JP2008501304A - 抗癌抗体およびその使用 - Google Patents
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Abstract
Description
プロテオミックリサーチは、新規の腫瘍標的の発見を大いに促進することが、広く期待されている。主な進歩は、診断目的についての標的の同定においてなされた。しかし、現在の技術の限界が、新規の治療標的の同定を妨害している。プロテオミクスにおいて一般的に使用される技術、例えば、二次元ゲル電気泳動、液体クロマトグラフィータンデム質量分析(LC/MS/MS)、マトリクス支援レーザー脱離イオン化/質量分析(MALDI−MS)、および酵母2−ハイブリッド系は、細胞表面マーカーのような“薬物化可能な(drugable)”標的についての要求を満たしていない。
本明細書において、癌(そして特に、肺癌)への結合について特異的親和性を有する、新規のシングルドメイン抗体AFAIおよびそのフラグメントが提供される。この抗体、およびその部分は、特に、癌の診断および治療において使用され得る。
プロテオミクスリサーチは、多くの新規の腫瘍標的を提供した。しかし、いくつかの制限に起因して、薬物適用に最もアクセス可能である標的を同定することは困難であった。腫瘍細胞に対してシングルドメイン抗体(sdAb)ライブラリをスクリーニングし、そして引き続いて単離された抗体の対応の抗原を同定することに基づく、新規の腫瘍抗原ディスカバリープラットフォーム(discovery platform)が、本明細書に記載される。非小細胞肺癌(non-small cell lung carcinoma)(A549細胞系)について特異的な、特異的sdAb、AFAIを、実施例1に記載のように、ラマの重鎖抗体レパートリーから誘導されたファージライブラリから単離した。非毒性ベロ毒素Bサブユニットのホモ五量体化特性(homopentamerization property)を、ES1ペンタボディー、AFAIの五量体形態を作製するために使用した。五量体化は、A549細胞へのAFAIの結合を劇的に向上した。免疫組織染色は、ES1が肺癌について非常に特異的であることを示した。
実施例1:
細胞培養物
非小細胞肺癌細胞系A549を、ATCC(Manassas, VA)から購入し、そして5%FBS(Gibco)および1%Antibiotic-Antimycotic(Gibco)が補充されたDMEM(Gibco, Rockville, MA)中において維持した。一次ヒト皮膚線維芽細胞は、親切なことに、Dr. J. Xu(Apotex Research Inc. Ottawa, ON)によって提供された。ポリクローナルウサギ抗−ベロ毒素抗血清は、親切なことに、Dr. Clifford Lingwood(Univ. of Toronto)によって提供された。
ナイーブラマシングルドメイン抗体ライブラリ(naive llama single domain antibody library)(Tanhaら、2002)は、腫瘍細胞(今回の場合、非小細胞肺癌細胞系A549)に特異的な抗体フラグメントの供給源として役立った。セルパンニング(cell panning)と呼ばれる、A549細胞へ結合するファージ抗体の単離を、パンニングの各ラウンドで、ヒト線維芽細胞における該ライブラリのプレ吸着を伴って、A549細胞を用いて行った。
細胞染色パートA:ファージ提示されたAFAIでの細胞染色
A549細胞を、第1抗体としてのAFAIファージで、続いて抗−M13モノクローナル抗体そしてFluor546標識化ヤギ抗−マウスIgGで免疫染色した場合、非常に強い蛍光シグナルが、細胞サブポピュレーション(cell sub-population)と関連することが観察された(図2)。陽性A549細胞の染色パターンは、AFAIが十分な膜抗原(abundant membrane antigen)へ結合することを示唆した。
細胞染色パートB:単量体および五量体AFAI sdAbの調製ならびに該sdAbでの細胞染色
AFAIの更なる評価およびキャラクタライゼーションのために、単量体および五量体AFAIを発現させそして精製した。AFAIをコードする遺伝子を、PCRによって増幅し、そして大腸菌発現ベクターへ挿入し、クローンpAFAIを作製した(図1B)。ペンタボディーの高アビディティ効果を活用するために、ES1と呼ばれる、AFAIの五量体形態を構築した(図1Bおよび図1Cを参照のこと)。発酵最適化無しでの、大腸菌TG1の1リットルフラスコ培養物からの精製されたAFAIおよびES1の収量(図1D)は、それぞれ、6mgおよび20mgであった。
腫瘍組織に対するES1の特異性の測定
ES1の組織特異性を測定するために、一次抗体としてES1を使用して、組織マイクロアレイ上において、広範囲の組織の免疫組織化学染色を行った。結果は、ES1は、中程度から強い免疫反応性を示すことによって、大抵の肺腺癌を認識することを示した。いずれの結腸腺癌もES1について強い免疫反応性を示さず、しかし、限局性の弱い(focal weak)〜中程度の免疫反応性が、数個のケースにおいて観察された。非癌性肺および結腸組織は、免疫反応性ではなかった(図4、表1)。
ES1の組織特異性を測定するために、広範囲の組織の免疫組織化学染色を、一次抗体としてES1を使用して行った。
ES1についての免疫反応性を、2人の病理学者によって評価し、そして、連続的な膜および/または細胞質染色パターンが存在した場合、中程度にまたは強く陽性の染色と、そして不連続な膜または弱い細胞質染色が存在した場合、弱く陽性と採点した。中程度または強い染色パターンを、更に、細胞の10%までを1、そして10%超を2、50%超の染色を示す場合において3と採点した。矛盾したスコアを含む場合をレビューした。
AFAI抗原は、肺腺癌において、分化の程度がより低い(less differentiated)腫瘍においてさえ、アップレギュレーションされるようである。ES1は、肺の乏しく分化した肺腺癌について、TTF1よりも感度の高いマーカーでありそうである。試験された大抵の正常な組織はES1−免疫反応性ではなかったので、ES1は、肺腺癌および多数の結腸癌および乳癌についてのスクリーニングテストの開発における使用に好適である。
Claims (30)
- 配列番号1に対して少なくとも90%の配列同一性を有するポリペプチド配列。
- 配列番号1の配列に対して少なくとも95%の配列同一性を有する、請求項1に記載のポリペプチド配列。
- 配列番号1の配列に対して少なくとも98%の配列同一性を有する、請求項1に記載のポリペプチド配列。
- 配列番号1の配列に対して少なくとも99%の配列同一性を有する、請求項1に記載のポリペプチド配列。
- 以下の3つの連続アミノ酸配列:KNLMG、TISGSGGTNYASSVEGおよびAFAIの少なくとも1つを含む少なくとも90アミノ酸を含むポリペプチド配列。
- 前記3つの連続アミノ酸配列の少なくとも2を含む、請求項5に記載のポリペプチド。
- 前記3つの連続アミノ酸配列の各々を少なくとも1つ含む、請求項5に記載のポリペプチド。
- 前記3つの連続アミノ酸配列の各々を少なくとも1つ含み、そして更に該連続アミノ酸配列の1つの少なくとももう1つのコピーを含む、請求項5に記載のポリペプチド。
- 残りのアミノ酸配列が、配列番号1の配列の等長部分(equally long portion)と少なくとも40%の全体的配列同一性(overall sequence identity)を提供するように選択および配置されている、請求項5〜8のいずれか1項に記載のポリペプチド。
- 残りのアミノ酸配列が、配列番号1の配列の等長部分と少なくとも60%の全体的配列同一性を提供するように選択および配置されている、請求項5〜8のいずれか1項に記載のポリペプチド。
- 残りのアミノ酸配列が、配列番号1の配列の等長部分と少なくとも80%の全体的配列同一性を提供するように選択および配置されている、請求項5〜8のいずれか1項に記載のポリペプチド。
- 残りのアミノ酸配列が、配列番号1の配列の等長部分と少なくとも90%の全体的配列同一性を提供するように選択および配置されている、請求項5〜8のいずれか1項に記載のポリペプチド。
- 前記請求項のいずれかに記載のポリペプチド配列を含む抗体。
- 癌細胞へカーゴ物質(cargo substance)を標的化することにおける、前記請求項のいずれかに記載の抗体の使用。
- 請求項13に記載の抗体とカーゴ物質とを含む、複合体。
- 哺乳類組織における癌を診断することにおける、請求項15に記載の複合体の使用。
- 哺乳類被験体における癌細胞の生存能(viability)または増殖能(proliferative ability)を減少させることにおける、請求項15に記載の複合体の使用。
- (a)請求項15に記載の複合体;および
(b)請求項16または17の使用を行うための使用説明書
を含む、キット。 - 請求項1に記載のアミノ酸配列を含むオリゴマー。
- サブユニットが、ペプチドリンカー;自己集合分子オリゴマー化ドメイン(self assembly molecule oligomerization domain)、および化学的カップリングの少なくとも1つを使用して連結されている、請求項19に記載のオリゴマー。
- 少なくとも2つの異なるサブユニットを含む、請求項19または20に記載のオリゴマー。
- 少なくとも2つの同一のサブユニットを含む、請求項19または20に記載のオリゴマー。
- 少なくとも1つのサブユニットが、AFAIとは異なる特異性を有する抗体である、請求項21に記載のオリゴマー。
- 少なくとも1つのサブユニットが酵素作用を有する、請求項21に記載のオリゴマー。
- 少なくとも1つのサブユニットがカーゴ物質を含む、請求項21に記載のオリゴマー。
- 癌特異的抗原を同定することにおける、請求項1または請求項6に記載のポリペプチド配列の使用。
- 配列番号5のポリペプチドをコードするヌクレオチド配列。
- 請求項27のヌクレオチド配列を含む、遺伝子治療ベクター。
- 請求項1に記載のポリペプチド配列と遺伝子治療ベクターとを含む、複合体。
- 配列番号1の配列を含む、請求項1に記載のポリペプチド配列。
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RU2011126896A (ru) | 2009-01-23 | 2013-02-27 | Дзе Хенри М. Джексон Фаундейшн Фо Дзе Эдвенсмент Оф Милитэри Медисин, Инк. | Композиция и полипептид для стимулирования иммунологической реакции на шига токсин 2 типа |
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US7872105B2 (en) | 2011-01-18 |
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EP1694845B1 (en) | 2017-07-05 |
EP1694845A4 (en) | 2008-07-02 |
CA2547034A1 (en) | 2005-06-09 |
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