Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

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

Williams, Wendy A.a; Linley, John E.b,*; Jones, Clare A.c; Shibata, Yokoa; Snijder, Arjand; Button, Jamesa; Hatcher, Jon P.b; Huang, Linga; Taddese, Brucka; Thornton, Peterb; Schofield, Darren J.a; Thom, Georgea; Popovic, Bojanaa; Dosanjh, Bhupindera; Wilkinson, Trevora; Hughes, Janeb; Dobson, Claire L.a; Groves, Maria A.a; Webster, Carl I.a; Billinton, Andyb; Vaughan, Tristan J.a; Chessell, Iainb

doi: 10.1097/j.pain.0000000000001587
Research Paper
Buy
SDC
C

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.

Anti-P2X4 monoclonal antibodies binding the head domain of P2X4 potently and specifically inhibit channel function and reverse neuropathic pain by targeting spinal P2X4 in mice.

aAntibody Discovery and Protein Engineering, R&D, AstraZeneca, Cambridge, United Kingdom

bNeuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom

cRespiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, Cambridge, United Kingdom

dDiscovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden

Corresponding author. Address: AstraZeneca, Aaron Klug Building, Granta Park, Cambridge CB21 6GH, United Kingdom. Tel.: +44 (0)203 749 6365. E-mail address: John.Linley@azneuro.com (J.E. Linley).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

W.A. Williams and J.E. Linley contributed equally to this work.

Received September 27, 2018

Received in revised form February 26, 2019

Accepted March 16, 2019

Online date: April 24, 2019

© 2019 International Association for the Study of Pain
You currently do not have access to this article

To access this article:

Note: If your society membership provides full-access, you may need to login on your society website