract 572: Development of a targeted copper theranostic to fibroblast activation protein (FAP) which shows high uptake and long-term retention at the tumor site
Authors: Jaclyn L. Lange, Lachlan E. Mclnnes, Jessica Van Zuylekom, Benjamin Blyth, Stacey E. Rudd, Paul S. Donnelly, Aidan Ingham, Jason S. Lewis, Matthew Harris
Journal: Cancer Research (2025)

Abstract Background and Purpose: Fibroblast Activation Protein (FAP), a membrane-bound enzyme and cell surface protein, is up-regulated in cancer-associated fibroblasts and is present in the tumor microenvironment across numerous cancers. There is low to no expression of FAP in healthy tissue. Targeted Copper Theranostics (TCTs) are radiopharmaceuticals that utilize copper-64 (Cu-64) for PET imaging and copper-67 (Cu-67) for therapy. Herein, we report preclinical evaluation of a mono- and bis-FAP targeting agent using Cu-64 in two FAP-positive tumor xenograft models. These agents enable the visualization of FAP as a potential pan-cancer imaging agent and therapy. Methods: We evaluated the imaging characteristics of SAR-FAP and a dimer, SAR-bisFAP, which utilize the FAP inhibitor (UAMC1110) conjugated to a sarcophagine chelator (SAR). We tested the compounds in two xenograft models which have high expression levels of FAP: NSG mice bearing a SK-MEL-187 xenograft (a human-derived metastatic cell line); or athymic nude mice bearing a U87MG xenograft (a human-derived glioblastoma cell line). The mice were administered ∼5 MBq of [64Cu]Cu-SAR-FAP or [64Cu]Cu-SAR-bisFAP and the biodistribution and tumor uptake assessed via microPET/CT imaging and ex vivo biodistribution at 1, 4 and 24 h post i.v. injection. A comparison study with [68Ga]Ga-FAPi-46 along with blocking studies with FAPi-46 (an industry standard) were also completed. Results: Imaging and an ex-vivo biodistribution study of the SK-MEL-187 xenograft NSG mice showed that both SAR-FAP tracers have specific binding to FAP-positive SK-MEL-187 tumors and higher uptake compared to 68Ga-FAPi-46 at 1 h. Additionally, both SAR-FAP tracers show FAPi-46 blockable uptake, confirming the tracer is binding specifically to FAP. Overall, the [64Cu]Cu-SAR-bisFAP has better retention at 24 h. In the U87MG xenografted athymic nude mice, the tumor uptake, as measured via ex vivo biodistribution for the [64Cu]Cu-SAR-FAP tracer was consistent over 4 hours (4.8% IA/g) which thereafter decreased to 0.8% IA/g at 24 hours. We were again able to observe higher uptake and long retention in the tumor after 24 hours (6.2% IA/g) for the [64Cu]Cu-SAR-bisFAP. Conclusion: Imaging and biodistribution studies demonstrated high tumor-specific uptake for [64Cu]Cu-SAR-FAP and [64Cu]Cu-SAR-bisFAP tracers in the SK-MEL-187 and U87MG tumor xenograft mouse models. The uptake and 24-hour retention of the [64Cu]Cu-SAR-bisFAP is very encouraging and indicates potential for therapeutic benefit with this tracer. Efficacy studies are underway to ascertain the therapeutic potential of [67Cu]Cu-SAR-bisFAP as a TCT. Citation Format: Jaclyn L. Lange, Lachlan E. Mclnnes, Jessica Van Zuylekom, Benjamin Blyth, Stacey E. Rudd, Paul S. Donnelly, Aidan Ingham, Jason S. Lewis, Matthew Harris. Development of a targeted copper theranostic to fibroblast activation protein (FAP) which shows high uptake and long-term retention at the tumor site [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 572.