First-in-human study of a potent anti-HBsAg neutralizing antibody

强效抗 HBsAg 中和抗体的首次人体研究

基本信息

批准号：
10550458
负责人：
Marina Caskey
金额：
$ 86.47万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-20 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10550458
关键词：
Acceleration Aftercare Amino Acids Animal Model Animals Antibodies Antigen-Antibody Complex Antigens Antiviral Agents Antiviral Therapy B-Lymphocytes Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell-Mediated Cytolysis Cells Cellular Immunity Chronic Chronic Hepatitis B Circular DNA Clinic Clinical Clinical Research DNA Integration Development Disease remission Dose Drug Kinetics Epitopes Event Experimental Models Exposure to Fc domain Fostering Genome HIV-1 Half-Life Hepatitis B Antibodies Hepatitis B Surface Antigens Hepatitis B Virus Hepatitis B e Antigens Human Biology Humoral Immunities IgG1 Immune Immune response Immunity Immunologics Immunotherapy Impairment In Vitro Individual Infection Infection Control Inflammation Innate Immune Response Liver Liver Cirrhosis Measures Mediating Membrane Modeling Modification Monoclonal Antibodies Passive Transfer of Immunity Persons Phagocytosis Pharmacologic Substance Primary carcinoma of the liver cells Rattus Recombinants Recovery Role Safety Serotyping Serum T-Lymphocyte Testing Therapeutic Tissues Transgenic Mice Vaccination Vaccinee Variant Viral Viral Antigens Viral Physiology Viremia Virus Virus Diseases Virus Replication acute infection adaptive immune response analog cancer cell cancer therapy chronic infection cross reactivity exhaustion experience experimental study extracellular first-in-human global health human monoclonal antibodies human study immunoregulation in vivo inflammatory marker manufacture nano neutralizing antibody nonhuman primate novel therapeutic intervention peripheral blood recruit response restoration seroconversion viral RNA

Acceleration Aftercare Amino Acids Animal Model Animals Antibodies Antigen-Antibody Complex Antigens Antiviral Agents Antiviral Therapy B-Lymphocytes Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell-Mediated Cytolysis Cells Cellular Immunity Chronic Chronic Hepatitis B Circular DNA Clinic Clinical Clinical Research DNA Integration Development Disease remission Dose Drug Kinetics Epitopes Event Experimental Models Exposure to Fc domain Fostering Genome HIV-1 Half-Life Hepatitis B Antibodies Hepatitis B Surface Antigens Hepatitis B Virus Hepatitis B e Antigens Human Biology Humoral Immunities IgG1 Immune Immune response Immunity Immunologics Immunotherapy Impairment In Vitro Individual Infection Infection Control Inflammation Innate Immune Response Liver Liver Cirrhosis Measures Mediating Membrane Modeling Modification Monoclonal Antibodies Passive Transfer of Immunity Persons Phagocytosis Pharmacologic Substance Primary carcinoma of the liver cells Rattus Recombinants Recovery Role Safety Serotyping Serum T-Lymphocyte Testing Therapeutic Tissues Transgenic Mice Vaccination Vaccinee Variant Viral Viral Antigens Viral Physiology Viremia Virus Virus Diseases Virus Replication acute infection adaptive immune response analog cancer cell cancer therapy chronic infection cross reactivity exhaustion experience experimental study extracellular first-in-human global health human monoclonal antibodies human study immunoregulation in vivo inflammatory marker manufacture nano neutralizing antibody nonhuman primate novel therapeutic intervention peripheral blood recruit response restoration seroconversion viral RNA

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项目摘要

Project Summary Hepatitis B virus (HBV) remains a major global health problem and chronic HBV (CHB) is a major cause of liver cirrhosis and hepatocellular carcinoma. While antiviral therapies achieve long-term viral suppression, they can rarely clear the infection or achieve a state of functional cure where long-term viral suppression is maintained in the absence of treatment. Along with persistence of viral antigens, impaired HBV-specific immunity contributes to the chronicity of infection. Chronic exposure to high levels of HBsAg may render HBV- specific immune cells overly activated and functionally tolerized Thus, decreasing serum HBsAg could be a valuable therapeutic strategy, due to its potential to alleviate functional exhaustion and confer immune control. Passive transfer of antibodies is a potential strategy in CHB for their dual functionality. Antibodies differ from direct-acting antivirals in that they can recruit immune effector functions through their Fc domains to accelerate clearance of viruses and infected cells. In addition, immune complexes are potent immunogens that can foster development of host immune responses. HepB monoclonal antibody (mAb)19 is a human monoclonal antibody to the a-determinant of the extracellular loop of HBsAg and binds the major HBV serotypes. HepB mAb19 showed exceptional in vitro neutralization activity with IC50 in the nanogram range and in vivo antiviral activity in an animal model of infection. The object of this proposal is to conduct a first-in-human dose-escalation study of a long-acting variant of HepB mAb19 in individuals with CHB on antiviral nucleos(t)ide analogue (NRTI) therapy. The hypothesis to be tested is that the administration of HepB mAb19-LS during suppressive NRTI therapy will be safe and well tolerated, will lead to decreased levels of circulating HBsAg, and enhance host innate and adaptive immune responses to HBV.

项目摘要丙型肝炎病毒（HBV）仍然是一个主要的全球健康问题，慢性HBV（CHB）是导致的主要原因肝肝硬化和肝细胞癌。尽管抗病毒疗法可以实现长期的病毒抑制作用，但很少会清除感染或达到长期病毒抑制的功能治愈状态在没有治疗的情况下保持。随着病毒抗原的持续性，HBV特异性受损免疫力有助于感染的慢性。长期暴露于高水平的HBSAG可能会导致HBV- 特定的免疫细胞过于激活并在功能上耐受性，因此血清HbSAG可能是一个有价值的治疗策略，因为它有可能减轻功能疲劳并赋予免疫控制。抗体的被动转移是CHB双重功能的潜在策略。抗体不同直接作用抗病毒药可以通过其FC域募集免疫效应器功能以加速清除病毒和感染细胞。另外，免疫复合物是有效的免疫原子，可以促进宿主免疫反应的发展。 HEPB单克隆抗体（MAB）19是人类单克隆抗体对HBSAG的细胞外环的A确定性，并结合主要的HBV血清型。 HEPB MAB19 在纳米图范围内和体内抗病毒活性中显示出与IC50的体外中和活性的特殊体外中和活性在感染动物模型中。该提案的目的是进行首次人类剂量升级研究抗病毒核（T）IDE类似物（NRTI）的CHB个体中HEPB MAB19的长效变体治疗。要检验的假设是抑制NRTI期间的HEPB MAB19-LS给药治疗将是安全且耐受性良好的，将导致循环HBSAG水平降低，并增强宿主对HBV的先天和适应性免疫反应。