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Abstract
Objective Anifrolumab is a fully human immunoglobulin G1 κ monoclonal antibody specific for subunit 1 of the type I interferon (IFN) α receptor. In a phase IIb study of adults with moderate to severe SLE, anifrolumab treatment demonstrated substantial reductions in multiple clinical endpoints. Here, we evaluated serum proteins and immune cells associated with SLE pathogenesis, type I interferon gene signature (IFNGS) test status and disease activity, and how anifrolumab affected these components.
Methods Whole blood samples were collected from patients enrolled in MUSE (NCT01438489) for serum protein and cellular assessments at baseline and subsequent time points. Data were parsed by IFNGS test status (high/low) and disease activity. Protein expression and immune cell subsets were measured using multiplex immunoassay and flow cytometry, respectively. Blood samples from healthy donors were analysed for comparison.
Results Baseline protein expression differed between patients with SLE and healthy donors, IFNGS test-high and -low patients, and patients with moderate and severe disease. Anifrolumab treatment lowered concentrations of IFN-induced chemokines associated with B, T and other immune cell migration in addition to proteins associated with endothelial activation that were dysregulated at baseline. IFNGS test-high patients and those with high disease activity were characterised by low baseline numbers of lymphocytes, circulating memory T-cell subsets and neutrophils. Anifrolumab treatment reversed lymphopenia and neutropenia in the total population, and normalised multiple T-cell subset counts in IFNGS test-high patients compared with placebo.
Conclusions Anifrolumab treatment reversed IFN-associated changes at the protein and cellular level, indicating multiple modes of activity.
Trial registration number NCT01438489.
- systemic lupus erythematosus
- type I interferon
- monoclonal antibody
- disease activity
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Footnotes
Contributors KAC contributed to the data analysis and interpretation as well as writing and review of the manuscript and approved the final manuscript for publication. XG contributed to the study design, data acquisition, data analysis and interpretation, and manuscript preparation and approved the final manuscript for publication. MA Smith contributed to data analysis and interpretation and manuscript preparation and approved the final manuscript for publication. SW contributed to data analysis and manuscript preparation and approved the final manuscript for publication. DS contributed to data banking and integration, review of data, manuscript preparation and approval of the final manuscript for publication. MA Sanjuan contributed to the study design, data interpretation and manuscript preparation and approved the final manuscript for publication. LW contributed to the study design, data acquisition, data analysis and interpretation, and manuscript preparation and approved the final manuscript for publication. GI contributed to data analysis and interpretation and manuscript preparation and approved the final manuscript for publication. WIW contributed to all biomarker plans and data interpretations as well as writing and review of the manuscript, and approved the final manuscript for publication RZ contributed to the early flow cytometry assay development and optimization GS contributed to data assessments from the flow cytometry work. SE contributed to early flow cytometry development. TDP contributed to early flow cytometry development. KO provided medical writing services. RP provided medical writing services.
Funding This study was sponsored by MedImmune, a member of the AstraZeneca Group.
Competing interests KAC, XG, MAS, SW, DS and WW are employees of MedImmune and hold stock and/or stock options in AstraZeneca. MAS was an employee of MedImmune at the time that this analysis was conducted; he is now an employee of Bristol-Myers Squibb. LW was an employee of MedImmune at the time that this analysis was conducted; he is now an employee of AstraZeneca. GI was an employee of MedImmune at the time that this analysis was conducted; he is now an employee of Viela Bio.
Patient consent Not required.
Ethics approval The MUSE study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice. Independent ethics committee or independent institutional review board approvals were obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure