TLR2配体合成的长肽偶联物的设计，用于慢性HBV患者的治疗性

StephenW

Antiviral Res. 2020 Feb 17:104746. doi: 10.1016/j.antiviral.2020.104746. [Epub ahead of print]
Design of TLR2-ligand-synthetic long peptide conjugates for therapeutic vaccination of chronic HBV patients.
Dou Y1, Jansen DTSL1, van den Bosch A1, de Man RA1, van Montfoort N1, Araman C2, van Kasteren SI2, Zom GG3, Krebber WJ3, Melief CJM3, Woltman AM1, Buschow SI4.
Author information

1
    Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
2
    Leiden Institute of Chemistry and the Institute for Chemical Immunology, Leiden University, Einsteinweg 55, 2333, CC Leiden, the Netherlands.
3
    ISA Pharmaceuticals BV, Leiden, the Netherlands.
4
    Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands. Electronic address: [email protected].

Abstract

Synthetic long peptide (SLP) vaccination is a promising new treatment strategy for patients with a chronic hepatitis B virus (HBV) infection. We have previously shown that a prototype HBV-core protein derived SLP was capable of boosting CD4+ and CD8+ T cell responses in the presence of a TLR2-ligand in chronic HBV patients ex vivo. For optimal efficacy of a therapeutic vaccine in vivo, adjuvants can be conjugated to the SLP to ensure delivery of both the antigen and the co-stimulatory signal to the same antigen-presenting cell (APC). Dendritic cells (DCs) express the receptor for the adjuvant and are optimally equipped to efficiently process and present the SLP-contained epitopes to T cells. Here, we investigated TLR2-ligand conjugation of the prototype HBV-core SLP. Results indicated that TLR2-ligand conjugation reduced cross-presentation efficiency of the SLP-contained epitope by both monocyte-derived and naturally occurring DC subsets. Importantly, cross-presentation was improved after optimization of the conjugate by either shortening the SLP or by placing a valine-citrulline linker between the TLR2-ligand and the long SLP, to facilitate endosomal dissociation of SLP and TLR2-ligand after uptake. HBV-core SLP conjugates also triggered functional patient T cell responses ex vivo. These results provide an import step forward in the design of a therapeutic SLP-based vaccine to cure chronic HBV.

Copyright © 2020. Published by Elsevier B.V.
KEYWORDS:

Chronic HBV infection; Cross-presentation; Hepatitis B virus; Immunotherapy; Synthetic long peptide; TLR2-Ligand

PMID:
    32081741
DOI:
    10.1016/j.antiviral.2020.104746

StephenW

抗病毒水库。 2020年2月17日：104746。Doi：10.1016 / j.antiviral.2020.104746。 [Epub提前发行]
TLR2配体合成的长肽偶联物的设计，用于慢性HBV患者的治疗性疫苗接种。
Dou Y1，Jansen DTSL1，van den Bosch A1，de Man RA1，van Montfoort N1，Araman C2，van Kasteren SI2，Zom GG3，Krebber WJ3，Melief CJM3，Woltman AM1，Buschow SI4。
作者信息

1个
荷兰鹿特丹大学医学中心，伊拉斯姆斯大学胃肠病和肝病学系。
2
莱顿大学莱顿化学研究所和化学免疫学研究所，Einsteinweg 55，2333，CC CC Leiden，荷兰。
3
ISA Pharmaceuticals BV，荷兰莱顿。
4
荷兰鹿特丹大学医学中心，伊拉斯姆斯大学胃肠病和肝病学系。电子地址：[email protected]。

抽象

合成长肽（SLP）疫苗接种是患有慢性乙型肝炎病毒（HBV）感染患者的有希望的新治疗策略。我们先前已经证明，在慢性HBV患者体内，在TLR2-配体存在的情况下，原型HBV核心蛋白衍生的SLP能够增强CD4 +和CD8 + T细胞应答。为了使治疗性疫苗在体内具有最佳功效，可以将佐剂与SLP偶联，以确保将抗原和共刺激信号传递到同一抗原呈递细胞（APC）。树突状细胞（DC）表达佐剂的受体，并具有最佳装备，可有效处理SLP抗原决定簇并将其呈递给T细胞。在这里，我们研究了原型HBV核心SLP的TLR2配体结合。结果表明，TLR2配体结合降低了单核细胞衍生的DC子集和自然存在的DC子集对SLP抗原决定簇的交叉呈递效率。重要的是，通过缩短SLP或通过在TLR2-配体和长SLP之间放置缬氨酸-瓜氨酸连接基来促进结合物的最佳化，从而改善了交叉呈递，以促进摄取后SLP和TLR2-配体的内体解离。 HBV核心SLP偶联物也触发了离体的功能性患者T细胞反应。这些结果为治疗慢性乙型肝炎的基于治疗性SLP的疫苗设计迈出了重要的一步。

版权所有©2020。由Elsevier B.V.发布。
关键字：

慢性HBV感染；交叉演示；乙型肝炎病毒；免疫疗法合成长肽； TLR2-配体

PMID：
32081741
DOI：
10.1016 / j.antiviral.2020.104746