JP6639412B2 - アルブミン結合部分を含んでなるアデノウイルス - Google Patents
アルブミン結合部分を含んでなるアデノウイルス Download PDFInfo
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- JP6639412B2 JP6639412B2 JP2016565257A JP2016565257A JP6639412B2 JP 6639412 B2 JP6639412 B2 JP 6639412B2 JP 2016565257 A JP2016565257 A JP 2016565257A JP 2016565257 A JP2016565257 A JP 2016565257A JP 6639412 B2 JP6639412 B2 JP 6639412B2
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Description
第2の態様において、本発明は、本発明によるアデノウイルスゲノムを有する組換えアデノウイルスに関する。
第3の態様において、本発明は、治療上有効な量の本発明による組換えアデノウイルスを薬学上許容可能な担体とともに含んでなる医薬組成物に関する。
第4の態様において、本発明は、医薬において使用するための本発明による組換えアデノウイルスまたは医薬組成物に関する。
さらなる態様において、本発明は、哺乳動物における癌の予防および/または治療において使用するための本発明による組換えアデノウイルスまたは医薬組成物に関し、前記アデノウイルスは、腫瘍溶解性アデノウイルス、またはゲノムに挿入された癌治療において使用される遺伝子を含んでなるアデノウイルスである。
本発明で得られた結果によると、アデノウイルスヘキソンタンパク質の外側表面にアルブミン結合部分を含んでなるアデノウイルスは、アルブミンで被覆されて、血中に存在する中和抗体からそれ自体を保護することができることを示す。この保護効果は複製型(ICOVIR15−ABD)および非複製型(AdGL−ABD)アデノウイルスの両方で見られる。
本発明はまた、アデノウイルスのゲノムを対象とする。一態様において、本発明は、ヘキソンタンパク質の超可変領域1(HVR1)のコード領域に挿入されたアルブミン結合部分をコードする配列を含んでなり、これによりヘキソンタンパク質とアルブミン結合部分を含んでなる融合タンパク質の発現がもたらされること、および前記アルブミン結合部分は、前記ヘキソンタンパク質がアデノウイルスキャプシドに組み立てられる際にヘキソンタンパク質の外側表面に位置することを特徴とするアデノウイルスゲノムに関する。
・その終了点の各個で独立のアデノウイルスITRを示す;
・パッケージングシグナルPsiの5’末端とそれに最も近いITRの3’末端の間の距離が、天然アデノウイルスのパッケージングを妨げる距離、すなわち、ヒト血清型5アデノウイルスの場合には200塩基対の距離(配列内のITRとパッケージングシグナルの間に自然状態でそれらを分離している配列を導入すると、アデノウイルスゲノムのパッケージング能が低下し、それらのパッケージングに必要な時間に有意な変化が見られないとしても、得られるアデノウイルス粒子の総数に減少を生じることから、この距離は、他の血清型の場合にもほぼ等しいと類推される)を超えないように配置された両ITRの間にパッケージングシグナルPsiを含んでなる;
・両ITRの末端間の距離が、キャプシドを形成するタンパク質が属する、天然に存在するアデノウイルスゲノムのサイズの105%を越えてはならない。
本発明の組換えアデノウイルスは、医薬組成物を作製するために使用することができる。よって、本発明の別の態様は、治療上有効な量の本発明による組換えアデノウイルスを薬学上許容可能な担体とともに含んでなる医薬組成物である。
遺伝子治療の分野およびワクチン接種の分野における複製欠陥アデノウイルスおよび複製可能アデノウイルスの使用には幅広い経験が存在する。
[1].ヘキソンタンパク質とアルブミン結合部分を含んでなる融合タンパク質の発現を生じさせる、ヘキソンタンパク質の超可変領域(HVR)のコード領域に挿入されたアルブミン結合部分をコードする配列を含んでなり、前記アルブミン結合部分は、前記ヘキソンタンパク質がアデノウイルスキャプシドに組み立てられる際にヘキソンタンパク質の外側表面に位置することを特徴とする、アデノウイルスゲノム。
[2].ゲノムがヒトアデノウイルス由来である、[1]に記載のアデノウイルスゲノム。
[3].ヒトアデノウイルスがヒトアデノウイルス血清型1〜57からなる群から選択される、[2]に記載のアデノウイルスゲノム。
[4].ヒトアデノウイルスがヒトアデノウイルス血清型5である、[3]に記載のアデノウイルスゲノム。
[5].前記アルブミン結合部分が、連鎖球菌Gタンパク質由来のアルブミン結合ドメイン、ペプトストレプトコッカス・マグヌスタンパク質PAB由来のアルブミン結合ドメイン、コア配列DICLPRWGCLW(配列番号9)を有するアルブミン結合ペプチドおよびそれらの機能的に等価な変異体から選択される、[1]、[2]、[3]または[4]のいずれか一項に記載のアデノウイルスゲノム。
[6].前記アルブミン結合部分が連鎖球菌Gタンパク質由来のアルブミン結合ドメイン3である、[5]に記載のアデノウイルスゲノム。
[7].連鎖球菌Gタンパク質由来のアルブミン結合ドメイン3の配列が配列番号1である、[6]に記載のアデノウイルスゲノム。
[8].ヘキソンタンパク質のHVRがHVR1、HVR2、HVR3、HVR4、HVR5、HVR6およびHVR7からなる群から選択される、[1]、[2]、[3]、[4]、[5]、[6]または[7]に記載のアデノウイルスゲノム。
[9].ヘキソンタンパク質のHVRがHVR1である、[8]に記載のアデノウイルスゲノム。
[10].生成する融合タンパク質がGenBank受託番号BAG48782.1を有するヘキソンタンパク質のナンバリングに従ってヘキソンタンパク質のD150アミノ酸の後にアルブミン結合部分を含むように、アルブミン結合部分をコードする配列が挿入されている、[9]に記載のアデノウイルスゲノム。
[11].ヘキソンタンパク質のHVRがHVR5である、[8]に記載のアデノウイルスゲノム。
[12].生成する融合タンパク質がGenBank受託番号BAG48782.1を有するヘキソンタンパク質のナンバリングに従ってヘキソンタンパク質のA274アミノ酸の後にアルブミン結合部分を含むように、アルブミン結合部分をコードする配列が挿入されている、[11]に記載のアデノウイルスゲノム。
[13].アルブミン結合部分のN末端および/またはC末端がリンカー配列によりヘキソンタンパク質に接続されている、[1]〜[12]のいずれか一項に記載のアデノウイルスゲノム。
[14].前記リンカー配列が配列GSGS(配列番号2)を含んでなる、[13]に記載のアデノウイルスゲノム。
[15].アデノウイルスゲノムが組織特異的プロモーターまたは腫瘍特異的プロモーターをさらに含んでなる、[1]〜[14]のいずれか一項に記載のアデノウイルスゲノム。
[16].前記組織特異的プロモーターまたは腫瘍特異的プロモーターが、E1a、E1b、E2、およびE4からなる群から選択される1以上の遺伝子の発現を制御するためのプロモーター配列である、[15]に記載のアデノウイルスゲノム。
[17].前記プロモーターがE2Fプロモーター、テロメラーゼhTERTプロモーター、チロシナーゼプロモーター、前立腺特異的抗原プロモーター、αフェトタンパク質プロモーター、およびCOX−2プロモーターからなる群から選択される、[16]に記載のアデノウイルスゲノム。
[18].アデノウイルスが腫瘍溶解性アデノウイルスである、[1]〜[17]のいずれか一項に記載のアデノウイルスゲノム。
[19].アデノウイルスゲノムが腫瘍における選択的複製を達成するためにE1a、E1b、E4、およびVA−RNAからなる群から選択される1以上の遺伝子に突然変異をさらに含んでなる、[18]に記載のアデノウイルスゲノム。
[20].アデノウイルスゲノムがアデノウイルスの感染力を高めるため、またはそれを腫瘍細胞に存在する受容体に標的化するためのキャプシド改変をさらに含んでなる、[1]〜[19]のいずれか一項に記載のアデノウイルスゲノム。
[21].キャプシドの改変がアデノウイルスファイバータンパク質のH1ループへのRGDモチーフの挿入である、[20]に記載のアデノウイルスゲノム。
[22].アデノウイルスゲノムが前記ゲノムに挿入された1以上のさらなる遺伝子を含んでなる、[1]〜[21]のいずれか一項に記載のアデノウイルスゲノム。
[23].前記さらなる遺伝子が遺伝子治療またはワクチン接種において使用される1以上の非アデノウイルス遺伝子である、[22]に記載のアデノウイルスゲノム。
[24].前記遺伝子が癌遺伝子治療において使用される遺伝子である、[23]に記載のアデノウイルスゲノム。
[25].前記癌遺伝子治療において使用される遺伝子が、プロドラッグ活性化遺伝子、腫瘍抑制遺伝子、抗腫瘍干渉RNAをコードする遺伝子および免疫刺激性遺伝子からなる群から選択される少なくとも1つの遺伝子である、[24]に記載のアデノウイルスゲノム。
[26].[1]〜[25]のいずれか一項に記載のアデノウイルスゲノムを有する組換えアデノウイルス。
[27].治療上有効な量の[26]に記載の組換えアデノウイルスを薬学上許容可能な担体とともに含んでなる医薬組成物。
[28].医薬で使用するための[26]に記載の組換えアデノウイルスまたは[27]に記載の医薬組成物。
[29].アデノウイルスが、腫瘍溶解性アデノウイルスまたは[24]もしくは[25]に記載のアデノウイルスゲノムを有するアデノウイルスである、哺乳動物において癌の予防および/または治療で使用するための、[26]に記載の組換えアデノウイルスまたは[27]に記載の医薬組成物。
[30].哺乳動物がヒトである、[28]または[29]に記載の使用のための組換えアデノウイルス。
[31].アデノウイルスが全身投与される、[28]、[29]または[30]に記載の使用のための組換えアデノウイルス。
細胞株
HEK293(ヒト胚腎臓)、A549(ヒト肺腺癌)、Sk−mel28(黒色腫)、およびMCF7(ヒト乳腺癌)細胞をthe American Type Culture Collection(ATCC、マナサス、VA)から入手した。MCF7を除く総ての腫瘍細胞株を、37℃、5%CO2にて、5%ウシ胎児血清を添加したダルベッコの改変イーグル培地で維持した。MCF7細胞は、10%ウシ胎児血清を添加したRPMI 1640培地で維持した。総ての細胞株をマイコプラズマの存在に関して定期的に検査した。
ICOVIR15腫瘍溶解性アデノウイルスは従前に記載されている(Rojas JJ, et al. Minimal RB-responsive E1A promoter modification to attain potency, selectivity, and transgene-arming capacity in oncolytic adenoviruses. Mol Ther 2010; 18 (11):1960-71)。AdGLは、pEGFPLuc(Clontech)由来のEGFP−ルシフェラーゼ融合タンパク質カセットを発現するE1欠失第一世代ベクターである。E1領域を置換するCMVプロモーター−EGFPLuc−ポリAカセットの挿入を、陽性−陰性選択を用いる細菌での相同組換えに基づくStanton et al. (Stanton RJ, et al. Re-engineering adenovirus vector systems to enable high-throughput analyses of gene function. Biotechniques 2008; 45(6):659-62, 664-8)から適合させたリコンビニアリングプロトコールに従って行った。E1相同領域により挟み込まれたCMV−GFPLucカセットを用いて、E1欠失アデノウイルスベクターを構築するために慣用されるpAd5−CV5−E3+の陽性−陰性選択マーカーを置換した。ICOVIR15をA549細胞で増殖させ、複製欠陥AdGLをHEK293細胞で増殖させた。
A549細胞に、80〜100%の感染が得られるように細胞当たり800ウイルス粒子(vp)の各ウイルスを感染させた。感染4時間後に細胞をPBSで3回洗浄し、新鮮培地でインキュベートした。示された時点で細胞を採取し、3回凍結−解凍して細胞抽出液を得た。ウイルス力価は、HEK293細胞で、抗ヘキソン染色に基づく方法(Cascallo M, et al. Systemic toxicity-efficacy profile of ICOVIR-5, a potent and selective oncolytic adenovirus based on the pRB pathway. Mol Ther 2007; 15:1607-15)により得た。
細胞傷害性アッセイは、96ウェルプレートに1ウェル当たり10,000のHEK293細胞、30,000のA549細胞、10,000のSk−mel28細胞および20,000のMCF−7細胞を播種することによって行った。感染前に、ウイルスを室温で1時間、培地または1mg/mlのヒト血清アルブミン(HSA)を含有する培地のいずれかでインキュベートした。細胞に、通常培地またはアルブミン含有培地中、10,000vp/細胞で始まる連続希釈系(HEK293、Sk−mel28およびMCF−7細胞では1/3、A549細胞では1/5)を感染させた。感染後7日目に、プレートをPBSで洗浄し、全タンパク質内容物に関して染色し(ビシンコニン酸アッセイ;Pierce Biotechnology、ロックフォード、IL)、吸光度を定量した。50%の増殖阻害をもたらすために必要とされる細胞当たりのvp(IC50)を用量反応曲線から、適合したヒル式を用いた標準非線形回帰(GraFit;Erithacus Software、ホーリー、UK)により決定した。
ヒト血清アルブミン(HSA)およびマウス血清アルブミン(MSA)との結合の検出は、Konig and Skerra (Konig T, Skerra A. Use of an albumin-binding domain for the selective immobilisation of recombinant capture antibody fragments on ELISA plates. J Immunol Methods 1998; 218:73-83)から適合させたELISAプロトコールに従って行った。室温で1時間インキュベーションを行った後、0.1%Tween20を含有するPBS200μlで3回の洗浄工程を行い、これはまたウイルスおよび抗体を希釈するために使用したバッファーでもあった。
抗体により媒介される中和を感染(ルシフェラーゼ−GFPリポーターアデノウイルスの形質導入)および複製(複製可能アデノウイルスにより媒介される細胞傷害性)のレベルで分析した。市販の抗体Ab6982(抗Ad5ウサギポリクローナル、Abcam)を中和抗体として使用した。感染力分析では、96ウェルプレートにて異なるアデノウイルス(AdGLまたはAdGL−ABD)を含有する培地で、1/100希釈の抗体原液から開始し、抗体の1/6連続希釈を行った。
インビボ試験はICO−IDIBELL施設(バルセロナ、スペイン)AAALACユニット1155で行い、IDIBELLの動物実験倫倫理委員会により承認された。Balb/C nu/nu雌マウスにICOVIR15とICOVIR15−ABD(1:1比)の混合物を、PBS中10ml/kgの容量で総用量5×1010vpとして静注した(n=5)。投与後5分、15分、1時間、4時間、および24時間に尾静脈から血液サンプルを採取した。血液サンプルを4℃、5000gで5分間遠心分離して細胞画分を分離し、血清を回収した。血清サンプルを54℃で45分間、その後90℃で10分間、プロテイナーゼKおよびSDSで消化し、キャプシドのタンパク質分解を行い、ウイルスDNAを放出させた。消化したサンプルをPCRによりヘキソンHVR1フランキングオリゴヌクレオチドAd19121F 5’−CTGGACATGGCTTCCACGTA−3’(配列番号25)およびAd19300R 5’−GCTCGTCTACTTCGTCTTCG−3’(配列番号26)を用いて増幅し、1%アガロースゲルでの電気泳動により分析した。ICOVIR15−ABDはHVR1の中央にABDの挿入を有するので、PCR産物のサイズはより長くなり、ICOVIR15からの199bpに対して、ICOVIR15−ABDから予想されるPCR産物は361bpである。
6週齢雌Balb/C nu/nuマウスの側腹部への1×107Sk−mel28細胞の注射により、皮下黒色腫異種移植腫瘍を確立した。腫瘍が150mm3に達した際(実験0日)に、マウスを無作為化し(1群当たりn=10〜12個体)、尾静脈からPBS中10ml/kgの容量で、PBSまたは5×1010vpのICOVIR15またはICOVIR15−ABDの単回静脈内投与を行った。腫瘍サイズおよびマウスの状態を週に3回モニタリングした。腫瘍体積はデジタルカリパスで測定し、式V(mm3)=π/6×W2×L(式中、WおよびLはそれぞれ腫瘍の幅および長さである)により定義した。処置群間の腫瘍サイズの違いの統計的有意性は、対応のない両側スチューデントのt検定により評価した。
黒色腫腫瘍は、6週齢雌C57BL6マウス(1群当たりn=4〜6個体)の両側腹部に1×106 B16−CAR細胞を皮下移植して確立した。腫瘍が100mm3に達した際に、マウスの腹膜内にPBS(ナイーブ群)または2×1010vpのhAd5wt(前免疫群)のいずれかを注射した。免疫誘導7日後、動物にマウス当たり3×1010ウイルス粒子の用量でPBS、AdGL、またはAdGL−ABDの単回静脈内投与を行った。ベクター注射3日後、マウスに250μLのD−ルシフェリン(15mg/mL;Biosynth、シュタート、スイス)の腹腔内注射を行い、マウスを生物発光イメージング(IVIS)用の肝臓および腫瘍採取のために犠牲にした。臓器をIVIS Lumina XR(Caliper Life Sciences、ホプキントン、MA)で画像化し、Living Image v4.0ソフトウエアを,用いて発光を定量した。
ICOVIR15−ABDの作出および同定
アルブミン結合アデノウイルスを作出するために、連鎖球菌属細菌のGタンパク質由来のアルブミン結合ドメイン3(配列番号1)をICOVIR15ヘキソンのHVR1に挿入し、腫瘍溶解性アデノウイルスICOVIR15−ABDを作出した(図1および2)。このドメインは、ヘキソン配列に欠失なく、HVR1の中央のD150アミノ酸の後に2つのリンカー(GSGS)(配列番号2)に挟み込まれて挿入された(図1)。
ICOVIR15−ABDとヒトアルブミンとの結合が証明されたので、この結合がウイルスを中和抗体(NAb)から保護できるかどうかを試験した。このために、ヘキソンにおいてABDで修飾されたGFP−ルシフェラーゼ融合タンパク質を発現するアデノウイルスベクター(AdGL−ABDと呼称)を構築した。HSAの存在下および非存在下で、市販の中和抗体Ab6982(Ad5に対するウサギポリクローナル抗体)の連続希釈系とともにインキュベートした後に、HEK293細胞におけるAdGL−ABDの形質導入効率を調べた。図6に示されるように、アルブミンインキュベーションにかかわらず、非改変AdGLベクターで同等レベルの形質導入が達成された。対照的に、HSAはAdGL−ABDを中和から保護した。興味深いことに、AdGL−ABDは、アルブミンとともにインキュベートしなかった場合でも、非改変ベクターAdGLよりも中和程度が低く、ABDによるHVR1の改変が一部のNAbの結合をすでに除外していたに過ぎないことを示す。
アルブミン結合がアデノウイルスの急速な血液クリアランスを軽減できるかどうかを検討するために、インビボ全身投与後のICOVIR15−ABDの薬物動態学を調べた。マウスにICOVIR15とICOVIR15−ABDの1:1比の混合物を、マウス当たり5×1010ウイルス粒子の総用量で注射し、種々の時点で血液サンプルを採取した。血清サンプル中のヘキソンHVR1の増幅をPCRにより行った。ABDの挿入のためICOVIR15−ABDでは361bpバンドが見られ、一方、ICOVIR15では、バンドのサイズはわずか199bpである。ゆえに、各時点でこれらのバンドの相対強度を比較すれば、どのウイルスが血流で長く存続するかを決定することが可能であった。図8は、数種類の比率のICOVIR15−ABD:ICOVIR15(0.2、1、5、10および50)、注射前対照、および水陰性対照とともに標準品を含む全サンプルのPCR反応の電気泳動を示す。注射前対照と注射5分後では等しい強度のバンドが得られた。その時から、ICOVIR15−ABDに相当するバンドがICOVIR15に相当するバンドより強くなるにつれ、バンド強度のシフトが見て取れる。注射後1時間で、両ウイルスの示差的残存率はICOVIR15−ABDに有利であることが明確である。これらのデータは、注射5分後にICOVIR15はICOVIR15−ABDよりもはるかに速く血流から排除されることを示し、ABD修飾ウイルスの薬物動態の改善を証明する。
ICOVIR15−ABDの血漿半減期の延長が示されたところで、これが全身投与後の抗腫瘍有効性の増強に表れたかどうかを試験した。Sk−mel28(黒色腫)異種移植腫瘍を担持するマウスに、単回静脈内用量のリン酸緩衝生理食塩水(PBS)、マウス当たり5×1010ウイルス粒子のICOVIR15またはICOVIR15−ABDを注射した。処置後38日目に、PBS処置腫瘍のサイズが大きくなったために動物を犠牲にした。両ウイルスともPBSに比べて腫瘍成長を有意に低減することができた(図9)。しかしながら、ICOVIR15−ABD処置は21日目から処置の終了まで腫瘍成長に統計的低減を示したが、ICOVIR15は35日目まで、統計的に腫瘍成長の制御ができなかった。38日目に動物を犠牲にした際、ICOVIR15−ABDでの2倍の低減に比べ、ICOVIR15が誘導したのは1.4倍の低減であった。
免疫応答性のB16−CAR黒色腫腫瘍担持C57BL6マウスに、2×1010ウイルス粒子のhAd5wtまたはPBS(前免疫群またはナイーブ群)の腹腔内注射で免疫誘導を行った。数日後、マウスにPBS、マウス当たり3×1010ウイルス粒子のAdGLまたはAdGL−ABDの単回静脈内用量を施した。ベクター注射3日後に、マウスを犠牲にし、インビボ生物発光イメージング(IVIS)のために肝臓および腫瘍を採取した。ナイーブ動物における肝臓および腫瘍形質導入においてベクター間で有意な違いは見られなかった(図10)。注目すべきは、動物を前免疫した場合、肝臓および腫瘍の形質導入は完全に無効となったことから、非改変AdGLベクターは完全な中和を受けた。対照的に、AdGL−ABDは、肝臓および腫瘍で同等レベルの形質導入を維持することができ、抗HAd5前免疫からの保護を示す。
この挿入がヘキソンの他の超可変領域で成し得る化合物どうかを調べるため、AdGL−H5−ABDベクターを構築した。HEK293細胞をpAdZGL−H5−ABDプラスミドでトランスフェクトしてAdGL−H5−ABDウイルスを作出した。トランスフェクション1週間後に、細胞および上清を採取し、3回の凍結−解凍サイクルにより溶解した。ウイルスを含有する細胞抽出液の力価をHEK293細胞でプラークアッセイにより測定した。希釈率1E6、1E7および1E8に相当するウェルを図11に示し、そこではウイルス増殖を示すプラークが明らかである。HVR5内へのABDの挿入は、ウイルスゲノムのシーケンシグによって確認した。これはウイルスの生存率に影響を及ぼさずに他の超可変領域内にABDを挿入できることを示す。
超可変領域5に挿入されたABDもアデノウイルスを中和抗体から保護できるかどうかを確認するために、HEK293細胞およびSk−mel28細胞において、HSAを含むまたは含まないAb6982 NAbの連続希釈系とともにインキュベートした後の、ベクターAdGL、AdGL−H1−ABDおよびAdGL−H5−ABDの形質導入効率を比較した。図6に見られるように、HSAを含むインキュベーションでは、両細胞株でAdGL−H1−ABDへの形質導入に明らかな優位性が示されたが、非改変ベクターAdGLに対してそれは重要な効果を持たなかった(図12)。驚くことに、ヒトアルブミンの添加はAdGL−H5−ABDの形質導入レベルを高めなかった。このことは、ABDがHVR1に挿入された場合には機能的であるがHVR5に挿入された場合には機能的でないことを示す。
[配列表]
SEQUENCE LISTING
<110> FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE (IDIBELL)
INSTITUT CATALA D'ONCOLOGIA (ICO)
<120> ADENOVIRUS COMPRISING AN ALBUMIN-BINDING MOIETY
<130> 16107101
<150> EP 14382162
<151> 2014-04-30
<160> 27
<170> PatentIn version 3.5
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<212> PRT
<213> Streptococcus
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Lys Thr His Val
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<212> PRT
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<220>
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<212> DNA
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<220>
<223> Complete modified adenoviral hexon having ABD inserted in HVR1
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atggctaccc cttcgatgat gccgcagtgg tcttacatgc acatctcggg ccaggacgcc 60
tcggagtacc tgagccccgg gctggtgcag tttgcccgcg ccaccgagac gtacttcagc 120
ctgaataaca agtttagaaa ccccacggtg gcgcctacgc acgacgtgac cacagaccgg 180
tcccagcgtt tgacgctgcg gttcatccct gtggaccgtg aggatactgc gtactcgtac 240
aaggcgcggt tcaccctagc tgtgggtgat aaccgtgtgc tggacatggc ttccacgtac 300
tttgacatcc gcggcgtgct ggacaggggc cctactttta agccctactc tggcactgcc 360
tacaacgccc tggctcccaa gggtgcccca aatccttgcg aatgggatga agctgctact 420
gctcttgaaa taaacctaga agaagaggac ggcagcggat ccctggccga ggctaaggtg 480
cttgcgaacc gggaactaga caaatacggt gtttctgatt attacaagaa tttgattaac 540
aatgccaaaa ccgtcgaggg cgtaaaggct ctgatcgacg aaatacttgc ggccctaccc 600
gggtctggta gcgatgacaa cgaagacgaa gtagacgagc aagctgagca gcaaaaaact 660
cacgtatttg ggcaggcgcc ttattctggt ataaatatta caaaggaggg tattcaaata 720
ggtgtcgaag gtcaaacacc taaatatgcc gataaaacat ttcaacctga acctcaaata 780
ggagaatctc agtggtacga aacagaaatt aatcatgcag ctgggagagt cctaaaaaag 840
actaccccaa tgaaaccatg ttacggttca tatgcaaaac ccacaaatga aaatggaggg 900
caaggcattc ttgtaaagca acaaaatgga aagctagaaa gtcaagtgga aatgcaattt 960
ttctcaacta ctgaggcagc cgcaggcaat ggtgataact tgactcctaa agtggtattg 1020
tacagtgaag atgtagatat agaaacccca gacactcata tttcttacat gcccactatt 1080
aaggaaggta actcacgaga actaatgggc caacaatcta tgcccaacag gcctaattac 1140
attgctttta gggacaattt tattggtcta atgtattaca acagcacggg taatatgggt 1200
gttctggcgg gccaagcatc gcagttgaat gctgttgtag atttgcaaga cagaaacaca 1260
gagctttcat accagctttt gcttgattcc attggtgata gaaccaggta cttttctatg 1320
tggaatcagg ctgttgacag ctatgatcca gatgttagaa ttattgaaaa tcatggaact 1380
gaagatgaac ttccaaatta ctgctttcca ctgggaggtg tgattaatac agagactctt 1440
accaaggtaa aacctaaaac aggtcaggaa aatggatggg aaaaagatgc tacagaattt 1500
tcagataaaa atgaaataag agttggaaat aattttgcca tggaaatcaa tctaaatgcc 1560
aacctgtgga gaaatttcct gtactccaac atagcgctgt atttgcccga caagctaaag 1620
tacagtcctt ccaacgtaaa aatttctgat aacccaaaca cctacgacta catgaacaag 1680
cgagtggtgg ctcccgggct agtggactgc tacattaacc ttggagcacg ctggtccctt 1740
gactatatgg acaacgtcaa cccatttaac caccaccgca atgctggcct gcgctaccgc 1800
tcaatgttgc tgggcaatgg tcgctatgtg cccttccaca tccaggtgcc tcagaagttc 1860
tttgccatta aaaacctcct tctcctgccg ggctcataca cctacgagtg gaacttcagg 1920
aaggatgtta acatggttct gcagagctcc ctaggaaatg acctaagggt tgacggagcc 1980
agcattaagt ttgatagcat ttgcctttac gccaccttct tccccatggc ccacaacacc 2040
gcctccacgc ttgaggccat gcttagaaac gacaccaacg accagtcctt taacgactat 2100
ctctccgccg ccaacatgct ctaccctata cccgccaacg ctaccaacgt gcccatatcc 2160
atcccctccc gcaactgggc ggctttccgc ggctgggcct tcacgcgcct taagactaag 2220
gaaaccccat cactgggctc gggctacgac ccttattaca cctactctgg ctctataccc 2280
tacctagatg gaacctttta cctcaaccac acctttaaga aggtggccat tacctttgac 2340
tcttctgtca gctggcctgg caatgaccgc ctgcttaccc ccaacgagtt tgaaattaag 2400
cgctcagttg acggggaggg ttacaacgtt gcccagtgta acatgaccaa agactggttc 2460
ctggtacaaa tgctagctaa ctataacatt ggctaccagg gcttctatat cccagagagc 2520
tacaaggacc gcatgtactc cttctttaga aacttccagc ccatgagccg tcaggtggtg 2580
gatgatacta aatacaagga ctaccaacag gtgggcatcc tacaccaaca caacaactct 2640
ggatttgttg gctaccttgc ccccaccatg cgcgaaggac aggcctaccc tgctaacttc 2700
ccctatccgc ttataggcaa gaccgcagtt gacagcatta cccagaaaaa gtttctttgc 2760
gatcgcaccc tttggcgcat cccattctcc agtaacttta tgtccatggg cgcactcaca 2820
gacctgggcc aaaaccttct ctacgccaac tccgcccacg cgctagacat gacttttgag 2880
gtggatccca tggacgagcc cacccttctt tatgttttgt ttgaagtctt tgacgtggtc 2940
cgtgtgcacc agccgcaccg cggcgtcatc gaaaccgtgt acctgcgcac gcccttctcg 3000
gccggcaacg ccacaacata a 3021
<210> 4
<211> 3021
<212> DNA
<213> Artificial Sequence
<220>
<223> Complete modified adenoviral hexon having ABD inserted in HVR5
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atggctaccc cttcgatgat gccgcagtgg tcttacatgc acatctcggg ccaggacgcc 60
tcggagtacc tgagccccgg gctggtgcag tttgcccgcg ccaccgagac gtacttcagc 120
ctgaataaca agtttagaaa ccccacggtg gcgcctacgc acgacgtgac cacagaccgg 180
tcccagcgtt tgacgctgcg gttcatccct gtggaccgtg aggatactgc gtactcgtac 240
aaggcgcggt tcaccctagc tgtgggtgat aaccgtgtgc tggacatggc ttccacgtac 300
tttgacatcc gcggcgtgct ggacaggggc cctactttta agccctactc tggcactgcc 360
tacaacgccc tggctcccaa gggtgcccca aatccttgcg aatgggatga agctgctact 420
gctcttgaaa taaacctaga agaagaggac gatgacaacg aagacgaagt agacgagcaa 480
gctgagcagc aaaaaactca cgtatttggg caggcgcctt attctggtat aaatattaca 540
aaggagggta ttcaaatagg tgtcgaaggt caaacaccta aatatgccga taaaacattt 600
caacctgaac ctcaaatagg agaatctcag tggtacgaaa cagaaattaa tcatgcagct 660
gggagagtcc taaaaaagac taccccaatg aaaccatgtt acggttcata tgcaaaaccc 720
acaaatgaaa atggagggca aggcattctt gtaaagcaac aaaatggaaa gctagaaagt 780
caagtggaaa tgcaattttt ctcaactact gaggcagccg caggcagcgg atccctggcc 840
gaggctaagg tgcttgcgaa ccgggaacta gacaaatacg gtgtttctga ttattacaag 900
aatttgatta acaatgccaa aaccgtcgag ggcgtaaagg ctctgatcga cgaaatactt 960
gcggccctac ccgggtctgg tagcggcaat ggtgataact tgactcctaa agtggtattg 1020
tacagtgaag atgtagatat agaaacccca gacactcata tttcttacat gcccactatt 1080
aaggaaggta actcacgaga actaatgggc caacaatcta tgcccaacag gcctaattac 1140
attgctttta gggacaattt tattggtcta atgtattaca acagcacggg taatatgggt 1200
gttctggcgg gccaagcatc gcagttgaat gctgttgtag atttgcaaga cagaaacaca 1260
gagctttcat accagctttt gcttgattcc attggtgata gaaccaggta cttttctatg 1320
tggaatcagg ctgttgacag ctatgatcca gatgttagaa ttattgaaaa tcatggaact 1380
gaagatgaac ttccaaatta ctgctttcca ctgggaggtg tgattaatac agagactctt 1440
accaaggtaa aacctaaaac aggtcaggaa aatggatggg aaaaagatgc tacagaattt 1500
tcagataaaa atgaaataag agttggaaat aattttgcca tggaaatcaa tctaaatgcc 1560
aacctgtgga gaaatttcct gtactccaac atagcgctgt atttgcccga caagctaaag 1620
tacagtcctt ccaacgtaaa aatttctgat aacccaaaca cctacgacta catgaacaag 1680
cgagtggtgg ctcccgggct agtggactgc tacattaacc ttggagcacg ctggtccctt 1740
gactatatgg acaacgtcaa cccatttaac caccaccgca atgctggcct gcgctaccgc 1800
tcaatgttgc tgggcaatgg tcgctatgtg cccttccaca tccaggtgcc tcagaagttc 1860
tttgccatta aaaacctcct tctcctgccg ggctcataca cctacgagtg gaacttcagg 1920
aaggatgtta acatggttct gcagagctcc ctaggaaatg acctaagggt tgacggagcc 1980
agcattaagt ttgatagcat ttgcctttac gccaccttct tccccatggc ccacaacacc 2040
gcctccacgc ttgaggccat gcttagaaac gacaccaacg accagtcctt taacgactat 2100
ctctccgccg ccaacatgct ctaccctata cccgccaacg ctaccaacgt gcccatatcc 2160
atcccctccc gcaactgggc ggctttccgc ggctgggcct tcacgcgcct taagactaag 2220
gaaaccccat cactgggctc gggctacgac ccttattaca cctactctgg ctctataccc 2280
tacctagatg gaacctttta cctcaaccac acctttaaga aggtggccat tacctttgac 2340
tcttctgtca gctggcctgg caatgaccgc ctgcttaccc ccaacgagtt tgaaattaag 2400
cgctcagttg acggggaggg ttacaacgtt gcccagtgta acatgaccaa agactggttc 2460
ctggtacaaa tgctagctaa ctataacatt ggctaccagg gcttctatat cccagagagc 2520
tacaaggacc gcatgtactc cttctttaga aacttccagc ccatgagccg tcaggtggtg 2580
gatgatacta aatacaagga ctaccaacag gtgggcatcc tacaccaaca caacaactct 2640
ggatttgttg gctaccttgc ccccaccatg cgcgaaggac aggcctaccc tgctaacttc 2700
ccctatccgc ttataggcaa gaccgcagtt gacagcatta cccagaaaaa gtttctttgc 2760
gatcgcaccc tttggcgcat cccattctcc agtaacttta tgtccatggg cgcactcaca 2820
gacctgggcc aaaaccttct ctacgccaac tccgcccacg cgctagacat gacttttgag 2880
gtggatccca tggacgagcc cacccttctt tatgttttgt ttgaagtctt tgacgtggtc 2940
cgtgtgcacc agccgcaccg cggcgtcatc gaaaccgtgt acctgcgcac gcccttctcg 3000
gccggcaacg ccacaacata a 3021
<210> 5
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 5
Ser Gly Gly Thr Ser Gly Ser Thr Ser Gly Thr Gly Ser Thr
1 5 10
<210> 6
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 6
Ala Gly Ser Ser Thr Gly Ser Ser Thr Gly Pro Gly Ser Thr Thr
1 5 10 15
<210> 7
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 7
Gly Gly Ser Gly Gly Ala Pro
1 5
<210> 8
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 8
Gly Gly Gly Val Glu Gly Gly Gly
1 5
<210> 9
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Core sequence of an albumin-binding peptide
<400> 9
Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp
1 5 10
<210> 10
<211> 4
<212> PRT
<213> Human adenovirus type 5
<400> 10
Lys Lys Thr Lys
1
<210> 11
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> modified capsid domain
<400> 11
Arg Gly Asp Lys
1
<210> 12
<211> 56
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide HVR1rpsLF
<400> 12
gccctggctc ccaagggtgc cccaaatcct tgcgaatggg gcctggtgat gatggc 56
<210> 13
<211> 65
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide HVR1rpsLR
<400> 13
gtaatattta taccagaata aggcgcctgc ccaaatacgt gagttcagaa gaactcgtca 60
agaag 65
<210> 14
<211> 90
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide ABDH1F
<400> 14
cccaagggtg ccccaaatcc ttgcgaatgg gatgaagctg ctactgctct tgaaataaac 60
ctagaagaag aggacggcag cggatccctg 90
<210> 15
<211> 49
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide ABDR1
<400> 15
cccggttcgc aagcacctta gcctcggcca gggatccgct gccccattc 49
<210> 16
<211> 49
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide ABDF2
<400> 16
gcttgcgaac cgggaactag acaaatacgg tgtttctgat tattacaag 49
<210> 17
<211> 50
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide ABDR2
<400> 17
cgacggtttt ggcattgtta atcaaattct tgtaataatc agaaacaccg 50
<210> 18
<211> 50
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide ABDF3
<400> 18
atgccaaaac cgtcgagggc gtaaaggctc tgatcgacga aatacttgcg 50
<210> 19
<211> 50
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide ABDR3
<400> 19
atacgtgagt gctaccagac ccgggtaggg ccgcaagtat ttcgtcgatc 50
<210> 20
<211> 91
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide ABDH1R
<400> 20
cagaataagg cgcctgccca aatacgtgag ttttttgctg ctcagcttgc tcgtctactt 60
cgtcttcgtt gtcatcgcta ccagacccgg g 91
<210> 21
<211> 58
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide H5rpsLF
<400> 21
gaaagctaga aagtcaagtg gaaatgcaat ttttctcaac tggcctggtg atgatggc 58
<210> 22
<211> 62
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide H5rpsLR
<400> 22
gtttctatat ctacatcttc actgtacaat accactttag gtcagaagaa ctcgtcaaga 60
ag 62
<210> 23
<211> 138
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide ABDH5F
<400> 23
ctggccgagg ctaaggtgct tgcgaaccgg gaactagaca aatacggtgt ttctgattat 60
tacaagaatt tgattaacaa tgccaaaacc gtcgagggcg taaaggctct gatcgacgaa 120
atacttgcgg ccctaccc 138
<210> 24
<211> 138
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide ABDH5R
<400> 24
ctggccgagg ctaaggtgct tgcgaaccgg gaactagaca aatacggtgt ttctgattat 60
tacaagaatt tgattaacaa tgccaaaacc gtcgagggcg taaaggctct gatcgacgaa 120
atacttgcgg ccctaccc 138
<210> 25
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide Ad19121F
<400> 25
ctggacatgg cttccacgta 20
<210> 26
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide Ad19300R
<400> 26
gctcgtctac ttcgtcttcg 20
<210> 27
<211> 952
<212> PRT
<213> Human adenovirus type 5
<400> 27
Met Ala Thr Pro Ser Met Met Pro Gln Trp Ser Tyr Met His Ile Ser
1 5 10 15
Gly Gln Asp Ala Ser Glu Tyr Leu Ser Pro Gly Leu Val Gln Phe Ala
20 25 30
Arg Ala Thr Glu Thr Tyr Phe Ser Leu Asn Asn Lys Phe Arg Asn Pro
35 40 45
Thr Val Ala Pro Thr His Asp Val Thr Thr Asp Arg Ser Gln Arg Leu
50 55 60
Thr Leu Arg Phe Ile Pro Val Asp Arg Glu Asp Thr Ala Tyr Ser Tyr
65 70 75 80
Lys Ala Arg Phe Thr Leu Ala Val Gly Asp Asn Arg Val Leu Asp Met
85 90 95
Ala Ser Thr Tyr Phe Asp Ile Arg Gly Val Leu Asp Arg Gly Pro Thr
100 105 110
Phe Lys Pro Tyr Ser Gly Thr Ala Tyr Asn Ala Leu Ala Pro Lys Gly
115 120 125
Ala Pro Asn Pro Cys Glu Trp Asp Glu Ala Ala Thr Ala Leu Glu Ile
130 135 140
Asn Leu Glu Glu Glu Asp Asp Asp Asn Glu Asp Glu Val Asp Glu Gln
145 150 155 160
Ala Glu Gln Gln Lys Thr His Val Phe Gly Gln Ala Pro Tyr Ser Gly
165 170 175
Ile Asn Ile Thr Lys Glu Gly Ile Gln Ile Gly Val Glu Gly Gln Thr
180 185 190
Pro Lys Tyr Ala Asp Lys Thr Phe Gln Pro Glu Pro Gln Ile Gly Glu
195 200 205
Ser Gln Trp Tyr Glu Thr Glu Ile Asn His Ala Ala Gly Arg Val Leu
210 215 220
Lys Lys Thr Thr Pro Met Lys Pro Cys Tyr Gly Ser Tyr Ala Lys Pro
225 230 235 240
Thr Asn Glu Asn Gly Gly Gln Gly Ile Leu Val Lys Gln Gln Asn Gly
245 250 255
Lys Leu Glu Ser Gln Val Glu Met Gln Phe Phe Ser Thr Thr Glu Ala
260 265 270
Ala Ala Gly Asn Gly Asp Asn Leu Thr Pro Lys Val Val Leu Tyr Ser
275 280 285
Glu Asp Val Asp Ile Glu Thr Pro Asp Thr His Ile Ser Tyr Met Pro
290 295 300
Thr Ile Lys Glu Gly Asn Ser Arg Glu Leu Met Gly Gln Gln Ser Met
305 310 315 320
Pro Asn Arg Pro Asn Tyr Ile Ala Phe Arg Asp Asn Phe Ile Gly Leu
325 330 335
Met Tyr Tyr Asn Ser Thr Gly Asn Met Gly Val Leu Ala Gly Gln Ala
340 345 350
Ser Gln Leu Asn Ala Val Val Asp Leu Gln Asp Arg Asn Thr Glu Leu
355 360 365
Ser Tyr Gln Leu Leu Leu Asp Ser Ile Gly Asp Arg Thr Arg Tyr Phe
370 375 380
Ser Met Trp Asn Gln Ala Val Asp Ser Tyr Asp Pro Asp Val Arg Ile
385 390 395 400
Ile Glu Asn His Gly Thr Glu Asp Glu Leu Pro Asn Tyr Cys Phe Pro
405 410 415
Leu Gly Gly Val Ile Asn Thr Glu Thr Leu Thr Lys Val Lys Pro Lys
420 425 430
Thr Gly Gln Glu Asn Gly Trp Glu Lys Asp Ala Thr Glu Phe Ser Asp
435 440 445
Lys Asn Glu Ile Arg Val Gly Asn Asn Phe Ala Met Glu Ile Asn Leu
450 455 460
Asn Ala Asn Leu Trp Arg Asn Phe Leu Tyr Ser Asn Ile Ala Leu Tyr
465 470 475 480
Leu Pro Asp Lys Leu Lys Tyr Ser Pro Ser Asn Val Lys Ile Ser Asp
485 490 495
Asn Pro Asn Thr Tyr Asp Tyr Met Asn Lys Arg Val Val Ala Pro Gly
500 505 510
Leu Val Asp Cys Tyr Ile Asn Leu Gly Ala Arg Trp Ser Leu Asp Tyr
515 520 525
Met Asp Asn Val Asn Pro Phe Asn His His Arg Asn Ala Gly Leu Arg
530 535 540
Tyr Arg Ser Met Leu Leu Gly Asn Gly Arg Tyr Val Pro Phe His Ile
545 550 555 560
Gln Val Pro Gln Lys Phe Phe Ala Ile Lys Asn Leu Leu Leu Leu Pro
565 570 575
Gly Ser Tyr Thr Tyr Glu Trp Asn Phe Arg Lys Asp Val Asn Met Val
580 585 590
Leu Gln Ser Ser Leu Gly Asn Asp Leu Arg Val Asp Gly Ala Ser Ile
595 600 605
Lys Phe Asp Ser Ile Cys Leu Tyr Ala Thr Phe Phe Pro Met Ala His
610 615 620
Asn Thr Ala Ser Thr Leu Glu Ala Met Leu Arg Asn Asp Thr Asn Asp
625 630 635 640
Gln Ser Phe Asn Asp Tyr Leu Ser Ala Ala Asn Met Leu Tyr Pro Ile
645 650 655
Pro Ala Asn Ala Thr Asn Val Pro Ile Ser Ile Pro Ser Arg Asn Trp
660 665 670
Ala Ala Phe Arg Gly Trp Ala Phe Thr Arg Leu Lys Thr Lys Glu Thr
675 680 685
Pro Ser Leu Gly Ser Gly Tyr Asp Pro Tyr Tyr Thr Tyr Ser Gly Ser
690 695 700
Ile Pro Tyr Leu Asp Gly Thr Phe Tyr Leu Asn His Thr Phe Lys Lys
705 710 715 720
Val Ala Ile Thr Phe Asp Ser Ser Val Ser Trp Pro Gly Asn Asp Arg
725 730 735
Leu Leu Thr Pro Asn Glu Phe Glu Ile Lys Arg Ser Val Asp Gly Glu
740 745 750
Gly Tyr Asn Val Ala Gln Cys Asn Met Thr Lys Asp Trp Phe Leu Val
755 760 765
Gln Met Leu Ala Asn Tyr Asn Ile Gly Tyr Gln Gly Phe Tyr Ile Pro
770 775 780
Glu Ser Tyr Lys Asp Arg Met Tyr Ser Phe Phe Arg Asn Phe Gln Pro
785 790 795 800
Met Ser Arg Gln Val Val Asp Asp Thr Lys Tyr Lys Asp Tyr Gln Gln
805 810 815
Val Gly Ile Leu His Gln His Asn Asn Ser Gly Phe Val Gly Tyr Leu
820 825 830
Ala Pro Thr Met Arg Glu Gly Gln Ala Tyr Pro Ala Asn Phe Pro Tyr
835 840 845
Pro Leu Ile Gly Lys Thr Ala Val Asp Ser Ile Thr Gln Lys Lys Phe
850 855 860
Leu Cys Asp Arg Thr Leu Trp Arg Ile Pro Phe Ser Ser Asn Phe Met
865 870 875 880
Ser Met Gly Ala Leu Thr Asp Leu Gly Gln Asn Leu Leu Tyr Ala Asn
885 890 895
Ser Ala His Ala Leu Asp Met Thr Phe Glu Val Asp Pro Met Asp Glu
900 905 910
Pro Thr Leu Leu Tyr Val Leu Phe Glu Val Phe Asp Val Val Arg Val
915 920 925
His Gln Pro His Arg Gly Val Ile Glu Thr Val Tyr Leu Arg Thr Pro
930 935 940
Phe Ser Ala Gly Asn Ala Thr Thr
945 950
Claims (15)
- ヘキソンタンパク質とアルブミン結合部分を含んでなる融合タンパク質の発現を生じさせる、ヘキソンタンパク質の超可変領域1(HVR1)のコード領域に挿入されたアルブミン結合部分をコードする配列を含んでなり、前記アルブミン結合部分はヘキソンタンパク質がアデノウイルスキャプシドに組み立てられる際にヘキソンタンパク質の外側表面に位置することを特徴とする、アデノウイルスゲノム。
- アルブミン結合部分が、連鎖球菌タンパク質G由来のアルブミン結合ドメイン、ペプトストレプトコッカス・マグヌス(Peptostreptococcus magnus)タンパク質PAB由来のアルブミン結合ドメインおよびコア配列DICLPRWGCLW(配列番号9)を有するアルブミン結合ペプチドから選択される、請求項1に記載のアデノウイルスゲノム。
- アルブミン結合部分が連鎖球菌タンパク質G由来のアルブミン結合ドメイン3である、請求項2に記載のアデノウイルスゲノム。
- 生成する融合タンパク質がGenBank受託番号BAG48782.1を有するヘキソンタンパク質(配列番号27)のナンバリングに従ってヘキソンタンパク質のD150アミノ酸の後にアルブミン結合部分を含むように、アルブミン結合部分をコードする配列が挿入されている、請求項1〜3のいずれか一項に記載のアデノウイルスゲノム。
- アデノウイルスが腫瘍溶解性アデノウイルスである、請求項1〜4のいずれか一項に記載のアデノウイルスゲノム。
- 前記アデノウイルスゲノムが腫瘍における選択的複製を達成するために、E1a、E1b、E4およびVA−RNAsからなる群から選択される1以上の遺伝子における突然変異をさらに含んでなる、請求項5に記載のアデノウイルスゲノム。
- アデノウイルスゲノムが、アデノウイルスの感染力を高めるための、または腫瘍細胞に存在する受容体を標的化するためのキャプシド改変をさらに含んでなる、請求項1〜6のいずれか一項に記載のアデノウイルスゲノム。
- キャプシドの改変が、アデノウイスルファイバータンパク質のH1ループへのRGDモチーフの挿入である、請求項7に記載のアデノウイルスゲノム。
- アデノウイルスゲノムがゲノムに挿入された1以上の非アデノウイルス遺伝子を含んでなり、該遺伝子が遺伝子治療またはワクチン接種において使用される遺伝子である、請求項1〜8のいずれか一項に記載のアデノウイルスゲノム。
- 請求項1〜9のいずれか一項に記載のアデノウイルスゲノムを有する組換えアデノウイルス。
- 治療上有効な量の請求項10に記載の組換えアデノウイルスを薬学上許容可能な担体とともに含んでなる、医薬組成物。
- 医薬において使用するための、請求項11に記載の医薬組成物。
- アデノウイルスが、a)腫瘍溶解性アデノウイルスおよびb)アデノウイルスのゲノムに挿入された癌遺伝子治療において使用される1以上の非アデノウイルス遺伝子を含んでなるアデノウイルスゲノムを有するアデノウイルスからなる群から選択される、哺乳動物の癌の予防および/または治療において使用するための、請求項11に記載の医薬組成物。
- 哺乳動物における感染性疾患の予防において使用するための、請求項11に記載の医薬組成物。
- アデノウイルスが全身投与される、請求項11〜14のいずれか一項に記載の医薬組成物。
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EP14382162.7A EP2940128A1 (en) | 2014-04-30 | 2014-04-30 | Adenovirus comprising an albumin-binding moiety |
EP14382162.7 | 2014-04-30 | ||
PCT/EP2015/059593 WO2015166082A1 (en) | 2014-04-30 | 2015-04-30 | Adenovirus comprising an albumin-binding moiety |
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WO2014153204A1 (en) | 2013-03-14 | 2014-09-25 | Salk Institute For Biological Studies | Oncolytic adenovirus compositions |
EP2940128A1 (en) | 2014-04-30 | 2015-11-04 | Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) | Adenovirus comprising an albumin-binding moiety |
KR20180112024A (ko) | 2016-02-23 | 2018-10-11 | 더 솔크 인스티튜트 포 바이올로지칼 스터디즈 | 바이러스 동역학에 미치는 영향 최소화를 위한 치료용 아데노바이러스의 외인성 유전자 발현 |
JP7054527B2 (ja) | 2016-02-23 | 2022-04-14 | ソーク インスティテュート フォー バイオロジカル スタディーズ | アデノウイルスの複製動態を測定するための高スループットアッセイ |
CN110062630A (zh) | 2016-12-12 | 2019-07-26 | 萨克生物研究学院 | 肿瘤靶向合成腺病毒及其用途 |
EP3665202A1 (en) | 2017-08-09 | 2020-06-17 | Massachusetts Institute Of Technology | Albumin binding peptide conjugates and methods thereof |
WO2019074842A1 (en) * | 2017-10-09 | 2019-04-18 | Keith Black | ONCOLYTIC ANTICANCER IMMUNOTHERAPIES AND METHODS OF USE |
WO2020047345A1 (en) | 2018-08-31 | 2020-03-05 | Yale University | Compositions and methods of using cell-penetrating antibodies in combination with immune checkpoint modulators |
JP2022502074A (ja) * | 2018-09-10 | 2022-01-11 | ジェネセイル バイオテック(シャンハイ)カンパニー リミテッド | 改変された腫瘍溶解性ウイルス、組成物、およびその使用 |
EP3906038A4 (en) * | 2018-11-21 | 2022-06-01 | Mayo Foundation for Medical Education and Research | ADENOVIRUS AND METHODS OF USE OF ADENOVIRUS |
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