JP2011517447A - 抗vegf抗体 - Google Patents
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- JP2011517447A JP2011517447A JP2011501758A JP2011501758A JP2011517447A JP 2011517447 A JP2011517447 A JP 2011517447A JP 2011501758 A JP2011501758 A JP 2011501758A JP 2011501758 A JP2011501758 A JP 2011501758A JP 2011517447 A JP2011517447 A JP 2011517447A
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Abstract
Description
新規の抗体は常に需要がある。
また方法も提供する。ある実施態様では、方法は、抗体が標的に結合して複合体を生成するために適切な条件下で対象の抗体を該抗体の標的と接触させることを含んでよい。
また、リガンドのそのレセプターへの結合を遮断する方法も提供する。ある実施態様では、この方法は、対象の抗体を被検体に投与することを含んでよく、このとき該抗体は該被検体においてそのレセプター又はそのリガンドに結合し、該リガンドとそのレセプターとの結合を遮断する。
選択された標的はVEGFであってよい。
本発明についてさらに記載する前に、本発明が、記載された特定の態様には限定されず、これらは当然ながら変わりうることが理解されるべきである。また、本明細書で用いる専門用語は特定の態様のみを説明することが目的であり、本発明の範囲は添付された特許請求の範囲のみによって限定されるので、限定することを意図するものではないことが理解されるべきである。
抗体を提供する。場合によって、抗体は、a)図1に示される選択された抗体の重鎖CDR領域と実質的に同一であるCDR領域を含む重鎖可変ドメインと、b)選択された抗体の軽鎖CDR領域と実質的に同一であるCDR領域を含む軽鎖可変ドメインとを含んでなり、このとき該抗体は選択された標的を結合する。具体的な実施態様では、抗体のCDR領域は、選択された抗体のCDR領域と比較して、あわせて例えば1、2、3、4、5又は最大10のアミノ酸の相違(例えばアミノ酸置換、欠失又は挿入)を含んでいてよい。ある実施態様では、抗体のCDR領域は、選択された抗体のCDR領域と同一でもよい。容易にわかるように、前記の抗体はCDRを位置づけるフレームワーク配列を更に含む。
上記の抗体は、少なくとも一のアミノ酸を置換、付加又は欠失させることによって変更されてよい。一実施態様では、上記の対象の抗体のアミノ酸配列が変更されて、ヒトの治療に使用するためのヒト化抗体又は他のタイプの変更抗体を提供する。通常は、これらの変更抗体は上記のウサギ抗体の一般的な特徴を有し、上記のウサギ抗体の少なくともCDRを含むか、又は、ある実施態様では、上記ウサギ抗体のCDRに非常に類似しているCDRを含む。
ゆえに、一実施態様では、本発明は、上記の抗体のヒト化バージョンを提供する。通常は、ヒト化抗体は、親の非ヒト抗体のフレームワーク領域のアミノ酸を置換することによって作製し、親の非ヒト抗体よりもヒトにおいて免疫原性が低い抗体を提供する。抗体は、例えば、CDR移植(欧州特許239400;PCT公報WO91/09967;米国特許第5225539号;同第5530101号;及び同第5585089号)、ベニヤリング又はリサーフェシング(欧州特許592106;欧州特許519596;Padlan, Molecular Immunology 28(4/5): 489-498 (1991);Studnicka et al., Protein Engineering 7(6): 805-814 (1994);Roguska. et al., PNAS 91 : 969-973 (1994))、及び、鎖シャッフリング(米国特許第5565332号)を含む当分野で公知の様々な技術を用いてヒト化されうる。ある実施態様では、CDRとフレームワークの残基の相互作用をモデリングし、抗原結合及び配列比較に重要なフレームワーク残基を識別し、特定の位置の異常なフレームワーク残基を同定することによって、フレームワーク置換が同定される(例として米国特許第5585089号;Riechmann et al., Nature 332:323 (1988))。本発明に用いられるために考慮される抗体をヒト化する更なる方法は、米国特許第5750078号;同第5502167号;同第5705154号;同第5770403号;同第5698417号;同第5693493号;同第5558864号;同第4935496同第;及び同第4816567号、及びPCT公報WO98/45331及びWO98/45332に記述される。具体的な実施態様では、対象のウサギ抗体は、公開された米国特許公開20040086979及び同20050033031に記載される方法に従ってヒト化されてよい。したがって、上記の抗体は、当分野で周知である方法を用いてヒト化されてよい。
上記の抗体は様々な方法で使用されてよい。そのような方法の一つには、抗体がその標的に結合して複合体を生成するために適する条件下で対象の抗体を抗体の標的と接触させることを含む。このような方法は、例えばELISAないしはウェスタンブロッティングによって又は当分野で公知の多くの免疫学的検出方法のいずれか一によって実施されうる。他の実施態様では、レセプターに対するリガンドの結合の遮断方法が提供される。これらの実施態様では、前記方法は、対象の抗体を被検体に投与することを含み、この抗体は前記被検体においてそのレセプター又はそのリガンドに結合し、その結合を遮断する。
ある実施態様では、対象の抗体はVEGFの存在下で細胞と接触されてよく、細胞のVEGF応答表現型がモニターされてよい。
多くの実施態様においては、対象のモノクローナル抗体をコードする核酸を宿主細胞に直接導入し、コードされる抗体の発現を誘導するために十分な条件下で細胞をインキュベートする。本方法の抗体は、当業者に周知の標準的な技術を本明細書中で提供するポリペプチド及び核酸配列と組み合わせて用いて調製される。ポリペプチド配列を用いて、開示される特定の抗体をコードする適切な核酸配列を決定してよい。当業者に周知の標準的な方法に従って様々な発現システムのための特定のコドン「選好」を表すために核酸配列を最適化してよい。
本発明の抗体は、医学的に許容範囲内である任意の方法で投与されてよい。これには、静脈内、血管内、動脈内、皮下、筋肉内、腫瘍内、腹膜内、脳室内、硬膜内又は他の経路といった非経口経路による注射、並びに、経口、経鼻、眼、直腸、又は、局所的なものが含まれる。また、貯蔵物質注射又は浸食性移植物質のような手段による徐放性投与も本発明に特に包含される。局在化した腫瘍に栄養を与えている血管や腎動脈といった、一又は複数の動脈へのカテーテルによる運搬のような手段による局所運搬も特に考慮される。
対象の抗体はその標的に関する疾患を治療するために有用である。
一実施態様では、本発明は、VEGF関連の状態のための被検体の治療方法を提供する。方法は、一般に、VEGF関連の疾患の少なくとも一の症状を治療するために有効な量で、VEGF関連の疾患を有する被検体に、対象の抗体を投与することを伴う。VEGF関連の状態は一般に、過剰な血管内皮細胞増殖、血管透過、浮腫又は炎症、例えば損傷、脳卒中又は腫瘍と関係する脳浮腫;関節リウマチを含む関節炎や乾癬のような炎症性疾患と関係する浮腫;喘息;熱傷と関係する全身性浮腫;腫瘍、炎症又は外傷と関係する腹水及び胸水;慢性気道炎症;毛細血管のリーク症候群;敗血症;タンパク質漏出の増加と関係する腎臓疾患;及び、加齢性黄斑変性及び糖尿病性網膜症などの眼疾患によって特徴付けられる。このような状態には、胸部、肺、結腸直腸及び腎臓の癌が含まれる。
また、対象の発明によって、上記のような対象の方法を実施するためのキットが提供される。対象のキットは、対象の抗体、それをコードする核酸、又はそれを含む細胞のうち一又は複数を少なくとも具備する。対象の抗体はヒト化されていてもよい。キットのその他の任意の構成要素には、抗体を投与するため又は活性アッセイを実施するためのバッファなどが含まれる。また、キットの核酸は、非ウサギ抗体核酸との連結を容易にするための制限酵素部位、マルチクローニング部位、プライマー部位などを含んでもよい。キットの種々の構成要素は別々の容器内に存在してもよく、又は適合性のある特定の構成要素を必要に応じて単一の容器内にあらかじめ合わせておいてもよい。
抗体の重鎖及び軽鎖をコードするcDNAをクローニングして、配列決定した。
Claims (9)
- a)図1に示される選択された抗体の重鎖CDR領域と実質的に同一であるCDR領域を含む重鎖可変ドメインと、
b)選択された抗体の軽鎖CDR領域と実質的に同一であるCDR領域を含む軽鎖可変ドメイン
とを含んでなり、このとき選択される標的を結合する抗体。 - 前記抗体が一価抗体である、請求項1に記載の抗体。
- 前記抗体が二価抗体である、請求項1に記載の抗体。
- 前記抗体が単鎖抗体である、請求項1に記載の抗体。
- 前記抗体がヒト化されている、請求項1に記載の抗体。
- 前記抗体がモノクローナル抗体である、請求項1に記載の抗体。
- 請求項1に記載の抗体がその標的に結合して複合体を生成するために適切な条件下で、請求項1に記載の抗体を該抗体の標的と接触させることを含む方法。
- 請求項1に記載の抗体を被検体に投与することを含むリガンドのそのレセプターへの結合を遮断する方法であって、該抗体が該被検体においてレセプターか又はリガンドに結合し、該レセプターの該リガンドへの結合を遮断するものである方法。
- 請求項1に記載の抗体と薬学的に許容可能な担体を含有してなる薬学的組成物。
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US8986692B2 (en) | 2009-08-28 | 2015-03-24 | Jiangsu Simcere Pharmaceutical R & D Co., Ltd. | Anti-VEGF monoclonal antibody and pharmaceutical composition comprising said antibody |
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EP2259795A1 (en) | 2010-12-15 |
AU2008353479B2 (en) | 2014-02-20 |
US20090246190A1 (en) | 2009-10-01 |
JP2014205674A (ja) | 2014-10-30 |
EP2259795B1 (en) | 2016-04-06 |
BRPI0822556A2 (pt) | 2020-08-18 |
WO2009120178A1 (en) | 2009-10-01 |
JP5823858B2 (ja) | 2015-11-25 |
CA2719400C (en) | 2017-11-14 |
CA2981887A1 (en) | 2009-10-01 |
CA3053675A1 (en) | 2009-10-01 |
CN103992405A (zh) | 2014-08-20 |
KR101581244B1 (ko) | 2015-12-31 |
US8088375B2 (en) | 2012-01-03 |
BRPI0822556B1 (pt) | 2022-03-03 |
CA2719400A1 (en) | 2009-10-01 |
CN102065888A (zh) | 2011-05-18 |
CN103992405B (zh) | 2016-08-17 |
CA2981887C (en) | 2019-09-03 |
US7803371B2 (en) | 2010-09-28 |
US20110008367A1 (en) | 2011-01-13 |
EP2259795A4 (en) | 2012-06-06 |
CN102065888B (zh) | 2014-03-26 |
KR20100132983A (ko) | 2010-12-20 |
HK1201280A1 (en) | 2015-08-28 |
AU2008353479A1 (en) | 2009-10-01 |
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