带有 IFNα 的工程抗 PDL1 靶向肝脏中的免疫抑制和激活信号，

StephenW

带有 IFNα 的工程抗 PDL1 靶向肝脏中的免疫抑制和激活信号，以破坏 HBV 免疫耐受

    Chao-Yang Meng1, Shiyu Sun1, Yong Liang2, Hairong Xu1, http://orcid.org/0000-0001-8126-8145Chao Zhang3, Min Zhang4, http://orcid.org/0000-0002-8043-6685Fu-王盛3，付阳新2，http://orcid.org/0000-0002-2482-5475Hua Peng1

    中国科学院生物物理研究所感染与免疫重点实验室彭华教授的通讯，中国北京； [email protected]；中国北京清华大学医学院基础医学系傅阳新教授； [email protected]

抽象的

目的本研究的目的是开发一种基于抗PDL1的干扰素（IFN）融合蛋白，以克服慢性乙型肝炎病毒（HBV）诱导的免疫耐受，并将该免疫疗法与HBV疫苗相结合，实现功能性治愈。慢性乙型肝炎（CHB）感染。

设计 我们设计了一种抗 PDL1-IFNα 异二聚体融合蛋白，其中一个臂来源于抗 PDL1 抗体，另一臂是 IFNα，以允许通过抗 PDL1 抗体将 IFNα 靶向递送到肝脏中。在慢性 HBV 携带小鼠中评估了抗 PDL1-IFNα 异二聚体对克服乙型肝炎表面抗原 (HBsAg) 疫苗耐药性的影响。

结果抗PDL1-IFNα异二聚体优先靶向肝脏并导致病毒抑制、PD1/PDL1免疫检查点阻断和树突状细胞活化/抗原呈递以激活HBsAg特异性T细胞，从而打破慢性HBV携带小鼠的免疫耐受性。当在抗 PDL1-IFNα 异二聚体治疗后不久给予 HBsAg 疫苗时，我们观察到在接受联合治疗的慢性 HBV 携带小鼠中，对于有效清除 HBsAg 的强烈抗 HBsAg 抗体和 HBsAg 特异性 T 细胞反应，但在那些接受联合治疗的小鼠中没有。无论是单一治疗。

结论 用工程化的抗 PDL1-IFNα 异二聚体靶向肝脏可以打破 HBV 诱导的对 HBsAg 疫苗的免疫耐受，为慢性乙型肝炎的功能性治愈提供了一种有前景的可转化治疗策略。
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http://dx.doi.org/10.1136/gutjnl-2022-327059

StephenW

Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance

    Chao-Yang Meng1, Shiyu Sun1, Yong Liang2, Hairong Xu1, http://orcid.org/0000-0001-8126-8145Chao Zhang3, Min Zhang4, http://orcid.org/0000-0002-8043-6685Fu-Sheng Wang3, Yang-Xin Fu2, http://orcid.org/0000-0002-2482-5475Hua Peng1

    Correspondence to Professor Hua Peng, Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; [email protected]; Professor Yang-Xin Fu, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China; [email protected]

Abstract

Objective The purpose of this study is to develop an anti-PDL1-based interferon (IFN) fusion protein to overcome the chronic hepatitis B virus (HBV)-induced immune tolerance, and combine this immunotherapy with a HBV vaccine to achieve the functional cure of chronic hepatitis B (CHB) infection.

Design We designed an anti-PDL1-IFNα heterodimeric fusion protein, in which one arm was derived from anti-PDL1 antibody and the other arm was IFNα, to allow targeted delivery of IFNα into the liver by anti-PDL1 antibody. The effect of the anti-PDL1-IFNα heterodimer on overcoming hepatitis B surface antigen (HBsAg) vaccine resistance was evaluated in chronic HBV carrier mice.

Results The anti-PDL1-IFNα heterodimer preferentially targeted the liver and resulted in viral suppression, the PD1/PDL1 immune checkpoint blockade and dendritic cell activation/antigen presentation to activate HBsAg-specific T cells, thus breaking immune tolerance in chronic HBV carrier mice. When an HBsAg vaccine was administered soon after anti-PDL1-IFNα heterodimer treatment, we observed strong anti-HBsAg antibody and HBsAg-specific T cell responses for efficient HBsAg clearance in chronic HBV carrier mice that received the combination treatment but not in those that received either single treatment.

Conclusions Targeting the liver with an engineered anti-PDL1-IFNα heterodimer can break HBV-induced immune tolerance to an HBsAg vaccine, offering a promising translatable therapeutic strategy for the functional cure of CHB.
Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.
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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

http://dx.doi.org/10.1136/gutjnl-2022-327059

StephenW

https://gut.bmj.com/content/gutj ... 022-327059.full.pdf