JP2017518303A - フォリスタチンポリペプチドによる障害の処置のための方法および組成物 - Google Patents
フォリスタチンポリペプチドによる障害の処置のための方法および組成物 Download PDFInfo
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- JP2017518303A JP2017518303A JP2016570806A JP2016570806A JP2017518303A JP 2017518303 A JP2017518303 A JP 2017518303A JP 2016570806 A JP2016570806 A JP 2016570806A JP 2016570806 A JP2016570806 A JP 2016570806A JP 2017518303 A JP2017518303 A JP 2017518303A
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- follistatin
- polypeptide
- amino acid
- acid sequence
- muscle
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Abstract
Description
この出願は、2014年6月4日に出願された米国仮出願第62/007,908号に対する優先権の利益を主張する。上記出願の明細書は、その全体が本明細書に援用される。
筋肉、骨、軟骨、および他の組織の変化は、適切なTGF−ベータファミリーメンバーにより媒介されるシグナル伝達にアゴニスト作用を及ぼすか、またはこれに拮抗することにより達成することができる。しかし、ファミリーのメンバーは、1つを超える組織に影響を及ぼし得るため、一部の患者ケア状況では、このファミリーのメンバーの治療的阻害を、全身的な様式ではなくて、局在化させた様式で達成することが望ましい。したがって、TGF−ベータシグナル伝達の強力な調節因子として機能し、局在化投与に適切な作用因子が必要とされている。
ある特定の態様では、本開示は、フォリスタチンポリペプチドに関する。本明細書で使用される場合、用語「フォリスタチン」は、任意の種に由来するフォリスタチン(FST)タンパク質およびフォリスタチン関連タンパク質のファミリーを指す。フォリスタチンとは、高等動物のほぼ全ての組織内で発現する自己分泌性糖タンパク質である。フォリスタチンは当初、濾胞液から単離され、下垂体前葉からの濾胞刺激ホルモン(FSH)の分泌を阻害するタンパク質画分として同定されたため、FSH抑制タンパク質(FSP)と命名された。その後、その主要な機能は、例えば、下垂体前葉内のFSHの分泌を増強する傍分泌ホルモンであるアクチビンを含む、TGF−βスーパーファミリーのメンバーの結合および中和であることが決定された。
2.フォリスタチンポリペプチド
3.フォリスタチンポリペプチドをコードする核酸
4.例示的な治療的使用
5.医薬組成物
本発明は、ここで、一般的に記載されるが、単に本発明の特定の実施形態を例示する目的のために含められる以下の実施例を参照するとより容易に理解される。これらの実施例は、本発明を限定するとは意図されない。
(実施例1)
フォリスタチン−Fcタンパク質の生成
(1)フォリスタチンリーダー:MVRARHQPGGLCLLLLLLCQFMEDRSAQA(配列番号23)
(2)組織プラスミノーゲンアクチベーター(TPA):MDAMKRGLCCVLLLCGAVFVSP(配列番号24)
(3)ミツバチメリチン(HBML):MKFLVNVALVFMVVYISYIYA(配列番号25)
について検討した。
(実施例2)
マウスにおける、フォリスタチン−Fcタンパク質の全身投与の、筋量および筋強度に対する効果
(実施例3)
フォリスタチン−Fcタンパク質の全身投与の、FSHレベルに対する効果
(実施例4)
マウスにおける、フォリスタチン−Fcタンパク質の局所投与の、筋量および筋強度に対する効果
(実施例5)
局所作用型フォリスタチン−Fc融合タンパク質のFc最適化
(実施例6)
最適化された局所作用型フォリスタチン−Fc融合タンパク質
(実施例7)
マウスにおける、FST(291)−IgG2タンパク質の局所投与の、筋量および筋強度に対する効果
(実施例8)
デュシェンヌ型筋ジストロフィーのマウスモデルにおける、FST(291)−IgG2タンパク質の局所投与の、筋肉に対する効果
参照による組込み
Claims (76)
- 配列番号43のアミノ酸配列を含むポリペプチド。
- 配列番号43からなるアミノ酸配列を含む、請求項1に記載のポリペプチド。
- 配列番号43の最後の(カルボキシ末端の)リシン(K)が、非存在である、請求項1または2に記載のポリペプチド。
- 配列番号42のアミノ酸配列を含むポリペプチド。
- 配列番号42からなるアミノ酸配列を含む、請求項4に記載のポリペプチド。
- 配列番号42の最後の(カルボキシ末端の)リシン(K)が、非存在である、請求項4または5に記載のポリペプチド。
- 請求項1から6のいずれかに記載の2つのポリペプチドを含むホモ二量体。
- 請求項1から6のいずれかに記載のポリペプチドを含む医薬製剤。
- 請求項7に記載のホモ二量体を含む医薬製剤。
- 請求項1から6のいずれかに記載のポリペプチドをコードする核酸。
- 請求項10に記載の核酸を含む細胞。
- 筋障害に罹患した筋肉を処置するための方法であって、前記筋肉に、請求項1から6のいずれか一項に記載のポリペプチドまたは請求項7に記載のホモ二量体を投与する工程を含む方法。
- 前記筋障害が、筋ジストロフィーである、請求項12に記載の方法。
- 筋障害に罹患した筋肉を処置するための方法であって、前記筋肉に、請求項8または9に記載の医薬調製物を投与する工程を含む方法。
- 前記筋障害が、筋ジストロフィーである、請求項14に記載の方法。
- 第1のアミノ酸配列および第2のアミノ酸配列を含むポリペプチドであって、前記第1のアミノ酸配列が、配列番号15および16からなる群から選択されるアミノ酸配列からなり、前記第2のアミノ酸配列が、免疫グロブリンの定常ドメインを含む、ポリペプチド。
- リンカーポリペプチドが、前記第1のアミノ酸配列と第2のアミノ酸配列との間に配置されている、請求項16に記載のポリペプチド。
- 前記リンカーポリペプチドが、配列TGGGを含む、請求項17に記載のポリペプチド。
- 前記第2のアミノ酸配列が、IgG免疫グロブリンの定常ドメインを含む、請求項16から18のいずれかに記載のポリペプチド。
- 前記第2のアミノ酸配列が、ADCC活性がヒトIgG1と比べて低減されたIgG免疫グロブリンの定常ドメインを含む、請求項16から18のいずれかに記載のポリペプチド。
- 前記第2のアミノ酸配列が、CDC活性がヒトIgG1と比べて低減されたIgG免疫グロブリンの定常ドメインを含む、請求項16から18のいずれかに記載のポリペプチド。
- 前記第2のアミノ酸配列が、群:IgG1、IgG2、およびIgG4から選択されるIgG免疫グロブリンの定常ドメインを含む、請求項16から21のいずれかに記載のポリペプチド。
- 前記第2のアミノ酸配列が、免疫グロブリンのFc部分を含む、請求項16から18のいずれかに記載のポリペプチド。
- 前記第2のアミノ酸配列が、IgG免疫グロブリンのFc部分を含む、請求項16から18のいずれかに記載のポリペプチド。
- 前記第2のアミノ酸配列が、ADCC活性がヒトIgG1と比べて低減されたIgG免疫グロブリンのFc部分を含む、請求項16から18のいずれかに記載のポリペプチド。
- 前記第2のアミノ酸配列が、CDC活性がヒトIgG1と比べて低減されたIgG免疫グロブリンのFc部分を含む、請求項16から18のいずれかに記載のポリペプチド。
- 前記第2のアミノ酸配列が、群:IgG1、IgG2、IgG4、およびIgG2/4ハイブリッド体から選択されるIgG免疫グロブリンのFc部分を含む、請求項16から18のいずれかに記載のポリペプチド。
- 配列番号38〜43の群から選択される配列と少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド。
- 配列番号26〜28および32〜34の群から選択される配列と少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド。
- 配列番号29〜31および35〜37の群から選択される配列と少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド。
- 請求項16から30のいずれかに記載の2つのポリペプチドを含む二量体。
- 請求項16から30のいずれかに記載の2つのポリペプチドを含むホモ二量体。
- 請求項16から30のいずれかに記載の二量体を含む医薬調製物。
- 請求項16から30のいずれかに記載のポリペプチドをコードする核酸配列を含む核酸。
- 請求項34に記載の核酸を含む細胞。
- 患者における筋サイズまたは筋強度を増大させる方法であって、フォリスタチンポリペプチドの有効量を、それを必要とする患者の標的とされる筋肉への筋内投与経路により投与する工程を含み、ここで、増大した筋サイズまたは筋強度が、前記標的とされる筋肉内で生じ、前記フォリスタチンポリペプチドが、筋サイズまたは筋強度に対する実質的な全身効果を及ぼさない、方法。
- 前記標的とされる筋肉が、損傷しているか、衰弱しているか、または欠損している、請求項36に記載の方法。
- 前記標的とされる筋肉は健常であるが、前記標的とされる筋肉の筋サイズまたは筋強度の増大が所望される、請求項36に記載の方法。
- 前記フォリスタチンポリペプチドを、1つだけの標的とされる筋肉に投与する、請求項36から38のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドを、1つを超える標的とされる筋肉に投与する、請求項36から38のいずれか一項に記載の方法。
- 標的とされる筋肉に対して対側の筋肉が、サイズまたは強度において実質的に増大しない、請求項36から40のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、ミオスタチン、GDF−11、アクチビンA、およびアクチビンBからなる群から選択される1つまたは複数のリガンドに、1nM、100pM、50pM、または10pM未満のKDで結合する、請求項36から41のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、ミオスタチンに、1nM、100pM、50pM、または10pM未満のKDで結合する、請求項36から41のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、アクチビンAに、1nM、100pM、50pM、または10pM未満のKDで結合する、請求項36から41のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、さらにアクチビンAに、1nM、100pM、50pM、または10pM未満のKDで結合する、請求項43に記載の方法。
- 前記フォリスタチンポリペプチドが、マスキングされていないヘパリン結合性ドメインを含む、請求項36から45のいずれか一項に記載の方法。
- 前記ヘパリン結合性ドメインが、配列番号5の内因性フォリスタチンヘパリン結合性配列を含む、請求項36から46のいずれか一項に記載の方法。
- 前記ヘパリン結合性ドメインが、異種ヘパリン結合性配列を含む、請求項36から46のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、融合タンパク質である、請求項36から48のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、マスキングされていないヘパリン結合性ドメインを含む、請求項49に記載の方法。
- 前記フォリスタチンポリペプチドが、二量体を形成する、請求項49または50に記載の方法。
- 前記フォリスタチンポリペプチドが、IgGの定常ドメインを含む、請求項49から51のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、IgGのFc部分を含む、請求項52に記載の方法。
- 前記IgGが、IgG1、IgG2、IgG4、およびIgG2/4ハイブリッド体からなる群から選択される、請求項52または53に記載の方法。
- 前記フォリスタチンポリペプチドが、実質的な抗体依存性細胞介在性傷害作用(ADCC)を媒介しない、請求項36から54のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、実質的な補体依存性細胞傷害作用(CDC)を媒介しない、請求項36から55のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、配列番号1〜4、7〜16および26〜43の群から選択されるアミノ酸配列と少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、請求項36に記載の方法。
- 前記フォリスタチンポリペプチドが、配列番号15または16と少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列からなるフォリスタチンに由来する第1のアミノ酸配列と;フォリスタチンに対して異種であり、IgGの定常ドメインを含む第2のアミノ酸配列とを含み、前記IgGの前記定常ドメインは、実質的なADCCおよび/または実質的なCDCを媒介しないように選択される、請求項36に記載の方法。
- 前記第1のアミノ酸配列が、前記フォリスタチンポリペプチドの唯一のアミノ酸配列であって、配列番号4のヒトフォリスタチン配列内に固有に見出されるアミノ酸配列である、請求項58に記載の方法。
- 前記IgGの前記定常ドメインが、実質的なADCCおよび実質的なCDCを媒介しないように選択される、請求項58に記載の方法。
- 前記第2のアミノ酸配列が、IgGのFc部分を含む、請求項58に記載の方法。
- IgGの前記Fc部分が、IgG1、IgG2、IgG4、IgG2/4ハイブリッド体からなる群から選択される、請求項61に記載の方法。
- 前記フォリスタチンポリペプチドが、二量体を形成する、請求項58から62のいずれか一項に記載の方法。
- 前記フォリスタチンポリペプチドが、ホモ二量体を形成する、請求項63に記載の方法。
- 前記患者において、血清FSHレベル、肝臓サイズ、ヘマトクリット、および網状赤血球レベルからなる群から選択される尺度に対して実質的な効果を引き起こさない、請求項36から64のいずれか一項に記載の方法。
- 配列番号15または16と少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列からなるフォリスタチンに由来する第1のアミノ酸配列と;フォリスタチンに対して異種であり、IgGの定常ドメインを含む第2のアミノ酸配列とを含む融合タンパク質であって、前記IgGの前記定常ドメインが、実質的なADCCまたは実質的なCDCを媒介しないように選択される、融合タンパク質。
- 前記第1のアミノ酸配列が、前記フォリスタチンポリペプチドの唯一のアミノ酸配列であって、配列番号4のヒトフォリスタチン配列内に固有に見出されるアミノ酸配列である、請求項66に記載の融合タンパク質。
- 前記IgGの前記定常ドメインが、ADCCおよびCDCを媒介しないように選択される、請求項66に記載の融合タンパク質。
- 前記第2のアミノ酸配列が、IgGのFc部分を含む、請求項66に記載の融合タンパク質。
- IgGの前記Fc部分が、IgG1、IgG2、IgG4、IgG2/4ハイブリッド体からなる群から選択される、請求項69に記載の融合タンパク質。
- 前記フォリスタチンポリペプチドが、二量体を形成している、請求項66から70のいずれかに記載の融合タンパク質。
- 前記フォリスタチンポリペプチドが、ホモ二量体を形成している、請求項66から70のいずれかに記載の融合タンパク質。
- 請求項66から72のいずれか一項に記載の融合タンパク質を含む医薬調製物。
- 実質的に発熱物質非含有である、請求項73に記載の医薬調製物。
- 請求項66から72のいずれかに記載の融合タンパク質をコードする核酸。
- 請求項75に記載の核酸を含む細胞。
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