Predicting Response to Antibody Drug Conjugates: A Focus on Antigens' Targetability

Area of Science:

• Oncology
• Pharmacology
• Biomarker Discovery

Background:

• Antibody-drug conjugates (ADCs) are key cancer therapeutics, delivering cytotoxic payloads by targeting tumor cell surface antigens.
• The 'bystander' effect allows ADCs to impact nearby cells lacking target antigen expression.
• Historically, specific target antigen expression was required for ADC clinical trial inclusion and approval.

Purpose of the Study:

• To investigate the role of target antigens as predictive biomarkers for antibody-drug conjugate (ADC) efficacy.
• To explore new biomarkers for guiding ADC use and sequencing, especially with multiple ADCs available.
• To examine antigen targetability based on surface expression or specific genetic aberrations (mutation, overexpression).

Main Methods:

• Review of approved ADCs and their biomarker requirements (e.g., ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, mirvetuximab soravtansine-gynx).
• Analysis of ADCs used without strict biomarker-based patient selection (e.g., sacituzumab govitecan).
• Discussion of novel assessment methods for target expression, including molecular imaging and in vitro assays.

Main Results:

• While some ADCs require specific antigen expression for approval, others are clinically used without this restriction.
• Target antigen characteristics (surface expression, mutations, overexpression) influence ADC efficacy and patient selection.
• Emerging technologies like molecular imaging offer potential for improved target assessment and patient stratification.

Conclusions:

• Identifying and quantifying target antigens is crucial for optimizing ADC therapy and patient selection.
• Advanced assessment methods are needed to refine biomarker analysis for better treatment outcomes.
• Robust biomarkers are essential for establishing optimal therapeutic sequences in the evolving landscape of ADC treatments.