JP2020527556A - がん治療用ペプチドサポリン複合体 - Google Patents
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Abstract
Description
本発明は、米国保険福祉省の国立がん研究所により授与された助成金番号第7R01CA164447−04号の下、国からの支援によりなされた。政府は、本発明に一定の権利を有する。
本明細書及び添付の特許請求の範囲で使用される場合、単数形の「a」、「an」、及び「the」は、文脈から明白に指定されない限り、複数に関する言及も含む。
MGSペプチド。本明細書中開示されるのは、分子誘導システムペプチド(MGS)または腫瘍標的指向性ペプチドである。これらのペプチドは、悪性腫瘍を含む腫瘍に選択的に結合することができる。開示される組成物で使用可能または修飾可能なMGSペプチドの例として、McGuire et al., Sci Rep. 2014 Mar 27;4:4480に開示されるMGSペプチドの1種以上が挙げられるが、これらに限定されない。開示される組成物及び方法で同じく使用可能なMGSペプチドの例として、表1ならびに図24及び図25に示されるMGS配列が挙げられるが、これらに限定されない。
表1.ペプチド配列
本明細書中開示されるのは、1種以上の本明細書中開示される組成物及び上記の医薬的に許容されるキャリアを含む医薬組成物である。態様によっては、MSGペプチドは、配列番号3であることが可能であり、細胞傷害剤は、サポリンまたはその生物学的変異体が可能であり、医薬組成物は、静脈内投与用に製剤化される。本開示の組成物は、治療上有効量の本明細書中記載されるとおりの細胞傷害剤も含有する。組成物は、様々な投与経路のいずれかによる投与用に配合することができ、1種以上の生理学的に許容される賦形剤を含むことができ、賦形剤は、投与経路に応じて変更可能である。本明細書中使用される場合、「賦形剤」という用語は、「キャリア」または「希釈剤」とも称することが可能なものを含め任意の化合物または物質を意味する。医薬的及び生理学的に許容される組成物の調製は、当該分野で日常的に検討されており、したがって、当業者なら、必要であれば、指針として多数の出典を参考にすることができる。
本明細書中開示されるのは、がん患者の治療法であり、本方法は以下を含む:(a)治療の必要がある対象を同定すること;及び(b)対象に、1種以上の分子誘導システム(MGS)ペプチド及び細胞傷害剤、ならびに薬学上許容されるキャリアを含む治療上有効量の医薬組成物を投与すること。MGSペプチドは、本明細書中開示されるMGSペプチドのどれでも可能である。細胞傷害剤は、サポリンまたはその生物学的変異体が可能である。
開示されるのは、開示される組成物の1種または複数用にコードする核酸配列を含むベクターである。態様によっては、ベクターは、開示される1種以上のMGSペプチドをコードすることができる核酸配列のみを含む。
上記の材料ならびに他の材料は、開示される方法を実行するのに、または実行を助けるのに有用なキットとして、任意の適切な組み合わせでまとめてパッケージ化することができる。所定のキット中のキット構成要素が、開示される方法で一緒に使用されるように設計されている及びそれに適合していれば、便利である。例えば、開示されるのは、開示される組成物を1種以上含むキットである。
ペプチドが臨床上有用な試薬であるためには、正常細胞とがん細胞を識別することが重要となる可能性がある。図1は、MGSペプチド、HCC15.2が、がん細胞に蓄積し、対照に比べて特異的であることを示す。HCC15.2結合は、フローサイトメトリー分析により分析した(図1を参照)。HCC15.2は、正常HBECには結合しないが、LC細胞株H1299には結合する。結合は、配列依存性であり、単一の組織病理学的クラスに関して特異的ではなかった(図2を参照)。
HCC15.2は、内部移行することができ、この内部移行は、受容体が介在することを示す実験が行われた(図3を参照)。より具体的には、HCC15.2は、NSCLC及び他の腫瘍細胞の特定のサブセットに結合する(図12を参照)。ファージブロッキング(Phage blocking)を対照として用いた。HCC15.2は、細胞株の特定パネルにより内部移行したが、他ではしなかった。結果は、受容体が介在する内部移行は配列特異的であったことも示す。HCC15.2を加える前に2分間トリプシンで処理すると、内部移行は起こらなかった。また、4℃でもHCC15.2は内部移行しない。
図5及び図15は、HCC15.2ペプチドのN末端及びC末端での切断により、最小結合配列が明らかになったことを示す。
図7は、MGSペプチドがリソソームと共存し、時間とともにリソソーム中に蓄積することを示す(図8及び図16を参照)。
サポリンと複合体形成したHCC15.2を細胞生存アッセイにおいて試験するため、さらなる実験を行った(図9及び表2を参照)。この目的で、腫瘍細胞株を、黒色壁透明平底96ウェルプレートに播種した。翌日、濃度勾配をつけたHcc15.2−サポリン、サポリン単独、または処理なしを用いて、培地を交換した。1時間インキュベーション後、処理を除去し、培養培地に交換した。72時間後、Cell Titer Glo(登録商標)を使用して細胞生存度を測定し、LjL Biosystems製のAnalyst HTで蛍光を測定した。Graphpad PrizmでIC50を計算した。
表2.複数の細胞株における細胞生存度。
フローサイトメトリーを行い、KDを測定する。細胞を、ペプチド−色素の濃度を上昇させながら、1時間処理する。細胞に進入するまたは入っていくMGSペプチド(複数可)は、色素を共に連れて行く。細胞を洗浄し、試験管に入れて、フローサイトメトリーを行う。フローサイトメーターは、10,000個以上の個別細胞の輝度を測定することができる。各濃度を、定量し、プロットする(図13及び図14を参照)。曲線を数学的にデータにあてはめると、中間点がKDである(例えば、結合がどのくらい良好であるかの測定)。
In vivo画像化。H2009腫瘍細胞を、106細胞/100μlで滅菌PBSに懸濁させ、メス胸腺欠損ヌードマウス(Jackson Labs.)の側腹部に皮下注射した。システイン標識化ペプチドを、滅菌PBS(pH7.4)中で1時間、マレイミドAlexafluor−750 C5(1:1.1)と複合体形成させた。ペプチド色素複合体を、滅菌PBSで100μlあたり色素15μgに希釈し、100ulを、4匹/群のマウスに外側尾静脈から静脈内注射した。12、24、48、及び72時間の時点で、マウスをIsothesiaで麻酔し、IVISで動物の全体画像を撮影した。次いで、72時間の時点で、Ex vivoで腫瘍及び臓器を、重量測定し、撮影した。
π/6*(長さ*幅)^3/2。
元来のMGSペプチドのアミノ酸1〜5番及び11〜20番を融合させた修飾MGSペプチド(配列番号31):LQWRRNFGVWARYRL(配列番号31)を評価した。このMGSペプチドは、そのがん特性を維持しており、オートファゴソームに送り込む能力を上昇させている。アセチル化は、in vivoでの分解から保護し、溶解性を改善する。このMGSペプチドは、動物において、NSCLC腫瘍に対する能力に磨きがかかる(図27を参照)。データは、非アセチル化型では腫瘍標的指向性は全く観察されなかったことを示す。このMGSペプチド(例えば、修飾15量体)は、心臓、肺、及び腎臓腫瘍で>2倍の減少を有する(図27を参照)。1299.3Ac−15量体と細胞の結合結果を、図28に示す。
図29は、選択されたMGSペプチドと複合体形成したまたは連結したサポリンを投与した様々な細胞株におけるIC50を示す。
Claims (42)
- 1種以上の分子誘導システム(MGS)ペプチド及び細胞傷害剤を含む、組成物。
- 前記1種以上のMGSペプチドは、配列番号1、2、3、34、35、36、37、38、39、40、41、41、42、43、44、45、46、47、48、49、50、51、52、5、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、またはそれらの組み合わせを含む、請求項1に記載の組成物。
- 前記1種以上のMGSペプチドは、配列番号1、2、3、34、35、36、37、38、39、40、41、41、42、43、44、45、46、47、48、49、50、51、52、5、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、または84を含む、請求項1または2に記載の組成物。
- 前記細胞傷害剤は、サポリンまたはその生物学的活性変異体である、請求項1から3のいずれか1項に記載の組成物。
- 前記1種以上のMGSペプチドは、配列番号3であり、前記細胞傷害剤は、サポリンである、請求項1に記載の組成物。
- 前記1種以上は、4つのMGSペプチドである、請求項1に記載の組成物。
- 前記1種以上のMGSペプチドは、四量体足場タンパク質を形成する、請求項6に記載の組成物。
- 前記1種以上のMGSペプチドは、N末端がアセチル化されている、請求項1に記載の組成物。
- 前記1種以上のMGSペプチドは、前記細胞傷害剤と化学結合している、請求項1から8のいずれか1項に記載の組成物。
- 化学結合は、ポリエチレングリコール(PEG)である、請求項9に記載の組成物。
- 前記PEGは、長さが11単位である、請求項10に記載の組成物。
- 前記1種以上のMGSタンパク質は、配列番号3を含み、配列番号3は、N末端がアセチル化されており、かつPEGと化学結合しており;かつ、前記細胞傷害剤は、サポリンであり、前記サポリンは、PEGと共有結合している、請求項1に記載の組成物。
- 脂質膜を横断する輸送用の膜透過性複合体であり、1種以上の分子誘導システム(MGS)ペプチド及び細胞傷害剤を含む、前記複合体。
- 前記1種以上のMGSペプチドは、配列番号1、2、3、34、35、36、37、38、39、40、41、41、42、43、44、45、46、47、48、49、50、51、52、5、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、またはそれらの組み合わせを含む、請求項13に記載の複合体。
- 前記1種以上のMGSペプチドは、配列番号1、2、3、34、35、36、37、38、39、40、41、41、42、43、44、45、46、47、48、49、50、51、52、5、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、または84を含む、請求項13または14に記載の複合体
- 前記細胞傷害剤は、サポリンまたはその生物学的活性変異体である、請求項13から15のいずれか1項に記載の組成物。
- 前記1種以上のMGSペプチドは、配列番号3であり、前記細胞傷害剤は、サポリンである、請求項13に記載の組成物。
- 前記1種以上のMGSペプチドは、4つのMGSペプチドである、請求項13に記載の組成物。
- 前記1種以上のMGSペプチドは、四量体足場タンパク質を形成する、請求項13に記載の組成物。
- 前記1種以上のMGSペプチドは、N末端がアセチル化されている、請求項13に記載の組成物。
- 前記1種以上のMGSペプチドは、前記細胞傷害剤と化学結合している、請求項13から20のいずれか1項に記載の組成物。
- 化学結合は、ポリエチレングリコール(PEG)である、請求項21に記載の組成物。
- 前記PEGは、長さが11単位である、請求項22に記載の組成物。
- 前記1種以上のMGSタンパク質は、配列番号3を含み、配列番号3は、N末端がアセチル化されており、かつPEGと化学結合しており;かつ、前記細胞傷害剤は、サポリンであり、前記サポリンは、PEGと共有結合している、請求項13に記載の組成物。
- 請求項1に記載の組成物及び薬学上許容されるキャリアを含む、医薬組成物。
- 前記医薬組成物は、静脈内投与用に製剤化されている、請求項1に記載の医薬組成物。
- がんを治療するための方法であって、(a)治療の必要がある患者を同定すること;(b)前記患者に、治療上有効量の請求項1から27のいずれか1項に記載の組成物を投与すること;及び(c)薬学上許容されるキャリア、を含む、前記方法。
- 前記患者は、ヒト患者である、請求項27に記載の方法。
- 前記がんは、原発性、続発性、難治性、または再発腫瘍である、請求項27に記載の方法。
- 前記がんは、肺癌、乳癌、結腸直腸癌、卵巣癌、または膵癌である、請求項27に記載の方法。
- さらに、前記患者に、治療上有効量の放射線療法、免疫療法、または化学療法、あるいはそれらの組み合わせを行うことを含む、請求項27に記載の方法。
- 細胞内標的を標的とする方法であって、細胞傷害剤と結合した1種以上のMGSペプチドを投与することを含み、前記細胞傷害剤は、細胞内標的を標的とする、前記方法。
- 前記細胞内標的は、リソソームである、請求項32に記載の方法。
- 1種以上の分子誘導システム(MGS)ペプチド及び細胞傷害剤を含む組成物であって、前記1種以上のMGSペプチドは、表1に列挙される群から選択される、前記組成物。
- 本明細書中開示されるとおりのMGSペプチド。
- 本明細書中開示されるMGSペプチドをコードすることができる、核酸配列。
- 請求項36に記載の核酸配列を含む、ベクター。
- 請求項34に記載のMGSペプチド、請求項36に記載の核酸配列、または請求項37に記載のベクターを含む、細胞株。
- 配列番号1、2、3、34、35、36、37、38、39、40、41、41、42、43、44、45、46、47、48、49、50、51、52、5、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、または84の配列を含む、MGSペプチド。
- 請求項39に記載のMGSペプチドをコードすることができる核酸配列。
- 請求項40に記載の核酸配列を含む、ベクター。
- 請求項39に記載のMGSペプチド、請求項40に記載の核酸配列、または請求項41に記載のベクターを含む、細胞株。
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