Identification of new functional region of human IgE using Fab libraries

• Project/Area Number: 20K08808
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Juntendo University
• Principal Investigator: Ando Tomoaki 順天堂大学, 大学院医学研究科, 助教 (10724669)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: IgE / マスト細胞 / アレルギー / 気管支喘息 / 抗体医薬 / アナフィラキシー

Outline of Research at the Start

アレルギー反応においては、マスト細胞のIgEを介した活性化が重要な役割を果たしている。最近、マウスIgE分子のCε2部位に結合する抗体のFab断片が、この活性化を抑制しうることが示されたが、IgE高親和性受容体FcεRIとの結合部位であるCε3とは異なり、Cε2部位のIgE-FcεRIシグナルに対する役割はまだ十分に明らかにされていない。本研究は、ヒトIgEのCε2領域に対する抗体Fab断片が、FcεRI上のIgEの安定性や機能に与える影響を多面的に明らかにし、Cε2領域がどのように即時型アレルギー反応に寄与するかを明らかにする。

Outline of Final Research Achievements

We developed new Fab fragments of antibodies against IgE, which is an important molecule involved in the pathogenesis of allergic diseases. These Fab fragments binds IgE at the sites which are different from the sites bound by conventional antibody drugs. These Fab fragments not only block binding of IgE to its receptors, but also facilitated dissociation of the already bound IgE from its receptors. By elucidating the detailed binding portions, we found new structurally important part for the IgE to stably bind to its receptor. These results would serve as a basis for the development of new antibody drugs targeting human IgE.

Academic Significance and Societal Importance of the Research Achievements

抗ヒトIgE抗体オマリズマブは気管支喘息、慢性特発性蕁麻疹、花粉症などの治療に役立てられており、IgEのアレルギー疾患における役割は近年ますます注目されているが、オマリズマブは効果を発揮するまでに数週間の期間を要するため、より早期に効果を発揮し、より強力な治療薬の開発が求められている。本研究で開発した抗体Fab断片は、すでに受容体に結合したIgEを解離させる能力が強く、オマリズマブよりも早期に効果を発揮することが期待される。今後の臨床応用が期待される抗体医薬である。

Research Products

• [Journal Article] Kaempferol Suppresses the Activation of Mast Cells by Modulating the Expression of FcεRI and SHIP1 (2023)
  • Author(s): Nagata Kazuki、Araumi Sanae、Ando Daisuke、Ito Naoto、Ando Miki、Ikeda Yuki、Takahashi Miki、Noguchi Sakura、Yasuda Yayoi、Nakano Nobuhiro、Ando Tomoaki、Hara Mutsuko、Yashiro Takuya、Hachisu Masakazu、Nishiyama Chiharu
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 6 Pages: 5997-5997
  • DOI: 10.3390/ijms24065997
  • Peer Reviewed / Open Access
• [Journal Article] Sensitization to macadamia 7S globulin amino-terminus with clinical relevance in Japanese children with macadamia nut allergy (2023)
  • Author(s): Ando T, Kitaura J, Maruyama N, Narita M, Miura K, Takasato Y, Nogami K, Nagao M, Okumura K, Ogawa H, Onishi H, Watanabe T, Ito K, Fujisawa T, Ebisawa M, Kawakami T, Matsumoto K, Hasegawa S, Ohya Y, Yasudo H.
  • Journal Title: Allergology International Volume: 72 Issue: 2 Pages: 351-353
  • DOI: 10.1016/j.alit.2022.11.005
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Immunoglobulin E-Dependent Activation of Immune Cells in Rhinovirus-Induced Asthma Exacerbation (2022)
  • Author(s): Kawakami Toshiaki、Kasakura Kazumi、Kawakami Yu、Ando Tomoaki
  • Journal Title: Frontiers in Allergy Volume: 3 Pages: 835748-835748
  • DOI: 10.3389/falgy.2022.835748
  • Peer Reviewed / Open Access
• [Journal Article] Predictive value of 7S globulin-specific IgE in Japanese macadamia nut allergy patients. (2022)
  • Author(s): Yasudo H, Ando T, Kitaura J, Maruyama N, Narita M, Natsume O, Uneoka K, Miura K, Morita Y, Kamei A, Okamoto Y, Shirakawa S, Kitabayashi T, Kurihara K, Nogami K, Takasato Y, Nagao M, Ito K, Fujisawa T, Ebisawa M, Kawakami T, Matsumoto K, Saito H, Hasegawa S, Ohya Y.
  • Journal Title: J Allergy Clin Immunol Pract. Volume: - Issue: 5 Pages: 1389-1391.e1
  • DOI: 10.1016/j.jaip.2021.12.039
  • Peer Reviewed
• [Journal Article] Development of mouse model for oral allergy syndrome to identify IgE cross-reactive pollen and food allergens: ragweed pollen cross-reacts with fennel and black pepper (2022)
  • Author(s): Kamei Anna、Izawa Kumi、Ando Tomoaki、Kaitani Ayako、Yamamoto Risa、Maehara Akie、Ide Takuma、Yamada Hiromichi、Kojima Mayuki、Wang Hexing、Tokushige Koji、Nakano Nobuhiro、Shimizu Toshiaki、Ogawa Hideoki、Okumura Ko、Kitaura Jiro
  • Journal Title: Frontiers in Immunology Volume: 13 Pages: 945222-945222
  • DOI: 10.3389/fimmu.2022.945222
  • Peer Reviewed / Open Access
• [Journal Article] Mucosal Mast Cell-Specific Gene Expression Is Promoted by Interdependent Action of Notch and TGF-β Signaling. (2022)
  • Author(s): Nakano N, Saida K, Hara M, Izawa K, Ando T, Kaitani A, Kasakura K, Yashiro T, Nishiyama C, Ogawa H, Kitaura J, Okumura K.
  • Journal Title: J Immunol. Volume: - Issue: 12 Pages: 3098-3106
  • DOI: 10.4049/jimmunol.2100112
  • Peer Reviewed
• [Journal Article] Pollen shells and soluble factors play non-redundant roles in the development of allergic conjunctivitis in mice (2021)
  • Author(s): Fukase S, Ando T, Matsuzawa M, Kimura M, Sone Y, Izawa K, Kaitani A, Kamei A, Kojima M, Nakano N, Maeda K, Shimizu T, Ogawa H, Okumura K, Nishiyama N, Murakami A, Ebihara N, Kitaura J.
  • Journal Title: Ocul Surf. Volume: 22 Pages: 153-162
  • DOI: 10.1016/j.jtos.2021.08.009
  • Peer Reviewed
• [Journal Article] IgE-Associating Molecules and Their Effects on IgE-Dependent Mast Cell Reactions. (2021)
  • Author(s): Ando T, Kitaura J.
  • Journal Title: Cells. Volume: 10 Issue: 7 Pages: 1697-1697
  • DOI: 10.3390/cells10071697
  • Peer Reviewed / Open Access
• [Journal Article] シリーズIgE、抗IgE 抗体のメカニズム 前編 (2021)
  • Author(s): 安藤 智暁
  • Journal Title: アロスエルゴン Volume: 1(2) Pages: 233-239
• [Journal Article] シリーズIgE、抗IgE 抗体のメカニズム 後編 (2021)
  • Author(s): 安藤 智暁
  • Journal Title: アロスエルゴン Volume: 1(3) Pages: 370-379
• [Journal Article] A possible association between a novel NLRP1 mutation and an autoinflammatory disease involving liver cirrhosis (2021)
  • Author(s): Yasudo Hiroki、Ando Taiki、Maehara Akie、Ando Tomoaki、Izawa Kumi、Tanabe Atsushi、Kaitani Ayako、Nomura Shigeru、Seki Masafumi、Yoshida Kenichi、Oda Hirotsugu、Okamoto Yoko、Wang Hexing、Kamei Anna、Kojima Mayuki、Kimura Meiko、Uchida Koichiro、Nakano Nobuhiro、Kaneko Junichi、et al.
  • Journal Title: Hepatology Volume: - Issue: 4 Pages: 2296-2299
  • DOI: 10.1002/hep.31818
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Notch signaling contributes to the establishment of sustained unresponsiveness to food allergens by oral immunotherapy (2021)
  • Author(s): Yoneyama Toshiyuki、Nakano Nobuhiro、Hara Mutsuko、Yamada Hiromichi、Izawa Kumi、Uchida Koichiro、Kaitani Ayako、Ando Tomoaki、Kitaura Jiro、Ohtsuka Yoshikazu、Ogawa Hideoki、Okumura Ko、Shimizu Toshiaki
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 147 Issue: 3 Pages: 1063-1076
  • DOI: 10.1016/j.jaci.2020.07.011
  • Peer Reviewed
• [Presentation] 安藤智暁：IgEを介したアレルギー反応が起こるまで (2022)
  • Author(s): 安藤智暁
  • Organizer: 第26回那須ティーチイン
  • Invited
• [Presentation] The effects of an antibody Fab library against human IgE Cε2 on the binding of IgE to its receptors (2022)
  • Author(s): Hexing Wang
  • Organizer: 第71回日本アレルギー学会学術大会
• [Presentation] Fab fragments against human IgE Cε2 inhibit the binding of IgE to its receptors (2022)
  • Author(s): Hexing Wang
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Staphylococcus aureus d-toxin in skin promotes the development of food allergy following epicutaneous sensitization (2021)
  • Author(s): Anna Kamei, Hiromichi Yamada, Kumi Izawa, Tomoaki Ando, Ayako Kaitani, Akie Maehara, Hexing Wang, Koji Tokushige, Shino Uchida, Nobuhiro Nakano, Ko Okumura, Jiro Kitaura
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] CD300f suppresses IgE- and mast cell-dependent allergic rhinitis (2021)
  • Author(s): Ayako Kaitani, Takuma Ide, Kumi Izawa, Anna Kamei, Tomoaki Ando, Akie Maehara, Hexing Wang, Koji Tokushige, Maeda Keiko, Nobuhiro Nakano, Ko Okumura, Jiro Kitaura
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Physiological expression of St6galnac1 protects mice from allergic conjunctivitis (2021)
  • Author(s): Tomoaki Ando, Moe Matsuzawa, Saaya Fukase, Meiko Kimura, Kumi Izawa, Ayako Kaitani, Nobuhiro Nakano, Keiko Maeda, Ko Okumura, Akira Murakami, Nobuyuki Ebihara, Jiro Kitaura
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] 結膜におけるシアル化酵素St6galnac1の生理的発現がアレルギー性結膜炎の発症を抑制する (2021)
  • Author(s): 松澤 萌、安藤 智暁、深瀬 紗綾、木村 芽以子、伊沢 久未、貝谷 綾子、中野 信浩、前田 啓子、奥村 康、村上 晶、海老原 伸行、北浦 次郎
  • Organizer: 第70回日本アレルギー学会学術大会
• [Presentation] ：Pollen shells and soluble components play non-redundant roles in the development of allergic conjunctivitis (2021)
  • Author(s): Saaya Fukase, Tomoaki Ando, Moe Matsuzawa, Meiko Kimura, Kumi Izawa, Ayako Kaitani, Anna Kamei, Goukyo Ou, Nobuhiro Nakano, Ko Okumura, Akira Murakami, Nobuyuki Ebihara, Jiro Kitaura
  • Organizer: 第70回日本アレルギー学会学術大会
• [Presentation] 結膜におけるシアル化酵素の生理的発現がアレルギー性結膜炎の発症を抑制する (2021)
  • Author(s): 松澤萌, 安藤智暁, 深瀬紗綾, 木村芽以子, 伊沢久未, 貝谷綾子, 中野信浩, 前田啓子, 奥村康, 村上晶, 北浦次郎, 海老原伸行
  • Organizer: 第125回日本眼科学会総会
• [Presentation] マウス花粉性結膜炎モデルの発症における花粉の粒子性と抽出成分の重要性 (2021)
  • Author(s): 深瀬紗綾, 安藤智暁, 松澤萌, 木村芽以子, 伊沢久未, 貝谷綾子, 亀井杏菜, 王合興,中野信浩, 奥村康, 村上晶, 北浦次郎, 海老原伸行
  • Organizer: 第125回日本眼科学会総会
• [Remarks] 順天堂大学 大学院医学研究科 アトピー疾患研究センター
  • URL: https://research-center.juntendo.ac.jp/atopy_center/research/g1/
• [Patent(Industrial Property Rights)] Anti-IgE antibodies to β5-helix region of Cε2 (2022)
  • Inventor(s): Tomoaki Ando 他4名
  • Industrial Property Rights Holder: Tomoaki Ando 他4名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2022
  • Overseas