Neutralizing Concentrations of Anti-Botulinum Toxin Antibodies Positively Correlate with Mouse Neutralization Assay Results in a Guinea Pig Model

• Published in: Toxins Vol. 13; no. 9; p. 671
• Main Authors: Tomic, Milan T, Farr-Jones, Shauna, Syar, Emily S, Niemuth, Nancy, Kobs, Dean, Hackett, Michael J, Espinoza, Yero, Martinez, Zacchary, Pham, Khanh, Snow, Doris M, Marks, James D, Cobb, Ronald R
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.09.2021; MDPI
• Subjects: aerosol; Animals; Antibodies; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - therapeutic use; Antitoxins; Antitoxins - immunology; Antitoxins - therapeutic use; botulinum neurotoxin; Botulinum toxin; Botulinum toxin type A; Botulinum toxin type B; Botulinum Toxins - toxicity; Botulism; Botulism - drug therapy; Clostridium botulinum - genetics; Disease Models, Animal; Drug Combinations; Estimates; Exposure; Food contamination; guinea pig inhalation model; Guinea Pigs; Inhalation; Injection; Intravenous administration; Mice; Monoclonal antibodies; monoclonal antibody (mAb); Neurotoxins; Neutralization; Neutralizing; oligoclonal antibody; Pharmacokinetics; Prophylaxis; Respiration; Respiratory failure; Serogroup; Swine; Toxins; United States > US; guinea pig inhalation model; botulism; botulinum neurotoxin; monoclonal antibody (mAb); mouse neutralization assay (MNA); oligoclonal antibody; aerosol; neutralizing antibody concentration (NAC)
• DOI: 10.3390/toxins13090671
• ISSN: 2072-6651

Botulinum neurotoxins (BoNT) are some of the most toxic proteins known and can induce respiratory failure requiring long-term intensive care. Treatment of botulism includes the administration of antitoxins. Monoclonal antibodies (mAbs) hold considerable promise as BoNT therapeutics and prophylactics, due to their potency and safety. A three-mAb combination has been developed that specifically neutralizes BoNT serotype A (BoNT/A), and a separate three mAb combination has been developed that specifically neutralizes BoNT serotype B (BoNT/B). A six mAb cocktail, designated G03-52-01, has been developed that combines the anti-BoNT/A and anti-BoNT/B mAbs. The pharmacokinetics and neutralizing antibody concentration (NAC) of G03-52-01 has been determined in guinea pigs, and these parameters were correlated with protection against an inhalation challenge of BoNT/A1 or BoNT/B1. Previously, it was shown that each antibody demonstrated a dose-dependent mAb serum concentration and reached maximum circulating concentrations within 48 h after intramuscular (IM) or intraperitoneal (IP) injection and that a single IM injection of G03-52-01 administered 48 h pre-exposure protected guinea pigs against an inhalation challenge of up to 93 LD s of BoNT/A1 and 116 LD s of BoNT/B1. The data presented here advance our understanding of the relationship of the neutralizing NAC to the measured circulating antibody concentration and provide additional support that a single IM or intravenous (IV) administration of G03-52-01 will provide pre-exposure prophylaxis against botulism from an aerosol exposure of BoNT/A and BoNT/B.