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<p>Snakebite envenoming, a neglected tropical disease, affects millions globally, causing significant morbidity and mortality. Developing broadly neutralising monoclonal antibodies offers a promising approach to address the antigenic variation present in snake venoms. In this study, we designed a long-chain consensus α-neurotoxin, LCC, to serve as an antigen in a phage display–based antibody discovery campaign. Utilising a yeast expression system, we expressed LCC and identified 21 variable domains of heavy-chain-only antibodies (V<sub>H</sub>Hs) from immune libraries. These V<sub>H</sub>Hs were assessed for their binding affinity to various long-chain α-neurotoxins and their neutralising capability in vitro. The V<sub>H</sub>H with the broadest cross-reactivity and highest affinity, TPL1158_01_C09, was co-crystallised with α-cobratoxin to elucidate its binding mechanism. In vivo rodent studies demonstrated the neutralisation potential of TPL1158_01_C09. Our findings highlight that the use of a consensus toxin as an antigen coincided with the discovery of broadly neutralising V<sub>H</sub>Hs against snake venom toxins.</p><p></p>

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Structural mechanisms behind the neutralisation of long-chain α-neurotoxins by broadly neutralising VHHs discovered using a consensus antigen

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月19日

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  • Anna Damsbo,
  • Nick J. Burlet,
  • Monica L. Fernández-Quintero,
  • Melisa Benard-Valle,
  • Max D. Overath,
  • Alid Guadarrama-Martínez,
  • Anneline Vlamynck,
  • Ida Bisbo,
  • Cesar Villalobos,
  • Tulika Tulika,
  • Alejandro Alagón,
  • Johannes R. Loeffler,
  • Andrew B. Ward,
  • Kim Boddum,
  • Jens Preben Morth,
  • Esperanza Rivera-de-Torre,
  • Andreas H. Laustsen

摘要

Snakebite envenoming, a neglected tropical disease, affects millions globally, causing significant morbidity and mortality. Developing broadly neutralising monoclonal antibodies offers a promising approach to address the antigenic variation present in snake venoms. In this study, we designed a long-chain consensus α-neurotoxin, LCC, to serve as an antigen in a phage display–based antibody discovery campaign. Utilising a yeast expression system, we expressed LCC and identified 21 variable domains of heavy-chain-only antibodies (VHHs) from immune libraries. These VHHs were assessed for their binding affinity to various long-chain α-neurotoxins and their neutralising capability in vitro. The VHH with the broadest cross-reactivity and highest affinity, TPL1158_01_C09, was co-crystallised with α-cobratoxin to elucidate its binding mechanism. In vivo rodent studies demonstrated the neutralisation potential of TPL1158_01_C09. Our findings highlight that the use of a consensus toxin as an antigen coincided with the discovery of broadly neutralising VHHs against snake venom toxins.