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

NEUROBIOLOGY OF DISEASE

卷:155

Article

Jacobson, Peer B.¹  Goody, Robin²  Lawrence, Matthew²  Mueller, Bernhard K.³  Zhang, Xiaomeng¹  Hooker, Bradley A.¹  Pfleeger, Kimberly⁴  Ziemann, Adam⁴  Locke, Charles⁵  Barraud, Quentin^6,17,18,19  Droescher, Mathias³  Bernhard, Joerg³  Popp, Andreas⁷  Boeser, Preethne⁷  Huang, Lili⁸  Mollon, Jennifer⁹  Mordashova, Yulia⁹  Cui, Yi-Fang³  Savaryn, John P.¹⁰  Grinnell, Christine¹⁰  Dreher, Ingeborg¹¹  Gold, Michael⁴  Courtine, Gregoire^6,17,18,19  Mothe, Andrea¹²  Tator, Charles H.^13,14  Guest, James D.^15,16 

[1] AbbVie Inc, Dept Translat Sci, Imaging Res, 1 North Waukegan Rd, N Chicago, IL 60064 USA

[2] Virscio, New Haven, CT USA

[3] AbbVie Deutschland GmbH & Co KG, Neurosci Res, Discovery Biol, Knollstr, D-67061 Ludwigshafen, Germany

[4] AbbVie Inc, Dept Neurosci Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA

[5] AbbVie Inc, Dept Biometr, 1 North Waukegan Rd, N Chicago, IL 60064 USA

[6] Swiss Fed Inst Technol EPFL, Sch Life Sci, Ctr Neuroprosthet & Brain Mind Inst, Geneva, Switzerland

[7] AbbVie Deutschland GmbH & Co KG, Neurosci Res, Dept Preclin Safety, Knollstr, D-67061 Ludwigshafen, Germany

[8] AbbVie Biores Ctr, AbbVie Biol, 381 Plantat St, Worcester, MA 01605 USA

[9] AbbVie Deutschland GmbH & Co KG, Neurosci Res, Data & Stat Sci, Knollstr, D-67061 Ludwigshafen, Germany

[10] AbbVie Inc, Dept Drug Metab & Pharmacokinet, 1 North Waukegan Rd, N Chicago, IL 60064 USA

[11] AbbVie Deutschland GmbH & Co KG, Neurosci Res, Dept Bioanalyt, Knollstr, D-67061 Ludwigshafen, Germany

[12] Univ Hlth Network, Toronto Western Hosp, Krembil Brain Inst, Toronto, ON, Canada

[13] Toronto Western Hosp, Div Neurosurg, Toronto, ON, Canada

[14] Univ Toronto, Toronto, ON, Canada

[15] Univ Miami, Miller Sch Med, Dept Neurosurg, Miami, FL 33136 USA

[16] Univ Miami, Miller Sch Med, Miami Project Cure Paralysis, Miami, FL 33136 USA

[17] Lausanne Univ Hosp CHUV, Dept Clin Neurosci, Lausanne, Switzerland

[18] Univ Lausanne UNIL, Lausanne, Switzerland

[19] CHUV UNIL EPFL, Defitech Ctr Intervent Neurotherapies, NeuroRestore, Lausanne, Switzerland

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

DOI  :  10.1016/j.nbd.2021.105385

来源: Elsevier

【 摘 要 】

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.