Samy Eileen, Wax Stephen, Huard Bertrand, Hess Henry, Schneider Pascal
a EMD Serono Research & Development Institute, Inc. , Billerica , Massachusetts , USA.
b Institute for Advanced Biosciences , University Grenoble Alpes , INSERM U1209, Grenoble , France.
Int Rev Immunol. 2017 Jan 2;36(1):3-19. doi: 10.1080/08830185.2016.1276903.
The B cell-stimulating molecules, BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand), are critical factors in the maintenance of the B cell pool and humoral immunity. In addition, BAFF and APRIL are involved in the pathogenesis of a number of human autoimmune diseases, with elevated levels of these cytokines detected in the sera of patients with systemic lupus erythematosus (SLE), IgA nephropathy, Sjögren's syndrome, and rheumatoid arthritis. As such, both molecules are rational targets for new therapies in B cell-driven autoimmune diseases, and several inhibitors of BAFF or BAFF and APRIL together have been investigated in clinical trials. These include the BAFF/APRIL dual inhibitor, atacicept, and the BAFF inhibitor, belimumab, which is approved as an add-on therapy for patients with active SLE. Post hoc analyses of these trials indicate that baseline serum levels of BAFF and BAFF/APRIL correlate with treatment response to belimumab and atacicept, respectively, suggesting a role for the two molecules as predictive biomarkers. It will, however, be important to refine future testing to identify active forms of BAFF and APRIL in the circulation, as well as to distinguish between homotrimer and heteromer configurations. In this review, we discuss the rationale for dual BAFF/APRIL inhibition versus single BAFF inhibition in autoimmune disease, by focusing on the similarities and differences between the physiological and pathogenic roles of the two molecules. A summary of the preclinical and clinical data currently available is also presented.
B细胞刺激分子BAFF（B细胞活化因子）和APRIL（增殖诱导配体）是维持B细胞库和体液免疫的关键因素。此外，BAFF和APRIL参与了多种人类自身免疫性疾病的发病机制，在系统性红斑狼疮（SLE）、IgA肾病、干燥综合征和类风湿关节炎患者的血清中检测到这些细胞因子水平升高。因此，这两种分子都是B细胞驱动的自身免疫性疾病新疗法的合理靶点，并且已经在临床试验中研究了几种BAFF抑制剂或BAFF与APRIL的联合抑制剂。其中包括BAFF/APRIL双重抑制剂阿他西普，以及被批准作为活动性SLE患者附加疗法的BAFF抑制剂贝利尤单抗。这些试验的事后分析表明，BAFF和BAFF/APRIL的基线血清水平分别与对贝利尤单抗和阿他西普的治疗反应相关，这表明这两种分子可作为预测性生物标志物。然而，未来的检测需要进一步完善，以识别循环中BAFF和APRIL的活性形式，以及区分同三聚体和异三聚体构型。在这篇综述中，我们通过关注这两种分子在生理和致病作用方面的异同，讨论了在自身免疫性疾病中双重抑制BAFF/APRIL与单一抑制BAFF的理论依据。同时还总结了目前可用的临床前和临床数据。
