JP6982362B2 - オリゴ核酸変異体ライブラリーとその合成 - Google Patents
オリゴ核酸変異体ライブラリーとその合成 Download PDFInfo
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Description
本出願は、2015年9月18日に出願された米国仮出願62/220,879号、2015年12月4日に出願された米国仮出願62/263,548号、および、2016年6月23日に出願された米国仮出願62/354,034号の利益を主張し、当該文献はすべて参照により本明細書に組み込まれる。
本出願は、ASCIIフォーマットで電子的に提出され、参照によって本明細書に組み込まれる配列表を含んでいる。2016年9月12日に作成された上記のASCIIコピーは、44854_718_601_SL.txtと命名され、7,841バイトのサイズである。
本明細書で言及されるすべての出版物、特許、および特許出願は、あたかも個々の出版物、特許、または特許出願が参照により組み込まれるように具体的かつ個々に指示される程度に、参照により本明細書に組み込まれる。
幾つかの事例では、合成された変異体ライブラリーが生成され、これは、発現構築物の一部をコードする。発現構築物の典型的な部分は、プロモーター、オープンリーディングフレーム、および終端領域を含む。幾つかの事例では、発現構築物は、1、2、3またはそれ以上の発現カセットをコードする。オリゴヌクレオチドライブラリーが生成され、これは、図11に示されるように、発現構築物カセットの部分を構成する、生成するかもしれない、単一の部位または複数の部位の別々の領域でコドン変異をコードする。2つの構築物を発現するカセットを生成するために、変異体オリゴ核酸は合成され、これは、第1のプロモーター(1110)、第1のオープンリーディングフレーム(1120)、第1のターミネーター(1130)、第2のプロモーター(1140)、第2のオープンリーディングフレーム(1150)、または第2のターミネーター配列(1160)の変異体配列の少なくとも一部をコードする。増幅のラウンド後に、前の例において記載されるように、1,024の発現構築物のライブラリーが生成された。
図11は一例の配置を提供する。幾つかの事例では、非翻訳制御領域(UTR)またはエンハンサー領域などの、追加の制御配列(regulator sequences)も、本明細書で言及される発現カセットに含まれる。発現カセットは、本明細書に記載される方法によって変異体配列が生成される1、2、3、4、5、6、7、8、9、10またはそれ以上の構成要素を含んでもよい。幾つかの事例では、発現構築物は、マルチシストロン性(multicistronic)ベクターに1つを超える遺伝子を含む。一例では、合成されたDNAのオリゴ核酸は、ウイルスベクター(例えばレンチウイルス)へと挿入され、その後、細胞への形質導入のためにパッケージ化されるか、または細胞への移動のために非ウイルスベクターへと挿入され、その後、スクリーニングおよび分析される。
本明細書には、革新的な合成プラットフォームを作るために、シリコン上のナノウェル内のオリゴ核酸合成から遺伝子アセンブリへの末端間プロセスの小型化、並列化、および垂直的統合を利用するプラットフォームアプローチが提供される。本明細書に記載される装置は、96ウェルのプレートと同じフットプリントを提供し、シリコン合成プラットフォームは、従来の合成方法と比較して、1,000倍まで又はそれ以上スループットを増加させることができ、単一の高度に並列されたラン(run)で、およそ1,000,000まで又はそれ以上のオリゴ核酸、または10,000またはそれ以上の遺伝子を産生することができる。
本明細書には、複数のクラスターを含む基質が提供され、ここでクラスターはそれぞれ、オリゴ核酸の付着および合成を支持する複数の遺伝子座を含む。本明細書で使用されるような用語「遺伝子座」は、表面から伸長する単一の予め決められた配列をコードするオリゴヌクレオチドに対する支持をする構造上の離散的領域を指す。幾つかの事例では、遺伝子座は、二次元表面、例えば、実質的に平らな表面上にある。幾つかの事例では、遺伝子座は、表面上の離散的な隆起した又は沈降した部位、例えば、ウェル、マイクロウェル、チャネル、またはポストを指す。幾つかの事例では、遺伝子座の表面は、オリゴ核酸合成のための少なくとも1つのヌクレオチド、または好ましくは、オリゴ核酸の集団の合成のための同一のヌクレオチドの集団に付着するために活発に官能基化される物質を含む。幾つかの事例では、オリゴ核酸は、同じ核酸配列をコードするするオリゴ核酸の集団を指す。幾つかの事例では、装置の表面は、基質の1つまたは複数の表面を包含する。
本明細書に提供される基質、装置およびリアクターは、本明細書に記載される方法および組成物に適したあらゆる様々な物質から作り上げられる。特定の事例では、低レベルのヌクレオチド結合を示すために、装置用の材料が作り上げられる。幾つかの事例では、装置用の材料は、高レベルのヌクレオチド結合を示す別々の表面を生成するために修正される。幾つかの事例では、装置用の材料は、可視光及び/又はUV光に対して透過性である。幾つかの事例では、装置用の材料は、十分に導電性である、例えば、基質のすべて又は一部にわたって均一な電場を形成することができる。幾つかの事例では、導電性材料は電気接地(electric ground)に接続される。幾つかの事例では、装置は、熱伝導性であるか又は断熱される。幾つかの事例では、材料は、化学的または生化学的な反応、例えばオリゴ核酸合成反応プロセスを支持するために耐薬品性および耐熱性である。幾つかの事例では、装置は可撓性材料を含む。可撓性材料は、限定することなく、改質ナイロン、非改質ナイロン、ニトロセルロース、ポリプロピレンなどを含む。幾つかの事例では、装置は剛性材料を含む。剛性材料は、限定することなく、ガラス、石英ガラス(fuse silica)、シリコン、二酸化ケイ素、窒化ケイ素、プラスチック(例えば、ポリテトラフルオロエチレン、ポリプロピレン、ポリスチレン、ポリカーボネート、および混合物など)、および金属(例えば、金、白金など)を含む。幾つかの事例では、装置は、シリコン、ポリスチレン、アガロース、デキストラン、セルロース系ポリマー、ポリアクリルアミド、ポリジメチルシロキサン(PDMS)、ガラス、またはそれらの任意の組み合わせを含む材料から作り上げられる。幾つかの事例では、装置は、本明細書にリストされた材料または当該技術分野において既知の他の適切な材料の組み合わせで製造される。
本明細書には、隆起した及び/又は沈降した特徴を含む装置が提供される。そのような特徴を有している1つの利点は、オリゴ核酸合成を支持する表面積の増大である。幾つかの事例では、隆起した及び/又は沈降した特徴を有する装置は、三次元基質と呼ばれる。幾つかの事例では、三次元装置は1つ以上のチャネルを含む。幾つかの事例では、1つ以上の遺伝子座はチャネルを含む。幾つかの事例では、チャネルは、オリゴ核酸シンセサイザーなどの堆積装置によって試薬の堆積に利用可能である。幾つかの事例では、試薬及び/又は流体は、1つ以上のチャネルと流体連通してより大きなウェルに集まる。例えば、装置は、クラスターを有する複数の遺伝子座に対応する複数のチャネルを含み、複数のチャネルは、クラスターの1つのウェルと流体連通している。幾つかの方法では、オリゴ核酸のライブラリーは、クラスターの複数の遺伝子座において合成される。
様々な事例では、装置表面あるいは装置表面の選択された部位または領域の1つ以上の化学的及び/又は物理的な物性を変更する付加または削除のプロセスによって、表面の化学的及び/又は物理的な変更のために、表面改質が利用される。例えば、表面改質は、限定することなく、(1)表面の湿潤性を変更すること、(2)表面を官能基化すること、つまり、表面官能基を提供する、修飾する、または置換すること、(3)表面を脱官能基化すること、つまり、表面官能基を除去すること、(4)そうでなければ、例えば、エッチングによって、表面の化学組成を変更すること、(5)表面粗さを増大させるか又は低減すること、(6)表面上にコーティング、例えば、表面の湿潤性とは異なる湿潤性を示すコーティングを提供すること、及び/又は(7)表面上に粒子を堆積させることを含む。
オリゴ核酸合成のための本開示の方法は、ホスホラミダイトの化学作用を含むプロセスを含み得る。幾つかの事例では、オリゴ核酸合成は、塩基をホスホラミダイトと結合することを含む。オリゴ核酸合成は、結合条件下でホスホラミダイトの堆積によって塩基を結合することを含んでもよく、ここで同じ塩基が、随意に、1回を超えて、即ち、二重の結合でホスホラミダイトとともに堆積される。オリゴ核酸合成は、未反応の部位のキャッピングを含んでもよい。幾つかの事例では、キャッピングは随意である。オリゴ核酸合成はまた、酸化または酸化工程を含んでもよい。オリゴ核酸合成は、非ブロック化、脱トリチル化、および硫化を含んでもよい。幾つかの事例では、オリゴ核酸合成は、酸化または硫化のいずれかを含む。幾つかの事例では、オリゴ核酸合成反応中の1つ又は各々の工程間で、装置は、例えば、テトラゾールまたはアセトニトリルを使用して洗浄される。ホスホラミダイト合成方法における任意の1工程に対する時間枠は、約2分、1分、50秒、40秒、30秒、20秒および10秒未満であり得る。
幾つかの方法では、キャッピング工程は、酸化に続いて実行される。持続し得る酸化からの残留水が続く結合を阻害することができるため、第2のキャッピング工程は装置の乾燥を可能にする。酸化に続いて、装置および成長しているオリゴ核酸は、随意に洗浄される。幾つかの事例では、酸化の工程は、オリゴヌクレオチドホスホロチオエートを得る硫化工程に置き換えられ、ここでキャッピング工程は硫化後に実行され得る。限定されないが、3−(ジメチルアミノメチリデン)アミノ)−3H−1,2,4−ジチアゾール−3−チオン、DDTT、Beaucage試薬としても知られている3H−1,2−ベンゾジチオール−3−オン1,1−ジオキシド、およびN,N,N’N’テトラエチルチウラムジスルフィド(TETD)を含む、多くの試薬が、効率的な硫黄移動を行うことができる。
98C、30秒
98C、10秒;63C、10秒;72C、10秒;12のサイクルを繰り返す;
72C、2分。
Claims (15)
- タンパク質ライブラリーを生成するための方法であって、
前記方法は、
a)少なくとも500のあらかじめ決められた核酸配列を準備するステップであって、前記少なくとも500のあらかじめ決められた核酸配列が、単一の鋳型配列と比較して、複数のコドン位置の各位置について19の変異体をコードする、ステップと、
b)複数のオリゴヌクレオチドを合成するステップであって、前記複数のオリゴヌクレオチドが前記少なくとも500のあらかじめ決められた核酸配列で準備された配列をコードする、ステップと、
c)変異体核酸のライブラリーを形成するために、前記複数のオリゴヌクレオチドと、DNAポリメラーゼおよび単一の鋳型配列とを混合するステップであって、前記変異体核酸のライブラリーは、少なくとも500のあらかじめ決められた核酸配列の約99%をコードする、ステップと、
d)インビトロで前記変異体核酸のライブラリーを細胞へ移して、複数の変異体タンパク質を発現させるステップと、
を含む、方法。 - 前記変異体核酸のライブラリーが変異体遺伝子あるいはそのフラグメントのための配列をコードする、請求項1に記載の方法。
- 前記複数の変異体タンパク質の1つの変異体タンパク質が抗体、酵素、あるいはペプチドである、請求項1に記載の方法。
- 前記少なくとも500のあらかじめ決められた核酸配列は、複数のコドン位置の各々についてコドン配列変異体の様々なあらかじめ決められた比率を含む、請求項1に記載の方法。
- 前記少なくとも500のあらかじめ決められた核酸配列は、少なくとも5つのコドン位置についてコドン配列変異体の様々なあらかじめ決められた比率を含む、請求項1に記載の方法。
- 前記変異体核酸のライブラリーが、単一の鋳型配列と比較して、少なくとも2つの隣接したコドン位置において変異体コドン配列をコードする核酸を含む、請求項1に記載の方法。
- 前記変異体核酸のライブラリーが、単一の鋳型配列と比較して、少なくとも2つの隣接していないコドン位置において変異体コドン配列をコードする核酸を含む、請求項1に記載の方法。
- 前記抗体は抗体フラグメントであり、前記抗体フラグメントは、Fab、Fab’、F(ab’)2、Fv、二重特異性抗体、線状抗体、単鎖抗体、または多重特異性抗体から選択される、請求項3に記載の方法。
- 前記抗体は抗体領域であり、前記抗体領域は、Fc領域、Fab領域、Fab領域の可変領域、Fab領域の定常領域、重鎖の可変ドメイン、軽鎖の可変ドメイン、可変重鎖の特異的な相補性決定領域(CDR)、または可変軽鎖の特異的なCDRから選択される、請求項3に記載の方法。
- 少なくとも5,000のあらかじめ決められた核酸配列が準備される、請求項1に記載の方法。
- 少なくとも100,000のあらかじめ決められた核酸配列が準備される、請求項1に記載の方法。
- 前記少なくとも500のあらかじめ決められた核酸配列の各々は、少なくとも20塩基の長さを含む、請求項1に記載の方法。
- 前記少なくとも500のあらかじめ決められた核酸配列の各々は、少なくとも100塩基の長さを含む、請求項1に記載の方法。
- 前記少なくとも500のあらかじめ決められた核酸配列の各々は、単一の鋳型配列と比較して、複数のコドン位置についてコドン配列変異体のあらかじめ決められた比率を含む、請求項1に記載の方法。
- 前記変異体核酸のライブラリーは、増幅後に、少なくとも500のあらかじめ決められた核酸配列の約99%をコードする請求項1に記載の方法。
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US20240158955A1 (en) | 2024-05-16 |
WO2017049231A1 (en) | 2017-03-23 |
GB201804999D0 (en) | 2018-05-09 |
IL258164B (en) | 2022-09-01 |
US10844373B2 (en) | 2020-11-24 |
JP2018532705A (ja) | 2018-11-08 |
CN108368482A (zh) | 2018-08-03 |
GB2557529A (en) | 2018-06-20 |
EP3350314A1 (en) | 2018-07-25 |
US20170081660A1 (en) | 2017-03-23 |
AU2022279404A1 (en) | 2023-03-02 |
EP3350314A4 (en) | 2019-02-06 |
HK1258869A1 (zh) | 2019-11-22 |
CA2998169A1 (en) | 2017-03-23 |
AU2016324296A1 (en) | 2018-04-12 |
US20210040476A1 (en) | 2021-02-11 |
IL258164A (en) | 2018-05-31 |
EA201890763A1 (ru) | 2018-08-31 |
KR20180050411A (ko) | 2018-05-14 |
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