JP6763545B2 - 標的化両親媒性ナノキャリア及びその製造方法 - Google Patents
標的化両親媒性ナノキャリア及びその製造方法 Download PDFInfo
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Description
項1. 標的化ポリペプチドと膜結合性ドメインの融合タンパク質を結合した標的化両親媒性ナノキャリア。
項2. 標的化ポリペプチドがペプチドホルモン、受容体のリガンド、抗体又はその抗原結合性フラグメントである、項1に記載の標的化両親媒性ナノキャリア。
項3. 標的化ポリペプチドが、Fab、Fab'、F(ab')2、一本鎖抗体断片(scFv)、二量体化V領域(Diabody)、ジスルフィド安定化V領域(dsFv)又はCDRを含むペプチドからなる群から選ばれる抗原結合性フラグメントである、項1に記載の標的化両親媒性ナノキャリア。
項4. 標的化ポリペプチドが一本鎖抗体断片(scFv)である、項3に記載の標的化両親媒性ナノキャリア。
項5. 両親媒性ナノキャリアがリポソームである、項1〜4のいずれか1項に記載の標的化両親媒性ナノキャリア。
項6. 融合タンパク質が、膜結合性ドメイン−scFv−膜結合性ドメイン(2つの膜結合性ドメインは、同一であっても異なっていてもよい)の構造を有する、項1〜5のいずれか1項に記載の標的化両親媒性ナノキャリア。
項7. 両親媒性ナノキャリアの存在下で、標的化ポリペプチドと膜結合性ドメインの融合タンパク質を無細胞タンパク質合成系で合成させることを特徴とする、前記融合タンパク質が結合された標的化両親媒性ナノキャリアの製造方法。
項8. 標的化ポリペプチドがペプチドホルモン、受容体のリガンド、抗体又はその抗原結合性フラグメントである、項7に記載の標的化両親媒性ナノキャリアの製造方法
項9. 標的化ポリペプチドが、Fab、Fab'、F(ab')2、一本鎖抗体断片(scFv)、二量体化V領域(Diabody)、ジスルフィド安定化V領域(dsFv)又はCDRを含むペプチドからなる群から選ばれる抗原結合性フラグメントである、項7に記載の標的化両親媒性ナノキャリアの製造方法。
項10. 標的化ポリペプチドが一本鎖抗体断片(scFv)である、項9に記載の標的化両親媒性ナノキャリアの製造方法。
項11. 両親媒性ナノキャリアがリポソームである、項7〜10のいずれか1項に記載の標的化両親媒性ナノキャリアの製造方法。
(1)融合タンパク質発現のためのベクターの調製
抗EGFR一本鎖抗体遺伝子は、抗体遺伝子ライブラリーからファージディスプレイ法を用いて抽出した。無細胞タンパク質合成システムを用いてリポソームへ直接抗体を組み込むために、標的化ポリペプチドと3種類の膜結合ドメインからなる4種類の融合タンパク質をデザインし、それらを発現するベクター(pDNA)を構築した(図1A)。融合タンパク質のデザインにあたり、標的化ポリペプチドとしては抗EGFR抗体のアミノ酸配列を選択し、N末端の膜結合性ドメインとしてはキメラ抗原受容体に用いられているCD28 TMDと生体膜に存在することが知られている血小板由来成長因子受容体(PDGFR)の膜貫通ドメイン(PDGFR TMD)を選択した。また分泌シグナルであるヒト免疫グロブリンGリーダー配列(LS)も膜結合性ドメインの1つとして選択し、併せてLSを挿入したベクターを構築した。各融合タンパク質の構成と番号を表1に示す。
各antiEGFR scTab発現プラスミド、リポソーム、再構成型無細胞発現系(PURESYSTEM)を混合し、37℃、4時間インキュベートした(図1B)。無細胞タンパク質合成系は、T7 プロモータ依存的なmRNAの転写に必要なT7RNAポリメラーゼ、アミノ酸、tRNA、リボソームの混合液(キット製品でマスターミックスになっているもの)にT7 プロモータを有するscTab発現プラスミドを200ngとリポソームを添加することで最終的な反応溶液量が25μLになるように調製した溶液である。scTabリポソームの精製・単離は、無細胞タンパク質合成後の反応溶液と密度媒体iodixanol(製品名OptiPrepTM)の濃度が42% w/vになるように混合した溶液1mLの上に25% w/v iodixanol 3mLを積層した。続いて100mM HEPES緩衝溶液0.5mLを積層し、197,000×g、4℃、2時間超遠心分離を行った。超遠心分離後の溶液を液面よりフラクション1−6として分画回収することで、scTabリポソームを単離した。
各antiEGFR scTabのリポソームへの組込み評価は、DOPCリポソーム存在下、PURESYSTEMを用いて各antiEGFR scTabの発現を行い、超遠心法で分離することで各分画を得て、western blot法にて行った。(図2A)。その結果、アミノ末端にLSを含むLS-antiEGFR scTab-PDGFR、あるいはLS-antiEGFR scTab-CD28は上清分画に各融合タンパク質由来のバンドが認められたことから、DOPCリポソームに組込まれることが明らかになった。一方、アミノ末端に LS を含まないantiEGFR scTab-PDGFR、あるいはantiEGFR scTab-CD28は上清分画に各融合タンパク質由来のバンドが認められるものの、LSを有するscTabと比べその存在量は少なかったことからもDOPCリポソームに組込まれにくいことが明らかになった。また、リポソーム存在下での製造において、上清分画に認められたLS-antiEGFR scTab-PDGFR、あるいはLS-antiEGFR scTab-CD28がDOPCリポソームのシャペロン活性による凝集抑制によるものかを検証する為に、リポソーム非存在下で無細胞タンパク質合成を行った(図2B)。その結果、リポソーム非存在下では沈殿分画にのみ各融合タンパク質が認められたことから、上清分画に存在する各融合タンパク質はリポソームに組込まれることで可溶化され、上清分画に移行したと考えられる。
リポソームへ組込まれた融合タンパク質(LS-antiEGFR scTab-PDGFR、LS-antiEGFR scTab-CD28)が標的タンパク質(EGFR)特異的に結合活性を有するかを検証するために、LS-antiEGFR scTab-PDGFRおよびLS-antiEGFR scTab-CD28提示DOPCリポソームをそれぞれプレートに固定化し、ELISA法にて確認した(図3A)。その結果、LS-antiEGFR scTab-CD28提示DOPCリポソームはLS-antiEGFR scTab-PDGFR提示DOPCリポソームより多くのEGFRと結合できることが明らかとなった。抗体と抗原との結合親和性の強度は用いている一本鎖抗体可変領域(scFv)のアミノ酸配列、強いては、その立体構造により規定される。膜結合性ドメインとしてPDGFRを用いた場合、疎水性が高いためリポソームへの組込みは安定されるが、EGFRとの結合親和性が低下するような抗原認識部位の立体構造が変化したと考えられる。そのことからも、単に疎水性の高い膜結合性ドメインを用いてリポソームへの組込みを安定させるだけではなく、scFvの結合親和性の低下を避けることが可能な活性と挿入のバランスに優れた疎水性ドメインを用いることが融合タンパク質提示DOPCリポソームの調製にあたり望まれた。
ローダミンBで蛍光標識したリポソーム(DOPC/DMPE-RhoB)にLS-antiEGFR scTabを提示したリポソーム(DOPC/DMPE-RhoB/LS-antiEGFR scTab)を用いて、EGFR発現細胞とDOPC/DMPE-RhoB/ LS-antiEGFR scTab-CD28リポソームとの結合親和性に関して、図6に示すEGFR発現量が異なる細胞株を用いてフローサイトメトリー(図4)と共焦点レーザー顕微鏡観察(図5)を行った。フローサイトメトリーの結果より、各細胞のEGFR発現量に依存的なDOPC/DMPE-RhoB/LS-antiEGFR scTabリポソームの結合が認められた。このことから、 LS-antiEGFR scTab提示リポソームは細胞膜に存在するEGFRを認識して細胞と結合することが明らかとなった。
(1)融合タンパク質発現のためのベクターの調製
リポソーム膜への組込み効率と結合親和性のバランスが調和した融合タンパク質の創出を目的に、LS-antiEGFRscTab-CD28(#2)を設計鋳型とし、標識化ポリペプチドにantiEGFR scFvを選択し、標的化ポリペプチドのN末端ドメインにはCD28 TMDとLSを選択した。また、標的化ポリペプチドのC末端ドメインにCD28 TMDとする融合タンパク質をデザインし、それらを発現するベクターを構築した。併せて、膜結合性ドメインを有さない融合タンパク質発現ベクターも構築した (図7)。各融合タンパク質の構成と番号を表2に示し、以降では融合タンパク質を番号で記載する。
上記ベクターを用いて、実施例1(2)の製造法と同様な無細胞蛋白質合成システムを用いて、各融合タンパク質がリポソームに組込まれた標的指向型キャリアを製造し、リポソームへの組込みを評価した(図8)。その結果、膜結合ドメインを有さない#4 scFv, #11 scFvではDOPCリポソームの添加に依らず、発現した融合タンパク質は上清分画には存在せず、全て沈殿分画に存在した。この結果より、実施例1(2)で明らかとなった#1 scTab、 #2 scTab、 #PD1 scTab、 #PD2 scTabのDOPCリポソームへの組込みは、標的化ポリペプチドは関係なく、膜結合性ドメインの有無のみで決定することが明らかとなった。また、LSしか膜結合性ドメインを有さない#3 scTabにおいては非常に僅かであるが、DOPCリポソームの添加によってDOPCリポソームへの組込みが認められた。以上の結果は、実施例1(2)で明らかとなったLSを有する#2 scTab、#PD2 scTabの方が、LSを有さない#1 scTab、#PD1 scTabより組込み効率が良いという結果を裏付けるものであり、LSにより翻訳途中のscTabが緩やかにリポソーム膜と相互作用し、続く翻訳によりTMDが合成されscTabがリポソーム膜に強固に組込まれると考えられる。一方で、CD28 TMDを有する他のscTab(#5 scTab, #6 scTab, #9 scTab, #10 scTab)は、CD28 TMDの融合部位に依らず良好な組込み効率を示した。また、#8 scTabの発現量は非常に少なく、リポソームへの組込みを評価する量の#8 scTabを得ることが出来なかった。
実施例1(3)と同様にscTab提示DOPCリポソームをマイクロプレートに固定化し、抗原であるEGFRとの結合親和性を評価した(図9)。検討にあたり、各ウェルあたりタンパク質量で33nM scTabを50μL添加し、固定化した。その結果、いずれのscTab 提示DOPCリポソームを固相化した場合でもEGFRとの結合親和性が認められ、特にN末端とC末端に膜結合性ドメインを有する融合タンパク質(#2、#6、#PD2、#7scTab)提示リポソームは強い結合親和性を示した。しかしながら、scTab分子内に膜結合性ドメインが1つしかない#5 scTab、#9 scTab 提示リポソームにおいては、EGFRとの結合親和性は低いものであった。scFvは熱力学的に不安定であり、タンパク質の構造変化によりそのままでは抗原との結合親和性が容易に減弱することが知られている。以上より、scTabが結合親和性を示すには、scFvの自由度を制限することで熱力学的な安定性をもたらすことが重要であり、それを可能とすると考えられるscFvの両末端に膜結合性ドメインを有することが望まれる。
上記#2 scTabベクターを用いて、実施例1(4)の製造法と同様な無細胞蛋白質合成システムを用いて、#2 scTabがDOPC/DMPE-RhoBリポソームに組込まれた標的化両親媒性ナノキャリアを製造し、正常マウスへ尾静脈内投与を行い血中からの消失を評価した(図11)。その結果、静脈内投与後のリポソームの血漿中プロファイルはDOPC/DMPE-RhoBリポソーム、#2 scTab組込みDOPC/DMPE-RhoBリポソームにおいて大きな差は認められなかった。
Claims (10)
- 標的化ポリペプチドと膜結合性ドメインの融合タンパク質を結合した標的化両親媒性ナノキャリアであって、前記融合タンパク質が、膜結合性ドメイン−標的化ポリペプチド−膜結合性ドメイン(2つの膜結合性ドメインは、同一であっても異なっていてもよい)の構造を有する、標的化両親媒性ナノキャリア。
- 前記融合タンパク質が、膜結合性ドメイン−scFv−膜結合性ドメイン(2つの膜結合性ドメインは、同一であっても異なっていてもよい)の構造を有する、請求項1に記載の標的化両親媒性ナノキャリア。
- 前記融合タンパク質が、膜結合性ドメイン−標的化ポリペプチド−膜結合性ドメイン(1つの膜結合性ドメインは、リーダー配列である)の構造を有する、請求項1に記載の標的化両親媒性ナノキャリア。
- 標的化ポリペプチドがペプチドホルモン、受容体のリガンド、抗体又はその抗原結合性フラグメントである、請求項1に記載の標的化両親媒性ナノキャリア。
- 両親媒性ナノキャリアがリポソームである、請求項1〜4のいずれか1項に記載の標的化両親媒性ナノキャリア。
- 両親媒性ナノキャリアの存在下で、標的化ポリペプチドと膜結合性ドメインの融合タンパク質を無細胞タンパク質合成系で合成させる工程を含み、前記融合タンパク質が、膜結合性ドメイン−標的化ポリペプチド−膜結合性ドメイン(2つの膜結合性ドメインは、同一であっても異なっていてもよい)の構造を有することを特徴とする、前記融合タンパク質が結合された標的化両親媒性ナノキャリアの製造方法。
- 前記融合タンパク質が、膜結合性ドメイン−scFv−膜結合性ドメイン(2つの膜結合性ドメインは、同一であっても異なっていてもよい)の構造を有する、請求項6に記載の標的化両親媒性ナノキャリアの製造方法。
- 前記融合タンパク質が、膜結合性ドメイン−標的化ポリペプチド−膜結合性ドメイン(1つの膜結合性ドメインは、リーダー配列である)の構造を有する、請求項6に記載の標的化両親媒性ナノキャリアの製造方法。
- 標的化ポリペプチドがペプチドホルモン、受容体のリガンド、抗体又はその抗原結合性フラグメントである、請求項6に記載の標的化両親媒性ナノキャリアの製造方法。
- 両親媒性ナノキャリアがリポソームである、請求項6〜9のいずれか1項に記載の標的化両親媒性ナノキャリアの製造方法。
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