An Inhaled Microbiome-Targeted Biotherapeutic for Treatment of COPD

一种吸入性微生物组靶向生物治疗药物，用于治疗慢性阻塞性肺病

• 批准号: 10917559
• 负责人: Teodora NICOLA
• 金额: $ 0.33万
• 依托单位: ALVEOLUS BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10917559
• 关键词: Acetylation; Acute; Address; Adrenal Cortex Hormones; Affect; American; Animals; Anti-Inflammatory Agents; Bacteria; Biological Response Modifier Therapy; Biology; Bronchodilator Agents; Cause of Death; Cell Culture Techniques; Cell model; Cells; Cessation of life; Chemicals; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Collaborations; Combined Modality Therapy; Complementary therapies; Data; Degenerative Disorder; Development; Disease; Disease Progression; Disease model; Dose; Drug Formulations; Dryness; Epithelial Cells; Extracellular Matrix; Extracellular Matrix Degradation; Formulation; Frequencies; Future; Gelatinase B; Generations; Glycine; Goals; Health Status; Human; In Vitro; Inflammation; Inflammatory; Inhalation; Inhalation Device; Interleukin-1 beta; Interleukin-8; Lactic acid; Lactobacillus; Lactobacillus acidophilus; Lactobacillus casei rhamnosus; Lactobacillus plantarum; Lead; Legal patent; Leukocyte Elastase; Licensing; Lipopolysaccharides; Lung; Lung diseases; Mammals; Modality; Modeling; Monitor; Mus; Particle Size; Patients; Peptide Hydrolases; Peptides; Peptidoglycan; Persons; Pharmaceutical Preparations; Phase; Phosphodiesterase Inhibitors; Pneumonia; Powder dose form; Probiotics; Process; Production; Proline; Property; Proteobacteria; Pulmonary Inflammation; Quality of life; Research; Respiratory Disease; Respiratory Stimulants; Safety; Smoking; Symptoms; TNF gene; Teichoic Acids; Testing; Therapeutic; Toxicology; Woman; airway remodeling; alternative treatment; bronchial epithelium; chemical stability; chemokine; chronic inflammatory lung disease; clinical efficacy; commercialization; comparison control; cytokine; density; dosage; drug development; drug inhalation; dysbiosis; efficacy evaluation; efficacy study; efficacy testing; exosome; experience; exposed human population; first-in-human; improved; in vivo; lead candidate; lung microbiome; men; microbial; microbiome; microbiome alteration; microbiome research; mortality risk; mouse model; neutrophil; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical study; pulmonary function; recruit; safety assessment; safety testing; screening; side effect; standard of care; therapeutic candidate; tobacco smoke exposure; treatment response

PROJECT SUMMARY - ResBiotic Inc. is developing its lead drug product, RB1000, a spray-dried powder com- prised of an inhaled biotherapeutic API for treatment of neutrophilic inflammation and disease progression in COPD patients. COPD is a chronic degenerative disease that is the fourth leading cause of death in the U.S., where it predominantly results from tobacco smoke exposure. Acute exacerbations are a sudden worsening of symptoms that can occur frequently, ≥ 2 per year in severe cases, and can result in reduced lung function, reduced health status, and increased risk for mortality. Treatment approaches including short- and long-acting bronchodilators, corticosteroids, phosphodiesterase inhibitors, cytokine blockers, and respiratory stimulants have been used but with limited clinical efficacy. Inhaled corticosteroids are used specifically to treat inflamma- tion but have potential for serious side effects, e.g., severe pneumonia and death. Combination therapies have demonstrated modest reductions in exacerbation frequency, but there is still significant room for improvement, as these therapeutics do not halt disease progression and often can have serious side effects. Recent research has demonstrated a strong association between neutrophilic inflammation that results from dysbiosis, i.e., an altered microbiome, of the lung in COPD. ResBiotic has demonstrated that heightened levels of proteobacteria can increase expression of matrix metalloproteinase 9 (MMP-9) and neutrophil elastase (NE), which are associ- ated with neutrophilic inflammation and can cause extracellular matrix degradation and airway remodeling. Res- Biotic has demonstrated in vitro and in vivo that anti-inflammatory Lactobacillus strains can reduce inflammation resulting from dysbiosis, including the expression of MMP-9 and NE, which may enable highly effective biother- apeutic drugs for COPD. Commercialization of a Lactobacillus-based biotherapeutic drug would provide an al- ternative anti-inflammatory approach with a different mechanism of action than currently available therapeutics. The goal of this proposal will be to develop a biotherapeutic drug that includes non-living components of a Lac- tobacillus bacterial extract that are responsible for the therapeutic response. Phase I will include screening dif- ferent cellular components at various dosages to identify several candidates that reduce MMP-9 expression in primary human bronchial epithelial cells taken from COPD patients. Phase II will include the development of a dry powder formulation of optimal candidates and safety and efficacy testing in preclinical mouse models of COPD. The deliverable for Phase II will be a lead candidate that has demonstrated efficacy in reduction of neutrophilic inflammation and improvements in lung function that is ready to advance to IND-enabling large mammal studies. Successful commercialization of the inhaled drug product RB1000 is expected to provide an alternative or complementary treatment modality to the standard of care to address neutrophilic inflammation resulting from dysbiosis in COPD, which is expected to reduce COPD exacerbations, potentially reduce disease progression, and improve patient quality of life.

项目摘要-ResBiical Inc.正在开发其主导药物产品RB1000，这是一种喷雾干燥粉末COM- 吸入生物治疗原料药治疗中性粒细胞炎症和疾病进展 慢性阻塞性肺疾病患者。慢性阻塞性肺病是一种慢性退行性疾病，在美国是第四大死亡原因， 在那里，它主要是由烟草烟雾暴露引起的。急性加重是指疾病的突然恶化 可能频繁出现的症状，严重时每年≥2次，并可能导致肺功能下降， 健康状况下降，死亡风险增加。治疗方法包括短效和长效 支气管扩张剂、皮质类固醇、磷酸二酯酶抑制剂、细胞因子阻滞剂和呼吸兴奋剂 已被使用，但临床疗效有限。吸入性皮质类固醇专门用于治疗炎症- 但有可能产生严重的副作用，例如严重的肺炎和死亡。综合疗法有 病情加重的频率略有下降，但仍有很大的改善空间， 因为这些疗法不能阻止疾病的发展，而且往往会产生严重的副作用。最新研究 已经证明了由生物失调引起的中性粒细胞炎症之间存在强烈的关联，即 慢性阻塞性肺疾病患者肺部微生物群改变。ResBitic已经证明，蛋白质细菌水平的提高 可增加基质金属蛋白酶9(MMP9)和中性粒细胞弹性蛋白酶(NE)的表达。 伴有中性粒细胞炎症，并可导致细胞外基质降解和呼吸道重塑。资源- Biotic已经在体外和体内证明了抗炎乳杆菌菌株可以减轻炎症 由生物失调引起，包括基质金属蛋白酶-9和去甲肾上腺素的表达，可能使高效的生物- 治疗慢性阻塞性肺疾病的药物。以乳酸菌为基础的生物治疗药物的商业化将提供一种新的 与目前可用的治疗方法不同的作用机制的替代抗炎方法。 这项提案的目标将是开发一种生物治疗药物，其中包括紫胶的非生物成分- 烟草杆菌细菌提取物，对治疗反应负责。第一阶段将包括筛选差异- 不同剂量的不同细胞成分以确定几种候选的降低MMP9表达的细胞 取自慢性阻塞性肺疾病患者的原代人支气管上皮细胞。第二阶段将包括开发一个 最佳候选药物的干粉配方及其在临床前小鼠模型中的安全性和有效性测试 慢性阻塞性肺疾病（慢阻肺）。第二阶段的交付成果将是一个主要候选方案，已证明在减少 中性粒细胞炎症和肺功能改善准备进展为IND-Enabling大 哺乳动物研究。吸入性药物产品RB1000的成功商业化预计将提供 中性粒细胞炎症治疗标准的替代或补充治疗方式 由于慢性阻塞性肺病的生态失调，预计将减少COPD的恶化，潜在地减少疾病 进步，提高患者的生活质量。