Presented at:
57th Annual Meeting of the American Academy of Neurology, Miami Beach, Florida, April 9-15, 2005.
A Phase I Trial of CTLA4Ig Treatment in MS
Khoury SJ, Viglietta V, Buckle G, Hafler D, Bourcier K, Guttmann C, Bikowski M, Rusche J, Landy H, McNally J, Jauregui K.
Harvard University, Boston, MA; Immune Tolerance Network, Bethesda, MD; Waltham, MA
OBJECTIVE: To determine the safety of RG2077 in patients with multiple sclerosis.
BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system initiated by autoreactive CD4+ T cells, which recognize and respond to myelin antigens. T cell activation depends on signals delivered through the T cell receptor and co-stimulation via CD28-CD80/CD86 interactions. CTLA4-Ig has been used to block CD28-CD80/86 costimulation in several animal models of autoimmune disease, with improvement in disease manifestations. Previous studies using another CTLA4Ig agent have shown clinical benefit in psoriasis and rheumatoid arthritis. RG2077 (Repligen) is a recombinant protein of CTLA4 (cytolytic-T-lymphocyte associated antigen-4) fused to the heavy chain constant region of the human immunoglobulin of the IgG4 isotype. The gene sequence encoding the immunoglobulin portion has been altered to remove the functional properties of binding the Fc receptor and fixation of complement.
DESIGN/METHODS: We performed an open-label, dose escalation study of RG2077 in relapsing-remitting MS patients. Each subject received a single infusion of RG2077 in the one of the following dosage groups: 2.0 mg/kg (n = 4), 10.0 mg/kg (n = 4), 20.0 mg/kg (n = 4) and 35.0 mg/kg (n = 4). Safety assessments included blood studies, a MRI, a neurological examination and physical examination. Mechanistic studies were performed at baseline, 1 week, 1 month and 3 months post infusion. Safety data on the first 2 dose groups were presented at the AAN in 2004. The study was supported by the Immune Tolerance Network.
RESULTS: We are currently dosing the 35.0 mg/kg cohort, and the last follow up visit is expected in March '05. No major adverse events have been observed to date. Immunologic/mechanistic studies have been performed and show evidence of biologic activity. The results of the safety data and analysis of the immunologic effects of the treatment on the whole study cohort will be presented.
CONCLUSIONS: CTLA4Ig treatment appears to be safe for MS patients. Supported by: The Immune Tolerance Network