JP2022505159A - 骨髄由来サプレッサー細胞に対する標的化療法のための細胞外小胞 - Google Patents
骨髄由来サプレッサー細胞に対する標的化療法のための細胞外小胞 Download PDFInfo
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Abstract
Description
本出願は、2018年10月19日に出願された米国仮出願第62/747,982号の利益を主張するものであり、その全体が参照により本明細書に組み込まれる。
本出願は、2019年10月16日に作成された「321501-2360 Sequence Listing_ST25」と題されるASCII.txtファイルとして電子形態で出願される配列表を含む。配列表の内容は、その全体が本明細書に組み込まれる。
開示されるEVは、いくつかの実施形態では、細胞によって分泌され得るいずれの小胞であり得る。細胞は、アポトーシス体(1~5μm)、微少胞(100~1000nmのサイズ)、およびエクソソーム(50~150nm)として知られるエンドソーム起源の小胞を含む広範囲の直径および機能を有する細胞外小胞(EV)を分泌する。
開示されるEVは、EVの表面で、MDSCの表面で発現される細胞表面部分に結合する標的化部分を発現することによってMDSCを標的とすることができる。好適な標的化部分の例は、標的化部分がエクソソームの表面で発現され得る限り、短いペプチド、scFv、および完全なタンパク質がある。ペプチド標的化部分は、一般的には、100アミノ酸長未満、例えば50アミノ酸長未満、30アミノ酸長未満、または10、5、または3アミノ酸の最小長であり得る。
開示される細胞外小胞は、治療剤をさらに装填されてもよく、細胞外小胞は、標的細胞に薬剤を送達する。好適な治療剤としては、治療薬(例えば、低分子薬)、治療用タンパク質、および治療用核酸(例えば、治療用RNA)が挙げられるが、これらに限定されない。いくつかの実施形態では、開示される細胞外小胞は、治療用RNA(本明細書では「カーゴRNA」とも称される)を含む。
開示されるEVを使用するための方法も本明細書で企図される。例えば、開示の細胞外小胞は、開示の治療用カーゴを骨髄由来サプレッサー細胞(MDSC)に送達するために使用することができ、その方法は、標的細胞を開示のEVと接触させることを含む。
DCを、miR146aのためのプラスミドでナノトランスフェクトした。EVを、ExoQuickを使用して培地から単離した。インビトロ有効性を評価するために、インビトロ単培養物を、がん細胞ではなくMDSCまたはマクロファージとともに使用した(A549)。細胞をカーゴEVで処理した。図4Aは、15分間のインキュベーション後に、ICAM-1で装飾されたEVがMDSCまたはマクロファージ(例えば、TAM)によって優先的に内部移行されたが、がん細胞(A549)ではされなかったことを示す(EVを緑色蛍光色素で標識した)。miR146aのrq-PCRを行った。図4Bは、装飾されたEVにおけるmiR-146aの装填を示す。Scr-CTは、スクランブルプラスミドで細胞をトランスフェクトすることによって作製された対照(CT)EVである。+
骨髄由来サプレッサー細胞に対する標的療法のためのデザイナーEVは、腫瘍増殖を妨げる(図5)。図6Aおよび6Bに示すように、EVベースの治療は、CD4およびCD8細胞を増加させ、MDSCを低減させることによって、腫瘍の免疫細胞構成に影響を与える(図6B)。
腫瘍環境の免疫調節を促進するためにTNTによって生成されたEVの直接注射。EVが実際に腫瘍進行の減少に関与していることを示すために、ナノ電気泳動を使用してEVをインビトロで生成し、次いで「操作されたEV」と称されるmiR146a、GLUT-1、およびICAM-1を装填した(図7)。操作されたEVは、皮膚モデルとして胚線維芽細胞から産生された。
Claims (11)
- ICAM-1と、エクソソームまたはリソソーム膜貫通タンパク質とを含む融合タンパク質。
- 請求項1に記載の融合タンパク質を含む細胞外小胞。
- 治療用カーゴをさらに含む、請求項2に記載の細胞外小胞。
- 前記治療用カーゴがmiR146aを含む、請求項3に記載の細胞外小胞。
- 前記治療用カーゴがイブルチニブを含む、請求項3または4に記載の細胞外小胞。
- 請求項1に記載の融合タンパク質をコードする核酸を含む細胞。
- 治療用RNAをコードする核酸をさらに含む、請求項6に記載の細胞。
- 細胞外小胞を産生する方法であって、請求項6または7に記載の細胞を、小胞分泌に好適な条件下で培養することと、前記細胞によって分泌された細胞外小胞を単離することと、を含む、方法。
- 前記細胞外小胞に治療薬を装填することをさらに含む、請求項8に記載の方法。
- 対象におけるがんを治療する方法であって、治療有効量の請求項3~5のいずれか一項に記載の細胞外小胞を前記対象に投与することを含む、方法。
- 前記対象が循環骨髄由来サプレッサー細胞(MDSC)を有する、請求項10に記載の方法。
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US201862747982P | 2018-10-19 | 2018-10-19 | |
US62/747,982 | 2018-10-19 | ||
PCT/US2019/057043 WO2020082005A2 (en) | 2018-10-19 | 2019-10-18 | Extracellular vesicles for targeted therapies against myeloid-derived suppressor cells |
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KR102620197B1 (ko) * | 2021-04-30 | 2024-01-02 | 가톨릭대학교 산학협력단 | 약물전달물질로서의 대장암 특이적 표적 엑소좀 조성물 및 이의 용도 |
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US20120315324A1 (en) * | 2010-02-05 | 2012-12-13 | University Of Louisville Research Foundation, Inc. | Exosomal compositions and methods for the treatment of disease |
US10308959B2 (en) * | 2013-01-18 | 2019-06-04 | Henry Ford Health System | Methods, systems, and compositions relating to MiRNA-146a |
WO2015002956A1 (en) * | 2013-07-01 | 2015-01-08 | Ohio State Innovation Foundation | Exosome delivery system |
US20160160181A1 (en) * | 2014-12-03 | 2016-06-09 | Capricor Thera[eitocs, Inc. | Processes for producing exosomes in reduced oxygen culture conditions |
WO2016179417A2 (en) * | 2015-05-06 | 2016-11-10 | The University Of Utah Research Foundation | Exosome delivery of micrornas |
GB2552473A (en) * | 2016-07-21 | 2018-01-31 | Evox Therapeutics Ltd | Surface decoration of extracellular vesicles |
GB201809622D0 (en) * | 2018-06-12 | 2018-07-25 | Evox Therapeutics Ltd | Engineering extracellular vesicles for affinity purification |
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CN113286826A (zh) | 2021-08-20 |
US20210332386A1 (en) | 2021-10-28 |
AU2019362064A1 (en) | 2021-05-20 |
BR112021007287A2 (pt) | 2021-07-27 |
EP3850104A2 (en) | 2021-07-21 |
SG11202103756XA (en) | 2021-05-28 |
IL282405A (en) | 2021-06-30 |
KR20210081362A (ko) | 2021-07-01 |
WO2020082005A3 (en) | 2020-07-30 |
EP3850104A4 (en) | 2022-07-06 |
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