Novel Immunoregulatory Therapeutics for Systemic Lupus Erythematosus

系统性红斑狼疮的新型免疫调节疗法

基本信息

批准号：
10546129
负责人：
Andrew Leber
金额：
$ 56.37万
依托单位：
BIOTHERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546129
关键词：
Abscisic Acid Adoptive Transfer Adrenal Cortex Hormones Agonist American Ames Assay Animal Disease Models Anti-Inflammatory Agents Antinuclear Antibodies Autoimmune Autoimmune Diseases Autophagocytosis Biological Markers Biological Response Modifier Therapy Biotechnology Cardiovascular Diseases Chromosome abnormality Clinical Clinical Trials Combined Modality Therapy Computer Models Data Development Disease Dose Genetic Genetic Transcription Goals Health Care Costs Healthcare Histologic Histopathology Human IL8 gene Immune Immunomodulators Immunosuppression Impairment In Vitro Inflammation Inflammatory Bowel Diseases Intercept Interleukin-2 Interleukin-6 Kidney Kidney Failure Kidney Transplantation Knowledge Lead Leadership Ligands Ligase Lupus Lupus Nephritis Mediating Metabolic Control Micronucleus Tests Modeling Mus Mutagenicity Tests Myeloid Cells No-Observed-Adverse-Effect Level Oral Organ Outcome Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Phagocytosis Pharmaceutical Preparations Phase Precision Health Predisposition Prednisone Preparation Program Development Proteinuria Quality of life RNA Rattus Regulatory Pathway Regulatory T-Lymphocyte Reporting Research Safety Sampling Serum Severity of illness Small Business Innovation Research Grant Systemic Lupus Erythematosus TLR7 gene TNF gene Target Populations Technology Therapeutic Toxic effect Treatment Efficacy Validation Whole Blood anti-dsDNA antibodies care burden chronic pain clinical development combinatorial commercial application commercialization comparative comparative efficacy drug development drug discovery ds-DNA effective therapy experience genetic signature genotoxicity healthy volunteer immunoregulation improved lanthionine mortality mouse model mycophenolate mofetil novel novel therapeutics precision medicine predictive signature public health relevance receptor resiquimod side effect standard of care therapeutically effective

项目摘要

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.

治疗系统性红斑狼疮的新型免疫调节药物 BioTherapeutics, Inc (BTI) 是一家新兴的生物技术公司，协同结合了先进的计算模型与转化实验，以加速新颖的开发公司领导层在开发新药方面拥有丰富的经验。从发现到后期临床开发。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。在之前对脱落酸的研究中，我们发现了脱落酸的抗炎和促调节免疫作用我们的先导化合物可减少关键的狼疮生物标志物和整体疾病。该项目将在 3 种小鼠模型中产生严重的免疫调节作用，并在人类 PBMC 中产生有效的免疫调节作用。评估我们的新型激动剂治疗 SLE 的比较疗效、安全性和可转化性。 SBIR 第二阶段申请的具体目标是： (1) 评估 BT-96 在 SLE NZB/W F1 模型中的组合和比较疗效。 F1小鼠将以最大有效剂量单独或组合接受BT-96治疗剂量具有 5 种标准护理或正在开发的药物：生存、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) 在大鼠中进行 IND 基因毒性和 3 个月重复剂量毒性研究。艾姆斯试验、染色体畸变研究和微核试验，以满足 FDA 的要求将进行为期 3 个月的毒性研究以评估总体安全性。 (3) 阐明 BT-96 的翻译特征，作为靶标参与的剂量范围标记。来自 NZB/W F1 全血的 RNA 样本将用于识别转录变化之间的相关性不同剂量的口服功效将与作用机制一致。组织学和生物标志物结果将在 SLE 患者 PBMC 中得到验证。预期的成功结果将包括：i) 相对于其他药物，BT-96 能更好地预防蛋白尿治疗；ii) NOAEL ≥ 500 mg/kg；以及 iii) 调节性 T 细胞和吞噬介导机制的验证。该项目的长期目标是开发一种新型免疫调节疗法，能够作为更安全、更有效地治疗 SLE，并为候选产品的商业化提供途径目标人口超过 500 万，市场规模超过 15 亿美元。