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.