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  • Identification of biomarkers of response to abatacept in patients with SLE using deconvolution of whole blood transcriptomic data from a phase IIb clinical trial

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Biomarker studies
Original research article
Identification of biomarkers of response to abatacept in patients with SLE using deconvolution of whole blood transcriptomic data from a phase IIb clinical trial
  1. Somnath Bandyopadhyay1,
  2. Sean E Connolly2,
  3. Omar Jabado1,
  4. June Ye3,
  5. Sheila Kelly2,
  6. Michael A Maldonado4,
  7. Rene Westhovens5,
  8. Peter Nash6,
  9. Joan T Merrill7 and
  10. Robert M Townsend8
  1. 1 Translational Bioinformatics, Bristol-Myers Squibb, Princeton, New Jersey, USA
  2. 2 US Medical, Bristol-Myers Squibb, Princeton, New Jersey, USA
  3. 3 Global Biometric Sciences, Bristol-Myers Squibb, Princeton, New Jersey, USA
  4. 4 Immunoscience R&D, Bristol-Myers Squibb, Princeton, New Jersey, USA
  5. 5 Department of Development and Regeneration KU Leuven, Skeletal Biology and Engineering Research Center; Rheumatology, University Hospitals Leuven, Leuven, Belgium
  6. 6 Department of Medicine, University of Queensland, Brisbane, Queensland, Australia
  7. 7 Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  8. 8 Clinical Biomarkers, Bristol-Myers Squibb, Princeton, New Jersey, USA
  1. Correspondence to Dr Somnath Bandyopadhyay; bandyopadhyay.som{at}gmail.com

Abstract

Objective To characterise patients with active SLE based on pretreatment gene expression-defined peripheral immune cell patterns and identify clusters enriched for potential responders to abatacept treatment.

Methods This post hoc analysis used baseline peripheral whole blood transcriptomic data from patients in a phase IIb trial of intravenous abatacept (~10 mg/kg/month). Cell-specific genes were used with a published deconvolution algorithm to identify immune cell proportions in patient samples, and unsupervised consensus clustering was generated. Efficacy data were re-analysed.

Results Patient data (n=144: abatacept: n=98; placebo: n=46) were grouped into four main clusters (C) by predominant characteristic cells: C1—neutrophils; C2—cytotoxic T cells, B-cell receptor-ligated B cells, monocytes, IgG memory B cells, activated T helper cells; C3—plasma cells, activated dendritic cells, activated natural killer cells, neutrophils; C4—activated dendritic cells, cytotoxic T cells. C3 had the highest baseline total British Isles Lupus Assessment Group (BILAG) scores, highest antidouble-stranded DNA autoantibody levels and shortest time to flare (TTF), plus trends in favour of response to abatacept over placebo: adjusted mean difference in BILAG score over 1 year, −4.78 (95% CI −12.49 to 2.92); median TTF, 56 vs 6 days; greater normalisation of complement component 3 and 4 levels. Differential improvements with abatacept were not seen in other clusters, except for median TTF in C1 (201 vs 109 days).

Conclusions Immune cell clustering segmented disease severity and responsiveness to abatacept. Definition of immune response cell types may inform design and interpretation of SLE trials and treatment decisions.

Trial registration number NCT00119678; results.

  • autoimmune diseases
  • DMARDs (biologic)
  • systemic lupus erythematosus

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-2017-000206

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    Footnotes

    • Contributors All authors meet the authorship requirements and have seen and approved the final version of the manuscript for submission.

    • Funding This study was sponsored by Bristol-Myers Squibb. Professional medical writing and editorial assistance was provided by Carolyn Tubby, PhD, at Caudex and was funded by Bristol-Myers Squibb.

    • Competing interests SB, SEC, OJ, SK, MAM and RMT are employees and shareholders of Bristol-Myers Squibb. JY is an employee of Bristol-Myers Squibb. RW has received grant/research support from Roche and UCB, is a consultant for Bristol-Myers Squibb, Galapagos and Janssen, and has participated in a speakers’ bureau for Bristol-Myers Squibb. PN has no conflicts of interest. JTM has received consulting fees from Abbott, Amgen, Astellas, Bristol-Myers Squibb, Cephalon, Eisai, EMD Serono, Genentech/Roche, Human Genome Sciences/GlaxoSmithKline, Lilly, MedImmune/AstraZeneca, Ono, Pfizer, Questcor, UCB, and research grants from Genentech/Roche, Pfizer and UCB.

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