1a. Objectives (from AD-416):
The objective of this cooperative research project is to use anti-botulism monoclonal antibodies to modulate circulating toxin levels in order to identify small molecules capable of inhibiting neurotoxin activity in vivo. Initial efforts will focus on identification of small molecules suitable for inhibiting toxin serotype A.
1b. Approach (from AD-416):
The USDA has a general interest in detection and prevention of foodborne botulism. The USDA ARS Foodborne Contaminants Research Unit, located in Albany, California, has developed a series of high-affinity monoclonal antibodies to botulinum neurotoxin and these have been formatted into sensitive immunoassays for detecting botulism in foods. Furthermore, many of these antibodies are capable of neutralizing toxin and rescuing animals after exposure. PanThera Biopharma LLC is a private company focused on addressing the urgent need for new drugs to combat emerging infectious diseases and potential biowarfare agents. PanThera’s proprietary technologies and its expertise in structure-based drug design, medicinal chemistry and high throughput virtual screening will result in the development and delivery of safe, effective drugs against life-threatening diseases. PanThera is developing an effective drug for the treatment of botulism. This project combines the resources and efforts of PanThera with those of ARS to produce synergistic results and further our understanding of botulinum neurotoxin. PanThera will utilize the USDA monoclonal antibodies as aids in identifying small molecule therapeutic drugs that can be used to treat botulism.
3. Progress Report:
ARS scientists continued to supply PanThera Biopharma, LLC with monoclonal antibodies specific for botulinum neurotoxin serotypes A and B. These antibodies are capable of neutralizing the toxin in vivo, and assist the Cooperator’s effort to identify small molecule therapeutics for botulism. Cooperator used ARS antibodies as positive controls in their assays, providing a benchmark for evaluating potential new small molecule therapeutics in a mouse model system. Leads from the primary screening will be refined via medicinal chemistry and validated in secondary bioassays. Research progress reported addresses objective 2: "Calibrate in vitro methodology against established animal bioassays, and develop new data on the bioavailability of toxins, the impact of food processing on toxin activities, and the significance of antibody-mediated clearance on toxicity, especially via the oral route of intoxication" of the parent project.