JP2010519931A - バリアントアクチビン受容体ポリペプチドおよびその使用 - Google Patents
バリアントアクチビン受容体ポリペプチドおよびその使用 Download PDFInfo
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Abstract
【選択図】図3
Description
本出願は、米国仮特許出願番号61/065,474、2008年2月11日出願、および米国仮特許出願番号60/905,459、2007年3月6日出願に基づく優先権を主張し、それらの開示内容に依存し、それらを本明細書に援用する。
本発明の技術分野は、トランスフォーミング増殖因子−β(TGF−β)ファミリーのメンバーおよび可溶性TGF−βの受容体、ならびに種々の障害の処置のためにTGF−βファミリーのメンバーの活性を調節する方法に関する。
本明細書中で用いる用語アクチビンIIB型受容体(ActRIIB)は、寄託番号NP 001097(SEQ ID NO:47)をもつヒトアクチビン受容体を表わす。可溶性ActRIIBという用語には、ActRIIBの細胞外ドメイン(SEQ ID NO:18)、ActRIIB5の細胞外ドメイン(SEQ ID NO:2)、ならびにこれらの配列の位置64のアルギニンがアラニンで置換されたものも含まれる。
本発明は、ヒトバリアント可溶性ActRIIB受容体ポリペプチド(本明細書中でvActRIIBポリペプチド、またはバリアントポリペプチドと表示する)を含む単離されたタンパク質を提供する。本明細書中で用いる用語“vActRIIBタンパク質”は、vActRIIBポリペプチドを含むタンパク質を表わす。本明細書中で用いる用語”単離された”は、内因性物質からある程度精製されたタンパク質またはポリペプチド分子を表わす。これらのポリペプチドおよびタンパク質は、アクチビンA、ミオスタチン、またはGDF−11のいずれか1つに結合してその活性を阻害する能力をもつことを特徴とする。ある態様において、アクチビンA、ミオスタチン、またはGDF−11に対するバリアントポリペプチドの結合親和性は野生型ポリペプチドと比較して改良されている。
本発明はさらに、バリアントActRIIBポリペプチドに結合する抗体を含み、これには本発明のvActRIIBポリペプチドに特異的に結合するものが含まれる。本明細書中で用いる用語“特異的に結合する”は、vActRIIBポリペプチドに対して106M−1以上の結合親和性(Ka)をもつ抗体を表わす。本明細書中で用いる用語“抗体”は、たとえば下記のものを含めた無傷の抗体を表わす:ポリクローナル抗体(たとえばAntibodies: A Laboratory Manual, Harlow and Lane (eds), Cold Spring Harbor Press, (1988)を参照)、およびモノクローナル抗体(たとえばU.S.Patent Nos.RE 32,011、4,902,614、4,543,439および4,411,993、ならびにMonoclonal Antibodies: A New Dimension in Biological Analysis, Plenum Press, Kennett, McKearn and Bechtol (eds.) (1980)を参照)。本明細書中で用いる用語“抗体”は、抗体のフラグメント、たとえばF(ab)、F(ab’)、F(ab’)2、Fv、Fc、および一本鎖抗体をも表わし、これらは組換えDNA技術により、または無傷抗体の酵素開裂もしくは化学的開裂により製造される。用語“抗体”は二重特異性または二重機能性抗体をも表わし、これらは2つの異なる重鎖/軽鎖対および2つの異なる結合部位をもつ人工ハイブリッド抗体である。二重特異性抗体は、ハイブリドーマの融合またはFab’フラグメントの連結を含めた多様な方法により製造できる(参照:Songsivilai et al, Clin. Exp. Immunol. 79:315-321 (1990), Kostelny et al., J. Immunol.148:1547-1553 (1992))。
本発明のvActRIIBタンパク質およびポリペプチドを含有する医薬組成物も提供される。そのような組成物は、治療または予防に有効な量のポリペプチドまたはタンパク質を医薬的に許容できる物質および生理的に許容できる配合物質と混合したものを含む。医薬組成物は、たとえば組成物のpH、モル浸透圧、粘度、澄明度、色、等張性、臭気、無菌性、安定性、溶解もしくは放出の速度、吸着または透過を改変、維持または保持するための配合物質を含有することができる。適切な配合物質には下記のものが含まれるが、これらに限定されない:アミノ酸(たとえばグリシン、グルタミン、アスパラギン、アルギニンまたはリジン);抗微生物薬;抗酸化剤(たとえばアスコルビン酸、亜硫酸ナトリウムまたは亜硫酸水素ナトリウム);緩衝剤(たとえばホウ酸塩、炭酸水素塩、トリス−HCl、クエン酸塩、リン酸塩、他の有機酸);増量剤(たとえばマンニトールまたはグリシン)、キレート化剤(たとえばエチレンジアミン四酢酸(EDTA));複合体形成剤(たとえばカフェイン、ポリビニルピロリドン、ベータ−シクロデキストリンまたはヒドロキシプロピル−ベータ−シクロデキストリン);充填剤;単糖類;二糖類および他の炭水化物(たとえばグルコース、マンノース、またはデキストリン);タンパク質(たとえば血清アルブミン、ゼラチンまたは免疫グロブリン);着色剤;着香剤および希釈剤;乳化剤;親水性ポリマー(たとえばポリビニルピロリドン);低分子量ポリペプチド;塩形成性の対イオン(たとえばナトリウム);保存剤(たとえば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、または過酸化水素);溶剤(たとえばグリセリン、プロピレングリコール、またはポリエチレングリコール);糖アルコール(たとえばマンニトールまたはソルビトール);懸濁化剤;界面活性剤または湿潤剤(たとえばpluronic類、PEG、ソルビタンエステル、polysorbate類、たとえばpolysorbate 20、polysorbate 80、トライトン(triton)、トロメタミン(tromethamine)、レシチン、コレステロール、チロキサパル(tyloxapal));安定性向上剤(ショ糖またはソルビトール);張性増強剤(たとえばアルカリ金属ハロゲン化物(好ましくは塩化ナトリウムまたは塩化カリウム、マンニトールソルビトール));送達ビヒクル;希釈剤;賦形剤および/または医薬佐剤(Remington’s Pharmaceutical Sciences, 18thEdition, A.R. Gennaro, ed., Mack Publishing Company, 1990)。
本発明は、ミオスタチン、アクチビンA、またはGDF−11の量または活性を、これらのポリペプチドとvActRIIBポリペプチドの接触によりインビボおよびインビトロで減少または中和するための方法および医薬組成物を提供する。vActRIIBポリペプチドは、ミオスタチン、アクチビンA、およびGDF−11に対して高い親和性をもち、ミオスタチン、アクチビンA、およびGDF−11のうち少なくとも1つの生物活性を低下および阻害することができる。ある態様において、vActRIIBポリペプチドは野生型ActRIIBポリペプチドと比較して改良された活性を示す。これを後記の実施例において証明する。
vActRIIBポリペプチドの発現および精製
バリアントActRIIBポリペプチドの発現および精製のために下記の方法を用いた。
構造分析、分子モデリング、および質量分析を組み合わせた方法で、グリコシレーションされていないActRIIBポリペプチド間の静電相互作用および水素結合相互作用により誘発された分子間ジスルフィド結合形成によってActRIIBに凝集(オリゴマー形成)が生じる可能性のあることが指摘された。残基28および40はActRIIB:ActRIIB相互作用に関与し、ActRIIBとそれのリガンドとの相互作用には関与しないと判定された。
下記の方法に従って、選択したクローンから細胞バンクを調製した。安定トランスフェクションした細胞の増殖プールを96−ウェルプレートに播種し、候補クローンを増殖および生産性能について小規模試験で評価した。約60個のバイアルのプレマスター細胞バンク(pre−master cell bank(PMCB))を、選択したクローンから調製した。すべてのPMCBを無菌性、マイコプラズマおよびウイルスについて試験した。
ActRIIB−Fc(IgG1およびIgG2の両方)、ActRIIB5−Fc (IgG1およびIgG2の両方)、およびこれらのバリアントを含有する約5Lのコンディショニングした培地を、5ft2の10Kメンブレン接線流フィルター(Pall)で濃縮した。濃縮された材料を、PBS(Dulbecco;塩化マグネシウムまたは塩化カルシウムを含まないもの)で平衡化した5mLのProtein A High Performance Column(商標)(GE Healthcare)にアプライした。カラムを280nmにおける吸光度(OD280)が0.1未満になるまでこの平衡化用緩衝液で洗浄した後、結合しているタンパク質を0.1Mグリシン−HCl、pH2.7で溶離し、直ちに1Mトリス−HCl、pH8.5で中和した。中和した溶出プールを1mlの体積に濃縮し、PBS(Dulbecco;塩化マグネシウムまたは塩化カルシウムを含まないもの)中で平衡化した320mlのSephacryl−200カラム(GE Healthcare)にアプライした。4〜20% SDS PAGEゲル(Invitrogen)に流して、プールすべき画分を判定した。これらのポリペプチドを活性および凝集度について下記に従って試験した。
インビトロ活性アッセイ
前記に従って精製したvActRIIBポリペプチドの試料をリン酸緩衝化生理食塩水(PBS:2.67mMの塩化カリウム、138mMの塩化ナトリウム、1.47mMの一塩基性リン酸カリウム、8.1mMの二塩基性リン酸ナトリウム、pH7.4)で0.2mg/mlに希釈し、37℃で6日間インキュベートし、次いでMALDI−MS(matrix-assisted laser desorption/ionization mass spectrometry、マトリックス支援レーザー脱離/イオン化質量分析)、SECおよび/またはSEC−LS分析を行なった。下記に従って、プロテインA精製工程後の野生型およびバリアントポリペプチドの凝集をSECまたはSEC−LSにより判定し、これらの分子の分子量をMALDI−MS法により確認した。
vActRIIB5−IgG1FcおよびvActRIIB−IgG1Fcバリアントを前記に従って製造した。これらのバリアントがアクチビンIIB受容体へのアクチビンAまたはミオスタチンの結合を阻害する能力を、下記に従って細胞ベースの活性アッセイにより試験した。
vActRIIBを用いたインビボ処置
下記の動物実験はすべて、トランケートした成熟vActRIIB−IgG2 Fc(E28W)ポリペプチド(SEQ ID NO:91)を用い、下記の方法に従って実施された。
インヒビン−αは自然界に存在するアクチビンA阻害物質である。インヒビン−αを欠如するマウスは、有意に上昇した循環中アクチビンA濃度を示し、腫瘍、たとえば卵巣癌、精巣癌および副腎癌の自然形成に関連する致命的な消耗症候群を伴う(Matzuk et al., PNAS 91(19):8817-21 (1994), Cipriano et al. Endocrinology 121(7): 2319-27(2000), Matzuk et al., Nature 360(6402):313-9 (1992))。下記の実験のために、インヒビン-αノックアウトマウス(C57BL/6J)をCharles River Laboratoriesから入手した。vActRIIB−IgG2 Fc E28W(SEQ ID NO:91)(以下、E28W、またはE28Wポリペプチド、または可溶性受容体E28W)が体重および筋量に及ぼす影響を、インヒビン−αノックアウトマウスにおいて調べた。8週齢の雄のインヒビン−αノックアウトマウスにおける14日間の一回注射試験を実施した。8週齢の時点で、雄のインヒビン−αノックアウトマウスは同齢の野生型同腹仔対照マウスと比較して体重が25%以上減少していた。5匹のノックアウトマウスに一回のE28W(30mg/kg)皮下注射を行ない、一方、5匹のノックアウトマウスに等体積のPBS(ビヒクル)を0日目に皮下投与した。ベースライン対照として、5匹の同齢の野生型マウスに0日目にビヒクルの一回皮下注射を行なった。マウスを0、7および14日目に秤量した。14日目の終了時にすべての動物を屠殺し、それらの除脂肪屠殺体重および腓筋量を剖検により分析した。14日間の試験期間にわたって、ビヒクル処置したノックアウトマウスの体重は0日目の22.5gから14日目の21.4gまで約1.1g減少した。これに対し、E28W処置したノックアウトマウスの平均体重は、0日目の22.1gから14日目の33.1gまで11gの劇的な増加を示した。最終剖検分析により、下記に示すようにインヒビン−αノックアウトマウスにおいてE28Wポリペプチドは除脂肪屠殺体重および腓筋量を実質的に倍増させることが明らかになった。E28W処置したノックアウトマウスの平均除脂肪屠殺体重は、約14.9gであった;ビヒクル処置したノックアウトマウスについての約8.0g、およびビヒクル処置した野生型マウスについての約12.1gと比較。E28W処置したノックアウトマウスの腓筋重量(両足からのもの)は、約426mgであった;ビヒクル処置したノックアウトマウスについての約209mg、およびビヒクル処置した野生型マウスについての約324mgと比較。これらの結果は、体重減少および筋消耗の疾病状態の処置に対するE28Wポリペプチドの有効性を示し、それらを下記の表にまとめる。
大腸−26腫瘍を保有するマウスは、癌性悪液質の研究のための前臨床動物モデルとして広く用いられている(Fujita et al., Int J Cancer 68(5):637-43 (1996), Kwak et al., Cancer Research 64(22):8193-8 (2004))。E28Wポリペプチドが体重変化、筋量および生存率に及ぼす影響を、この腫瘍保有マウスにおいて調べた。大腸−26(C−26)腫瘍細胞を10週齢の雄CDF1マウス40匹にマウス当たり0.5x106細胞で皮下移植した。腫瘍の移植を0日目に実施した。腫瘍移植後5日目に開始して、20匹のC−26マウスを10mg/kgのvActRIIB IgG2 Fc E28W(SEQ ID NO:91)の皮下注射により毎週処置し、一方、20匹のC−26マウスをビヒクル(PBS)で処置した。同時に10匹の同齢および同体重の正常マウスをビヒクル(PBS)のみで処置した。体重および飼料摂取量を週3回測定した。腫瘍保有マウスを生存について1日2回検査した。腫瘍サイズを、PCコンピューターに接続したカリパス(Ultra−Cal IV IP65電気カリパス、Fred V Fowler Co.、マサチュセッツ州ボストン)で測定し、数値をMicrosoft Excelデータファイルのワークシートに自動的に記録した。図5に示すように、腫瘍移植の2週間後に、C−26腫瘍を保有するマウスは重篤な悪液質を発症し、それらの体重が劇的に減少した。E28W処置は、腫瘍保有マウスにおいて体重減少を効果的に軽減した。E28Wで処置した腫瘍保有マウスの平均体重は、ビヒクルで処置した腫瘍保有マウスのものより有意に高かった(p<0.001、腫瘍移植後7日目から33日目まで、不対T検定、Graph pad Software Inc.、カリフォルニア州サンディエゴ)。
後足懸垂マウスモデルを用いて、vActRIIB−IgG2 Fc E28W(SEQ ID NO:91)が非活動状態の筋量に及ぼす影響を調べた。後足懸垂法は、先にCarlson CJ el al(Carlson CJ, Booth FW and Gordon SE: Am J Physiol Regul Integr Comp Physiol. 277: R601-RR606, 1999)が報告したものと本質的に同じである。9週齢の雌C57BL/6マウスを試験に用いた。合計60匹のマウスを下記に従って3グループに分けた:1.懸垂しないベースライン対照グループ(20匹)をビヒクル(PBS)で処置したもの、2.後足懸垂グループ(20匹)をビヒクルで処置したもの、および3.後足懸垂マウスグループ(20匹)をvActRIIB−IgG2 Fc,E28Wで処置したもの。具体的には、30mg/kgのvActRIIB−IgG2 Fc E28Wまたはビヒクルの一回皮下注射を、前記のグループそれぞれに後足懸垂の開始時点で行なった。長期間にわたり体重変化を週2〜3回測定した。各グループから5匹のマウスを下記の4つの異なる時点で屠殺した:1日目、3日目、7日目、および14日目。腓筋重量を剖検により測定した。
卵巣摘除した雌C57Bl6マウス(OVX)は、雌の生殖腺機能低下症および骨粗鬆症のモデルであるとみなされる。24匹の雌C57Bl6マウスを3カ月齢で卵巣摘除し、3カ月間回復させた。6カ月齢で24匹のOVXマウスおよび24匹の同齢の擬似手術した対照C57Bl6マウスを、体重、筋量および脂肪量(NMRにより)、ならびに骨量(PIXImus-GE LUNAR Corporation)の長期間にわたる変化について3カ月間の処置期間にわたって測定した。この期間の終了時に動物を屠殺し、最終剖検に際して骨組織を採集し、Faxitron X線分析およびmicroCT分析(Faxitron X−ray CorporationおよびGE Medical system)を行なった。E28Wバリアント受容体(SEQ ID NO:91)は体重、具体的には除脂肪筋量および骨量を増加させ、一方ではマウスの脂肪含量を卵巣摘除していないマウスにみられるレベルまで低下させるのに有効であることが証明された。具体的には、12週間にわたって、除脂肪筋量はE28Wで処置したOVXマウスについて20gから27.0gまで増加した;E28Wで処置した擬似手術マウスについての20gから27.5gまでと比較、OVX+ビヒクルまたは擬似手術+ビヒクルについて除脂肪筋量がほとんど増加しなかった(OVX+ビヒクルについては約19g、野生型+ビヒクルについては約20g)のと比較。同じ試験において、E28Wで処置したOVXマウスは、12週間の試験の終了時までに動物当たり8g平均から動物当たり4g平均までの脂肪量減少を示した;これは擬似手術した動物に匹敵する。これに対し、ビヒクルで処置したOVXマウスは、試験期間中のいずれの時点でも脂肪量が減少しなかった。最後に、骨量は、E28Wで処置したOVXマウスにおいてビヒクル処置したOVXマウスと比較して増加した。最終剖検に際して採集した大腿骨/脛骨のBMC(骨無機質含量)分析をpQCT分析(Peripheral Quantitative Computed Tomography、末梢定量コンピュータ断層撮影)により行なった。E28Wで処置したOVXマウスは、約0.045g/cmのBMCが12週間の試験の終了時に約0.055g/cmに増加した;これは擬似手術したビヒクル処置動物の最終BMCに匹敵する。ビヒクルで処置したOVXマウスは、12週間の試験の終了時にほぼ同じ約0.045g/cmのBMCを示した。E28W処置した野生型マウスは、12週間の試験の終了時に0.054g/cmから約0.065g/cmまでのBMC増加を示した。これらの試験は、加齢における虚弱質、骨粗鬆症、および肥満症の有望な処置としてのE28Wポリペプチドの有効性を証明する。
Claims (47)
- バリアントアクチビンIIB受容体ポリペプチド(vActRIIB)を含む単離されたタンパク質であって、該ポリペプチドが、位置28または位置40における一アミノ酸置換以外はポリペプチド配列SEQ ID NO:2またはSEQ ID NO:18を含み、該ポリペプチドがミオスタチン、アクチビンAまたはGDF−11を結合することができる、前記タンパク質。
- バリアントアクチビンIIB受容体ポリペプチド(vActRIIB)を含む単離されたタンパク質であって、該ポリペプチドが、位置28および位置40における一アミノ酸置換以外はポリペプチド配列SEQ ID NO:2およびSEQ ID NO:18を含み、該ポリペプチドがミオスタチン、アクチビンAまたはGDF−11を結合することができる、前記タンパク質。
- vActRIIBポリペプチドの位置28における置換が、Eに代わってA、F、Q、V、I、L、M、K、H、WおよびYからなる群から選択される、請求項1のタンパク質。
- vActRIIBポリペプチドの位置28における置換が、Eに代わってA、F、Q、V、I、L、M、K、H、WおよびYからなる群から選択される、請求項2のタンパク質。
- vActRIIBポリペプチドの位置28における置換が、Eに代わってA、WおよびYからなるアミノ酸の群から選択される、請求項1のタンパク質。
- vActRIIBポリペプチドの位置28における置換が、Eに代わってA、WおよびYからなるアミノ酸の群から選択される、請求項2のタンパク質。
- vActRIIBポリペプチドの位置40における置換が、Rに代わってG、Q、M、H、KおよびNからなるアミノ酸の群から選択される、請求項1のタンパク質。
- vActRIIBポリペプチドの位置40における置換が、Rに代わってA、G、Q、M、H、KおよびNからなるアミノ酸の群から選択される、請求項2のタンパク質。
- vActRIIBポリペプチドの位置28における置換がEに代わってA、F、Q、V、I、L、M、K、H、WおよびYからなるアミノ酸の群から選択され、かつ位置40における置換がRに代わってA、G、Q、M、H、KおよびNのアミノ酸の群から選択される、請求項2のタンパク質。
- vActRIIBポリペプチドの位置28における置換が、Eに代わってWである、請求項1のタンパク質。
- vActRIIBポリペプチドの位置28における置換がEに代わってAであり、かつ位置40における置換がRに代わってAである、請求項2のタンパク質。
- vActRIIBポリペプチドがN−末端シグナル配列を欠如する、請求項1〜11のいずれか1項のタンパク質。
- vActRIIBポリペプチドがN−末端酸シグナル配列および成熟N−末端の4または6個のアミノ酸を欠如する、請求項1〜11のいずれか1項のタンパク質。
- vActRIIBポリペプチドが少なくとも1つのヘテロロガスポリペプチドに融合している、請求項12のタンパク質。
- vActRIIBポリペプチドが少なくとも1つのヘテロロガスポリペプチドに融合している、請求項13のタンパク質。
- ヘテロロガスポリペプチドがヒトFcドメインである、請求項14のタンパク質。
- ヘテロロガスポリペプチドがヒトFcドメインである、請求項15のタンパク質。
- ポリペプチドがSEQ ID NO:60、62、64、68、70および72からなる群から選択される、請求項16のタンパク質。
- ポリペプチドがSEQ ID NO:91、93、95および97からなる群から選択される、請求項17のタンパク質。
- vActRIIBポリペプチドを含む単離されたタンパク質であって、ポリペプチドがSEQ ID NO:4、6、8、10、12、14、16、20、22、24、26、28、30、32、34、36、38、40、42、44、46、52、54、56、60、62、64、66、68、70、72、87、88、91、93、95、および97の配列を有するポリペプチドの群から選択されるタンパク質。
- 下記からなる群から選択されるポリヌクレオチドを含む、単離された核酸分子:
(a)SEQ ID NO:3、5、7、9、11、13、15、19、21、23、25、27、29、31、33、35、37、39、41、43、45、51、53、55、59、61、63、65、67、69、71、92、94、および96からなる群に示す配列を有するポリヌクレオチドまたはその相補体;ならびに
(b)SEQ ID NO:4、6、8、10、12、14、16、20、22、24、26、28、30、32、34、36、38、40、42、44、46、52、54、56、60、62、64、66、68、70、72、87、88、91、93、95、および97からなる群に示すアミノ酸配列を有するポリペプチドをコードするポリヌクレオチド。 - ポリヌクレオチドが転写または翻訳調節配列に作動可能な状態で結合している、請求項21の核酸分子。
- 転写または翻訳配列が転写プロモーターまたはエンハンサーを含む、請求項22の核酸分子。
- 請求項21の核酸分子の発現を指令する組換えベクター。
- 請求項21の核酸分子を発現するように遺伝子工学的に処理された宿主細胞。
- 宿主細胞が哺乳動物細胞である、請求項25の宿主細胞。
- 請求項20のタンパク質を産生するように遺伝子工学的に処理された宿主細胞。
- vActRIIBポリペプチドを製造する方法であって、請求項27の宿主細胞を該タンパク質の発現を促進する条件下で培養し、そして該タンパク質を回収することを含む、前記方法。
- 有効量の請求項20のタンパク質を医薬的に許容できるキャリヤーと混合したものを含む医薬組成物。
- その処置を必要とする対象においてミオスタチン活性を阻害する方法であって、療法有効量の請求項29の組成物を対象に投与することを含む、前記方法。
- その処置を必要とする対象において除脂肪筋量を増加させる方法であって、療法有効量の請求項29の組成物を対象に投与することを含む、前記方法。
- その処置を必要とする対象において脂肪に対する除脂肪筋量の比率を高める方法であって、療法有効量の請求項29の組成物を対象に投与することを含む、前記方法。
- その処置を必要とする対象において筋消耗性の疾患または障害を処置する方法であって、療法有効量の請求項29の組成物を対象に投与することを含む、前記方法。
- 筋消耗性の疾患が癌性悪液質である、請求項33の方法。
- 筋消耗性の疾患または障害が、筋ジストロフィー、筋萎縮性側索硬化症、うっ血性閉塞性肺疾患、慢性心不全、癌性悪液質、エイズ、腎不全、尿毒症、リウマチ性関節炎、加齢性サルコペニア、臓器萎縮症、手根管症候群、アンドロゲン欠乏、火傷傷害、糖尿病、および長期間の床上安静、脊髄損傷、卒中、骨折、加齢または極微重力曝露による筋消耗から選択される、請求項33の方法。
- その処置を必要とする対象において代謝障害を処置する方法であって、療法有効量の請求項29の組成物を対象に投与することを含む、前記方法。
- 代謝障害が、糖尿病、肥満症、高血糖症、および骨損失から選択される、請求項36の方法。
- 代謝障害が骨損失である、請求項36の方法。
- その処置を必要とする対象においてアクチビンが過剰発現する疾患を処置する方法であって、療法有効量の請求項29の組成物を対象に投与することを含む、前記方法。
- 疾患が癌である、請求項39の方法。
- 疾患が精巣または卵巣の癌である、請求項40の方法。
- その処置を必要とする対象において悪液質を処置する方法であって、有効量の請求項29の組成物を対象に投与することを含む、前記方法。
- 悪液質が、癌、糖尿病性腎障害、火傷傷害、腎不全、およびリウマチ性関節炎から生じる、請求項42の方法。
- その処置を必要とする対象において腫瘍塊のサイズを縮小する方法であって、有効量の請求項29の組成物を対象に投与することを含む、前記方法。
- 腫瘍塊が精巣または卵巣の癌から生じる、請求項44の方法。
- その処置を必要とする対象において筋消耗性障害を処置する方法であって、請求項24のベクターを対象に投与することを含み、その際ベクターは対象においてvActRIIBポリペプチドの発現を指令することができる、前記方法。
- ベクターがAAVベクターである、請求項46の方法。
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