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.