JP5087625B2 - 非ヒトトランスジェニック動物におけるヒトまたはヒト化免疫グロブリンの発現強化 - Google Patents
非ヒトトランスジェニック動物におけるヒトまたはヒト化免疫グロブリンの発現強化 Download PDFInfo
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Description
本発明は、正常B細胞の発生を促進することにより、およびヒト(化)免疫グロブリンローカスを持つ非ヒト動物におけるヒト(化)抗体の発現を維持することにより非ヒトトランスジェニック動物におけるヒト(化)免疫グロブリンの発現を改善する方法に関する。特に、本発明は、B細胞レセプターの構成要素であるヒト化Igαおよび/またはIgβをコードする導入遺伝子ならびに一つまたは複数のヒト(化)免疫グロブリンローカスをコードする導入遺伝子の同時発現に関する。この方法は、例えばトランスジェニック非ヒト動物の血液、乳汁または卵にヒト(化)抗体を優位に発現させる。
抗体は、ガン、アレルギー疾患、移植拒絶の予防および宿主対移植片病などの様々なヒト疾患および状態の処置にうまく使用されてきた重要な種類の医薬品である。
一局面では、本発明は、BCRのキメラIgαサブユニットをコードする導入遺伝子構築物を提供し、ここで、キメラIgαサブユニットは、非ヒトIgαポリペプチド配列の細胞内ドメイン配列および膜貫通ドメイン配列、ならびにさらに配列番号1のヒトIgαの細胞外ドメインと少なくとも85%の配列同一性を有するポリペプチドを含む。
定義
別に定義しない限り、本明細書に使用する技術用語および科学用語は、本発明が属する技術分野の技術者に通例了解されるものと同じ意味を有する。Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994)およびMarch, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, NY 1992)は、本出願に使用される用語の多くについて全般的な指針を当業者に与える。
本発明は、非ヒトトランスジェニック動物におけるヒトまたはヒト化免疫グロブリン(免疫グロブリン鎖を含む)の産生が、その動物のB細胞におけるヒトまたはヒト化Igαおよび/またはIgβを同時発現することにより顕著に増加することができるという認識に少なくとも部分的に基づく。トランスジェニック動物のB細胞にヒトまたはヒト化Igαおよび/またはIgβが含まれることは、B細胞レセプタータンパク質間の相互作用を再構成および改善することにより、そのような導入遺伝子を保持するB細胞の抗原認識、B細胞発生および生存を高めると考えられる。ヒトまたはヒト化Igαおよび/またはIgβ導入遺伝子をすでに保持するトランスジェニック動物におけるヒト化免疫グロブリンの同時発現は、ヒト化免疫グロブリン産生を大いに改善するであろう。好ましくは内因性Igと内因性Igαおよび/またはIgβの両方のノックアウトバックグラウンドに対してヒトまたはヒト化Igαおよび/またはIgβ導入遺伝子と、ヒト化免疫グロブリン導入遺伝子との両方を発現させることが追加的に望ましいであろう。
B細胞レセプターは、膜結合型免疫グロブリンと、IgαおよびIgβと呼ばれる二つのジスルフィド結合糖タンパク質からなるシグナル伝達性ヘテロ二量体とからなる。加えて、BCR関連タンパク質(BAP)が記載されている。
B細胞レセプター、その構成要素、および五つの免疫グロブリンクラスとのその関連は、Wienands et al., EMBO J. 9(2): 449-455 (1990)、Venkitaraman et al., Nature 352: 777-781 (1991)、Herren et al., Immunologic Res. 26(1-3): 35-43 (2002)に記載されている。BCR関連タンパク質は、Adachi et al., EMBO J 15(7): 1534-1541 (1996)およびSchamel et al., PNAS 100(17): 9861-9866 (2003)に記載されている。B細胞の発生および生存にB細胞レセプターが及ぼす影響は、Reth, Annual Reviews of Immunology 10: 97-121 (1992)、Kraus et al., Cell 117(6): 787-800 (2004)、Sayegh et al., Immunological Reviews 175: 187-200 (2000)、Reichlin et al., Journal of Experimental Medicine 193(1): 13-23 (2001)、Pike et al., Journal of Immunology 172: 2210-2218 (2004)、Pelanda et al., Journal of Immunology 169: 865-872 (2002)により記載されている。BCRシグナル伝達のレギュレーションならびにB細胞の発生およびアポトーシスにおけるその影響は、Cronin et al., J. Immunology 161 : 252-259 (1998)、Muller et al., PNAS 97 (15): 8451-8454 (2000)、Cragg et al., Blood 100: 3068-3076 (2002)、Wang et al., J. Immunology 171 : 6381-6388 (2003)、Fuentes-Panana et al., J. Immunology 174: 1245-1252 (2005)に記載されている。上に引用した参考文献の開示は、その全体が参照により本明細書に組み入れられる。
本発明の化合物を投与するための薬学的組成物は、投薬ユニット形態で好都合に提示してもよく、薬剤学の分野で周知の方法により調製してもよい。使用に適した方法および担体は、当技術分野で十分に説明されたもの、例えばRemington, The Science and Practice of Pharmacy, ed. Gennaro et al., 20th Ed. (2000)に説明されたものであるものの、免疫学分野の専門家は、他の方法が公知であり、本発明の組成物の調製に適することを容易に認識している。全ての方法は、活性成分を、一つまたは複数の補助成分を構成する担体と関連させるステップを含む。全般に、薬学的組成物は、活性成分を、液体担体もしくは微粉化固体担体またはその両方と均一および密接に関連させ、次に必要に応じてその産物を所望の製剤に形作ることにより調製される。薬学的組成物において、活性成分は、疾患の過程または状態に所望の効果を生じるために十分な、上に論じた有効量で含められる。さらに、抗体分子の持続性長時間放出のための製剤は、米国特許第6,706,289号に記載されており、この方法は、参照により本明細書に組み入れられる。
ヒトIgαおよびIgβを用いたウサギB細胞系のトランスフェクション
ウサギB細胞におけるヒトmIgMの発現にヒトIgαおよびIgβが及ぼす効果を実証するために、ヒトIgαもしくはIgβまたはヒトmIgMをコードする発現ベクターをこの細胞にトランスフェクションする。
ヒトIgαおよびIgβを用いた任意の動物由来B細胞系のトランスフェクション
動物由来B細胞におけるヒトmIgMの発現にヒトIgαおよびIgβが及ぼす効果を実証するために、ニワトリ(DT40)、ウシおよびブタ由来B細胞に、ヒトIgαもしくはIgβまたはヒトmIgMをコードする発現ベクターをトランスフェクションする。
ヒトIgαおよび/またはIgβの存在下または不在下でヒト化免疫グロブリン軽鎖および/または重鎖導入遺伝子を発現するトランスジェニックウサギ
Fanら(Pathol. Int. 49: 583-594, 1999)により記載されるようにトランスジェニックウサギを作製した。簡潔には、標準法を使用して雌ウサギから過剰排卵させ、雄ウサギと交配させた。前核段階の接合子を輸卵管から集め、20%ウシ胎仔血清を補充したDulbeccoリン酸緩衝食塩水などの適切な培地に入れた。一対のマニピュレーターの助けを借りて、外因性DNA(例えばヒト(化)免疫グロブリンローカスまたはヒトIgαもしくはヒトIgβを有する発現ベクター)を前核にマイクロインジェクションした。形態学的に生存している接合子を偽妊娠ウサギの輸卵管に移植した。偽妊娠は、ヒト絨毛性ゴナドトロピン(hCG)の注射により誘導した。注射された接合子の約0.1〜1%が生きたトランスジェニックウサギに発育した。ゲノムへの導入遺伝子の組み込みは、PCRおよびFISHにより確認した。
Claims (11)
- (a)配列番号1の完全長ヒトIgαサブユニットをコードする導入遺伝子構築物、および/または
(b)配列番号7の完全長ヒトIgβサブユニットをコードする導入遺伝子構築物、ならびに
(c)ヒト免疫グロブリンローカスをコードする導入遺伝子構築物
を含む、非ヒト霊長類、げっ歯類、ウサギ、ブタ、ヒツジ、ヤギ、ウマ、ウシ、ロバ、ニワトリ、シチメンチョウ、アヒルおよびガチョウからなる群より選択される非ヒトトランスジェニック動物であって、結果として生じる導入遺伝子産物が組み合わされてヒトB細胞レセプター複合体を形成する非ヒトトランスジェニック動物。 - 任意の内因性Ig産生ならびに/またはIgαおよび/もしくはIgβサブユニットの発現が、実質的に減少している、請求項1記載の非ヒトトランスジェニック動物。
- ウサギである、請求項1または2記載の非ヒトトランスジェニック動物。
- 配列番号1のネイティブなヒトIgαサブユニットおよび/または配列番号7のネイティブなヒトIgβサブユニット、ならびにヒト免疫グロブリンローカスを発現する、請求項1記載の非ヒトトランスジェニック動物由来の単離されたB細胞。
- 不死化されている、請求項4記載の単離されたB細胞。
- B細胞がウサギ由来である、請求項4または5記載の単離されたB細胞。
- 非ヒト霊長類、げっ歯類、ウサギ、ブタ、ヒツジ、ヤギ、ウマ、ウシ、ロバ、ニワトリ、シチメンチョウ、アヒルおよびガチョウからなる群より選択される非ヒト動物においてヒト抗体を産生させるための方法であって、以下:
(a)配列番号1のネイティブなヒトIgαサブユニットをコードする導入遺伝子構築物、および/または配列番号7のネイティブなヒトIgβサブユニットをコードする導入遺伝子構築物を該非ヒト動物に導入し、そして発現させること;
(b)ヒト免疫グロブリンローカスをコードする導入遺伝子構築物を該非ヒト動物に導入し、そして発現させること;
(c)該動物を抗原刺激に供すること;ならびに
(d)該動物からヒト抗体を単離すること
を含む方法。 - 抗体がポリクローナルまたはモノクローナル抗体である、請求項7記載のヒト抗体を産生させるための方法。
- 非ヒト霊長類、げっ歯類、ウサギ、ブタ、ヒツジ、ヤギ、ウマ、ウシ、ロバ、ニワトリ、シチメンチョウ、アヒルおよびガチョウからなる群より選択されるヒト抗体を発現する非ヒト動物を産生させるための方法であって、
(a)配列番号1のネイティブなヒトIgαサブユニットをコードする導入遺伝子構築物、および/または配列番号7のネイティブなヒトIgβサブユニットもしくはキメラIgβサブユニットのいずれかをコードする導入遺伝子構築物を該非ヒト動物のB細胞に導入し、そして発現させること;ならびに
(b)ヒト(化)免疫グロブリンローカスをコードする導入遺伝子構築物を該非ヒト動物に導入し、そして発現させること
を含み、ここで結果として生じる導入遺伝子産物が組み合わされてヒトB細胞レセプター複合体を形成する、方法。 - 請求項9記載の方法であって、該動物が、遺伝子変換および/または体細胞超突然変異により抗体多様性を創出する方法。
- 動物がウサギである、請求項10記載の方法。
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