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

Neurorehabil Neural Repair. 2018 Jun;32(6-7):578-589. doi: 10.1177/1545968318776371. Epub 2018 Jun 5.


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.

Keywords: clinical trial; neuronal plasticity; paraplegia; regeneration; spinal cord injuries; tetraplegia.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Dose-Response Relationship, Drug
  • Feasibility Studies
  • Female
  • Humans
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / therapeutic use*
  • Injections, Spinal
  • Male
  • Middle Aged
  • Nerve Regeneration / drug effects*
  • Neurites / drug effects*
  • Nogo Proteins / immunology*
  • Paraplegia / drug therapy*
  • Paraplegia / etiology
  • Quadriplegia / drug therapy*
  • Quadriplegia / etiology
  • Recovery of Function / drug effects
  • Spinal Cord Injuries / drug therapy*
  • Treatment Outcome
  • Young Adult


  • Immunoglobulin G
  • Nogo Proteins