Antibodies binding the head domain of P2X4 inhibit channel function and reverse neuropathic pain.

Animals Antibodies, Monoclonal / administration & dosage Cells, Cultured Female HEK293 Cells Humans Injections, Spinal Mice Mice, Inbred C57BL Neuralgia / metabolism Protein Binding / physiology Purinergic P2X Receptor Antagonists / administration & dosage Rats Rats, Sprague-Dawley Receptors, Purinergic P2X4 / metabolism

Journal

Pain

ISSN: 1872-6623

Titre abrégé: Pain

Pays: United States

ID NLM: 7508686

Informations de publication

Date de publication:
09 2019

Historique:

pubmed: 3 5 2019

medline: 28 7 2020

entrez: 3 5 2019

Statut: ppublish

Résumé

P2X4 is a ligand-gated ion channel implicated in neuropathic pain. Drug discovery efforts targeting P2X4 have been unsuccessful largely because of the difficulty in engineering specificity and selectivity. Here, we describe for the first time the generation of a panel of diverse monoclonal antibodies (mAbs) to human and mouse P2X4, capable of both positive and negative modulation of channel function. The affinity-optimised anti-P2X4 mAb IgG#151-LO showed exquisite selectivity for human P2X4 and induced potent and complete block of P2X4 currents. Site-directed mutagenesis of P2X4 revealed the head domain as a key interaction site for inhibitory mAbs. Inhibition of spinal P2X4 either by intrathecal delivery of an anti-P2X4 mAb or by systemic delivery of an anti-P2X4 bispecific mAb with enhanced blood-spinal cord barrier permeability produced long-lasting (>7 days) analgesia in a mouse model of neuropathic pain. We therefore propose that inhibitory mAbs binding the head domain of P2X4 have therapeutic potential for the treatment of neuropathic pain.

Identifiants

DOI: 10.1097/j.pain.0000000000001587 PMID: 31045747

pubmed: 31045747

doi: 10.1097/j.pain.0000000000001587

pii: 00006396-201909000-00010

doi:

Substances chimiques

Antibodies, Monoclonal 0

Purinergic P2X Receptor Antagonists 0

Receptors, Purinergic P2X4 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

1989-2003

Commentaires et corrections

Type : CommentIn

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