Engineering TGF-β superfamily ligands for clinical applications

•TGF-β superfamily ligands are amenable to therapeutic protein engineering.•Crystal structures of TGF-β superfamily ligands reveal that they share a similar architecture.•Ligands can be divided into six structural segments, providing a basis for the random assembly of segmental chimera and heteromers.•Through segmental recombination an enormous number of chimeric ligands can be created.

TGF-β superfamily ligands govern normal tissue development and homeostasis, and their dysfunction is a hallmark of many diseases. These ligands are also well defined both structurally and functionally. This review focuses on TGF-β superfamily ligand engineering for therapeutic purposes, in particular for regenerative medicine and musculoskeletal disorders. We describe the key discovery that structure-guided mutation of receptor-binding epitopes, especially swapping of these epitopes between ligands, results in new ligands with unique functional properties that can be harnessed clinically. Given the promising results with prototypical engineered TGF-β superfamily ligands, and the vast number of such molecules that remain to be produced and tested, this strategy is likely to hold great promise for the development of new biologics.