NECTIN4 (Nectin Cell Adhesion Molecule 4)

Multiple nectin-4-targeted radiotracers-comprising antibody- and peptide-based agents-have demonstrated high specificity and strong affinity for nectin-4-overexpressing tumors, particularly in urothelial carcinoma and triple-negative breast cancer. Exploratory preclinical and clinical data consistently showed comparable diagnostic accuracy to standard molecular imaging methods (e.g., [18F]FDG-based PET), enhanced detection of metastatic lesions, and effective monitoring of therapeutic response and eventual treatment resistance to nectin-4-targeted antibody-drug conjugates.

Further, patient-derived PDAC organoids were treated with the standard of care therapies FOLFIRINOX, gemcitabine plus paclitaxel, or the antibody-drug conjugate enfortumab vedotin...Targeting Nectin-4 with the antibody-drug conjugate enfortumab vedotin inhibited tumor growth in multiple patient-derived PDAC organoids. Collectively, our data underscores Nectin-4 as a novel therapeutic target and provides the rationale to test this agent in PDAC patients.

We provide a detailed characterization of toxicity progression and corresponding clinical management strategies, identifying dermatologic, oromucosal, and gastrointestinal toxicities as the most clinically significant adverse events. Despite Nectin-4 being a valuable drug target, our study underscores the necessity of systematic risk assessment in the development of Nectin-4-targeted cell therapies.

Recent trials demonstrate encouraging outcomes with ADC such as Enfortumab Vedotin (EV), Sacituzumab Govitecan (SG), Trastuzumab Deruxtecan (T-DXd), and Disitamab Vedotin (DV) in UC, improving response rates and Progression-Free Survival (PFS). In RCC, ADC against ENPP3, CD70, and TIM-1 show durable responses in early trials, though challenges such as dose-limiting toxicities require further investigation. Overall, this review underscores ADC as a transformative approach in uro-oncology, highlighting ongoing advancements in combination strategies and biomarker-driven applications to refine therapeutic outcomes and expand treatment options for these challenging malignancies.

Recent therapeutic advances, particularly Nectin-4-targeted ADCs, anti-TIGIT ICIs, and bispecific antibodies (BsAbs), underscore their clinical promise. This review integrates current understanding of Nectin family members in oncogenesis and immunoregulation, focusing on their biological functions, mechanisms of immune modulation, therapeutic strategies, and remaining challenges in clinical translation.

Furthermore, we propose an innovative four-part mRNA vaccine approach to balance therapeutic effectiveness with clinical practicalities. Both vaccine formulations showed intense immune stimulation in silico, indicating their potential as promising candidates for immunotherapy against TNBC, which will require further experimental exploration.

These findings are hypothesis generating and provide rationale for future clinical trials of ADCs and immune checkpoint inhibitors in VSCC. Results suggest HPV-independent tumors may be immunogenically active.

IDH1-mutant tumors demonstrated attenuated ADC target expression. These data provide rationale for evaluating ADC strategies in CCA.

In vivo, the probe targeted lung cancer tissues, indicating potential for intraoperative navigation. Nectin-4 is a promising target for lung cancer and intraoperative navigation, guiding further research.

These developments reflect a shift toward precision medicine that integrates immunotherapy, antiangiogenic, and targeted agents; however, challenges persist in optimizing treatment sequences, overcoming resistance, and identifying biomarkers to personalize care. Addressing global disparities in prevention and treatment access remains essential to achieving the WHO's goal of eliminating cervical cancer by 2030.

P1/2, N=329, Active, not recruiting, BicycleTx Limited | Recruiting --> Active, not recruiting

These findings identify NECTIN4 amplification as a stable, predictive biomarker that may guide treatment decisions in mUC. Data from TCGA further suggest a cross-entity relevance of NECTIN4 amplification, supporting future clinical exploration of EV in other solid tumors.