Abstract

ADC Synthesis in Flow

Graham Jones, Professor/Head, Northeastern University

Antibody-drug conjugates (ADC’s) are a unique and rapidly emerging class of targeted therapeutics. The use of a monoclonal antibody to direct a cytotoxin to a specific cellular target (e.g. the surface antigens of a tumor cell), reduces the potential for bystander toxicity and offers the potential to require lower therapeutic doses of the drug. Central to this strategy is the need for a covalent linker which preserves the fidelity of the conjugate until it reaches target. Simplistic in its approach [oft considered the embodiment of Ehrlich’s ‘magic bullet’ concept] a number of challenging obstacles need to be addressed in the choice of linker and the chemical coupling reactions in order that consistency required for regulatory approval is attained. As the ADC product pipeline grows there is increasing need for robust chemistries which allow selective and efficient functionalization of the antibody cores for introduction of appropriate linkers and spacer groups. Under conventional bioconjugation conditions product heterogeneity often results, and the drug-to-antibody ratios (DAR) are inconsistent. Based on our experience in protein derivatization we have investigated the potential for continuous flow microreactor technology to expedite and facilitate such processes.