POS0185 BELIMUMAB DISRUPTS MEMORY B-CELL TRAFFICKING IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
POS0185 BELIMUMAB DISRUPTS MEMORY B-CELL TRAFFICKING IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
复制标题
POS0185 BELIMUMAB 扰乱系统性红斑狼疮患者的记忆 B 细胞运输
DOI：
--
复制
发表时间：
2022
影响因子：
27.4
通讯作者：
Y. Teng
中科院分区：
文献类型：
--
作者：
E. J. Arends;M. Zlei;C. Tipton;J. Cotic;Z. Osmani;F. D. de Bie;S. Kamerling;A. van Maurik;R. Dimelow;Y. Gregan;N. Fox;T. Rabelink;D. Roth;I. Sanz;J. V. van Dongen;C. van Kooten;Y. Teng
Belimumab （BEL）是一种针对b细胞活化因子（BAFF）的重组人单克隆抗体，是首个获批用于治疗活动性系统性红斑狼疮（SLE）和狼疮肾炎（LN）患者的生物制剂BEL通过消耗依赖BAFF生存的naïve B细胞来抑制原发性体液免疫反应，而记忆B细胞（MBCs）的继发性体液免疫反应保持完整。事实上，一些研究报道了bba中和后循环MBCs的增加。2-4到目前为止，BEL对SLE患者MBC室的影响尚未被调查。本研究旨在建立BEL治疗SLE患者循环MBCs的动态，并深入分析BEL对MBC室的影响。首先，通过汇集来自四项随机临床试验（NCT00071487、NCT00410384 [BLISS-76]、3NCT01632241 [EMBRACE]、5NCT01649765 [PLUTO]6）的1245例SLE患者的个体MBC流式细胞术数据，进行了回顾性荟萃分析。其次，采用基于EuroFlow方案的高灵敏度流式细胞术（HSFC）对接受BEL治疗的活动性SLE患者（来自blis - believe试验[NCT03312907]）8和严重SLE/LN患者（来自SynBioSe-2试验[NCT03747159]）9进行了广泛的b细胞亚群表型分析。此外，通过单细胞RNA测序（scRNA-seq）对循环中激增的MBCs进行了深入表征。通过比较BEL治疗和pbo治疗的SLE患者，在BEL开始治疗4周后，循环MBC计数显著增加，到第52周逐渐恢复到基线。在接受bel治疗的SLE疾病活动性较高（SLE疾病活动性指数bbbb9）、血清学活跃（dsDNA阳性和/或补体水平低）和年龄较小（18岁以下）的患者中，MBCs的增加最为显著。HSFC证实，这种增加是非特异性的，并且在广泛的MBC亚类中观察到，早在BEL开始后2周就达到了峰值。随后对新出现的MBCs进行的scRNA-seq分析显示出非增殖表型，激活状态显著降低。在这些循环的MBCs中，大量迁移和粘附基因被下调，这表明BEL处理后MBCs的积累与它们受损的细胞-细胞粘附、破坏细胞运输和阻止外渗有关。在BEL治疗开始后，循环MBCs的显著增加是确定的，并且在严重的血清学活跃的SLE/LN患者中最为显著。循环MBCs的激增似乎与MBCs的淋巴细胞运输中断有关，从而提示BEL对SLE中MBCs的一种新的潜在治疗机制。这些发现对我们理解和改进活动性SLE和LN患者的b细胞靶向治疗策略具有重要意义，因为循环中的MBC积累可能允许更有效地靶向b细胞区室。Benlysta美国处方信息。2021[2]华莱士DJ，等。风湿关节炎2009；[3]刘建军，刘建军，刘建军，等。风湿关节炎2011；[3]张建军，张建军，张建军，等。风湿关节炎2012；[4]李建军，张建军，张建军，等。风湿性关节炎2022；[4]刘建军，刘建军，刘建军，等。临床药物开发2021；[10]张建军，张建军，张建军，等。[J]中华过敏症杂志2018；[1]邓永强等。中华医学杂志2019；9(3):e025687 b[9]ClinicalTrials.gov NCT03747159。这项对GSK Study 205646的分析由葛兰素史克（GSK）资助。Nicholas Thomas博士，fishhawack Indicia Ltd.提供编辑支持。英国，Fishawack Health的一部分，由GSK资助。基于euroflow的HFSC由Alita van der Sluijs和Sandra de Bruin提供技术支持，数据采集在莱顿大学医学中心的流式细胞仪核心设施进行。Eline J. Arends：未声明，Mihaela Zlei资助/研究支持：GSK （GSK BLISS-BELIEVE研究NCT03312907的流式细胞术研究），Christopher M. Tipton：未声明，Jasna Cotic: GSK股东，GSK员工，Zgjim Osmani：未声明，Fenna de Bie资助/研究支持：GSK （GSK BLISS-BELIEVE研究NCT03312907的流式细胞术研究），Sylvia Kamerling：未声明，Andre van Maurik: GSK股东，GSK员工，Richard Dimelow股东：GSK， GSK员工，Yun Irene Gregan， GSK股东，GSK员工，Norma Lynn Fox， GSK股东，GSK员工，Ton Rabelink：未声明，David Roth， GSK股东，GSK员工，Ignacio Sanz，顾问：是的。GSK， BMS, Janssen, Kyverna, Jacques J.M. van Dongen: BD Biosciences and Cytognos顾问（LUMC费用），GSK资助/研究支持（GSK BLISS-BELIEVE研究NCT03312907的流式细胞术研究），Cees van Kooten：未声明，Y.K. Onno Teng顾问：GSK， auriniia Pharmaceuticals, Novartis, KezarBio，资助/研究支持：GSK
Belimumab (BEL), a recombinant human monoclonal antibody directed against B-cell activating factor (BAFF), is the first approved biological agent for patients with active systemic lupus erythematosus (SLE) and lupus nephritis (LN).1 BEL inhibits primary humoral immune responses by depleting naïve B cells that are dependent on BAFF for their survival while secondary humoral immune responses by memory B cells (MBCs) remain intact. Indeed, some studies reported an increase of circulating MBCs following neutralisation of BAFF.2-4 So far, these effects of BEL on the MBC compartment in SLE patients have not been investigated.This study aimed to establish the dynamics of circulating MBCs in patients with SLE treated with BEL and to perform an in-depth analysis of the impact of BEL on the MBC compartment.First, a retrospective meta-analysis was performed by pooling individual patient MBC flow cytometry data from 1245 patients with SLE treated with BEL 10 mg/kg IV or placebo (PBO) from four randomised clinical trials (NCT00071487, NCT00410384 [BLISS-76],3NCT01632241 [EMBRACE],5NCT01649765 [PLUTO]6). Second, extensive B-cell subset phenotyping was performed prospectively by employing high-sensitivity flow cytometry (HSFC) based on EuroFlow protocols7 in patients with active SLE (from the BLISS-BELIEVE trial [NCT03312907])8 and with severe SLE/LN (from the SynBioSe-2 trial [NCT03747159])9 treated with BEL. Additionally, in-depth characterisation of surging MBCs in circulation was performed by single-cell RNA sequencing (scRNA-seq).By comparing BEL-treated with PBO-treated patients with SLE, a substantial increase in circulating MBC counts was established 4 weeks after BEL initiation, gradually returning to baseline by Week 52. The increase of MBCs was most prominent in BEL-treated patients with higher SLE disease activity (SLE Disease Activity Index >9), serologically active patients (dsDNA positive and/or low complement levels) and with younger age (below 18 years). HSFC established that the increase was non-specific and observed in a broad range of MBC subclasses peaking as early as 2 weeks after BEL initiation. Subsequent scRNA-seq analysis of the emerging MBCs revealed a non-proliferating phenotype with a prominent decrease in activation status. In these circulating MBCs, a large amount of migration and adhesion genes were downregulated suggesting that the accumulation of MBCs following BEL treatment was related to their impaired cell-cell adhesion, disrupting cell-trafficking and preventing extravasation.After initiation of BEL treatment, a substantial increase of circulating MBCs was firmly established and was most notable in patients with severe, serologically active SLE/LN. The surge of circulating MBCs appeared to be associated with disrupted lymphocyte trafficking of MBCs, thereby suggesting a new potential therapeutic mechanism of BEL on MBCs in SLE. These findings have important implications to our understanding and consequent improvement of B-cell targeted treatment strategies in patients with active SLE and LN, as MBC accumulation in circulation might allow for more efficient targeting of the B-cell compartment.[1]GlaxoSmithKline. Benlysta US prescribing information. 2021[2]Wallace DJ, et al. Arthritis Rheumatol 2009;61(9):1168–78[3]Furie R et al. Arthritis Rheumatol 2011;63(12):3918–30[4]Stohl W et al. Arthritis Rheumatol 2012;64(7):2328–37[5]Ginzler E et al. Arthritis Rheumatol 2022;74(1):122–3[6]Dimelow R et al. Clin Pharmacol Drug Dev 2021;10(6):622–33[7]Blanco E et al. J Allergy Clin Immunol 2018;141(6):2208–19[8]Teng YKO et al. BMJ Open 2019;9(3):e025687[9]ClinicalTrials.gov NCT03747159. Accessed January 19 2022This analysis of the GSK Study 205646 was funded by GlaxoSmithKline (GSK). Editorial support was provided by Nicholas Thomas, PhD, Fishawack Indicia Ltd. UK, part of Fishawack Health, and was funded by GSK. The EuroFlow-based HFSC was technically supported by Alita van der Sluijs and Sandra de Bruin and data acquisition was performed at the Flow cytometry Core Facility of Leiden University Medical Center, Leiden, NL.Eline J. Arends: None declared, Mihaela Zlei Grant/research support from: GSK (flow cytometry studies for GSK BLISS-BELIEVE study NCT03312907), Christopher M. Tipton: None declared, Jasna Cotic Shareholder of: GSK, Employee of: GSK, Zgjim Osmani: None declared, Fenna de Bie Grant/research support from: GSK (flow cytometry studies for GSK BLISS-BELIEVE study NCT03312907), Sylvia Kamerling: None declared, Andre van Maurik Shareholder of: GSK, Employee of: GSK, Richard Dimelow Shareholder of: GSK, Employee of: GSK, Yun Irene Gregan Shareholder of: GSK, Employee of: GSK, Norma Lynn Fox Shareholder of: GSK, Employee of: GSK, Ton Rabelink: None declared, David Roth Shareholder of: GSK, Employee of: GSK, Ignacio Sanz Consultant of: Yes. GSK, BMS, Janssen, Kyverna, Jacques J.M. van Dongen Consultant of: BD Biosciences and Cytognos (fees for LUMC), Grant/research support from: GSK (flow cytometry studies for GSK BLISS-BELIEVE study NCT03312907), Cees van Kooten: None declared, Y.K. Onno Teng Consultant of: GSK, Aurinia Pharmaceuticals, Novartis, KezarBio, Grant/research support from: GSK