JPWO2018164262A1 - 治療有効性の予測方法 - Google Patents
治療有効性の予測方法 Download PDFInfo
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- JPWO2018164262A1 JPWO2018164262A1 JP2019503867A JP2019503867A JPWO2018164262A1 JP WO2018164262 A1 JPWO2018164262 A1 JP WO2018164262A1 JP 2019503867 A JP2019503867 A JP 2019503867A JP 2019503867 A JP2019503867 A JP 2019503867A JP WO2018164262 A1 JPWO2018164262 A1 JP WO2018164262A1
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Abstract
Description
本発明において実験動物は、具体的にはヒトの病変部の組織またはそれに由来する細胞が移植された実験動物であることが好ましい。例えば、ヒト(患者)の病変部が腫瘍である場合、腫瘍部から採取した腫瘍組織またはがん細胞を移植した実験動物であってもよいし、採取した腫瘍組織またはがん細胞をクローン化した培養細胞を移植した実験動物であってもよく、換言すればそのような場合「実験動物」は担腫瘍動物である。またその他にも、目的に応じて様々な実験動物、例えば、アルツハイマー病モデル、糖尿病モデル、遺伝病モデル、感染症モデルなどの病変モデル動物を実験動物として用いることができる。動物種の例としては、マウス、ラット、ウサギ、モルモット、スナネズミ、ハムスター、フェレット、イヌ、ミニブタ、サル、ウシ、ウマ、ヒツジなど、ある程度の遺伝学的な制御がなされており、均質な遺伝的要件を備えている動物が挙げられるが、飼育や実験が容易であるという観点から特にマウスが広く用いられている。
(担腫瘍モデルマウス)
本発明の実験動物として担腫瘍動物を用いる場合、担腫瘍モデルマウスを用いることが好ましく、後述するPDXモデルマウスを用いることがより好ましい。担腫瘍モデルマウスは、大きく自然誘発腫瘍マウス、培養がん細胞移植マウス、患者腫瘍組織移植マウスの3つに分類できる(表1参照;Kohrt et al., Defining the optimal murine models to investigate immune checkpoint blockers and their combination with other immunotherapies. Annals of Oncology 00: 1-9, 2016)。
(特定バイオマーカー)
本発明において「特定バイオマーカー」とは、ヒトの病変部に存在している生体物質(タンパク質、核酸等)であり、好ましくはヒトの病変部に含まれる細胞が発現している生体物質であり、典型的には病変組織に含まれる細胞に特異的に発現する生体物質である。
「がん関連タンパク質」としては、代表的には「がん細胞に発現する免疫系タンパク質」、「がん細胞に発現するパスウェイ系タンパク質」、「がん細胞に発現する転移系タンパク質」が挙げられる。それぞれに分類されるがん関連タンパク質には様々なものが知られており、診断または治療の目的、使用する薬剤の作用機序等に応じて適切なものを選択することができ、特に限定されるものではない。なお、nCounterが提供するがん関連遺伝子発現パネルに含まれる、免疫系(Immune)遺伝子パネル、パスウェイ系(Pathway)遺伝子パネル、転移系(Progression)遺伝子パネルの遺伝子(各770遺伝子)がコードしているタンパク質が、それぞれがん細胞に発現する免疫系タンパク質、パスウェイ系タンパク質、転移系タンパク質に該当する。また、これらの遺伝子の変異遺伝子に対応する変異タンパク質も、免疫系タンパク質、パスウェイ系タンパク質、転移系タンパク質に含むことができる。
「免疫細胞に発現するタンパク質」としては、例えば、PD−1、CTLA−4、TIM3、Foxp3、CD3、CD4、CD8、CD25、CD27、CD28、CD70、CD40、CD40L、CD80、CD86、CD160、CD57、CD226、CD112、CD155、OX40(CD134)、OX40L(CD252)、ICOS(CD278)、ICOSL(CD275)、4−1BB(CD137)、4−1BBL(CD137L)、2B4(CD244)、GITR(CD357)、B7−H3(CD276)、LAG-3(CD223)、BTLA(CD272)、HVEM(CD270)、GITRL、ガレクチン−9(Galectin−9)、B7−H4、B7−H5、PD−L2、KLRG−1、E−Cadherin、N−Cadherin、R−CadherinおよびIDO、TDO、CSF−1R、HDAC、CXCR4、FLT−3、TIGITが挙げられる。
また、本明細書における特定バイオマーカーは、腫瘍細胞および免疫細胞以外の細胞において発現するものであってもよい。腫瘍細胞および免疫細胞以外の細胞において発現する生体物質の具体例としては、間質に含まれるタンパク質等が挙げられる。
CD109(Platelet activation factor、 8A3、 E123)…活性化T細胞、血小板、血管内皮、巨核球、CD34+前駆細胞サブセット;
CD140a(PDGF-R、 PDGFR2)…線維芽細胞、巨核球、単球、赤血球、骨髄系前駆細胞、内皮細胞;
CD140b(PDGF-R、 PDGFR1)…内皮細胞、ストローマ細胞;
CD141(Thrombomodulin)…血管内皮、骨髄系細胞、血小板、平滑筋;
CD142(Tissue Factor(TF)、 Thromboplastin)…上皮細胞、活性化単球、活性化血管内皮;
CD143(ACE: アンジオテンシン転換酵素)…血管内皮、上皮細胞、活性化マクロファージ;
CD144(VE-Cadherin、 Cadherin-5)…血管内皮;
CD145(7E9、 P7A5)…内皮細胞;
CD146(MUC18、 s-endo、Mel-CAM)…血管内皮、活性化T細胞、黒色腫;
CD147(Basigin、 M6、 EMMRRIN)…白血球、赤血球、血管内皮、血小板;
CD201(EPCR:血管内皮細胞プロテインCレセプター)…血管内皮;
CD202(TIE2、TEK)…血管内皮、造血幹細胞サブセット;
CD280(Endo180、TEM22、uPARAP(uPAR-associated protein))…骨髄前駆細胞,線維芽細胞,内皮細胞サブセット,マクロファージサブセット;
CD299(DC-SIGN-related、 L-SIGN(Liver/Lympho node specific ICAM3-grabbing nonintegrin))…内皮細胞;
CD309(VEGFR2( Vascular endothelial growth factor receptor2)、 KDR)…内皮細胞、巨核球、血小板、幹細胞サブセット;
CD322(JAM2(Junctional adhesion molecule 2))…内皮細胞、単球、B細胞、T細胞サブセット;
CD331(FGFR1(Fibroblast growth factor receptor1))…線維芽細胞、上皮細胞;
CD332(FGFR2、Keratinocyte growth factor receptor)…上皮細胞;
CD333(FGFR3、 JTK4)…線維芽細胞、上皮細胞;
CD334(FGFR4、JTK2、 TKF)…線維芽細胞、上皮細胞;
CD339(Jagged-1、 JAG1)…ストローマ細胞、上皮細胞。
(特定バイオマーカーの発現状態)
本発明における特定バイオマーカーの発現状態とは、特定バイオマーカーの発現量、特定バイオマーカーを発現している細胞の種類、数および/または形態、特定バイオマーカーの発現部位(実験動物として担腫瘍動物モデルを用いる場合には、腫瘍組織または腫瘍部内の分布、専有面積)等の情報によって形作られる特徴をいう。
本発明の方法における特定バイオマーカーの発現状態の情報としては、例えば検体(標本スライド)における、(1)特定バイオマーカーの細胞当たりの、または組織の単位面積あたりの発現量、(2)特定バイオマーカーの細胞あたりの発現量とそれに対応する細胞数によって表されるヒストグラム、(3)特定バイオマーカーの細胞あたりの発現量とそれに対応する細胞数によって表される曲線、(4)複数の特定バイオマーカーの相互の位置情報(距離)に関する情報、(5)特定バイオマーカーの細胞内における局在パターン、特定細胞群(例えば、がん細胞群)の注目領域内(ROI:region of intrest)における局在パターンなどのパターンに係る情報等が挙げられる。これらの情報は画像情報(デジタル画像として変換されたものを含む)として取得されたものであることが好ましく、さらに定量的な情報として変換し得るものであることが好ましい。発現状態の情報は上記のいずれか一つだけでなく、複数が組み合わされたものであってもよいし、また、特定バイオマーカーを複数選択してそれぞれの発現状態の情報が組み合わされたものであってもよい。
同様に特定バイオマーカーの組織の単位面積あたりの発現量を求める場合、画像中の特定の領域にある組織に含まれる細胞における輝点数または粒子数について計測した後、その組織の面積で割るようにすればよい。
本発明の1つの側面においては、患者から採取した病変部(病変組織)である検体の遺伝子解析による変異情報をもとに特定バイオマーカーを特定し、さらに当該病変部を移植した実験動物の病変組織における当該特定バイオマーカーの発現状態の情報(画像情報を含む)およびその解析結果、当該実験動物における治療(薬剤)の効果や副作用および予後などの医薬情報などを一連の情報として関連付けて多角的に解析することで、当該患者における治療の有効性について精度の高い予測が可能となる。
本発明のさらなる側面では、特定バイオマーカーの発現状態の情報を含む1以上の情報を治療の有効性の予測や評価のために提供することができる。具体的には特定バイオマーカーの発現状態の情報、その解析結果、医薬情報およびその他の情報を含めた情報群を統合したデータベースとして、例えば医療機関や企業等に提供することで、疾患の治療方法・薬剤の効果の予測、治験・臨床試験、治療計画の構築等、様々な場面で有用に用いることができる。これらの情報は公開されている公知の情報が含まれてもよく、さまざまな検体における蛍光ナノ粒子を用いた蛍光免疫染色を行なうことによって取得した情報が含まれていてもよい。以下、PDXマウスを用いたデータベースの作製や利用形態について説明するが、特に限定されるものではない。
例えば患者から採取した検体、または患者から採取した組織を移植したPDXマウスの検体における特定バイオマーカーの発現状態と前記データベースとを照合して、発現状態に係る情報が類似しているサンプルをデータベースから1以上抽出し、そのサンプルに含まれる医薬情報を参照して、当該患者における薬剤の効果や副作用を投薬前に予測することが可能となる。
また、PDXマウスやそのデータベースを治験や臨床試験において有効に使用することもできる。例えば治験では1〜3の3つのフェーズと呼ばれる各段階があり、それぞれの段階での薬剤の安全性や有効性を確認している。実際に患者(ヒト)において候補となる薬剤を投与する前に、PDXマウスを作製し、試験を行なうことで、薬効の期待度や起こり得るリスクを予測することができる。以下にその具体的な一例をあげる。
さらに、データベースに含まれるサンプルの多い、つまり対象患者の多い領域(例えば乳がんや肺がんなど)においては、ある特定の患者の治療方針を決定するためにデータベースを利用することもできる。例えば、あるがん患者から採取した検体、または患者から採取した組織を移植したPDXマウスの検体において様々な特定バイオマーカー(例えば複数のがん関連タンパク質や核酸等)の発現状態の情報を取得し、データベースとを照合して発現状態に係る情報が類似しているサンプルを抽出することで、その腫瘍組織にはどの薬剤を選択し、さらにどのように投与することが効果的であるかを予測できることができる。
50mMTris溶液に、2次抗体として用いる抗ウサギIgG抗体50μgを溶解した。この溶液に、最終濃度3mMとなるようにDTT(ジチオトレイトール)溶液を添加、混合し、37℃で30分間反応させた。その後、反応溶液を脱塩カラム「Zeba Desalt Spin Columns」(サーモサイエンティフィック社、Cat.#89882)に通して、DTTで還元化した2次抗体を精製した。精製した抗体全量のうち200μLを50mMTris溶液に溶解して抗体溶液を調製した。その一方で、リンカー試薬「Maleimide-PEG2-Biotin」(サーモサイエンティフィック社、製品番号21901)を、DMSOを用いて0.4mMとなるように調整した。このリンカー試薬溶液8.5μLを前記抗体溶液に添加、混合し、37℃で30分間反応させることにより、抗ウサギIgG抗体にPEG鎖を介してビオチンを結合させた。この反応溶液を脱塩カラムに通して精製した。脱塩した反応溶液について、波長300nmにおける吸光度を、分光高度計(日立製「F−7000」)を用いて測定することにより、反応溶液中のタンパク質(ビオチン修飾2次抗体)の濃度を算出した。50mMTris溶液を用いて、ビオチン修飾2次抗体の濃度を250μg/mLに調整した溶液を、ビオチン修飾2次抗体の溶液とした。
テキサスレッド色素分子「Sulforhodamine 101」(シグマアルドリッチ社)2.5mgを純水22.5mLに溶解した後、ホットスターラーにより溶液の温度を70℃に維持ながら20分間撹拌した。撹拌後の溶液に、メラミン樹脂「ニカラックMX−035」(日本カーバイド工業株式会社)1.5gを加え、さらに同一条件で5分間加熱撹拌した。撹拌後の溶液にギ酸100μLを加え、溶液の温度を60℃に維持しながら20分間攪拌した後、その溶液を放置して室温まで冷却した。冷却した後の溶液を複数の遠心用チューブに分注して、12,000rpmで20分間遠心分離して、溶液に混合物として含まれるテキサスレッド集積メラミン樹脂粒子を沈殿させた。上澄みを除去し、沈殿した粒子をエタノールおよび水で洗浄した。得られた粒子の1000個についてSEM観察を行い、平均粒子径を測定したところ、平均粒子径152nmであった。このようにして作製されたテキサスレッド集積メラミン樹脂粒子を、次の手順に従ってストレプトアビジンで表面修飾し、得られたストレプトアビジン修飾テキサスレッド集積メラミン樹脂粒子を実施例1および3における蛍光体集積粒子(PID)として使用した。
作製例2で得られた粒子0.1mgをEtOH1.5mL中に分散し、アミノプロピルトリメトキシシラン「LS−3150」(信越化学工業社製)2μLを加えて8時間反応させて表面アミノ化処理を行なった。
5名の乳がん患者(A〜E)それぞれの乳がん組織について網羅的遺伝子解析を行い、得られた遺伝子の変異情報に基づいてバイオマーカーを特定した。特定されたバイオマーカー(特定バイオマーカー)は、HER2およびERであった。また当該5名の患者の乳がん組織から単離したがん細胞をSCID(Sevefe Combined ImmunoDeficiency)マウスの皮下に移植した(各患者の腫瘍組織に対して5匹ずつ作製、計25匹)作製した。腫瘍体積が約100mm3となった時点(移植約3か月後)から、これらのマウスにトラスツズマブ(商品名:ハーセプチン)尾静脈内投与を開始した(15mg/kg:4日に1回:計4回)。投与前後における腫瘍体積の測定を行なうとともに、初回投与前、初回投与から1週間後、2週間後、3週間後および4週間後の各時点において堵殺したマウスから組織切片(腫瘍組織)を採取した。採取した各組織切片について常法に従ってホルマリン固定およびパラフィン包埋を行い、さらに薄切することで、各処理時点のマウスについてそれぞれ二枚ずつの標本スライドを作製した。
(1)HER2タンパク質の免疫染色
(1−1)標本スライド前処理
評価準備−1において作製した標本スライドを脱パラフィン処理した後、水で洗浄した。洗浄した標本スライドを10mMクエン酸緩衝液中(pH6.0)中で121℃、15分間オートクレーブ処理することで、抗原の賦活化処理を行った。賦活化処理後の組織スライドをPBSにより洗浄し、洗浄した標本スライドに対してBSAを1%含有するPBSを用いて1時間ブロッキング処理を行った。
上記処理を行った各処理時点のマウスの標本スライドについて目的タンパク質HER2の蛍光免疫染色を行った。
蛍光標識処理を行った標本スライドを、マイヤーヘマトキシリン液で5分間染色してヘマトキシリン染色を行った後、45℃の流水で3分間洗浄した。
各染色を終えた標本スライドに対して、純エタノールに5分間浸漬する操作を4回行う固定化・脱水処理を行った。続いて、キシレンに5分間浸漬する操作を4回行う透徹処理を行った。最後に、標本に封入剤「エンテランニュー」(メルク社)を載せて、カバーガラスを被せる封入処理を行い、観察に用いる標本とした。
(2−1)観察・撮影工程
この工程における励起光の照射および蛍光の発光の観察には蛍光顕微鏡「BX−53」(オリンパス株式会社)を用い、蛍光免疫染色像および形態観察用染色像(各400倍)の撮影には、当該蛍光顕微鏡に取り付けた顕微鏡用デジタルカメラ「DP73」(オリンパス株式会社)を用いた。
この工程における画像処理には、画像処理ソフトウェア「ImageJ」(オープンソース)を用いた。
(1‐2)において抗HER2ウサギモノクローナル抗体「4B5」を抗ERウサギポリクローナル抗体「ab180900、アブカム社」を用いる以外は、HER2と同様の方法によってERの免疫染色および発現状態の評価を行った。
実施例1および2の結果を表2−1および表2−2に示す。遺伝子が大きな変異をおこしている患者由来のPDXマウスの方が、投薬によるHER2タンパク質の減少率が大きいことが確認された。また、遺伝子情報との関連性が大きいと判断された患者A、B間、あるいは遺伝子情報との関連性が中程度とされた患者C、D間であっても、HER2の発現量(PIDスコア)の推移には若干の差が見られる。
さらにこのような遺伝情報、医薬情報、発現情報(PIDスコア)についての情報を集積し、他の患者の治療にあたっても当該患者の情報と蓄積された情報とを照合することで、当該患者においてもその医薬の有効性の有無を判断することができるという可能性を提示することができる。
肺がん患者4名(F、G、H、I)から採取した腫瘍組織について遺伝子解析を行ない、特定バイオマーカーとしてEGRFを特定した。さらに各患者に投薬を開始すると同時に腫瘍組織を採取し、当該腫瘍組織の2mm角をSCID(Sevefe Combined ImmunoDeficiency)マウスの皮下へ移植した(各患者の腫瘍組織に対してマウス5匹ずつ作製、計20匹)。腫瘍体積が約300mm3となった時点(移植約1か月後)から各マウスに、抗ヒトEGFRモノクローナル抗体医薬品であるゲフィチニブ(商品名;イレッサ(Iressa))100mg/kgを1日2回、計4回尾静脈内投与した。投与1日後および投与100日後のマウスから腫瘍組織を採取して評価準備−1と同様の手法を用いて標本スライドを作製した。
抗HER2ウサギモノクローナル抗体「4B5」(ベンタナ社)の代わりに、抗EGFRウサギモノクローナル抗体(clone「5B7」ロッシュ社)を用いる以外は、HER2と同様の方法によってEGFRの免疫染色を行ない、さらに観察・撮影・画像処理を行ってPIDスコアの平均値をそれぞれ算出するとともに、細胞内における局在状態に基づいて局在A〜Cの3パターンに分類した。
(考察)
以上の結果から、薬剤耐性を引き起こした患者の腫瘍組織から作製したPDXマウスにおいては患者と同様に薬剤耐性が確認されることがわかる。このことから、候補となる治療薬を実際に患者に投与する前にPDXマウスに投与することで、患者が薬剤耐性を引き起こす可能性があるかどうかをあらかじめ予測することが可能となるのではないかと考えられる。また、薬剤耐性(医療情報)と特定バイオマーカーの発現を関連させた情報を集積することで、より短い日数で薬剤耐性が起きる可能性を予測することができるようになる。本実施例を例にあげると、100日後の時点でPDXマウスにおいて薬剤耐性が確認されず、特定バイオマーカー(EGFR)の局在が変化していなかったら薬剤耐性は発現しないことが期待できる。一方で、100日後の時点でPDXマウスにおいて薬剤耐性が確認されなかったとしても、特定バイオマーカーの局在(EGFR)が変化していたら薬剤耐性が起きる可能性があると予測され、患者においても同様に薬剤耐性が引き起こされると予測することができ、その時点で他の薬や治療法を選択するという決定が可能になり得る。
Claims (16)
- ヒトから採取した病変部である検体を用いて、特定バイオマーカーの発現状態の情報を含む1以上の情報を取得して、当該情報を治療の有効性の予測のために用いる方法。
- ヒトから採取した病変部の組織またはそれに由来する細胞を移植した実験動物の、当該移植部から採取した病変部である検体を用いて、特定バイオマーカーの発現状態の情報を含む1以上の情報を取得して、当該情報を治療の有効性の予測のために用いる方法。
- ヒトから採取した病変部である検体を用いて、特定バイオマーカーの発現状態の情報を含む1以上の情報を取得し、さらに当該ヒトから採取した病変部の組織またはそれに由来する細胞を移植した実験動物の、当該移植部から採取した病変部である検体を用いて、特定バイオマーカーの発現状態の情報を含む1以上の情報を取得し、取得された情報を組み合わせて治療の有効性の予測のために用いる方法。
- 遺伝子検査により、前記検体における遺伝子の変異情報を解析し、当該遺伝子の変異情報から前記特定バイオマーカーを特定する、請求項1または3に記載の方法。
- 前記治療が、特定バイオマーカーをターゲットとした薬剤である分子標的薬の投薬である請求項1〜4のいずれか一項に記載の方法。
- 前記特定バイオマーカーが、免疫チェックポイントタンパク質、がん細胞増殖因子、がん細胞増殖因子受容体、細胞表面抗原、血管増殖因子、血管増殖因子受容体、サイトカインおよびサイトカイン受容体からなる群より選択される少なくとも1つである、請求項1〜5のいずれか一項に記載の方法。
- 前記病変部が腫瘍である請求項1〜6のいずれか一項に記載の方法。
- 前記特定バイオマーカーが、腫瘍組織に発現するタンパク質である、請求項1〜7のいずれか一項に記載の方法。
- 前記分子標的薬が抗がん剤である請求項5〜8のいずれか一項に記載の方法。
- 前記特定バイオマーカーの発現状態の情報が当該特定バイオマーカーの発現量および発現分布を含む、請求項1〜9のいずれか一項に記載の方法。
- 前記特定バイオマーカーの発現状態の情報が画像情報によって取得される、請求項1〜10のいずれか一項に記載の方法。
- 前記特定バイオマーカーの発現状態の情報が画像情報を解析することによって取得される、請求項1〜11のいずれか一項に記載の方法。
- 前記画像情報が、蛍光ナノ粒子の輝点が表された蛍光画像である、請求項11または12に記載の方法。
- 前記画像情報が、蛍光ナノ粒子を用いた免疫染色法により取得される、請求項11〜13のいずれか一項に記載の方法。
- 前記特定バイオマーカーが、リン酸化されるタンパク質である、請求項1〜14のいずれか一項に記載の試験方法。
- 前記発現状態の情報が、検体中の血管占有率に関する情報を含む、請求項1〜15のいずれか一項に記載の方法。
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