JP2018007669A - Dna発現構築物 - Google Patents
Dna発現構築物 Download PDFInfo
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- JP2018007669A JP2018007669A JP2017134493A JP2017134493A JP2018007669A JP 2018007669 A JP2018007669 A JP 2018007669A JP 2017134493 A JP2017134493 A JP 2017134493A JP 2017134493 A JP2017134493 A JP 2017134493A JP 2018007669 A JP2018007669 A JP 2018007669A
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Abstract
【解決手段】プロモーター配列、コード配列及び終結シグナルを含む線状の開鎖されたDNA二本鎖であり、少なくとも1つのL−DNAヌクレオチドを含む、遺伝子発現のためのDNA構築物。更には、ヒト、動物又は真核生物細胞の安定な又は一過性のトランスフェクションのための、及び遺伝子治療又はDNAワクチン接種のための上記DNA構築物の使用。
【選択図】図1
Description
本開示のさらなる目的は、感染症または寄生虫に対する予防的または治療的ワクチン接種のための上記DNA構築物の使用である。
本開示は、開示された実施形態に限定されることなく例および図により以下にさらに例証される。
図1は、本開示によるDNA構築物(2L−M)の略図を示す。表1に示されているように、末端オリゴヌクレオチドはL−立体配座でのヌクレオチドを含み、これは、二本鎖構築物の末端の図1のグレーの四角により示されている。故に、DNA構築物全体が、エキソヌクレアーゼによる分解に対して保護される。図1に描かれた構築物は、分解に対して保護されるための一方または両方の末端におけるヘアピンループを有さずまたは必要としない。
本開示によるDNA構築物の製造は、EP 0 941 318のものと似ている。しかし、ヘアピンオリゴヌクレオチドは、表1に要約されたいわゆる「L−アダプター」に置き換えられる。両方のアダプターは、それぞれ、個々のキメラDNA分子、配列番号1および配列番号2(L−アダプター1)または配列番号3および配列番号4(L−アダプター2)から成った(表1)。アダプターは、40mM Tris−HCl、10mM MgC12、10mM DTT、0.5mM ATP(25℃でpH7.8)において、90℃から25℃に徐々に低下する温度で、40分間、0.28mg/mlで等モル濃度の表1による一本鎖DNA分子をハイブリダイゼーションして生成した。EP 0 941 318において合成された発現カセットに両方のアダプターをライゲーションした後、続いてT7ポリメラーゼによる線状D−DNAの除去、および生成物の最終HPLC精製を実施した。この構築物は「2L−M」と称される。
DNA構築物を細胞に導入するために、異なるトランスフェクション方法、例えばリポフェクションまたはエレクトロポレーションを使用することができる。リポフェクションは次のように行った:6×104CHO−K1細胞を3.8cm2組織培養マトリックスに播種し、24時間後にeGFP発現DNAの指示量を、Fugene HD(Roche社)と1:4を混合してトランスフェクトし、製造者により勧められたように処理した。トランスフェクション1日後、細胞をトリプシン処理により回収し、フローサイトメトリーにより蛍光について分析した(10.000イベントをカウント)。
エレクトロポレーションは次のように行った:2×106CHO−K1細胞を500μl増殖培地に再懸濁し、eGFP発現DNAの指示量プラス11μgサケ精子と混合し、1650μF、270 Vでパルスした。この後、細胞を9.5cm2組織培養マトリックスに播種し、培養した。トランスフェクション1日後、細胞をトリプシン処理により回収し、フローサイトメトリーにより蛍光について分析した(10,000イベントをカウント)。
HBsAgコード配列は、強力なウイルスPCMVプロモーターの制御下に置いた。HBsAgをコードするL−MIDGEベクターはODN CKm362〜365を用いて生成し(表1と比較されたい)、HBsAgをコードするMIDGEベクターはEP 0 941 318に従って生成した。Balb/cマウス(1群あたり6匹)を、3週間間隔で2回、10μg/25μl L−MIDGE−HBsAgベクター(8.14pmol)または10μg/25μl MIDGE−HBsAgベクター(8.179pmol)で皮内免疫した。2回目の免疫2週間後、血清を得、ならびにHBsAg被覆ELISAプレート(Dade Behring社;Enzygnost Anti−HBs II;カタログ番号OQNE17またはOQNE11)、二次抗体としてのラット抗マウスIgG1およびIgG2a(BD社;カタログ番号559626および553391)、標準としてのマウス抗HBsAg IgG2a(Affinity BioReagents社、カタログ番号MA1−19264)および標準としてのマウス抗HBsAg IgG1(Affinity BioReagents社、カタログ番号MA1−19263)を用いて、HBsAg特異的IgG1およびIgG2a抗体についてELISAを介して分析した。
Claims (15)
- プロモーター配列、コード配列および終結シグナルを含む線状の開鎖されたDNA二本鎖であり、少なくとも1つのL−DNAヌクレオチドを含む、遺伝子発現のためのDNA構築物。
- 少なくとも1つのL−DNAヌクレオチドが、5’および/または3’末端の最後の5つのヌクレオチド内に含まれる、請求項1に記載の構築物。
- DNA構築物の少なくとも1つの末端が一本鎖ループを含む、請求項1または2に記載の構築物。
- 部分的にまたは完全に二本鎖である、請求項1から3のいずれかに記載の構築物。
- 少なくとも1つのL−またはD−DNAヌクレオチドが、カルボキシル、アミン、アミド、アルジミン、ケタール、アセタール、エステル、エーテル、ジスルフィド、チオールおよびアルデヒド基からなる群から選択される官能基で修飾されている、請求項1から4のいずれかに記載の構築物。
- 修飾されたヌクレオチドが、ペプチド、タンパク質、炭水化物、抗体、合成分子、ポリマー、マイクロプロジェクタイル、金属粒子、ナノ粒子、脂質、または固相からなる群から選択される化合物に連結されている、請求項5に記載の構築物。
- プロモーターが、人間、動物または真核生物細胞において作動可能であるプロモーター配列からなる群から選択される、請求項1から6のいずれかに記載の構築物。
- タンパク質、ペプチド、抗体、ホルモン、サイトカインまたは他の生物学的活性物質をコードする、請求項1から7の少なくとも一項に記載の構築物。
- 生物学的活性物質が免疫調節物質である、請求項8に記載の構築物。
- 請求項1から9のいずれかに記載のDNA構築物を含む医薬組成物。
- 化学療法薬をさらに含む、請求項14に記載の医薬組成物。
- ヒト、動物または真核生物細胞の安定なまたは一過性のトランスフェクションのための、請求項1から9のいずれかに記載のDNA構築物、または請求項10もしくは11に記載の医薬組成物の使用。
- 生体外遺伝子治療またはDNAワクチン接種のための、請求項1から9のいずれかに記載のDNA構築物、または請求項10もしくは11に記載の医薬組成物の使用。
- 癌または自己免疫疾患の治療のための、請求項1から9のいずれかに記載のDNA構築物、または請求項10もしくは11に記載の医薬組成物の使用。
- 非コード免疫調節性DNA構築物と併用される、請求項1から9のいずれかに記載のDNA構築物、または請求項10もしくは11に記載の医薬組成物の使用。
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HK1188608A1 (en) | 2014-05-09 |
JP2014508512A (ja) | 2014-04-10 |
PT2655620E (pt) | 2015-10-26 |
IL227104A (en) | 2017-02-28 |
MX343699B (es) | 2016-11-16 |
WO2012085282A1 (en) | 2012-06-28 |
ES2549192T3 (es) | 2015-10-23 |
ZA201304998B (en) | 2014-03-26 |
KR20130107350A (ko) | 2013-10-01 |
AU2011347086A1 (en) | 2013-07-25 |
EP2655620A1 (en) | 2013-10-30 |
PL2655620T3 (pl) | 2016-01-29 |
DK2655620T3 (en) | 2015-11-09 |
RU2013132149A (ru) | 2015-01-27 |
US20130287814A1 (en) | 2013-10-31 |
CN103370413A (zh) | 2013-10-23 |
CA2822367A1 (en) | 2012-06-28 |
KR101517365B1 (ko) | 2015-05-06 |
MX2013007285A (es) | 2013-09-26 |
CN103370413B (zh) | 2016-06-01 |
RU2604186C2 (ru) | 2016-12-10 |
SG191327A1 (en) | 2013-07-31 |
EP2655620B1 (en) | 2015-08-12 |
AU2011347086B2 (en) | 2015-07-16 |
GB201021873D0 (en) | 2011-02-02 |
JP6377349B2 (ja) | 2018-08-22 |
BR112013015819A2 (pt) | 2018-05-29 |
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