JP7503864B2 - 免疫抗がん療法に対するバイオマーカーおよびその用途 - Google Patents
免疫抗がん療法に対するバイオマーカーおよびその用途 Download PDFInfo
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Description
実験材料および実験方法
細胞培養
マウス黒色腫B16F1、B16F10細胞株およびヒト卵巣がんSKOV3細胞株は、韓国細胞株バンク(KCLB-ソウル、韓国)から購入した。細胞を5%CO2の加湿大気下で37℃の温度で10%ウシ胎児血清(WELGENE、韓国)が添加されたDMEM培地で培養した。B16F10細胞株において遺伝子発現に対する低酸素症の効果は、93%N2、5%CO2および2%O2で構成されたガス混合物を維持したマルチガスインキュベーター(Galaxy R、New Brunswick Scientific)で細胞をインキュベートすることでテストした。
6週齢の雌C57BL/6マウスをオリエントバイオ(釜山、韓国)から購入した。マウスを特定の病原体のない条件下で蔚山大学校の実験室の動物施設で飼育し、蔚山大学校の動物管理および使用委員会の指針によって使用した。
TCGA正常(normal)と比較したTCGA腫瘍のPD-L1(CD274)遺伝子発現およびGEPIA(Gene Expression Profiling Interactive Analysis)を用いたGTExデータに基づいて全体生存率(Overall survival、OS)分析を行った。仮説検定と関連して、GEPIAは、ログ順位検定を考慮した。50%(中央値)のCD274発現臨界値によってCD274高発現と低発現コホート(cohort)を分類した。したがって、CD274発現レベルが50%よりも高いかまたは低いサンプルをそれぞれ高発現コホート(cutoff-high)および低発現コホート(cutoff-low)に分類した。DRG2発現プロファイルおよび一部の患者の臨床情報を含むデータは、GEPIA(Gene Expression Profiling Interactive Analysis)を使用して収得した。サンプルのレベル(Fragments Per Kilobase of transcript per Million(FPKM)標準化)を得た。
マウスDRG2に対するshRNA(DRG2-shRNA、TRC0000047195、5’-CCGGGCTCATCCTACATGAATACAACTCGAGTTGTATTCATGTAGGATGAGCTTTTTG-3’(配列番号25))を含むプラスミドコンストラクトpLKO-DRG2-shRNAおよび非ターゲットshRNA対照群ベクター(MISSION pLKO.1-puro non-mammalian shRNA control plasmid DNA,SHC002)をSigmaから購入した。マウス/ヒトに対するsiRNA(siDRG2,5’-CAUUGAAUACAAAGGUGCCAACA-3’(配列番号26))および対照群siRNA(scRNA)は、GenePharmaから購入した。
TRIzol試薬(Invitrogen)を使用して細胞からトータルRNAを抽出した。NanoDropTM2000システム(Thermo Fisher Scientific,Waltham,MA,USA)を使用してRNA濃度を測定した後、トータルRNA2μgおよびM-MLV逆転写酵素(Promega)を使用してcDNAを合成し、表1に記載された遺伝子特異的プライマーを使用したリアルタイムおよび半定量PCRで鋳型として使用した。SYBR Green PCR Master Mix(QIAGEN)を使用してABI 7500 Fast Real-Time PCRシステム(Applied Biosystems)でリアルタイムqRT-PCRを実施した。Taq polymerase(Solgent、大田、韓国)を使用して半定量RT-PCRを実施した。
脱グリコシル化分析(deglycosylation assay)のために、細胞抽出物内タンパク質または濃縮された上清液をSDS-PAGEで分離し、anti-DRG2(Proteintech)、mouse anti-PD-L1(Abcam)、anti-phospho STAT1(cell signaling)、anti-β-acin(Sigma)希釈液をそれぞれ処理した。免疫反応性(Immunoreactivity)バンドは、Pierce ECL Western blotting substrate(Thermo Scientific)を使用して検出した。
PD-1とPD-L1タンパク質相互作用を測定するために、懸濁細胞を4%パラホルムアルデヒドで常温で15分間固定し、組換えヒトPD-1 Fcタンパク質(R&D Systems)と共に1時間の間インキュベートした。2次抗体としてanti-human Alexa Fluor 488 dye conjugate(Life Technologies)を使用した。核をDAPI(blue;Life Technologies)で染色した。そして、FACSフローサイトメーター(Becton Dickinson,Inc.)を使用してAlexa Fluor 488 dyeの蛍光強度を測定した。
免疫細胞化学の分析のために、細胞を4%パラホルムアルデヒドで常温で15分間固定して、5% Triton X-100で5分間透過させた(permeabilized)後、1次抗体を使用して染色した。2次抗体としてanti-mouse Alexa Fluor 488または594 dye conjugateおよび/またはanti-rabbit Alexa Fluor 488または594 dye conjugate(Life Technologies)を使用した。核は、4’,6-diamidino-2-phenylindole(DAPI;blue;Life Technologies)で染色した。マウントした(mounting)後、Olympus 1000/1200 laser-scanning confocal systemを使用して細胞を観察した。
T細胞の不活性化に対する腫瘍細胞の影響を分析するために、腫瘍細胞をマウスT-Activator CD3/CD28(Life Technologies)で活性化したマウス脾臓CD4 T細胞と共培養した。5:1(Jurkat:tumour cell)の比で48時間の間インキュベートした。培地内に分泌されたIL-2のレベルをマウスIL-2 ELISAキット(Thermo Scientific)を使用して測定した。
すべての実験は、最小3回以上繰り返し行い、結果は、平均値±標準偏差で示した。統計的有意性は、Student’s t-testで確認し、P<0.05であれば、統計的に有意性があると判断した。Nsは、non-significant、*は、P<0.05、**は、P<0.01、***は、P<0.001、****は、P<0.0001を示す。
実施例1.PD-L1と生存率の相関関係の確認
存知のように、PD-L1のレベルが高いとき、低い生存率を示すかについて、臨床データを用いて確認した。その結果は、図1aおよび図1bに示した。
DRG2発現レベルががんに及ぼす影響を確認するために、マウスにがんを注入し、がんの成長と免疫細胞の分布を確認した。その結果は、図2a~図2eに示した。
DRG2のレベル減少が直接的にPD-L1に及ぼす影響を確認するために、in vitro上で実験を実施した。その結果は、図3a~図3fに示した。T細胞とがん組織間の交流を模倣するために、培地にPD-L1の発現を増加させるサイトカインであるIFN-gammaを共に処理し、実験を進めた。
DRG2のレベルが減少したがんにおいてPD-L1の発現量は増加するが、正常に機能しない理由を確認するために、一次的にT細胞の表面タンパク質であるPD-1とがん細胞の表面タンパク質であるPD-L1の結合程度を確認した。その結果は、図4a~図4cに示した。
DRG2のレベル減少は、PD-L1の発現を増加させるが、PD-L1の機能を抑制させる機序を確認するために、PD-L1のグリコシル化程度とPD-L1ががん細胞内に存在する位置を確認した。その結果は、図5a~図5dに示した。
Claims (20)
- DRG2(Developmentally-regulated GTP-binding protein 2)遺伝子またはDRG2タンパク質のレベルを測定する製剤を含む、免疫抗がん剤に対する治療反応性または予後予測用組成物であって、
前記免疫抗がん剤は、抗PD-1抗体または抗PD-L1抗体である、免疫抗がん剤に対する治療反応性または予後予測用組成物。 - 前記DRG2遺伝子のレベルを測定する製剤は、DRG2遺伝子に特異的に結合するプライマーまたはプローブであることを特徴とする請求項1に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記DRG2タンパク質のレベルを測定する製剤は、DRG2タンパク質に特異的に結合する抗体またはアプタマーであることを特徴とする請求項1に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記抗PD-1抗体は、ペムブロリズマブ(Pembrolizumab)、ニボルマブ(Nivolumab)またはセミプリマブ(Cemiplimab)であることを特徴とする請求項1に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記抗PD-L1抗体は、アテゾリズマブ(Atezolizumab)、アベルマブ(Avelumab)またはデュルバルマブ(Durvalumab)であることを特徴とする請求項1に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記組成物は、PD-L1陽性がんの免疫抗がん剤に対する治療反応性または予後予測用であることを特徴とする請求項1~5のいずれか1項に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記組成物は、対照群と比較して、DRG2遺伝子またはDRG2タンパク質の発現レベルが減少したがんを免疫抗がん剤に対する治療反応性の低いがんまたは予後の悪いがんと予測することを特徴とする請求項1~6のいずれか1項に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記組成物は、対照群と比較して、DRG2遺伝子またはDRG2タンパク質の発現レベルが減少したPD-L1陽性がんを免疫抗がん剤に対する治療反応性の低いがんまたは予後の悪いがんと予測することを特徴とする請求項1~7のいずれか1項に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記DRG2遺伝子またはDRG2タンパク質の発現減少は、がん細胞の表面で発現したPD-L1レベルの減少を示すことを特徴とする請求項1~8のいずれか1項に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記がん細胞表面におけるPD-L1発現レベルの減少は、がん細胞PD-L1とT細胞PD-1との結合減少を示すことを特徴とする請求項9に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記DRG2遺伝子またはDRG2タンパク質のレベルは、がん患者から分離した生物学的試料から測定することを特徴とする請求項1~10のいずれか1項に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 前記生物学的試料は、がん細胞、がん組織、血液、血漿、血清、骨髄、唾液、尿、および便からなる群から選択されたいずれか一つ以上であることを特徴とする請求項11に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物。
- 請求項1から12のいずれか一項に記載の免疫抗がん剤に対する治療反応性または予後予測用組成物を含む、免疫抗がん剤に対する治療反応性または予後予測用キット。
- DRG2(Developmentally-regulated GTP-binding protein 2)遺伝子またはDRG2タンパク質のレベルを測定する製剤を含む、PD-L1陽性がんにおける免疫抗がん剤に対する治療反応性または予後予測のためのコンパニオン診断(companion diagnosis)用組成物。
- 請求項14に記載のPD-L1陽性がんにおける免疫抗がん剤に対するコンパニオン診断用組成物を含む、PD-L1陽性がんにおける免疫抗がん剤に対するコンパニオン診断(companion diagnosis)用キット。
- がん患者から分離した生物学的試料からDRG2(Developmentally-regulated GTP-binding protein 2)遺伝子またはDRG2タンパク質のレベルを測定する段階を含む、免疫抗がん剤に対する治療反応性または予後予測のための情報提供方法であって、
前記免疫抗がん剤は、抗PD-1抗体または抗PD-L1抗体である、免疫抗がん剤に対する治療反応性または予後予測のための情報提供方法。 - 前記DRG2遺伝子またはDRG2タンパク質のレベルが、対照群と比較して減少した場合、免疫抗がん剤に対する治療反応性が低いかまたは予後が悪いものと予測することを特徴とする請求項16に記載の免疫抗がん剤に対する治療反応性または予後予測のための情報提供方法。
- PD-L1陽性がん患者から分離した生物学的試料からDRG2(Developmentally-regulated GTP-binding protein 2)遺伝子またはDRG2タンパク質のレベルを測定する段階を含む、PD-L1陽性がんにおける免疫抗がん剤に対する治療反応性または予後予測のための情報提供方法。
- 前記DRG2遺伝子またはDRG2タンパク質のレベルが、対照群と比較して減少した場合、免疫抗がん剤に対する治療反応性が低いかまたは予後が悪いものと予測することを特徴とする請求項18に記載のPD-L1陽性がんにおける免疫抗がん剤に対する治療反応性または予後予測のための情報提供方法。
- DRG2(Developmentally-regulated GTP-binding protein 2)遺伝子またはDRG2タンパク質のレベルを測定する製剤を含む、免疫抗がん剤に対する治療反応性または予後予測のための薬剤を製造するための組成物の使用であって、
前記免疫抗がん剤は、抗PD-1抗体または抗PD-L1抗体である、治療反応性または予後予測のための薬剤を製造するための組成物の使用。
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KR1020210039303A KR102528973B1 (ko) | 2020-03-30 | 2021-03-26 | 면역항암요법에 대한 바이오마커 및 이의 용도 |
PCT/KR2021/003834 WO2021201526A1 (ko) | 2020-03-30 | 2021-03-29 | 면역항암요법에 대한 바이오마커 및 이의 용도 |
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KR20230143864A (ko) * | 2022-04-06 | 2023-10-13 | 울산대학교 산학협력단 | 암의 난소 전이 예측용 바이오마커로서의 drg2의 용도 |
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JP2007236253A (ja) | 2006-03-07 | 2007-09-20 | Toray Ind Inc | 疾患又は疾患マーカーの検出方法 |
US20150226744A1 (en) | 2012-09-17 | 2015-08-13 | Ait Austrian Institute Of Technology Gmbh | Colon Cancer Diagnostic Method and Means |
JP2018509135A (ja) | 2014-12-23 | 2018-04-05 | イマティクス バイオテクノロジーズ ゲーエムベーハー | 肝細胞がん(hcc)およびその他のがんに対する免疫療法で使用するための新規ペプチドおよびペプチド組み合わせ |
WO2018225063A1 (en) | 2017-06-04 | 2018-12-13 | Rappaport Family Institute For Research In The Medical Sciences | Method of predicting personalized response to cancer treatment with immune checkpoint inhibitors and kits therefor |
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US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
US4800159A (en) | 1986-02-07 | 1989-01-24 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences |
KR20150003946A (ko) * | 2013-07-01 | 2015-01-12 | 울산대학교 산학협력단 | Drg2 억제제를 유효성분으로 포함하는 항암용 조성물 |
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JP2007236253A (ja) | 2006-03-07 | 2007-09-20 | Toray Ind Inc | 疾患又は疾患マーカーの検出方法 |
US20150226744A1 (en) | 2012-09-17 | 2015-08-13 | Ait Austrian Institute Of Technology Gmbh | Colon Cancer Diagnostic Method and Means |
JP2018509135A (ja) | 2014-12-23 | 2018-04-05 | イマティクス バイオテクノロジーズ ゲーエムベーハー | 肝細胞がん(hcc)およびその他のがんに対する免疫療法で使用するための新規ペプチドおよびペプチド組み合わせ |
WO2018225063A1 (en) | 2017-06-04 | 2018-12-13 | Rappaport Family Institute For Research In The Medical Sciences | Method of predicting personalized response to cancer treatment with immune checkpoint inhibitors and kits therefor |
Non-Patent Citations (1)
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CN115427812A (zh) | 2022-12-02 |
US20230287505A1 (en) | 2023-09-14 |
JP2023520475A (ja) | 2023-05-17 |
WO2021201526A1 (ko) | 2021-10-07 |
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