Rapid Systematic Screening\nof Bispecific Antibody\nSurrogate Geometries for T‑Cell Engagement Using DNA Nanotechnology

Bispecific antibodies (bsAbs) are emerging immune-therapeutics,\nand many formats exist that differ considerably in structure. However,\nlittle systematic data exist about how the spatial organization of\ntheir components influences activity, requiring innovative approaches\ncombining empirical and quantitative frameworks. This study presents\na modular DNA nanotechnology platform to generate numerous bsAbs with\nsurrogate geometries that span the structural features of the BiTE,\nIgG-like, and IgG-conjugate platforms to screen for T-cell engagement.\nResults highlight interesting structure–activity relationships\nregarding bsAb potency and selectivity and raise questions regarding\nthe molecular phenomena underlying activity. To elucidate some effects,\nthe platform was paired with a simple mathematical model. This work\nis thus one of the first to systematically investigate and reveal\nthe importance of the spatial organization of bsAb components on activity\nand equally provides an accessible and convenient tool for rapidly\nmapping out such trends for other combinations of target epitopes.