JP2006516098A - 新脈管形成を調節するα5β1インテグリンへのキメラ及びヒト化抗体 - Google Patents
新脈管形成を調節するα5β1インテグリンへのキメラ及びヒト化抗体 Download PDFInfo
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Abstract
Description
本発明は、α5β1インテグリンに対する治療的キメラ及びヒト化抗体;これらの抗体の精製方法、及び所望されない組織での新脈管形成を含む症状の治療におけるそれらの使用方法を提供する。
I.定義
特に断わりのない限り、本明細書において使用される全ての技術的及び科学的用語は、本発明に属する分野における当業者により一般に理解される意味を有す。以下の参考文献は、本発明において用いられる用語の多くの一般的な定義と共に当業者に提供される: Singleton等., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994);The Cambridge Dictionary of Science and Technology (Walker ed.,1988);The Glossary of Genetics, 5th Ed. , R. Rieger 等. (eds. ), Springer Verlag (1991) ;及びHale & Marham, The Harper Collins Dictionary of Biology (1991)。本明細書において用いられる以下の用語は、特に制限のない限り本来の意味を有す。
本発明は、既存の抗-α5β1インテグリン抗体の特性を改良させたキメラ及びヒト化抗-α5β1インテグリン抗体を提供する。本発明は、新規抗体を含む医薬組成物、並びに新血管形成により悪化した病態及び組織への傷害を治療するための改良方法も提供する。
上記提供された開示から理解できるように、本発明は多種多様な適用を有す。従って、以下の実施例は目的を説明するために提供され、そして任意の方法において、本発明に制限を構成することを意図したものではない。当業者等は、本質的に同様の結果を生じさせるために変化又は修飾させることができる多種の非基準的パラメーターのバラエティーを容易に認識するであろう。
A.IIA1並びに200-4 VH及びVL ドメインの出発DNA配列
動物はレーザー処置前に一晩断食させて投与した。動物は、レーザー処置及び投与手順のため、塩酸ケタミン(有効性のため、筋肉内投与)により、引き続き、静脈内へのケタミン及びジアゼパムの組合せ(有効性のため)により落ち着かせた。
免疫グロブリン(検査) 、又はコントロール品目の硝子体内への注入はそれぞれの眼で実施した。1日目の注入に引き続き迅速にレーザー処置を施す。投薬前に、散瞳剤(1%トロピカミド)をそれぞれの眼に滴下した。眼を希釈消毒液(5%Betadine(登録商標)溶液又は相当物)でゆすぎ、当該消毒液を0.9%殺菌食塩水(又は相当物)ですすぎ、そして2滴の局所麻酔薬(プロパラカイン又は相当物)を眼中へ滴下した。目蓋鏡を処置の間、目蓋を開けたまま挿入し、そして眼球を後退(retracted)させた。 投薬シリンジの注射針を、およそ4mm後方の縁への強膜及び平面部に通した。当該注射針を、中央のガラス体中へのレンズ後方へ導いた。検査品目をガラス体中へゆっくり注入した。ピンセットは、注射針の回収前にシリンジに巻き付く結膜をつかむために使用した。結膜がピンセットでつかまれる間に、短時間で注射針を回収した。瞼鏡をその後取り外した。投与後迅速に、任意の視認できる投与後の問題を同定するために、間接的な検眼鏡により眼を検査した。局所抗生物質(Tobrex(登録商標)又は相当物)は、感染予防のために、投与後迅速に、及び投与1日経過後に、それぞれの眼に投与することができる。当該動物は麻酔から十分に回復した時、ケージに戻された。
間接的な検眼鏡検査は、後眼房(posterior chamber)を検査するために使用され、そして生体鏡検査は、眼の前部セグメントを検査するために使用された。眼は標準の手順(Robert B. Hackett及びT. O. McDonald. 1996,Dermatotoxicology.第5版Ed. By F. B. Marzulli及びH. I. Maibach. Hemisphere Publishing Corp. , Washington, D. C)を用いて記録された。
フルオレセイン血管造影イメージの分析は、13日及び20日のCNVの存在を明確に示すそれらの群を使用することにより産出した。CNVは、コントロール群中(例えば、群1、4(左眼)及び5(左眼))で28日まで持続した。対照的に、当該CNVはM200及びF200で処置された眼(例えば群2,3,4 (右眼)及び5 (右眼))において著しく減少した。図19において見られるように、20日でのM200で処置した眼はコントロールのみで処置された眼と比較してCNVの徴候が殆ど見られなかった。
AABl/B2Fc及びIIA1、M200又はF200の間のアフィニティーは、BIAcore 3000及び2000(BIAcore、Sweden)を用いて分析された。IIA1、M200又はF200は標準的なアミンカップリングキット(BIAcore)を用いてPioneerF1チップ上に固定された。表面プラスモン共鳴は24℃で50ul/分の流動比率で測定した。AABl/B2Fc(会合相)の注入は、180秒かけて行う。その後3時間解離をモニターした。結合動力学はBIA評価プログラムを用いて、5つの異なる検体(320nM、160nM、80nM、40nM、20nM)の濃度で獲得されたデータから計算した。2重の参照は、コントロールのみ、参照の表面及び緩衝剤からの応答を除去するために適用した。KDは検体の一連の濃度からのセンサーグラム(sensorgram)の会合及び解離相を同時に適合させることにより得られた。M200 KDが0.367±0.132 nMになるように決定した。F200 KDが0.332±0.065nMとなるように決定した。
ELISA結合競合アッセイは、IIA1及びM200を比較したHuM200の結合アフィニティーを決定するために実施してよい。
Claims (50)
- pH感受性抗-α5β1インテグリン抗体の精製のための方法であって、以下:
(a)基質と結合した抗体アフィニティーマトリックス上へ当該抗体を吸着させ;そして
(b)約3.0 から約5.5のpHを有す溶出液を使用して当該基質−結合抗体アフィニティーマトリックスから当該抗体を溶出する、を含んで成る方法。 - 以下のステップ:
(c)前記精製した抗体を回収する、を更に含んで成る、請求項1に記載の方法。 - 前記溶出液が約3.3から約5.5のpHを有す、請求項1に記載の方法。
- 前記溶出液が約3.5から約5.5のpHを有す、請求項1に記載の方法。
- 前記溶出液が約3.5から約4.2のpHを有す、請求項1に記載の方法。
- 前記溶出液が約4.2から約5.5のpHを有す、請求項1に記載の方法。
- 前記抗体が、SEQ ID NOS:2-6、16及び20から成る群から選定される配列を有する可変重鎖領域、並びにSEQ ID NOS:8-12、18及び22から成る群から独立的に選定される可変軽鎖領域を含んで成る、請求項1に記載の方法。
- 前記抗体アフィニティーマトリックスは、ポリペプチド、ポリサッカライド、脂肪酸、脂質、核酸アプタマー、糖タンパク質、リポタンパク質、糖脂質、マルチタンパク質複合体、生物学的膜、ウィルス、プロテインA、プロテインG、レクチン、及びFc受容体から成る群から選定される、請求項1に記載の方法。
- 塩基性溶液により溶出された抗体を含む前記溶出溶液を中和するステップを更に含んで成り、それによって当該中和された溶液のpHが約6.0から約8.0の間になる、請求項2に記載の方法。
- キメラ又はヒト化抗-α5β1インテグリン抗体により調節される生理学的な影響を評価するための方法であって、当該方法は以下:
(a)脈管再生可能な生育組織サンプルを提供し;
(b)脈絡膜の新生血管形成を生み出すために十分な生育組織中で病変を作り出し;
(c)生育組織へキメラ又はヒト化抗-α5β1インテグリン抗体の1以上の投与量を適用し;そして
(d)当該投与された再血管形成のための生育組織をモニタリングすること
を含んで成る方法。 - ステップ(a)の前記生育組織が眼組織である、請求項10に記載の方法。
- 前記眼組織が生きている霊長類動物の目の一部分である、請求項11に記載の方法。
- 前記ステップ(c)の適用が、ヒト化された抗-α5β1インテグリン抗体をガラス体内へ注入することを含んで成る、請求項12に記載の方法。
- 前記生育組織が眼の黄斑である、請求項11に記載の方法。
- 前記作製ステップが、レーザー光により前記生育組織を接触させることを含んで成る、請求項10に記載の方法。
- 前記レーザー光が約300から約700mワットであり、暴露時間がわずか0.1秒である、請求項15に記載の方法。
- 前記ステップ(b)の病変が、直径約50から約100μmである、請求項10に記載の方法。
- 前記モニタリングステップが、ステップ(c)において投与された病変を定期的に撮影することを含んで成る、請求項10に記載の方法。
- 前記モニタリングステップが、更に眼球の後眼房の間接的な検眼鏡検査実験、及び前眼部の生体顕微鏡検査実験を含んで成る、請求項18に記載の方法。
- 前記モニタリングステップは、フルオレセイン染色を静注すること、及びフルオレセイン血管造影法により生育組織を調査することを含んで成る、請求項10に記載の方法。
- ステップ(c)の前記キメラ又はヒト化抗-α5β1インテグリン抗体が、抗体又はFabフラグメントである、請求項10に記載の方法。
- ステップ(c)の前記ヒト化抗-α5β1インテグリン抗体が、SEQ ID NOS:2-6、16及び20から成る群から選定される配列を有する可変重鎖領域、並びにSEQ ID NOS:8-12、18及び 22から成る群から独立的に選定される可変軽鎖領域を含んで成る、請求項10に記載の方法。
- キメラ又はヒト化抗-α5β1インテグリン抗体のポリペプチドをコードする核酸であって、SEQ ID NOS:2-6、8-12、16、18、20、22、25、26、28、31及び32から成る群から選定されるアミノ酸配列を含む前記ポリペプチドをコードする核酸。
- 前記ポリペプチドが一本鎖抗体又はFabである、請求項23に記載の核酸。
- 前記ポリペプチドがSEQ ID NOS:26及び28を含んで成る、請求項24に記載の核酸。
- 前記ポリペプチドがSEQ ID NOS:25及び26を含んで成る、請求項23に記載の核酸。
- 前記ポリペプチドがSEQ ID NOS:31及び32を含んで成る、請求項23に記載の核酸。
- SEQ ID NOS:2-6、8-12、16、18、20、22、25、26、28、31及び32から成る群から選定される1以上のアミノ酸配列を含んで成るポリペプチド。
- アミノ酸配列SEQ ID NOS:25及び26を含んで成る、請求項28に記載のポリペプチド。
- アミノ酸配列SEQ ID NOS:26及び28を含んで成る、請求項28に記載のポリペプチド。
- アミノ酸配列SEQ ID NOS:31及び32を含んで成る、請求項28に記載のポリペプチド。
- SEQ ID NOS.:15、17、19、21、23、24、27、29及び32から成る群から選定される1以上の核酸を含んで成るベクター。
- 前記核酸がSEQ ID NOS:19及び21を含んで成る、請求項32に記載のベクター。
- SEQ ID NOS:15、17、19、21、23、24、27、29及び32から成る群から選定される1以上の核酸を含んで成る発現ベクターにより形質転換された細胞。
- 前記ベクターが核酸SEQ ID NOS.:19及び21を含んで成る、請求項34に記載の細胞。
- 以下:
(a)SEQ ID NOS:1、7、16、18、20、22、25、26、28、31及び32から成る群から選定された1以上のアミノ酸配列を含む第一の出所からの第一のポリペプチド配列;及び
(b)第二の出所の抗体の不変領域配列を含む第二の出所からの第二のポリペプチド、を含んで成る、キメラ抗-α5β1インテグリン抗体であり、ここで第一及び第二のポリペプチド配列は、α5β1インテグリンと免疫反応性であるタンパク質複合体を形成する抗体。 - 前記第一のポリペプチド配列がSEQ ID NOS:25及び26を含んで成る、請求項36に記載のキメラ抗体。
- 前記第一のポリペプチド配列がSEQ ID NOS:26及び28を含んで成る、請求項36に記載のキメラ抗体。
- 前記第一のポリペプチド配列がSEQ ID NOS:31及び32を含んで成る、請求項36に記載のキメラ抗体。
- 前記抗体がSEQ ID NOS:1、7、16、18、20、22、25、26、28、31及び32から成る群から選定されたアミノ酸配列を含む、キメラ又はヒト化抗-α5β1インテグリン抗体を含んで成る医薬組成物。
- 前記抗体がアミノ酸配列SEQ ID NOS:25及び26を含んで成る、請求項40に記載の医薬組成物。
- 前記抗体がアミノ酸配列SEQ ID NOS:26及び28を含んで成る、請求項40に記載の医薬組成物。
- 前記抗体がアミノ酸配列SEQ ID NOS:31及び32を含んで成る、請求項40に記載の医薬組成物。
- 損傷した組織にキメラ又はヒト化抗-α5β1インテグリン抗体の1回以上の投与を適用させることを含んで成る、損傷した組織中の血管形成を調節する方法。
- 前記キメラ化又はヒト化抗-α5β1インテグリン抗体がSEQ ID NOS:20、22、25、26、28、31及び32から成る群から選定されるアミノ酸を含んで成る、請求項44に記載の方法。
- 以下:
(a)SEQ ID NOS:2-6、16、20から成る群から選定される可変重鎖領域、及びSEQ ID NOS.:8-12、18、22から成る群から独立的に選定された可変軽鎖領域を含んで成る治療抗体を含む医薬を提供し、
(b)損傷した組織に治療抗体を適応し、ここで当該損傷した組織が新生血管形成を通してその血流を増加させることにより損傷に応答し、そして当該治療抗体が前記新生血管形成を阻害する、
を含んで成る治療抗体を投与する方法。 - 前記医薬が注入可能なものである、請求項46に記載の方法。
- 前記適用ステップが全身的に医薬を注入することを含んで成る、請求項46に記載の方法。
- 前記損傷した組織が片眼又は両眼である、請求項46に記載の方法。
- 前記損傷した組織が、個体の両眼であり、そして当該適用ステップでは片眼に医薬を注入し、それによって当該医薬が両目に接触することにより損傷した組織における新生血管形成を阻害する、を含んで成る、請求項46に記載の方法。
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