JP2014526885A - B型肝炎ウイルス表面抗原のエピトープおよびその使用 - Google Patents
B型肝炎ウイルス表面抗原のエピトープおよびその使用 Download PDFInfo
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Abstract
Description
本発明は、B型肝炎ウイルス(以下、「HBV」と称す)に特異的なエピトープおよびその使用に関する。本明細書に開示されたエピトープが、変異による改変から保存的な位置(「変異誘発」による変異が起こらない)であるため、エピトープに対する抗体を含む組成物または上述のエピトープを含むワクチン組成物は、HBV変異による治癒効果の悪化を起こす可能性が非常に低く、それゆえ、HBV治療に非常に有用である。
HBVは、ヘパドナウイルス科ファミリーに属するDNAゲノムを有するウイルスであり、急性および/または慢性肝炎を引き起こす。一般に、HBVは少なくとも8%の互いに異なる遺伝子配列を有する8つの遺伝子型に分類されるか、他方では、HBV表面抗原(HBsAg)の2つの抗原決定基(すなわち、エピトープ)(d/y、w/r)に基づいて9つの抗原型(すなわち、adw、adr、ayw、ayr、など)に分類される。世界中の3億5000万人が慢性のHBVに感染し、特に、韓国および中国の人口の約5〜8%が慢性HBV感染を有している。HBV感染はこれらの地域の肝疾患と肝臓癌の主な原因である。現在、ワクチンの開発によって上記の感染がいくらか保護できるが、多くの患者が、まだHBVによって引き起こされた慢性のB型肝炎感染に罹患している。HBVによって引き起こされた慢性感染は、肝炎ならびに肝硬変および肝がんを誘発し得、非感染の人々と比べると、慢性感染症の人は約300倍の肝臓癌の増加を示す。WHO調査によると、慢性B型肝炎は肝臓癌の主な原因の約80%であるとされる。
技術課題
上記の問題を解決するために、本発明は、RFLWE(配列番号:4)またはKFLWE(配列番号:5)および、特にHBVの生存に必要な部位であり、それゆえ変異が起こらない保存的位置に相当する、FARFLWEWASVRFSW(配列番号:6)またはFGKFLWEWASARFSW(配列番号:7)などのアミノ酸配列を有するエピトープを含む、HBV特異的エピトープを提供する。
本発明の発明者らは;HBV表面抗原に特異的に結合するヒト抗体(PCT/KR2010/004445を参照、以下、「発明の抗体」と称する)のエピトープがRFLWE(配列番号:4)またはKFLWE(配列番号:5)を含む配列、および、特にFARFLWEWASVRFSE(配列番号:6)またはFGKFLWEWASARFSE(配列番号:7)またはその部分に相当し;そのようなエピトープ部位が有利に保存的であり、HBV複製に重要でHBV生存に必要であることを見出した。その結果、本発明は上記の発見により完成された。前述のエピトープのうち、配列番号:4および配列番号:6を有するエピトープはHBVのadrサブタイプ(配列番号:1)である一方で、配列番号:5および配列番号:7を有するエピトープは、HBVのaywサブタイプのエピトープに相当する。
詳細な説明から明らかなように、本発明により提供されるHBV特異的エピトープは実質的に、突然変異誘発を起こさない保存的位置である。したがって、前述のエピトープに対する抗体を含む組成物またはワクチン組成物は、HBV変異などによる治癒効果の悪化を起こす可能性が比較的低く、結果としてHBV治療および/または診断に友好的に使用される。
本発明の上記および他の目的、特徴、および利点は添付の図面に関連して提供される好ましい実施形態の以下の記載から明らかになるであろう。
以下に、本発明の好ましい実施形態が実施例を詳細に参照して説明されるが、そのような実施例は説明に役立つ目的だけのためであり、本発明の範囲を限定する意図ではない。
Claims (29)
- RFLWE(配列番号:4)またはKFLWE(配列番号:5)を含む、B型肝炎ウイルス(HBV)特異的エピトープ。
- FARFLWEWASVRFSW(配列番号:6)またはFGKFLWEWASARFSW(配列番号:7)で示される配列を含む、請求項1に記載のエピトープ。
- 請求項1または2に記載のHBV特異的エピトープと担体の組み合わせを含む複合体。
- 担体が、ペプチド、血清アルブミン、免疫グロブリン、ヘモシアニンおよび多糖類から選択される少なくとも1つである、請求項3に記載の複合体。
- 請求項1または2に記載のHBV特異的エピトープをコードするポリヌクレオチド。
- 請求項5に記載のポリヌクレオチドを含む組換えベクター。
- 微生物細胞またはウイルス、または哺乳動物細胞の表面でのHBV特異的エピトープの発現を導くプロモーターまたはシグナルタンパク質をコードする配列をさらに含む、請求項6に記載の組換えベクター。
- 請求項6または7に記載の組換えベクターで形質転換された組換え微生物またはウイルスまたは哺乳動物細胞。
- 形質転換された組換え微生物またはウイルスまたは哺乳動物細胞が、組換え大腸菌(E.coli)、組換え酵母、組換えバクテリオファージ、および組換え哺乳動物細胞から選択される、請求項8に記載の組換え微生物またはウイルスまたは哺乳動物細胞。
- 請求項6〜9のいずれか1項に記載の組換えベクター、組換え微生物またはウイルスまたは哺乳動物細胞を培養する段階を含む、配列番号4〜7のいずれか1つで決定されるHBV特異的エピトープを生産する方法。
- 請求項1〜5のいずれか1項に記載のエピトープ、エピトープを含む複合体、またはエピトープをコードするポリヌクレオチドを含むワクチン組成物。
- in vivoで注入されたときに抗体の形成を促進する、医薬上許容されるアジュバントをさらに含む、請求項11に記載のワクチン組成物。
- アジュバントが、アルミニウム塩(Al(OH)3、ALPO4)、スクワレン、ソルビタン、ポリソルベート80、CpG、リポソーム、コレステロール、モノホスホリル脂質A(MPL)、およびグルコピラノシル脂質A(GLA)から選択される少なくとも1つである、請求項12に記載のワクチン組成物。
- ポリヌクレオチドが医薬上許容される担体中に含まれる、請求項11に記載のワクチン組成物。
- 医薬上許容される担体がウイルスベクターまたは非ウイルスベクターである、請求項14に記載のワクチン組成物。
- 配列番号4〜7のいずれか1つで決定されるHBV特異的エピトープ、前記エピトープを含む複合体、または前記エピトープをコードするポリヌクレオチドを使用する、配列番号4〜7のいずれか1つで決定されるHBV特異的エピトープに特異的に結合する抗体または抗体断片を製造するための方法。
- 抗体が、ポリクローナル抗体またはモノクローナル抗体である、請求項16に記載の方法。
- 配列番号4〜7のいずれか1つで決定されるHBV特異的エピトープ、前記エピトープを含む複合体、または前記エピトープをコードするポリヌクレオチドを使用する抗体の製造方法が、HBV特異的エピトープ、複合体またはポリヌクレオチドを動物に接種し、接種された動物から配列番号4〜7のいずれか1つで決定されるHBV特異的エピトープに特異的に結合する抗体をスクリーニングおよび生成することを含む、請求項16に記載の方法。
- ヒト化または脱免疫化工程をさらに含む、請求項18に記載の方法。
- ヒト化工程が、動物から生産された抗体のCDR配列を、ヒト抗体のフレームワークに接合することを含む、請求項19に記載の方法。
- 親和性を増加させ、免疫原性を減少させるために、少なくとも1つのアミノ酸配列を置換、挿入および欠失させる工程をさらに含む、請求項20に記載の方法。
- 動物が、ヒト由来配列と同じ抗体を生産できるトランスジェニック動物である、請求項18に記載の方法。
- トランスジェニック動物が、トランスジェニックマウスである、請求項22に記載の方法。
- ディスプレイ技術が用いられる、請求項16に記載の方法。
- ディスプレイ技術がファージディスプレイ、バクテリアディスプレイまたはリボゾームディスプレイのいずれかから選択される、請求項24に記載の方法。
- ディスプレイ技術に用いられるライブラリーが、ヒト由来抗体の配列を有するように設計される、請求項24または25に記載の方法。
- 配列番号4〜7のいずれか1つで決定されるHBV特異的エピトープまたは前述のエピトープを含む複合体を使用して、配列番号4〜7のいずれか1つで決定されるHBV特異的エピトープに特異的に結合する抗体をスクリーニングする(すなわち、パニングを実施する)ことをさらに含む、請求項24〜26のいずれか1項に記載の方法。
- 請求項1〜5のいずれか1項に記載のエピトープ、エピトープを含む複合体またはエピトープをコードするポリヌクレオチドを含む、HBV特異的エピトープ検出のための組成物。
- 請求項1〜5のいずれか1項に記載のエピトープ、エピトープを含む複合体またはエピトープをコードするポリヌクレオチドを検出可能な、HBV検出キット。
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US10507240B2 (en) | 2014-11-28 | 2019-12-17 | Celltrion, Inc. | Epitope of hepatitis B virus surface antigen and binding molecule specifically binding to same for neutralizing hepatitis B virus |
WO2016093823A1 (en) * | 2014-12-10 | 2016-06-16 | National Health Research Institutes | Antibodies and method for determining deletions in hbv pre-s2 region |
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RU2585525C2 (ru) | 2016-05-27 |
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