JP2017507146A - Nrp−1/obr複合体シグナル伝達経路により媒介される疾患の処置のための方法及び医薬組成物 - Google Patents
Nrp−1/obr複合体シグナル伝達経路により媒介される疾患の処置のための方法及び医薬組成物 Download PDFInfo
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Abstract
Description
1) インビトロでレプチンは、細胞増殖を低減して、遊走を増加させたが、これらの効果はNRP−1発現に依存的であった。T47DでのNRP−1過剰発現、又はMDA−MB231でのNRP−1サイレンシングのいずれかによる異種移植モデルでのインビボでの研究でも、NRP−1発現とリンパ節浸潤との相関性が示されており、またこの浸潤は、レプチンでの腫瘍処置に伴い増加した。
2) NRP−1はOBRと複合体を形成する。
3) NRP−1/OBR複合体形成はレプチン依存的である。
4) NRP−1/OBR複合体は、核に転位する。
5) NRP−1/OBR複合体形成及び核転位は、セリン/トレオニンタンパク質キナーゼCK2(CK2)によるNRP−1及びOBRリン酸化に依存する。これは、異なる3種の化学的化合物(TBB、DRB及びCX4945)によるCK2の阻害によって、またNRP−1及びOBRリン酸化のみならずNRP−1/OBR複合体の形成及び核転位をも防止するRNAサイレンシングによって確認された。
6) 他の公知のNRP−1リガンド(VEGF、Sema3A、TGFβ及びPDGF)のように、NRP−1は、レプチンに直接結合し、そしてOBRへのレプチン結合に伴いOBRオリゴマー化を誘発する。オリゴマー化の結果、OBRシグナル伝達増加が起こる。VEGF及びSEMAの場合にNRP−1/OBR複合体により誘発される転移をブロックしたように、この最後の結果は、レプチンが真のNRP−1リガンドとしてターゲティングされ得、その結合を防止することを示す。
(i)本発明のNRP−1/OBRシグナル伝達経路のアンタゴニストが、シグナル伝達をトリガーせずにNRP−1又はOBRに結合して、NRP−1/OBR複合体の形成を低減又はブロックする;
(ii)NRP−1/OBRシグナル伝達経路のアンタゴニストが、タンパク質−キナーゼCK2により媒介されるリン酸化を妨害することによりNRP−1/OBR複合体の安定性を阻害する;又は
(iii)NRP−1/OBRシグナル伝達経路のアンタゴニストが、調節鎖の一部である分子に結合するか又は別途にその活性を阻害し、これが阻害されない場合には、NRP−1/OBR複合体によって媒介されるシグナル伝達を刺激するか又は別途に促進する結果を有するものである
という場合に起こり得る。
(1)CK2の調節サブユニットをターゲティングするインヒビター(例えば、遺伝子的に選択されたペプチドアプタマー);
(2)CK2の触媒活性のインヒビター(例えば、キノベン(quinobene)、TBB、DMAT、IQA);及び
(3)多くの場合CK2サブユニットインターフェースに結合する分子であり、そのサブユニットの高親和性相互作用を阻害する、CK2ホロ酵素の攪乱物質。
各クラスのCK2インヒビターは、小分子、機能的核酸、又はペプチド模倣体など、いかなるタイプの分子でもあり得る。典型的には、CK2インヒビターは多種多様な化学物質からなり、フラボノイド(例えば、アピゲニン)、ヒドロキシアントラキノン/キサンテノン(xantenones)の誘導体(例えば、エモジン)、ヒドロキシクマリンの誘導体(例えば、DBC)、テトラブロモトリアゾール/イミダゾールの誘導体(例えば、DRB、TBB、DMAT、TBCA、TBBz)、及びインドロキナゾリンの誘導体(例えば、IQA)が含まれる。より具体的には、CK2の多くのATP競合インヒビターが文献に報告されており、これらに含まれるのは、5,6−ジクロロ−l−P−D−リボフラノシルベンズイミダゾール(DB)、6−メチル−1,3,8−トリヒドロキシアントラキノン(エモジン)、2−ジメチルアミノ−4,5,6,7−テトラブロモ−lH−ベンゾイミダゾール(DMAT)、4,5,6,7−テトラブロモベンゾトリアゾール(TBB)、レゾルフィン、4,4’,5,5’,6,6’−ヘキサヒドロキシジフェン酸、2,6,2’,6’−ジラクトン(エラグ酸)、[5−オキソ−5,6−ジヒドロインドロ−(l,2−a)キナゾリン−7−イル]酢酸(IQA)、及び2−(3,4−ジヒドロキシフェニル)−3,5,7−トリヒドロキシ−4H−クロメン−4−オン(ケルセチン)である。例えば、Zhu et al., 2009, Mol. Cell. Biochem. 333 : 159-67; Lopez-Ramos et al., 2010, Faseb J. 24: 3171 -85;及びCozza et al, 2010, Med. Res. Rev. 30: 419-62を参照されたい。
を有する化合物(化合物1又は化合物2)又は薬学的に許容し得るその塩若しくはエステルである。
及びその薬学的に許容し得る塩又はエステルからなる群より選択される。
− Maksym O. Chekanov, Olga V. Ostrynska, Sergii S. Tarnavskyi, Anatoliy R. Synyugin, Nadiia V. Briukhovetska, Volodymyr G. Bdzhola, Alexander E. Pashenko, Andrey A. Fokin, Sergiy M. Yarmoluk 新しいクラスのCK2インヒビターとしての、2−アミノピリミジノン及びそれらの6−アザ−類似体の設計、合成及び生物学的評価 Journal of Enzyme Inhibition and Medicinal Chemistry
− Maksym O. Chekanov, Olga V. Ostrynska, Anatoliy R. Synyugin, Volodymyr G. Bdzhola, Sergiy M. Yarmoluk 新しいクラスのヒトタンパク質キナーゼCK2インヒビターとしての、2−フェニルイソチアゾリジン−3−オン−1,1−ジオキシドの設計、合成及び評価 Journal of Enzyme Inhibition and Medicinal Chemistry(2013年4月11日にオンラインで投稿)。
− Giorgio Cozza, Lorenzo A Pinna, Stefano Moro タンパク質キナーゼCK2インヒビター:特許レビュー Expert Opinion on Therapeutic Patents Sep 2012, Vol. 22, No. 9, Pages 1081-1097
を有するD3.1である。
を有するM4である。
(a)被検物質の各々を、NRP−1/OBR/レプチンシグナル伝達経路を阻害するその能力について試験すること、及び
(b)前記経路を阻害することができる被検物質を陽性として選択すること
からなる工程を含む方法に関する。
i)NRP−1とOBR及び/又はレプチンとの複合体の形成を阻害するかどうか、
特にNRP1及びOBRの細胞外ドメイン間の相互作用を阻害するかどうか、
ii)CK2により誘発されるOBR及びNRP1のリン酸化を阻害するかどうか、
iii)NRP−1/OBR複合体の核転位を阻害するかどうか、及び
iv)NRP−1/OBR/レプチンシグナル伝達経路の制御下に発現される遺伝子の発現を阻害するかどうか
を判定することからなり得る。
a1)試験すべき前記被検物質を、第1のNRP−1ポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列、及び(2)第2のOBRポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列、及び/又は(3)レプチンポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列の混合物と接触させること、
a2)前記NRP−1ポリペプチドと前記第2のOBRポリペプチドとの結合を、前記被検物質がモデュレーションする能力を判定すること、及び/又は前記NRP−1ポリペプチドと前記第2のレプチンポリペプチドとの結合を、前記被検物質がモデュレーションする能力を判定すること
からなる。
a1)試験すべき前記被検物質を、第1のNRP−1若しくはOBRポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列、及び(2)第2のCK2αポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列の混合物と接触させること、
a2)前記NRP−1若しくはOBRポリペプチドと前記第2のCK2αポリペプチドとの結合を、前記被検物質がモデュレーションする能力を判定すること
からなる。
a1)試験すべき前記被検物質を、第1のNRP−1若しくはレプチンポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列、及び(2)第2のCK2αポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列の混合物と接触させること、
a2)前記NRP−1若しくはレプチンポリペプチドと前記第2のCK2アルファポリペプチドとの結合を、前記被検物質がモデュレーションする能力を判定すること
からなる。
(1)
− (i)前記と同義の第1のポリペプチドと(ii)転写因子の第1タンパク質部分との第1融合ポリペプチド
− (i)前記と同義の第2のポリペプチドと(ii)転写因子の第2部分との第2融合ポリペプチド
を発現している宿主細胞を提供すること、
ここで、第1及び第2タンパク質部分が一緒に結合している場合、前記転写因子は、DNAのターゲット調節配列に対して活性であり、
前記宿主細胞は、(i)前記活性転写因子によって活性化され得る調節DNA配列及び(ii)前記調節配列に作動可能に連結されているDNAレポート配列を含む核酸も含有する、
(2)工程1)で提供された前記宿主細胞を試験すべき被検物質と接触させること、
(3)前記DNAレポーター配列の発現レベルを判定すること。
(1)前記と同義の第1のポリペプチド及び第2のポリペプチドを提供すること、
(2)試験すべき前記被検物質を前記ポリペプチドと接触させること、
(3)工程(2)で得られたような前記ポリペプチド及び前記被検物質を用いて適切な泳動基材上でゲル泳動アッセイを行うこと、
(4)工程(3)で行われた泳動アッセイで前記ポリペプチド間に形成された複合体を検出及び定量すること。
(1)
− 第1抗原と融合された第1のポリペプチド、
− 第2抗原と融合された第2のポリペプチド、
− 試験すべき被検物質
を含むプレアッセイ試料を接触させること、
(2)工程(2)の前記プレアッセイ試料に:
− 特異的に前記第1抗原に対する、European Cryptateでラベルされた少なくとも一つの抗体、
− 前記第2抗原に対する、XL665でラベルされた少なくとも一つの抗体
を添加すること、
(3)工程(2)のアッセイ試料を前記European Cryptateの励起波長で照射すること、
(4)XL665の発光波長で発光された蛍光シグナルを検出及び/又は定量すること、
(5)工程(4)で得られた蛍光シグナルを、工程(1)のプレアッセイ試料が試験すべき被検物質の非存在下で調製されたときに得られた蛍光と比較すること。
先ず、MBA−MB−231及びT47D乳ガン細胞株を、それぞれそれらの高く且つ検出不可能なNRP−1発現と、レプチンレセプター(OBR)の発現のために、選択した。乳ガン細胞株遊走でのNRP−1及びレプチンの関連性を検討するために、本発明者らは、siRNA若しくはshRNAアプローチか、又はT47DでのNRP−1過剰発現を用いて、MDA−MB−231におけるNRP−1発現サイレンシングに着手した。いくつかの公開されたデータとは異なり、本発明者らはレプチン刺激下にMDA−MB−231及びT47D−NRP−1増殖を観察することができなかった。驚くべきことに、RNAサイレンシングによるNRP−1抑制は、MDA−MD−231増殖を誘発する。対照的に、レプチンはMDA−MB−231遊走を誘発したが、これはsiNRP−1条件で低減した。インビトロのデータを、ヌードマウスにおけるMDA−MB−231及びT47D異種移植片によりインビボで確認した。MDA−MB−231におけるshRNAサイレンシング、又はT47Dにおける過剰発現のいずれかによるNRP−1発現のモデュレーションは、レプチンで処理されたマウスにおいて、MDA−MB−231−shNRP−1による増殖の強化及びリンパ節浸潤の低下と、T47D−NRP−1−RFPによる増殖の低下及びリンパ節浸潤とを誘発した。
乳ガン細胞遊走における、NRP−1とレプチンとの直接会合を確認するため、本発明者らはMDA−MB−231において、及びT47D−NRP−1において近接ライゲーションアッセイ技術(Duolink)を用いることにより、NRP−1及びOBR相互作用を検証した。OBRはクラスIサイトカインレセプターファミリーのメンバーであるので、本発明者らは複合体NRP−1/OBRの形成がレプチンによってモデュレーションされ得るか否かという疑問を提起した。この疑問を、MDA−MB−231において内因的に、又はNRP−1によるか、NRP−1/OBR若しくはOBR単独によるかのいずれかでのT47Dの一過性トランスフェクションにより検証した。24時間のトランスフェクション後に、細胞を、16時間血清不足に付し、次いでレプチン(10nM)で刺激した。3時間後、培地を除去することにより刺激を停止し、細胞を先ず洗浄して、その後固定し、DuolinkインサイチュProximity Ligation Assay(PLA)により、及び共焦点鏡検法検出により、NRP−1/OBR複合体形成を分析した。共局在を、JACoP(ImageJ; National Institutes of Health, Bethesda, MD)ソフトウェアを用いて分析した。分子間の共局在は、陽性Pearson係数(r)によって示された。先ず、トランスフェクションしたT47DにおけるNRP−1の発現を、RT−PCRによって確認した。pcDNA3−NRP−1でトランスフェクションした細胞において赤色ドットとしてDuolink検出により表されるように、NRP−1は、内在性のOBRと複合体を形成する。NRP−1とOBRとでコトランスフェクションしたT47Dにおいて、Duolinkシグナルは増加した。空ベクターpcDNA3、又はOBR発現ベクターのいずれかでトランスフェクションしたT47DにおけるDuolinkシグナルは類似していた。同じ結果がMDA−MB−231で観察される。驚くべきことに、Duolinkシグナルを、白色ドットで表されるように核において検出した。細胞内タンパク質画分キットを使用することによって、総溶解液中、又は共免疫沈降後のいずれかでウエスタンブロット法により、細胞質内(C)、膜(M)内、総核抽出物(N)中又は可溶性核(SN)及びクロマチン結合画分(CB)中のNRP−1及びOBR局在を分析した。各々の画分の特異的タンパク質の検出、例えばC画分についてはHsp90、SN及びCB画分についてはSP1及びHDAC2、そして具体的には、核画分内のER膜画分による混入を検出するために、小胞体(ER)についてはカルレチクリンの検出によって、画分の純度を算定した。推測されるとおり、OBRは、MDA−MB−231の細胞質内(C)及び核画分(N)中でNRP−1で共免疫沈降されたが、T47Dでは共免疫沈降されなかった。リン酸化OBR(P−OBR)も同様に、NRP−1は、細胞質画分中と、37℃で3時間にわたり10nMのレプチンで刺激した、16時間血清不足に付したMDA−MB−231の核画分SN及びCB中において、検出された。P−OBR及びNRP−1は、核画分において共免疫沈降され、共焦点鏡検によって観察するとレプチン刺激に伴い増加していた。
レプチン及びOBRリン酸化によるNRP−1/OBR複合体形成のモデュレーションに加え、本発明者らは、複合体の核への転位をレギュレーションすることができるNRP−1のリン酸化の可能性を想定した。NRP−1の二つの推定上のリン酸化部位が報告されているがそれ以上の検討はなされていない。細胞外Bドメインの第一のものはShintaniらにより2009年に報告されたとおりであって利用可能な抗体はなく、また第二のものは細胞質内ドメイン内に位置する第916位のトレオニンにあってKyleらにより2011年に報告されたとおりである。T916でのP−NRP−1に対する特異的抗体が入手可能であったので、本発明者らは共免疫沈降によって、血清不足に付してレプチン(10nM)により刺激した後のMDA−MB−231においてP−NRP−1の検出を検討した。驚くべきことに、NRP−1はレプチン刺激に伴いリン酸化され、P−OBRと共にクロマチン結合画分内又は可溶性画分内のいずれかの、核内に局在する。このリン酸化状態を確認するために、本発明者らは、セリン/トレオニンキナーゼCK2の関与の可能性を、その第一の化学的インヒビター(DRB)の一つを使用して検証した。血清不足条件において、MDA−MB−231の細胞質及び核内の偏スポットとしてP−NRP−1を検出した。興味深いことに、レプチン(10nM)で刺激されたMDA−MB−231において、P−NRP−1は核内の広汎染色として検出された。レプチンで刺激された細胞のDRB処理(50μM)は、広汎な核P-NRP−1染色の阻害のみならず、刺激なしの細胞で観察されたP-NRP−1偏スポットの減少ももたらした。同じ希釈のDRBでDMSOと組み合わせた刺激条件において、本発明者らは広汎核P-NRP−1染色を観察することができたので、阻害は特異的であった。
核内、とりわけクロマチン結合画分内におけるNRP−1検出に基づき、本発明者らは、16時間血清不足に付し、用量を増加したレプチン(0、2及び10nM)で3時間処理されたMDA−MB−231にてChip−Seqを実施した。クロマチン免疫沈降(ChIP)アッセイは、精製されたポリクローナルウサギ抗NRP−1(Alex Kolodkinチームからの好意により入手)を用い、EZ-Magna ChIPTM Aで行った。試料を以下の様に設計する:インプットミックス(input mix)は、無刺激細胞(NS)、2nMのレプチンで刺激した細胞及び10nMのレプチンで刺激した細胞のインプットを含む。IgG対照用に、本発明者らは、NS、2nMのレプチンで刺激した細胞及び10nMのレプチンで刺激した細胞のIgG対照とチップの混合物(mixt)を分析した。Chip−Seq分析は、1)ホモサピエンスの完全ゲノム(GRCh37)での読み取り値のマッピング、2)ピークを参照ゲノムについて検出し、IP試料(NS、2nM及び10nMのレプチン)の一つに富化(enrich)されているが両者の対照試料(インプットミックス及びIgG混合物)には存在しない知見領域(finding region)にあるマッピングされた読み取り値での、それらの包括の演算を行うことによる、ピーク検出及び包括(coverage)、並びに3)ライブラリーの正規化及び比較に要約できる。各ライブラリーに対するマッピングされた読み取り値の数と百分率は、NSチップ試料については23’226’278(79.66%)、2nM チップ試料については25’247’185(76.13%)、及び10nMチップ試料については29’694’919(75.27%)であった。ピーク検出は、ソフトウェアSEQMONKを用いて実施した。合計20’495のピークを検出し、各ピークの10kb以内に位置する最も近い遺伝子に着目した。本発明者らは、遺伝子から10kbより遠い距離(distance>10kb)で3,844のピーク、遺伝子とオーバーラップしている13,893のピーク、遺伝子から下流の1,336のピーク<10kb、及び遺伝子から上流の1,422のピーク>10kbを検出した。興味深いことに、検出されるピークの数はレプチンの濃度に伴って増えた。本発明者らは、全試料からの20’495ピークの着目対象に認められる3181の遺伝子を解釈する。本発明者らは次いで、遺伝子のセットをGene Ontology ターム(GO)データベース及びReactomeデータベースからのPathwaysでマッピングし、50の最も示されるターム及び本データベースからの経路を抽出する。より興味深いことに、同定した経路は、シグナル伝達、代謝、免疫系、軸索誘導及び脂質の代謝など、レプチン及びNRP−1に関与することが広く公知である。
ニューロピリン(Neuropolin)−1は、レプチン/OBR複合体により乳ガン遊走及びリンパ節浸潤を誘発した。
いくつかの研究で、NRP−1が、VEGF及びセマフォリンなどの、その公知のリガンドと関係なく腫瘍の進行及び転移に関連付けられている。NRP−1による顆粒球生成のレギュレーションにおける脂肪細胞の役割についての、及び肥満症とガン進行との関係の増大についての、本発明者らの公開されたデータに基づき、本発明者らは、アディポカインであるレプチン及びその主要レセプターOBRは、NRP−1の新しいパートナーであり得ると想定した。この仮説を確認するために、本発明者らは、乳ガン細胞株遊走に関連付けられるNRP−1及びレプチンを検討すべく選択した。MDA−MB−231及びT47D細胞株を、それぞれのNRP−1の高く且つ検出不可能な発現(しかしOBRを異なるレベルで発現する)について、選択した。
NRP−1及びレプチンの乳ガン細胞株遊走への直接的な関連を、MDA−MB−231、及びNRP−1を過剰発現しているT47DにおけるNRP−1/OBR複合体の検出により確認した。
共焦点顕微鏡により明らかとなるDuolink PLAアッセイは、白色ドットにて表されるように核内のNRP−1/OBR複合体を示し、これは赤色ドットのDuolinkの共局在分析とJacopソフトウェアを用いた核のDAPI染色に起因している。膜複合体レセプターが核に転位することが報告されるのは初めてである。この意外な結果を、レプトマイシンBを用いてNRP−1/OBR複合体の核搬出を阻害することにより確認した。レプチン及びレプトマイシンBで共処理されたMDA−MB−231はレプチン単独で処理されたMDA−MB−231よりも核でのDuolinkによるNRP−1/OBR複合体検出が高いことが示された。NRP−1及びOBRの局在は、クロマチンへの結合におけるよりも、核画分や、さらには可溶性フォームでのNRP−1及びOBRの検出によって確認された。本発明者らは小胞体膜の何らかの混入によるものであり得るカルレチクリンを検出していないので、この局在は特異的である。このレベルででも、核におけるNRP−1の機能は同定されず、本発明者らは、NRP−1/OBR複合体の核転位はそれらのリン酸化によってレギュレーションされているはずであるということを示唆した。文献に報告されているとおり、NRP−1はCK2のターゲットになることができる。化学的なCK2インヒビターTBB又はDRBを使用することにより、本発明者らはNRP−1が、CK2で媒介されるリン酸化に対するターゲットであることのみならず、このリン酸化がNRP−1/OBR複合体安定性及びその核転位に不可欠であることも確認でき、これらは特異的抗P-NRP−1を用いることでDuolinkにより立証された。血清不足及び刺激なしのMDA−MB−231では、P−NRP−1が核周囲に濃縮しているので、P−NRP−1の免疫染色は、NRP−1転位がそのリン酸化状態に依存することを明らかに示している。刺激条件では、本発明者らは核内にP-NRP−1の蓄積を観察することができ、そのうえこの局在はCK2インヒビターによって阻害される。
インビトロ及びインビボの乳ガン細胞遊走と、MDA−MB−231及びT47D−NRP−1−RFPの核内でのその検出、主にクロマチン結合画分における検出とNRP−1の関連性から、NRP−1が細胞移動、遊走及び転移に関与する遺伝子配列に会合できるかという疑問が生じた。NRP−1 Chip−Seq分析は、レプチン刺激とピーク数の増加との相関性を明らかに示しており、これはNRP−1とOBRシグナル伝達との関連性を確認するものであった。さらに興味深いことに、リッチピークはレプチン機能に関連する遺伝子に対応しており、これはNRP−1/OBR作用についての別の議論となる可能性がある。ENCODEプロジェクトからのNRP−1 Chip−Seq及び転写因子Chip−Seqデータの配列比較で、RNAポリメラーゼII(Pol2)と転写因子の結合配列の同定がもたらされる。主なリッチ配列は、CTCF、TPB(TATA結合タンパク質)、TAF1(転写開始因子TFIIDサブユニット1又はTBPに関連付けられる因子250kDa)、及びp300に対するものであった。興味深いことに、CTCF結合に対応するリッチ配列の数は、Pol2とCTCFとの間に結合を作製した、既に報告された研究(MOLECULAR AND CELLULAR BIOLOGY, Mar. 2007, p. 1631-1648 ;Nature, vol 4 7 9 | 3 November 2011)に一致するPol2結合配列とおよそ同じレベルで増加した。同じ結論を、TBP及びTAF1(ref)についても下すことができる。これらの観察全てから、本発明者らはNRP−1の役割の可能性について、転写因子又はアクティベーター又は超アクティベーター因子と結論付けるが、これを確認するにはさらなる検討が必要である。
NRP−1過剰発現の結果、腫瘍の拡大と細胞運動性が引き起こされることが明らかに認められた。しかしながら、細胞遊走及び転移に関連付けられる分子機構は充分に解明されておらず、VEGFなどのその公知リガンドと関係なくNRP−1機能の報告もなされている。Mikael Klagsbrunチームは、NRP−1過剰発現後の腫瘍細胞遊走の増加はVEGFと無関係であることを既に示しており、彼らはNRP−1過剰発現は細胞運動性を担う下流の遺伝子を誘導すると想定した(FASEB. 2000, vol 14)。
本出願全体をとおして、種々の参照文献が、本発明の属する技術分野の水準を記載している。これらの参照文献の開示は、参照により本開示に援用される。
Claims (16)
- ガン、肥満症及び肥満症関連疾患、悪液質、食欲不振、尿管閉塞性腎疾患、自己免疫疾患及び感染症からなる群より選択される疾患を、その必要がある対象者において処置するための方法であって、治療的に有効な量のNRP−1/OBRシグナル伝達経路のアンタゴニストを前記対象者に投与することを含む、方法。
- 前記NRP−1/OBRシグナル伝達経路のアンタゴニストが、抗体、有機小分子、ポリペプチド及びアプタマーからなる群より選択される、請求項1記載の方法。
- 前記NRP−1/OBRシグナル伝達経路のアンタゴニストが、CK2インヒビターである、請求項1記載の方法。
- 前記CK2インヒビターが、アロステリックCK2インヒビターである、請求項3記載の方法。
- 前記NRP−1/OBRシグナル伝達経路のアンタゴニストが、NRP−1とOBRとの相互作用をブロックする能力又はNRP−1とレプチンとの相互作用をブロックする能力を有する抗体からなる群より選択される、請求項1記載の方法。
- 前記抗体が、NRP−1若しくはOBRの細胞外ドメイン又はレプチンのドメインに対するものである、請求項6記載の方法。
- 前記NRP−1/OBRシグナル伝達経路のアンタゴニストが、ガンの処置の抗VEGF剤と併用される、請求項1記載の方法。
- その必要がある対象者においてガンを処置するための方法であって、治療的に有効な量の抗VEGF剤と、治療的に有効な量のCK2インヒビターとを前記対象者に投与することを含む、方法。
- ガンに罹患している対象者において、抗VEGF処置に長期間曝されることにより誘発される適応性−回避的応答を予防又は低下するための方法であって、治療的に有効な量のNRP−1/OBRシグナル伝達経路のアンタゴニストを前記対象者に投与することを含む、方法。
- 前記NRP−1/OBR/レプチンシグナル伝達経路が、CK2インヒビターである、請求項9記載の方法。
- ガン、肥満症及び肥満症関連疾患、悪液質、食欲不振、尿管閉塞性腎疾患、自己免疫疾患並びに感染症からなる群より選択される疾患の予防又は処置に有用な複数の被検物質をスクリーニングするための方法であって、
(a)被検物質の各々を、NRP−1/OBR/レプチンシグナル伝達経路を阻害するその能力について試験すること、及び
(b)前記経路を阻害することができる被検物質を陽性として選択すること
からなる工程を含む、方法。 - 工程(a)が、前記被検物質が
i)NRP−1とOBR又はレプチンとの複合体の形成を阻害するかどうか、
特にNRP1及びOBRの細胞外ドメインと、NRP−1と相互作用するレプチンのドメインとの相互作用を阻害するかどうか、
ii)CK2により誘発されるOBR及びNRP1のリン酸化を阻害するかどうか、
iii)NRP−1/OBR複合体の核転位を阻害するかどうか、及び
iv)NRP−1/OBR/レプチンシグナル伝達経路の制御下にある遺伝子の発現を阻害するかどうか
を判定することからなる、請求項11記載の方法。 - 工程a)が、以下の工程:
a1)試験すべき前記被検物質を、第1のNRP−1ポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列、及び(2)第2のOBRポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列の混合物と接触させること、
a2)前記NRP−1ポリペプチドと前記第2のOBRポリペプチドとの結合を、前記被検物質がモデュレーションする能力を判定すること
からなる、請求項11記載の方法。 - 工程a)が、以下の工程:
a1)試験すべき前記被検物質を、第1のNRP−1ポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列、及び(2)第2のレプチンポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列の混合物と接触させること、
a2)前記NRP−1ポリペプチドと前記第2のレプチンポリペプチドとの結合を、前記被検物質がモデュレーションする能力を判定すること
からなる、請求項11記載の方法。 - 工程a)が、以下の工程:
a1)試験すべき前記被検物質を、第1のNRP−1若しくはOBRポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列、及び(2)第2のCK2アルファポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列の混合物と接触させること、
a2)前記NRP−1若しくはOBRポリペプチドと前記第2のCK2αポリペプチドとの結合を、前記被検物質がモデュレーションする能力を判定すること
からなる、請求項11記載の方法。 - 工程a)が、以下の工程:
a1)試験すべき前記被検物質を、第1のNRP−1若しくはレプチンポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列、及び(2)第2のCK2アルファポリペプチド又はその実質的に相同若しくは実質的に類似のアミノ酸配列の混合物と接触させること、
a2)前記NRP−1若しくはレプチンポリペプチドと前記第2のCK2アルファポリペプチドとの結合を、前記被検物質がモデュレーションする能力を判定すること
からなる、請求項11記載の方法。
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