Biologics Discovery

Generating highly potent and efficacious antibodies to the ligand-gated ion channel P2X4 for the treatment of neuropathic pain

• WW

  Wendy Williams, PhD

  Scientist II
  MedImmune, UK

Ion channels are involved in numerous biological processes and have been implicated in many different disease states. Drug discovery approaches have focussed on small molecule compounds to modulate the activity of ion channels, however due to the high homology between family members and difficulty in achieving selective compounds the subsequent off target toxicities has limited their use. Antibodies are renowned for their high affinity and highly specific interactions with their targets and have been of increasing interest to the ion channel drug discovery field. However, ion channels are challenging targets for antibody therapeutics, mainly due to their complex membrane-integrated structures and multiple conformational states. This makes them hard to express and purify, which has limited the ability to utilise ion channels in antibody isolation campaigns. P2X4 is a ligand gated ion channel proposed to be involved in the onset and maintenance of neuropathic pain. Here we describe the isolation and characterisation of a panel of P2X4 specific modulatory antibodies using phage display and hybridoma technologies, together with automated patch clamp electrophysiology and calcium influx assays. Furthermore, we demonstrate in vivo efficacy of our antibodies in a relevant model of neuropathic pain. This is the first example, to date, of antibodies that can modulate the P2X4 ion channel directly with high potency and specificity. This highlights the exciting potential therapeutic opportunity of an antibody for modulating this type of ion channel.