*5.1.2 Other molecules (SHIP-1, PI3K, CD200)*

Many new regulatory molecules are recently evaluated for their potential inhibitory effect on mast cell degranulation. Some of them are under development and are to be included in the pipe-line of clinical trials for the treatment of CSU. Among these molecules are SHIP and CD200R, which deserve our attention. It has been shown that SHIP-negative mast cells are more likely to degranulate following IgE binding [85]. The inhibitory effects of SHIP-1 occur through the hydrolysis of phosphatidylinositol 3, 4, 5-trisphosphate by limiting the entry of extracellular calcium, thereby decreasing phosphoinositide 3-kinase (PI3K)-mediated mast cell activation [86–88]. CD200R is a member of the Ig supergene family that is

primarily expressed on myeloid cells. In vivo studies demonstrated that CD200R is an inhibitory receptor that is capable of regulating the activation threshold of inflammatory immune responses. Furthermore, CD200R was also shown to be expressed on mouse and human mast cells and that engagement of CD200R by agonist Abs or ligand results in a potent inhibition of mast cell degranulation and cytokine secretion responses. The proposed mechanism for that effect was possibly due to the inhibition of FcεRI activation that was observed both in vitro and in vivo. [88] Considering their regulatory functions on mast cells, the use of SHIP, CD200R antibodies, or PI3K inhibitors for the treatment of CSU is of great interest.

#### *5.1.3 Anti-histamine H4 receptor*

The emerging field of histamine H4 receptors in allergy and clinical immunology is continuously growing. H4 histamine receptor, is a member of the G protein-coupled receptor superfamily that is largely expressed in haematopoietic cells and plays an increasing role in the regulation of immune responses. H4 receptors modulate eosinophil migration and selective recruitment of mast cells that leads to an increased histamine-release and chronic inflammation. It is also involved in T cell differentiation thereby is involved in many immunomodulatory pathways. The observation that H4 is a histamine receptor on many immune cells shed light on the potential of their targeting in inflammatory disorders, such as allergy, chronic pruritus and autoimmune diseases e.g. CSU [89]. Several ongoing clinical studies currently taking place are aimed at evaluating the beneficial effect of targeting H4 receptors in patients suffering from atopic dermatitis and pruritus (JNJ-7777120, ZPL-3893787). Preliminary results have indicated a significant reduction in histamine-mediated scratch and Th2-induced inflammation in atopic dermatitis [90, 91]. These results are encouraging and indicate the need to further evaluate any potential benefits of these drugs in the treatment of CSU.

#### *5.1.4 Mas-related gene X2*

MrgX2 is a member of Mas-related genes that is primarily expressed in human dorsal root ganglia and mast cells and is activated by basic peptides. MrgX2 is a multi-ligand receptor responding to various exogenous and endogenous stimuli. As they are highly expressed on skin mast cells, MRGPRX2 triggers their degranulation and release of pro inflammatory mediators, thus promoting multicellular signaling cascades, such as itch induction and transmission in sensory neurons. The expression of MRGPRX2 by skin mast cells and the levels of the MRGPRX2 agonists (eg, substance P, major basic protein, eosinophil peroxidase) are up-regulated in the serum and skin of patients with inflammatory and pruritic skin diseases, such as CSU and atopic dermatitis. Thus, MRGPRX2 and its agonists might possibly be potential biomarkers for the progression of cutaneous inflammatory diseases and the response to treatment in the future. In addition, they may well represent promising targets for the prevention and treatment of signs and symptoms in patients with skin diseases or drug reactions [92].

### **6. Anti-IgE, B cells**

#### **6.1 Quilizimab**

Quilizumab, is another new humanized monoclonal antibody directed specifically against membrane-bound IgE. This molecule was also evaluated for its efficacy *New Biological Treatment Options in CSU DOI: http://dx.doi.org/10.5772/intechopen.97647*

and safety for the treatment of CSU in a phase II trial. Unfortunately, following a 20-week treatment with quilizumab 450 mg or a placebo every 4 weeks, no statisticallly significant differences were observed in all clinical scores ISS7, HSS7, and UAS7 – between the two groups. Moreover, even in the minimally important difference (MID) range the quilizumab group also failed to attain significant differences. [93]. Thus, further development of quilizumab for CSU was discontinued.
