Development of low-cost, field-ready nanobodies against snake venom

PROJECT SUMMARY
Snakebite constitutes one of the largest and most tenacious public health issues on a global scale. Every year,
up to 5 million people will suffer snakebite envenomation, causing approximately 125,000 deaths and 400,000
left with permanent physical disability. Nearly 8,000 snakebites occur in the United States each year. The regions
most affected are in Asia, Africa, Latin America, and Oceania where snakebite has a high socioeconomic impact
on both the local and global economies. As of 2017, the WHO has labeled snakebite as a Category A Neglected
Tropical Disease. Therapies for snakebite victims are animal-based antivenoms, which for over a century have
consisted of the whole sera or purified antibodies of large mammals (horses and sheep) that have been
hyperimmunized with snake venoms. These antivenoms contain a relatively small fraction of effective venom-
specific antibodies, requiring multiple doses that can cause adverse immunogenic effects in patients. Antivenom
also has relatively high batch-to-batch variation and its efficacies are largely species-specific, requiring a match
between the species used in immunization and the venom in need of neutralization. The economics of antivenom
manufacture are challenging to scale to profitability, leading to scarce and unreliable supplies. Further
complicating the issue is the reliance on cold chain storage and distribution and consequential lack of availability
to snakebite victims in remote locations where the bulk of envenomations occur. Despite these issues, antivenom
is one of the few biological therapies that has yet to enter the modern era of mainstream biologics, despite the
presence of an overwhelmingly large patient population.
In order to address the complex medical and economic requirements of snakebite, we propose the use of an
oligoclonal mixture of single-domain antibodies, also known as nanobodies (Nbs). These antibody fragments (15
kDa in molecular weight) are the variable heavy chain regions (VHH) of camelid or shark antibodies with several
attractive properties for the space, including low immunogenicity, high biodistribution and tissue penetration, low
cost of scaled production, and tunable pharmacokinetics. Nbs are also often highly thermostable, allowing for
accessibility in much-needed developing countries. Nbs have long, flexible complementarity-determining regions
(CDRs) which can increase the likelihood of binding conserved or cryptic epitopes on these toxins, allowing for
broad species coverage critical to pan-specificities. Towards this end, Venomyx Therapeutics, Inc. is working in
collaboration with the Chang lab at UCSD to exploit a powerful platform to discover Synthetically Evolved Nbs
(SENs) for high affinity and efficacy against venom targets of interest. Together with the snake venom expertise
at Venomyx, we will generate low-cost, thermostable, broadly-effective Nbs against snake venom toxin as leads
for future development, preclinical testing, and eventual human trials to neutralize venom from snakebite.PROJECT NARRATIVE
Snakebite is a global neglected tropical disease that affects millions of people per year and constitutes one of
the world’s largest public health issues. Treatment currently relies on antiquated animal-based antivenoms that
present significant safety, efficacy, and availability drawbacks. We propose the use of drug discovery techniques
and a particularly well-suited antibody discovery platform to address these issues to discover and produce
modern recombinant antivenoms.