title: Antibody-mediated targeting of the Orai1 calcium channel inhibits T cell function.
abstract: Despite the attractiveness of ion channels as therapeutic targets, there are no examples of monoclonal antibodies directed against ion channels in clinical development. Antibody-mediated inhibition of ion channels could offer a directed, specific therapeutic approach. To investigate the potential of inhibiting ion channel function with an antibody, we focused on Orai1, the pore subunit of the calcium channel responsible for store-operated calcium entry (SOCE) in T cells. Effector T cells are key drivers of autoimmune disease pathogenesis and calcium signaling is essential for T cell activation, proliferation, and cytokine production. We show here the generation of a specific anti-human Orai1 monoclonal antibody (mAb) against an extracellular loop of the plasma membrane-spanning protein. The anti-Orai1 mAb binds native Orai1 on lymphocytes and leads to cellular internalization of the channel. As a result, T cell proliferation, and cytokine production is inhibited in vitro. In vivo, anti-Orai1 mAb is efficacious in a human T cell-mediated graft-versus host disease (GvHD) mouse model. This study demonstrates the feasibility of antibody-mediated inhibition of Orai1 function and, more broadly, reveals the possibility of targeting ion channels with biologics for the treatment of autoimmunity and other diseases.
authors.affiliation: Department of Cellular Immunology, Novo Nordisk Research Center, Seattle, Washington, United States of America.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Cox
authors.affiliation: Department of Cellular Immunology, Novo Nordisk Research Center, Seattle, Washington, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Hussell
authors.affiliation: Department of Immunopharmacology, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Søndergaard
authors.affiliation: Department of Histology, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Roepstorff
authors.affiliation: Department of Cellular Immunology, Novo Nordisk Research Center, Seattle, Washington, United States of America.
authors.forename: John-Vu
authors.initials: JV
authors.lastname: Bui
authors.affiliation: Department of Molecular Immunology, Novo Nordisk Research Center, Seattle, Washington, United States of America.
authors.forename: Jen Running
authors.initials: JR
authors.lastname: Deer
authors.affiliation: Department of Cell Biology, Beijing Novo Nordisk Pharmaceuticals Science & Technology Co., Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology & Immunology, Beijing University People's Hospital, Beijing, China.
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Li
authors.affiliation: Department of Screening and Cell Technology, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Lamberth
authors.affiliation: Department of Histology, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Peter Helding
authors.initials: PH
authors.lastname: Kvist
authors.affiliation: Department of Protein Structure and Biophysics, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Padkjær
authors.affiliation: Department of Immunopharmacology, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Haase
authors.affiliation: Department of Antibody Technology, Novo Nordisk A/S, Maløv, Denmark.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahn
authors.affiliation: Department of Cellular Immunology, Novo Nordisk Research Center, Seattle, Washington, United States of America.
authors.forename: Valerie H
authors.initials: VH
authors.lastname: Odegard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D015220:Calcium Channels / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D017136:Ion Transport; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D000071740:ORAI1 Protein; D061251:Primary Cell Culture
chemical_list: D000911:Antibodies, Monoclonal; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D002118:Calcium