Integrin-Targeted Novel Oral Therapeutics for Lupus Nephritis

项目摘要 狼疮性肾炎(LN)仍然是系统性红斑狼疮患者发病率和死亡率的最强预测因子 红斑狼疮(SLE)是一种自身免疫性疾病，对女性和少数民族的影响不成比例。这个 目前对LN、糖皮质激素和免疫抑制剂的护理标准有许多副作用和 长期毒性。因此，存在着对靶向治疗的迫切和未得到满足的需求。系统性红斑狼疮的特点是 免疫细胞中Toll样受体(TLR)信号的异常激活驱动炎性白细胞 激活并流入主要器官，大约。40%的狼疮患者表现为肾小球损害和肾脏 疾病，LN.整合素CD11b主要在髓系细胞上表达，是一种免疫受体，调节 这些细胞的功能。在它的许多作用中，它调节组织中的白细胞内流，最近已经 显示还控制这些细胞中过度活跃的TLR信号。最近的全球气候变化研究显示高度的相关性 ITGAM中编码CD11b的SNPs与SLE和LN的发病率之间的关系。研究亦包括 研究表明，三个最常见的编码ITGAM的SNPs主要降低CD11b作为TLR变阻器的作用- 在不影响CD11b表面表达的情况下，信号传递表明CD11b功能减弱是SLE的贡献者 和LN。提示CD11b活化可作为狼疮肾炎的潜在治疗策略。朝向 我们的联合创始人(Vineet Gupta)发现，通过变构激活整合素CD11b是一种新的治疗方法 这是一种针对这种整合素的有效方法，可以减少白细胞的激活和组织内流。他 他的团队开发了第一代CD11b小分子变构激动剂，称为La1，它选择性地 在体内结合CD11b，口服生物利用度，无毒，减少自身免疫性疾病并显著减少 炎性髓系细胞涌入组织。古普塔博士、巴博萨博士和团队还开发了一种LA1 类似物，称为GB1275，已被翻译为口服疗法，目前处于1/2期临床 在癌症患者身上进行试验。这项提议的主要目标是寻找和开发一系列新的变构 CD11b激动剂，具有易处理的SAR，类药物特性，并具有比第一代更强的效力 可以长期服用的化合物，用于治疗自身免疫性疾病，如LN。我们已经开发出 一个测试平台和一个集中的整合素靶向文库，可用于快速鉴定~800种化合物 并开发新的、高效的CD11b激动剂候选药物，信心十足。在这里，我们提出两个具体的 目的是设计、筛选和鉴定比LA1更有效的新型CD11b激动剂，并表征 它们在体外和体内为药物开发做好了准备。我们的长远目标是开发新的 将化合物转化为治疗人类狼疮性肾炎的下一代疗法。

Project Summary Lupus nephritis (LN) remains the strongest predictor of morbidity and mortality for people with Systemic Lupus Erythematosus (SLE), an autoimmune disease disproportionately affecting women and minorities. The current standard of care for LN, glucocorticoids and immunosuppressive agents, has many side effects and long-term toxicity. Therefore, there is an urgent and unmet need for targeted therapies. SLE is characterized by an aberrant activation of toll-like receptor (TLR) signaling in immune cells that drives inflammatory leukocyte activation and influx into major organs, with approx. 40% of lupus patients showing glomerular injury and renal disease, LN. The integrin CD11b, expressed primarily on myeloid cells, is an immune receptor that modulates functions of these cells. Among its many roles, it mediates leukocyte influx in tissues and has recently been shown to also control overactive TLR signaling in these cells. Recent GWAS studies showed high correlation between patients with SNPs in ITGAM, which codes for CD11b, and incidence of SLE and LN. Studies also showed that the three most common coding ITGAM SNPs primarily reduce CD11b’s role as a rheostat of TLR- signaling, without affecting its surface expression, suggesting reduced CD11b function as a contributor to SLE and LN. It also suggested that CD11b activation could serve as a potential therapeutic strategy for LN. Towards that, our co-founder (Vineet Gupta) discovered that allosteric activation of integrin CD11b is a novel therapeutic strategy and is an effective method to target this integrin for reducing leukocyte activation and tissue influx. He and his team developed a first-generation CD11b small molecule allosteric agonist, called LA1, that selectively engages CD11b in vivo, is orally bioavailable, non-toxic, reduces autoimmune disease and significantly reduces influx of inflammatory myeloid cells into tissues. Drs Gupta, Barbosa and the team also developed an LA1 analog, called GB1275, that has been translated as an oral therapeutic that is currently under Phase 1/2 clinical trials in cancer patients. The primary goal of this proposal is to find and develop a new series of allosteric agonists of CD11b with tractable SAR, drug-like properties and with enhanced potency over the first-generation compounds that can be administered chronically for treating autoimmune diseases, like LN. We have developed an assay platform and a focused integrin targeting library of ~800 compounds that can be used to rapidly identify and develop novel, highly potent CD11b agonist candidates with high confidence. Here, we propose two specific aims to design, screen and identify novel CD11b agonists with improved potency over LA1 and to characterize them in vitro and in vivo for their readiness for drug development. Our long-term goal is to develop the new compounds into a next generation of therapeutics to treat lupus nephritis in humans.