Mechanisms of Resistance to Antibody-Drug Conjugates

Area of Science:

• Oncology
• Pharmacology
• Biotechnology

Background:

• Drug resistance remains a significant challenge in cancer therapy, limiting treatment efficacy.
• Antibody-drug conjugates (ADCs) are engineered therapeutics delivering cytotoxic payloads to cancer cells via tumor-specific antigens.
• Mechanisms of resistance to ADCs are not fully understood, but preclinical studies suggest multifactorial origins.

Purpose of the Study:

• To review recent advancements in understanding drug resistance to antibody-drug conjugates (ADCs).
• To highlight emerging mechanisms of resistance specific to ADC structure and function.
• To discuss strategies for developing preclinical models of ADC resistance.

Main Methods:

• Literature review of preclinical studies on ADC resistance.
• Analysis of emerging resistance mechanisms including antigen downregulation, drug efflux, and intracellular processing.
• Discussion of approaches to generate and characterize ADC-refractory models.

Main Results:

• Resistance to ADCs can arise from decreased cell-surface antigen expression, reduced antibody binding, and increased drug transporter activity (e.g., MDR1, MRP1).
• Novel resistance mechanisms include altered antibody trafficking, impaired ADC processing, and inefficient intracellular drug release.
• The modular design of ADCs offers opportunities to engineer second-generation therapies overcoming acquired resistance.

Conclusions:

• Understanding the diverse mechanisms of ADC resistance is critical for advancing cancer treatment.
• Development of preclinical models is essential for characterizing and overcoming resistance.
• Engineering next-generation ADCs holds promise for improving durable responses in cancer patients.