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

AI Article Synopsis

  • Genetic research has pinpointed the Na1.7 sodium channel as a significant target for pain treatment, revealing challenges with traditional pain therapies like small molecules and monoclonal antibodies.
  • Innovative single-domain antibodies (VHs) have been created by utilizing a 70 amino-acid peptide from Na1.7, enhancing the design to retain its natural structure for effective targeting.
  • One specific VH was identified that not only binds to hNa1.7 but also effectively slows its deactivation and alleviates pain responses in animal models, suggesting its potential as a new pain relief therapy and a model for targeting other challenging proteins.

Article Abstract

Genetic studies have identified the voltage-gated sodium channel 1.7 (Na1.7) as pain target. Due to the ineffectiveness of small molecules and monoclonal antibodies as therapeutics for pain, single-domain antibodies (VHs) are developed against the human Na1.7 (hNa1.7) using a novel antigen presentation strategy. A 70 amino-acid peptide from the hNa1.7 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 VH in order to maintain the native 3D conformation of the peptide. This antigen is used to isolate one VH able to i) bind hNa1.7, ii) slow the deactivation of hNa1.7, iii) reduce the ability of eliciting action potentials in nociceptors, and iv) reverse hyperalgesia in in vivo rat and mouse models. This VH 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11516162PMC
http://dx.doi.org/10.1002/advs.202405432DOI Listing

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