Multiple sclerosis (MS) is an idiopathic inflammatory disease of the central nervous
system, which is characterized pathologically by demyelination and subsequent axonal
degeneration. Infiltrating macrophages have been identified to contribute
significantly to demyelination in both clinical MS and animal models of MS. GM-CSF
stimulates proliferation and activation of macrophages, monocytes, neutrophils,
eosinophils, dendritic cells and microglia with subsequent induction of
pro-inflammatory biomolecules. GM-CSF might therefore be involved in the
inflammatory processes related to MS. Elevated concentrations of GM-CSF have been
shown in the cerebrospinal fluid but not in the serum of patients suffering from
relapsing-remitting or secondary progressive MS [1], [2]. Similarly, GM-CSF levels were
reported to be higher in the cerebrospinal fluid, but not in the serum of patients
with active phase of relapsing-remitting MS and in patients with remission in
comparison to control patients suffering from other non-inflammatory neurological
diseases [3].
Additional preclinical findings support a role of anti-GM-CSF therapy for MS. GM-CSF
-/- mice are resistant to EAE and administration of an anti-GM-CSF antibody
prevented the onset of clinical disease. In contrast, the administration of
recombinant GM-CSF worsened the disease in the EAE mouse model [4]. Moreover it was observed that autoreactive T cells are the source of
GM-CSF responsible for EAE and that GM-CSF serves a non-redundant function in the
initiation of this autoimmune inflammation [5], [6], [7]. In addition it has
been shown that GM-CSF is required for recruitment of peripheral myeloid cells into
the CNS and the ability of systemic myeloid cells to respond to GM-CSF was found to
be critical for the development of EAE [6], [8].
Blockade of GM-CSF activity might thus be a therapeutic approach in the treatment
of
inflammatory diseases such as MS. MOR103 is a fully human monoclonal antibody (mAb)
directed towards human GM-CSF. Preclinical studies have shown that MOR103
neutralizes the biological function of human GM-CSF and significantly reduces
inflammation by blocking its interaction with cell surface receptors of inflammatory
cells, thus inhibiting their activation. These studies suggest that GM-CSF is
involved in the pathogenesis of autoimmune diseases such as rheumatoid arthritis and
multiple sclerosis.
In September 2012, MorphoSys announced results from the phase 1b/2a clinical trial
evaluating MOR103 in rheumatoid arthritis (RA) patients. The positive data make
MOR103 the first anti-GM-CSF antibody to demonstrate clinical efficacy in RA and
underline the compoundʼs potential to become an important new drug in an area of
unmet medical need. The safety of MOR103 in patients with MS is currently being
investigated in a phase Ib trial in Europe. MOR103 has recently been licensed to
GlaxoSmithKline.
