ORAI1 constitutes the pore-forming subunit of the calcium release-activated calcium (CRAC) channel, which is responsible for store-operated calcium entry into lymphocytes. It is known that ORAI1 is essential for the activation of T cells and mast cells and is considered to be a potent therapeutic target for autoimmune and allergic diseases. Here, we obtained a new humanized antibody, DS-2741a, that inhibits ORAI1 function. DS-2741a bound to human-ORAI1 with high affinity and without cross-reactivity to rodent Orai1. DS-2741a demonstrated suppression of CRAC-mediated human and mouse T-cell activation and mast cell degranulation in human ORAI1 knock-in mice. Furthermore, DS-2741a ameliorated house dust mite antigen-induced dermatitis in the human ORAI1 knock-in mouse. Taken together, DS-2741a inhibited T-cell and mast cell functions, thus improving skin inflammation in animal models of atopic dermatitis and reinforcing the need for investigation of DS-2741a for the treatment of allergic diseases in a clinical setting.
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| http://dx.doi.org/10.1096/fba.2020-00008 | DOI Listing |
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