CDH6 (Cadherin 6)

Currently, three ADCs have received Food and Drug Administration (FDA) approval for use in gynecologic malignancies: mirvetuximab soravtansine, tisotumab vedotin, and trastuzumab deruxtecan. Furthermore, the inherent complexities of these drugs and their mechanisms of action underscore the need for further research into the relevance of biomarkers, methods of therapy resistance, and the potential for re-utilization of payloads and targets later in the disease course. This review focuses on the mechanisms of action of ADCs, their developmental trajectory, successes in gynecologic cancers, emerging areas of investigation, the prospective landscape, and current challenges in the field.

Current literature is dominated by correlative and in-vitro studies, and prospective clinical validation is scarce. GARS is a promising but incompletely defined oncologic and immunobiologic node; targeted, standardized, and clinically anchored studies are now feasible and necessary.

This study represents the most extensive molecular characterization of RMC to date, identifying TROP2 and other potential therapeutic targets. Sacituzumab govitecan demonstrates potential clinical benefit, warranting further evaluation in prospective trials to confirm its efficacy and explore additional targets identified herein.

Enfortumab vedotin is an NECTIN4-targeting antibody-drug conjugate that is approved for the treatment of urothelial cancer, whereas other ADCs or derivatives that target NECTIN4, such as bulumtatug fuvedotin, SHR-A2102 and zelenectide pevedotin, are being studied in randomized phase III clinical trials. In contrast, arcotatug tavatecan, garetatug rezetecan, sonesitatug vedotin and tecotabart vedotin are anti-CLDN18.2 ADCs in phase III clinical trials for the treatment of CLDN18.2-positive gastric or gastroesophageal junction adenocarcinomas, and raludotatug deruxtecan is an anti-CDH6 ADC in a phase II/III clinical trial for the treatment of platinum-resistant ovarian cancer. ADCs that target cell-cell adhesion molecules are a rapidly emerging class of cancer therapeutics, and bispecific ADCs and longitudinal companion diagnostics are emerging to further improve the clinical benefits of conventional ADCs.

Notably, 3C-toxin showed superior target promiscuity compared to traditional DT3C methods, expanding applicability to a broader range of antigens. This platform provides a scalable solution for antibody internalization analysis, positioned to accelerate ADC discovery by providing reliable early-stage screening metrics.

CDH6 expression is elevated in RA FLS due to epigenetic and local conditions of synovitis promoting migration, survival and cell growth, which are characteristic features of aggressive RA FLS. The intracellular distribution suggests additional functions beyond adhesion and homotypic aggregation, such as signaling and gene regulation. These data suggest CDH6 contributes to RA pathogenesis by influencing pathologic FLS behavior and could be a therapeutic target.

CUSP06 demonstrated a favorable safety profile in GLP-compliant toxicology studies in Sprague Dawley rats and cynomolgus monkeys. The preclinical data highlighted the therapeutic potential of CUSP06 in multiple CDH6-positive human cancers.

Indeed, higher expression of TRIM29, S100P and β-catenin associates with reduced recurrence free survival. This work proposes TRIM29 as an important node that modulates a unique gene network in chemoresistant TNBC and whose biological impact is mediated by modulation of S100P and β-catenin.

Notably, miR-1233-3p had the opposite effect and reversed the promotion effect of circ_0000517 on the malignant biological behavior of NSCLC cells. Our study revealed a promising novel endogenous regulatory network that m6A-modified circ_0000517 accelerated malignant evolution of NSCLC by targeting the miR-1233-3p/CDH6 axis.

The molecularly classified EC-PDX panel, enriched with detailed antigen profiles and genetic data, provides a robust platform for investigating novel ADC therapies and precision treatment strategies for high-grade EC.

P=N/A, N=70, Active, not recruiting, Peking University People's Hospital

Although platinum-based chemotherapy, PARP inhibitors and bevacizumab have prolonged long term survival and increased the overall response rate for platinum-sensitive ovarian cancer (PSOC), the treatment options for platinum-resistant ovarian cancer (PROC) are still limited. Since mirvetuximab soravtansine (MIRV) received approval by the US Food and Drug Administration (FDA) as the first ADC for PROC in 2022, the development of novel ADCs for various targets in PROC has accelerated. In this review, we summarise the recent evidence and future prospects of ADCs targeting Folate Receptor alpha (FRα), mesothelin, cadherin-6, NaPi2b, human epidermal growth factor receptor 2 (HER2), dipeptidase 3 (DPEP3), B7-H4 (VTCN1), claudin-6 (CLDN6) and trophoblast antigen protein 2 (TROP2), in order to enhance our understanding of the clinical applications of ADCs and offer new insights for clinical practice and further research.