DEVELOPMENT OF UM-1098: A NOVEL SYNTHETIC TH17 INDUCING ADJUVANT AND DELIVERY SYSTEM

UM-1098 的开发：一种新型合成 TH17 诱导佐剂和递送系统

• 批准号: 10935819
• 负责人: JAY EVANS
• 金额: $ 241.99万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10935819
• 关键词: Adjuvant; Antigens; Aspergillus fumigatus; Bordetella pertussis; Candida albicans; Cells; Chemistry; Clinical Trials; Contractor; Contracts; Development; Drug Kinetics; Excretory function; Family suidae; Formulation; Human; Humoral Immunities; Immune response; Immunity; Investigation; Ligands; Mediating; Metabolism; Modeling; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; National Institute of Allergy and Infectious Disease; Production; Property; Pseudomonas aeruginosa; Rodent; Safety; Staphylococcus aureus; Streptococcus pneumoniae; Structure-Activity Relationship; System; Toxicology; Trehalose; Vaccination; Vaccine Adjuvant; Vaccines; absorption; combat; efficacy study; immunogenicity; improved; manufacture; mouse model; nanoparticle delivery; nonhuman primate; novel; novel vaccines; pathogen; pathogenic bacteria; pathogenic fungus; programs; receptor; research clinical testing; thermostability

The development and clinical evaluation of safe and effective Th17 inducing adjuvants is urgently needed for the advancement of vaccines to combat the ongoing threat of bacterial and fungal pathogens including Mycobacterium tuberculosis (Mtb), Bordetella pertussis, Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Candida albicans, Aspergillus fumigatus and others. Vaccination against TB and other bacterial and fungal pathogens has been hampered by the lack of appropriate adjuvants for inducing Th17 immunity. Thus, the next generation of vaccine adjuvants capable of inducing broadly protective immune responses against emerging bacterial and fungal pathogens represents a critical unmet need. This Adjuvant Development Contract will advance one such adjuvant – UM-1098: a Th17 inducing synthetic Mincle ligand– towards human clinical trials. UM-1098 was identified through the NIAID Adjuvant Discovery Program via a comprehensive and iterative structure-activity relationship (SAR) investigations to identify a novel synthetic diaryl trehalose Mincle receptor ligand paired with a novel nanoparticle delivery system. This adjuvant and delivery system has a well-established safety and efficacy profile in mice, pigs and non-human primates (NHPs) across multiple highly relevant antigen/pathogen platforms including TB and Bordetella pertussis. The advantages of UM-1098 over previously developed Mincle adjuvants includes improved formulation physiochemical properties, thermostability, robust safety profile, and most importantly, superior antigen-specific Th17, Th1, and humoral immunity across rodents, pigs and NHPs. When co-administered with an antigen, UM-1098 adjuvant induces durable cell-mediated and humoral immunity with demonstrated protection against Mtb and Bordetella pertussis challenge.

迫切需要开发和临床评估安全有效的 Th17 诱导佐剂，以促进疫苗的发展，以对抗细菌和真菌病原体的持续威胁，包括结核分枝杆菌 (Mtb)、百日咳博德特氏菌、金黄色葡萄球菌、铜绿假单胞菌、肺炎链球菌、念珠菌 白色念珠菌、烟曲霉等。由于缺乏诱导 Th17 免疫力的适当佐剂，针对结核病以及其他细菌和真菌病原体的疫苗接种受到阻碍。因此，能够诱导针对新出现的细菌和真菌病原体的广泛保护性免疫反应的下一代疫苗佐剂代表了一个未得到满足的关键需求。该佐剂开发合同将推动此类佐剂——UM-1098：一种诱导 Th17 的合成 Mincle 配体——走向人体临床试验。 UM-1098 是通过 NIAID 佐剂发现计划通过全面和迭代的结构-活性关系 (SAR) 研究确定的，以确定与新型纳米颗粒递送系统配对的新型合成二芳基海藻糖 Mincle 受体配体。该佐剂和递送系统在小鼠、猪和非人灵长类动物 (NHP) 中在多个高度相关的抗原/病原体平台（包括结核病和百日咳博德特氏菌）中具有公认的安全性和有效性。与之前开发的 Mincle 佐剂相比，UM-1098 的优势包括改进的制剂理化特性、热稳定性、强大的安全性，最重要的是，在啮齿动物、猪和 NHP 中具有优异的抗原特异性 Th17、Th1 和体液免疫。当与抗原共同给药时，UM-1098 佐剂可诱导持久的细胞介导免疫和体液免疫，并已证明可以抵抗 Mtb 和百日咳博德特氏菌的攻击。