Anti-ORAI1 antibody DS-2741a, a specific CRAC channel blocker, shows ideal therapeutic profiles for allergic disease via suppression of aberrant T-cell and mast cell activation

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Anti-ORAI1 antibody DS-2741a, a specific CRAC channel blocker, shows ideal therapeutic profiles for allergic disease via suppression of aberrant T-cell and mast cell activation (1)

Calcium ion (Ca2+) entry from the CRAC channel is also strictly controlled and mediated by IgE‐FcεRI signaling upon cross‐linking by antigens, leading to degranulation of mast cells. ORAI1, the critical pore subunit of the CRAC channel, is important in immune regulation. Therefore, the specific inhibition of ORAI1 could be a potential mechanism for the treatment of Atopic dermatitis (AD) and other immune diseases.

Induction of passive cutaneous anaphylaxis (PCA) reaction by which ovalbumin (OVA)‐specific IgE was intradermally administered to the ears of mice, followed by an intravenous injection of 10 mg/kg of antigen (OVA) after 24 hours. Twenty‐six hours prior to the antigen injection, DS‐2741a or control IgG was administered to the mice. The anaphylaxis responses were studied by means of assessing the leakage of Evans blue dye. After stimulation of a human T‐cell line (Jurkat cells) with thapsigargin, Ca2+ entry was increased as determined by Fra2‐AM, and the increase was inhibited by DS‐2741a. DS‐2741a inhibited IL‐2 production in PMA/Iono‐ or CD3/28‐stimulated human peripheral blood peripheral blood mononuclear cells (PBMCs).

DS‐2741a showed dose‐dependent and continuous inhibition of DTH response as judged by footpad thickness and foot volume.

DS‐2741a showed inhibition of thapsigargin‐induced mast cell degranulation compared to control IgG as judged by β‐hexosaminidase release. DS‐2741a inhibited PCA reaction significantly. Since PCA reaction reflects the IgE‐mediated mast cell degranulation in vivo, these data support the substantial effect of DS‐2741a in mast cell regulation under physiological conditions.

As an AD model, human ORAI1 knock‐in mice were frequently treated with mite antigen and Staphylococcal enterotoxin B (SEB). Two weeks after initial mite antigen treatment, ear swelling to twice the size of that prior to the induction of dermatitis and extensive lesions of dermatitis on the dorsal skin of mice were observed. Therapeutic administration of DS‐2741a also significantly ameliorated dermatitis to a similar extent as cyclosporine A.

The Th2 cytokines IL‐4 and IL‐13 are recognized as key drivers of AD, especially in the acute phase. Although the importance of the IL‐4/IL‐13 cytokine pathway has been confirmed in humans, AD is heterogeneous and also involves other T‐helper cell subsets, including Th17, Th22, and Th1 cytokine pathways.

1. A. Aki, K. Tanaka, N. Nagaoka, T. Kimura, D. Baba, Y. Onodera, T. Wada, H. Maeda, T. Nakanishi, T. Agatsuma, Others, Anti-ORAI1 antibody DS-2741a, a specific CRAC channel blocker, shows ideal therapeutic profiles for allergic disease via suppression of aberrant T-cell and mast cell activation. FASEB BioAdvances. 2, 478–488 (2020).

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