JP2018528263A - Dpep−1結合組成物および使用の方法 - Google Patents
Dpep−1結合組成物および使用の方法 Download PDFInfo
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- JP2018528263A JP2018528263A JP2018527025A JP2018527025A JP2018528263A JP 2018528263 A JP2018528263 A JP 2018528263A JP 2018527025 A JP2018527025 A JP 2018527025A JP 2018527025 A JP2018527025 A JP 2018527025A JP 2018528263 A JP2018528263 A JP 2018528263A
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Abstract
Description
DPEP−1経路は、炎症、白血球動員、および腫瘍転移をモジュレートするための新規経路である。本明細書に提示する組成物および方法は、炎症、腫瘍転移のモジュレーション、および関連した状態の処置に対する新規かつ特有のアプローチを提供する。
I.別の態様では、本明細書に記載する化合物または薬剤、ならびにその改変形態および修飾形態は、治療的使用の医薬組成物として提供される。一実施形態では、医薬製剤は、配列LSALTPSPSWLKYKALを含有する単離されたペプチドを含み、本明細書では「LSALT」と命名する。別の実施形態では、医薬製剤は、ファージウイルス内への挿入物として含有される単離されたペプチドを含み、ならびに/またはLSALTPSPSWLKYKAL配列のN末端および/もしくはC末端に、1、2、3、4、5個の追加のアミノ酸残基をさらに含み得る。
腎臓内の腎ジペプチダーゼ(DPEP−1)の特徴付け
in vivoでの内因性DPEP−1活性
DPEP−1の肺発現
DPEP−1の触媒活性は、in vitroでの結合には必要でない
RACINEおよびヒトDPEP−1に対するLSALT結合
LSALTおよびGFE−1は、in vitroでは、ヒトDPEP2およびDPEP3と結合しない
GFE−1およびLSALTは、LPSの存在下、肝シヌソイドにおいて好中球接着を阻害する:
DPEP−1が発現すると、COS−7細胞内でLSALTおよびGFE−1の結合が増強された
DPEP−1が発現すると、COS−7細胞に対するLSALTの結合が増強された
LSALTは、膜ジペプチダーゼ(DPEP−1)酵素活性を阻害しない
敗血症期間中に腎ジペプチダーゼを阻害すると、炎症が低減される
腎虚血再灌流傷害期間中にジペプチダーゼを阻害すると、炎症が低減される
静脈内造影剤期間中にジペプチダーゼ(DPEP−1)を阻害すると、炎症が低減される
DPEP−1結合による炎症性メディエーターの阻害
70Wヒトメラノーマ細胞は、DPEP−1を発現するCOS−1単層にin vitroで結合する
LSALTは、同遺伝子型動物モデルにおけるメラノーマ肺転移をin vivoで阻害する
腎虚血再灌流傷害期間中にアミノホスフィン酸誘導体を用いてジペプチダーゼを阻害すると、炎症が低減される
静脈内造影剤期間中に、アミノホスフィン酸誘導体によりジペプチダーゼ(DPEP−1)を阻害すると、炎症が低減される
Claims (35)
- それを必要とする対象において炎症を処置するための方法であって、DPEP−1と結合する有効量の化合物を前記対象に投与し、これにより炎症を処置するステップを含む方法。
- 前記化合物が、DPEP−1の競合的アンタゴニスト、非競合的アンタゴニスト、および不競合的アンタゴニスト、もしくはサイレントアンタゴニスト、またはそれらの組合せから選択される、請求項1に記載の方法。
- 前記化合物が、ペプチドを含む、請求項1に記載の方法。
- 前記ペプチドが、LSALT配列(LSALTPSPSWLKYKAL)を含む、請求項3に記載の方法。
- 前記ペプチドが、
CGFECVRQCPERC(GFE−1)またはCGFELETC(GFE−2)
から選択されるGFEトリペプチド配列を含む、請求項3に記載の方法。 - 前記ペプチドが、シラスタチンとコンジュゲートしていない、請求項5に記載の方法。
- 前記化合物が、DPEP−1の遮断抗体を含む、請求項1に記載の方法。
- 前記化合物が、小分子を含む、請求項1に記載の方法。
- 前記小分子が、式:
式中、Xは、任意のハロゲン、またはC1〜C6ハロアルキル、またはC1〜C6ジもしくはトリハロアルキル、またはC1〜C6アルキル、NH2、N(C1〜C6アルキル)2、およびNH(C1〜C6アルキル)、CF3NR’、またはF、Cl、Br、I125、I、CF3NR’からなる群から選択され、Yは、任意のハロゲン、H、CH3、OCH3、NH2、N(C1〜C6アルキル)2、およびNH(C1〜C6アルキル)、NR’、またはC1〜C6ハロアルキル、またはC1〜C6アルコキシ基、またはC1〜C6ジもしくはトリハロアルキル、またはC1〜C6アルキルからなる群から選択され、NR’は、NH2、N(C1〜C6アルキル)2、およびNH(C1〜C6アルキル)から選択され、Zは、OまたはSから選択される、請求項8に記載の方法。 - 前記化合物が、医薬組成物として提供される、請求項1に記載の方法。
- 前記医薬組成物が、非経口または静脈内投与に適する、請求項10に記載の方法。
- 前記有効量が、約0.01mg/kg〜約100mg/kgの間にある、請求項1に記載の方法。
- 前記炎症が、急性腎傷害と関連する、請求項1に記載の方法。
- 診断テストを実施して炎症を低減する必要性を決定することにより、前記対象を識別するステップをさらに含む、請求項1に記載の方法。
- それを必要とする対象において白血球動員をブロックするための方法であって、DPEP−1と結合する有効量の組成物を前記対象に投与し、これにより白血球動員をブロックするステップを含む方法。
- それを必要とする対象において腫瘍転移を低減または予防するための方法であって、有効量のDPEP−1結合剤を投与し、これにより腫瘍転移を低減または予防するステップを含む方法。
- それを必要とする対象において敗血症と関連した臓器損傷を処置または予防するための方法であって、DPEP−1と結合する有効量の組成物を前記対象に投与し、これにより敗血症と関連した臓器損傷を低減または予防するステップを含む方法。
- 診断テストを実施して、敗血症と関連した臓器損傷を低減または予防する必要性を決定することにより、前記対象を識別するステップをさらに含む、請求項17に記載の方法。
- 前記敗血症が、細菌、ウイルス、真菌、または寄生虫感染症と関連する、請求項17に記載の方法。
- 前記組成物が、敗血症の症状が低減または良化するまで投与される、請求項17に記載の方法。
- それを必要とする対象において急性腎傷害を処置または予防するための方法であって、DPEP−1と結合する有効量の組成物を前記対象に投与し、これにより急性腎傷害を低減または予防するステップを含む方法。
- 診断テストを実施して、急性腎傷害を処置または予防する必要性を決定することにより、前記対象を識別するステップをさらに含む、請求項21に記載の方法。
- 前記急性腎傷害が、虚血/再灌流、ショック、敗血症と関連する、または毒性の薬剤、例えば抗生物質もしくは静脈内X線写真造影剤等による、請求項21に記載の方法。
- 前記急性腎傷害が、敗血症と関連する、請求項21に記載の方法。
- 前記急性腎傷害が、虚血再灌流の結果である、請求項21に記載の方法。
- それを必要とする対象において虚血再灌流傷害を処置または予防するための方法であって、DPEP−1と結合する有効量の組成物を前記対象に投与し、これにより虚血再灌流傷害を低減または予防するステップを含む方法。
- 診断テストを実施して、虚血再灌流傷害を低減または予防する必要性を決定することにより、前記対象を識別するステップをさらに含む、請求項26に記載の方法。
- 前記虚血再灌流傷害が、移植用のドナー臓器を採取することと関連する、請求項26に記載の方法。
- 前記虚血再灌流傷害が、ドナー調達、ex vivoでの取り扱い、または移植レシピエントへの移植期間中の同種異系移植臓器と関連する、請求項26に記載の方法。
- 炎症を阻害する化合物を識別するための方法であって、(a)試験化合物のライブラリーを、組織内でDPEP−1に結合するその能力についてスクリーニングするステップと、(b)選択的結合親和性を示す試験化合物を選択し、これにより候補化合物を提供するステップと、(c)前記候補化合物を、炎症阻害活性について試験するステップと、(d)候補化合物が炎症を阻害する場合は、その候補化合物を選択し、これにより炎症を阻害する化合物を提供するステップとを含む方法。
- 前記組織が、肺組織または肝組織である、請求項30に記載の方法。
- (e)炎症を阻害する前記化合物を、固形腫瘍を担持する患者において、腫瘍転移を阻害するその能力について試験するステップと、(f)ステップ(e)で、前記化合物が腫瘍転移を阻害する場合は、前記化合物を選択するステップとをさらに含む、請求項30に記載の方法。
- (e)炎症を阻害する前記化合物を、肺または肝臓に転移することが知られている固形腫瘍を担持する患者において、肺および肝臓への腫瘍転移を阻害するその能力について試験するステップと、(f)ステップ(e)で、前記化合物が腫瘍転移を阻害する場合は、前記化合物を選択するステップとをさらに含む、請求項30に記載の方法。
- (e)前記化合物を、患者において敗血症を処置するその能力について試験するステップと、(f)ステップ(e)で、前記化合物が敗血症を処置する場合は、前記化合物を選択するステップとをさらに含む、請求項30に記載の方法。
- (e)前記化合物を、患者において急性腎損傷を処置するその能力について試験するステップと、(f)ステップ(e)で、前記化合物が急性腎損傷を処置する場合は、前記化合物を選択するステップとをさらに含む、請求項30に記載の方法。
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