JP2011526303A - エラスチン様ペプチドを含む治療剤 - Google Patents
エラスチン様ペプチドを含む治療剤 Download PDFInfo
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Abstract
【選択図】 図12
Description
[0003] 本明細書と共に電子的に提出されたテキストファイルの内容を、本明細書においてそのまま参考として援用する。配列表のコンピューターで読取り可能なフォーマットのコピー(ファイルネーム:PHAS_010_01US_SeqList_ST25.txt、記録日:2009年6月26日、ファイルサイズ50kb)。
[0042] 本発明の治療剤は、1つまたは複数のELP成分を含み得る。ELP成分は、エラスチンタンパク質に関連する、または由来する構造的なペプチドユニットもしくは配列を含み、またはそれらから構成される。かかる配列は、表1に掲載されているもののほか、GLP−1受容体作動薬(例えば、GLP-1またはエキセンジン-4)、インスリン、および第VII/VIIa因子等の、治療用タンパク質の特性を、生物学的利用能、治療有効量、生物学的作用、処方適合性、タンパク質分解に対する抵抗性、溶解性、投与後の体内における半減期またはそのほかの持続性に関する指標、および/または体内から排除される速度のうちの1つまたは複数において改善するのに有用である。
(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、ここでXは、天然または非天然の任意のアミノ酸残基であり、またXは任意選択により、ポリマーの繰返しまたはオリゴマーの繰返しの中で変化する;
(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−X−Gly、またはIPGXG(配列番号5)、ここでXは、天然または非天然の任意のアミノ酸残基であり、またXは任意選択により、ポリマーの繰返しまたはオリゴマーの繰返しの中で変化する;
(e)ペンタペプチドIle−Pro−Gly−Val−Gly、またはIPGVG(配列番号6);
(f)ペンタペプチドLeu−Pro−Gly−X−Gly、またはLPGXG(配列番号7)、ここでXは、天然または非天然の任意のアミノ酸残基であり、またXは任意選択により、ポリマーの繰返しまたはオリゴマーの繰返しの中で変化する;
(g)ペンタペプチドLeu−Pro−Gly−Val−Gly、またはLPGVG(配列番号8);
(h)ヘキサペプチドVal−Ala−Pro−Gly−Val−Gly、またはVAPGVG(配列番号9);
(I)オクタペプチドGly−Val−Gly−Val−Pro−Gly−Val−Gly、またはGVGVPGVG(配列番号10);
(J)ノナペプチドVal−Pro−Gly−Phe−Gly−Val−Gly−Ala−Gly、またはVPGFGVGAG(配列番号11);および
(K)ノナペプチドVal−Pro−Gly−Val−Gly−Val−Pro−Gly−Gly、またはVPGVGVPGG(配列番号12)。
配列番号1〜12で定義されるかかる構造的ユニットは、構造的繰返しユニットを形成することができ、または本発明に基づきELP成分を形成するために組み合わせて用いることができる。いくつかの実施形態では、ELP成分は、配列番号1〜12から選択される構造的ユニットのうちの1つまたは組み合わせたもの(例えば、2、3、または4個を)から、全体的に(またはほぼ全体的に)形成される。別の実施形態では、ELP成分の少なくとも75%、または少なくも80%、または少なくとも90%は、配列番号1〜12から選択される構造的ユニットのうちの1つまたは組み合わせたものから形成され、これらは繰返しユニットとして存在し得る。
[0064] 本発明の特定の実施形態では、治療剤はGLP−1、エキセンジン−4、またはこれらの機能的アナログ等のGLP−1受容体作動薬と融合した、または結合したELP成分を含む。
[0094] 別の実施形態では、本発明は、インスリンと結合した(例えば、融合または結合による)ELP成分を含む治療剤を提供する。糖尿病を治療するために、インスリン注射、例えばヒトインスリン注射が利用可能である。体内のインスリン産生細胞はβ−細胞と呼ばれ、同細胞は膵臓分泌腺中に見出される。これらの細胞は、共に凝集して「ランゲルハンス島」を形成するが、「ランゲルハンス」は、これを説明したドイツ人医学生の名に由来する。
[0114] 特定の実施形態では、本発明は、第VII/VIIa因子と結合(例えば、融合または結合による)したELP成分を含む治療剤を提供する。凝固は、多くの異なるセリンプロテアーゼのほか、その必須補助因子および阻害剤が関与する、血液凝固物形成の生物学的プロセスである。凝固は、第VII因子(FVII)および第VIIa因子(FVIIa)が、膜結合補助因子である組織因子(TF)に暴露されることにより開始し、第Xa因子(FXa)、およびさらなるVIIaの産生を引き起こす。当該プロセスは、第IXa因子(FIXa)およびさらなるFXaの産生に乗じて伝播し、これらの因子は、その補助因子であるFVIIIaおよびFVaと結合すると、血小板結合複合体を形成し、最終的にトロンビンおよびフィブリン塊の形成を引き起こす。トロンビンは、FVおよびFVII等の補助因子、ならびに第XI因子等のチモーゲンの活性化による凝固をさらに増幅する機能も果たす。さらにトロンビンは、血小板を活性化して止血血栓形成に必要な血小板凝集を引き起こす。
[0133] 本発明は、ELP成分、および表1から選択される少なくとも1つの治療用タンパク質を含む治療剤をさらに提供する。ELP成分および治療用タンパク質は、本明細書に記載する遺伝子組換え融合または化学結合により結合可能である。かかる治療用タンパク質は、タンパク質名およびGeneSeqアクセッション番号別に表1に掲載されている。各治療用タンパク質のアミノ酸配列は、当技術分野で公知であるが、表1に掲載する各治療用タンパク質について、本明細書において参考として援用する。かかる治療用タンパク質は、やはり表1に掲載されている米国特許または国際公表にさらに記載されているが、かかる米国特許および国際公表を本明細書において、特にかかる治療用タンパク質の構造および記載された機能的アナログに関して、参考として援用する。
[0140] 別の態様では、本発明は、本発明の治療剤をコードするヌクレオチド配列を含むポリヌクレオチドを提供する。かかるポリヌクレオチドは、ELP成分および治療成分をコードする配列に加えて、1つまたは複数の発現制御要素をさらに含む。例えば、ポリヌクレオチドは、発現制御要素として、1つまたは複数のプロモーター、または転写エンハンサー、リボソーム結合部位、転写終結シグナル、およびポリアデニレーションシグナルを含み得る。当該ポリヌクレオチドは、任意の適するベクター内に挿入可能で、同ベクターは、発現用の任意の適する宿主細胞内に含まれ得る。
[0142] 本発明は、薬学的に許容される担体または賦形剤と共に、本発明の治療剤(上記のような)を含む医薬組成物をさらに提供する。かかる医薬組成物は、それぞれの治療用タンパク質、例えば表1に掲載する治療用タンパク質、GLP−1受容体作動薬、インスリン、および第VII/VIIa因子の実施形態に関して上記治療方法で利用可能である。
[0160] クローニング工程は、大腸菌株XL1−Blue(rec A1、endA1、gyrA96、thi-1、hsdR17(rk −, mk +)、supE44、relA1、lac[F'、proAB、/αclqZΔM15、Tn10(Tetr)])(Stratagene La Jolla、CA)内で実施した。pUC19(NEB、Beverly、MA)を、ELP構築物のクローニングベクターとして用いた(MeyerおよびChilkoti、Nat. Biotechnol.、第17巻(11):1112〜5頁、1999年)。pET15bベクターおよびpET24dベクター(Novagen)の改変形態を、BL21 Star(DE3)株(F-、ompT、hsdSB(rB -mB -)、gal、dcm、rne131、(DE3))(Invitrogen Carlsbed、CA)、またはBLR(DE3)(F-、ompT、hsdSB(rB -mB -)、gal、dcm、Δ(srl-recA)306::Tn10(TcR)(DE3))(Novagen Madison、WI)内でELPおよびELP融合タンパク質を発現させるために用いた。合成DNAオリゴは、Integrated DNA Technologies、Coralville、IAより購入した。すべてのベクター構築物を、標準的な分子生物学プロトコール(例えば、Current Protocols in Molecular Biology、Ausubelら編、1995年)を用いて作製した。
[0161] ELP1[V5A2G3]シリーズは、ペンタペプチドVPGXG(配列番号3)からなる複数の繰返しユニットを含むポリペプチドを指し、Xは、相対比が5:2:3のバリン、アラニン、およびグリシンである。
[0163] ELP1[K1V2F1]シリーズは、ペンタペプチドVPGXG(配列番号3)からなる複数の繰返しユニットを含むポリペプチドを指し、Xは、相対比が1:2:1のリジン、バリン、およびフェニルアラニンである。
[0165] ELP1[K1V7F1]シリーズは、ペンタペプチドVPGXG(配列番号3)からなる複数の繰返しユニットを含むポリペプチドを指し、Xは、相対比が1:7:1のリジン、バリン、およびフェニルアラニンである。
[0167] ELP1[V]シリーズは、ペンタペプチドVPGXG(配列番号3)からなる複数の繰返しユニットを含むポリペプチドを指し、Xはもっぱらバリンである。
[0169] ELP2シリーズは、ペンタペプチドAVGVPからなる複数の繰返しユニットを含むポリペプチドを指す。
[0171] ELP3[V]シリーズは、ペンタペプチドIPGXG(配列番号5)からなる複数の繰返しユニットを含むポリペプチドを指し、Xはもっぱらバリンである。
[0173] ELP4[V]シリーズは、ペンタペプチドLPGXG(配列番号7)からなる複数の繰返しユニットを含むポリペプチドを指し、Xはもっぱらバリンである。
[0188] ELP−InsA融合タンパク質には、下記事項が含まれた:
[0196] ELP1の薬物動態は、leg/flank FaDu異種移植片を有するヌードマウス(Balb/c nu/nu)に[14C]ELP1を静脈内注射し、投与後の様々な時間において血液サンプルを収集することにより決定された。血液薬物動態は特徴的な分布、および大型の巨大分子に対して排除反応を示したが、これは、二相性の指数プロセスにより良く説明された。
14C標識ELP1−150および/または14C標識ELP2−160
[0199] 14C標識ELP1−150および/または14C標識ELP2−160を、FaDu腫瘍を有するヌードマウスに投与した(平均+/-SD、n=6)。腫瘍を、ELPの投与後に41.5℃のウォーターバス中で加温した。分布は、血液含量が最も高い器官:肝臓、腎臓、脾臓、および肺で最大であった。
[0200] 14C標識ELP2−[V1A8G7−160](Tt>60℃)を、血漿濃度が15μMとなるようにヌードマウスに投与した。ヌードマウスの右後肢に位置する移植したFaDu腫瘍を1時間加温(41℃)した後、ELP濃度を求めた。データを平均値と95%信頼区間として示す。N=6。
[0202] エキセンジン−4(Ex-4)のDNA配列(配列番号14)は、大腸菌の発現に最適化されたコドンを用いて、アミノ酸配列から逆翻訳された。エキセンジン−4をコードするDNA配列は、プラスミドpET24d−ELP1−90(図1)内の制限部位NdeIおよびXhoIに適合性を有するオーバーハンギング5’および3’末端を備えた合成オリゴヌクレオチドを共にアニーリングすることにより構築された。このプラスミドは、制限酵素NdeIおよびXhoIで消化され、アニーリングされたDNA配列はカットベクターにライゲートされた。挿入は、制限消化およびDNA配列決定により確認された。得られたプラスミドは、pET24d−Ex−4 ELP1−90として定義され(図2A)、得られたエキセンジン−4−ELP融合体の配列を、図2Bに示す。融合体構築物のプライマーも示す。
[0211] ELPプラスミド構築物が、2種類のGLP1−ELP融合タンパク質、GLP1(A8G, 7〜37)ELP1−90およびGLP1(A8G, 7〜37)ELP1−120を調製するために用いられた。このプラスミド構築物、融合体をコードするヌクレオチド配列、ならびに得られた融合タンパク質のアミノ酸配列を図5および6に示す。
[0213] 凝固第VII因子(FVII)遺伝子は、cDNAクローン(Oragene)に基づきPCR法を用いて改変して、5’末端および3’末端に、ELP含有ベクターにクローニングするための制限部位を付け加えた。5’末端にNheI部位を付加し、3’末端にはNotI部位を付加した。第VII因子遺伝子のDNA配列およびアミノ酸配列を、添付の配列リストにそれぞれ配列番号34および33として示す。第VII因子(FVII)遺伝子をPCR増幅するために用いた5’および3’プライマーのDNA配列は以下の通りであった:
P13:CTAGCTAGCATGGTCTCCCAGGCCCTC(配列番号49)
P14:TATTCTTGCGGCCGCGGGAAATGGGGCTCGCAG(配列番号50)
[0217] ヒトインスリン遺伝子のcDNAは、pET24d−ELP1−90に挿入するために、5’末端および3’末端で改変を受ける。5’プライマーには、細菌発現させるためのN末端メチオニン、およびNdeI制限酵素部位が付加される。3’プライマーには、XhoI制限酵素部位が付加される。PCR産物およびプラスミドは、共に制限酵素NdeIおよびXhoIで消化され、共にライゲートされる。ELP1に融合したインスリン(B、C、およびA鎖)の配列を図8Aに示す。
[0222] 50個のアミノ酸をコードする遺伝子が、標準的な分子生物学プロトコールを用いて化学的に合成されたオリゴヌクレオチドから構築された。50個のアミノ酸配列には、ペンタペプチドVPGXG(配列番号3)の10回の繰返しが含まれ、ゲスト残基(5:3:2のモル比のV、G、およびA)は、Ttが40℃となるように選択された。この遺伝子は、標準的な分子生物学の技術により、端と端が結合するようにオリゴマー化されて、オリゴマー化したELP遺伝子が生み出された。さらに、ペンタペプチドVPGXG(配列番号3)を10回繰り返したポリペプチドを含む、単一の50個のアミノ酸配列が構築されたが、ゲスト残基は、4:3:2:1のモル比のV、G、A、およびCである。この配列は、構築物の長さ方向の選択されたポイントで、1つのシステイン残基を最終構築物に導入するように、オリゴマー化プロセスの任意のサイクルで付加され得る。
[039] 図11は、第VIIa因子−ELP1−90、および比較として第VIIa因子による第X因子の活性化を示す図である。第VII因子−ELPは、HEK細胞中で産生された。第VIIa因子はヒト血漿から得られた。示す通り、第VIIa因子−ELPは、全活性を維持している。
[0132] GLP−1受容体(GLP1R)が活性化されると、cAMPの二次メッセンジャーが細胞中に産生される。したがって、GLP−1またはエキセンジン−4アナログ、および関連する治療剤は、細胞表面上のGLP1Rを活性化させ、またcAMPを産生させるこれらの能力に基づき試験することができる。
[0135] GLP−1、またはエキセンジンアナログ、または関連する治療剤の活性は、動物中で試験可能である。本アッセイでは、健常動物または糖尿病動物を用いることができる。血糖濃度が300〜500mg/dlの糖尿病動物に、異なる用量のGLP−1、またはエキセンジンアナログ、または関連する治療剤を注射し、血糖の変化をグルコメーターでモニターする。投与後の異なる時点におけるグルコースの低下を、標準量のGLP−1またはエキセンジン−4ペプチドから得られた結果と比較するか、本発明の治療剤の融合していない、または結合していない対照物の結果と比較する。あるいは、体外からグルコースを投与した後の所定の時間における健常動物または糖尿病動物の血糖上昇を、GLP−1またはエキセンジン−4(または、治療剤の融合していない、または結合していない対照物)と比較する。このようにして、アナログおよび融合タンパク質の活性を、天然型のペプチドと比較することができる。
Claims (100)
- エラスチン様ペプチド(ELP)成分、および治療成分を含む治療剤であって、前記治療成分単独と比較したときに、前記治療成分の循環半減期が延長され、および/または治療有効量が低減されている治療剤。
- 前記治療成分が、表1に掲載されている治療用タンパク質、またはその機能的部分、もしくは機能的アナログである、請求項1に記載の治療剤。
- ELP成分が前記治療用タンパク質と、そのNおよび/またはC末端で共有結合している、請求項2に記載の治療剤。
- 治療成分が前記ELP成分と、前記ELP成分のN末端で共有結合し、第2の治療成分が前記ELP成分と、前記ELP成分のC末端で共有結合している、請求項1から3のいずれか一項に記載の治療剤。
- 治療成分が前記ELP成分と、そのNおよび/またはC末端で共有結合している、請求項1から4のいずれか一項に記載の治療剤。
- 第1のELP成分が前記治療成分と、前記治療成分のN末端で共有結合し、および第2のELP成分が前記治療成分と、前記治療成分のC末端で共有結合している、請求項1から5のいずれか一項に記載の治療剤。
- 前記ELP成分と前記治療成分との間に、スペーサー部分をさらに含む、請求項1から6のいずれか一項に記載の治療剤。
- 前記スペーサー部分が、1つまたは複数のプロテアーゼ抵抗性部分、非ペプチド性化学的部分、およびプロテアーゼ切断部位を含む、請求項7に記載の治療剤。
- 前記プロテアーゼ切断部位が、トロンビン切断部位、第Xa因子切断部位、メタロプロテアーゼ切断部位、エンテロキナーゼ切断部位、Tev切断部位、およびカテプシン切断部位である、請求項8に記載の治療剤。
- 前記スペーサー部分が、式[(Gly)n−Ser]m(配列番号22)を有する非切断可能部分を含み、式中、nは1〜4であり、mは1〜4である、請求項9に記載の治療剤。
- 前記ELPが、配列番号1〜12より選択される少なくとも1つの繰返しユニットを含む、請求項1から10のいずれか一項に記載の治療剤。
- 前記繰返しユニットが、VPGXG(配列番号3)である、請求項11に記載の治療剤。
- Xが任意の天然または非天然のアミノ酸残基であり、Xは少なくとも2つのユニット間で変化する、請求項12に記載の治療剤。
- 各Xが、アラニン、アルギニン、アスパラギン、アスパラギン酸、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、セリン、トレオニン、トリプトファン、チロシン、およびバリン残基から独立に選択される、請求項13に記載の治療剤。
- 約50kDa未満の分子量を有する、請求項1から14のいずれか一項に記載の治療剤。
- 前記ELP成分が、37℃より高いTtを有する、請求項1から15のいずれか一項に記載の治療剤。
- 遺伝的にコードされた融合タンパク質である、請求項1から16のいずれか一項に記載の治療剤。
- 請求項17に記載の治療剤をコードするヌクレオチド配列を含むポリヌクレオチド。
- 前記ヌクレオチド配列に作動可能に連結した発現制御要素をさらに含む、請求項18に記載のポリヌクレオチド。
- 前記発現制御要素がプロモーターを含む、請求項19に記載のポリヌクレオチド。
- 請求項18から20のいずれか一項に記載のポリヌクレオチドを含むベクター。
- 請求項21に記載のベクター、または請求項18から20のいずれか一項に記載のポリヌクレオチドを含む単離された宿主細胞。
- 請求項1から18のいずれか一項に記載の治療剤、および薬学的に許容される担体および/または賦形剤を含む医薬組成物。
- 請求項1から17のいずれか一項に記載の治療剤、または請求項23に記載の医薬組成物の有効量を、これを必要とする対象に投与する工程を含む、対象の疾患、障害、または状態を治療または予防するための方法。
- 前記対象が、表1に掲載する効能を有する、請求項24に記載の方法。
- エラスチン様ペプチド(ELP)成分、およびグルカゴン様ペプチド(GLP)−1受容体作動薬を含む治療剤。
- 前記GLP−1受容体作動薬が、GLP−1またはその機能的アナログである、請求項26に記載の治療剤。
- 前記GLP−1受容体作動薬が、エキセンジン−4またはその機能的アナログである、請求項26に記載の治療剤。
- 前記ELP成分が前記GLP−1受容体作動薬と、そのNおよび/またはC末端で共有結合している、請求項26から28のいずれか一項に記載の治療剤。
- 第1のGLP−1受容体作動薬が前記ELP成分と、前記ELP成分のN末端で共有結合し、および第2のGLP−1受容体作動薬が前記ELP成分と、前記ELP成分のC末端で共有結合している、請求項26から29のいずれか一項に記載の治療剤。
- 前記GLP−1受容体作動薬が前記ELP成分と、そのNおよび/またはC末端で共有結合している、請求項26から30のいずれか一項に記載の治療剤。
- 第1のELP成分が前記GLP−1受容体作動薬と、前記GLP−1受容体作動薬のN末端で共有結合し、および第2のELP成分が前記GLP−1受容体作動薬と、前記GLP−1受容体作動薬のC末端で共有結合している、請求項26から31のいずれか一項に記載の治療剤。
- 前記ELP成分と前記GLP−1受容体作動薬との間に、スペーサー部分をさらに含む、請求項26から32のいずれか一項に記載の治療剤。
- 前記スペーサー部分が、1つまたは複数のプロテアーゼ抵抗性部分、非ペプチド性化学的部分、およびプロテアーゼ切断部位を含む、請求項33に記載の治療剤。
- 前記プロテアーゼ切断部位が、トロンビン切断部位、第Xa因子切断部位、メタロプロテアーゼ切断部位、エンテロキナーゼ切断部位、Tev切断部位、およびカテプシン切断部位である、請求項34に記載の治療剤。
- 前記スペーサー部分が、式[(Gly)n−Ser]m(配列番号22)を有する非切断可能部分を含み、式中、nは1〜4であり、mは1〜4である、請求項34に記載の治療剤。
- 前記ELPが、配列番号1〜12より選択される少なくとも1つの繰返しユニットを含む、請求項26から36のいずれか一項に記載の治療剤。
- 前記繰返しユニットが、VPGXG(配列番号3)である、請求項37に記載の治療剤。
- Xが任意の天然または非天然のアミノ酸残基であり、Xは少なくとも2つのユニット間で変化する、請求項38に記載する治療剤。
- 各Xが、アラニン、アルギニン、アスパラギン、アスパラギン酸、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、セリン、トレオニン、トリプトファン、チロシン、およびバリン残基から独立に選択される、請求項38に記載の治療剤。
- 約50kDa未満の分子量を有する、請求項26から40のいずれか一項に記載の治療剤。
- 前記ELP成分が、37℃より高いTtを有する、請求項26から40のいずれか一項に記載の治療剤。
- 遺伝的にコードされた融合タンパク質である、請求項26から42のいずれか一項に記載の治療剤。
- 請求項43に記載の治療剤をコードするヌクレオチド配列を含むポリヌクレオチド。
- 前記ヌクレオチド配列に作動可能に連結した発現制御要素をさらに含む、請求項44に記載のポリヌクレオチド。
- 前記発現制御要素が、プロモーターを含む、請求項45に記載のポリヌクレオチド。
- 請求項44から46のいずれか一項に記載のポリヌクレオチドを含むベクター。
- 請求項47に記載のベクター、または請求項44から46のいずれか一項に記載のポリヌクレオチドを含む単離された宿主細胞。
- 請求項26から43のいずれか一項に記載の治療剤、および薬学的に許容される担体および/または賦形剤を含む医薬組成物。
- 請求項26から43のいずれか一項に記載の治療剤、または請求項49に記載の医薬組成物の有効量を、これを必要とする対象に投与する工程を含む、対象の生物学的状態、障害、または疾患を治療または予防するための方法。
- 前記対象が糖尿病を有する、請求項50に記載の方法。
- エラスチン様ペプチド(ELP)成分、およびインスリンまたはその機能的アナログを含む治療剤。
- 前記ELP成分が前記インスリンまたは機能的アナログと、そのNおよび/またはC末端で共有結合している、請求項52に記載の治療剤。
- 第1のインスリンまたは機能的アナログが前記ELP成分と、前記ELP成分のN末端で共有結合し、および第2のインスリンまたは機能的アナログが前記ELP成分と、前記ELP成分のC末端で共有結合している、請求項52または53に記載の治療剤。
- 前記インスリンまたは機能的アナログが前記ELP成分と、そのNおよび/またはC末端で共有結合している、請求項52に記載の治療剤。
- 第1のELP成分が前記インスリンまたは機能的アナログと、そのN末端で共有結合し、および第2のELP成分が前記インスリンまたは機能的アナログと、そのC末端で共有結合している、請求項52または53に記載の治療剤。
- 前記ELP成分と前記インスリンまたは機能的アナログとの間に、スペーサー部分をさらに含む、請求項52から56のいずれか一項に記載の治療剤。
- 前記スペーサー部分が、1つまたは複数のプロテアーゼ抵抗性部分、非ペプチド性化学的部分、およびプロテアーゼ切断部位を含む、請求項57に記載の治療剤。
- 前記プロテアーゼ切断部位が、トロンビン切断部位、第Xa因子切断部位、メタロプロテアーゼ切断部位、エンテロキナーゼ切断部位、Tev切断部位、またはカテプシン切断部位である、請求項58に記載の治療剤。
- 前記スペーサー部分が、式[(Gly)n−Ser]m(配列番号22)を有する非切断可能部分を含み、式中、nは1〜4であり、mは1〜4である、請求項58に記載の治療剤。
- 前記ELP成分が、配列番号1〜12より選択される少なくとも1つの繰返しユニットを含む、請求項52から60のいずれか一項に記載の治療剤。
- 前記繰返しユニットが、VGPXG(配列番号3)である、請求項61に記載の治療剤。
- 前記繰返しユニットが、Ile−Pro−Gly−X−Gly(配列番号5)、またはLeu−Pro−Gly−X−Gly(配列番号7)であり、Xは任意の天然または非天然のアミノ酸残基であり、Xは少なくとも2つのユニット間で変化する、請求項61に記載の治療剤。
- 各Xが、アラニン、アルギニン、アスパラギン、アスパラギン酸、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、セリン、トレオニン、トリプトファン、チロシン、およびバリン残基から独立に選択される、請求項62または63に記載の治療剤。
- 約50kDa未満の分子量を有する、請求項52から64のいずれか一項に記載の治療剤。
- 前記ELP成分が、37℃より高いTtを有する、請求項52から65のいずれか一項に記載の治療剤。
- 遺伝的にコードされた融合タンパク質である、請求項52から66のいずれか一項に記載の治療剤。
- 請求項67に記載の治療剤をコードするヌクレオチド配列を含むポリヌクレオチド。
- 前記ヌクレオチド配列に作動可能に連結した発現制御要素をさらに含む、請求項68に記載のポリヌクレオチド。
- 前記発現制御要素がプロモーターを含む、請求項69に記載のポリヌクレオチド。
- 請求項68から70のいずれか一項に記載のポリヌクレオチドを含むベクター。
- 請求項71に記載のベクター、または請求項68から70のいずれか一項に記載のポリヌクレオチドを含む単離された宿主細胞。
- 請求項52から67のいずれか一項に記載の治療剤、および薬学的に許容される担体および/または賦形剤を含む医薬組成物。
- 請求項52から67のいずれか一項に記載の治療剤、または請求項73に記載の医薬組成物の有効量を、これを必要とする対象に投与する工程を含む、対象の生物学的状態、障害、または疾患を治療または予防するための方法。
- 前記対象が糖尿病を有する、請求項74に記載の方法。
- エラスチン様ペプチド(ELP)成分、および第VII/VIIa因子またはその機能的アナログを含む治療剤。
- 前記ELP成分が、前記第VII/VIIa因子または機能的アナログと、前記第VII/VIIa因子のNおよび/またはC末端で共有結合している、請求項76に記載の治療剤。
- 第1の第VII/VIIa因子または機能的アナログが前記ELPと、前記ELP成分のN末端で共有結合し、および第2の第VII/VIIa因子または機能的アナログが前記ELP成分と、前記ELP成分のC末端で共有結合している、請求項76または77に記載の治療剤。
- 前記第VII/VIIa因子または機能的アナログが前記ELP成分と、前記ELP成分のNおよび/またはC末端で共有結合している、請求項76に記載の治療剤。
- 第1のELP成分が前記第VII/VIIa因子または機能的アナログと、そのN末端で共有結合し、および第2のELP成分が前記第VII/VIIa因子または機能的アナログと、そのC末端で共有結合している、請求項76または77に記載の治療剤。
- 前記ELP成分と第VII/VIIa因子または機能的アナログとの間に、スペーサー部分をさらに含む、請求項76から80のいずれか一項に記載の治療剤。
- 前記スペーサー部分が、1つまたは複数のプロテアーゼ抵抗性部分、非ペプチド性化学的部分、およびプロテアーゼ切断部位を含む、請求項81に記載の治療剤。
- 前記プロテアーゼ切断部位が、トロンビン切断部位、第Xa因子切断部位、メタロプロテアーゼ切断部位、エンテロキナーゼ切断部位、Tev切断部位、およびカテプシン切断部位である、請求項82に記載の治療剤。
- 前記スペーサー部分が、式[(Gly)n−Ser]m(配列番号22)を有する非切断可能部分を含み、式中、nは1〜4であり、mは1〜4である、請求項82に記載の治療剤。
- 前記ELP成分が、配列番号1〜12より選択される少なくとも1つの繰返しユニットを含む、請求項76から84のいずれか一項に記載の治療剤。
- 前記繰返しユニットが、VPGXG(配列番号3)である、請求項85に記載の治療剤。
- Xが任意の天然または非天然のアミノ酸残基であり、Xは少なくとも2つのユニット間で変化する、請求項86に記載する治療剤。
- 各Xが、アラニン、アルギニン、アスパラギン、アスパラギン酸、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、セリン、トレオニン、トリプトファン、チロシン、およびバリン残基から独立に選択される、請求項86に記載の治療剤。
- 約70kDa未満の分子量を有する、請求項76から88のいずれか一項に記載の治療剤。
- 前記ELP成分が37℃より高いTtを有する、請求項76から89のいずれか一項に記載の治療剤。
- 遺伝的にコードされた融合タンパク質である、請求項76から90のいずれか一項に記載の治療剤。
- 請求項91に記載の治療剤をコードするヌクレオチド配列を含むポリヌクレオチド。
- 前記ヌクレオチド配列に作動可能に連結した発現制御要素をさらに含む、請求項92に記載のポリヌクレオチド。
- 前記発現制御要素がプロモーターを含む、請求項93に記載のポリヌクレオチド。
- 請求項92から94のいずれか一項に記載のポリヌクレオチドを含むベクター。
- 請求項95に記載のベクター、または請求項92から95のいずれか一項に記載のポリヌクレオチドを含む単離された宿主細胞。
- 請求項76から91のいずれか一項に記載の治療剤、および薬学的に許容される担体および/または賦形剤を含む医薬組成物。
- 請求項76から91までのいずれか一項に記載の治療剤、または請求項97に記載の医薬組成物の有効量を、これを必要とする対象に投与する工程を含む、生物学的状態、障害、または疾患について対象を予防または治療するための方法。
- 前記対象が出血を有する、請求項98に記載の方法。
- 前記対象が血友病を有する、請求項98または99に記載の方法。
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JP2014534265A (ja) * | 2011-11-28 | 2014-12-18 | フェーズバイオ ファーマシューティカルズ,インコーポレイテッド | インスリンアミノ酸配列を含む治療薬 |
JP2018500291A (ja) * | 2014-11-21 | 2018-01-11 | フェーズバイオ ファーマシューティカルズ,インコーポレイテッド | 制御放出および持続的放出のためのelp融合タンパク質 |
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US9127047B2 (en) | 2015-09-08 |
US20130085099A1 (en) | 2013-04-04 |
US20190091297A1 (en) | 2019-03-28 |
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US20230000952A1 (en) | 2023-01-05 |
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CA2953975C (en) | 2019-11-26 |
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CA2726894A1 (en) | 2009-12-30 |
CN105727261A (zh) | 2016-07-06 |
EP2926825A1 (en) | 2015-10-07 |
EP3412300A1 (en) | 2018-12-12 |
JP2015218177A (ja) | 2015-12-07 |
US20160030521A1 (en) | 2016-02-04 |
CN102131516A (zh) | 2011-07-20 |
EP2307038A4 (en) | 2013-03-27 |
WO2009158704A3 (en) | 2010-03-18 |
JP2019085420A (ja) | 2019-06-06 |
CN102131516B (zh) | 2016-03-16 |
US20160120952A1 (en) | 2016-05-05 |
CA2953975A1 (en) | 2009-12-30 |
US20200282022A1 (en) | 2020-09-10 |
HK1215182A1 (zh) | 2016-08-19 |
US20100022455A1 (en) | 2010-01-28 |
US8178495B2 (en) | 2012-05-15 |
US20130085104A1 (en) | 2013-04-04 |
JP2017088627A (ja) | 2017-05-25 |
US9200083B2 (en) | 2015-12-01 |
US9821036B2 (en) | 2017-11-21 |
US20130079277A1 (en) | 2013-03-28 |
US11103558B2 (en) | 2021-08-31 |
WO2009158704A2 (en) | 2009-12-30 |
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