JP2018019700A - キメラ主要組織適合複合体(mhc)ii分子を発現する遺伝子改変されたマウス - Google Patents
キメラ主要組織適合複合体(mhc)ii分子を発現する遺伝子改変されたマウス Download PDFInfo
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Abstract
Description
本願は、2011年10月28日に出願された米国仮出願第61/552,584号の優先権の利益を主張する。この出願は、その全体が本明細書に参考として援用される。
本発明は、ヒト化主要組織適合複合体(MHC)クラスIIタンパク質を発現するように遺伝子操作された非ヒト動物、例えば、げっ歯動物(例えば、マウスもしくはラット)、ならびにこれを発現する胚、組織、および細胞に関する。本発明は、さらに、ヒト化MHC IIタンパク質を発現する遺伝子改変された非ヒト動物を作製するための方法に関する。また、リンパ球を活性化しそしてT細胞に会合するペプチドを同定するため、そしてヒトワクチンおよび他の治療剤を開発するための、ヒト化MHCクラスIIタンパク質を発現する非ヒト動物、細胞、および組織を用いる方法も、提供する。
獲得免疫応答において、外来性抗原が、Bリンパ球(例えば、免疫グロブリン)およびTリンパ球(例えば、T細胞受容体すなわちTCR)上の受容体分子によって認識される。これらの外来性抗原は、特殊文化したタンパク質、一般に主要組織適合複合体(MHC)分子と呼ばれるタンパク質によって、細胞の表面にペプチド断片として提示される。MHC分子は、約4Mbに及ぶ遺伝子の連結したクラスターとして見出される複数の遺伝子座によってコードされる。マウスにおいて、MHC遺伝子は、第17番染色体上に見出され、歴史的な理由から、組織適合性2(H−2)遺伝子と呼ばれる。ヒトにおいて、上記遺伝子は、第6染色体上に見出され、ヒト白血球抗原(HLA)遺伝子と呼ばれる。マウスおよびヒトにおける遺伝子座は、多遺伝子性である;これらは、ヒトゲノムとマウスゲノムとにおいて類似の構成(organization)を示すMHC遺伝子の3つの高度多形性クラス(クラスI、IIおよびIII)を含む(それぞれ、図2および図3を参照されたい)。
ヒトMHCクラスIIタンパク質およびそのキメラに関連し、CD4+T細胞に結合するペプチドを生成するかまたは同定するための生物系が提供される。細胞性免疫応答において機能するヒト化分子を発現する非ヒト細胞を含む非ヒト動物が提供される。ヒト化MHC IIタンパク質をコードするヒト化げっ歯動物遺伝子座もまた提供される。ヒト化MHC分子を発現するヒト化げっ歯動物細胞もまた提供される。1種または複数種のヒト化免疫系分子を発現するヒト化げっ歯動物細胞を含む、in vivo系およびin vitro系が提供される。
特定の実施形態では、例えば以下が提供される:
(項目1)
内在性主要組織適合複合体II(MHC II)α遺伝子の遺伝子座にヒト/非ヒトキメラMHC II αポリペプチドをコードするヌクレオチド配列を含む非ヒト動物であって、
該ヒト/非ヒトキメラMHC II αポリペプチドのヒト部分が、ヒトMHC II α細胞外ドメインを含み、
該動物が、該動物の細胞の表面に機能的なMHC II複合体を発現する、
非ヒト動物。
(項目2)
前記ヒトMHC II α細胞外ドメインが、ヒトα1ドメインおよびα2ドメインを含む、項目1に記載の動物。
(項目3)
前記ヌクレオチド配列が、内在性非ヒトMHC II αプロモーターおよび調節エレメントの調節制御下で発現される、項目1に記載の動物。
(項目4)
前記ヒト/非ヒトキメラMHC II αポリペプチドの非ヒト部分が、内在性非ヒトMHC II αポリペプチドの膜貫通ドメインおよび細胞質ドメインを含む、項目1に記載の動物。
(項目5)
前記ヒト/非ヒトキメラMHC II αポリペプチドの前記ヒト部分が、HLA−DR、HLA−DQ、およびHLA−DPからなる群より選択されるヒトHLAクラスIIタンパク質に由来する、項目1に記載の動物。
(項目6)
前記ヒト/非ヒトキメラMHC II αポリペプチドの前記ヒト部分が、ヒトHLA−DR4タンパク質に由来する、項目5に記載の動物。
(項目7)
げっ歯動物である、項目1に記載の動物。
(項目8)
マウスである、項目7に記載のげっ歯動物。
(項目9)
内在性MHC II β遺伝子の遺伝子座にヒト/非ヒトキメラMHC II βポリペプチドをコードするヌクレオチド配列をさらに含む、項目1に記載の動物。
(項目10)
内在性MHC II β遺伝子の遺伝子座にヒト/非ヒトキメラMHC II βポリペプチドをコードするヌクレオチド配列を含む非ヒト動物であって、該ヒト/非ヒトキメラMHC II βポリペプチドのヒト部分が、ヒトMHC II β細胞外ドメインを含み、かつ該動物は、該動物の細胞の表面に機能的なMHC II複合体を発現する、非ヒト動物。
(項目11)
前記ヒトMHC II β細胞外ドメインが、ヒトβ1ドメインおよびβ2ドメインを含む、項目10に記載の動物。
(項目12)
前記ヌクレオチド配列が、内在性非ヒトMHC II βプロモーターおよび調節エレメントの調節制御下で発現される、項目10に記載の動物。
(項目13)
前記ヒト/非ヒトキメラMHC II βポリペプチドの非ヒト部分が、内在性非ヒトMHC II βポリペプチドの膜貫通ドメインおよび細胞質ドメインを含む、項目10に記載の動物。
(項目14)
前記ヒト/非ヒトキメラMHC II βポリペプチドの前記ヒト部分が、HLA−DR、HLA−DQ、およびHLA−DPからなる群より選択されるヒトHLAクラスIIタンパク質に由来する、項目10に記載の動物。
(項目15)
前記ヒト/非ヒトキメラMHC II βポリペプチドの前記ヒト部分が、ヒトHLA−DR4タンパク質に由来する、項目14に記載の動物。
(項目16)
げっ歯動物である、項目10に記載の動物。
(項目17)
マウスである、項目16に記載のげっ歯動物。
(項目18)
内在性MHC II α遺伝子の遺伝子座にヒト/非ヒトキメラMHC II αポリペプチドをコードするヌクレオチド配列をさらに含む、項目10に記載の動物。
(項目19)
内在性MHC II遺伝子の遺伝子座にヒト/げっ歯動物キメラMHC II αポリペプチドをコードする第1のヌクレオチド配列およびヒト/げっ歯動物キメラMHC II βポリペプチドをコードする第2のヌクレオチド配列を含むげっ歯動物であって、
該ヒト/げっ歯動物キメラMHC II αポリペプチドのヒト部分が、ヒトMHC II α細胞外ドメインを含み、該ヒト/げっ歯動物キメラMHC II βポリペプチドのヒト部分が、ヒトMHC II β細胞外ドメインを含み、
該ヒト/げっ歯動物キメラMHC II αポリペプチドおよびMHC II βポリペプチドが、該げっ歯動物の細胞の表面に機能的なMHC II複合体を形成する、
げっ歯動物。
(項目20)
前記ヒトMHC II α細胞外ドメインが、ヒトα1ドメインおよびα2ドメインを含む、項目19に記載のげっ歯動物。
(項目21)
前記ヒトMHC II β細胞外ドメインが、ヒトβ1ドメインおよびβ2ドメインを含む、項目19に記載のげっ歯動物。
(項目22)
前記第1のヌクレオチド配列が、内在性げっ歯動物MHC II αプロモーターおよび調節エレメントの調節制御下で発現され、前記第2のヌクレオチド配列が、内在性げっ歯動物MHC II βプロモーターおよび調節エレメントの調節制御下で発現される、項目19に記載のげっ歯動物。
(項目23)
前記ヒト/げっ歯動物キメラMHC II αポリペプチドのげっ歯動物部分が、内在性げっ歯動物MHC II αポリペプチドの膜貫通ドメインおよび細胞質ドメインを含む、項目19に記載のげっ歯動物。
(項目24)
前記ヒト/げっ歯動物キメラMHC II βポリペプチドのげっ歯動物部分が、内在性げっ歯動物MHC II βポリペプチドの膜貫通ドメインおよび細胞質ドメインを含む、項目19に記載のげっ歯動物。
(項目25)
前記ヒト/げっ歯動物キメラMHC II αポリペプチドおよびβポリペプチドの前記ヒト部分が、HLA−DR、HLA−DQ、およびHLA−DPからなる群より選択されるヒトHLAクラスIIタンパク質に由来する、項目19に記載のげっ歯動物。
(項目26)
前記ヒト/げっ歯動物キメラMHC II αポリペプチドおよびβポリペプチドの前記ヒト部分が、ヒトHLA−DR4タンパク質に由来する、項目25に記載のげっ歯動物。
(項目27)
マウスである、項目19に記載のげっ歯動物。
(項目28)
前記キメラMHC II αポリペプチドおよびβポリペプチドのげっ歯動物部分が、マウスH−2Eタンパク質に由来する、項目27に記載のマウス。
(項目29)
項目19に記載のげっ歯動物であって、それらの内在性げっ歯動物MHC II遺伝子座から、機能的な内在性MHC IIポリペプチドを発現しない、げっ歯動物。
(項目30)
内在性マウスMHC II遺伝子座にヒト/マウスキメラMHC II αポリペプチドをコードする第1のヌクレオチド配列およびヒト/マウスキメラMHC II βポリペプチドをコードする第2のヌクレオチド配列を含むマウスであって、
該キメラMHC II αポリペプチドのヒト部分が、ヒトHLA−DR4タンパク質のαポリペプチドに由来する細胞外ドメインを含み、該キメラMHC II βポリペプチドのヒト部分が、ヒトHLA−DR4タンパク質のβポリペプチドに由来する細胞外ドメインを含み、
該キメラMHC II αポリペプチドのマウス部分が、マウスH−2E α鎖の膜貫通ドメインおよび細胞質ドメインを含み、該キメラMHC II βポリペプチドのマウス部分が、マウスH−2E β鎖の膜貫通ドメインおよび細胞質ドメインを含み、
該マウスが、該マウスの細胞の表面に機能的なキメラHLA−DR4/H−2E MHC
II複合体を発現する、
マウス。
(項目31)
前記αポリペプチドの前記細胞外ドメインが、ヒトα1ドメインおよびα2ドメインを含む、項目30に記載のマウス。
(項目32)
前記βポリペプチドの前記細胞外ドメインが、ヒトβ1ドメインおよびβ2ドメインを含む、項目30に記載のマウス。
(項目33)
前記第1のヌクレオチド配列が、内在性マウスMHC II αプロモーターおよび調節エレメントの調節制御下で発現され、前記第2のヌクレオチド配列が、内在性マウスMHC II βプロモーターおよび調節エレメントの調節制御下で発現される、項目30に記載のマウス。
(項目34)
項目30に記載のマウスであって、それらの内在性マウス遺伝子座から、機能的な内在性MHC IIポリペプチドを発現しない、マウス。
(項目35)
ヒト/マウスキメラMHC II複合体を発現するようにマウスのMHC II遺伝子座を改変する方法であって、該内在性マウスMHC II遺伝子座において、マウスMHC II複合体をコードするヌクレオチド配列を、ヒト/マウスキメラMHC II複合体をコードするヌクレオチド配列で置き換える工程を含む、方法。
(項目36)
前記ヒト/マウスキメラMHC II複合体をコードする前記ヌクレオチド配列が、ヒトMHC II αポリペプチドの細胞外ドメインおよびマウスMHC II αポリペプチドの膜貫通ドメインおよび細胞質ドメインをコードする第1のヌクレオチド配列と、ヒトMHC II βポリペプチドの細胞外ドメインおよびマウスMHC II βポリペプチドの膜貫通ドメインおよび細胞質ドメインをコードする第2のヌクレオチド配列とを含む、項目35に記載の方法。
(項目37)
前記キメラMHC II複合体のヒト部分が、HLA−DR、HLA−DQ、およびHLA−DPからなる群より選択されるヒトHLAクラスIIタンパク質に由来する、項目35に記載の方法。
(項目38)
前記キメラMHC II複合体のマウス部分が、マウスH−2Eタンパク質に由来し、該キメラMHC II複合体のヒト部分が、ヒトHLA−DR4タンパク質に由来する、項目35に記載の方法。
(項目39)
キメラMHC II αポリペプチドおよびβポリペプチドのヒト部分が、HLA−DR、HLA−DQ、およびHLA−DPからなる群より選択されるヒトHLAクラスIIタンパク質に由来する、項目36に記載の方法。
(項目40)
キメラMHC II αポリペプチドおよびβポリペプチドのマウス部分が、マウスH−2Eタンパク質に由来し、キメラMHC II αポリペプチドおよびβポリペプチドのヒト部分が、ヒトHLA−DR4タンパク質に由来する、項目36に記載の方法。
(項目41)
前記置き換えが、単一のES細胞において行われ、該単一のES細胞が、マウス胚に導入されて、マウスを作製する、項目35に記載の方法。
定義
本発明は、ヒトまたはヒト化MHC IIポリペプチドを発現する遺伝子改変された非ヒト動物(例えば、マウス、ラット、ウサギなど);これらを含む胚、細胞および組織;これらを作製する方法;ならびにこれらを使用する方法を提供する。他に定義されない限り、本明細書中で使用される全ての用語および語句は、反対のことが明らかに示されない限り、またはこの用語もしくは語句が使用される文脈から別段明らかにされない限り、この用語および語句が当該分野で果たしている意味を含む。
種々の態様では、本発明は、一般に、そのゲノムにヒトまたはヒト化MHC II複合体をコードするヌクレオチド配列を含む、遺伝子改変された非ヒト動物を提供する;従って、該動物は、ヒトまたはヒト化MHC II複合体(例えば、MHC IIのαポリペプチドおよびβポリペプチド)を発現する。
種々の実施形態では、本明細書中で記載される遺伝子改変された非ヒト動物は、その細胞表面にヒトまたはヒト化MHC IIを有するAPCを作製し、結果として、サイトゾルタンパク質に由来するペプチドを、T細胞に対するエピトープとしてヒト様の様式で提示する(何故なら、その複合体の構成要素の実質的に全てが、ヒトまたはヒト化であるからである)。本発明の遺伝子改変された非ヒト動物は、ヒト化動物においてヒト免疫系の機能を研究するため;免疫応答を惹起する抗原および抗原エピトープ(例えば、T細胞エピトープ、例えば、独特なヒトがんエピトープ)を同定するため、例えば、ワクチン開発に使用するため;ワクチン候補の評価および他のワクチン戦略のため;ヒト自己免疫を研究するため;ヒト感染症を研究するため;および別の方法で、ヒトMHC発現に基づくより良い治療戦略を案出するために、使用され得る。
内在性MHCクラスII H−2AおよびH−2E遺伝子座の欠失
内在性MHCクラスII H−2Ab1、H−2Aa、H−2Eb1、H−2Eb2、およびH−2Ea遺伝子の欠失を導入するためのターゲッティングベクターを、VELOCIGENE(登録商標)遺伝子操作技術を用いて作製した(例えば、米国特許第6,586,251号およびValenzuelaら、上掲を参照されたい)。細菌人工染色体(BAC)RP23−458i22(Invitrogen)DNAを、内在性MHCクラスII遺伝子H−2Ab1、H−2Aa、H−2Eb1、H−2Eb2、およびH−2Eaを欠失させるために改変した。
ヒト化H−2Eb1およびH−2Ea遺伝子を含む大型ターゲッティングベクター(LTVEC)の生成
ヒト化MHC II配列を導入するためのターゲッティングベクターを、図4に図示するように設計した。VELOCIGENE(登録商標)遺伝子操作技術を用い、細菌人工染色体(BAC)RP23−458i22 DNAを、種々のステップにおいて改変して:(1)BALB/c H−2Ea遺伝子由来の機能的なI−E αエクソン1を含むベクターを創製し(図4A);(2)マウスI−E β遺伝子のエクソン2および3の、ヒトDRβ1*04のエクソン2および3での置き換えならびにマウスI−E αのエクソン2および3の、ヒトDRα1*01のエクソン2および3での置き換えを含むベクターを創製し(図4B);(3)残りのマウスI−E βエクソンの中でヒトDRβ1*04のエクソン2および3、ならびに残りのマウスI−E αエクソンの中でヒトDRα1*01のエクソン2および3を担持し、BALB/cマウス由来の機能的なI−E αエクソン1を含むベクターを創製し(ステップ(1)(図4C);かつ(4)(3)で生成したベクターの潜在スプライス部位を除去した(図4D)。
ヒト化MHC IIマウスの作製
実施例2のベクターを用いてヒト化MHC IIマウスを作製するための戦略の簡略図を、図5および8に提示する。
遺伝子改変されたマウスにおけるキメラHLA−DR4の発現
WTマウスまたはヘテロ接合型ヒト化HLA−DR4マウス(「1681 HET」)由来の脾臓を、コラゲナーゼD(Roche Bioscience)で灌流させ、ACK溶解緩衝液で赤血球を溶解させた。脾細胞を、2日間にわたって、25マイクログラム/mLのポリ(I:C)と共に培養し、MHC−II遺伝子の発現を刺激した。ヒトHLA−DR4の細胞表面発現を、蛍光色素コンジュゲートした抗CD3(17A2)、抗CD19(1D3)、抗CD11c(N418)、抗F480(BM8)、抗I−A/I−E(M15)および抗HLADR(L243)を用い、FACSによって分析した。BD−LSRIIを用いてフローサイトメトリーを行った。ヒトHLA−DR4の発現は、CD19+B細胞の表面で明らかに検出可能であり、toll様受容体アゴニストのポリ(I:C)による刺激によって有意に上方制御された(図9を参照されたい)。
当業者は、慣用的実験以上のものを用いることなく、本明細書中で記載される本発明の特定の実施形態の多くの均等物を認識するか、または確かめることができる。このような均等物は、以下の特許請求の範囲によって包含されることが企図される。
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- 本願明細書に記載の発明。
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