Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy

Abstract

Purpose Fibroblast activation protein (FAP) is a membrane-bound protease that has limited expression in normal adult tissues but is highly expressed in the tumor microenvironment of many solid cancers. FAP-2286 is a FAP-binding peptide coupled to a radionuclide chelator that is currently being investigated in patients as an imaging and therapeutic agent. The potency, selectivity, and efficacy of FAP-2286 were evaluated in preclinical studies. Methods FAP expression analysis was performed by immunohistochemistry and autoradiography on primary human cancer specimens. FAP-2286 was assessed in biochemical and cellular assays and in in vivo imaging and efficacy studies, and was further evaluated against FAPI-46, a small molecule–based FAP-targeting agent. Results Immunohistochemistry confirmed elevated levels of FAP expression in multiple tumor types including pancreatic, breast, and sarcoma, which correlated with FAP binding by FAP-2286 autoradiography. FAP-2286 and its metal complexes demonstrated high affinity to FAP recombinant protein and cell surface FAP expressed on fibroblasts. Biodistribution studies in mice showed rapid and persistent uptake of 68Ga-FAP-2286, 111In-FAP-2286, and 177Lu-FAP-2286 in FAP-positive tumors, with renal clearance and minimal uptake in normal tissues. 177Lu-FAP-2286 exhibited antitumor activity in FAP-expressing HEK293 tumors and sarcoma patient-derived xenografts, with no significant weight loss. In addition, FAP-2286 maintained longer tumor retention and suppression in comparison to FAPI-46. Conclusion In preclinical models, radiolabeled FAP-2286 demonstrated high tumor uptake and retention, as well as potent efficacy in FAP-positive tumors. These results support clinical development of 68Ga-FAP-2286 for imaging and 177Lu-FAP-2286 for therapeutic use in a broad spectrum of FAP-positive tumors.

Integration of organoids in peptide drug discovery: rise of the high-throughput screening

“…Radiopharmaceutical therapy (RPT) is a novel treatment for cancer patients, involving the targeted delivery of radionuclides to tumors by conjugating to small molecules, peptides or antibodies [60][61][62][63][64][65][66][67][68][69][70][71] . RPT has advantages over existing therapeutic modalities, which makes it a safe, precise and effective option to treat many kinds of diseases, especially cancers 72,73 .…”

Peptidomimetics in cancer targeting

“…In the case of LLP2A, 64Cu-LLP2A has been suggested to allow accurate molecular imaging of multiple myeloma (MM) lesions, which will significantly impact the diagnosis of the disease at its early stages and, over time, on the diagnosis and selection of treatment in these patients (Beaino and Anderson 2014 ). FAP-2286 is another study for diagnostic peptidomimetics, which binds to fibroblast activation protein (FAP) to evaluate the uptake, retention, and ability to detect metastatic disease of radiotracers in a variety of solid tumors (Zboralski et al 2022 ). In general, molecular imaging is one promising potential factor for cancer diagnosis with peptidomimetics.…”

Highlight selection of radiochemistry and radiopharmacy developments by editorial board

“…Although they showed very promising results for cancer imaging, their relatively low tumor retention is a concern for targeted radionuclide therapy. To address this issue, the preclinical evaluation of a cyclic peptide, namely FAP-2286, which was labeled with gallium-68 and indium-111 for imaging and lutetium-177 for therapeutic use was recently reported (Zboralski et al 2022 ). The authors anticipated that a cyclic peptide targeting FAP would have an improved tumor retention time over the small molecule-based radiopharmaceuticals.…”