Advancing Antivenom Therapy with ADDovenom: Targeting Neurotoxins in Mamba Snake Envenoming Using ADDobodies and ADDomers

The proposed project seeks to address the current deficiencies in antivenom treatment for snakebite envenoming (SBE) and alleviate
the substantial burden of mortality and morbidity caused by this Neglected Tropical Disease. SBE affects economically and medically
disadvantaged farming communities in Asia, sub-Saharan Africa, and Latin America, leading to up to 138,000 deaths and 400,000
disabilities annually.
Currently, a major obstacle stems from the weak efficacy of existing antivenoms derived from hyperimmunized animals, requiring the
usage of multiple vials and leading to increased adverse effects and treatment costs. Additionally, the wide variation in snake venoms
at different taxonomic levels, especially with low-molecular mass toxins displaying limited immunogenicity, further complicates the
issue with antivenom development.
The proposed project is part of the larger ADDOvenom initiative but will have a specific focus on neutralizing the effects of
neurotoxins responsible for descending neuromuscular paralysis after envenoming by Dendroaspis mambas. The project will select
toxin candidates from mambas venoms and use them as a basis for designing consensus-toxins with cross-affinity towards different
neurotoxins. These engineered consensus-toxins and original toxins will then be recombinantly produced to search for effective
binders.
To identify the specific agents with high affinity for the target toxins, the project will employ the advanced technique of Ribosome
Display. This involves a diverse DNA library encoding ADDobodies, which are adenovirus-based protein scaffolds with the capacity to
bind various molecules. Through in vitro evolution, these ADDobodies will be refined to effectively neutralize neurotoxins, offering a
promising treatment for envenoming by the Dendroaspis mambas.