Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B-Infected Cells.
Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B-Infected Cells.
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DOI：
10.1002/hep.31503
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Knox A
中科院分区：
文献类型：
--
作者：
Fergusson JR;Wallace Z;Connolly MM;Woon AP;Suckling RJ;Hine DW;Barber C;Bunjobpol W;Choi BS;Crespillo S;Dembek M;Dieckmann N;Donoso J;Godinho LF;Grant T;Howe D;McCully ML;Perot C;Sarkar A;Seifert FU;Singh PK;Stegmann KA;Turner B;Verma A;Walker A;Leonard S;Maini MK;Wiederhold K;Dorrell L;Simmons R;Knox A
慢性B型肝炎病毒（HBV）感染的治疗是迫切需要的，因为病毒整合，病毒抗原表达的持续性，HBV特异性免疫应答不足，以及需要终身坚持以抑制病毒的治疗方案。抗病毒免疫动员单克隆T细胞受体（ImmTAV）分子代表了一种结合亲和力增强的T细胞受体与抗CD 3 T细胞活化部分的治疗策略。这种双特异性融合蛋白重定向T细胞以特异性裂解表达由人白细胞抗原（HLA）呈递的靶病毒衍生肽的感染细胞。对来自HBV包膜、聚合酶和核心抗原的HLA-A *02：01限制性表位特异性的ImmTAV分子进行工程化。使用细胞因子分泌试验和基于成像的杀伤试验评估ImmTAV-Env激活多克隆T细胞并将其重定向至含有整合的HBV的细胞和感染HBV的细胞的能力。使用病毒RNA测定的改良荧光杂交进一步定量感染细胞的消除。在这里，我们证明了皮摩尔浓度的ImmTAV-Env可以将来自健康和HBV感染供体的T细胞重定向到含有整合HBV DNA的肝细胞癌（HCC）细胞，导致细胞因子释放，这可以通过体外添加皮质类固醇来抑制。重要的是，ImmTAV-Env重定向T细胞在体外诱导抗原阳性HCC细胞和HBV感染细胞的细胞溶解，导致B e肝炎抗原减少和表达病毒RNA的细胞特异性丢失。ImmTAV平台有可能通过重定向内源性非HBV特异性T细胞，绕过耗尽的HBV特异性T细胞来消除感染细胞。这代表了治疗慢性B型肝炎的一种有前途的治疗选择，我们的主要候选药物现在正在进入试验。
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.
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影响因子：
25.7
作者：
Lebosse, Fanny;Testoni, Barbara;Zoulim, Fabien
通讯作者：
Zoulim, Fabien
DOI：
10.1093/protein/gzg087
发表时间：
2003-09-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Boulter, JM;Glick, M;Jakobsen, BK
通讯作者：
Jakobsen, BK
影响因子：
2.5
作者：
Lok, A. S.;Ganova-Raeva, L.;Ghany, M. G.
通讯作者：
Ghany, M. G.
影响因子：
82.9
作者：
Liddy, Nathaniel;Bossi, Giovanna;Jakobsen, Bent K.
通讯作者：
Jakobsen, Bent K.
影响因子：
46.9
作者：
Li, Y;Moysey, R;Boulter, JM
通讯作者：
Boulter, JM