ADC Conjugation Strategies: From Technological Evolution to a Practical Selection Framework

Area of Science:

• Oncology
• Biotechnology
• Pharmaceutical Sciences

Background:

• Antibody-drug conjugates (ADCs) are crucial in oncology, with success depending on optimizing antibody, linker, payload, and conjugation.
• Conjugation strategy critically influences ADC properties like drug-to-antibody ratio (DAR), pharmacokinetics, manufacturability, and safety.

Purpose of the Study:

• To review the evolution of ADC conjugation technologies from stochastic to site-specific and site-selective approaches.
• To discuss the trade-offs of each platform and propose a framework for selecting the optimal conjugation strategy.

Main Methods:

• Literature review of ADC conjugation technologies.
• Analysis of clinical and translational examples.
• Development of a selection framework for ADC conjugation platforms.

Main Results:

• ADC conjugation has evolved through three generations: stochastic, site-specific, and site-selective.
• Each generation presents distinct advantages and disadvantages regarding control, complexity, and clinical validation.
• First-generation methods are clinically validated but heterogeneous; second-generation offers control but increases complexity; third-generation aims for simplicity but has limited sites and experience.

Conclusions:

• The choice of ADC conjugation strategy should be tailored to specific program requirements, including payload, desired DAR, antibody stability, manufacturability, and regulatory considerations.
• A practical framework aids in selecting platforms for next-generation ADCs, including dual-payload and bispecific formats.
• No single technology hierarchy exists; selection must be program-specific.