CD180 targeted immunotherapeutic for chronic HBV in HIV infected patients

CD180靶向免疫疗法治疗HIV感染者的慢性乙型肝炎

基本信息

批准号：
9913651
负责人：
Deborah H. Fuller
金额：
$ 90.77万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-18 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913651
关键词：
Acquired Immunodeficiency Syndrome Address Adjuvant Animals Anti-Retroviral Agents Antibodies Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Apoptosis B-Lymphocytes CD8-Positive T-Lymphocytes Cells Cessation of life Chronic Chronic Hepatitis B Cirrhosis DNA Vaccines Dendritic Cells Development Dose Exhibits Face Fc domain Formulation Frequencies Geography HIV HIV Seronegativity Health Hepatitis B Antigens Hepatitis B Core Antigen Hepatitis B Surface Antigens Hepatitis B Vaccines Hepatitis B Virus Human IgG1 Immune Immune System Diseases Immune checkpoint inhibitor Immune response Immunity Immunization Immunocompromised Host Immunodeficient Mouse Immunoglobulin Variable Region Immunotherapeutic agent Immunotherapy Impairment Individual Infection Interruption Lead Light Liver diseases Macaca Macaca mulatta Malignant Neoplasms Malignant neoplasm of liver Mature B-Lymphocyte Mediating Memory Modeling Mus Patients Pattern recognition receptor Pharmacotherapy Population Prevalence Primary carcinoma of the liver cells Proteins Recombinant Proteins Regimen Regulatory T-Lymphocyte Risk Route SIV SLEB2 gene T cell response T memory cell T-Lymphocyte Testing Time Vaccination Vaccines Viral Antigens Viral Load result Work anti-PD1 antibodies base checkpoint receptors co-infection exhaustion experimental study immune checkpoint immunogenic immunogenicity improved novel vaccines pre-clinical response therapeutic vaccine transmission process vaccine immunotherapy

Acquired Immunodeficiency Syndrome Address Adjuvant Animals Anti-Retroviral Agents Antibodies Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Apoptosis B-Lymphocytes CD8-Positive T-Lymphocytes Cells Cessation of life Chronic Chronic Hepatitis B Cirrhosis DNA Vaccines Dendritic Cells Development Dose Exhibits Face Fc domain Formulation Frequencies Geography HIV HIV Seronegativity Health Hepatitis B Antigens Hepatitis B Core Antigen Hepatitis B Surface Antigens Hepatitis B Vaccines Hepatitis B Virus Human IgG1 Immune Immune System Diseases Immune checkpoint inhibitor Immune response Immunity Immunization Immunocompromised Host Immunodeficient Mouse Immunoglobulin Variable Region Immunotherapeutic agent Immunotherapy Impairment Individual Infection Interruption Lead Light Liver diseases Macaca Macaca mulatta Malignant Neoplasms Malignant neoplasm of liver Mature B-Lymphocyte Mediating Memory Modeling Mus Patients Pattern recognition receptor Pharmacotherapy Population Prevalence Primary carcinoma of the liver cells Proteins Recombinant Proteins Regimen Regulatory T-Lymphocyte Risk Route SIV SLEB2 gene T cell response T memory cell T-Lymphocyte Testing Time Vaccination Vaccines Viral Antigens Viral Load result Work anti-PD1 antibodies base checkpoint receptors co-infection exhaustion experimental study immune checkpoint immunogenic immunogenicity improved novel vaccines pre-clinical response therapeutic vaccine transmission process vaccine immunotherapy

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项目摘要

PROJECT SUMMARY Chronic HBV (CHB) infection in HIV infected patients is six times more likely to lead to chronic cirrhosis, end stage liver disease and hepatocellular carcinomas than the HIV negative population. Immunotherapies that improve HBV-specific immunity in HIV-negative patients with chronic hepatitis B (CHB) could reduce this risk but vaccine immunogenicity in HIV infected patients is significantly compromised due to persistent immune dysfunction in this population. As a result, HBV vaccines that are highly effective even in the setting of immune dysfunction are needed. To address this, we developed a novel vaccine platform capable of inducing strong immune responses even in immunodeficient individuals. HBV antigens (HBsAg, HBcAg) are fused to an antibody (Ab) specific for the pattern recognition receptor CD180/RP105 (anti-human CD180). Our preliminary results in mice and rhesus macaques show that our CD180 vaccine platform induces robust, polyfunctional T cell responses and antibody that exceed levels induced by traditional recombinant protein vaccines. This remarkable potency is achieved by activating Ag-specific B cells including immature B cells to become efficient Ag presenting cells (APCs) and CD180-based vaccines retain immunogenic potency even in immunodeficient mice lacking mature B cells. By circumventing traditional antigen presentation pathways, we propose that our HBV-αCD180 vaccine will overcome limitations of current HBV vaccines and induce strong HBV specific immune responses in immunodeficient HIV infected patients. We will investigate this hypothesis in a preclinical SIV macaque model for AIDS. Our aims will 1) determine the optimum immunization regimen to induce strong HBV specific antibody and CD4+ and CD8+ T cell responses in chronically SIV infected rhesus macaques receiving antiretroviral drug therapy and 2) Determine if co-administration of a checkpoint inhibtor enhances the immunogenicity of the lead CD180scAb-HBV vaccine regimen in ART treated SIV infected rhesus macaques. If successful, this work will support further development of the HBV-αCD180 vaccine platform for immunotherapy of chronic HBV in HIV infected patients.

项目摘要 HIV感染患者的慢性HBV（CHB）感染导致慢性肝硬化的可能性高六倍肝病和肝细胞癌比HIV阴性人群。免疫疗法改善HIV阴性患者的HBV特异性免疫力B（CHB）可以降低这种风险但是，由于持续的免疫该人群的功能障碍。结果，即使在免疫的情况下也非常有效的HBV疫苗需要功能障碍。为了解决这个问题，我们开发了一个能够诱发强大的新型疫苗平台即使在免疫缺陷的个体中也会产生免疫反应。 HBV抗原（HBSAG，HBCAG）融合抗体（AB）针对模式识别受体CD180/RP105（抗人CD180）。我们的初步导致小鼠和恒河猕猴的结果表明，我们的CD180疫苗平台可诱导强大的多功能t 细胞反应和抗体超过传统重组蛋白疫苗诱导的水平。这通过激活包括未成熟B细胞的Ag特异性B细胞来实现显着的效力 AG呈现细胞（APC）和基于CD180的疫苗即使在免疫缺陷中也保留免疫原性缺乏成熟B细胞的小鼠。通过规避传统的抗原演示途径，我们建议我们 HBV-αCD180疫苗将克服当前HBV疫苗的局限性并诱导强大的HBV特异性免疫缺陷的HIV感染患者的免疫反应。我们将在临床前研究这一假设 SIV猕猴的艾滋病模型。我们的目标将1）确定最佳免疫方案以诱导强大 HBV特异性抗体以及CD4+和CD8+ T细胞反应在慢性SIV感染的恒河猕猴中接受抗逆转录病毒药物治疗，2）确定检查点抑制剂的共同给药是否增强铅CD180SCAB-HBV疫苗治疗方案的免疫原性在ART治疗的SIV感染恒河猴中猕猴。如果成功，这项工作将支持HBV-αCD180疫苗平台的进一步开发 HIV感染患者的慢性HBV免疫疗法。