JP2018046872A - Vlドメインを含む結合タンパク質を作製するマウス - Google Patents
Vlドメインを含む結合タンパク質を作製するマウス Download PDFInfo
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Abstract
【解決手段】遺伝子改変マウス、ならびにそれらを作製および使用するための方法が提供され、上記マウスは、全てのまたは実質的に全ての免疫グロブリン重鎖のV遺伝子セグメント、D遺伝子セグメント、およびJ遺伝子セグメントの、少なくとも1つの軽鎖V遺伝子セグメントおよび少なくとも1つの軽鎖J遺伝子セグメントによる置き換えを含む。重鎖定常領域に作動可能に連結した軽鎖可変ドメインを含む結合タンパク質を作製するマウスが提供される。重鎖定常領域と融合している、体細胞超変異している軽鎖可変ドメインを含めた免疫グロブリン軽鎖可変ドメインを含有する結合タンパク質が提供される。上記結合タンパク質を作製するための配列をコードする改変細胞、胚、およびマウスが提供される。
【選択図】図3
Description
例えば、本発明は、以下の項目を提供する:
(項目1)
マウスであって、重鎖定常領域の核酸配列と作動可能に連結した、再構成されていない軽鎖Vセグメントおよび再構成されていないJセグメントを該マウスの生殖系列に含む、マウス。
(項目2)
上記再構成されていない軽鎖Vセグメントが、ヒトκセグメント、ヒトλセグメント、およびこれらの組合せから選択される、項目1に記載のマウス。
(項目3)
上記重鎖定常領域の核酸配列が、CH1配列、ヒンジ配列、CH2配列、CH3配列、およびこれらの組合せからなる群から選択される、項目1に記載のマウス。
(項目4)
上記再構成されていない軽鎖Vセグメントおよび上記再構成されていないJセグメントにより、マウス内因性重鎖遺伝子座におけるマウス内因性重鎖Vセグメントおよびマウス内因性重鎖Jセグメントが置き換えられる、項目1に記載のマウス。
(項目5)
上記再構成されていない軽鎖Vセグメントにより、上記マウス内因性重鎖遺伝子座の、全てのまたは実質的に全ての機能的なマウス重鎖Vセグメントが置き換えられる、項目4に記載のマウス。
(項目6)
上記再構成されていないJセグメントが軽鎖Jセグメントを含み、該軽鎖Jセグメントにより、上記マウス内因性重鎖遺伝子座の、全てのまたは実質的に全ての機能的なマウス重鎖Jセグメントが置き換えられる、項目4に記載のマウス。
(項目7)
上記再構成されていない軽鎖Vセグメントと上記再構成されていない軽鎖Jセグメントとが作動可能に連結され、上記マウスが、上記再構成されていない軽鎖Vセグメントと上記再構成されていない軽鎖Jセグメントとの間で機能的なDセグメントを欠いている、項目6に記載のマウス。
(項目8)
上記再構成されていない軽鎖Vセグメントがヒトκセグメントであり、上記再構成されていない軽鎖Jセグメントがヒトκセグメントである、項目7に記載のマウス。
(項目9)
マウス定常領域遺伝子に作動可能に連結したヒトκ可変領域を含む再構成された免疫グロブリン遺伝子を上記マウスのゲノムに含むB細胞を含む、項目1に記載のマウス。
(項目10)
上記再構成された免疫グロブリン遺伝子が、マウス内因性免疫グロブリン重鎖遺伝子座に位置する、項目1に記載のマウス。
(項目11)
軽鎖定常遺伝子に作動可能に連結したヒト軽鎖Vセグメントおよびヒト軽鎖Jセグメントを上記マウスの生殖系列にさらに含む、項目1に記載のマウス。
(項目12)
上記軽鎖定常遺伝子が、マウス軽鎖定常遺伝子である、項目11に記載のマウス。
(項目13)
上記ヒト軽鎖Vセグメントが、ヒトκVセグメントである、項目12に記載のマウス。
(項目14)
上記マウス軽鎖定常遺伝子が、マウスκ軽鎖定常遺伝子である、項目13に記載のマウス。
(項目15)
マウスであって、免疫グロブリン重鎖定常領域と融合している第1のヒト軽鎖可変領域配列を含む第1のポリペプチドと、免疫グロブリン軽鎖定常領域と融合している第2のヒト軽鎖可変領域を含む第2のポリペプチドとを含む免疫グロブリンを該マウスの生殖系列から発現する、マウス。
(項目16)
上記第1のヒト軽鎖可変領域配列がヒトκ可変領域配列を含み、上記第2のヒト軽鎖可変領域がヒトκ可変領域およびヒトλ可変領域から選択される、項目15に記載のマウス。
(項目17)
上記免疫グロブリン重鎖定常領域が、ヒト重鎖定常領域およびマウス重鎖定常領域から選択される、項目16に記載のマウス。
(項目18)
上記免疫グロブリン軽鎖定常領域が、ヒト軽鎖定常領域およびマウス軽鎖定常領域から選択される、項目16に記載のマウス。
(項目19)
上記第1のポリペプチドを、機能的な内因性重鎖V遺伝子セグメントを欠く、改変されたマウス内因性免疫グロブリン重鎖遺伝子座から発現する、項目16に記載のマウス。
(項目20)
上記第2のポリペプチドを、機能的な内因性軽鎖V遺伝子セグメントを欠く、改変されたマウス内因性免疫グロブリン軽鎖遺伝子座から発現する、項目19に記載のマウス。
(項目21)
マウスであって、該マウスの生殖系列におけるマウス内因性免疫グロブリン重鎖遺伝子座で、全てのまたは実質的に全ての機能的なマウス内因性重鎖可変遺伝子セグメントの、少なくとも6つ以上の再構成されていない軽鎖V遺伝子セグメントおよび1または複数の再構成されていないJ遺伝子セグメントによる置き換えを含み、ここで該再構成されていない軽鎖V遺伝子セグメントと該J遺伝子セグメントとが作動可能に連結されており、ここで該マウスは重鎖V遺伝子セグメントに由来する免疫グロブリン重鎖を発現することが不可能であり、ここで該マウスは野生型マウスの脾性B細胞集団(B220+/IgM+)の少なくとも約75%のサイズである脾性B細胞集団(B220+/IgM+)を含む、マウス。
(項目22)
ヒト軽鎖可変ドメインを含む結合タンパク質を生成させるための、上記項目のいずれかに記載のマウスの使用。
(項目23)
抗体を生成させるための、項目1から21のいずれかに記載のマウスの使用。
(項目24)
上記抗体がヒト抗体である、項目23に記載の使用。
(項目25)
二重特異性抗体を生成させるための、項目1から21のいずれか一項に記載のマウスの使用。
(項目26)
項目1から21のいずれか一項に記載のマウスに由来する細胞または組織。
(項目27)
ES細胞、B細胞、およびハイブリドーマから選択される、項目26に記載の細胞。
免疫グロブリン遺伝子座のエレメントによりコードされる結合タンパク質であって、免疫グロブリン軽鎖可変ドメインと融合している免疫グロブリン重鎖定常領域を含む結合タンパク質が提供される。さらに、マウスにおける免疫グロブリン重鎖遺伝子座を、免疫グロブリン軽鎖遺伝子座によりコードされるエレメントを含有する結合タンパク質をコードするように遺伝子改変する複数の戦略が提供される。このような遺伝子改変マウスは、免疫グロブリン構造を有するが、従来の抗体を上回る多様性の増強を呈示する結合タンパク質の固有の集団を生成させるための供給源を表す。
多様な態様では、再構成されていない免疫グロブリン軽鎖V遺伝子セグメントおよび再構成されていない(例えば、軽鎖または重鎖)J遺伝子セグメントを含むマウスがまた、Jセグメントと組み換えて、再構成されたD/J配列を形成することが可能である、再構成されていないDH遺伝子セグメントであって、この再構成されたD/J配列を、次に、上記軽鎖Vセグメントと共に再構成して、(a)軽鎖Vセグメント、(b)DHセグメント、および(c)(例えば、軽鎖または重鎖)Jセグメントに由来する再構成された可変配列を形成することが可能であり、この場合、上記再構成された可変配列が、重鎖定常配列に作動可能に連結される(例えば、CH1、ヒンジ、CH2、CH3、およびこれらの組合せから選択される重鎖定常配列に作動可能に連結される、例えば、マウスまたはヒトのCH1、ヒンジ、CH2、およびCH3に作動可能に連結される)、再構成されていないDH遺伝子セグメントも含む。
本明細書で記載される結合タンパク質およびそれらをコードするヌクレオチド配列は、多重特異性結合タンパク質、例えば、二重特異性結合タンパク質を作製するのに用いることができる。この態様では、本質的にCH領域と融合している第1のVLドメインから本質的になる第1のポリペプチドが、CH領域と融合している第2のVLドメインから本質的になる第2のポリペプチドと会合することができる。上記第1のVLドメインと上記第2のVLドメインとが異なるエピトープに特異的に結合する場合は、その2つのVLドメインを用いて二重特異性結合分子を作製することができる。上記CH領域は、同じ場合もあり、異なる場合もある。一実施形態では、例えば、上記CH領域のうちの1つが、プロテインAに対する結合決定基を消失させるように改変され得る一方、他の重鎖定常領域は、そのように改変されない。この特定の配列は、例えば、ホモ二量体(例えば、上記第1のポリペプチドのホモ二量体または第2のポリペプチドのホモ二量体)の混合物からの二重特異性結合タンパク質の単離を単純化する。
軽鎖遺伝子セグメントの重鎖遺伝子座への導入
VELOCIGENE(登録商標)遺伝子操作法(例えば、米国特許第6,586,251号、およびValenzuela, D.M.、Murphy, A.J.、Frendewey, D.、Gale, N.W.、Economides, A.N.、Auerbach, W.、Poueymirou, W.T.、Adams, N.C.、Rojas, J.、Yasenchak, J.、Chernomorsky, R.、Boucher, M.、Elsasser, A.L.、Esau, L.、Zheng, J.、Griffiths, J.A.、Wang, X.、Su, H.、Xue, Y.、Dominguez, M.G.、Noguera, I.、Torres, R.、Macdonald, L.E.、Stewart, A.F.、DeChiara, T.M.、Yancopoulos, G.D.(2003年)、「High−throughput engineering of the mouse genome coupled with high−resolution expression analysis」、Nat Biotechnol、21巻、652〜659頁を参照されたい)を用いて、マウスゲノムの細菌人工染色体(BAC)ライブラリーを改変するための多様なターゲティング構築物を作製した。再構成されていないヒト生殖系列のκ軽鎖遺伝子配列の挿入(図2の上方)を確保するために、マウスBAC DNAを相同組換えにより改変して、VH遺伝子セグメント、DH遺伝子セグメント、およびJH遺伝子セグメントのターゲティングされた欠失を介してマウス内因性重鎖遺伝子座を不活化した。
内因性重鎖遺伝子座においてヒト軽鎖遺伝子セグメントを保有する、ターゲティングされたES細胞の同定
マウスES細胞を電気穿孔して、VL結合タンパク質(すなわち、マウス重鎖定常領域に作動可能に連結したヒトκ軽鎖遺伝子セグメント)を発現するキメラマウスを発生させるための、改変されたES細胞を作製するのに、前出の実施例において作製された、ターゲティングされたBAC DNAを用いた。再構成されていないヒトκ軽鎖遺伝子セグメントの挿入を含有するES細胞は、定量的PCRアッセイであるTAQMAN(登録商標)により同定した(LieおよびPetropoulos、1998年、Curr. Opin. Biotechnology、9巻:43〜48頁)。ヒトκ配列および関連する選択カセットを挿入し、マウス重鎖配列を消失させ、かつ、内因性重鎖遺伝子座に隣接するマウス配列を保持するために、特異的なプライマーセットおよびプローブをデザインした。
VL結合タンパク質を発現するマウスの発生および解析
上記で記載したターゲティングされたES細胞をドナーES細胞として用い、VELOCIMOUSE(登録商標)法により、8細胞期のマウス胚に導入した(例えば、米国特許第7,294,754号、およびPoueymirou, W.T.、Auerbach, W.、Frendewey, D.、Hickey, J.F.、Escaravage, J.M.、Esau, L.、Dore, A.T.、Stevens, S.、Adams, N.C.、Dominguez, M.G.、Gale, N.W.、Yancopoulos, G.D.、DeChiara, T.M.、Valenzuela, D.M.(2007年)、「F0 generation mice fully derived from gene−targeted embryonic stem cells allowing immediate phenotypic analyses」、Nat Biotechnol、25巻、91〜99頁を参照されたい)。上記マウス重鎖遺伝子座においてヒトκ遺伝子セグメントを個別に保有するVELOCIMICE(登録商標)(上記ドナーES細胞に完全に由来するF0世代のマウス)は、内因性重鎖遺伝子座における固有のヒトκ遺伝子セグメントの存在を検出した(Valenzuelaら、前出)対立遺伝子アッセイの変法(前出)を用いて遺伝子型決定することにより同定した。マウス仔を遺伝子型決定し、ハイブリッド重鎖遺伝子の遺伝子座についてヘテロ接合性であるマウス仔を、VL結合タンパク質の発現を特徴付けるために選択する。
mice)と比較して正常であると考えられた(データは示さない)。
VL結合タンパク質を発現するマウスの増殖
VL結合タンパク質の新規の生成を創出するために、再構成されていないヒトκ遺伝子セグメントを保有するマウスを、他の内因性重鎖対立遺伝子の欠失を含有する別のマウスに交配させることができる。このようにすれば、得られる後代は、実施例Iで記載したハイブリッド重鎖だけを発現する。交配は、当技術分野において認知される標準的な技法により実施するが、代替的には、企業、例えば、Jackson Laboratoryに実施させる。ハイブリッド重鎖遺伝子座を保有するマウス株を、固有のハイブリッド重鎖の存在および従来のマウス重鎖の非存在についてスクリーニングする。
VL結合タンパク質の生成
上記再構成されていないハイブリッド重鎖遺伝子座を含有するマウスを、他の内因性Ig遺伝子座の改変および欠失を含有する、所望される多様なマウス株に交配させた(実施例IVで記載した)後で、選択されたマウスを対象の抗原で免疫することができる。
Ana、CA)でブロッキングした。個別のプレートにおいて、抗抗原X VL結合タンパク質を含有する上清を、緩衝液中で1:10に希釈した。上記VL結合タンパク質のものと同じ成分を含む偽上清を、陰性対照として用いた。抗原Xの細胞外ドメイン(ECD)を、マウスIgG2aのFc部分とコンジュゲートした(抗原X−mFc)。抗原X−mFcを、0.150nMの最終濃度まで添加し、室温で1時間にわたりインキュベートした。次いで、VL結合タンパク質/抗原X−mFc混合物を、リガンドYを含有するプレートに添加し、室温で1時間にわたりインキュベートした。リガンドYに結合した抗原X−mFcの検出は、抗ペンタHis抗体(Qiagen、Valencia、CA)にコンジュゲートした西洋ワサビペルオキシダーゼ(HRP)により決定し、テトラメチルベンジジン(TMB)基質(BD Biosciences、San Jose、CA)を用い、硫酸により中和した標準的な比色反応により発色させた。吸光度は、OD450で0.1秒間にわたり読み取った。抗原Xを含まない試料のバックグラウンドの吸光度を、全ての試料から差し引いた。>250(3つの96ウェルプレート)の抗原X特異的VL結合タンパク質について、バックグラウンドを差し引いた各試料のMFIを、調整された陰性対照値で除し、100を乗じ、結果として得られる値を100から差し引くことにより、遮断の百分率を計算した。
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