Treating Multiple Sclerosis With Monoclonal Antibodies

Mathias Buttman, MD; Peter Rieckmann, MD, FRCPC

Disclosures

Expert Rev Neurother. 2008;8(3):433-455. 

In This Article

Abstract and Introduction

Therapeutic monoclonal antibodies (mAbs) are potent new tools for a molecular targeted approach to modify the course of multiple sclerosis (MS). Besides natalizumab, which was approved in 2006, three other mAbs (alemtuzumab, rituximab and daclizumab) were successfully tested in Phase II MS trials. In this review, introductory notes on the development and systematic nomenclature of therapeutic mAbs in general, set the stage for a detailed discussion of the four mAbs mentioned. We summarize non-MS indications, expression and function of target antigens, scientific rationales for MS therapy, putative modes of action and pharmacological aspects. Particularly, we provide a critical discussion of clinical MS trials, including protocols and interim analyses of trials currently underway. The natalizumab section pays special attention to the clinical handling of safety issues and the diagnostic use of neutralizing antibodies. We finally develop a scenario for how each of the four mAbs might evolve into the market of MS therapeutics within the coming years.

Impressive clinical efficacy along with a favorable adverse-effect profile in two large Phase III trials and accelerated US FDA approval in November 2004 raised realistic hopes in people with multiple sclerosis (MS) and neurologists that natalizumab (NATA, Tysabri®; Biogen Idec and Elan Pharmaceuticals) could be an eagerly awaited ‘silver bullet’ of MS therapy. However, initial euphoria was soon followed by a rude awakening when three cases of progressive multifocal leukoencephalopathy (PML), a rare but in most cases fatal opportunistic virus infection, in NATA-treated patients became known.[1,2,3] NATA was voluntarily withdrawn from the market until a careful examination had been performed where no further PML cases or any other severe opportunistic infection could be identified.[4] It was reapproved in 2006, and to date, more than 20,000 people worldwide have been treated with NATA.[5] No new PML case in NATA-treated patients has occurred and increasing optimism for its use in patients with active relapsing-remitting MS (RRMS) has returned. Besides NATA, other therapeutic monoclonal antibodies (mAbs) demonstrated promising results in Phase II MS trials and may enter the market of MS therapeutics within the next few years. In this review, we summarize the current state of mAb therapy for MS and provide a perspective how this dynamic field might develop in the short term.

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