JP2012520287A - 好中球減少症の処置におけるセリンプロテアーゼ阻害剤の使用 - Google Patents
好中球減少症の処置におけるセリンプロテアーゼ阻害剤の使用 Download PDFInfo
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Abstract
【選択図】なし
Description
・または、好中球減少症もしくは好中球の機能障害を有する患者への注入のために、好中球およびそれらの骨髄前駆体を使用するために、
好中球およびそれらの骨髄前駆体の生体外で調製における使用のためのセリンプロテアーゼ阻害剤がさらに開示される。好ましくは、このセリンプロテアーゼ阻害剤は、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18またはこれらの混合物を含む群から選択される。
(1)遺伝子治療のために行われる骨髄細胞の形質移入の間および後、
(2)造血の再構成のために行われる血液幹細胞動員の間、および/または
(3)遺伝子治療のための造血の再構成のため、または好中球の注入による好中球減少症の処置のための、骨髄系の細胞の注入の間の、
必要とする前記患者への、治療上有効量のセリンプロテアーゼ阻害剤の投与を含む、方法を提供する。好ましくは、このセリンプロテアーゼ阻害剤は、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18またはこれらの混合物を含む群から選択される。
I.非極性またはわずかに極性を有する低分子量の脂肪族残基:Ala、Ser、Thr、Pro、Gly
II.極性を有する正に荷電した残基:His、Arg、Lys
III.極性を有する負に荷電した残基およびそれらのアミド:Asp、Asn、Glu、Gln
IV.高分子量の芳香族残基:Phe、Tyr、Trp
V.高分子量で非極性の脂肪族残基:Met、Leu、Ile、Val、Cys。
i)少なくとも4時間のインキュベーション後における11.7以下の阻害化学量論(stoichiometry of inhibition(SI))と、
ii)少なくとも7500M−1s−1の会合速度(Ka)と、
iii)少なくとも30分間のインキュベーション後における100%の阻害活性と、
を有する。
生体外での好中球の生存率を評価するために、健康なドナーからの末梢血を赤血球溶解し、好中球または末梢血単核球(PBMC)を単離した。RPMI 10%FCSの中での培養は、特段の記載がない限り96穴のマイクロタイタープレート(5×105細胞/ウェル)で行った。アポトーシス好中球またはPBMCの百分率を、蛍光アネキシンV−タンパク質結合の結合、またはFACS(蛍光発色セルソーター)分析によるCD11bまたはCD16細胞表面発現の測定に基づいて評価した。
図1:プロテアーゼ阻害剤MDPK67bおよびMD0KG9とともにインキュベーションした際の好中球およびT細胞のアネキシン−V染色。
図1a:MDPK67bとともにインキュベーションした際の好中球およびT細胞のアネキシン−V染色。
示すように6μM〜60μMの範囲の濃度のMDPK67b、または対照としてのPBSとともに、24または48時間細胞をインキュベーションした。アネキシンV染色およびFACS分析によって、アポトーシスを評価した。示した白血球ポピュレーションは、前方散乱光/側方散乱光FACSドットプロットにおける(好中球)またはCD3に対する陽性染色法による(T細胞)それらの外観に基づいてゲーティングした。
図1b:MDPK67bまたはMDOKG9(OKDG9)とともにインキュベーションした際の好中球のアネキシン−V染色。
示したように60μM(希釈1)〜60pM(希釈7)の範囲のMDPK67bまたはMDOKG9濃度とともに、好中球を18時間インキュベーションした。上に概略を示したようにして、アポトーシスを評価した。
結論:60μM〜0.6μMの範囲の用量のMDPK67bは好中球のアポトーシスを阻害する。MDOKG9は、好中球がアポトーシスに誘導されることから保護するという同様の効果を有する。この効果は好中球に特異的であり、MDPK67Bは、単球またはリンパ球のアポトーシスを阻害しなかった。
図2:MDPK67b処置された好中球のアネキシン−V染色を通した種々の細胞培養条件の比較。
好中球を、示した濃度のMDPK67bとともに培養した。MDPK67bを含まないPBSが対照としての役割を果たした。5×106/ml(高密度)または3×105/ml(低密度)のいずれかで好中球をプレーティングし(100μl/ウェル)、アネキシンV染色およびFACS分析によって、好中球のアポトーシスを評価した。RPMI 10% FCSの代わりの無血清培地(X−Vivo 15)中での5×106/mlの好中球の培養を、並行して評価した。
結論:MDPK67bは、増殖培地中の細胞密度および血清の有無によらずに、生体外で好中球のアポトーシスを阻害する。
図3:チロシンキナーゼ阻害剤によるMDPK67b媒介性好中球保護の復帰。
図3a:培養された好中球のCD16およびCD11bのレベルに対するMDPK67bの効果。好中球を、示した濃度のMDPK67bとともに培養し、高レベルのCD16またはCD11bを発現する好中球の百分率をFACSによって評価した。代表的なFACSプロットを示す。
図3b:PP2による、CD16およびCD11b好中球レベルに対するMDPK67bの効果の復帰。好中球を、Srcチロシンキナーゼ阻害剤PP2(最終濃度10μM)の存在下または不存在下で、示した濃度のMDPK67bとともに培養した。CD11bおよびCD16を高く発現する好中球のアポトーシスおよび相対頻度を、FACS分析によって測定した。
結論:MDPK67bは、CD16およびCD11bを高レベルで発現する好中球の頻度(これは、アポトーシスの減少と関連する)を用量依存的に増加させる。MDPK67bの存在下でのCD11bを高く発現する好中球の頻度の増加およびアポトーシスの減少は、Srcチロシンキナーゼ阻害剤PP2の存在下で逆転させることができる。細胞内シグナル伝達経路を遮断する他のキナーゼ阻害剤(PI3K阻害剤Ly294002およびERK阻害剤PD98059が挙げられる)で、同様の効果を観察した。
図4:好中球の生体外アポトーシスに対するG−CSFの効果。
好中球を、示した濃度のG−CSFとともに培養し、好中球アポトーシス(a)およびCD16発現の下方制御(b)を、FACSによって分析した。(c)好中球は、MDPK67b(0.6μM)および滴定された量のG−CSF(濃度は示すとおり)とともに培養した。培地およびPBS(MDPK67bを含まない)の中で培養した好中球は、対照としての役割を果たした。
結論:好中球アポトーシスに対するMDPK67bの効果は、単独では好中球アポトーシスに対する軽度の防御効果しか有しないG−CSFによっては影響されない。
図5:MDPK67bおよびエトポシドで処置した好中球のアネキシン−VおよびCD16染色。
図5a:MDPK67bおよびエトポシドで処置した好中球のアネキシン−V染色。
エトポシド(125μg/ml)を加えたMDPK67b(6μM)、エトポシド単独またはPBSとともに、細胞を18時間インキュベーションした。アネキシンV染色およびFACS分析によって、アポトーシスを評価した。関連する白血球ポピュレーションは、前方散乱光または側方散乱光FACSドットプロットにおけるそれらの外観に基づいてゲーティングした。
図5b:低MDPK67bおよび増加するエトポシド濃度で処置された好中球のアネキシン−V染色。
細胞を、MDPK67b(0.06μM)単独、または示すとおりの増加する濃度のエトポシド(μg/ml単位)を加えたMDPK67b(0.06μM)またはPBSとともに、18時間インキュベーションした。アネキシンV染色によって、アポトーシスを評価し、FACS分析を上記のようにして行った。
図5c:MDPK67bおよびエトポシドで処置した好中球のCD16染色。
細胞を、MDPK67b(0.06μM)単独、または示すとおりの増加する濃度のエトポシド(μg/ml単位)を加えたMDPK67b(0.06μM)またはPBSとともに、18時間インキュベーションした。CD16を高く発現する好中球の百分率を、FACS分析によって評価した。
結論:細胞増殖抑制剤であるエトポシドの高用量(125μg/mlまで)でさえ、部分的にしかMDPK67bのアポトーシス低下効果を遮断しない。
物質および方法:
DU−145、PC−3、T47D、OVCAR−3、HL−60、THP1およびU937細胞株を、10%不活性化ウシ胎仔血清を含む適切な標準的な培地の中で培養し、5% CO2とともに37℃でインキュベーションした。単核細胞および好中球細胞を単離した。トリゾール試薬(Life Technologies,Inc.)およびPureLink Micro−to−Midi キット(Invitrogen)を使用して上記細胞から全RNAを抽出し、2μgの全RNAを、製造業者の取扱説明書に従って、20μl反応液の中でSuperscript III(Invitrogen)を使用してfirst−strand cDNAへと逆転写した。各カリクレインに特異的プライマーおよび対照としてのアクチンプライマーを使用してPCR反応を行った。すべてのプライマーは、すでに文献に記載されていた(Harvey TJら、J Biol Chem、2000年12月1日;275(48):37397−406)。Yousef GMら、J Biol Chem. 2001年1月5日;276(1):53−61。Yousef GMら、Cancer Res. 2001年4月15日;61(8):3425−31)。PCR反応によっては、DU−145、PC−3、T47D、OVCAR−3を含めた異なる細胞株から単離したRNAを、KLK発現についての陽性対照として使用した(Harvey TJら、J Biol Chem、2000年12月1日;275(48):37397−406)。
循環条件は、主にHarvey TJら(J Biol Chem、2000年12月1日;275(48):37397−406)によって記載されているとおり、標的遺伝子に依存していた。PCR混合物を2%アガロースゲル上で電気泳動にかけ、臭化エチジウム染色によって可視化した。示したところでは、予想されるサイズのDNAバンドを、電気泳動後に第2の2%アガロースゲルから切り取り、回収したDNAを配列決定した。
表2:白血病細胞株ならびにドナー由来の単核細胞および好中球細胞におけるRT−PCR分析によって得た15のKLK遺伝子の発現パターン。使用した以下の記号は、以下の内容を表す:++、中/高発現;+、低発現;(1)予想されるサイズのPCR産物を配列決定し、正しい配列であることを確認した。
白血病細胞株および単離されたヒト血液細胞におけるKLK発現レベルのRT−PCR分析は、複数のKLKが発現されるということ、および異なる細胞はKLKプロテアーゼファミリーについて非常に多様な発現パターンを有するということを示した。KLK発現レベルのこのような差は、記載した好中球細胞におけるアポトーシスに対する保護のような、これらの細胞の生体外培養物に対してカリクレイン阻害剤が有する異なる効果に関与している可能性がある。
Claims (22)
- 好中球減少症に罹患している患者の処置または予防のための方法であって、必要とする前記患者への、治療上有効量のセリンプロテアーゼ阻害剤の投与を含む、方法。
- 前記セリンプロテアーゼ阻害剤はカリクレイン阻害剤である、請求項1に記載の方法。
- 前記カリクレイン阻害剤は、hK2、hK3、hK4、hK5、hK6、hK7、hK8、hK9、hK10、hK11、hK12、hK13、hK14、hK15阻害剤またはこれらの混合物から選択される、請求項2に記載の方法。
- 前記カリクレイン阻害剤は、hK2、hK4、hK11、hK5、hK14阻害剤またはこれらの混合物から選択される、請求項3に記載の方法。
- 前記カリクレイン阻害剤はhK2阻害剤である、請求項4に記載の方法。
- 前記セリンプロテアーゼ阻害剤は、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18またはこれらの混合物を含む群から選択される、請求項1に記載の方法。
- 感染、敗血症、化学療法、照射、毒性化学物質に起因して、またはいずれかの医薬の副作用として発症する、患者における好中球減少症を処置または予防する方法における使用のためのセリンプロテアーゼ阻害剤。
- 好中球の数および/または活性化状態は低下している、請求項7に記載の好中球減少症を処置または予防する方法における使用のためのセリンプロテアーゼ阻害剤。
- 好中球が細胞死を経る糖尿病患者における皮膚潰瘍、または皮膚における低酸素条件および好中球機能障害およびアポトーシスと関連する末梢動脈疾患を有する患者において発症する皮膚潰瘍を処置または予防する方法における使用のための、請求項8に記載のセリンプロテアーゼ阻害剤。
- 悪性腫瘍の処置の過程、原子力プラントでの事故または核兵器の使用で起こる、骨髄系細胞の照射によって誘導される損傷を処置または予防する方法における使用のための、請求項7に記載のセリンプロテアーゼ阻害剤。
- 前記セリンプロテアーゼ阻害剤はカリクレイン阻害剤である、請求項7から請求項10のいずれか1項に記載のセリンプロテアーゼ阻害剤。
- 前記カリクレイン阻害剤は、hK2、hK3、hK4、hK5、hK6、hK7、hK8、hK9、hK10、hK11、hK12、hK13、hK14、hK15阻害剤またはこれらの混合物から選択される、請求項11に記載のセリンプロテアーゼ阻害剤。
- 前記セリンプロテアーゼ阻害剤は、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18またはこれらの混合物を含む群から選択される、請求項7から請求項12のいずれか1項に記載のセリンプロテアーゼ阻害剤。
- ・好中球減少症もしくは骨髄系の遺伝的障害を有する患者への骨髄系細胞注入に先立つ遺伝子治療のために分子操作を行うために、
・または、好中球減少症もしくは好中球の機能障害を有する患者への注入のために、好中球およびそれらの骨髄前駆体を使用するために、
好中球およびそれらの骨髄前駆体の生体外で調製における使用のためのセリンプロテアーゼ阻害剤。 - 前記セリンプロテアーゼ阻害剤は、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18またはこれらの混合物を含む群から選択される、請求項14に記載のセリンプロテアーゼ阻害剤。
- 患者の骨髄系細胞のアポトーシスの予防のための方法であって、
(1)遺伝子治療のために行われる骨髄細胞の形質移入の間および後、
(2)造血の再構成のために行われる血液幹細胞動員の間、および/または
(3)遺伝子治療のための造血の再構成のため、または好中球の注入による好中球減少症の処置のための、骨髄系の細胞の注入の間の、
必要とする前記患者への、治療上有効量のセリンプロテアーゼ阻害剤の投与を含む、方法。 - 前記セリンプロテアーゼ阻害剤は、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18またはこれらの混合物を含む群から選択される、請求項16に記載の方法。
- 哺乳動物における好中球減少症の診断、予後診断、予防または処置のためのキットであって、セリンプロテアーゼ阻害剤と、必要に応じて試薬および/または取扱説明書とを含むことを特徴とする、キット。
- 前記セリンプロテアーゼ阻害剤は、検出可能な標識を含むか、または検出可能な標識に結合して検出可能な複合体を形成することができる、請求項18に記載のキット。
- 前記セリンプロテアーゼ阻害剤はカリクレイン阻害剤である、請求項18または請求項19に記載のキット。
- 前記カリクレイン阻害剤は、hK2、hK3、hK4、hK5、hK6、hK7、hK8、hK9、hK10、hK11、hK12、hK13、hK14、hK15阻害剤またはこれらの混合物から選択される、請求項20に記載のキット。
- 前記セリンプロテアーゼ阻害剤は、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18またはこれらの混合物を含む群から選択される、請求項18から請求項21のいずれか1項に記載のキット。
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