Matchmaking at the cell surface using bispecifics to put cells on their best behavior.

Intermolecular relationships at the cell surface dictate the behavior and regulatory network of cells. Such interactions often require precise spatial control for optimal response. By binding simultaneously to two different target sites, bispecific binders can bridge molecules of interest. Despite decades of bispecific development, only recently have bispecifics been engineered with programmable, tuneable geometries to replicate natural interaction geometries or achieve new responses from unnatural arrangements. This review highlights emerging methods of protein engineering and modular bioconjugation to control pairing and orientation of binders in bispecific scaffolds. We also describe novel biophysical and phenotypic assays, which reveal how bispecific geometries change cell fate. These approaches are informing design of next-generation precision therapeutics, as well as uncovering fundamental features of signal integration.