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PLoS One. 2013 Dec 23;8(12):e82944. doi: 10.1371/journal.pone.0082944. eCollection 2013.

Antibody-mediated targeting of the Orai1 calcium channel inhibits T cell function.

Author information

1
Department of Cellular Immunology, Novo Nordisk Research Center, Seattle, Washington, United States of America.
2
Department of Immunopharmacology, Novo Nordisk A/S, Maløv, Denmark.
3
Department of Histology, Novo Nordisk A/S, Maløv, Denmark.
4
Department of Molecular Immunology, Novo Nordisk Research Center, Seattle, Washington, United States of America.
5
Department of Cell Biology, Beijing Novo Nordisk Pharmaceuticals Science & Technology Co., Beijing, China.
6
Department of Rheumatology & Immunology, Beijing University People's Hospital, Beijing, China.
7
Department of Screening and Cell Technology, Novo Nordisk A/S, Maløv, Denmark.
8
Department of Protein Structure and Biophysics, Novo Nordisk A/S, Maløv, Denmark.
9
Department of Antibody Technology, Novo Nordisk A/S, Maløv, Denmark.

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.

PMID:
24376610
PMCID:
PMC3871607
DOI:
10.1371/journal.pone.0082944
[Indexed for MEDLINE]
Free PMC Article

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