B.J. Berube
HDT Bio Corp., Washington, United States
Keywords: toxin countermeasures, botulinum neurotoxin, LION nanoparticles, biodefense, rapid response platform
Biological toxins present high-priority threats to national security due to their extreme potency, ease of dissemination, and limited treatment options. To address this threat, we developed a versatile therapeutic platform based on replicating RNA (repRNA) encoding for high-affinity nanobodies - single domain camelid antibodies - that can be rapidly adapted to neutralize an array of toxins. The platform integrates immunization of alpacas with inactivated toxins, high-throughput screening for neutralizing nanobodies, and in silico optimization to identify binders with enhanced potency and breadth. Selected nanobodies are encoded into repRNA and formulated with our RNA delivery platform, LION™, for in vivo delivery and expression. To validate the platform, we applied this approach to Botulinum neurotoxin (BoNT), the most potent biological toxin known. The current treatment, equine-derived heptavalent botulinum antitoxin (HBAT), has limitations in efficacy, scalability, and response time. In a murine model of lethal BoNT intoxication and in a guinea pig trigger-to-treat model, which simulates delayed therapeutic administration, our repRNA/LION product conferred 100% protection, outperforming HBAT in both cases. These results highlight the platform’s ability to generate potent, fast-acting countermeasures with a favorable therapeutic window.