De novo designed single-domain antibodies protect against lethal cobra venom neurotoxicity in vivo

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De novo designed single-domain antibodies protect against lethal cobra venom neurotoxicity in vivo

bioRxiv (preprint) 2026
Max D. Overath, Emil V. S. Lundquist, Kasper H. Björnsson, Samuel Kerwin, Christian P. Jacobsen, Mark von Bülow Møiniche, Diego Ruiz Espi, Kim Boddum, Melisa Benard-Valle, Monica L. Fernández-Quintero, Stephen P. Mackessy, Timothy P. Jenkins

This preprint shows that de novo designed single-domain antibodies (VHHs) can neutralise α-cobratoxin, the long-chain neurotoxin of the monocled cobra, and protect mice against a lethal dose. Flow Induced Dispersion Analysis (FIDA), on a Fida 1 instrument, was the method of first choice for finding which designs bound: the whole set of purified candidates was screened in free solution against fluorescently labelled α-cobratoxin, with complex formation read directly as an increase in the hydrodynamic radius of the labelled toxin. Only the target carried a label, the designs themselves needed none and nothing was immobilised on a surface, and sub-stoichiometric binder was enough to see the complex, so a whole designed library could be triaged in solution from small amounts of protein. Only the candidates FIDA identified were taken forward to a surface-based method for the follow-up characterisation. It is an example of using FIDA as the first-choice, in-solution binding screen across a designed protein library, selecting the few candidates worth characterising further.

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De novo designed single-domain antibodies protect against lethal cobra venom neurotoxicity in vivo
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