Abstract
Preclinical evaluation and first-in-human case of [68Ga]Ga-PSV377, a novel cyclic radiopeptide targeting fibroblast activation protein, for positron emission tomography (PET) imaging of multiple cancers
The Journal of nuclear medicine (1978), Vol.66(Suppl 1), p.251863
06/01/2025
Abstract
Introduction: Fibroblast activation protein (FAP) is a type II transmembrane serine protease that is considered a promising target for theranostic radiopharmaceuticals in cancer. Using phage display with site specific cyclization, we have developed a novel cyclic radiopeptide PSV359 that exhibits high tumor targeting, long tumor retention, and minimal accumulation in normal organs, leading potentially to optimal anti-tumor effects when labeled with lead-212 ([212Pb]Pb-PSV359). In this study, we report the development and evaluation of a PET imaging surrogate (PSV377) that was developed by conjugating NOTA chelator to the cyclic peptide pharmacophore. We also report the first-in-human case of [68Ga]Ga-PSV377 PET/MRI imaging in gastrointestinal cancer where standard 18F-FDG often falls short due to low sensitivity, high physiological uptake, and low tumor uptake. Methods: Binding affinity of PSV377 to FAP was determined by enzyme inhibition assay Z-Gly-Pro-AMC substrate (n=4). Radiosynthesis and quality control of [68Ga]Ga-PSV377 were conducted using in-house protocols. In vitro uptake of [68Ga]Ga-PSV377 was determined in FAP-positive HT1080-FAP and FAP-negative HT1080WT cells, and compared with [68Ga]Ga-FAPI04. In female athymic nude mice bearing HT1080-FAP xenografts, ex vivo biodistribution of [67Ga]Ga-PSV377 surrogate was determined at 1, 4, 24 hours (n=2-3). Micro-PET/CT imaging was performed in a HT1080-FAP xenograft model (n=3) at 0.5 to 4 h post injection of 3.7 MBq [68Ga]Ga-PSV377. FIH PET/MRI imaging was performed in a male (34-year-old) patient with metastatic colorectal cancer (mCRC) at 30 min after injection of 118 MBq (3.2 mCi) of [68Ga]Ga-PSV377. Static PET scanning was completed within 15 min. Standard 18F-FDG PET/CT imaging was also performed in the same patient at 60 min post injection of 251 MBq (6.8 mCi) 18F-FDG. Results: Superior binding affinity of PSV377 to FAP (Ki=0.17 nM) was observed in vitro. In HT1080-FAP cells, compared with [68Ga]Ga-FAPI04, significantly higher uptake of [68Ga]Ga-PSV377 was found at all time points (3.3-fold at 0.5 h,11.9-fold 4 h), with minimal uptake in FAP-negative HT1080WT, indicating high binding specificity of [68Ga]Ga-PSV377. The ex vivo biodistribution study of [67Ga]Ga-PSV377 demonstrated rapid and high uptake of the tracer in HT1080-FAP xenografts in mice with sustained tumor retention (15.1 %ID/g at 1 h and 13.8 %ID/g at 24 h). Micro-PET/CT imaging of [68Ga]Ga-PSV377 demonstrated high tumor uptake, with fast clearance from background, and minimal retention in kidneys (and other organs). In FIH case, compared with standard 18F-FDG, [68Ga]Ga-PSV377demonstrated higher uptake in most primary and metastatic lesions, with minimal absorption in kidneys, the most common dose-limiting organ radiopeptide-based therapies. Conclusions: In this study, we report on [68Ga]Ga-PSV377, a novel NOTA-conjugated cyclic radiopeptide targeting FAP. Our results demonstrated fast tumor targeting, high tumor accumulation, with minimal accumulation in normal organs in both preclinical and clinical settings. These results suggest that [68Ga]Ga-PSV377 is not only a promising PET agent for diagnosis and staging, but also an ideal PET imaging surrogate for selecting patients for its alpha-particle emitting therapeutic counterpart [212Pb]Pb-PSV359 that is entering a phase 1 clinical trial (NCT06710756).
Details
- Title: Subtitle
- Preclinical evaluation and first-in-human case of [68Ga]Ga-PSV377, a novel cyclic radiopeptide targeting fibroblast activation protein, for positron emission tomography (PET) imaging of multiple cancers
- Creators
- Lianbo ZhouWenjie FuXiaowei MaBrianna CagleNeha ParanjapeZhiming DaiNicholas BaumhoverMichael SchultzMengshi Li
- Resource Type
- Abstract
- Publication Details
- The Journal of nuclear medicine (1978), Vol.66(Suppl 1), p.251863
- ISSN
- 0161-5505
- eISSN
- 1535-5667
- Publisher
- Society of Nuclear Medicine
- Language
- English
- Date published
- 06/01/2025
- Academic Unit
- Radiology; Occupational and Environmental Health
- Record Identifier
- 9984927089002771
Metrics
1 Record Views