Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

Abstract

Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing-remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood-brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial.

Natalizumab for Multiple Sclerosis: A Case in Point for the Impact of Translational Neuroimmunology

“…Because natalizumab inhibits trafficking of lymphocytes from the blood into the CNS, its clinical benefit can be postulated in secondary progressive MS, in which CNScompartmentalized inflammatory processes may predominate (24). Also, previous studies suggested evidence of improved tissue integrity and enhanced axonal metabolism in some natalizumab-treated RRMS patients (25,26).…”

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

“…Treatments for relapsing multiple sclerosis generally act on the peripheral immune response. 14 Their limited effects on progressive disability suggest that the mechanisms of tissue injury are diverse in progressive multiple sclerosis. Particular interest has emerged in the intrathecal immune response, which is shielded from peripherally acting agents behind the blood-brain barrier.…”

“…Particular interest has emerged in the intrathecal immune response, which is shielded from peripherally acting agents behind the blood-brain barrier. 14 Natalizumab, a recombinant humanised monoclonal antibody against α4 integrin (very late antigen4), is highly effective in relapsingremitting multiple sclerosis 15 and appears to suppress intrathecal inflammation. 14 Natalizumab inhibits leucocyte transmigration across the blood-brain barrier, interferes with chemokinemediated inflammatorycell recruitment into the CNS, and disrupts the production of molecules required to sustain intrathecal inflammation.…”

“…14 Natalizumab, a recombinant humanised monoclonal antibody against α4 integrin (very late antigen4), is highly effective in relapsingremitting multiple sclerosis 15 and appears to suppress intrathecal inflammation. 14 Natalizumab inhibits leucocyte transmigration across the blood-brain barrier, interferes with chemokinemediated inflammatorycell recruitment into the CNS, and disrupts the production of molecules required to sustain intrathecal inflammation. [16][17][18] Results from early phase trials in progressive multiple sclerosis show that natalizumab treatment suppresses CSF markers of inflammation and neurodegeneration, including concentrations of osteo pontin and the Bcell chemokine CXCL13, 14 and suggest that treatment also improves ambulation and upperlimb function.…”

“…14 Natalizumab inhibits leucocyte transmigration across the blood-brain barrier, interferes with chemokinemediated inflammatorycell recruitment into the CNS, and disrupts the production of molecules required to sustain intrathecal inflammation. [16][17][18] Results from early phase trials in progressive multiple sclerosis show that natalizumab treatment suppresses CSF markers of inflammation and neurodegeneration, including concentrations of osteo pontin and the Bcell chemokine CXCL13, 14 and suggest that treatment also improves ambulation and upperlimb function. [19][20][21] On the basis of these considerations, we aimed to investigate whether treatment with natalizumab is safe and slows the accumulation of disability unrelated to relapse in patients with secondary progressive multiple sclerosis.…”