Nectin-4-Targeting Radiotracers: Novel Theranostic Agents for Precision Oncology in Cancer

Abstract

Nectin cell adhesion molecule 4 (Nectin-4) is specifically overexpressed in most cancers of epithelial origin but downregulated in normal tissue, representing an ideal target for positron emission tomography imaging. The development of positron emission tomography imaging probes targeting Nectin-4 has gained significant attention in recent years, especially after the approval in December 2019 by the US Food and Drug Administration of enfortumab vedotin-an antibody drug conjugate targeting Nectin-4-in patients with locally advanced or metastatic bladder cancer. This article aims to comprehensively review original research articles discussing preclinical development or early translational clinical applications of radiolabeled probes targeting Nectin-4. The main radioactive compounds investigated belong to two classes, antibody-based radiopharmaceuticals and peptide-drug conjugates, in particular novel bicyclic peptides. While monoclonal antibody-based probes have demonstrated theranostic potential in preclinical studies, their clinical application has been hindered by their slow pharmacokinetic properties. However, peptide-based positron emission tomography/computed tomography tracers offer several advantages, such as ease of handling in synthesis, a more favorable biodistribution, and lower immunogenicity and have been tested in preliminary clinical experiences.

Fig. 1

Diffuse expression of Nectin cell adhesion molecule 4 in a urothelial carcinoma of the bladder

Fig. 2

Radiopharmaceuticals targeting Nectin-4 cell adhesion molecule. d day, hr hour, min minutes

Fig. 3

Theranostic model with radiolabeled Nectin cell adhesion molecule 4 (Nectin-4) probes in bladder cancer, breast cancer, and melanoma. Created with Biorender.com