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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：
10654040
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/10654040
关键词：
Abscisic Acid Acceleration Adoptive Transfer Adrenal Cortex Hormones Agonist American Ames Assay Animal Disease Models Anti-Inflammatory Agents Antinuclear Antibodies Autoimmune Autoimmune Diseases Autophagocytosis Biological Availability 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 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 Marketing 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 immune modulating agents immunoregulation improved interferon alpha receptor 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