JP2008517600A - ヒト以外のトランスジェニック動物における内因性免疫グロブリン発現の抑制 - Google Patents
ヒト以外のトランスジェニック動物における内因性免疫グロブリン発現の抑制 Download PDFInfo
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Abstract
Description
本発明は内因性免疫グロブリンを発現するB細胞では自殺遺伝子を選択的に発現するが、ヒトまたはヒト化免疫グロブリンまたは免疫グロブリン鎖のような外因性免疫グロブリンまたは免疫グロブリン鎖を発現するB細胞では発現しないことにより、ヒト以外のトランスジェニック動物における内因性免疫グロブリン発現を抑制する方法に関する。この方法により例えばヒト以外のトランスジェニック動物の血液、乳および卵中のヒトまたはヒト化抗体の優勢な発現が可能になる。
ヒトマウスキメラ抗体を発現するマウスの作製は非特許文献1に記載されている。ヒト免疫グロブリンポリペプチドを発現するマウスの作製は非特許文献2;非特許文献3;および非特許文献4により記載されており、ならびにBACクローンを用いるトランスジェニックマウスの作製は非特許文献5に記載されている。ヒト抗体を発現するウシの作製は非特許文献6に記載されている。
本発明はトランスジェニック動物における内因性免疫グロブリン生成を抑制するための方法に関する。方法は内因性免疫グロブリンを発現するB細胞において自殺遺伝子を選択的に発現するが、ヒトまたはヒト化免疫グロブリンを発現するB細胞では自殺遺伝子を発現しないことを伴う。とりわけ本発明は1つまたはいくつかのヒトまたはヒト(化)免疫グロブリン導入遺伝子座を含有するヒト以外のトランスジェニック動物において内因性免疫グロブリン遺伝子座の発現を抑制するための方法に関係する。結果的にヒト(化)導入遺伝子座はヒト以外のトランスジェニック動物において遺伝子再構成および変異過程を被り、実質的に内因性免疫グロブリン生成の不在下で多様化されたヒト(化)抗体レパートリーを生成することができる。
定義
特記しない場合、本明細書で用いる技術的および科学的用語は本発明が属する分野の当業者により一般に理解されるのと同一の意味を有する。Singletonら、Dictionary of Microbiology and Molecular Biology、第2版、J.Wiley & Sons(ニューヨーク、ニューヨーク州、1994年)およびMarch、Advanced Organic Chemistry Reactions, Mechanisms and Structure、第4版、John Wiley & Sons(ニューヨーク、ニューヨーク州、1992年)は本出願で用いる多くの用語に対する一般的な手引きを当業者に提供する。
本発明は、例えば動物を(複数の)ヒト(化)免疫グロブリンの発現にさらに適当なものにする目的で、ヒト以外の動物における内因性免疫グロブリン生成を抑制するための方法を提供する。
loxPが導入されたDT−A発現ベクターの構築
DT−A自殺遺伝子のB細胞特異的発現を達成するために、ウサギカッパ1をコードするBACクローン179L1(ジェンバンク受け入れ番号AY495827)を修飾する。V1の下流のスペーサーからJ遺伝子座を通るカッパ1遺伝子座、イントロンエンハンサー、定常領域をコードするエクソン、3’エンハンサーの下流の配列に対する3’エンハンサーを含むBACクローンの46kbフラグメントをETクローニングによりサブクローニングする。さらなるゲンタマイシン選択カセットを有するpBELOBACベクター骨格をBAC179L1に相同な50bpを有するプライマーでPCR増幅する。加えて順方向プライマーはAttBインテグラーゼ認識部位およびPvuI制限酵素認識部位を有する。加えて逆方向プライマーはPvuI制限酵素認識部位を有する。
IgMの膜形態、2A自己切断ペプチド、Creリコンビナーゼからなる融合タンパク質をコードするヒト(化)重鎖遺伝子座の構築
定常、可変、および連結遺伝子セグメントまたは3’エンハンサー領域に特異的なプローブを用いてゲノムDNAライブラリーからウサギ免疫グロブリン重鎖遺伝子座配列を含有するBACおよびフォスミドクローンを単離した。単離したBAC27N5(ジェンバンク受け入れ番号AY386696)、219D23(ジェンバンク受け入れ番号AY386695)、225P18(ジェンバンク受け入れ番号AY386697)、38A2(ジェンバンク受け入れ番号AY386694)およびフォスミドFos15B(ジェンバンク受け入れ番号AY3866968)をシークエンシングした(Rosら、Gene 330:49−59)。
ヒト化軽鎖遺伝子座の構築
ウサギゲノムBACライブラリーのスクリーニングによりウサギ軽鎖K1遺伝子セグメント(ジェンバンク受け入れ番号AY495827、AY495826)を含有する2つのBAC(179L1および215M22)の同定に至った。
ヒト化重鎖免疫グロブリンを発現するトランスジェニックマウスおよびウサギの作成
カッパ軽鎖プロモーター/エンハンサー配列の制御下でヒト化重および軽鎖免疫グロブリン遺伝子座およびloxPが導入されたジフテリア毒素A遺伝子を含有するトランスジェニックウサギおよびマウスを、受精卵母細胞の前核へのDNAの注射および、続く里親への胚の移入により作成する。トランスジェニック創始動物をPCRにより同定する。ヒト(化)免疫グロブリンMおよびGの発現をELISAにより測定する。ヒト化IgGの発現は1〜5mg/mlである。マウスおよびウサギIgGの発現は各々1〜5μg/mlである。
ヒト化重鎖免疫グロブリンを発現するトランスジェニックニワトリの作成
精巣媒介の遺伝子移入によりトランスジェニックニワトリを作成する。DNA構築物を
(50μg)を0.9%NaCl 500μl中リポフェクション試薬(スーパーフェクト)250μlと混合し、そしてオンドリの精巣に注射する。3〜4週後、トランスジェニック精子を有するオンドリをPCR分析により同定し、そしてメンドリと交配させる。トランスジェニック子孫をPCRにより同定する。ヒト化IgGの発現は1〜5mg/mlである。ニワトリIgYの発現は各々1〜5μg/mlである。
Claims (35)
- ヒト以外のトランスジェニック動物の内因性免疫グロブリンを生成するB細胞において少なくとも1つの自殺遺伝子を選択的に発現するが、外因性免疫グロブリンを生成するB細胞では発現しないこと含み、それにより内因性免疫グロブリンを生成するB細胞は枯渇し、そして内因性免疫グロブリンの生成は抑制されるが該外因性免疫グロブリンの生成は抑制されない外因性免疫グロブリン導入遺伝子座を担持する該ヒト以外のトランスジェニック動物のB細胞における内因性免疫グロブリン生成の選択的抑制のための方法。
- 該外因性免疫グロブリンがヒト(化)免疫グロブリン重および/または軽鎖配列である請求項1に記載の方法。
- 該ヒト以外のトランスジェニック動物のB細胞に導入された該自殺遺伝子がB細胞特異的プロモーターの制御下にあり、そして組換え配列によりフランキングされる請求項1または請求項2に記載の方法。
- 該ヒト(化)免疫グロブリン鎖導入遺伝子座をさらに該組換え配列を認識するリコンビナーゼをコードする発現構築物の一部として該ヒト以外のトランスジェニック動物のB細胞に導入し、ここで該自殺遺伝子の発現が該ヒト(化)免疫グロブリン導入遺伝子座を発現するB細胞における該リコンビナーゼの発現により不活性化される請求項3に記載の方法。
- 該自殺遺伝子が細菌性、真菌性、殺虫性および植物の毒素からなる群から選択される請求項1または請求項2に記載の方法。
- 該自殺遺伝子がジフテリア毒素A鎖である請求項1または請求項2に記載の方法。
- 該自殺遺伝子がプロドラッグ変換酵素である請求項1または請求項2に記載の方法。
- プロドラッグ変換酵素が非哺乳動物起源である請求項7に記載の方法。
- 非哺乳動物起源の該プロドラッグ変換酵素がウイルス性チミジンキナーゼ(TK)、細菌性サイトシンデアミナーゼ(CD)、細菌性カルボキシペプチダーゼG2(CPG2)、プリンヌクレオチドホスホリラーゼ(PNP)、チミジンホスホリラーゼ(TP)、ニトロリダクターゼ(NR)、D−アミノ酸オキシダーゼ(DAAO)、キサンチン−グアニンホスホリボシルトランスフェラーゼ(XGPRT)、ペニシリン−Gアミダーゼ(PGA)、β−ラクタマーゼ、多剤活性化酵素(MDAE)、β−ガラクトシダーゼ(β−Gal)、西洋ワサビベルオキシダーゼ(HRP)およびデオキシリボヌクレオチドキナーゼ(DRNK)からなる群から選択される請求項8に記載の方法。
- プロドラッグ変換酵素がヒト起源である請求項7に記載の方法。
- ヒト起源のプロドラッグ変換酵素がデオキシシチジンキナーゼ(dCK)、カルボキシルエステラーゼ(CE)、カルボキシペプチダーゼA(CPA)、β−グルクロニダーゼ(−Glu)およびチトクロームP450(CYP)からなる群から選択される請求項10に記載の方法。
- 該リコンビナーゼがCre、Cre様、Flp、φC31、λインテグラーゼ、ファージR4リコンビナーゼ、TP901−1リコンビナーゼ、原核細胞性トランスポーゼス、真核細胞性トランスポーゼス、ウイルス性レトロトランスポーゼス、ショウジョウバエコピア様レトロトランスポーゼスおよび非ウイルス性レトロトランスポーゼスからなる群から選択される請求項4に記載の方法。
- 該トランスポーゼスまたはレトロトランスポーゼスがTn1、Tn2、Tn3、Tn4、Tn5、Tn6、Tn9、Tn10、Tn30、Tn101、Tn501、Tn903、Tnl000、Tn1681、Tn2901、ショウジョウバエマリナー、sleeping beautyトランスポーゼス、ショウジョウバエPエレメント、トウモロコシAc、Ds、Mp、Spm、En、ドット、Mu、I、L1、Tol2 Tc1、Tc3、マリナー(Himar1)、マリナー(mos1)およびミノスからなる群から選択される請求項12に記載の方法。
- 該ヒト以外のトランスジェニック動物が若年期の遺伝子再構成により抗体多様化を実質的に停止する請求項1または請求項2に記載の方法。
- 該ヒト以外のトランスジェニック動物が生まれて1か月以内に抗体多様化を実質的に停止する請求項14に記載の方法。
- 該ヒト以外のトランスジェニック動物がげっ歯類、ウサギ、鳥類、ウシ、ブタ、ヒツジ、ヤギおよびウマからなる群から選択される請求項1または請求項2に記載の方法。
- 該げっ歯類がマウスまたはラットである請求項16に記載の方法。
- (1)導入遺伝子、(2)ヒトまたはヒト化免疫グロブリン重および/または軽鎖導入遺伝子座(3)自己切断ペプチドならびに(4)リコンビナーゼを含む遺伝子導入発現構築物。
- (1)導入遺伝子および(2)B細胞特異的プロモーターの制御下であり、そしてリコンビナーゼにより認識される組換え部位によりフランキングされた自殺遺伝子を含む遺伝子導入発現構築物。
- ヒトまたはヒト化免疫グロブリン重および/または軽鎖遺伝子座、自己切断ペプチドおよびリコンビナーゼをさらに含む第1の導入遺伝子ならびにB細胞特異的プロモーターの制御下であり、そして該リコンビナーゼにより認識される組換え部位によりフランキングされた自殺遺伝子をさらに含む第2の導入遺伝子を含む遺伝子導入発現構築物。
- 該リコンビナーゼがCre、Cre様、Flp、φC31、λインテグラーゼ、ファージR4リコンビナーゼおよびTP901−1リコンビナーゼからなる群から選択される部位特異的リコンビナーゼである請求項18、19または20に記載の遺伝子導入発現構築物。
- 該リコンビナーゼが原核細胞性または真核細胞性トランスポーゼスのいずれかである請求項18、19または20に記載の遺伝子導入発現構築物。
- 該リコンビナーゼがウイルス性、ショウジョウバエコピア様または非ウイルス性レトロトランスポーゼスのいずれかである請求項22に記載の遺伝子導入発現構築物。
- 該レトロトランスポーゼスがTn1、Tn2、Tn3、Tn4、Tn5、Tn6、Tn9、Tn10、Tn30、Tn101、Tn501、Tn903、Tnl000、Tn1681、Tn2901、ショウジョウバエマリナー、sleeping beautyトランスポーゼス、ショウジョウバエPエレメント、トウモロコシAc、Ds、Mp、Spm、En、ドット、Mu、I、L1、Tol2 Tc1、Tc3、マリナー(Himar1)、マリナー(mos1)およびミノスからなる群から選択される請求項23に記載の遺伝子導入発現構築物。
- 該組換え部位がloxP部位、FRT部位、細菌性ゲノム組換え部位およびファージ組換え部位からなる群から選択される請求項19または20に記載の遺伝子導入発現構築物。
- 該細菌性ゲノム組換え部位がattBであり、そして該ファージ組換え部位がattPまたは偽attPまたは偽attB部位である請求項25に記載の遺伝子導入発現構築物。
- 該自己切断ペプチドがウイルス性2A/2Bまたは2A様/2B配列から得られる請求項18または20に記載の遺伝子導入発現構築物。
- 該ウイルスがピコルナウイルス科ウイルスファミリー、ウマ鼻炎A(ERAV)ウイルスファミリー、ピコルナウイルス様昆虫ウイルスファミリーからなる群からまたはC型ロタウイルスファミリーから選択される請求項27に記載の遺伝子導入発現構築物。
- 該ウイルスが口蹄疫ウイルス(FMDV)、ウマ鼻炎A(ERAV)ウイルス、またはゾセア・アシグナ(Thosea asigna)ウイルス(TaV)からなる群から選択される請求項27に記載の遺伝子導入発現構築物。
- CD19、CD20、CD21、CD22、CD23、CD24、CD40、CD72、Blimp−1、CD79b、mb−1、チロシンキナーゼblk、VpreB、免疫グロブリンカッパ軽鎖、免疫グロブリンラムダ軽鎖および免疫グロブリンJ鎖またはその修飾体からなる群から選択されるプロモーター/エンハンサーを用いてB細胞において該自殺遺伝子が特異的に発現される請求項19または20に記載の遺伝子導入発現構築物。
- 該B細胞特異的プロモーター/エンハンサーがカッパ軽鎖遺伝子プロモーターまたはその修飾体である請求項30に記載の遺伝子導入発現構築物。
- 請求項18および19または20に記載の遺伝子導入発現構築物を発現するヒト以外のトランスジェニック動物。
- 実質的に遺伝子変換により抗体多様性を作成する請求項32に記載のヒト以外のトランスジェニック動物。
- げっ歯類、ウサギ、ニワトリ、シチメンチョウ、アヒルおよびガチョウを含む鳥類からなる群から選択される請求項32に記載のヒト以外のトランスジェニック動物。
- マウスまたはラットのいずれかである請求項34に記載のヒト以外のトランスジェニック動物。
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- 2005-10-21 JP JP2007538110A patent/JP2008517600A/ja active Pending
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- 2005-10-21 US US11/665,852 patent/US20080184380A1/en not_active Abandoned
- 2005-10-21 EP EP05819960A patent/EP1812578A2/en not_active Withdrawn
- 2005-10-21 CN CNA2005800425778A patent/CN101084317A/zh active Pending
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JP2020150951A (ja) * | 2009-07-08 | 2020-09-24 | カイマブ・リミテッド | 動物モデルおよび治療用分子 |
JP7141427B2 (ja) | 2009-07-08 | 2022-09-22 | カイマブ・リミテッド | 動物モデルおよび治療用分子 |
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US20080184380A1 (en) | 2008-07-31 |
EP1812578A2 (en) | 2007-08-01 |
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CA2584814A1 (en) | 2006-05-04 |
CN101084317A (zh) | 2007-12-05 |
US20060117398A1 (en) | 2006-06-01 |
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