Non-covalent albumin-binding ligands for extending the circulating half-life of small biotherapeutics

Peptides and small protein scaffolds are gaining increasing interest as therapeutics. Similarly to full-length antibodies, they can bind a target with a high binding affinity and specificity while remaining small enough to diffuse into tissues. However, despite their numerous advantages, small biotherapeutics often suffer from a relatively short circulating half-life, thus requiring frequent applications that ultimately restrict their ease of use and user compliance. To overcome this limitation, a large variety of half-life extension strategies have been developed in the last decades. Linkage to ligands that non-covalently bind to albumin, the most abundant serum protein with a circulating half-life of ∼19 days in humans, represents one of the most successful approaches for the generation of long-lasting biotherapeutics with improved pharmacokinetic properties and superior efficacy in the clinic. This review provides a detailed examination and comparison of the diverse non-covalent albumin-binding ligands developed until now to extend the half-life of different small biotherapeutics.