Serum Concentrations of Natalizumab, Endogenous IgG4, and sVCAM-1 in Natalizumab-Treated PML Patients (P05.159)

OBJECTIVE: With the goal of identifying natalizumab patients at higher or lower risk of developing progressive multifocal leukoencephalopathy (PML), serum concentrations of natalizumab, immunoglobulin G 4 (IgG 4 ), and soluble vascular cell adhesion molecule-1 (sVCAM-1) in multiple sclerosis (MS) natalizumab-treated patients who developed PML were compared with those of non-PML patients. BACKGROUND: Natalizumab is a recombinant humanized anti-α 4 integrin antibody approved for the treatment of relapsing-remitting MS. PML is infrequently associated with natalizumab treatment. DESIGN/METHODS: Serum concentrations of natalizumab were quantified in natalizumab-treated MS patients with PML (n=21) and without PML (n=560). Also, since natalizumab undergoes half-antibody exchange with endogenous IgG 4 in vivo to generate bispecific molecules, serum concentration of IgG 4 was measured as a surrogate marker of exposure to unexchanged natalizumab (PML patients, n=28; non-PML patients, n=283). Concentrations of sVCAM, a pharmacodynamic marker of natalizumab, were measured in 10 PML and 173 non-PML patients. RESULTS: No significant difference was observed between median serum concentrations of IgG 4 in PML and non-PML patients (225 µg/mL vs 250 µg/mL). Similarly, no significant difference in sVCAM-1 concentrations was noted between PML and non-PML patients either prior to or during natalizumab treatment. The median serum concentrations of natalizumab in PML patients after approximately 12 and 24 months of natalizumab treatment were 21 µg/mL and 31 µg/mL, respectively, and did not differ significantly from those of non-PML patients (20 µg/mL and 27 µg/mL). CONCLUSIONS: Although this analysis was performed on PML samples collected outside of controlled clinical studies and may be confounded by small sample size and varying intervals between natalizumab infusion and sample collection, serum concentrations of natalizumab, endogenous IgG 4 , and sVCAM-1 do not appear to differ in natalizumab patients who develop PML and those who do not and therefore do not appear to provide a practical approach to stratify patients9 risk for developing PML. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Plavina has received personal compensation for activities with Biogen Idec. Dr. Plavina holds stock and/or stock options in Biogen Idec. Dr. Hochman has received personal compensation for activities with Biogen Idec as an employee. Dr. Hochman holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Hochman was involved as an investigator. Dr. Hochman has received research support from Biogen Idec. Dr. Kuesters has received personal compensation for activities with Biogen Idec. Dr. Kuesters holds stock and/or stock options in Biogen Idec. Dr. Njenga has nothing to disclose. Dr. Shapiro has received personal compensation for activities with Biogen Idec as an employee. Dr. Shapiro holds stock and/or stock options in Biogen Idec, which sponsors research in which Dr. Shapiro has involved as an investigator. Dr. Woodworth has received personal compensation for activities with Biogen Idec as an employee. Dr. Woodworth holds stock and/or stock options in Biogen Idec. Dr. Yednock has received personal compensation for activities with Elan Corporation as an employee. Dr. Goelz has received personal compensation for activities with Elan Pharmaceuticals and Biogen Idec. Dr. Goelz holds stock and/or stock options in Elan Pharmaceuticals. Dr. Compton has received personal compensation for activities with Biogen Idec. Dr. Subramanyam has received personal compensation for activities with Biogen Idec. as an employee. Dr. Subramanyam holds stock in Biogen Idec Inc., which sponsored research in which Dr. Subramanyam was involved as an investigator.