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Botulinum neurotoxins (BoNT) are extremely potent and can induce respiratory failure, requiring long-term intensive care to prevent death. Recombinant monoclonal antibodies (mAbs) hold considerable promise as BoNT therapeutics and prophylactics. In contrast, equine antitoxin cannot be used prophylactically and has a short half-life. Two three-mAb combinations are in development that specifically neutralize BoNT serotype A (BoNT/A) and B (BoNT/B). The three-mAb combinations addressing a single serotype provided pre-exposure prophylaxis in the guinea pig inhalation model. A lyophilized co-formulation of six mAbs, designated G03-52-01, that addresses both A and B serotypes is in development. Here, we investigated the efficacy of G03-52-01 to protect guinea pigs against an aerosol exposure challenge of BoNT/A1 or BoNT/B1. Previously, it was found that each antibody demonstrated a dose-dependent exposure and reached maximum circulating concentrations within 48 h after intramuscular (IM) or intravenous (IV) injection. Here we show that G03-52-01, in a single IM injection of G03-52-01 administered 48 h pre-exposure, protected guinea pigs against an aerosol challenge of up to 238 LD50s of BoNT/A1 and 191 LD50s of BoNT/B1. These data suggest that a single IM administration of G03-52-01 provides pre-exposure prophylaxis against botulism from an aerosol exposure of BoNT/A1 or BoNT/B1.
Doris Snow; Ronald Cobb; Juan Martinez; Isaac Finger-Baker; Laura Collins; Sara Terpening; Emily Syar; Nancy Niemuth; Dean Kobs; Roy Barnewall; Shauna Farr-Jones; James Marks; Milan Tomic. A Monoclonal Antibody Combination against both Serotypes A and B Botulinum Toxin Prevents Inhalational Botulism in a Guinea Pig Model. Toxins 2021, 13, 31 .
AMA StyleDoris Snow, Ronald Cobb, Juan Martinez, Isaac Finger-Baker, Laura Collins, Sara Terpening, Emily Syar, Nancy Niemuth, Dean Kobs, Roy Barnewall, Shauna Farr-Jones, James Marks, Milan Tomic. A Monoclonal Antibody Combination against both Serotypes A and B Botulinum Toxin Prevents Inhalational Botulism in a Guinea Pig Model. Toxins. 2021; 13 (1):31.
Chicago/Turabian StyleDoris Snow; Ronald Cobb; Juan Martinez; Isaac Finger-Baker; Laura Collins; Sara Terpening; Emily Syar; Nancy Niemuth; Dean Kobs; Roy Barnewall; Shauna Farr-Jones; James Marks; Milan Tomic. 2021. "A Monoclonal Antibody Combination against both Serotypes A and B Botulinum Toxin Prevents Inhalational Botulism in a Guinea Pig Model." Toxins 13, no. 1: 31.
Botulinum neurotoxins (BoNT) are some of the most toxic proteins known, with a human LD50 of ~1 ng/kg. Equine antitoxin has a half-life in circulation of less than 1 day and is limited to a treatment rather than a prevention indication. The development of monoclonal antibodies (mAbs) may represent an alternative therapeutic option that can be produced at high quantities and of high quality and with half-lives of >10 days. Two different three mAb combinations are being developed that specifically neutralize BoNT serotypes A (BoNT/A) and B (BoNT/B). We investigated the pharmacokinetics of the anti-BoNT/A and anti-BoNT/B antibodies in guinea pigs (Cavia porcellus) and their ability to protect guinea pigs against an aerosol challenge of BoNT/A1 or BoNT/B1. Each antibody exhibited dose-dependent exposure and reached maximum circulating concentrations within 48 h post intraperitoneal or intramuscular injection. A single intramuscular dose of the three mAb combination protected guinea pigs against an aerosol challenge dose of 93 LD50 of BoNT/A1 and 116 LD50 of BoNT/B1 at 48 h post antibody administration. These mAbs are effective in preventing botulism after an aerosol challenge of BoNT/A1 and BoNT/B1 and may represent an alternative to vaccination to prevent type A or B botulism in those at risk of BoNT exposure.
Milan T. Tomic; Yero Espinoza; Zachary Martinez; Khanh Pham; Ronald R. Cobb; Doris M. Snow; Christopher G. Earnhart; Traci Pals; Emily S. Syar; Nancy Niemuth; Dean J. Kobs; Shauna Farr-Jones; James D. Marks. Monoclonal Antibody Combinations Prevent Serotype A and Serotype B Inhalational Botulism in a Guinea Pig Model. Toxins 2019, 11, 208 .
AMA StyleMilan T. Tomic, Yero Espinoza, Zachary Martinez, Khanh Pham, Ronald R. Cobb, Doris M. Snow, Christopher G. Earnhart, Traci Pals, Emily S. Syar, Nancy Niemuth, Dean J. Kobs, Shauna Farr-Jones, James D. Marks. Monoclonal Antibody Combinations Prevent Serotype A and Serotype B Inhalational Botulism in a Guinea Pig Model. Toxins. 2019; 11 (4):208.
Chicago/Turabian StyleMilan T. Tomic; Yero Espinoza; Zachary Martinez; Khanh Pham; Ronald R. Cobb; Doris M. Snow; Christopher G. Earnhart; Traci Pals; Emily S. Syar; Nancy Niemuth; Dean J. Kobs; Shauna Farr-Jones; James D. Marks. 2019. "Monoclonal Antibody Combinations Prevent Serotype A and Serotype B Inhalational Botulism in a Guinea Pig Model." Toxins 11, no. 4: 208.