title: Inhibition of CRAC with a human anti-ORAI1 monoclonal antibody inhibits T-cell-derived cytokine production but fails to inhibit a T-cell-dependent antibody response in the cynomolgus monkey.
abstract: ORAI1 is the pore-forming component of calcium release-activated calcium (CRAC) channels. CRAC channels are the primary route for calcium ion (Ca(2+)) entry into T-cells following antigen stimulation. This Ca(2+) entry induces proliferation and cytokine production through activation of calcineurin and the nuclear factor of activated T-cells (NFAT) transcription factor along with subsequent cytokine-related genes. It was hypothesized that the in vivo inhibition of T-cell function by blocking ORAI1 or calcineurin would lead to similar functional consequences. To test this hypothesis the activity of 2C1.1, a fully human anti-ORAI1 monoclonal antibody, and cyclosporin A (CsA) were tested in vivo for their suppressive effect on T-cell-derived cytokine production and a T-cell-dependent antibody response (TDAR) using sheep red blood cells (SRBC) in cynomolgus monkeys. Despite showing similar inhibition of ex vivo interleukin (IL)-2 production by stimulated T-cells, both molecules exhibited different pharmacologic effects on the SRBC antibody response. CsA blocked the development of SRBC-specific antibodies, while 2C1.1 failed to inhibit the antigen-specific antibody response. These surprising observations suggest that full inhibition of the CRAC channel is required to inhibit a functional immune response, consistent with findings from human patients with loss of function mutations in ORAI1.
authors.affiliation: Department of Inflammation Research .
authors.forename: Kevin
authors.initials: K
authors.lastname: Gaida
authors.forename: Hossein
authors.initials: H
authors.lastname: Salimi-Moosavi
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.forename: Valerie
authors.initials: V
authors.lastname: Almon
authors.forename: Anna
authors.initials: A
authors.lastname: Knize
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Lin
authors.forename: Hung Q
authors.initials: HQ
authors.lastname: Nguyen
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: John K
authors.initials: JK
authors.lastname: Sullivan
authors.forename: Min
authors.initials: M
authors.lastname: Wong
authors.forename: Helen J
authors.initials: HJ
authors.lastname: McBride
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000917:Antibody Formation; D019703:Calcineurin / Q000378:metabolism; D015220:Calcium Channels / Q000276:immunology / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage*; D004912:Erythrocytes / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D008252:Macaca fascicularis; D008297:Male; D050778:NFATC Transcription Factors / Q000378:metabolism; D000071740:ORAI1 Protein; D012756:Sheep; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015220:Calcium Channels; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D016572:Cyclosporine; D019703:Calcineurin
keywords: CRAC; CsA; ORAI1; SRBC; TDAR; cynomolgus monkey