Summary
New treatments are available for early relapsing-remitting multiple sclerosis (MS). The authors studied the effect of a humanised monoclonal antibody, alemtuzumab, in people with early relapsing-remitting MS and found that it significantly reduced the risk of relapse and accumulation of disability compared with interferon beta-1a in a phase 2 trial. Jones JL, Anderson JM, Phuah CL, Fox EJ, Selmaj K, Margolin D, Lake SL, Palmer J, Thompson SJ, Wilkins A, Webber DJ, Compston DA, Coles AJ. Brain. 2010 Jul 21. [Epub ahead of print]
Details
Treatment of early relapsing-remitting multiple sclerosis with
the lymphocyte-depleting humanized monoclonal antibody
alemtuzumab (Campath™) significantly reduced the risk of relapse
and accumulation of disability compared with interferon beta-1a
in a phase 2 trial [Coles et al., (Alemtuzumab vs. interferon
beta-1a in early multiple sclerosis. N Engl J Med 2008; 359:
1786-801)].
Patients treated with alemtuzumab experienced an improvement in
disability at 6 months that was sustained for at least 3 years.
In contrast, those treated with interferon beta-1a steadily
accumulated disability. Here, by post hoc subgroup analyses of
the CAMMS223 trial, authors show that among participants with no
clinical disease activity immediately before treatment, or any
clinical or radiological disease activity on-trial, disability
improved after alemtuzumab but not following interferon
beta-1a.
This suggests that disability improvement after alemtuzumab is
not solely attributable to its anti-inflammatory effect. Authors
hypothesized that lymphocytes, reconstituting after
alemtuzumab, permit or promote brain repair. They suggest that
after alemtuzumab, and only when specifically stimulated with
myelin basic protein, peripheral blood mononuclear cell cultures
produced increased concentrations of brain-derived neurotrophic
factor, platelet-derived growth factor and ciliary neurotrophic
factor.
Analysis by reverse transcriptase polymerase chain reaction of
cell separations showed that the increased production of ciliary
neurotrophic factor and brain-derived neurotrophic factor after
alemtuzumab is attributable to increased production by T cells.
Media from these post-alemtuzumab peripheral blood mononuclear
cell cultures promoted survival of rat neurones and increased
axonal length in vitro, effects that were partially reversed by
neutralizing antibodies against brain-derived nerve growth factor
and ciliary neurotrophic factor. This conditioned media also
enhanced oligodendrocyte precursor cell survival, maturation and
myelination.
Taken together, the clinical analyses and laboratory findings
support the interpretation that improvement in disability after
alemtuzumab may result, in part, from neuroprotection associated
with increased lymphocytic delivery of neurotrophins to the
central nervous system.