Clinical Application of PET Imaging Targeting Nectin-4 in Malignant Tumors

Malignant tumors are one of the major diseases leading to death worldwide, and their high incidence and mortality rates pose a serious threat to human health. According to the World Health Organization (WHO), there will be about 19.3 million new cancer cases and 10 million deaths globally in 2020, with a significant increase in the incidence of malignant tumors such as lung and breast cancers in particular. Early diagnosis and load assessment of tumors are crucial for improving patient survival. Currently, there are limitations in the commonly used clinical diagnostic imaging tools. For example, traditional anatomical imaging techniques (e.g., ultrasound, CT, and MRI) have high resolution in displaying the anatomical structure of tumors, but it is difficult to accurately differentiate between benign and malignant lesions, and is not sufficiently sensitive to the performance of some tumors rich in fibrotic and necrotic tissues. Enhanced magnetic resonance imaging (ceMRI) has limited effectiveness in the detection of certain solid tumors, and is particularly deficient in the identification of microscopic lesions and some deep tumors. \[18F\]FDG PET/CT, a current widely used molecular imaging technique, enables functional imaging of tumors by reflecting the level of glucose metabolism. However, \[18F\]FDG is not a tumor-specific imaging agent, and non-malignant lesions such as inflammation, infection, and tuberculosis can also lead to an increase in local FDG uptake, producing false-positive results. In addition, \[18F\]FDG uptake is low in some tumors with low metabolic activity (e.g., poorly differentiated carcinomas and some brain tumors), leading to false-negative results and limiting its use in early tumor diagnosis and precision assessment. Therefore, the development of more specific and sensitive molecular imaging probes has significant clinical value. Nectin-4, a cell adhesion molecule, belongs to an important member of the Nectin family, which is mainly expressed in the embryonic developmental stage and is less expressed in normal adult tissues. However, studies have shown that Nectin-4 is highly expressed in a variety of malignant tumors, including bladder, breast, lung, ovarian and pancreatic cancers, etc. It is closely related to tumor proliferation, invasion, metastasis, and the poor prognosis of patients, and it has gradually become a potential marker for tumor diagnosis and treatment. Especially in bladder cancer, the high expression of Nectin-4 is closely related to tumor stage and malignancy degree, and has become an important molecular target for targeted therapy. In recent years, breakthroughs have been made in the research of targeted drugs against Nectin-4, and the U.S. FDA has approved Enfortumab Vedotin (EV), the first antibody-drug coupling (ADC) targeting Nectin-4, for the treatment of recurrent or refractory uroepithelial cancers, which has shown remarkable efficacy and good prospects for clinical application. However, how to screen patients suitable for targeted Nectin-4 therapy and dynamically evaluate the therapeutic efficacy remain clinical challenges. Therefore, the development of molecular imaging probes targeting Nectin-4 and the realization of non-invasive, real-time quantitative detection of Nectin-4 expression by PET imaging are expected to provide an imaging basis for targeted therapy. This can not only be used to screen patient groups with high Nectin-4 expression, thus precisely guiding the clinical application of targeted drugs, but also to assess drug efficacy in real time during the treatment process and promote the implementation of individualized treatment plans. In summary, the aim of this project is to explore the clinical application of PET imaging technology targeting Nectin-4 in malignant tumors, through the use of targeted Nectin-4 PET imaging agent (in the case of \[68Ga\]Ga-NOTA-Nectin-4 antibody fragment) with a view to be used for diagnosis and staging of malignant tumor patients, assessing tumor load and Nectin-4 expression abundance, and helping to determine therapeutic options. At the same time, preliminary pharmacokinetic analysis was performed in healthy volunteers to clarify the metabolic pattern and adverse effects of the drug in vivo.