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

项目摘要 B型肝炎病毒（HBV）仍然是一个主要的全球性健康问题，慢性HBV（CH B）是导致HBV感染的主要原因。 肝硬化和肝癌。虽然抗病毒疗法可以实现长期的病毒抑制，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。沿着病毒抗原的持续存在， 免疫力有助于感染的慢性化。长期暴露于高水平的HBsAg可能使HBV- 特异性免疫细胞过度活化和功能性耐受。因此，降低血清HBsAg可能是一种 有价值的治疗策略，由于其缓解功能衰竭和赋予免疫控制的潜力。 抗体的被动转移是CHB中的一种潜在策略，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结构域募集免疫效应子功能，以加速 清除病毒和感染细胞。此外，免疫复合物是有效的免疫原， 宿主免疫反应的发展。HepB单克隆抗体（mAb）19是人源性单克隆抗体 与HBsAg细胞外环的α-决定簇结合并结合主要HBV血清型。HepB单抗19 显示出优异的体外中和活性，IC 50在纳克范围内， 在动物感染模型中。本提案的目的是进行首次人体剂量递增研究 HepB mAb 19的长效变体在CHB患者中的抗病毒核苷（酸）类似物（NRTI） 疗法待检验的假设是，在抑制性NRTI期间HepB mAb 19-LS的给药 治疗将是安全和耐受性良好的，将导致循环HBsAg水平降低，并增强宿主免疫应答。 对HBV的先天性和适应性免疫应答。

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.