JP6720227B2 - 癌細胞及び腫瘍関連マクロファージを同時に標的する融合ペプチドを有効成分として含む抗癌及び癌転移抑制用薬学的組成物 - Google Patents
癌細胞及び腫瘍関連マクロファージを同時に標的する融合ペプチドを有効成分として含む抗癌及び癌転移抑制用薬学的組成物 Download PDFInfo
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Description
前記目的を達成するために本発明は、配列番号1のアミノ酸配列を有する、インターロイキン-4(IL-4)受容体を特異的に標的するペプチド及びアポトーシス誘導ペプチドが結合された融合ペプチドを有効成分として含む抗癌及び癌転移抑制用薬学的組成物を提供する。
前記で記載したとおり、本発明の融合ペプチドを有効成分として含む薬学的組成物は、腫瘍細胞及び腫瘍関連マクロファージを同時に標的して死滅させる効果があって、優れた抗癌効果及び癌転移抑制効果を示し、従来の抗癌薬剤と併用投与して従来の抗癌効果の副作用を減少させながら抗癌及び癌転移抑制効果を示した。
1,細胞株及び培養
マウス腫瘍細胞である4T1、マウスマクロファージのRaw 264.7、ヒトの腫瘍細胞であるA549及びMDA MB 231細胞株は、Dulbeccos modified Eagles medium(Gibco、USA)又はRPMI培地にATCCの指示に応じて培養した。
腫瘍関連マクロファージのM2型マクロファージは、Raw 264.7細胞及び/又はマウス脾臓由来のマクロファージを、10IU/mlのマウス組換えIL-4(R and D system、US)で処理して得ることができ、M1型マクロファージは、100IU/mlのIFN-γ(R and D system、US)及び10ng/mlのLPS(sigma-aldrich)を処理して得られた。
IL-4受容体に特異的に結合する配列番号1のアミノ酸配列を有する、IL4RPep-1ペプチドのN末端に、フルオレセインイソチオシアネート(FITC)又はビオチンを結合して、in vitroの実験に使用した。Flamma675に結合されたIL4RPep-1ペプチドをin vivo光学イメージ実験に使用した。NSSSVDKアミノ酸配列を有するペプチドを対照群ペプチドに利用した。
細胞にペプチドが結合するか否かをテストするために腫瘍細胞は、最初に1%BSA溶液でブロッキングされ、その後、10のFITC標識されたIL4R0Pep1ペプチドを4℃で1時間インキュベーションした。細胞を洗浄した後、4%PFAで固定してDAPIで核を染色した。
腫瘍細胞を、1%BSAで30分間、室温でブロッキングして、多様な濃度(1〜80)のビオチンラベルされたIL4RPep-1ペプチドを1時間インキュベーションした。PBSで洗浄した後、細胞をNeutravidin HRP(1:10000)と共に常温で30分間インキュベーションした。HRP活性はTMB基質を利用して測定し、反応は2M硫酸を利用して中断された。吸光度は、TECANマイクロプレートリーダーを用いて450nmで測定した。Kd値は、Graph Pad Prism 6ソフトウェアを利用して計算した。
6−1.動物モデル
雌の野生型Balb/cマウスをオリエントバイオから購入してIL-4受容体欠損マウスを作製した。マウスの腫瘍モデルは1X106個の4T1腫瘍細胞を野生型及びIL-4受容体欠損マウスの脇腹上部皮下に注射して作成し、同所移植動物モデルは、1X106個の4T1細胞をマウス乳房脂肪組織に注入して作成した。
Flamma 675で標識されたIL4RPep-1ペプチドとNSSSVDK対照群ペプチドを4T1腫瘍細胞が移植された野生型マウス及びIL-4受容体欠損マウスの尻尾の静脈を通じて投与した。in vivoイメージングは、Optiximaging system(ARTInc.,Canad)を利用して1時間及び2時間循環後測定した。マウスはイメージング後、最後に犠牲にして腫瘍及び臓器を切除してex vivoイメージングを行った。
4T1細胞は、M2型マクロファージに分化されたマウス脾臓由来のマクロファージが50%含まれたDMEM培地を利用して培養した。TAMが含有された培養培地は、使用する前に遠心分離及びストレーナーを利用して残渣を除去した。サイトカインに誘導された上皮間葉移行は、細胞をマウスIL-10及びマウスIL-4で24時間培養するか、又はマウスTFGβが含まれた培養培地で48時間培養して実施した。その後、細胞は間葉マーカーであるN.cadherinで染色してIL-4受容体の発現度を評価した。
M2型マクロファージから分泌されるIL-10サイトカイン又はエキソソーム形態は、マウスIL-10 ELISAキットを製造者の指示に応じて評価した。吸光度を450nmで測定し、IL-10の濃度は得られた標準曲線に代入して換算した。
エキソソーム(exosome)はExoquick TC kit(SBI Bioscience)を用いて条件培地から分離された。エキソソームが欠乏したFBSが含まれたDMEM培地で培養された4T1腫瘍細胞は、50/mlの分離されたエキソソームと共に24時間培養された。その後、細胞はIL-4受容体及びEMTマーカーであるN.cadherinを観察するために染色され、蛍光顕微鏡を通じて観察された。
IL4RPep-1-KLAの細胞毒性は、CCK8キットを利用して製造社の指示に応じて評価した。簡潔に説明すると、IL-4受容体を発現するA549細胞を多様な濃度(0〜160)のIL4RPep-1-KLAと共に1時間培養した後、CCK溶液を添加して、1〜4時間培養した。450nmで吸光度を測定して細胞毒性は以下の式で計算した。
A blank =試験物質は含まれているが、細胞が含まれていないwellの吸光度値
A control =細胞及びCCK8溶液のみが含まれているwellの吸光度値
Orthotropic 4T1腫瘍モデルは1X106個の4T1細胞を野生型Balb/cマウスの左側の乳房脂肪体に移植することにより作成した。腫瘍は約100mm3の大きさに成長するまで放置され、その後、ランダムに群を分離して投与を行った。マウスは、各群当たり5匹ずつ、合計6個の群に分離した。ペプチド(KLA + IL4RPep-1及びIL4RPep-1-KLA融合ペプチド)は、同じモル濃度(1mMペプチド200/20g-マウス体重、週に3回ずつ、合計4週間投与)で尻尾静脈を通じて投与された。他の三グループのマウス群は、ペプチド投与に追加的に8mg/kg濃度のパクリタキセル(paclitaxel)を週に一回ずつ腹腔投与した。二つの対照群のマウス群は、PBS又はパクリタキセルをそれぞれ投与した。
冷凍保管された腫瘍組織を1gのBSA、0.2gのゼラチン及び0.05gのサポニンがPBSに溶解されたブロッキング溶液でブロッキングした後、1次抗体を利用して1時間30分インキュベーションした。その後、HRP標識された2次抗体を利用して、45分間室温で染色した。前記染色された組織を、DABを利用して露出した後、ヘマトキシリンで対比染色を5分間室温で行った。各段階は10%ブロッキング溶液を含むPBSで洗浄した後、次の段階を行った。最後に、組織を明視野顕微鏡で観察した。
<実施例1>
IL4RPep-1ペプチドがIL-4受容体に結合するかどうかについてのin vitro実験結果
IL4RPep-1ペプチドがIL-4受容体に結合するかどうかについてのin vivo実験結果
腫瘍関連マクロファージが4T1腫瘍細胞の上皮間葉移行を誘導するかどうか
腫瘍関連マクロファージが4T1腫瘍細胞の上皮間葉移行及びIL-4受容体の発現誘導をしているかどうか
図7に示したとおり、TAM条件の培地及びrmIL-10含有培地で培養された4T1細胞において、IL-4受容体だけでなく、間葉マーカーであるN.Cadherinの発現が増加した。
IL4RPep-1-KLA融合ペプチドの抗癌及び癌転移抑制活性評価
配列番号1のアミノ酸配列を有するIL4RPep-1ペプチドとアポトーシス誘導ペプチドである(KLAKLAK)2が結合された融合ペプチドの細胞毒性を評価した。
Claims (6)
- 配列番号3のアミノ酸配列を有する融合ペプチドを有効成分として含む、抗癌及び癌転移抑制用薬学的組成物であって、
前記組成物は、癌細胞及び腫瘍関連マクロファージを同時に標的することを特徴とする、薬学的組成物。 - 前記癌は、IL-4受容体が過剰発現される癌であることを特徴とする請求項1記載の薬学的組成物。
- 前記IL-4受容体が過剰発現される癌は、肺癌、脳腫瘍、乳癌、肝臓癌、皮膚癌、食道癌、睾丸癌、腎臓癌、大腸癌、直腸癌、胃癌、腎臓癌、膀胱癌、卵巣癌、胆嚢癌、子宮癌、子宮頸癌、前立腺癌、頭頸部癌、膵臓癌、及び扁平上皮癌からなる群より選ばれた1種以上であることを特徴とする請求項2記載の薬学的組成物。
- 前記組成物は、抗癌薬剤と併用して投与されることを特徴とする請求項1記載の薬学的組成物。
- 前記抗癌薬剤はドキソルビシン、パクリタキセル、ビンクリスチン、ダウノールビシン(daunorubicin)、ビンブラスチン(vinblastine)、アクチノマイシン-D(actinomycin-D)、ドセタキセル、エトフォーサイド(etoposide)、テニポーサイド(teniposide)、ビサントレン(bisantrene)、ホモハリングトニン(homoharringtonine)、(グリーベック; Gleevec; STI-571)、シスプラチン、5-フルオロウラシル、アドリアマイシン、メトトレキサート、ブスルファン(busulfan)、クロラムブシル(chlorambucil)、シクロホスファミド(cyclophosphamide)、メルファラン(melphalan)、ニトロゲンムスタード(nitrogen mustard)、及びニトロソウレラ(nitrosourea)からなる群より選ばれた1種以上であることを特徴する請求項4記載の薬学的組成物。
- 抗癌及び癌転移抑制用薬剤の製造の用途のための、配列番号3のアミノ酸配列を有する融合ペプチドの使用であって、
前記融合ペプチドは、癌細胞及び腫瘍関連マクロファージを同時に標的することを特徴とする、使用。
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AU2006339072A1 (en) * | 2005-03-14 | 2007-10-25 | Board Of Regents Of The University Of Texas System | Bioactive FUS1 peptides and nanoparticle-polypeptide complexes |
EP2414389A1 (en) * | 2009-04-01 | 2012-02-08 | Schmidt-Wolf, Ingo | Tumor targeting peptides, therapeutic and diagnostic compositions comprising the peptides |
TWI397428B (zh) * | 2009-12-29 | 2013-06-01 | Ind Tech Res Inst | 標的第四介白素受體之傳輸系統 |
US9487590B2 (en) * | 2012-09-25 | 2016-11-08 | Cytomx Therapeutics, Inc. | Activatable antibodies that bind interleukin-6 receptor and methods of use thereof |
WO2014123399A1 (ko) * | 2013-02-08 | 2014-08-14 | 경북대학교 산학협력단 | 인간 페리틴 유래 융합폴리펩티드 |
CN105764926A (zh) * | 2013-09-24 | 2016-07-13 | 梅迪塞纳医疗股份有限公司 | 白介素-4受体结合融合蛋白及其应用 |
-
2015
- 2015-06-30 KR KR1020150093576A patent/KR101741594B1/ko active IP Right Grant
- 2015-11-12 JP JP2017567431A patent/JP6720227B2/ja active Active
- 2015-11-12 WO PCT/KR2015/012162 patent/WO2017003044A1/ko active Application Filing
-
2017
- 2017-12-28 US US15/856,740 patent/US20180201651A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US20180201651A1 (en) | 2018-07-19 |
WO2017003044A1 (ko) | 2017-01-05 |
KR101741594B1 (ko) | 2017-05-30 |
KR20170003203A (ko) | 2017-01-09 |
JP2018521998A (ja) | 2018-08-09 |
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