Integrin-Targeted Novel Oral Therapeutics for Lupus Nephritis

整合素靶向狼疮性肾炎新型口服疗法

• 批准号: 10760773
• 负责人: Darlah Michelle Lopez
• 金额: $ 30.65万
• 依托单位: 149 BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10760773
• 关键词: Affect; Agonist; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biological Assay; Biological Availability; Cancer Patient; Cell physiology; Cells; Characteristics; Chemicals; Chronic; Circulation; Clinical; Clinical Trials; Code; Development; Dose; Dose Limiting; Drug Kinetics; Evaluation; Formulation; Future; Generations; Glucocorticoids; Goals; Government; Half-Life; Human; ITGAM gene; ITGB2 gene; Immune; Immunologic Receptors; Immunosuppressive Agents; Impairment; In Vitro; Incidence; Inflammatory; Injury; Injury to Kidney; Integrin alpha Chains; Integrins; Interferon Type I; Interferons; Kidney; Kidney Diseases; Laboratories; Lead; Leukocytes; Libraries; Lupus; Lupus Nephritis; Macrophage-1 Antigen; Mediating; Methods; Minority; Morbidity - disease rate; Mutation; Myeloid Cell Activation; Myeloid Cells; Myeloid-derived suppressor cells; Oncology; Oral; Organ; Pathogenicity; Patients; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Plasminogen; Production; Property; Proteins; Readiness; Receptor Activation; Receptor Signaling; Risk; Role; Series; Single Nucleotide Polymorphism; Small Business Innovation Research Grant; Solubility; Structure-Activity Relationship; Surface; Systemic Lupus Erythematosus; Testing; Therapeutic; Tissues; Toll-like receptors; Toxic effect; Translating; Urokinase; Woman; analog; associated symptom; clinical candidate; clinical development; design; drug development; drug efficacy; experimental study; follow-up; genome wide association study; immune activation; immune modulating agents; improved; in silico; in vivo; leukocyte activation; lupus like nephritis; migration; mortality; next generation; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; protective effect; renal damage; side effect; small molecule; standard of care; targeted treatment; tumor; virtual screening

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.

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，不成比例地影响妇女和少数民族。的 目前LN的标准治疗，糖皮质激素和免疫抑制剂，有许多副作用， 长期毒性。因此，对靶向治疗存在迫切且未满足的需求。SLE的特征在于 免疫细胞中Toll样受体（TLR）信号传导的异常激活，可驱动炎症性白细胞 激活并流入主要器官，大约40%的狼疮患者表现出肾小球损伤和肾损害， 疾病，LN。整合素CD 11b主要在骨髓细胞上表达，是一种免疫受体， 这些细胞的功能。在它的许多作用中，它介导组织中的白细胞流入，并且最近被认为是 显示也控制这些细胞中过度活跃的TLR信号传导。最近的GWAS研究表明， ITGAM（编码CD 11b）中SNP与SLE和LN发病率之间的关系。研究还 表明，三种最常见的编码ITGAM SNP主要降低CD 11b作为TLR变阻器的作用。 信号转导，而不影响其表面表达，表明CD 11b功能降低是SLE的贡献者 和LN。提示CD 11b活化可能成为LN的一种潜在治疗策略。朝向 我们的共同创始人（Vineet Gupta）发现整合素CD 11b的变构活化是一种新的治疗方法， 是一种靶向这种整合素以减少白细胞活化和组织流入的有效方法。他 他的团队开发了第一代CD 11b小分子变构激动剂，称为LA 1， 在体内与CD 11b结合，是口服生物可利用的，无毒的，减少自身免疫性疾病，并显著减少 炎性骨髓细胞流入组织。古普塔博士、巴博萨博士和团队还开发了一种LA 1 类似物，称为GB 1275，已被翻译为口服治疗，目前正在进行1/2期临床试验 在癌症患者中进行的试验。该提案的主要目标是寻找和开发一系列新的变构药物， 具有易于处理的SAR、药物样特性和比第一代更强的效力的CD 11b激动剂 可以长期施用用于治疗自身免疫性疾病如LN的化合物。我们已经开发 一个分析平台和一个约800种化合物的集中整合素靶向文库，可用于快速鉴定 并以高置信度开发新型、高效的CD 11b激动剂候选物。在这里，我们提出两个具体的 旨在设计、筛选和鉴定与LA 1相比具有改善效力的新型CD 11b激动剂，并表征 它们在体外和体内用于药物开发的准备。我们的长期目标是开发新的 将这些化合物转化为下一代治疗人类狼疮性肾炎的药物。