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Updated: Jul 6, 2026
Intravitreous Injection for Establishing Ocular Diseases Model
Published on: October 1, 2007
Mechanistic Insights into Anti-Nectin4-VcMMAE-Induced Ocular Toxicity: From Cellular Uptake Pathways to Molecular
Jialing Zhang1, Meng Li1, Weiyu Li1
1Division of Monoclonal Antibodies, Institute for Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China.
Abstract:
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.
Insights
Enfortumab vedotin (PADCEV) causes ocular toxicity by binding to nectin-4 and through pinocytosis. Modifying PADCEV
Area of Science:
- Oncology
- Ophthalmology
- Molecular Biology
Background:
- Antibody-drug conjugates (ADCs) are a promising cancer therapy.
- Enfortumab vedotin (PADCEV) shows efficacy but causes ocular toxicity.
- Understanding PADCEV's ocular toxicity mechanisms is crucial for patient safety.
Purpose of the Study:
- To investigate the molecular mechanisms of enfortumab vedotin (PADCEV)-induced ocular toxicity.
- To identify key factors involved in PADCEV cellular uptake in ocular tissues.
- To explore strategies for mitigating PADCEV-related ocular side effects.
Main Methods:
- Established an ocular toxicity model in Sprague Dawley (SD) rats.
- Conducted in vitro experiments using human primary corneal epithelial cells (HCE-T).
- Utilized a modified PADCEV variant with Fc region point mutations.
Main Results:
- Nectin-4 was identified as a critical factor for PADCEV cellular uptake.
- Non-specific pinocytosis also contributes to PADCEV uptake.
- A PADCEV variant with Fc region mutations demonstrated reduced corneal epithelial toxicity.
Conclusions:
- Nectin-4 and pinocytosis are key mediators of PADCEV ocular toxicity.
- Fc region modification offers a potential strategy to reduce ADC-induced ocular toxicity.
- Findings inform safer ADC design and improved cancer treatment strategies.
