RETRACTED: A Monoclonal Antibody that Targets a NaV1.7 Channel Voltage Sensor for Pain and Itch Relief

Voltage-gated sodium (NaV) channels control the upstroke of the action potentials in excitable cells. Multiple studies have shown distinct roles of NaV channel subtypes in human physiology and diseases, but subtype-specific therapeutics are lacking and the current efforts have been limited to small molecules. Here, we present a monoclonal antibody that targets the voltage-sensor paddle of NaV1.7, the subtype critical for pain sensation. This antibody not only inhibits NaV1.7 with high selectivity, but also effectively suppresses inflammatory and neuropathic pain in mice. Interestingly, the antibody inhibits acute and chronic itch despite well-documented differences in pain and itch modulation. Using this antibody, we discovered that NaV1.7 plays a key role in spinal cord nociceptive and pruriceptive synaptic transmission. Our studies reveal that NaV1.7 is a target for itch management, and the antibody has therapeutic potential for suppressing pain and itch. Our antibody strategy may have broad applications for voltage-gated cation channels.

[1]  A. Basbaum,et al.  Excitatory Superficial Dorsal Horn Interneurons Are Functionally Heterogeneous and Required for the Full Behavioral Expression of Pain and Itch , 2013, Neuron.

[2]  R. Bolognesi,et al.  Abnormal ventricular repolarization mimicking myocardial infarction after heterocyclic antidepressant overdose. , 1997, The American journal of cardiology.

[3]  Min Li,et al.  Antibody therapeutics targeting ion channels: are we there yet? , 2013, Acta Pharmacologica Sinica.

[4]  F. Zufall,et al.  Loss-of-function mutations in sodium channel Nav1.7 cause anosmia , 2011, Nature.

[5]  M. Lei,et al.  Generation of functional ion-channel tools by E3 targeting , 2005, Nature Biotechnology.

[6]  T. Zimmer,et al.  SCN5A channelopathies--an update on mutations and mechanisms. , 2008, Progress in biophysics and molecular biology.

[7]  N. Damann,et al.  Advances in Targeting Voltage‐Gated Sodium Channels with Small Molecules , 2012, ChemMedChem.

[8]  R. Gordon,et al.  Monoclonal antibodies against the voltage-sensitive Na+ channel from mammalian skeletal muscle. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[9]  W. Catterall,et al.  THE CRYSTAL STRUCTURE OF A VOLTAGE-GATED SODIUM CHANNEL , 2011, Nature.

[10]  R. L. Kirby,et al.  The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32. , 2001, American journal of human genetics.

[11]  Hussain Jafri,et al.  An SCN9A channelopathy causes congenital inability to experience pain , 2006, Nature.

[12]  Christian Bailly,et al.  Strategies and challenges for the next generation of therapeutic antibodies , 2010, Nature Reviews Immunology.

[13]  E. Carstens,et al.  Neural processing of itch , 2013, Neuroscience.

[14]  W. Pardridge,et al.  Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. , 2012, Methods in enzymology.

[15]  H. Komatsu [Antibody therapy in cancer]. , 2010, Nihon rinsho. Japanese journal of clinical medicine.

[16]  H L Greene,et al.  Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. , 1991, The New England journal of medicine.

[17]  Yan-Gang Sun,et al.  A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord , 2007, Nature.

[18]  R. MacKinnon,et al.  Mapping the Receptor Site for Hanatoxin, a Gating Modifier of Voltage-Dependent K+ Channels , 1997, Neuron.

[19]  W. Catterall,et al.  Voltage Sensor–Trapping Enhanced Activation of Sodium Channels by β-Scorpion Toxin Bound to the S3–S4 Loop in Domain II , 1998, Neuron.

[20]  S. Dib-Hajj,et al.  Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn , 2012, Molecular pain.

[21]  Román A. Corfas,et al.  Loss of Inhibitory Interneurons in the Dorsal Spinal Cord and Elevated Itch in Bhlhb5 Mutant Mice , 2010, Neuron.

[22]  John N. Wood,et al.  SCN9A Mutations in Paroxysmal Extreme Pain Disorder: Allelic Variants Underlie Distinct Channel Defects and Phenotypes , 2006, Neuron.

[23]  Francisco Bezanilla,et al.  Charge Movement Associated with the Opening and Closing of the Activation Gates of the Na Channels , 1974, The Journal of general physiology.

[24]  A. Dickenson,et al.  Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons , 2012, Nature Communications.

[25]  B. Wallace,et al.  Binding of the Anticonvulsant Drug Lamotrigine and the Neurotoxin Batrachotoxin to Voltage-gated Sodium Channels Induces Conformational Changes Associated with Block and Steady-state Activation* , 2003, The Journal of Biological Chemistry.

[26]  M. Zhuo,et al.  Glutamate acts as a neurotransmitter for gastrin releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord , 2011, Molecular pain.

[27]  R. MacKinnon,et al.  A membrane-access mechanism of ion channel inhibition by voltage sensor toxins from spider venom , 2004, Nature.

[28]  M. D. de Groot,et al.  Subtype‐selective targeting of voltage‐gated sodium channels , 2009, British journal of pharmacology.

[29]  Charles N Serhan,et al.  Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions , 2010, Nature Medicine.

[30]  John N. Wood,et al.  Neurological perspectives on voltage-gated sodium channels , 2012, Brain : a journal of neurology.

[31]  Yiyuan Cui,et al.  A subpopulation of nociceptors specifically linked to itch , 2012, Nature Neuroscience.

[32]  A. Todd,et al.  Neuronal circuitry for pain processing in the dorsal horn , 2010, Nature Reviews Neuroscience.

[33]  Q. Ma Labeled lines meet and talk: population coding of somatic sensations. , 2010, The Journal of clinical investigation.

[34]  G. Wilcox,et al.  Intrathecal morphine in mice: a new technique. , 1980, European journal of pharmacology.

[35]  J. Xing,et al.  Blockade of Persistent Sodium Currents Contributes to the Riluzole-Induced Inhibition of Spontaneous Activity and Oscillations in Injured DRG Neurons , 2011, PloS one.

[36]  Martin Koltzenburg,et al.  ProTx-II, a Selective Inhibitor of NaV1.7 Sodium Channels, Blocks Action Potential Propagation in Nociceptors , 2008, Molecular Pharmacology.

[37]  M. Cadene,et al.  X-ray structure of a voltage-dependent K+ channel , 2003, Nature.

[38]  Francisco Bezanilla,et al.  Voltage Sensors in Domains III and IV, but Not I and II, Are Immobilized by Na+ Channel Fast Inactivation , 1999, Neuron.

[39]  F. Lehmann-Horn,et al.  Sodium channelopathies of skeletal muscle result from gain or loss of function , 2010, Pflügers Archiv - European Journal of Physiology.

[40]  W. Dixon,et al.  Efficient analysis of experimental observations. , 1980, Annual review of pharmacology and toxicology.

[41]  Andrew Escayg,et al.  Sodium channel SCN1A and epilepsy: Mutations and mechanisms , 2010, Epilepsia.

[42]  E. Carstens,et al.  Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch , 2014, PAIN®.

[43]  Youxing Jiang,et al.  The principle of gating charge movement in a voltage-dependent K+ channel , 2003, Nature.

[44]  Charles N. Serhan,et al.  Resolving TRPV1- and TNF-α-Mediated Spinal Cord Synaptic Plasticity and Inflammatory Pain with Neuroprotectin D1 , 2011, The Journal of Neuroscience.

[45]  Yang Liu,et al.  VGLUT2-Dependent Glutamate Release from Nociceptors Is Required to Sense Pain and Suppress Itch , 2010, Neuron.

[46]  Andrew C. Chan,et al.  Therapeutic antibodies for autoimmunity and inflammation , 2010, Nature Reviews Immunology.

[47]  New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? , 2013, Pflügers Archiv - European Journal of Physiology.

[48]  R. MacKinnon,et al.  Hanatoxin Modifies the Gating of a Voltage-Dependent K+ Channel through Multiple Binding Sites , 1997, Neuron.

[49]  M. D. de Groot,et al.  Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels , 2013, Proceedings of the National Academy of Sciences.

[50]  A. A. Alabi,et al.  Portability of paddle motif function and pharmacology in voltage sensors , 2007, Nature.

[51]  L. Cornelius,et al.  Chronic itch development in sensory neurons requires BRAF signaling pathways. , 2013, The Journal of clinical investigation.

[52]  Xinzhong Dong,et al.  TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. , 2012, The Journal of clinical investigation.

[53]  S. Mishra,et al.  The Cells and Circuitry for Itch Responses in Mice , 2013, Science.

[54]  E. Boyden,et al.  Anti-Ca2+ channel antibody attenuates Ca2+ currents and mimics cerebellar ataxia in vivo , 2008, Proceedings of the National Academy of Sciences.

[55]  G. King,et al.  Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models , 2013, Proceedings of the National Academy of Sciences.