CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial

Neurology. 2008 Sep 16;71(12):917-24. doi: 10.1212/01.wnl.0000325915.00112.61.

Abstract

Background: The modulation of costimulatory pathways represents an original therapeutic approach to regulate T cell-mediated autoimmune diseases by preventing or reducing autoantigen-driven T-cell activation in humans. Autoreactive CD4(+) T cells play a critical role in initiating the immune response leading to the chronic inflammation and demyelination characteristic of multiple sclerosis (MS).

Methods: We used IV infusions of CTLA4Ig to block the CD28/B7 T-cell costimulatory pathway in a phase 1 dose-escalation study in MS. Sixteen patients with relapsing-remitting MS received a single CTLA4Ig infusion and were monitored for up to 3 months after treatment. In an extension study, four additional subjects received four doses of CTLA4Ig.

Results: CTLA4Ig was well tolerated in patients with MS, and most adverse events were rated as mild. Immunologic assessment of the patients showed a reduction in myelin basic protein (MBP) proliferation within 2 months of infusion and decreased interferon-gamma production by MBP-specific lines.

Conclusions: Inhibiting costimulatory molecule interactions by using CTLA4Ig seems safe in multiple sclerosis (MS), and the immunologic effects suggest that it may be a promising approach to regulate the inflammatory process associated with MS.

Publication types

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

MeSH terms

  • Abatacept
  • Brain / pathology
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Humans
  • Immune System / drug effects
  • Immunoconjugates / administration & dosage*
  • Immunoconjugates / adverse effects
  • Immunoconjugates / therapeutic use
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use
  • Interferon-gamma / antagonists & inhibitors
  • Magnetic Resonance Imaging
  • Multiple Sclerosis, Relapsing-Remitting / diagnosis
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / physiopathology
  • Myelin Basic Protein / antagonists & inhibitors
  • Time Factors

Substances

  • Immunoconjugates
  • Immunosuppressive Agents
  • Myelin Basic Protein
  • Abatacept
  • Interferon-gamma