Antibody-drug conjugates (ADCs) are an exciting class of therapeutics currently receiving much interest. Their targeted delivery of cytotoxic agents (payloads) gives them a unique and promising position in oncology research. However, the conjugation processes can be very complex and often require removal of conjugation related impurities further downstream in the manufacturing process. Due to the relatively small size of the payloads and their small corresponding selectivity changes, removal of these impurities can be quite challenging using conventional chromatography resins. While hydrophobic interaction chromatography has shown some success separating such impurities, the potential of multimodal chromatography has been less explored.<br/>In this work, we present a methodology to identify and optimize suitable chromatographic conditions to remove undesired conjugation variants (<i>i.e.</i> unconjugated and under-conjugated species) using multimodal chromatography. First, filter plate binding and elution screening studies were carried out using several resins, salt types of varying kosmotropic strength, and pH values for both the impurities and products conjugated with two different payloads. These screening studies identified suitable separation conditions that were then carried forward to gradient elution column experiments. From the gradient studies, steric mass-action (SMA) model parameters were estimated for column simulation. The operating conditions were then optimized using the column model and the results were verified experimentally.<br/>The results presented here set forth a systematic screening and optimization protocol and demonstrate the utility of multimodal chromatography for ADC purification. Its implementation in process development can help to quickly overcome known challenges in bring these promising therapeutics to clinic.

Utilizing multimodal chromatography and column modeling for antibody-drug conjugate purification

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.