JP5802250B2 - 融合ペプチド治療用組成物 - Google Patents
融合ペプチド治療用組成物 Download PDFInfo
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- JP5802250B2 JP5802250B2 JP2013217181A JP2013217181A JP5802250B2 JP 5802250 B2 JP5802250 B2 JP 5802250B2 JP 2013217181 A JP2013217181 A JP 2013217181A JP 2013217181 A JP2013217181 A JP 2013217181A JP 5802250 B2 JP5802250 B2 JP 5802250B2
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- Prior art keywords
- elp
- protein
- elp1
- thioredoxin
- peptide
- Prior art date
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Description
本出願は、全体が本明細書に参照により組み込まれる、2006年9月6日に出願された米国特許出願第60/842,464号の35U.S.C.§119(e)に基づく優先権を主張するものである。
(a)テトラペプチドVal−Pro−Gly−Gly、またはVPGG(配列番号1);
(b)テトラペプチドIle−Pro−Gly−Gly、またはIPGG(配列番号2);
(c)ペンタペプチドVal−Pro−Gly−X−Gly(配列番号3)、またはVPGXG(式中、Xは、任意の天然または非天然のアミノ酸残基であり、Xは、ポリマーまたはオリゴマー反復の間で任意選択により変動してよい);
(d)ペンタペプチドAla−Val−Gly−Val−Pro、またはAVGVP(配列番号4);
(e)ペンタペプチドIle−Pro−Gly−Val−Gly、またはIPGVG(配列番号5);
(f)ペンタペプチドLeu−Pro−Gly−Val−Gly、またはLPGVG(配列番号6);
(g)ヘキサペプチドVal−Ala−Pro−Gly−Val−Gly、またはVAPGVG(配列番号7);
(h)オクタペプチドGly−Val−Gly−Val−Pro−Gly−Val−Gly、またはGVGVPGVG(配列番号8);
(i)ノナペプチドVal−Pro−Gly−Phe−Gly−Val−Gly−Ala−Gly、またはVPGFGVGAG(配列番号9);および
(j)ノナペプチドVal−Pro−Gly−Val−Gly−Val−Pro−Gly−Gly、またはVPGVGVPGG(配列番号10)。
Tt=M0+M1X+M2X2
(式中、XはFPのMWであり、M0=116.21;M1=−1.7499;M2=0.010349)。
(実施例1)
提示される事例研究では、ELP−(TEV)−ペプチド/タンパク質構築物を含有する大腸菌BL21 star菌株(Invitrogen社製)を、抗生剤を補足した培地で、誘導なしに37℃で24時間にわたり増殖させた。培養物を回収し、50mMトリス−HCL pH8.0および1mM EDTA中に再懸濁させた。細胞は、氷上における超音波破壊により溶解させた。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。25℃の溶解物に1.5Mの最終濃度までNaClを添加することにより、逆温度転移を誘導した後、25℃、20,000gで15分間にわたり遠心分離した。結果として得られるペレットは、ELP−(TEV)−ペプチド/タンパク質融合およびNaClによる非特異的な沈殿タンパク質を含有した。ペレットは、40mlの氷冷緩衝液中に再懸濁させ、4℃、20,000gで15分間にわたり遠心分離し、非特異的な不溶性タンパク質を除去した。温度転移サイクルをさらに3回繰り返し、ELP−TEV融合タンパク質の純度を高め、最終容量を5ml未満に減少させた。
上述の系(deltaPhase(商標))を用いて、37アミノ酸ペプチドを発現させ精製した。数ラウンドの転移により、発現したELP−ペプチド融合体を精製した。精製された融合体は、TEVプロテアーゼと共にインキュベートし、ペプチドを切断した。TEVプロテアーゼは、インキュベーション後に切断されたELPと共に溶液から除去させる別の実験において、ELP融合体として調製された。結果を図1に示すが、ここで、Mは分子量マーカー、Sは超音波分解後における溶解物、Pは遠心分離(転移前)から得られるペレット、Lは可溶性溶解物、Tnはn回目の転移から得られるペレットである。
次いで、ペプチド系列に可能なスループットおよび純度を決定した。表1に示す結果は、ペプチド系列を通じて一貫した成果物を産生する能力を示す。かつては、化学合成の限界により、ペプチド産生は3〜6週間ごとに1ペプチドに制限され、これによりペプチド最適化の速度が制限された。前出のdeltaPhase(商標)系を用いたところ、以下の6つのペプチドを2週間未満で産生することができた。この系を並行処理できるようになって、スループットは、数週間で容易に数百倍に増大した。
チオレドキシンおよびテンダミスタットは、(1)ペプチド活性治療剤が、高レベルで過剰発現し、高い可溶性である(チオレドキシン)、および(2)ペプチド活性治療剤が、大部分、不溶性の封入体として発現する(テンダミスタット)という、タンパク質発現の2つの限界的シナリオを例示する。
(実施例3)
5ポリペンタペプチドであるELPのVPGVG配列遺伝子は、PflMI適合末端およびHinDIIIの適合末端を有する2本鎖標準DNAを産出する、2つの5’側リン酸化合成オリゴヌクレオチド(アイオワ州、コーラルビル、Integrated DNA Technologies社製)をアニールすることにより構築した。この遺伝子を、PflMI/HinDIIIにより直鎖化し脱リン酸化した改変pUC−19ベクター(マサチューセッツ州、ビバリー、New England Biolabs社製)中に挿入し、PflMIおよびBglIを有する再帰的有向連結を用いてポリマー化し(Meyer, 1999; Meyer, 2000)、20ポリペンタペプチドのELP配列遺伝子を産生した。次いで、このELP遺伝子を、PflMIおよびBglIにより切断し、ゲル精製し(カリフォルニア州、バレンシア、Qiagen社製、QIAquickゲル抽出キット)、SfiIにより直鎖化し脱リン酸化した改変pET32bベクター(ウィスコンシン州、マジソン、Novagen社製;Meyer, 1999)内に挿入した。次いで、この発現ベクターを、BLR(DE3)(Novagen社製)大腸菌発現菌株内に形質転換した。
(実施例4)
細菌の菌株とプラスミド
クローニング工程は、大腸菌XL1−Blue菌株(recA1、endA1、gyrA96、thi−1、hsdR17(rk −,mk +)、supE44、relA1、lac[F’、proAB、lacIqZцΔM15、Tn10(TetI)])(カリフォルニア州、ラジョラ、Stratagene社製)内で行った。ELP構築物のクローニングベクターとしては、pUC19(マサチューセッツ州、ビバリー、NEB社製)を用いた(Meyer and Chilkoti, 1999)。pET15bベクターおよびpET24dベクターの改変形態(Novagen社製)を用いて、BL21 Star(DE3)菌株(F’’、ompT,hsdSB(rB −mB −)、gal、dcm、rnel31、(DE3))(カリフォルニア州、カールスバード、Invitrogen社製)、または、BLR(DE3)(F’’、ompT,hsdSB(rB −mB −)、gal、dcm、Δ(srl−recA)306::Tn10(TcR)(DE3))(ウィスコンシン州、マジソン、Novagen社製)内においてELPおよびELP融合タンパク質を発現した。合成DNAオリゴは、アイオワ州、コーラルビル、Integrated DNA Technologies社から購入した。すべてのベクター構築物は、標準的な分子生物学プロトコールを用いて作製した(Ausubel, et al., 1995)。
ELP1[V5A2G3]系列とは、Xが、5:2:3の相対比率でバリン、アラニン、およびグリシンである、ペンタペプチドVPGXGの多数回反復単位を含有するポリペプチドを指す。
ELP1[K1V2F1]系列とは、Xが、1:2:1の相対比率でリジン、バリン、およびフェニルアラニンである、ペンタペプチドVPGXGの多数回反復単位を含有するポリペプチドを指す。
ELP1[K1V7F1]系列とは、Xが、1:7:1の相対比率でリジン、バリン、およびフェニルアラニンである、ペンタペプチドVPGXGの多数回反復単位を含有するポリペプチドを指す。
ELP1[V]系列とは、Xがバリンに限る、ペンタペプチドVPGXGの多数回反復単位を含有するポリペプチドを指す。
ELP2系列とは、ペンタペプチドAVGVPの多数回反復単位を含有するポリペプチドを指す。
ELP3[V]系列とは、Xがバリンに限る、ペンタペプチドIPGXGの多数回反復単位を含有するポリペプチドを指す。
ELP4[V]系列とは、Xがバリンに限る、ペンタペプチドLPGXGの多数回反復単位を含有するポリペプチドを指す。
(実施例5)
以下の融合タンパク質が、特定の組合せにおける各種のペプチド活性治療剤およびELP種を例示することに注意されたい。
間にエンテロキナーゼプロテアーゼ切断部位を有する、インスリンAペプチドおよびELP1[V−60]ポリペプチド(配列番号23);
間にエンテロキナーゼプロテアーゼ切断部位を有する、インスリンAペプチドおよびELP1[V5A2G3−90]ポリペプチド(配列番号24);
間にエンテロキナーゼプロテアーゼ切断部位を有する、インスリンAペプチドおよびELP1[V−120]ポリペプチド(配列番号25);
間にエンテロキナーゼプロテアーゼ切断部位を有する、インスリンAペプチドおよびELP1[V5A2G3−180]ポリペプチド(配列番号26);
間にエンテロキナーゼプロテアーゼ切断部位を有する、T20ペプチドおよびELP1[V−60]ポリペプチド(配列番号27);
間にエンテロキナーゼプロテアーゼ切断部位を有する、T20ペプチドおよびELP1[V5A2G3−90]ポリペプチド(配列番号28);
間にエンテロキナーゼプロテアーゼ切断部位を有する、T20ペプチドおよびELP1[V−120]ポリペプチド(配列番号29);
間にトロンビンプロテアーゼ切断部位を有する、T20ペプチドおよびELP1[V−60]ポリペプチド(配列番号30);
間にトロンビンプロテアーゼ切断部位を有する、T20ペプチドおよびELP1[V5A2G3−90]ポリペプチド(配列番号31);
間にトロンビンプロテアーゼ切断部位を有する、T20ペプチドおよびELP1[V−120]ポリペプチド(配列番号32);
間にタバコエッチウイルス(TEV)プロテアーゼ切断部位(QS残基間の切断)を有する、T20ペプチドおよびELP1[V−60]ポリペプチド(配列番号33);
間にTEVプロテアーゼ切断部位(QS残基間の切断)を有する、T20ペプチドおよびELP1[V5A2G3−90]ポリペプチド(配列番号34);
間にTEVプロテアーゼ切断部位(QS残基間の切断)を有する、T20ペプチドおよびELP1[V−120]ポリペプチド(配列番号35);
間にTEVプロテアーゼ切断部位(QY残基間の切断)を有する、T20ペプチドおよびELP1[V−60]ポリペプチド(配列番号36);
間にTEVプロテアーゼ切断部位(QY残基間の切断)を有する、T20ペプチドおよびELP1[V5A2G3−90]ポリペプチド(配列番号37);
間にTEVプロテアーゼ切断部位(QY残基間の切断)を有する、T20ペプチドおよびELP1[V−120]ポリペプチド(配列番号38);
間にトロンビンプロテアーゼ切断部位を有する、インターフェロンアルファ2Bタンパク質およびELP1[V5A2G3−90]ポリペプチド(配列番号39);
間にトロンビンプロテアーゼ切断部位を有する、タバコエッチウイルスプロテアーゼおよびELP1[V−60]ポリペプチド(配列番号40);
間にトロンビンプロテアーゼ切断部位を有する、タバコエッチウイルスプロテアーゼおよびELP1[V5A2G3−90]ポリペプチド(配列番号41);
間にトロンビンプロテアーゼ切断部位を有する、タバコエッチウイルスプロテアーゼおよびELP1[V−120]ポリペプチド(配列番号42);
間にトロンビンプロテアーゼ切断部位を有する、タバコエッチウイルスプロテアーゼおよびELP1[V5A2G3−180]ポリペプチド(配列番号43);
間にトロンビンプロテアーゼ切断部位を有する、小ヘテロダイマーパートナーオーファン受容体およびELP1[V5A2G3−90]ポリペプチド(配列番号44);
間にトロンビンプロテアーゼ切断部位を有する、アンドロゲン受容体リガンド結合ドメインおよびELP1[V5A2G3−90]ポリペプチド(配列番号45);
間にトロンビンプロテアーゼ切断部位を有する、アンドロゲン受容体リガンド結合ドメインおよびELP1[V5A2G3−180]ポリペプチド(配列番号46);
間にトロンビンプロテアーゼ切断部位を有する、グルココルチコイド受容体リガンド結合ドメインおよびELP1[V5A2G3−90]ポリペプチド(配列番号47);
間にトロンビンプロテアーゼ切断部位を有する、エストロゲン受容体リガンド結合ドメインおよびELP1[V5A2G3−60]ポリペプチド(配列番号48);
間にトロンビンプロテアーゼ切断部位を有する、エストロゲン受容体リガンド結合ドメインおよびELP1[V5A2G3−90]ポリペプチド(配列番号49);
間にトロンビンプロテアーゼ切断部位を有する、エストロゲン受容体リガンド結合ドメインおよびELP1[V5A2G3−180]ポリペプチド(配列番号50);
間にTEVプロテアーゼ切断部位(QG残基間の切断)を有する、エストロゲン受容体リガンド結合ドメインおよびELP1[V5A2G3−90]ポリペプチド(配列番号51);
間にトロンビンプロテアーゼ切断部位を有する、Gタンパク質アルファQおよびELP1[V5A2G3−90]ポリペプチド(配列番号52);
間にトロンビンプロテアーゼ切断部位を有する、Gタンパク質アルファQおよびELP1[V5A2G3−180]ポリペプチド(配列番号53);
間にトロンビンプロテアーゼ切断部位を有する、1−デオキシ−D−キシルロース5−リン酸レダクトイソメラーゼペプチドおよびELP1[V5A2G3−60]ポリペプチド(配列番号54);
間にトロンビンプロテアーゼ切断部位を有する、1−デオキシ−D−キシルロース5−リン酸レダクトイソメラーゼペプチドおよびELP1[V5A2G3−90]ポリペプチド(配列番号55);
間にトロンビンプロテアーゼ切断部位を有する、1−デオキシ−D−キシルロース5−リン酸レダクトイソメラーゼペプチドおよびELP1[V5A2G3−180]ポリペプチド(配列番号56);
間にTEVプロテアーゼ切断部位(QG残基間の切断)を有する、1−デオキシ−D−キシルロース5−リン酸レダクトイソメラーゼペプチドおよびELP1[V5A2G3−90]ポリペプチド(配列番号57);および
間にトロンビンプロテアーゼ切断部位を有する、Gタンパク質アルファSおよびELP1[V5A2G3−90]ポリペプチド(配列番号58)
を大腸菌内において形成した。
各ELP−InsA融合タンパク質を含有する大腸菌BLR(DE3)菌株(Novagen社製)の単一コロニーを、100μg/mlアンピシリン(Sigma社製)を補足した5mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、37℃、250rpmで振盪しながら5時間にわたり増殖させた。次いで、5mlの培養物を500mlの培養液に接種し、25℃で16時間にわたり増殖させた後、1mM IPTGにより25℃で4時間にわたり誘導した。培養物を回収し、40mlの20mMトリス−HCL pH7.4、50mM NaCl、1mM DTT、および完全EDTA非含有プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
各ELP−T20融合タンパク質を含有する大腸菌BLR(DE3)菌株(Novagen社製)の単一コロニーを、100μg/mlアンピシリン(Sigma社製)を補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、37℃、250rpmで振盪しながら24時間にわたり増殖させた。培養物を回収し、40mlの50mMトリスpH8.0、0.5mM EDTA、および完全プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
ELP−IFNA2融合タンパク質およびCodon Plus−RILプラスミド(Stratagene社製)を含有する大腸菌BL21(DE3)TrxB菌株(Novagen社製)の単一コロニーを、100μg/mlアンピシリン(Sigma社製)、25ug/mlクロラムフェニコール(Sigma社製)を補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、27℃、250rpmで振盪しながら48時間にわたりインキュベートした。培養物を回収し、50mMトリス−HCL pH7.4、50mM NaCl、および完全EDTA非含有プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
pET15b−SD5−ELP−TEV構築物およびCodon Plus−RILプラスミド(Stratagene社製)を含有する大腸菌BL21 star菌株またはBRL(DE3)菌株の単一コロニーを、100μg/mlアンピシリン(Sigma社製)、25ug/mlクロラムフェニコール(Sigma社製)を補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、27℃、250rpmで振盪しながら48時間にわたりインキュベートした。培養物を回収し、50mMトリス−HCL pH8.0、1mM EDTA、5mM DTT、10%グリセロール、および1mM PMSF中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
ELP−SHP融合タンパク質を含有する大腸菌BL21 Star(DE3)菌株の単一コロニーを、100μg/mlアンピシリン(Sigma社製)および10%スクロースを補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、27℃、250rpmで振盪しながら48時間にわたり増殖させた。培養物を回収し、50mMトリス−HCL pH8.0、150mM KCL、1mM DTT、1mM EDTA、および完全EDTA非含有プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。可溶性溶解物中のDNAおよびRNAは、2μlベンゾナーゼ(Novagen社製)を添加し、4℃で30分間にわたりインキュベートすることによりさらに分解した。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
ELP−AR−LBD融合タンパク質を含有する大腸菌BL21 Star(DE3)菌株の単一コロニーを、100μg/mlアンピシリン(Sigma社製)および10μM DHTを補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、27℃、250rpmで振盪しながら48時間にわたり増殖させた。培養物を回収し、40mlの50mMヘペスpH7.5、150mM NaCl、0.1% N−オクチルグルコシド、10%グリセロール、1mM DTT、1μM DHT、および完全EDTA非含有プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。可溶性超音波分解物中のDNAおよびRNAは、2μlベンゾナーゼ(Novagen社製)を添加し、4℃で30分間にわたりインキュベートすることによりさらに分解した。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
ELP−GR−LBD融合タンパク質を含有する大腸菌BL21 Star(DE3)菌株の単一コロニーを、100μg/mlアンピシリン(Sigma社製)を補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、37℃、250rpmで振盪しながら24時間にわたり増殖させた。培養物を回収し、50mMヘペスpH7.5、150mM NaCl、1mM DTT、10%グリセロール、0.1% CHAPS、および完全EDTA非含有プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。可溶性溶解物中のDNAおよびRNAは、2μlベンゾナーゼ(Novagen社製)を添加し、4℃で30分間にわたりインキュベートすることによりさらに分解した。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
各ELP−ERα−LBD融合タンパク質を含有する大腸菌BL21 Star(DE3)菌株の単一コロニーを、100μg/mlアンピシリン(Sigma社製)、10%スクロース(Sigma社製)を補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、27℃、250rpmで振盪しながら48時間にわたり増殖させた。培養物を回収し、40mlの50mMトリス−HCL pH8.0、150mM KCL、1mM EDTA、1mM DTT、および完全EDTA非含有プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。可溶性溶解物中のDNAおよびRNAは、2μlベンゾナーゼ(Novagen社製)を添加し、4℃で30分間にわたりインキュベートすることによりさらに分解した。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
各ELP−Gαq融合タンパク質を含有する大腸菌BL21 Star(DE3)菌株の単一コロニーを、100μg/mlアンピシリン(Sigma社製)および1μM GDPを補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、37℃、250rpmで振盪しながら24時間にわたり増殖させた。培養物を回収し、40mlの50mMヘペスpH7.5、150mM NaCl、1.0% CHAPS、10%グリセロール、1mM DTT、10μM GDP、および完全EDTA非含有プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。可溶性溶解物中のDNAおよびRNAは、2μlベンゾナーゼ(Novagen社製)を添加し、4℃で30分間にわたりインキュベートすることによりさらに分解した。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
各ELP−DXR融合タンパク質を含有する大腸菌BL21 Star(DE3)菌株の単一コロニーを、100μg/mlアンピシリン(Sigma社製)、1mM MnCl2(VWR社製)を補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、37℃、250rpmで振盪しながら24時間にわたり増殖させた。培養物を回収し、40mlの0.1MトリスpH7.6、1mM DTT、および完全EDTA非含有プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。可溶性溶解物中のDNAおよびRNAは、2μlベンゾナーゼ(Novagen社製)を添加し、4℃で30分間にわたりインキュベートすることによりさらに分解した。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
ELP−Gαs融合タンパク質を含有する大腸菌BL21 Star(DE3)菌株の単一コロニーを、100μg/mlアンピシリン(Sigma社製)を補足した500mlのCircleGrow培地(カリフォルニア州、サンディエゴ、Q-BIOgene社製)に接種し、37℃、250rpmで振盪しながら24時間にわたり増殖させた。培養物を回収し、40mlのPBS、10%グリセロール、1mM DTT、および完全EDTA非含有プロテアーゼ阻害剤ペレット1個(イリノイ州、インディアナポリス、Roche社製)中に懸濁させた。細胞は、30秒間の冷却間隔を挟み、35%出力で10秒間の破壊からなる、氷上で3分間にわたる超音波破壊により溶解させた。可溶性溶解物中のDNAおよびRNAは、2μlベンゾナーゼ(Novagen社製)を添加し、4℃で30分間にわたりインキュベートすることによりさらに分解した。細胞破砕物は、4℃、20,000gで30分間にわたる遠心分離により除去した。
(実施例6)
前出の実施例1に記載のdeltaPhase(商標)系法により、10個のタンパク質の発現および精製を試験することに成功した。表2、および、3つのタンパク質について図3のSDS−PAGE図に示した結果は、多様なタンパク質が、>95%の純度まで精製できることを明確に示す。ELP1[V5A2G3−90]との融合タンパク質および固定化金属アフィニティ−クロマトグラフィー(IMAC)法による精製用タグとの融合タンパク質として発現した、青色蛍光タンパク質(BFP)、チオレドキシン(Trx)、クロラムフェニコールアセチルトランスフェラーゼ(CAT)、カルモジュリン(CalM)、およびアンジオスタチン(K1−3)を完全に特徴づけることにより、ELP融合タンパク質の発現および精製に対する体系的な評価を行った。発現は、大腸菌内で行った。ELP融合タンパク質の精製に対して得られた収量を、表2で一覧にする。
(実施例7)
前出の実施例1に記載のdeltaPhase(商標)系を用いて、サイズが2.0〜6.2kDaの範囲にあり、等電点が4.11〜12.3の範囲にある、医薬的に有意義な10ペプチドを発現させ精製した。以下の表3に示す通り、多数の発現条件および精製条件を変化させる広範な作業の後、90%を超える純度およびリットル当たり17〜23mgの収量を有する6つのペプチドを、発現させ精製することに成功した。
(実施例8)
融合ペプチドによる治療用タンパク質は、以下の4つのタンパク質:青色蛍光タンパク質(BFP)、クロラムフェニコールアセチルトランスフェラーゼ(CAT)、チオレドキシン(Trx)、およびインターロイキン1受容体拮抗物質(IL−1Ra)を用いて産生した。各組成物は、ELP1[V5A2G3−90]を用いて、ELP/タンパク質およびタンパク質/ELPの両方の配向で産生された。
CAT/ELP CAT−VENLYFQGGMG(配列番号59)−ELP
ELP/CAT ELP−VPGWPSSGDYDIPTTENLYFQGAH(配列番号60)−CAT
Trx/ELP Trx−GSGSGHMHHHHHHSSGLVPRGSGK(配列番号61)−ELP
ELP/Trx ELP−VPGWPSSGDYDIPTTENLYFQGAH(配列番号62)−Trx
BFP/ELP BFP−VDKLAAALDMHHHHHHSSGLVPRGSGK(配列番号63)−ELP
ELP/BFP ELP−VPGWPSSGDYDIPTTENLYFQGAH(配列番号64)−BFP
IL−1Ra/ELP IL−1Ra−LENLYFQGGMG(配列番号65)−ELP
ELP/IL−1Ra ELP−VPGWPSSGDYDIPTTENLYFQGAH(配列番号66)−IL−1Ra
(実施例9)
ELP1の薬物動態は、脚部/脇腹にFaDu異種移植を有するヌードマウス(Balb/c nu/nu)に[14C]ELP1を静脈内投与し、投与後の各時間経過後に血液試料を採取することにより決定した。血液濃度の経時推移および血漿半減期(初期t1/2αおよび終末t1/2β)を図5に示す。血中薬物動態は、高分子に対する特徴的な分布および排出応答を示し、これは、二重指数関数過程により十分に記載された。
(実施例10)
14Cで標識したELP1−150および/または14Cで標識したELP2−160
FaDu腫瘍を有するヌードマウスに、14Cで標識したELP1−150および/または14Cで標識したELP2−160を投与した(平均±SD、n=6)。腫瘍は、ELPの投与後に41.5℃の水浴中で加熱した。図6に見られる通り、分布は、最高血液含量器官である、肝臓、腎臓、脾臓、および肺において最高である。
15μMの血漿濃度で、ヌードマウスに14Cで標識したELP2−[V1A8G7−160](Tt>60℃)を投与した。ELP濃度は、ヌードマウスの右後脚に位置する、植え込んだFaDu腫瘍の1時間の加熱(41℃)後に決定した。データは、平均に95%信頼区間を加えて示す(N=6)。
Claims (17)
- 融合タンパク質及び医薬的に許容される担体を含む治療用組成物であって、
前記融合タンパク質が、N末端に含まれる治療用タンパク質、及び少なくとも1つのエラスチン様タンパク質(ELP)成分を含み、
前記治療用タンパク質が、その非融合対応物と比較して血液循環において延長された半減期を示し、且つ、
前記治療用タンパク質が、インスリンであり、該インスリンがプロテアーゼ切断性スペーサーにより前記ELP成分から分離されていない、治療用組成物。 - 前記ELP成分が、配列番号1〜12で定義される1つ以上の反復ペプチド単位から構築される、請求項1に記載の治療用組成物。
- 前記ELP成分が、VPGXG、IPGXG及び/又はLPGXG反復を含み、式中、Xは遺伝子にコードされたアミノ酸である、請求項2に記載の治療用組成物。
- 前記ELP成分が、VPGXG反復を含み、式中、各Xは、V、A、及びGから独立して選択されるか、又はK、V、及びFから独立して選択される、請求項3に記載の治療用組成物。
- Xは、約5:2:3の割合のV、A、及びGである、請求項4に記載の治療用組成物。
- Xは、約1:2:1の割合のK、V、及びFである、請求項4に記載の治療用組成物。
- 各Xは、Vである、請求項4に記載の治療用組成物。
- 前記ELP成分は、少なくとも60のVPGXG反復単位を含み、式中、各XはV、A、及びGから独立して選択される、請求項4に記載の治療用組成物。
- 前記ELP成分は、少なくとも90のVPGXG反復単位を含み、式中、各XはV、A、及びGから独立して選択される、請求項4に記載の治療用組成物。
- 前記ELP成分は、少なくとも120のVPGXG反復単位を含み、式中、各XはV、A、及びGから独立して選択される、請求項4に記載の治療用組成物。
- 前記ELP成分は、少なくとも60のVPGXG反復単位を含み、式中、Xは約5:2:3の割合のV、A、及びGである、請求項5に記載の治療用組成物。
- 前記ELP成分は、少なくとも90のVPGXG反復単位を含み、式中、Xは約5:2:3の割合のV、A、及びGである、請求項5に記載の治療用組成物。
- 前記ELP成分は、少なくとも120のVPGXG反復単位を含み、式中、Xは約5:2:3の割合のV、A、及びGである、請求項5に記載の治療用組成物。
- インスリンのC末端にELP成分を有する、請求項1〜13のいずれか1項に記載の治療用組成物。
- 前記組成物が非経口投与用に製剤化される、請求項1〜14のいずれか1項に記載の治療用組成物。
- 前記組成物が皮下投与、筋内投与、静脈内投与用に製剤化される、請求項15に記載の治療用組成物。
- 治療による処置方法で使用するための、請求項1〜16のいずれか1項に記載の治療用組成物。
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