JP2009520467A - がん関連抗原 - Google Patents
がん関連抗原 Download PDFInfo
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- JP2009520467A JP2009520467A JP2008546058A JP2008546058A JP2009520467A JP 2009520467 A JP2009520467 A JP 2009520467A JP 2008546058 A JP2008546058 A JP 2008546058A JP 2008546058 A JP2008546058 A JP 2008546058A JP 2009520467 A JP2009520467 A JP 2009520467A
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Abstract
Description
本発明は、がんと関連する新規の抗原ならびにがんを処置するおよび検出するための方法および組成物に関する。
2000年には、推定2200万人が世界中でがんに罹患し、620万例の死亡はこの部類の疾患によるものであった。毎年、1000万例を越える新たな症例があり、この推定値は次の15年で50%増加すると予想されている(WHO, World Cancer Report. Bernard W. Stewart and Paul Kleihues, eds. IARC Press, Lyon, 2003)。現在のがん処置は侵襲的手術法、放射線療法および化学療法に限られており、その全てが重篤となる可能性のある副作用、非特異的な毒性、ならびに/または人の身体像および/もしくは生活の質に対して精神的外傷を与える変化のいずれかを引き起こす。がんは化学療法に不応性となり、さらなる処置の選択肢を狭め、成功の可能性を低くすることがある。一部のがんの予後は他のがんよりも不良であり、ほとんど常に致死的であるものもある。さらに、処置成功率の比較的高い一部のがんもその高い発生率が原因で依然として主要な死因のままである。
本発明者らは新規のがん関連タンパク質を同定した。したがって、本発明は、がんの処置および診断において使用できる新規のがん関連抗原を提供する。特に、この抗原は膠芽細胞腫、黒色腫、乳がん、肺がん、卵巣がん、リンパ腫、結腸がん、胃がんおよび/または前立腺がんと関連する。
(1) 結合タンパク質-抗原複合体を生成させるためがん細胞上の抗原に特異的に結合する結合タンパク質と被験体から採取された試験サンプルを接触させる段階;
(2) 試験サンプル中の結合タンパク質-抗原複合体の量を測定する段階; および
(3) 試験サンプル中の結合タンパク質-抗原複合体の量を対照と比較する段階。
(A) 定義
「細胞」という用語は単一の細胞および複数の細胞または細胞の集団を含む。細胞に作用物質(がん関連タンパク質など)を投与することは、インビトロおよびインビボ双方の投与を含む。
本発明は、がん細胞の表面に発現されかつ正常細胞の表面に有意には発現されない新規のがん関連抗原を提供する。新規のがん関連抗原は哺乳類スクラッチの変種である。それは、哺乳類スクラッチに存在しない膜貫通ドメインを有する。膜貫通ドメインの配列はSEQ ID NO:2に示されている。がん関連変種の配列はSEQ ID NO:1に示されている。
本発明は、がん細胞の表面に発現されかつ正常細胞の表面に有意には発現されない新規のがん関連抗原を提供する。すなわち、新規のがん関連抗原はインビボで免疫反応を誘発するための本発明の単離タンパク質の使用を含む、がんを処置するおよび予防するための治療法において使用することができる。さらに、本発明は、新規のがん関連抗原を検出する段階を含むがんの診断方法を含む。
本発明の一つの局面は、適当な希釈剤または担体との混合物の中に本発明の単離タンパク質の有効量を含む薬学的組成物である。本発明の別の局面は、適当な希釈剤または担体との混合物の中に本発明の単離核酸の有効量を含む薬学的組成物である。本発明のさらなる局面は、適当な希釈剤または担体との混合物の中に本発明の組換え発現ベクターの有効量を含む薬学的組成物である。
新規のがん関連抗原はがん細胞に発現され、かつ正常細胞に有意には発現されておらず、すなわち新規のがん関連抗原の検出はがんの診断方法として使用することができる。
(a) 被験体由来のサンプルを提供する段階;
(b) サンプル中のがん関連抗原のレベルを検出する段階; および
(c) サンプル中のがん関連抗原のレベルを対照サンプルと比較する段階
を含み、対照と比べてがん関連抗原のレベルの増大が、被験体ががんを有することを示唆する、
被験体においてがん細胞を検出する方法が提供される。
(a) 被験体由来のサンプルを提供する段階;
(b) サンプル中のがん関連抗原の発現レベルを判定する段階;
(c) 段階(a)および(b)をさらに後の時点で繰り返す段階ならびに段階(b)の結果を段階(c)の結果と比較する段階
を含み、
がん関連抗原の発現レベルの相違が被験体におけるがんの進行を示す、
被験体においてがんの進行をモニターする方法を企図する。
一つの態様において、本発明の方法は、がん関連抗原をコードする核酸分子の検出を含む。当業者は、サンプル中のがん関連抗原をコードする核酸配列の検出に用いられるヌクレオチドプローブを構築することができる。適当なプローブは、SEQ ID NO:6またはSEQ ID NO:25に示される核酸配列に基づいて調製することができる。適当なプローブは、がん関連抗原の領域からの少なくとも5個の連続アミノ酸をコードする核酸配列に基づく核酸分子を含み、好ましくはそれらは15〜30ヌクレオチドを含む。ヌクレオチドプローブは、32P、3H、14Cなどのような、適切なシグナルを供与するかつ十分な半減期を有する放射性標識のような検出可能な物質によって標識することができる。使用できる他の検出可能な物質は、特異的な標識抗体によって認識される抗原、蛍光化合物、酵素、標識抗原に特異的な抗体、および発光化合物を含む。適切な標識は、検出されるヌクレオチドに対するプローブのハイブリダイゼーションおよび結合の比率、ならびにハイブリダイゼーションに利用可能なヌクレオチドの量を考慮して選択することができる。標識プローブはSambrook et al, 1989, Molecular Cloning, A Laboratory Manual (2nd ed.)に一般的に記述されているように、ニトロセルロースフィルタまたはナイロン膜のような固相支持体上の核酸にハイブリダイズされることができる。核酸プローブは、好ましくはヒト細胞において、がん関連抗原をコードする遺伝子を検出するために使用することができる。ヌクレオチドプローブは同様に、がん関連抗原が関与する障害の診断において、このような障害の進行のモニタリングにおいて、または治療的処置のモニタリングにおいて有用でありうる。一つの態様において、プローブはがん、好ましくは婦人科がんの診断において、およびその進行のモニタリングにおいて使用される。
(a) 被験体由来のサンプルを提供する段階;
(b) がん関連抗原またはその一部分をコードする核酸分子をサンプルから抽出する段階;
(c) 抽出された核酸分子をポリメラーゼ連鎖反応を用いて増幅する段階;
(d) がん関連抗原をコードする核酸分子の存在を判定する段階; および
(e) サンプル中のがん関連抗原をコードする核酸分子のレベルを対照サンプルと比較する段階
を含み、対照と比べてがん関連抗原をコードする核酸分子のレベルの増大が、被験体ががんを有することを示唆する、
被験体においてがん細胞を検出する方法を提供する。
(a) 被験体由来のサンプルを提供する段階;
(b) 野生型スクラッチまたはスクラッチのがん関連変種をコードする核酸分子をサンプルから抽出する段階;
(c) 核酸分子をKpnI制限酵素で消化する段階; および
(d) 消化された核酸分子のサイズを判定する段階
を含み、未消化の核酸分子の存在が、被験体ががんを有することを示唆する、
がんを有するかまたは有する疑いがある被験体においてがん細胞を検出するかまたはがんをモニターする方法を提供する。
別の態様において、本発明の方法はがん関連抗原の検出を含む。一つの態様において、がん関連抗原は、がん関連抗原に特異的に結合する抗体を用いて検出される。がん関連抗原に対する抗体は、当技術分野において公知の技術を用いて調製することができる。
(a) 被験体由来のサンプルを提供する段階;
(b) がん関連抗原に結合する抗体とサンプルを接触させる段階;
(c) サンプル中のがん関連抗原のレベルを検出する段階; および
(d) サンプル中のがん関連抗原のレベルを対照サンプルと比較する段階
を含み、対照と比べてがん関連抗原のレベルの増大が、被験体ががんを有することを示唆する、
被験体においてがんを検出する方法を提供する。
上記のように、新規のがん関連抗原は、がん細胞に存在しているが、しかし正常細胞に有意には存在していない。したがって、新規のがん関連抗原は、がんを予防するおよび処置するために、治療方法において使用することができる。さらに、新規のがん関連抗原またはその断片を、インビボにおいて、例えばワクチンにおいて、またはインビトロにおいて免疫反応を誘発するために使用することができる。
(a) 哺乳類スクラッチのがん関連変種を発現する細胞を試験化合物と接触させる段階; および
(b) 哺乳類スクラッチのがん関連変種の発現または機能を判定する段階; および
(c) 哺乳類スクラッチのがん関連変種の発現または機能を対照と比較する段階
を含み、
対照と比べて哺乳類スクラッチのがん関連変種の発現または機能の低下が、がんを予防するかまたは処置するのに有用な化合物を示す。
本発明の別の局面は、本発明の単離タンパク質に結合する、結合タンパク質、好ましくは抗体または抗体断片である。このような結合タンパク質は「本発明の結合タンパク質」、または好ましくは「本発明の抗体または抗体断片」と本明細書において総称されうる。
(1) 結合タンパク質-抗原複合体を生成させるためがん細胞上の抗原に特異的に結合する結合タンパク質と被験体から採取された試験サンプルを接触させる段階;
(2) 試験サンプル中の結合タンパク質-抗原複合体の量を測定する段階; および
(3) 試験サンプル中の結合タンパク質-抗原複合体の量を対照と比較する段階
を含む、被験体においてがんを検出するかまたはモニターする方法を提供する。
(1) 被験体から採取された試験サンプル中の本発明の抗体の量を測定する段階; および
(2) 試験サンプル中の本発明の抗体の量を対照と比較する段階
を含む、被験体においてがんを検出するかまたはモニターする方法である。
新規のがん関連抗原、結合タンパク質、好ましくは抗体および抗体断片のような本発明のタンパク質は、いくつかの方法のいずれかにて調製できるが、組換え法を用いて調製されるのが最も好ましいことを当業者なら理解すると考えられる。
実施例1: がん関連スクラッチの単離および同定
実験計画
黒色腫細胞株(A-375)、神経膠腫細胞株(U118MGおよびU87MG)、乳がん細胞株(MDA-MB 435S)、膵臓細胞株(PANC-1)ならびにT細胞株(Daudi)を研究に使用した(表1)。これらの細胞株は、フローサイトメトリーによる腫瘍細胞株プロファイリングの結果に基づき選択した。
研究における細胞株は、ATCCから購入し、ATCCの指針および推奨にしたがって培養した。細胞は集密度90%で収集し、生存度>90%であった。
予備的な特徴付けデータは、ドットブロットアッセイ法によるゲルに基づいた手法の実行可能性を評価するために設計された実験から; および抗原と関連するエピトープの性質を判定するために行われた実験から得た。
ブロット可能性の研究の予備的データからレクチンに基づく精製法がVB3-011に対する最良の抗原提示法と特定された。大規模な実験から、グリカン修飾はCS (コンドロイチン硫酸)の可溶型を含み、これらのうちの二つ(CSBおよびCSE)は組織分布が限られていることが明らかにされた。したがって、グリカン修飾はCSAに起因し、それほどではないにせよヒアルロン酸に起因しうる。
グリカン-Neu5Ac (α2→6) Gal (β1→4) Glcに特異的に結合する組換えHA分子を旋回装置(nutator)上にて室温で2時間抗HA抗体に結合させた後に、HA-抗HA複合体のプロテインG-セファロースへの結合を行った。これに引き続き遠心分離工程を行って、未結合の画分を除去した。固定化複合体を次いで、すぐ近くに存在する公知の架橋タンパク質であるピメルイミド酸ジメチル(DMP)により架橋した。過剰のまたは未使用の架橋剤および未結合の材料を短時間の遠心分離工程によって除去した。架橋結合工程の副産物として生じた可能性がある非特異的なアミン群を室温にて2時間、トリエタノールアミンで中和した。このように作出されたレクチンに基づく試薬をPBSで十分に洗浄し、2〜8℃にて0.05% NaN3含有のPBSで貯蔵した。HA試薬のほか、さらに良好な抗原回復を検出するようCon-A-アガロースおよびWGA-アガロースもアフィニティー精製試薬として使用した。
1D-PAGE:
精製タンパク質を還元条件のサンプル調製に供し、その後SDS-PAGE/ウエスタンブロッティングによって分析した。還元条件を用いた場合には、単離抗原を15分間65℃にて1%β-メルカプトエタノール含有のサンプル緩衝液で処理した。得られたブロットをVB3-011およびHRPに抱合された対応の二次抗体でプロービングして、化学発光により精製タンパク質を可視化した。
精製タンパク質を二次元ゲル電気泳動により分離して、1D-PAGE分析で生じた可能性がある任意のタンパク質スタッキングの影響を解消した。2D-ゲル電気泳動では、第一の次元においてタンパク質をその等電点(pI)により、および第二の次元においてその分子量に基づき分離した。このように分離されたタンパク質を終夜ニトロセルロース膜に転写し、1D-PAGEの場合と同様に処理した。ウエスタンブロットをVB3-011でプロービングし、反応性のタンパク質を化学発光によって可視化した。
ゲル内および溶液内トリプシン消化からのペプチド抽出:
トリプシン消化を最終的にはペプチドの抽出に至る20時間のペプチド抽出過程において配列決定等級のトリプシンによって行い、そのペプチドを使用流量20〜50 nL/分のナノソースが装備された、QSTAR Pulsar-I (ESI-qTOF-MS/MS)にて分析した。ペプチドは、イオン化し、二価、三価または四価分子として検出され、これらがその各質量に精緻化される。同定されたタンパク質の新規配列決定も可能なら行った。ペプチドを陽性および陰性の両細胞株から抽出して、それが的確な抗原であることを確実にした。質量スペクトルから抽出されたペプチド質量を直接的に使用して、MASCOT検索エンジンをによりアクセス可能な、タンパク質データベースにて得られたMOWSEスコアにしたがい抗原を同定した。ペプチドをゲル片からもおよび溶液内からも抽出し(U118MG、U87MG、A-375、435S)、これらをMS分析に供した。
HA試薬の固定化
組換えHA分子は、抗体ではなく、それゆえ、固定化パートナーとして直接的にプロテインG-スファロースに結合しない。この分子が抗原精製過程において機能的であることを可能とするため、HAに特異的に結合しうる抗HA抗体に、HAを結合し、この分子を連続的にプロテインG-スファロースによって固定化した。これによって、図2に図示されるように、複合体が固定化されるだけでなく、抗HAの存在から生じうる任意の非特異的な相互作用が遮断されると考えられる。固定化されたHA-抗HA複合体をその後、ピメルイミド酸ジメチル、つまり各種の反応物質の近接性を維持する架橋剤を用いて安定化した。最終的な複合体は、HA分子上の反応性の結合部位以外に、過程においていくつかの反応性アミンをもたらした。これらの反応性基を1 Mトリエタノールアミンによって持続的に遮断し、このようにしてHA分子上の反応部位の最大限の曝露を確実にした。
全ての精製反応は、予備浄化されたタンパク質で行った。非特異性を最小限にするためにおよび同種抗原-抗体複合体の安定性を増強するために、いっそう長いインキュベーション時間を使用した。6種の細胞株(A-375、U118MG、U87MG、MDA-MB-435S、Panc-1およびDaudi)をこの研究において使用した。SDS-PAGEにて単離された抗原の分析の前に、サンプル調製用の還元条件を用いた。ウエスタンブロットをVB3-011でプロービングして、精製された抗原がVB3-011に対する同種の結合パートナーであることを確実にした。
HA試薬が使用された場合、抗原陽性の細胞株(A-375)おいて還元条件の下では、1D-PAGEでの分離後に約50 kDaの位置に一本の特異的なバンドしか検出されず(図3A)、これは陰性の細胞株(Panc-1)では存在していなかった。非特異的な相互作用がCon-AおよびWGAレクチンで観察されたことから、VB3-011抗原上に存在するグリカンがHAによって認識されるものであることが示唆された。神経膠腫細胞株(U118MGおよびU87MG)も、HA試薬を用いて精製された場合に、約50 kDaの位置に単一バンドの存在を示した(図3B)。サンプルをSDS-PAGEでのその分離の前に1時間室温で放置させた場合、約36 kDaの主要なバンドおよびかすかな50 kDaのバンドが抗原陽性の細胞株(A-375、U118MGおよびU87MG)において観察された(図4)。
等電点(pI)を判定するためにおよび1D-PAGE分析でのタンパク質スタッキングの可能性を評価するために、HAによって精製された抗原を、第一の次元での分離がpIに基づきかつ第二の次元での分離が分子量に基づく、二次元ポリアクリルアミドゲル電気泳動(2D-PAGE)にて分離した。次いで、このゲルをニトロセルロース膜に転写し、標準的なウエスタンブロッティング処理に供した。2Dゲルでのタンパク質の検出に必要な量は1Dゲルに対する必要条件よりも約4倍高いので、4回の別反応から精製された抗原を一回の2D-PAGE分析のために一緒にしてプールした。二枚の別個のゲルをウエスタンブロット分析のために同時に処理して、クマシー染色ゲルにて検出されるタンパク質がウエスタンブロットで観察されるものと同じであることを確実にした。2DウエスタンブロットをVB3-011でプロービングし、ECL (化学発光)により検出した。図5において分かるように、一つの単一のスポットが約36 kDa/pI = 9.7±0.2で検出された。
VB3-011に特異的に結合する抗原を精製するために、A-375、U 87MGおよびU118 MGの膜を使用した。図3Aおよび3Bにおいて示されるように、約50 kDaのバンドが全三種の細胞株において観察された。タンパク質のバンドをクマシー染色ゲルから切り出し、ゲル内消化に用いてMS分析用のペプチドを抽出した。
ペプチド分析を二通りの方法で行った。
・タンパク質のIDを得るため、回収されかつその正確な質量にまで再構築された全てのペプチドをペプチド質量フィンガープリンティング工程で直接使用した。
・「y」イオンおよび「b」イオンを用いてその一次構造を推測する、さらなるMS/MSイオン断片化のため、豊富にありかつよくイオン化されるペプチドを選択した。その後、タンパク質IDに関するタンパク質データベースで、これらの配列を相同性について検索した。
2D-ゲルから切り出されたタンパク質によりスクラッチが特定された。pIおよび分子量は哺乳類スクラッチと明らかに適合していた。各ペプチドが元のタンパク質に対し100%の相同性を示す、15の適合ペプチドで計37%の配列包括度(sequence coverage)が回収された(図6参照)。
全三種の細胞株(U87MG、U118MGおよびA375)の質量スペクトルから得られたデータより、哺乳類スクラッチがVB3-011に結合する抗原と示唆される。スクリーニングされた全ての細胞株のうち、神経膠腫細胞株(U87MGおよびU118MG)が最高スコアの同一性を示した。黒色腫細胞株A-375も該抗原の過剰発現を示した。上記の細胞株のほか、元のスクラッチ分子の配列番号158-366に対し100%の相同性を有するスクラッチの切断型、すなわち、17.823 kDaのタンパク質gi|15928387の存在を示したMDA-MB-435Sを除くが、MDA-MB-435S、PC-3、A-549およびCFPAC-1のような、上皮細胞株も同じようにスクリーニングした。図7 (SEQ ID NO:4)を参照されたい。HA試薬を用いてVB3-011抗原をアフィニティー精製するために、これらの細胞株の各々からの膜調製物を使用した。ほかの上皮細胞株は検出可能なタンパク質を示さなかった。
ナノソースに取り付けられた別個のナノスプレーヘッドを本目的に使用した。衝突エネルギーは48Vで、カーテンガスおよびCADガスをそれぞれ25および6で維持し、安定な質量イオン断片化を得るのにサンプルを1.667分間(100サイクル)循環させた。ペプチドのうち二つ(2402.978172 - 802.00000, 3+; 2134.985448 - 1068.500000, 2+)のMS/MS断片化によって、図14および15に示される断片イオンが生じた。ペプチド質量2402.97812由来のペプチドの一つ
はスクラッチ由来の配列に100%マッピングされた一方、ペプチド質量2134.985448由来のペプチド
は隣接配列において100%の相同性を示したが、中央の配列によっては示さなかったことから、新規配列の同定が示唆された。この配列の存在はタンパク質で利用可能な唯一の膜貫通ドメインに関与する。データベース内で利用可能な哺乳類スクラッチ配列は概念的翻訳の結果であり、配列の中に膜貫通ドメインがない。回収されたタンパク質配列は、データベース内で利用可能な哺乳類スクラッチタンパク質に対して67%の相同性を示し、膜貫通ドメインの存在により細胞表面に存在していることを示唆している。スペクトルから得られたほかのペプチドは、哺乳類スクラッチ由来の配列に明らかに適合し、それゆえ主要なヒットとしてプルダウンされた。イオン断片化データによって、VB3-011に対する同種抗原としてのスクラッチの新規形態の同一性がさらに確認されている。
IgG MAbのVB3-011はViventiaの専売プラットフォーム技術Hybridomics(商標)およびImmunoMine(商標) (国際公開公報第97/044461号参照)を用いて、中等度(grade II)の星細胞腫と診断された患者から単離された末梢血リンパ球(PBL)より作出された。この抗体は、各々が異なるがんの徴候を代表する多くの他の細胞株に対する反応性を示す。広範な腫瘍細胞型の反応性に関するこの実証にもかかわらず、VB3-011は正常組織に対してわずかな結合しか示さない。VB3-011抗原はCSAに起因した、グリカン修飾を有する「ブロット不可能な」抗原と分類された。
は隣接配列において100%の相同性を示したが、中央の配列によっては示さなかったことから、新規配列の同定が示唆された。この配列の存在はタンパク質で利用可能な唯一の膜貫通ドメインに関与しており、スクラッチを細胞質ゾルとは対照的に細胞表面に配する。これは、哺乳類スクラッチを細胞表面の腫瘍抗原と表現する最初の報告である。
HDホルマリン固定TMAを用い、哺乳類スクラッチに特異的な抗体を腫瘍特異性について試験した。正常組織の場合には表3および腫瘍特異的な膜結合の場合には表4を参照されたい。正常組織の膜上でのスクラッチ抗原の検出は認められなかった。しかしながら、強度に陽性の膜染色がさまざまな腫瘍組織にて見出された。
がんの指標としてのスクラッチタンパク質の異常な局在性:
野生型スクラッチタンパク質はNakakura et al, 2001によって記述されているように、細胞の核内に発現パターンが限られている。しかしながら、腫瘍組織型およびがん細胞型の場合の発現は、本発明者らによって細胞の細胞質内でおよび膜上で立証された。フローサイトメトリー(flow cytometery)、免疫組織化学、細胞の膜画分のウエスタンブロッティングのような当技術分野において公知の技術を用いて、スクラッチタンパク質およびその変種の異常な発現をがん細胞の細胞質内でおよび膜上で立証することができる。局在性のこの変化は、がんを示す診断として使用することができる。
膜貫通ドメインを含有する哺乳類スクラッチの変種mRNAの高感度検出用RT-PCR法:
伝令RNAを異なる種類の腫瘍細胞から単離し、第一鎖相補DNA (cDNA)を逆転写酵素およびオリゴdTプライマーを用いて合成する。その後、以下のプライマーを用いてPCRにより、野生型スクラッチ mRNAならびに考えられる変種および具体的には膜貫通変異体の発現について試験するためにcDNAを使用する。
5'プライマー1: wtおよび変種用(ヌクレオチド番号51〜82に対応する)
5'プライマー2: 膜貫通変種用(ヌクレオチド番号76〜105に対応する)
ここでX1はTまたはCであり、X2はAまたはGでありおよびX3はA、G、C、またはTである。
3'プライマー: (ヌクレオチド番号183〜210に対応する)
PCR反応物には、以下を含有する反応容量50 μLが含まれた。
10×PCR緩衝液 5 μL
2 mM dNTPs 5 μL
プライマー5' 20 pmol
プライマー3' 20 pmol
Tag DNAポリメラーゼ 2.5 U
鋳型DNA 50 ng
ヒト哺乳類スクラッチタンパク質をコードする遺伝子は、第8染色体q24.3に位置付けられており、二つのエクソンからなる。がんに関連する膜結合型スクラッチ変種に対する遺伝子配列は、エクソン特異的PCR増幅、またはプライマーから始まり公知の配列までの直接的DNA配列決定のような、当技術分野において公知の遺伝子配列決定技術を用いて容易に決定することができる。
VB6-011は、腫瘍細胞表面の哺乳類スクラッチタンパク質を特異的に認識する抗体との修飾ボウガニン(bouganin)抱合体の免疫複合体である。細胞表面の膜貫通ドメインを含んだ変種スクラッチを発現する細胞の処理によって、免疫複合体の特異的な取込みおよびその後の細胞死が起こる。
VB6-011の細胞毒性をMTSアッセイ法によって測定した。手短に言えば、抗原陽性および抗原陰性の細胞を1ウェル当たり細胞1000個で播種し、3時間37℃でインキュベートした。その後に、さまざまな濃度のVB6-011および脱ボウガニン(de-bouganin)を細胞に添加し、5日後、細胞生存率を測定した。
*スコア記録は尺度0〜4+にて評価し、0 = 染色なしおよび1+未満だが、0よりも大きいものを微量とした。等級1+〜4+は染色強度の増大を表し、強い濃褐色の染色を4+とした。
*得点記録は尺度0〜4+にて評価し、0 = 染色なしおよび1+未満だが、0よりも大きいものを微量とした。等級1+〜3+は染色強度の増大を表し、強い濃褐色の染色を4+とした。nd: 測定されず。
Claims (31)
- がん細胞の表面に発現される哺乳類スクラッチ(Scratch)のがん関連変種を含む、単離タンパク質。
- 哺乳類スクラッチのがん関連変種が膜貫通ドメインを含む、請求項1記載の単離タンパク質。
- 哺乳類スクラッチのがん関連変種がSEQ ID NO:1に示されるアミノ酸配列またはその変種を含む、請求項1記載の単離タンパク質。
- 哺乳類スクラッチのがん関連変種がSEQ ID NO:2に示されるアミノ酸配列またはその変種を含む、請求項1記載の単離タンパク質。
- 請求項1〜4のいずれか一項記載の単離タンパク質またはその断片をコードする、単離核酸配列。
- SEQ ID NO:6に示される配列またはその断片を有する、請求項5記載の単離核酸配列。
- SEQ ID NO:25に示される配列またはその断片を有する、請求項6記載の単離核酸配列。
- 請求項5〜7のいずれか一項記載の核酸配列を含む、組換え発現ベクター。
- 請求項8記載の組換え発現ベクターを含む、宿主細胞。
- がんを有するかまたは有する疑いがある被験体においてがん細胞を検出するかまたはがんをモニターする方法であって、
請求項1〜4のいずれか一項記載のタンパク質またはその断片を、サンプル中の細胞上にて検出する段階を含み、該タンパク質が細胞上にて検出される場合にがんが示唆される方法。 - (a) 被験体由来のサンプルを提供する段階;
(b) タンパク質に結合する抗体とサンプルを接触させる段階;
(c) サンプル中のタンパク質のレベルを検出する段階; および
(d) サンプル中のレベルを対照サンプルと比較する段階
を含み、
対照と比べてタンパク質のレベルの増大が、被験体ががんを有することを示唆する、
請求項10記載の方法。 - がんを有するかまたは有する疑いがある被験体においてがん細胞を検出するかまたはがんをモニターする方法であって、
請求項5〜7のいずれか一項記載の核酸配列またはその断片を、サンプル中にて検出する段階を含み、核酸配列が検出される場合にがんが示唆される方法。 - (a) 被験体由来のサンプルを提供する段階;
(b) 請求項5〜7のいずれか一項記載の核酸分子をサンプルから抽出する段階;
(c) 抽出された核酸分子をポリメラーゼ連鎖反応を用いて増幅する段階;
(d) タンパク質をコードする核酸分子の存在を判定する段階; および
(e) サンプル中の核酸配列のレベルを対照サンプルと比較する段階
を含み、
対照と比べて核酸配列のレベルの増大が、被験体ががんを有することを示唆する、
請求項12記載の方法。 - 核酸分子が、SEQ ID NO:27に示される配列を有するプライマーを用いて増幅される、請求項13記載の方法。
- (a) 被験体由来のサンプルを提供する段階;
(b) 野生型スクラッチまたはスクラッチのがん関連変種をコードする核酸分子をサンプルから抽出する段階;
(c) 核酸分子をKpnI制限酵素で消化する段階; および
(d) 消化された核酸分子のサイズを判定する段階
を含み、
未消化の核酸分子の存在が、被験体ががんを発症する素因を有することを示唆する、
がんを有するかまたは有する疑いがある被験体においてがん細胞を検出するかまたはがんをモニターする方法。 - 適当な希釈剤または担体との混合物の中に請求項1〜4のいずれか一項記載の単離タンパク質またはその断片の有効量を含む、薬学的組成物。
- アジュバントをさらに含む、請求項14記載の薬学的組成物。
- 適当な希釈剤または担体との混合物の中に請求項5〜7のいずれか一項記載の単離核酸配列の有効量を含む、薬学的組成物。
- アジュバントをさらに含む、請求項18記載の薬学的組成物。
- 適当な希釈剤または担体との混合物の中に請求項8記載の組換え発現ベクターの有効量を含む、薬学的組成物。
- アジュバントをさらに含む、請求項20記載の薬学的組成物。
- がんを処置するかまたは予防するための請求項1〜4のいずれか一項記載の単離タンパク質またはその断片の使用。
- 免疫反応を誘発するための請求項1〜4のいずれか一項記載の単離タンパク質またはその断片の使用。
- がんを処置するかまたは予防するための請求項5〜7のいずれか一項記載の単離核酸配列の使用。
- 被験体において免疫反応を誘発するための請求項5〜7のいずれか一項記載の単離核酸配列の使用。
- がんを処置するかまたは予防するための請求項8記載の組換え発現ベクターの使用。
- 被験体において免疫反応を誘発するための請求項8記載の組換え発現ベクターの使用。
- 哺乳類スクラッチのがん関連変種の機能を阻止する段階または低減する段階を含む、被験体においてがんを処置するかまたは予防するための方法。
- 請求項1〜4のいずれか一項記載のタンパク質に結合する結合タンパク質が哺乳類スクラッチのがん関連変種の機能を阻止するかまたは低減するために使用される、請求項28記載の方法。
- 哺乳類スクラッチのがん関連変種の機能が、細胞における哺乳類スクラッチのがん関連変種の発現を低減するかまたは阻止することで阻止されるかまたは低減される、請求項29記載の方法。
- がんの予防能または処置能について化合物を同定する方法であって、
以下の段階:
(a) 請求項1〜4のいずれか一項記載の単離タンパク質を発現する細胞を試験化合物と接触させる段階;
(b) 単離タンパク質の発現または機能を判定する段階; および
(c) 単離タンパク質の発現または機能を対照と比較する段階
を含み、
対照と比べて単離タンパク質の発現または機能の低下が、がんを予防するかまたは処置するのに有用な化合物を示す方法。
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