JP2018533963A - ヒト化されたlymphocyte−activation gene 3遺伝子を有する非ヒト動物 - Google Patents
ヒト化されたlymphocyte−activation gene 3遺伝子を有する非ヒト動物 Download PDFInfo
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Abstract
Description
本出願は、2015年11月20日出願の米国仮特許出願第62/258,181号、および2016年8月3日出願の米国仮特許出願第62/370,430号、の利益を主張するものであり、これらの仮特許出願の内容全体は参照により本明細書に組み込まれる。
配列表の参照による組み込み
本発明は本明細書に記述された特定の方法および実験条件に限定されないが、それはこのような方法および条件は変化する場合があるからである。本発明の範囲は請求項によって定義されるので、本明細書に使用される用語は、特定の実施形態のみを記述する目的で使用されており、意図しないことも理解される。
[発明を実施するための形態]
Lymphocyte−activation gene 3(Lag−3)
Lag−3配列
DNA構築物
ヒト化Lymphocyte−Activation Gene 3を有する非ヒト動物の作製
ヒト化Lag−3遺伝子を有する非ヒト動物を用いる方法
キット
実施例1 内因性Lymphocyte−activation gene 3のヒト化
実施例3 LAG3およびPD1調節因子のインビボ有効性
均等
Claims (79)
- ヒト化Lag−3ポリペプチドを発現する齧歯類であって、前記ヒト化Lag−3ポリペプチドがヒト部分および内因性部分を含む、齧歯類。
- 前記ヒト化Lag−3ポリペプチドの前記内因性部分が、内因性Lag−3ポリペプチドの細胞内部分を含む、請求項1に記載の齧歯類。
- 前記ヒト化Lag−3ポリペプチドの前記内因性部分が、内因性Lag−3ポリペプチドの膜貫通部分をさらに含む、請求項2に記載の齧歯類。
- 前記ヒト化Lag−3ポリペプチドの前記内因性部分が、配列番号2または配列番号4の齧歯類Lag−3ポリペプチドに存在する、相当するアミノ酸配列と少なくとも95%同一のアミノ酸配列を有する、請求項3に記載の齧歯類。
- 前記ヒト化Lag−3ポリペプチドの前記ヒト部分が、ヒトLAG−3ポリペプチドのアミノ酸29〜260を含む、請求項1〜4のいずれか一項に記載の齧歯類。
- 前記ヒト化Lag−3ポリペプチドの前記ヒト部分が、配列番号6のヒトLAG−3ポリペプチドに存在する、相当するアミノ酸配列と少なくとも95%同一のアミノ酸配列を含む、請求項1〜4のいずれか一項に記載の齧歯類。
- 前記ヒト化Lag−3ポリペプチドが、内因性Lag−3座位に配置された核酸配列によりコードされる、請求項1〜6のいずれか一項に記載の齧歯類。
- 前記ヒト化Lag−3ポリペプチドの内因性部分が、内因性Lag−3のエクソン1、5、6、7および8によりコードされる、請求項7に記載の齧歯類。
- 前記齧歯類が、ヒト部分および内因性部分を含むヒト化PD−1ポリペプチドをさらに発現する、請求項1〜8のいずれか一項に記載の齧歯類。
- 前記ヒト化PD−1ポリペプチドの前記内因性部分が、内因性PD−1ポリペプチドの細胞内部分および/または膜貫通部分を含む、請求項9に記載の齧歯類。
- 前記ヒト化PD−1ポリペプチドの前記ヒト部分が、ヒトPD−1ポリペプチドのアミノ酸26〜169を含む、請求項9または10に記載の齧歯類。
- そのゲノムが内因性部分およびヒト部分を含むヒト化Lag−3遺伝子を含む齧歯類であって、前記内因性およびヒト部分が齧歯類Lag−3プロモーターと動作可能に連結した、齧歯類。
- 前記齧歯類Lag−3プロモーターが、内因性齧歯類Lag−3プロモーターである、請求項12に記載の齧歯類。
- 前記ヒト化Lag−3遺伝子の前記内因性部分が、内因性Lag−3のエクソン1、5、6、7および8を含む、請求項12または13に記載の齧歯類。
- 前記内因性Lag−3遺伝子のエクソン1、5、6、7および8は、配列番号1または配列番号3の齧歯類Lag−3 mRNA配列中に存在する、相当するエクソン1、5、6、7および8に対し、少なくとも95%同一である、請求項14に記載の齧歯類。
- 前記ヒト化Lag−3遺伝子の前記ヒト部分が、ヒトLAG−3ポリペプチドの少なくともアミノ酸29〜260をコードする、請求項12〜15のいずれか一項に記載の齧歯類。
- 前記ヒト化Lag−3遺伝子の前記ヒト部分が、ヒトLAG−3遺伝子のエクソン2〜4を含む、請求項12〜15のいずれか一項に記載の齧歯類。
- ヒトLAG−3遺伝子のエクソン2〜4が、配列番号5のヒトLAG−3 mRNA中に存在する、相当するエクソン2〜4に対し、少なくとも95%同一である、請求項17に記載の齧歯類。
- 前記ヒト化Lag−3遺伝子の前記ヒト部分が、前記齧歯類における発現のためにコドン最適化された配列を含む、請求項17に記載の齧歯類。
- 齧歯類の前記ゲノムが、内因性部分およびヒト部分を含むヒト化Pdcd1遺伝子をさらに含み、前記内因性およびヒト部分が齧歯類Pdcd1プロモーターと動作可能に連結した、請求項12〜19のいずれか一項に記載の齧歯類。
- 前記齧歯類Pdcd1プロモーターが、内因性齧歯類Pdcd1プロモーターである、請求項20に記載の齧歯類。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、内因性Pdcd1エクソン1、4および5を含む、請求項20または21に記載の齧歯類。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、内因性Pdcd1エクソン3の全部または一部をさらに含む、請求項22に記載の齧歯類。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、ヒトPD−1ポリペプチドのアミノ酸26〜169をコードする、請求項20〜23のいずれか一項に記載の齧歯類。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、ヒトPDCD1遺伝子のエクソン2を含む、請求項20〜23のいずれか一項に記載の齧歯類。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、ヒトPDCD1エクソン3の全部または一部をさらに含む、請求項25に記載の齧歯類。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、前記齧歯類における発現のためにコドン最適化された配列を含む、請求項20〜26のいずれか一項に記載の齧歯類。
- 前記齧歯類がラットまたはマウスである、請求項1〜27のいずれか一項に記載の齧歯類。
- 請求項1〜28のいずれか一項に記載の齧歯類によって作製されるヒト化Lag−3ポリペプチド。
- 前記ヒト化Lag−3ポリペプチドが、配列番号8のヒト化LAG−3ポリペプチド中に存在するアミノ酸配列に対し、少なくとも95%同一であるアミノ酸配列を含む、請求項29に記載のヒト化Lag−3ポリペプチド。
- ヒト部分および内因性部分を有するヒト化Lag−3ポリペプチドをコードするヒト化Lag−3遺伝子を含むゲノムを有する単離された齧歯類の細胞または組織であって、前記部分が齧歯類Lag−3プロモーターと動作可能に連結した、単離された齧歯類の細胞または組織。
- ヒト部分および内因性部分を有するLag−3ポリペプチドをコードするヒト化Lag−3遺伝子を含むゲノムを有する齧歯類胚性幹細胞であって、前記部分が齧歯類Lag−3プロモーターと動作可能に連結した、齧歯類胚性幹細胞。
- 請求項32に記載の胚性幹細胞から生成される齧歯類胚。
- 内因性Lag−3遺伝子座からLag−3ポリペプチドを発現する齧歯類を作製する方法であって、前記Lag−3ポリペプチドがヒト配列を含み、前記方法が、
(a)齧歯類胚性幹細胞の内因性Lag−3遺伝子にゲノム断片を配置することであって、前記ゲノム断片が、ヒトLAG−3ポリペプチドの全部または一部をコードするヌクレオチド配列を含む、配置することと、
(b)(a)で生成された齧歯類胚性幹細胞を得ることと、
(c)(b)の前記齧歯類胚性幹細胞を使用して齧歯類を作製すること、とを含む、方法。 - 前記ヒト配列が、ヒトLAG−3ポリペプチドのアミノ酸29〜260を含む、請求項34に記載の方法。
- 前記ヌクレオチド配列がヒトLAG−3エクソン2〜4を含む、請求項34または35のいずれかに記載の方法。
- 前記ヌクレオチド配列が、ヒトLAG−3ポリペプチドの少なくともアミノ酸29−260をコードしている、請求項34または35に記載の方法。
- 前記ヌクレオチド配列が、一つ以上の選択マーカーを含む、請求項34〜37のいずれか一項に記載の方法。
- 前記ヌクレオチド配列が、一つ以上の部位特異的組み換え部位を含む、請求項34〜38のいずれか一項に記載の方法。
- 前記方法が、(a)の前記齧歯類胚性幹細胞の内因性Pdcd1遺伝子へゲノム断片を配置するステップをさらに含み、前記ゲノム断片は、ヒトPD−1ポリペプチドの全部または一部をコードするヌクレオチド配列を含む、請求項34〜39のいずれか一項に記載の方法。
- ヒトPD−1ポリペプチドの全部または一部をコードするヌクレオチド配列を含む前記ゲノム断片が、前記ヒトLAG−3ポリペプチドの全部または一部をコードするヌクレオチド配列を含むゲノム断片を内因性Lag−3遺伝子内に配置する前、または配置と同時、または配置した後に、(a)の前記齧歯類胚性幹細胞の前記内因性Pdcd1遺伝子内に配置される、請求項40に記載の方法。
- 前記方法が、第二の齧歯類と、(c)の前記齧歯類を交配させることをさらに含み、前記第二の齧歯類が、ヒト部分と内因性部分を含むPD−1ポリペプチドをコードするPdcd1遺伝子を含むゲノムを有する、請求項34〜39のいずれか一項に記載の方法。
- ヒト部分および内因性部分を有するLag−3ポリペプチドをコードするLag−3遺伝子を含むゲノムを有する齧歯類を作製する方法であって、前記部分が齧歯類Lag−3プロモーターと動作可能に連結し、前記方法が、
ヒト部分および内因性部分を有するLag−3ポリペプチドをコードするLag−3遺伝子を含むように齧歯類のゲノムを改変することであって、前記部分が齧歯類Lag−3プロモーターと動作可能に連結し、それによって前記齧歯類を作製する、改変すること、を含む、方法。 - 前記齧歯類Lag−3プロモーターが内因性齧歯類Lag−3プロモーターである、請求項43に記載の方法。
- 前記ヒト部分がヒトLag−3ポリペプチドのアミノ酸29〜260を含む、請求項43または44に記載の方法。
- 前記Lag−3遺伝子が、ヒトLAG−3のエクソン2〜4を含むように改変される、請求項43〜45のいずれか一項に記載の方法。
- 前記Lag−3遺伝子が、ヒトLAG−3ポリペプチドの少なくともアミノ酸29−260をコードするよう改変される、請求項43〜45のいずれか一項に記載の方法。
- 前記方法が、そのゲノムがヒト部分と内因性部分を含むPD−1ポリペプチドをコードするPdcd1遺伝子を含むように、前記齧歯類の前記ゲノムを改変することをさらに含む、請求項43〜47のいずれか一項に記載の方法。
- ゲノムがヒト部分と内因性部分を含むPD−1ポリペプチドをコードするPdcd1 遺伝子を含むように前記齧歯類の前記ゲノムを改変することが、そのゲノムがヒト部分と内因性部分を有するLag−3ポリペプチドをコードするLag−3遺伝子を含むように前記齧歯類の前記ゲノムを改変する前、同時、または後に行われる、請求項48に記載の方法。
- 前記方法が、そのゲノムがヒト部分と内因性部分を有するLAG−3ポリペプチドをコードするLag−3遺伝子を含む前記齧歯類を第二の齧歯類と交配させることをさらに含み、前記第二の齧歯類が、ヒト部分と内因性部分を含むPD−1ポリペプチドをコードするPD−1ポリペプチドをコードするPdcd1遺伝子を含むゲノムを有する、請求項43〜47のいずれか一項に記載の方法。
- 前記齧歯類がマウスまたはラットである、請求項34〜50のいずれか一項に記載の方法。
- 請求項34〜51のいずれか一項に記載の方法から得られる齧歯類。
- ヒトLAG−3を標的とする薬剤の抗腫瘍効果を評価する方法であって、前記方法が、
そのゲノムがヒト部分および内因性部分を有するヒト化Lag−3ポリペプチドをコードするヒト化Lag−3遺伝子を含む齧歯類に前記薬剤を投与するステップであって、前記部分が齧歯類Lag−3プロモーターと動作可能に連結した、投与するステップと、
前記ヒトLAG−3を標的とする薬剤の1つ以上の抗腫瘍特性を決定するアッセイを行うステップ、とを含む、方法。 - ヒトLAG−3を標的とする薬剤の薬物動態特性を評価する方法であって、前記方法が、
そのゲノムがヒト部分および内因性部分を有するヒト化Lag−3ポリペプチドをコードするヒト化Lag−3遺伝子を含む齧歯類に前記薬剤を投与するステップであって、前記部分が齧歯類Lag−3プロモーターと動作可能に連結した、投与するステップと、
前記ヒトLAG−3を標的とする薬剤の一つ以上の薬物動態特性を決定するアッセイを行うステップと、を含む、方法。 - 前記ヒト化Lag−3ポリペプチドの前記ヒト部分が、ヒトLAG−3ポリペプチドのアミノ酸29〜260を含む、請求項53または54に記載の方法。
- 前記ヒトLAG−3を標的とする薬剤がLag−3拮抗薬である、請求項53〜55のいずれか一項に記載の方法。
- 前記ヒトLAG−3を標的とする薬剤が、Lag−3拮抗薬である、請求項54または55に記載の方法。
- 前記ヒトLAG−3を標的とする薬剤が、抗Lag−3抗体である、請求項53〜55のいずれか一項に記載の方法。
- 前記ヒトLAG−3を標的とする薬剤が、前記齧歯類に静脈内投与される、請求項53〜58のいずれか一項に記載の方法。
- 前記ヒトLAG−3を標的とする薬剤が、前記齧歯類に腹腔内投与される、請求項53〜58のいずれか一項に記載の方法。
- 前記ヒトLAG−3を標的とする薬剤が、前記齧歯類に皮下投与される、請求項53〜58のいずれか一項に記載の方法。
- 前記齧歯類Lag−3プロモーターが、内因性齧歯類Lag−3プロモーターである、請求項53〜61のいずれか一項に記載の方法。
- 齧歯類の前記ゲノムが、内因性部分およびヒト部分を含むヒト化Pdcd1遺伝子をさらに含み、前記内因性およびヒト部分が齧歯類Pdcd1プロモーターと動作可能に連結した、請求項53〜62のいずれか一項に記載の方法。
- 前記齧歯類Pdcd1プロモーターが、内因性齧歯類Pdcd1プロモーターである、請求項63に記載の方法。
- 前記ヒト化Pdcd1遺伝子の前記内因性部分が、内因性Pdcd1エクソン1、4および5を含む、請求項63または64に記載の方法。
- 前記ヒト化Pdcd1遺伝子の前記内因性部分が、内因性Pdcd1エクソン3の全部または一部をさらに含む、請求項65に記載の方法。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、ヒトPD−1ポリペプチドのアミノ酸26〜169をコードする、請求項63〜66のいずれか一項に記載の方法。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、ヒトPDCD1遺伝子のエクソン2を含む、請求項63〜66のいずれか一項に記載の方法。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、ヒトPDCD1エクソン3の全部または一部をさらに含む、請求項68に記載の方法。
- 前記ヒト化Pdcd1遺伝子の前記ヒト部分が、前記齧歯類における発現のためにコドン最適化された配列を含む、請求項63〜69に記載の方法。
- 前記齧歯類がマウスまたはラットである、請求項53〜70のいずれか一項に記載の方法。
- そのゲノムが、ヒト化Lag−3遺伝子を含む齧歯類であって、前記遺伝子が、
内因性Lag−3エクソン1、5、6、7および8を含む内因性部分と、
ヒトLAG−3遺伝子のエクソン2〜4を含むヒト部分と、を含み、
前記内因性部分とヒト部分は、内因性齧歯類Lag−3プロモーターに動作可能に連結され、前記齧歯類は、ヒトLAG−3ポリペプチドのアミノ酸29〜260を含むヒト化Lag−3ポリペプチドを発現する、齧歯類。 - 前記齧歯類により発現されるヒト化Lag−3ポリペプチドが、配列番号8のヒト化Lag−3ポリペプチド中に存在するアミノ酸配列に対して少なくとも95%同一であるアミノ酸配列を含む、請求項72に記載の齧歯類。
- 前記ヒト化Lag−3遺伝子の前記ヒト部分が、前記齧歯類における発現のためにコドン最適化された配列を含む、請求項72または73に記載の齧歯類。
- 前記齧歯類の前記ゲノムが、ヒト化Pdcd1遺伝子をさらに含み、前記遺伝子が、
内因性Pdcd1エクソン1、3の全部または一部、エクソン4および5を含む内因性部分と、
ヒトPDCD1遺伝子のエクソン2およびエクソン3の全部または一部を含むヒト部分と、を含み、
前記内因性部分とヒト部分は、内因性齧歯類Pdcd1プロモーターに動作可能に連結され、前記齧歯類が、ヒトPD−1ポリペプチドのアミノ酸26〜169を含むPD−1ポリペプチドを発現する、請求項72〜76のいずれか一項に記載の齧歯類。 - 前記ヒト部分が、前記齧歯類における発現のためにコドン最適化された配列を含む、請求項75に記載の齧歯類。
- 前記齧歯類が、ラットまたはマウスである、請求項74〜76のいずれか一項に記載の齧歯類。
- 前記ヒト化Lag−3遺伝子のヒト部分が、前記ヒトLAG−3ポリペプチドのイムノグロブリン様ドメイン1および2のアミノ酸配列をコードするか、または前記ヒト化Lag−3ポリペプチドのヒト部分が、前記ヒトLAG−3ポリペプチドのイムノグロブリン様ドメイン1および2のアミノ酸配列を含む、請求項1〜28、52、および72〜77のいずれか一項に記載の齧歯類、または請求項34〜51および53〜71のいずれか一項に記載の方法。
- 前記ヒト化Lag−3遺伝子の前記ヒト部分が、MHCII結合に関与するヒトLAG−3ポリペプチドのアミノ酸配列をコードするか、または前記ヒト化Lag−3ポリペプチドの前記ヒト部分が、MHCII結合に関与するヒトLAG−3ポリペプチドのアミノ酸配列を含む、請求項1〜28、52、および72〜77のいずれか一項に記載の齧歯類、ならびに請求項34〜51および53〜71のいずれか一項に記載の方法。
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Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2018005389A (es) | 2015-11-20 | 2018-09-05 | Regeneron Pharma | Animales no humanos que tienen un gen 3 de activacion linfocitaria humanizado. |
CN109068621B (zh) | 2016-02-29 | 2021-07-20 | 再生元制药公司 | 具有人源化的tmprss基因的啮齿类动物 |
EP3476865B1 (en) | 2016-06-28 | 2023-09-13 | Biocytogen Pharmaceuticals (Beijing) Co., Ltd. | Method for constructing pd-1 gene-modified humanized animal model and use thereof |
CN107815468B (zh) | 2016-08-31 | 2021-03-16 | 百奥赛图(北京)医药科技股份有限公司 | 人源化基因改造动物模型的制备方法及应用 |
WO2018086583A1 (en) * | 2016-11-11 | 2018-05-17 | Beijing Biocytogen Co., Ltd | Genetically modified non-human animal with human or chimeric lag-3 |
CN108070613B (zh) | 2016-11-11 | 2020-03-13 | 百奥赛图江苏基因生物技术有限公司 | 人源化基因改造动物模型的制备方法及应用 |
US11696572B2 (en) * | 2017-06-27 | 2023-07-11 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a humanized ASGR1 locus |
WO2019028032A1 (en) | 2017-07-31 | 2019-02-07 | Regeneron Pharmaceuticals, Inc. | EMBRYONIC STEM CELLS OF TRANSGENIC MOUSE CASES AND MICE AND USES THEREOF |
AU2018309708A1 (en) | 2017-07-31 | 2020-02-06 | Regeneron Pharmaceuticals, Inc. | CRISPR reporter non-human animals and uses thereof |
CN109666701B (zh) * | 2017-10-13 | 2021-08-24 | 百奥赛图(北京)医药科技股份有限公司 | 一种pd-1基因修饰人源化动物模型的构建方法及其应用 |
WO2019072241A1 (en) * | 2017-10-13 | 2019-04-18 | Beijing Biocytogen Co., Ltd | NON-HUMAN ANIMAL GENETICALLY MODIFIED WITH PD-1 HUMAN OR CHIMERIC |
JP7361031B2 (ja) * | 2017-11-30 | 2023-10-13 | 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 | ヒト化trkb遺伝子座を含む非ヒト動物 |
WO2019183123A1 (en) | 2018-03-19 | 2019-09-26 | Regeneron Pharmaceuticals, Inc. | Transcription modulation in animals using crispr/cas systems |
KR20210004994A (ko) | 2018-03-26 | 2021-01-13 | 리제너론 파마슈티칼스 인코포레이티드 | 치료제를 시험하기 위한 인간화된 설치류 |
KR20210031868A (ko) | 2018-07-16 | 2021-03-23 | 리제너론 파마슈티칼스 인코포레이티드 | Ditra 질환의 비인간 동물 모델 및 이의 용도 |
WO2020125763A1 (en) * | 2018-12-20 | 2020-06-25 | Biocytogen Jiangsu Co., Ltd. | Genetically modified non-human animal with human or chimeric lag3 |
CN109929875B (zh) * | 2019-03-12 | 2021-02-19 | 江苏集萃药康生物科技股份有限公司 | 一种lag3基因人源化动物模型的构建方法及其应用 |
WO2020206139A1 (en) | 2019-04-04 | 2020-10-08 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a humanized coagulation factor 12 locus |
JP2022534867A (ja) | 2019-06-04 | 2022-08-04 | 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 | ベータスリップ変異を有するヒト化ttr遺伝子座を含む非ヒト動物と使用方法 |
BR112021022722A2 (pt) | 2019-06-07 | 2022-01-04 | Regeneron Pharma | Animal não humano, célula de animal não humana, genoma de animal não humano, gene de albumina animal não humana humanizada, vetor de alvejamento, método de avaliação da atividade de um reagente, e, método de otimização da atividade de um reagente |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004536556A (ja) * | 2000-10-31 | 2004-12-09 | 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 |
JP2006523226A (ja) * | 2003-02-28 | 2006-10-12 | ザ ジョンズ ホプキンス ユニバーシティ | T細胞調節方法 |
JP2014532413A (ja) * | 2011-10-28 | 2014-12-08 | 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Regeneron Pharmaceuticals, Inc. | 遺伝子改変t細胞受容体マウス |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0758383B1 (fr) * | 1994-05-06 | 2007-01-24 | Institut Gustave Roussy | Fractions polypeptidiques solubles de la proteine lag-3; procede de production; composition therapeutique; anticorps anti-idiotype |
US5670356A (en) | 1994-12-12 | 1997-09-23 | Promega Corporation | Modified luciferase |
US5874304A (en) | 1996-01-18 | 1999-02-23 | University Of Florida Research Foundation, Inc. | Humanized green fluorescent protein genes and methods |
PT1802193E (pt) | 2004-10-19 | 2014-06-23 | Regeneron Pharma | Método para gerar um murganho homozigótico para uma modificação genética |
AR072999A1 (es) * | 2008-08-11 | 2010-10-06 | Medarex Inc | Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos |
RU2425880C2 (ru) * | 2009-07-30 | 2011-08-10 | Учреждение Российской академии наук Институт общей генетики им. Н.И. Вавилова РАН | Способ получения трансгенных мышей |
WO2011020014A1 (en) | 2009-08-14 | 2011-02-17 | Regeneron Pharmaceuticals, Inc. | Promoter-regulated differentiation-dependent self-deleting cassette |
AU2010303737B2 (en) | 2009-10-06 | 2014-05-29 | Institute For Research In Biomedicine (Irb) | Genetically modified mice and engraftment |
US20130061340A1 (en) | 2011-09-02 | 2013-03-07 | Stem Centrx, Inc. | Identification and Enrichment of Cell Subpopulations |
PT2675271T (pt) | 2011-02-15 | 2018-10-11 | Univ Yale | Ratinhos humanizados para m-csf |
EP4311833A3 (en) | 2011-10-28 | 2024-05-01 | Regeneron Pharmaceuticals, Inc. | Genetically modified major histocompatibility complex mice |
KR101926442B1 (ko) | 2011-10-28 | 2018-12-12 | 리제너론 파아마슈티컬스, 인크. | 키메라 주요 조직적합성 복합체 (mhc) ii 분자들을 발현하는 유전자 변형된 마우스 |
EP2818478B1 (en) | 2011-10-28 | 2017-02-01 | Regeneron Pharmaceuticals, Inc. | Humanized IL-6 and IL-6 receptor |
UY34887A (es) * | 2012-07-02 | 2013-12-31 | Bristol Myers Squibb Company Una Corporacion Del Estado De Delaware | Optimización de anticuerpos que se fijan al gen de activación de linfocitos 3 (lag-3) y sus usos |
RU2768282C2 (ru) | 2012-09-07 | 2022-03-23 | Йель Юниверсити | Генетически модифицированные не принадлежащие к человеческому роду животные и способ их использования |
DK2900061T3 (da) * | 2012-09-17 | 2020-03-02 | Galectin Therapeutics Inc | Fremgangsmåde til forstærkning af specifikke immunterapier ved cancerbehandling |
DK3939423T3 (da) | 2012-11-05 | 2024-05-06 | Regeneron Pharma | Genetisk modificerede ikke-humane dyr og fremgangsmåder til anvendelse deraf |
EP2958938B1 (en) | 2013-02-20 | 2019-04-17 | Regeneron Pharmaceuticals, Inc. | Mice expressing humanized t-cell co-receptors |
US20150342163A1 (en) | 2013-02-22 | 2015-12-03 | Regeneron Pharmaceuticals, Inc. | Genetically modified major histocompatibility complex mice |
SI2958937T1 (sl) | 2013-02-22 | 2018-12-31 | Regeneron Pharmaceuticals, Inc. | Miš, ki izraža humanizirani poglavitni histokompatibilnostni kompleks |
PT3456831T (pt) | 2013-04-16 | 2021-09-10 | Regeneron Pharma | Modificação alvejada do genoma de rato |
IL297607B2 (en) | 2013-09-23 | 2024-01-01 | Regeneron Pharma | Non-human animals with a humanized gene for SIGNAL-REGULATORY PROTEIN |
EP3409110A1 (en) | 2013-11-19 | 2018-12-05 | Regeneron Pharmaceuticals, Inc. | Non-human animals having a humanized b-cell activating factor gene |
SG11201604886WA (en) | 2014-04-08 | 2016-07-28 | Regeneron Pharma | Non-human animals having humanized fc-gamma receptors |
NO2785538T3 (ja) | 2014-05-07 | 2018-08-04 | ||
RU2711744C1 (ru) | 2014-05-19 | 2020-01-21 | Ридженерон Фармасьютикалз, Инк. | Генетически модифицированные животные, отличные от человека, экспрессирующие epo человека |
EP3157956B1 (en) | 2014-06-19 | 2020-02-05 | Regeneron Pharmaceuticals, Inc. | Non-human animals having a humanized programmed cell death 1 gene |
LT3689140T (lt) | 2014-11-24 | 2022-08-25 | Regeneron Pharmaceuticals, Inc. | Gyvūnai, išskyrus žmones, ekspresuojantys humanizuotą cd3 kompleksą |
FI3850946T3 (fi) | 2014-12-05 | 2023-12-28 | Regeneron Pharma | Ei-ihmiseläimiä, joilla on humanisoitu erilaistumisklusterin 47 geeni |
CN107257624B (zh) | 2014-12-09 | 2021-07-13 | 瑞泽恩制药公司 | 具有人源化分化簇274基因的非人动物 |
AU2016246698B2 (en) | 2015-04-06 | 2022-06-02 | Regeneron Pharmaceuticals, Inc. | Humanized T cell mediated immune responses in non-human animals |
MX2018005389A (es) | 2015-11-20 | 2018-09-05 | Regeneron Pharma | Animales no humanos que tienen un gen 3 de activacion linfocitaria humanizado. |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004536556A (ja) * | 2000-10-31 | 2004-12-09 | 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 |
JP2006523226A (ja) * | 2003-02-28 | 2006-10-12 | ザ ジョンズ ホプキンス ユニバーシティ | T細胞調節方法 |
JP2014532413A (ja) * | 2011-10-28 | 2014-12-08 | 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Regeneron Pharmaceuticals, Inc. | 遺伝子改変t細胞受容体マウス |
Non-Patent Citations (7)
Title |
---|
CANCER RESEARCH, vol. 72, JPN6020039616, 2011, pages 917 - 927, ISSN: 0004522470 * |
CANCER RESEARCH, vol. Vol. 75, Issue 15 Supplement, JPN6020039607, August 2015 (2015-08-01), pages 266, ISSN: 0004522465 * |
EUROPEAN JOURNAL OF IMMUNOLOGY, vol. 32, JPN6020039613, 2002, pages 2255 - 2263, ISSN: 0004522468 * |
JOURNAL OF EXPERIMENTAL MEDICINE, vol. 171, JPN6020039608, 1990, pages 1393 - 1405, ISSN: 0004522466 * |
NATURE REVIEWS GENETICS, vol. 13, JPN6020039610, 2012, pages 14 - 20, ISSN: 0004522467 * |
ONCOTARGET, vol. 6, no. 29, JPN7020003311, 23 July 2015 (2015-07-23), pages 27359 - 27377, ISSN: 0004522471 * |
SCIENCE, vol. 272, JPN7020003310, 1996, pages 405 - 408, ISSN: 0004522469 * |
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