期刊
NATURE REVIEWS CHEMISTRY
卷 6, 期 12, 页码 844-861出版社
NATURE PORTFOLIO
DOI: 10.1038/s41570-022-00438-x
关键词
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资金
- Global Research Technologies
- Novo Nordisk A/S
This article reviews the physicochemical origins of non-specific interactions in antibodies and discusses the role of surface patches in inducing these interactions. These non-specific interactions have an impact on macroscopic development issues such as the physical stability and in vivo half-life of drugs. The article highlights the challenges and opportunities for optimizing protein binding specificity and minimizing non-specificity.
Antibodies are highly potent therapeutic scaffolds with more than a hundred different products approved on the market. Successful development of antibody-based drugs requires a trade-off between high target specificity and target binding affinity. In order to better understand this problem, we here review non-specific interactions and explore their fundamental physicochemical origins. We discuss the role of surface patches - clusters of surface-exposed amino acid residues with similar physicochemical properties - as inducers of non-specific interactions. These patches collectively drive interactions including dipole-dipole, pi-stacking and hydrophobic interactions to complementary moieties. We elucidate links between these supramolecular assembly processes and macroscopic development issues, such as decreased physical stability and poor in vivo half-life. Finally, we highlight challenges and opportunities for optimizing protein binding specificity and minimizing non-specificity for future generations of therapeutics.
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