論文 - 詳細
| RRC ID | 44823 |
|---|---|
| 著者 | Cox JH, Hussell S, Søndergaard H, Roepstorff K, Bui JV, Deer JR, Zhang J, Li ZG, Lamberth K, Kvist PH, Padkjær S, Haase C, Zahn S, Odegard VH. |
| タイトル | Antibody-mediated targeting of the Orai1 calcium channel inhibits T cell function. |
| ジャーナル | PLoS One |
| 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. |
| 巻・号 | 8(12) |
| ページ | e82944 |
| 公開日 | 2013-1-1 |
| DOI | 10.1371/journal.pone.0082944 |
| PII | PONE-D-13-37115 |
| PMID | 24376610 |
| PMC | PMC3871607 |
| MeSH | Amino Acid Sequence Animals Antibodies, Monoclonal / biosynthesis Antibodies, Monoclonal / isolation & purification Antibodies, Monoclonal / pharmacology* Calcium / metabolism Calcium Channel Blockers / isolation & purification Calcium Channel Blockers / metabolism Calcium Channel Blockers / pharmacology* Calcium Channels / genetics* Calcium Channels / immunology Disease Models, Animal Female Gene Expression Graft vs Host Disease / immunology Graft vs Host Disease / metabolism Graft vs Host Disease / pathology Graft vs Host Disease / prevention & control* Humans Hybridomas / immunology Ion Transport Jurkat Cells Leukocytes, Mononuclear / cytology Leukocytes, Mononuclear / drug effects* Leukocytes, Mononuclear / immunology Mice Molecular Sequence Data ORAI1 Protein Primary Cell Culture |
| IF | 2.74 |
| 引用数 | 22 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 12 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3(RCB0805) |