Modulation of botulinum toxin-induced changes in neuromuscular function with antibodies directed against recombinant polypeptides or fragments

Abstract

Botulinum toxin is an agent that is typically encountered in two settings: as an agent that can cause disease (e.g. botulism), and as an agent that can be used to treat disease (i.e., a variety of neurologic disorders). In both cases it would be advantageous to develop a sound understanding of the mechanisms by which antibodies neutralize the toxin. In the present study, recombinant antigens were used to generate antibodies against the carboxyterminal half of the toxin heavy chain (HC50), the entire toxin light chain (LC), and the HA17, HA35 and HA70 components of the progenitor toxin complex. These antibodies were then evaluated for their respective abilities to alter botulinum toxin-induced changes in locomotor behavior in mice. The botulinum toxin type A complex was shown to produce dose-dependent depression of locomotor behavior within the dose range of 0.3–0.7 mouse LD50 units. At a dose of 0.5 LD50, the toxin typically reduced running behavior by 90% or more, and full recovery was not observed for approximately 4 weeks. Mice that were actively or passively vaccinated against the HC50 polypeptide were resistant to toxin action, presumably because the antibodies occluded the toxin binding domain. Interestingly, mice that were actively or passively vaccinated against LC were also resistant to toxin action. This effect may have been due to steric hindrance of the binding process. There was no scenario in which anti-HA antibodies altered the effects of toxin on locomotor behavior. This absence of effect was likely due to the fact that HAs and neurotoxin in the progenitor toxin complex spontaneously dissociate in physiologic media.