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, π-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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This work was supported by Global Research Technologies, Novo Nordisk A/S.
The authors declare no competing interests.
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- Affinity maturation
The process of improving the binding affinity between an antibody and its target.
Molecules recognized by antibodies via a binding event that induces complexation between antibody and antigen.
The suitability of a drug candidate for successful development into a therapeutic. Includes considerations of feasibility of bioprocesses like expression and purification, suitability of formulation (stability during storage and administration), and in vivo behaviour such as immunogenicity potential and optimal in vivo half-life.
The specific structural and molecular feature or region that is recognized by the antibody.
- Monoclonal antibodies (mAbs)
Antibodies encoded with the same genetic code, hence sharing a single defined protein sequence.
- Off-target binding
The binding of the antibody to targets other than the intended one; may be sub-classified as poly-specific or non-specific binding.
The antigen-binding site of an antibody capable of recognizing a specific epitope.
Reversible interactions of the antibody with itself, leading to dimer, trimer, oligomer and larger network formation. Commonly manifested as, for example, poor solubility, phase separation or high solution viscosity.
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Ausserwöger, H., Schneider, M.M., Herling, T.W. et al. Non-specificity as the sticky problem in therapeutic antibody development. Nat Rev Chem 6, 844–861 (2022). https://doi.org/10.1038/s41570-022-00438-x