Mechanisms of therapeutic efficacy of BAFF inhibition using belimumab

描述（由申请人提供）：BAFF是一种TNF样细胞因子，其支持B细胞的存活和选择，并与其三种受体BAFF-R、TACI和BCMA一起增强先天性和适应性免疫应答。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使用导致了这类药物在人类临床试验中的快速发展。这些药物中的第一种，贝利木单抗，一种可溶性BAFF特异性单克隆抗体，已在中度活动性SLE的3期研究中证明了疗效，目前已被批准用于SLE治疗。这类其他药物，包括atacicept（BAFF和APRIL的抑制剂）和blisibimod（BAFF拮抗剂），已在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，贝利木单抗相对于目前标准治疗的效果有限，仅50%的治疗患者有临床反应，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获得最大的治疗效果。该提案的前两个目的将集中于BAFF对IG转基因小鼠SLE模型和人类SLE患者中B细胞存活、选择和活化的主要阶段的贡献，并将揭示BAFF抑制对每个B细胞发育阶段的B细胞的影响。这些研究应确定BAFF抑制对多个检查点的自身反应性B细胞存活和选择的影响，并将首次确定贝利木单抗是否实际上改变了所有或部分SLE患者的B细胞选择以及改变的时间范围。在本建议的第三个目的中，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，特别是外周血单核细胞中的作用。这些研究将开始提供除了调节B细胞选择之外的BAFF抑制的治疗功效的其他潜在机制的见解。

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.