JP2014027947A - 内在性免疫グロブリン遺伝子を阻害し、そして、トランスジェニック・ヒト・イディオタイプ抗体を製造するための組成物及び方法 - Google Patents
内在性免疫グロブリン遺伝子を阻害し、そして、トランスジェニック・ヒト・イディオタイプ抗体を製造するための組成物及び方法 Download PDFInfo
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Abstract
【解決手段】少なくとも1の不活性化された内在性Ig遺伝子座を持つ生育可能な生殖細胞の製造方法であって、生殖細胞、受精卵母細胞、若しくは胎仔において少なくとも1のメガヌクレアーゼを発現して、少なくとも1の不活性化された内在性Ig遺伝子座を持つ生育可能な生殖細胞を産生するステップを含んでなり、ここで、上記メガヌクレアーゼが、上記内在性Ig遺伝子座内又はその近位に存在しているメガヌクレアーゼ標的配列を認識する前記方法。
【選択図】図1
Description
当該出願は、2007年6月1日に出願された米国特許仮出願番号第60/941,619号、及び2008年4月11日に出願された米国特許仮出願番号第61/044,324号に対する優先権を主張する。前記文献の全体を本明細書中に援用する。
本発明は、1又は複数の不活性化された内在性免疫グロブリン遺伝子座を持つトランスジェニック動物、及びその製造方法に関する。本発明は、こうしたトランスジェニック動物を使用したヒト化及び完全なヒト抗体の製造のための組成物及び方法、並びにそうやって作り出された抗体にさらに関する。
Claims (34)
- 少なくとも1の不活性化された内在性Ig遺伝子座を持つ生育可能な生殖細胞の製造方法であって、生殖細胞、受精卵母細胞、若しくは胎仔において少なくとも1のメガヌクレアーゼを発現して、少なくとも1の不活性化された内在性Ig遺伝子座を持つ生育可能な生殖細胞を産生するステップを含んでなり、ここで、上記メガヌクレアーゼが、上記内在性Ig遺伝子座内又はその近位に存在しているメガヌクレアーゼ標的配列を認識する前記方法。
- 内在性Ig遺伝子座が不活性化された少なくとも1の生殖系列を含んでなるトランスジェニック動物の製造方法であって、請求項1に記載の方法に従って製造した少なくとも1の不活性化された内在性Ig遺伝子座を持つ生育可能な生殖細胞、又はその生殖細胞の子孫からトランスジェニック動物を誘導するステップを含んでなり、ここで、上記トランスジェニック動物が、鳥類、齧歯動物類、及びイタチ類から成る群から選択される前記方法。
- 前記の少なくとも1の不活性化された内在性Ig遺伝子座を持つ生育可能な生殖細胞が、人工Ig遺伝子座をさらに含んでなり、ここで、上記トランスジェニック動物が、人工Ig遺伝子座を含んでなる、請求項2に記載の方法。
- 前記の少なくとも1の不活性化された内在性Ig遺伝子座を持つ生育可能な生殖細胞、又はその生殖細胞の子孫、又はそこから誘導された受精卵母細胞若しくは胎仔に、人工Ig遺伝子座を導入するステップをさらに含んでなり、それにより、前記トランスジェニック動物が人工Ig遺伝子座を含んでなる、請求項2に記載の方法。
- 前記の少なくとも1の不活性化された内在性Ig遺伝子座を持つ生育可能な生殖細胞からトランスジェニック動物を誘導するステップが、前記の生育可能な生殖細胞又はその生殖細胞の子孫を、人工Ig遺伝子座を含んでなる配偶子と組み合わせるステップを含んでなり、それにより、前記トランスジェニック動物が人工Ig遺伝子座を含んでなる、請求項2に記載の方法。
- 前記人工Ig遺伝子座が(i)生殖系列をコードする少なくとも1のヒトV遺伝子セグメント、又は高頻度変異ヒトV領域アミノ酸配列を含んでなるV領域;(ii)1又は複数のJ遺伝子セグメント;及び(iii)1又は複数の定常領域遺伝子セグメントを含んでなり、ここで、上記人工Ig遺伝子座は、前記生殖細胞から得られたトランスジェニック動物において、機能的であり、且つ、遺伝子再配列を受けて、人工免疫グロブリンのレパートリーを産生する能力がある、請求項3〜5のいずれか1項に記載の方法。
- 前記配偶子が、少なくとも1の不活性化された内在性Ig遺伝子座を持つ、請求項5に記載の方法。
- 前記メガヌクレアーゼ標的配列が、前記の少なくとも1の内在性Ig遺伝子座の中のJ遺伝子セグメント内又はその近位に存在している、請求項1に記載の方法。
- 前記メガヌクレアーゼ標的配列が、免疫グロブリン定常領域遺伝子内又はその近位に存在している、請求項1に記載の方法。
- 前記の生殖細胞、受精卵母細胞、若しくは胎仔において第2のメガヌクレアーゼを発現するステップをさらに含んでなり、ここで、上記第2のメガヌクレアーゼは、前記内在性Ig遺伝子座内又はその近位に存在している第2のメガヌクレアーゼ標的配列を認識する、請求項1に記載の方法。
- 前記の生殖細胞、受精卵母細胞、若しくは胎仔が、前記メガヌクレアーゼをコードする核酸に作動できるように連結された誘導性発現制御部位を含んでなるゲノム・メガヌクレアーゼ発現構築物を含んでなり、且つ、前記メガヌクレアーゼが、上記ゲノム・メガヌクレアーゼ発現構築物の発現を誘導することによって前記の生殖細胞、受精卵母細胞、若しくは胎仔において発現される、請求項1に記載の方法。
- 前記ゲノム・メガヌクレアーゼ発現構築物の発現を誘導するステップを繰り返すステップを含んでなる、請求項11に記載の方法。
- 前記の生殖細胞、受精卵母細胞、若しくは胎仔が、第2のメガヌクレアーゼをコードする核酸に作動できるように連結された第2の誘導性発現制御部位を含んでなる第2のゲノム・メガヌクレアーゼ発現構築物を含んでなり、ここで、上記第2のコードされたメガヌクレアーゼは、前記内在性Ig遺伝子座内に存在している第2のメガヌクレアーゼ標的配列を認識し、ここで、上記方法が、前記の生殖細胞、受精卵母細胞、若しくは胎仔において前記第2のメガヌクレアーゼをコードする核酸の発現を誘導するステップをさらに含んでなる、請求項11に記載の方法。
- 請求項1に記載の方法によって製造した、少なくとも1の不活性化された内在性Ig遺伝子座を持つ生育可能な生殖細胞。
- 請求項2に記載の方法によって製造したトランスジェニック動物。
- 請求項3〜5のいずれか1項に記載の方法によって製造したトランスジェニック動物。
- 前記トランスジェニック動物が、機能的な内在性Ig軽鎖遺伝子座を欠いている、請求項15又は16に記載のトランスジェニック動物。
- 前記トランスジェニック動物が、機能的な内在性Ig重鎖遺伝子座を欠いている、請求項15又は16に記載のトランスジェニック動物。
- 前記トランスジェニック動物が、ヒト・イディオタイプを持つ免疫グロブリンを産生する能力がある、請求項16に記載のトランスジェニック動物。
- 前記トランスジェニック動物が、機能的なIg軽鎖遺伝子座を欠き、且つ、人工Ig重鎖遺伝子座を含んでなり、そして、前記トランスジェニック動物が、重鎖のみ抗体を産生する能力がある、請求項16に記載のトランスジェニック動物。
- 前記トランスジェニック動物が、機能的なCH1ドメインをコードする配列を欠いている少なくとも1のC領域遺伝子を持つ少なくとも1のIg重鎖遺伝子座を含んでなり、且つ、機能的なIg軽鎖遺伝子座を欠いている、請求項16に記載のトランスジェニック動物。
- ゲノム・メガヌクレアーゼ発現構築物を含んでなるトランスジェニック動物であって、ここで、上記構築物は、メガヌクレアーゼをコードする核酸に作動できるように連結された誘導性発現制御部位を含んでなり、そして、ここで、上記のコードされたメガヌクレアーゼは、上記トランスジェニック動物の内在性Ig遺伝子座内又はその近位に存在しているメガヌクレアーゼ標的配列を認識し、ここで、鳥類、齧歯動物類、及びイタチ類から成る群から選択される前記トランスジェニック動物。
- 前記トランスジェニック動物のゲノムが、少なくとも1の人工Ig遺伝子座をさらに含んでなる、請求項22に記載のトランスジェニック動物。
- 請求項16に記載のトランスジェニック動物を、免疫原によって免疫するステップを含んでなる、抗体の製造方法。
- 請求項24に記載の方法によって製造したポリクローナル抗血清組成物。
- 以下のステップ(i)請求項16に記載のトランスジェニック動物を免疫原で免疫し;(ii)上記トランスジェニック動物からモノクローナル抗体産生細胞を単離し、ここで、上記モノクローナル抗体産生細胞は、上記免疫原に特異的に結合するモノクローナル抗体を産生する;そして(iii)上記免疫原に特異的に結合する上記モノクローナル抗体を産生する上記モノクローナル抗体産生細胞を使用するか、又は上記モノクローナル抗体産生細胞を使用して、上記モノクローナル抗体を産生するハイブリドーマ細胞を作出し、そして、そのハイブリドーマ細胞を使用して、上記モノクローナル抗体を製造する、を含んでなるモノクローナル抗体の製造方法。
- 以下のステップ(i)請求項16に記載のトランスジェニック動物を免疫原で免疫し;(ii)上記トランスジェニック動物からモノクローナル抗体産生細胞を単離し、ここで、上記モノクローナル抗体産生細胞は、上記免疫原に特異的に結合するモノクローナル抗体を産生する;(iii)上記モノクローナル抗体産生細胞から、上記免疫原に特異的に結合する上記モノクローナル抗体をコードするモノクローナル抗体核酸を単離し;そして(iv)上記モノクローナル抗体核酸を使用して、上記免疫原に特異的に結合する上記モノクローナル抗体を製造する、を含んでなるモノクローナル抗体の製造方法。
- 前記モノクローナル抗体が、ヒト・イディオタイプを持つ、請求項26又は27に記載の方法。
- 完全なヒト・モノクローナル抗体の製造方法であって、以下のステップ(i)請求項16に記載のトランスジェニック動物を免疫原で免疫し;(ii)上記トランスジェニック動物からモノクローナル抗体産生細胞を単離し、ここで、上記モノクローナル抗体産生細胞は、上記免疫原に特異的に結合するモノクローナル抗体を産生する;(iii)上記モノクローナル抗体産生細胞から、上記免疫原に特異的に結合する上記モノクローナル抗体をコードするモノクローナル抗体核酸を単離し;(iv)上記モノクローナル抗体核酸を修飾して、完全なヒト・モノクローナル抗体をコードする組み換え核酸を製造し;そして(v)上記の完全なヒト・モノクローナル抗体をコードする組み換え核酸を使用して、コードされた完全なヒト・モノクローナル抗体を製造する、を含んでなる前記方法。
- 請求項26、27、又は29のいずれか1項に記載の方法によって製造したモノクローナル抗体。
- 人体成分の中での抗原性実体の中和方法であって、上記人体成分を、請求項25に記載のポリクローナル抗血清組成物と接触させるステップを含んでなり、ここで、上記ポリクローナル抗血清組成物が、上記抗原性実体に特異的に結合し、そして、中和する免疫グロブリン分子を含んでなる前記方法。
- 人体成分の中での抗原性実体の中和方法であって、上記人体成分を、請求項30に記載のモノクローナル抗体と接触させるステップを含んでなり、ここで、上記モノクローナル抗体が、上記抗原性実体に特異的に結合し、そして、中和する前記方法。
- 重鎖のみ抗体の製造方法であって、請求項20又は21に記載のトランスジェニック動物を免疫するステップを含んでなる前記方法。
- 請求項33に記載の方法によって製造した重鎖のみ抗体。
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