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Open AccessArticle

Camelid VHH Antibodies that Neutralize Botulinum Neurotoxin Serotype E Intoxication or Protease Function

1
Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA
2
The United States Army Medical Research Institute of Chemical Defense, Fort Detrick, MD 21010, USA
3
Department of Physiology & Biophysics, University of California, Irvine, CA 92697-4560, USA
4
Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA
5
Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Ft. Detrick, MD 21702-5011, USA
6
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA
*
Author to whom correspondence should be addressed.
Toxins 2020, 12(10), 611; https://doi.org/10.3390/toxins12100611
Received: 18 August 2020 / Revised: 2 September 2020 / Accepted: 11 September 2020 / Published: 24 September 2020
(This article belongs to the Special Issue Inhibitors and Countermeasures against Bacterial and Plant Toxins)
Botulinum neurotoxin (BoNT) serotype E is one of three serotypes that cause the preponderance of human botulism cases and is a Tier 1 Select Agent. BoNT/E is unusual among BoNT serotypes for its rapid onset and short duration of intoxication. Here we report two large panels of unique, unrelated camelid single-domain antibodies (VHHs) that were selected for their ability to bind to BoNT/E holotoxin and/or to the BoNT/E light chain protease domain (LC/E). The 19 VHHs which bind to BoNT/E were characterized for their subunit specificity and 8 VHHs displayed the ability to neutralize BoNT/E intoxication of neurons. Heterodimer antitoxins consisting of two BoNT/E-neutralizing VHHs, including one heterodimer designed using structural information for simultaneous binding, were shown to protect mice against co-administered toxin challenges of up to 500 MIPLD50. The 22 unique VHHs which bind to LC/E were characterized for their binding properties and 9 displayed the ability to inhibit LC/E protease activity. Surprisingly, VHHs selected on plastic-coated LC/E were virtually unable to recognize soluble or captured LC/E while VHHs selected on captured LC/E were poorly able to recognize LC/E coated to a plastic surface. This panel of anti-LC/E VHHs offer insight into BoNT/E function, and some may have value as components of therapeutic antidotes that reverse paralysis following BoNT/E exposures. View Full-Text
Keywords: botulinum neurotoxin; botulism; toxin; antitoxin; single-domain antibody; VHH; neutralization; protease botulinum neurotoxin; botulism; toxin; antitoxin; single-domain antibody; VHH; neutralization; protease
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MDPI and ACS Style

Tremblay, J.M.; Vazquez-Cintron, E.; Lam, K.-H.; Mukherjee, J.; Bedenice, D.; Ondeck, C.A.; Conroy, M.T.; Bodt, S.M.L.; Winner, B.M.; Webb, R.P.; Ichtchenko, K.; Jin, R.; McNutt, P.M.; Shoemaker, C.B. Camelid VHH Antibodies that Neutralize Botulinum Neurotoxin Serotype E Intoxication or Protease Function. Toxins 2020, 12, 611. https://doi.org/10.3390/toxins12100611

AMA Style

Tremblay JM, Vazquez-Cintron E, Lam K-H, Mukherjee J, Bedenice D, Ondeck CA, Conroy MT, Bodt SML, Winner BM, Webb RP, Ichtchenko K, Jin R, McNutt PM, Shoemaker CB. Camelid VHH Antibodies that Neutralize Botulinum Neurotoxin Serotype E Intoxication or Protease Function. Toxins. 2020; 12(10):611. https://doi.org/10.3390/toxins12100611

Chicago/Turabian Style

Tremblay, Jacqueline M.; Vazquez-Cintron, Edwin; Lam, Kwok-Ho; Mukherjee, Jean; Bedenice, Daniela; Ondeck, Celinia A.; Conroy, Matthieu T.; Bodt, Skylar M.L.; Winner, Brittany M.; Webb, Robert P.; Ichtchenko, Konstantin; Jin, Rongsheng; McNutt, Patrick M.; Shoemaker, Charles B. 2020. "Camelid VHH Antibodies that Neutralize Botulinum Neurotoxin Serotype E Intoxication or Protease Function" Toxins 12, no. 10: 611. https://doi.org/10.3390/toxins12100611

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