JP2011530599A - 赤血球レベルを高めるためのgdfトラップの使用 - Google Patents
赤血球レベルを高めるためのgdfトラップの使用 Download PDFInfo
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Abstract
Description
この出願は、2008年8月14日に出願された米国仮出願第61/189,094号の利益を主張する。上記米国仮出願の教示の全ては、参照によって本明細書に援用される。
成熟した赤血球(red blood cell)、すなわちエリスロサイト(erythrocyte)は、脊椎動物の循環系において酸素の輸送を担っている。赤血球は、比較的高い酸素分圧(pO2)の肺において酸素を結合し、そして、比較的低いpO2の身体の領域へと酸素を運搬するタンパク質であるヘモグロビンを高濃度で有する。
一部、本開示は、赤血球およびヘモグロビンのレベルを高めるために、GDFトラップを用いることができることを実証する。他のActRIIBリガンド、例えばGDF11および/またはミオスタチンと比較して、アクチビン(例えば、アクチビンAおよび/またはアクチビンB)に有意に低い親和性を有する改変体ActRIIBポリペプチドは、GDFトラップと称す。本明細書で記載されるActRIIB改変体は、特に明記しない限りGDFトラップである。詳細には、本開示は、配列番号1の79位に酸性残基を有するActRIIBポリペプチドの可溶性の形であるGDFトラップがインビボで投与されると、血液中の赤血球レベルを高めることを実証する。したがって、特定の実施形態において、本開示は、患者で赤血球およびヘモグロビンのレベルを高めるため、およびその必要性のある患者で低い赤血球またはヘモグロビンのレベルに関連する障害を処置するために、GDFトラップを用いる方法を提供する。参照により本明細書に組み込まれる米国特許出願第12/012,652号に記載されているように、GDFトラップは、筋肉量を増加させ、脂肪量を減少させるのに用いることができる。
(1.概要)
トランスフォーミング増殖因子−β(TGF−β)スーパーファミリーは、共通の配列エレメントと構造モチーフを共有する、種々の増殖因子を含む。これらのタンパク質は、脊椎動物および無脊椎動物の両方における広範な種々の細胞型に対して生物学的作用を発揮することが公知である。このスーパーファミリーのメンバーは、胚発生の間に、パターン形成および組織の特異化において重要な機能を果たし、そして、脂質生成、筋発生、軟骨形成、心臓発生、造血、神経発生および上皮細胞分化を含む種々の分化プロセスに影響を及ぼし得る。このファミリーは、2つの一般的な枝:BMP/GDFの枝およびTGF−β/アクチビン/BMP10の枝、に分けられ、これらのメンバーは、多様な、しばしば相補的な作用を有する。TGF−βファミリーのメンバーの活性を操作することによって、しばしば、生物において有意な生理学的変化を引き起こすことが可能である。例えば、ウシのPiedmonteseおよびBelgian Blue品種は、GDF8(ミオスタチンとも呼ばれる)遺伝子に機能喪失変異を有しており、筋肉量の顕著な増加を引き起こしている。Grobetら、Nat Genet.1997年、17巻(1号):71〜4頁。さらに、ヒトでは、GDF8の不活性な対立遺伝子は、筋肉量の増加、および、報告によれば、非常に優れた強度と関連している。Schuelkeら、N Engl J Med 2004年、350巻:2682〜8頁。
特定の態様では、本発明はGDFトラップポリペプチド、例えば、可溶性の改変体ActRIIBポリペプチド、例えば、ActRIIBポリペプチドのフラグメント、機能的改変体、および修飾された形態を含めたものに関する。特定の実施形態では、GDFトラップポリペプチドは、少なくとも1の、対応する野生型ActRIIBポリペプチドと同様または同一の生物活性を有する。例えば、本発明のGDFトラップポリペプチドは、ActRIIBリガンドに結合し、その機能を阻害し得る(例えば、アクチビンA、アクチビンAB、アクチビンB、Nodal、GDF8、GDF11またはBMP7)。任意選択で、GDFトラップポリペプチドは赤血球レベルを増加させる。GDFトラップポリペプチドの例としては、1つまたは複数の配列の差異を有するヒトActRIIB前駆体ポリペプチド(配列番号1または39)、および1つまたは複数の配列の差異を有する可溶性ヒトActRIIBポリペプチド(例えば、配列番号2、3、7、11、26、28、29、32、37、38、40および41)が挙げられる。GDFトラップは、例えばGDF11および/またはミオスタチンを含めた他のActRIIBリガンドと比較してアクチビンに対する親和性が減少したActRIIBポリペプチドを指す。
特定の態様では、本発明は、本明細書中に開示されるGDFトラップポリペプチドのいずれかをコードする単離されたおよび/または組換えの核酸を提供する。配列番号4は、天然に存在するActRIIB前駆体ポリペプチドをコードし、一方配列番号5は、可溶性ActRIIBポリペプチドをコードし、配列番号25、27、30および31は可溶性GDFトラップをコードする。本主題の核酸は、一本鎖もしくは二本鎖であり得る。このような核酸は、DNA分子もしくはRNA分子であり得る。これらの核酸は、例えば、GDFトラップポリペプチドを作製するための方法において、または(例えば、遺伝子治療アプローチにおいて)直接的な治療剤として使用され得る。
特定の態様では、本発明は、ActRIIBポリペプチドのアゴニストまたはアンタゴニストである化合物(因子)を同定するための、本主題のGDFトラップポリペプチド(例えば、可溶性の改変体ActRIIBポリペプチド)の使用に関する。このスクリーニングによって同定された化合物は、インビボまたはインビトロでの、赤血球、ヘモグロビンおよび/または網状赤血球のレベルを調節する能力を評価するために試験され得る。これらの化合物は、例えば、動物モデルにおいて試験され得る。
特定の実施形態では、本発明のGDFトラップポリペプチドは、げっ歯類および霊長類、特に、ヒト患者のような哺乳動物における赤血球のレベルを増加させるために使用され得る。特定の実施形態では、本発明は、治療上有効量のGDFトラップポリペプチドを個体に投与することによって、処置または予防を必要とする個体における貧血を処置または予防する方法を提供する。これらの方法は、哺乳動物、特に、ヒトの治療的および予防的な処置に使用され得る。
特定の実施形態では、本発明の化合物(例えば、GDFトラップポリペプチド)は、薬学的に受容可能なキャリアと共に処方される。例えば、GDFトラップポリペプチドは、単独で、または、薬学的処方物(治療用組成物)の成分として投与され得る。本主題の化合物は、ヒトまたは獣医学における医薬での使用のために任意の簡便な方法で投与するために処方され得る。
本発明は、ここで、一般的に記載されてきたが、単に特定の実施形態および本発明の実施形態を例示する目的のために含められ、本発明を限定することは意図されない以下の実施例を参照するとより容易に理解される。
出願人は以下の通りGDFトラップを構築した。GDF11および/またはミオスタチンと比較してアクチビンAへの結合が大幅に減少している(配列番号1の79位におけるロイシンからアスパラギン酸への置換の結果として)修飾されたActRIIB細胞外ドメインを有するポリペプチドを、間に最小限のリンカー(3つのグリシンアミノ酸)を用いて、ヒトもしくはマウスのFcドメインに融合させた。この構築物を、それぞれ、ActRIIB(79D 20〜134)−hFcおよびActRIIB(L79D 20〜134)−mFcと呼ぶ。79位にアスパラギン酸ではなくグルタミン酸を持つ代替の形態について同様に行った(L79E)。以下の配列番号7について、226位にバリンではなくアラニンを持つ代替の形態も作製し、試験された全ての点において同等に実施した。79位のアスパラギン酸(配列番号1に対して、または配列番号7に対して第60位)に以下で灰色のマーカーを付す。配列番号7に対して、226位のバリンも以下で灰色のマーカーを付す。
A−204レポーター遺伝子アッセイを、GDF−11およびアクチビンAによるシグナル伝達に対するActRIIB−Fcタンパク質およびGDFトラップの作用を評価するために使用した。細胞株:ヒト横紋筋肉腫(筋肉から誘導された)。レポーターベクター:pGL3(CAGA)12(Dennlerら、1998年、EMBO 17巻:3091〜3100頁に記載されている)。CAGA12モチーフはTGF−ベータ応答性遺伝子(PAI−1遺伝子)に存在するので、このベクターは、一般的に、Smad2および3を介するシグナル伝達の因子に用いる。
1日目:A−204細胞を48ウェルプレート中に分ける。
2日目:A−204細胞を、10ugのpGL3(CAGA)12またはpGL3(CAGA)12(10ug)+pRLCMV(1ug)およびFugeneでトランスフェクトする。
3日目:因子を加える(培地+0.1%BSA中に希釈)。インヒビターは、細胞への追加前に因子と一緒に1時間プレインキュベートする必要がある。6時間後、細胞をPBSでリンスし、そして細胞を溶解する。
N末端および/またはC末端における切断を伴うActRIIB(20〜134)−hFcの改変体を作製し、GDF−11およびアクチビンのインヒビターとしての活性について試験した。活性を以下に示す(条件培地において測定)。
ActRIIB−Fcタンパク質およびGDFトラップの活性を、上記の細胞ベースのアッセイで試験した。結果を以下の表に要約する。いくつかの改変体を異なるC末端切断構築物において試験した。上記のように、5または15アミノ酸の切断は活性の低下を引き起こした。GDFトラップ(L79DおよびL79E改変体)は、アクチビンの結合の実質的な損失を示した一方、ほとんど野生型のGDF−11阻害を保持した。
特定のActRIIB−Fcタンパク質およびGDFトラップのリガンドへの結合をBiaCoreTMアッセイにおいて試験した。
雄性および雌性のカニクイザルに、ActRIIB(20〜134)−hFc(IgG1)を、1カ月間、週一回、皮下注射により投与した。48匹のカニクイザル(24匹/性別)を、4つの処置群(6匹の動物/性別/群)のうちの1つに割り当て、そして、4週間にわたり、週一回(合計5用量)、ビヒクルまたは3mg/kg、10mg/kgもしくは30mg/kgのActRIIB−hFcのいずれかの皮下注射を施した。評価したパラメータには、一般的な臨床病理学(血液学、臨床化学、凝固および尿検査)を含めた。ActRIIB−hFcは、処置した動物において、15日目までに、平均の絶対的網状赤血球値の統計的に有意な上昇を引き起こした。36日目までに、ActRIIB−hFcは、平均絶対的網状赤血球および赤血球分布幅の値の上昇、ならびに、平均血球ヘモグロビン濃度の低下を含む、いくつかの血液学的変化を引き起こした。全ての処置群および両方の性別が影響を受けた。これらの作用は、骨髄からの未成熟な網状赤血球の放出に対するActRIIB−hFcの正の作用と一致している。この作用は、処置した動物から薬物を洗い出した後に逆転した(研究の56日目までに)。したがって、本発明者らは、ActRIIB−hFcが赤血球生成を刺激すると結論付ける。
この試験では、骨髄および脾臓内の造血前駆細胞の頻度に対するActRIIB(20−134)−mFcのインビボ投与の効果を分析した。C57BL/6マウスの1群に、対照としてPBSを注射し、マウスの第2群に、10mg/kgのActRIIB−mFcを2用量投与し、両群を8日後に屠殺した。末梢血を使用して完全血球計算を行い、大腿および脾臓を使用してインビトロクローン原性アッセイを行って、各器官内のリンパ球前駆細胞、赤血球前駆細胞および骨髄系前駆細胞の含量を査定した。この研究の短期間の枠では、処置したマウスにおいて赤血球、ヘモグロビンまたは白血球のレベルの有意な変化は見られなかった。大腿では、対照と処置群との間で、有核細胞数または前駆細胞含量に差異はなかった。脾臓では、化合物で処置した群は、皿当たりの成熟赤血球前駆細胞(CFU−E)コロニー数、脾臓当たりの頻度および全前駆細胞数で、統計学的に有意な増加を経験した。さらに、脾臓当たりの骨髄系前駆細胞(CFU−GM)、未成熟赤血球前駆細胞(BFU−E)の数および全前駆細胞数の増加を認めた。
6〜8週齢の雌性C57BL/6マウス16匹を試験に使用した。マウス8匹について、1日目および3日目に10mg/kgの用量の試験化合物ActRIIB−mFcを皮下注射し、マウス8匹について、対照ビヒクルのリン酸緩衝生理食塩水(PBS)をマウス当たり100μLの量で皮下注射した。全てのマウスを、最初の注射の8日後に、関連する動物の取り扱いに関するガイドライン(Animal Care Guidelines)に従って屠殺した。個々の動物からの末梢血(PB)試料を心臓穿刺によって採取し、完全血球計算および鑑別(CBC/Diff)に使用した。各マウスから大腿および脾臓を収集した。
(CBC/Diff計算)
心臓穿刺によって各マウスからPBを採取し、適切なマイクロティナ(microtainer)管内に置いた。試料を、CellDyn3500カウンターで分析するためにCLVに送った。
骨髄系列、赤血球系列およびリンパ球系列のクローン原性前駆細胞を、下記のインビトロのメチルセルロースベース培地系を使用して査定した。
成熟赤血球系列のクローン原性前駆細胞(CFU−E)を、組換えヒト(rh)エリスロポイエチン(3U/mL)を含有するメチルセルロースベース培地MethoCultTM3334中で培養した。
リンパ球系列のクローン原性前駆細胞(CFU−pre−B)を、rhインターロイキン7(10ng/mL)を含有するメチルセルロースベース培地MethoCult(登録商標)3630中で培養した。
顆粒球−単球系列のクローン原性前駆細胞(CFU−GM)、赤血球系列のクローン原性前駆細胞(BFU−E)および多分化能系列のクローン原性前駆細胞(CFU−GEMM)を、組換えマウス(rm)幹細胞因子(50ng/mL)、rhインターロイキン6(10ng/mL)、rmインターロイキン3(10ng/mL)およびrhエリスロポイエチン(3U/mL)を含有するメチルセルロースベース培地MethoCultTM3434中で培養した。
マウスの大腿および脾臓を、標準のプロトコルによって処理した。簡単に述べると、21ゲージの針および1ccの注射器を使用して2%のウシ胎仔血清を含有するイスコフ改変ダルベッコ培地(Iscove’s Modified Dulbecco’s Media)(IMDM2%FBS)で大腿腔を洗い流すことによって骨髄を得た。70μMのフィルターを通して脾臓をつぶし、そのフィルターをIMDM2%FBSですすぐことによって脾臓細胞を得た。次いで、Neubauer計算チャンバーを使用して単一の細胞懸濁物について3%氷酢酸中での有核細胞の計算を行って、器官当たりの全細胞を算出することができるようにした。次いで、混入した赤血球を除去するために、全脾臓細胞を3倍量の塩化アンモニウム溶解緩衝液で希釈し、氷上で10分間インキュベートした。次いで細胞を洗浄し、IMDM2%FBSに再懸濁させ、第2の細胞計算を行って溶解後の細胞の細胞濃度を決定した。
クローン原性アッセイの3連の培養物ならびに全データセットについての対照群および処置群について平均+/−1標準偏差を計算した。
皿当たりのプレーティングされた細胞
皿当たりのスコア化した平均CFC
の通り計算した。
スコア化された全CFC×大腿または脾臓当たりの有核細胞数(RBC溶解の後)
培養された有核細胞の数
の通り計算した。
12週齢の雄性C57BL/6NTacマウスを、2つの処置群のうちの1つに割り当てた(N=10)。マウスに、ビククルまたは改変体ActRIIBポリペプチド(「GDFトラップ」)[ActRIIB(L79D 20〜134)−hFc]のいずれかを、4週間、週2回、10mg/kgを皮下注射(SC)により投薬した。研究の終了時に、全血を心臓穿刺によりEDTA含有管に採取し、HM2血液分析器(Abaxis,Inc)を使用して細胞分布について分析した。
19週齢の雄性C57BL/6NTacマウスを、3つの群のうちの1つに無作為に割り当てた。マウスに、ビヒクル(10mMのトリス緩衝生理食塩水、TBS)、野生型ActRIIB(20〜134)−mFc、またはGDFトラップActRIIB(L79D 20〜134)−hFcを、3週間、週に2回、皮下注射により投薬した。ベースライン、および投薬の3週間後に、血液を頬出血で採取し、血液分析器(HM2、Abaxis,Inc.)を使用して細胞分布について分析した。
実施例1に記載されるように、ActRIIB(L79D 20〜134)−hFcと呼ばれるGDFトラップを、TPAリーダーの、ロイシンからアスパラギン酸への置換(配列番号1の残基79において)を含有するActRIIB細胞外ドメイン(配列番号1の残基20〜134)へのN末端融合、および最小限のリンカー(3つのグリシン残基)を用いたヒトFcドメインのC末端融合により作製した(図3)。この融合タンパク質に対応するヌクレオチド配列を図4に示す。
GDFトラップおよび他のActRIIB−hFcタンパク質の、いくつかのリガンドに対する親和性を、BiacoreTM機器を用いてインビトロで評価した。結果を以下の表に要約する。konおよびkoffの正確な決定を妨害した、複合体の非常に急速な会合と解離のため定常状態親和性フィットによりKd値を得た。
ActRIIB(L79D 25〜131)−hFcを作製するために、ネイティブな79位(配列番号1)においてアスパラギン酸置換を持ち、N末端およびC末端の切断を伴うヒトActRIIB細胞外ドメイン(配列番号1の残基25〜131)を、ネイティブなActRIIBリーダーではなくTPAリーダー配列とN末端融合させ、最小限のリンカー(3つのグリシン残基)を介してヒトFcドメインとC末端融合させた(図5)。この融合タンパク質をコードするヌクレオチド配列の1つを図6(配列番号27)に示し、正確に同じ融合タンパク質をコードする代替のヌクレオチド配列を図9(配列番号30)に示す。このタンパク質を、実施例1に記載される方法体系を使用して発現させおよび精製した。
ActRIIB(L79D 25〜131)−hFcを、赤血球前駆体の増殖に対するその作用を決定するために評価した。雄性のC57BL/6マウス(8週齢)を、1日目および4日目に、ActRIIB(L79D 25〜131)−hFc(10mg/kg、s.c.;n=6)またはビヒクル(TBS;n=6)で処置し、次いで8日目に、脾臓、脛骨、大腿骨、および血液を採取するために安楽死させた。脾臓および骨髄の細胞を単離し、5%ウシ胎仔血清を含有するイスコフ改変ダルベッコ培地中に希釈し、特殊化メチルセルロースベース培地に懸濁させ、2日間または12日間培養して、コロニー形成単位−赤血球(CFU−E)段階およびバースト形成単位−赤血球(BFU−E)段階で、それぞれ、クローン原性の前駆体のレベルを評価した。BFU−Eの決定用のメチルセルロースベース培地(MethoCult M3434、Stem Cell Technologies)には、CFU−Eの決定用のメチルセルロース培地(MethoCult M3334、Stem Cell Technologies)には存在しない組換えのマウス幹細胞因子、インターロイキン3、およびインターロイキン6を含めたが、どちらの培地も、他の構成成分の中でエリスロポエチンを含有した。BFU−EおよびCFU−Eの両方について、各組織試料から誘導された2連の培養プレートにおいてコロニーの数を決定し、結果の統計分析は処置群当たりのマウスの数に基づいた。
出願人は、微小管重合を遮断することによって細胞分裂を阻害するパクリタキセルに基づく化学療法誘発性貧血のマウスモデルにおいて、赤血球生成のパラメータに対するActRIIB(L79D 25〜131)−hFcの作用を調査した。雄性のC57BL/6マウス(8週齢)を4つの処置のうちの1つに割り当てた:
1)パクリタキセル(25mg/kg、i.p.)
2)ActRIIB(L79D 25〜131)−hFc(10mg/kg、i.p.)
3)パクリタキセル+ActRIIB(L79D 25〜131)−hFc
4)ビヒクル(TBS)。
出願人は、腎摘出された慢性腎疾患マウスモデルにおける貧血に対するActRIIB(L79D 25〜131)−hFcの作用を調査した。雄性のC57BL/6マウス(11週齢)について、偽手術またはエリスロポエチン生成能を低下させるための片側腎摘出のいずれかを行った。手術後回復のためにマウスに1週間与え、次いでActRIIB(L79D 25〜131)−hFc(10mg/kg、i.p.;条件当たりn=15)またはビヒクル(TBS;条件当たりn=15)で週2回、全部で4週間処置した。投薬開始前および処置の4週間後に血液試料を採取した。ビヒクルで処置した腎摘出されたマウスは、4週間の処置期間にわたって赤血球数の有意な減少を示したが、一方、ActRIIB(L79D 25〜131)−hFcを用いた処置では、腎臓のエリスロポエチン生成能が低下したにもかかわらず、赤血球細胞レベルの減少を妨げただけでなく、ベースライン上に17%増加させた(P<0.001)(図12)。腎摘出されたマウスにおいて、ActRIIB(L79D 25〜131)−hFcは、ヘモグロビン濃度およびヘマトクリットレベルにおいてもベースラインからの有意な増加を生じ、そして、注目すべきことに、これらの赤血球生成のパラメータそれぞれを、腎摘出された条件下で、偽手術の条件下とほぼ同程度まで刺激した(図13)。したがって、切断されたActRIIB細胞外ドメインを持つGDFトラップは、慢性腎疾患モデルにおいて貧血を逆転させるために十分に赤血球レベルを増加させ得る。
出願人は、急性失血によって誘発される貧血(急性出血後貧血)のラットモデルにおいて赤血球生成のパラメータに対するActRIIB(L79D 25〜131)−hFcの作用を調査した。雄性のSprague−Dawleyラット(およそ300g)に、供給メーカー(Harlan)において長期にわたる頸静脈カテーテルを受けさせた。−1日目に、各ラットから、イソフルラン麻酔下でカテーテルを介して5分間にわたって全血液量の20%を抜き取った。除去した血液量は、Leeおよび共同研究者(J Nucl Med 25巻:72〜76頁、1985年)によって、120gを超える体重のラットに対して導かれた以下の関係:
全血液量(ml)=0.062×体重(g)+0.0012
に従って計算された全血液量についての値に基づいた。
2つのGDFトラップ、ActRIIB(L79D 20〜134)−hFcおよびActRIIB(L79D 25〜131)−hFcを、カニクイザルにおける赤血球生成を刺激するそれらの能力について評価した。サルを、1日目および8日目にGDFトラップ(10mg/kg;n=雄性4/雌性4)、またはビヒクル(n=雄性2/雌性2)で皮下に処置した。1日目(前処置ベースライン)、3日目、8日目、15日目、29日目、および44日目に血液試料を採取し、赤血球レベル(図15)、ヘマトクリット(図16)、ヘモグロビンレベル(図17)、および網状赤血球レベル(図18)について分析した。ビククルで処置したサルは、処置後の全ての時点で、繰り返しの血液試料採取の予想された影響である、赤血球、ヘマトクリット、およびヘモグロビンのレベルの低下を示した。対照的に、ActRIIB(L79D 20〜134)−hFcまたはActRIIB(L79D 25〜131)−hFcを用いた処置では、最初の処置後の時点(3日目)までにこれらのパラメータが増加し、この研究の継続期間中、実質的に上昇したレベルを持続した(図15〜17)。重要なことに、ActRIIB(L79D 20〜134)−hFcまたはActRIIB(L79D 25〜131)−hFcで処置したサルにおける網状赤血球レベルは、8日目、15日目、および29日目において、ビヒクルと比較して実質的に増加した(図18)。この結果は、GDFトラップの処置が、赤血球前駆体の生成を増加させ、赤血球レベルの上昇をもたらすことを実証している。
ActIIB膜貫通ドメインを含むエクソン4が異なるC末端配列で置き換わった、代替の、可溶性の形態のActRIIB(ActRIIB5と呼ばれる)が報告された(WO2007/053775)。
本明細書中で言及される全ての刊行物および特許は、各個々の刊行物または特許が、具体的かつ個別に参考として援用されると示されるかのように、その全体が本明細書に参考として援用される。
Claims (53)
- 患者において赤血球レベルを高めるかまたは貧血を処置する方法であって、赤血球レベルを高めることまたは貧血を処置することを必要とする患者に、配列番号1のアミノ酸29〜109の配列に少なくとも90%同一であるアミノ酸配列を含むポリペプチドの有効量を投与する工程を含み、前記ポリペプチドが、配列番号1の79位に対応する位置に酸性アミノ酸を含む、方法。
- 前記酸性アミノ酸が、グルタミン酸およびアスパラギン酸からなる群より選択される、請求項1に記載の方法。
- 前記ポリペプチドが、配列番号1のアミノ酸29〜109の配列に少なくとも95%同一であるアミノ酸配列を含む、請求項1に記載の方法。
- 前記ポリペプチドが、配列番号1のアミノ酸25〜118の配列に少なくとも95%同一であるアミノ酸配列を含む、請求項1に記載の方法。
- 前記ポリペプチドが、配列番号1のアミノ酸25〜128の配列に少なくとも95%同一であるアミノ酸配列を含む、請求項1に記載の方法。
- 前記ポリペプチドが、配列番号1のアミノ酸25〜131の配列に少なくとも97%同一であるアミノ酸配列を含む、請求項1に記載の方法。
- 前記ポリペプチドが、配列番号7、28、29、32、37および38からなる群より選択されるアミノ酸配列を含む、請求項1に記載の方法。
- 前記患者が腎臓障害に関連する貧血を有する、請求項1から7のいずれかに記載の方法。
- 前記患者が慢性腎臓疾患に関連する貧血を有する、請求項8に記載の方法。
- 前記患者が化学療法処置に関連する貧血を有する、請求項1から7のいずれかに記載の方法。
- 前記化学療法処置がタキサンである、請求項10に記載の方法。
- 前記患者が失血の結果としての貧血を有する、請求項1から7のいずれかに記載の方法。
- 配列番号29のアミノ酸配列を含むポリペプチド。
- 免疫グロブリンの定常ドメインをさらに含む、請求項13に記載のポリペプチド。
- Fcドメインをさらに含む、請求項13に記載のポリペプチド。
- 配列番号28のアミノ酸配列を含む、請求項13に記載のポリペプチド。
- 配列番号32のアミノ酸配列を含むポリペプチド。
- 免疫グロブリンの定常領域をさらに含む、請求項17に記載のポリペプチド。
- Fcドメインをさらに含む、請求項17に記載のポリペプチド。
- 配列番号7のアミノ酸配列を含む、請求項17に記載のポリペプチド。
- ActRIIBに由来する前記ポリペプチドの部分が、配列番号29のアミノ酸配列からなるアミノ酸配列を有する、請求項17に記載のポリペプチド。
- グリコシル化アミノ酸、PEG化アミノ酸、ファルネシル化アミノ酸、アセチル化アミノ酸、ビオチン化アミノ酸、脂質部分に結合体化されたアミノ酸、および有機誘導体化剤に結合体化されたアミノ酸から選択される、1つまたは複数の修飾されたアミノ酸残基をさらに含む、請求項13から21のいずれかに記載のポリペプチド。
- 式A−B−Cで示されるアミノ酸配列を含む融合タンパク質であって、
Bは配列番号29のアミノ酸配列からなるアミノ酸配列を有するポリペプチドであり、
AおよびCは、独立に0、1または1個超のアミノ酸であり、
AおよびCは、Bと異種である、融合タンパク質。 - ホモダイマーを形成する、請求項23に記載の融合タンパク質。
- AまたはCの少なくとも1つが、インビボ安定性、インビボ半減期、取込み/投与、組織局在化もしくは分布、タンパク質複合体の形成、および/または精製の1つまたは複数を増強するポリペプチド部分を含む、請求項23または24に記載の融合タンパク質。
- AまたはCの少なくとも1つが、IgG重鎖に由来する定常領域を含む、請求項23または24に記載の融合タンパク質。
- IgG重鎖に由来する前記定常領域がFcドメインである、請求項26に記載の融合タンパク質。
- A、CまたはAおよびCが、リンカーを用いてBに融合される、請求項23に記載の融合タンパク質。
- 前記リンカーがGly−Gly−Glyを含む、請求項28に記載の融合タンパク質。
- グリコシル化アミノ酸、PEG化アミノ酸、ファルネシル化アミノ酸、アセチル化アミノ酸、ビオチン化アミノ酸、脂質部分に結合体化されたアミノ酸、および有機誘導体化剤に結合体化されたアミノ酸から選択される、1つまたは複数の修飾されたアミノ酸残基を含む、請求項23から29のいずれかに記載の融合タンパク質。
- Bが少なくとも1つの修飾されたアミノ酸残基を含む、請求項30に記載の融合タンパク質。
- 請求項13から31のいずれか一項に記載のポリペプチドを含む医薬調製物。
- 請求項13から31のいずれかに記載のポリペプチドをコードする核酸を含む培養細胞。
- 前記細胞が哺乳動物の細胞である、請求項33に記載の培養細胞。
- 前記細胞がCHO細胞である、請求項34に記載の培養細胞。
- 前記核酸が、ストリンジェントなハイブリダイゼーション条件下で配列番号12、25、27、30、31、33、34および35からなる群より選択される核酸配列とハイブリダイズする、請求項33に記載の培養細胞。
- 前記核酸が、配列番号12、25、27、30、31、33、34および35からなる群より選択される核酸配列に少なくとも95%同一である、請求項33に記載の培養細胞。
- 前記核酸が、配列番号12、25、27、30、31、33、34および35からなる群より選択される、請求項33に記載の培養細胞。
- ActRIIB由来のアミノ酸配列、リンカー配列および/または免疫グロブリン配列をコードする前記核酸の部分が、配列番号12、25、27、30、31、33、34および35からなる群より選択される核酸配列からなる、請求項33に記載の培養細胞。
- 患者において赤血球レベルを高めるかまたは貧血を処置する方法であって、赤血球レベルを高めることまたは貧血を処置することを必要とする患者に改変体ActRIIBポリペプチドの有効量を投与する工程を含み、前記改変体ActRIIBポリペプチドが、配列番号1のアミノ酸29〜109の配列に少なくとも90%同一であるアミノ酸配列を含み、前記改変体ActRIIBポリペプチドが、対応する野生型ActRIIBポリペプチドの比よりも大きいGDF11:アクチビン結合比を有する、方法。
- 前記改変体ActRIIBポリペプチドが、配列番号1の79位に対応する位置に酸性アミノ酸を含む、請求項40に記載の方法。
- 前記患者がヒト患者である、請求項40に記載の方法。
- 前記改変体ActRIIBポリペプチドが、対応する野生型ActRIIBポリペプチドの比よりも大きいGDF11:アクチビンA結合比を有する、請求項40に記載の方法。
- 前記改変体ActRIIBポリペプチドが、(a)配列番号1のアミノ酸22〜24のいずれかから始まり、配列番号1のアミノ酸133〜134のいずれかで終わる配列、(b)配列番号1のアミノ酸21〜29のいずれかから始まり、配列番号1のアミノ酸118〜134のいずれかで終わる配列、(c)配列番号1のアミノ酸21〜29のいずれかから始まり、配列番号1のアミノ酸128〜134のいずれかで終わる配列、(d)配列番号1のアミノ酸21〜24のいずれかから始まり、配列番号1のアミノ酸109〜134のいずれかで終わる配列、(e)配列番号1のアミノ酸21〜24のいずれかから始まり、配列番号1のアミノ酸118〜134のいずれかで終わる配列、(f)配列番号1のアミノ酸21〜24のいずれかから始まり、配列番号1のアミノ酸128〜134のいずれかで終わる配列、(g)配列番号1のアミノ酸20〜29のいずれかから始まり、配列番号1のアミノ酸109〜133のいずれかで終わる配列、(h)配列番号1のアミノ酸20〜29のいずれかから始まり、配列番号1のアミノ酸118〜133のいずれかで終わる配列、(i)配列番号1のアミノ酸20〜29のいずれかから始まり、配列番号1のアミノ酸128〜133のいずれかで終わる配列、(j)配列番号1のアミノ酸20〜24のいずれかから始まり、配列番号1のアミノ酸109〜133のいずれかで終わる配列、(k)配列番号1のアミノ酸20〜24のいずれかから始まり、配列番号1のアミノ酸118〜133のいずれかで終わる配列、(l)配列番号1のアミノ酸20〜24のいずれかから始まり、配列番号1のアミノ酸128〜133のいずれかで終わる配列、および(m)配列番号1のアミノ酸20から始まり、配列番号1のアミノ酸134で終わる配列、からなる群より選択される配列に少なくとも90%同一であるアミノ酸配列を含む、請求項40に記載の方法。
- 前記改変体ActRIIBポリペプチドが、グリコシル化アミノ酸、PEG化アミノ酸、ファルネシル化アミノ酸、アセチル化アミノ酸、ビオチン化アミノ酸、脂質部分に結合体化されたアミノ酸、および有機誘導体化剤に結合体化されたアミノ酸から選択される、1つまたは複数の修飾されたアミノ酸残基を含む、請求項40から44のいずれかに記載の方法。
- 赤血球レベルの増加が血中ヘモグロビンレベルの増加として測定される、請求項40から44のいずれかに記載の方法。
- 前記患者の骨格筋量の15%未満の増加を引き起こす、請求項40から44のいずれかに記載の方法。
- 前記改変体ActRIIBポリペプチドが、改変体ActRIIBポリペプチドドメインに加えて、インビボ安定性、インビボ半減期、取込み/投与、組織局在化もしくは分布、タンパク質複合体の形成および/または精製の1つまたは複数を強化する1つまたは複数のポリペプチド部分を含む融合タンパク質である、請求項40から44のいずれかに記載の方法。
- 前記融合タンパク質が、免疫グロブリンFcドメインおよび血清アルブミンからなる群より選択されるポリペプチド部分を含む、請求項40から44のいずれかに記載の方法。
- 前記融合タンパク質が、
a)配列番号7、11、28、29、32、37および38のアミノ酸配列に少なくとも90%同一であるアミノ酸配列、
b)配列番号7、11、28、29、32、37および38のアミノ酸配列に少なくとも95%同一であるアミノ酸配列、ならびに
c)配列番号7、11、28、29、32、37および38のアミノ酸配列
からなる群より選択されるアミノ酸配列を含む改変体ActRIIB−Fc融合タンパク質である、請求項49に記載の方法。 - 前記改変体ActRIIB−Fc融合タンパク質が、15〜30日の血清半減期を有する、請求項50に記載の方法。
- 前記改変体ActRIIB−Fc融合タンパク質が、週に1回以下の頻度で前記患者に投与される、請求項50に記載の方法。
- 前記改変体ActRIIB−Fc融合タンパク質が、月に1回以下の頻度で前記患者に投与される、請求項50に記載の方法。
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