Monoclonal Antibodies in MS Treatment

Hans-Peter Hartung
Department of Neurology, Heinrich-Heine-University Düsseldorf, Germany

Monoclonal antibodies allow to specifically target molecules crucial in pathogenetic pathways or displayed on cells playing a fundamental role in disease causation. 
Introduction of the anti-VLA4-monoclonal antibody natalizumab more than a decade ago presented a quantum leap in the treatment of relapsing MS beyond platform injectables.

Natalizumab prevents the influx of  predominantly T lymphocytes from the  periphery into the CNSand thereby almost completely  suppresses inflammatory activity gleaned through MRI. In general natalizumab, approved with an administration interval of one month, is well tolerated but infrequently associated with the risk  of developing PML. Risk factors have been identified and include prior exposure to immunosuppressants, duration of administration and JCV antibody titer (index). 

The second monoclonal antibody approved for the treatment of relapsing MS is alemtuzumab, directed against the  CD52 antigen expressed on T cells, B cells and monocytes. Two short annual courses result in sustained reduction of T cells in the periphery and most likely causes a reconfiguration of the disturbed immune system by the re-emerging lymphocytes. Alemtuzumab  has been shown to provide lasting efficacy and disease control years beyond its administration. Major risks associated with alemtuzumab therapy include B cell mediated secondary autoimmune disorders such as ITP, glomerulonephritis and most frequently thyroid disease. While overall rare, examples of serious infections are on record.

The first exploration of the utility of a  B cell depleting approach was undertaken with the CD20 directed antibody rituximab.  Targeting the CD20 antigen on cells of theBb cell lineage leaves stem cells, pre-B cells  and plasma cells functionally intact. Following encouraging results in phase II, the further development programme utilized the humanized anti-CD20-monoclonal antibody ocrelizumab which showed similar high efficacy in large scale pivotal trials both in naive and treatment experienced patients. Treatment is delivered following an  induction over 14 days at 6 monthly intervals. 

Key in the mode of action appears to be  depletion of  B cells as antigen presenting cells. Ocrelizumab is also the first drug shown to be efficacious in  primary progressive MS. Here, particularly patients at a younger age with a shorter disease duration and evidence of inflammatory activity obtained benefit in terms of slowing of disability progression.

Initial concerns centered a potential heightened risk of malignancies, in particular breast cancer.

Another anti-CD20 monoclonal antibody, ofatumumab,  delivered subcoutaneously, is in late phase III evaluation.

A promising monoclonal antibody directed at the CD25 antigen (daclizumab) with a potentially distinct unique mode of action (propagation of regulatory cells) had to be withdrawn earlier this year due to instances of severe hepatic failure and autoimmune antibody-mediated encephalitides. 

Beyond immunomodulation, one monoclonal antobody, opicinumab directed against LINGO-1, has been studied in terms of its potential to promote remyelination in acute optic neuritis and relapsing MS. 

Clearly, monoclonal antibodies have shown high efficacy in controlling disease activity in relapsing MS. One drug has shown promise in treating PPMS. The exact positioning in the therapeutic arsenal  still neeeds to be defined. Pharmacovigilance is of utmost importance. Biomarkers that would identify patients best suited for an individual treatment are badly needed.