Real-Time Observation of Protein Aggregates in Pharmaceutical Formulations Using Liquid Cell Electron Microscopy

Lynn M. DiMemmo, A. Cameron Varano, Jonathan Haulenbeek, Yanping Liang, Kaya Patel, Madeline J. Dukes, Songyan Zheng, Mario Hubert, Steven P. Piccoli and Deborah F. Kelly, 2016

Image courtesy of Lab on Chip


Understanding the properties of protein-based therapeutics is a common goal of biologists and physicians. Technical barriers in the direct observation of small proteins or therapeutic agents can limit our knowledge of how they function in solution and in the body. Electron microscopy (EM) imaging performed in a liquid environment permits us to peer into the active world of cells and molecules at the nanoscale. Here, we employ liquid cell EM to directly visualize a protein-based therapeutic in its native conformation and aggregate state in a time-resolved manner. In combination with quantitative analyses, information from this work contributes new molecular insights toward understanding the behaviours of immunotherapies in a solution state that mimics the human body.

Impact Statement

Aggregation of protein derived drugs leads to reduced efficacy, shelf life and immunogenic responses in patients. In this study, the the aggregation behavior of the drug, PEGylated Interferon α2a, was studied in response to different conditions using LC-TEM. Researchers were able to observe aggregate migration, association and growth in solution of protein based therapeutics through the use of LC-TEM which can n provide insight into strategies for prevention of protein aggregation and thereby reduce potential for immunogenic responses in patients during drug therapy.
Keywords: Pharmaceuticals, drugs, antibodies, aggregation