JP6467604B2 - ネトリン−1干渉薬および化学療法薬による併用治療 - Google Patents
ネトリン−1干渉薬および化学療法薬による併用治療 Download PDFInfo
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Description
- 乳癌ホルモン療法薬:例えば、タモキシフェン、レトロゾール、アナストロゾール、エキセメスタン、ファスロデックス、
- 前立腺ホルモン療法薬:例えば、LHRHアゴニスト、ビカルタミド、アビラテロン、
- モノクローナル抗体:例えば、セツキシマブ、パニツムマブ、ベバシズマブ、
- キナーゼ阻害剤:例えば、イマチニブ、ニロチニブ、ダサチニブ、エルロチニブ、ゲフィチニブ、アファチニブ、スニチニブ、ソラフェニブ、パゾパニブ、クリゾチニブ、アキシチニブ
などの抗悪性腫瘍薬である。
- UNC5Aタンパク質をコードする配列番号5;nt(ヌクレオチド);nt1〜6 HindIII制限部位、nt7〜15 kozak配列、nt16〜72 Kappa2シグナル配列、nt73〜666 UNC5Aコーディング配列、nt667〜672 XpnI制限部位;
- UNC5Bタンパク質をコードする配列番号6;nt(ヌクレオチド);nt1〜6 HindIII制限部位、nt7〜15 kozak配列、nt16〜72 Kappa2シグナル配列、nt73〜660 UNC5Bコーディング配列、nt661〜666 XpnI制限部位;
- UNC5Cタンパク質をコードする配列番号7;nt(ヌクレオチド);nt1〜6 HindIII制限部位、nt7〜15 kozak配列、nt16〜72 Kappa2シグナル配列、nt73〜666 UNC5Cコーディング配列、nt667-672 XpnI制限部位;
- UNC5Dタンパク質をコードする配列番号8;nt(ヌクレオチド);nt1〜6 HindIII制限部位、nt7〜15 kozak配列、nt16〜72 Kappa2シグナル配列、nt73〜666 UNC5Dコーディング配列、nt667-672 XpnI制限部位;
- ヒトIgG1 Fc(ヒンジ+CH2+CH3 DNA配列、nt7〜693)ならびに1〜6nt位にKpnI制限部位および694〜699位にXbaI制限部位をコードする配列番号9。
1.ネトリン-1発現または過剰発現の評価を可能にする定量的RT-PCR
全RNAは、NucleoSpin(登録商標)RNA IIキット(Macherey Nagel社、Duren、Germany)を使用し、製造者の指示に従って抽出した。RT-PCR反応は、iScript(登録商標)cDNA合成キット(Biorad社)で実施した。全RNA1μgを、以下のプログラム:25℃5分間、42℃30分間および85℃5分間を使用して逆転写した。発現試験では、標的転写物をLightCycler(登録商標)2.0装置(Roche Applied Science社)で、LightCycler FastStart DNA Master SYBR Green Iキット(Roche Applied Science社)を使用して増幅した。標的遺伝子の発現は、ハウスキーピング遺伝子として使用したグリセルアルデヒド3-リン酸脱水素酵素(GAPDH)およびホスホグリセリン酸キナーゼ(PGK)遺伝子に正規化した。ハウスキーピング遺伝子に正規化した標的転写物の量は、比較CT法を使用して算出した。標的およびハウスキーピング遺伝子の効率がほぼ同じであることを示すために、検証実験を実施した。プライマーの配列は以下の通りである。
フォワードプライマー:aaaagtactgcaagaaggactatgc 配列番号11。
リバースプライマー:ccctgcttatacacggagatg 配列番号12。
イムノブロット分析では、細胞を改変RIPA緩衝液(50mM Tris-HCl、pH7.5、NaCl 150mM、1%NP-40、0.5%デオキシコール酸ナトリウム、0.1%SDS、EDTA 1mM、プロテアーゼ阻害剤カクテルおよびDTT 5mM)中で超音波処理することによって溶解し、4℃で1時間インキュベートした。細胞残渣を遠心分離(10.000g 15秒、4℃)によってペレットにし、タンパク質抽出物(1列当たり200μg)を10%SDS-ポリアクリルアミドゲルに添加し、PVDFシート(Millipore Corporation社、Billerica、MA、U.S.A.)にブロットした。フィルターをPBS/0.1%Tween20(PBS-T)に溶かした10%脱脂粉乳および5%BSAで一晩ブロックし、次いでウサギポリクローナルα-ネトリン-1(1:500希釈、クローンH104、Santa Cruz Biotechnology社、Santa Cruz、CA、USA)およびマウスモノクローナルβ-アクチン(Santa Cruz Biotechnologies社)抗体で2時間インキュベートした。PBS-Tで3回洗浄後、フィルターを適切なHRP結合2次抗体(1:10000、Jackson ImmunoResearch社、Suffolk、UK)で1時間インキュベートした。West Dura Chemiluminescence System(Pierce社、Rockford、IL、U.S.A.)を使用して、検出を実施した。
細胞死は、異なる方法によって評価した。全細胞死アッセイでは、96ウェルプレートでウェル当たり5*103細胞を血清の少ない培地中で成長させ、ドキソルビシンで処理した。48時間後、細胞死は生物発光細胞傷害性アッセイToxiLight(Lonza社、Basel、Switzerland)を使用して、製造者の指示に従って評価した。あるいは、細胞死パーセントは、アクリジンオレンジおよびDAPI染色によって、NucleoCounter NC-3000システム(ChemoMetec A/S社、Allerod、Denmark)を使用して測定した。簡単に説明すると、5*104細胞を12ウェルプレートに播種し、ドキソルビシンで処理した。処理して48時間後、浮遊している細胞および接着した細胞を収集し、PBS中に懸濁し、2種類の異なる色素と混合し、アクリジンオレンジで細胞の全集団を染色し、4',6-ジアミジノ-2-フェニルインドール(DAPI)で生育不能な細胞を染色した。その後、全細胞集団中のDAPI陽性細胞として測定した細胞死率は、NucleoCounter NC-3000によって、製造者の使用注意書に従って測定した。細胞生存は、MTSアッセイ(CellTiter 96 AQueous One Solution Cell Proliferation Assay、Promega社)によって96ウェルプレートで測定した。MTSアッセイは、血清が少ない培地中で16時間成長させ、その後血清を含まない培地中で指示したドキソルビシン濃度で48時間処理した3*103細胞において、製造者の手順に従って実施した。カスパーゼ-3活性アッセイは、カスパーゼ3/CPP32蛍光定量アッセイキット(Gentaur Biovision社、Brussel、Belgium)を使用して、製造者の使用説明書に従って、既に記載された通りに実施した(21)。カスパーゼ活性(活性/分/タンパク質のマイクログラム)は、分光蛍光光度計(405nm/510nm、Infinite F500、Tecan社、Mannedorf、Switzerland)で1時間の動力学的周期の読み取りから計算した。
TRAP-ネトリンDCCおよびTRAP-ネトリンUNC5Aはそれぞれ、IgG1 Fc部分に融合したDCC外部ドメインの5番目のフィブロネクチンドメインおよびUNC5A外部ドメインの2個のイムノグロブリン(Ig1-Ig2)ドメインである。これらの2種類の組換えタンパク質は、それぞれ293-free-styleおよびCHO-free-styleで生成した。
プラスミドの構築
Sambrook, J.ら、Molecular Cloning: A laboratory manual; Cold Spring Harbor Laboratory Press、Cold Spring Harbor、New York、1989に記載されたように、標準的方法を使用してDNAを操作した。分子生物学的試薬は、製造者の使用説明書に従って使用した。所望する遺伝子断片は、遺伝子合成によって調製した。合成した遺伝子断片は、特定の発現ベクターにクローニングした。サブクローニングした遺伝子断片のDNA配列は、DNA配列決定によって確認した。
組換えタンパク質は、293 Freestyle培養培地(Invitrogen社)に懸濁して、8%CO2、37℃で成長させたFreestyle HEK 293細胞(Invitrogen社)の一時的遺伝子導入によって得た。遺伝子導入のために、製造者の使用説明書に従って、293fectin(登録商標)試薬(Invitrogen社)を使用した。遺伝子導入の3日後、上清を収集し、遠心分離(200gで10分間)によって透明にした。Fc-融合タンパク質は、プロテインGセファロース4FFを使用して、製造者の使用説明書に従って精製した。溶出は、0.1MグリシンpH2.8で実施した。溶出液は、1Mトリス-Hcl pH9.0中で中和し、PBSで一晩透析した。最終的な分析は、変性および非変性条件下で、ポリアクリルアミドゲル電気泳動を使用して、その後クーマシーブルー染色か、またはニトロセルロース移行後のウェスタンブロット分析(抗ヒトIgG(Fc特異的)-HRP抗体、Sigma社)を使用することによって実施した。
7週齢(体重20〜22g)の雌胸腺欠損nu/nuマウスは、チャールスリバー動物施設から入手した。マウスは、フィルターで覆った滅菌ケージに収容し、無菌の動物施設で維持した。A549細胞は、PBS200μLに溶かした107個をマウスの右側腹部にs.c.注射することによって移植した。一旦腫瘍が形成されたら(V=100mm3)、マウスをネトリン-1干渉薬および/または細胞障害性薬で2週間処理した。腫瘍の大きさは、ノギスで測定した。腫瘍の体積は、式v=0.5*(長さ*幅2)で算出した。処理の最後に、腫瘍を摘出し、重量を測定し、7.5%ゼラチン-スクロース0.12M中に包埋し、20μmの切片に切断した。
報告されたデータは、それぞれ3連で実施した少なくとも3回の独立した測定の平均±S.D.である。統計学的解析は、指示しない限り、ノンパラメトリックマンホイットニーのU検定によって実施した。
1.ネトリン-1およびその受容体は、従来の化学療法を受けた腫瘍細胞で上方制御される。
まず、定量的RT-PCRによって、2種類の肺癌細胞系A549およびH460におけるドキソルビシンに応答したネトリン-1のレベルを分析した。図1に示したように、両細胞系におけるネトリン-1 mRNAレベルは、ドキソルビシン2μMによる処理によって大幅に増加した(それぞれ、430倍および300倍)。mRNAのこの増加は、ネトリン-1タンパク質発現の活発な増加が関係した[図2および免疫蛍光法(示さず)]。
ネトリン-1およびその受容体の両方が従来の薬物処理によって上方制御されるという事実は、ネトリン-1に対する生存の依存性が化学療法を受けた癌細胞において増幅されることを示唆している。したがって、まず、siRNA戦略によって、ネトリン-1をサイレンシングした際にドキソルビシンが誘導する細胞死を分析した。次に、A549細胞に、ネトリン-1 siRNAを遺伝子導入して、増加する濃度のドキソルビシンで処理した。細胞透過性の欠如(図10)、細胞生存(図11)、DAPI排除(図12)、カスパーゼ活性化(図13)またはDNA断片化(図14)の測定によって示されるように、ネトリン-1をサイレンシングすると、ドキソルビシンが誘導する細胞死の著しい増強が伴った。この感受性の増加が、結合していないネトリン-1依存性受容体のアポトーシス誘発機序によるものかどうかを測定するために、A549細胞においてドキソルビシン処理によって発現する主要なネトリン-1受容体であるUNC5Bをサイレンシングした設定で同様の実験を実施した。図15に示したように、UNC5Bのサイレンシングは、ネトリン-1サイレンシングおよびドキソルビシン処理によって誘導された細胞死の増強の阻害を伴った。
次に、前記で見られたインビトロの効果が、治療的観点においてインビボに転換できるかどうかを評価した。A549細胞をヌードマウスに移植し、触知可能な腫瘍を有する動物を媒体またはTRAP-ネトリンUNC5A20mg/kg単独もしくはドキソルビシン2mg/kgと組み合わせて週2回i.p.注射によって治療した。これらの投与計画および投薬に際して使用した単一薬剤(TRAP-ネトリンUNC5Aまたはドキソルビシン)治療は、検出可能ではあるが弱い腫瘍増殖阻害効果しか引き起こさなかった(図22)。しかし、ドキソルビシンとTRAP-ネトリンUNC5Aで同時処理すると、腫瘍増殖の強力で長い阻害が伴った。これらのデータを一緒に考え合わせると、従来の化学療法とネトリン-1干渉をベースにした治療の組合せは、相乗的な抗癌効果を伴うという見解が支持される。
ここで、癌細胞系は、細胞障害性薬による処理に応答して、ネトリン-1の発現を上方制御することを示す。ドキソルビシン、シスプラチン、5FUおよびパクリタキセル(タキソール)を含むここで試験した細胞障害性薬は通常、非小細胞肺癌、乳癌、結腸癌および卵巣癌の患者の管理において、補助療法および高度な療法の両方で使用される。さらに、今までの限られたヒト試料パネルを使用して、カルボプラチン/タキソールで治療した患者から得られた原発卵巣腫瘍は、治療前の同腫瘍と比較して、ネトリン-1レベルの増加を呈示したことを示した。細胞培養では、このネトリン-1上方制御は使用した薬物および癌細胞の種類に応じて動力学および大きさが異なるが(図1)、これらの薬物が様々な細胞機構に影響を及ぼすことが知られているという事実によって、ネトリン-1上方制御が特定の化学療法薬によって影響を受ける特定の経路の特定の変化ではなく、一般的な生存ストレス応答であるという見解が支持される。それゆえ、このネトリン-1上方制御がこれらの薬物に応答して癌細胞が使用する生存機構であり得ると推測されたことは興味深い。
ネトリン-1を過剰発現する症例のパーセントを、ネトリン-1およびその受容体の発現を定量した癌の種類それぞれについて挙げる。
- 転移性乳癌の60%(Fitamantら、PNAS 2008)、
- 非小細胞肺癌の47%(Delloye-Bourgeoisら、JNCI 2009)、
- 侵襲性神経芽細胞腫の38%(Delloye-Bourgeoisら、J. Exp. Med. 2009)、
- 膵臓腺癌の61%(Linkら、Annals of Chir. Onco. 2007;Dumartinら、Gastro 2010)、
- 原発性黒色腫(n=7)、黒色腫転移(n=6)の100%(Kaufmannら、Cellular Oncology 2009)、
- 卵巣癌の76%(Panastasiouら、Oncotarget 2011)、
- 神経膠芽腫の65%、
- 急性骨髄性白血病および慢性リンパ性白血病の>60%、
- 侵襲性B細胞リンパ腫の>50%、
- 肉腫の30%、
- 腎臓腺癌の40%、
- 頭部および頸部癌の22%、
- 精巣癌(胚性癌腫の36%、奇形腫の50%、卵黄嚢腫瘍の100%)、
- 腎臓癌の50%、
- 胃癌の26%、
- 子宮癌の19%。
Claims (12)
- 薬学的に許容される担体または媒体中に、癌細胞におけるネトリン-1の発現もしくは過剰発現を誘導することができる、ドキソルビシン、5-フルオロウラシル(5FU)、またはパクリタキセルから選択される化学療法薬およびネトリン-1干渉薬またはインビボにおいてネトリン-1干渉薬を発現することができるベクターを含む、ネトリン-1受容体を有し、ネトリン-1を発現または過剰発現する癌を治療するための医薬組成物であって、前記ネトリン-1干渉薬が、癌細胞上のネトリン-1受容体に対するネトリン-1の結合を阻害し、ネトリン-1受容体誘導性アポトーシスを促進し、前記ネトリン-1干渉薬が、ネトリン-1に結合する抗体、ネトリン-1受容体に結合する抗体、前記ネトリン-1受容体の細胞外ドメインから成るネトリン-1受容体の断片を含む化合物である、組成物。
- 前記ネトリン-1干渉薬が、ネトリン-1受容体DCC、UNC5A、UNC5B、UNC5CもしくはUNC5Dの細胞外ドメインを含む化合物である、請求項1に記載の組成物。
- 前記ネトリン-1干渉薬が、ネトリン-1受容体の細胞外ドメインおよび抗体Fc部分を含む融合タンパク質である、請求項1または2に記載の組成物。
- 前記ネトリン-1干渉薬が、ネトリン-1受容体に結合することができ、この結合がネトリン-1受容体によるアポトーシス誘導をブロックするネトリン-1の能力を妨害することができるペプチド部分を含む化合物である、請求項1に記載の組成物。
- 前記ネトリン-1の発現が前記化学療法薬に依存する癌の治療のための、請求項1から4のいずれか一項に記載の組成物。
- 前記化学療法薬が、癌細胞におけるネトリン-1受容体の上方制御を誘導することができる、請求項1から5のいずれか一項に記載の組成物。
- 前記化学療法薬が、癌細胞におけるDCCの上方制御を誘導することができる、請求項1から6のいずれか一項に記載の組成物。
- 前記化学療法薬が、癌細胞におけるUNC5AまたはUNC5Bの上方制御を誘導することができる、請求項1から6のいずれか一項に記載の組成物。
- 前記癌が、転移性乳癌、非小細胞肺癌、侵襲性神経芽細胞腫、膵臓腺癌、原発性黒色腫(n=7)、黒色腫転移(n=6)、卵巣癌、神経膠芽腫、急性骨髄性白血病、慢性リンパ性白血病、侵襲性B細胞リンパ腫、肉腫、腎臓腺癌、頭部および頸部癌、精巣癌、腎臓癌、胃癌、子宮癌から選択される、請求項1から8のいずれか一項に記載の組成物。
- ネトリン-1受容体を有し、ネトリン-1を発現または過剰発現する癌を治療するために、ネトリン-1干渉薬またはインビボにおいてネトリン-1干渉薬を発現することができるベクターと組み合わせて患者に使用する抗癌医薬品として使用するための、癌細胞においてネトリン-1の発現または過剰発現を誘導することができる、ドキソルビシン、5-フルオロウラシル(5FU)、またはパクリタキセルから選択される化学療法薬を含む医薬組成物であって、前記ネトリン-1干渉薬が、ネトリン-1に結合する抗体、ネトリン-1受容体に結合する抗体、前記ネトリン-1受容体の細胞外ドメインから成るネトリン-1受容体の断片を含む化合物である、組成物。
- ネトリン-1を発現または過剰発現する癌を治療するために、癌細胞におけるネトリン-1の発現または過剰発現を誘導することができる、ドキソルビシン、5-フルオロウラシル(5FU)、またはパクリタキセルから選択される化学療法薬と組み合わせて、またはその後に、患者に使用する抗癌医薬品として使用するための、ネトリン-1干渉薬またはインビボにおいてネトリン-1干渉薬を発現することができるベクターを含む医薬組成物であって、前記ネトリン-1干渉薬が、ネトリン-1に結合する抗体、ネトリン-1受容体に結合する抗体、前記ネトリン-1受容体の細胞外ドメインから成るネトリン-1受容体の断片を含む化合物である、組成物。
- 患者に同時に、別々に、または順次に投与するための、化学療法薬およびネトリン-1干渉薬またはインビボにおいてネトリン-1干渉薬を発現することができるベクターを含む、請求項1から11のいずれか一項に記載の組成物。
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CA1223831A (en) | 1982-06-23 | 1987-07-07 | Dean Engelhardt | Modified nucleotides, methods of preparing and utilizing and compositions containing the same |
US5792608A (en) | 1991-12-12 | 1998-08-11 | Gilead Sciences, Inc. | Nuclease stable and binding competent oligomers and methods for their use |
US5525711A (en) | 1994-05-18 | 1996-06-11 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Pteridine nucleotide analogs as fluorescent DNA probes |
AU2001293870A1 (en) * | 2000-10-16 | 2002-04-29 | Bayer Aktiengesellschaft | Regulation of human netrin binding membrane receptor unc5h-1 |
US7312243B1 (en) * | 2003-08-29 | 2007-12-25 | Jay Pravda | Materials and methods for treatment of gastrointestinal disorders |
US20060025335A1 (en) | 2004-01-30 | 2006-02-02 | Kinane Thomas B | Netrin compositions and methods of using the same |
AU2005250185A1 (en) | 2004-06-04 | 2005-12-15 | Laboratoires Serono Sa | Splice variant of UNC5H2 |
WO2006019904A1 (en) * | 2004-07-14 | 2006-02-23 | University Of Utha Research Foundation | Netrin-related compositions and uses |
CA2587921A1 (fr) * | 2004-11-22 | 2006-05-26 | Centre National De La Recherche Scientifique | Netrine 4 mutee, ses fragments et leur utilisation comme medicaments |
US20060153840A1 (en) * | 2005-01-12 | 2006-07-13 | Anne Eichmann | Methods for preventing or treating a condition or a disease associated with angiogenesis |
DK1989546T3 (en) | 2006-02-28 | 2016-11-21 | Centre Léon Bérard | SCREENING FOR ANTI-CANCER CONNECTIONS USING netrin-1 ACTIVITY |
WO2009141440A1 (en) * | 2008-05-21 | 2009-11-26 | Centre National De La Recherche Scientifique (Cnrs) | Netrin-1 overexpression as a biological marker and a survival factor for aggressive neuroblastoma |
AR074369A1 (es) * | 2008-11-20 | 2011-01-12 | Genentech Inc | Anticuerpos anti-unc 5b (receptor de netrina) y metodos de uso |
EP2208738A1 (en) * | 2009-01-09 | 2010-07-21 | Centre National pour la Recherche Scientifique (CNRS) | Method for the selection of endothelial cells death inducers via netrin-1 and its applications |
KR20140004632A (ko) | 2010-08-26 | 2014-01-13 | 에프. 호프만-라 로슈 아게 | DCC의 제 5 피브로넥틴 유형 III 도메인의 재조합 Fc-융합 단백질 |
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US20150246116A1 (en) | 2015-09-03 |
MX2015003343A (es) | 2015-10-22 |
AU2013314320A1 (en) | 2015-04-02 |
CA2884834A1 (en) | 2014-03-20 |
EP2895173A2 (en) | 2015-07-22 |
EP2708231A1 (en) | 2014-03-19 |
BR112015005443A2 (pt) | 2017-12-05 |
US9895439B2 (en) | 2018-02-20 |
CN104853756A (zh) | 2015-08-19 |
HK1208379A1 (en) | 2016-03-04 |
AU2013314320B2 (en) | 2017-04-06 |
IL237702B (en) | 2018-11-29 |
SG11201501877WA (en) | 2015-04-29 |
EP2895173B1 (en) | 2018-11-14 |
AU2013314320A2 (en) | 2015-04-09 |
CA2884834C (en) | 2020-11-17 |
CN110522913A (zh) | 2019-12-03 |
ES2702733T3 (es) | 2019-03-05 |
JP2015529675A (ja) | 2015-10-08 |
ZA201502269B (en) | 2019-05-29 |
WO2014041088A2 (en) | 2014-03-20 |
WO2014041088A3 (en) | 2014-07-03 |
KR20150079599A (ko) | 2015-07-08 |
KR102424439B1 (ko) | 2022-07-21 |
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