JP2017119701A - バイオ医薬の送達のためのエキソソーム - Google Patents
バイオ医薬の送達のためのエキソソーム Download PDFInfo
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Abstract
【解決手段】例えば樹状細胞に由来するエキソソームを含む組成物であって、エキソソームには外因性タンパク質及び/又はペプチドがエレクトロポレーション等の方法によって搭載されている組成物。前記タンパク質及び/又はペプチドは抗体又はその抗原結合フラグメントであることが好ましい。
【選択図】なし
Description
本明細書で記載されているように、好ましい実施形態において、エキソソームに組み込まれるタンパク質及び/又はペプチドは抗体又は抗体フラグメントである。本明細書において、「抗体」という語は、抗体全体及び任意の抗原結合フラグメント(すなわち「抗原結合部位」)又はそれらの単鎖を包含する。抗体とは、ジスルフィド結合で相互に連結された少なくとも2つの重(H)鎖及び2つの軽(L)鎖、又はそれらの抗原結合部分を含む糖タンパク質を指す。各重鎖は、重鎖可変領域(本明細書ではVHと略記)及び重鎖定常領域で構成される。各軽鎖は、軽鎖可変領域(本明細書ではVLと略記)及び軽鎖定常領域で構成される。重度及び軽鎖の可変領域は、抗原と相互作用する結合ドメインを含む。VH及びVL領域は、より高度に保存された領域(フレームワーク領域(FR)と呼ばれる。)が散在した超可変領域(相補性決定領域(CDR)と呼ばれる。)にさらに分類することができる。
本発明のエキソソームは所望の細胞型又は組織に対してターゲティングされ得る。このターゲティングは、標的となる細胞の表面で発現する細胞表面部分に結合するターゲティング部分をエキソソームの表面で発現させることによって達成される。典型的には、ターゲティング部分は、エキソソームの表面で通常発現する膜貫通タンパク質との融合タンパク質として発現するペプチドである。
本発明の構築物は任意の適切な方法によって投与され得る。ヒト又は動物の対象に対する投与は、非経口、筋肉内、脳内、血管内(例えば静脈内)、皮下、鼻腔内、心臓内、脳室内、腹腔内又は経皮投与から選択され得る。典型的には、送達の方法は注射によるものである。好ましくは、注射は筋肉内又は血管内(例えば静脈内)注射である。医師は、個々の患者ごとに必要とされる投与経路を決定することができる。
エレクトロポレーション緩衝液(1.15mMリン酸カリウム(pH7.2)、25mM KCl、21%オプティプレップ(Optiprep))中で、ヒト胎児由来腎臓細胞(HEK)エキソソームをフィコエリトリン(PE)結合ヤギ抗ウサギIgG抗体と混合し、ローディングされないままにする(抗体との混合は行ったが、エレクトロポレーションは行わない)か、又は200mVでエレクトロポレートした。次いで、抗体搭載エキソソームをHEK細胞に添加し、2時間インキュベートして575nmで蛍光を測定した。次いで、HEK細胞をリン酸緩衝生理食塩水(PBS)で洗浄し、画像化した。Figure1は、200mVでローディングされたエキソソーム(B)で細胞を処理した場合の、(抗体と混合されたが、エレクトロポレートされていない対照エキソソーム(A)と比較した)PE−抗体シグナルの細胞質内及び核内局在を示す。
ポリヌクレオチド配列:ggctggaccctgaacagcgcgggctatctgctgggcaaaattaacctgaaagcgctggcggcgctggcga aaaaaattctg(配列番号3)によってコードされたトランスポータンペプチド:GWTLNSAGYLLGKINLKALAALAKKIL(配列番号2)を、国際公開第2010/119256号に記載されたLamp2b発現ベクター内に挿入した。
2 Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi−Castagnoli P, Raposo G, Amigorena S (1998), Eradication of established murine tumors using a novel cell−free vaccine: dendritic cell−derived exosomes, Nat Med 4:594−600.
3 Hao S, Moyana T, Xiang J (2007), Review: cancer immunotherapy by exosome−based vaccines, Cancer Biother Radiopharm 22:692−703.
4 Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007), Exosome−mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells, Nat Cell Biol 9(6):654−9.
5 Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena−Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008), Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers, Nat Cell Biol 10(12):1470−6.
6 WO2010/119256
実施形態1:
エキソソームを含む組成物であって、エキソソームには外因性タンパク質及び/又はペプチドが搭載されており、前記タンパク質及び/又はペプチドは抗体又はその抗原結合フラグメントである、組成物。
実施形態2:
エキソソームは樹状細胞に由来する、実施形態1に記載の組成物。
実施形態3:
前記タンパク質及び/又はペプチドは、ヒト又は動物の身体に治療を行う方法における使用のためのものである、実施形態1又は2に記載の組成物。
実施形態4:
前記タンパク質及び/又はペプチドは、癌、自己免疫状態、及び/又は臓器若しくは細胞移植拒絶反応の治療及び/又は予防における使用のためのものである、実施形態3に記載の組成物。
実施形態5:
エキソソームは、該エキソソームの表面で発現するターゲティング部分を含む、実施形態1〜4のいずれかに記載の組成物。
実施形態6:
前記ターゲティング部分は、標的となる細胞上に存在する部分に結合するペプチドを含む、実施形態5に記載の組成物。
実施形態7:
エキソソームは、前記ペプチドターゲティング部分を組み込むように修飾されたエキソソーム膜貫通タンパク質を含む、実施形態6に記載の組成物。
実施形態8:
エキソソーム膜貫通タンパク質は、Lamp−1、Lamp−2、CD13、CD86、フロチリン、及びシンタキシン−3から選択される、実施形態7に記載の組成物。
実施形態9:
エキソソーム膜貫通タンパク質はLamp−2bである、実施形態8に記載の組成物。
実施形態10:
前記抗体又はそのフラグメントはモノクローナル抗体又はそのフラグメントである、実施形態1〜9のいずれかに記載の組成物。
実施形態11:
エキソソームにタンパク質及び/又はペプチドを搭載する方法であって、エキソソームの組成物を用意するステップと、エレクトロポレーションによってエキソソームにタンパク質及び/又はペプチドを搭載するステップと、を含み、前記タンパク質及び/又はペプチドは抗体又はその抗原結合フラグメントである、方法。
実施形態12:
エレクトロポレーションは20〜100v/cmの電圧で行われる、又はエレクトロポレーションは200mVの電圧で行われる、実施形態11に記載の方法。
実施形態13:
エキソソームにタンパク質及び/又はペプチドを搭載する方法であって、エキソソームの組成物を用意するステップと、カチオン性リポソームトランスフェクション剤を使用して、トランスフェクションによってエキソソームにタンパク質及び/又はペプチドを搭載するステップと、を含み、前記タンパク質及び/又はペプチドは抗体又はその抗原結合フラグメントである、方法。
実施形態14:
前記抗体又はそのフラグメントはモノクローナル抗体又はそのフラグメントである、実施形態11〜13のいずれかに記載の方法。
実施形態15:
エキソソームは樹状細胞に由来する、実施形態11〜14のいずれかに記載の方法。
本発明は、以下の実施例を参照してより詳細に説明される。
Claims (15)
- エキソソームを含む組成物であって、エキソソームには外因性タンパク質及び/又はペプチドが搭載されており、前記タンパク質及び/又はペプチドは抗体又はその抗原結合フラグメントである、組成物。
- エキソソームは樹状細胞に由来する、請求項1に記載の組成物。
- 前記タンパク質及び/又はペプチドは、ヒト又は動物の身体に治療を行う方法における使用のためのものである、請求項1又は2に記載の組成物。
- 前記タンパク質及び/又はペプチドは、癌、自己免疫状態、及び/又は臓器若しくは細胞移植拒絶反応の治療及び/又は予防における使用のためのものである、請求項3に記載の組成物。
- エキソソームは、該エキソソームの表面で発現するターゲティング部分を含む、請求項1〜4のいずれか一項に記載の組成物。
- 前記ターゲティング部分は、標的となる細胞上に存在する部分に結合するペプチドを含む、請求項5に記載の組成物。
- エキソソームは、前記ペプチドターゲティング部分を組み込むように修飾されたエキソソーム膜貫通タンパク質を含む、請求項6に記載の組成物。
- エキソソーム膜貫通タンパク質は、Lamp−1、Lamp−2、CD13、CD86、フロチリン、及びシンタキシン−3から選択される、請求項7に記載の組成物。
- エキソソーム膜貫通タンパク質はLamp−2bである、請求項8に記載の組成物。
- 前記抗体又はそのフラグメントはモノクローナル抗体又はそのフラグメントである、請求項1〜9のいずれか一項に記載の組成物。
- エキソソームにタンパク質及び/又はペプチドを搭載する方法であって、エキソソームの組成物を用意するステップと、エレクトロポレーションによってエキソソームにタンパク質及び/又はペプチドを搭載するステップと、を含み、前記タンパク質及び/又はペプチドは抗体又はその抗原結合フラグメントである、方法。
- エレクトロポレーションは20〜100v/cmの電圧で行われる、又はエレクトロポレーションは200mVの電圧で行われる、請求項11に記載の方法。
- エキソソームにタンパク質及び/又はペプチドを搭載する方法であって、エキソソームの組成物を用意するステップと、カチオン性リポソームトランスフェクション剤を使用して、トランスフェクションによってエキソソームにタンパク質及び/又はペプチドを搭載するステップと、を含み、前記タンパク質及び/又はペプチドは抗体又はその抗原結合フラグメントである、方法。
- 前記抗体又はそのフラグメントはモノクローナル抗体又はそのフラグメントである、請求項11〜13のいずれか一項に記載の方法。
- エキソソームは樹状細胞に由来する、請求項11〜14のいずれか一項に記載の方法。
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JP2020023503A (ja) | 2020-02-13 |
JP6145595B2 (ja) | 2017-06-14 |
EP2788019A2 (en) | 2014-10-15 |
EP3192526A3 (en) | 2017-08-30 |
CN104053451A (zh) | 2014-09-17 |
EP3192526A2 (en) | 2017-07-19 |
WO2013084000A3 (en) | 2013-10-10 |
EP2788019B1 (en) | 2017-04-05 |
US20210346504A1 (en) | 2021-11-11 |
US11103586B2 (en) | 2021-08-31 |
WO2013084000A2 (en) | 2013-06-13 |
EP3563866A1 (en) | 2019-11-06 |
US20140356382A1 (en) | 2014-12-04 |
ES2625863T3 (es) | 2017-07-20 |
JP2015500825A (ja) | 2015-01-08 |
GB201121070D0 (en) | 2012-01-18 |
DK2788019T3 (en) | 2017-06-19 |
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