JP2007515394A - ドメイン交換結合分子、その使用方法および製造方法 - Google Patents
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Abstract
Description
本発明は、米国国立衛生研究所から、助成金番号GM46192号およびAI33292号により助成を受けて行った。米国政府は本発明において一定の権利を保有する可能性がある。
本発明は、一般的に免疫学の分野、特に特有の結合特性を有するドメイン交換結合分子に関する。
糖質は、莢膜多糖類として、または脂質と結合した場合にはリポ多糖類のいずれかとして細菌細胞エンベロープの表面に存在する。これらの表面多糖類は、細菌ビルレンス因子として作用する様々な細菌科の中でも血清群および血清型分類の基礎となり得、感染時に宿主免疫の主要な標的となる。微生物病原体に対する保護免疫応答は、その細胞表面に存在する多糖類に対して産生された抗糖質抗体にしばしば基づいている。多くの細菌多糖類が免疫原性であることから、抗菌ワクチン接種に多糖類を利用する可能性は、ますます科学者の関心が高まりつつある領域である。
本発明は、表面上に整列した抗原、および典型的に糖質のような反復単位を有する抗原に関して親和性の増加および結合力の増大を有する特有のドメイン交換結合分子の構造を精液中に発見したことに基づく。本発明のドメイン交換結合分子は、特有の構造および結合特徴を有し、これまで得られていない親和性で異なるタイプの抗原に対して結合することができる。
本発明は、少なくとも一つの非通常結合部位を提供するために免疫グロブリン分子の重鎖可変領域と咬み合うドメイン交換結合分子を精液中で発見したことに基づいている。重鎖VHは、第一のVH領域が反対のVL、ならびに選択的にCH1およびCLと相互作用するように、第二のVH領域と交換(ドメイン交換(スワップ(swap))または交換(exchange))する。この配置は、二つの絡み合った平行に並んだ領域から形成され、二つの通常の抗原結合部位、および第三または第四の結合領域として作用しうるVH-VH界面から形成される少なくとも一つの非通常部位からなる多価結合部位を形成する。VH-VH界面が一つまたは二つの抗原結合部位を提供して、通常の結合部位は抗原に結合しないということが起こりうる。本発明のドメイン交換結合分子の一つの説明的な例には、完全なFab領域を含むVL-VH-VH-VLが含まれる。
Man9GlcNAc2オリゴ糖の調製は、ヒドラジン分解によって行った。大豆アグルチニンをSigma(L-1395、Glycine Maxからのレクチン)から購入した。糖タンパク質100 mgを0.1%トリフルオロ酢酸に溶解して、これに対して透析し、凍結乾燥して48時間低温乾燥した。試料をアルゴン下で無水ヒドラジン5 mlに溶解して、10℃/時間の速度で加熱し85℃で12時間維持した。過剰量のヒドラジンを真空下での蒸発によって除去した後、トルエン5 mlの付加および蒸発を5回繰り返した。放出されたグリカンを氷中で重炭酸ナトリウム飽和溶液9 mlによって溶解した後、無水酢酸1.1 mlを軽く攪拌しながら添加することによって再N-アセチル化を行い、無水酢酸1.1 mlをさらに10分後に加えて、混合物を室温で50分間インキュベートした。アセチル化試料を54番濾紙(Whatman)によって濾過して、濾液中のナトリウム塩をDowex AG50W-X12(H+)カラム(2 cm×15 cm、200〜400メッシュ、Bio-Rad)によって除去し、グリカンを水300 mlによって5回溶出した。溶出液を全て凍結乾燥して水15 ml、エタノール15 ml、およびn-ブタノール60 mlに連続的に溶解した。ペプチドを、ブタノール:エタノール:水(4:1:1、v/v/v)によって平衡化したセルロースカラム(1.5×25 cm)によって除去して、カラム容積の6倍量の溶液によって洗浄し、無水エタノールの1カラム容積によって洗浄した。グリカンを水によって3 mlの分画20個に溶出した。糖質陽性分画は、フェノール-硫酸法(74)によって同定した。Lis and Sharon(23)によって報告されたように、グリカン構造は、2-アミノベンズアミド(24、25)による蛍光標識およびMALDI-TOF質量分析によって、Man9であると確認された。
結晶構造の決定は下記のように実施した。ヒトモノクローナル抗体2G12(IgG1、κ)をチャイニーズハムスター卵巣細胞における組換え型発現によって産生した。Fab断片を免疫グロブリンのパパインによる消化によって産生した後、プロテインAおよびプロテインGカラム上での精製を行い、濃度〜30 mg/mlに濃縮した。1.05 M硫酸アンモニウム、18%PEG 6000、および0.1 Mリンゴ酸イミダゾール、pH 6.0のウェル溶液(1 ml)によるシッティングドロップ(sitting drop)拡散蒸着法によって、非リガンド結合Fab 2G12結晶を成長させた。Fab 2G12をManα1-2Manと5:1(糖質:Fab)のモル比で混合した。Fab 2G12+Manα1-2Man結晶を2 M 燐酸Na/K、pH 7.0から成長させた。Man9GlcNAc2も同様にFab 2G12と5:1(糖質:Fab)のモル比で混合して、25%PEG 400、0.2 Mリンゴ酸イミダゾールpH 7.0のウェル溶液から結晶を成長させた。全ての場合において、タンパク質1 μlを等量のリザーバー溶液と混合した。全ての結晶に関して、データをStanford Synchotron Radiation Laboratory(SSRL)ビームライン11-1で100 Kで回収した。非リガンドFab 2G12結晶は、20%エチレングリコールを含むリザーバー溶液に急に沈めることによって凍結保護し、Fab2G12+Manα1-2Manは、25%グリセロールによって同様に凍結保護した。Fab2G12+Man9GlcNAc2結晶は抗凍結剤を必要としなかった。非リガンド結合Fab 2G12データおよびManα1-2Man複合体は、斜方晶系空間群P212121において減少し、単位格子の大きさはそれぞれa=76.8Å、b=94.2Å、c=171.1Å、およびa=81.7Å、b=94.0Å、c=169.2Åであった。Fab2G12+Man9GlcNAc2データは、斜方晶系空間群I222において減少し、単位格子の大きさはそれぞれa=135.8Å、b=145.7Å、c=148.6Åであった。データは全て、指標をつけて(indexing)まとめて(integrating)、全ての知見に関して>-3.0σを用いてHKL2000(26)によって評価(scaling)した。
これらの結晶学知見により、本発明者らは、2G12 Fab二量体が溶液中に存在するのか、または単なる結晶のアーチファクトであるか否かを調べようとした。本発明者らは、沈降平衡分析的超遠心およびゲル濾過によってFabオリゴマー状態を調べた(図2A)(上記を参照されたい)。
これまでのデータは、2G12が、gp120(13、14)に共有結合したMan9GlcNAc2部分(図3A)を認識することが示されている。結合の特異性を調べるために、本発明者らは、Fab 2G12をMan9GlcNAc2と共結晶化した。共結晶は、非常に異方性であり、中等度の分解能(3Å)で回折するに過ぎないが、Man9GlcNAc2の電子密度は通常、タンパク質表面から遠くに離れていると(予想される)B値の増加にもかかわらず、糖質リガンドに関して著しく十分に定義されている(図3B)。Man9GlcNAc2の二つの分岐点(糖3および4';図3A)は明らかに見えて、それによって電子密度が曖昧に解釈される。本発明者らのこれまでの研究により、二糖Manα1-2Manも同様に2G12に結合できることが示された(13)。したがって、本発明者らは、2G12をこの二糖と共結晶させた。複合体のこの高分解能構造(1.75Å)において、Manα1-2Manの密度は極めて十分に定義され、そのコンフォメーションは、この特定の二糖の好ましい範囲内である(図4A)(51)。これらのMan9GlcNAc2およびManα1-2Manとの二つの独立した2G12結晶構造から得られた意外な結論は、2G12ドメイン交換二量体が糖質のために多数の異なる結合部位を含むことである:2個は通常の抗体結合部位に対応し、2個〜新規部位は、ドメイン交換において産生されたVH/VH'界面内に存在する(図3C)。
gp120に対する2G12の結合におけるドメイン交換および多価相互作用の役割を調べるために、Fab2G12の変異誘発を行った。2G12においてドメイン交換と共にリガンド結合において役割を果たすことが疑われる残基をアラニン残基によって置換して、gp120JR-FLとの結合に関してアッセイした(図6;表2)。生殖系列の残基または体細胞変異の関与がまれである状況において、最も近い生殖系列遺伝子によってコードされる残基への逆変異を導入した。一次結合部位を構成する残基の多くをアラニン置換すると、gp120JR-FLに対する2G12の結合は消失した。しかし、VH/VH'界面に存在する残基に及ぼすアラニン置換の効果はより顕著であった。これらの置換はほぼ全てがgp120JR-FLに対する結合を減少させた。重要なことに、ProH113のアラニンまたはセリン置換によってgp120JR-FLに対する2G12の結合は完全に消失した。ProH113と相互作用するValH84をアラニン置換しても同様に、結合の実質的な減少を認めた。さらに、二次結合部位においてMan9GlcNAc2のD2アームの結合に関与する残基の多くをアラニン置換すると、gp120結合は減少し、特有のVH/VH'界面がgp120に対する2G12の多価結合において役割を有する証明をさらに提供した。
本発明者らは、抗体2G12のVHドメインが、二つの通常の結合部位と新規ホモ二量体VH/VH'界面からなる広範な多価結合表面を形成するように、その二つの隣接するFab断片の間で交換することを説明するために、決定的な生化学的、生物物理学的および結晶学的証拠を示した。2G12 VH/VH'界面は、多くの保存された生殖系列コード残基から構成されるが、三つの一般的でない変異(IleH19、ArgH57、およびPheH77)がこの新規相互作用の安定化を促進するように思われる。H113位のプロリンはまた、このVH/VH'ドメイン交換を促進するように思われ、エルボー領域におけるヒンジペプチドの通常でない伸長したコンフォメーションは、ProH113とValH84の間の疎水性相互作用によって安定化されるように思われる。Kabat抗体配列データベースの分析では、おそらくそれらが独立した体細胞変異事象から発生するために、IleH19、ArgH57、PheH77、およびProH113を正確に組み合わせた他の重鎖配列は得られなかった(45)。しかし、変異の他の組み合わせは、ドメイン交換および都合のよいVH/VH'相互作用を促進できるということを確かに想像することができるであろう。
Claims (36)
- 可変領域および定常領域を有する重鎖、ならびに二つの通常抗原結合部位および隣接して配置される重鎖可変領域の間の界面によって形成された少なくとも一つの非通常結合部位を含む多価結合表面を含む、単離されたドメイン交換結合分子であって、2G12抗体ではない分子。
- 抗体である、請求項1記載のドメイン交換結合分子。
- 糖質に対して親和性を有する、請求項1記載のドメイン交換結合分子。
- HIVに結合する、請求項1記載のドメイン交換結合分子。
- CD20に結合する、請求項1記載のドメイン交換結合分子。
- 可変領域および定常領域を有する重鎖、ならびに二つの通常抗原結合部位および隣接して配置される重鎖可変領域の間の界面によって形成された少なくとも一つの非通常結合部位を含む多価結合表面を含む、天然に存在しないドメイン交換結合分子。
- 抗体である、請求項6記載の天然に存在しないドメイン交換結合分子。
- 糖質に対して親和性を有する、請求項6記載の天然に存在しないドメイン交換結合分子。
- HIVに結合する、請求項6記載の天然に存在しないドメイン交換結合分子。
- CD20に結合する、請求項6記載の天然に存在しないドメイン交換結合分子。
- ライブラリーの各メンバーが、可変領域および定常領域を有する重鎖、ならびに二つの通常抗原結合部位および隣接して配置される重鎖可変領域の間の界面によって形成された少なくとも一つの非通常結合部位を含む多価結合表面を含む、複数のドメイン交換結合分子を含むライブラリー。
- ドメイン交換結合分子が抗体である、請求項11記載のライブラリー。
- Fab領域である、請求項1または6記載のドメイン交換結合分子。
- 以下の段階を含む、被験者における感染症または疾患を検出する方法:
(a)感染症または疾患を有することが疑われる被験者からの試料を、試料中の分子をドメイン交換結合分子に結合させるために適当な条件で十分な時間、請求項1または6記載のドメイン交換結合分子に接触させる段階;および
(b)ドメイン交換結合分子が分子に結合すれば、被験者に感染症または疾患が存在することが示される、分子が結合したドメイン交換結合分子を検出する段階。 - 感染症または疾患がHIV誘導疾患である、請求項14記載の方法。
- 分子がHIV分子である、請求項15記載の方法。
- 感染症または疾患が腫瘍細胞である、請求項14記載の方法。
- 感染症または疾患が転移である、請求項14記載の方法。
- ドメイン交換結合分子が担体に結合している、請求項14記載の方法。
- 接触する段階が遮断剤の存在下で行われる、請求項14記載の方法。
- 接触する段階が、ドメイン交換結合分子に対して親和性を有する検出可能に標識された抗体の存在下で行われる、請求項14記載の方法。
- ドメイン交換結合分子がハプテンにカップリングされている、請求項14記載の方法。
- ドメイン交換結合分子が、酵素、放射性同位元素、蛍光化合物、コロイド金属、化学発光化合物、燐光化合物、生物発光化合物、またはその組み合わせのいずれか一つによって標識される、請求項14記載の方法。
- 請求項1または6記載のドメイン交換結合分子を含む薬学的組成物。
- ドメイン交換結合分子が糖質に対して親和性を有する、請求項24記載の薬学的組成物。
- ドメイン交換結合分子がHIVに結合する、請求項24記載の薬学的組成物。
- ドメイン交換結合分子がCD20に結合する、請求項24記載の薬学的組成物。
- 薬学的に許容される担体をさらに含む、請求項24記載の薬学的組成物。
- 請求項1または6記載の少なくとも一つのドメイン交換結合分子を含む、試料中の抗原の有無を決定するためのキット。
- ドメイン交換結合分子の他に、個別包装された試薬として抗体をさらに含む、請求項29記載のキット。
- 請求項1または6記載のドメイン交換結合分子の治療的有効量を被験者に投与して、それによって被験者に対して受動免疫を提供する、感染症または疾患を有するまたはそれらのリスクを有する被験者を治療する方法。
- 感染症または疾患がその表面上に反復単位を有する病原体または物質によって引き起こされる、請求項31記載の方法。
- ドメイン交換結合分子が抗体である、請求項31記載の方法。
- ドメイン交換結合分子が糖質に対して親和性を有する、請求項31記載の方法。
- ドメイン交換結合分子がHIVに結合する、請求項31記載の方法。
- ドメイン交換結合分子がCD20に結合する、請求項31記載の方法。
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US46850303P | 2003-05-06 | 2003-05-06 | |
PCT/US2004/013349 WO2004101738A2 (en) | 2003-05-06 | 2004-04-30 | Domain-exchanged binding molecules, methods of use and methods of production |
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JP2007515394A true JP2007515394A (ja) | 2007-06-14 |
JP2007515394A5 JP2007515394A5 (ja) | 2008-12-11 |
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US (1) | US20050003347A1 (ja) |
EP (1) | EP1627046A4 (ja) |
JP (1) | JP2007515394A (ja) |
AU (2) | AU2004239233B2 (ja) |
CA (1) | CA2525370A1 (ja) |
WO (1) | WO2004101738A2 (ja) |
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US7832400B2 (en) * | 2001-01-04 | 2010-11-16 | Salter Labs | Nasal and oral cannula having two capabilities and method of producing same |
US7565907B2 (en) * | 2005-06-17 | 2009-07-28 | Salter Labs | Nasal and oral cannula having two capabilities and method of producing same |
EP2084296B1 (en) * | 2006-09-29 | 2015-08-05 | Agendia N.V. | High-throughput diagnostic testing using arrays |
WO2009009103A2 (en) * | 2007-07-10 | 2009-01-15 | Medimmune, Llc | CRYSTALS AND STRUCTURE OF HUMAN IgG Fc VARIANT |
AU2009293640A1 (en) * | 2008-09-22 | 2010-03-25 | Calmune Corporation | Methods and vectors for display of 2G12 -derived domain exchanged antibodies |
US20100081575A1 (en) * | 2008-09-22 | 2010-04-01 | Robert Anthony Williamson | Methods for creating diversity in libraries and libraries, display vectors and methods, and displayed molecules |
GB0914691D0 (en) | 2009-08-21 | 2009-09-30 | Lonza Biologics Plc | Immunoglobulin variants |
WO2011035205A2 (en) | 2009-09-18 | 2011-03-24 | Calmune Corporation | Antibodies against candida, collections thereof and methods of use |
WO2011049836A1 (en) * | 2009-10-20 | 2011-04-28 | The Scripps Research Institute | Antibody heavy chain variable region (vh) domain exchange |
WO2012074863A2 (en) * | 2010-12-01 | 2012-06-07 | Albert Einstein College Of Medicine Of Yeshiva University | Constructs and methods to identify antibodies that target glycans |
WO2015197919A1 (en) | 2014-06-25 | 2015-12-30 | Glykos Finland Oy | Antibody drug conjugates binding to high-mannose n-glycan |
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US5831034A (en) * | 1987-11-13 | 1998-11-03 | Hermann Katinger | Human monoclonal anti-HIV-I-antibodies |
EP0570357B1 (en) * | 1992-05-14 | 1997-06-25 | Polymun Scientific Immunbiologische Forschung GmbH | Peptides that induce antibodies which neutralize genetically divergent HIV-1 isolates |
US5652138A (en) * | 1992-09-30 | 1997-07-29 | The Scripps Research Institute | Human neutralizing monoclonal antibodies to human immunodeficiency virus |
EP0822941B1 (en) * | 1995-04-19 | 2002-06-12 | Polymun Scientific Immunbiologische Forschung GmbH | Monoclonal antibodies against hiv-1 and vaccines made thereof |
US6756674B1 (en) * | 1999-10-22 | 2004-06-29 | Lsi Logic Corporation | Low dielectric constant silicon oxide-based dielectric layer for integrated circuit structures having improved compatibility with via filler materials, and method of making same |
US7329728B1 (en) * | 1999-10-25 | 2008-02-12 | The Scripps Research Institute | Ligand activated transcriptional regulator proteins |
WO2003033666A2 (en) * | 2001-10-16 | 2003-04-24 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Broadly cross-reactive neutralizing antibodies against human immunodeficiency virus selected by env-cd4-co-receptor complexes |
WO2005028499A2 (en) * | 2003-09-19 | 2005-03-31 | The Scripps Research Institute | Peptide that binds to a broadly neutralizing anti-hiv antibody-structure of 4e10 fab fragment complex, uses thereof, compositions therefrom |
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2004
- 2004-04-30 AU AU2004239233A patent/AU2004239233B2/en not_active Ceased
- 2004-04-30 US US10/838,153 patent/US20050003347A1/en not_active Abandoned
- 2004-04-30 JP JP2006532514A patent/JP2007515394A/ja active Pending
- 2004-04-30 WO PCT/US2004/013349 patent/WO2004101738A2/en active Application Filing
- 2004-04-30 EP EP04750977A patent/EP1627046A4/en not_active Ceased
- 2004-04-30 CA CA002525370A patent/CA2525370A1/en not_active Abandoned
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2009
- 2009-04-07 AU AU2009201353A patent/AU2009201353B2/en not_active Ceased
Non-Patent Citations (3)
Title |
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JPN6010007640, Mol. Immunol., vol. 41, pages 1001−1011 (2004) * |
JPN6010007641, Science, vol. 300, pages 2065−2071 (June 2003) * |
JPN6010007644, Proc. Natl. Acad. Sci. USA, vol. 102, pages 14943−14948 (2005) * |
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AU2004239233B2 (en) | 2009-01-08 |
EP1627046A4 (en) | 2008-02-13 |
WO2004101738A3 (en) | 2006-06-22 |
AU2009201353A1 (en) | 2009-04-30 |
WO2004101738A2 (en) | 2004-11-25 |
AU2004239233A1 (en) | 2004-11-25 |
AU2009201353B2 (en) | 2011-09-15 |
EP1627046A2 (en) | 2006-02-22 |
CA2525370A1 (en) | 2004-11-25 |
US20050003347A1 (en) | 2005-01-06 |
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