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Physiology, Biochemistry, and Pathology of Neuromuscular Transmission
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
The venom of the cobra and the banded krait snakes, contain low molecular weight proteins of about 8 kDa, α-cobratoxin and α-bungarotoxin that combine with high affinity to the ACh binding site of the a-subunit of the AChR. Especially the α-bungarotoxin has proven to be a tool of immense value for the research on AChRs and myasthenia gravis.
In vitro discovery of a human monoclonal antibody that neutralizes lethality of cobra snake venom
Published in mAbs, 2022
Line Ledsgaard, Andreas H. Laustsen, Urska Pus, Jack Wade, Pedro Villar, Kim Boddum, Peter Slavny, Edward W. Masters, Ana S. Arias, Saioa Oscoz, Daniel T. Griffiths, Alice M. Luther, Majken Lindholm, Rachael A. Leah, Marie Sofie Møller, Hanif Ali, John McCafferty, Bruno Lomonte, José M. Gutiérrez, Aneesh Karatt-Vellatt
In this study, we demonstrate that a recombinant human monoclonal IgG antibody, discovered and optimized entirely in vitro by phage display technology, was able to neutralize lethality in mice challenged i.v. with whole venom from N. kaouthia when venom and antibody were preincubated before administration. This clearly showcases the utility of in vitro selection methods for the discovery of efficacious antivenom antibodies against animal toxins with reduced immunogenicity, which may be challenging for traditional in vivo-based discovery approaches. Moreover, this study has also elucidated the mechanism of action of the neutralizing antibody using receptor blocking and automated patch clamp electrophysiology assays, which revealed that the antibody could abrogate neurotoxicity by preventing the medically most important toxin present in the venom of N. kaouthia, α-cobratoxin from interacting with the nAChR. This first report of a recombinant monoclonal antibody neutralizing whole venom from a snake thus presents an integrated approach for future discovery and evaluation of recombinant antibodies against toxins from snake and other animal venoms. Our study was designed to assess whether a neutralizing antibody could be generated using the experimental platform described, which was clearly demonstrated. Assessing the therapeutic efficacy of this antibody in a setting that would more closely resemble the actual circumstances of envenoming, i.e., by using a rescue-type neutralization protocol, was beyond the goals of this work and should be approached in future investigations.