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Clinical trials and drug discovery
Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus
  1. Jeffrey M Riggs1,
  2. Richard N Hanna1,
  3. Bhargavi Rajan2,
  4. Kamelia Zerrouki1,
  5. Jodi L Karnell1,
  6. Divya Sagar1,
  7. Inna Vainshtein2,
  8. Erika Farmer3,
  9. Kimberly Rosenthal4,
  10. Chris Morehouse5,
  11. Melissa de los Reyes5,
  12. Kevin Schifferli1,
  13. Meina Liang2,
  14. Miguel A Sanjuan1,
  15. Gary P Sims1 and
  16. Roland Kolbeck1
  1. 1 Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA
  2. 2 Clinical Pharmacology and DMPK, MedImmune LLC, Mountain View, California, USA
  3. 3 Analytical Sciences, MedImmune LLC, Gaithersburg, Maryland, USA
  4. 4 Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland, USA
  5. 5 Translational Medicine, MedImmune LLC, Gaithersburg, Maryland, USA
  1. Correspondence to Dr Gary P Sims; simsg{at}medimmune.com

Abstract

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.

  • cytokines
  • dmards (biologic)
  • interferon
  • systemic lupus erythematosus
  • treatment

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/lupus-2018-000261

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    Footnotes

    • JMR and RNH contributed equally.

    • Contributors JMR and RNH equally contributed to study conception, design and execution; analysis and interpretation of data and manuscript preparation. MAS, GPS and RK contributed to study design, interpretation of data and manuscript preparation. BR, KZ, JLK, DS, IV, EF, KR, CM, MdlR, KS and ML contributed to assay design and execution, data analysis and interpretation and manuscript preparation.

    • Funding This study was funded by MedImmune, LLC.

    • Competing interests All authors are employees of MedImmune, LLC.

    • Ethics approval Study protocols involving human cells were approved by the MedImmune institutional review board (protocol number: 2010-001 v6.0).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Assay protocols are available upon request. Study data are available upon request and completion of a data sharing agreement with MedImmune via the Data Request Portal (https://astrazenecagroup-dt.pharmacm.com//DT/Home/Index/).

    • Presented at Some of the data have been published in abstract form following presentation at the 2017 Annual Meeting of the American College of Rheumatology (Sims GP, Riggs J, Hanna R, et al. Arthritis Rheumatol 2017; 69 (Suppl 10)).