JP6709844B2 - 移植拒絶反応を治療するための分子構築物 - Google Patents
移植拒絶反応を治療するための分子構築物 Download PDFInfo
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Description
GGS,
GSG,
GGGS(配列番号: 1),
GSGS(配列番号: 2),
GGSG(配列番号: 3),
GSGGS(配列番号: 4),
SGGSG(配列番号: 5),
GGGGS(配列番号: 6),
GGSGGS(配列番号: 7),
GGSGGSG(配列番号: 8),
SGSGGSGS(配列番号: 9),
GSGGSGSGS(配列番号: 10),
SGGSGGSGSG(配列番号: 11),
GGSGGSGGSGS(配列番号: 12),
SGGSGGSGSGGS(配列番号: 13),
GGGGSGGSGGGGS(配列番号: 14),
GGGSGSGSGSGGGS(配列番号: 15), 又は
SGSGGGGGSGGSGSG(配列番号: 16)であり得る。
Ac-CGGSGGSGGSKGSGSKGSK(配列番号: 18),又は
Ac-CGSKGSKGSKGSKGSKGSKGSKGSKGSKGSK(配列番号: 19),
ここで、Acは、アセチル基を示す。
Ac-AAH-(SG2-4)1-8-(GSK)2-7,
Ac-AAH-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-C,
Ac-C-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-AAH,
Ac-K-(Xaa2-12-K)2-4-Xaa2-12-AAH,
Ac-AAH-Xaa2-12-K-(Xaa2-12-K)2-4,
Ac-AAH-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-C, 又は
Ac-C-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-AAHである。
Ac-GHP-(SG2-4)1-8-(GSK)2-7,
Ac-GHP-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-C,
Ac-C-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-GHP,
Ac-K-(Xaa2-12-K)2-4-Xaa2-12-GHP,
Ac-GHP-Xaa2-12-K-(Xaa2-12-K)2-4,
Ac-GHP-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-C, 又は
Ac-C-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-GHPである。
Ac-GHPGGSGGSGGSKGSGSKGSK(配列番号: 21),
Ac-AAHGGSGGSGGSKGSGSKGSK(配列番号: 22),
Ac-GHPGGSGGSGGSKGSGSKGSGSC(配列番号: 23),
Ac-C-Xaa2-K-Xaa2-K-Xaa2-K(配列番号: 24),又は
Ac-C-Xaa6-K-Xaa6-K-Xaa6-K-Xaa6-K-Xaa6-K(配列番号: 25),
Ac-(GSK)2-7-(G2-4S)1-8-C-Xaa2-12-歪んだアルキン,
Ac-K-(Xaa2-12-K)2-4-Xaa2-12-C-Xaa2-12-テトラジン,
Ac-K-(Xaa2-12-K)2-4-Xaa2-12-C-Xaa2-12-歪んだアルキン,
テトラジン-Xaa2-12-C(Ac)-(SG2-4)1-8-(GSK)2-7,
歪んだアルキン-Xaa2-12-C(Ac)-(SG2-4)1-8-(GSK)2-7,
テトラジン-Xaa2-12-C(Ac)-Xaa2-12-K-(Xaa2-12-K)2-4, 及び
歪んだアルキン-Xaa2-12-C(Ac)-Xaa2-12-K-(Xaa2-12-K)2-4を含むが、これらに限定されない。
Ac-AAH-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-C-Xaa2-12-歪んだアルキン,
テトラジン-Xaa2-12-C(Ac)-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-AAH,
歪んだアルキン-Xaa2-12-C(Ac)-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-AAH,
Ac-AAH-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-C-Xaa2-12-テトラジン,
Ac-AAH-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-C-Xaa2-12-歪んだアルキン,
テトラジン-Xaa2-12-C(Ac)-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-AAH,
歪んだアルキン-Xaa2-12-C(Ac)-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-AAH,
Ac-GHP-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-C-Xaa2-12-テトラジン,
Ac-GHP-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-C-Xaa2-12-歪んだアルキン,
テトラジン-Xaa2-12-C(Ac)-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-GHP,
歪んだアルキン-Xaa2-12-C(AC)-(SG2-4)0-7-(GSK)2-6-(G2-4S)1-8-GHP,
Ac-GHP-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-C-Xaa2-12-テトラジン,
Ac-GHP-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-C-Xaa2-12-歪んだアルキン,
テトラジン-Xaa2-12-C(Ac)-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-GHP, 及び
歪んだアルキン-Xaa2-12-C(Ac)-Xaa2-12-K-(Xaa2-12-K)1-3-Xaa2-12-GHPである。
氷浴で、CH2Cl2(109mL)に溶解したシロリムス(1, 1.992g, 2.179mmol, 1.0当量)及びイミダゾール(0.1494g, 2.194mmol. 1.0当量)に塩化トリメチルシリル(TMSCl, 1.0 M in CH2Cl2, 13.0 mL, 13.0mmol, 6.0当量)をゆっくりと加えた。0℃で反応混合物を撹拌し、反応をTLCにより監視した。反応が完了した後(約10分間)、溶液を減圧下で濃縮した。50% EtOAc(ヘキサン)を溶離液としてフラッシュカラムクロマトグラフィーにより残基を精製することにより、28,40-bis-O-TMSシロリムス(2.261g, 2.136mmol): ESI-MS: 1080.62(M + Na)+を得た。得られた28,40-Bis-O-TMSシロリムスをイミダゾール(2.250g,33.05mmol,15当量)及びイミダゾール塩酸塩(3.463g, 33.13mmol, 16当量)とCH2Cl2(218mL)で混合した。反応混合物を室温で撹拌し、反応をTLCにより監視した。反応が完了した後(約3時間)、溶液を減圧下で濃縮し、フラッシュカラムクロマトグラフィーにより、50% EtOAc(ヘキサン)を溶離液として残留物を精製することにより、合計収率82%で28-O-TMSシロリムス(2,1.772g,1.796mmol)(ESI-MS: 1008.58(M + Na)+)を得た。
化合物2(0.305g, 0.309mmole, 1.0当量)、トリチルグリシン(3, 0.592g, 1.87mmol, 6.1当量)及びDMAP(0.065g, 0.532mmol, 1.7当量)を含む無水CH2Cl2(10mL)溶液にDCC(0.386g, 1.87mmol, 6.当量)を含む無水CH2Cl2(5.0mL)をゆっくりと加えた。反応混合物を室温で撹拌し、反応をTLCにより監視した。反応が完了した後(約3時間)、溶液にH2O(1.0mL)を添加し、ろ過して白色のDBU沈殿物を得た。濾液をEtOAcで希釈し、飽和NaHCO3で洗浄した。有機層をMgSO4で乾燥させ、ろ過し、減圧下で濃縮した。カラムクロマトグラフィーにより、25% EtOAc(ヘキサン中)を溶離液として残留物を精製することにより、収率75%で5a(300mg, 0.233mmol)を得た。
化合物5aの調製と同様に、化合物2(0.305g, 0.309mmol, 1.0当量)、トリチルグリシングリシン(4, 0.347g, 0.927mmol, 3.0当量)、DMAP(11mg, 0.090mmol, 0.30当量)及びDCC(0.240g, 1.16mmol, 3.8当量)を用いて化合物5bを調製した。反応により>99%の収率で5b(0.535g, 0.398mmol)を得た。HRMS calcd for C77H107N3NaO15Si(M + H)+ 1364.7364, found 1364.7275。
氷浴で、化合物5a(0.193g, 0.150mmol, 1.0当量)を含むTHF(10mL)にH2O(2.0mL)及び0.10N HCl(0.50mL)を加えた。反応混合物を室温で12時間撹拌した。溶液にNaHCO3(0.10M, 1.0mL)を加え、EtOAcで希釈した。溶液を水で洗浄し、MgSO4で乾燥させ、減圧下で濃縮した。カラムクロマトグラフィーにより、50% EtOAc(ヘキサン中)を溶離液として残留物を精製することにより、99%の収率で化合物6a(180mg, 0.148mmol)を得た。HRMS calcd for C72H97N2O14(M + H)+ 1213.6934, found 1213.6887。
化合物6aと同様に、5b(0.535g, 0.398mmol, 1.0当量)を用いて化合物6bを調製した。反応により、85%の収率で化合物6b(0.431g, 0.339mmol)を得た。HRMS calcd for C74H100N3O15(M + H)+ 1270.7149, found 1270.7054。
化合物6a(0.168g, 0.138mmol, 1.0当量)を0.10M HOBtのトリフルオロエタノール溶液(1.0mL)に溶解し、反応をTLCにより監視した。反応が完了した後(~12h)、溶液にH2O(0.10mL)を加え、EtOAcで希釈した。溶液を飽和Na2CO3で洗浄し、MgSO4で乾燥させ、ろ過し、減圧下で濃縮した。カラムクロマトグラフィーにより残留物を精製することにより、61%の収率で化合物7a(82mg, 0.084mmol)を得た。HRMS calcd for C53H83N2O14(M + H)+ 971.5839, found 971.5806; 1H NMR(CD3OD)δ 6.48-6.36(m, 2 H), 6.30-6.03(m, 3 H), 5.47(s, 1 H), 5.42(d, 1 H), 5.21(d, 1 H), 5.06(d, 1 H), 4.68(s, 1 H), 4.15(d, 1 H), 4.08(d, 1 H), 3.98(d, 1 H), 3.66(d, 1 H), 3.56-3.50(m, 1 H), 3.41(s, 2 H), 3.36(s, 3 H), 3.26(s, 3 H), 3.12(s, 3 H), 2.84-2.80(m, 1 H), 2.79-2.76(m, 1 H), 2.48-2.40(m, 2 H), 2.35-0.90(m, 52 H)。
化合物7aと同様に、化合物6b(0.431g, 0.339mmol, 1.0当量)を用いて化合物7bを調製した。反応により27%の収率で7b(96mg, 0.093mmol)を得た。1H NMR(DMSO-d6)δ 6.70-6.53(m, 1 H), 6.48-6.22(m, 2 H), 6.23-6.00(m, 3 H), 5.58-5.33(m, 1 H), 5.29-5.10(m, 2 H), 4.98-4.84(m, 2 H), 4.60-4.41(m, 2 H), 4.14-4.01(m, 5 H), 3.99-3.46(m, 2 H), 3.76-3.46(m, 3 H), 3.21(s, 3 H), 3.12(s, 3 H), 3.00(s, 1 H), 2.94(s, 3 H), 2.75-2.60(m, 2 H), 2.39-2.28(m, 1 H), 2.26-2.16(m, 1 H), 2.15-1.75(m, 3 H), 1.68-0.53(m, 45 H)。
Claims (12)
- 中心コア、複数のリンクアーム、複数の第1成分、必要に応じてカップリングアーム、及び必要に応じて第2成分を含むリンカーユニットであって、
前記中心コアは、(1)第1ポリペプチド又は(2)第2ポリペプチドを含み、前記第1ポリペプチドが2〜15個のK残基及び各K残基との次のK残基を区切る1以上の充填配列を含み、上記充填配列は、グリシン(G)及びセリン(S)残基を含み、前記第2ポリペプチドは、(Xaa−K)2−15配列を含み、前記Xaaが2〜12個のエチレングリコール(EG)の繰り返し単位を有するPEG化アミノ酸であり、
前記複数のリンクアームは、それぞれ前記中心コアのK残基に結合され、
前記中心コアのN末端又はC末端にあるアミノ酸残基は、アジド又はアルキン基を有し、或いは、前記中心コアのN末端又はC末端にあるアミノ酸残基は、システイン残基であり、システイン残基のチオール基がカップリングアームに結合され、
前記カップリングアームは、その遊離末端にアジド基、アルキン基、テトラジン基、シクロオクテン基、又はシクロオクチン基を有し、
前記複数の第1成分は、それぞれ前記複数のリンクアームに、それらの間にアミド結合を形成することにより結合され、又は、チオール−マレイミド反応、銅触媒型アジド−アルキン環化付加(CuAAC)反応、歪み促進型アジド−アルキンクリックケミストリー(SPAAC)反応若しくは逆電子要請型ディールス・アルダー(iEDDA)反応により結合され、
前記第2成分が存在する場合に、前記第2成分は、CuAAC反応、SPAAC反応又はiEDDA反応により前記中心コア又は前記カップリングアームに結合され、
各前記第1成分は標的化成分であり、前記第2成分はエフェクター成分であり、 又はその逆もまた然りであり、前記標的化成分は、ドナー移植物の細胞のみに存在するヒト白血球抗原(HLA)アロタイプに特異的な抗体断片であり、前記エフェクター成分は、免疫抑制剤、免疫チェックポイントタンパク質、又はCD25に特異的な抗体断片であり、
前記複数の第1成分がCuAAC又はSPAAC反応によりそれぞれ前記複数のリンクアームに結合される場合に、前記中心コアのN末端又はC末端にあるアミノ酸残基は、システイン残基であり、前記カップリングアームの遊離末端は、テトラジン基又はシクロオクテン基であり、
前記複数の第1成分がiEDDA反応によりそれぞれ複数のリンクアームに結合される場合に、前記中心コアのN末端又はC末端にあるアミノ酸残基は、アジド基又はアルキン基を有し、或いは、前記中心コアのN末端又はC末端にあるアミノ酸残基は、システイン残基であり、カップリングアームの遊離末端は、アジド基、アルキン基、又はシクロオクチン基であるリンカーユニット。 - 前記HLAアロタイプは、HLA−A、HLA−B、又はHLA−Cである請求項1に記載のリンカーユニット。
- 前記免疫抑制剤は、ラパマイシンの哺乳動物標的(mTOR)の阻害剤、又はカルシニューリンの阻害剤である請求項1に記載のリンカーユニット。
- 前記mTORの阻害剤は、シロリムス又はエベロリムスであり、又は前記カルシニューリンの阻害剤は、タクロリムスである請求項3に記載のリンカーユニット。
- 前記免疫抑制剤は、フィンゴリモドである請求項1に記載のリンカーユニット。
- 前記免疫チェックポイントタンパク質は、細胞傷害性Tリンパ球関連タンパク質4(CTLA−4)の細胞外ドメイン、又はプログラム細胞死リガンド1(PD−L1)の細胞外ドメインである請求項1に記載のリンカーユニット。
- 前記充填配列は、GS、GGS、GSG、又は配列番号: 1−16の配列を含む請求項1に記載のリンカーユニット。
- 各前記リンクアームは、2−20個のEGの繰り返し単位を有するPEG鎖であり、
前記カップリングアームは、2−12個のEGの繰り返し単位を有するPEG鎖である請求項1に記載のリンカーユニット。 - 前記アジド基を有するアミノ酸残基は、L−アジドホモアラニン(AHA)、4−アジド−L−フェニルアラニン、4−アジド−D−フェニルアラニン、3−アジド−L−アラニン、3−アジド−D−アラニン、4−アジド−L−ホモアラニン、4−アジド−D−ホモアラニン、5−アジド−L−オルニチン、5−アジド−d−オルニチン、6−アジド−L−リジン、又は6−アジド−D−リジンであり、
前記アルキン基を有するアミノ酸残基は、L−ホモプロパギルグリシン(L−HPG)、D−ホモプロパギルグリシン(D−HPG)、又はβ−ホモプロパギルグリシン(β−HPG)であり、
前記シクロオクテン基は、トランス−シクロオクテン(TCO)であり、前記シクロオクチン基は、ジベンゾシクロオクチン(DBCO)、ジフルオロシクロオクチン(DIFO)、ビシクロノニン(BCN)、又はジベンゾシクロオクチン(DICO)であり、
前記テトラジン基は、1,2,3,4−テトラジン、1,2,3,5−テトラジン若しくは1,2,4,5−テトラジンである請求項1に記載のリンカーユニット。 - 前記第2成分は、CuAAC反応又はSPAAC反応により前記中心コアのN末端又はC−末端アミノ酸残基のアジド基又はアルキン基に結合される請求項1に記載のリンカーユニット。
- iEDDA反応により前記カップリングアームに結合される第3成分をさらに含む請求項10に記載のリンカーユニット。
- ドナー移植物を受けている被験体の移植拒絶を治療するための医薬組成物であって、請求項1に記載のリンカーユニットを含む医薬組成物。
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