Pulmonary innate immune activation for bioterror defense

肺部先天免疫激活用于生物恐怖防御

• 批准号: 6797375
• 负责人: Arthur M. Krieg
• 金额: $ 248.27万
• 依托单位: COLEY PHARMACEUTICAL GROUP, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6797375
• 关键词: CpG islands; Primates; antimicroorganism antibody; antiviral agents; bactericidal immunity; biotechnology; bioterrorism /chemical warfare; cooperative study; drug screening /evaluation; enzyme linked immunosorbent assay; flow cytometry; immunoconjugates; immunocytochemistry; immunologic substance development /preparation; immunomodulators; immunotherapy; laboratory mouse; microorganism immunology; nonhuman therapy evaluation; pharmacokinetics; polymerase chain reaction; pulmonary respiration; radioimmunoassay; sheep; swine; toll like receptor

DESCRIPTION (provided by applicant): Civilians in the US and other countries face a growing threat from bioterrorism. It is not feasible to develop effective vaccines or treatments for all possible biowarfare agents that may be encountered. Furthermore, the identity of the bioterror agent(s) employed in an attack may not be known in time to administer specific therapies. Therefore, it is highly desirable to develop broad-spectrum nonspecific therapies that can protect against a wide range of pathogens. In theory, pre-activating the appropriate innate defenses should reduce morbidity and mortality, and improve the response to supportive therapy. Hundreds of millions of years of evolution have endowed humans with an extraordinary range of innate immune defenses against viruses, bacteria, fungi, and parasites. This innate immunity is thought to depend in large part on a family of molecules called "Toll like receptors" (TLRs), which bind molecules that are present in microbes, but not in normal host tissues. Recent studies show that ligands for TLR9, called CpG motifs, are particularly effective at activating broad-spectrum innate immune defenses, and can protect animals against a wide range of pathogens. Preclinical studies show that pretreatment with a synthetic CpG oligodeoxynucleotide (ODN) protects mice against a wide variety of viruses, bacteria, and intracellular parasites, including the Category A agents anthrax, tularemia, and Ebola. For protection against an inhaled pathogen, the optimal route of administration for the CpG ODN also appears to be inhaled. Three classes of CpG ODN have been identified, CpG-A, CpG-B, and CpG-C, with distinct immune profiles with human cells in vitro and in vivo in mice. Phase I/II human clinical trials in over 300 subjects administered a CpG-B ODN suggest strong enhancement of immune responses and an excellent safety profile. The overall goal of this proposal is to identify a CpG ODN that provides broad-spectrum defense against pathogens in animal challenge models, and to develop this CpG for protection of civilians against a bioterror agent. Based on studies of over 3000 ODN in the three classes, one optimized ODN from each class has been selected for comparison in this program: CpG-A 10108, CpG-B 10105, and CpG-C 10107. Our proposal is based on the hypothesis that the prophylactic activation of particular innate immune defenses with a CpG ODN will protect against a subsequent exposure to one or more bioterror agents. It is expected that pretreatment with CpG would reduce morbidity and mortality from bioterror and prolong the "golden hour" during which supportive therapy and specific countermeasures could be administered. If successful, the proposed studies would provide supportive data for human safety clinical trials and an eventual NDA submission. This goal will be accomplished through the following specific aims: Specific Aim 1. Determine the efficacy of different CpG classes in protecting mice against inhaled Category A pathogens. Specific Aim 2. Determine the efficacy of different CpG classes in protecting against other inhaled pathogens. Specific Aim 3. Determine the effect of inhaled CpG classes on respiratory tract immune function. Specific Aim 4. Identification of peripheral biomarkers for inhaled CpG ODN (mice, swine, sheep, primates). Specific Aim 5. Characterize the toxicity of inhaled CpG ODN. Specific Aim 6. Characterize the absorption, distribution, metabolism, and excretion of inhaled CpG ODN.

描述（由申请人提供）： 美国和其他国家的平民面临着越来越严重的生物恐怖主义威胁。为可能遇到的所有可能的生物战剂开发有效的疫苗或治疗方法是不可行的。此外，攻击中使用的生物恐怖剂的身份可能无法及时获知以实施特定的治疗。因此，非常需要开发能够预防多种病原体的广谱非特异性疗法。理论上，预先激活适当的先天防御应该可以降低发病率和死亡率，并改善对支持治疗的反应。数亿年的进化赋予人类针对病毒、细菌、真菌和寄生虫的非凡的先天免疫防御能力。人们认为这种先天免疫在很大程度上取决于称为“Toll 样受体”(TLR) 的分子家族，这些分子与存在于微生物中但不存在于正常宿主组织中的分子结合。最近的研究表明，TLR9 的配体（称为 CpG 基序）在激活广谱先天免疫防御方面特别有效，并且可以保护动物免受多种病原体的侵害。临床前研究表明，用合成 CpG 寡脱氧核苷酸 (ODN) 进行预处理可以保护小鼠免受多种病毒、细菌和细胞内寄生虫的侵害，包括 A 类病原体炭疽、兔热病和埃博拉病毒。为了防止吸入病原体，CpG ODN 的最佳给药途径似乎也是吸入。已鉴定出三类 CpG ODN：CpG-A、CpG-B 和 CpG-C，它们在体外和小鼠体内与人类细胞具有不同的免疫特征。对超过 300 名受试者进行的 I/II 期人体临床试验表明，CpG-B ODN 可以显着增强免疫反应并具有出色的安全性。该提案的总体目标是确定一种 CpG ODN，它可以在动物挑战模型中提供针对病原体的广谱防御，并开发这种 CpG 来保护平民免受生物恐怖分子的侵害。基于对这三个类别中 3000 多个 ODN 的研究，在该计划中从每个类别中选择了一种优化的 ODN 进行比较：CpG-A 10108、CpG-B 10105 和 CpG-C 10107。我们的建议基于这样的假设：用 CpG ODN 预防性激活特定的先天免疫防御将防止随后暴露于一种或多种生物恐怖剂。预计 CpG 预处理将降低生物恐怖的发病率和死亡率，并延长可以实施支持治疗和特定对策的“黄金时间”。如果成功，拟议的研究将为人类安全临床试验和最终的 NDA 提交提供支持数据。 这一目标将通过以下具体目标来实现： 具体目标 1. 确定不同 CpG 类别在保护小鼠免受吸入 A 类病原体侵害方面的功效。 具体目标 2. 确定不同 CpG 类别在预防其他吸入病原体方面的功效。 具体目标 3. 确定吸入 CpG 类对呼吸道免疫功能的影响。 具体目标 4. 鉴定吸入 CpG ODN 的外周生物标志物（小鼠、猪、羊、灵长类动物）。 具体目标 5. 表征吸入 CpG ODN 的毒性。 具体目标 6. 表征吸入 CpG ODN 的吸收、分布、代谢和排泄。