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CTLA4Ig treatment in patients with multiple sclerosis

An open-label, phase 1 clinical trial

From the Center for Neurologic Diseases (V.V., G.J.B., B.H., H.L.W., D.A.H., S.J.K.), Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; ITN (Immune Tolerance Network) (K.B.), Bethesda, MD; Center for Neurological Imaging (S.E., C.R.G.G.), Brigham and Women’s Hospital, Boston, MA; and Repligen Corporation (J.R.R.), Waltham, MA.

Address correspondence and reprint requests to Dr Khoury, Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, HIM 712, Boston, MA 02115 skhoury{at}rics.bwh.harvard.edu

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- 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.

GLOSSARY: 1M = 1 month after infusion; 2M = 2 months after infusion; 3M = 3 months after infusion; 8D = 8 days after infusion; AE = adverse event; AI = Ambulation Index; APC = antigen-presenting cell; BL = baseline; BL2 = second baseline; BPF = brain parenchymal fraction; CTLA-4 = cytotoxic T lymphocyte–associated gene 4; EDSS = Expanded Disability Status Scale; FDA = Food and Drug Administration; Gd+ = gadolinium-enhanced; hMBP = human myelin basic protein; IDO = indolamine 2,3-dioxygenase; IFN = interferon; IL = interleukin; MBP = myelin basic protein; MS = multiple sclerosis; MSFC = Multiple Sclerosis Functional Composite; PBMC = peripheral blood mononuclear cell; RA = rheumatoid arthritis; TE = echo time; TR = repetition time; URI = upper respiratory infection; UTI = urinary tract infection; WBC = white blood cell.

Supplemental data at www.neurology.org

Supported by the Immune Tolerance Network.

Disclosure: J.R.R. is an employee of Repligen Corporation, which supplied the CTLA4Ig.

Received November 27, 2007. Accepted in final form June 11, 2008.

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