*5.1.1 Siglec-8*

The Siglecs are a family of sialic-acid-binding immunoglobulin-like lectins, which are thought to promote cell–cell interactions and regulate the functions of cells in the innate and adaptive immune systems through glycan recognition. These proteins have regulatory effects on intercellular and intracellular signaling such as the inhibition of cellular proliferation/activation and the induction of apoptosis [76, 77]. Siglec-8 is highly and selectively expressed by eosinophils, but it became clear that it is also expressed by human mast cells and weakly, but consistently, by human basophils. Studies showed that the activation of Siglec-8 induces eosinophil apoptosis (in a caspase-, mitochondrial-, and reactive oxygen species–dependent way). It was also shown that activated eosinophils are especially sensitive to Siglec-8-induced death [78]. It also inhibits the release of FcεRI-mediated histamine and PGD2 from mast cells [79, 80]. In a recent phase I, randomized, placebo-controlled study conducted with more than 50 healthy volunteers, a single dose of a monoclonal anti-Siglec-8 antibody, namely- AK002 (autolimab) (0.001, 0.003, 0.01, 0.03, 0.1, 0.3, and 1 mg/kg IV), resulted in the complete depletion of circulating eosinophils within one hour from the infusion. This effect was maintained for up to 84 days only in the group who received 1 mg/kg. This result pointed to a possible administration schedule of AK002 at monthly or quarterly intervals [81]. Additionally, in another additional study it was also demonstrated that treatment with AK002 provided symptomatic and histologic improvement in patients with eosinophilic esophagitis [82]. Taking this into consideration, a phase IIa study in CSU and CIndU (cholinergic urticaria and symptomatic dermographism) patients was conducted. These patients received six doses of AK002. At week 22, following treatment, based on changes in UCT score - the response rates in CSU patients were the following, complete + partial response in 92% and 86% in omalizumab-naive (*n* = 14) and omalizumab refractory (*n* = 12) patients, respectively. In the 12-month open-label extension phase, the response was sustained. No adverse events were observed, with only mild-tomoderate infusion-related reactions recorded [83, 84]. These results suggest that in the future, anti-Siglec-8 antibodies might be a treatment option for CSU patients, who are either omalizumab naïve or refractory to omalizumab.
