Neuropathic pain is a persistent and debilitating condition, which is challenging to manage. Current first-line treatments have central nervous system side-effects which could be avoided if treatments targeting the peripheral nervous system (PNS), particularly sensory neurons in the dorsal root ganglia (DRG), were found to be effective. Seizure-related protein-6 (Sez6) is a neuronal protein essential for excitatory synapse development and maintenance and our previous studies have indicated Sez6 involvement in neuropathic pain. Sez6 is expressed in sensory neurons of the DRG, with high levels in peptidergic C-fibres which sense noxious heat. Moreover, conditional deletion of Sez6 in peripheral neurons, including DRG neurons, in Advillin-Cre^ERT2xSez6^fl/fl mice, significantly ameliorated heat hyperalgesia after a chronic constriction injury of the sciatic nerve.  These data indicate that blocking Sez6 function in the peripheral nervous system is a promising means of inhibiting chronic pain hypersensitivity while avoiding adverse central nervous system side-effects.                       
With the aim of mimicking the effects of Sez6 cKO in the peripheral nervous system, we isolated anti-Sez6 monoclonal antibodies (mAbs) through biopanning a naïve human antibody single-chain variable fragment [scFv] phage display library.  Testing of the reformatted mAbs in vitro, in Cos 7 cells exogenously expressing transmembrane Sez6 (Sez6 tII) on their surface, has revealed that several of these mAbs enhance Sez6 endocytosis and decrease levels of internalised Sez6 over time. In conclusion, these mAbs are effective at modifying the cellular distribution of Sez6 and may interfere with Sez6 function.