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建立阻断乙型肝炎病毒感染的人类 NTCP 单克隆抗体

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才高八斗

发表于 2022-3-10 11:52 |显示全部帖子
建立阻断乙型肝炎病毒感染的人类 NTCP 单克隆抗体
作者:Toshitada Takemori [email protected]、Akiko Sugimoto-Ishige、Hironori Nishitsuji、Yushi Futamura、Michishige Harada、Tomomi Kimura-Someya、Takehisa Matsumoto、……显示所有……、Teruki Honma、Miho Tanaka、Masami Yaguchi、 Kyoichi Isono、Haruhiko Koseki、Hiroyuki Osada、Daiki Miki、Takashi Saito、Takashi Tanaka、Takehiro Fukami、Toshio Goto、Mikako Shirouzu、Kunitada Shimotohno [email protected]、Kazuaki Chayama https://orcid.org/0000 -0002-5530-5341 [email protected] 显示更少的作者信息和附属机构
DOI:
https://doi.org/10.1128/jvi.01686-21
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合资公司
第 96 卷,第 5 期
2022 年 3 月 9 日

    抽象的
    介绍
    结果
    讨论
    材料和方法
    致谢
    参考

抽象的
乙型肝炎病毒 (HBV) 感染全球 2.4 亿人。目前的治疗可显着抑制 HBV 复制,但需要长期维持治疗。因此,仍然存在对有效治愈HBV的医学需求。 HBV 通过病毒 L 蛋白的 preS1 结构域与 Na+/牛磺胆酸盐协同转运多肽 (NTCP) 结合进入宿主细胞。因此,NTCP 应该是开发抗 HBV 疗法的关键目标。事实上,myrcludex B 是一种合成形式的肉豆蔻酰化 preS1 肽,可有效减少 HBV/丁型肝炎病毒 (HDV) 感染,并已在欧洲被批准为 Hepcludex,用于治疗慢性 HDV 感染患者。我们建立了一种单克隆抗体 (MAb),即 N6HB426-20,它可识别人 NTCP 的细胞外结构域并在体外阻止 HBV 进入人肝细胞,但对胆汁酸摄取的抑制作用要小得多。在体内,在小鼠模型系统中接种 HBV 后,N6HB426-20 MAb 的给药可长时间预防 HBV 病毒血症,而不会强烈抑制胆汁酸的吸收。在 NTCP 的细胞外环 (ECL) 中,ECL1 中的氨基酸 (aa) 84 至 87 区域和跨膜结构域 5 的 ECL2 附近的氨基酸 (aa) 区域 157 至 165 对 HBV/HDV 感染至关重要。表位作图和 NTCP 结构的三维 (3D) 模型表明,N6HB426-20 MAb 可以识别 ECL4 末端的 aa 276/277 并干扰 HBV 与 aa 84 至 87 区域的结合。总结,我们鉴定了一种能够预防HBV感染的体内中和NTCP靶向抗体。该药疗效的进一步提高将为其临床应用铺平道路。
重要性 许多进入抑制剂正在开发中,以加强对 HBV 患者的口服核苷/核苷酸类似物 (NA) 的治疗。为了扩大 NA 治疗的有效性,已经做出了一些努力来开发具有中和活性的治疗性 MAb,以对抗 HBs 抗原。然而,这些 MAb 的中和作用可能会因感染患者血液中大量过量的 HBsAg 阳性非感染性颗粒而减弱。 NTCP 靶向 HBV 进入抑制剂的优势在于,无论病毒基因型、病毒突变和亚病毒颗粒的存在如何,它们都能保持有效。尽管 N6HB426-20 需要比 myrcludex 更高的剂量才能在模型小鼠系统中获得同等的 HBV 抑制,但它在给药后长时间保持抑制效果,与 IgG MAb 的半衰期成正比。我们相信,进一步的改进将使这种抗体成为慢性乙型肝炎患者的一种有希望的治疗选择。

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才高八斗

发表于 2022-3-10 11:52 |显示全部帖子
Establishment of a Monoclonal Antibody against Human NTCP That Blocks Hepatitis B Virus Infection
Authors: Toshitada Takemori [email protected], Akiko Sugimoto-Ishige, Hironori Nishitsuji, Yushi Futamura, Michishige Harada, Tomomi Kimura-Someya, Takehisa Matsumoto, … Show All … , Teruki Honma, Miho Tanaka, Masami Yaguchi, Kyoichi Isono, Haruhiko Koseki, Hiroyuki Osada, Daiki Miki, Takashi Saito, Takashi Tanaka, Takehiro Fukami, Toshio Goto, Mikako Shirouzu, Kunitada Shimotohno [email protected], Kazuaki Chayama https://orcid.org/0000-0002-5530-5341 [email protected] Show FewerAuthors Info & Affiliations
DOI:
https://doi.org/10.1128/jvi.01686-21
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JVI
Volume 96, Number 5
9 March 2022

    ABSTRACT
    INTRODUCTION
    RESULTS
    DISCUSSION
    MATERIALS AND METHODS
    ACKNOWLEDGMENTS
    REFERENCES

ABSTRACT
Hepatitis B virus (HBV) infects 240 million people worldwide. Current therapy profoundly suppresses HBV replication but requires long-term maintenance therapy. Therefore, there is still a medical need for an efficient HBV cure. HBV enters host cells by binding via the preS1 domain of the viral L protein to the Na+/taurocholate cotransporting polypeptide (NTCP). Thus, NTCP should be a key target for the development of anti-HBV therapeutics. Indeed, myrcludex B, a synthetic form of the myristoylated preS1 peptide, effectively reduces HBV/hepatitis D virus (HDV) infection and has been approved as Hepcludex in Europe for the treatment of patients with chronic HDV infection. We established a monoclonal antibody (MAb), N6HB426-20, that recognizes the extracellular domain of human NTCP and blocks HBV entry in vitro into human liver cells but has much less of an inhibitory effect on bile acid uptake. In vivo, administration of the N6HB426-20 MAb prevented HBV viremia for an extended period of time after HBV inoculation in a mouse model system without strongly inhibiting bile acid absorption. Among the extracellular loops (ECLs) of NTCP, regions of amino acids (aa) 84 to 87 in ECL1 and aa 157 to 165 near ECL2 of transmembrane domain 5 are critically important for HBV/HDV infection. Epitope mapping and the three-dimensional (3D) model of the NTCP structure suggested that the N6HB426-20 MAb may recognize aa 276/277 at the tip of ECL4 and interfere with binding of HBV to the region from aa 84 to 87. In summary, we identified an in vivo neutralizing NTCP-targeting antibody capable of preventing HBV infection. Further improvements in efficacy of this drug will pave the way for its clinical applications.
IMPORTANCE A number of entry inhibitors are being developed to enhance the treatment of HBV patients with oral nucleoside/nucleotide analogues (NA). To amplify the effectiveness of NA therapy, several efforts have been made to develop therapeutic MAbs with neutralizing activity against HBs antigens. However, the neutralizing effect of these MAbs may be muted by a large excess of HBsAg-positive noninfectious particles in the blood of infected patients. The advantage of NTCP-targeted HBV entry inhibitors is that they remain effective regardless of viral genotype, viral mutations, and the presence of subviral particles. Although N6HB426-20 requires a higher dose than myrcludex to obtain equivalent suppression of HBV in a model mouse system, it maintained the inhibitory effect for a long time postadministration in proportion to the half-life of an IgG MAb. We believe that further improvements will make this antibody a promising treatment option for patients with chronic hepatitis B.

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才高八斗

发表于 2022-3-10 11:53 |显示全部帖子

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发表于 2022-3-13 18:03 |显示全部帖子
Establishment of a Monoclonal Antibody against Human NTCP That Blocks Hepatitis B Virus Infection
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