Current and future therapeutics targeting mast cells in disease

Mast cells (MCs) are tissue resident immune cells which are best known for their detrimental role in allergy. Increasing evidence indicates that MCs are also central to the pathogenesis of chronic urticaria. Abnormal increase in MC burden, in most cases driven by gain-of-function mutations in the receptor KIT, can also lead to mastocytosis, a potentially severe malignant disease. Thus, MCs represent important therapeutic targets in all these diseases, and likely in a number of additional inflammatory conditions. In recent years, several monoclonal antibodies (mAbs) and small molecule inhibitors have been developed to directly target MCs or their mediators. Some of these therapeutics, including antagonists of the receptor MRGPRX2, tyrosine kinase inhibitors, anti-Siglec-6 and anti-KIT mAbs are now undergoing clinical evaluation. In this review, we describe the main mechanisms leading to MC activation, and their known functions in allergic diseases, chronic urticaria and mastocytosis. We then discuss recent preclinical and clinical data obtained with novel biologics aimed at targeting MCs in these diseases.