T 細胞接合抗體使 T 細胞能夠控制 HBV 感染並靶向小鼠中的 HBs

StephenW

T 細胞接合抗體使 T 細胞能夠控制 HBV 感染並靶向小鼠中的 HBsAg 陽性肝癌

    奧利弗·奎特 #
    羅姍姍#, †
    馬丁邁耶
    格哈德·莫登豪爾
    弗蘭克·蒙伯格
    烏爾里克·普羅策
   
發佈時間：2021年6月22日DOI：https://doi.org/10.1016/j.jhep.2021.06.022

強調

    •
    HBV 治愈很可能需要重建抗 HBV 免疫。
    •
    我們設計了 T 細胞接合器，可結合 T 細胞上的 HBV 包膜蛋白和 CD3/CD28。
    •
    HBV 特異性 T 細胞接合劑激活 T 細胞並刺激其抗病毒活性。
    •
    參與的 T 細胞控制 HBV 複製並在體內消除 HBV 陽性肝癌。

背景與目標
目前的抗病毒療法控制但很少消除 HBV，使慢性 HBV 攜帶者面臨發展為肝細胞癌 (HCC) 的風險。缺乏或功能失調的病毒特異性適應性免疫會阻止對 HBV 的控制並使病毒持續存在。恢復抗病毒 T 細胞免疫可能導致慢性感染患者的 HBV 消除和治愈。
方法
我們構建了雙特異性 T 細胞接合抗體，旨在通過同時結合受感染肝細胞上的 HBV 包膜蛋白 (HBVenv) 和 T 細胞上的 CD3 或 CD28 來誘導抗病毒免疫。 T 細胞接合抗體用於與健康供體淋巴細胞和 HBV 感染的靶細胞的共培養。通過檢測促炎細胞因子、效應子功能（通過細胞毒性）和抗病毒作用來確定 T 細胞反應的激活。為了研究體內功效，免疫缺陷小鼠被移植了 HBVenv 陽性和陰性肝癌細胞。
結果
2 T 細胞接合抗體協同激活 T 細胞成為多功能效應器，進而通過殺死受感染的細胞而引發有效的抗病毒作用，此外還通過非細胞溶解、細胞因子介導的抗病毒機制控制 HBV。在小鼠體內，抗體將 T 細胞特異性地吸引到表達 HBVenv 的腫瘤上，導致 T 細胞活化、腫瘤浸潤和腫瘤負荷減少。
結論
該研究表明，HBVenv 靶向 T 細胞接合抗體的給藥促進了 T 細胞向 HBV 陽性靶細胞的穩健重定向，並為治療慢性病毒性肝炎和 HBV 相關 HCC 提供了一種可行且有前景的方法。
奠定總結
T 細胞接合抗體是一種有趣的新型治療工具，可用於恢復慢性乙型肝炎患者的免疫力。作為雙特異性抗體，它們結合乙型肝炎病毒 (HBV) 表面的包膜蛋白和 T 細胞上的 CD3 或 CD28。這樣，它們會誘導有效的抗病毒和細胞毒性 T 細胞反應，從而消除 HBV 陽性細胞。這些雙特異性 T 細胞接合抗體是慢性乙型肝炎和 HBV 相關肝細胞癌的令人興奮的治療候選者。

StephenW

T-cell engager antibodies enable T cells to control HBV infection and to target HBsAg-positive hepatoma in mice

    Oliver Quitt #
    Shanshan Luo #, †
    Marten Meyer
    Gerhard Moldenhauer
    Frank Momburg
    Ulrike Protzer
   
Published:June 22, 2021DOI:https://doi.org/10.1016/j.jhep.2021.06.022

Highlights

    •
    HBV cure most likely requires reconstitution of anti-HBV immunity.
    •
    We designed T-cell engagers that bind HBV envelope proteins and CD3/CD28 on T cells.
    •
    HBV-specific T-cell engagers activate T cells and stimulate their antiviral activity.
    •
    Engaged T cells control HBV replication and eliminate HBV-positive hepatoma in vivo.

Background & Aims
Current antiviral therapies control but rarely eliminate HBV, leaving chronic HBV carriers at risk of developing hepatocellular carcinoma (HCC). Lacking or dysfunctional virus-specific adaptive immunity prevents control of HBV and allows the virus to persist. Restoring antiviral T-cell immunity could lead to HBV elimination and cure of chronically infected patients.
Methods
We constructed bispecific T-cell engager antibodies that are designed to induce antiviral immunity through simultaneous binding of HBV envelope proteins (HBVenv) on infected hepatocytes and CD3 or CD28 on T cells. T-cell engager antibodies were employed in co-cultures with healthy donor lymphocytes and HBV-infected target cells. Activation of the T-cell response was determined by detection of pro-inflammatory cytokines, effector function (by cytotoxicity) and antiviral effects. To study in vivo efficacy, immune-deficient mice were transplanted with HBVenv-positive and -negative hepatoma cells.
Results
The 2 T-cell engager antibodies synergistically activated T cells to become polyfunctional effectors that in turn elicited potent antiviral effects by killing infected cells and in addition controlled HBV via non-cytolytic, cytokine-mediated antiviral mechanisms. In vivo in mice, the antibodies attracted T cells specifically to the tumors expressing HBVenv resulting in T-cell activation, tumor infiltration and reduction of tumor burden.
Conclusion
This study demonstrates that the administration of HBVenv-targeting T-cell engager antibodies facilitates a robust T-cell redirection towards HBV-positive target cells and provides a feasible and promising approach for the treatment of chronic viral hepatitis and HBV-associated HCC.
Lay summary
T-cell engager antibodies are an interesting, novel therapeutic tool to restore immunity in patients with chronic hepatitis B. As bispecific antibodies, they bind envelope proteins on the surface of the hepatitis B virus (HBV) and CD3 or CD28 on T cells. This way, they induce a potent antiviral and cytotoxic T-cell response that leads to the elimination of HBV-positive cells. These bispecific T-cell engager antibodies are exciting therapeutic candidates for chronic hepatitis B and HBV-associated hepatocellular carcinoma.