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Pain. 2019 Apr 24. doi: 10.1097/j.pain.0000000000001587. [Epub ahead of print]

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

Author information

1
Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Cambridge, CB21 6GH, UK.
2
Neuroscience, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
3
Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Cambridge, CB21 6GH, UK.
4
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

Abstract

P2X4 is a ligand-gated ion channel implicated in neuropathic pain. Drug discovery efforts targeting P2X4 have been unsuccessful largely due to 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 systemic delivery of an anti-P2X4 bi-specific 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.

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