JP2022535588A - 核酸ポリペプチド組成物およびその使用 - Google Patents
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Abstract
Description
本出願は配列表を包含しており、これは、ASCIIフォーマットで電子的に提出され、その全体を引用することで本明細書に組み込まれる。2020年6月6日に作成された前記ASCIIのコピーは、45532-734_601_SL.txtという名称であり、3,143,382バイトのサイズである。
R1はそれぞれ独立して、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6フルオロアルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
R2はそれぞれ独立して、水素、重水素、置換または非置換のC1-C6アルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
もしくは、2つのR2は、それらが結合している窒素原子と一体となって、置換または非置換のC2-C10ヘテロシクロアルキルを形成し、
L1は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
L2は、結合、O、S、NR3、置換または非置換のC4-C7シクロアルキレン、置換または非置換のC4-C7ヘテロシクロアルキレン、置換または非置換のC5-C8アリーレン、あるいは置換または非置換のC4-C8ヘテロアリーレンであり、
R3は、存在する場合、水素、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、および非置換または置換の単環式の複素環から選択され、
L3は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、ならびに、
L1、L2、およびL3の少なくとも2つは結合ではない。
R1はそれぞれ独立して、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6フルオロアルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
L1は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
L2は、結合、O、S、NR3、置換または非置換のC4-C7シクロアルキレン、置換または非置換のC4-C7ヘテロシクロアルキレン、置換または非置換のC5-C8アリーレン、あるいは置換または非置換のC4-C8ヘテロアリーレンであり、
R3は、存在する場合、水素、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、および非置換または置換の単環式の複素環から選択され、
L3は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
Jは、ポリヌクレオチドの隣接するヌクレオチドに結合するヌクレオチド間結合基であり、ならびに、
L1、L2、およびL3の少なくとも2つは結合ではない。
A-B
式(I)
式中、
Aは結合部分であり、
Bは式(IIa)のヌクレオチド化合物を含むオリゴヌクレオチドであり、
R1はそれぞれ独立して、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6フルオロアルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
L1は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
L2は、結合、O、S、NR3、置換または非置換のC4-C7シクロアルキレン、置換または非置換のC4-C7ヘテロシクロアルキレン、置換または非置換のC5-C8アリーレン、あるいは置換または非置換のC4-C8ヘテロアリーレンであり、
R3は、存在する場合、水素、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、および非置換または置換の単環式の複素環から選択され、
L3は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
Jは、ポリヌクレオチドの隣接するヌクレオチドに結合するヌクレオチド間結合基であり、ならびに、
L1、L2、およびL3の少なくとも2つは結合ではない。
いくつかの実施形態では、本明細書に記載されるオリゴヌクレオチドコンジュゲート(例えば、治療用オリゴヌクレオチドコンジュゲート)は、1つ以上の修飾されたヌクレオチドを含むポリ核酸分子とポリマーとにコンジュゲートした結合部分を含む。いくつかの実施形態では、オリゴヌクレオチドコンジュゲートは、式(I)または式(I-A)の化合物を含み、
A-B
式(I)
(式中、
Aは結合部分であり、および、
Bは式(II)の化合物を含むオリゴヌクレオチドである)、
A-B-C
式(I-A)
(式中、
Aは結合部分であり、および、
Bは式(II)または(IIa)の化合物を含むオリゴヌクレオチドであり、
Cは任意選択的にポリマーである)。
R1はそれぞれ独立して、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6フルオロアルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
R2はそれぞれ独立して、水素、重水素、置換または非置換のC1-C6アルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
もしくは、2つのR2は、それらが結合している窒素原子と一体となって、置換または非置換のC2-C10ヘテロシクロアルキルを形成し、
L1は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
L2は、結合、O、S、NR3、置換または非置換のC4-C7シクロアルキレン、置換または非置換のC4-C7ヘテロシクロアルキレン、置換または非置換のC5-C8アリーレン、あるいは置換または非置換のC4-C8ヘテロアリーレンであり、
R3は、存在する場合、水素、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、および非置換または置換の単環式の複素環から選択され、
L3は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、ならびに、
L1、L2、およびL3の少なくとも2つは結合ではない。
R1はそれぞれ独立して、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6フルオロアルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
R2はそれぞれ独立して、水素、重水素、置換または非置換のC1-C6アルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
もしくは、2つのR2は、それらが結合している窒素原子と一体となって、置換または非置換のC2-C10ヘテロシクロアルキルを形成し、
L1は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
L2は、結合、O、S、NR3、置換または非置換のC4-C7シクロアルキレン、置換または非置換のC4-C7ヘテロシクロアルキレン、置換または非置換のC5-C8アリーレン、あるいは置換または非置換のC4-C8ヘテロアリーレンであり、
R3は、存在する場合、水素、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、および非置換または置換の単環式の複素環から選択され、
L3は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、ならびに、
L1、L2、およびL3の少なくとも2つは結合ではない。
R1はそれぞれ独立して、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6フルオロアルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
L1は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
L2は、結合、O、S、NR3、置換または非置換のC4-C7シクロアルキレン、置換または非置換のC4-C7ヘテロシクロアルキレン、置換または非置換のC5-C8アリーレン、あるいは置換または非置換のC4-C8ヘテロアリーレンであり、
R3は、存在する場合、水素、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、および非置換または置換の単環式の複素環から選択され、
L3は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
Jは、ポリヌクレオチドの隣接するヌクレオチドに結合するヌクレオチド間結合基であり、ならびに、
L1、L2、およびL3の少なくとも2つは結合ではない。
いくつかの例では、追加の修飾は、リボース部分、リン酸塩部分、ヌクレオシド部分、またはこれらの組み合わせの1つ以上における修飾を含む合成または人工のヌクレオチドアナログまたは塩基を含む。
A-B
式(I)、
A-B-C
式(I-A)
式中、
Aは結合部分であり、
Cは任意選択的にポリマーであり、
Bは式(II)のヌクレオチド化合物または式(II)由来のヌクレオチド化合物を含むオリゴヌクレオチド(例えば、式(II)のホスホロアミダイト基はオリゴヌクレオチド構造においてリン酸基に変換する)であり、
R1はそれぞれ独立して、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6フルオロアルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
R2はそれぞれ独立して、水素、重水素、置換または非置換のC1-C6アルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
もしくは、2つのR2は、それらが結合している窒素原子と一体となって、置換または非置換のC2-C10ヘテロシクロアルキルを形成し、
L1は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
L2は、結合、O、S、NR3、置換または非置換のC4-C7シクロアルキレン、置換または非置換のC4-C7ヘテロシクロアルキレン、置換または非置換のC5-C8アリーレン、あるいは置換または非置換のC4-C8ヘテロアリーレンであり、
R3は、存在する場合、水素、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、および非置換または置換の単環式の複素環から選択され、
L3は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、ならびに、
L1、L2、およびL3の少なくとも2つは結合ではない。
A-X-B’-Y-C
式(Xa)
式中、
Aは結合部分であり、
B’は式(II)のポリヌクレオチド化合物であり、
Cは任意選択的にポリマーであり、
Xは単結合または第1のリンカーであり、および、
Yは単結合または第2のリンカーであり、
ポリヌクレオチドはさらに、1つ以上の追加の非天然のヌクレオチドを含み、および、
AとCは同じ末端でBに結合しない。
いくつかの実施形態では、ポリ核酸分子は結合部分にコンジュゲートする。いくつかの例では、結合部分は、アミノ酸、ペプチド、ポリペプチド、タンパク質、抗体、抗原、毒素、ホルモン、脂質、ヌクレオチド、ヌクレオシド、糖類、炭水化物、ポリエチレングリコールとポリプロピレングリコールなどのポリマー、ならびに、これらのクラスの物質のすべてのアナログまたは誘導体を含む。結合部分の追加の例はさらに、ステロイド、例えば、コレステロール、リン脂質、ジアシルグリセロールおよびトリアシルグリセロール、脂肪酸、炭化水素(例えば、飽和したもの、不飽和のもの、または、置換を含むもの)、酵素基質、ビオチン、ジゴキシゲニン、および多糖類などを含む。いくつかの例では、結合部分は、抗体またはその結合フラグメントである。いくつかの例では、ポリ核酸分子はさらにポリマーにコンジュゲートされ、随意にエンドソーム溶解性部分にコンジュゲートされる。
いくつかの実施形態では、結合部分Aはポリペプチドである。いくつかの例では、ポリペプチドは、抗体またはそのフラグメントである。場合によっては、フラグメントは結合フラグメントである。いくつかの例では、抗体またはその結合フラグメントは、ヒト化抗体またはその結合フラグメント、ヒト抗体またはその結合フラグメント、抗ネズミ抗体(例えば、抗マウス抗体、抗ラット抗体など)、抗ヒト抗体(例えば、抗ヒトトランスフェリン受容体抗体)、ネズミ抗体またはその結合フラグメント、キメラ抗体またはその結合フラグメント、モノクローナル抗体またはその結合フラグメント、一価Fab’、二価Fab2、F(ab)’3フラグメント、一本鎖可変フラグメント(scFv)、bis-scFv、(scFv)2、ダイアボディ、ミニボディ、ナノボディ、トリアボディ、テトラボディ、ジスルフィド安定化Fvタンパク質(dsFv)、単一ドメイン抗体(sdAb)、Ig NAR、ラクダ科抗体またはその結合フラグメント、二重特異性抗体またはその結合フラグメント、あるいはこれらの化学修飾された誘導体を含む。
いくつかの実施形態では、結合部分は血漿タンパク質である。いくつかの例では、血漿タンパク質はアルブミンを含む。いくつかの例では、結合部分Aはアルブミンである。いくつかの例では、アルブミンは、本明細書に記載されるコンジュゲーション化学の1つ以上によって、ポリ核酸分子にコンジュゲートされる。いくつかの例では、アルブミンは、天然のライゲーション化学によってポリ核酸分子にコンジュゲートされる。いくつかの例では、アルブミンは、リジン結合によってポリ核酸分子にコンジュゲートされる。
いくつかの実施形態では、ポリ核酸分子Bは、癌遺伝子上の標的領域にハイブリダイズするポリ核酸分子(またはポリヌクレオチド)である。いくつかの例では、癌遺伝子は、いくつかのカテゴリー:成長因子または分裂促進因子、受容体チロシンキナーゼ、細胞質チロシンキナーゼ、細胞質セリン/トレオニンキナーゼ、制御性GTPアーゼ、および転写因子にさらに分類される。例示的な成長因子はc-Sisを含む。例示的な受容体チロシンキナーゼは、上皮増殖因子受容体(EGFR)、血小板由来増殖因子受容体(PDGFR)、血管内皮増殖因子受容体(VEGFR)、およびHER2/neuを含む。例示的な細胞質チロシンキナーゼは、Srcファミリーチロシンキナーゼ、チロシンキナーゼのSyk-ZAP-70ファミリー、チロシンキナーゼのBTKファミリー、および、CMLにおけるAbl遺伝子を含む。例示的な細胞質セリン/トレオニンキナーゼはRafキナーゼおよびサイクリン依存性キナーゼを含む。例示的な制御性GTPアーゼは、KRASなどのタンパク質のRasファミリーを含む。例示的な転写因子はMYC遺伝子を含む。いくつかの例では、本明細書に記載された癌遺伝子は、成長因子または分裂促進因子、受容体チロシンキナーゼ、細胞質チロシンキナーゼ、細胞質セリン/トレオニンキナーゼ、制御性GTPアーゼ、または転写因子から選択された癌遺伝子を含む。いくつかの実施形態では、ポリ核酸分子は、成長因子または分裂促進因子、受容体チロシンキナーゼ、細胞質チロシンキナーゼ、細胞質セリン/トレオニンキナーゼ、制御性GTPアーゼ、または転写因子から選択された癌遺伝子の標的領域にハイブリダイズするポリ核酸分子である。
カーステンラット肉腫ウイルス癌遺伝子ホモログ(GTPアーゼKRas、V-Ki-rasカーステンラット肉腫ウイルス癌遺伝子ホモログ、またはKRASとしても知られている)は、細胞分裂の調節に関与する。K-Rasタンパク質はRasスーパーファミリーに属するGTPアーゼである。いくつかの例では、K-Rasは細胞周期進行を調節し、様々な環境トリガー(例えば、細胞ストレス、紫外線、熱ショック、またはイオン化放射線照射)の下で、成長停止、アポトーシス、および複製老化を誘導する。場合によっては、野生型KRAS遺伝子は様々なタイプの癌における腫瘍進行中に頻繁に失われることが示されているが、KRAS遺伝子の突然変異は癌の発生に関連している。いくつかの例では、KRAS増幅も、癌の発生に関与している(例えば、Valtorta et al.”KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy,” Int. J. Cancer 133: 1259-1266 (2013)を参照)。そのような場合、癌は、患者が特定の阻害剤、または阻害剤のクラスに対して耐性を獲得した難治性の癌に関連する。
いくつかの実施形態では、本明細書に記載されるポリペプチド(例えば、抗体とその結合フラグメント)は、とりわけ、化学合成によって、または組換え発現によって、ポリペプチド(例えば、抗体)の合成に役立つように当該技術分野で知られている任意の方法を使用して生成され、および、好ましくは組換え発現技術によって生成される。
いくつかの実施形態では、ポリマー部分Cはさらに、本明細書に記載されるポリ核酸分子、本明細書に記載される結合部分、またはこれらの組み合わせにコンジュゲートする。いくつかの例では、ポリマー部分Cはポリ核酸分子にコンジュゲートされる。場合によっては、ポリマー部分Cは結合部分にコンジュゲートされる。他の場合には、ポリマー部分Cはポリ核酸分子-結合部分分子にコンジュゲートされる。さらなる場合には、ポリマー部分Cは、治療用分子プラットフォームの段落で議論されたとおりにコンジュゲートされる。
いくつかの実施形態では、式(Xa):A-X1-B’-X2-Cの分子はさらに、付加的なコンジュゲート部分を含む。いくつかの例では、追加のコンジュゲート部分は、エンドソーム溶解性部分および/または細胞膜貫通部分である。場合によっては、エンドソーム溶解性部分は、細胞区画放出成分、例えば、エンドソーム、リソソーム、小胞体(ER)、ゴルジ体、微小管、ペルオキシソーム、または細胞を有する他の小胞体などの、当該技術分野で知られている細胞区画のいずれかから放出することができる化合物である。場合によっては、エンドソーム溶解性部分は、エンドソーム溶解性ポリペプチド、エンドソーム溶解性ポリマー、エンドソーム溶解性脂質、またはエンドソーム溶解性小分子を含む。場合によっては、エンドソーム溶解性部分はエンドソーム溶解性ポリペプチドを含む。他の場合では、エンドソーム溶解性部分はエンドソーム溶解性ポリマーを含む。場合によっては、細胞膜貫通部分は、細胞透過性ペプチド(CPP)を含む。他の場合には、細胞膜貫通部分は、細胞透過性脂質を含む。他の場合には、細胞膜貫通部分は、細胞透過性小分子を含む。
いくつかの実施形態では、式(Xa):A-X1-B-X2-Cの分子は、エンドソーム溶解性ポリペプチドとさらにコンジュゲートする。場合によっては、エンドソーム溶解性ポリペプチドはpH依存性膜活性ペプチドである。場合によっては、エンドソーム溶解性ポリペプチドは両親媒性ポリペプチドである。さらなる場合には、エンドソーム溶解性ポリペプチドはペプチド模倣薬である。いくつかの例では、エンドソーム溶解性ポリペプチドは、INF、メリチン、ムチン(meucin)、またはそのそれぞれの誘導体を含む。いくつかの例では、エンドソーム溶解性ポリペプチドは、INFまたはその誘導体を含む。他の場合には、エンドソーム溶解性ポリペプチドは、メリチンまたはその誘導体を含む。さらなる場合には、エンドソーム溶解性ポリペプチドは、ムチンまたはその誘導体を含む。いくつかの例では、エンドソーム溶解性ポリペプチドは、Pep-1(Simian Virus 40ラージ抗原およびHIVの逆転写酵素からのNLSに由来する)、Pvec(VE-カドヘリンに由来する)、VT5(合成ペプチドに由来する)、C105Y(1-アンチトリプシンに由来する)、トランスポータン(ガラニンとマストパランに由来する)、TP10(ガラニンとマストパランに由来する)、MPG(HIV gp41とSV40 T抗原のNLSの融合配列の疎水性ドメインに由来する)、GH625(HSV I型の糖タンパク質gHに由来する)、CADY(PPTG1ペプチド)、GALA(合成ペプチド)、INF(インフルエンザHA2融合ペプチド)、HA2E5-TAT(インフルエンザウイルスX31株融合ペプチドのインフルエンザHA2サブユニット)、HA2-ペネトラチン(インフルエンザウイルスX31株融合ペプチドのインフルエンザHA2サブユニット)、HA-K4(インフルエンザウイルスX31株融合ペプチドHA2サブユニット)、HA2E4(インフルエンザウイルスX31株融合ペプチドHA2サブユニット)、H5WYG(HA2アナログ)、GALA-INF3-(PEG)6-NH(INF3融合ペプチド)、またはCM18-TAT11(セクロピンA-メリトチン2-12(CM18)融合ペプチド)を含む。
いくつかの実施形態では、エンドソーム溶解性部分は脂質(例えば、融合性脂質)である。いくつかの実施形態では、式(Xa):A-X1-B’-X2-Cの分子はさらに、エンドソーム溶解性脂質(例えば、融合性脂質)にコンジュゲートする。例示的な融合性脂質は、1,2-ジレオイル(dileoyl)-sn-3-ホスホエタノールアミン(DOPE)、ホスファチジルエタノールアミン(POPE)、パルミトイルオレオイルホスファチジルコリン(POPC)、(6Z,9Z,28Z,31Z)-ヘプタトリアコンタ-6,9,28,31-テトラエン-19-オール(Di-Lin)、N-メチル(2,2-ジ((9Z,12Z)-オクタデカ-9,12-ジエニル)-1,3-ジオキソラン-4-イル)メタンアミン(DLin-k-DMA)、およびN-メチル-2-(2,2-ジ((9Z,12Z)-オクタデカ-9,12-ジエニル)-1,3-ジオキソラン-4-イル)エタンアミン(XTC)を含む。いくつかの例では、エンドソーム溶解性部分は、PCT公開公報第WO09/126,933号に記載される脂質(例えば、融合性脂質)である。
いくつかの実施形態では、エンドソーム溶解性部分は小分子である。いくつかの実施形態では、式(Xa):A-X1-B’-X2-Cの分子はさらに、エンドソーム溶解性小分子にコンジュゲートされる。エンドソーム溶解性部分として適切な例示的な小分子としては、限定されないが、キニーネ、クロロキン、水酸化クロロキン、アモジアキン(カルノキン(carnoquines))、アモピロキン、プリマキン、メフロキン、ニバキン(nivaquines)、ハロファントリン、キノンイミン、またはそれらの組み合わせが挙げられる。いくつかの例では、キノリンエンドソーム溶解性部分としては、限定されないが、7-クロロ-4-(4-ジエチルアミノ-1-メチルブチル-アミノ)キノリン(クロロキン)、7-クロロ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチル-アミノ)キノリン(ヒドロキシクロロキン)、7-フルオロ-4-(4-ジエチルアミノ-1-メチルブチル-アミノ)キノリン、4-(4-ジエチルアミノ-1-メチルブチルアミノ)キノリン、7-ヒドロキシ-4-(4-ジエチル-アミノ-1-メチルブチルアミノ)キノリン、7-クロロ-4-(4-ジエチルアミノ-1-ブチルアミノ)キノリン(デスメチルクロロキン)、7-フルオロ-4-(4-ジエチルアミノ-1-ブチルアミノ)キノリン、4-(4-ジエチル-アミノ-1-ブチルアミノ)キノリン、7-ヒドロキシ-4-(4-ジエチルアミノ-1-ブチルアミノ)キノリン、7-クロロ-4-(1-カルボキシ-4-ジエチルアミノ-1-ブチルアミノ)キノリン、7-フルオロ-4-(1-カルボキシ-4-ジエチル-アミノ-1-ブチルアミノ)キノリン、4-(1-カルボキシ-4-ジエチルアミノ-1-ブチルアミノ)キノリン、7-ヒドロキシ-4-(1-カルボキシ-4-ジエチルアミノ-1-ブチルアミノ)キノリン、7-クロロ-4-(1-カルボキシ-4-ジエチルアミノ-1-メチルブチルアミノ)キノリン、7-フルオロ-4-(1-カルボキシ-4-ジエチル-アミノ-1-メチルブチルアミノ)キノリン、4-(1-カルボキシ-4-ジエチルアミノ-1-メチルブチルアミノ)キノリン、7-ヒドロキシ-4-(1-カルボキシ-4-ジエチルアミノ-1-メチルブチルアミノ)キノリン、7-フルオロ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン、4-(4-エチル-(2-ヒドロキシ-エチル)-アミノ-1-メチルブチルアミノ-)キノリン、7-ヒドロキシ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン、ヒドロキシクロロキンホスフェート、7-クロロ-4-(4-エチル-(2-ヒドロキシエチル-1)-アミノ-1-ブチルアミノ)キノリン(デスメチルヒドロキシクロロキン)、7-フルオロ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン、4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン、7-ヒドロキシ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン、7-クロロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン、7-フルオロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン、4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン、7-ヒドロキシ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン、7-クロロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン、7-フルオロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン、4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン、7-ヒドロキシ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン、8-[(4-アミノペンチル)アミノ-6-メトキシジヒドロクロリドキノリン、1-アセチル-1,2,3,4-テトラヒドロキノリン、8-[(4-アミノペンチル)アミノ]-6-メトキシキノリンジヒドロクロリド、1-ブチリル-1,2,3,4-テトラヒドロキノリン、3-クロロ-4-(4-ヒドロキシ-α,α’-ビス(2-メチル-1-ピロリジニル)-2,5-キシリジノキノリン、4-[(4-ジエチル-アミノ)-1-メチルブチル-アミノ]-6-メトキシキノリン、3-フルオロ-4-(4-ヒドロキシ-α,α’-ビス(2-メチル-1-ピロリジニル)-2,5-キシリジノキノリン、4-[(4-ジエチルアミノ)-1-メチルブチル-アミノ]-6-メトキシキノリン、4-(4-ヒドロキシ-α,α’-ビス(2-メチル-1-ピロリジニル)-2,5-キシリジノキノリン、4-[(4-ジエチルアミノ)-1-メチルブチル-アミノ]-6-メトキシキノリン、3,4-ジヒドロ-1-(2H)-キノリンカルボキシアルデヒド、1,1’-ペンタメチレンキノリニウムジヨージド、8-硫酸キノリノール、およびそのアミノ、アルデヒド、カルボン酸、ヒドロキシル、ハロゲン、ケト、スルフヒドリル、ならびにビニル誘導体またはアナログが挙げられる。いくつかの例では、エンドソーム溶解性部分は、Naisbitt et al (1997,J Pharmacol Exp Therapy 280:884-893)および米国特許第5,736,557号に記載される小分子である。
細胞透過性ポリペプチド(CPP)
いくつかの実施形態では、細胞透過性ポリペプチドは、5~30個のアミノ酸を有する正電荷の短いペプチドを含む。いくつかの実施形態では、細胞透過性ポリペプチドは、アルギニンまたはリジンリッチのアミノ酸配列を含む。いくつかの実施形態では、細胞透過性ポリペプチドは、アンテナペディアペネトラチン(Antennapedia Penetratin)(43-58)、HIV-1 TATタンパク質(48-60)、pVEC カドヘリン(615-632)、トランスポータンガラニン/マストパラン、MPG HIV-gp41/SV40 T-抗原、Pep-1 HIV-逆転写酵素/SV40 T-抗原、ポリアルギニン、MAP、R6W3、NLS、8-リジン、ARF(1-22)、およびアズリン-p28を含む、任意のポリペプチドまたはその組み合わせを含む。
いくつかの実施形態では、本明細書に記載されるリンカーは、切断可能なリンカーまたは切断不可能なリンカーである。いくつかの例では、リンカーは切断可能なリンカーである。いくつかの例では、リンカーは酸切断可能なリンカーである。いくつかの例では、リンカーは切断不可能なリンカーである。いくつかの例では、リンカーはC1-C6アルキル基(例えば、C5、C4、C3、C2、またはC1アルキル基)を含む。いくつかの例では、リンカーはホモ二官能性架橋リンカー、ヘテロ二官能性架橋リンカーなどを含む。いくつかの例では、リンカーはトレースレスリンカー(または、長さがゼロのリンカー)である。いくつかの例では、リンカーは非ポリマーリンカーである。場合によっては、リンカーは非ペプチドリンカーまたはアミノ酸残基を含まないリンカーである。
いくつかの実施形態では、ポリ核酸分子にコンジュゲートした結合部分およびポリマーを含む、本明細書に記載される組成物あるいは医薬製剤は、疾患または障害の処置に使用される。いくつかの例では、疾患または障害は、筋肉ジストロフィー、筋萎縮症、および/または筋消耗である。筋肉ジストロフィーは、筋肉量の減少および/または筋肉の進行性の衰弱と変性を指す。場合によっては、筋肉量の減少および/または筋肉の進行性の衰弱と変性は、高いタンパク質分解率、低いタンパク質合成率、あるいはその両方の組み合わせによって生じる。場合によっては、高い筋タンパク質分解率は、筋タンパク質異化作用(つまり、糖新生のために基質としてアミノ酸を使用するための筋タンパク質の分解)が原因である。いくつかの例では、疾患または障害は癌である。いくつかの実施形態では、本明細書に記載される組成物または医薬製剤は、疾患または障害の処置のための免疫療法として使用される。いくつかの例では、免疫療法は癌免疫療法である。
いくつかの実施形態では、本明細書に記載される組成物または医薬製剤は、癌の処置に使用される。いくつかの例では、癌は固形腫瘍である。いくつかの例では、癌は血液悪性腫瘍である。いくつかの例では、癌は再発性あるいは難治性の癌、または転移性癌である。いくつかの例では、固形腫瘍は、再発性あるいは難治性の固形腫瘍、または転移性の固形腫瘍である。場合によっては、血液悪性腫瘍は、再発性あるいは難治性の血液悪性腫瘍、または転移性の血液悪性腫瘍である。
いくつかの実施形態では、本明細書に記載される組成物または医薬製剤は、疾患または障害の処置のための免疫療法として使用される。いくつかの例では、免疫療法は癌免疫療法である。いくつかの例では、癌免疫療法は、能動的、受動的、あるいは組み合わせ(能動的と受動的)の方法に分類される。能動癌免疫療法では、例えば、腫瘍関連抗原(TAA)が免疫系に提示され、これらのTAAを提示する癌細胞への攻撃を引き起こす。いくつかの例では、能動癌免疫療法は、腫瘍標的化および/または免疫標的化剤(例えば、モノクローナル抗体などのチェックポイント阻害剤)、および/または、ワクチン、例えば、インサイチュのワクチン接種および/または細胞ベースあるいは非細胞ベース(例えば、樹状細胞ベース、腫瘍細胞ベース、抗原、抗イディオタイプ、DNA、あるいはベクターベース)のワクチンを含む。いくつかの例では、細胞ベースのワクチンは、患者自身の免疫系から得られ、その後、患者自身の癌によって活性化される、活性化免疫細胞を使用して生成されるワクチンである。いくつかの例では、能動癌免疫療法は、非特異的能動免疫療法と特異的能動免疫療法にさらに細分される。いくつかの例では、非特異的能動免疫療法は、一般的な免疫系応答を誘発するために、サイトカインおよび/または他の細胞シグナル伝達成分を利用する。場合によっては、特異的能動免疫療法は、免疫応答を誘発するために、特定のTAAを利用する。
一実施形態では、筋肉ジストロフィーは筋力の著しい減少を指す。筋力の著しい減少とは、対照の対象の同じ筋組織と比較して、対象の病気の、損傷した、または不使用の筋組織における強度の低下を意味する。ある実施形態では、筋力の著しい減少とは、対照の対象の同じ筋組織と比較して、少なくとも10%、少なくとも15%、少なくとも20%、少なくとも25%、少なくとも30%、少なくとも35%、少なくとも40%、少なくとも45%、少なくとも50%、またはそれ以上の強度の低下である。別の実施形態では、筋力の著しい減少とは、不使用期間前の同じ対象の同じ筋組織の筋力と比較して、不使用の筋組織の強度の低下を意味する。ある実施形態では、筋肉強度の著しい減少とは、不使用期間前の同じ対象の同じ筋組織の筋力と比較して、少なくとも10%、少なくとも15%、少なくとも20%、少なくとも25%、少なくとも30%、少なくとも35%、少なくとも40%、少なくとも45%、少なくとも50%、またはそれ以上の低下である。
いくつかの実施形態では、本明細書に記載される医薬製剤は、限定されないが、非経口(例えば、静脈内、皮下、筋肉内)、経口、鼻腔内、頬側、直腸、または経皮の投与経路を含む、複数の投与経路によって対象に投与される。いくつかの例では、本明細書に記載される医薬組成物は、非経口(例えば、静脈内、皮下、筋肉内)投与のために製剤化される。他の例では、本明細書に記載される医薬組成物は、経口投与用に製剤化される。さらに他の例では、本明細書に記載される医薬組成物は、鼻腔内投与用に製剤化される。
いくつかの実施形態では、本明細書に記載される医薬組成物は治療用途のために投与される。いくつかの実施形態では、医薬組成物は、1日1回、1日2回、1日3回、またはそれ以上投与される。医薬組成物は、毎日、1日おき、週5日、週1日、1週おき、月2週間、月3週間、月1回、月2回、月3回、またはそれ以上投与される。医薬組成物は、少なくとも1か月、2か月、3か月、4か月、5か月、6か月、7か月、8か月、9か月、10か月、11か月、12か月、18か月、2年、3年、またはそれ以上にわたって投与される。
ある実施形態では、本明細書に記載される1つ以上の組成物および方法とともに使用されるキットおよび製品が本明細書で開示される。このようなキットは、バイアル、チューブなどの1つ以上の容器を収容するために仕切られた運搬装置、包装、または容器を含み、各容器は、本明細書中に記載されている方法を使用するための別個の要素の1つを備える。適切な容器としては、例えば、ボトル、バイアル、注射器、および試験管が挙げられる。一実施形態では、容器は、ガラスまたはプラスチックなどの様々な材料から形成される。
別段の定めのない限り、本明細書で使用される技術用語および科学用語はすべて、主題が属する当該技術分野の当業者によって一般に理解されるものと同じ意味を有する。前述の一般的な記載および以下の詳細な記載が例示的かつ説明的なものにすぎず、いかなる請求される主題も限定するものではないことが理解されよう。本出願では、単数の使用は、特に別記されない限り複数を含む。明細書および添付の請求項内で用いられる場合、単数形「a」、「an」、および「the」は、文脈が明確に他のことを定めていない限り、複数の参照対象を含む。本出願では、「または」の使用は、特に明記されない限り、「および/または」を意味する。さらに、「含む(including)」という用語の使用は、「含む(include)」、「含む(includes)」、および「含まれる(included)」といった他の形態と同様に、限定的なものではない。
本明細書で使用される略語は、化学分野および生物学分野内でのその従来の意味を有している。本明細書に記載される化学構造および式は、化学分野で既知の化学結合価の標準規則に従って構築される。
(i)オキソ、ハロゲン、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC=(O)NHNH2、-NHC=(O)NH2、-NHSO2H、-NHC=(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、および
(ii)以下から選択される少なくとも1つの置換基で置換された、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール:
(a)オキソ、ハロゲン、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC=(O)NHNH2、-NHC=(O)NH2、-NHSO2H、-NHC=(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、および
(b)以下から選択される少なくとも1つの置換基で置換された、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール:オキソ、ハロゲン、-CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC=(O)NHNH2、-NHC=(O)NH2、-NHSO2H、-NHC=(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール。
化学合成の実施例
表1の化合物は、以下の実施例に記載されるように調製される。
1H NMR:400MHz,CD3CN:δ ppm 3.51-3.75(m,2H),3.55-3.70(m,10H),2.64(t,J=6.02 Hz,2H),1.76-1.83(m,4H),1.16-1.18(m,12H)
31P NMR:162MHz,CD3CN:δ ppm 147.19(s,1P),34.03(s,1P).
1H NMR:400MHz,CDCl3:δ ppm 3.51-3.65(m,4H),1.43-1.66(m,4H),0.80-0.86(m,9H),-0.06-0.03(m,6H).
1H NMR:400MHz,CDCl3:δ ppm 3.64(t,J=6.2 Hz,2H),3.23(t,J=7.0 Hz,2H),1.92(q,J=7.2 Hz,2H),1.58-1.68(m,2H),0.89-0.93(m,9H),0.03-0.08(m,6H).
1H NMR:400MHz,CDCl3:δ ppm 3.74(d,J=10.8 Hz,6H),3.62(t,J=6.0 Hz,2H),1.57-1.83(m,7H),0.89(s,9H),0.05(s,6H)
31P NMR:162MHz CDCl3:δ ppm 34.93(s,1P).
1H NMR:400MHz,CD3CN:δ ppm 3.71-3.84(m,2H),3.56-3.70(m,10H),2.64(t,J=6.02 Hz,2H),1.58-1.79(m,7H),1.13-1.20(m,14H).
31P NMR:162MHz,CD3CN:δ ppm 147.03(s,1P),34.12(s,1P).
31P NMR:162MHz,CDCl3:δ ppm 147.81(s,1P),31.39(s,1P).
1H NMR:400MHz,CDCl3:δ ppm 3.55-3.61(m,4 H),1.88(s,1H),1.53-1.56(m,4H),1.46-1.51(m,2H),0.82-0.85(m,9H),0.00-0.01(m,6H).
1H NMR:400MHz,CDCl3:δ ppm 3.62(t,J=6.2 Hz,2H),3.20(t,J=7.0 Hz,2H),1.85(q,J=7.2 Hz,2H),1.51-1.58(m,2H),1.41-1.49(m,2H),0.88-0.92(m,9H),0.06(d,J=0.8 Hz,6H).
1H NMR:400MHz,CDCl3:δ ppm 3.72(d,J=10.8 Hz,6H),3.63(t,J=6.36 Hz,2H),1.69-1.80(m,2H) 1.60-1.69(m,2H) 1.52-1.60(m,2H) 1.41-1.50(m,2H).
31P NMR:162MHz,CD3CN:δ ppm 146.93(s,1P),34.24(s,1P).
実施例1.HCT116細胞中のホスホネートのインビトロの活性
siRNAの設計および合成:21merのSSBガイド鎖をマウスSSBに対して設計した。ガイド鎖/アンチセンス鎖の配列(5’~3’)は、UUACAUUAAAGUCUGUUGUUUであった。ホスホネート修飾ヌクレオチド構造(化合物1、2、および4)を取り込む3つのバージョンを作成した。ガイドおよび完全に相補的なRNAパッセンジャー鎖を、標準のホスホロアミダイト化学を使用して固体相上で組み立て、HPLCで精製した。RNAiの分野で十分に説明されている塩基、糖、およびリン酸の修飾を使用して、二本鎖の潜在能を最適化し、免疫原性を減少させた。精製された一本鎖を二重にして、上に記載される二本鎖siRNAを得た。
ヒト横紋筋肉腫ヒト細胞(SJCRH30、ATCC CRL-2061)において、および明らかに健康なヒト由来の不死化骨格筋芽細胞(MB)(Denis Furling,Institut de Myologie,Franceから得た)において、siRNAの活性を評価した。10%の熱不活性化FBS(Gibco)および10mMのHEPESおよび1mMのピルビン酸ナトリウムで補足されたDMEM中で、SJCRH30細胞を成長させた。完全な骨格筋細胞増殖培地(PromoCell)中でヒトMBを成長させた。トランスフェクションの24時間前に、1ウェル当たり8500(SJCRH30)細胞または4000(MB)細胞で、96ウェル組織培養プレート上で、細胞を三通でプレーティングした。50nM、5.5556nM、0.6173nM、0.0686nM、0.0076nM、0.0008nM、および0.0001nMの最終濃度で、siRNAを両方の細胞型にトランスフェクトした。製造者の「フォワードトランスフェクション」のプロトコルの説明書に従って、siRNAを市販のトランスフェクション試薬、Lipofectamine RNAiMAX(Life Technologies)を用いて製剤化した。トランスフェクションの48時間後、細胞をPBSで洗浄し、TRIzol(登録商標)試薬(Life Technologies)を用いて収集した。製造者の説明書に従って、Direct-zol-96 RNA Kit(Zymo Research)を使用して、RNAを単離した。製造者の説明書に従って、High Capacity cDNA Reverse Transcription Kit(Applied Biosystems)を使用して、10μlのRNAをcDNAに逆転写した。TaqMan(登録商標) Fast Advanced Master Mix(Applied Biosystems)を使用して、SSB特異的、MSTN特異的、およびPPIB特異的なTaqMan遺伝子発現プローブ(Thermo Fisher)を用いて、qPCRによってcDNA試料を評価した。SSBおよびMSTNの発現値を、各試料内でPPIB遺伝子発現に対して正規化した。SSBおよびMSTNダウンレギュレーションの定量化を、基準2-ΔΔCt法を使用して実施した。すべての実験を三連で実施した。
コンジュゲートを、インビボの実験において、筋組織中のMSTN mRNAダウンレギュレーションを媒介するそれらの能力について評価した(野生型CD-1マウス)。PBSビヒクル対照、および指定されたASCと投与量を、静脈内(iv)注射によってマウスに投与した。168時間後、腓腹筋(gastroc)、四頭筋(quadricepts)(quad)、前脛骨筋(tib)、および横隔膜の組織を収集し、液体窒素中で急速冷凍(snap-frozen)した。標的組織中のmRNAノックダウンは、比較用のqPCRアッセイを使用して決定した。全RNAを組織から抽出し、逆転写し、適切に設計されたプライマーおよびプローブを用い、TaqMan qPCRを使用して、mRNAのレベルを定量化した。PPIB(ハウスキーピング遺伝子)を内部RNAローディング対照(internal RNA loading control)として使用し、結果を比較Ct方法によって算出し、標的遺伝子Ct値とPPIB Ct値(ΔCt)との差を算出し、その後、第2の差(ΔΔCt)を得ることによってPBSの対照群に対してさらに正規化した。
Claims (58)
- オリゴヌクレオチドの合成に適した化合物であって、前記化合物は式(II)を含み、
R1はそれぞれ独立して、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6フルオロアルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
R2はそれぞれ独立して、水素、重水素、置換または非置換のC1-C6アルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
もしくは、2つのR2は、それらが結合している窒素原子と一体となって、置換または非置換のC2-C10ヘテロシクロアルキルを形成し、
L1は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
L2は、結合、O、S、NR3、置換または非置換のC4-C7シクロアルキレン、置換または非置換のC4-C7ヘテロシクロアルキレン、置換または非置換のC5-C8アリーレン、あるいは置換または非置換のC4-C8ヘテロアリーレンであり、
R3は、存在する場合、水素、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、および非置換または置換の単環式の複素環から選択され、
L3は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、ならびに、
L1、L2、およびL3の少なくとも2つは結合ではない、
化合物。 - L2は結合である、請求項1に記載の化合物。
- L2はO、S、またはNR3である、請求項1に記載の化合物。
- L2は置換または非置換のC4-C7シクロアルキレンである、請求項1に記載の化合物。
- L2は置換または非置換のC5-C8アリーレンである、請求項1に記載の化合物。
- L2はフェニレンである、請求項1に記載の化合物。
- L2はシクロヘキシルである、請求項1に記載の化合物。
- L1はC1-C5アルキレン、C1-C3アルケニレン、またはC1-C5アルキニレンであり、および、
L3はC1-C5アルキレン、C1-C3アルケニレン、またはC1-C5アルキニレンである、請求項1に記載の化合物。 - L1はC1-C5アルキレンであり、および、L3はC1-C5アルキレンである、請求項1に記載の化合物。
- L2はメチレンである、請求項9に記載の化合物。
- L2は結合、O、S、または、NR3である、請求項9に記載の化合物。
- R1はそれぞれ独立して置換または非置換のC1-C6アルキルである、請求項1-11のいずれか1つに記載の化合物。
- R1はそれぞれ独立して、-CH3、-CH2CH3、-CH2CH2CH3、または-CH2(CH3)2である、請求項1-11のいずれか1つに記載の化合物。
- R1はそれぞれ-CH3である、請求項1-11のいずれか1つに記載の化合物。
- R2はそれぞれ独立して、置換または非置換のC1-C6アルキルである、請求項1-14のいずれか1つに記載の化合物。
- R2はそれぞれ独立して、-CH3、-CH2CH3、-CH2CH2CH3、または-CH2(CH3)2である、請求項1-14のいずれか1つに記載の化合物。
- R2はそれぞれ-CH2(CH3)2である、請求項1-14のいずれか1つに記載の化合物。
-
式中、Rxは、H、ハロゲン、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、非置換または置換の単環式の複素環、-CN、-OH、-O-アルキル、-CO2H、-CO2-アルキル、-CH2CO2H、-CH2CO2-アルキル、-C(=O)NH2、-C(=O)NH-アルキル、-CH2C(=O)NH2、-CH2C(=O)NH-アルキル、NH2、-NH-アルキル、-CH2NH2、-CH2NH-アルキル、-NHC(=O)アルキル、-CH2NHC(=O)アルキル、-SH、-S-アルキル、-S(=O)H、-S(=O)アルキル、-SO2H、-SO2-アルキル、-SO2NH2、または-SO2NH-アルキルである、請求項1-17のいずれか1つに記載の化合物。 - 式(IIa)の化合物を含むオリゴヌクレオチドであって、
R1はそれぞれ独立して、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6フルオロアルキル、あるいは置換または非置換のC1-C6ヘテロアルキルであり、
L1は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
L2は、結合、O、S、NR3、置換または非置換のC4-C7シクロアルキレン、置換または非置換のC4-C7ヘテロシクロアルキレン、置換または非置換のC5-C8アリーレン、あるいは置換または非置換のC4-C8ヘテロアリーレンであり、
R3は、存在する場合、水素、非置換または置換のC1-C6アルキル、非置換または置換のC1-C6フルオロアルキル、非置換または置換のC1-C6ヘテロアルキル、非置換または置換の単環式の炭素環、および非置換または置換の単環式の複素環から選択され、
L3は、結合、置換または非置換のC1-C5アルキレン、置換または非置換のC2-C5アルケニレン、あるいは置換または非置換のC2-C5アルキニレンであり、
Jは、ポリヌクレオチドの隣接するヌクレオチドに結合するヌクレオチド間結合基であり、ならびに、
L1、L2、およびL3の少なくとも2つは結合ではない、
オリゴヌクレオチド。 - オリゴヌクレオチドはRNAオリゴヌクレオチドである、請求項19に記載のオリゴヌクレオチド。
- 少なくとも1つの修飾をさらに含む、請求項19または20に記載のオリゴヌクレオチド。
- 少なくとも1つの2’修飾されたヌクレオチドをさらに含む、請求項19~21のいずれか1つに記載のオリゴヌクレオチド。
- 2’-O-メチル、2’-O-メトキシエチル(2’-O-MOE)、2’-デオキシ、2-デオキシ-2’-フルオロ、2’-O-アミノプロピル(2’-O-AP)、2’-O-ジメチルアミノエチル(2’-O-DMAOE)、2’-O-ジメチルアミノプロピル(2’-O-DMAP)、2’-O-ジメチルアミノエチルオキシエチル(2’-O-DMAEOE)、または、2’-O-N-メチルアセトアミド(2’-O-NMA)修飾されたヌクレオチドから選択される少なくとも1つの2’修飾されたヌクレオチドをさらに含む、請求項19-22のいずれか1つに記載のオリゴヌクレオチド。
- ロックド核酸(LNA)またはエチレン核酸(ENA)から選択される少なくとも1つの2’修飾されたヌクレオチドをさらに含む、請求項19-23のいずれか1つに記載のオリゴヌクレオチド。
- 少なくとも1つの修飾されたヌクレオチド間結合をさらに含む、請求項19-24のいずれか1つに記載のオリゴヌクレオチド。
- ホスホロチオエート結合、ホスホロジチオエート結合、メチルホスホネート結合、ホスホトリエステル結合、またはアミド結合から選択される少なくとも1つの修飾されたヌクレオチド間結合をさらに含む、請求項19-25のいずれか1つに記載のオリゴヌクレオチド。
- 式(IIa)の化合物は、オリゴヌクレオチドの5’-末端に位置する、請求項19に記載のオリゴヌクレオチド。
- オリゴヌクレオチドは結合部分にコンジュゲートする、請求項19に記載のオリゴヌクレオチド。
- 式(IIa)の化合物はオリゴヌクレオチドの5’-末端に位置し、結合部分はオリゴヌクレオチドの3’-末端にコンジュゲートする、請求項28に記載のオリゴヌクレオチド。
- 結合部分は抗体またはその結合フラグメントを含む、請求項28-29のいずれか1つに記載のオリゴヌクレオチド。
- 抗体またはその結合フラグメントは、ヒト化抗体またはその結合フラグメント、キメラ抗体またはその結合フラグメント、モノクローナル抗体またはその結合フラグメント、一価Fab’、二価Fab2、一本鎖可変フラグメント(scFv)、ダイアボディ、ミニボディ、ナノボディ、単一ドメイン抗体(sdAb)、またはラクダ科抗体、あるいはその結合フラグメントを含む、請求項30に記載のオリゴヌクレオチド。
- 結合部分はペプチドまたは小分子を含む、請求項28に記載のオリゴヌクレオチド。
- 結合部分はアプタマーを含む、請求項28に記載のオリゴヌクレオチド。
- 約8~約50のヌクレオチドを含む、請求項19-32のいずれか1つに記載のオリゴヌクレオチド。
- 約10~約30のヌクレオチドを含む、請求項19-33のいずれか1つに記載のオリゴヌクレオチド。
- 約15~約25のヌクレオチドを含む、請求項19-33のいずれか1つに記載のオリゴヌクレオチド。
- オリゴヌクレオチドは、
RNAオリゴヌクレオチドであり、
結合部分にコンジュゲートし、
約10~約30のヌクレオチドであり、
少なくとも1つの2’修飾されたヌクレオチドを含み、および、
少なくとも1つの修飾されたヌクレオチド間結合を含む、請求項19-36のいずれか1つに記載のオリゴヌクレオチド。 - オリゴヌクレオチドは、標的遺伝子配列の少なくとも8つの隣接する塩基にハイブリダイズする、請求項19-37のいずれか1つに記載のオリゴヌクレオチド。
- オリゴヌクレオチドはRNA干渉を媒介する、請求項19-38のいずれか1つに記載のオリゴヌクレオチド。
- オリゴヌクレオチドはセンス鎖である、請求項19-37のいずれか1つに記載のオリゴヌクレオチド。
- オリゴヌクレオチドは第2のオリゴヌクレオチドとハイブリダイズすることで、二本鎖オリゴ核酸分子を形成する、請求項40に記載のオリゴヌクレオチド。
- 第2のオリゴヌクレオチドはアンチセンス鎖である、請求項41に記載のオリゴヌクレオチド。
- 第2のオリゴヌクレオチドはRNAオリゴヌクレオチドである、請求項41または42に記載のオリゴヌクレオチド。
- 第2のオリゴヌクレオチドは少なくとも1つの修飾を含む、請求項41-43のいずれか1つに記載のオリゴヌクレオチド。
- 第2のオリゴヌクレオチドは少なくとも1つの2’修飾されたヌクレオチドを含む、請求項44に記載のオリゴヌクレオチド。
- 第2のオリゴヌクレオチドは、2’-O-メチル、2’-O-メトキシエチル(2’-O-MOE)、2’-デオキシ、2-デオキシ-2’-フルオロ、2’-O-アミノプロピル(2’-O-AP)、2’-O-ジメチルアミノエチル(2’-O-DMAOE)、2’-O-ジメチルアミノプロピル(2’-O-DMAP)、2’-O-ジメチルアミノエチルオキシエチル(2’-O-DMAEOE)、または、2’-O-N-メチルアセトアミド(2’-O-NMA)修飾されたヌクレオチドから選択された少なくとも1つの2’修飾されたヌクレオチドを含む、請求項44または45に記載のオリゴヌクレオチド。
- 第2のオリゴヌクレオチドは、ロックド核酸(LNA)またはエチレン核酸(ENA)から選択される少なくとも1つの2’修飾されたヌクレオチドを含む、請求項44-46のいずれか1つに記載のオリゴヌクレオチド。
- 第2のオリゴヌクレオチドは、少なくとも1つの修飾されたヌクレオチド間結合を含む、請求項44-47のいずれか1つに記載のオリゴヌクレオチド。
- 第2のオリゴヌクレオチドは、ホスホロチオエート結合、ホスホロジチオエート結合、メチルホスホネート結合、ホスホトリエステル結合、またはアミド結合から選択される少なくとも1つの修飾されたヌクレオチド間結合を含む、請求項44-48のいずれか1つに記載のオリゴヌクレオチド。
- オリゴヌクレオチドはポリマーを含む、請求項19-37または40-49のいずれか1つに記載のオリゴヌクレオチド。
- オリゴヌクレオチドはポリエチレングリコールを含む、請求項50に記載のオリゴヌクレオチド。
- オリゴヌクレオチドは第1の鎖と第2の鎖を含み、
第1の鎖は、
センス鎖であり、
RNAオリゴヌクレオチドであり、
結合部分、ポリマー、またはその組み合わせにコンジュゲートし、
約10~約30ヌクレオチドであり、
少なくとも1つの2’修飾されたヌクレオチドを含み、および、
少なくとも1つの修飾されたヌクレオチド間結合を含み、ならびに、第2の鎖は、
アンチセンス鎖であり、
RNAオリゴヌクレオチドであり、
約10~約30ヌクレオチドであり、
少なくとも1つの2’修飾されたヌクレオチドを含み、および、
少なくとも1つの修飾されたヌクレオチド間結合を含む、請求項19-37または40-51のいずれか1つに記載のオリゴヌクレオチド。 - タンパク質の発現不全を特徴とする疾患または疾病を抱える対象を処置する方法であって、前記方法は、タンパク質をコードする遺伝子の発現を調節するために、請求項19-52のオリゴヌクレオチドを対象に投与する工程であって、それによってタンパク質の発現不全を特徴とする疾患または疾病を処置する、工程を含む、方法。
- タンパク質の過剰発現を特徴とする疾患または疾病を抱える対象を処置する方法であって、前記方法は、タンパク質をコードする遺伝子の発現を調節するために、請求項19-52のオリゴヌクレオチドを対象に投与する工程であって、それによって、タンパク質の過剰発現を特徴とする疾患または疾病を処置する、工程を含む、方法。
- 疾患または疾病は癌である、請求項53または54に記載の方法。
- 疾患または疾病は、神経筋疾患、筋ジストロフィー、筋萎縮、筋消耗、遺伝病、癌、遺伝性疾患、または心血管疾患である、請求項53または54に記載の方法。
- 対象はヒトである、請求項53-56のいずれか1つに記載の方法。
- 請求項1-18の化合物または請求項19-52のオリゴヌクレオチドを含む、キット。
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