Expert Review of Neurotherapeutics
Treating Multiple Sclerosis With Monoclonal Antibodies
Mathias Buttman, MD; Peter Rieckmann, MD, FRCPC
Expert Rev Neurother. 2008;8(3):433-455.
Systematic Nomenclature of Therapeutic Monoclonal Antibodies
The systematic name of a mAb may be a tongue-twister. However it always provides information about the disease group it was originally developed for and about its species source(s). The prefix of the name is unique for each Ab and most often has no deeper sense. The second part explains which disease group the Ab was originally developed for, such as -tu(m)- for tumor therapy. The consonant in brackets is used only if the next syllable begins with a vowel. The third part explains which species the mAb was derived from, using the first vowel occurring in the species name. The name of the mAb always ends with the syllable -mab, which stands for monoclonal antibody. Table 2 provides a key for understanding the naming of mAbs together with the mAbs covered in this review.
Expert Rev Neurother. 2008;8(3):433-455. © 2008 Future Drugs Ltd.
FDA- and EMEA-approved Disease-modifying Drugs for Mulitple Sclerosis (as of November 2007)
Systematic Nomenclature of Monoclonal Antibodies and Examples
Effects of 'Persistently Positive' nAbs on 2-year Treatment Response in the AFFIRM Trial
Mathias Buttmann, MD, Julius-Maximilians University, Department of Neurology, Josef-Schneider-Str. 11, 97080 Würzburg, Germany.
Peter Rieckmann, MD, FRCPC, Multiple Sclerosis Society of Canada Research Chair, Director of MS Program at UBC, Division of Neurology, Department of Medicine, University of British Columbia and Vancouver Coastal Health, 2211 Wesbrook Mall, Room S113-116, Vancouver BC, V6T 2B5, Canada.
Financial & Competing Interests Disclosure: Mathias Buttmann and Peter Rieckmann have received honoraria from Bayer Schering Pharma AG, Merck Serono, Biogen Idec and Teva/Aventis for giving lectures. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Sidebar: Key Issues
Based on the AFFIRM monotherapy trial and the SENTINEL combination with IFN-β1a once weekly intramuscular trial, natalizumab, which is a humanized IgG4κ antibody raised against α4-integrin (CD49d) was approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) in 2006.
Natalizumab is thought to act mainly through blockade of leukocyte adhesion to the vessel wall. However, a more complex picture of its immunological effects is currently emerging.
To date, altogether more than 20,000 RRMS patients worldwide have been treated with natalizumab. While two patients in the combination therapy trial developed progressive multifocal leukoencephalopathy, a deadly opportunistic virus infection of the CNS, so far no case has been identified in MS patients receiving natalizumab monotherapy - raising hope that natalizumab is safe when administered as a monotherapy.
Neutralizing antibodies (nAbs) against natalizumab, detected over a period of more than 6 weeks ('persistently positive'), are observed in 6% of the patients and reduce the efficacy of the drug. nAbs detected only at a single time point do not reduce the 2-year efficacy of natalizumab. nAbs may especially develop during the first 6 months of treatment. Approximately half of the persistently positive patients seem to become negative again during the further course of treatment.
Alemtuzumab is a humanized IgG1κ antibody directed against CD52. It induces sustained T-cell depletion and transient B-cell and monocyte depletion. It is approved for B-cell chronic lymphocytic leukemia.
The CAMMS223 Phase II trial demonstrated high efficacy of alemtuzumab monotherapy in high-dose interferon (IFN) nonresponders. However, dosing was prematurely terminated in September 2005 due to idiopathic thrombocytopenic purpura, finally developing in 2.8% of patients, with the first case taking a fatal outcome and the remaining five patients showing a favorable outcome. A total of 11.1% of alemtuzumab-treated patients developed thyroid clinical adverse events.
The Phase III program CARE-MS, investigating alemtuzumab monotherapy in comparison to high-dose IFN therapy in treatment-naive RRMS patients (CARE-MS1) and in treatment-experienced patients with breakthrough disease (CARE-MS2) is currently underway.
Rituximab is a human/mouse chimeric IgG1κ antibody raised against CD20, which is expressed on B cells but not on plasma cells. It acts as a B cell-depleting antibody. Rituximab was first approved in 1997 for non-Hodgkin lymphoma and it has been used in more than 300,000 lymphoma patients.
Rituximab was effective and generally well tolerated in a Phase II trial, enrolling 104 patients with RRMS (HERMES). A Phase II/III trial (OLYMPUS) with primary progressive multiple scelorsis patients is currently underway.
Daclizumab is a humanized IgG1 antibody raised against the α-chain of the human IL-2 receptor (CD25). In 1997, it was first approved for renal allograft rejection and showed a favorable adverse-effect profile in more than 50,000 transplant recipients.
In MS patients, daclizumab is currently thought to take its therapeutic effect through a blockade of IL-2 signaling and an expansion of CD56bright IL-10-producing negative regulatory natural killer cells; however, leaving many open questions.
The Phase II CHOICE trial, investigating daclizumab as an add-on therapy in RRMS patients not stable under IFN-β monotherapy, demonstrated modest efficacy and a favorable adverse-effect profile of daclizumab in this context. The SELECT Phase II trial will study daclizumab monotherapy in patients with RRMS.
The most important ongoing or recently completed clinical monoclonal antibody trials in MS are summarized in Table 4 .
Review of Intermittent Catheterization and Current Best Practices
Optic Neuritis as the Initial Clinical Presentation of Limbic Encephalitis
MS May Increase Cancer Risk
What's Hot at EAN 2019?
Diseases & Conditions Multiple Sclerosis
Diseases & Conditions Neuro-Ophthalmologic Manifestations of Multiple Sclerosis (MS)
Diseases & Conditions Pediatric Multiple Sclerosis
News Intrathecal IgG Synthesis Linked to Disability Worsening in Multiple Sclerosis
Drugs Related to Multiple Sclerosis (MS)
ozanimod
diroximel fumarate
dalfampridine
fingolimod
alemtuzumab
daclizumab
Compassion Fatigue and the Hardship of Caring
'Be Nice' and Document to Prevent Malpractice Suits
Vitamins and Supplements Are a Waste of Money
Medical Cannabis Safe, Effective for Neurologic Symptoms in the Elderly
MS May Increase Cancer Risk News
Diroximel Fumarate Shows Low GI Adverse Events in MS News
Depression Called a 'Core Symptom' of MS News
ORACLE-MS: Cladribine Effective in MS Subgroups News