Anticalin® proteins: from bench to bedside

Introduction Anticalin proteins are engineered versions of lipocalins that constitute a novel class of clinical-stage biopharmaceuticals. The lipocalins exhibit a central β-barrel with eight antiparallel β-strands and an α-helix attached to its side. Four structurally variable loops at the open end of the β-barrel form a pronounced binding pocket, which can be reshaped to generate specificities toward diverse disease-relevant molecular targets.Areas covered This article reviews the current status of Anticalin engineering, from the basic principles to the development of Anticalins with high target affinity and specificity via combinatorial protein design and directed evolution, including examples of Anticalin-based drug candidates under preclinical and clinical development.Expert opinion Combinatorial gene libraries together with powerful molecular selection techniques have enabled the expansion of the natural ligand specificities of lipocalins from small molecules to peptides and proteins. This biomolecular concept has been validated by structural analyses of a series of Anticalin•target complexes. Promising Anticalin lead candidates have reached different preclinical and clinical development stages in the areas of (immuno)oncology, metabolic, and respiratory diseases, as antidotes to treat intoxications and as novel antibiotics. Thus, Anticalins offer an alternative to antibodies with promising and potentially superior features as next-generation biologics.