Development and preclinical evaluation of a new F(ab')₂ antitoxin against botulinum neurotoxin serotype A.
Concern about the malicious applications of botulinum neurotoxin has highlighted the need for a new generation of safe and highly potent antitoxins. In this study, we developed and evaluated the preclinical pharmacology and safety of a new F(ab')₂ antitoxin against botulinum neurotoxin serotype A (BoNT/A). As an alternative to formalin-inactivated toxoid, the recombinant Hc domain of botulinum neurotoxin serotype A (rAHc) was used to immunize horses, and the IgGs from the hyperimmune sera were digested to obtain F(ab')₂ antitoxin. The protective effect of the new F(ab')₂ antitoxin against BoNT/A was determined both in vitro and in vivo. The results showed that the F(ab')₂ antitoxin could prevent botulism in mice challenged with BoNT/A and effectively delayed progression of paralysis from botulism in the therapeutic setting. The preclinical safety of the new F(ab')₂ antitoxin was also evaluated, and it showed neither harmful effects on vital functions nor adverse effects such as acute toxicity, or immunological reactions in mice and dogs. Thus, our results provide valuable experimental data for this new antitoxin as a potential candidate for treatment of botulism caused by BoNT/A, and our findings support the safety of the new F(ab')₂ antitoxin for clinical use. Our study further demonstrates the proof of concept for development of a similar strategy for obtaining potent antitoxin against other BoNT serotypes.
Yu
Yun-Zhou
YZ
Beijing Institute of Biotechnology, Beijing, PR China.
Zhang
Shu-Ming
SM
Wang
Wen-Bing
WB
Du
Yun
Y
Zhu
Heng-Qi
HQ
Wang
Rui-Lin
RL
Zhou
Xiao-Wei
XW
Lin
Jian-Bo
JB
Wang
Shuang
S
Yu
Wei-Yuan
WY
Huang
Pei-Tang
PT
Sun
Zhi-Wei
ZW
D000818:Animals; D000992:Antitoxins / Q000276:immunology*; D001905:Botulinum Toxins / Q000276:immunology; D001906:Botulism / Q000276:immunology / Q000517:prevention & control*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D007114:Immunization / Q000379:methods*; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D051379:Mice; D009498:Neurotoxins / Q000276:immunology; D016896:Treatment Outcome
D000992:Antitoxins; D007140:Immunoglobulin Fab Fragments; D009498:Neurotoxins; D001905:Botulinum Toxins