Non-specificity as the sticky problem in therapeutic antibody development

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.

Automated summary

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.