title: Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function.
abstract: 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 alpha4-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 alpha4-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 alpha4-integrin saturation was not reduced after PLEX, it was reduced to less than 50% when natalizumab concentrations were below 1 mug/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 mug/mL, desaturation of alpha4-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.
authors.affiliation: Regional Multiple Sclerosis Center and Center for Neurological Disorders, Aurora St. Luke's Medical Center, Milwaukee, WI, USA.
authors.forename: B O
authors.initials: BO
authors.lastname: Khatri
authors.forename: S
authors.initials: S
authors.lastname: Man
authors.forename: G
authors.initials: G
authors.lastname: Giovannoni
authors.forename: A P
authors.initials: AP
authors.lastname: Koo
authors.forename: J-C
authors.initials: JC
authors.lastname: Lee
authors.forename: B
authors.initials: B
authors.lastname: Tucky
authors.forename: F
authors.initials: F
authors.lastname: Lynn
authors.forename: S
authors.initials: S
authors.lastname: Jurgensen
authors.forename: J
authors.initials: J
authors.lastname: Woodworth
authors.forename: S
authors.initials: S
authors.lastname: Goelz
authors.forename: P W
authors.initials: PW
authors.lastname: Duda
authors.forename: M A
authors.initials: MA
authors.lastname: Panzara
authors.forename: R M
authors.initials: RM
authors.lastname: Ransohoff
authors.forename: R J
authors.initials: RJ
authors.lastname: Fox
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D039001:Integrin alpha Chains / Q000187:drug effects / Q000378:metabolism; D039441:Integrin alpha4 / Q000187:drug effects / Q000378:metabolism; D007964:Leukocytosis / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy; D008137:Longitudinal Studies; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D000069442:Natalizumab; D010951:Plasma Exchange / Q000379:methods*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D039001:Integrin alpha Chains; D000069442:Natalizumab; D039441:Integrin alpha4