JP2019208422A - ヒアルロニダーゼを含む新規な組換えエキソソーム及びその用途 - Google Patents
ヒアルロニダーゼを含む新規な組換えエキソソーム及びその用途 Download PDFInfo
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- JP2019208422A JP2019208422A JP2018106832A JP2018106832A JP2019208422A JP 2019208422 A JP2019208422 A JP 2019208422A JP 2018106832 A JP2018106832 A JP 2018106832A JP 2018106832 A JP2018106832 A JP 2018106832A JP 2019208422 A JP2019208422 A JP 2019208422A
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Abstract
Description
本明細書で使われる用語「エキソソーム(exosome)」は、多くの、おそらく血液、尿、及び細胞培養の培養培地を含むあらゆる生物学的液体に存在するかも知れない、ナノサイズの細胞由来の小胞(vesicle)である。エキソソームのサイズは、30nm〜100nmと知られており、多小胞体(multivesicular body)が細胞膜と融合する時、細胞から分泌されるか、細胞膜を通じて直接分泌される。エキソソームは、凝固、細胞間信号伝逹、及び代謝廃棄物の管理のような多様な過程で重要な役割を果たしていると知られている。
本発明の一観点によれば、膜に組換えヒアルロニダーゼが提示された及び組換えエキソソームが提供される。
本発明の薬学的組成物は、経口または非経口投与されうるが、非経口投与される場合、静脈内注射、鼻腔内吸入、筋肉内投与、腹腔内投与、経皮吸収など多様な経路を通じて投与することが可能である。
本発明に使われた一般的な実験方法は、下記の通りである:
細胞培養:HEK293T細胞を10%ウシ胎児血清及び1%抗生剤が添加されたダルベッコ改変イーグル培地(Dulbecco’s modified Eagle’s medium:DMEM)で成長させた。ヒトPC3前立腺癌細胞及びラットの4T1乳房癌細胞を10%ウシ胎児血清及び1%抗生剤を含有するRPMI培地で保持させた。あらゆる細胞株は、37℃で5% CO2で保持された。
HEK293T細胞を150mm皿当たり6x106個の濃度で播種した。グルタマックス(最終濃度1%、Gibco)が補充された新たな無血清DMEM培地に培地を交換した後、HEK293T細胞をリポフェクタミン3000(lipofectamine 3000、Invitrogen,USA)を使用して、GPIアンカー付着部位を含む全長PH20(36−490 a.a、配列番号1)を暗号化する遺伝子が含まれたプラスミド(pCMV6−HuPH20)18μgで形質感染させた。残骸物及び微小小嚢(microvesicle)を除去するために、上澄み液を収穫し、異なるRCFで遠心分離した。簡略に、上澄み液をまず300gで10分間遠心分離し、引き続き、2,000gで10分間、最後に、10,000gで30分間遠心分離した。最後に、0.22μmフィルターを通じる濾過後、エキソソーム含有上澄み液を45Tiローター(Beckman Instruments)で150,000gで3時間超遠心分離した。エキソソームをタンパク質分解酵素抑制剤(Roche)が含まれたPBSに再懸濁し、4℃で保管した。PH20遺伝子に形質感染されていない細胞からエキソソームを収得して、対照群として使用した。
本発明者らは、固形腫瘍治療に広範囲に使われるドキソルビシン(Dox)のような化学療法薬物が同時にPH20と共に伝達されれば、抗腫瘍効能が強化されるという仮説を立てた。ドキソルビシンは、10.2±0.3%の最終積載量で簡単なインキュベーション方法を通じてエキソソームにカプセル化された。
1−1:in vitro分析
本発明者らは、前記PH20表面提示エキソソームがヒト組換えPH20に比べて、高い酵素活性を有するかを確認するために、ヒアルロン酸(HA)−依存性細胞外基質を生成することができるヒト前立腺癌細胞PC3の細胞外基質に対するPH20同一質量に換算されたヒト組換えPH20とExo−PH20との分解能を比較した。具体的に、試験管内でHA細胞外基質を視覚化するために、固定された赤血球を用いて、前述したように、粒子排除分析を行った。PC3のHA−high細胞外基質は、ヒト組換えPH20とExo−PH20処理後、濃度依存的に枯渇したが、ヒト組換えPH20に比べて、Exo−PH20が相対的にさらに多く細胞外基質を枯渇させ、対照エキソソーム(Exo−Con)では、そのような効果が表われなかった(図3A及び図3B)。PC3細胞を利用した時間経過実験は、HAがExo−PH20処理後、60分以内にほぼ減少することを示した(図3C)。
HAを枯渇させるExo−PH20の坑癌活性も、PC3(HA−high)−保有異種正位移植マウスモデルで評価した。Exo−PH20(PH20タンパク質:26.5μg/kg、エキソソーム:5mg/kg)の単一腫瘍内投与時に、投与後、6時間以内に腫瘍ECMでHAが効果的に除去された(図4A及び図4B)。Exo−PH20−媒介HA枯渇は、HAの漸進的再構築と共に48時間以上保持された。
引き続き、本発明者らは、静脈内投与されたExo−PH20の抗腫瘍効能を調査するのに先立って、PC3腫瘍保有マウスで静脈内投与されたExo−PH20のラットの体内分布程度を調査した。経時的にcy5.5−蛍光染料で標識されたエキソソームは、ほとんど肝に蓄積されるにもかかわらず、EPR効果によって癌に移動することを確認し、静脈内投与24時間後に摘出した臓器及び癌でエキソソームが蓄積されていることを確認することができた(図5A及び図5B)。
このような結果によって、本発明者らは、Exo−PH20−媒介腫瘍ECM再構築がHA−枯渇した腫瘍組織でナノ粒子浸透を向上させるか否かをさらに調査した。HAが枯渇した後のナノ粒子の浸透を評価するために、Exo−PH20前処理の不在または存在下で蛍光体−接合PEG−リポソームをPC3腫瘍保有マウスに静脈内注射した。リポソーム蓄積は、処理されていない腫瘍組織では最小であったが、Exo−PH20処理後に劇的に増加した(図6)。このような結果は、Exo−PH20が血液灌流を増加させるだけではなく、HA枯渇による腫瘍微小環境の癲癇耐圧を減少させて、腫瘍でのナノ粒子の拡散を増加させることを立証することである。
引き続き、本発明者らは、免疫能力マウスで全身投与されたExo−PH20の効能を調査した。対照群と比較して、腫瘍成長は、4T1細胞に移植されたBALB/c免疫能力マウスでExo−PH20によって有意に減少した(図7A及び図7B)。引き続き、本発明者らは、腫瘍組織の免疫蛍光染色を行って、局所腫瘍浸潤CD8+T細胞の存在を分析した。4T1腫瘍保有免疫能力マウスモデルで、対照群と比較して、Exo−PH20投与時に、腫瘍で幅広いT細胞浸潤が観察された(図7C及び図7D)。総合的に見る時、このような結果は、Exo−PH20が腫瘍微小環境でHAを成功的に分解し、腫瘍組織でナノ粒子及び兔疫細胞の浸透を向上させるということを示す。
前記実施例2から製造されたExo−PH20Doxの治療可能性は、PC3異種移植片を使用して生体内で分析した。試験の結果、Exo−PH20Doxの処理は、上昇的に腫瘍成長を抑制したが、これは、組合わせ治療が抗腫瘍効能を著しく向上させるということを意味する(図8Aないし図8C)。特に、Exo−PH20の強化された浸透は、腫瘍組織で効果的な薬物放出を確実に保証した。Exo−PH20Doxを投与した腫瘍保有マウスの腫瘍組織薄片で対照群と比較して有意に高く、均一に分布されたDox蛍光信号が血管から観察された(図8D)。総合すれば、Exo−PH20は、化学療法の効能を向上させ、この効果は、PH20によるHAの枯渇、後続腫瘍のECM再構築及び増加した血管灌流を通じるドキソルビシンの腫瘍浸透の結果である(図8E)。
本発明は、実施例を参考にして説明されたが、これは例示的なものに過ぎず、当業者ならば、これより多様な変形及び均等な他実施例が可能であるという点を理解できるであろう。したがって、本発明の真の技術的保護範囲は、特許請求の範囲の技術的思想によって決定されるべきである。
Claims (23)
- 膜に組換えヒアルロニダーゼが提示された組換えエキソソーム。
- 前記ヒアルロニダーゼは、GPI−アンカリングされた形態の膜結合ヒアルロニダーゼである請求項1に記載の組換えエキソソーム。
- 前記GPI−アンカリングされた形態の膜結合ヒアルロニダーゼは、全長PH20である請求項2に記載の組換えエキソソーム。
- 前記PH20は、配列番号1〜30に記載されるアミノ酸配列のうち何れか1つを含む請求項3に記載の組換えエキソソーム。
- 請求項1ないし請求項4のうち何れか一項に記載の組換えエキソソームを有効成分として含む癌治療用組成物。
- 膜に組換えヒアルロニダーゼが提示され、内部に坑癌化合物が封入された組換えエキソソームを有効成分として含む癌治療用薬学的組成物。
- 膜に組換えヒアルロニダーゼが提示された組換えエキソソーム及び坑癌化合物を有効成分として含む癌治療用薬学的組成物。
- 前記坑癌化合物は、免疫原性細胞死誘導剤、免疫チェックポイント阻害剤、有糸分裂阻害剤、代謝拮抗剤、ホルモン剤、アルキル化剤、Flt3リガンド、及びトポイソメラーゼ阻害剤で構成される群から選択される1つまたは2つ以上の組合わせである請求項6または7に記載の薬学的組成物。
- 前記免疫原性細胞死誘導剤は、アントラサイクリン系抗癌剤、セツキシマブ(Cetuximab)、タキサン系抗癌剤、ブレオマイシン(Bleomycin)、シクロホスファミド、強心性配糖体、GADD34/PP1阻害剤、ミトキサントロン(mitoxantrone)またはオキサリプラチンである請求項8に記載の薬学的組成物。
- 前記アントラサイクリン系抗癌剤は、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、ピクサントロン、サバルビシン、またはバルビシンである請求項9に記載の薬学的組成物。
- 前記強心性配糖体は、非免疫原性細胞死誘導剤と組合わせられて使われる請求項9に記載の薬学的組成物。
- 前記GADD34/PP1阻害剤は、マイトマイシンと組合わせられて使われる請求項9に記載の薬学的組成物。
- 前記タキサン系抗癌剤は、パクリタキセルまたはドセタキセルである請求項9に記載の薬学的組成物。
- 前記免疫チェックポイント阻害剤は、PD−1/PD−L1相互作用阻害剤またはCTLA−4/B7−1/B7−2相互作用阻害剤である請求項8に記載の薬学的組成物。
- 前記PD−1/PD−L1相互作用阻害剤は、ペムブロリズマブ、ニボルマブ、アテゾリズマブまたはアベルマブである請求項14に記載の薬学的組成物。
- 前記CTLA−4/B7−1/B7−2相互作用阻害剤は、イピリムマブである請求項14に記載の薬学的組成物。
- 請求項1に記載の組換えエキソソームを癌にかかった個体に投与する段階を含む前記個体の癌治療方法。
- 坑癌化合物を前記個体にさらに投与する請求項17に記載の癌治療方法。
- 前記坑癌化合物は、前記組換えエキソソームと同時に投与されるか、間隔を置いて順次に投与される請求項18に記載の癌治療方法。
- 追加的に、前記個体に光力学治療法または放射線治療法を施行する請求項17に記載の癌治療方法。
- 追加的に、前記個体に光力学治療法または放射線治療法を施行する請求項18に記載の癌治療方法。
- 治療的に有効な量の膜に組換えヒアルロニダーゼが提示され、内部に坑癌化合物が封入された組換えエキソソームを癌にかかった個体に投与する段階を含む前記個体の癌治療方法。
- 追加的に、前記個体に光力学治療法または放射線治療法を施行する請求項22に記載の癌治療方法。
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