Natalizumab in the Treatment of Patients with Multiple Sclerosis

Abstract

Multiple sclerosis (MS) usually develops in young adults with a complex predisposing genetic background. Polymorphisms in the gene for chemokine receptor CCR5 have been proposed to confer susceptibility to or protection from MS. Study of molecules participating in the inflammatory process contributed to the development of a new humanized monoclonal antibody, natalizumab, aimed at the adhesive molecule VLA-4. Natalizumab (Biogen Idec/Elan) went through successful clinical studies and its clinical testing was also carried out in the Czech Republic. Twenty-one patients with MS were included in the AFFIRM study (2-year, placebo-controlled study and consecutive 7-month unblinded natalizumab treatment); immunophenotyping of the cerebrospinal fluid (CSF)- CD4+CCR5+CXCR3+ lymphocytes, using flow cytometer FACSCalibur and monoclonal antibodies (BD Biosciences), was done at the end of natalizumab treatment and 1 year after the therapy withdrawal. Compared to MS patients receiving other therapy, the patients treated with natalizumab had statistically significantly (P < 0.0001) higher levels of CCR5+ and lower levels of CD4+ T lymphocytes in CSF, whereas the levels of CXCR3+ lymphocytes were almost the same as in other patients. CCR5-positive CSF lymphocytes decreased 1 year after treatment withdrawal. Natalizumab treatment alters the percentage of CCR5+ and CD4+ cells in CSF. In view of the excellent temporary clinical results of the therapy, which are yet to be assessed in the course of a longer time period, our results show a possible explanation for the therapeutic success of this drug as well as for the development of progressive multifocal leukoencephalopathy.

Increased numbers of circulating hematopoietic stem/progenitor cells are chronically maintained in patients treated with the CD49d blocking antibody natalizumab

“…20,21 It is thus tempting to hypothesize that circulating HSPCs may contribute to the anecdotal cases of neurologic improvement under therapy, which may not be explained by the main mechanism of natalizumab in MS (ie, attenuated lymphocyte recruitment). 22,23 Although in natalizumabtreated MS patients significant numbers of HSPCs continuously circulate outside the protective BM environment, their likelihood to acquire deleterious mutations is probably small, given their G 0 cycling status, but this possibility needs to be considered. Thus far, an increased propensity of natalizumab patients for hematologic malignancies has not been reported; however, further long-term observations are needed.…”

Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders

“…Specific blocking of either α4-integrins or VCAM-1 inhibits the development of EAE, indicating that α4-integrin interactions with VCAM-1 play a critical role in the recruitment of Teffs across the BBB[ 133 , 134 ]. Natalizumab, a drug indicated for relapsing-remitting MS, is a human monoclonal antibody that specifically blocks the α4 subunit of integrins and has yielded favorable clinical outcomes[ 135 ]. A marked increase in ICAM-1 was found within the SN at sites of T cell infiltration following MPTP-intoxication[ 104 ] and numbers of peripheral CD4+ T cells that expressed α4β7 integrin were diminished and inversely correlated to clinical severity in PD patients[ 102 ] suggesting that Teffs are removed from the peripheral circulation, either by elimination or dissemination to sites of CNS inflammation, and may play a role in disease progression.…”

“…CNS degenerative disorders wherein T cell extravasation is thought critical for disease initiation and progression is best documented in the EAE model. Blocking antibodies and multiple drugs have been utilized to target specific subunits of CAMs with the ultimate goal of blocking BBB migration of encephalitogenic Teffs that are specific for the self-antigen[ 27 , 135 , 151 ]. One consensus is that extravasation of T cells in inflammation-associated neurodegenerative disorders such as MS is dependent not only on the CAMs and ligands utilized by ECs and T cells, but also on the cellular architecture and the site at which T cells migrate.…”

Early relapses after the first dose of natalizumab in active multiple sclerosis patients

“…Many recent reports confirm the efficacy of natalizumab in MS [3][4][5], and no further cases of PML have been reported [6]. Other mentioned adverse events include the formation of new T2 lesions in patients who abruptly discontinued the treatment [7], and reduced clinical efficacy and persistent infusion-related adverse events in patients who developed anti-natalizumab antibodies [8].…”