JP6932340B2 - 細胞透過性ペプチド - Google Patents
細胞透過性ペプチド Download PDFInfo
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- JP6932340B2 JP6932340B2 JP2020543392A JP2020543392A JP6932340B2 JP 6932340 B2 JP6932340 B2 JP 6932340B2 JP 2020543392 A JP2020543392 A JP 2020543392A JP 2020543392 A JP2020543392 A JP 2020543392A JP 6932340 B2 JP6932340 B2 JP 6932340B2
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Description
この出願は、2019年6月21日に出願された日本国特許出願番号2019−115222の出願日の利益を主張し、その全内容は、参照により本明細書に組み込まれる。
〔2〕糖タンパク質に特異的に結合する、〔1〕に記載の細胞透過性ペプチド。
〔3〕前記細胞透過性ペプチドの完全長が、40個以下のアミノ酸で構成される、〔1〕または〔2〕に記載の細胞透過性ペプチド。
〔4〕配列番号1、配列番号34、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8および配列番号9からなる群から選択される、アミノ酸配列と少なくとも80%の配列同一性を有するアミノ酸配列を有する、〔1〕〜〔3〕のいずれか一項に記載の細胞透過性ペプチド。
〔5〕配列番号1、配列番号34、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8および配列番号9からなる群から選択される、アミノ酸配列を有する、〔1〕〜〔4〕のいずれか一項に記載の細胞透過性ペプチド。
〔6〕〔1〕〜〔5〕のいずれか一項に記載の細胞透過性ペプチドを有効成分として含有する、がんの治療または予防のための医薬組成物。
〔7〕〔1〕〜〔5〕のいずれか一項に記載の細胞透過性ペプチドを核内の薬剤送達キャリアとして含有する、がんの治療または予防のための医薬組成物。
〔8〕薬剤が、前記細胞透過性ペプチドのN末端部分および/またはC末端部分に結合する、〔6〕または〔7〕に記載の医薬組成物。
〔9〕薬剤が、ドキソルビシン、マイトマイシンC、ビンデシン、メトトレキサート、レチノイン酸、カルボプラチン、ネダプラチン、オキサリプラチン、エピルビシン、アクチノマイシンD、ゲムシタビンおよびオテラシルカリウムからなる群から選択される、〔8〕に記載の医薬組成物。
〔10〕がんが、上皮細胞がんまたは癌腫、非上皮性がんまたは肉腫または血液がんである、〔6〕〜〔9〕のいずれか一項に記載の医薬組成物。
〔11〕がんが、肺癌、胃癌、胆のう・胆管癌、すい臓癌、肝癌、結腸癌、直腸癌、乳癌、骨肉腫、脂肪肉腫、血管肉腫、横紋筋肉腫、平滑筋肉腫、急性骨髄性白血病、急性リンパ性白血病、急性前骨髄性白血病、慢性骨髄性白血病、慢性リンパ性白血病、悪性リンパ腫および多発性骨髄腫からなる群から選択される、〔10〕に記載の医薬組成物。
本発明で用いるペプチドは、化学的に合成することもできるし、遺伝子工学的に生産することもできる。本発明で用いるペプチドまたは薬剤を付加したペプチドは、当業者に公知の一般法に従って調製され得る。なおペプチドは、株式会社医学生物学研究所(日本)またはジェンスクリプトジャパン株式会社(日本)に委託により作成した。合成方法を簡単に述べると、H−Cys(Trt)−2−クロトトリチルクロライド(CTC)樹脂(Merck)を、DMFで膨潤した。次に、Fmoc−アミノ酸(4当量)、DIC(4当量)およびHOBt(4当量)の条件下で1時間撹拌し、カップリング反応により、Lys(Boc)、Trp(Boc)、Glu(OtBu),Gly、Arg(Pbf)、Gly、Asn(Trt)、Gly、Thr(tBu)、Cys(Trt)、Val、Cys(Trt)、Gln(Trt)、Leu、Leu、Asn(Trt)、Gly、Arg(Pbf)、Asn(Trt)、Asp(OtBu)およびLys(Boc)をそれぞれ順次導入した。さらに樹脂を20%ピペリジン/DMFで処理した後、メタノールで洗浄および乾燥し、ペプチド−樹脂を得た。得られたペプチド−樹脂100mgを、3mLのクリーベイジカクテル(TFA/1,2ーエタンジチオール/チオアニソール/フェノール/H2O/トリイソプロピルシラン=68.5/10/10/5/3.5/1V/V)で、30℃で4時間処理した。さらに、これに冷ジエチルエーテルを添加し、室温で乾燥させた。続いて、得られたペプチドを、逆相−HPLCにより、カラム:C18、流速:1ml/min、溶出:A液(100%水、0.1%TFA)とB液(100%アセトニトリル、0.1%TFA)の直線的勾配および検出:210nmの条件下で、分取精製したペプチドを実施例1(配列番号1)(株式会社医学生物学研究所)とした。
ミトコンドリア膜電位の変化測定試験では、ヒト線維肉腫由来HT−1080細胞(HT−1080細胞、JCRB細胞バンク)を、In vitroでのがん細胞の細胞死誘導試験および実施例2の核移行試験では、HT−1080細胞、ヒト骨肉腫細胞株Hos細胞(Hos細胞、JCRB細胞バンク)、ヒト組織球性リンパ腫・マクロファージU937細胞(U937細胞、JCRB細胞バンク)、ヒト骨髄性白血病細胞HL−60細胞(HL−60細胞、JCRB細胞バンク)、急性単球性白血病THP−1細胞(THP−1細胞、JCRB細胞バンク)、ヒト肺胞基底上皮腺癌細胞A549細胞(A549細胞、東北大学加齢医学研究所附属医用細胞資源センター)、ヒト膵臓がん細胞MIA Paca2細胞(MIA Paca2細胞、東北大学加齢医学研究所附属医用細胞資源センター)および高分化型ヒト肝癌由来細胞株HuH7細胞(HuH7細胞、東北大学加齢医学研究所附属医用細胞資源センター)を、がん細胞として用いた、また、対照として正常ヒト歯肉線維芽細胞Gin−1(Gin−1細胞、(株)DSファーマバイオメディカル)を用いた。上記細胞を、それぞれ96穴培養プレート(Falcon)に5000個/100μlで播種し、以下の試験に供した。
HT−1080細胞(1×107個/200μl)を5週齢BALB/cヌードマウス(日本チャールス・リバー)の背中へ皮下移植した。さらに、移植後の腫瘍が30〜60mm3に達したことを確認した後、これを以下の試験に供した。
実施例1、比較例1〜3の合成ペプチドをそれぞれ細胞に添加して、血清添加培地(α−MEM+10%FBS)で培養し、またコントロールとして血清添加培地(α−MEM+10%FBS)のみで培養した。7日間培養後、リン酸緩衝生理食塩水(PBS)で一回洗浄し、2μMのJC−1で、37℃、5%CO2細胞培養器中で30分間染色した。さらにPBSで一回洗浄し、PBSを100μl添加し、共焦点レーザースキャン顕微鏡LSM800(Zeiss)で画像を取得した後、ImageJで解析した。
In vitroでのがん細胞の細胞死誘導試験をするために、配列番号1のペプチドをFITCでラベルしたペプチド(実施例2)用いた。実施例2を100μl添加し、さらに10%FBSを加え、血清添加培地(Alpha modification of Eagle’s MEM(α−MEM)(Thermo Fisher Scientific)+10%FBS)200μlの条件下で9日間、培養した試験例を作成した。さらに実施例2添加培地を7日間ごとに全量交換し21日間培養した試験例も作成した。また対照としは血清添加培地(α−MEM+10%FBS)のみで培養した細胞を用いた。培養終了後、上清を除きPBSで一回洗浄、生細胞染色用蛍光色素Calcein−AM(同仁化学研究所)(最終濃度0.1μg/ml)と死細胞染色用蛍光色素Propidium Iodide(PI)(同仁化学研究所)(最終濃度0.3μg/ml)添加したPBS中で、37℃、5%CO2細胞培養器内で30分間染色した。その後、共焦点レーザースキャン顕微鏡LSM800で、Calcein−AMとPIで生細胞と死細胞を染め分けた画像を取得した。次に、ImageJを用い、全細胞数に対する死細胞の比率の解析を行った。
In vitroでのがん細胞の細胞死誘導試験をするために、配列番号34のペプチドをFITCでラベルしたペプチドを実施例4、配列番号2のペプチドをFITCでラベルしたペプチドを実施例5、および配列番号6のペプチドをFITCでラベルしたペプチドを実施例6として用いた。
実施例2および4〜6をそれぞれ12.5、25、50および100μg/mlとなるよう調整し、上記試験例2Aと同じ方法でHT−1080細胞を用い、9日間の投与試験を行った。細胞染色および、その後の全細胞数に対する死細胞の比率解析は上記試験例2Aと同様に行った。
実施例2の投与量を50μg/mlになるよう調整し、上記試験例2Aと同じ方法でA549細胞、MIA Paca2細胞またはHuH7細胞を用い、9日、16日または23日間の投与試験を行った。細胞染色および、その後の全細胞数に対する死細胞の比率解析は上記試験例2Aと同様に行った。
実施例2(80μg/400μl)をHT1080細胞(4000万個)に4℃で2時間作用させた。次いでPBSで洗浄後、遠心した細胞を、Halt Protease & Phosphatase inhibitor Single−Use Cocktail,EDTA−free(Thermo Fisher Scientific)(10μl)添加したIP Lysis/Wash buffer 1000μl(Thermo Fisher Scientific)で4℃、5分間の条件で溶解した。4℃で10分間遠心分離し、上清を採取した。タンパク質1mgとした上清に、80μlのA/Gアガロースを加え、4℃で1時間撹拌し、さらに1分間遠心分離し、これを前処理溶解液とした。前処理溶解液(1mg/600μl)に、IgG Fraction Monoclonal Mouse Anti−Fluorescein(FITC)(Jackson ImmunoResearch)10μg、またはMouse IgG Isotype Control(Thermo Fisher Scientific)10μgをそれぞれ添加して、4℃で一晩振とうした。その後、20μlのA/Gアガロースを加え、4℃で2時間振とうした。上記洗浄バッファーで3回洗浄後、A/Gアガロースに2×Non−reducing Lane Marker Sample Buffer(Thermo Fisher Scientific)20μlを添加した。これを100℃で5分間加熱し、1分間遠心分離した後、サンプルを回収した。サンプルをSDS−PAGEゲル(8%)にロードした。ウェスタンブロティングでは、1次抗体として、PE標識ヒトCD13抗体(Clone:WM−15 Biolegend)、IgG Fraction Monoclonal Mouse Anti−Fluorescein(FITC)またはHRP−標識抗tubulin抗体(MBLライフサイエンス)、2次抗体としてHRP−標識抗マウスIgG抗体(Abcam)を用いた。
PE標識ヒトCD13抗体(Clone:WM−15 Biolegend)(1μg/100μl)と実施例2(1μg/100μl)を各細胞(50万個/100μl)に添加し、4℃で1時間染色した。PBSで洗浄した後、HT1080細胞の蛍光強度を基準に各細胞のCD13発現と実施例2の結合部位を、共焦点レーザースキャン顕微鏡LSM800で観察した。HT1080細胞とGin−1細胞には、最もCD13(赤色)発現が強く、実施例2(緑色)の発光も強かった。さらに重ね合わせ写真では、強い黄色が観察されたことから、実施例2とCD13は共局在していることが観察された。さらに、CD13の発現がU937細胞、HL−60細胞、THP−1細胞およびHos細胞でも上記と同様の現象が認められた(図示せず)。
実施例2を最終的濃度50μg/mlになるように、血清添加培地(α−MEM+10%FBS)200μl下で、3日または9日間培養した。なお培養3日間では、細胞死が認められなかった。一方で、培養9日間では細胞死が認められたため、上記細胞培養日数で試験した。上記それぞれの細胞をはがして、Cellviewガラスボトムシャーレ(35×10mm)(Greiner)に移した。培養3日目の細胞は、10%ホルマリンエタノールで固定した後、DAPI染色した。培養9日目の細胞は、固定せずに、DAPI染色した。さらに経時的に共焦点レーザースキャン顕微鏡LSM800で観察した。
実施例2を最終的濃度50μg/mlになるように、血清添加培地(α−MEM+10%FBS)4mlに調整し、HT1080細胞(2000万個)を、37℃、5%CO2細胞培養器中で5日間培養した。PBSで洗浄、細胞を回収後、NE−PER Nuclear and Cytoplasmic Extraction Reagents (PIERCE)で、細胞質と核からタンパク質をそれぞれ回収した。細胞質および核のタンパク質1mgに、80μlのA/Gアガロースをそれぞれ加え、4℃で1時間撹拌し試料の前処理を行った。前処理溶解液(1mg/600μl)に、IgG Fraction Monoclonal Mouse Anti−Fluorescein(FITC)(Jackson ImmunoResearch)10μgを添加して、4℃で一晩振とうした。その後、20μlのA/Gアガロースを加え、4℃で2時間振とうした。洗浄バッファーで3回洗浄後、A/GアガロースにElution Buffer (Thermo Fisher Scientific)50μlを添加しサンプルを回収、Neutralization Buffer(Thermo Fisher Scientific)5μlを添加しpHを中性に調整し、これを実施例2に結合するタンパク質同定のための試料として用いた。Waters Xevo G2−XS Qtof(Waters Xevo G2−XS)を用い、ショットガン解析により網羅的にタンパク質を同定した。
実施例2を無菌水で溶解し、2倍濃度α−MEM(グルタミンおよび抗生物質を含まない)を加え、200μg/200μlへ調整した。これを、がんマウスの腹腔内に10mg/kgになるように3日ごとに投与した。対照投与群には、200μlの1倍濃度α−MEMを用い、これをがんマウスの腹腔内に3日ごとに投与した。3日ごとにDRETEC体重計(株式会社ドリテック、Japan)で体重を測定し、ノギス(最大150mm、最小0.05mm)(MITUTOYO、Japan)で腫瘍の大きさ(推定体積(短径×長径×高さ×π/6mm3))を測定した。
実施例3を5mg/kg、および比較例4(Dox)を1.2mg/kgにそれぞれなるように、実施例2と同様に処理し、これをがんマウスに供した後、同様の手法で、腫瘍の大きさを測定した。
Claims (11)
- RGNのN末側のモチーフとNGRのC末側のモチーフ、またはLYNのN末側のモチーフと配列番号44および配列番号45からなる群から選択されるC末側のモチーフとを含み、前記それぞれのN末側およびC末側のモチーフとの間にβストランド構造を有する、単離された細胞透過性ペプチドであって、ここで、前記細胞透過性ペプチドの完全長が、40個以下のアミノ酸で構成される、細胞透過性ペプチド。
- 糖タンパク質に特異的に結合する、請求項1に記載の細胞透過性ペプチド。
- βストランド構造が、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号38および配列番号42からなる群から選択されるペプチド、または配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号38および配列番号42からなる群から選択されるペプチドの1または2個のアミノ酸が置換、欠失、および/または付加されたペプチドを含む、請求項1または2に記載の細胞透過性ペプチド。
- 配列番号1、配列番号34、配列番号2、配列番号3、配列番号6および配列番号7からなる群から選択される、アミノ酸配列を有する、請求項1〜3のいずれか一項に記載の細胞透過性ペプチド。
- 請求項1〜4のいずれか一項に記載の細胞透過性ペプチドを有効成分として含有する、がんの治療または予防のための医薬組成物。
- 請求項1〜4のいずれか一項に記載の細胞透過性ペプチドを核内の薬剤の送達キャリアとして含有する、がんの治療または予防のための医薬組成物。
- 薬剤が、前記細胞透過性ペプチドのN末端部分および/またはC末端部分に結合する、請求項6に記載の医薬組成物。
- 薬剤が、ドキソルビシン、マイトマイシンC、ビンデシン、メトトレキサート、レチノイン酸、カルボプラチン、ネダプラチン、オキサリプラチン、エピルビシン、アクチノマイシンD、ゲムシタビンおよびオテラシルカリウムからなる群から選択される、請求項6または7に記載の医薬組成物。
- がんが、上皮細胞がんまたは癌腫、肉腫または血液がんである、請求項5または6に記載の医薬組成物。
- がんが、肺癌、胃癌、胆のう・胆管癌、すい臓癌、肝癌、結腸癌、直腸癌、乳癌、骨肉腫、脂肪肉腫、血管肉腫、横紋筋肉腫、平滑筋肉腫、急性骨髄性白血病、急性リンパ性白血病、急性前骨髄性白血病、慢性骨髄性白血病、慢性リンパ性白血病、悪性リンパ腫および多発性骨髄腫からなる群から選択される、請求項5または6に記載の医薬組成物。
- 配列番号1、配列番号34、配列番号2および配列番号6からなる群から選択されるアミノ酸配列を有する、ペプチドであって、ここで前記ペプチドの完全長が、40個以下のアミノ酸で構成される、ペプチド。
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