A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway.
A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway.
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靶向细胞内 HBx 的细胞穿透全分子抗体通过 TRIM21 依赖性途径抑制乙型肝炎病毒
作者：
Zhang JF;Xiong HL;Cao JL;Wang SJ;Guo XR;Lin BY;Zhang Y;Zhao JH;Wang YB;Zhang TY;Yuan Q;Zhang J;Xia NS
研究背景：主要针对细胞外或细胞表面分子的单抗已广泛应用于各种疾病的治疗。然而，单抗不能像小分子化合物那样有效地穿过细胞膜，因此限制了它们对细胞内靶点的使用。将抗体运送到活细胞中的方法可以极大地扩展基于单抗的领域的研究和应用。乙肝病毒X蛋白(HBx)是乙肝病毒生命周期中一种重要的细胞内多功能病毒蛋白。HBx在病毒感染和复制中起着重要作用，并与乙肝病毒相关的癌变密切相关。方法：在抗HBx(9D11)的单抗重链的C末端融合细胞穿透肽(CPP)，制备针对HBx(9D11-TAT)的细胞穿透性全分子抗体。在模拟慢性乙肝病毒感染的细胞和小鼠模型上，研究了9D11-TAT的抗乙肝病毒作用及其机制。结果：重组9D11-TAT抗体在体内外均能有效地内化到活细胞内，并显著抑制病毒的转录、复制和蛋白质的产生。进一步的分析表明，内化的9D11-Tat抗体可以通过Fc结合受体TRIM21介导的蛋白质降解来显著降低细胞内的HBx。这个过程同时刺激了核因子-κB、AP-1和干扰素-β的激活，从而促进了宿主细胞的抗病毒状态。结论：综上所述，我们的研究为通过工程化细胞穿透性单抗靶向细胞内致病相关蛋白提供了一种新的途径，扩大了其治疗应用的潜力。此外，9D11-Tat抗体可能为人类慢性乙肝病毒感染提供一种新的治疗手段。
Rationale: Monoclonal antibodies (mAbs) mostly targeting extracellular or cell surface molecules have been widely used in the treatment of various diseases. However, mAbs cannot pass through the cell membrane as efficiently as small compounds, thus limiting their use against intracellular targets. Methods to shuttle antibodies into living cells may largely expand research and application in areas based on mAbs. Hepatitis B virus X protein (HBx) is an important intracellular multi-functional viral protein in the life cycle of hepatitis B virus (HBV). HBx plays essential roles in virus infection and replication and is strongly associated with HBV-related carcinogenesis. Methods: In this study, we developed a cell-penetrating whole molecule antibody targeting HBx (9D11-Tat) by the fusion of a cell penetrating peptide (CPP) on the C-terminus of the heavy chain of a potent mAb specific to HBx (9D11). The anti-HBV effect and mechanism of 9D11-Tat were investigated in cell and mouse models mimicking chronic HBV infection. Results: Our results demonstrated that the recombinant 9D11-Tat antibody could efficiently internalize into living cells and significantly suppress viral transcription, replication, and protein production both in vitro and in vivo. Further analyses suggested the internalized 9D11-Tat antibody could greatly reduce intracellular HBx via Fc binding receptor TRIM21-mediated protein degradation. This process simultaneously stimulated the activations of NF-κB, AP-1, and IFN-β, which promoted an antiviral state of the host cell. Conclusion: In summary, our study offers a new approach to target intracellular pathogenesis-related protein by engineered cell-penetrating mAb expanding their potential for therapeutic applications. Moreover, the 9D11-Tat antibody may provide a novel therapeutic agent against human chronic HBV infection.
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