Suppression of Rheumatoid Arthritis B Cells by XmAb5871, an Anti-CD19 Antibody That Coengages B Cell Antigen Receptor Complex and Fcγ Receptor IIb Inhibitory Receptor
Suppression of Rheumatoid Arthritis B Cells by XmAb5871, an Anti-CD19 Antibody That Coengages B Cell Antigen Receptor Complex and Fcγ Receptor IIb Inhibitory Receptor
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DOI：
10.1002/art.38334
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发表时间：
2014-05-01
影响因子：
13.3
通讯作者：
Szymkowski, David E.
中科院分区：
文献类型：
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作者：
Chu, Seung Y.;Yeter, Karen;Szymkowski, David E.
Objective. Fc γ受体II B b（Fc γ RIIb）的结合抑制B细胞活化，并代表了用于治疗自身免疫的有前景的靶标。本研究的目的是表征由Fc工程抗体XmAb5871介导的B细胞免疫抑制，该抗体XmAb5871将Fc γ RIIb与B细胞抗原受体（BCR）复合物共接合，目前正在临床开发中用于治疗类风湿性关节炎（RA）。由于类风湿因子（RF）可能干扰XmAb5871与Fc γ RIIb的结合，我们将RF滴度与XmAb5871的效力相关联。我们分析了来自50例RA患者和66例健康供体的初始和记忆B细胞上的CD 19、Fc γ RIIb和CD 86的表达，定量了XmAb 5871诱导的活化B细胞中Fc γ RIIb磷酸化的促进和钙流的抑制，测量了全血中的CD 86抑制，并将RF和抗瓜氨酸化蛋白抗体（ACPA）水平与药物效价相关联。我们将RA外周血单个核细胞（PBMC）移植到SCID小鼠中，用XmAb5871处理它们，并定量体内人总IgG、总IgM和抗破伤风IgG抗体水平。来自所有供体的B细胞表达CD 19和Fc γ RIIb，并且与健康供体相比，来自患有RA的供体的幼稚B细胞上Fc γ RIIb的表达更高，但不是记忆B细胞。XmAb5871抑制BCR介导的钙流，并与Fc γ RIIb磷酸化相关。XmAb5871抑制CD86诱导，RF和ACPA水平不影响疗效。XmAb5871抑制B细胞活化，与疾病严重程度无关。在移植RA患者PBMC的SCID小鼠中，XmAb5871抑制体液应答。XmAb 5871与BCR复合物和Fc γ RIIb的共结合抑制B细胞活化和功能。在RA患者和健康供体中的相似效力和自身抗体干扰的缺乏表明XmAb5871可能代表抑制RA中自身反应性B细胞的新治疗策略。
Objective. Engagement of Fc gamma receptor IIb (Fc gamma RIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. The aim of this study was to characterize B cell immunosuppression mediated by the Fc-engineered antibody, XmAb5871, which coengages Fc gamma RIIb with the B cell antigen receptor (BCR) complex and that is currently in clinical development for the treatment of rheumatoid arthritis (RA). Because rheumatoid factor (RF) might interfere with the binding of XmAb5871 to Fc gamma RIIb, we correlated RF titers with the potency of XmAb5871.Methods. We analyzed the expression of CD19, Fc gamma RIIb, and CD86 on naive and memory B cells from 50 patients with RA and 66 healthy donors, quantified XmAb5871-induced promotion of Fc gamma RIIb phosphorylation and suppression of calcium flux in activated B cells, measured CD86 inhibition in whole blood, and correlated RF and anti-citrullinated protein antibody (ACPA) levels with drug potency. We engrafted RA peripheral blood mononuclear cells (PBMCs) into SCID mice, treated them with XmAb5871, and quanti-fied human total IgG, total IgM, and anti-tetanus IgG antibody levels in vivo.Results. B cells from all donors expressed CD19 and Fc gamma RIIb, and the expression of Fc gamma RIIb was higher on naive, but not memory, B cells from donors with RA compared with healthy donors. BCR-mediated calcium flux was suppressed by XmAb5871 and was associated with Fc gamma RIIb phosphorylation. XmAb5871 inhibited CD86 induction, and the levels of RF and ACPAs did not affect efficacy. XmAb5871 suppressed B cell activation regardless of disease severity. In SCID mice engrafted with PBMCs from a patient with RA, XmAb5871 suppressed humoral responses.Conclusion. Coengagement of the BCR complex and Fc gamma RIIb by XmAb5871 inhibits B cell activation and function. The similar potency in patients with RA and healthy donors and the absence of autoantibody interference suggest that XmAb5871 may represent a new therapeutic strategy to suppress autoreactive B cells in RA.