Engineering growth factor ligands and receptors for therapeutic innovation

HighlightsGrowth factors play pivotal roles in controlling cellular activities in the context of health and disease, and serve as a crucial therapeutic target in cancer.Engineering natural growth factor ligands or receptors represents a promising and emerging approach within the realm of molecular design.Several growth factor pathways have been engineered for therapeutic development, including the vascular endothelial growth factor, epidermal growth factor, nerve growth factor, platelet-derived growth factor, and insulin-like growth factor systems.Strategies for engineering growth factor receptors include the design of decoy receptors to sequester growth factor ligands and vaccines that incorporate mutated growth factor receptor fragments.Strategies for engineering growth factor ligands include molecular fusions, dual specificity formulations, and affinity modulation.AbstractGrowth factors signal through engagement and activation of their respective cell surface receptors to choreograph an array of cellular functions, including proliferation, growth, repair, migration, differentiation, and survival. Because of their vital role in determining cell fate and maintaining homeostasis, dysregulation of growth factor pathways leads to the development and/or progression of disease, particularly in the context of cancer. Exciting advances in protein engineering technologies have enabled innovative strategies to redesign naturally occurring growth factor ligands and receptors as targeted therapeutics. We review growth factor protein engineering efforts, including affinity modulation, molecular fusion, the design of decoy receptors, dual specificity constructs, and vaccines. Collectively, these approaches are catapulting next-generation drugs to treat cancer and a host of other conditions.