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First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury

Kucher, Klaus, Johns, Donald, Maier, Doris, Abel, Rainer, Badke, Andreas, Baron, Hagen, Thietje, Roland, Casha, Steven, Meindl, Renate, Gomez-Mancilla, Baltazar, Pfister, Christian, Mir, Anis Khusro, Rupp, Rüdiger, Weidner, Norbert, Schwab, Martin and Curt, Armin (2018) First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury. Neurorehabilitation and Neural Repair, 32 (6-7). pp. 578-589. ISSN 1545-96831552-6844


Background. Neutralization of central nervous system neurite growth inhibitory factors, for example, Nogo-A, is a promising approach to improving recovery following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of anti-Nogo-A antibodies promoted regenerative neurite growth and functional recovery. Objective. This first-in-man study assessed the feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administration in patients with acute, complete traumatic paraplegia and tetraplegia. Methods. Patients (N = 52) started treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, respectively, over 4 weeks). Results. ATI355 was well tolerated up to 1-year follow-up. All patients experienced ≥1 adverse events (AEs). The 581 reported AEs were mostly mild and to be expected following acute SCI. Fifteen patients reported 16 serious AEs, none related to ATI355; one bacterial meningitis case was considered related to intrathecal administration. ATI355 serum levels showed dose-dependency, and intersubject cerebrospinal fluid levels were highly variable after infusion and bolus injection. In 1 paraplegic patient, motor scores improved by 8 points. In tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from complete to incomplete SCI occurred in 7/19 patients with tetraplegia. Conclusions. ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI.

Item Type: Article
Keywords: clinical trial neuronal plasticity paraplegia regeneration spinal cord injuries tetraplegia
Date Deposited: 08 Aug 2018 00:45
Last Modified: 08 Aug 2018 00:45


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