Potential Risk of Progressive Multifocal Leukoencephalopathy With Natalizumab Therapy

Stüve, Olaf; Marra, Christina M.; Cravens, Petra D.; Singh, Mahendra Pratap; Hu, Wei; Lovett-Racke, Amy E.; Monson, Nancy; Phillips, J. Theodore; Tervaert, Jan Willem Cohen; Nash, Richard A.; Hartung, Hans Peter; Kieseier, Bernd C.; Racke, Michael; Frohman, Elliot M.; Hemmer, Bernhard

doi:10.1001/archneur.64.2.169

Cited by 60 publications

(32 citation statements)

References 82 publications

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“…Natalizumab is a monoclonal antibody directed against α 4 -β 1 integrin (very late activation antigen 4, VLA-4), a surface molecule found on all leukocytes with exception of neutrophils [1,2]. The expression of VLA-4 can be measured with monoclonal antibodies directed against CD49d.…”

Section: Introductionmentioning

confidence: 99%

Effects of Natalizumab on Circulating B Cells, T Regulatory Cells and Natural Killer Cells

et al. 2010

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Background: Natalizumab is a humanized monoclonal antibody directed against very late activation antigen 4 (VLA-4) and has a potent effect on disease activity in multiple sclerosis. Blockade of VLA-4 with natalizumab may not only interfere with autoimmunological mechanisms but also with central nervous system immune surveillance. Methods: Longitudinal ex vivo and in vitro study to determine the effect of natalizumab on the frequency of distinct immune cells and on the frequency and suppressive function of natural CD4+CD25+ regulatory T cells (Tregs). Results: Natalizumab binding to VLA-4 was more marked for B cells than for T cells (49% reduction in VLA-4-expressing B cells compared to 24.5% reduction of T cells). There was an increase in circulating B cells over T cells (2.6 vs. 1.5 fold, p < 0.001). Natural killer cells increased 1.5-fold (p = 0.01). Natalizumab led to a relative decrease in CD4+CD25+ Tregs from 18.9 to 14.1% (p = 0.04). The impaired suppressive capacity of Tregs was not restored. Conclusion: Natalizumab reduces VLA-4 expression on all investigated immune cells, but changes were most marked for B cells. Further differential effects on immune cells may be relevant to opportunistic central nervous system infections during treatment with natalizumab.

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Section: Introductionmentioning

confidence: 99%

Effects of Natalizumab on Circulating B Cells, T Regulatory Cells and Natural Killer Cells

et al. 2010

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“…This could restore immune function, potentially improving the clinical outcome from PML. 20,21 Immune reconstitution is the only intervention with demonstrated efficacy for PML, including patients with HIV infection taking highly active antiretroviral therapy 22,23 and in transplant patients after reduction in immunosuppressant medications. 24,25 Little is known about how to remove therapeutic proteins from the body and whether their removal will restore the native function of the endogenous targets.…”

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confidence: 99%

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

Bo¹,

Man²,

Giovannoni³

et al. 2009

Neurology

265

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“…This is of particular importance, since there is currently only circumstantial evidence that treatments promoting immune reconstitution such as hematopoietic growth factors, plasma exchange, intravenous immunoglobulins and leukopheresis with autotransfusion of leukocytes as well as experimental approaches with antiviral treatment, immunomodulatory therapy, antiserum of recombinant natalizumab-blocking molecules may alter the clinical course of PML patients who received natalizumab [75].…”

Section: ■ Future Prospectsmentioning

confidence: 99%

Monoclonal antibodies in the therapy of multiple sclerosis

et al. 2008

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With the generation of monoclonal antibodies (mAbs), a new therapeutical concept has gained importance. MAbs aim against selective antigens and so have changed our treatment strategies from non-specific to specific. Four therapeuticals have gained importance in the therapy of multiple sclerosis (MS): One has already been approved for therapy (natalizumab), whereas the other three are either in clinical trials or are about to enter phase III studies. Currently, two phase III studies that evaluate the efficacy of alemtuzumab have begun with recruitment (MS CARE I and II). Another mAb (daclizumab) under study is directed to the interleukin-2alpha chain (CD25). Results of clinical trials are promising by reporting reduction of relapses and progression in relapsing remitting and secondary progressive MS accompanied by reduction of new lesions in magnetic resonance imaging. A multicenter randomized controlled trial of daclizumab in MS is going to be initiated. Trials with a humanised antibody directed against the cell surface molecule CD20 are under development. Although the future will emphasise this trend to mAbs, the risks should not be ignored as has been shown in recent news. Still, mAbs have the possibility to revolutionise therapeutical concepts in the treatment of immune-mediated diseases, and will therefore be a useful addition to current therapeutic concepts.

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Potential Risk of Progressive Multifocal Leukoencephalopathy With Natalizumab Therapy

Cited by 60 publications

References 82 publications

Effects of Natalizumab on Circulating B Cells, T Regulatory Cells and Natural Killer Cells

Effects of Natalizumab on Circulating B Cells, T Regulatory Cells and Natural Killer Cells

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

Monoclonal antibodies in the therapy of multiple sclerosis

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