期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 429, 期 8, 页码 1244-1261出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2017.03.014
关键词
protein folding; monoclonal antibody; protein aggregation; protein engineering
资金
- Boehringer Ingelhelm Pharma GmbH Co.
- VIB
- University of Leuven
- Funds for Scientific Research Flanders (FWO)
- Flanders Institute for Science and Technology (IWT)
- Federal Office for Scientific Affairs of Belgium (Belspo) [IUAP P7/16]
- European Research Council under European Union, ERC [647458]
Protein aggregation remains a major area of focus in the production of monoclonal antibodies. Improving the intrinsic properties of antibodies can improve manufacturability, attrition rates, safety, formulation, titers, immunogenicity, and solubility. Here, we explore the potential of predicting and reducing the aggregation propensity of monoclonal antibodies, based on the identification of aggregation-prone regions and their contribution to the thermodynamic stability of the protein. Although aggregation-prone regions are thought to occur in the antigen binding region to drive hydrophobic binding with antigen, we were able to rationally design variants that display a marked decrease in aggregation propensity while retaining antigen binding through the introduction of artificial aggregation gatekeeper residues. The reduction in aggregation propensity was accompanied by an increase in expression titer, showing that reducing protein aggregation is beneficial throughout the development process. The data presented show that this approach can significantly reduce liabilities in novel therapeutic antibodies and proteins, leading to a more efficient path to clinical studies. (C) 2017 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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