JP2018512873A - 筋消耗疾患治療用の新規なハイブリッドactriibリガンド捕集タンパク質 - Google Patents
筋消耗疾患治療用の新規なハイブリッドactriibリガンド捕集タンパク質 Download PDFInfo
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Abstract
Description
本出願は、2015年4月22日に出願した米国暫定出願第62/150,994号及び2015年12月2日出願した米国暫定出願第62/262,356号の利益を主張する。これらの出願は、引用により全体が本明細に組み込まれている。
L48、Y36、S38、R40、S42、T45、K51、F58、Q64、E65、A68、T69、E70、E71、N72、Q74、F84、R88、T90、H91、L92、E94、A95、G96、G97、P98、E99、V100、Y102、E103、P105、P106、T107、A108、あるいはT110の少なくとも25が、別のアミノ酸で置換されており、ハイブリッドActRIIB−ECDポリペプチドが、ミオスタチンとアクチビンAに結合可能であるが、野生型ActRIIB−ECDポリペプチドへのBMP9の結合親和性は減少している。様々な実施例において、ハイブリッドActRIIBリガンド捕集タンパク質は、アミノ酸配列番号:1を有するハイブリッド可溶性ActRIIB−ECDポリペプチドを含み、ここで、アミノ酸残基、R3、I6、Y7、Y8、L14、E15、S20、L22、R24、E26、E28、Q29、L33、L48、Y36、S38、R40、S42、T45、K51、F58、Q64、E65、A68、T69、E70、E71、N72、Q74、F84、R88、T90、H91、L92、E94、A95、G96、G97、P98、E99、V100、Y102、E103、P105、P106、T107、A108、あるいはT110の少なくとも30が、別のアミノ酸で置換されており、ハイブリッドActRIIB−ECDポリペプチドが、ミオスタチンとアクチビンAに結合可能であるが、野生型ActRIIB−ECDポリペプチドへのBMP9の結合親和性は減少している。
用語「ポリペプチド」、「ペプチド」、及び「タンパク質」は、本明細書では、アミノ酸残基のポリマを意味しており、同じ意味で使われている。様々な実施例において、「ペプチド」、「ポリペプチド」、及び「タンパク質」は、α炭素がペプチド結合を介してリンクしているアミノ酸の鎖である。この鎖の一端(アミノ末端)にある末端アミノ酸は、したがって遊離アミノ基を持ち、この鎖の他端(カルボキシ末端)にある末端アミノ酸は、遊離カルボキシル基を持つ。本明細書で用いられているように、用語「アミノ末端」(略して、N−末端)は、ペプチドのアミノ末端にあるアミノ酸上の遊離αアミノ基、あるいは、ペプチド内のその他の位置にあるアミノ酸のαアミノ基(ペプチド結合に関与する場合のイミノ基)を意味する。同様に、用語「カルボキシ末端」は、ペプチドのカルボキシ末端の遊離カルボキシル基、又は、ペプチド内のその他の位置にあるアミノ酸のカルボキシル基を意味する。ペプチドは、また、限定するものではないが、アミド結合と逆に、エーテルで結合したアミノ酸などのペプチド模倣体を含むポリアミノ酸を基本的に含んでいる。
1) アラニン(A)、セリン(S)とスレオニン(T)
2) アスパラギン酸(D)とグルタミン酸(E)
3) アスパラギン(N)とグルタミン(Q)
4) アルギニン(R)とリジン(K)
5) イソロイシン(I)、ロイシン(L)、メチオニン(M)、とバリン(V)
6) フェニルアラニン(F)、チロシン(Y)、とトリプトファン(W)
本明細書で使用されているように、アクチビンIIB型受容体(ActRIIB)は、受入番号NP_001097.2(配列番号:45)及びその異形を有するヒトアクチビン受容体を意味する。用語「野生型ActRIIB−ECD」は、ActRIIBの細胞外ドメイン、アミノ酸1乃至134(シグナル配列付)、又は配列番号45のアミノ酸19乃至134(シグナル配列無)(ここでは、配列番号:46)を意味する。用語アクチビンIIA型受容体(ActRIIA)は、受入番号UniProtKB/Swiss-Prot P27037.1(配列番号:47)のヒトアクチビン受容体と、その異形を意味する。用語「野生型ActRIIB−ECD」は、ActRIIAの細胞外ドメイン、アミノ酸1乃至135(シグナル配列付)、又は配列番号46のアミノ酸20乃至135(シグナル配列無)(ここでは、配列番号:48)を意味する。
本発明は、野生型ActRIIB−ECD及び野生型ActRIIA−ECD由来の新規なハイブリッド可溶性ActRIIB−ECDポリペプチドを提供する。このハイブリッド可溶性ActRIIBポリペプチドは、欠失野生型ActRIIB−ECDの一またはそれ以上のアミノ酸を、欠失野生型ActRIIA−ECDからのアミノ酸で、そのアミノ酸レベルで、二つの欠失ActRIIECDドメイン間の配列アラインメントに基づく対応する位置において、置換することで特異的に改変されている。一またはそれ以上のアミノ酸の置換は、特に、ハイブリッド可溶性ActRIIB−ECDポリペプチドを提供する目的で選択される。これは、野生型ActRIIB−ECDポリペプチドと比べてBMP9中和の著しい低減を示すが、強いミオスタチンとアクチビンAの中和は完全に維持する。
もう一つの態様では、ハイブリッドActRIIリガンドトラップは、ハイブリッド可溶性ActRIIB−ECDポリペプチドと、このActRIIB−ECDポリペプチドに直接又はリンカー配列を介して付着された少なくとも一の異種タンパク質を含み、ハイブリッドActRIIBリガンドトラップと呼ばれる融合タンパク質を形成する。本明細書で使用されているように、用語「融合タンパク質」は、組み換えDNA技術を用いて付着させた異種ポリペプチドを有するタンパク質を意味する。様々な実施例において、異種タンパク質は、限定するものではないが、ポリヒスチジンタグ、Glu−Glu、グルタチオンSトランスフェラーゼ(GST)、チオレドキシン、タンパク質A、タンパク質G、蛍光タンパク質、マルトース結合タンパク質(MBP)、ヒト血清アルブミン又はFcポリペプチド、あるいはFcドメインである。様々な実施例において、FcドメインはヒトIgG Fcドメインである。様々な実施例において、Fcドメインは、配列番号:38に記載されたヒトIgG1重鎖定常領域配列由来である。様々な実施例において、Fcドメインは、配列番号:39に記載されたアミノ酸を有するFcドメインである。様々な実施例において、Fcドメインは、配列番号:40に記載されたヒトIgG2重鎖常領域配列である。様々な実施例において、Fcドメインは、配列番号:41に記載されたアミノ酸を有するFcドメインである。様々な実施例において、Fcドメインは、配列番号:42に記載された記載されたヒトIgG4重鎖定常領域配列由来である。様々な実施例において、Fcドメインは、配列番号:43に記載されたアミノ酸を有するFcドメインである。
ハイブリッドActRIIBリガンドトラップは、選択的に、「リンカー」又は「ヒンジリンカー」配列をさらに含んでいてもよい。リンカーは、主にハイブリッド可溶性ActRIIB−ECDポリペプチドと異種タンパク質間の、あるいは、2又はそれ以上のハイブリッド可溶性ActRIIB−ECDポリペプチド間のスペーサとして作用する。様々な実施例において、異種タンパク質は、ハイブリッド可溶性ActRIIB−ECDポリペプチドにリンカー又はヒンジリンカーペプチドによって付着している。リンカーおよび/又はヒンジリンカーは、二次構造が比較的自由である5、10、15、20、30、40又はそれ以上のアミノ酸間の人工配列であってもよい。様々な実施例において、このリンカーは、グリシン、アラニン、プロリン、アスパラギン、グルタミン、及びリシンから選択されたアミノ酸を含む。様々な実施例において、リンカーはほとんどが、グリシンやアラニンなどの立体障害のないアミノ酸と、ポリグリシン(特に、(Gly)5,(Gly)8,poly(Gly−Ala))と、ポリアラニンでできている。様々な実施例において、リンカーは、G/S含有量が多く(例えば、リンカー中の少なくとも約60%、70%、80%、90%、又はそれ以上のアミノ酸は、G又はSである)。様々な実施例において、リンカーは、(GGGGS(配列番号:44)nモチーフを有しており、ここでn=1−6である。このようなリンカー及びヒンジリンカーは、この分野では広く記載されている(例えば、US8,410,043号(Sun et al)であり、これは、このようなリンカーを教示する目的で本明細書に引用により組み込まれている。)様々な実施例において、配列番号:44に記載のアミノ酸配列を有するリンカー及び配列番号:118に記載のアミノ酸配列を有するヒンジリンカーは、ヒトIgG1 Fc(配列番号:39)又はヒトIgG4 Fc(配列番号:43)を、本発明のハイブリッド可溶性ActRIIB−ECDポリペプチドにリンクさせるのに使用されている。
更なる態様では、本発明は、本発明のハイブリッド可溶性ActRIIB−ECDポリペプチドをエンコードするポリヌクレオチドを含む遊離核酸分子を提供する。対象の核酸は、一本鎖であっても、二本鎖であってもよい。このような核酸は、DNA又はRNA分子である。DNAは、例えば、cDNA、ゲノムDNA、合成DNA、PCRで増幅したDNA、及びこれらの組み合わせを含む。ActRIIBポリペプチドをエンコードするゲノムDNAは、多数の主が入手可能であるゲノムライブラリーから入手できる。合成DNAは、重なったオリゴヌクレオチド断片を化学合成して、そのフラグメントを集合させてコーディング領域と隣接する配列の一部又はすべてを再構築して入手することができる。RNAは、原核生物発現ベクターから得られる。これは、T7プロモータとRNAポリメラーゼを用いるベクターなど、mRNAの高レベルな合成を行う。cDNAは、ActRIIBを発現する様々な組織から遊離したmRNAから調製したライブラリィから得られる。本発明のDNA分子は、完全な遺伝子並びにポリヌクレオチドとその断片を含む。完全な遺伝子は、また、N末端シグナル配列をエンコードする配列を含んでいてもよい。
別の態様では、本発明は、薬学的に許容可能なキャリアの混合物中に遊離ハイブリッド可溶性ActRIIBポリペプチド又はハイブリッドActRIIBリガンド捕集タンパク質を含む医薬組成物を提供する。このような薬学的に許容可能なキャリアは当業者に良く知られており、理解されるとともに、広く記載されている(例えば、Remington’s Pharmaceutical Sciences, 18th Edition, A.R. Gennaro, ed., Mack Publishing Company, 1990)。この薬学的に許容可能なキャリアは、組成物の、例えば、pH、オスモル濃度、粘度、溶状、色、等張性、順序、無菌状態、安定性、分解又は放出速度、吸収又は透過率を変更、維持、又は保存する目的で含めることができる。このような医薬組成物は、ポリペプチドの物理的状態、安定性、インビボでの放出速度、インビボでのクリアランス速度に影響する。適切な薬学的に許容可能なキャリアには、限定するものではないが、アミノ酸(グリシン、グルタミン、アスパラギン、アルギニン、又はリジンなど);抗菌剤、抗酸化剤(アスコルビン酸、硫化ナトリウム、亜硫酸水素ナトリウムなど);バッファ(ホウ酸塩、重炭酸塩、Tris−HCl、クエン酸塩、リン酸塩、その他の有機酸);増量剤(マンニトール又はグリシン)、キレート剤(エチレンジアミン四酢酸(EDTA)など);錯化剤(カフェイン、ポリビニルピロリドン、β−シクロデキストリンまたはヒドロキシプロピル−β−シクロデキストリンなど);充填剤;単糖類;二糖類及びその他の糖質(グルコース、マンノース、又はデキシトリン);タンパク質(血清アルブミン、ゼラチン、又は免疫グロブリン);着色剤、香料添加剤及び希釈剤;乳化剤;親水性ポリマー(ポリビニルピロリドン);低分子ポリペプチド;塩形態カウンターイオン(ナトリウムなど);保存料(塩化ベンザルコニウム、安息香酸、サリチル酸、チメロサール、フェネチル・アルコール、メチルパラベン、プロピルパラベン、クロルヘキシジン、ソルビン酸又は過酸化水素);溶剤(グリセリン、プロピレングリコール又はポリエチレングリコール);糖アルコール(マンニトール又はソルビトール);懸濁化剤;界面活性剤又は湿潤剤(プルロニック、PEG、ソルビタンエステル、ポリソルベート20、ポリソルベート80などのポリソルベート、トリトン、トロメタミン、レシチン、コレステロール、チロキサパールなど);安定性強化剤(スクロース又はソルビトール);等張化強化剤(ハロゲン化アルカリ金属(好ましくは、塩化ナトリウム又は塩化カリウム、マンニトール、ソルビトール)など);送達ビークル、希釈剤、賦形剤及び/又は補助薬。
別の態様では、本発明は、対象におけるミオスタチン関連のあるいはアクチビンA関連の疾病の治療方法を提供するものであり、この方法は、薬学的に許容可能なキャリア中に治療的に有効量の本発明のハイブリッドActRIIBリガンドトラップを対象に投与するステップを具える。重要なことは、本発明の医薬組成物は、体重のパーセンテージとして無駄のない筋肉量を増加させ、体重のパーセンテージとして脂肪量を減らすのに使用することができるが、現存のActRIIB−Fc融合タンパク質ベースの治療法で報告されている安全性の問題を回避していることである。
本明細書で使用されているように、「組み合わせ投与」、「組み合わせ投与した」、あるいは「組み合わせて」の用語は、本発明のハイブリッドActRIIBリガンドトラップと一またはそれ以上のその他の治療薬剤を意味し、投与は、以下のことを意味しそれを含む:このような成分が単一の投与形態に製剤されており、対象にほぼ同時にこの成分を放出する場合、本発明のハイブリッドActRIIBリガンドトラップと治療薬剤のこのような組み合わせを、治療の必要に応じて対象へ同時投与すること;このような成分が、別の投与形態で互いから離れて製剤されており、対象によってほぼ同時に摂取される場合、本発明のハイブリッドActRIIBリガンドトラップと治療薬剤のこのような組み合わせを治療の必要に応じて対象にほぼ同時に投与し、その時その成分が、対象にほぼ同時に放出されること;このような成分がこのような成分が、別の投与形態で互いから離れて製剤されており、各投与間に有意な時間インターバルをもって対象によって連続的に摂取される場合、本発明のハイブリッドActRIIBリガンドトラップと治療薬剤のこのような組み合わせを治療の必要に応じて対象にシーケンシャルに投与し、この成分は、対象に実質的に異なる時間に放出されること;及び、このような成分が、制御された態様で放出される単一投与形態で製剤されている場合、本発明のハイブリッドActRIIBリガンドトラップと治療薬剤のこのような組み合わせ治療の必要に応じて対象にシーケンシャルに投与され、この成分は、対象に、同時に、連続して、及び/又は、同時に及び/又は異なる時間に重なって放出され、各部分が同じ又は異なるルートで投与できること;を意味しており、これらを含む。
当業者に良く知られている組み換えDNA技術にしたがって、本発明のポリペプチドを調整することができる。この例では、ハイブリッド可溶性ActRIIB−ECDポリペプチドの調製を一般的に述べる。
この実験例では、図1に示す構造のハイブリッドActRIIBリガンド捕集タンパク質について一般的に述べる。
この例では、7つのハイブリッドActRIIBリガンド捕集タンパク質のミオスタチンとBMP9の結合活性を評価する。
ハイブリッドActRIIBリガンド捕集タンパク質を、野生型ActRIIB−ECD−Fc融合タンパク質と比較して、ミオスタチンとBMP9に対する結合特性を調べた。結果は、ハイブリッドActRIIBリガンド捕集タンパク質が、野生型ActRIIB−ECD−Fc融合タンパク質に比べてBMP9に対する結合親和性が極めて低いことを示す。多数のハイブリッドActRIIBリガンド捕集タンパク質が劇的に低くなったBMP9に対する結合親和性を示しており、これは、野生型ActRIIB−ECD−Fcタンパク質のものより100倍以上弱く、一方で、ミオスタチンとの結合親和性は強いままであり、これは野生型ActRIIB−ECD−Fcタンパク質のものと同様である。Octet Red社の分析によって得られた予備的な結合データの概要を表3に示す。
KinExA社の分析によって得られた予備的結合データの概要を表4に示す。このデータは、野生型ActRIIBと同様に、二つの例示ハイブリッドActRIIBリガンド捕集タンパク質が、ミオスタチンとアクチビンAの両方について、一桁のpM範囲で、高い親和性を有することを示している。しかしながら、二つのハイブリッドActRIIBリガンド捕集タンパク質は、BMP9に対して一桁のpM範囲で強い結合親和性を示す野生型ActRIIB−ECD−Fcとは反対に、BMP9に対する結合が検出できていないことを示している。
この例では、ミオスタチン/アクチビンAシグナリングアッセイと、BMP9シグナリングアッセイについて、述べている。これらは、ハイブリッドActRIIBリガンド捕集タンパク質のミオスタチン/アクチビンA−ブロック活性と、BMP9−ブロック活性をそれぞれ定量化するのに使用した。
この結果は、野生型ActRIIB−ECD−Fcタンパク質と比較して、二つの例示的ハイブリッドActRIIBリガンド捕集タンパク質が、強いミオスタチン−及びアクチビンA−中和活性を維持しているが、BMP9−中和活性は際立って低いことを示した(図2参照)。図2は、2つの例示的ハイブリッドActRIIBリガンド捕集タンパク質、AG−0003(配列番号:5)及びAG−0005(配列番号:7)について、ミオスタチン、アクチビンA、及びBMP9に対する細胞ベースの中和活性を、野生型コントロールActRIIB−ECD−Fcタンパク質のものと比較して示す。
この例では、実験例4で述べたミオスタチン/アクチビンAシグナリングアッセイ、及びBMP9シグナリング活性を用いて、以下のハイブリッドActRIIBリガンド捕集タンパク質のミオスタチン/アクチビンA−ブロック活性と、BMP9−ブロック活性をそれぞれ定量化した:AG−0003(配列番号:5)、AG−0014(配列番号:16)、AG−0023(配列番号:25)、AG−0024(配列番号:26)、AG−0025(配列番号:27)、AG−0027(配列番号:29)、AG−0028(配列番号:30)、AG−0029(配列番号:31)、及びAG−0035(配列番号:37)。
この結果は、野生型ActRIIB−ECD−Fcタンパク質に比べて、これらのハイブリッドActRIIBリガンド捕集タンパク質のうちのいくつかは、強いミオスタチン−及びアクチビンA−中和活性を維持しているが、BMP9−中和活性が著しく低下していることを示した。図3は、2つの例示的ハイブリッドActRIIBリガンド捕集タンパク質、AG−0014及びAG−0027について、ミオスタチン、アクチビンA、及びBMP9に対する細胞ベースの中和活性を、野生型コントロールActRIIB−ECD−Fcタンパク質のものと比較して示す。
この例では、PBS(ビークル)、野生型ActRIIB−Fc(WT)、AG−0014(配列番号:16)とAG−0027(配列番号:29)を、それぞれ、10mg/kgの容量で、1週間に一度、皮下注射した9週齢のオスC57BI/6マウスの体重と筋肉量の影響を評価した。体重は、0日目、5日目、12日目及び18日目に記録した。グループ当たり、n=6/8.体重変化の値を、0日目のベースラインからの体重増加率として計算した。各動物から個々のふくらはぎの筋肉を切除して、最終解剖の間に検量した。値は、ビークル群に比較して各処理群の平均ふくらはぎ筋肉量の増加率として表した。図4及び表7に記載したように、野生型ActRIIB−Fcと同様に、二つの例示的ハイブリッドリガンド捕集タンパク質の各々の投与によって、マウスの体重増加が著しく見られた。
この例では、PBS(ビークル)、野生型ActRIIB−Fc(WT)、AG−0014(配列番号:16)とAG−0027(配列番号:29)を、それぞれ、10mg/kgの容量で、1週間に一度、皮下注射した8週齢のオスBalbCマウスの、腹腔、睾丸、及び肺組織における効果を評価した。処置の2週間後に、200μlのEvansブルー染料(PBS中0.5%、pH7.2)を各動物群(n=4)に尾静脈を介して注入した。Evansブルー染料注入後90分で解剖した。各群の外科的に露出させた腹腔、切除した睾丸器官、及び切除した肺組織の代表的な画像を、図6−8に、それぞれラベル化して示す。青色は、血管組織の漏れを示す。睾丸と肺組織を検量して、フォルムアミドを含むバイアルに個別において、Evansブルー染料を抽出した。55℃で24時間インキュベーションしたのち、サンプルを遠心分離した。各サンプルの水性相の吸収を、分光光度計を用いて波長610nmで測定した。別の処置群における湿潤肺組織(左側パネル)と睾丸組織(右側パネル)のmg当たりの滲出したEvansブルー染料の量を図9に示す。
自動ELISA分析を行って、野生型ActRIIB−Fc(WT ActRIIB−Fc)と野生型ActRIIA−Fc(WT ActRIIA−Fc)と比較して、異なる濃度におけるハイブリッドActRIIBリガンド捕集タンパク質のBMP9結合を特性化した。図12に示すように、二つの例示的ハイブリッドタンパク質AG−0014(配列番号:16)とAG−0027(配列番号:29)が、それぞれ、WT ActRIIB−FcとWT ActRIIA−Fcと比較して、BMP9−結合の大幅な低下を示した。これらのデータは、ハイブリッドActRIIBリガンド捕集タンパク質が、WT ActRIIB−FcとWT ActRIIA−Fcと異なる、顕著なBMP9結合選択性を有することを示している。
添付のシーケンスリストに記載された核酸及びアミノ酸配列は、37C.F.R.1.822に規定されているように、ヌクレオチド塩基の標準略号とアミノ酸の3文字標記を用いて示されている。
Claims (42)
- ハイブリッド可溶性アクチビンIIB受容体−細胞外ドメイン(ActRIIB−ECD)ポリペプチドを含む遊離タンパク質において、前記ハイブリッド可溶性ActRIIB−ECDポリペプチドが、配列番号:1のアミノ酸配列を含み、配列番号:1のアミノ酸残基R3、I6、Y7、Y8、L14、E15、S20、L22、R24、E26、E28、Q29、L33、L48、Y36、S38、R40、S42、T45、K51、F58、Q64、E65、A68、T69、E70、E71、N72、Q74、F84、R88、T90、H91、L92、E94、A95、G96、G97、P98、E99、V100、Y102、E103、P105、P106、T107、A108、あるいはT110の少なくとも一つが、別のアミノ酸で置換されており、前記ハイブリッドActRIIBECDポリペプチドが、ミオスタチンとアクチビンAに結合可能であるが、野生型ActRIIB−ECDポリペプチドへのBMP9に対して結合親和性が減少している、ことを特徴とする遊離タンパク質。
- 請求項1に記載の遊離タンパク質において、配列番号:1のアミノ酸残基R3、I6、Y7、Y8、L14、E15、S20、L22、R24、E26、E28、Q29、L33、L48、Y36、S38、R40、S42、T45、K51、F58、Q64、E65、A68、T69、E70、E71、N72、Q74、F84、R88、T90、H91、L92、E94、A95、G96、G97、P98、E99、V100、Y102、E103、P105、P106、T107、A108、あるいはT110の少なくとも一つが、配列番号:2の対応する位置にあるアミノ酸で置換されており、前記ハイブリッドActRIIB−ECDポリペプチドが、ミオスタチンとアクチビンAに結合可能であるが、野生型ActRIIB−ECDポリペプチドへのBMP9に対して結合親和性が減少している、ことを特徴とする遊離タンパク質。
- 請求項1に記載の遊離タンパク質において、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、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、配列番号:14、配列番号:15、配列番号:16、配列番号:17、配列番号:18、配列番号:19、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:26、配列番号:27、配列番号:28、配列番号:29、配列番号:30、配列番号:31、配列番号:32、配列番号:33、配列番号:34、配列番号:35、配列番号:36、及び配列番号:37からなる群から選択されたアミノ酸配列を含むことを特徴とする遊離タンパク質。
- 請求項1に記載の遊離タンパク質において、配列番号:51、配列番号:52、配列番号:53、配列番号:54、配列番号:55、配列番号:56、配列番号:57、配列番号:58、配列番号:59、配列番号:60、配列番号:61、配列番号:62、配列番号:63、配列番号:64、配列番号:65、配列番号:66、配列番号:67、配列番号:68、配列番号:69、配列番号:70、配列番号:71、配列番号:72、配列番号:73、配列番号:74、配列番号:75、配列番号:76、及び配列番号:77、配列番号:78、配列番号:79、配列番号:80、配列番号:81、配列番号:82、配列番号:83、配列番号:84、配列番号:85、配列番号:86、配列番号:87、配列番号:88、配列番号:89、配列番号:90、配列番号:91、配列番号:92、配列番号:93、配列番号:94、配列番号:95、配列番号:96、配列番号:97、配列番号:98、配列番号:99、配列番号:100、配列番号:101、配列番号:102、配列番号:103、配列番号:104、配列番号:110、配列番号:111、配列番号:112、配列番号:113、配列番号:114、配列番号:115、配列番号:116、及び配列番号:117からなる群から選択されたアミノ酸配列を含むことを特徴とする遊離タンパク質。
- 請求項1乃至4の何れか1項に記載のタンパク質において、前記ハイブリッド可溶性ActRIIB−ECDポリペプチドが、少なくとも一の異種タンパク質において融合していることを特徴とするタンパク質。
- 請求項5に記載のタンパク質において、前記異種タンパク質が免疫グロブリンの定常ドメインを含むことを特徴とするタンパク質。
- 請求項6に記載のタンパク質において、前記異種タンパク質が免疫グロブリンのFcドメインを含むことを特徴とするタンパク質。
- 請求項7に記載のタンパク質において、前記Fcドメインが、ヒトIgG1のFcドメイン、ヒトIgG2のFcドメイン、又はヒトIgG4のFcドメインから選択されることを特徴とするタンパク質。
- 請求項5に記載のタンパク質において、前記異種タンパク質がリンカー配列によって前記ハイブリッド可溶性ActRIIB−ECDポリペプチドに融合していることを特徴とするタンパク質。
- 請求項1乃至9の何れか1項に記載のポリペプチドをエンコードするポリヌクレオチドを含むことを特徴とする遊離核酸分子。
- 請求項10に記載の遊離核酸分子において、前記ポリヌクレオチドがさらに、少なくとも一の異種タンパク質をエンコードするポリヌクレオチドを含むことを特徴とする遊離核酸分子。
- 請求項11に記載の核酸分子を含むことを特徴とする組み換えベクター。
- 請求項12に記載の組み換えベクターを含むことを特徴とするホスト細胞。
- 前記ホスト細胞が哺乳動物細胞であることを特徴とする請求項13に記載のホスト細胞。
- ハイブリッドActRIIBタンパク質を作成する方法において、請求項14に記載のホスト細胞を、前記タンパク質の発現を促進する条件下で培養するステップと、前記タンパク質を回復させるステップとを具えることを特徴とする方法。
- 薬学的に許容可能なキャリアと混合した治療的有効量の請求項1乃至9の何れか1項に記載のタンパク質を含むことを特徴とする医薬組成物。
- 対象におけるミオスタチン関連のあるいはアクチビンAに関連する疾患を治療する方法において、前記対象に、治療上有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 対象における筋消耗疾患を治療する方法において、請求項16に記載の組成物を、前記対象に治療上有効量投与するステップを具えることを特徴とする方法。
- 請求項18に記載の方法において、前記筋消耗疾患が、筋ジストロフィー、筋萎縮性側索硬化症、筋炎、ICU筋疾患、薬物誘発性筋疾患(例えば、副腎皮質ステロイド筋疾患及びスタチン筋疾患)、アンドロゲン遮断療法筋疾患、うっ血性閉塞性肺疾患、気腫、嚢胞性線維症、慢性心疾患、心臓委縮、がん性悪質液、腎不全、尿毒症、タンパク質エネルギィ消耗、拒食症、栄養不良、サルコペニア、AIDS、敗血症、火傷、糖尿病、ハンチントン病、パーキンソン病、アルツハイマー病、手根管症候群、及び、長期にわたるベッドでの静養、脊椎損傷、脳卒中、骨折、加齢、及び微小重力への露出からなる群から選択されることを特徴とする方法。
- 治療的に有効量の請求項16に記載の組成物を対象に投与するステップを具えることを特徴とする筋消耗疾患を治療する方法。
- 請求項20に記載の方法において、前記心臓血管疾患が、心不全、心臓移植、高血圧、心筋炎、冠動脈疾患、心筋梗塞、心不整脈、心臓弁疾患、心筋症、心膜疾患、大動脈疾患、心臓移植、及びマルファン症候群からなる群から選択されることを特徴とする方法。
- 対象のメタボリック疾患を治療する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項22に記載の方法において、前記メタボリック疾患が、インスリン抵抗、糖尿病、肥満、筋肉減少性肥満、脂質異常症、及び脂肪肝疾患からなる群から選択されることを特徴とする方法。
- 対象の癌細胞を治療する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項24に記載の方法において、前記癌が、肺癌、すい臓癌、前立腺癌、胃癌、食道癌、大腸癌、乳癌、頭頸部癌、卵巣癌、精巣癌、多発性骨髄腫、リンパ腺癌、白血病、骨髄異形成症候群、又は横紋筋肉腫、及びその他の癌からなる群から選択されることを特徴とする方法。
- 対象の腎疾患を治療する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項26に記載の方法において、前記腎疾患が、慢性腎疾患、末期腎疾患、尿毒症、タンパク質エネルギィ消費、及び腎移植からなる群から選択されることを特徴とする方法。
- 対象の炎症性/自己免疫性疾患を治療する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項28に記載の方法において、前記炎症性/自己免疫性疾患が、関節リュウマチ、炎症性腸疾患、紅斑性狼瘡、及び多発性硬化症からなる群から選択されることを特徴とする方法。
- 対象の繊維症疾患を治療する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項30に記載の方法において、前記繊維症疾患が、肺線維症、肝硬変、心筋繊維化、腎繊維症、骨髄線維症、特発性腹膜後線維化症、腎性線維化性皮膚症、クローン病、ケロイド、強皮症、全身性硬化症、及び関節線維化からなる群から選択されることを特徴とする方法。
- 対象の貧血を治療する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項32に記載の方法において、前記貧血が、鉄分欠乏性貧血、地中海貧血、溶血性貧血、鎌状細胞貧血、悪性貧血、ファンコニ貧血、及び再生不良貧血(癌に関連する貧血及び化学療法誘発性貧血を含む)からなる群から選択されることを特徴とする方法。
- 対象の痛みを治療する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項34に記載の方法において、前記痛みが、神経障害性の痛み、体性痛、内臓痛、炎症性の痛み、癌性の痛み、背痛、及び関節痛からなる群から選択されることを特徴とする方法。
- 対象の加齢による症状を治療する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項36に記載の方法において、前記加齢による症状が、高齢者のフレイル、加齢性サルコペニア、及び骨粗しょう症からなる群から選択されることを特徴とする方法。
- 対象の組織修復又は器官再生のために幹細胞成長を促進する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項38に記載の方法において、前記幹細胞が、筋幹(衛星)細胞、心幹細胞、骨髄由来間葉幹細胞、及び多能性幹細胞からなる群から選択されることを特徴とする方法。
- 対象の骨疾患を治療する方法において、前記対象に治療的に有効量の請求項16に記載の組成物を投与するステップを具えることを特徴とする方法。
- 請求項40に記載の方法において、前記骨疾患が、骨軟化症、骨粗しょう症、骨形成不全症、進行性骨化性線維異形成症、コルチコステロイド誘発性骨量減少、骨折、及び骨への転移からなる群から選択されることを特徴とする方法。
- 対象の筋消耗疾患、又はメタボリック疾患、又は線維性疾患、又は炎症性疾患、又はアクチビン関連疾患を治療する方法において、前記対象に請求項12に記載のベクターを投与するステップを具え、前記ベクターが、前記対象におけるハイブリッドActRIIBタンパク質を発現させることができることを特徴とする方法。
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