Anticalins®: the lipocalin family as a novel protein scaffold for the development of next-generation immunotherapies

Anticalins are engineered ligand-binding proteins based on the human lipocalin scaffold. Their architecture is characterized by a rigid beta-barrel that supports four structurally hypervariable loops. Similar to antibodies, these loops form the natural ligand-binding site, usually for vitamins, hormones or secondary metabolites. Anticalins with novel specificities can be engineered by reshaping this loop region, using targeted random mutagenesis in combination with functional display and guided selection. Several drug candidates with specificities for exogenous low-molecular-weight substances, peptides and even protein targets (e.g., several disease-related cell surface receptors) have been obtained in this way. Owing to their exquisite specificity and high affinity, Anticalins are particularly attractive as antagonists for the manipulation of immune mechanisms, leading to either inhibitory or stimulatory effects. Compared with antibodies, Anticalins offer several practical advantages as they are much smaller, consist of a single polypeptide chain and can be produced easily in microbial expression systems.