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

项目摘要 乙肝病毒(乙肝)仍然是一个主要的全球健康问题，而慢性乙肝(CHB)是导致 肝硬变和肝细胞癌。虽然抗病毒疗法实现了长期的病毒抑制，但它们 很少能清除感染或达到长期病毒抑制的功能性治愈状态 在没有治疗的情况下维持。随着病毒抗原的持续存在，受损的乙肝病毒特异性 免疫有助于感染的慢性化。慢性暴露于高水平的乙肝表面抗原可能会使乙肝病毒- 特异性免疫细胞过度激活和功能耐受，因此，降低血清乙肝表面抗原可能是一种 有价值的治疗策略，由于其潜在的缓解功能衰竭和赋予免疫控制。 抗体的被动转移是一种潜在的治疗慢性乙肝的策略，因为它们具有双重功能。抗体不同于 直接作用的抗病毒药物，因为它们可以通过其Fc结构域招募免疫效应器功能来加速 清除病毒和受感染细胞。此外，免疫复合体是有效的免疫原，可以促进 宿主免疫反应的发展。乙肝单抗(MAb)19是一种人类单抗 与乙肝表面抗原胞外环的a决定簇结合，并与主要的乙肝病毒血清型结合。乙肝单抗19 显示出优异的体外中和活性，IC50在纳克范围内，在体内具有抗病毒活性 在感染的动物模型中。这项提议的目的是进行一项首次人类剂量递增研究 慢性乙型肝炎患者抗病毒核糖核酸(T)类似物(NRTI)长效HBmAb19变异的研究 心理治疗。需要检验的假设是，在抑制性NRTI期间给予HepB mAb19-LS 治疗将是安全和耐受性良好的，将导致循环中的乙肝表面抗原水平下降，并增强宿主 针对乙肝病毒的先天和获得性免疫反应。

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.