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:
- 金额:$ 56.37万
- 依托单位:
- 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:
- 关键词:Abscisic AcidAccelerationAdoptive TransferAdrenal Cortex HormonesAgonistAmericanAmes AssayAnimal Disease ModelsAnti-Inflammatory AgentsAntinuclear AntibodiesAutoimmuneAutoimmune DiseasesAutophagocytosisBiological AvailabilityBiological MarkersBiological Response Modifier TherapyBiotechnologyCardiovascular DiseasesChromosome abnormalityClinicalClinical TrialsCombined Modality TherapyComputer ModelsDataDevelopmentDiseaseDoseGeneticGenetic TranscriptionGoalsHealth Care CostsHealthcareHistologicHistopathologyHumanIL8 geneImmuneImmunosuppressionImpairmentIn VitroInflammationInflammatory Bowel DiseasesInterceptInterleukin-2Interleukin-6KidneyKidney FailureKidney TransplantationKnowledgeLeadLeadershipLigandsLigaseLupusLupus NephritisMarketingMediatingMetabolic ControlMicronucleus TestsModelingMusMutagenicity TestsMyeloid CellsNo-Observed-Adverse-Effect LevelOralOrganOutcomePathogenesisPathway interactionsPatientsPeripheral Blood Mononuclear CellPhagocytosisPharmaceutical PreparationsPhasePrecision HealthPredispositionPrednisonePreparationProgram DevelopmentProteinuriaQuality of lifeRNARattusRegulatory PathwayRegulatory T-LymphocyteReportingResearchSafetySamplingSerumSeverity of illnessSmall Business Innovation Research GrantSystemic Lupus ErythematosusTLR7 geneTNF geneTarget PopulationsTechnologyTherapeuticToxic effectTreatment EfficacyValidationWhole Bloodanti-dsDNA antibodiescare burdenchronic painclinical developmentcombinatorialcommercial applicationcommercializationcomparativecomparative efficacydrug developmentdrug discoveryds-DNAeffective therapyexperiencegenetic signaturegenotoxicityhealthy volunteerimmune modulating agentsimmunoregulationimprovedinterferon alpha receptorlanthioninemortalitymouse modelmycophenolate mofetilnovelnovel therapeuticsprecision medicinepredictive signaturepublic health relevancereceptorresiquimodside effectstandard of caretherapeutically 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,它协同结合了
先进的计算建模与平移实验,以加速开发新的
精准医疗和健康产品。公司领导层在推进新药方面有经验
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。通过我们
在以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。
新型口服狼疮治疗剂。我们的先导化合物减少关键的狼疮生物标志物和整体疾病
在3种小鼠模型中的严重性,并在人PBMC中诱导有效的免疫调节作用。该项目将
评价我们的新型激动剂治疗SLE的疗效、安全性和可转化性。
SBIR第二阶段应用的具体目标是:
(1)评估BT-96在SLE的NZB/W F1模型中的组合和比较功效。NZB/W
F1小鼠将以最大有效剂量单独或联合治疗性给予BT-96
5种标准治疗或开发中的药物。生存率、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)在大鼠中进行IND使能遗传毒性和3个月重复给药毒性研究。我们将执行
艾姆斯试验、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,以评价总体安全性。
(3)阐明BT-96的翻译特征,作为靶点接合的剂量范围标记。
来自NZB/W F1全血的RNA样本将用于鉴定转录变化之间的相关性
和各种剂量的口服功效。转录变化将与作用机制一致,
组织学和生物标志物结果。将在SLE患者PBMC中验证签名。
预期的成功结果将包括:i)相对于其他药物,BT-96改善了对蛋白尿的保护
治疗; ii)NOAEL ≥ 500 mg/kg;和iii)验证调节性T细胞和吞噬介导的机制。
该项目的长期目标是开发一种新型免疫调节治疗剂,
更安全、更有效的SLE治疗,并为候选产品的商业化提供了途径
目标人口超过500万,市场规模超过15亿美元。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrew Leber其他文献
Andrew Leber的其他文献
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{{ truncateString('Andrew Leber', 18)}}的其他基金
Immunoregulatory Therapeutics for Ulcerative Colitis
溃疡性结肠炎的免疫调节治疗
- 批准号:
10697464 - 财政年份:2023
- 资助金额:
$ 56.37万 - 项目类别:
Novel Immunoregulatory Therapeutics for Systemic Lupus Erythematosus
系统性红斑狼疮的新型免疫调节疗法
- 批准号:
10546129 - 财政年份:2021
- 资助金额:
$ 56.37万 - 项目类别:
Developing Novel NLRX1-Based Immuno-Oncology Therapeutics
开发基于 NLRX1 的新型免疫肿瘤疗法
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10080198 - 财政年份:2020
- 资助金额:
$ 56.37万 - 项目类别:
Validation of Immunometabolic NLRX1 Therapeutics for IBD
IBD 免疫代谢 NLRX1 疗法的验证
- 批准号:
10163181 - 财政年份:2019
- 资助金额:
$ 56.37万 - 项目类别:
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