Anticalins: A viable alternative to nanobodies? -from discovery to AI-driven development: A review

Anticalins are a class of small, human-derived protein binders engineered from the lipocalin scaffolds and are increasingly discussed as an alternative to nanobodies. With a molecular weight of approximately 20 kD and a fully human protein framework, Anticalins generally exhibit low immunogenicity, high structural stability, and favorable tissue penetration. In this review, we outline key milestones in Anticalin development, summarize commonly used library construction and screening strategies, and provide an overview of their current clinical progress. We further compare Anticalins with nanobodies with respect to structural organization, humanization requirements, and engineering flexibility, highlighting features that arise from their fully human origin. In addition, recent advances in artificial intelligence are briefly discussed in the context of Anticalin research, particularly in structure modeling and affinity optimization, where AI-assisted approaches are beginning to complement established experimental workflows. Taken together, available evidence suggests that Anticalins represent a versatile binder modality with distinct strengths, rather than a direct replacement for nanobodies, and may find particular value in selected therapeutic and diagnostic applications as computational and experimental platforms continue to evolve.