Mechanisms of adenovirus neutralization

腺病毒中和机制

• 批准号: 10264157
• 负责人: PHOEBE L STEWART
• 金额: $ 70.01万
• 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/10264157
• 关键词: Acute; Address; Adenovirus Vector; Adenoviruses; Animals; Antigen-Antibody Complex; Antiviral Agents; 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; Structure; System; Therapeutic; Therapeutic Intervention; 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.

摘要