Development of world's first fully human broad spectrum anti-snake venom

ABSTRACT In this Phase I SBIR grant, Distributed Bio proposes to develop the next generation of safer and more effective antivenom biotherapeutics by isolating and characterizing broadly neutralizing fully human antivenom antibodies for treating snakebite envenoming. In 2018, snakebite envenoming continues to be ranked on the World Health Organization’s list of neglected tropical diseases, killing between 81,000- 138,000 people and leaving another 150,000 permanently disabled Over 4,000 snakebite envenoming cases were reported in 2016 to United States Poison Control Centers, where 59.3% resulted in moderate to major outcomes and 3 deaths. Besides native venomous species including copperheads, coral snakes, cottonmouths and rattlesnakes, exotic snake species also pose a risk, with 50 exotic venomous snake envenoming cases reported in 2016. For over a century, snakebite envenoming treatment has been immunotherapy with animal-derived antivenom preparations containing either immunoglobulin G (IgG) or derivative antigen-binding fragments (Fabs) from a single venom. While effective, heterologous antivenom serotherapies present several challenges; depending on the antivenom, up to 59% of patients experience early-onset adverse reactions to animal plasma derived antivenoms including early adverse anaphylactic reactions. Polyclonal Fab based formulations can lead to treatments with shortened half-lives and inconsistent batch quality in comparison to monoclonal IgGs. Antivenom developed for a single species requires the correct identification of the specific snake that bit the victim, which can be almost impossible for bite victims and healthcare workers not well-versed in snake phenotypes. Although a global public health problem, major pharmaceutical companies do not invest in improved envenoming treatments due to the venom toxin heterogeneity across species. This Aims of this project are designed to isolate and characterize broadly neutralizing fully human antivenom antibodies to treat snakebite envenoming. Monoclonal fully human-derived IgG will greatly reduce the potential for adverse effects pervasive in animal-derived antivenom, as it creates molecules with low immunogenicity that could relatively be easily optimized to have better safety profiles and potentially higher efficacy. In addition, antibodies will be thermostabilized antibodies to have more lenient storage requirements, longer-shelf life, greatly expanding the types of health centers that can store and access it. Distributed Bio will identify and characterize a pool of cross-reactive, high affinity antibody candidates and characterize whole venom pool epitopes. The efficacy of the antivenom antibodies will be studied in mice by performing in vivo challenge studies. The Distributed Bio approach to designing and developing a universal antivenom vaccine has far-reaching potential in medical practice.NARRATIVE Snakebite envenoming is ranked on the World Health Organization’s list of neglected tropical diseases, killing between 81,000- 138,000 people each year and leaving 150,000 permanently disabled. Available antivenoms suffer from a variety of drawbacks including serious side effects; large pharmaceutical companies do not invest in developing improved antivenoms due to the large diversity of venom toxins across snake species. In this application, Distributed Bio will develop a single, effective antivenom capable of neutralizing venom from many snake species with inherent reduced potential for negative side effects. If successful, this broadly neutralizing antivenom would represent a significant step forward in tackling this neglected tropical disease.