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

被引:17
|
作者
Tremblay, Jacqueline M. [1 ]
Vazquez-Cintron, Edwin [2 ]
Lam, Kwok-Ho [3 ]
Mukherjee, Jean [1 ]
Bedenice, Daniela [4 ]
Ondeck, Celinia A. [2 ]
Conroy, Matthieu T. [2 ]
Bodt, Skylar M. L. [2 ]
Winner, Brittany M. [2 ]
Webb, Robert P. [5 ]
Ichtchenko, Konstantin [6 ]
Jin, Rongsheng [3 ]
McNutt, Patrick M. [2 ]
Shoemaker, Charles B. [1 ]
机构
[1] Tufts Univ, Cummings Sch Vet Med, Dept Infect Dis & Global Hlth, North Grafton, MA 01536 USA
[2] US Army, Med Res Inst Chem Def, Aberdeen Proving Ground, MD 21010 USA
[3] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92697 USA
[4] Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA 01536 USA
[5] US Army, Med Res Inst Infect Dis, Bacteriol Div, Ft Detrick, MD 21702 USA
[6] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA
关键词
botulinum neurotoxin; botulism; toxin; antitoxin; single-domain antibody; VHH; neutralization; protease; SINGLE; BINDING; NANOBODIES; AGENTS; CHALLENGE; PROTECTS; DOMAINS; TOXINS; MICE; PH;
D O I
10.3390/toxins12100611
中图分类号
TS2 [食品工业];
学科分类号
0832 ;
摘要
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.
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页数:18
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