單克隆抗體的建立廣泛中和乙型肝炎病毒的感染

StephenW

單克隆抗體的建立廣泛中和乙型肝炎病毒的感染
和張 1 , 伊藤由美 1 , 鈴木達也 1 , 井原菅一郎 2 , 田中智久 3 , 羽賀沙織 1 , Hajime Enatsu 1 , Maho Yumiya 1 , 木村麻里 1 , 高田明 1 , 伊藤大樹 1 4 , 柴崎由里 1 , Shuto Nakao 1 4 , Sachiyo Yoshio 5 , Kei Miyakawa 6 , Yuki Miyamoto 7 , Hanae Sasaki 7 , Tadahiro Kajita 7 , Masaya Sugiyama 8 , Masashi Mizokami 8 , Taro Tachibana 2 , Akihide Ryo 6 , Kohji Moriishi 3 , Eiji Miyoshi 4 ,關東達也 5 、岡本徹 1 9 、松浦義春 10 9
隸屬關係
隸屬關係

    1
    高級共同創造研究所，研究，微生物疾病研究所，大阪大學，大阪，日本。
    2
    日本大阪市立大學工程研究生院應用化學與生物工程系。
    3
    日本山梨大學山梨大學醫學院微生物學系。
    4
    大阪大學醫學研究生院分子生物化學與臨床研究系，大阪，日本。
    5
    國家全球健康與醫學中心肝炎與免疫學研究中心，日本千葉。
    6
    日本神奈川縣橫濱市立大學醫學研究生院微生物學系。
    7
    Bio Matrix Research, Inc，日本千葉。
    8
    基因組醫學科學項目，國家全球健康與醫學中心，日本市川。
    9
    大阪大學傳染病教育與研究中心，日本大阪。
    10
    病毒控制實驗室，微生物疾病研究所，大阪大學，大阪，日本。

    PMID：35084739 DOI：10.1111/1348-0421.12964

抽象的

乙型肝炎病毒 S 蛋白抗體可預防乙型肝炎病毒 (HBV) 感染。因此，含有 HBsAb 的乙型肝炎免疫球蛋白 (HBIG) 在臨床上被用作治療 HBV 感染的方法。在這項研究中，我們獲得了一系列能夠識別多種 HBV 基因型的單克隆抗體。所有抗體均識別 S 蛋白的構象表位，但不識別線性表位。幾種抗體中和了HBV感染並表現出很強的親和力和中和活性。抗原表位分析表明，他們識別了 S 蛋白的殘基 Ile152，該殘基位於“a”決定簇之外。 Ile152高度保守，該殘基的突變導致大乙肝表面蛋白（L蛋白）的表達降低，提示該位置的氨基酸參與了L蛋白的表達。此外，抗體中和了丁型肝炎病毒的感染，該病毒在 S 蛋白中具有 Gly145 突變為 Arg，這是眾所周知的針對 HBIG 治療的逃逸突變。使用小鼠單克隆抗體，我們成功地建立了具有與原始小鼠抗體相似的親和力和中和活性的人源化抗體。本研究中產生的抗體可能具有用於 HBV 感染的替代抗體療法的潛力。本文受版權保護。版權所有。

關鍵詞：乙型肝炎病毒；丁型肝炎病毒；人源化抗體；單克隆抗體；中和抗體。

本文受版權保護。版權所有。

StephenW

Establishment of monoclonal antibodies broadly neutralize infection of hepatitis B virus
He Zhang  1 , Yumi Itoh  1 , Tatsuya Suzuki  1 , Kan-Ichiro Ihara  2 , Tomohisa Tanaka  3 , Saori Haga  1 , Hajime Enatsu  1 , Maho Yumiya  1 , Mari Kimura  1 , Akira Takada  1 , Daiki Itoh  1   4 , Yuri Shibazaki  1 , Shuto Nakao  1   4 , Sachiyo Yoshio  5 , Kei Miyakawa  6 , Yuki Miyamoto  7 , Hanae Sasaki  7 , Tadahiro Kajita  7 , Masaya Sugiyama  8 , Masashi Mizokami  8 , Taro Tachibana  2 , Akihide Ryo  6 , Kohji Moriishi  3 , Eiji Miyoshi  4 , Tatsuya Kanto  5 , Toru Okamoto  1   9 , Yoshiharu Matsuura  10   9
Affiliations
Affiliations

    1
    Institute for Advanced Co-Creation Studies,Research, Institute for Microbial Diseases, Osaka University, Osaka, Japan.
    2
    Department of Applied Chemistry and Bioengineering, Graduate School of Engineering, Osaka City University, Osaka, Japan.
    3
    Department of Microbiology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
    4
    Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan.
    5
    The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan.
    6
    Department of Microbiology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
    7
    Bio Matrix Research, Inc, Chiba, Japan.
    8
    Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan.
    9
    Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan.
    10
    Laboratory of Viral Control, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.

    PMID: 35084739 DOI: 10.1111/1348-0421.12964

Abstract

Antibodies against hepatitis B virus S protein can protect against hepatitis B virus (HBV) infection. Therefore, hepatitis B immunoglobulin (HBIG), which contains HBsAb, is used clinically as a therapy for HBV infection. In this study, we obtained a series of monoclonal antibodies that recognize multiple HBV genotypes. All the antibodies recognized conformational epitopes of S protein, but not linear epitopes. Several antibodies neutralized HBV infection and exhibited strong affinities and neutralizing activities. Antigenic epitope analysis demonstrated that they recognized residue Ile152 of S protein, which is localized outside the "a" determinant. Ile152 is highly conserved, and a mutation in this residue resulted in reduced expression of large hepatitis B surface proteins (L protein), suggesting that the amino acid at this position is involved in the expression of L protein. In addition, the antibodies neutralized the infection of hepatitis D virus possessing a Gly145 mutation to Arg in S protein, which is a well-known escape mutation against HBIG treatment. Using mouse monoclonal antibodies, we successfully established a humanized antibody possessing affinities and neutralizing activities similar to those of the original mouse antibody. The antibodies generated in this study may have potential for use in alternative antibody therapies for HBV infection. This article is protected by copyright. All rights reserved.

Keywords: hepatitis B virus; hepatitis D virus; humanized antibody; monoclonal antibody; neutralizing antibody.

This article is protected by copyright. All rights reserved.