Mechanisms of adenovirus neutralization

腺病毒中和机制

• 批准号: 10461859
• 负责人: PHOEBE L STEWART
• 金额: $ 69.59万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461859
• 关键词: Acute; Address; Adenovirus Vector; Adenoviruses; Animals; Antigen-Antibody Complex; Antiviral Response; Attenuated; Binding; Biological; Blood; Blood Coagulation Factor; Cancer Patient; Cell Compartmentation; Cells; Cessation of life; Clinical; Clinical Trials; Coagulation Process; Complement; Complement Receptor; Complex; Cryo-electron tomography; Defense Mechanisms; Development; Disseminated Malignant Neoplasm; Distant; Dose-Limiting; Enrollment; Ensure; Exhibits; Fc Receptor; Funding; Gene Transfer; Generations; Genetic Diseases; Hematopoietic stem cells; Hepatocyte; Hepatotoxicity; High Prevalence; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin M; Immunologics; Infection; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Innate Immune System; Intervention; Intravenous; Iron; Knowledge; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Natural Immunity; Patients; Phagocytes; Pharmacology; Phylogenetic Analysis; Population; Prevalence; Production; Property; Research Personnel; Role; Safety; Sampling; Science; Serotyping; Serum; Signal Pathway; System; Therapeutic; Therapeutic Intervention; Viral; Virus; Virus Inactivation; adaptive immunity; arm; base; cancer therapy; cell type; clinical application; clinical development; clinical practice; cytokine; improved; in vivo; insight; intravenous administration; macrophage; neutralizing antibody; novel; novel strategies; oncolytic vector; patient stratification; public health relevance; receptor; response; sample fixation; systemic inflammatory response; systemic toxicity; therapeutic development; therapeutic gene; tool; vector; virtual delivery

ABSTRACT Intravascular administration of adenovirus (Ad) vectors holds great promise for improving survival of patients with disseminated metastatic cancer and ameliorating numerous genetic diseases through permanent correction of the hematopoietic stem cell compartment. Although potentially advantageous, intravascular delivery makes therapeutic Ads vulnerable to humoral components of the innate and adaptive arms of the immune system. Extensive previous analyses by us and others showed that binding of coagulation FX to HAdv-5-based vectors in the blood facilitates highly efficient hepatocyte transduction, triggering hepatotoxicity. Furthermore, a relatively high prevalence of HAdv-5-neutralizing antibodies (NAbs) in the human population, prompted active development of therapeutic vectors based on alternate Ad serotypes that don't interact with FX and exhibit low NAb prevalence. Our preliminary studies indicate however, that both pre-existing neutralizing and non- neutralizing humoral immunity can significantly exacerbate the host inflammatory antiviral response. We found that the majority of human sera that lack HAdv-5-neutralizing activity are still able to trigger complement fixation on the virus, leading to potentiated inflammatory cytokine production by immune cells. Moreover, we found that immunization of mice with adenovirus HAdv-11 triggers generation of non-neutralizing antibodies, which are highly efficient at complement fixation on phylogenetically-distant HAdv-5 virus. Based on these findings, we propose a novel concept of cryptic opsonizing non-neutralizing antibodies, or CON-Abs, which bind to Ad after systemic delivery, trigger complement fixation on the virus, and target Ad-immune complexes (Ad-ICs) to immune phagocytic cells, leading to drastically potentiated systemic inflammation. The molecular mechanisms mediating the immune-stimulatory properties of pre-existing non-neutralizing immunity and its effect on the safety of systemic Ad delivery are virtually unknown. Therefore, in Specific Aim 1 of this project we will analyze how phylogenetically-distant HAdv serotypes trigger generation of CON-Abs to HAdv-5. In Specific Aim 2, we will determine the structural bases for CON-Ab-mediated complement fixation on the virus and complement- mediated virus neutralization. In Specific Aim 3 we will determine specific cell types and their receptors that sequester Ad-ICs in vivo; and in Specific Aim 4 we will determine specific signaling pathways responsible for the exacerbated inflammatory response to Ad-ICs and develop targeted pharmacological approaches to improve the safety of systemic Ad delivery in gene transfer and cancer therapy models. The proposed studies will provide new mechanistic insights into fundamental functions of innate and adaptive immunity and host anti-viral defense, as well as allow for the development of novel patient stratification tools and pharmacological approaches to improve the safety of clinical interventions that rely on systemic delivery of therapeutic Ads.

抽象的 腺病毒（AD）载体的血管内给药具有改善患者存活率的巨大希望 传播转移性癌症并通过永久性纠正改善众多遗传疾病 造血干细胞室的。虽然有可能有利，但血管内分娩使 治疗广告容易受到免疫系统先天和适应性臂的体液组成部分。 我们和其他人进行了广泛的先前分析表明，凝结FX与基于HADV-5的向量的结合 在血液中，促进了高效的肝细胞转导，从而触发肝毒性。此外，相对 人口中HADV-5中和抗体（NABS）的高流行率促使主动 基于与FX不相互作用且表现低的替代AD血清型的治疗矢量开发 NAB患病率。但是，我们的初步研究表明，预先存在中和和非 - 中和体液免疫会显着加剧宿主炎症性抗病毒反应。我们发现 缺乏HADV-5中和活动的大多数人血清仍然能够触发补体固定 在病毒上，导致免疫细胞产生炎症细胞因子。而且，我们发现 用腺病毒HADV-11触发非中和抗体的腺病毒hadv-11触发的小鼠免疫， 对系统发育偏离的HADV-5病毒的补体固定效率高。基于这些发现，我们 提出了一个新颖的非中和抗体抗体或con-abs的新颖概念，该抗体与AD结合后 全身传递，对病毒的触发补体固定以及靶向Ad-rmmune复合物（AD-ICS） 免疫吞噬细胞，导致严重增强的全身性炎症。分子机制 介导预先存在的非中和免疫的免疫刺激特性及其对安全性的影响 系统性广告交付几乎是未知的。因此，在该项目的特定目的1中，我们将分析如何 距离距HADV血清型触发con-abs的HADV-5触发。在特定的目标2中，我们将 确定对病毒介导的补体固定和补体的结构碱基 介导的病毒中和。在特定目标3中，我们将确定特定的细胞类型及其受体 体内隔离广告；在特定目标4中，我们将确定负责 加剧对AD-IS的炎症反应，并开发出针对性的药理学方法以改善 基因转移和癌症治疗模型中系统性广告递送的安全性。拟议的研究将提供 对先天和适应性免疫和托管反病毒防御的基本功能的新机械洞察力， 还允许开发新的患者分层工具和药理学方法 提高依赖于全身交付治疗广告的临床干预措施的安全性。