Abstract

Tetanus neurotoxin (TeNT) produced by Clostridium tetani is one of the most poisonous protein substances. Neutralizing antibodies against TeNT can effectively prevent and cure toxicosis. Using purified Hc fragments of TeNT (TeNT-Hc) as an antigen, three specific neutralizing antibody clones recognizing different epitopes were selected from a human immune scFv antibody phage display library. The three antibodies (2-7G, 2-2D, and S-4-7H) can effectively inhibit the binding between TeNT-Hc and differentiated PC-12 cells in vitro. Moreover, 2-7G inhibited TeNT-Hc binding to the receptor via carbohydrate-binding sites of the W pocket while 2-2D and S-4-7H inhibited binding of the R pocket. Although no single mAb completely protected mice from the toxin, they could both prolong survival when challenged with 20 LD50s (50% of the lethal dose) of TeNT. When used together, the mAbs completely neutralized 1000 LD50s/mg Ab, indicating their high neutralizing potency in vivo. Antibodies recognizing different carbohydrate-binding pockets could have higher synergistic toxin neutralization activities than those that recognize the same pockets. These results could lead to further production of neutralizing antibody drugs against TeNT and indicate that using TeNT-Hc as an antigen for screening human antibodies for TeNT intoxication therapy from human immune antibody library was convenient and effective.

Highlights

  • IntroductionOften fatal disease of humans caused by the tetanus neurotoxin (TeNT)

  • Tetanus is an acute, often fatal disease of humans caused by the tetanus neurotoxin (TeNT)produced by the bacterium Clostridium tetani

  • The purpose of this study was to screen for specific neutralizing antibodies against TeNT from the human immune scFv antibody phage display library using purified TeNT-Hc and TeNT as the antigen

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Summary

Introduction

Often fatal disease of humans caused by the tetanus neurotoxin (TeNT). It is characterized by generalized rigidity and convulsive spasms of the skeletal muscles. The muscle stiffness usually involves lockjaw, the neck, and becomes generalized. Hippocrates first described tetanus over 24 centuries ago [1]. As one of the most potent toxins known, even today it causes paralytic death to hundreds of thousands of humans annually [2]. As of December 2007, there were 47 countries remaining that had not eliminated neonatal tetanus (MNT) [3]

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