Immunocore Ltd, Abingdon, United Kingdom.
Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom.
Hepatology. 2020 Nov;72(5):1528-1540. doi: 10.1002/hep.31503.
Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV-specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity-enhanced T Cell receptor with an anti-CD3 T Cell-activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus-derived peptides presented by human leukocyte antigen (HLA).
ImmTAV molecules specific for HLA-A*02:01-restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV-Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging-based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV-Env can redirect T cells from healthy and HBV-infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV-Env redirection of T cells induced cytolysis of antigen-positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA.
The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non-HBV-specific T cells, bypassing exhausted HBV-specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials.
由于病毒整合、病毒抗原表达持续存在、HBV 特异性免疫反应不足以及需要终身坚持抑制病毒的治疗方案，慢性乙型肝炎病毒 (HBV) 感染的治疗方法迫在眉睫。针对病毒的免疫动员单克隆 T 细胞受体（ImmTAV）分子代表了一种治疗策略，即将亲和力增强的 T 细胞受体与抗 CD3 T 细胞激活部分结合在一起。这种双特异性融合蛋白将 T 细胞重新定向，以特异性裂解表达人白细胞抗原 (HLA) 呈递的靶病毒衍生肽的受感染细胞。
设计了针对 HBV 包膜、聚合酶和核心抗原的 HLA-A*02:01 限制性表位的 ImmTAV 分子。使用细胞因子分泌测定法和基于成像的杀伤测定法评估了 ImmTAV-Env 激活和重新定向包含整合 HBV 和感染 HBV 的细胞的多克隆 T 细胞的能力。使用改进的病毒 RNA 荧光杂交测定法进一步定量感染细胞的消除。在这里，我们证明 ImmTAV-Env 的皮摩尔浓度可以将来自健康和 HBV 感染供体的 T 细胞重新定向到含有整合 HBV DNA 的肝细胞癌 (HCC) 细胞，导致细胞因子释放，这可以在体外通过添加皮质类固醇来抑制。重要的是，ImmTAV-Env 重新定向 T 细胞诱导抗原阳性 HCC 细胞和感染 HBV 的细胞在体外发生细胞溶解，导致乙型肝炎 e 抗原减少和表达病毒 RNA 的细胞特异性丧失。
ImmTAV 平台有可能通过重新定向内源性非 HBV 特异性 T 细胞来消除受感染的细胞，从而绕过耗尽的 HBV 特异性 T 细胞。这代表了慢性乙型肝炎治疗的一种有前途的治疗选择，我们的领先候选药物现已进入临床试验。
