Structural characterization of key venom toxin neutralization vulnerabilities (360G-Wellcome-227858_Z_23_Z)

Snakebite is one of the world’s most Neglected Tropical Diseases. It primarily affects impoverished people but is absent from the global health agenda and receives limited resources which perpetuates poverty cycles. Snakebite is also associated with stigma / social exclusion. More than 500,000 individuals are killed or maimed by snakes annually, and this is set to increase as we continue to encroach on the natural world and drive habitat redistribution by climate change. Currently, antivenom is the only effective treatment for envenomation, but its manufacture relies on an extremely outdated technology of plasma therapy from animals (primarily horses). It is allergenic, impure, unstable, and has to be administered in large doses at a hospital. To develop highly specific, thermostable, modern antivenoms, we need a better understanding of the key toxins responsible for poor outcomes, their mode of action, and how they can be neutralized. Here, we will isolate monoclonal antibodies from South African antivenom producing horses that target single toxins or toxin families, as well as broadly cross-reactive antibodies that recognise conserved protein motifs required for function, or specific toxin folds independent of sequence homology. These data will reveal key vulnerabilities that can be exploited by modern monoclonal recombinant antivenoms.