Antibody-drug conjugates in precision oncology

Area of Science:

• Oncology
• Pharmacology
• Biomarker Development

Background:

• Antibody-drug conjugates (ADCs) are a rapidly expanding therapeutic class in oncology, achieving significant clinical successes.
• Despite successes, ADC efficacy is limited to specific tumor types, with frequent clinical setbacks due to challenges in patient selection, biomarker standardization, chemical design, and preclinical model limitations.
• Current ADC development often lacks validated biomarkers, with activity influenced by factors beyond target antigen expression, including tumor-intrinsic features and the tumor microenvironment.

Purpose of the Study:

• To review the successes and setbacks of antibody-drug conjugates (ADCs) in oncology.
• To link ADC performance to mechanisms of efficacy, resistance, and toxicity.
• To discuss the role of biomarkers, ADC combinations, novel platforms, and curative strategies in precision oncology.

Main Methods:

• Literature review synthesizing current evidence on ADC development and clinical outcomes.
• Analysis of factors influencing ADC efficacy, resistance, and toxicity.
• Discussion of emerging concepts in ADC therapy, including tumor ecosystem targeting and multidimensional determinants.

Main Results:

• ADC activity is influenced by a complex interplay of factors, including tumor-intrinsic features and the tumor microenvironment, not solely target antigen expression.
• Existing preclinical models have limited predictive value for ADC efficacy.
• A shift in conceptualizing ADCs from strictly targeted agents to tumor-ecosystem-targeting therapies is supported by emerging evidence.

Conclusions:

• Antibody-drug conjugates (ADCs) represent a promising but challenging therapeutic modality in oncology.
• Future precision oncology frameworks must integrate advanced biomarkers, combination strategies, next-generation platforms, and curative-intent approaches to overcome current limitations.
• Understanding ADCs as therapies targeting the broader tumor ecosystem is crucial for maximizing their clinical benefit.