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

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.

• Authors: Peer B Jacobson, Robin Goody, Matthew Lawrence, Bernhard K Mueller, Xiaomeng Zhang, Bradley A Hooker, Kimberly Pfleeger, Adam Ziemann, Charles Locke, Quentin Barraud, Mathias Droescher, Joerg Bernhard, Andreas Popp, Preethne Boeser, Lili Huang, Jennifer Mollon, Yulia Mordashova, Yi-Fang Cui, John P Savaryn, Christine Grinnell, Ingeborg Dreher, Michael Gold, Grégoire Courtine, Andrea Mothe, Charles H Tator, James D Guest
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 155 Pg. 105385 (07 2021) ISSN: 1095-953X [Electronic] United States
• PMID: 33991647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• GPI-Linked Proteins
• Nerve Tissue Proteins
• RGMA protein, human

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Monoclonal (administration & dosage, genetics)
• Chlorocebus aethiops
• Exercise Test (methods)
• GPI-Linked Proteins (antagonists & inhibitors)
• Humans
• Injections, Spinal
• Male
• Nerve Tissue Proteins (antagonists & inhibitors)
• Neuronal Plasticity (drug effects, physiology)
• Neuroprotection (drug effects, physiology)
• Primates
• Recovery of Function (drug effects, physiology)
• Spinal Cord Injuries (drug therapy, pathology, physiopathology)
• Thoracic Vertebrae (injuries)