Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus
| Autor: | Erika Farmer, Kamelia Zerrouki, Inna Vainshtein, Meina Liang, Jeffrey M. Riggs, Bhargavi Rajan, Chris Morehouse, Kevin Schifferli, Kimberly Rosenthal, Richard N. Hanna, Divya Sagar, Melissa de los Reyes, Roland Kolbeck, Miguel A. Sanjuan, Gary P. Sims, Jodi L. Karnell |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Immunology Plasmacytoid dendritic cell Proinflammatory cytokine Flow cytometry 03 medical and health sciences systemic lupus erythematosus Interferon Plasma cell differentiation Clinical Trials and Drug Discovery Medicine STAT1 B cell Antibody-dependent cell-mediated cytotoxicity treatment biology medicine.diagnostic_test business.industry dmards (biologic) interferon General Medicine cytokines 030104 developmental biology medicine.anatomical_structure biology.protein Cancer research business medicine.drug |
| Zdroj: | Lupus Science & Medicine |
| ISSN: | 2053-8790 |
| Popis: | Objective We investigated the mechanistic and pharmacological properties of anifrolumab, a fully human, effector-null, anti-type I interferon (IFN) alpha receptor 1 (IFNAR1) monoclonal antibody in development for SLE. Methods IFNAR1 surface expression and internalisation on human monocytes before and after exposure to anifrolumab were assessed using confocal microscopy and flow cytometry. The effects of anifrolumab on type I IFN pathway activation were assessed using signal transducer and activator of transcription 1 (STAT1) phosphorylation, IFN-stimulated response element–luciferase reporter cell assays and type I IFN gene signature induction. The ability of anifrolumab to inhibit plasmacytoid dendritic cell (pDC) function and plasma cell differentiation was assessed by flow cytometry and ELISA. Effector-null properties of anifrolumab were assessed in antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays with B cells. Results Anifrolumab reduced cell surface IFNAR1 by eliciting IFNAR1 internalisation. Anifrolumab blocked type I IFN-dependent STAT1 phosphorylation and IFN-dependent signalling induced by recombinant and pDC-derived type I IFNs and serum of patients with SLE . Anifrolumab suppressed type I IFN production by blocking the type I IFN autoamplification loop and inhibited proinflammatory cytokine induction and the upregulation of costimulatory molecules on stimulated pDCs. Blockade of IFNAR1 suppressed plasma cell differentiation in pDC/B cell co-cultures. Anifrolumab did not exhibit CDC or ADCC activity. Conclusions Anifrolumab potently inhibits type I IFN-dependent signalling, including the type I IFN autoamplification loop, and is a promising therapeutic for patients with SLE and other diseases that exhibit chronic dysfunctional type I IFN signalling. |
| Databáze: | OpenAIRE |
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