JP2015506704A - 腫瘍関連異種抗原を発現するアデノウイルス - Google Patents
腫瘍関連異種抗原を発現するアデノウイルス Download PDFInfo
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Abstract
Description
本出願は、その内容全体が参照により本明細書に組み入れられる、2012年2月2日に出願された米国仮特許出願第61/594,005号の恩典を主張する。
配列表は、SEQ.tx(4KB、2013年2月1日)という名前のファイルで本出願に添付され、参照により本明細書に組み入れられる。
本発明は、概して、腫瘍学および癌治療の分野に関する。特に、本発明は免疫原性アデノウイルスに関する。
世界中で、癌は依然としてヒトの罹患率および死亡率の主な原因の一つである。手術、化学療法、および放射線を利用して癌を治癒することにいくらか成功しているものの、新規戦略が必要とされている。正常細胞よりも腫瘍細胞中で多く複製されるウイルスは腫瘍崩壊剤として有望である。アデノウイルスを使用した遺伝子導入および腫瘍溶解の実現可能性は十分に確立されてきている(Kirn、1999;Bischoffら、1996;Wildnerら、1999a;Wildnerら、1999b;(Stermanら、Hum. Gene Ther. 9:1083-1092(1998))。
複製能を有するアデノウイルスが抗癌治療をもたらし得るメカニズムは少なくとも4つある。第一に、アデノウイルスは、溶解感染を開始および完了することで細胞を溶解することができる(腫瘍崩壊)。第二に、アデノウイルスは、チミジンキナーゼ(HSVtk)遺伝子またはシトシンデアミナーゼ-チミジンキナーゼ融合タンパク質等の自殺遺伝子を発現でき(Rogulskiら、Clin. Cancer Res. 3:2081-2088(1997))、これにより腫瘍崩壊活性が増強される。第三に、アデノウイルスの投与を化学療法(任意の薬物療法を含む)または放射線と組み合わせて、各薬剤の腫瘍崩壊活性を高めることができる(Nielsenら、Cancer Gene Ther. 4:835-846(1997))。最後に、ウイルスは、免疫賦活剤として、または免疫賦活分子を発現するベクターとして機能でき、腫瘍抗原に対して特異的な免疫エフェクター細胞の刺激をもたらす。腫瘍崩壊および免疫刺激を使用した併用戦略は、「ワクチン効果」を通じて長期的かつ持続的な応答を提供し得るために特に魅力的である。従って、本発明以前には、腫瘍関連抗原を発現または提示する腫瘍細胞に対する選択性が改善した複製選択性アデノウイルスが当技術分野で依然として必要とされていた。
、チロシナーゼ(Tyr)、ミッドカイン(MK)、BAGE、CASP-8、β-カテニン、CA-125、CDK-1、ESO-1、gp75、gplOO、MART-1、ムチン(MUC-1)、MUM-1、p53、PAP、PSA、PSMA、ras、trp-1、HER-2、TRP-2、IL13Rα、AIM-3、またはNY-ESOlが含まれるがこれらに限定されない。特定の局面において、TAAは、C9orf112、SART1、BRAP、RTN4、GLEA2、TNKS2、KIAA0376、ING4、HSPH1、C13orf24、RBPSUH、C6orf153、NKTR、NSEP1、U2AF1L、CYNL2、TPR、SOX2、またはGOLGAである。アデノウイルスは、完全長の腫瘍関連抗原またはその免疫原性ペプチドを発現し得る。
からなるか、それから本質的になるか、またはそれを含む8〜20アミノ酸のペプチドをコードする。例えば、ペプチドは、
からなる群より選択される配列を有することができる。特に好適な態様において、EGFRvIII免疫原性ペプチドは
であり、ファイバータンパク質をコードする遺伝子、好ましくはH1ループに挿入される。別の態様では、EGFRvIII細胞外ドメイン全体をコードする核酸が、アデノウイルスの表面タンパク質をコードする遺伝子に挿入される。
をコードする(異種)核酸を含むゲノムを有する組換えアデノウイルス、および癌の治療におけるその使用を提供する。NY-ESO-1またはその免疫原性ペプチドをコードする核酸は表面タンパク質をコードする遺伝子に挿入されて、それによりアデノウイルスが、NY-ESO-1またはその免疫原性ペプチドを含むキメラ表面タンパク質を発現することが好ましい。一局面では、NY-ESO-1またはその免疫原性ペプチドをコードする核酸は、アデノウイルスのヘキソンをコードする遺伝子の超可変領域5に挿入される。アデノウイルスのこの領域は、抗原発現に有用であることが示されている(Crawford-MikszaおよびSchnurr、J. Virol.、70:1836-44(1996))。NY-ESO-1またはその免疫原性ペプチドをコードする核酸は、任意のアデノウイルスの1種以上の表面タンパク質をコードする遺伝子に挿入され得る。一局面では、アデノウイルスはデルタ-24である。別の局面では、癌は原発性または転移性の脳腫瘍である。
をコードする核酸、(b)アデノウイルスの欠失したE3領域に挿入されたMAGEまたはその免疫原性ペプチドをコードする核酸、および(c)アデノウイルスヘキソンタンパク質をコードする遺伝子の超可変領域5に挿入されたNY-ESO-1またはその免疫原性ペプチドをコードする核酸、を含むゲノムを有する組換えアデノウイルス、ならびに癌の治療におけるその使用を提供する。一局面では、アデノウイルスはデルタ-24である。別の局面では、癌は原発性または転移性の脳腫瘍である。
(図2)免疫原性腫瘍抗原を発現する新規アデノウイルスの構築。パネルA.免疫原性EGFRvIIIペプチド
がデルタ-24-ワクチンファイバータンパク質のH1ループ中にクローニングされている。パネルB.H1ループ中にペプチドをクローニングするのに使用される技術戦略が記載されている(Suzukiら、Clin. Cancer Res. 7:120-6(2001)。ファイバータンパク質遺伝子を含むプラスミドをPCR突然変異誘発を使用してペプチドを含むように(すなわち挿入するように)改変した後、デルタ-24突然変異を含むアデノウイルスの残りの配列を含むプラスミドと共に、細菌における相同組換えに供した。その後、最終生成物を、293細胞を用いて増幅させた。
(図3)免疫原性EGFRvIIIペプチドの発現。パネルAは、EGFRvIIIエピトープが、改変されたデルタ-24アデノウイルスの表面上に発現されることを実証するウェスタンブロットを示す。図2に従って構築された、EGFRvIIIエピトープを含むファイバータンパク質を発現しているデルタ-24アデノウイルス(D24-EGFRvIII)を、細胞溶解、タンパク質抽出、およびウェスタンブロット分析に供した。アデノウイルスファイバータンパク質またはEGFRvIIIペプチドに対する抗体を用いて、EGFRvIII抗原の高発現を確認する。アクチンをローディングコントロールとして使用した。パネルBは、ウイルスに対する抗体(ヘキソン)、EGFRvIIIペプチドに対する抗体(EGFRvIII)、および4',6-ジアミジノ-2-フェニルインドール(DAPI)を使用した、D24-EGFRvIIIに感染した癌細胞の免疫蛍光分析を示す。画像は、D24-EGFRvIIIに感染した細胞がEGFRvIIIペプチドを発現することを示す。DNA染色(DAPI)により、感染細胞のみがEGFRvIIIペプチドを発現することが確認される。アデノウイルスカプシドが核内で形成される。
(図4)D24-EGFRvIII-感染細胞の表面上におけるEGFRvIIIエピトープの提示の評価。HeLa細胞を50 pfu/細胞のm.o.i.で表示のアデノウイルスに感染させた。48時間後、マウスモノクローナル抗EGFRvIIII抗体L8A4で細胞を染色した。EGFRvIIIエピトープを表面上に有する細胞のパーセントをフローサイトメトリーで評価した。D24(EGFRvIIIエピトープを発現していないデルタ-24アデノウイルス)をウイルス感染の対照として使用した。マウスIgGを抗体についての陰性対照として使用した。
(図5)デルタ-24-RGDは抗腫瘍免疫応答を誘発する。GL261細胞をC57BL/6マウスに頭蓋内移植した。7日目および9日目にデルタ-24-RGDを腫瘍に注入した。最後のウイルス注射の7日後に、マウス脾細胞を単離し、GL261細胞と共培養した。リンパ球が分泌したIFN-γをELISAで測定した。
(図6)デルタ-24-RGD治療により、腫瘍部位にCD8+T細胞およびCD4+T細胞が動員された。GL261細胞をC57BL/6マウスに頭蓋内移植した。7日目および10日目にデルタ-24-RGDを腫瘍に注射した。最後のウイルス注射の7日後に、リンパ球を脳から単離し、フローサイトメトリーにより特徴決定した。
本発明の方法および組成物は、腫瘍関連抗原に対する免疫応答を引き起こし、抗腫瘍療法を向上させるアデノウイルスワクチンの構築および検証を含む。
ヒトに感染するが、幅広い宿主範囲を示す、アデノウイルス(Ad)は、大きい(約36 kbの)DNAウイルスである。物理的には、アデノウイルスは、二本鎖の直線状DNAゲノムを含む20面体ウイルスである。ヒトアデノウイルスにはおよそ50個の血清型があり、分子学的、免疫学的、および機能的基準に基づいて6つのファミリーに分類される。成人期には、実質的に全てのヒトが、より一般的なアデノウイルス血清型に感染したことがあり、主な作用は風邪のような症状である。
本発明の特定の態様では、本明細書に記載する方法は、TAAをコードする核酸配列を含み、ここで、該核酸は「発現カセット」に含まれている。「発現カセット」という用語は、核酸コード配列の一部または全てが転写可能である、遺伝子生成物(例えば、抗原決定基)をコードする核酸を含む任意の種類の遺伝子構築物を含むことを意味する。
本発明は、遺伝学的な抗癌免疫法の開発、および腫瘍の溶解に有用である。抗癌ワクチン接種戦略の開発は、癌細胞の特異的マーカーとして免疫系に認識され得、それによりこれらの細胞が標的として同定される腫瘍関連抗原(TAA)が近年同定されたことによって理論づけされている。これらの腫瘍関連抗原には、腫瘍細胞に固有の突然変異または再編成を有する遺伝子によってコードされるタンパク質、再活性化される胚性遺伝子、組織特異的分化抗原、および多数の他の自己タンパク質が含まれる。しかし、これらの標的が同定されたにも関わらず、これらの弱い自己由来抗原に対する良好なワクチン接種の手段を欠いていたために、有効な抗癌ワクチン接種戦略の開発が大幅に限定されてきた。従って、強力な抗腫瘍関連抗原免疫応答の生成は、効率的な抗癌免疫戦略の開発において鍵となる課題であると認識されている。
、チロシナーゼ(Tyr)、ミッドカイン(MK)、BAGE、CASP-8、β-カテニン、CA-125、CDK-1、ESO-1、gp75、gp100、MART-1、ムチン(MUC-1)、MUM-1、p53、PAP、PSA、PSMA、ras、trp-1、HER-2、TRP-2、IL13Rα、AIM-3、NY-ESOl、C9orf112、SART1、BRAP、RTN4、GLEA2、TNKS2、KIAA0376、ING4、HSPH1、C13orf24、RBPSUH、C6orf153、NKTR、NSEP1、U2AF1L、CYNL2、TPR、SOX2、またはGOLGAのペプチドが含まれるがこれらに限定されない。本発明は、上に列挙したTAAをコードする遺伝子には決して限定されない。他のTAAは当業者に公知であり、米国特許第4,514,506号に開示されているものなどの公知の方法により簡単に調製され得る。
本発明は、本発明の任意の組成物および薬学的に許容される担体を含む、医薬組成物も提供する。本発明は、本発明の任意の組成物を含むワクチン組成物も提供する。ワクチン組成物は、少なくとも1つのアジュバントをさらに含み得る。
Claims (25)
- 腫瘍抗原をコードする1種以上の異種核酸配列を含むゲノムを有する組換えアデノウイルスであって、該腫瘍抗原を自身の表面上に発現する、組換えアデノウイルス。
- MAGE-1、MAGE-2、MAGE-3、CEA、チロシナーゼ、ミッドカイン、BAGE、CASP-8、β-カテニン、CA-125、CDK-1、ESO-1、gp75、gplOO、MART-1、MUC-1、MUM-1、p53、PAP、PSA、PSMA、ras、trp-1、HER-2、TRP-1、TRP-2、IL13Rα、IL13Rα2、AIM-2、AIM-3、NY-ESO-1、C9orf112、SART1、SART2、SART3、BRAP、RTN4、GLEA2、TNKS2、KIAA0376、ING4、HSPH1、C13orf24、RBPSUH、C6orf153、NKTR、NSEP1、U2AF1L、CYNL2、TPR、SOX2、GOLGA、BMI1、COX-2、EGFRvIII、EZH2、LICAM、Livin、Livinβ、MRP-3、ネスチン、OLIG2、ART1、ART4、B-サイクリン、Gli1、Cav-1、カテプシンB、CD74、E-カドヘリン、EphA2/Eck、Fra-1/Fosl 1、GAGE-1、ガングリオシド/GD2、GnT-V,β1,6-Ν、Ki67、Ku70/80、PROX1、PSCA、SOX10、SOX11、サバイビン、UPAR、およびWT-1、またはそれらの免疫原性ペプチドからなる群より選択される腫瘍抗原をそれぞれがコードする1〜5種の異種核酸配列を含む組換えアデノウイルスであって、1〜5種の腫瘍抗原を自身の表面上に発現する、請求項1に記載の組換えアデノウイルス。
- CEAまたはその免疫原性ペプチドをコードする異種核酸を含む組換えアデノウイルスであって、CEAまたはその免疫原性ペプチドを含むキメラ表面タンパク質を発現する、請求項1または2に記載の組換えアデノウイルス。
- CEAの免疫原性ペプチドがSEQ ID NO:1である、請求項3に記載の組換えアデノウイルス。
- 異種核酸が、アデノウイルスのヘキソン遺伝子の超可変領域5に挿入されている、請求項3または4に記載の組換えアデノウイルス。
- EGFRvIIIまたはその免疫原性ペプチドをコードする異種核酸を含む組換えアデノウイルスであって、EGFRvIIIまたはその免疫原性ペプチドを含むキメラ表面タンパク質を発現する、請求項1または2に記載の組換えアデノウイルス。
- EGFRvIIIの免疫原性ペプチドがSEQ ID NO:2〜6からなる群より選択される、請求項6に記載の組換えアデノウイルス。
- 異種核酸が、アデノウイルスファイバー遺伝子のH1ループ領域に挿入されている、請求項6または7に記載の組換えアデノウイルス。
- それぞれが腫瘍抗原をコードする2〜5種の異種核酸配列を含むゲノムを有する組換えアデノウイルスであって、該腫瘍抗原を自身の表面上に発現する、前記請求項のいずれか一項に記載の組換えアデノウイルス。
- MAGEまたはその免疫原性ペプチドをコードする異種核酸を含む、前記請求項のいずれか一項に記載の組換えアデノウイルス。
- E3遺伝子領域の一部または全体に欠失を含む、請求項10に記載の組換えアデノウイルス。
- 異種核酸がアデノウイルスのE3欠失遺伝子領域に挿入されている組換えアデノウイルスであって、MAGEまたはその免疫原性ペプチドを自身の表面上に発現する、請求項11に記載の組換えアデノウイルス。
- NY-ESO-1またはその免疫原性ペプチドをコードする異種核酸を含む組換えアデノウイルスであって、NY-ESO-1またはその免疫原性ペプチドを含むキメラ表面タンパク質を発現する、前記請求項のいずれか一項に記載の組換えアデノウイルス。
- NY-ESO-1の免疫原性ペプチドがSEQ ID NO:7である、請求項13に記載の組換えアデノウイルス。
- 異種核酸が、アデノウイルスのヘキソン遺伝子の超可変領域5に挿入されている、請求項13または14に記載の組換えアデノウイルス。
- E3遺伝子領域の一部または全体に欠失を有し、かつ
a. アデノウイルスのヘキソン遺伝子の超可変領域5に挿入されている、CEAまたはその免疫原性ペプチドをコードする異種核酸;
b. アデノウイルスのファイバー遺伝子のH1ループ領域に挿入されている、EGFRvIIIまたはその免疫原性ペプチドをコードする異種核酸;
c. アデノウイルスのE3欠失遺伝子領域に挿入されている、MAGEまたはその免疫原性ペプチドをコードする異種核酸;および
d. アデノウイルスのヘキソン遺伝子の超可変領域5に挿入されている、NY-ESO-1またはその免疫原性ペプチドをコードする異種核酸
を含むゲノムを有する、請求項1に記載の組換えアデノウイルス。 - ヒトアデノウイルス5型、またはヒトアデノウイルス5型構成要素を含むハイブリッドである、前記請求項のいずれか一項に記載のアデノウイルス。
- デルタ-24、またはデルタ-24-RGDである、請求項17に記載のアデノウイルス。
- ICOVIR-5、ICOVIR-7、ONYX-015、ColoAd1、H101、およびAD5/3-D24-GMCSFから選択される、請求項1〜16のいずれか一項に記載のアデノウイルス。
- 請求項1〜19のいずれか一項に記載の組換えアデノウイルスを患者に投与する工程を含む、それを必要とする患者において癌を治療するための方法。
- 患者が、原発性または転移性脳癌、黒色腫、腺癌、胸腺腫(thyoma)、リンパ腫、肉腫、肺癌、肝癌、結腸癌、非ホジキンリンパ腫、ホジキンリンパ腫、白血病、子宮癌、乳癌、前立腺癌、卵巣癌、子宮頸癌、膀胱癌、腎癌、および膵臓癌から選択される癌を有する、請求項20に記載の方法。
- 患者が低レベルまたは高レベルの神経膠腫を有する、請求項21に記載の方法。
- アデノウイルスが、腫瘍内に、血管内に、または神経幹細胞担体もしくは間葉系幹細胞担体に入れて投与される、請求項20〜22のいずれか一項に記載の方法。
- アデノウイルスが、108〜1013プラーク形成単位(pfu)の用量で単回または複数回投与される、請求項20〜23のいずれか一項に記載の方法。
- 患者がヒトである、請求項20〜24のいずれか一項に記載の方法。
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EP2809788A2 (en) | 2014-12-10 |
JP2018138033A (ja) | 2018-09-06 |
US20140377294A1 (en) | 2014-12-25 |
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HK1205182A1 (en) | 2015-12-11 |
CN110042086A (zh) | 2019-07-23 |
EP2809788B1 (en) | 2019-09-04 |
ES2759785T3 (es) | 2020-05-12 |
US11155599B2 (en) | 2021-10-26 |
CA2863523A1 (en) | 2013-08-08 |
AU2013214776B2 (en) | 2017-11-09 |
ZA201405755B (en) | 2020-05-27 |
CN104271748B9 (zh) | 2019-05-24 |
BR112014019049A2 (pt) | 2017-07-04 |
AU2013214776A1 (en) | 2014-08-21 |
NZ628213A (en) | 2016-10-28 |
KR102100092B1 (ko) | 2020-04-13 |
CN104271748A (zh) | 2015-01-07 |
KR20140125834A (ko) | 2014-10-29 |
CN104271748B (zh) | 2019-03-29 |
DK2809788T3 (da) | 2019-12-09 |
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