Mechanistic Insights into Anti-Nectin4-VcMMAE-Induced Ocular Toxicity: From Cellular Uptake Pathways to Molecular Modification

作者：Jialing Zhang, Meng Li, W. G. Li, Yuxuan Yang, Gang Wu, Peng Guo, Chuanfei Yu, Lan Wang · 发表于：International Journal of Molecular Sciences · 年份：2025 · DOI：10.3390/ijms26114996 · 被引用次数：4 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Glycosylation and Glycoproteins Research、HER2/EGFR in Cancer Research

Antibody-drug conjugates (ADCs) represent a novel approach to cancer treatment. Enfortumab vedotin (PADCEV), as a prominent example, has demonstrated remarkable clinical efficacy. However, its ocular toxicity has raised concerns. This study aimed to explore the molecular mechanisms underlying PADCEV-induced ocular toxicity. SD rats, whose ocular structures are similar to those of humans, were selected to establish an ocular toxicity model to mimic the human response. In vitro experiments were conducted using human primary corneal epithelial cells, HCE-T. The results confirmed that nectin-4 plays a crucial role in the cellular uptake of PADCEV, and non-specific pinocytosis is also involved. Additionally, a variant was obtained by introducing point mutations in the Fc region of PADCEV, which was found to reduce corneal epithelial toxicity. The findings of this study not only deepen our understanding of ADC-induced ocular toxicity but also provide new insights into optimizing ADC design and enhancing treatment safety.