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

• 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
• 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

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.

项目概要 乙型肝炎病毒（HBV）仍然是一个主要的全球健康问题，慢性乙型肝炎（CHB）是导致乙型肝炎的主要原因 肝硬化和肝细胞癌。虽然抗病毒疗法可以实现长期病毒抑制，但它们 在长期病毒抑制的情况下，很少能清除感染或达到功能性治愈的状态 在没有治疗的情况下维持。随着病毒抗原的持续存在，乙肝病毒特异性受损 免疫力导致感染的慢性化。长期接触高水平的 HBsAg 可能会导致 HBV- 特异性免疫细胞过度激活和功能耐受因此，降低血清 HBsAg 可能是一个 有价值的治疗策略，因为它有缓解功能衰竭和赋予免疫控制的潜力。 抗体的被动转移因其双重功能而成为 CHB 的潜在策略。抗体不同于 直接作用抗病毒药物，因为它们可以通过其 Fc 结构域招募免疫效应子功能，以加速 清除病毒和受感染的细胞。此外，免疫复合物是有效的免疫原，可以促进 宿主免疫反应的发展。 HepB 单克隆抗体 (mAb)19 是一种人单克隆抗体 与 HBsAg 细胞外环的 a 决定簇结合并结合主要 HBV 血清型。乙肝单克隆抗体19 显示出卓越的体外中和活性（IC50 在纳克范围内）和体内抗病毒活性 在感染的动物模型中。该提案的目的是进行首次人体剂量递增研究 HepB mAb19 长效变体对慢性乙型肝炎患者使用抗病毒核苷类似物 (NRTI) 的影响 治疗。要测试的假设是在抑制性 NRTI 期间施用 HepB mAb19-LS 治疗将是安全且耐受性良好的，将导致循环 HBsAg 水平下降，并增强宿主 对 HBV 的先天性和适应性免疫反应。