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TitleExceptionally potent human monoclonal antibodies are effective for prophylaxis and treatment of tetanus in mice.
Journal, issue, pagesJ Clin Invest, Vol. 131, Issue 22, Year 2021
Publish dateNov 15, 2021
AuthorsMarco Pirazzini / Alessandro Grinzato / Davide Corti / Sonia Barbieri / Oneda Leka / Francesca Vallese / Marika Tonellato / Chiara Silacci-Fregni / Luca Piccoli / Eaazhisai Kandiah / Giampietro Schiavo / Giuseppe Zanotti / Antonio Lanzavecchia / Cesare Montecucco /
PubMed AbstractWe used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for ...We used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for hyperimmune sera to treat tetanus in mice. By screening memory B cells from immune donors, we selected 2 tetanus neurotoxin-specific mAbs with exceptionally high neutralizing activities and extensively characterized them both structurally and functionally. We found that these antibodies interfered with the binding and translocation of the neurotoxin into neurons by interacting with 2 epitopes, whose identification pinpoints crucial events in the cellular pathogenesis of tetanus. Our observations explain the neutralization ability of these antibodies, which we found to be exceptionally potent in preventing experimental tetanus when injected into mice long before the toxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential for therapeutic use via intrathecal injection. As such, we believe these humAbs, as well as their Fab derivatives, meet the requirements to be considered for prophylactic and therapeutic use in human tetanus and are ready for clinical trials.
External linksJ Clin Invest / PubMed:34618682 / PubMed Central
MethodsEM (single particle)
Resolution3.9 - 8.0 Å
Structure data

12890

7oh0

EMDB-12890, PDB-7oh0:
Tetanus neurotoxin HC domain in complex with TT104-Fab1
Method: EM (single particle) / Resolution: 3.9 Å

12891

7oh1

EMDB-12891, PDB-7oh1:
Tetanus neurotoxin LC-HN domain in complex with TT110-Fab1
Method: EM (single particle) / Resolution: 8.0 Å

Source
  • clostridium tetani (bacteria)
  • homo sapiens (human)
KeywordsTOXIN / tetanus / tetanus neurotoxin / humAbs / monoclonal antibody / tetanus prophylaxis / spastic paralysis / tetanus immunoglobulin / TIG

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