JP5248494B2 - タンパク質、それをコードする核酸および関連する使用方法 - Google Patents
タンパク質、それをコードする核酸および関連する使用方法 Download PDFInfo
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Description
米国特許法第119条(e)の下で、本出願は、2006年7月11日に出願された米国仮特許出願第60/830,013号;および2006年12月22日に出願された第60/876,871号(これらの両方をすべての目的のためにその全体を本明細書に参照により組み入れる)の恩典を主張する。
米国特許法施行規則第1.52条(e)(5)に応じて、コンパクトディスクに含まれる配列情報、ファイル名Ma_2007utility SEQ List_ST25.txt;サイズ61KB;作成:2007年6月29日;PatentIn−3.4およびChecker 4.4.0使用、の全体を本明細書に参照により組み入れる。コンピュータ読み取り可能形態(CRF)で記録された配列表情報は、本明細書とともに提供される書面の配列表と同一である。配列表の紙の写しおよび本明細書とともに提出される配列表のコンピュータ読み取り可能形態のデータは、新規事項を含んでおらず、米国仮特許出願第60/830,013号;および第60/876,871号の優先権出願によって完全に支持されている。
米国政府は、米国国立衛生研究所(NIH)によるJianjie Ma博士に対して授与された以下の助成金:RO1−CA095739;RO1−AG015556;RO1−HL069000に従って本発明における特定の権利を有する。
本発明は、ポリペプチド、それをコードする核酸、前記ポリペプチドに免疫特異的に(immunospecifically)結合する抗体、および関連する使用方法に関する。
外部の損傷および内部の変性に応答して、身体の細胞は、その機能および生物の健康を維持するために、各々個々の細胞を取り囲む膜を修復しなければならない。外部の膜を修復する細胞の能力の欠損は、多くの疾患および病理学的状態、例えば、神経変性疾患(例えば、パーキンソン病)、心臓発作、心不全、筋ジストロフィー、褥瘡、糖尿病性潰瘍、酸化障害、ならびに化学療法薬の投与に由来する副作用として生じる副鼻腔炎等の組織損傷と結び付けられている。また、種々の疾患および正常な加齢過程と関連した筋力低下および萎縮が、変化した膜の修復と関連付けられている。これらの細胞が、急性損傷に応答してその膜を修復するために、それらは、小胞と呼ばれる細胞の内側にある膜の小さな包みを利用する。これらの小胞は、通常、細胞内に見出されるが、細胞膜への損傷に際して、これらの小胞は、損傷部位へ移動し、細胞の完全性を維持するためにパッチを形成する。この必須の機能がなければ、細胞は死滅し得、この細胞傷害の累積的な効果は、最終的には組織または器官の機能障害を生じ得る。
本発明は、細胞膜損傷の修復に関与するタンパク質の驚くべきかつ予想外の発見に関する。本発明は一般的に、核酸に関し、そして本発明の核酸からコードされるポリペプチドを含む。より具体的には、本発明は、組成物、例えば、標的核酸の転写または翻訳を阻害するのに有用な核酸;細胞質、核、膜結合および分泌ポリペプチドをコードする核酸;およびベクター、宿主細胞、抗体、組換えタンパク質、シュードペプチド、融合タンパク質、化合物、およびそれらを産生するための方法に関する。
本発明は、新規ヌクレオチドおよびそれによってコードされるポリペプチドを提供する。本発明には、新規核酸配列およびそのコードされるポリペプチドが含まれる。配列を、本明細書で「MG53核酸」または「MG53ポリヌクレオチド」と総称し、対応するコードされるポリペプチドを、「MG53ポリペプチド」または「MG53タンパク質」という。別段の記載がなければ、「MG53」は、本明細書に開示される新規配列のいずれかを指すことを意味する。
本明細書で使用する「核酸分子」という用語は、DNA分子(例えば、cDNAまたはゲノムDNA)、RNA分子(例えば、mRNA)、ヌクレオチドアナログを使用して生成されるDNAまたはRNAのアナログ、ならびにそれらの誘導体、フラグメントおよびホモログを含むことが意図される。核酸分子は、一本鎖または二本鎖であり得るが、好ましくは、二本鎖DNAを含む。
発現プロファイルと臨床データとの相関に加えて、またはそれと共同して、発現パターンを1つ以上の遺伝子座での対象の遺伝子型と相関させるか、または発現プロファイルおよび遺伝子座データの両方を臨床データと相関させることはしばしば望ましい。選択された遺伝子座は、例えば、疾患(または疾患の診断基準)であるかまたは疾患と推定上関連することが知られている候補ライブラリー、マーカー遺伝子座のための多型アレル、または代替的な疾患関連遺伝子座(候補ライブラリーに寄与しない)の1つ以上のメンバーに対応する染色体遺伝子座であり得る。実際、遺伝子座における(多型)アレルが、疾患(または疾患に対する素因)と関連付けられる場合、アレルの存在がそれ自体、疾患の診断基準であり得ることが理解される。
他の実施態様において、本発明は、MG53、MG53結合タンパク質、および/またはMG53受容体ポリペプチド、抗体ポリペプチド、またはそれらの生物的に活性な部分をコードする単離された核酸分子に関する。複合体のポリペプチドを、例えば、標準的な方法に従ってペプチド合成装置を使用して;または細胞もしくは細胞抽出物中で個別に各ポリペプチドを発現させ、次いでこのポリペプチドを単離および精製することによって形成することができる。
本明細書で使用する「抗体」という用語は、免疫グロブリン分子および免疫グロブリン(Ig)分子の免疫学的に活性な部分、すなわち、少なくとも1つの、好ましくは2つの重(H)鎖可変領域(本明細書ではVHと略記する)および少なくとも1つの、好ましくは2つの軽(L)鎖可変領域(本明細書ではVLと略記する)を含む抗原に特異的に結合する(免疫反応する)抗原結合部位を含有する分子を指す。このような抗体には、ポリクローナル、モノクローナル、キメラ、単鎖、Fab、Fab’およびF(ab’)2フラグメント、およびFab発現ライブラリーが含まれるが、それらに限定されるわけではない。VH領域およびVL領域をさらに、より保存された「フレームワーク領域」(FR)と呼ばれる領域によって分散された「相補性決定領域」(「CDR」)と呼ばれる超可変性の領域へ細分することができる。フレームワーク領域およびCDRの範囲は、厳密に規定されている(Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242、およびChothia, C. et al. (1987) J. Mol. Biol. 196:901-917(本明細書に参照により組み入れる)参照)。各VHおよびVLは、アミノ末端からカルボキシ末端へ以下の順序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4で配置される3つのCDRおよび4つのFRから構成される。一般的に、ヒトから得られた抗体分子は、分子中に存在する重鎖の性質によって互いに異なるIgG、IgM、IgA、IgEおよびIgDのクラスのいずれかと関連する。特定のクラスはさらにIgG1、IgG2、およびその他のようなサブクラスを有する。さらに、ヒトにおいて、軽鎖は、κ鎖またはλ鎖であり得る。抗体に対する本明細書における言及には、このようなクラス、サブクラスおよびヒト抗体種の型のすべてに対する言及が含まれる。
完全ヒト抗体は本質的に、CDRを含む軽鎖および重鎖の両方の配列全体が、ヒト遺伝子から生じる抗体分子に関する。このような抗体は、本明細書において「ヒト抗体」、または「完全ヒト抗体」と呼ばれる。ヒトモノクローナル抗体を、トリオーマ(trioma)技術;ヒトB細胞ハイブリドーマ技術(Kozbor, et al., 1983 Immunol Today 4: 72参照)およびヒトモノクローナル抗体を産生するためのEBVハイブリドーマ技術(Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96参照)によって調製することができる。ヒトモノクローナル抗体は、本発明の実施において利用され得、ヒトハイブリドーマを使用することによって(Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030参照)、またはヒトB細胞をエプスタイン・バーウイルスでインビトロでトランスフォームすることによって(Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96)産生され得る。
本発明によれば、技術を、本発明の抗原性タンパク質に特異的な単鎖抗体の産生のために適応させることができる(例えば、米国特許第4,946,778号参照)。さらに、方法を、タンパク質またはその誘導体、フラグメント、アナログもしくはホモログに対する所望される特異性を有するモノクローナルFabフラグメントの迅速かつ効果的な同定を可能にするように、Fab発現ライブラリーの構築(例えば、Huse, et al., Science 246:1275-1281 (1989)参照)に適応させることができる。タンパク質抗原に対するイディオタイプを含有する抗体フラグメントは、(i)抗体分子のペプシン消化によって産生されるF(ab’)2フラグメント;(ii)F(ab’)2フラグメントのジスルフィド架橋を還元することによって生成されるFabフラグメント;(iii)パパインおよび還元剤での抗体分子の処理によって生成されるFabフラグメント、ならびに(iv)Fvフラグメントを含むが、それらに限定されない当技術分野で公知の技術によって産生され得る。
二重特異性抗体は、少なくとも2つの異なる抗原に対する結合特異性を有するモノクローナル抗体、好ましくはヒト抗体またはヒト化抗体である。本発明の場合、結合特異性のうちの1つは、本発明の抗原性タンパク質に対するものである。第二の結合標的は、いずれかの他の抗原であり、有利には、細胞表面タンパク質または受容体または受容体サブユニットである。二重特異性抗体を作製するための方法は、当技術分野において公知である。従来、二重特異性抗体の組換え産生は、2つの免疫グロブリン重鎖/軽鎖対の同時発現に基づいており、ここで、2つの重鎖は、異なる特異性を有する(Milstein and Cuello, Nature, 305:537-539 (1983))。免疫グロブリン重鎖および軽鎖の無作為な取り合わせの故に、これらのハイブリドーマ(クアドローマ)は、10個の異なる抗体分子の潜在的な混合物を産生し、そのうち、1つのみが、適正な二重特異性構造を有する。同様の手順は、1993年5月13日に発行されたWO 93/08829およびTraunecker et al., EMBO J., 10:3655-3659 (1991)に開示される。
ヘテロ抱合抗体も、本発明の範囲内である。ヘテロ抱合抗体は、2つの共有結合した抗体から構成される。このような抗体は、例えば、免疫系細胞を望ましくない細胞に標的化するため(米国特許第4,676,980号)、およびHIV感染の処置のため(WO 91/00360;WO 92/200373;EP 03089)に提唱されている。抗体が、架橋剤を包含するものを含む、合成タンパク質化学における公知の方法を使用して、インビトロで調製され得ることが意図される。例えば、免疫毒素を、ジスルフィド交換反応を使用して、またはチオエーテル結合を形成することによって構築することができる。この目的に適した試薬の例には、イミノチオラートおよびメチル−4−メルカプトブチルイミダート、ならびに例えば、米国特許第4,676,980号に開示されるものが含まれる。
本発明は、化学薬剤または放射性同位体(すなわち、放射性抱合体)へ抱合した抗体を含む免疫抱合体にも関する。抗体および細胞傷害性薬物の抱合体は、N−スクシンイミジル−3−(2−ピリジルジチオール)プロピオナート(SPDP)、イミノチオラン(IT)、イミドエステルの二官能性誘導体(ジメチルアジピミダートHCL等)、活性型エステル(ジスクシンイミジルスベラート等)、アルデヒド(グルタルアルデヒド等)、ビス−アジド化合物(ビス(p−アジドベンゾイル)ヘキサンジアミン等)、ビス−ジアゾニウム誘導体(ビス(p−ジアゾニウムベンゾイル)−エチレンジアミン等)、(トリレン2,6−ジイソシアナート等の)ジイソシアナート塩、およびビス活性フッ素化合物(1,5−ジフルオロ−2,4−ジニトロベンゼン等)等の種々の二官能性タンパク質カップリング剤を使用して作製される。例えば、リシン免疫毒素を、Vitetta et al., Science, 238: 1098 (1987)に記載されるように調製することができる。炭素14標識1−イソチオシアナ−トベンジル−3−メチルジエチレントリアミン五酢酸(MX−DTPA)は、抗体への放射性核種の抱合のための例示的なキレート剤である。WO94/11026を参照されたい。
本明細書に開示する抗体を、イムノリポソーム(immunoliposome)として製剤することもできる。抗体を含有するリポソームは、Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985);Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980);ならびに米国特許第4,485,045号および第4,544,545号に記載されるような当技術分野で公知の方法によって調製される。増強された循環時間を有するリポソームは、米国特許第5,013,556号に開示される。
分析物タンパク質を検出するための薬物は、分析物タンパク質へ結合できる抗体、好ましくは検出可能な標識を有する抗体である。抗体は、ポリクローナルであり得るか、またはより好ましくはモノクローナルであり得る。インタクトな抗体、またはそのフラグメント(例えば、FabまたはF(ab)2)を、使用することができる。プローブまたは抗体に関する「標識」という用語は、検出可能な物質をプローブまたは抗体へ結合させる(すなわち、物理的に連結させる)ことによるプローブまたは抗体の直接的な標識、および直接標識された別の試薬との反応性によるプローブまたは抗体の間接的な標識を包含することが意図される。間接的標識の例には、蛍光標識された二次抗体を使用する一次抗体の検出、および、それにより蛍光標識されたストレプトアビジンを用いて検出することができる、ビオチンでのDNAプローブの末端標識が含まれる。「生物学的試料」という用語は、対象から単離された組織、細胞および生物学的液体、ならびに対象内に存在する組織、細胞および液体を含むことが意図される。それゆえ、「生物学的試料」という用語の使用には、血液ならびに、血清、血漿、またはリンパ液を含む血液の画分または成分が含まれる。すなわち、本発明の検出方法を、生物学的試料中の分析物mRNA、タンパク質、またはゲノムDNAをインビトロおよびインビボで検出するために使用することができる。例えば、分析物mRNAの検出のためのインビトロ技術には、ノーザンハイブリダイゼーションおよびインサイチュハイブリダイゼーションが含まれる。分析物タンパク質の検出のためのインビトロ技術には、酵素結合免疫吸着測定法(ELISA)、ウェスタンブロット、免疫沈降、および免疫蛍光が含まれる。分析物ゲノムDNAの検出のためのインビトロ技術には、サザンハイブリダイゼーションが含まれる。イムノアッセイを実施するための手順は、例えば、"ELISA: Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, N.J., 1995;"Immunoassay", E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, Calif., 1996;および"Practice and Thory of Enzyme Immunoassays", P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985に記載される。さらに、分析物タンパク質の検出のためのインビボ技術には、標識抗分析物タンパク質抗体の対象への導入が含まれる。例えば、抗体を、対象中でのその存在および位置が、標準的な画像処理技術によって、腔内、または経皮的に、単独でまたはエフェクター細胞を用いて検出され得る放射性マーカーで標識することができる。
筋特異的TRIMファミリータンパク質であるMG53の発見
横紋筋細胞における筋形成、Ca2+シグナル伝達および膜の完全性の維持に関与する新規タンパク質の同定を可能にする以前に確立されたイムノプロテオミクス(immuno-proteomic)アプローチを使用して、MG53を単離した。簡潔には、このアプローチは、ウサギ骨格筋由来の三つ組富化膜で免疫化されたマウスから生成された約6500個のクローンを含有するモノクローナル抗体ライブラリーを使用する。免疫蛍光顕微鏡下で観察される横紋筋切片のZ線染色パターンに基づいて、目的の抗体を選択した。抗体アフィニティカラムを通して標的タンパク質を精製し、精製されたタンパク質の部分アミノ酸配列を得た。部分アミノ酸配列に基づいて、標的遺伝子をコードする完全cDNAを骨格筋cDNAライブラリーから単離した。次いで、相同遺伝子スクリーニングを使用して、他の興奮性組織における同定された遺伝子の異なるアイソフォームの存在について検索した。最後に、トランスジェニックまたはノックアウトマウスモデルを生成して、目的の遺伝子のインビボでの生理学的機能を研究した。
MG53の同定およびクローニング − ウサギ骨格筋のミクロソームタンパク質についてのmAbライブラリーの調製およびスクリーニングは以前に記載されている(21)。mAb5259(IgG1サブクラス)の調製およびイムアフィニティ精製を、以前に記載されるように実施した(21)。精製MG53をアミノ酸配列分析に供し、決定されたすべての配列はウサギMG53 cDNAにおいてコードされていた(データは示さず)。ウサギ部分アミノ酸配列を使用したデータベースにおける相同性検索によって、マウスおよびヒトMG53が見出された。マウスMG53遺伝子のエキソン領域をマウスゲノムDNAから増幅し、32P標識したエキソンフラグメントを使用してウサギおよびマウス骨格筋ライブラリーをスクリーニングして、全長cDNAを得た。
Claims (11)
- ポリペプチドを含む医薬組成物であって、ポリペプチドが以下:
i)配列番号1、3、または5の少なくとも1つのアミノ酸配列または
ii)配列番号1、3、または5の少なくとも1つとの少なくとも90%の配列同一性を有する、アミノ酸配列
からなる、医薬組成物であって、前記ポリペプチドが、損傷を受けた細胞膜の修復を促進できる、医薬組成物。 - 前記ポリペプチドが、配列番号1、3、または5のアミノ酸配列からなる、請求項1記載の医薬組成物。
- 細胞損傷の予防または処置における使用のための、請求項1または2記載の医薬組成物。
- 配列番号8からなるポリペプチドをさらに含む、請求項3記載の医薬組成物。
- 筋細胞損傷の予防または処置における使用のための、請求項1〜4のいずれか1項記載の医薬組成物。
- 熱傷を罹患している対象の処置における使用のための、請求項1〜5のいずれか1項記載の医薬組成物。
- 細胞損傷が心血管障害、運動、きびしい身体活動、または外科手順もしくはデバイスに起因する、請求項3〜5のいずれか1項記載の医薬組成物。
- 美容的に許容される担体と一緒に、ポリペプチドを含む、化粧組成物であって、ここでポリペプチドが以下:
i)配列番号1、3、または5の少なくとも1つのアミノ酸配列または
ii)配列番号1、3、または5の少なくとも1つとの少なくとも90%の配列同一性を有する、アミノ酸配列
からなる、化粧組成物であって、前記ポリペプチドが、損傷を受けた細胞膜の修復を促進できる、化粧組成物。 - 前記ポリペプチドが、配列番号1、3、または5のアミノ酸配列からなる、請求項8記載の化粧組成物。
- 配列番号1、3、または5のアミノ酸配列からなるポリペプチド部分、およびアミノ末端、カルボキシ末端、またはその両方のいずれかに位置する少なくとも1つの他のポリペプチド部分を含む融合タンパク質を含む医薬組成物であって、ポリペプチド部分が、単一の連続したポリペプチド鎖中に配置され、融合タンパク質が損傷を受けた細胞膜の修復を促進できる、医薬組成物。
- 単離された核酸を含む発現ベクターを含む医薬組成物であって、核酸が以下:
i)配列番号2、4、または6の核酸配列、または
ii)配列番号2、4、または6の少なくとも1つとの少なくとも90%の配列同一性を有する核酸配列であって、損傷を受けた細胞膜の修復を促進できるミツグミン53ポリペプチドをコードする、核酸配列
からなる、医薬組成物。
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JP2013121357A (ja) * | 2006-07-11 | 2013-06-20 | Univ Of Medicine & Dentistry Of New Jersey | タンパク質、それをコードする核酸および関連する使用方法 |
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EP2037737A2 (en) | 2009-03-25 |
JP2013121357A (ja) | 2013-06-20 |
ES2479668T3 (es) | 2014-07-24 |
AU2007314477B2 (en) | 2012-03-29 |
CA2657319A1 (en) | 2008-05-08 |
CN103275980A (zh) | 2013-09-04 |
EP2037737B1 (en) | 2014-04-02 |
CN103275980B (zh) | 2015-09-09 |
EP2471815B1 (en) | 2016-03-30 |
WO2008054561A9 (en) | 2008-06-26 |
US20090318348A1 (en) | 2009-12-24 |
AU2007314477A1 (en) | 2008-05-08 |
US20110287015A1 (en) | 2011-11-24 |
EP2471809A1 (en) | 2012-07-04 |
CA2657319C (en) | 2016-06-21 |
US20110287004A1 (en) | 2011-11-24 |
JP2009543551A (ja) | 2009-12-10 |
EP2471815A1 (en) | 2012-07-04 |
CN101511181B (zh) | 2013-08-21 |
WO2008054561A3 (en) | 2008-10-16 |
US7981866B2 (en) | 2011-07-19 |
CN101511181A (zh) | 2009-08-19 |
WO2008054561A2 (en) | 2008-05-08 |
EP2037737A4 (en) | 2010-02-24 |
EP2471809B1 (en) | 2015-09-02 |
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