JP2017526625A - 変性された潜在関連蛋白質構成物 - Google Patents
変性された潜在関連蛋白質構成物 Download PDFInfo
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/495—Transforming growth factor [TGF]
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/50—Fusion polypeptide containing protease site
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/73—Fusion polypeptide containing domain for protein-protein interaction containing coiled-coiled motif (leucine zippers)
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Abstract
Description
それらは様々な多面発現性のアクションを有し、それらのうちのいくらかは治療目的のために利用することができる。scFv(Lode et al.,Pharmacol.Ther,80,277-292(1998))およびvWF(Gordon et al.,Human Gene Therapy,8,1385-1394(1997))を使用する特定の細胞タイプへのサイトカインのターゲティングは、サイトカイン複合体の活性なサイトカイン部位の全体に注目した。ターゲットとされている組織で生物学上有効な濃度を達成するために非常に高濃度で体系的に適用されなければならない、薬理学的に活性なタンパク質あるいはそのような作用薬に基づいた他の薬は、それらの使用と効能を制限する不適当な全身性の影響(例えば毒性)の上昇を与える傾向がある。
LAPは、図1に示されるようにTGFβ1、2、3、4、あるいは5のLAPを含んでもよい(Roberts and Sporn,Peptide Growth Factors and their Receptors:Sporn,MB and Roberts,AB,Springer-Verlag,Chapter 8,422(1996))。
HNEFRQRETYMVF
DVQEFRGVTAVIR
E−[AFVLMY]−X(0,1)−[RK]−X(2,3)−[ST]−[VYIFWMLA]
このようにLTBPを開裂することのできる酵素としてはトロンボスポンジンが挙げられるが、これに制限はされない(Schultz et al.,The Journal of Biological Chemistry,269,26783-26788(1994);Crawford et al.,Cell,93,1159-1170(1998)),トランスグルタミナーゼ(Nunes et al.,J.Cell,Biol.136,1151-1163(1997);Kojima et al.,The Journal of Cell Biology,121,439-448(1993))、MMP9およびMMP2(Yu and Stamenkovic,Genes and Dev,14,163-176(2000))。
ワクシニアウィルス、アデノウイルス、鶏痘ウイルス、仮性狂犬病ウイルスおよびレトロウイルス)からのベクター、およびそれらの組み合わせに由来したベクター、たとえばプラスミドとバクテリオファージの遺伝要素(たとえばコスミドとファージミド)に由来するベクターを含むことができる。一般に、宿主の中でポリペプチドを発現する核酸を維持するか、広めるか、発現するのに適切な任意のベクターが、この点に関して発現のために使用されてもよい。ベクターは、上に定義された複数の核酸、たとえば2以上の核酸構成物を含んでもよい。
細胞は「宿主」細胞と名付けられてもよい。それはクローニングを含む核酸の操作に役立つ。あるいは、細胞は核酸の発現を得る細胞であることができる。本発明の核酸構成物の発現のための適切な宿主細胞の代表的な例は、ウイルス・ベクターの中への核酸のカプセル化を許可するウイルス・パッケージング細胞;細菌細胞(たとえば連鎖球菌、ブドウ球菌、大腸菌、ストレプトマイシーズおよび枯草菌);単離細胞(たとえば酵母菌(例えばビール酵母菌、およびアスペルギルス細胞);昆虫細胞(たとえばショウジョウバエS2およびハスモンヨトウ(Spodoptera) Sf9細胞);動物細胞(たとえばCHO、COS、C127、3T3、PHK.293およびBowes株メラノーマ細胞)および他の適切なヒト細胞;および植物細胞(例えばシロイヌナズナ)が挙げられる。
実施例1:
IL−2およびマウスLAPのシグナルペプチド間のIgG1 Fcのクローニング
本発明の構成物の調製の一例は、以下のとおりである。マウスIgG1のPCRが、muLAP−MMP−IFNのシグナルペプチドの後にEcoR1部位へIgG1 Fcのクローンを作るために使用された。次のオリゴヌクレオチドはコード領域フレームにリンクするために設計された。
センスオリゴ:
5’ATG AAT TCC GGT TGT AAG CCTTGCATA
アンチセンスオリゴ:
5’ GT GA ATT CCT CCA TGG AAG CTT TTT ACC AGG AGA GTG GGA GAG
20分の室温の後、50μlが不透明なプレートに転送され、照度計でルミネセンス(内因的なATPレベル)が読まれた。50%の細胞の生存率は感染していないL929細胞と比較したルシフェラーゼ活性の半分として評価された(MMP分裂がIg−LAP−IFNからIFN活性を示ことを示す表2を参照)。
懸濁液中のCHO細胞内のアグリカナーゼ特異性切断部位を有する、抗herNeu2(Herceptin(登録商標)−Markivら、BMCバイオテクノロジー、11:117 2011)抗体を備えたIg−ヒトLAP構成物が作成された。分泌のシグナルペプチドは、IL−2(ヌクレオチド1−54)に由来し、ヒトCH2およびCH3領域はIgG1(ヌクレオチド55−757)に由来した。構成物内では、ユニークな制限部位HindIIIおよびNco1(ヌクレオチド758−771)を備えたスペーサーがヒトCH2およびCH3領域に続く。ヒトLAPシーケンス(ヌクレオチド772−1515)は、GGGGSリンカー(ヌクレオチド1516−1584)によってフランクされたアグリカナーゼ切断部位に続く。Herceptin(登録商標)scFvはポリHisテイル(ヌクレオチド1585−2370)内で終わる。プロテインAカラムを使用して、親和性クロマトグラフィーにより細胞上澄みから融合蛋白質は純化された。純化された材料からのフラクションは、アグリカナーゼによる分裂の前に、あるいはその分裂の後に、Her/neu2(SKBR3)を発現している乳癌細胞あるいは発現していない(MDA−MD−231)に適用された。Herceptin(登録商標)は、蛍光団でラベルが付けられた抗His抗体によって検知された(図9)。
Claims (30)
- 潜在関連ペプチド(LAP)、薬学的に活性な作用薬、および二量体化領域を含むアミノ酸配列を含み、該LAPと薬学的に活性な作用薬が、タンパク質分解切断部位を含むアミノ酸配列によって結合される融合蛋白質。
- 該二量体化領域が、ロイシンジッパー、インロイシンジッパー、ジンクフィンガー、または抗体フラグメントポリペプチドである、請求項1記載の融合蛋白質。
- 該抗体フラグメントポリペプチドが、Fc領域ポリペプチド、免疫グロブリンヒンジポリペプチド、CH3領域ポリペプチド、CH4領域ポリペプチド、CH1領域ポリペプチドあるいはCL領域ポリペプチドである、請求項2記載の融合蛋白質。
- 該抗体フラグメントポリペプチドが、Fc領域ポリペプチドである、請求項2記載の融合蛋白質。
- 該Fc領域ポリペプチドが、IgGまたはIgA抗体から誘導される、請求項4記載の融合蛋白質。
- 該二量体化領域が、潜在関連ペプチドへ、任意にリンカー配列を介してリンクされる、請求項1から5のいずれか1項記載の融合蛋白質。
- 該潜在関連ペプチド(LAP)が、TGFβの前駆体領域である、請求項1から6のいずれか1項記載の融合蛋白質。
- 該潜在関連ペプチド(LAP)が、TGFβ−1,TGFβ−2,TGFβ−3,TGFβ−4,またはTGFβ−5の前駆体領域である、請求項7記載の融合蛋白質。
- 該タンパク質分解切断部位が、マトリックスメタロプロテアーゼ切断部位、またはアグリカナーゼ切断部位である、請求項1から8のいずれか1項記載の融合蛋白質。
- 該薬学的に活性な作用薬がポリペプチドである、請求項1から9のいずれか1項記載の融合蛋白質。
- 該薬学的に活性な作用薬が、成長因子、分化因子、サイトカインレセプター;フリーラジカルスカベンジング酵素、プロドラッグ転換酵素、ペプチドミミック、プロテアーゼ阻害剤、メタロプロテアーゼの組織阻害剤、セリンプロテアーゼ阻害剤、抗体または抗体フラグメントである、請求項10記載の融合蛋白質。
- 少なくとも2つの、請求項1から11のいずれか1項記載の融合蛋白質を含み、該融合蛋白質がそれぞれの融合蛋白質内の二量体化領域で結合される組成物。
- 請求項1から11のいずれか1項記載の融合蛋白質を含む、医薬品組成物。
- 少なくとも2つの、請求項1から11のいずれか1項記載の融合蛋白質を含み、該融合蛋白質がそれぞれの融合蛋白質内の二量体化領域で結合される医薬品組成物。
- 薬学的に活性な作用薬をコード化する第1の核酸配列、LAPをコード化する第2の核酸配列、および二量体化領域ポリペプチドをコード化する第3の核酸配列を含む核酸構成物。
- 該二量体化領域ポリペプチドが、IgGまたはIgA抗体から誘導されるFc領域ポリペプチドである、請求項15記載の核酸構成物。
- 該核酸構成物が、タンパク質分解切断部位をコード化する核酸配列をさらに含む、請求項16記載の核酸構成物。
- 該薬学的に活性な作用薬が、成長因子、分化因子、サイトカインレセプター;フリーラジカルスカベンジング酵素、プロドラッグ転換酵素、ペプチドミミック、プロテアーゼ阻害剤、メタロプロテアーゼの組織阻害剤、セリンプロテアーゼ阻害剤、抗体または抗体フラグメントである、請求項15から17のいずれか1項記載の核酸構成物。
- ベクターの形式である、請求項15から18のいずれか1項記載の核酸構成物。
- 請求項15から19のいずれか1項記載の核酸構成物によりコード化された融合蛋白質。
- 請求項19記載のベクターまたは請求項15から18のいずれか1項記載の核酸構成物を含む細胞。
- 請求項15から19のいずれか1項記載の核酸構成物または請求項21記載の細胞を含む、医薬品組成物。
- 炎症状体または癌を治療するための、請求項13,14または22記載の医薬品組成物。
- 潜在関連蛋白質、二量体化領域および薬学的に活性な作用薬を含む融合蛋白質を含む組成物の被検者への適用を含む、炎症状態あるいは癌の治療のための方法。
- 炎症状態あるいは癌の治療に使用するための、請求項19記載の核酸構成物。
- 炎症状態あるいは癌の治療に使用するための、請求項1から11のいずれか1項記載の融合蛋白質。
- 請求項15から19のいずれか1項記載の核酸構成物もまたは請求項21記載の細胞を対象に投与することを含む、炎症状態あるいは癌の治療方法。
- 請求項1から11のいずれか1項記載の融合蛋白質、請求項15から19のいずれか1項記載の核酸構成物、または請求項21記載の細胞と、適用のためのビヒクルを含むキット。
- 宿主細胞中の発現による組み換えの融合蛋白質の生産、発現された融合蛋白質の精製、およびペプチド結合リンケージ、水素あるいは塩結合または化学的架橋リンケージにより、精製された融合蛋白質への薬学的に活性な作用薬の結合を提供することを含む請求項1から11のいずれか1項記載の融合蛋白質の調製方法。
- 潜在関連ペプチドをコード化する核酸配列、二量体化領域、タンパク質分解切断シーケンス、および薬学的に活性な作用薬を結合することを含み、任意にタンパク質分解切断部位の一方にリンカー・シーケンスを含む、請求項15から19のいずれか1項記載の核酸構成物を調製する方法。
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