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Published on: February 3, 2015
First-in-Human Study of the Radioligand 68Ga-N188 Targeting Nectin-4 for PET/CT Imaging of Advanced Urothelial
Xiaojiang Duan1, Lei Xia2,3, Zhuochen Zhang1
1Department of Nuclear Medicine, Peking University First Hospital, Beijing, China.
Purpose:
Nectin-4 is an emerging biomarker for cancer diagnosis and therapy. Recently, enfortumab vedotin (EV) was approved by the FDA as the first nectin-4 targeting antibody-drug conjugate for treating advanced urothelial carcinoma (UC). A PET imaging method to noninvasively quantify nectin-4 expression level would potentially help to select patients most likely to respond to EV and predict the response.
Experimental Design:
In this study, we designed a bicyclic peptide-based nectin-4 targeting radiotracer 68Ga-N188. Initially, we performed preclinical evaluations of 68Ga-N188 in UC cell lines and xenograft mouse models. Next, we performed the translational study in healthy volunteers and a pilot cohort of patients with advanced UC on uEXPLORER total-body PET/CT.
Results:
In the preclinical study, 68Ga-N188 showed high affinity to nectin-4, specific uptake in a nectin-4(+) xenograft mouse model, and suitable pharmacokinetic and safety profiles. In the translational study, 2 healthy volunteers and 14 patients with advanced UC were enrolled. The pharmacokinetic profile was determined for 68Ga-N188, and the nectin-4 relative expression level in different organs was quantitatively imaged.
Conclusions:
A clear correlation between PET SUV value and nectin-4 expression was observed, supporting the application of 68Ga-N188 PET as a companion diagnostic tool for optimizing treatments that target nectin-4. See related commentary by Jiang et al., p. 3259.
Insights
A novel PET imaging agent, 68Ga-N188, was developed to quantify nectin-4 expression in advanced urothelial carcinoma. This tracer shows promise as a companion diagnostic tool to guide nectin-4 targeted therapies like enfortumab vedotin.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Nectin-4 is a key biomarker in cancer diagnosis and therapy.
- Enfortumab vedotin (EV) is an FDA-approved nectin-4 targeting antibody-drug conjugate for advanced urothelial carcinoma (UC).
- Noninvasive quantification of nectin-4 expression via PET imaging could aid patient selection and response prediction for EV therapy.
Purpose of the Study:
- To design and evaluate a novel bicyclic peptide-based radiotracer, 68Ga-N188, for targeting and imaging nectin-4.
- To assess the preclinical efficacy and safety of 68Ga-N188 in UC models.
- To conduct a translational study in humans to determine the pharmacokinetic profile and quantitatively image nectin-4 expression.
Main Methods:
- Development of a bicyclic peptide-based radiotracer, 68Ga-N188.
- Preclinical evaluation in UC cell lines and nectin-4(+) xenograft mouse models.
- Translational study involving 2 healthy volunteers and 14 patients with advanced UC using uEXPLORER total-body PET/CT.
Main Results:
- 68Ga-N188 demonstrated high affinity for nectin-4 and specific uptake in preclinical models.
- The tracer exhibited suitable pharmacokinetic and safety profiles.
- Quantitative imaging in humans revealed a clear correlation between PET SUV values and nectin-4 expression levels.
Conclusions:
- 68Ga-N188 PET imaging accurately quantifies nectin-4 expression.
- This PET tracer shows potential as a companion diagnostic tool for optimizing nectin-4 targeted therapies.
- Further application in patient selection and treatment monitoring for advanced UC is supported.
