JP6712254B2 - 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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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 (16)
- 受容非ヒト生殖細胞、非ヒト受精卵母細胞又は非ヒト胚への人工免疫グロブリン(Immunoglobulin:Ig)遺伝子座の標的化組み込みのための方法であって、受容非ヒト生殖細胞、非ヒト受精卵母細胞又は非ヒト胚の中に、内在性Ig遺伝子座を標的とする部位特異的メガヌクレアーゼと、人工Ig遺伝子座を含むトランスジェニックベクターとを導入し、これにより前記人工Ig遺伝子座が、受容非ヒト生殖細胞、非ヒト受精卵母細胞又は非ヒト胚のゲノム内に標的化組み込みにより組み込まれ、相同組換により前記内在性Ig遺伝子座又はその一部を置換することを含むと共に、前記メガヌクレアーゼが、二本鎖DNA開裂を介した相同組換の頻度を増加させる、方法。
- 前記メガヌクレアーゼが調節可能な発現コンストラクトにより供される、請求項1に記載の方法。
- 前記メガヌクレアーゼが誘導プロモーターに作動式に連結されてなる、請求項2に記載の方法。
- 人工Ig遺伝子座が標的化部位に組み込まれると共に、調節可能なメガヌクレアーゼ発現コンストラクトがゲノム内に組み込まれた細胞を選択することを更に含む、請求項1〜3の何れか一項に記載の方法。
- 選択された細胞を、分化全能性且つ機能的な新生仔を形成する能力を有する、除核した核移植ユニット細胞と融合させ、形成された細胞を得ることを更に含む、請求項4に記載の方法。
- 前記除核した核移植ユニット細胞が卵母細胞又は胚性幹細胞、請求項4又は5に記載の方法。
- i)選択された細胞を分化中の非ヒト胚に注入し、又は、
ii)得られた細胞を適切な培地で培養し、得られた細胞をトランスジェニック非ヒト動物を産生するために同期させた受容者内に移す
ことを更に含む、請求項4〜6の何れか一項に記載の方法。 - 前記人工Ig遺伝子座が、ヒト及び非ヒトのIg遺伝子座の断片を含む、請求項1〜7の何れか一項に記載の方法。
- 前記人工Ig遺伝子座が、少なくとも1つのヒトV遺伝子セグメントを含む、請求項1〜8の何れか一項に記載の方法。
- 前記人工Ig遺伝子座が複数の免疫グロブリン遺伝子セグメントを含み、ここで前記遺伝子セグメントが、少なくとも1つのV領域遺伝子セグメント、1又は2以上のJ遺伝子セグメント、1又は2以上のD遺伝子セグメント、及び、1又は2以上の定常領域遺伝子を含む、請求項1〜9の何れか一項に記載の方法。
- 前記メガヌクレアーゼ標的配列が、J遺伝子セグメント及び定常領域遺伝子セグメントから選択される遺伝子セグメントの内部又は近傍に存在する、請求項1〜10の何れか一項に記載の方法。
- 前記方法が第二のメガヌクレアーゼの使用を更に含むと共に、前記第二のメガヌクレアーゼが、前記内在性Ig遺伝子座の内部又は近傍に存在する第二のメガヌクレアーゼ標的配列を認識し、前記第一のメガヌクレアーゼと共に、但し前記第一のメガヌクレアーゼの切断部位とは異なる部位で、前記内在性Ig遺伝子座を選択的に切断し、それにより少なくとも1つの内在性Ig遺伝子座を不活性化する、請求項1〜11の何れか一項に記載の方法。
- 請求項9に記載の方法により得られうるトランスジェニック非ヒト動物であって、
i)少なくとも1つの調節可能なゲノム内メガヌクレアーゼ発現コンストラクト;及び、
ii)内在性Ig遺伝子座を置換した人工Ig遺伝子座を含み、
ここで前記動物は、ヒトイディオタイプを有する抗体を産生する能力を有する、トランスジェニック動物。 - 前記動物が、鳥、齧歯動物、及びイタチから選択される、請求項13に記載のトランスジェニック動物。
- 前記動物がラットである、請求項14に記載のトランスジェニック動物。
- インビトロでの標的化組み込みにおけるトランスジェニックベクターの使用であって、前記トランスジェニックベクターが、内在性Ig遺伝子座を標的する部位特異的メガヌクレアーゼをコードする核酸と、当該核酸に作動式に連結された誘導発現調節領域とを含み、ここで当該使用が、前記トランスジェニックベクターを受容非ヒト生殖細胞、非ヒト受精卵母細胞、又は非ヒト胚に導入し、これにより前記トランスジェニックベクターが前記生殖細胞、受精卵母細胞、又は胚のゲノムに組み込まれ、更に人工Ig遺伝子座を含むトランスジェニックベクターを前記受容非ヒト生殖細胞、非ヒト受精卵母細胞又は非ヒト胚内に導入し、これにより前記人工遺伝子座が標的化組み込みにより受容非ヒト生殖細胞のゲノム、受精卵母細胞又は胚内に組み込まれる、使用。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US12016313B2 (en) | 2017-01-19 | 2024-06-25 | Omniab Operations, Inc. | Human antibodies from transgenic rodents with multiple heavy chain immunoglobulin loci |
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