Disruption of memory B-cell trafficking by belimumab in patients with systemic lupus erythematosus

Eline J Arends; Mihaela Zlei; Christopher M Tipton; Jasna Cotic; Zgjim Osmani; Fenna J de Bie; Sylvia W A Kamerling; Andre van Maurik; Richard Dimelow; Yun Irene Gregan; Norma Lynn Fox; Ton J Rabelink; David A Roth; Ignacio Sanz; Jacques J M van Dongen; Cees van Kooten; Y K Onno Teng

doi:10.1093/rheumatology/keae286

Disruption of memory B-cell trafficking by belimumab in patients with systemic lupus erythematosus

Rheumatology (Oxford). 2024 May 22:keae286. doi: 10.1093/rheumatology/keae286. Online ahead of print.

Authors

Eline J Arends¹, Mihaela Zlei^{2

3}, Christopher M Tipton^{4

5}, Jasna Cotic⁶, Zgjim Osmani¹, Fenna J de Bie², Sylvia W A Kamerling¹, Andre van Maurik⁷, Richard Dimelow⁸, Yun Irene Gregan⁹, Norma Lynn Fox¹⁰, Ton J Rabelink¹, David A Roth¹¹, Ignacio Sanz⁴, Jacques J M van Dongen¹², Cees van Kooten¹, Y K Onno Teng¹

Affiliations

¹ Expert Center for Lupus-, Vasculitis-, and Complement-mediated Systemic diseases (LuVaCs), Department of Internal Medicine-section Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.
² Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands.
³ Medical Laboratory, Department of Flow Cytometry, Regional Institute of Oncology, Iasi, Romania.
⁴ Lowance Centre for Human Immunology, Emory University School of Medicine, Atlanta, GA, USA.
⁵ Department of Medicine, Division of Rheumatology, Emory University, Atlanta, GA, USA.
⁶ Clinical Statistics, Brentford, GSK, UK, Middlesex.
⁷ Clinical Pharmacology and Experimental Medicine, Stevenage, Hertfordshire, GSK, UK.
⁸ Clinical Pharmacology Modelling and Simulation, Stevenage, Hertfordshire, GSK, UK.
⁹ Clinical Science Immunology, Collegeville, GSK, USA, PA.
¹⁰ Clinical Development, Collegeville, GSK, USA, PA.
¹¹ Research and Development, Collegeville, GSK, USA, PA.
¹² Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer (CIC-IBMCC, USAL-CSIC-FICUS) and Department of Medicine, University of Salamanca, Salamanca, Spain.

PMID: 38775637
DOI: 10.1093/rheumatology/keae286

Abstract

Objectives: Autoreactive memory B cells contribute to chronic and progressive courses in autoimmune diseases like systemic lupus erythematosus (SLE). The efficacy of belimumab (BEL), the first approved biologic treatment for SLE and lupus nephritis (LN), is generally attributed to depletion of activated naïve B cells and inhibition of B cell activation. BEL's effect on memory B cells (MBCs) is currently unexplained. We performed an in-depth cellular and transcriptomic analysis of BEL's impact on the blood MBC compartment in patients with SLE.

Methods: A retrospective meta-analysis was conducted, pooling flow cytometry data from four randomized trials involving 1245 patients with SLE treated with intravenous BEL or placebo. Then, extensive MBC phenotyping was performed using high-sensitivity flow cytometry in patients with mild/moderate SLE and severe SLE/LN treated with subcutaneous BEL. Finally, transcriptomic characterization of surging MBCs was performed by single-cell RNA sequencing.

Results: In BEL-treated patients, a significant increase in circulating MBCs, in a broad range of MBC subsets, was established at week 2, gradually returning to baseline by week 52. The increase was most prominent in patients with higher SLE disease activity, serologically active patients, and patients aged ≤18 years. MBCs had a non-proliferating phenotype with a prominent decrease in activation status and downregulation of numerous migration genes.

Conclusion: Upon BEL initiation, an increase of MBCs was firmly established. In the small cohort investigated, circulating MBCs were de-activated, non-proliferative, and demonstrated characteristics of disrupted lymphocyte trafficking, expanding on our understanding of the therapeutic mechanism of B cell-activating factor inhibition by BEL.

Trial registration: ClinicalTrials.gov NCT00071487, NCT00410384, NCT01632241, NCT01649765, NCT03312907, NCT03747159.

Keywords: B-lymphocyte; biologicals; gene expression; lupus nephritis; systemic lupus erythematosus (SLE).

Associated data

ClinicalTrials.gov/NCT00410384
ClinicalTrials.gov/NCT01632241
ClinicalTrials.gov/NCT03312907
ClinicalTrials.gov/NCT03747159
ClinicalTrials.gov/NCT01649765
ClinicalTrials.gov/NCT00071487