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.

Figures

Figure 1 Effects of plasma exchange on serum concentration of natalizumab and α4-integrin saturation Effects of plasma exchange (PLEX) on serum concentration of natalizumab (A) and α4-integrin saturation (B). Historic data were obtained from a separate group of patients with multiple sclerosis after six monthly doses of natalizumab, with no PLEX. For α4-integrin saturation (B), PLEX patients were divided into two groups: those with sustained natalizumab concentration of less than 1 μg/mL after PLEX and those with natalizumab concentration of 1 μg/mL or greater after PLEX.

Figure 2 Relationship between serum natalizumab concentration and α4-integrin saturation The steady-state correlation between serum natalizumab concentration (log scale) and α4-integrin saturation in plasma exchange (PLEX) patients is shown. At serum natalizumab concentrations below 1.0 μg/mL, there is reliable α4-integrin desaturation. To allow for re-equilibration, only data points ≥24 hours after each PLEX session are shown.

Figure 3 Absolute peripheral blood mononuclear cell transmigration to chemokine CCL2 in natalizumab-treated patients Induced transmigration (i.e., difference in transmigrating peripheral blood mononuclear cells across an in vitro blood–brain barrier in the presence and absence of CCL2) is shown at two time points before plasma exchange (PLEX; no shading) and after PLEX (lighter shading). Black bars represent the mean. For comparison, values for eight patients with multiple sclerosis (MS) not receiving any MS treatment or PLEX and values for seven healthy patients also are shown (darker shading).

Figure 4 Population pharmacokinetic and pharmacodynamic modeling of plasma exchange Through population modeling of five alternating-day plasma exchange (PLEX) sessions (blue arrows) starting 7 days after natalizumab dosing, PLEX reduces natalizumab concentration to less than 1 μg/mL by day 15. Without PLEX, the same concentration would be expected by day 97.