Bench-to-Bedside Perspectives on Ocular Toxicity of Antibody-Drug Conjugates: Toxicology, Clinical Management and
Jialing Zhang1, Weiyu Li1, Meng Li1
1State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, Zip code: 102629, P.R. China.
Objectives:
The present review aims to provide comprehensive bench-to-bedside insights into ADC-related ocular toxicity for drug designers, pharmaceutical manufacturers, toxicologists, and medical staff, thereby enhancing the safety of ADC therapeutic applications.
Methods:
The review comprehensively analyzes the recent progress in the pathological mechanisms of ADC-related ocular toxicity, evaluates existing non-clinical risk assessment strategies based on animal toxicological studies, and highlights future optimization directions. It also summarizes clinical adverse events to demonstrate the typical profile of ocular surface toxicity and provides clinical management strategies.
Results:
ADC ocular toxicity primarily affects the ocular surface via on-target (antibody-mediated) and off-target (non-specific uptake) mechanisms. Key determinants include payload type (e.g., MMAF and DM4, which exhibit higher toxicity due to intracellular retention), linker properties (cleavable linkers mitigate off-target effects), and ADCs' physicochemical characteristics. Non-clinical models effectively predict corneal injury but poorly recapitulate conjunctival responses. Clinical management relies on early ophthalmic monitoring and dose adjustment, with 42.9%-100% of adverse events being reversible.
Conclusion:
This review offers valuable insights into ADC ocular toxicity, emphasizing the importance of early-stage selection and optimization of ADCs and their components to reduce ocular toxicity risks. It provides a reference for mitigating ADC-related ocular toxicity risks and facilitates the future development of ADCs with improved safety and efficacy.
Insights
Antibody-drug conjugate (ADC) ocular toxicity impacts the ocular surface through on-target and off-target mechanisms. Early selection and optimization of ADCs and components are crucial for reducing risks.
Area of Science:
- Pharmacology
- Toxicology
- Ophthalmology
Background:
- Antibody-drug conjugates (ADCs) are targeted therapies with potential for ocular toxicity.
- Understanding ADC ocular toxicity is critical for safe therapeutic applications.
Purpose of the Study:
- To provide bench-to-bedside insights into ADC-related ocular toxicity.
- To enhance the safety of ADC therapeutic applications for drug designers, manufacturers, toxicologists, and medical staff.
Main Methods:
- Comprehensive analysis of pathological mechanisms of ADC ocular toxicity.
- Evaluation of non-clinical risk assessment strategies using animal models.
- Summary of clinical adverse events and management strategies.
Main Results:
- ADC ocular toxicity affects the ocular surface via on-target and off-target mechanisms.
- Payload type, linker properties, and ADC physicochemical characteristics are key determinants.
- Non-clinical models predict corneal injury but not conjunctival responses; clinical management involves monitoring and dose adjustment, with reversible adverse events.
Conclusions:
- Early-stage selection and optimization of ADCs and their components are vital for reducing ocular toxicity risks.
- This review serves as a reference for mitigating ADC-related ocular toxicity.
- Facilitates the future development of safer and more effective ADCs.
Related Concept Videos
01:28Biopharmaceutics and Pharmacokinetics: Overview
01:22Bioavailability Enhancement: Determination and Conceptual Approaches in Overcoming Bioavailability Problems
01:28Preclinical Development: Overview
01:21Drug Distribution: Tissue Binding
For...
01:16Drug Biotransformation: Overview
01:22Biopharmaceutical Factors Influencing Drug Product Design: Overview