JP5932658B2 - 脳腫瘍を治療するためのペプチド及びその方法 - Google Patents
脳腫瘍を治療するためのペプチド及びその方法 Download PDFInfo
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Description
(ii)自己複製し、外来の有糸分裂促進因子及び成長因子添加がなくとも、神経球を生成し、免疫不全マウスの脳に移植された場合にin vivoで腫瘍形成を誘発することができる幹細胞様性質により、特徴づけられるヒトGBM細胞の脳腫瘍原始細胞(BTIC)のサブタイプの、1つへ優先的に結合する能力について選択された、12−20の間のアミノ酸長のペプチドを含む、ペプチド組成物を、投与する工程を含む。標的となったHIGC及び/又はBTICサブタイプの細胞において、このペプチド組成物の局在は、(i)ペプチド組成物がペプチドに結合している検出可能な放射性造影剤を含むことで、標的となった検出されるべきサブタイプの細胞の存在を明らかにし、
(ii)ペプチド組成物がペプチドへの結合した抗がん剤を含むことで、標的となったHIGC又はGTIC細胞を抑制又は死滅させることができ、及び
(iii)ペプチド単独により抑制されるべき腫瘍部位へHIGC細胞を移動(転移)させることができる。
(a)(i)細胞が注射された脳の半球から、反対側の脳半球へ移動する能力により特徴付けられるヒトGBM細胞の高浸潤性細胞(HIGC)サブタイプ、並びに
(ii)自己複製し、外来の有糸分裂促進因子又は成長因子の添加なしに、神経球を形成し、及び免疫不全マウスの脳に移植した時に生体内で腫瘍形成を誘発することができる幹細胞様性質により特徴づけられるヒトGBM細胞の脳腫瘍原始細胞(BTIC)サブタイプ、から選択される、ヒトGBM細胞のサブタイプに特異的に結合する能力についてのファージ提示ペプチドスクリーニング、
II.U87R細胞特異ペプチド
A.グリオーマ細胞有糸分裂を抑制するU87R特異ペプチドの単離となる、ファージ提示ライブラリーの選択バイオパニング
B.H10はGM1含有構造及び他の脂質ラフト成分のターンオーバーに影響する
III.BTIC特異ペプチド
A.バイオパニングされたBTIC単離体からのペプチドは培養された神経球内で異質性を示す
V.ペプチド組成物及びペプチド会合体
A.ペプチド
B.ペプチド会合体及び組成物
C.担持ペプチド
VI.診断及び治療方法
VII.スクリーニング方法
VIII.実施例の方法
A.細胞培養
B.バクテリオファージ培養
C.U87R(浸潤グリオーマ)特異ペプチド配列のバイオパニング
D.BTIC特異結合配列のバイオパニング
E.全細胞ELISA
F.トランスウェルアッセイ
G.共焦点顕微鏡検査
H.In vitroファージホーミング
I.スクロース/イオジキサノール勾配
J.In vivoファージホーミング:
K.免疫組織学
Claims (13)
- (i)細胞が注入された1つの脳半球から反対側の脳半球に転移することにより特徴付けられるヒト多形グリオブラストーマ(GBM)細胞の高浸潤グリオーマ細胞(HIGC)サブタイプ、及び
(ii)自己複製し、外来の有糸分裂促進因子又は成長因子の添加なしでの神経半球を形成し、及び免疫不全マウスの脳に移植したときにin vivoで腫瘍を誘発する能力により特徴付けられるヒトGBM細胞の脳腫瘍原始細胞(BTIC)サブタイプ、の1つに優先的に結合するペプチド組成物であって、ペプチドが、優先的に結合するのに有効な量の、12−20アミノ酸の単離ペプチドであり、HIGCの優先的結合についての配列番号2−5、7、8、および10から選択される配列を含み、及びBTICの優先的結合についての配列番号11−16からなる群より選択される配列を含むことを特徴とするペプチド組成物。 - 前記ペプチドが、L−アミノ酸からなる、請求項1のペプチド組成物。
- ヒトGBM腫瘍を有する個体においてHIGC又はBTICの局在化のために用いるものであり、かつ前記ペプチドに結合している放射性造影剤を更に含む、請求項1に記載のペプチド組成物。
- ヒトGBM腫瘍を有する個体においてHIGC又はBTICを抑制又は死滅させるため用いるものであり、かつ前記ペプチドに結合した抗がん剤を更に含む、請求項1のペプチド組成物。
- HIGCのターゲティングに用いるものであり、かつ前記ペプチドが配列番号2−5、7、8、および10からなる群より選択される配列を含む、請求項1に記載のペプチド組成物。
- 前記ペプチド組成物が配列番号2または7からなる群より選択される配列を含む、請求項5のペプチド組成物。
- 前記ペプチドが配列番号7で定義される配列を含む、請求項6のペプチド組成物。
- BTICのターゲティングに用いるものであり、かつ前記ペプチドが配列番号11−16からなる群より選択される配列を含む、請求項1のペプチド組成物。
- 前記ペプチドが配列番号11、13、及び16から選択される配列を含む、請求項8のペプチド組成物。
- 前記ペプチドが配列番号11で定義される配列を含む、請求項9のペプチド組成物。
- 脳血液関門を通過してヒトGBM細胞を個体に届けるための使用において、前記ペプチドが配列番号17又は18で定義されるキャリアペプチドに結合されている、請求項1のペプチド組成物。
- 前記ペプチドがポリ(ラクチドco−グリセリド)コポリマー、シクロデキストリン、又はセチルアルコール/ポリソルベートからなるナノ粒子内に封入されている、請求項1のペプチド組成物。
- 脳に神経薬理学的抗がん剤を届けるための組成物であって、前記神経薬理学的抗がん剤が、配列番号7で定義される配列を含み、かつ12−20アミノ酸長である単離されたキャリアペプチドに結合されている、組成物。
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