一种噬菌体展示衍生的双环肽用于 EphA2 特异性 PET 成像的开发及首批临床经验

Background: Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a tyrosine kinase receptor overexpressed in multiple solid tumors including pancreatic, bladder, head and neck, breast, colon, prostate, and lung cancers. EphA2 is associated with increased severity, metastatic disease and poor clinical prognosis. Following successful preclinical optimization of a phage display-derived EphA2-specific bicyclic peptide 1 , this study outlines the first in-human application of EphA2-targeting [ 68 Ga]Ga-BCY18469 in PET/CT imaging. Methods: Preclinical characterization of the EphA2-targeting bicyclic peptide BCY18469 was conducted by assessing stability, binding affinity, internalization, biodistribution and μPET/MR imaging in EphA2 + HT1080 and EphA2 - MCF-7 xenograft tumor-bearing nude mice. For clinical translation, seven patients with histologically confirmed pancreatic cancer (5 metastatic, 2 newly diagnosed) underwent [ 68 Ga]Ga-BCY18469-PET/CT (compassionate use). Four patients were examined at 15, 30, 45, 60, and 180 min p.i. for biodistribution and dosimetry assessment, three additional patients at 45 min p.i. (172±42 MBq). Time-activity curves were fitted monoexponentially, and dosimetry calculations were done using IDAC-Dose-Software. Results: [ 68 Ga]Ga-BCY18469 demonstrated EphA2-specific binding and internalization, proteolytic stability up to 72 hours, and rapid background clearance with high tumor uptake, thereby enhancing imaging contrast within 30 minutes in mice. In clinical cases, [ 68 Ga]Ga-BCY18469 demonstrated rapid tumor uptake and was predominantly excreted via the kidneys. Notably, hepatic uptake remained favorably low (SUVmean 0.9±0.3 at 45 min p.i). Mean absorbed doses were 0.49 ± 0.24 mGy/MBq (kidneys), 0.14 ± 0.08 mGy/MBq (salivary glands), and 0.016 ± 0.003 mGy/MBq (liver). EphA2-targeted PET imaging successfully detected 13 liver metastases (SUVmax 6.9±3.4), 2 bone lesions (SUVmax 6.1±0.5), 13 lymph node metastases (SUVmax 5.0±1.1), and 2 peritoneal lesions (SUVmax 5.1±0.8). Primary tumor uptake was observed in 6 of 7 patients, albeit with lower intensity compared to liver metastases (SUVmax 4.8±1.6). Two pulmonary foci and 7 liver lesions identified on CT as morphologically consistent with metastases showed no uptake on EphA2-PET. Conclusion: This first-in-human application of EphA2-targeting [ 68 Ga]Ga-BCY18469 demonstrates the feasibility for visualization of EphA2-expressing primary tumors and metastases, which is in line with the preclinical findings. These initial clinical results support further investigation of [ 68 Ga]Ga-BCY18469 as a diagnostic tool with potential to improve tumor characterization and patient management strategies in EphA2-positive cancers. Reference: 1 El Fakiri M, et al. Theranostics. 2024 Aug 6;14(12):4701-4712.