JP5847755B2 - 細胞を検出する方法、およびこれに有用な薬剤 - Google Patents
細胞を検出する方法、およびこれに有用な薬剤 Download PDFInfo
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Description
本発明は一般に、対象または対象由来の生物試料における異常細胞、より詳細にはアポトーシス細胞を検出する方法、およびこれに有用な薬剤に関する。異常細胞または異常細胞群の存在は、特定の疾患もしくは状態、または疾患もしくは状態を発症する傾向の指標となる。より詳細には、本発明は、核外の核分子、特にLaの存在、または核外の核分子レベルの相対的増加を検出することによる、アポトーシス細胞を検出する方法を意図する。本発明はさらに、1個または複数の細胞における核外核分子レベルの上方制御をスクリーニングすることによる、対象または対象由来の生物試料における異常な、望ましくない、またはさもなければ不適当な細胞アポトーシスを特徴とする状態を診断またはモニターする方法を提供する。本発明は、これらの分子を検出するのに有用な診断薬も提供する。そのような診断薬には、抗体等の免疫相互作用分子が含まれる。
本明細書において本発明者らが言及する出版物の書誌的詳細は、本記載の末尾にアルファベット順に収載する。
本発明の1つの局面は、対象または対象由来の生物試料におけるアポトーシス細胞を検出する方法であって、対象または生物試料に由来する細胞または細胞抽出物を、核分子またはその抗原性部分に対する相互作用分子と接触させる段階、および相互作用分子-核分子複合体の形成をスクリーニングする段階を含み、複合体の非核局在性によってアポトーシス細胞であることが示される方法を意図する。
(1) 核分子またはその抗原決定基に対する相互作用分子を、そのような核分子を含む疑いがある生物試料と接触させる段階;および
(2) 段階(1)で形成された複合体をシグナル検出段階に供する段階
を含み、相互作用分子-核分子複合体の非核形成を検出することによってアポトーシス細胞であることが示されるアッセイ法を意図する。
本発明は、免疫相互作用分子を利用した核外の核分子発現のスクリーニングにより、インビトロまたはインビボにおいてアポトーシス細胞の存在を検出する、非常に特異的でありかつ確実な手段が提供されるという驚くべき決定を一部前提とする。アポトーシス細胞に関連する抗原のスクリーニング(およびそれによる同定)を対象とした以前の実験研究では、核分子、特にLaを候補抗原であると同定していなかったため、この知見は特に重要である。むしろ、ホスファチジルセリン等の他の非関連抗原が繰り返し同定された。残念なことに、これらの非関連分子は顕著な不利点、特に、細胞の機械的破壊または他の破壊のような非アポトーシス事象に起因して一過性の細胞外発現が起こり得るという事実を示す。さらに、細胞染色が、一部のアポトーシス細胞による、細胞表面の抗体-抗原複合体の内部取り込みという活発な過程の結果であると考えられたことに基づき、La等の以前に解析された核分子は、それ自体アポトーシス細胞のマーカーとして却下された。すなわち、細胞への抗体移入の経路としての膜透過性が却下されていた。したがって、アポトーシス細胞自体を1つの種類として同定する手段は開発されていなかった。しかし、今、抗核免疫相互作用分子、特に抗La/SS-B免疫相互作用分子を用いて、後期アポトーシス細胞およびアポトーシス小体をインビトロおよびインビボ検出する方法が開発された。本方法は直接的であり、本発明の出現以前に必要とされていたような、結合を実証するための透過処理等のさらなる段階を必要としない。以前は、抗核抗体結合はアポトーシス誘導に関連がない、その結合は細胞の透過処理に依存する、その結合は表面膜に関連し、受動的移入およびアポトーシス小体に含まれる抗原への特異的結合以外の結合機構に依存すると理解されていた。
または電気的)の存在下で、体細胞と骨髄腫細胞をそれぞれ10:1の割合(この割合は約20:1から約1:1まで変動し得る)で混合する段階を含む。融合方法は以前に記載されている(Kohler and Milstein, 1975, 前記;Gafter et al., Somatic Cell Ganet. 3: 231-236, 1977;Volk et al., 1982, 前記)。このような研究者らによって用いられた融合促進性の作用因子は、センダイウイルスおよびポリエチレングリコール(PEG)であった。
(3) 核分子またはその抗原決定基に対する相互作用分子を、そのような核分子を含む疑いがある生物試料と接触させる段階;および
(4) 段階(1)で形成された複合体をシグナル検出段階に供する段階
を含み、相互作用分子-核分子複合体の非核形成を検出することによってアポトーシス細胞であることが示されるアッセイ法を意図する。
(a) レポーター分子と抗体との直接的な結合;
(b) レポーター分子と抗体との間接的な結合;すなわち、レポーター分子と後に抗体に結合させる別のアッセイ試薬との結合;および
(c) 抗体の以後の反応産物との結合。
(i) 作用して免疫応答の1つまたは複数の局面を誘導または増強し、それによりバイスタンダーの死滅を増大させる、マクロファージ、樹状細胞、および/またはT細胞活性化因子等のサイトカイン、ケモカイン、または他の因子に結合している抗体の使用。例えば、走化性ペプチド、N-ホルミル-メチオニル-ロイシル-フェニルアラニン(FMLP)(Morikawa et al. Cancer Immunol Immunother 27(1):1-6, 1998)および新規細菌リポペプチド、JBT 2002(Shinohara et al. J Immunother 23(3):321-331, 2000)はどちらも、腫瘍関連マクロファージの活性化因子である。
(ii) 毒素に結合している抗体の使用。
本明細書において用いた抗La抗体はマウスモノクローナル抗体ハイブリドーマ3B9であり、これはヒト型およびマウス型の低分子リボ核タンパク質抗原、La/SS-Bを認識する。この抗体はTom Gordon教授、Flinder Medical Centre、南オーストラリア州、アデレードから分与されたものであり、この教授はこの抗体をM. Bachmann博士、Oklahona Medical Research Foundation、米国、オクラホマ州、オクラホマシティーから入手した。3B9は、Dr. Gordonのグループによって公表された(Tran et al. 2002a)。対応するアイソタイプ対照抗体ハイブリドーマはSal5である。
抗La抗体はアポトーシス細胞および壊死細胞と結合する
インビトロにおいてアポトーシスが誘導され進行するにつれて、アポトーシス細胞は膜の完全性を失うために次第に漏出性となり、これが核酸およびDNA結合色素、それぞれヨウ化プロピジウム(PI)および7-アミノ-アクチノマイシンD(7AAD)の結合活性の増加として現れる。アポトーシス細胞に対する抗La抗体の結合は、PI結合よりも緩やかな時間経過を有する。しかし、観察される抗La抗体染色の蛍光強度から、この抗体は、PI染色の強度が高いかまたは中程度であるかにかかわらず、同様の結合活性でアポトーシス細胞と結合することが示される(図3)。以下に示すように、PI中程度亜集団はアポトーシス小体を含む。中程度の染色はPI濃度の変化にかかわらず存在するため、これはクエンチングによる人為的結果によるものではない。
アポトーシス小体に対する抗La抗体結合はカスパーゼ3に依存する
実施例2に述べたように、より詳細なフローサイトメトリー解析により抗La抗体がアポトーシス小体に結合することが示されたが、アポトーシス小体は核成分および細胞小器官の膜結合残遺物を様々な比率で含むために、小さなサイズ、および内部複雑度の減少を特徴とする(図10)。さらに、抗La抗体結合にはアポトーシス小体の形成が必要であることが示される。MCF-7細胞は、プロカスパーゼ3の遺伝子を欠くヒト乳癌細胞株である。
他の核抗原およびリボ核抗原に対する他のモノクローナル抗体もまたアポトーシス細胞と結合する
共焦点スキャンレーザー顕微鏡観察研究において観察されたのと同様に、フローサイトメトリーによっても、核抗原およびリボ核抗原に特異的な多くのmAbの類似の結合動力学および結合パターンが示される。抗チューブリンmAbを、透過性アポトーシス細胞における細胞質結合の対照として含める(図16)。同様に、これらのmAbのいくつかは、MCF-7細胞にプロカスパーゼ3遺伝子をトランスフェクションした後に形成されるアポトーシス小体に特異的に結合する(図17)。
ヒトLa/SS-Bに対する他の抗体もまたアポトーシス細胞を検出する
ヒト抗La自己抗体(図18)、およびヒトLa/SS-Bに特異的な別のmAb、クローンSW3(図19)のアポトーシス細胞に対する結合について検討した。
抗La抗体はヒト種および齧歯類種の初期および悪性アポトーシス性細胞と結合する
抗La抗体は、アポトーシス性初期ヒト細胞との結合に加えて(図15)、デキサメタゾンまたはスタウロスポリンによりインビトロにおいてアポトーシスを誘導したマウスおよびラットの胸腺に由来するアポトーシス性初期細胞とも結合する。抗La抗体は、どちらの刺激によって誘導されたアポトーシスにも応答して、PI+胸腺細胞と特異的に結合する(図20)。増殖性細胞核抗原(PCNA)に対するmAbを用いた場合にも、同様の結合パターンが観察された。抗La抗体はまた、細胞毒性薬に応答してインビボでアポトーシスを起こした腫瘍細胞を含む齧歯類種のアポトーシス性腫瘍細胞(図21)、および多くのアポトーシス性ヒトおよびサル腫瘍細胞株(図22)とも結合する。
Claims (18)
- 対象における、新生物状態を処置するための、Laまたはその抗原性部分に対する免疫相互作用分子を含む薬剤であって、該状態が、膜完全性を喪失し、かつLaの細胞質局在性を示すアポトーシス性新生物細胞によって特徴付けられ、該相互作用分子が、該状態を処置するのに十分な時間および条件の下で、腫瘍細胞の増殖を下方制御するタンパク質性または非タンパク質性分子と連結、結合、または会合し、該免疫相互作用分子が、モノクローナル抗体、ポリクローナル抗体、ヒト化抗体、キメラ抗体、ミニボディ、一本鎖抗体、非免疫化抗体、Fv抗体、Fab断片、Fab'断片、F(ab')2断片、(scFv-Fc)2、一本鎖Fv断片、ジスルフィド安定化Fv断片、または一本鎖可変領域ドメイン(dAb)抗体である、前記剤。
- 対象における、新生物状態を処置するための、腫瘍細胞の増殖を下方制御するタンパク質性または非タンパク質性分子に結合しているLa免疫相互作用分子を含む薬剤であって、該免疫相互作用分子が、モノクローナル抗体、ポリクローナル抗体、ヒト化抗体、キメラ抗体、ミニボディ、一本鎖抗体、非免疫化抗体、Fv抗体、Fab断片、Fab'断片、F(ab') 2 断片、(scFv-Fc) 2 、一本鎖Fv断片、ジスルフィド安定化Fv断片、または一本鎖可変領域ドメイン(dAb)抗体であり、該状態が、膜完全性を喪失し、かつLaの細胞質局在性を示すアポトーシス性新生物細胞によって特徴付けられる、前記剤。
- 新生物細胞が、中枢神経系腫瘍、網膜芽細胞腫、神経芽細胞腫もしくは他の小児腫瘍、頭頸部癌、乳癌および前立腺癌、肺癌、腎臓癌、食道胃癌、肝細胞癌、膵胆管新形成、結腸直腸癌、子宮頸癌および肛門癌、子宮癌および他の生殖器官の癌、尿路癌、胚細胞癌、卵巣癌、原発不明の癌腫、ヒト免疫不全関連悪性腫瘍、リンパ腫、白血病、悪性黒色腫、肉腫、内分泌腫瘍、中皮腫および他の胸膜腫瘍、神経内分泌腫瘍、又はカルチノイド腫瘍の細胞である、請求項1〜2記載のいずれか一項記載の剤。
- 頭頸部癌が扁平細胞癌であり、肺癌が小細胞肺癌または非小細胞肺癌であり、腎臓癌が腎細胞腺癌であり、膵胆管新形成が腺癌島細胞腫瘍であり、胚細胞癌が精巣癌または卵巣癌であり、卵巣癌が卵巣上皮癌であり、ヒト免疫不全関連悪性腫瘍がカポジ肉腫であり、および内分泌腫瘍が甲状腺の腫瘍である、請求項3記載の剤。
- 状態が、中枢神経系腫瘍、網膜芽細胞腫、神経芽細胞腫または他の小児腫瘍、頭頸部癌、乳癌および前立腺癌、肺癌、腎臓癌、食道胃癌、肝細胞癌、膵胆管新形成、結腸直腸癌、子宮頸癌および肛門癌、子宮癌および他の生殖器官の癌、尿路癌、胚細胞癌、卵巣癌、原発不明の癌腫、ヒト免疫不全関連悪性腫瘍、リンパ腫、白血病、悪性黒色腫、肉腫、内分泌腫瘍、中皮腫および他の胸膜腫瘍、神経内分泌腫瘍、ならびにカルチノイド腫瘍である、請求項1または2記載の剤。
- 頭頸部癌が扁平細胞癌であり、肺癌が小細胞肺癌および非小細胞肺癌であり、腎臓癌が腎細胞腺癌であり、膵胆管新形成が腺癌島細胞腫瘍であり、胚細胞癌が精巣癌または卵巣癌であり、卵巣癌が卵巣上皮癌であり、ヒト免疫不全関連悪性腫瘍がカポジ肉腫であり、および内分泌腫瘍が甲状腺の腫瘍である、請求項5記載の剤。
- 対象が哺乳動物である、請求項1〜6のいずれか一項記載の剤。
- 哺乳動物がヒトである、請求項7記載の剤。
- 新生物が転移癌である、請求項1〜8のいずれか一項記載の剤。
- タンパク質性または非タンパク質性分子が以下から選択される、請求項1〜9のいずれか一項記載の剤:
- サイトカイン
- ケモカイン
- マクロファージ、樹状細胞、もしくはT細胞活性化因子;または
- 毒素。 - マクロファージ活性化因子が、N-ホルミル-メチオニル-ロイシル-フェニルアラニンまたは細菌リポペプチドである、請求項10記載の剤。
- 細菌リポペプチドが、JBT 2002またはその誘導体もしくは類似体である、請求項11記載の剤。
- 毒素が放射性同位元素である、請求項10記載の剤。
- 放射性同位元素が、α線放射体、β線放射体、またはγ線放射体である、請求項13記載の剤。
- α放射体がTb-149またはBi-213である、請求項14記載の剤。
- 毒素が、リシン、プロドラッグ、または生物学的薬物である、請求項10記載の剤。
- プロドラッグが、抗体指向性プロドラッグ変換酵素である、請求項16記載の剤。
- 生物学的薬物が触媒抗体である、請求項16記載の剤。
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