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Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function

From the Regional Multiple Sclerosis Center and Center for Neurological Disorders (B.O.P.), Aurora St. Luke’s Medical Center, Milwaukee, WI; Neuroinflammation Research Center, Lerner Research Institute (S.M., B.T., R.M.R.), Mellen Center for Multiple Sclerosis Treatment and Research (R.M.R., R.J.F.), Department of Hematology (A.P.K.), and Department of Quantitative Health Sciences (J.-C.L.), Cleveland Clinic, Cleveland, OH; Institute of Cell and Molecular Science (G.G.), Barts and London Queen Mary’s School of Medicine and Dentistry, London, UK; Biogen Idec, Inc. (F.L., P.W.D., S.J., J.W., S.G., M.A.P.), Cambridge, MA; and Cleveland Clinic Lerner College of Medicine (R.M.R., R.J.F.), Case Western Reserve University, Cleveland, OH.

Address correspondence and reprint requests to Dr. Robert J. Fox, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, 9500 Euclid Ave., U-10, Cleveland, OH 44195 foxr{at}ccf.org

Background: Accelerating the clearance of therapeutic monoclonal antibodies (mAbs) from the body may be useful to address uncommon but serious complications from treatment, such as progressive multifocal leukoencephalopathy (PML). Treatment of PML requires immune reconstitution. Plasma exchange (PLEX) may accelerate mAb clearance, restoring the function of inhibited proteins and increasing the number or function of leukocytes entering the CNS. We evaluated the efficacy of PLEX in accelerating natalizumab (a therapy for multiple sclerosis [MS] and Crohn disease) clearance and 4-integrin desaturation. Restoration of leukocyte transmigratory capacity was evaluated using an in vitro blood–brain barrier (ivBBB).

Methods: Twelve patients with MS receiving natalizumab underwent three 1.5-volume PLEX sessions over 5 or 8 days. Natalizumab concentrations and 4-integrin saturation were assessed daily throughout PLEX and three times over the subsequent 2 weeks, comparing results with the same patients the previous month. Peripheral blood mononuclear cell (PBMC) migration (induced by the chemokine CCL2) across an ivBBB was assessed in a subset of six patients with and without PLEX.

Results: Serum natalizumab concentrations were reduced by a mean of 92% from baseline to 1 week after three PLEX sessions (p < 0.001). Although average 4-integrin saturation was not reduced after PLEX, it was reduced to less than 50% when natalizumab concentrations were below 1 µg/mL. PBMC transmigratory capacity increased 2.2-fold after PLEX (p < 0.006).

Conclusions: Plasma exchange (PLEX) accelerated clearance of natalizumab, and at natalizumab concentrations below 1 µg/mL, desaturation of 4-integrin was observed. Also, CCL2-induced leukocyte transmigration across an in vitro blood–brain barrier was increased after PLEX. Therefore, PLEX may be effective in restoring immune effector function in natalizumab-treated patients.

Abbreviations: AE = adverse event; BBB = blood–brain barrier; BW = body weight; EDSS = Expanded Disability Status Scale; hIgG4-PE = human IgG4 monoclonal antibody conjugated with phycoerythrin; Ig = immunoglobulin; ivBBB = in vitro blood–brain barrier; mAb = monoclonal antibody; MFI = mean fluorescence intensity; MS = multiple sclerosis; PBMC = peripheral blood mononuclear cell; PLEX = plasma exchange; PML = progressive multifocal leukoencephalopathy; TDL = total drug load; V1 = volume of distribution of the central compartment; Vd = volume of distribution.

Supplemental data at www.neurology.org

*These authors contributed equally to this work.

Supported by Biogen Idec, Inc., Elan Pharmaceuticals, Inc., NIH P50NS38667 (R.M.R.), and K23 47211-01 (R.J.F.).

Disclosure: Author disclosures are provided at the end of the article.

Received August 18, 2008. Accepted in final form October 16, 2008.

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