Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Most cited references 33

Record: found
Abstract: found
Article: found

Is Open Access

Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus

Richard Furie, Munther A. Khamashta, Joan Merrill … (2017)

Objective To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double‐blind, placebo‐controlled study of adults with moderate‐to‐severe systemic lupus erythematosus (SLE). Methods Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4‐gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]–based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent‐to‐treat (ITT) population and type I IFN–high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2‐sided), within each of the 2 study populations for the primary end point analysis. Results The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo‐treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ‐specific end points. Herpes zoster was more frequent in the anifrolumab‐treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively). Conclusion Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate‐to‐severe SLE.

0 comments Cited 306 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo.

Agnès Le Bon, Giovanna Schiavoni, Giuseppina D'agostino … (2001)

Type I interferons (IFN-I) are rapidly induced following infection and play a key role in nonspecific inhibition of virus replication. Here we have investigated the effects of IFN-I on the generation of antigen-specific antibody responses. The data show that IFN-I potently enhance the primary antibody response to a soluble protein, stimulating the production of all subclasses of IgG, and induce long-lived antibody production and immunological memory. In addition, endogenous production of IFN-I was shown to be essential for the adjuvant activity of CFA. Finally, IFN-I enhanced the antibody response and induced isotype switching when dendritic cells were the only cell type responding to IFN-I. The data reveal the potent adjuvant activity of IFN-I and their important role in linking innate and adaptive immunity.

0 comments Cited 228 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease.

Kyriakos Kirou, Christina Lee, Sandhya George … (2005)

Gene-expression studies have demonstrated increased expression of interferon (IFN)-inducible genes (IFIGs) in peripheral blood mononuclear cells (PBMCs) of many patients with systemic lupus erythematosus (SLE), with a predominant effect of type I IFN. This study examined the hypothesis that increased disease severity and activity, as well as distinct autoantibody specificities, characterize SLE patients with activation of the type I IFN pathway. Freshly isolated PBMCs from 77 SLE patients, 22 disease controls, and 28 healthy donors were subjected to real-time polymerase chain reaction for 3 IFIGs that are preferentially induced by IFNalpha, and the data were used to derive IFNalpha scores for all individuals. Expression of IFIGs was significantly higher in SLE patients compared with disease controls or healthy donors. SLE patients with high and low IFNalpha scores were compared for clinical manifestations of disease, disease severity, disease activity, serologic features, and potential confounders, by bivariate and multivariate analyses. SLE patients with a high IFNalpha score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did SLE patients with low IFNalpha scores. Patients with high scores showed increased disease activity, as measured by lower C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score. The presence of antibodies specific for Ro, U1 RNP, Sm, and dsDNA, but not phospholipids, was significantly associated with a high IFNalpha score. Logistic regression analysis confirmed that renal disease, higher SDI scores, low complement levels, and presence of anti-RNA binding protein (RBP) autoantibodies were associated with a high IFNalpha score. Activation of the IFNalpha pathway defines a subgroup of SLE patients whose condition is characterized by increased disease severity, including renal disease, increased disease activity, reflected in complement activation, and autoreactivity to RBP.

0 comments Cited 213 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Lupus Sci Med

Journal ID (iso-abbrev): Lupus Sci Med

Journal ID (hwp): lupusscimed

Journal ID (publisher-id): lupus

Title: Lupus Science & Medicine

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2053-8790

Publication date Collection: 2018

Publication date (Electronic): 5 April 2018

Volume: 5

Issue: 1

Electronic Location Identifier: e000261

Affiliations

[1 ]departmentRespiratory, Inflammation and Autoimmunity , MedImmune LLC , Gaithersburg, Maryland, USA

[2 ]departmentClinical Pharmacology and DMPK , MedImmune LLC , Mountain View, California, USA

[3 ]departmentAnalytical Sciences , MedImmune LLC , Gaithersburg, Maryland, USA

[4 ]departmentAntibody Discovery and Protein Engineering , MedImmune LLC , Gaithersburg, Maryland, USA

[5 ]departmentTranslational Medicine , MedImmune LLC , Gaithersburg, Maryland, USA

Author notes

[Correspondence to ] Dr Gary P Sims; simsg@ 123456medimmune.com

Article

Publisher ID: lupus-2018-000261

DOI: 10.1136/lupus-2018-000261

PMC ID: 5890856

PubMed ID: 29644082

SO-VID: f2f3d57b-72cb-4de8-a714-ff71a53fa285

License:

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/

History

Date received : 24 January 2018

Date revision received : 02 March 2018

Date accepted : 08 March 2018

Funding

Funded by: MedImmune, LLC;

Custom metadata

special-feature unlocked

Keywords: cytokines,dmards (biologic),interferon,systemic lupus erythematosus,treatment

Data availability:

Keywords: cytokines, dmards (biologic), interferon, systemic lupus erythematosus, treatment

Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus

Read this article at

Abstract

Objective

Methods

Results

Conclusions

Related collections

Cures Within Reach: Autoimmune Lymphoproliferative Syndrome (ALPS)

Most cited references 33

Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus

Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo.

Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease.

Author and article information

Journal

Affiliations

Author notes

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 185

Cited by 43

Most referenced authors 793