JP2012518420A - TGF−βスーパーファミリーのデザイナーリガンド - Google Patents
TGF−βスーパーファミリーのデザイナーリガンド Download PDFInfo
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Abstract
【選択図】 図19
Description
本明細書に記載したのと類似または同等の方法および材料を開示した方法の実施および組成物に使用することができ、例示の方法、デバイスおよび材料を本明細書に記載する。
これらの新規TGF-βリガンドを作製するために、改変した定方向進化手法を利用した。典型的にはこの技法は、相同遺伝子の配列を混合するかまたは無作為な突然変異を挿入することにより103を超える大量の無作為タンパク質配列を作り、次いで所望のリガンド特性をスクリーニングすることに関わる。一式の実験において、効率的にリフォールドすることが知られる骨格リガンド(back bone)と名付けた配列を、標的リガンドを模倣する所望のシグナル伝達特性を含有する第2リガンドと組み合わせた。構造に手引きされる手法を用いて、いくつかのTGF-βリガンド結晶構造を分析して6つの区切られたセクションに分割した。これらのセクションはおおまかに次のリガンド領域:セクション1、N末端およびβストランド1;セクション2、βストランド2;セクション3、プレへリックスループ;セクション4、αへリックス;セクション5、βストランド3;およびセクション6、βストランド4およびC末端を包含する。このプロトコルを用いると、組換えのために選んだTGF-βリガンドの各セットについて64通りの異なるリガンド組み合わせが可能である。2以上の親鎖が異なるサブファミリー(例えばBMP/GDF対TGFβ)に由来する場合、それらのシグナル伝達機構の間の相違はセクション3と4が分離されていれば、捕獲することができない。デザイン原理として広く応用可能であるために、2つの構造セグメント、セクション3と4を両方の親遺伝子の1セクション(セクション3*4と呼ぶ)として処理できるようにすることもデザインの一部である。
アクチビン/BMP-2、1bキメラ、およびBMP-2maキメラを典型的な大腸菌発現系を用いて発現し、全部で32キメラを封入体画分中に見出した。発現された封入体を単離し、精製し、そしてリフォールドした。リフォールドしたリガンドをHi-Trapヘパリンカラム(GE Healthcare)と逆相クロマトグラフィ(GraceVydac)を用いて精製した。リガンドを凍結乾燥し、全ての細胞に基づくアッセイ用に4mM HCl、pH 1に、または全ての生物物理アッセイ用に10mM酢酸ナトリウム、pH 4に再懸濁した。アクチビン-βAを、安定してトランスフェクトしたCHO細胞株に発現して当技術分野で公知の技法を用いて精製した。先に記載したプロトコルに基づいてNogginを発現して精製した。
Smad1依存ルシフェラーゼ アッセイを当技術分野で公知の技法を用いて実施した。簡単に説明すると、C2C12筋芽細胞を、L-グルタミンと抗生物質を補充したダルベッコ最小必須培地(DMEM)+5%FBSで培養した。ルシフェラーゼレポーターアッセイについては、細胞をトリプシンで処理し、PBSで2回洗浄し、そしてDMEM+0.1%FBSを用いて48ウエルプレート中にプレーティングした。24時間後、細胞をSmad結合部位(Id1-Luc)、Smad1発現構築物、およびCAGGS-LacZプラスミドを含有する-1147Id1-ルシフェラーゼ構築物で、Fugene6(Roche)を用いて製造業者取扱説明書に従ってトランスフェクトし、そしてトランスフェクションの24時間後、加えた増加量のBMP-2maまたは様々なアクチビン/BMP-2キメラで細胞を刺激した。ルシフェラーゼ活性をリガンドによる刺激の24時間後に測定し、その値をトランスフェクション効率についてβ-ガラクトシダーゼ活性を用いて規準化した。ルシフェラーゼレポーターの活性は、Smad結合ドメインを欠く-927Id1-ルシフェラーゼ(Id1-Luc mut)を用いることにより得た対照値と比較して誘導倍数で表現した。リガンドのSmad1シグナル伝達を減衰するNogginの能力を試験するために、ルシフェラーゼアッセイを上記のように、アッセイに含まれる1セットのNogginの用量で繰り返した。
HEK293T 細胞を、ポリリシンでコートした25ウエルプレート中に150,000細胞/ウエルの密度でまいた。24時間後、細胞を一晩、A3 Lux(25ng)とβ-ガラクトシダーゼ(25ng)レポータープラスミド、転写因子FAST2(50ng)、および空のpCDNA3ベクター(400ng)の混合物で、製造業者の推奨に従ってPerfectin(登録商標)トランスフェクション試薬(GenLantis)を用いてトランスフェクトした。次いで細胞を、増加用量のアクチビン-βAまたはアクチビン/BMP-2キメラで16〜24時間処理した。細胞を氷冷した溶解バッファー(25mMグリシルグリシン中の1% Triton X-100、4nM EGTA、1mMジチオトレイトールを含有する15mM MgSO4)に収穫し、標準方法を用いてルシフェラーゼおよびβ-ガラクトシダーゼ活性を試験した。公知のTGF-β共受容体と結合するアクチビン/BMP-2キメラの能力を評価するために、HEK293T細胞を増加用量のアクチビン-βAまたはアクチビン/BMP-2キメラで、トランスフェクトしたCriptoの存在または非存在のもとで16〜24時間処理した(マウスCripto構築物はMalcolm Whitman (Department of Cell Biology, Harvard Medical School, Boston, MA)からの好意の贈物である)。
本アッセイを当技術分野で従来記載された通り実施した。簡略に説明すると、数匹の動物からの雌性Sprague-Dawleyラット内部下垂体由来の新しく単離した細胞を組み合わせて、96ウエルプレート中に、50,000細胞/ウエルの密度で、2%ウシ胎児血清および適当な増殖因子を補充したβPJ培地にまいた。24時間後に細胞を増加用量のアクチビン-βAまたはアクチビン/BMP-2キメラs(0〜40nM)で処理した。72時間後、培地を収穫し、分泌したFSHの濃度をラジオイムノアッセイにより測定した。
リガンドのBMPRIa、ActRII、およびActRIIbとのアフィニティをBiacore 3000(GE Healthcare)を用いてモニターし、そのデータをBIA評価ソフトウエアver.4.1(GE Healthcare)を用いて分析した。一次アミンカップリングを用いて、受容体ECDをCM5チップ上に固定した。受容体を独立してフローセル2〜4上に10分間、流量5μL/分でかつ10mM酢酸Na中の濃度20μM、pH4.0にて固定した。フローセル1はブランクで残し、ネガティブ対照としてタンパク質を固定しなかった。実験は流量50μL/分、20mM Tris-HCl、pH 7.9、250 mM NaCl、0.36% 3-[(3-コールアミドプロピル)ジメチルアンモニオ]-1-プロパンスルホナート (CHAPS)、および0.005% Tween-20で実施した。最小5レベルの濃度に加えて0濃度をサンプル毎に動力学分析用に試験し、そのデータを物質移動によるグローバル1:1 Langmuir結合を用いることによってフィットさせた。
BMP2-BMPRIa-ActRIIbの結晶構造は、各受容体分子が細胞外結合せずかつ4つの異なるリガンド-受容体界面を有することを示した。これは、ヘテロ二量体が2つの異なるI型界面と2つの異なるII型界面を有しうることを示唆した。BMPリガンドの機能性と他の態様を特徴づけるために、組換えヘテロ二量体を合成した。タンパク質の純度はドデシル硫酸ナトリウム-ポリアクリルアミドゲル電気泳動(SDS-PAGE)により立証した。図1aはBMP2/BMP6ヘテロ二量体の移動を、SDS-PAGE上の非還元下の単一バンド(レーン1)としておよび還元条件下の2つの異なるバンド(lane3)として図解する。2つの異なるバンドはBMP2/BMP6ヘテロ二量体の2つの異なる単量体種(それぞれ約13および15kDa)に関連する。この確証はさらに、表面増強レーザ脱離/イオン化飛行時間質量分析(SELDI-TOF-MS)のデータにより支持される。BMP2とBMP6のホモ二量体およびBMP2/BMP6ヘテロ二量体の3つの別々の精製サンプルをSELDI-TOF-MSで試験した。図1bは、3つのサンプルはそれらの予想される質量に対応し、他の汚染種が存在しないことを実証する。これらのアッセイは純粋なBMP2/BMP6ヘテロ二量体が作られたことを示す。
BMP2/BMP6ヘテロ二量体とI型およびII型TGF-β受容体ECDとの間の相互作用を試験するために、表面プラズモン共鳴を利用してin vitroアフィニティを測定した。TGF-β受容体をチップに固定し、TGF-βリガンドを表面上に流しながら、相互作用をモニターした。表3は、試験したリガンドとI型およびII型受容体ECDに対するアフィニティの変化を総括する。BMP2/BMP6ヘテロ二量体の場合、そのBMP2およびBMP6単量体サブユニットのそれぞれと大きいアフィニティを有する。示されたように、BMP2/BMP6ヘテロ二量体はI型受容体に対してBMP2ホモ二量体と類似したアフィニティを有する。しかし、BMP2サブユニットのII型受容体ECDとのアフィニティの代わりに、BMP2/BMP6ヘテロ二量体はII型受容体に対してBMP6と類似したアフィニティを有する。これは、II型受容体ECDに対する高いアフィニティにはBMP6単量体サブユニットが寄与する一方、I型受容体ECDに対する高いアフィニティにはBMP2単量体サブユニットが寄与することを示す。
ヒトBMP2(残基1-110)とヒトBMP6(残基1-132)の成熟ドメインを大腸菌に封入体として発現させた。野生型リガンド配列への変異は、先に公開されたリガンド-受容体界面を破壊する知見(Keller et al., 2004; Kirsch et al., 2000)に基づいた。発現された封入体を単離し、精製し、そしてリフォールドした。リフォールドしたBMP2およびBMP6ホモ二量体、ならびにBMP2/BMP6ヘテロ二量体を、HiTrapヘパリンカラム(GE Healthcare)と逆相クロマトグラフィ(GraceVydac)を用いて精製した。リガンドを凍結乾燥し、10mM酢酸ナトリウムpH 4.0に再懸濁した。ヒトBMPRIa(残基1-129)およびマウスActRIIb(残基1-98)のECDを大腸菌にチオレドキシン融合タンパク質として発現させた。マウスActRII-ECD(残基1-102)を発現させ、P. pastoris発現系から精製した。
リガンドのBMPRIa、ActRII、およびACTRIIbとのアフィニティを、Biacore 3000(GE Healthcare)を用いてモニターし、そのデータを、BIAevaluation ソフトウエア ver.4.1(GE Healthcare)を用いて分析した。一級アミンカップリングを用いて、受容体ECDをCM5チップ上に固定した。受容体を独立してフローセル2〜4上に10分間、5μL/分の流量および10mM酢酸ナトリウム中の濃度20μM、pH4.0にて固定した。フローセル1はネガティブ対照としてタンパク質を固定せずブランクのままとした。実験は20mM Tris-HClで50μL/分の流量、pH 7.9、250mM NaCl、0.36% 3-[(3-コールアミドプロピル)ジメチルアンモニオ]-1-プロパンスルホナート(CHAPS)、および0.005% Tween-20にて実施した。1サンプル当たり少なくとも5レベルの濃度に加えて0濃度を動力学分析用に試験し、そのデータを物質移動によるグローバル1:1 Langmuir結合を用いてフィットさせた。
Smad1依存ルシフェラーゼアッセイを実施した。簡略に説明すると、C2C12細胞を、L-グルタミンと抗生物質を補充したダルベッコ最小必須培地(DMEM)+5%FBSで培養した。ルシフェラーゼレポーターアッセイについては、細胞をトリプシンで処理し、PBSで2回洗浄し、そしてDMEM+0.1%FBSを用いて48ウエルプレート中にプレーティングした。24時間後、細胞をSmad結合部位(Id1-Luc)(Nakashima ら、2001)、Smad1発現構築物、およびCAGGS-LacZプラスミドを含有する-1147Id1-ルシフェラーゼ構築物で、Fugene6(Roche)を用いて製造業者取扱説明書に従ってトランスフェクトした。ルシフェラーゼ活性をリガンドによる刺激の24時間後に測定し、その値をトランスフェクション効率についてβ-ガラクトシダーゼ活性を用いて規準化した。ルシフェラーゼレポーターの活性は、Smad結合ドメインを欠く-927Id1-ルシフェラーゼ(Id1-Luc mut)を用いることにより得た対照値と比較して誘導倍数で表現した。
ニワトリ胚(Hamburger-Hamiltonステージ23-24(Hamburger and Hamilton, 1951))を、Ca2+およびMg2+を含有するハンクス液に採集し、肢芽の遠位1/3部分を解体した。外胚葉板をトリプシン処理(Ca2+およびMg2+を含むハンクス液中で0.5%)、氷上で30分間により取除いて、次いで間葉組織を回収し、そしてCa2+およびMg2+を含まないハンクス液中で37℃にて15分間インキュベートした。間葉細胞を、1%FBSを含有するOptiMEM培地(Invitrogen)にピペッティングして単細胞に分離した。培養を96-ウエルプレート中に4x105細胞/ウエルでまいた。1時間後、各リガンドを含有する培地を加えた。リガンドを含む新鮮な培地を毎日変え、軟骨小結節を可視化するAlcian 青色 染色により細胞の軟骨形成を分析し、記載のように軟骨形成を定量した(Wada et al., 2003)。
5μgの精製ActRII-ECD単独および10μgのBMP2/BMP6を伴うもの、単一の活性II型受容体界面を伴うBMP2/BMP6、または活性II型受容体界面無しのBMP2を、50mM Tris-HCl、pH 7.9、700mM NaCl、および1.8%CHAPS中の未変性PAGEゲル上に供給した。クーマシーブリリアントブルー(Bio-Rad)で染色したゲルを、「積分密度(Integrated Density)」関数を用いてNIH ImageJ ソフトウエア (Abramoff et al., 2004)により分析した。
無フィーダー条件でヒト胚幹細胞(hESC)を培養するには多能を維持する複合体処方培地が必要である。残念ながら、培地に要求される増殖因子は哺乳動物細胞で産生するのが困難であるため、市販培地は非常に高価である。本発明者らはmTeSR1製剤を用いて新しい培地(CIVA培地またはmCIVA)を誘導し、ヒト胚幹(hES)細胞を培養し、誘導した多能幹(iPS)細胞を誘導しかつ培養した(図2参照)。CIVA培地はmTeSR1中のTGFβ1をAB2-008、アクチビン-Aと類似の活性を持つ新しいキメラタンパク質に置き換えた。マトリゲルコーティング上のこの培地で培養したhES細胞は、核型異常なしに20継代以上、多能性の形態学を維持する。これらの細胞はまた、多能マーカーTRA-1-60およびSSEA-4に対してポジティブであり、BMP-2処置に応答して分化する。この培地で培養したiPS細胞はまた、多能性の形態学的特徴および多能マーカーの発現を保持する。この新しいCIVA培地はまた、ヒト包皮繊維芽細胞からiPS細胞を誘導するのに好適である。CIVA培地はhES細胞に対する他の市販培地の所望の特性を全て有するが、現在入手しうる培地より相当安いコストで処方することができる。図2 H9 hES細胞株を用いるmCIVA処方の開発。
Von Kossa染色を用いて、Ca沈着による細胞外石灰化についてプレ骨芽細胞細胞株(MC3T3-E1)の発生をモニターした。AB2-004とAB2-011は10倍以上の強度の染色の劇的な増加を示す。AB2-015は最大の増加を示すが、7日後である(ここに示してない)。
成人ラットのP3指を切断した。アガロースゲルビーズに浸漬したBMP2またはAB2-004を手術の部位に加えた。骨再成長をモニターした。BMP2で処理した組織は骨回復を示さなかった。AB2-004で処理した指は全回復した。
AB2-008、AB2-009、およびAB2-010はSmad2経路をアクチビン-βAとほとんど区別のつかない程度に活性化する。キメラに対する効力はアクチビン-βAと比較してわずかに低下し、5〜20倍である(図11参照)。
アクチビン-βAは特異的にSmad-2をリン酸化しかつSmad-1をリン酸化しない。これは、特異的にSmad-1をリン酸化しかつSmad-2をリン酸化しないBMP-2と対照的である。AB2-008、AB2-009、およびAB2-010はアクチビン-βAと同じSmad-2リン酸化パターンを示す。これは、これらの3リガンド全てがアクチビン-βAと類似の方式でアクチビン-βA シグナル伝達 経路を刺激することの確証である(図11参照)。
アクチビン-βAをラット内部下垂体細胞に加えると、用量に依存する卵胞刺激ホルモン(FSH)放出を誘発する。アクチビン-βA が誘導するFSHの放出はアンタゴニストのインヒビンを加えることによってブロックすることができる。アクチビン-βAと同様に、AB2-008、AB2-009、および AB2-010はFSHの放出を誘発し、この刺激はインヒビンの存在で減少する。
Criptoの添加はアクチビン-βAとAB2-008両方のシグナル伝達を比較しうるレベルだけ低下する。これらのデータは、AB2-008がCripto、アクチビン-βA共受容体と結合する能力を有することを示し、AB2-008とアクチビン-βAの機能的類似性の確証となる。
AB2-008は、ActRIIと高いアフィニティを有しかつBMPRIaとアフィニティの無いアクチビン-βAのプロファイルと類似した受容体結合プロファイルを示す。さらに、この2つのリガンドはほぼ同じ結合アフィニティを有する。AB2-008はアクチビン-βAよりほぼ1.7弱い。
AB2-004、AB2-011、AB2-012、およびAB2-015は、BMP-2より強力にSmad-1経路を活性化する。この活性化はBMP-2より3〜8倍高い(図14)。
AB2-004、AB2-011、AB2-012、およびAB2-015はActRIIに対してアクチビン-βAと類似の結合アフィニティを示す。これはBMP-2が同じ受容体に対して有する結合よりほぼ100倍高い。ABキメラに対するI型受容体結合は、BMP-2レベル(AB2-004)近くからアクチビン-βAレベルまでの範囲である(AB2-015についてはBMPRIaと無結合)。
Nogginはリガンドと直接複合体化することによりシグナル伝達活性を抑制し、自身のシグナル伝達用受容体と結合できなくする。Nogginの存在のもとでバックグランドレベル近くまでブロックされるBMP-2とは対照的に、AB2-004、AB2-011、およびAB2-015の高いシグナル伝達はNogginによって阻害されない。AB2-012は部分的にNoggin 阻害に非感受性であり、Nogginの添加によってシグナル伝達はほぼ50%減少する(図15)。この特性は、これらの細胞の骨再生を含むin vivoでのシグナル伝達能力を特に強力にする。
BMP2/BMP6ヘテロ二量体はBMP2のI型受容体BMPRIaに対する結合特性とBMP6のII型受容体ActRIIbに対する結合特性とを有する。ヘテロ二量体リガンドはそれぞれの受容体に対して高いアフィニティを維持するので、BMP2/BMP6ヘテロ二量体はそのホモ二量体対応物、BMP2およびBMP6ホモ二量体よりシグナル伝達活性が強い(表7)。
BMP2/BMP6ヘテロ二量体はBMP2またはBMP6単独のいずれよりもはるかに活性が高い。BMP2/BMP6はBMP2またはBMP6単独より少なくとも1オーダー高いEC50を有する。さらに、BMP2/BMP6によって到着される最大応答は、BMP2およびBMP6単独によって到着される最大シグナルの組み合わせより高い。
BMP2/BMP6は軟骨形成をBMP2またはBMP6ホモ二量体のいずれよりも強力に誘発する。ニワトリ肢芽間葉細胞の微量培養軟骨形成アッセイにおいて、3日後にBMP2/BMP6が両方ともBMP2またはBMP6のいずれよりも低い濃度においてかつより高いレベルへ軟骨形成を誘発することを本発明者らは観察した。
キメラを創製するための第1ステップは、各セグメントに対する境界を何処に作るかを決定することである。キメラライブラリーをアクチビン-βAとBMP-2を2つの配列源として用いて構築した。アクチビン/BMP-2(AB)キメラを作るセクションに対するカットオフ領域(接合部)をデザインするために、タンパク質配列アラインメントと一緒に構造を手引きとした手法を用いた。最初に、アクチビン-βA(Harrington et al., 2006)とBMP-2(Allendorph et al., 2006)の3次元結晶構造を構造的に検査した。この分析から、リガンドをおおまかに6つの異なるセクションに分割した(図7、セグメント1〜6を参照されたい)。正確なセグメント接合部は、最終的に、接合部の接続結果としてどちらかのタンパク質配列のどの配列変化も最小化する2つのリガンドのタンパク質配列アラインメントに従って決定した。さらに、セグメント領域を受容体結合部位から離れた構造領域に位置するように選んだ。
Claims (30)
- 少なくとも2つのペプチドセグメント、第1のTGF-βファミリータンパク質と少なくとも80%の同一性を有する配列を含むポリペプチドの第1のセグメントと第2のTGF-βファミリータンパク質と少なくとも80%の同一性を有する配列を含む第2のセグメント、またはそれらの組み合わせを含む組換えポリペプチドであって、前記セグメントは機能しうる形で連結されかつ第1もしくは第2の親TGF-βファミリータンパク質の少なくとも1つの活性、または新しいin vivoシグナル伝達および細胞特性の活性を有する前記組換えポリペプチド。
- ポリペプチドは1-2-3-4-5-6の全体配列順序を有する5または6つのドメインを含み、各ドメインは配列順序で少なくとも1つの他のTGF-βファミリーポリペプチド由来の少なくとも1つの他のドメインで組換えられていてもよい、請求項1に記載のポリペプチド。
- ポリペプチドが5つのドメインを含む、請求項2に記載のポリペプチド。
- キメラポリペプチドで少なくとも1つの他のドメインがシャッフルされる場合、ドメイン3だけがシャッフルされる、請求項2または3に記載のポリペプチド。
- ドメインが表Aに記載されている、請求項2に記載のポリペプチド。
- ポリペプチドがBMP-2由来のN末端セグメントを含む、請求項1に記載のポリペプチド。
- 少なくとも2つのポリペプチドセグメントがN〜C末端に機能しうる形で連結された6つのペプチドセグメントを含む、請求項1に記載のポリペプチド。
- 第1と第2のTGF-βファミリータンパク質のそれぞれが構造類似性を有し、各セグメントがセグメントの構造モチーフに対応する、請求項7に記載のポリペプチド。
- 第1のTGF-βファミリータンパク質はBMP-2でありかつ第2のTGF-βファミリータンパク質はアクチビンである、請求項1に記載のポリペプチド。
- 第1のTGF-βファミリータンパク質はBMP-2でありかつ第2のTGF-βファミリータンパク質はアクチビンまたは他のファミリーメンバーである、請求項7に記載のポリペプチド。
- BMP-2タンパク質のセグメントはセグメント1、すなわち配列番号2のアミノ酸残基約1〜約x1("1b");セグメント2、すなわち配列番号2のアミノ酸残基約x1〜約x2("2b”);セグメント3、すなわち配列番号2のアミノ酸残基約x2〜約x3("3b");セグメント4、すなわち配列番号2のアミノ酸残基約x3〜約x4(“4b”);セグメント5、すなわち配列番号2のアミノ酸残基約x4〜約x5("5b");およびセグメント6、すなわち配列番号2のアミノ酸残基約x5〜約x6("6b")を含み;かつここで:x1は配列番号2の残基25、26、27、28、29、30、31、32、33、34、または35であり;x2は配列番号2の残基45、46、47、または48であり;x3は配列番号2の残基65、66、67、または68であり;x4は配列番号2の残基76、77、78、79、80、81または82であり;x5は配列番号2の残基88、89、90、91、92、93、または94であり;そしてx6は配列番号2の残基112、113または114であって、BMP-2のC末端に対応し;そしてアクチビンタンパク質のセグメントはセグメント1、すなわち配列番号5のアミノ酸残基約1〜約x1("1a");セグメント2、すなわち配列番号5のアミノ酸残基約x1〜約x2("2a”);セグメント3、すなわち配列番号5のアミノ酸残基約x2〜約x3("3a");セグメント4、すなわち配列番号5のアミノ酸残基約x3〜約x4(“4a”);セグメント5、すなわち配列番号5のアミノ酸残基約x4〜約x5("5a");およびセグメント6、すなわち配列番号5のアミノ酸残基約x5〜約x6("6a")を含み;かつここで:x1は配列番号5の残基22、23、24、25、26、27、28、29、30、31または32であり;x2は配列番号5の残基42、43、44、または45であり;x3は配列番号5の残基61、62、63、または64であり;x4は配列番号5の残基78、79、80、81、82、83または84であり;x5は配列番号5の残基90、91、92、93、94、95または96であり;そしてx6は配列番号5の残基114、115、または116であり;そしてポリペプチドはセグメントをセグメント1-セグメント2-セグメント3-セグメント4-セグメント5-セグメント6の順で有する、請求項10に記載のポリペプチド。
- ポリペプチドは1b2b3b4b5b6a;1b2b3b4b5a6a;1b2b3b4b5a6b;1b2b3a4a5a6a;1b2b3a4a5b6a;1b2a3a4a5a6a;1b2a3a4a5a6aL66V/V67I;1b(1a_II)2a3a4a5a6a;1b2a3a4a5a6b;1b2a3a4a5b6b;1b2a3a4a5b6a;1b2a3b4b5b6a;1b2a3b4b5a6a;および1b2a3b4b5a6bからなる群より選択されるセグメントの配列を含む、請求項10に記載のポリペプチド。
- ポリペプチドは配列番号7、9、11、13、15、17、19、1、23、25、2、29、31、33、35、37、39または41に記載した配列と80%、90%、95%、98%または99%の同一性を含み、ここで該ポリペプチドはSMADまたはDAXX経路をモジュレートする、請求項1に記載のポリペプチド。
- ポリペプチドは配列番号7、9、11、13、15、17、19、1、23、25、2、29、31、33、35、37、39および41からなる群より選択される配列を含む、請求項13に記載のポリペプチド。
- 第2の異なるTGF-βファミリータンパク質のセグメントと機能しうる形で連結された第1のTGF-βファミリータンパク質のセグメントを含んで、SMADまたはDAXXをモジュレートする活性を有するキメラポリペプチドを与えるキメラTGF-βファミリーポリペプチド。
- 第1のTGF-βファミリータンパク質はBMP-2でありかつ第2のTGF-βファミリータンパク質はアクチビンである、請求項15に記載のポリペプチド。
- BMP-2タンパク質のセグメントはセグメント1、すなわち配列番号2のアミノ酸残基約1〜約x1("1b");セグメント2、すなわち配列番号2のアミノ酸残基約x1〜約x2("2b”);セグメント3、すなわち配列番号2のアミノ酸残基約x2〜約x3("3b");セグメント4、すなわち配列番号2のアミノ酸残基約x3〜約x4(“4b”);セグメント5、すなわち配列番号2のアミノ酸残基約x4〜約x5("5b");およびセグメント6、すなわち配列番号2のアミノ酸残基約x5〜約x6("6b")を含み;かつここで:x1は配列番号2の残基25、26、27、28、29、30、31、32、33、34、または35であり;x2は配列番号2の残基45、46、47、または48であり;x3は配列番号2の残基65、66、67、または68であり;x4は配列番号2の残基76、77、78、79、80、81または82であり;x5は配列番号2の残基88、89、90、91、92、93、または94であり;そしてx6は配列番号2の残基112、113または114であって、BMP-2のC末端に対応し;そしてアクチビンタンパク質のセグメントはセグメント1、すなわち配列番号5のアミノ酸残基約1〜約x1("1a");セグメント2、すなわち配列番号5のアミノ酸残基約x1〜約x2("2a”);セグメント3、すなわち配列番号5のアミノ酸残基約x2〜約x3("3a");セグメント4、すなわち配列番号5のアミノ酸残基約x3〜約x4(“4a”);セグメント5、すなわち配列番号5のアミノ酸残基約x4〜約x5("5a");およびセグメント6、すなわち配列番号5のアミノ酸残基約x5〜約x6("6a")を含み;かつここで:x1は配列番号5の残基22、23、24、25、26、27、28、29、30、31または32であり;x2は配列番号5の残基42、43、44、または45であり;x3は配列番号5の残基61、62、63、または64であり;x4は配列番号5の残基78、79、80、81、82、83または84であり;x5は配列番号5の残基90、91、92、93、94、95または96であり;そしてx6は配列番号5の残基114、115、または116であり;そしてポリペプチドはセグメント1-セグメント2-セグメント3-セグメント4-セグメント5-セグメント6の順で有する、請求項16に記載のポリペプチド。
- ポリペプチドは1b2b3b4b5b6a;1b2b3b4b5a6a;1b2b3b4b5a6b;1b2b3a4a5a6a;1b2b3a4a5b6a;1b2a3a4a5a6a;1b2a3a4a5a6aL66V/V67I;1b(1a_II)2a3a4a5a6a;1b2a3a4a5a6b;1b2a3a4a5b6b;1b2a3a4a5b6a;1b2a3b4b5b6a;1b2a3b4b5a6a;および1b2a3b4b5a6bからなる群より選択される配列を含む、請求項16に記載のポリペプチド。
- 請求項1または請求項15のポリペプチドをコードするポリヌクレオチド。
- 機能しうる形で連結された複数のTGF-βファミリーポリヌクレオチド由来の配列を含んで、SMADまたはDAXXをモジュレートする活性を有する機能性キメラポリペプチドをコードする、請求項19に記載のポリヌクレオチド。
- 請求項20に記載のポリペプチドをコードするポリヌクレオチド。
- 6、8、10、12、14、16、18、20、22、24、26、28、30、32、24、26、28、および40からなる群より選択される配列を含むポリヌクレオチド。
- 請求項21または22に記載のポリヌクレオチドを含むベクター。
- 請求項23に記載のベクターを含む宿主細胞。
- 請求項21または請求項22に記載のポリヌクレオチドを含む宿主細胞。
- キメラTGF-βポリペプチドを作製する方法であって、
(a)少なくとも2つのTGF-βファミリーメンバータンパク質の配列をアライメントするステップ;
(b)少なくとも2つのファミリーメンバータンパク質の構造的に関係するドメインを同定するステップ;
(c)構造的に関係するドメインのどちらかまたは両方にある領域であって、少なくとも5つの連続アミノ酸にわたって少なくとも80%、95%、98%、99%または100%の配列同一性を含む該領域を含む、少なくとも2つのTGF-βタンパク質のクロスオーバーの点を同定するステップ;
(d)第1のTGF-βファミリーメンバータンパク質由来の少なくとも1つのドメインと
第2のTGF-βファミリーメンバータンパク質由来の少なくとも1つのドメインを含み、そのドメインがクロスオーバーの点で連結されているキメラTGF-βポリペプチドを作製するステップ;および
(e)キメラTGF-βポリペプチドをI型およびII型リガンド結合能力について試験するステップを含むものである前記方法。 - 請求項26に記載の方法から作製したキメラポリペプチド。
- SmadまたはDAXX経路に関連する細胞増殖または活性をモジュレートする方法であって、細胞を請求項1、15または27のいずれか1項に記載のキメラポリペプチドと接触させるステップを含む前記方法。
- 骨、軟骨、神経学的組織、心組織、骨格筋肉または内分泌組織に関連する疾患または障害を治療する方法であって、組織を請求項1、15または27のいずれか1項に記載のキメラポリペプチドと接触させるステップを含む前記方法。
- 細胞増殖性疾患または障害を治療する方法であって、細胞増殖性疾患または障害を有する細胞を請求項1、15または27のいずれか1項に記載のキメラポリペプチドと接触させるステップを含む前記方法。
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