JP6983417B2 - 抗癌性および抗炎症性の治療剤 - Google Patents
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- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 201000007905 transthyretin amyloidosis Diseases 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 108020005087 unfolded proteins Proteins 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
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Description
本発明は、国立衛生研究所から付与された助成金番号DK038772およびDK060051に基づく政府の支援によりなされた。政府は本発明に一定の権利を有する。
本出願は、2015年10月19日に出願された米国仮出願第62/243,612号、2016年1月21日に出願された同第62/281,702号、および2016年8月29日に出願された同第62/380,525号の優先権の利益を主張し、その各々の全内容は、全ての目的のためにそれらの全体が参照により本明細書に援用される。
以下の定義は、当業者によって一般的に理解される概念の要約として提供され、本明細書に開示される主題の理解のために提供される。この定義は本発明または本明細書の特許請求の範囲を限定するように意図されるものではない。
SRP/ERで切断された CP
NH2−
MLERGGEAAAAAAAAAAAPGRGSESPVTISRAGNAGELVSPLLLPPTRRRRRRHIQGPGPV
1 10 20 30
40 50 60
変異体#
1 PTEN_cp_IBS
2 PTEN_cp_IBS122
2,2’,2’’−トリクロロトリエチルアミン;トリコテセン(特にT−2トキシン、ベラクリン(verracurin)A、ロリジンAおよびアングイジン);ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミトブロニトール;ミトラクトール;ピポブロマン;ガシトシン(gacytosine);アラビノシド(「Ara−C」);シクロホスファミド;チオテパ;タキソイド、例えば、TAXOL(登録商標)(パクリタキセル;Bristol−Myers Squibb Oncology、ニュージャージー州プリンストン)、ABRAXANE(登録商標)(クレモフォールを含まない)、パクリタキセルのアルブミン処理ナノ粒子製剤(American Pharmaceutical Partners、シャウムベルク、111。)およびTAXOTERE(登録商標)(ドセタキセル;Rhone−Poulenc Rorer、アントニー、仏国);クロランブシル(chloranbucil);GEMZAR(登録商標)(ゲムシタビン);6−チオグアニン;メルカプトプリン;メトトレキサート;白金類似体、例えばシスプラチンおよびカルボプラチン;ビンブラスチン;エトポシド(VP−16);イホスファミド;ミトキサントロン;ビンクリスチン;NAVELBINE(登録商標)(ビノレルビン);ノバントロン;テニポシド;エダトレキサート;ダウノマイシン;アミノプテリン;カペシタビン(XELODA(登録商標));イバンドロナート(ibandronate);CPT−11;トポイソメラーゼ阻害剤RFS2000;ジフルオロメチロミチン(DMFO);レチノイド、例えばレチノイン酸;上記の任意の薬学的に受容し得る塩、酸または誘導体が含まれる。
(表3)
表3.
加齢 Chungら、2002;Adlerら、2007;Csizarら、2008
アレルギー Cousinsら、2008
頭痛 Reuterら、2003
疼痛 Tegederら、2004;Niederberger&Geisslinger、2008
複雑な局所疼痛症候群 Hettneら、2007
心臓肥大 Purcell&Molkentin、2003;Freundら、2005;Sen&Roy、
2005
筋ジストロフィー(2A型) Baghdiguianら、1999
筋肉疲労 Hasselgren、2007
異化障害 Holmes-McNary、2002
糖尿病、1型 Ho&Bray、1999;Eldorら、2006
真性糖尿病、2型 Yuanら、2001;Lehrkeら、2004;Chen、2005
肥満 Gilら、2007
胎児の成長遅延作用 Mammonら、2005
高コレステロール血症 Wilsonら、2000
アテローム性動脈硬化症 Rossら、2001;Li&Gao、2005
心臓疾患 Valenら、2001
慢性心不全 Frantzら、2003;Gongら、2007
虚血/再灌流 Toledo-Pereyraら、2004;Nichols、2004; Ridder&
Schwaninger、2008
ストローク Herrmannら、2005
脳動脈瘤 Aokiら、2007;2009
狭心症 Ritchie、1998
肺疾患 Christmanら、2000
嚢胞性線維症 Pollardら、2005;Carrabinoら、2006;Rottnerら、2007
酸誘発性肺傷害 Madjdpourら、2003
肺高血圧 Sawadaら、2007
慢性障害肺疾患(COPD) Barnes、2002;Rahman&Kilty、2006
ヒアリン膜疾患 Cheahら、2005
腎臓病 Guijarro&Egido、2001;Camici、2006;Guzik&Harrison、
2007
糸球体疾患 Zhengら、2005
アルコール性肝疾患 Zima&Kalousova、2005
レプトスピラ症腎臓病 Yangら、2001
腸疾患 Neurathら、1998
腹膜子宮内膜症 Gonzalez-Ramosら、2007
皮膚疾患 Bellら、2003
鼻腔炎 Xuら、2006
無汗性外胚葉異形成−ID Puelら、2005
ベーチェット病 Todaroら、2005
色素失調症 Courtois&Israel、2000
結核 Zeaら、2006
喘息 Pahl&Szelenyi、2002
関節炎 Roshakら、2002;Roman-Blas&Jimenez、2006;Aud&Peng、
2006;Okamoto、2006
クローン病 Pena&Penate、2002
大腸炎(ラット) Chenら、2005
眼性アレルギー Bieloryら、2002
緑内障 Zhouら、2005
虫垂炎 Penningtonら、2000
パジェット病 Linら、2007
膵炎 Weber&Adler、2001;Grayら、2006
歯周炎 Nicholsら、2001;Ambiliら、2005
子宮内膜症 Guo、2006;Celikら、2008
炎症性腸疾患 Dijkstraら、2002;Atreyaら、2008
炎症性肺疾患 Park&Christman、2006
敗血症 Wrattenら、2001;Abraham、2003
シリカ誘発性 Chen&Shi、2002
睡眠時無呼吸 Lavie、2003
AIDS(HIV−1) Hiscottら、2001
自己免疫 Hayashi&Faustman、2000;Bacher&Schmitz、2004
抗リン脂質症候群 Lopez-Pedreraら、2005
狼瘡 Kammer&Tsokos、2002;Okamoto、2006;Oikonomidouら、
2007
ループス腎炎 Zhengら、2006、2008
慢性疾患症候群 Maesら、2007
家族性地中海熱 Onen、2005
遺伝性周期性熱症候群 Jeruら、2008
心理社会的ストレス疾患 Bierhausら、2004
神経病理学的疾患 Cechetto、2001;Mattson&Camandola、2001;
Pizzi&Spano、2006
家族性アミロイド性多発ニューロパシー、炎症性ニューロパチー Mazzeoら、2004
外傷性脳傷害 Hangら、2005
脊髄損傷 Brambillaら、2005
パーキンソン病 Soosら、2004、Mogiら、2006
多発性硬化症 Satohら、2007
リウマチ性疾患 Okamoto、2006;Greethamら、2007
アルツハイマー病 Mattson&Camandola、2001;Collister&Albensi、2005
筋萎縮性側索硬化症 Xuら、2006
ハンチントン病 Khoshnanら、2004
網膜疾患 Kitaokaら、2004
白内障 Yang、2006
聴力損失 Merchantら、2005;Langら、2006
癌 Gilmoreら、2002;Karinら、2002:Leeら、2007
(http://www.bu.edu/nf-kb/physiological-mediators/diseases/を参照)
DKK3bの生物学的意義を、人工ヌクレアーゼおよび相同組換えを用いた標的遺伝子編集によってマウスで評価した。ジンクフィンガーヌクレアーゼ(ZFN、図16a、b)を用いて、Dkk3遺伝子のTSS2とエクソン3の間にloxPに挟まれた(floxed)シアン蛍光タンパク質(CFP)レポーターを挿入した(HR、図17)。(Guptaら、2012 Nature Methods 9、588〜590。)イントロン2のこの破壊は、TSS1駆動(driven)DKK3発現を維持するが、ホモ接合動物におけるDKK3bの選択的機能欠損をもたらすはずのCFPレポーターに続くTSS2駆動転写を終結させる。マウス胚における適用の前に、ZFN仲介ドナーDNA挿入の効率を、Cel−Iアッセイおよび一本鎖オリゴヌクレオチドの組換え相同修復(directed homology repair)を用いてC57Bl/6jマウスから単離した不死のC8D1A細胞で検証した(データは示さず)。CFP HRカセットのZFN仲介挿入は、不死化C8D1A細胞株においてCFPの弱い発現をもたらし、Dkk3遺伝子座での(複数の)CpGアイランドの過剰メチル化によってDkk3発現はサイレンシングされる(図7a)。(Kobayashiら、2002 Gene 282、151〜158;Tsujiら、2000 Biochem Biophys Res Commun 268、20〜24;Xiangら、2013 Journal of Cellular and Molecular Medicine 17、1236〜1246。)遺伝子編集C8D1Acfp/+レポーター細胞においてDNAメチルトランスフェラーゼ活性が阻害された場合、CFP発現は>5倍増加し、Dkk3b発現に関してTSS2駆動CFP置換が実証される(図7a)。
IBSとWnt/β−カテニンシグナル伝達経路の関係を、細胞増殖、プロモーター駆動レポーターアッセイ、および細胞移動分析によって定義した。Tet誘導性IBSまたはDKK3構築物の限定された抗生物質誘導を用いて、過剰発現の不都合な影響を回避した。IBSは細胞周期のG0/G1期(図8b)でPC3細胞増殖を停止させ(図8a)、誘導の24〜36時間までにIBS発現細胞をほぼ完全に消失させた(図8a)。以前の過剰発現研究とは異なり、制御されたDKK3発現はPC3細胞増殖の速度を変化させなかった(図8a、b)。(Veeckら、2012 Biochim Biophys Acta 1825、18〜28;Hsiehら、2004 Oncogene 23、9183〜9189;Abarzuaら、2005 Cancer Res 65、9617〜9622;Edamuraら、2007 Cancer Gene Ther 14、765〜772。)
悪性細胞を用いて行った生体外研究により、IBS作用の分子メカニズムに対する重要な手がかりがもたらされた。DKK3の過剰発現は核関連β−カテニンを減少させ、酵母ツーハイブリッドスクリーニングにより、DKK3がβ−カテニンに結合するE3ユビキチンタンパク質リガーゼサブユニットである細胞質βTrCPと相互作用することが見出された。(Leeら、2009 Int J Cancer 124、287〜297;Yueら、2008 Carcinogenesis 29、84〜92。)細胞内IBSの発見に先立ち、β−カテニン輸送に影響を与える細胞質複合体を形成することができるDKK3エフェクターは知られていなかった。
最初の研究は、分泌型PTENタンパク質から「借りた」SRP−cpの使用に基づいていた。より一般的な事例では、本発明者らは、ER膜においてSRP受容体(トランスロコン)と係合する任意の分泌認識ペプチドドメインが、分泌のためにER膜を横切って成長するポリペプチド鎖を移動させるために必要とすることに気付いた。さらに、本発明者らは、静電的相互作用によって融合タンパク質を細胞表面に「付着させる」ために必要な細胞透過性ドメイン−ポリカチオン性α−ヘリックス−を一般化できることに気付いた。さらに、本発明者らは、精製エピトープタグ−6his−およびこれらの精製助剤を除去するための酵素切断部位を兼ねるFLAGエピトープを含めた。ScpIBSの一般的な構成を図20に図示する。
機能に必要とされる20残基長のN末端。
機能に必要とされるN1の50残基長のシステインリッチドメイン。
C1の約70残基長のシステインリッチドメインは、機能を変えることなく排除することができる。
機能に必要とされる20残基長のC末端。
最も端にあるN末端で3つのグルタミン酸突然変異体をグリシンに突然変異させた。これはIBS分子を不活性化した。
N末変異体
20残基のN末端の排除によりIBS分子は不活性化された。
IBSの最後の20残基の排除は前記タンパク質を不活性化した。
N末端の20残基、N1ドメインおよびC末端の20残基からなる突然変異体IBSは、完全長IBSと同じTOPFLASHサイレンシング活性を有していた。
IBSのN−1ドメインは、β−カテニンシグナル伝達のサイレンシングに必要な重大なドメインである。全てのDKKファミリーメンバーのN−1ドメインの配置により、全てのファミリーメンバーにおけるこのドメインがIBSのN−1ドメインのように機能し得る可能性を高める重要な組織的保存が明らかになった。IBS機能に対するDKKファミリーのN−1ドメインの影響を評価するために、DKK1、DKK2およびDKK4のN−1ドメインをIBS(DKK3b)のN−1ドメインと交換し、HEK293T TopFlashレポーター細胞で同時シストトロニックGFP−T2A−IBSとして一過性トランスフェクションによって発現させた。β−カテニンシグナル伝達のIBSサイレンシングに対するドメイン置換の影響を、LiCl刺激レポーター細胞で評価した。データは5回の独立したトランスフェクションの3回の平均±SEを示す。(図22参照。)
特許、特許出願、特許公報、雑誌、書籍、論文、ウェブコンテンツなどの他の文献への参照および引用は、本開示においてなされている。全てのそのような文献は、全ての目的のためにその全体が参照により本明細書に援用される。本明細書において参照により援用されると言われているが、本明細書に明示的に記載された既存の定義、言及または他の開示材料と矛盾する任意の材料またはその一部分は、援用された材料と本発明の開示材料の間で矛盾が生じない範囲のみ援用される。矛盾が生じた場合、その矛盾は本開示を好ましい開示として支持して解決されるべきである。
代表的な実施例は、本発明の説明を助けることを意図するものであり、本発明の範囲を限定することを意図するものではなく、またそのように解釈されるものでもない。実際に、本明細書に示され説明されたものに加えて、本発明の様々な変更および多くのそのさらなる実施形態は、本明細書に含まれる実施例ならびに科学的文献および特許文献への参照を含む、本明細書の全内容から当業者に明らかになるであろう。前記実施例は、その様々な実施形態およびその均等物において本発明の実施に適合させることができる重要な追加情報、例示および指針を含む。
Claims (16)
- 組換えヒトDKK3bの変異体であって、
(i)ヒトDKK3bのN末端のアミノ酸1〜20、
(ii)ヒトDKK3bのN末端のシステインリッチドメイン、および
(iii)ヒトDKK3bのC末端の20アミノ酸
を含み、
前記変異体はβ−カテニンシグナル伝達のインヒビターであり、かつ
前記変異体はアミノ酸21〜71およびアミノ酸125〜260からなる群より選択されるヒトDKK3bの1つまたは複数のアミノ酸配列を含まない、変異体。 - 請求項1に記載の変異体を含む融合タンパク質。
- 前記融合タンパク質は、前記変異体のN末端に融合した細胞透過性(cp)ドメインを含む、請求項2に記載の融合タンパク質。
- 前記cpドメインは、ポリカチオン性α−ヘリックスを含む、請求項3に記載の融合タンパク質。
- 前記cpドメインは、ポリアルギニンまたはTATを含む、請求項3に記載の融合タンパク質。
- 前記融合タンパク質はさらに、前記cpドメインのN末端に融合したシグナル認識ペプチド(SRP)ドメインを含む、請求項3〜5のいずれか一項に記載の融合タンパク質。
- 前記SRPドメインは、小胞体(ER)膜におけるSRP受容体と係合する任意の分泌タンパク質のSRPドメインを含む、請求項6に記載の融合タンパク質。
- 前記SRPドメインは、ヒトPTENのSRPドメインを含む、請求項6に記載の融合タンパク質。
- 前記融合タンパク質は、前記SRPドメインおよび前記細胞透過性ポリアルギニンドメインから構成されるヒトPTENタンパク質のN末端の62アミノ酸を含む、請求項8に記載の融合タンパク質。
- 前記SRPドメインは、アズロシジンまたはヘパリン結合タンパク質を含む、請求項8に記載の融合タンパク質。
- 請求項1に記載の変異体をコードする核酸分子。
- 請求項11に記載の核酸分子を含む発現ベクターで形質転換された宿主細胞。
- 前記宿主細胞は、細菌性宿主細胞および哺乳類宿主細胞から選択される、請求項12に記載の宿主細胞。
- 請求項1に記載の変異体、および薬学的に許容し得る担体を含む医薬組成物。
- 前記医薬組成物は、癌を治療するかまたは腫瘍の進行を阻害するために使用される、請求項14に記載の医薬組成物。
- 前記医薬組成物はさらに、第2の活性抗腫瘍剤を含む、請求項14に記載の医薬組成物。
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