A Novel Antigen Design Strategy to Isolate Single-Domain Antibodies that Target Human Nav1.7 and Reduce Pain in Animal Models.

Autor: Martina M; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Banderali U; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Yogi A; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Arbabi Ghahroudi M; Human Health Therapeutics Research Centre, National Research Council Canada, 100 Sussex Drive, Ottawa, ON, K1N 5A2, Canada., Liu H; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Sulea T; Human Health Therapeutics Research Centre, National Research Council Canada, 6100 Royalmount Avenue Montréal, Quebec, H4P 2R2, Canada., Durocher Y; Human Health Therapeutics Research Centre, National Research Council Canada, 6100 Royalmount Avenue Montréal, Quebec, H4P 2R2, Canada., Hussack G; Human Health Therapeutics Research Centre, National Research Council Canada, 100 Sussex Drive, Ottawa, ON, K1N 5A2, Canada., van Faassen H; Human Health Therapeutics Research Centre, National Research Council Canada, 100 Sussex Drive, Ottawa, ON, K1N 5A2, Canada., Chakravarty B; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Liu QY; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Iqbal U; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Ling B; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Lessard E; Human Health Therapeutics Research Centre, National Research Council Canada, 6100 Royalmount Avenue Montréal, Quebec, H4P 2R2, Canada., Sheff J; Human Health Therapeutics Research Centre, National Research Council Canada, 100 Sussex Drive, Ottawa, ON, K1N 5A2, Canada., Robotham A; Human Health Therapeutics Research Centre, National Research Council Canada, 100 Sussex Drive, Ottawa, ON, K1N 5A2, Canada., Callaghan D; Human Health Therapeutics Research Centre, National Research Council Canada, 100 Sussex Drive, Ottawa, ON, K1N 5A2, Canada., Moreno M; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Comas T; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Ly D; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada., Stanimirovic D; Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Oct; Vol. 11 (40), pp. e2405432. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1002/advs.202405432
Abstrakt: Genetic studies have identified the voltage-gated sodium channel 1.7 (Na v 1.7) as pain target. Due to the ineffectiveness of small molecules and monoclonal antibodies as therapeutics for pain, single-domain antibodies (V H Hs) are developed against the human Na v 1.7 (hNa v 1.7) using a novel antigen presentation strategy. A 70 amino-acid peptide from the hNa v 1.7 protein is identified as a target antigen. A recombinant version of this peptide is grafted into the complementarity determining region 3 (CDR3) loop of an inert V H H in order to maintain the native 3D conformation of the peptide. This antigen is used to isolate one V H H able to i) bind hNa v 1.7, ii) slow the deactivation of hNa v 1.7, iii) reduce the ability of eliciting action potentials in nociceptors, and iv) reverse hyperalgesia in in vivo rat and mouse models. This V H H exhibits the potential to be developed as a therapeutic capable of suppressing pain. This novel antigen presentation strategy can be applied to develop biologics against other difficult targets such as ion channels, transporters and GPCRs.
(© 2024 His Majesty the King in Right of Canada. Advanced Science published by Wiley‐VCH GmbH. Reproduced with the permission of the Minister of Innovation, Science, and Economic Development.)
Databáze: MEDLINE
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