JP6471385B2 - 標的化剤としてのGlaドメイン - Google Patents
標的化剤としてのGlaドメイン Download PDFInfo
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- JP6471385B2 JP6471385B2 JP2016502002A JP2016502002A JP6471385B2 JP 6471385 B2 JP6471385 B2 JP 6471385B2 JP 2016502002 A JP2016502002 A JP 2016502002A JP 2016502002 A JP2016502002 A JP 2016502002A JP 6471385 B2 JP6471385 B2 JP 6471385B2
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Description
本開示は、Glaドメインペプチドおよびポリペプチドを使用する、細胞膜上のホスファチジルセリン(PtdS)の標的化に関する。診断剤および治療剤としてのこれらのペプチドおよびポリペプチドの使用を開示する。
ホスファチジルセリン(PtdS)は、通常は細胞膜の内部小葉(inner−leaflet)(細胞膜側)に局在している負荷電リン脂質成分である。しかし、PtdSは内部小葉から外部小葉へとスクランブラーゼ(フリッパーゼファミリーのメンバー)により輸送され、細胞表面上に露出されうる。非常に少数の例外を除き、PtdSのこの活性外在化は細胞損傷に対する応答である(van den Eijndeら,2001;ErwigおよびHenson,2008)。例えば、組織損傷は血小板、白血球および内皮細胞にシグナル伝達して、PtdSを迅速かつ可逆的に再分布させ、これは細胞表面上の補体活性化および凝固の促進を招く。同様に、アポトーシスシグナルはPtdSの外在化を引き起こすが、これはより穏やか且つ持続的な様態で生じる。この外部PtdSは、マクロファージが周辺組織からの瀕死細胞を摂取することを可能にする鍵認識マーカーを与える(ErwigおよびHenson,2008)。この除去プロセスは組織恒常性に必須であり、「健常」環境においてはそれは極めて効率的である。実際、1日当たり>109個の細胞の喪失にもかかわらず、アポトーシス細胞の組織学的検出は正常組織においては稀な事象である(ElltiotおよびRavichandran,2010;Elltiotら,2009)。しかし、多数の病態においては、アポトーシス細胞除去のプロセスが圧倒され、遅延し、または存在しないという証拠が存在する(ElltiotおよびRavichandran,2010;Lahorteら,2004)。例えば、幾つかの腫瘍学研究は、高いアポトーシス指数がより高い悪性度の腫瘍、転移速度の増加および患者の予後不良に関連づけられることを示唆している(Nareshら,2001;Looseら,2007;Kuriharaら,2008;Kietselaerら,2002)。これらの研究およびそれらの類似研究は、アポトーシスおよび外部PtdS発現が疾患の強力なマーカーでありうることを示唆している(ElltiotおよびRavichandran,2010)。
したがって、本開示においては、(a)ガンマ−カルボキシグルタミン酸(Gla)ドメインを含みプロテアーゼまたはホルモン結合ドメインを欠く単離されたポリペプチドを準備し、(b)該ペプチドを細胞表面と接触させて、該ポリペプチドを細胞膜上のPtdSに結合させることを含む、細胞膜ホスファチジルセリン(PtdS)を標的化する方法を提供する。細胞膜は心細胞膜、神経細胞膜、内皮細胞膜、ウイルス感染細胞膜、アポトーシス細胞膜、血小板膜または癌細胞膜でありうる。該ポリペプチドは更に、EGF結合ドメイン、クリングル(Kringle)ドメインおよび/または芳香族アミノ酸スタックドメインを含みうる。Glaドメインは第II因子、第VII因子、第IX因子、第X因子、プロテインSまたはプロテインCからのものでありうる。
アネキシンと同様に、ガンマ−カルボキシグルタミン酸(Gla)−ドメインタンパク質、例えば第II因子、第VII因子、第IX因子、第X因子、プロテインCおよびプロテインSはアニオン性膜に結合する。実際、アポトーシス特異的プローブとなるように合理的に設計された小分子のモデルとして、Gla−ドメインが使用されている(Cohenら,2009)。ここで、本発明者らは、アポトーシスおよび疾患に特異的な生物学的プローブの新規クラスとしてのこれらのGla−ドメインタンパク質の膜標的化部分の利用を提示する。これらの天然に存在する標的化タンパク質の使用は、より小さいサイズ(<30kDa)という付加的利点と共に、現在のプローブと比較して増強した特異性をもたらしうる。EGFおよび/またはクリングルドメインを含む、より大きな実施形態においてさえも、これらのタンパク質はアネキシンV(37kDa)より尚も小さくなることが可能であり、潜在的には僅か<5kDaとなりうる。これらの生物学的プローブはインビトロおよびインビボの両方においてPtdS細胞表面発現を標的化しうる。したがって、アフィニティ、特異性およびサイズにおいてアネキシンVより優れており、治療剤としての使用の付加的可能性を有するアポトーシス/疾患標的化プローブを開発することが可能である。本開示のこれらの及び他の態様を以下に更に詳細に説明する。
A.構造および合成
ホスファチジルセリン(PtdS、Ptd−L−SerまたはPSと略される)は、フリッパーゼと称される酵素により細胞膜の内部小葉(サイトゾル側)上で通常は維持されるリン脂質成分である。細胞がアポトーシスを受けると、ホスファチジルセリンはもはや膜のサイトゾル部分に局在せず、細胞の表面上に露出されるようになる。PtdSの化学式はC13H24NO10Pであり、385.304の分子量を有する。その構造は以下のとおりである。
ホスファチジルセリンの初期研究はウシの脳から化学物質を蒸留した。現在の研究および商業的に入手可能な製品は、狂牛病に関する懸念ゆえに、ダイズから製造される。ダイズ製品におけるセリンに結合している脂肪酸はウシ製品におけるものと同一ではなく、そしてまた、不純物である。ラットにおける予備的研究は、ダイズ製品が少なくともウシ由来製品と同程度に強力であることを示している。
A.Glaドメイン
Gla−ドメインタンパク質の一般構造はGlaドメインおよびそれに続くEGFドメインおよびそれに続くC末端セリンプロテアーゼドメインの構造である。例外は、EGFドメインの代わりにクリングルドメインを含有するプロトロンビン、およびセリンプロテアーゼドメインを有さないが、その代わりに性ホルモン結合性グロブリン様(SHBG)ドメインを有するプロテインSである(HanssonおよびStenflo,2005)。アニオン性膜に対するGla−ドメインタンパク質のアフィニティは様々である。大雑把に言うと、それらは以下の3つの範疇に含まれる:1)30〜50nMのKdを有する高アフィニティ結合体、2)100〜200nMのKdを有する中アフィニテイ結合体、および3)1000〜2000nMのKdを有する低アフィニティ結合体。高アフィニティGlaドメインタンパク質は、プロテインSを含有するアニオン性膜に結合することが示されており、このことは特に、アポトーシス細胞への、PtdSとのその相互作用を介した結合を示している(Webbら,2002)。低アフィニティGlaドメインタンパク質は、細胞膜に結合するために二次受容体を用いる。例えば、FVIIは組織因子(TF)を用いる。Glaドメイン/第1 EGFドメインはFVIIの高アフィニティTF結合ドメインを構成すると考えられている。このアプローチに関して重要なことに、結腸直腸癌、NSCL癌および乳癌を含む癌細胞の表面上のTFアップレギュレーションを示している多数の研究が存在し、これらの高いTFレベルは予後不良に関連づけられている(Yuら,2004)。アニオン性膜に対するアフィニティはFVIIに関しては比較的低いが、癌における実証されているTFアップレギュレーションと共に高アフィニティTF相互作用の付加はそれを潜在的に興味深い癌特異的プローブにする。
1.第II因子
凝固第II因子としても公知であるプロトロンビンはタンパク質分解切断されて凝固カスケードにおいてトロンビンを形成し、これは最終的に出血の抑制をもたらす。トロンビンは今度はセリンプロテアーゼとして作用し、これは可溶性フィブリノーゲンを不溶性フィブリン鎖へと変換し、多数の他の凝固関連反応を触媒する。それは主として肝臓で発現される。
第VII因子(かつてはプロコンベルチンとして公知)は、凝固カスケードにおいて血液凝固を引き起こすタンパク質の1つである。第VII因子の遺伝子は第13染色体(13q34)に位置する。それはセリンプロテアーゼクラスの酵素であり、ヒト第VIIa因子の組換え形態(NovoSeven)は血友病患者における無制御な出血に関して米国食品医薬品局(U.S.Food and Drug Administration)の承認を受けている。それは、安全性の懸念が存在するものの、重篤な制御不能な出血においては無認可で使用されることもある。組換え活性化第VII因子の生物類似(Biosimilar)形態(AryoSeven)はAryoGen Biopharmaにより製造されている。
第IX因子(またはクリスマス因子)は凝固系のセリンプロテアーゼの1つである。それはペプチダーゼファミリーS1に属する。第IX因子の遺伝子は第10染色体(Xq27.1−q27.2)に位置し、したがって、X染色体連鎖劣性である。この遺伝子における突然変異は女性より男性において遥かに頻繁に影響を及ぼす。このタンパク質の欠乏は血友病Bを引き起こす。第IX因子は、不活性前駆体であるチモーゲンとして産生される。それは、シグナルペプチドを除去するようにプロセシングされ、グリコシル化され、ついで(接触経路の)第XIa因子または(組織因子経路の)第VIIa因子により切断されて、ジスルフィド架橋により鎖が連結された二本鎖形態を生成する。Ca2+、膜リン脂質および第VIII補因子の存在下、第IXa因子へと活性化されると、それは第X因子における1つのアルギニン−イソロイシン結合を加水分解して第Xa因子を生成する。第IX因子はアンチトロンビンにより抑制される。
第X因子(スチュアート−プロワー因子;プロトロンビナーゼ)は凝固カスケードの酵素である。ヒト第X因子遺伝子は第13染色体(13q34)に位置する。それはセリンエンドペプチダーゼ(プロテアーゼ群S1)である。第X因子は肝臓で合成され、その合成にビタミンKを要する。第X因子は第IX因子(内因性Xアーゼとして公知の複合体において、その補因子である第VIII因子を伴う)および第VII因子[その補因子である組織因子(外因性Xアーゼとして公知の複合体)を伴う]の両方により第Xa因子へと活性化される。第X因子の半減期は40〜45時間である。したがって、それは最終共通経路またはトロンビン経路の最初のメンバーである。それは、2つの位置(arg−thr結合およびついでarg−ile結合)でプロトロンビンを切断することにより作用し、これは活性トロンビンを生成する。この過程は、第Xa因子がプロトロンビナーゼ複合体において活性化補因子Vと複合体形成した場合に最適化される。第X因子は新鮮凍結血漿およびプロトロンビナーゼ複合体の一部である。唯一の商業的に入手可能な濃縮物は、CSL Behringにより製造された「第X因子P Behring」である。
プロテインSは、内皮において合成されるビタミンK依存性血漿糖タンパク質である。循環中、プロテインSは、遊離形態と、補体タンパク質C4b結合タンパク質(C4BP)に結合した複合体形態との2つの形態で存在する。ヒトにおいては、プロテインSはPROS1遺伝子によりコードされる。プロテインSの最もよく特徴づけられている機能は抗凝固経路におけるその役割であり、これにおいて、それは第Va因子および第VIIa因子の不活性化におけるプロテインCの補因子として機能する。
オートプロトロンビンIIAおよび血液凝固因子XIVとしても公知であるプロテインCは酵素原(不活性)タンパク質であり、ヒトおよび他の動物において血液凝固、炎症、細胞死の調節および血管壁の透過性の維持において重要な役割を果たす活性化形態である。活性化プロテインC(APC)は、主としてタンパク質第Va因子および第VIIIa因子をタンパク質分解的に不活性化することにより、これらの作用を達成する。APCは、その活性部位にセリンの残基を含有するため、セリンプロテアーゼとして分類される。ヒトにおいては、プロテインCはPROC遺伝子によりコードされ、これは第2染色体上で見出される。
本開示は種々のGlaドメイン含有ペプチドおよびポリペプチドの設計、製造および使用を含む。これらの分子の構造的特徴は以下のとおりである。第1に、該ペプチドまたはポリペプチドは、Glaドメインを構成する約30〜45個の連続的残基を含有するGlaドメインを有する。したがって、「「X」以下の連続的残基を有するペプチド」なる語は、「含む」なる語を包含する場合でさえも、より多数の連続的残基を含むとは理解され得ない。第2に、該ペプチドおよびポリペプチドは追加的な非Glaドメイン残基、例えばEGFドメイン、クリングルドメイン、Fcドメインなどを含有しうる。
固相合成技術(Merrifield,1963)を用いて、ペプチドおよびポリペプチドを製造することが好都合であろう。他のペプチド合成技術は当業者によく知られている(Bodanszkyら,1976;Peptide Synthesis,1985;Solid Phase Peptide Synthelia,1984)。そのような合成に使用される適当な保護基が前記テキストおよびProtective Groups in Organic Chemistry(1973)に見出されるであろう。これらの合成方法は、伸長しつつあるペプチド鎖への1以上のアミノ酸残基または適当な保護アミノ酸残基の逐次的付加を含む。通常、第1アミノ酸残基のアミノまたはカルボキシル基を、選択的に除去可能な適当な保護基で保護する。反応性側鎖を含有する含有するアミノ酸、例えばリシンには、選択的に除去可能な異なる保護基を使用する。
Glaドメインペプチドまたはポリペプチドを他のタンパク質配列(例えば、抗体Fcドメイン)に融合させるためには、リンカーまたは架橋剤が使用されうる。アフィニティマトリックスの製造、多様な構造体の修飾および安定化、リガンドおよび受容体結合部位の特定ならびに構造研究を含む種々の目的に、二官能性架橋試薬が広範に使用されている。2つの同一官能基を含有するホモ二官能性試薬は、同じ及び異なる巨大分子または巨大分子のサブユニット間の架橋、ならびにポリペプチドリガンドの、それらの特異的結合部位への連結の誘発に非常に効率的であることが判明している。ヘテロ二官能性試薬は2つの異なる官能基を含有する。それらの2つの異なる官能基の反応性の相違を利用することにより、選択的かつ連続的に架橋が制御されうる。該二官能性架橋試薬はそれらの官能基の特異性(例えば、アミノ−、スルフヒドリル−、グアニジノ−、インドール−またはカルボキシル−特異的基)に従い分類されうる。これらのうち、遊離アミノ基に対する試薬は、それらの商業的入手可能性、合成のし易さ、およびそれらが適用されうる穏和な反応条件ゆえに、特に好評となっている。大多数のヘテロ二官能性架橋試薬は第一級アミン反応性基およびチオール反応性基を含有する。
薬物開発が達成しようとする1つの要因は適度な循環半減期であり、これは、投薬、薬物投与および有効性に影響を及ぼし、これは生物学的療法には特に重要である。60kD未満の小さなタンパク質は腎臓により迅速に除去され、したがって、それらの標的に到達しない。これは、有効性を達成するためには高用量が必要であることを意味する。循環中のタンパク質の半減期を増加させるために現在用いられている修飾には、ペグ化(PEGylation);タンパク質、例えばトランスフェリン(WO06096515A2)、アルブミン、成長ホルモン(米国特許公開第2003104578AA号)との結合または遺伝的融合;セルロースとの結合(LevyおよびShoseyov,2002);Fcフラグメントとの結合または融合;グリコシル化および突然変異誘発アプローチ(Carter,2006)が含まれる。
本開示のペプチドおよびポリペプチドは診断目的で、例えば、癌細胞またはウイルス感染細胞を特定するために(組織化学検査におけるそれらの使用を含む)、標識に結合されうる。本開示における標識は、アッセイを用いて検出されうるいずれかの部分と定義される。受容体分子の非限定的な例には、酵素、放射能標識、ハプテン、蛍光標識、リン光分子、化学発光分子、発色団、光親和性分子、着色粒子またはリガンド、例えばビオチンが含まれる。
A.医薬製剤および投与経路
臨床適用が想定される場合には、意図される適用に適した形態の医薬組成物を製造することが必要であろう。一般に、これは、発熱物質およびヒトまたは動物に有害でありうる他の不純物を実質的に含有しない組成物を製造することを含む。
1.癌
癌は組織からの細胞のクローン集団の増殖により生じる。発癌と称される、癌の発生は、幾つかの方法でモデル化され、特徴づけられうる。癌の発生と炎症との関連性が古くから認識されている。炎症応答は微生物感染に対する宿主防御に関与し、組織修復および再生をも導く。相当な証拠が炎症と癌発生リスクとの関連性を指摘している。すなわち、慢性炎症は異形成を招きうる。数百個の異なるヒト癌形態が存在し、癌の基礎をなす遺伝学および生物学の理解が深まるにつれて、これらの形態は更に細分され、再分類されている。
ウイルスは、生物の生きた細胞内でのみ複製可能な小さな感染因子である。ウイルスは動物および植物から細菌および古細菌にわたる全てのタイプの生物に感染しうる。数百万の異なるタイプが存在するが、約5,000のウイルスが詳細に記載されている。ウイルスは地球上のほとんど全ての生態系に見られ、生物学的実体の最も豊富なタイプである。
ペプチドおよびポリペプチドは、単独で又は前記疾患を治療する他の薬物と共に、哺乳動物対象(例えば、ヒト患者)に投与されうる。必要な投与量は投与経路の選択;該ポリペプチドに伴う追加的物質を含む製剤の性質;患者の疾患の性質;対象のサイズ、体重、表面積、年齢および性別;更なる組合せ療法;ならびに担当医師の判断に左右される。適当な投与量は0.0001〜10mg/kgの範囲である。種々の化合物が利用可能であること、および種々の投与経路が様々な効率を示すことを考慮すると、必要な投与量の広範な変動が予想される。例えば、経口投与は静脈注射による投与よりも高い投与量を要すると予想される。これらの投与量レベルの変動は、当技術分野で十分に理解されているとおり、最適化のための標準的な経験的常套手段を用いて調節されうる。投与は1回または複数回(例えば、2回、3回、4回、6回、8回、10回、20回、50回、100回、150回またはそれ以上)でありうる。適当な運搬媒体(例えば、高分子微粒子または移植可能な装置)内へのポリペプチドの封入は、経口運搬の場合には特に、運搬の効率を増加させうる。
以下の実施例は、本開示の特定の実施形態を実証するために記載されている。以下の実施例に開示されている技術は、本開示の実施において十分に機能することが本発明者により見出された技術の代表例であり、したがって、その実施のための好ましい形態を構成するとみなされうる、と当業者に理解されるべきである。しかし、本開示の精神および範囲から逸脱することなく、開示されている特定の実施形態には多数の変更が施されることが可能であり、同様または類似の結果を尚も与えうる、と当業者は本開示を考慮して理解すべきである。
細胞膜に対するGla−ドメインタンパク質のアフィニティは、調製されたリン脂質小胞を使用することにより、インビトロで決定されている(Shahら,1998;Nelsestuen,1999)。しかし、これらのインビトロ値がインビボ状況にどのような置き換わるかについては十分には解明されていない。例えば、TFとのFVIIの相互作用は、これらのタンパク質のGlaドメインは非常に相同であるが、それらの細胞膜結合特異性およびアフィニティにおける追加的相違はそれらのEGFおよび/またはクリングルドメインによってもたらされうることを強調している。残念ながら、これらの相互作用は、リン脂質小胞のみに基づく研究によっては再現され得ず、依然として未特定のままであろう。
Claims (24)
- 5〜15個のガンマ−カルボキシグルタミン酸(Gla)残基を有するヒトプロテインS GlaドメインおよびEGFドメインを含み、プロテアーゼまたはホルモン結合ドメインを欠く、単離されたホスファチジルセリンに特異的な、4.5〜30kDのサイズを有するポリペプチドであって、該ポリペプチドは標識、タンパク質配列、および治療剤から選択されるペイロードに結合していることを特徴とする、単離されたポリペプチド。
- 前記Glaドメインが9〜13個のGla残基を有する、請求項1に記載のポリペプチド。
- 前記Glaドメインが11個のGla残基を有する、請求項2に記載のポリペプチド。
- 少なくとも1つのジスルフィド結合を有する、請求項1〜3のいずれか一項に記載のポリペプチド。
- 2〜5個のジスルフィド結合を有する、請求項1〜4のいずれか一項に記載のポリペプチド。
- 前記EGF結合ドメインがプロテインS由来のものである、請求項1〜5のいずれか一項に記載のポリペプチド。
- さらにクリングル(Kringle)ドメインを含む、請求項1〜6のいずれか一項に記載のポリペプチド。
- 300アミノ酸以下であり、例えば、100〜300の範囲のアミノ酸である、請求項1〜7のいずれか一項に記載のポリペプチド。
- 前記ペイロードが検出可能な標識を含む、請求項1〜8のいずれか一項に記載のポリペプチド。
- 前記検出可能な標識が蛍光標識、化学発光標識、放射能標識、酵素、色素またはリガンドである、請求項9に記載のポリペプチド。
- 前記ペイロードが治療剤である、請求項1〜10のいずれか一項に記載のポリペプチド。
- 前記治療剤ペイロードが抗癌剤である、請求項11に記載のポリペプチド。
- 前記抗癌剤が化学療法剤、放射線療法、サイトカイン、ホルモン、抗体もしくは抗体フラグメントまたは毒素である、請求項12に記載のポリペプチド。
- 前記抗癌剤が化学療法剤、放射線療法または毒素である、請求項13に記載のポリペプチド。
- 前記治療剤が抗ウイルス剤である、請求項11に記載のポリペプチド。
- 前記抗ウイルス剤がアバカビル(Abacavir)、アシクロビル(Aciclovir)、アシクロビル(Acyclovir)、アデフォビル(Adefovir)、アマンタジン(Amantadine)、アンプレナビル(Amprenavir)、アンプリジェン(Ampligen)、アルビドール(Arbidol)、アタザナビル(Atazanavir)、アトリプラ(Atripla)、ボセプレビレルテット(Boceprevirertet)、シドフォビル(Cidofovir)、コンビビル(Combivir)、ダルナビル(Darunavir)、デラビルジン(Delavirdine)、ジダノシン(Didanosine)、ドコサノール(Docosanol)、エドクスジン(Edoxudine)、エファビレンツ(Efavirenz)、エムトリシタビン(Emtricitabine)、エンフビルチド(Enfuvirtide)、エンテカビル(Entecavir)、侵入インヒビター、ファムシクロビル(Famciclovir)、ホミビルセン(Fomivirsen)、ホスアンプレナビル(Fosamprenavir)、ホスカルネット(Foscarnet)、ホスホネット(Fosfonet)、ガンシクロビル(Ganciclovir)、イバシタビン(Ibacitabine)、イムノビル(Imunovir)、イドクスウリジン(Idoxuridine)、イミキモド(Imiquimod)、インジナビル(Indinavir)、イノシン(Inosine)、インテグラーゼインヒビター、インターフェロンIII型、インターフェロンII型、インターフェロンI型、インターフェロン、ラミブジン(Lamivudine)、ロピナビル(Lopinavir)、ロビリド(Loviride)、マラビロク(Maraviroc)、モロキシジン(Moroxydine)、メチサゾン(Methisazone)、ネルフィナビル(Nelfinavir)、ネビラピン(Nevirapine)、ネキサビル(Nexavir)、ヌクレオシド類似体、オセルタミビル(Oseltamivir)、ペグインターフェロンアルファ−2a、ペンシクロビル(Penciclovir)、ペラミビル(Peramivir)、プレコナリル(Pleconaril)、ポドフィロトキシン(Podophyllotoxin)、プロテアーゼインヒビター、ラルテグラビル(Raltegravir)、逆転写酵素インヒビター、リバビリン(Ribavirin)、リマンタジン(Rimantadine)、リトナビル(Ritonavir)、ピラミジン(Pyramidine)、サキナビル(Saquinavir)、スタブジン(Stavudine)、相乗的増強剤(抗レトロウイルス)、ティーツリーオイル(Tea tree oil)、テラプレビル(Telaprevir)、テノホビル(Tenofovir)、テノホビルジソプロキシル(Tenofovir disoproxil)、チプラナビル(Tipranavir)、トリフルリジン(Trifluridine)、トリジビル(Trizivir)、トロマンタジン(Tromantadine)、ツルバダ(Truvada)、バラシクロビル(Valaciclovir)、バルガンシクロビル(Valganciclovir)、ビクリビロック(Vicriviroc)、ビダラビン(Vidarabine)、ビラミジン(Viramidine)、ザルシタビン(Zalcitabine)、ザナミビル(Zanamivir)およびジドブジン(Zidovudine)から選択される、請求項15に記載のポリペプチド。
- 前記治療剤が、プロドラッグ変換酵素などの酵素である、請求項11〜16のいずれか一項に記載のポリペプチド。
- 前記治療剤が、サイトカイン、増殖因子、凝固因子または抗凝固剤である、請求項11〜17のいずれか一項に記載のポリペプチド。
- さらに抗体Fc領域を含む、請求項1〜18のいずれか一項に記載のポリペプチド。
- 請求項1〜19のいずれか一項に記載のポリペプチドを含む医薬製剤。
- 癌を治療するための医薬の製造における使用のための、請求項1〜19のいずれか一項に記載のポリペプチドまたは請求項20の医薬製剤。
- 前記癌が乳癌、脳癌、胃癌、肺癌、前立腺癌、卵巣癌、精巣癌、結腸癌、皮膚癌、直腸癌、子宮頸癌、子宮癌、肝臓癌、膵臓癌、頭頸部癌または食道癌である、請求項21に記載のポリペプチドまたは医薬製剤。
- ウイルス性疾患を治療するための医薬の製造における使用のための、請求項1〜19のいずれか一項に記載のポリペプチドまたは請求項20に記載の医薬製剤。
- 前記ウイルス性疾患がインフルエンザ、ヒト免疫不全ウイルス、デングウイルス、西ナイルウイルス、天然痘ウイルス、呼吸器合胞体ウイルス、朝鮮出血熱ウイルス、水痘、水痘帯状疱疹ウイルス、単純ヘルペスウイルス1または2、エプスタイン−バーウイルス、マールブルグウイルス、ハンタウイルス、黄熱病ウイルス、A、B、CまたはE型肝炎、エボラウイルス、ヒトパピローマウイルス、ライノウイルス、コクサッキーウイルス、ポリオウイルス、麻疹ウイルス、風疹ウイルス、狂犬病ウイルス、ニューカッスル病ウイルス、ロタウイルスまたはHTLV−1もしくは2である、請求項23に記載のポリペプチドまたは医薬製剤。
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