JP7078400B2 - 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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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。
Claims (16)
- 抗原結合タンパク質であって、
(i)第1の免疫グロブリン(Ig)重鎖定常領域(CH)と融合した第1のヒトIg軽鎖可変ドメイン(VL1)を含む、第1のポリペプチド;および
(ii)第1のIg軽鎖定常領域(CL)と融合した第2のヒトIg軽鎖可変ドメイン(VL2)を含む、第2のポリペプチド
を含む二量体を含み、(i)の該VL1と(ii)の該VL2がコグネイトでありかつ同一でなく、(i)の該第1のIg CHと(ii)の該第1のIg CLとが会合することにより、該二量体が、該VL1および該VL2を備えた第1のFabを含み、該第1のFabが対象の抗原に特異的に結合し、(i)の該第1のCHおよび(ii)の該第1のCLがそれぞれ、マウスCHおよびマウスCLであり;
ここで、該抗原結合タンパク質は、マウスから得られ、ここで、該マウスは、重鎖定常領域の核酸配列と作動可能に連結した、少なくとも1つの再構成されていないヒト軽鎖V L 遺伝子セグメントおよび少なくとも1つの再構成されていないヒト軽鎖J L 遺伝子セグメントを含むハイブリッド免疫グロブリン遺伝子座を該マウスの生殖系列に含み、
ここで、該少なくとも1つの再構成されていないヒトV L 遺伝子セグメントおよび該少なくとも1つの再構成されていないJ L 遺伝子セグメントのそれぞれが、該マウスがさらに、該ハイブリッド免疫グロブリン遺伝子座に由来する該免疫グロブリン重鎖定常領域の核酸配列と連結した、再構成されたヒト免疫グロブリン軽鎖可変領域(V L /J L )ヌクレオチド配列を含むように、該再構成されていないヒトV L 遺伝子セグメントと、該再構成されていないヒトJ L 遺伝子セグメントに組換えを生じさせる組換えシグナル配列を含み、そして、
ここで、該少なくとも1つの再構成されていないヒト軽鎖V L 遺伝子セグメントおよび前記少なくとも1つの再構成されていないヒト軽鎖J L 遺伝子セグメントにより、該マウス内因性重鎖遺伝子座において、内因性重鎖V H 遺伝子セグメント、全ての内因性重鎖D H 遺伝子セグメント、および、全ての内因性重鎖J H 遺伝子セグメントを含む連続する内因性配列が置き換えられる、抗原結合タンパク質。 - VL1とVL2が同一でない、請求項1に記載の抗原結合タンパク質。
- VL1とVL2がVκドメインおよびVλドメインから独立して選択される、請求項1に記載の抗原結合タンパク質。
- VL1がVκドメインである、請求項1に記載の抗原結合タンパク質。
- 前記CHが、CH1、ヒンジ、CH2、CH3、およびこれらの組合せから選択される、請求項1に記載の抗原結合タンパク質。
- 前記CHが、IgM、IgD、IgG、IgAおよびIgEからなる群より選択されるアイソタイプである、請求項1に記載の抗原結合タンパク質。
- 前記アイソタイプが、IgG1、IgG2A、IgG2b、IgG2C、IgG3、およびIgG4からなる群より選択されるIgGである、請求項6に記載の抗原結合タンパク質。
- 前記アイソタイプが、IgG1、IgG2およびIgG4から選択される、請求項7に記載の抗原結合タンパク質。
- 前記IgG CH3ドメインが、該IgG CH3のプロテインAへの結合を低減または消失させる修飾を含む、請求項8に記載の抗原結合タンパク質。
- VL1もVL2も、DH遺伝子セグメント由来のアミノ酸配列を含まない、請求項1に記載の抗原結合タンパク質。
- 前記VL1が、
(a)VL2に存在する体細胞超変異の数の約1.5~約5倍以上、または、それより多い数の体細胞超変異、および/または
(b)1、2、3、4、5、6、7、8、9、もしくは、10、または、それより多いN付加
を含む配列によってコードされる、請求項1に記載の抗原結合タンパク質。 - さらに、
(iii)第2のIg重鎖定常領域(CH)と融合した第3のIg軽鎖可変ドメイン(VL3)を含む、第3のポリペプチド;および
(iv)第2のIg軽鎖定常領域(CL)と融合した第4のIg軽鎖可変ドメイン(VL4)を含む、第4のポリペプチド
を含む第2の二量体を含み、(iii)の該VL3と(iv)の該VL4がコグネイトでありかつ同一でなく、(iii)の該第2のIg重鎖定常領域と(iv)の該第2のIg軽鎖定常領域とが会合することにより、該第2の二量体が、該VL3および該VL4を備えた第2のFabを含み、該第2のFabが対象の抗原に特異的に結合し、ここで(i)の該第1のCHおよび(ii)の該第1のCLがそれぞれ、マウスCHおよびマウスCLであり、そして、(iii)の該第2のCHおよび(iv)の該第2のCLもまたそれぞれ、マウスCHおよびマウスCLであり、該第1および該第2の二量体が、(Fab)2とFcを含む四量体抗原結合分子を形成し、該(Fab)2が該第1のFabと該第2のFabとを含む、請求項1に記載の抗原結合タンパク質。 - (a)VL1とVL3が同一である、および/または
(b)VL2とVL4が同一である、
請求項12に記載の抗原結合タンパク質。 - 二重特異性である、請求項12に記載の抗原結合タンパク質。
- 前記第1と第2の免疫グロブリン重鎖定常領域が同じアイソタイプであるが、他の免疫グロブリン重鎖と比較して、該第1または第2の免疫グロブリン重鎖定常領域の一方がプロテインAに結合できない点で異なり、該アイソタイプがIgG1、IgG2、IgG3またはIgG4である、請求項14に記載の抗原結合タンパク質。
- 前記CHがマウスCH1ドメインであり、前記CLがマウスCκドメインである、請求項1に記載の抗原結合タンパク質。
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Families Citing this family (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110123527A1 (en) * | 2008-05-23 | 2011-05-26 | Hiroaki Shizuya | Method of generating single vl domain antibodies in transgenic animals |
DK3622813T3 (da) | 2009-07-08 | 2021-05-03 | Kymab Ltd | Dyremodeller og terapeutiske molekyler |
US20120204278A1 (en) | 2009-07-08 | 2012-08-09 | Kymab Limited | Animal models and therapeutic molecules |
US9445581B2 (en) | 2012-03-28 | 2016-09-20 | Kymab Limited | Animal models and therapeutic molecules |
US9796788B2 (en) | 2010-02-08 | 2017-10-24 | Regeneron Pharmaceuticals, Inc. | Mice expressing a limited immunoglobulin light chain repertoire |
US10143186B2 (en) | 2010-02-08 | 2018-12-04 | Regeneron Pharmaceuticals, Inc. | Common light chain mouse |
US20130045492A1 (en) | 2010-02-08 | 2013-02-21 | Regeneron Pharmaceuticals, Inc. | Methods For Making Fully Human Bispecific Antibodies Using A Common Light Chain |
DK2597945T3 (da) | 2010-07-26 | 2020-09-21 | Trianni Inc | Transgene dyr og fremgangsmåder til anvendelse deraf |
US10793829B2 (en) | 2010-07-26 | 2020-10-06 | Trianni, Inc. | Transgenic mammals and methods of use thereof |
US10662256B2 (en) | 2010-07-26 | 2020-05-26 | Trianni, Inc. | Transgenic mammals and methods of use thereof |
NZ707327A (en) | 2010-08-02 | 2017-01-27 | Regeneron Pharma | Mice that make binding proteins comprising vl domains |
PT3572517T (pt) | 2011-08-05 | 2021-06-23 | Regeneron Pharma | Murganhos da cadeia leve universal humanizada |
ES2612935T3 (es) | 2011-09-19 | 2017-05-19 | Kymab Limited | Anticuerpos, dominios variables y cadenas adaptados para su uso en seres humanos |
WO2013041845A2 (en) | 2011-09-19 | 2013-03-28 | Kymab Limited | Animals, repertoires & methods |
EP2761008A1 (en) | 2011-09-26 | 2014-08-06 | Kymab Limited | Chimaeric surrogate light chains (slc) comprising human vpreb |
PL2627773T3 (pl) | 2011-10-17 | 2017-11-30 | Regeneron Pharmaceuticals, Inc. | Ograniczony łańcuch ciężki immonoglobuliny pochodzącej od myszy |
US9253965B2 (en) | 2012-03-28 | 2016-02-09 | Kymab Limited | Animal models and therapeutic molecules |
SI2793567T1 (sl) | 2011-12-20 | 2019-05-31 | Regeneron Pharmaceuticals, Inc. | Humanizirane lahkoverižne miši |
ES2753774T3 (es) * | 2012-02-01 | 2020-04-14 | Regeneron Pharma | Ratones humanizados que expresan cadenas pesadas que contienen dominios VL |
EP3121194A1 (en) | 2012-03-14 | 2017-01-25 | Innovative Targeting Solutions Inc. | Generating targeted sequence diversity in fusion proteins |
CA2867231C (en) * | 2012-03-14 | 2021-10-19 | Innovative Targeting Solutions Inc. | Generating targeted sequence diversity in proteins |
US10251377B2 (en) | 2012-03-28 | 2019-04-09 | Kymab Limited | Transgenic non-human vertebrate for the expression of class-switched, fully human, antibodies |
GB2502127A (en) | 2012-05-17 | 2013-11-20 | Kymab Ltd | Multivalent antibodies and in vivo methods for their production |
ME03551B (me) | 2012-06-12 | 2020-07-20 | Regeneron Pharma | Humanizovane nehumane živoтinje sa ograničenim lokusima imunoglobulinskog тeškog lanca |
WO2014022540A1 (en) | 2012-08-02 | 2014-02-06 | Regeneron Pharmaceuticals, Inc. | Multivalent antigen-binding proteins |
WO2014130690A1 (en) * | 2013-02-20 | 2014-08-28 | Regeneron Pharmaceuticals, Inc. | Non-human animals with modified immunoglobulin heavy chain sequences |
PL3501272T3 (pl) * | 2013-03-13 | 2023-07-03 | Regeneron Pharmaceuticals, Inc. | Mysz eksprymująca ograniczony repertuar lekkiego łańcucha immunoglobuliny |
MX2015011348A (es) | 2013-03-15 | 2016-01-15 | Regeneron Pharma | Moleculas biologicamente activas, conjugados de las mismas, y usos terapeuticos. |
US9788534B2 (en) | 2013-03-18 | 2017-10-17 | Kymab Limited | Animal models and therapeutic molecules |
US9783618B2 (en) | 2013-05-01 | 2017-10-10 | Kymab Limited | Manipulation of immunoglobulin gene diversity and multi-antibody therapeutics |
US11707056B2 (en) | 2013-05-02 | 2023-07-25 | Kymab Limited | Animals, repertoires and methods |
US9783593B2 (en) | 2013-05-02 | 2017-10-10 | Kymab Limited | Antibodies, variable domains and chains tailored for human use |
CN105530942B (zh) | 2013-08-26 | 2019-10-11 | 瑞泽恩制药公司 | 一种包含大环内酯类非对映体的药物组合物、其制备方法和用途 |
CA2925723A1 (en) | 2013-10-01 | 2015-04-09 | Kymab Limited | Animal models and therapeutic molecules |
FR3011249A1 (ja) * | 2013-10-01 | 2015-04-03 | Kymab Ltd | |
CN106255410B (zh) | 2014-03-21 | 2020-01-10 | 瑞泽恩制药公司 | 产生单结构域结合蛋白的非人动物 |
SG10201808083VA (en) | 2014-03-21 | 2018-10-30 | Regeneron Pharma | Vl antigen binding proteins exhibiting distinct binding characteristics |
CA2979702A1 (en) * | 2015-03-19 | 2016-09-22 | Regeneron Pharmaceuticals, Inc. | Non-human animals that select for light chain variable regions that bind antigen |
EP3273998B1 (en) | 2015-03-27 | 2019-09-04 | Regeneron Pharmaceuticals, Inc. | Maytansinoid derivatives, conjugates thereof, and methods of use |
UA126272C2 (uk) * | 2015-06-05 | 2022-09-14 | Дженентек, Інк. | Антитіло проти тау-білка та спосіб його застосування |
US10813346B2 (en) | 2015-12-03 | 2020-10-27 | Trianni, Inc. | Enhanced immunoglobulin diversity |
CN114478801A (zh) | 2016-01-25 | 2022-05-13 | 里珍纳龙药品有限公司 | 美登素类化合物衍生物、其偶联物和使用方法 |
US11053288B2 (en) | 2016-02-04 | 2021-07-06 | Trianni, Inc. | Enhanced production of immunoglobulins |
RU2745563C2 (ru) | 2016-05-20 | 2021-03-29 | Регенерон Фармасьютикалс, Инк. | Способы преодоления иммунологической толерантности с использованием множества направляющих рнк |
SI3462853T1 (sl) | 2016-06-03 | 2023-05-31 | Regeneron Pharmaceuticals, Inc. | Glodavci, ki izražajo eksogeno terminalno deoksinukleotidiltransferazo |
JP7330101B2 (ja) | 2016-11-08 | 2023-08-21 | レゲネロン ファーマシューティカルス,インコーポレーテッド | ステロイド及びそのタンパク質コンジュゲート |
WO2018106781A1 (en) | 2016-12-07 | 2018-06-14 | Genentech, Inc | Anti-tau antibodies and methods of use |
EP3551655A2 (en) | 2016-12-07 | 2019-10-16 | Genentech, Inc. | Anti-tau antibodies and methods of their use |
CN110662421B (zh) * | 2017-01-19 | 2023-03-24 | 欧莫诺艾比公司 | 来自具有多个重链免疫球蛋白基因座的转基因啮齿类动物的人抗体 |
CN110944718A (zh) | 2017-05-18 | 2020-03-31 | 里珍纳龙药品有限公司 | 环糊精蛋白质药物偶联物 |
WO2019051164A1 (en) | 2017-09-07 | 2019-03-14 | Augusta University Research Institute, Inc. | ANTIBODIES AGAINST PROTEIN 1 OF PROGRAMMED CELL DEATH |
CA3086926A1 (en) | 2018-01-08 | 2019-07-11 | Regeneron Pharmaceuticals, Inc. | Steroids and antibody-conjugates thereof |
CN112040769B (zh) | 2018-03-24 | 2023-05-16 | 瑞泽恩制药公司 | 用于产生针对肽-mhc复合物的治疗抗体的经过基因修饰的非人动物、制造方法和用途 |
CA3093850A1 (en) | 2018-03-26 | 2019-10-03 | Regeneron Pharmaceuticals, Inc. | Humanized rodents for testing therapeutic agents |
BR112020022400A2 (pt) | 2018-05-09 | 2021-02-02 | Regeneron Pharmaceuticals, Inc. | anticorpos anti-msr1 e métodos de uso dos mesmos |
KR102444180B1 (ko) | 2018-06-14 | 2022-09-16 | 리제너론 파마슈티칼스 인코포레이티드 | 면역글로불린 중쇄 암호화 서열에서 dh-dh 재배열 가능한 비인간 동물 |
JP2020146306A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146298A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146297A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146300A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146314A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146312A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146305A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146313A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146316A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146308A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146304A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146317A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146301A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146309A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146315A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146318A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146307A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146302A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146303A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146299A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
JP2020146310A (ja) * | 2019-03-14 | 2020-09-17 | 株式会社三洋物産 | 遊技機 |
WO2021211984A1 (en) | 2020-04-16 | 2021-10-21 | Regeneron Pharmaceuticals, Inc. | Diels-alder conjugation methods |
EP4178625A1 (en) | 2020-07-13 | 2023-05-17 | Regeneron Pharmaceuticals, Inc. | Camptothecin analogs conjugated to a glutamine residue in a protein, and their use |
CA3187680A1 (en) | 2020-09-11 | 2022-03-17 | Yashu Liu | Identification and production of antigen-specific antibodies |
MX2023002974A (es) | 2020-09-14 | 2023-05-25 | Regeneron Pharma | Conjugados de anticuerpo-farmaco que comprenden peptidomimeticos glp1 y usos de los mismos. |
IL303626A (en) | 2020-12-16 | 2023-08-01 | Regeneron Pharma | Mice expressing human FC alpha receptors |
TW202241934A (zh) | 2020-12-23 | 2022-11-01 | 美商再生元醫藥公司 | 編碼錨定修飾抗體之核酸及其用途 |
US20230287138A1 (en) | 2022-01-12 | 2023-09-14 | Regneron Pharmaceuticals, Inc. | Protein-drug conjugates comprising camptothecin analogs and methods of use thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004524841A (ja) | 2001-02-16 | 2004-08-19 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | 真核生物細胞を改変する方法 |
WO2009143472A2 (en) | 2008-05-23 | 2009-11-26 | Aliva Biopharmaceuticals, Inc. | Method of generating single vl domain antibodies in transgenic animals |
Family Cites Families (129)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4977081A (en) | 1987-05-04 | 1990-12-11 | Adi Diagnostics, Inc. | Stable rabbit-mouse hybridomas and secretion products thereof |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
US5075181A (en) | 1989-05-05 | 1991-12-24 | Kennametal Inc. | High hardness/high compressive stress multilayer coated tool |
WO1991000906A1 (en) | 1989-07-12 | 1991-01-24 | Genetics Institute, Inc. | Chimeric and transgenic animals capable of producing human antibodies |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6657103B1 (en) | 1990-01-12 | 2003-12-02 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6673986B1 (en) | 1990-01-12 | 2004-01-06 | Abgenix, Inc. | Generation of xenogeneic antibodies |
US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
EP1690935A3 (en) | 1990-01-12 | 2008-07-30 | Abgenix, Inc. | Generation of xenogeneic antibodies |
WO1992001043A1 (fr) | 1990-07-10 | 1992-01-23 | Nkk Corporation | Hydridomes produisant une immunoglobuline g aviaire specifique |
US5770429A (en) * | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US7041871B1 (en) | 1995-10-10 | 2006-05-09 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US6255458B1 (en) | 1990-08-29 | 2001-07-03 | Genpharm International | High affinity human antibodies and human antibodies against digoxin |
JP2835787B2 (ja) | 1991-03-22 | 1998-12-14 | キヤノン株式会社 | 強誘電性液晶素子 |
CA2078539C (en) * | 1991-09-18 | 2005-08-02 | Kenya Shitara | Process for producing humanized chimera antibody |
US5150584A (en) | 1991-09-26 | 1992-09-29 | General Motors Corporation | Method and apparatus for detecting low refrigerant charge |
EP0583980A1 (en) | 1992-08-20 | 1994-02-23 | Eli Lilly And Company | Method for generating monoclonal antibodies from rabbits |
US6005079A (en) | 1992-08-21 | 1999-12-21 | Vrije Universiteit Brussels | Immunoglobulins devoid of light chains |
DK1589107T3 (da) | 1992-08-21 | 2010-04-26 | Univ Bruxelles | Immonuglobuliner uden lette kæder |
US6765087B1 (en) | 1992-08-21 | 2004-07-20 | Vrije Universiteit Brussel | Immunoglobulins devoid of light chains |
WO1994012215A1 (en) | 1992-12-01 | 1994-06-09 | Protein Design Labs, Inc. | Humanized antibodies reactive with l-selectin |
DE4309308C1 (de) | 1993-03-23 | 1994-04-14 | Siemens Nixdorf Inf Syst | Belüftungssystem für Schränke mit stark wärmeerzeugenden elektronischen Funktionseinheiten |
IL109168A0 (en) * | 1993-04-01 | 1994-06-24 | Univ Columbia | A retroviral vector capable of transducing the aldehyde dehydrogenase-1 gene and making cells resistant to the chemotherapeutic agent cyclophosphamide and its derivatives and analogs |
AU6819494A (en) | 1993-04-26 | 1994-11-21 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5523226A (en) | 1993-05-14 | 1996-06-04 | Biotechnology Research And Development Corp. | Transgenic swine compositions and methods |
EP0739981A1 (en) | 1995-04-25 | 1996-10-30 | Vrije Universiteit Brussel | Variable fragments of immunoglobulins - use for therapeutic or veterinary purposes |
US6632976B1 (en) | 1995-08-29 | 2003-10-14 | Kirin Beer Kabushiki Kaisha | Chimeric mice that are produced by microcell mediated chromosome transfer and that retain a human antibody gene |
AU7326796A (en) | 1995-10-30 | 1997-05-22 | Spectral Diagnostics Inc. | Stable chicken b-cell line and method of use thereof |
CA2250830A1 (en) | 1996-06-26 | 1997-12-31 | Binhai Zheng | Chromosomal rearrangement by insertion of two recombination substrates |
ATE387495T1 (de) | 1996-12-03 | 2008-03-15 | Amgen Fremont Inc | Vollkommen humane antikörper die egfr binden |
CN1203922A (zh) | 1997-03-21 | 1999-01-06 | 三共株式会社 | 人源化抗人fas抗体 |
US20020062010A1 (en) | 1997-05-02 | 2002-05-23 | Genentech, Inc. | Method for making multispecific antibodies having heteromultimeric and common components |
US6774279B2 (en) | 1997-05-30 | 2004-08-10 | Carnegie Institution Of Washington | Use of FLP recombinase in mice |
GB9823930D0 (en) | 1998-11-03 | 1998-12-30 | Babraham Inst | Murine expression of human ig\ locus |
EP1183344A4 (en) | 1999-05-27 | 2003-06-25 | Human Genome Sciences Inc | ADAM POLYNUCLEOTIDES AND POLYPEPTIDES |
GB0001448D0 (en) | 2000-01-21 | 2000-03-08 | Novartis Ag | Organic compounds |
AU8470301A (en) * | 2000-08-03 | 2002-02-18 | Wim-Van Schooten | Production of humanized antibodies in transgenic animals |
US7105348B2 (en) | 2000-10-31 | 2006-09-12 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US6586251B2 (en) | 2000-10-31 | 2003-07-01 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
PE20020574A1 (es) | 2000-12-06 | 2002-07-02 | Wyeth Corp | Anticuerpos humanizados que reconocen el peptido amiloideo beta |
GB0110029D0 (en) | 2001-04-24 | 2001-06-13 | Grosveld Frank | Transgenic animal |
US7034134B2 (en) | 2001-04-26 | 2006-04-25 | Bristol-Myers Squibb Company | Polynucleotide encoding a novel metalloprotease highly expressed in the testis, MMP-29 |
EP1632571B1 (en) | 2001-05-11 | 2012-11-28 | Kyowa Hakko Kirin Co., Ltd. | Human artificial chromosome containing human antibody Lambda light chain and non-human animal containing the human artificial chromosome capable of genetic transmission |
GB0115256D0 (en) | 2001-06-21 | 2001-08-15 | Babraham Inst | Mouse light chain locus |
DE60237282D1 (de) | 2001-06-28 | 2010-09-23 | Domantis Ltd | Doppelspezifischer ligand und dessen verwendung |
FR2827302B1 (fr) * | 2001-07-13 | 2003-10-10 | Genoway | Cellule et animal transgenique modelisant la presentation antigenique humaine et leurs utilisations |
US20060199204A1 (en) | 2001-10-05 | 2006-09-07 | U.S. Epa | Genetic testing for male factor infertility |
US20030108925A1 (en) | 2001-10-05 | 2003-06-12 | U.S. Epa | Genetic testing for male factor infertility |
US7435871B2 (en) | 2001-11-30 | 2008-10-14 | Amgen Fremont Inc. | Transgenic animals bearing human Igλ light chain genes |
AU2002357060A1 (en) | 2001-12-03 | 2003-06-17 | Abgenix, Inc. | Antibody categorization based on binding characteristics |
US20050246782A1 (en) | 2002-03-22 | 2005-11-03 | Origen Therapeutics | Transgenic aves producing human polyclonal antibodies |
EP1517921B1 (en) | 2002-06-28 | 2006-06-07 | Domantis Limited | Dual specific ligands with increased serum half-life |
FI117110B (fi) | 2002-07-05 | 2006-06-15 | Outokumpu Oy | Anodin syöttö sulatusreaktoriin |
DK2314629T4 (da) | 2002-07-18 | 2023-02-06 | Merus Nv | Rekombinant produktion af blandinger af antistoffer |
US20040101920A1 (en) | 2002-11-01 | 2004-05-27 | Czeslaw Radziejewski | Modification assisted profiling (MAP) methodology |
GB0228210D0 (en) * | 2002-12-03 | 2003-01-08 | Babraham Inst | Single chain antibodies |
GB0230203D0 (en) * | 2002-12-27 | 2003-02-05 | Domantis Ltd | Fc fusion |
AU2003290330A1 (en) | 2002-12-27 | 2004-07-22 | Domantis Limited | Dual specific single domain antibodies specific for a ligand and for the receptor of the ligand |
GB0230201D0 (en) | 2002-12-27 | 2003-02-05 | Domantis Ltd | Retargeting |
GB2398784B (en) | 2003-02-26 | 2005-07-27 | Babraham Inst | Removal and modification of the immunoglobulin constant region gene cluster of a non-human mammal |
US20100069614A1 (en) | 2008-06-27 | 2010-03-18 | Merus B.V. | Antibody producing non-human mammals |
AU2004242614B2 (en) * | 2003-05-30 | 2011-09-22 | Merus N.V. | Fab library for the preparation of anti vegf and anti rabies virus fabs |
WO2005001087A2 (en) | 2003-06-11 | 2005-01-06 | Regeneron Pharmaceuticals, Inc. | Methods of modifying genes in eukaryotic cells |
CA2532117C (en) | 2003-07-15 | 2012-07-10 | Therapeutic Human Polyclonals, Inc. | Humanized immunoglobulin loci |
US20050153392A1 (en) | 2003-08-11 | 2005-07-14 | Roland Buelow | Transgenesis with humanized immunoglobulin loci |
RU2251699C1 (ru) | 2003-09-25 | 2005-05-10 | Киселев Всеволод Иванович | Способ ранней и доклинической диагностики цервикального рака |
WO2005038001A2 (en) | 2003-10-14 | 2005-04-28 | Therapeutic Human Polyclonals, Inc. | Improved transgenesis by sperm-mediated gene transfer |
FR2861255B1 (fr) | 2003-10-24 | 2006-02-17 | Centre Nat Rech Scient | Mammifere non-humain transgenique pour la region constante de la chaine lourde des immunoglobulines humaines de classe a et ses applications. |
PT2311874T (pt) * | 2004-07-22 | 2017-08-25 | Univ Erasmus Med Ct Rotterdam | Moléculas de ligação |
ES2667169T3 (es) | 2004-10-19 | 2018-05-09 | Regeneron Pharmaceuticals, Inc. | Método para generar un animal no humano homocigótico para una modificación genética |
CN101084317A (zh) | 2004-10-22 | 2007-12-05 | 人类多克隆治疗公司 | 对内源免疫球蛋白表达的抑制 |
GB0618345D0 (en) * | 2006-09-18 | 2006-10-25 | Univ Erasmus | Binding molecules |
EP1991580A2 (en) | 2006-01-25 | 2008-11-19 | Erasmus University Medical Center Rotterdam | Generation of heavy-chain only antibodies in transgenic animals |
AU2007235496B2 (en) | 2006-03-31 | 2013-11-21 | E. R. Squibb & Sons, L.L.C. | Transgenic animals expressing chimeric antibodies for use in preparing human antibodies |
MY159787A (en) | 2006-06-02 | 2017-01-31 | Regeneron Pharma | High affinity antibodies to human il-6 receptor |
CN102719444B (zh) | 2006-09-01 | 2016-12-14 | 人类多细胞株治疗学公司 | 人或人源化免疫球蛋白在非人转基因动物中增强的表达 |
PL2769992T3 (pl) | 2006-10-02 | 2021-08-02 | Regeneron Pharmaceuticals, Inc. | Przeciwciała ludzkie o wysokim powinowactwie względem ludzkiego receptora IL-4 |
RU2448979C2 (ru) | 2006-12-14 | 2012-04-27 | Ридженерон Фармасьютикалз, Инк. | Антитела человека к дельта-подобному лиганду-4 человека |
DK2602323T3 (en) | 2007-06-01 | 2018-04-16 | Open Monoclonal Tech Inc | Compositions and Methods for Inhibiting Endogenous Immunoglobin Genes and Producing Transgenic Human Idiotypic Antibodies |
WO2009013620A2 (en) | 2007-06-11 | 2009-01-29 | Erasmus University Medical Center Rotterdam | Homologous recombination |
ITMI20071522A1 (it) | 2007-07-27 | 2009-01-28 | Areta Internat S R L | Vaccino idiotipico |
AU2008282218A1 (en) * | 2007-07-31 | 2009-02-05 | Medimmune, Llc | Multispecific epitope binding proteins and uses thereof |
EP3255144A1 (en) | 2007-08-10 | 2017-12-13 | E. R. Squibb & Sons, L.L.C. | Recombineering construct for preparing transgenic mice capable of producing human immunoglobulin |
AU2008294074B2 (en) | 2007-08-30 | 2015-01-22 | Walter And Eliza Hall Institute Of Medical Research | Dendritic cell marker and uses thereof |
KR102467302B1 (ko) | 2007-09-26 | 2022-11-14 | 추가이 세이야쿠 가부시키가이샤 | 항체 정상영역 개변체 |
EP2050764A1 (en) * | 2007-10-15 | 2009-04-22 | sanofi-aventis | Novel polyvalent bispecific antibody format and uses thereof |
WO2009129247A2 (en) | 2008-04-14 | 2009-10-22 | Innovative Targeting Solutions Inc. | Sequence diversity generation in immunoglobulins |
US20100122358A1 (en) | 2008-06-06 | 2010-05-13 | Crescendo Biologics Limited | H-Chain-only antibodies |
KR102261586B1 (ko) * | 2008-06-27 | 2021-06-08 | 메뤼스 엔.페. | 항체 생산 비-인간 포유동물 |
KR102362774B1 (ko) | 2008-09-30 | 2022-02-15 | 아블렉시스, 엘엘씨 | 키메라 항체의 제조를 위한 인간 이외의 포유동물 |
MX2011007660A (es) | 2008-12-18 | 2011-08-17 | Kingdon Craig R | Animales transgenicos no humanos que expresan anticuerpos humanizados y usos de los mismos. |
US9085795B2 (en) | 2009-02-04 | 2015-07-21 | Molecular Innovations, Inc. | Methods for screening candidate agents for modulating prorenin and renin, assays for detecting prorenin and antibodies |
GB0905023D0 (en) | 2009-03-24 | 2009-05-06 | Univ Erasmus Medical Ct | Binding molecules |
KR20110124368A (ko) * | 2009-04-07 | 2011-11-16 | 로슈 글리카트 아게 | 이중특이적 항―erbb―2/항―c―met 항체 |
CN103833855A (zh) | 2009-06-26 | 2014-06-04 | 瑞泽恩制药公司 | 容易地分离的具有天然免疫球蛋白形式的双特异性抗体 |
US20120204278A1 (en) | 2009-07-08 | 2012-08-09 | Kymab Limited | Animal models and therapeutic molecules |
DK3622813T3 (da) | 2009-07-08 | 2021-05-03 | Kymab Ltd | Dyremodeller og terapeutiske molekyler |
US9445581B2 (en) | 2012-03-28 | 2016-09-20 | Kymab Limited | Animal models and therapeutic molecules |
CN101620635A (zh) * | 2009-08-07 | 2010-01-06 | 中兴通讯股份有限公司 | 页面数据获取方法及服务器、页面更新方法及服务器 |
DK2954779T3 (da) | 2009-12-10 | 2019-05-13 | Regeneron Pharma | Mus, der frembringer tungkædeantistoffer |
US20120021409A1 (en) | 2010-02-08 | 2012-01-26 | Regeneron Pharmaceuticals, Inc. | Common Light Chain Mouse |
US20130045492A1 (en) | 2010-02-08 | 2013-02-21 | Regeneron Pharmaceuticals, Inc. | Methods For Making Fully Human Bispecific Antibodies Using A Common Light Chain |
US10143186B2 (en) | 2010-02-08 | 2018-12-04 | Regeneron Pharmaceuticals, Inc. | Common light chain mouse |
US20130185821A1 (en) | 2010-02-08 | 2013-07-18 | Regeneron Pharmaceuticals, Inc. | Common Light Chain Mouse |
CN105695415A (zh) * | 2010-06-17 | 2016-06-22 | 科马布有限公司 | 动物模型及治疗分子 |
KR20220150430A (ko) | 2010-06-22 | 2022-11-10 | 리제너론 파아마슈티컬스, 인크. | 사람 람다 가변 영역 및 마우스 불변 영역을 갖는 경쇄를 발현하는 마우스 |
NZ707327A (en) | 2010-08-02 | 2017-01-27 | Regeneron Pharma | Mice that make binding proteins comprising vl domains |
WO2012063048A1 (en) | 2010-11-08 | 2012-05-18 | Kymab Limited | Cells & vertebrates for enhanced somatic hypermutation and class switch recombination |
DE12192727T1 (de) | 2011-02-25 | 2013-07-11 | Regeneron Pharmaceuticals, Inc. | ADAM6 Mäuse |
CA2824824A1 (en) | 2011-02-28 | 2012-09-07 | F. Hoffmann-La Roche Ag | Monovalent antigen binding proteins |
US20120310284A1 (en) | 2011-06-03 | 2012-12-06 | Royal Oak Industries | Polyaxial pedicle screw |
PT3572517T (pt) | 2011-08-05 | 2021-06-23 | Regeneron Pharma | Murganhos da cadeia leve universal humanizada |
ES2612935T3 (es) | 2011-09-19 | 2017-05-19 | Kymab Limited | Anticuerpos, dominios variables y cadenas adaptados para su uso en seres humanos |
WO2013041845A2 (en) | 2011-09-19 | 2013-03-28 | Kymab Limited | Animals, repertoires & methods |
EP2761008A1 (en) | 2011-09-26 | 2014-08-06 | Kymab Limited | Chimaeric surrogate light chains (slc) comprising human vpreb |
PL2627773T3 (pl) | 2011-10-17 | 2017-11-30 | Regeneron Pharmaceuticals, Inc. | Ograniczony łańcuch ciężki immonoglobuliny pochodzącej od myszy |
GB2496375A (en) | 2011-10-28 | 2013-05-15 | Kymab Ltd | A non-human assay vertebrate comprising human antibody loci and human epitope knock-in, and uses thereof |
US9253965B2 (en) | 2012-03-28 | 2016-02-09 | Kymab Limited | Animal models and therapeutic molecules |
GB201122047D0 (en) | 2011-12-21 | 2012-02-01 | Kymab Ltd | Transgenic animals |
SI2793567T1 (sl) | 2011-12-20 | 2019-05-31 | Regeneron Pharmaceuticals, Inc. | Humanizirane lahkoverižne miši |
ES2753774T3 (es) | 2012-02-01 | 2020-04-14 | Regeneron Pharma | Ratones humanizados que expresan cadenas pesadas que contienen dominios VL |
GB2502127A (en) | 2012-05-17 | 2013-11-20 | Kymab Ltd | Multivalent antibodies and in vivo methods for their production |
TWI682941B (zh) | 2013-02-01 | 2020-01-21 | 美商再生元醫藥公司 | 含嵌合恆定區之抗體 |
US9788534B2 (en) | 2013-03-18 | 2017-10-17 | Kymab Limited | Animal models and therapeutic molecules |
HUE040575T2 (hu) | 2013-04-16 | 2019-03-28 | Regeneron Pharma | A patkány genom célzott módosítása |
CN106255410B (zh) | 2014-03-21 | 2020-01-10 | 瑞泽恩制药公司 | 产生单结构域结合蛋白的非人动物 |
SG10201808083VA (en) | 2014-03-21 | 2018-10-30 | Regeneron Pharma | Vl antigen binding proteins exhibiting distinct binding characteristics |
CA2979702A1 (en) | 2015-03-19 | 2016-09-22 | Regeneron Pharmaceuticals, Inc. | Non-human animals that select for light chain variable regions that bind antigen |
-
2011
- 2011-08-02 NZ NZ707327A patent/NZ707327A/en unknown
- 2011-08-02 WO PCT/US2011/046196 patent/WO2012018764A1/en active Application Filing
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