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A Novel Antigen Design Strategy to Isolate Single-Domain Antibodies that Target Human Nav1.7 and Reduce Pain in
Marzia Martina1, Umberto Banderali1, Alvaro Yogi1
1Human Health Therapeutics Research Center, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa, ON, K1A 0R6, Canada.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|August 29, 2024
Summary
Researchers developed novel single-domain antibodies (VHHs) targeting the Nav1.7 sodium channel for pain relief. This approach shows promise for developing new pain therapeutics by overcoming limitations of existing treatments.
Area of Science:
- Biochemistry
- Neuroscience
- Immunology
Background:
- Genetic studies implicate the voltage-gated sodium channel 1.7 (Nav1.7) as a key target for pain management.
- Limitations of small molecules and monoclonal antibodies necessitate alternative therapeutic strategies for pain.
Purpose of the Study:
- To develop single-domain antibodies (VHHs) targeting the human Nav1.7 (hNav1.7) channel using a novel antigen presentation strategy.
- To evaluate the therapeutic potential of these VHHs in preclinical pain models.
Main Methods:
- A 70 amino-acid peptide from hNav1.7 was identified as a target antigen.
- The peptide was grafted into the CDR3 loop of an inert VHH to preserve its native conformation.
- Isolated VHHs were tested for binding to hNav1.7, effects on channel kinetics, action potential generation in nociceptors, and in vivo pain reversal.
Main Results:
- A VHH was successfully isolated that binds hNav1.7, slows channel deactivation, and reduces action potential firing in nociceptors.
- This VHH demonstrated efficacy in reversing hyperalgesia in rat and mouse models.
- The novel antigen presentation strategy proved effective for targeting difficult proteins like ion channels.
Conclusions:
- The developed VHH targeting hNav1.7 shows significant potential as a therapeutic agent for pain suppression.
- The innovative antigen presentation method can be broadly applied to develop biologics against challenging targets, including ion channels, transporters, and GPCRs.
