JP4344242B2 - Igf結合タンパク質由来のペプチドまたは低分子 - Google Patents
Igf結合タンパク質由来のペプチドまたは低分子 Download PDFInfo
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- JP4344242B2 JP4344242B2 JP2003529895A JP2003529895A JP4344242B2 JP 4344242 B2 JP4344242 B2 JP 4344242B2 JP 2003529895 A JP2003529895 A JP 2003529895A JP 2003529895 A JP2003529895 A JP 2003529895A JP 4344242 B2 JP4344242 B2 JP 4344242B2
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Description
本発明者は、驚いたことに、ヒトIGFBP−3配列の一部を含むIGFBP−3またはペプチドが、多数の有用な物理的性質および生物学的性質を示し得ることを見出している。特に、本発明者は、IGFBP−3のCD−74様ドメインが、多数の以前に記述されていない性質(例えば、亜鉛およびニッケルなどの金属に選択的に結合する能力)を示すことを実証している。本発明者はまた、インタクトなIGFBP−3のいくつかの以前に示された活性を、本分子のこの領域に位置付けている。ペプチドについての配列境界の正確な位置は、特にプロアポトーシスペプチドの場合において、それらの生物学的活性に決定的である。発明者はまた、IGFBP−3のこの領域由来の22アミノ酸配列を表現するペプチドが、共有結合されたより大きなタンパク質(緑色蛍光タンパク質)のインターナリゼーションを、生ヒト胎児由来腎臓(HEK293)細胞へと方向付けるのに十分であるという、驚くべきかつ誘発性の観察を行っている。IGFBP−3により使用される、標的細胞に入るための機構は、よく分かっていないが、細胞表面レセプターの存在が提唱されている。
本明細書中で使用される場合、用語「IGF結合タンパク質」および「IGFBP」は、6つのヒトインスリン様増殖因子結合タンパク質1〜6のいずれかに基づく天然分子および誘導体分子をいう。「誘導体ペプチドまたは低分子」は、本発明に適切なIGFBPの構造的性質を保持するか、あるいは模倣する、ペプチドまたはペプチドも模倣物をいう。本明細書中の誘導体ペプチドは、IGFBP−3の全長よりも短い配列を含む。本明細書中で使用される場合、その配列または構造がIGFBPに対して同一であるか、または相同的である場合、ペプチドまたは低分子はIGFBP「由来」である。
本発明の方法に従う使用のためのIGF結合タンパク質誘導体ペプチドまたは低分子は、任意の種由来であり得るが、種が一致したIGF結合タンパク質(すなわち、IGF結合タンパク質誘導体ペプチドまたは低分子を投与するべき被験体と同じ種由来のネイティブ配列に基づいた、IGF結合タンパク質誘導体ペプチドまたは低分子)が、好ましい(例えば、IGF結合タンパク質誘導体ペプチドまたは低分子がヒト被験体に投与されることが意図される場合、IGF結合タンパク質誘導体ペプチドまたは低分子は、ヒトIGFBP由来であることが好ましい)。本発明における使用のためのIGF結合タンパク質誘導体ペプチドまたは低分子は、非複合体化IGF結合タンパク質誘導体ペプチドまたは低分子であり、すなわち、IGFの非存在下で投与され(例えば、IGF−I複合体として投与されない)、そして、好ましくはいかなるIGFタンパク質も含まないで投与される。好ましくは、IGF結合タンパク質誘導体ペプチドまたは低分子は、IGFBP−3由来である。
(H2N)...DKKGFYKKKQCRPSKGRKRGFCW...(COOH)(配列番号1);
(H2N)...GFYKKKQCRPSKGRKRGFCW...(COOH)(配列番号2);
(H2N)...QCRPSKGRKRGFCW...(COOH)(配列番号3);および
(H2N)...CRPSKGRKRGFC...(COOH)(配列番号4)
のうちの1つ以上は、IGFBP−3の生物学的効果のいくつかを模倣するのに十分であり得るが、本発明の特定の実施形態は、配列DKKGFYKKKQCRPSKGRKRGFCWおよび配列QCRPSKGRKRGFCWを含むか、または配列DKKGFYKKKQCRPSKGRKRGFCWおよび配列QCRPSKGRKRGFCWからなるペプチドを排除し得る。
IGF結合タンパク質または誘導体は、通常、IGFBP配列における全ての可能な改変体の生成を可能にする組換え法によって生成される。組換えDNAの操作に関する技術は、当該分野で周知であるタンパク質の組換え生成に関する技術とも同様である(例えば、Sambrookら、MOLECULAR CLONING:A LABORATORY MANUAL、1〜3巻(Cold Spring Harbor Laboratory Press、第2版、(1989);または、F.Ausubelら、CURRENT PROTOCOLS IN MOLECULAR BIOLOGY(Green Publishing and Wiley−Interscience:New York、1987)および定期的な最新情報を参照のこと)。公知の組成の誘導体ペプチドまたは低分子はまた、当該分野で周知の方法を使用して、化学合成によっても生成され得る。
本明細書中で開示するように、ペプチドKKGFYKKKQCRPSKGRKRGFCWは、無関係のタンパク質の細胞インターナリゼーションを方向付けることが可能である。従って、本発明は、IGFBP由来のインターナリゼーションペプチドおよび低分子と、細胞内に内部移行されることが所望される分子との、融合物ならびに/または結合体を提供する。融合物パートナー分子は、通常(例えば、大きいサイズ、親水性などの理由で)内部移行されないポリペプチド、核酸、または低分子であり得る。当業者に明らかであるように、このような融合/結合体は、医薬品(通常は内部移行されない治療分子のインターナリゼーションを促進するため)、遺伝子治療(遺伝子治療構築物のインターナリゼーションを促進するため)、および研究(インターナリゼーションマーカータンパク質を用いる細胞の「マーキング」を可能にする)を含む、多数の異なる分野において有用である。好ましいIGFBP由来のインターナリゼーション促進ペプチドは、配列KKGFYKKKQCRPSKGRKRGFCWまたは上記配列と少なくとも80、85、90、95、98、もしくは99%の相同性を有する配列を含むペプチドであり、ここで、このペプチドは、IGFBP−3の完全配列を含まない。IGFBP由来のインターナリゼーションペプチドとポリペプチドとの融合物は、好ましくは、融合タンパク質をコードするDNA構築物の作製によって生成されるが、このような融合物はまた、インターナリゼーションペプチドと目的のポリペプチドとの化学連結反応によって作製され得る。IGFBP由来のインターナリゼーションペプチドと核酸または低分子との結合体は、当該分野で公知の化学架橋技術を使用して作製され得る。好ましくは、結合体は、ヘテロ二官能性架橋剤を使用して生成され、インターナリゼーションペプチドのマルチマーの生成を回避する。
IGF結合タンパク質誘導ペプチドまたはIGF結合タンパク質誘導低分子は、細胞損傷もしくはストレスを起こす薬剤または処置レジメンと併用して、細胞傷害性または細胞増殖抑制性の処置が指示される任意の疾患または障害(例えば、癌(好ましくは乳癌、前立腺癌、結腸癌および肺癌)、炎症関連細胞または他の免疫関連細胞の増殖を含む過増殖性障害、ならびに動脈再狭窄(例えば、血管形成術および/または冠動脈バイパス手術後の)を含む)の処置のために使用され得る。特定の実施形態において、同時投与薬剤は、IGFBP由来のECM結合ペプチドと結合体化されて標的化および局在化を提供し得る、化学療法剤(例えば、パクリタキセル、ビンクリスチンなど)である。
本発明は、IGFBP由来のペプチドまたは低分子を備えるキットを提供する。このキットは、IGFBP由来のペプチドまたは低分子を含む組成物を含む少なくとも1つのパッケージを備える。必要に応じて、キットはまた、組成物の使用に関する説明書のセットを備える。
ヒト胚性肝臓293(HEK293)細胞を、2%、4%、6%または8%のウシ胎児血清を補充したダルベッコの改変イーグル培地(D−MEM)中で増殖させた。細胞が80〜85%コンフルエンシー(細胞の力価:1プレートあたりおよそ2.1×106細胞)に到達したとき、5μgのIGFBP−3または緩衝液コントロールを各プレートに添加した。細胞を、37℃で一晩培養した。次の日、培地を除去し、細胞をトリプリン−EDTA(0.25%トリプシン、1mM EDTA)+1×リン酸緩衝生理食塩水でリンスした。細胞を遠心分離し、そして上清を除去した。Clontech Inc(Palo Alto,CA)製のApoAlertカスパーゼ3アッセイキットを使用して、アポトーシスを測定した。細胞を50μlの冷却した細胞溶解緩衝液に再懸濁し、氷上で10分間インキュベートした。得られた細胞溶解物をBeckman マイクロ遠心分離機中、14000rpmで4℃で3分間遠心分離した。上清を新しいチューブに移し、50μlの2×反応緩衝液/DTT+5μlの1mMカスパーゼ3基質を各チューブに添加した。水浴中37℃で1時間インキュベートした後、サンプルをマイクロプレートリーダーの405nmで読んだ。この実験の結果を、図3に示す。
図3Aに示すように、そして共有に係る米国特許出願番号09/956,508に開示されるように、IGFBP−3は、アポトーシス促進活性を有する。IGFBP−3由来のペプチドを、本質的に実施例1に記載されるように、アポトーシス促進活性について試験した。
図5に示すように、インタクトなIGFBP−3は、固定化されたニッケルおよび亜鉛に結合し、60mMイミダゾールで樹脂から溶出され得る。このIGFBP−3の以前まで知られていなかった特性は、魅力的であり、そして多数の実用的な意味を有し、その中で、固定化金属アフィニティ(IMAC)樹脂を使用して産物を捕捉する能力が、治療、ハイスループットな発見、および他の研究領域における多数の潜在的な用途をもたらす。
ペプチド1:(H2N)...DKKGFYKKKQCRPSKGRKRGFCW...(COOH);
ペプチド2:(H2N)...QCRPSKGRKRGFCW...(COOH)。
IGFBP−3のTAXOL(登録商標)との併用の、LAPC−4移植片モデルを利用する前立腺癌細胞の増殖および死に対する効果を分析するための研究を実施した。100万個の細胞(100μl中)をSCIDマウスにSQ注入した。4週間後に、蝕知可能な腫瘍が観察された。4群を処置した(1群あたり6マウス):1)生理食塩水コントロール;2)IGFBP−3(4mg/kg/日で腹腔内);3)TAXOL(登録商標)(2mg/kg/日で5〜8日目に腹腔内);4)TAXOL(登録商標)とIGFBP−3の併用。毎週の触診により、腫瘍をサイズについて分析し、血清を採取した。動物を21日目に屠殺し、腫瘍重量を評価した。この実験の結果は、併用治療による減少した腫瘍サイズ(40%)の傾向を示した。この生物学的作用は、IGFBP−3のアポトーシス促進活性に起因すると考えられる。
規定されたIGFBP−3サブドメインを、E.coli発現系において可溶性融合タンパク質として発現される構築物から生成した。この融合体の一般的な構造は、以下である:
IVS−1:DsbA(mut)...[3C]...ドメイン1...[3C]...ドメイン2/3
IVS−2:DsbA(mut)...[3C]...ドメイン1/2...[3C]...ドメイン3。
(実施例6:細胞インターナリゼーションペプチドの同定)
3つのペプチド伸長を、緑色蛍光タンパク質(gfp;Clontech)に関する遺伝子とインフレームでそれぞれクローン化し、E.coli(JM109)中に発現させた。各構築物は、6Hタグをさらに含む。産物をHis−Bind Resin(Novagen)で捕捉し、60mMイミダゾール、0.5M NaClで溶出し、次いで、HIC(フェニルSEPHAROSE(登録商標)高性能樹脂、Amersham)樹脂でさらに精製し、50mMリン酸緩衝生理食塩水で溶出した。精製されたペプチド−gfpを、HEK293(ヒト胚性肝細胞株)上の細胞インターナリゼーションについて試験した。HEK293細胞を、80〜85%コンフルエント(1プレートあたり約2.1×106細胞)になるまでダルベッコの改変イーグル培地中で培養した。各ペプチド(1プレートあたり11μg)を含む新鮮な培地をプレートに添加した。細胞を、およそ30分間37℃でインキュベートした。培地を除去し、細胞をトリプシン処理し、1×リン酸緩衝生理食塩水で2回洗浄した。蛍光を測定するために、細胞を長波長UVランプ下で維持した。サンプルの写真を図7に示す。サンプル「d」が、強い蛍光を示した唯一のサンプルであった。従って、ペプチドKKGFYKKKQCRPSKGRKRGFCWが、大きい無関係のタンパク質の、HEK293細胞内へのインターナリゼーションを指示するのに必須の全配列情報を含むようである。この同じ配列の部分に属すると考えられる公知の核転座特性と組み合わされ、このペプチドは、細胞取り込みならびに種々の分子(例えば、タンパク質、核酸および小さな化学成分)に関する核トランスポーターとして有用であり得る。従来のおよび遺伝子治療、細胞画像化、研究、ならびにハイスループットスクリーニングへの適用が、予見される。
種々の金属で荷電された固定化金属アフィニティクロマトグラフィー(IMAC)樹脂へのIGFBP−3の結合を測定した。約1mgのIGFBP−3を、各カラム(NTA樹脂、Sigma Chemical Co.、St.Louis、MO)に充填した。充填、フロースルー(flowthrough)、洗浄、および60mMイミダゾールでの溶出のOD280を測定することによって、「結合割合」を算出した。代表的な回収率は、85〜95%であった。結果を表2にまとめる。
パクリタキセルと組み合わせたIGFBP−3の共アポトーシス活性を、実施例1で記載したHEK293アッセイで測定した。HEK293細胞を、DMEM+8%FCS中で増殖させ、次いで、0.3ng/mlのパクリタキセル(TAXOL(登録商標))中か、50ng/mlのIGFBP−3中か、またはこの2つの組み合せにおいてインキュベートした。いくつかの培養物を、200ng/mlの抗−β−1−インテグリン抗体(Pharmingen)で30分間、前処置した。Clontech Inc.製のApoAlertカスパーゼ−3キットを使用して、カスパーゼ−3をアッセイした。
ペプチドKKGHAKDSQRYKVDYESQS(無関係なペプチドGFP31)、ペプチドKKGFYKKKQCRPSKGRKRGFCW(長いペプチドGFP32)、ペプチドKKGFYKKK(上流ペプチドGFP34)、およびペプチドQCRPSKGRKRGFCW(MBD2を含む下流ペプチドGFP35)をコードするポリヌクレオチドを、pGFPuvベクター(Clontech Inc.、Palo Alto、CA)中のGFPコード配列の5’末端へのインフレーム融合としてクローン化した。発現するタンパク質を金属アフィニティークロマトグラフィーおよび疎水性相互作用クロマトグラフィーを通して精製した。
ペプチド(50ng/ml)を、ペプチドと併用して0.3ng/mlパクリタキセルを補填したDMEM中で増殖させた、80%コンフルエントのHEK293細胞に添加した。カスパーゼ−3活性を、添加8時間後の細胞抽出物において測定した。
MBDペプチドの抗原性プロファイルを、ELISAによってアッセイした。MBDペプチドまたはIGFBP−3を、96ウェルNi−NTAプレート(Qiagen Inc.、Carlsbad、CA)のウェルに15分間添加し、PBS Tween緩衝液で2回洗浄し、次いで、同じ緩衝液中3%BSAで4時間ブロックした。西洋ワサビペルオキシダーゼと結合体化した二次抗体を使用して、検出を比色定量分析的に(colorimetrically)(吸光度単位で記録して)行った。
パクリタキセルと、MBDペプチドまたはIGFBP−3との共アポトーシス活性を、2つの血漿タンパク質;フィブロネクチンおよびフィブリノーゲンの存在下または非存在下で試験した。MBDペプチドまたはIGFBP−3、(50ng/ml)、0.3ng/mlパクリタキセル、および血漿タンパク質(200ng/ml)を、本質的に実施例8に記載されるように、DMEM中で増殖させた80%コンフルエントのHEK293細胞に添加した。カスパーゼ−3を、8時間のインキュベーション後に測定した。
Claims (21)
- IGF結合タンパク質由来のペプチドを含む組成物であって、ここで、該ペプチドが、重量基準で、全長の成熟IGF結合タンパク質と同等または、より大きい程度の生物学的特性を示し、該生物学的特性が、プロアポトーシス、金属結合、および細胞内在化からなる群から選択され、該ペプチドが、DKKGFYKKKQCRPSKGRKRGFCW(配列番号1)、GFYKKKQCRPSKGRKRGFCW(配列番号2)、QCRPSKGRKRGFCW(配列番号3)、QCRPSKGRKRGFC(配列番号8)、CRPSKGRKRGFCW(配列番号9)、およびCRPSKGRKRGFC(配列番号4)からなる群より選択される配列からなる、組成物。
- 前記ペプチドが、配列DKKGFYKKKQCRPSKGRKRGFCW(配列番号1)からなる、請求項1に記載の組成物。
- 前記ペプチドが、配列GFYKKKQCRPSKGRKRGFCW(配列番号2)からなる、請求項1に記載の組成物。
- 前記ペプチドが、配列QCRPSKGRKRGFCW(配列番号3)からなる、請求項1に記載の組成物。
- 前記ペプチドが、配列QCRPSKGRKRGFC(配列番号8)からなる、請求項1に記載の組成物。
- 前記ペプチドが、配列CRPSKGRKRGFCW(配列番号9)からなる、請求項1に記載の組成物。
- 前記ペプチドが、配列CRPSKGRKRGFC(配列番号4)からなる、請求項1に記載の組成物。
- 前記ペプチドが、治療分子もしくはマーカー分子に融合または結合体化される、請求項1〜7のいずれか一項に記載の組成物。
- 前記治療分子が、ポリペプチドである、請求項8に記載の組成物。
- 前記生物学的特性が、プロアポトーシスである、請求項1〜9のいずれか一項に記載の組成物。
- 前記生物学的特性が、金属結合である、請求項1〜9のいずれか一項に記載の組成物。
- 前記生物学的特性が、細胞内在化である、請求項1〜9のいずれか一項に記載の組成物。
- 癌の症状を緩和するための組成物であって、該組成物は、有効量のIGF結合タンパク質由来のペプチドまたは低分子を含み、該組成物は癌に罹患している個体に投与されることを特徴とし、そして該ペプチドは、DKKGFYKKKQCRPSKGRKRGFCW(配列番号1)、GFYKKKQCRPSKGRKRGFCW(配列番号2)、QCRPSKGRKRGFCW(配列番号3)、QCRPSKGRKRGFC(配列番号8)、CRPSKGRKRGFCW(配列番号9)、およびCRPSKGRKRGFC(配列番号4)からなる群より選択される配列からなる、組成物。
- 前記ペプチドが、治療分子に融合または結合体化される、請求項13に記載の組成物。
- 前記治療分子が、ポリペプチドである、請求項14に記載の組成物。
- 前記癌が乳癌、前立腺癌、結腸癌、卵巣癌、膵臓癌、胃癌および肺癌からなる群から選択される、請求項13〜15のいずれか一項に記載の組成物。
- 同時投与される薬剤と組み合わせて投与されることを特徴とする、請求項13に記載の組成物。
- 請求項17に記載の組成物であって、ここで、前記同時投与される薬剤が、ドキソルビシン、パクリタキセル、メトトレキサート、タモキシフェン、シクロホスファミド、ビンクリスチン、エトポシド、ストレプトゾトシンおよび5−フルオロウラシルからなる群から選択される化学薬剤である、組成物。
- 前記癌が前立腺癌である、請求項18に記載の組成物。
- 前記同時投与される薬剤が、パクリタキセルである、請求項19に記載の組成物。
- 請求項13〜19のいずれか一項に記載の組成物であって、前記組成物が、0.001〜40mg/kg全体重/日(mg/kg/日)で投与されることを特徴とする、組成物。
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US32326701P | 2001-09-18 | 2001-09-18 | |
PCT/US2002/025532 WO2003025121A2 (en) | 2001-09-18 | 2002-08-09 | Igf-binding protein-derived peptide or small molecule |
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JP2005504801A JP2005504801A (ja) | 2005-02-17 |
JP4344242B2 true JP4344242B2 (ja) | 2009-10-14 |
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JP2003529895A Expired - Fee Related JP4344242B2 (ja) | 2001-09-18 | 2002-08-09 | Igf結合タンパク質由来のペプチドまたは低分子 |
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EP (1) | EP1435986B1 (ja) |
JP (1) | JP4344242B2 (ja) |
AT (1) | ATE382364T1 (ja) |
AU (1) | AU2002324672B2 (ja) |
CA (1) | CA2460719A1 (ja) |
DE (1) | DE60224419D1 (ja) |
HK (1) | HK1062923A1 (ja) |
WO (1) | WO2003025121A2 (ja) |
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2002
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- 2002-08-09 AT AT02759330T patent/ATE382364T1/de not_active IP Right Cessation
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EP1435986A4 (en) | 2006-01-11 |
ATE382364T1 (de) | 2008-01-15 |
CA2460719A1 (en) | 2003-03-27 |
US20030059430A1 (en) | 2003-03-27 |
US6861406B2 (en) | 2005-03-01 |
DE60224419D1 (de) | 2008-02-14 |
JP2005504801A (ja) | 2005-02-17 |
EP1435986B1 (en) | 2008-01-02 |
EP1435986A2 (en) | 2004-07-14 |
WO2003025121A3 (en) | 2004-01-22 |
AU2002324672B2 (en) | 2007-11-08 |
HK1062923A1 (en) | 2004-12-03 |
WO2003025121A2 (en) | 2003-03-27 |
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