Neutralization of botulinum neurotoxin by a human monoclonal antibody specific for the catalytic light chain.

Authors

Sharad P Adekar, Lankenau Institute for Medical Research, Wynnewood, PAFollow
Tsuyoshi Takahashi, Division of Infectious Diseases and Environmental Medicine, Thomas Jefferson University, Philadelphia, PA
R Mark Jones, Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
Fetweh H Al-Saleem, Division of Infectious Diseases and Environmental Medicine, Thomas Jefferson University, Philadelphia, PAFollow
Denise M Ancharski, Division of Infectious Diseases and Environmental Medicine, Thomas Jefferson University, Philadelphia, PAFollow
Michael J Root, Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PAFollow
B P Kapadnis, Department of Microbiology, University of Pune, Pune, India
Lance L Simpson, Division of Infectious Diseases and Environmental Medicine, Thomas Jefferson University, Philadelphia, PAFollow
Scott K Dessain, Lankenau Institute for Medical Research, Wynnewood, PAFollow

Document Type

Article

Publication Date

8-1-2008

Comments

This article has been peer reviewed and is published in PLoS One 2008, 3(8). The published version is available at DOI: 10.1371/journal.pone.0003023. © Public Library of Science

Abstract

BACKGROUND: Botulinum neurotoxins (BoNT) are a family of category A select bioterror agents and the most potent biological toxins known. Cloned antibody therapeutics hold considerable promise as BoNT therapeutics, but the therapeutic utility of antibodies that bind the BoNT light chain domain (LC), a metalloprotease that functions in the cytosol of cholinergic neurons, has not been thoroughly explored.

METHODS AND FINDINGS: We used an optimized hybridoma method to clone a fully human antibody specific for the LC of serotype A BoNT (BoNT/A). The 4LCA antibody demonstrated potent in vivo neutralization when administered alone and collaborated with an antibody specific for the HC. In Neuro-2a neuroblastoma cells, the 4LCA antibody prevented the cleavage of the BoNT/A proteolytic target, SNAP-25. Unlike an antibody specific for the HC, the 4LCA antibody did not block entry of BoNT/A into cultured cells. Instead, it was taken up into synaptic vesicles along with BoNT/A. The 4LCA antibody also directly inhibited BoNT/A catalytic activity in vitro.

CONCLUSIONS: An antibody specific for the BoNT/A LC can potently inhibit BoNT/A in vivo and in vitro, using mechanisms not previously associated with BoNT-neutralizing antibodies. Antibodies specific for BoNT LC may be valuable components of an antibody antidote for BoNT exposure.

Recommended Citation

Adekar, Sharad P; Takahashi, Tsuyoshi; Jones, R Mark; Al-Saleem, Fetweh H; Ancharski, Denise M; Root, Michael J; Kapadnis, B P; Simpson, Lance L; and Dessain, Scott K, "Neutralization of botulinum neurotoxin by a human monoclonal antibody specific for the catalytic light chain." (2008). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 32.
https://jdc.jefferson.edu/bmpfp/32

PubMed ID

18714390