Antibody–Drug Conjugate Synthesis Using Continuous Flow Microreactor Technology

Abstract

Continuous flow reactors enable chemical reactions to occur within shielded pipes and tubes. This synthetic process is considered to overcome some limitations of commonly used batch reactors. Many successful examples of the synthesis of small molecules by continuous flow processes have been reported; however, their application in bioconjugation reactions, such as antibody–drug conjugate (ADC) syntheses, is extremely limited in the scientific literature. To our knowledge, we herein report the first continuous flow process-mediated ADC synthesis in the peer-reviewed literature. The optimized mixer type, reaction time, and mixer diameter are discussed. From these results, ADCs with clinically relevant drug–antibody ratios were produced. All of the flow reaction steps were conducted using a scaled-down manufacturing approach utilizing a stepwise mixing system to perform sequential reduction/conjugation processes. Furthermore, the established continuous flow methodology could be applied to combinations of three different antibodies and three different payloads, and the same trends were observed for each of the nine attempted ADC syntheses. These results demonstrate that continuous flow chemistry can be employed to develop reliable and robust processes for producing ADCs.