2. Academic Validation
  3. Elezanumab, a human anti-RGMa monoclonal antibody, promotes neuroprotection, neuroplasticity, and neurorecovery following a thoracic hemicompression spinal cord injury in non-human primates

Elezanumab, a human anti-RGMa monoclonal antibody, promotes neuroprotection, neuroplasticity, and neurorecovery following a thoracic hemicompression spinal cord injury in non-human primates

  • Neurobiol Dis. 2021 Jul;155:105385. doi: 10.1016/j.nbd.2021.105385.
Peer B Jacobson 1,  Robin Goody 2,  Matthew Lawrence 2,  Bernhard K Mueller 3,  Xiaomeng Zhang 4,  Bradley A Hooker 4,  Kimberly Pfleeger 5,  Adam Ziemann 5,  Charles Locke 6,  Quentin Barraud 7,  Mathias Droescher 3,  Joerg Bernhard 3,  Andreas Popp 8,  Preethne Boeser 8,  Lili Huang 9,  Jennifer Mollon 10,  Yulia Mordashova 10,  Yi-Fang Cui 3,  John P Savaryn 11,  Christine Grinnell 11,  Ingeborg Dreher 12,  Michael Gold 5,  Grégoire Courtine 7,  Andrea Mothe 13,  Charles H Tator 14,  James D Guest 15
Affiliations

Affiliations

  • 1 Department of Translational Sciences, Imaging Research, AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States of America. Electronic address: [email protected].
  • 2 Virscio, New Haven, CT, United States of America.
  • 3 Discovery Biology, AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany.
  • 4 Department of Translational Sciences, Imaging Research, AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States of America.
  • 5 Department of Neuroscience Development, AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States of America.
  • 6 Department of Biometrics, AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States of America.
  • 7 Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Geneva, Switzerland; Department of Clinical Neuroscience, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland; Defitech Center for Interventional Neurotherapies, (NeuroRestore), CHUV/UNIL/EPFL, Lausanne, Switzerland.
  • 8 Department of Preclinical Safety, AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany.
  • 9 AbbVie Biologics, AbbVie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, United States of America.
  • 10 Data and Statistical Sciences, AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany.
  • 11 Department of Drug Metabolism and Pharmacokinetics, AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States of America.
  • 12 Department of Bioanalytics, AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany.
  • 13 Krembil Brain Institute, Toronto Western Hospital, University Health Network, Toronto, Canada.
  • 14 Division of Neurosurgery, Toronto Western Hospital, and University of Toronto, Toronto, Canada.
  • 15 Department of Neurosurgery and The Miami Project to Cure Paralysis, The Miller School of Medicine, University of Miami, Miami, FL, United States of America.
PMID: 33991647 DOI: 10.1016/j.nbd.2021.105385
Abstract

Spinal cord injury (SCI) is a devastating condition characterized by loss of function, secondary to damaged spinal neurons, disrupted axonal connections, and myelin loss. Spontaneous recovery is limited, and there are no approved pharmaceutical treatments to reduce ongoing damage or promote repair. Repulsive guidance molecule A (RGMa) is upregulated following injury to the central nervous system (CNS), where it is believed to induce neuronal Apoptosis and inhibit axonal growth and remyelination. We evaluated elezanumab, a human anti-RGMa monoclonal antibody, in a novel, newly characterized non-human primate (NHP) hemicompression model of thoracic SCI. Systemic intravenous (IV) administration of elezanumab over 6 months was well tolerated and associated with significant improvements in locomotor function. Treatment of Animals for 16 weeks with a continuous intrathecal infusion of elezanumab below the lesion was not efficacious. IV elezanumab improved microstructural integrity of extralesional tissue as reflected by higher fractional anisotropy and magnetization transfer ratios in treated vs. untreated Animals. IV elezanumab also reduced SCI-induced increases in soluble RGMa in cerebrospinal fluid, and membrane bound RGMa rostral and caudal to the lesion. Anterograde tracing of the corticospinal tract (CST) from the contralesional motor cortex following 20 weeks of IV elezanumab revealed a significant increase in the density of CST fibers emerging from the ipsilesional CST into the medial/ventral gray matter. There was a significant sprouting of serotonergic (5-HT) fibers rostral to the injury and in the ventral horn of lower thoracic regions. These data demonstrate that 6 months of intermittent IV administration of elezanumab, beginning within 24 h after a thoracic SCI, promotes neuroprotection and neuroplasticity of key descending pathways involved in locomotion. These findings emphasize the mechanisms leading to improved recovery of neuromotor functions with elezanumab in acute SCI in NHPs.

Keywords

ABT-555; Acute spinal cord injury; African green; BDA; DTI; Elezanumab; Hemicompression; MRI; Monoclonal antibody; Neuroplasticity; Neuroprotection; Neurorestoration; Non-human primate; RGMa; Serotonin; Thoracic.

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