Novel synthetic TLR4 agonists

新型合成 TLR4 激动剂

基本信息

批准号：
10005111
负责人：
Juhienah Khalaf
金额：
$ 58.02万
依托单位：
INIMMUNE CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-09 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005111
关键词：
Adenoviruses Agonist Anti-Bacterial Agents Antibiotics Antiviral Agents Benchmarking Biological Biological Products Bioterrorism Bunyaviridae Burkholderia pseudomallei Candidiasis Cells Chemicals Clinical Trials Communicable Diseases Cyclic GMP Development Dose Ebola Embryo Esters Evaluation Exposure to Flaviviridae Formulation Francisella tularensis Glycosides Hour Human Immunomodulators Immunotherapeutic agent In Vitro Individual Influenza Innate Immune Response Investigation Lead Liposomes Mediating Medical Metabolic Middle East Respiratory Syndrome Coronavirus Modeling Modification Molecular Morbidity - disease rate Mus Opportunistic Infections Peripheral Blood Mononuclear Cell Phase Population Populations at Risk Regimen Reporter Resistance Risk Route Safety Schedule Self Administration Severe Acute Respiratory Syndrome Small Business Innovation Research Grant Species Specificity Staphylococcus aureus Structure-Activity Relationship TLR4 gene Therapeutic Intervention Time Toxic effect Treatment Protocols Upper Respiratory Infections Vaccines Work Yersinia pestis ZIKA analog aqueous chikungunya cytokine cytotoxicity high risk improved in vivo influenza virus strain influenzavirus inorganic phosphate kidney cell lead candidate lead optimization mortality mouse model novel pandemic influenza pathogen pathogen exposure phosphonate pre-clinical prevent receptor respiratory seasonal influenza

项目摘要

Project Summary There are currently no approved vaccines for most emerging biological pathogens (Ebola, Chikungunya, MERS CoV, SARS, Zika), opportunistic infections (S. aureus, Candidiasis, adenovirus) or potential bioterrorism agents (Y. pestis, B. Pseudomallei, F. tularensis, Bunyaviridae, Flaviviridae), and therapeutic interventions such as antibiotics and antivirals are only effective for a select few pathogens. A promising approach for rapidly neutralizing the risk of pathogen exposure is the use of immunomodulators capable of eliciting a robust innate immune response within hours of administration that would provide protective resistance against a wide range of infectious diseases. Proof-of-principle has been established that a new class of chemically and metabolically more stable synthetic TLR4 agonists provide safe and effective protection to mice when administered intranasally two days before a lethal influenza virus challenge. In this Phase II application, we will further optimize these new synthetic TLR4 agonists and formulations for stability, potency and safety, and optimize an administration schedule to provide weeks-long non-specific resistance against influenza virus. We will also assess the potential toxicity of the new TLR4 agonists in mice and develop a scalable cGMP synthesis of the lead candidate. This phase II proposal has the potential to develop a new broad-spectrum immunomodulator that would provide non-specific protective resistance (NSR) against a wide range of biological pathogens, and is primarily targeted for preventing upper respiratory tract infections in individuals or populations at risk for emerging or opportunistic pathogen exposure. Such treatment could reduce morbidity and mortality associated with seasonal or pandemic influenza viruses as well as other respiratory pathogens of significant medical concern. The work proposed herein will comprise the pre-clinical basis for IND-filing and human clinical trials using a safe and effective synthetic TLR4 agonist for individuals or populations with a high risk of exposure to seasonal and pandemic influenza viruses.

项目概要目前还没有针对大多数新兴生物病原体（埃博拉、埃博拉、基孔肯雅热、中东呼吸综合征冠状病毒、SARS、寨卡病毒）、机会性感染（金黄色葡萄球菌、念珠菌病、腺病毒）或潜在的生物恐怖主义制剂（鼠疫耶尔森氏菌、假马氏杆菌、土拉氏杆菌、布尼亚病毒科、黄病毒科），以及抗生素和抗病毒药物等治疗干预措施仅对少数病原体有效。快速消除病原体暴露风险的一种有前途的方法是使用免疫调节剂能够在给药后数小时内引发强大的先天免疫反应这将为多种传染病提供保护性抵抗力。原理证明已经建立，一类新的化学和代谢更稳定的两种合成 TLR4 激动剂鼻内给药时可为小鼠提供安全有效的保护致命流感病毒挑战前几天。在本次二期应用中，我们将进一步优化这些新的合成 TLR4 激动剂和配方具有稳定性、效力和安全性，并优化了提供针对流感病毒长达数周的非特异性抵抗力的给药时间表。我们将还评估新 TLR4 激动剂在小鼠中的潜在毒性并开发可扩展的 cGMP 主要候选药物的合成。该二期提案有可能开发出一种新的广谱免疫调节剂，将提供针对多种生物病原体的非特异性保护性抗性（NSR），主要针对预防个人或人群的上呼吸道感染新出现或机会性病原体暴露的风险。这种治疗可以降低发病率并与季节性或大流行性流感病毒以及其他呼吸道病原体相关的死亡率具有重大的医学意义。本文提出的工作将包括 IND 申请的临床前基础使用安全有效的合成 TLR4 激动剂对个人或人群进行人体临床试验接触季节性和大流行性流感病毒的风险很高。