JP5544290B2 - 神経浸潤抑制剤 - Google Patents
神経浸潤抑制剤 Download PDFInfo
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- JP5544290B2 JP5544290B2 JP2010515932A JP2010515932A JP5544290B2 JP 5544290 B2 JP5544290 B2 JP 5544290B2 JP 2010515932 A JP2010515932 A JP 2010515932A JP 2010515932 A JP2010515932 A JP 2010515932A JP 5544290 B2 JP5544290 B2 JP 5544290B2
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Description
〔1〕 インターロイキン6(IL-6)阻害剤を有効成分とする膵癌治療剤。
〔2〕 IL-6阻害剤を有効成分とする細胞の神経浸潤抑制剤。
〔3〕 癌細胞の神経浸潤を抑制することを特徴とする〔2〕に記載の抑制剤。
〔4〕 膵癌細胞の神経浸潤を抑制することを特徴とする〔3〕に記載の抑制剤。
〔5〕 中枢側への神経浸潤を抑制することを特徴とする〔2〕〜〔4〕いずれかに記載の抑制剤。
〔6〕 IL-6阻害剤がIL-6受容体に結合する物質であることを特徴とする〔1〕〜〔5〕いずれかに記載の治療剤又は抑制剤。
〔7〕 IL-6阻害剤が抗IL-6受容体抗体であることを特徴とする〔6〕に記載の治療剤又は抑制剤。
〔8〕 抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である〔7〕に記載の治療剤又は抑制剤。
〔9〕 IL-6阻害剤を対象に投与する工程を含む、膵癌の治療方法。
〔10〕 IL-6阻害剤を対象に投与する工程を含む、細胞の神経浸潤抑制方法。
〔11〕 癌細胞の神経浸潤を抑制することを特徴とする〔10〕に記載の方法。
〔12〕 膵癌細胞の神経浸潤を抑制することを特徴とする〔11〕に記載の方法。
〔13〕 中枢側への神経浸潤を抑制することを特徴とする〔10〕〜〔12〕いずれかに記載の方法。
〔14〕 IL-6阻害剤がIL-6受容体に結合する物質であることを特徴とする〔9〕〜〔13〕いずれかに記載の方法。
〔15〕 IL-6阻害剤が抗IL-6受容体抗体であることを特徴とする〔14〕に記載の方法。
〔16〕 抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である〔15〕に記載の方法。
〔17〕 膵癌治療剤を製造するための、IL-6阻害剤の使用。
〔18〕 細胞の神経浸潤抑制剤を製造するための、IL-6阻害剤の使用。
〔19〕 癌細胞の神経浸潤を抑制することを特徴とする〔18〕に記載の使用。
〔20〕 膵癌細胞の神経浸潤を抑制することを特徴とする〔19〕に記載の使用。
〔21〕 中枢側への神経浸潤を抑制することを特徴とする〔18〕〜〔20〕いずれかに記載の使用。
〔22〕 IL-6阻害剤がIL-6受容体に結合する物質であることを特徴とする〔17〕〜〔21〕いずれかに記載の使用。
〔23〕 IL-6阻害剤が抗IL-6受容体抗体であることを特徴とする〔22〕に記載の使用。
〔24〕 抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である〔23〕に記載の使用。
〔25〕 膵癌を治療する方法に使用するためのIL-6阻害剤。
〔26〕 細胞の神経浸潤の抑制するための方法に使用するためのIL-6阻害剤。
〔27〕 癌細胞の神経浸潤を抑制することを特徴とする〔26〕に記載のIL-6阻害剤。
〔28〕 膵癌細胞の神経浸潤を抑制することを特徴とする〔27〕に記載のIL-6阻害剤。
〔29〕 中枢側への神経浸潤を抑制することを特徴とする〔26〕〜〔28〕いずれかに記載のIL-6阻害剤。
〔30〕 IL-6阻害剤がIL-6受容体に結合する物質であることを特徴とする〔25〕〜〔29〕いずれかに記載のIL-6阻害剤。
〔31〕 IL-6阻害剤が抗IL-6受容体抗体であることを特徴とする〔30〕に記載のIL-6阻害剤。
〔32〕 抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である〔31〕に記載のIL-6阻害剤。
又、本発明はIL-6阻害剤を、膵癌を発症した対象または発症する可能性がある対象に投与する工程を含む、対象において膵癌を治療および/または予防する方法に関する。
細胞
ヒト膵癌細胞株である、Capan-1、BxPC-3をAmerican Type Culture Collection (ATCC)より購入し、ATCCが推奨するマニュアルに沿って、培養および継代を37度で5%CO2の条件を維持できる恒温槽を用いて行った。
細胞をdishより採取し、トリパンブルーおよび血球計測盤を用いて生細胞を計測した。
底面に8μmのポアを有するCell culture insert (BD Falcon)を24ウェルに挿入し、Cell culture insertをupper chamberとして、ウェルをlower chamberとして用いた。Lower chamberに、非血清培養液とヒトリコンビナントIL-6(hrIL6)(R&D systems)を用いて調製したhrIL6 vehicle 0、1、10、100ng/mlを600μl注入し、upper chamberに2×106個/mlの細胞浮遊液 100μlを注入した。24時間培養した後、ポアを通過した細胞数を計測した。各群12回の測定を行い、hrIL6 0ng/ mlでポアを通過する平均細胞数を除算した数を補正値として記録した。
24ウェルに3×105個/mlの細胞浮遊液を1 mlずつ注入して24時間培養する。非血清培地に交換して24時間培養した後、ウェルの中央部分をガラス棒でこすり帯状の無細胞領域を作製し、その幅を計測し、hrIL6 vehicle 0、1、10、100ng/mlに培地を交換する。24時間培養した後、無細胞領域の幅の変化を測定した。各群12回の測定を行い、hrIL6 0ng/ mlでの平均変化長を除算した数を補正値として記録した。
ウエスタンブロットに使用した一次抗体は、抗リン酸化STAT3抗体(Santa Cruz)、抗STAT3抗体(Santa Cruz)、抗リン酸化Erk1/2抗体(Cell Signaling)、抗Erk1/2抗体(Cell Signaling)、抗リン酸化Akt抗体(Cell Signaling)、抗Akt抗体(Cell Signaling)、抗Actin抗体(Santa Cruz)であった。蛍光免疫染色に用いた一次抗体は、抗S100抗体(DAKO)、抗マウスIL-6抗体(Santa Cruz)であり、核染色はDRAQ5(AXXORA)を用いた。免疫染色には、抗リン酸化STAT3抗体(Santa Cruz)を用いた。
Lysate buffer (20mM Hepes-NaOH pH7.0、0.5% NP-40、15% Glycerol、300mM NaCl、1mM EDTA、10mM NaF)を用いて細胞溶解液を作製した。蛋白濃度をBCA Protein Assay Kit (PIERCE)を用いて測定した後、20 mgの蛋白を含有する細胞溶解液を7.5%もしくは12% アクリルアミドゲルを用いて電気泳動し、polyvinylidene difluoride membrane (Millipore)に転写した。メンブレンに抗体を添加し、蛋白発現をEnhanced Chemiluminescence Reagent (Amersham Biosciences)を用いて画像化した。
抗原賦活は10mMクエン酸バッファー内で95℃ 10分間のマイクロウェーブを用いた加熱処理にて行い、発色はDABを用いた。検体として、4週経過した26匹のマウス神経浸潤モデルより採取した坐骨神経26本を用いた。神経浸潤部の中枢側先端および末梢側先端を関心領域として、対物40倍レンズを用いて、1視野当たりのがん細胞数とリン酸化STAT3陽性がん細胞数を計測してlabeling indexを次の計算式で算出した:(リン酸化STAT3陽性がん細胞数)/(がん細胞数)。
使用するマウスは、6週令、オスの重度免疫不全マウス(SCIDマウス)である。バルビタール50mg/kgをマウス腹腔内投与して麻酔し、左坐骨神経を露出して、坐骨神経内に1.0×104個/μlのがん細胞浮遊液2.5μlをマイクロシリンジおよび30ゲージ針を用いて直接注入した。評価する時期にがん細胞を注入した坐骨神経を採取し、組織標本を作製する場合には、4%パラホルムアルデヒドの中で4℃ 一昼夜の間静置して固定した。固定した前記坐骨神経は、3μmの厚みで薄切し、神経浸潤距離の測定のためヘマトキシリン・エオジン染色または、免疫染色した。神経浸潤距離の測定は、神経長軸方向に薄切された切片と対物ミクロメーター(三啓)を用い、全腫瘍範囲の長軸を計測した。組織中mRNA抽出には、採取組織をただちにマルチビーズショッカー(安井器械)で破砕した検体を用いた。
Dishより採取した細胞ペレット、もしくは破砕した組織断片をからTRIzol(Life Technologies)を用いてtotal RNAを採取した。cDNAは、1×103 ngのtotal RNAより、ExScript RT reagent Kit (Takara-bio)およびTakara PCR Thermal Cycler Dice (Takara-bio)を用いて、Takara-bio社が推奨するマニュアルに従って合成した。Real time RT-PCRは、Smart Cycler II System(Cepheid)、SYBR RT-PCR kit (Takara-bio)を用いた。プライマーは、ヒトIL-6α受容体(IL6R)、ヒトIL-6β受容体(gp130)、ヒトGAPDH、マウスIL-6、マウスEGF、マウスGAPDHのcDNAをそれぞれ特異的に増幅するプライマーを用いた。プライマー配列は、ヒトIL6R:forward tgagctcagatatcgggctgaac(配列番号:1);reverse cgtcgtggatgacacagtgatg(配列番号:2)、ヒトgp130:forward gaagcaagtgggatcacctatgaa(配列番号:3);reverse ctgtagccttgagtatgggatgga(配列番号:4)、ヒトGAPDH:forward gcaccgtcaaggctgagaac(配列番号:5);reverse atggtggtgaagacgccagt(配列番号:6)、マウスIL-6:forward ccacttcacaagtcggaggctta(配列番号:7);reverse gcaagtgcatcatcgttgttcatac(配列番号:8)、マウスEGF:forward catcatggtggtggctgtctg(配列番号:9);reverse cacttccgcttggctcatca(配列番号:10)、マウスGAPDH:forward aaatggtgaaggtcggtgtg(配列番号:11);reverse tgaaggggtcgttgatgg(配列番号:12)、であった。定量はTakara-bio社が推奨する方法にて行った。
mRNA発現のノックダウンには、Ambion社が作製したsiRNAを用いた。使用したsiRNAは、ヒトIL6R siRNA、ヒトgp130 siRNA、Negative Control#1 siRNAであった。がん細胞を3.5cm dishに2×105個撒き、48時間培養した後、siRNA 20μMおよびDharmaFECT transfection reagent 4 (Dharmacon) 8μlを加えた。24時間後に細胞を採取し、mRNA発現解析もしくは神経浸潤モデルに使用した。
解析ソフトは、STATVIEW 5.0を用いた。平均値の差の検定は、student-t両側検定を用いた。図中のエラーバーは標準偏差を示すように作成した。
ヒト膵がん細胞株における、IL-6α受容体(IL6R)およびIL-6β受容体(gp130)の細胞内mRNA発現をreal time RT-PCRを用いて検討した。ヒト膵がん細胞株において、IL6R mRNA(図1A)およびgp130 mRNA(図1B)の明瞭な発現を認めた。
ヒトリコンビナントIL-6を用いて、IL-6のヒト膵がん細胞株に対する増殖能、走化能、遊走能への影響を、細胞数の経時的計測(図2AおよびB)、chemotaxis assay(図2C)、wound healing assay(図2D)を用いて検討した。IL-6は膵がん細胞株の細胞増殖には影響を及ぼさないが、走化能および遊走能を亢進させることが明らかとなった。
ヒトリコンビナントIL-6(rhIL6)を用いて、IL-6のヒト膵がん細胞株Capan-1に対する細胞内シグナルへの影響を、リン酸化STAT3(pSTAT3)(図3A)、リン酸化Erk1/2 (pErk1/2)(図3B)、リン酸化Akt(pAkt) (図3C)についてウエスタンブロット法を用いて評価した。細胞内のリン酸化STAT3蛋白発現はrhIL6を添加して15分後に、リン酸化Erk1/2蛋白発現は1時間後にそれぞれ明らかな亢進を認めた。リン酸化Akt発現への影響は認められなかった。
膵がんの重要な浸潤様式は神経浸潤距離である。神経浸潤を再現し、かつ神経浸潤距離が計測可能なマウス神経浸潤モデルを作製することは、膵がんの重要な腫瘍浸潤様式を制御する治療法を検討する上で重要である。神経浸潤モデルは、免疫不全マウスの坐骨神経内にヒト膵がん細胞株Capan-1を直接注入することで作製された。肉眼的に、神経浸潤部は表面不整で明らかに正常神経より太い(図4A)。組織学的神経浸潤距離は、注入時Capan-1神経内拡散距離よりも、1週間後で明らかに長く、その距離は経時的に増大する(図4B)。また、神経浸潤は注入部より中枢側へ進展しており(図4C)、これはヒト膵がん神経浸潤と同一の特徴である。
ヒト膵がん神経浸潤は、腫瘍周囲の神経組織を損傷することが報告されている。神経損傷は、損傷部より末梢側の神経組織においてIL-6発現を亢進させることがわかっている。神経浸潤による神経組織のIL-6発現動態を検討するため、神経浸潤モデルを用いて、神経浸潤中枢側および末梢側の神経組織内(図5B)に発現するマウスIL-6(mIL6) mRNAをそれぞれreal time RT-PCR法にて評価した。mIL6は神経浸潤中枢側で高発現していたが、その他の神経損傷モデルではその傾向を認めなかった(図5B)。mIL6蛋白発現を蛍光免疫染色にて確認すると、シュワン細胞のマーカーであるS100陽性細胞領域に一致してIL6陽性顆粒を認めた(図5C)。神経浸潤モデルにおいてmIL6分泌細胞の一つはシュワン細胞であることが明らかとなった。また、EGFは神経損傷において高発現するとされる分子であるが、マウスEGF(mEGF) mRNA発現動態はmIL6とは異なり中枢側で高発現する傾向を認めなかった。この結果は、神経浸潤部における腫瘍-神経相互作用にはIL-6が強く関わっていることを示唆する。
IL-6の重要な細胞内シグナルであるリン酸化STAT3(pSTAT3)蛋白の膵がん細胞内発現を、免疫染色を用いて検討すると、神経浸潤中枢方向に一致してリン酸化STAT3発現が亢進していた(図6)。この結果は、神経浸潤中枢側の神経組織におけるIL-6発現の亢進と分布が一致する。
IL-6による細胞内シグナルには、gp130の介在が必要である。siRNAを用いて膵がん細胞のgp130 mRNA発現をノックダウンした膵がん細胞株を用いて神経浸潤モデルを作製すると、神経浸潤距離が抑制された(図7)。この結果は、神経浸潤には、IL-6由来を含むgp130を介するシグナルが重要であることを示す。
IL-6による細胞内シグナルには、IL-6受容体(IL6R)の介在が必要である。siRNAを用いて膵がん細胞のIL6R mRNA発現をノックダウンした膵がん細胞株を用いて神経浸潤モデルを作製すると、神経浸潤距離が抑制された(図8)。この結果は、神経浸潤には、IL-6を介するシグナルが重要であることを示す。
次に、マウス神経浸潤モデルにJAK阻害剤又は抗IL-6受容体抗体を投与し、これらの阻害剤の神経浸潤への影響を確認した。
JAK阻害剤のマウス神経浸潤モデルへの投与実験
STAT3リン酸化を阻害するJAK阻害剤 AG490(CALBIOCHEM)をDMSOに溶解し、生理食塩水で希釈し、DMSO 1%のAG490液を調製した。神経浸潤モデル作製2日後より、AG490 0.5mgをマウスの腹腔内へ連日投与し、モデル作製から2週後にがん細胞を注入した坐骨神経を採取し、神経浸潤距離を測定した。コントロール群は、DMSO 1%液を同様の方法で投与した。使用したマウスの数は、AG490群とDMSO群ともに7匹であった。
抗IL-6受容体抗体のマウス神経浸潤モデルへの投与実験
ヒトIL-6受容体を阻害する抗IL-6受容体抗体(中外製薬、トシリズマブ)を生理食塩水に溶解し、マウス神経浸潤モデルにモデル作製1週後より、抗IL-6抗体阻害抗体 5μg/gを週2回投与した。モデル作製から3週後にがん細胞を注入した坐骨神経を採取し、神経浸潤距離を測定した。コントロール群は、生理食塩水に溶解したヒトIgG(Sigma)5μg/gを同様の方法で投与した。使用したマウスの数は、抗IL-6受容体抗体群 6匹、コントロール群4匹であった。
統計解析
解析ソフトは、STATVIEW 5.0を用いた。平均値の差の検定は、student-t両側検定を用いた。図中のエラーバーは標準偏差を示すように作成した。
また、ヒトIL-6の阻害作用をするため、抗ヒトIL-6受容体抗体をがん細胞注入1週後より週2回投与を2週間継続すると、神経浸潤が抑制されることが明らかとなった(図9B)。この結果から、ヒト膵癌神経浸潤が抗ヒトIL-6受容体抗体により阻害されたと考えられる。
Claims (5)
- 抗インターロイキン6(IL-6)受容体抗体を有効成分とする細胞の神経浸潤抑制剤。
- 癌細胞の神経浸潤を抑制することを特徴とする請求項1に記載の抑制剤。
- 膵癌細胞の神経浸潤を抑制することを特徴とする請求項2に記載の抑制剤。
- 中枢側への神経浸潤を抑制することを特徴とする請求項1〜3いずれかに記載の抑制剤。
- 抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である請求項1〜4いずれか一項に記載の抑制剤。
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WO2009148148A1 (ja) | 2009-12-10 |
EP2305306A1 (en) | 2011-04-06 |
EP2305306B1 (en) | 2016-02-10 |
TW201006491A (en) | 2010-02-16 |
CA2728243C (en) | 2020-03-10 |
CN104906581A (zh) | 2015-09-16 |
US20110150869A1 (en) | 2011-06-23 |
CA2728243A1 (en) | 2009-12-10 |
EP2305306A4 (en) | 2012-08-29 |
CN102256623A (zh) | 2011-11-23 |
KR101665729B1 (ko) | 2016-10-12 |
US10717781B2 (en) | 2020-07-21 |
KR20110046399A (ko) | 2011-05-04 |
TWI528973B (zh) | 2016-04-11 |
JPWO2009148148A1 (ja) | 2011-11-04 |
TW201503898A (zh) | 2015-02-01 |
HK1214514A1 (zh) | 2016-07-29 |
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