Treatments that inhibit mast cell activation
More recent attempts to target MCs therapeutically aim at the inhibition
of activating signals and receptors (Figure 4). These include, for
example, the high affinity receptor for IgE, FcεRI, as well as the
intracellular signals involved in translating receptor activation into
degranulation and mediator release. Examples for the latter include
Bruton’s tyrosine kinase (BTK) and spleen associated tyrosine kinase
(SYK). Inhibitors of BTK or SYK inhibit the degranulation of human MCs
induced via FcεRI. Two BTK inhibitors, Fenebrutinib and Remibrutinib, as
well as the SYK inhibitor GSK2646264 are currently under development for
the treatment of patients with CU.
In chronic spontaneous urticaria (CSU), the activation of skin MCs via
FcεRI, either by IgE to autoallergens or by autoantibodies to its alpha
chain, is held to drive the development of signs and symptoms, itchy
wheals and angioedema, in most patients 100,101.
Treatment with omalizumab, an anti-IgE antibody, is effective in CSU102 and prevents MC activation by reducing the levels
of free IgE and FcεRI expression. Newer anti-IgEs, including ligelizumab
and GI-301, with higher affinity to IgE than omalizumab, are in clinical
development 103.
Several other activating signals and receptors are held to contribute to
the activation and degranulation of MCs and, thereby, to the development
of signs and symptoms of MC-driven diseases. These include the receptors
for thymic stromal lymphopoietin (TSLP), IL-33, IL-4, IL-5, and
complement C5a as well as MRGPRX2. For all of these receptors,
inhibitory compounds (or compounds that inhibit their ligands) are
currently in clinical development for MC-driven diseases, primarily CU104.
The benefit of targeting MC-activating signals, receptors, and pathways
is that this approach protects from the release and, therefore, the
effects of all MC mediators rather than only one. The limitation is that
only one of many pathways of MC activation and degranulation is shut
down. Other pathways are untouched, remain viable, and can lead to MC
activation, as they often do in most MC-driven diseases.