Mechanisms of therapeutic efficacy of BAFF inhibition using belimumab

描述(申请人提供)：BAFF是一种类似肿瘤坏死因子的细胞因子，支持B细胞的存活和选择，与其三种受体BAFF-R、TACI和BCMA一起，增强先天和获得性免疫反应。同源分子APRIL与TACI和BCMA结合，是浆细胞存活的重要介质。BAFF/APRIL抑制剂在小鼠自身免疫模型中的成功应用，导致了这类药物在人类临床试验中的快速发展。第一种药物Belimumab是一种针对可溶性BAFF的单抗，已在中等活动的SLE的3期研究中显示出疗效，目前已被批准用于SLE的治疗。其他这类药物包括BAFF和APRIL的抑制剂atacicept和BAFF拮抗剂blisibimod，已经在第二阶段证明有效，并正在进入第三阶段研究。尽管有这些令人兴奋的进展，Belimumab的温和效果超过了目前的护理治疗标准，只有50%的接受治疗的患者有临床反应，这要求我们更好地了解BAFF和APRIL在SLE中的生物学，以便我们可以使用这种干预措施来达到最大的治疗效果。这项建议的前两个目标将集中在BAFF在Ig转基因小鼠SLE模型和人类SLE患者B细胞存活、选择和激活的主要阶段的贡献，并揭示BAFF抑制每个B细胞发育阶段对B细胞的影响。这些研究应该确定在多个检查点抑制BAFF对自身反应性B细胞存活和选择的影响，并将首次确定belimumab是否真的改变了全部或部分SLE患者的B细胞选择，以及在多长时间内。在这项建议的第三个目标中，我们将开始研究BAFF/BAFF-R相互作用在B细胞以外的免疫细胞中的作用，特别是外周血单核细胞。这些研究将开始深入了解除调节B细胞选择外，抑制BAFF治疗效果的其他潜在机制。

DESCRIPTION (provided by applicant): BAFF is a TNF-like cytokine that supports survival and selection of B cells and together with its three receptors BAFF-R, TACI and BCMA, augments both innate and adaptive immune responses. The homologous molecule APRIL binds to TACI and BCMA and is an important mediator of plasma cell survival. The successful use of BAFF/APRIL inhibitors in murine models of autoimmunity has led to the rapid development of this class of drugs for clinical testing in humans. The first of these drugs, belimumab, a monoclonal antibody specific for soluble BAFF, has demonstrated efficacy in phase 3 studies of moderately active SLE and is now approved for SLE treatment. Other drugs of this class including atacicept, an inhibitor of both BAFF and APRIL, and blisibimod, a BAFF antagonist, have demonstrated efficacy in phase 2 and are moving forward into phase 3 studies. Despite these exciting advances, the modest effect of belimumab over current standard of care therapies, with clinical responses in only 50% of treated patients, mandate that we better understand the biology of BAFF and APRIL in SLE, so that we can use this intervention to maximal therapeutic effect. The first two aims of this proposal will focus on the contribution of BAFF to the major stages of B cell survival, selection and activation in Ig transgenic murine SLE models and in human SLE patients and will uncover the effects of BAFF inhibition on B cells at each B cell developmental stage. These studies should determine the effects of BAFF inhibition on the survival and selection of autoreactive B cells at multiple checkpoints and will determine for the first time whether belimumab actually alters B cell selection in all or some SLE patients and over what time frame. In the third aim of this proposal we will begin to investigate the role o BAFF/BAFF-R interactions in immune cells other than B cells, particularly peripheral blood monocytes. These studies will begin to give insights into other potential mechanisms for the therapeutic efficacy of BAFF inhibition apart from regulating B cell selection.