A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D

• Published in: Toxins Vol. 13; no. 9; p. 641
• Main Authors: Garcia-Rodriguez, Consuelo, Yan, Shude, Geren, Isin N, Knopp, Kristeene A, Dong, Jianbo, Sun, Zhengda, Lou, Jianlong, Conrad, Fraser, Wen, Wei-Hua, Farr-Jones, Shauna, Smith, Theresa J, Brown, Jennifer L, Skerry, Janet C, Smith, Leonard A, Marks, James D
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10-09-2021; MDPI
• Subjects: Adverse events; Affinity; Amino acids; Animals; Antibodies, Monoclonal - therapeutic use; antibody engineering; Antiinfectives and antibacterials; Antimicrobial agents; Antitoxins; botulinum neurotoxin; Botulinum toxin; Botulinum Toxins - immunology; Botulism; Botulism - immunology; Cattle; Chemotherapy; Epitopes; Female; Food contamination; Humans; Libraries; Mice; Molecular evolution; Monoclonal antibodies; Mosaics; Neurotoxins; Neutralization; oligoclonal antibodies; recombinant antibodies; Serogroup; serotype C botulism; serotype D botulism; Serotypes; Toxins; Yeast; Yeasts; antibody engineering; serotype D botulism; serotype C botulism; mouse neutralization assay; oligoclonal antibodies; recombinant antibodies; botulinum antitoxin; botulinum neurotoxin
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins13090641

Human botulism can be caused by botulinum neurotoxin (BoNT) serotypes A to G. Here, we present an antibody-based antitoxin composed of four human monoclonal antibodies (mAbs) against BoNT/C, BoNT/D, and their mosaic toxins. This work built on our success in generating protective mAbs to BoNT /A, B and E serotypes. We generated mAbs from human immune single-chain Fv (scFv) yeast-display libraries and isolated scFvs with high affinity for BoNT/C, BoNT/CD, BoNT/DC and BoNT/D serotypes. We identified four mAbs that bound non-overlapping epitopes on multiple serotypes and mosaic BoNTs. Three of the mAbs underwent molecular evolution to increase affinity. A four-mAb combination provided high-affinity binding and BoNT neutralization of both serotypes and their mosaic toxins. The mAbs have potential utility as therapeutics and as diagnostics capable of recognizing and neutralizing BoNT/C and BoNT/D serotypes and their mosaic toxins. A derivative of the four-antibody combination (NTM-1634) completed a Phase 1 clinical trial (Snow et al., Antimicrobial Agents and Chemotherapy, 2019) with no drug-related serious adverse events.