Mechanisms of therapeutic efficacy of BAFF inhibition using belimumab

描述（由申请人提供）：BAFF是一种类似tnf的细胞因子，支持B细胞的生存和选择，并与其三种受体BAFF- r、TACI和BCMA一起增强先天和适应性免疫反应。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，促进了这类药物在人类临床试验中的快速发展。这些药物中的第一个是belimumab，一种针对可溶性BAFF的单克隆抗体，已经在中度活动性SLE的3期研究中证明了疗效，现在被批准用于SLE治疗。该类别的其他药物包括阿他塞普（BAFF和APRIL的抑制剂）和布利比mod （BAFF拮抗剂），已经在2期研究中证明了疗效，并正在进入3期研究。尽管取得了这些令人兴奋的进展，但与目前的标准治疗疗法相比，贝利姆单抗的效果有限，只有50%的治疗患者有临床反应，这就要求我们更好地了解BAFF和APRIL在SLE中的生物学作用，以便我们可以使用这种干预措施来达到最大的治疗效果。本提案的前两个目标将集中在BAFF对Ig转基因小鼠SLE模型和人类SLE患者中B细胞存活、选择和激活的主要阶段的贡献，并将揭示BAFF在每个B细胞发育阶段对B细胞的抑制作用。这些研究将确定BAFF抑制在多个检查点对自身反应性B细胞存活和选择的影响，并将首次确定贝利单抗是否真的改变了所有或部分SLE患者的B细胞选择，以及在什么时间范围内。在本提案的第三个目标中，我们将开始研究BAFF/BAFF- r相互作用在除B细胞以外的免疫细胞中的作用，特别是外周血单核细胞。这些研究将开始揭示除调节B细胞选择外BAFF抑制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.