JP2018509409A - 「インターフェロン遺伝子刺激因子」依存性シグナル伝達の活性化のための組成物及び方法 - Google Patents
「インターフェロン遺伝子刺激因子」依存性シグナル伝達の活性化のための組成物及び方法 Download PDFInfo
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Abstract
Description
本出願は、EFS−Webを介してASCIIフォーマットで提出した、参照することによってその全体が本明細書に組み込まれる配列表を含む。2016年3月9日に作成した該ASCIIのコピーは、名称がANZ1004PCT_SeqListing.txtであり、サイズは22キロバイトである。
本発明は、疾患に対する免疫反応を調節する組成物及び方法を提供することを目的とする。本発明はさらに、哺乳類、好ましくはヒトのSTINGの活性化に使用する際に改良された特性を呈する環状プリンジヌクレオチド類似体を提供する組成物及び方法を提供することを目的とする。本発明はさらに、がんの治療用の組成物及び方法を提供することを目的とする。
R7またはR11の各々は、独立して−CR−または−N−であり;R8は、−C(R)2−、−O−、または−NR−であり;R9、R10、R12、R13、またはR14の各々は、独立して、水素、ハロゲン、−CN、−OR、−SR、−N(R)2、−C(O)R、−CO2R、−S(O)R、−S(O)2R,−C(O)N(R)2、−SO2N(R)2、−OC(O)R、−N(R)C(O)R、−N(R)N(R)2、−C=NOR、−N(R)C(O)N(R)2,−N(R)SO2N(R)2、−N(R)SO2R、−OC(O)N(R)2、または、任意に置換される置換基からなる群から選択され、該置換基は、C1−12脂肪族、フェニル、3−7員の飽和もしくは部分不飽和単環式炭素環式環、7−10員の飽和もしくは部分不飽和二環式炭素環式環、窒素、酸素、もしくはイオウから独立して選択される1−2個のヘテロ原子を有する3−7員の飽和もしくは部分不飽和ヘテロ環式環、窒素、酸素、もしくはイオウから独立して選択される1−3個のヘテロ原子を有する7−10員の飽和もしくは部分不飽和二環式ヘテロ環式環、及び、窒素、酸素、もしくはイオウから独立して選択される1−3個のヘテロ原子を有する5−6員のヘテロアリール環からなる群から選択され、ここで、各Rは、独立して、C1−12脂肪族、フェニル、3−7員の飽和もしくは部分不飽和単環式炭素環式環、7−10員の飽和もしくは部分不飽和二環式炭素環式環、窒素、酸素、もしくはイオウから独立して選択される1−2個のヘテロ原子を有する3−7員の飽和もしくは部分不飽和ヘテロ環式環、窒素、酸素、もしくはイオウから独立して選択される1−3個のヘテロ原子を有する7−10員の飽和もしくは部分不飽和二環式ヘテロ環式環、及び、窒素、酸素、もしくはイオウから独立して選択される1−3個のヘテロ原子を有する5−6員のヘテロアリール環からなる群から選択される、任意に置換される置換基であるか、または、同じ窒素上の2つのR基は、それらの介在原子と一緒になって任意に置換される3−7員の飽和、部分不飽和、もしくは窒素、酸素、もしくはイオウから独立して選択される1−4個のヘテロ原子を有するヘテロアリール環を形成する。C1−12脂肪族、フェニル、3−7員の飽和もしくは部分不飽和単環式炭素環式環、7−10員の飽和もしくは部分不飽和二環式炭素環式環、3−7員の飽和もしくは部分不飽和ヘテロ環式環、7−10員の飽和もしくは部分不飽和二環式ヘテロ環式環、及び5−6員のヘテロアリール環の各々、または同じ窒素上の、一緒になって3−7員の飽和、部分不飽和、もしくはヘテロアリール環を形成する2つのR基は、ハロゲン、−CN、−NO2、−OH、=O、−NH2、C1−6アルキル、C1−6アルコキシ、C1−6アルキルアミノ、及びC1−6ジアルキルアミノからなる群から選択される、1〜5、1〜4、1〜3、1〜2、もしくは1つの、独立して選択される置換基で任意に置換される。
R17及びR18は、独立して、N9位を介して該構造に結合するグアニンまたはアデニンであり、アデニンの6位のアミンはベンゾイル基で任意に置換され、グアニンの2位のアミンはイソブチリル基で任意に置換され;
R19及びR20は、独立してOHまたはFであり、ただしR19及びR20のうちの少なくとも一方はFである。
R23及びR24は、独立してN9位を介して該構造に結合するグアニンまたはアデニンであり;
R25及びR26の一方はOHであり、R25及びR26の他方はFである。
式中:
R27及びR28は、独立してOHまたはFであり、ただし、R27及びR28のうちの少なくとも一方はFであり;
R29及びR30は、独立してHまたはベンゾイルである。
式中:
R31及びR32は、独立してOHまたはFであり、ただしR31及びR32のうちの少なくとも一方はFであり;
R33及びR34は、独立してHまたはブチリルである。
式中:
R35及びR36は、独立してOHまたはFであり、ただし、R35及びR36のうちの少なくとも一方はFであり;
R37は、Hまたはベンゾイルであり;
R38は、Hまたはブチリルである。
本発明は、STING(インターフェロン遺伝子刺激因子)として知られる細胞質受容体を介してDCを活性化する、モノ−またはジ−フルオロ置換ビス−3’,5’環状ジヌクレオチド(モノ−またはジ−F−CDN)免疫促進剤の製造及び使用に関する。特に、本発明のCDNは、1つ以上のモノまたはジ−F−CDN化合物、最も好ましくは、1つ以上のジチオRp,Rpジ−F−CDNを含む組成物の形態で提供される。
ヒト、哺乳類、哺乳類対象、動物、獣医学的対象、プラセボ対象、研究用対象、実験用対象、細胞、組織、器官、または生物学的流体に関して本明細書で用いられる「投与」とは、制限なく、外因性リガンド、試薬、プラセボ、小分子、医薬品、治療薬、診断薬、または組成物の、該対象、細胞、組織、器官、または生物学的流体等への接触を指す。「投与」は、例えば治療的、薬物動態学的、診断的、研究的、プラセボ、及び実験的方法を指すことができる。細胞の処理には、該細胞への試薬の接触、ならびに流体への試薬の接触が包含され、この場合、該流体は該細胞と接触している。「投与」には、試薬、診断、結合組成物による、または別の細胞による、例えば細胞のインビトロ及びエキソビボの処理も包含される。「administered together(一緒に投与される)」または「co−administered(併用される)」とは、2つ以上の薬剤が単一の組成物として投与されるという意味を含むことを意図しない。単一組成物としての投与は本発明で企図されるものの、かかる薬剤は、別個の投与として単一の対象に送達される場合があり、これは、同時または異なる時点の場合があり、また、同一の投与経路または異なる投与経路の場合がある。「同時に投与される」とは、2つ以上の薬剤が基本的に同時に投与されるという意味を含むことを意図するが、必ずしも単一の組成物として、または同一の投与経路によって投与されるとは限らない。
本明細書に記載のモノ−またはジ−F−CDN化合物及びそれらの組成物に加えて、本発明の組成物または方法はさらに、それらの性質のために免疫系を刺激またはさもなければ利用するように作用して標的腫瘍細胞(複数可)上に存在するがん抗原に応答することができる1つ以上のさらなる物質を含み得る。かかるアジュバントとしては、脂質、リポソーム、自然免疫を誘導する不活化細菌(例えば、不活化または弱毒化Listeria monocytogenes)、トール様受容体(TLR)、(NOD)様受容体(NLR)、レチノイン酸誘導性遺伝子系(RIG)−I様受容体(RLR)、C型レクチン受容体(CLR)、及び/または病原体関連分子パターン(「PAMP」)を介して自然免疫活性化を媒介する組成物が挙げられるがこれらに限定されない。PAMPの例としては、リポタンパク質、リポポリペプチド、ペプチドグリカン、ザイモサン、リポ多糖、ナイセリア・ポリン、フラジェリン、プロフィリン、ガラクトセラミド、ムラミルジペプチドが挙げられる。ペプチドグリカン、リポタンパク質、及びリポテイコ酸は、グラム陽性の細胞壁成分である。リポ多糖は、ほとんどの細菌によって発現され、MPLは1つの例である。フラジェリンは、病原性及び共生細菌によって分泌される細菌性鞭毛の構造成分を指す。α−ガラクトシルセラミド(α−GalCer)は、ナチュラルキラーT(NKT)細胞の活性化因子である。ムラミルジペプチドは、すべての細菌に共通の生物活性ペプチドグリカンモチーフである。このリストは限定することを意図しない。好ましいアジュバント組成物を以下に記載する。
本明細書に記載のモノ−またはジ−F−CDN化合物は、CTLA−4経路アンタゴニスト、PD−1経路アンタゴニスト、Tim−3経路アンタゴニスト、Vista経路アンタゴニスト、BTLA経路アンタゴニスト、LAG−3経路アンタゴニスト、またはTIGIT経路アンタゴニストからなる群から選択される免疫チェックポイント阻害剤等の免疫チェックポイント阻害剤と組み合わせて使用することができる。いくつかの実施形態では、該免疫チェックポイント阻害剤は、抗CTLA−4抗体、抗PD−1抗体、抗Tim−3抗体、抗Vista抗体、抗BTLA抗体、抗LAG−3抗体、または抗TIGIT抗体からなる群から選択される。
本明細書に記載のモノ−またはジ−F−CDN化合物は、T細胞受容体アゴニスト、例えば、CD28アゴニスト、OX40アゴニスト、GITRアゴニスト、CD137アゴニスト、CD27アゴニスト、またはHVEMアゴニストと組み合わせて使用することができる。
Pam3Cys、TLR−1/2アゴニスト;
CFA、TLR−2アゴニスト;
MALP2、TLR−2アゴニスト;
Pam2Cys、TLR−2アゴニスト;
FSL−1、TLR−2アゴニスト;
Hib−OMPC、TLR−2アゴニスト;
ポリリボシニック(polyribosinic):ポリリボシチジン酸(polyribocytidic acid)(ポリI:C)、TLR−3アゴニスト;
ポリアデノシン−ポリウリジル酸(ポリAU)、TLR−3アゴニスト;
ポリL−リジン及びカルボキシメチルセルロース(Hiltonol(登録商標))で安定化されたポリイノシン−ポリシチジル酸、TLR−3アゴニスト;
モノホスホリルリピドA(MPL)、TLR−4アゴニスト;
LPS、TLR−4アゴニスト;
細菌フラジェリン、TLR−5アゴニスト;
シアリルTn(STn)、複数のヒトがん細胞上のMUC1ムチンに伴う炭水化物及びTLR−4アゴニスト;
イミキモド、TLR−7アゴニスト;
レシキモド、TLR−7/8アゴニスト;
ロキソリビン、TLR−7/8アゴニスト;ならびに
非メチル化CpGジヌクレオチド(CpG−ODN)、TLR−9アゴニスト。
リポソームは、1層(「単層」)または複層(「多重膜」)のリン脂質から形成される小胞である。該リン脂質構成要素の両親媒性の性質のため、リポソームは通常、親水性の外面を提示し、親水性のコアを包み込む親水性層を含む。親水性/疎水性成分の組み込みにおけるリポソームの多様性、それらの非毒性、生分解性、生体適合性、アジュバント性、細胞性免疫の誘導、徐放性、及びマクロファージによる速やかな摂取は、それらを抗原の送達用の魅力的な候補にしている。
本明細書に記載の方法のさらなる実施形態において、本明細書に記載のモノ−またはジ−F−CDN化合物は、化学療法剤(例えば、小分子医薬化合物)と組み合わせて使用される。従って、該方法はさらに、当該対象に対して、有効量の1つ以上の化学療法剤を追加治療または併用治療として投与することを含む。特定の実施形態では、該1つ以上の化学療法剤は、酢酸アビラテロン、アルトレタミン、無水ビンブラスチン、アウリスタチン、ベキサロテン、ビカルタミド、BMS 184476、2,3,4,5,6−ペンタフルオロ−N−(3−フルオロ−4−メトキシフェニル)ベンゼンスルホンアミド、ブレオマイシン、N,N−ジメチル−L−バリル−L−バリル−N−メチル−L−バリル−L−プロリル−1−Lプロリン−t−ブチルアミド、カケクチン、セマドチン、クロラムブシル、シクロホスファミド、3’,4’−ジデヒドロ−4’−デオキシ−8’−ノルビンカロイコブラスチン、ドセタキソル(docetaxol)、ドキセタキセル(doxetaxel)、シクロホスファミド、カルボプラチン、カルムスチン、シスプラチン、クリプトフィシン、シクロホスファミド、シタラビン、ダカルバジン(DTIC)、ダクチノマイシン、ダウノルビシン、デシタビンドラスタチン、ドキソルビシン(アドリアマイシン)、エトポシド、5−フルオロウラシル、フィナステリド、フルタミド、ヒドロキシ尿素及びヒドロキシ尿素タキサン類、イホスファミド、リアロゾール、ロニダミン、ロムスチン(CCNU)、エンザルタミド、メクロレタミン(ナイトロジェンマスタード)、メルファラン、イセチオン酸ミボブリン、リゾキシン、セルテネフ(sertenef)、ストレプトゾシン、マイトマイシン、メトトレキサート、タキサン類、ニルタミド、オナプリストン、パクリタキセル、プレドニムスチン、プロカルバジン、RPR109881、リン酸ストラムスチン(stramustine phosphate)、タモキシフェン、タソネルミン、タキソール、トレチノイン、ビンブラスチン、ビンクリスチン、硫酸ビンデシン、ならびにビンフルニンからなる群から選択される。
「不活化腫瘍細胞」とは、当該細胞の分裂を防ぐように処理された腫瘍細胞(当該患者にとって「自己」または「同種異系」のいずれか)を意味する。本発明の目的のため、かかる細胞はそれらの免疫原性及びそれらの代謝活性を保つ。かかる腫瘍細胞は、がん治療の一部として、患者内で発現される導入遺伝子を発現するように遺伝子操作される。従って、本発明の組成物またはワクチンは、治療を受ける患者にとって自己または同種異系の新生(例えば、腫瘍)細胞を含み、最も好ましくは、該患者を苦しめているのと同じ一般型の腫瘍細胞である。例えば、メラノーマに罹患している患者は通常、メラノーマ由来の遺伝子操作された細胞を投与される。本発明で使用される腫瘍細胞の不活化方法、例えば、照射の使用は、当技術分野では周知である。
特定の実施形態では、該CDN組成物は、1つ以上の所定の抗原に対する免疫反応を刺激することを目的とする1つ以上のワクチンとともに投与される。本発明で用途を見出し得る標的抗原の例を以下の表に記載する。該標的抗原はまた、該表に記載の抗原の免疫学的に活性な部分を含む断片または融合ポリペプチドであってもよい。このリストは、限定することを意図しない。
表1.抗原
目的の抗原を含む不活化もしくは弱毒化細菌またはウイルスであって、これらは、これらを病原性侵襲の開始に無効または非効率的にするためのある変性条件で処理された粒子である;
精製抗原、これらは、通常、当該病原体の細胞培養もしくは当該病原体を含む組織試料から精製される自然に産生される抗原、または、それらの組換え型である;
組み換え技術によって、当該対象の宿主細胞で抗原を発現及び/または分泌するように作られた生ウイルスまたは細菌送達ベクター。これらの方法は、当該ウイルスまたは細菌ベクターを非病原性及び非毒性に弱毒化する(例えば、遺伝子操作によって)ことに依存している;
抗原提示細胞(APC)ベクター、例えば、樹状細胞(DC)ベクター、これらは、抗原を負荷された細胞、または該抗原をコードする核酸を含む組成物でトランスフェクトされた細胞を含む(例えば、去勢抵抗性転移性前立腺がんの治療用のProvenge(登録商標)(Dendreon Corporation));
リポソーム抗原送達媒体;ならびに
遺伝子銃、エレクトロポレーション、細菌ゴースト、ミクロスフェア、微粒子、リポソーム、ポリカチオン性ナノ粒子等によって投与され得る裸のDNAベクター及び裸のRNAベクター。
液相オリゴヌクレオチド合成に適した無水溶媒及び試薬は、商業的供給業者(Aldrich,ChemGenes Corporation、米国マサチューセッツ州ウィルミントン)から入手し、無水技術を用いて乾燥アルゴンまたは窒素下で取り扱った。ホスホラミダイトカップリング反応及びH−ホスホネート環化は、乾燥アルゴンまたは窒素下で、無水アセトニトリルまたはピリジン中で行った。特に断りのない限り、乾燥ピリジン中でのすべての反応用の出発物質は、ピリジンからの濃縮(3回)によって乾燥した。クロマトグラフィー条件は、下記実施例で特に断りのない限り、以下の通りであった。分取シリカゲルフラッシュクロマトグラフィーは、中圧クロマトグラフィー(MPLC)下、RediSep Rfシリカカラム(Teledyne Isco、ネブラスカ州リンカーン)を用い、Combiflash Rf+UV−Vis(Teledyne Isco)にて、ジクロロメタン中のメタノール勾配を用いて行った。逆相分取クロマトグラフィーは、MPLC条件下、RediSep Rf C18 Aqカラム(Teledyne Isco)を用い、Combiflash Rf+UV−Visにて、10mMのTEAA水溶液中のアセトニトリル勾配を用いて実行した。分析用高速液体クロマトグラフィー(HPLC)は、Shimadzu Prominence HPLCシステムと、2つのLC−20ADポンプ、及び254nmで監視するSPD−M30Aフォトダイオードアレイ検出器にて行った。アセトニトリル中10mMのTEAAまたはアセトニトリル中20mMのNH4OAcの勾配は、5ミクロン(Thermo Scientific Acclaim 120)C−18カラム(4.6×250mm)または10ミクロン(Thermo Scientific Hypersil)C−18カラム(4.0×250mm)のいずれかとともに室温で用いた。分取HPLCは、254nmで監視するSPD−20A UV/Vis検出器を備えたShimadzu分取LC20−AP HPLCシステムにて、Varian Microsorb 60−8 C−18 41.6×250mmカラムで、10mMのTEAA及びアセトニトリルの勾配を流量50ml/分で用いて行った。C−18 Sep−Pak(Waters)を用いた固相抽出は、3%(wt/wt)のローディングで行った。分析用LCMSは、Shimadzu LCMS−2020シングル四重極型質量分析計に連結されたProminence HPLCを用いたShimadzu LCMSシステムを用い、エレクトロスプレーイオン化源(ESI)を用いて記録した。
3’3’−RR−(2’F−A)(2’F−A)またはジチオ−(Rp,Rp)−環状−[2’F−A(3’,5’)p−2’F−A(3’,5’)p]とも呼ばれる(2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)−2,9−ビス(6−アミノ−9H−プリン−9−イル)−3,10−ジフルオロ−5,12−ジメルカプトオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン5,12−ジオキシド(6)、及び(2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR)−2,9−ビス(6−アミノ−9H−プリン−9−イル)−3,10−ジフルオロ−5,12−ジメルカプトオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン5,12−ジオキシド(6a)、3’3’−RS−(2’F−A)(2’F−A)、またはジチオ−(Rp,Sp)−環状−[2’F−A(3’,5’)p−2’F−A(3’,5’)p]は、以下のスキーム1に従って調製した。
3’3’−RR−(2’F−G)(2’F−A)またはジチオ−(Rp,Rp)−環状−[2’F−G(3’,5’)p−2’F−A(3’,5’)p]とも呼ばれる2−アミノ−9−((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)−9−(6−アミノ−9H−プリン−9−イル)−3,10−ジフルオロ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−1,9−ジヒドロ−6H−プリン−6−オン(14)及び3’3’−RS−(2’F−G)(2’F−A)またはジチオ−(Rp,Sp)−環状−[2’F−G(3’,5’)p−2’F−A(3’,5’)p]とも呼ばれる2−アミノ−9−((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR)−9−(6−アミノ−9H−プリン−9−イル)−3,10−ジフルオロ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−1,9−ジヒドロ−6H−プリン−6−オン(14a)を、以下のスキーム2に従って調製した。
3’3’−RR−(2’F−G)(2’F−G)またはジチオ−(Rp,Rp)−環状−[2’F−G(3’,5’)p−2’F−G(3’,5’)p]とも呼ばれる9,9’−((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)−3,10−ジフルオロ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2,9−ジイル)ビス(2−アミノ−1,9−ジヒドロ−6H−プリン−6−オン)(17)、及び3’3’−RS−(2’F−G)(2’F−G)またはジチオ−(Rp,Sp)−環状−[2’F−G(3’,5’)p−2’F−G(3’,5’)p]とも呼ばれる9,9’−((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR)−3,10−ジフルオロ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2,9−ジイル)ビス(2−アミノ−1,9−ジヒドロ−6H−プリン−6−オン)(17a)を、以下のスキーム3に従って調製した。
3’3’−RR−(A)(2’F−A)またはジチオ−(Rp,Rp)−環状−[A(3’,5’)p−2’F−A(3’,5’)p]とも呼ばれる(2R,3R,3aR,5R,7aR,9R,10R,10aS,12R,14aR)−2,9−ビス(6−アミノ−9H−プリン−9−イル)−3−フルオロ−10−ヒドロキシ−5,12−ジメルカプトオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン5,12−ジオキシド(22)、及び3’3’−RS−(A)(2’F−A)またはジチオ−(Rp,Rp)−環状−[A(3’,5’)p−2’F−A(3’,5’)p]とも呼ばれる(2R,3R,3aR,5S,7aR,9R,10R,10aS,12R,14aR)−2,9−ビス(6−アミノ−9H−プリン−9−イル)−3−フルオロ−10−ヒドロキシ−5,12−ジメルカプトオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン5,12−ジオキシド(22a)を、以下のスキーム4に従って調製した。
3’3’−RR−(2’F−G)(A)またはジチオ−(Rp,Rp)−環状−[2’F−G(3’,5’)p−A(3’,5’)p]とも呼ばれる2−アミノ−9−((2R,3R,3aR,5R,7aR,9R,10R,10aS,12R,14aR)−9−(6−アミノ−9H−プリン−9−イル)−3−フルオロ−10−ヒドロキシ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−1,9−ジヒドロ−6H−プリン−6−オン(23)、及び3’3’−SR−(2’F−G)(A)またはジチオ−(Sp,Rp)−環状−[2’F−G(3’,5’)p−A(3’,5’)p]とも呼ばれる2−アミノ−9−((2R,3R,3aR,5S,7aR,9R,10R,10aS,12R,14aR)−9−(6−アミノ−9H−プリン−9−イル)−3−フルオロ−10−ヒドロキシ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−1,9−ジヒドロ−6H−プリン−6−オン(23a)
3’3’−RR−(G)(2’F−A)またはジチオ−(Rp,Rp)−環状−[G(3’,5’)p−2’F−A(3’,5’)p]とも呼ばれる2−アミノ−9−((2R,3R,3aS,5R,7aR,9R,10R,10aR,12R,14aR)−9−(6−アミノ−9H−プリン−9−イル)−10−フルオロ−3−ヒドロキシ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−1,9−ジヒドロ−6H−プリン−6−オン(24)及び3’3’−RS−G)(2’F−A)またはジチオ−(Rp,Sp)−環状−[G(3’,5’)p−2’F−A(3’,5’)p]とも呼ばれる2−アミノ−9−((2R,3R,3aS,5R,7aR,9R,10R,10aR,12S,14aR)−9−(6−アミノ−9H−プリン−9−イル)−10−フルオロ−3−ヒドロキシ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−1,9−ジヒドロ−6H−プリン−6−オン(24a)
3’3’−RR−(2’F−iBuG)(2’F−BzA)またはジチオ−(Rp,Rp)−環状−[2’F−iBuG(3’,5’)p−2’F−BzA(3’,5’)p]とも呼ばれるN−(9−((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)−3,10−ジフルオロ−9−(2−イソブチラミド−6−オキソ−1,6−ジヒドロ−9H−プリン−9−イル)−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−9H−プリン−6−イル)ベンズアミド(25)、及び3’3’−RS−(2’F−iBuG)(2’F−BzA)またはジチオ−(Rp,Sp)−環状−[2’F−iBuG(3’,5’)p−2’F−BzA(3’,5’)p]とも呼ばれるN−(9−((2R,3R,3aR,5S,7aR,9R,10R,10aR,12R,14aR)−3,10−ジフルオロ−9−(2−イソブチラミド−6−オキソ−1,6−ジヒドロ−9H−プリン−9−イル)−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−9H−プリン−6−イル)ベンズアミド(25a)は、以下のスキーム5に従って調製した。
RR−(2’F−iBuG)(2’F−A)またはジチオ−(Rp,Rp)−環状−[2’F−iBuG(3’,5’)p−2’F−A(3’,5’)p]とも呼ばれるN−(9−((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)−9−(6−アミノ−9H−プリン−9−イル)−3,10−ジフルオロ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−6−オキソ−6,9−ジヒドロ−1H−プリン−2−イル)イソブチラミド(26)を、以下のスキーム6に従って調製した。
3’3’−RR−(2’F−BzA)(2’F−BzA)またはジチオ−(Rp,Rp)−環状−[2’F−BzA(3’,5’)p−2’F−BzA(3’,5’)p]とも呼ばれるN,N’−(((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)−3,10−ジフルオロ−5,12−ジメルカプト−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2,9−ジイル)ビス(9H−プリン−9,6−ジイル))ジベンズアミド(27)を以下のスキーム7に従って調製した。
3’3’−(2’F−G)(2’F−A)または環状−[2’F−G(3’,5’)p−2’F−A(3’,5’)p]とも呼ばれる2−アミノ−9−((2R,3R,3aR,7aR,9R,10R,10aR,14aR)−9−(6−アミノ−9H−プリン−9−イル)−3,10−ジフルオロ−5,12−ジヒドロキシ−5,12−ジオキシドオクタヒドロ−2H,7H−ジフロ[3,2−d:3’,2’−j][1,3,7,9]テトラオキサ[2,8]ジホスファシクロドデシン−2−イル)−1,9−ジヒドロ−6H−プリン−6−オンを以下のスキーム8に従って調製した。
アミノ酸140−379(Swiss Prot Q86WV6に対応するアミノ酸ナンバリング)をコードするDNAをヒトSTING対立遺伝子の完全長配列を含むプラスミドから、ポリメラーゼ連鎖反応を介して、以下のプライマーで増幅した:フォワードTACTTCCAATCCAATGCAGCCCCAGCTGAGATCTCTG(配列番号8)及びリバースTTATCCACTTCCAATGTTATTATTATCAAGAGAAATCCGTGCGGAG(配列番号9)。STINGの変異型対立遺伝子は、Yi, et al, (2013), PLoS One, 8(10), e77846 (DOI: 10.1371/journal.pone.0077846に従って割り当てた。PCR産物は、ライゲーション非依存性クローニング(Aslanidis, et al, (1990) Nucleic acids research, 18.20, 6069−6074)を用いて、N末端のヘキサヒスチジン親和性タグ(6×HIS)に続いて、低分子ユビキチン様修飾因子(SUMO)溶解性配列(Butt, et al, (2005) Protein expression and purification 43.1, 1−9)及びタバコエッチ病ウイルスのプロテアーゼ切断部位(TEV)をコードする細菌発現ベクターにクローニングした。
2つの既知の天然ヒトSTING変異型であるhSTING(WT)及びhSTING(REF)の天然及びフッ素置換CDN化合物に応答してシグナル伝達する能力を評価するため、我々は、hSTING(WT)またはhSTING(REF)を安定に発現するヒト胎児腎臓(HEK)293T細胞株でのIFN−βレポーターの活性を測定した。hSTING(REF)対立遺伝子の配列は、記載されており(Ishikawa, H., and Barber, G.N. (2008). Nature 455, 674−678)、NCBI参照配列NP_938023(図6)を有する。hSTING(WT)及びhSTING(REF)変異型対立遺伝子の配列はまた、Yi, et al., 2013, PLoS One, 8(10), e77846 (DOI: 10.1371/journal.pone.0077846に記載されている。
I型インターフェロンの誘導を、ヒト一次血中単核細胞(human primary blood mononuclear cell)(hPBMC)中で測定し、本明細書に記載のモノ−またはジ−F−CDN化合物の効力を評価した。2人の独特のドナーからのhPBMCを用いた。一方のドナーは、野生型(WT)STING対立遺伝子に関してホモ接合(STINGWT/WT)であり、他方のドナーは、いわゆる参照(REF)STING対立遺伝子に関してホモ接合(STINGREF/REF)であった。これらのドナーのSTING遺伝子型は、PCR増幅及びシークエンシングによって決定した。ゲノムDNAは104個のhPBMCから、Quick Extract DNA抽出溶液(Epicentre)を用いて単離し、これを用いてヒトSTING遺伝子のエキソン3、6、及び7の領域を増幅した。増幅及びシークエンシング用のプライマーは:hSTINGエキソン3F GCTGAGACAGGAGCTTTGG(配列番号10)、hSTINGエキソン3R AGCCAGAGAGGTTCAAGGA(配列番号11)、hSTINGエキソン6F GGCCAATGACCTGGGTCTCA(配列番号12)、hSTINGエキソン6R CACCCAGAATAGCATCCAGC(配列番号13)、hSTINGエキソン7F TCAGAGTTGGGTATCAGAGGC(配列番号14)、hSTINGエキソン7R ATCTGGTGTGCTGGGAAGAGG(配列番号15)であった。STING変異型対立遺伝子は、Yi, et al., 2013, PLoS One, 8(10), e77846 (DOI: 10.1371/journal.pone.0077846)に従って割り当てた。
アジュバントの効力のシグネチャーとして、モノ−またはジ−F−CDNの各々によってヒト細胞において誘導されるI型インターフェロンの相対レベルを測定するため、100,000個のTHP1−Dual細胞(5つのIFN刺激反応要素からなるプロモーターの制御下で分泌型ルシフェラーゼを発現するIRF−3誘導性分泌型ルシフェラーゼレポーター遺伝子(Invivogen)をトランスフェクトしたhSTING HAQ対立遺伝子を含むヒト単球細胞株)を、96ウェルのディッシュで、30ng/mlのホルボール12−ミリステート13−アセテートで一夜活性化させた。細胞を新鮮な培地で洗浄し、PB緩衝液(50mMの4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸、100mMのKCl、3mMのMgCl2、0.1mMジチオスレイトール、85mMスクロース、1mMのATP、0.1mMのGTP、及び0.2%ウシ血清アルブミン)中、2,000〜0.0338μMの3倍滴定ステップの化合物で、37℃、5%CO2にて30分間インキュベートした。30分後、細胞を洗浄し、10%のFBSを含む新鮮RPMI培地を加え、細胞を37℃、5%CO2でインキュベートした。一夜のインキュベート後、各試料から細胞培養上清を回収し、この細胞培養上清10μLをQUANTI−Luc試薬(Invivogen)50μLに加えた。I型インターフェロンの活性化は、分泌型ルシフェラーゼレベルをSpectraMax M3分光光度計(Molecular Devices)にて測定することによって決定した。EC50値は、表5に記載の本アッセイで試験した参照化合物及び本発明の化合物の連続希釈からの10濃度についての用量反応曲線から決定した。これらの結果は、ジF化合物である3’3’−RR−(2’F−A)(2’F−A)、3’3’−RS−(2’F−A)(2’F−A)、3’3’−RR−(2’F−G)(2’F−G)、3’3’−RR−(2’F−G)(2’F−A)、3’3’−RS−(2’F−G)(2’F−A)、及び3’3’−RR(2’F−iBuG)(2’F−A)についての活性がそれらのOH参照化合物の各々に対して改良されることを示す。モノ−F誘導体である3’3’−RR(2’F−G)(A)及び3’3’−RR−(G)(2’F−A)もまた、OH参照化合物である3’3’−RR−(G)(A)に対して改良された活性を示した。
これらの誘導体分子が抗腫瘍免疫を誘発するかどうかを判断するため、6〜8週齢の雌C57BL/6マウス(1群当たり8匹のマウス)に、B16.SIY細胞(100μLのPBS中、5×105細胞)を移植した。マウスを参照化合物の3’3’−RR−(A)(A)及びジ−F化合物の3’3’−RR−(2’F−A)(2’F−A)(総体積40μLのHBSS中、5、50、100μg)、またはHBSSの溶媒対照で処理した。処理は、腫瘍移植後9日目、腫瘍が体積約100mm3に達したときに始めた。これらのCDN化合物を、27ゲージ針を用いて腫瘍の中心(IT)に皮下注射によって投与した。腫瘍移植後16日目にマウスを採血し、PBMCをフィコール勾配(Miltenyi Biotech)によって単離した。1×105個のPBMCを抗CD16/32モノクローナル抗体でプレインキュベートして潜在的な非特異的結合をブロックし、SIYRYYGL(SIY、配列番号16)ペプチドに複合化したマウスH−2Kb、抗TCRβ−AF700(H57−597)、抗CD8−Pacific Blue(53−6.7)、抗CD4−Pacific Orange(RM4−5)(抗体はすべてBioLegend製)、及びFixable Viability Dye eFluor 450(eBioscience)からなるPE−MHCクラスIペンタマー(Proimmune)で標識した。染色された細胞は、FACS Versaサイトメーターを用い、FACSDivaソフトウェア(BD)で分析した。データ分析は、FlowJoソフトウェア(Tree Star)で行った。
これらフッ素化誘導体化合物の多様なマウス腫瘍モデルにおける抗腫瘍免疫の促進能を評価するため、腫瘍細胞を6〜8週齢のC57BL/6雌マウスの背下部に皮下移植した(PBS100μL中)。処理は、腫瘍移植後約14日目、腫瘍が体積約100mm3に達したときに始めた(腫瘍型、細胞数、及びIT注入日については以下の表参照)。CDN化合物はIT注入(総体積40μLのHBSS中、10または100μg)によって投与し、合計3回の注入を3日ごとに繰り返した。化合物3’3’−RR−(2’F−A)(2’F−A)及び3’3’−RR−(2’F−G)(2’F−A)ならびに対照マウスは所与の媒体のみ(HBSS40μL)を投与した。腫瘍を週に2回測定した。
フッ素化誘導体がHIVgag特異的なCD4+及びCD8+T細胞反応を誘発できるかどうかを判断するため、BALB/cマウス(n=4)に、2%スクアレン水(Adda Vax、Invivogen)にHIVgag p55タンパク質5μgとともに処方されたCDN0μg(CDNなし)、1μg、または5μgで皮下免疫を施した。このワクチン接種の7日後、これらのマウスから脾臓を採取し、脾細胞を調製した。2×105個の脾細胞をIFNγELISPOTアッセイで、培地のみ(非刺激)または1μMのHIVgag p55 CD4+及びCD8+特異的ペプチドで一夜刺激した。IFNγELISPOTは、CTLプレートリーダー及びImmunoSpotソフトウェアを用いて現像及び定量化した。3’3’−RR−(2’F−A)(2’F−A)及び3’3’−RR−(2’F−G)(2’F−A)を、それらのHIVgag特異的免疫反応の誘導能について評価した。
モノ−及びジ−F−CDN化合物の結合を、表面プラズモン共鳴を用いて評価し、結合定数を決定した。タンパク質配列:
を含むE.coli発現構築物(ヒトSTING[E149−S379]H232R)を調製し、E.coliでのヒトSTING[E149−S379]H232R発現を18℃で誘導し、このタンパク質を続いてニッケルアフィニティークロマトグラフィー及びサイズ排除クロマトグラフィーの両方を用いて精製した。一定分量を調製し、−80℃で30mMのトリスpH7.5/100mM NaCl/10%グリセロール中で保存した。
Claims (16)
- 式III:
-
- 式IIIa:
- R21及びR22がともにアデニンである、請求項3に記載の化合物。
- R21がアデニンであり、R22がグアニンである、請求項3に記載の化合物。
- 構造:
- 構造:
- 前記化合物が、そのナトリウム、カリウム、カルシウム、マグネシウム、亜鉛、アルミニウム、アンモニウム、ジエチルアミン、オラミン、ベンザチン、ベネタミン、トロメタミン(2−アミノ−2−(ヒドロキシメチル)プロパン−1,3−ジオール)、モルホリン、エポラミン、ピペリジン、ピコリン、ジシクロヘキシルアミン、N,N’−ジベンジルエチレンジアミン、2−ヒドロキシエチルアミン、トリ(2−ヒドロキシエチル)アミン、クロロプロカイン、コリン、デアノール、イミダゾール、ジエタノールアミン、エチレンジアミン、メグルミン(N−メチルグルカミン)、プロカイン、ジベンジルピペリジン、デヒドロアビエチルアミン、グルカミン、コリジン、キニーネ、キノロン、エルブミン、リジン、またはアルギニン塩である、請求項1から7のいずれか一項に記載の化合物。
- 前記化合物がそのナトリウム塩である、請求項1から7のいずれか一項に記載の化合物。
- 請求項1から9のいずれか一項に記載の1つ以上の化合物及び医薬的に許容される賦形剤を含む医薬組成物。
- 請求項1から9のいずれか一項に記載の1つ以上の化合物、別の治療薬、及び医薬的に許容される賦形剤を含む医薬組成物。
- がんに罹患している個体の治療方法であって、前記個体に、請求項1から9のいずれか一項に記載の化合物、または請求項10もしくは11に記載の組成物の有効量を、非経口的でなく、または非経口的に投与することを含む、前記方法。
- さらに、前記個体に対する1つ以上のさらなるがん治療の実施を含む請求項12に記載の方法であって、前記1つ以上のさらなるがん治療が、放射線療法、外科手術、化学療法、または免疫療法からなる群から選択される、前記方法。
- 個体の疾患の治療方法であって、それを必要とする前記個体に対して、i)請求項1から9のいずれか一項に記載の化合物または請求項10もしくは11に記載の組成物の有効量;及びii)抗体依存性細胞傷害性を誘導する1つ以上の治療抗体の有効量を投与することを含み、前記疾患が、がん、臓器移植の急性拒絶、I型糖尿病、関節リウマチ、乾癬、クローン病、再狭窄、及びアレルギー性喘息からなる群から選択される、前記方法。
- がんの治療に用いる、請求項1から9のいずれか一項に記載の化合物。
- がん、臓器移植の急性拒絶、I型糖尿病、関節リウマチ、乾癬、クローン病、再狭窄、及びアレルギー性喘息からなる群から選択される疾患の治療に用いる、請求項1から9のいずれか一項に記載の化合物。
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JP7296398B2 (ja) | 2018-04-06 | 2023-06-22 | インスティチュート オブ オーガニック ケミストリー アンド バイオケミストリー エーエスシーアール,ヴイ.ヴイ.アイ. | 3’3’-環状ジヌクレオチド |
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