JP2021510835A - Tas1r3タンパク質を発現する腫瘍に関する治療目的、診断目的及び/又は予後診断目的のマーカーとしてのtas1r3タンパク質の使用 - Google Patents
Tas1r3タンパク質を発現する腫瘍に関する治療目的、診断目的及び/又は予後診断目的のマーカーとしてのtas1r3タンパク質の使用 Download PDFInfo
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Abstract
Description
本発明では、「TAS1R3受容体」は、味蕾においてだけでなく、肝臓及び膵臓等の他の組織並びに腫瘍細胞においても発現される味覚Gタンパク質共役型膜貫通受容体として理解される。この受容体には、HGNC:15661(NCBI Vega:OTTHUMG00000003071)、Entrez Gene:83756、Ensembl:ENSG00000169962、OMIM:605865、o UniProtKB:Q7RTX0等の多くの参照が存在する。該受容体は、TAS1R1受容体又はTAS1R2とヘテロ二量体を形成し、種々のアミノ酸、グルコース等によって活性化される甘味又はうま味の検出器として機能することが分かっている。TAS1R3受容体及びそのリガンドの図に関する図12を参照。
本発明の著者らは、CTC(循環腫瘍細胞)(実施例1を参照)及び腫瘍において、新しい受容体であるTAS1R3(味覚の受容体)を特定し、その受容体の発現がグルコースの存在に応じて変化し、原発性腫瘍細胞、播種性腫瘍細胞又は転移性腫瘍細胞の存在に関連していることを突き止めた。
a)患者から単離された少なくとも1つの生体試料、好ましくは血液、血清若しくは血漿の試料又は組織の試料、好ましくは固定された試料、より好ましくはパラフィンに固定及び包埋された試料から始める工程と、
b)細胞型特定技術によって、組織又は血清若しくは血漿の血液試料等の生体試料の細胞におけるTAS1R3の発現レベルを測定する工程と、
c)上記発現レベルと、健康な個体又は健康な器官若しくは組織の一部の生体試料又は腫瘍病変を有しない生体試料におけるTAS1R3受容体の発現レベル又は参照値とを比較する工程と、
を含み、健康な個体又は健康な器官若しくは組織の一部の生体試料又は腫瘍病変を有しない生体試料におけるTAS1R3受容体の発現レベル又は参照値と比較して増加した発現レベルが、患者における腫瘍の病変又は存在(腫瘍性又は転移性の病変又は存在)の指標であることを特徴とする、方法に関する。
a)患者から単離された少なくとも1つの生体試料、好ましくは血液、血清若しくは血漿の試料又は腫瘍組織の試料、好ましくは固定された試料、より好ましくはパラフィン中に包み込まれ固定された試料から始める工程と、
b)細胞型特定技術によって、組織又は血清若しくは血漿の血液試料等の生体試料の細胞におけるTAS1R3の発現を測定する工程と、
c)上記発現レベルと、項目a)の生体試料よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値とを比較する工程と、
を含み、項目a)の生体試料よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値と比較して増加した発現レベルが、患者の消極的な臨床的進化の指標であることを特徴とする、方法に関する。
a)患者から単離された少なくとも1つの生体試料、好ましくは血液、血清若しくは血漿の試料又は腫瘍組織の試料、好ましくは固定された試料、より好ましくはパラフィン中に包み込まれ固定された試料から始める工程と、
b)細胞型特定技術によって、組織又は血液、血清若しくは血漿の試料等の生体試料の細胞におけるTAS1R3の発現を測定する工程と、
c)上記発現レベルと、項目a)の生体試料よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値とを比較する工程と、
を含み、項目a)の生体試料よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値と比較して増加した発現レベルが、患者の消極的な臨床的進化の指標であることを特徴とする、方法に関する。
a)患者から単離された少なくとも1つの生体試料、好ましくは血液、血清若しくは血漿の試料又は腫瘍組織の試料、好ましくは固定された試料、より好ましくはパラフィンに固定及び包埋された試料から始める工程と、
b)細胞型特定技術によって、組織又は血清若しくは血漿の血液試料等の生体試料の細胞におけるTAS1R3の発現を測定する工程と、
c)上記発現レベルと、項目a)の生体試料よりも早い時点で得られた同じ患者の生体試料におけるTAS1R3受容体の発現レベル又は参照値とを比較する工程と、
を含み、項目a)の生体試料よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値と比較して増加した発現レベルが、患者の治療に対する応答の欠如の指標であることを特徴とする、方法に関する。
アセチル−LSQQLRMKGDYVLGGC−アミド(配列番号1)
アセチル−ERLKIRWHTSDNQKPVSRC−アミド(配列番号2)
i)試料を前処理する工程と、
ii)免疫染色する工程と、
iii)対比染色する工程と、
iv)免疫染色分析する工程と、
を含む。
特異的な標的剤、典型的には、TAS1R3受容体と相互作用することができる分子、例えば、単糖及び二糖、スクラロース、シクラメート、ネオエスペリジン、ジヒドロカルコン及び誘導体等の人工甘味料、ラクチゾール及び誘導体等の甘味阻害剤、ブラゼイン等のタンパク質、並びに抗体、抗体のフラグメント、ペプチド、アプタマー、小分子、タンパク質等の選択系によって特に設計された他の分子と、
細胞毒性剤、例えば細胞毒性剤又は抗腫瘍薬、放射性同位体、ナノ構造物又はナノエマルジョンと、
のコンジュゲートを提供する。
転移性肺癌患者のCTC(循環腫瘍細胞)におけるTAS1R3受容体の遺伝子発現の分析を、末梢血試料(患者=10、コントロールn=4)から、その分離のために磁性粒子(EpCAMベースのCELLection(商標)Epithelial Enrich Dynabeads(商標)キット)を使用して、図13に示される図に従って行った。試料からRNAを抽出した後に、それらのRNAを遺伝子発現アレイにおいてハイブリダイズさせた。シグナルを取り込み、処理することで、患者におけるコントロールと比べて発現が異なる遺伝子のリストを得たところ、その中にTAS1R3受容体があった。要約すると、CTCのトータルRNAを増幅し、相補的DNAを遺伝子発現マイクロアレイ(Agilent社)においてハイブリダイズさせ、生データを処理することで、品質の基準を満たす2392個の点(7.01%)が得られた。平均シグナルは60889ユニットであり、患者群及びコントロール群について、それぞれ76597ユニット及び16979ユニットであった。正規化後に、少なくとも8人の患者及び2人のコントロールにおいて、211を超える発現を有する1810個のプローブを後続の分析のために考慮した。進行性非小細胞肺癌患者から分離されたCTCの集団を特徴付ける遺伝子を、ソフトウェアMeV v4.7(Multiexperiment Viewer)(TM4 Microarray Software Suite)を適用することにより特定した。厳しい基準で候補遺伝子を選択するために2つのクラスのマイクロアレイデータ分析(SAM)アルゴリズムを使用して有意性を得た。偽発見率(FDR)=0の中央値についてのデルタパラメーターが3.3であると仮定すると、進行NSCLC患者のCTCの集団を明確に特徴付ける1.5より大きいlog2比を有する529個のプローブのみを考慮して、2461個の遺伝子のリストが示された。有意に発現されたこれらの遺伝子で、MeVを使用して階層的グループ化(HCL)を実施した。距離メトリックとして、ピアソン相関を選択し、MeVオプションにおいて絶対距離及び完全リンクグループ化パラメーターを使用した。
結腸系統SW620におけるTAS1R3の発現は、培養培地中のグルコース含有量に応じて変動する(高レベルのグルコースは、低含有量のグルコース中で培養された細胞について図6Aで観察されたものと比較して、より低い発現を引き起こす)。この結果を、ウエスタンブロットによって更に確認した(図6B)。さらに、図6から分かるように、SW620結腸細胞をグルコースの不存在下で成長させると、受容体の発現が増加することから、この受容体の発現は細胞代謝に関連付けられる。
TAS1R3受容体のリガンドであるラクチゾールが培養培地中に存在すると、研究対象の受容体の発現に増加が引き起こされる(図8A)。より高い濃度では、リガンドの存在は細胞増殖を妨害するが(図8B)、実際、細胞老化の誘導に関連付けられた(図8D)。さらに、ウエスタンブロットによって、SW620の培養培地中にラクチゾール又はグルコース(HG)等のTAS1R3のリガンドが存在すると、p−ERK、p−AKT又はIGF−IR等の腫瘍の進行に関連付けられた経路が活性化されることも分かった(図8E)。また、ブラゼイン及びシクラメートから誘導されたペプチドであるTAS1R3の他のリガンドがどのようにして、濃度及び各分子に応じて多かれ少なかれ増殖を妨げるのかも突き止めた(図8F)。
TAS1R3に対する種々のリガンドによるナノエマルジョンの機能付与を、以下のように行った。ナノエマルジョンは、オレイン酸及びスフィンゴミエリン(それぞれ5mg及び500μg)を含む100μLのエタノールと一緒にC16〜C18鎖に共有結合された500μgのラクチゾールを、穏やかに磁気撹拌しながら1mLのMilli−Q水(Millipore社 Milli−Q system(商標))に加えた後に自発的に得られた。G7111Aポンプ、G7129Aオートサンプラー及びG7114A UV−Vis検出器を備えたHPLCシステム(1260 Infinity II、Agilent社)と共にInfinityLab Poroshell 120EC−C18カラム(Agilent社、4.6×00mm、4μmポアサイズ)を使用した高速液体クロマトグラフィー(HPLC)を使用して、ナノエマルジョン中にリガンドが含まれていることを確認した。
量子ドットをヒトタンパク質TAS1R3に対する抗体で機能付与した。TAS1R3に対する抗体(参照sc50353、SCBT社)を、SiteClick(商標)Qdot(商標)655抗体標識キット(参照S10453、ThermoFisher社)を使用して、供給元の使用説明書に従って、量子ドットにコンジュゲートさせた。最終調製物中の濃度は、指定された波長で光学密度を計測した後に、式A=εcL(式中、Aは吸光度であり、εはモル吸光係数であり、cはモル濃度であり、Lは光路長である)を使用して測定した。量子ドットのサイズ分布を確認し、約400nmの過半数集団の存在を観察した。
Claims (15)
- 腫瘍バイオマーカーとしてのTAS1R3膜細胞受容体のin vitroでの使用。
- 患者における腫瘍の存在、新生物の存在又は転移の存在をin vitroで診断する方法であって、以下の工程:
a)前記患者から単離された少なくとも1つの生体試料から出発して、前記生体試料の細胞におけるTAS1R3の発現レベルを測定する工程と、
c)前記発現レベルを、健康な個体又は健康な器官若しくは組織の一部の生体試料又は腫瘍の存在を有しない生体試料におけるTAS1R3受容体の発現レベル又は参照値と比較する工程と、
を含み、健康な個体又は健康な器官若しくは組織の一部の生体試料又は腫瘍の存在を有しない生体試料におけるTAS1R3受容体の発現レベル又は参照値と比較して増加した発現レベルが、患者における腫瘍の存在、新生物の存在又は転移の存在の指標である、方法。 - 患者における腫瘍の存在、新生物の存在又は転移の存在に見舞われている患者の臨床経過をin vitroで予後診断する方法であって、以下の工程:
a)前記患者から単離された少なくとも1つの生体試料から出発して、前記生体試料の細胞におけるTAS1R3の発現を測定する工程と、
c)前記発現レベルと、項目a)の生体試料を得た時点よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値とを比較する工程と、
を含み、項目a)の生体試料を得た時点よりも早い時点で得られた生体試料におけるTAS1R3受容体の発現レベル又は参照値と比較して増加した発現レベルが、患者の消極的な臨床的進化の指標である、方法。 - 腫瘍の存在、新生物の存在又は転移の存在に見舞われている患者の臨床経過をin vitroでモニタリングする方法であって、以下の工程:
a)前記患者から単離された少なくとも1つの生体試料から出発して、前記生体試料の細胞におけるTAS1R3の発現を測定する工程と、
c)前記発現レベルと、項目a)の生体試料を得た時点よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値とを比較する工程と、
を含み、項目a)の生体試料を得た時点よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値と比較して増加した発現レベルが、患者の消極的な臨床的進化の指標である、方法。 - 腫瘍の存在、新生物の存在又は転移の存在に見舞われている患者の治療に対する応答をモニタリングする方法であって、以下の工程:
a)前記患者から単離された少なくとも1つの生体試料から出発して、前記生体試料の細胞におけるTAS1R3の発現を測定する工程と、
c)前記発現レベルと、項目a)の生体試料を得た時点よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値とを比較する工程と、
を含み、項目a)の生体試料を得た時点よりも早い時点で得られた同じ患者からの生体試料におけるTAS1R3受容体の発現レベル又は参照値と比較して増加した発現レベルが、治療に対する応答の欠如の指標である、方法。 - 前記生体試料の細胞におけるTAS1R3の発現の測定は、TAS1R3受容体に選択的に結合することができるFv、Fab、Fab’及びF(ab’)2、scFv、又はダイアボディ、トリアボディ、テトラボディ及び/又はヒト化抗体からなる群に属するアプタマー、抗体又はそのフラグメントを用いて行われる、請求項2〜5のいずれか一項に記載の方法。
- 前記アプタマー、前記抗体若しくはそのフラグメント、又は前記ダイアボディ、前記トリアボディ、前記テトラボディ及び/又は前記ヒト化抗体は、配列番号1又は配列番号2の配列のいずれかに選択的に結合することができる、請求項6に記載の方法。
- 前記存在する腫瘍は固形腫瘍である、又は前記患者は、乳癌、黒色腫、ブドウ膜黒色腫、膵臓癌、肺癌、前立腺癌、胃癌、頭頸部癌、肉腫、神経膠芽腫、神経芽腫、結腸及び直腸の癌、頭頸部の癌、腎臓癌及び膀胱癌並びに肝癌からなる群より選択される疾患を患っている、請求項2〜7のいずれか一項に記載の方法。
- 前記受容体のリガンド、好ましくはコンジュゲート又は免疫毒素の形のリガンドの使用により腫瘍細胞に向かって療法薬を誘導するための分子マーカー/腫瘍バイオマーカーとして使用される、細胞膜受容体TAS1R3。
- 前記受容体のリガンド、好ましくは放射性医薬品とのコンジュゲートの形のリガンドの使用によりin vivo診断するための分子マーカー/腫瘍バイオマーカーとして使用される、細胞膜受容体TAS1R3。
- 腫瘍細胞に対する療法で使用される又はin vivo診断での腫瘍バイオマーカーとして使用される、
a)TAS1R3受容体と相互作用又は結合することができる特異的な標的剤と、
b)細胞毒性剤、放射性同位体、ナノ構造物又はナノエマルジョンと、
を含むコンジュゲート。 - 前記TAS1R3受容体と相互作用又は結合することができる標的剤は、単糖及び二糖、スクラロース、シクラメート、ネオエスペリジン、ジヒドロカルコン等の人工甘味料、ラクチゾール等の甘味阻害剤、ブラゼイン等のタンパク質、抗体又は抗体のフラグメント、ペプチド、アプタマー又は小分子からなる群より選択される、請求項11に記載のコンジュゲート。
- 前記標的剤は、アプタマー、抗体、Fv、Fab、Fab’及びF(ab’)2、scFvからなる群より選択される抗体のフラグメント、又はダイアボディ、トリアボディ、テトラボディ及び/又はヒト化抗体からなる群より選択され、ここで、前記標的剤は、配列番号1又は配列番号2の配列のいずれかに選択的に結合することができる、請求項11に記載のコンジュゲート。
- a)ブラゼイン及びラクチゾールからなる群より選択される特異的な標的剤と、
b)細胞毒性剤、放射性同位体、ナノ構造物又はナノエマルジョンと、
を含む、コンジュゲート。 - 固形腫瘍、好ましくは、以下の群:乳癌、黒色腫、ブドウ膜黒色腫、膵臓癌、肺癌、前立腺癌、胃癌、頭頸部癌、肉腫、神経膠芽腫、神経芽腫、結腸及び直腸の癌、頭頸部の癌、腎臓癌及び膀胱癌並びに肝癌から選択される腫瘍の治療又はin vivo診断のために使用される、請求項11〜13のいずれか一項に記載のコンジュゲート。
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TOYONO, T. ET AL.: "CCAAT/Enhancer-binding protein β regulates expression of human T1R3 taste receptor gene in the bile", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1769, JPN6022035924, 2007, pages 641 - 648, XP022349465, ISSN: 0005006630 * |
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