Structural Design & Stapling Strategies to Engineer Stable Dual VHH Bispecifics
- From stability to signaling, the rise of covalent constraints: tracing the evolution from early VH–VL disulfide bridges to linker-anchored staples and multi-SS rigidification-solutions that transformed scFv and Fab formats into developable, aggregation-resistant scaffolds while preserving potency and dialing receptor agonism.
- Geometry as a dial, tuning agonism through structure: reviewing how mAb hinge disulfide rewiring and engineered nanobody interfaces exploit compactness and reduced flexibility to favor productive, tuneable receptor clustering, thus moving beyond “on/off” to graded, epitope-independent control
- Convergence of developability and function: highlighting attempts of combining thermostability gains and aggregation resistance alongside precise modulation of signaling