免疫动员的单克隆T细胞受体介导特异性和快速消除乙型肝炎

StephenW

Immune-mobilising monoclonal T cell receptors mediate specific and rapid elimination of Hepatitis B-infected cells
Joannah R Fergusson  1 , Zoë Wallace  1 , Mary M Connolly  1 , Amanda P Woon  1 , Richard J Suckling  1 , Dominic W Hine  1 , Claire Barber  1 , Wilawan Bunjobpol  1 , Beak-San Choi  1 , Sara Crespillo  1 , Marcin Dembek  1 , Nele Dieckmann  1 , Jose Donoso  1 , Luis F Godinho  1 , Tressan Grant  1 , Dawn Howe  1 , Michelle L McCully  1 , Carole Perot  1 , Anshuk Sarkar  1 , Florian U Seifert  1 , Praveen K Singh  1 , Kerstin A Stegmann  2 , Bethany Turner  1 , Anil Verma  1 , Andrew Walker  1 , Sarah Leonard  1 , Mala K Maini  2 , Katrin Wiederhold  1 , Lucy Dorrell  1   3   4 , Ruth Simmons  1 , Andrew Knox  1
Affiliations
Affiliations

    1
    Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, UK.
    2
    Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
    3
    Nuffield Department of Medicine, University of Oxford, Oxford, UK.
    4
    Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.

    PMID: 32770836 DOI: 10.1002/hep.31503

Abstract

Background & aims: New therapies for chronic HBV infection are urgently needed due to viral integration, persistence of viral antigen expression, inadequate HBV-specific immune responses and treatment regimens that require life-long adherence to suppress the virus. Immune mobilising monoclonal T cell receptors Against Virus (ImmTAV® ) molecules represent a novel 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).

Approach & results: 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 towards 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 hybridisation of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV-Env can redirect T cells from healthy and HBV-infected donors towards 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 resulted in cytolysis of antigen-positive HCC cells and cells infected with HBV in vitro, resulting in a reduction of HBeAg and specific loss of cells expressing viral RNA.

Conclusions: 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 first-in-human trials.

Keywords: CD3; Immunotherapy; T cell redirection; TCR; bispecific.

This article is protected by copyright. All rights reserved.

StephenW

免疫动员的单克隆T细胞受体介导特异性和快速消除乙型肝炎感染的细胞
Joannah R Fergusson 1，ZoëWallace 1，Mary M Connolly 1，Amanda P Woon 1，Richard J Suckling 1，Dominic W Hine 1，Claire Barber 1，Wilawan Bunjobpol 1，Beak-San Choi 1，Sara Crespillo 1，Marcin Dembek 1 ，Nele Dieckmann 1，Jose Donoso 1，Luis F Godinho 1，Tressan Grant 1，Dawn Howe 1，Michelle L McCully 1，Carole Perot 1，Anshuk Sarkar 1，Florian U Seifert 1，Praveen K Singh 1，Kerstin A Stegmann 2， Bethany Turner 1，Anil Verma 1，Andrew Walker 1，Sarah Leonard 1，Mala K Maini 2，Katrin Wiederhold 1，Lucy Dorrell 1 3 4，Ruth Simmons 1，Andrew Knox 1
隶属关系
隶属关系

    1个
    Immunocore Ltd，英国牛津郡阿宾登公园路92号。
    2
    英国伦敦大学学院免疫与移植研究所感染与免疫科。
    3
    英国牛津牛津大学纳菲尔德分校。
    4
    英国牛津，牛津大学，牛津NIHR生物医学研究中心。

    PMID：32770836 DOI：10.1002 / hep.31503

抽象

背景与目的：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以抑制病毒的治疗方案，迫切需要用于慢性HBV感染的新疗法。针对病毒的免疫动员单克隆T细胞受体代表一种新的治疗策略，该策略结合了亲和力增强的T细胞受体与抗CD3 T细胞活化部分。这种双特异性融合蛋白将T细胞重定向至特异性裂解感染的细胞，以表达人白细胞抗原（HLA）呈递的靶标病毒衍生肽。

方法与结果：设计了针对HLA-A * 02：01限制的HBV包膜，聚合酶和核心抗原的抗原决定簇的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激活多克隆T细胞并将其重定向至含有整合HBV的细胞和感染HBV的细胞的能力。使用修饰的病毒RNA荧光杂交进一步量化感染细胞的消除。在这里，我们证明了皮摩尔浓度的ImmTAV-Env可以将T细胞从健康的和HBV感染的供体重定向到含有整合的HBV DNA的HCC细胞，导致细胞因子释放，这可以通过在体外添加皮质类固醇来抑制。重要的是，T细胞的ImmTAV-Env重定向导致抗原阳性的HCC细胞和体外感染HBV的细胞发生细胞溶解，从而导致HBeAg减少和表达病毒RNA的细胞特异性丢失。

结论：ImmTAV平台具有通过重定向内源性非HBV特异性T细胞，绕过疲惫的HBV特异性T细胞来消除感染细胞的潜力。这是治疗慢性乙型肝炎的一种有前途的治疗选择，我们的主要候选药物目前已进入人体首次试验。

关键字：CD3；免疫疗法T细胞重定向； TCR；双特异性的。

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