Novel Immunoregulatory Therapeutics for Systemic Lupus Erythematosus

治疗系统性红斑狼疮的新型免疫调节药物 生物治疗公司(BTI)是一家新兴的生物技术公司，它协同结合了 先进的计算建模和平移实验加速了小说的发展 精准医疗和健康产品。公司领导层在推进新药研发方面有经验 从发现到临床晚期发展。 系统性红斑狼疮(SLE)是一种自身免疫性疾病，困扰着150万美国人。通过我们的 在先前关于脱落酸的研究中，我们发现了一种抗炎和促进免疫调节的作用 新型口腔狼疮治疗学。我们的先导化合物可降低狼疮的关键生物标志物和整体疾病 在3个小鼠模型中的严重程度，并在人的PBMCs中诱导强大的免疫调节作用。这个项目将 评估我们治疗系统性红斑狼疮的新型激动剂的疗效、安全性和可译性。 这项SBIR第二阶段应用的具体目标是： (1)评价BT-96在系统性红斑狼疮NZB/W F1模型中的联合疗效和比较疗效。NZB/W F1小鼠将单独或联合使用最大有效剂量的BT-96进行治疗 使用5种标准护理或正在开发的药物。存活率、抗核抗体、蛋白尿和肾脏 组织病理学将作为终点进行评估。 (2)大鼠IND致遗传毒性和3个月重复给药毒性研究。我们将表演 Ames试验、染色体畸变研究和微核试验以完成FDA对 遗传毒性。将进行为期3个月的毒性研究，以评估一般安全性。 (3)阐明BT-96的翻译标记作为靶点接触的剂量范围标记。 来自NZB/W F1全血的RNA样本将被用来识别转录变化之间的相关性 以及不同剂量的口服效果。转录变化将与作用机制和 组织学和生物标志物结果。签名将在SLE患者的PBMC中进行验证。 预期的成功结果将包括：i)与其他药物相比，BT-96改善了对蛋白尿的保护 治疗；ii)NOAEL≥500 mg/kg；以及iii)调节T细胞和吞噬调节机制的验证。 该项目的长期目标是开发一种新的免疫调节疗法，能够作为一种 治疗系统性红斑狼疮更安全有效，并为候选产品的商业化提供了一条途径 目标人口超过500万，市场规模超过15亿美元。

Novel Immunoregulatory Drugs for Systemic Lupus Erythematosus BioTherapeutics, Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. The company leadership has experience in advancing novel drugs from discovery to late-stage clinical development. Systemic lupus erythematosus (SLE) is an autoimmune disease that afflicts 1.5 million Americans. Through our previous research on abscisic acid, we discovered the anti-inflammatory and pro-regulatory immune effects of a novel class of oral lupus therapeutics. Our lead compound reduces key lupus biomarkers and overall disease severity in 3 mouse models and induces potent immunoregulatory effects in human PBMCs. This project will evaluate the comparative efficacy, safety and translatability of our novel agonists for the treatment of SLE. The Specific Aims for this SBIR Phase II application are to: (1) Evaluate the combinatorial and comparative efficacy of BT-96 in the NZB/W F1 model of SLE. NZB/W F1 mice will be therapeutically dosed with BT-96 at the maximally effective dose, independently or in combination with 5 standard-of-care or in-development drugs. Survival, anti-nuclear antibodies, proteinuria, and kidney histopathology will be assessed as endpoints. (2) Conduct IND-enabling genotoxicity and a 3-month repeat dose toxicity study in rats. We will perform an Ames test, chromosomal aberration study and micronucleus test to complete the FDA’s requirement for genetic toxicity. A 3-month toxicity study will be conducted to evaluate general safety. (3) Elucidate a translational signature of BT-96 to serve as a dose-ranging marker of target engagement. RNA samples from NZB/W F1 whole blood will be used to identify correlates between transcriptional changes and oral efficacy at various doses. Transcriptional changes will be aligned with mechanism of action and histological and biomarker results. Signature will be validated in SLE patient PBMCs. Expected successful outcomes will include: i) improved protection from proteinuria with BT-96 relative to other therapies; ii) NOAEL ≥ 500 mg/kg; and iii) validation of regulatory T cell and phagocytosis-mediated mechanisms. The long-term goal of this project is to develop a novel immunomodulatory therapeutic capable of serving as a safer and more effective treatment for SLE and provide a path towards commercialization of a product candidate with a target population of over 5 million resulting in a market of over $1.5 billion.