JP2022122928A - 核酸ポリペプチド組成物とその使用 - Google Patents
核酸ポリペプチド組成物とその使用 Download PDFInfo
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Abstract
Description
本出願は、ASCIIフォーマットで電子的に提出され、参照により全体として本明細書に組み込まれる配列表を含んでいる。2017年3月28日に作成された上記のASCIIのコピーは、45532-707_601_SL.txtのファイル名であり、615,666バイトのサイズである。
Aは結合部分であり、
Bはポリヌクレオチドであり、
Cはポリマーであり、
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、および、
ここで、ポリヌクレオチドは、少なくとも1つの2’修飾されたヌクレオチド、少なくとも1つの修飾されたヌクレオチド間結合、あるいは少なくとも1つの逆位脱塩基部分を含む。
Aは結合部分であり、
Bはポリヌクレオチドであり、
Cはポリマーであり、
Xは単結合または第1のリンカーであり、
Yは単結合または第2のリンカーであり、
Lは単結合または第3のリンカーであり、
Dはエンドソーム溶解性部分であり、および、
nは0から1までの整数であり、および、
ここで、ポリヌクレオチドは、少なくとも1つの2’修飾されたヌクレオチド、少なくとも1つの修飾されたヌクレオチド間結合、あるいは少なくとも1つの逆位脱塩基部分を含み、および、Dは、A、B、あるいはCのいかなる場所にも抱合する。
いくつかの実施形態において、本明細書に記載される分子(例えば、治療用分子)は、ポリ核酸分子とポリマーに抱合した結合部分を含む。いくつかの実施形態において、分子(例えば、治療用分子)は式(I)に係る分子を含み、
Aは結合部分であり、
Bはポリヌクレオチドであり、
Cはポリマーであり、
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、および、
ここで、ポリヌクレオチドは、少なくとも1つの2’修飾されたヌクレオチド、少なくとも1つの修飾されたヌクレオチド間結合、あるいは少なくとも1つの逆位脱塩基部分を含む。
Aは結合部分であり、
Bはポリヌクレオチドであり、
Cはポリマーであり、
Xは単結合または第1のリンカーであり、
Yは単結合または第2のリンカーであり、
Lは単結合または第3のリンカーであり、
Dはエンドソーム溶解性部分であり、および、
cは0から1までの整数であり、および、
ここで、ポリヌクレオチドは、少なくとも1つの2’修飾されたヌクレオチド、少なくとも1つの修飾されたヌクレオチド間結合、あるいは少なくとも1つの逆位脱塩基部分を含み、および、Dは、A、B、あるいはCのいかなる場所にも抱合する。
Aは結合部分であり、
Bはポリヌクレオチドであり、
Cはポリマーであり、
Dはエンドソーム溶解性部分であり、
Xは単結合または第1のリンカーであり、
Yは単結合または第2のリンカーであり、
Lは単結合または第3のリンカーであり、
aとbは独立して1から3までの整数であり、
cは0から3までの整数であり、および、
nは0から10までの整数であり、および、
ここで、ポリヌクレオチドは、少なくとも1つの2’修飾されたヌクレオチド、少なくとも1つの修飾されたヌクレオチド間結合、あるいは少なくとも1つの逆位脱塩基部分を含み、Aは、B、C、あるいはD上のいかなる場所でも抱合し、Bは、A、C、あるいはD上のいかなる場所でも抱合し、Cは、A、B、あるいはD上のいかなる場所でも抱合し、および、Dは、A、B、あるいはC上のいかなる場所でも抱合する。
Aは結合部分であり、
Bはポリヌクレオチドであり、
Cはポリマーであり、
Dはエンドソーム溶解性部分であり、
Xは単結合または第1のリンカーであり、
Yは単結合または第2のリンカーであり、
Lは単結合または第3のリンカーであり、
aとbは独立して1から3までの整数であり、
cは0から3までの整数であり、
nは0から10までの整数であり、および、
mは1-3までの整数であり、および、
ここで、ポリヌクレオチドは、少なくとも1つの2’修飾されたヌクレオチド、少なくとも1つの修飾されたヌクレオチド間結合、あるいは少なくとも1つの逆位脱塩基部分を含み、Cは、BあるいはD上のいかなる場所でも抱合し、および、Dは、BあるいはC上のいかなる場所でも抱合する。
いくつかの実施形態において、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(あるい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。典型的な成長因子はc-Sisを含んでいる。典型的な受容体チロシンキナーゼは表皮成長因子受容体(EGFR)、血小板由来増殖因子受容体(PDGFR)、血管内皮細胞増殖因子受容体(VEGFR)、およびHER2/neuを含んでいる。典型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のエブル遺伝子を含んでいる。典型的な細胞質セリン/トレオニンキナーゼは、Rafキナーゼとサイクリン依存性キナーゼを含んでいる。典型的な制御性GTPアーゼは、KRASなどのタンパク質のRasファミリーを含む。典型的な転写因子はMYC遺伝子を含んでいる。いくつかの例では、本明細書に記載される癌遺伝子は、成長因子または分裂促進因子から選択された癌遺伝子、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、あるいは転写因子を含む。いくつかの実施形態において、ポリ核酸分子は、成長因子または分裂促進因子から選ばれた癌遺伝子、受容体チロシンキナーゼ、細胞質のチロシンキナーゼ、細胞質のセリン/トレオニンキナーゼ、制御性のGTPアーゼあるいは転写因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。
Kirstenラット肉腫ウイルスの癌遺伝子ホモログ(GTPアーゼKRas、V-Ki-ras2 Kirstenラット肉腫ウイルスの癌遺伝子ホモログ、あるいは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、様々な環境上のトリガー(例えば、細胞ストレス、紫外線、熱ショック、あるいはイオン化照射)下での成長停止、アポプトーシス、および複製老化を引き起こすのと同様に、細胞周期進行を調節する。場合によっては、KRAS遺伝子の突然変異が癌の発生にリンクされている一方、野性型KRAS遺伝子は様々なタイプの癌で腫瘍進行中に頻繁に失われることを示された。いくつかの例では、KRAS増幅も、癌の発生に関与してきた(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あるいは特定のクラスの阻害剤に対する抵抗性を獲得した難治性癌に関連する。
表皮成長因子受容体(EGFR、ErBb-1、あるいはHER1)は、膜貫通性チロシンキナーゼ受容体と、HER2/c-neu(ErBb-2)、Her3(ErBb-3)、およびHer4(ErBb-4)も含む受容体のErbBファミリーのメンバーである。いくつかの例では、EGFR突然変異は、RAS/RAF/MAPK、PI3K/AKT、および/または、JAK/STAT経路の下流の活性化を駆り立て、これは、有糸分裂、細胞増殖、およびアポプトーシスの抑制を引き起こす。加えて、野生型のEGFR遺伝子の増幅は、神経膠芽腫と非小細胞肺癌などの癌の発生に関与している(Talasila,et al.,“EGFR Wild-type Amplification and Activation Promote Invasion and Development of Glioblastoma Independent of Angiogenesis,”Acta Neuropathol.125(5):683-698(2013); Bell et al.,“Epidermal Growth Factor Receptor Mutations and Gene Amplification in Non-Small-Cell Lung Cancer: Molecular Analysis of the IDEAL/INTACT Gefitinib Trials,”J.Clinical Oncology 23(31):8081-8092 (2005))。
アンドロゲン受容体(AR)(さらにNR3C4、核受容体サブファミリー3、群C、遺伝子4としても知られている)は、関連するメンバー:エストロゲン受容体(ER)、グルココルチコイド受容体(GR)、プロゲステロン受容体(PR)、およびミネラルコルチコイド受容体(MR)と共に、核受容体スーパーファミリーのステロイドホルモン群に属する。アンドロゲン(すなわちステロイドホルモン)は、アンドロゲン受容体によるタンパク質合成と組織リモデリングを調節する。ARタンパク質は、標的遺伝子発現を調節するリガンド誘導可能なジンクフィンガー転写因子である。AR遺伝子中の突然変異の存在は、いくつかのタイプの癌(例えば、前立腺癌、乳癌、膀胱癌、あるいは食道癌)で観察され、いくつかの例では、転移の進行に関連付けられている。
カテニンベータ-1(CTNNB1、β-カテニン、あるいはベータ-カテニンとしても知られている)は、カテニンタンパク質ファミリーのメンバーである。ヒトでは、それはCTNNB1遺伝子によってコードされ、その二元機能-細胞間接着と遺伝子転写は知られている。ベータ-カテニンはカドヘリンベースの接着結合の不可欠な構造成分で、細胞間の細胞の成長と接着を調節し、アクチン細胞骨格を固定する。ある例では、ベータ-カテニンは、いったん上皮シートが完了すると、細胞に分割することをやめさせる接触阻害シグナルを送信することに関与する。ベータ-カテニンはWntシグナル伝達経路の重要な核エフェクターでもある。いくつかの例では、ベータ-カテニンの構造的特性とシグナル伝達特性の不均衡は、疾患や、癌などの悪性腫瘍に関係する無秩序な成長を引き起こす。例えば、ベータ-カテニンの過剰発現は、胃癌などの癌に関連付けられている(Suriano、et al.、“Beta-catenin(CTNNB1) gene amplification: a new mechanism of protein overexpression in cancer,” Genes Chromosomes Cancer 42(3): 238-246(2005))。場合によっては、CTNNB1遺伝子中の突然変異は、癌の発生(例えば、結腸癌、黒色腫、肝細胞癌、卵巣癌、子宮内膜癌、髄芽腫毛母腫、あるいは前立腺癌)に関連付けられており、いくつかの例では、転移の進行に関連付けられている。さらなる例では、CTNNB1遺伝子中の突然変異は、外部刺激を与えることなくベータ-カテニンを核へ移動させ、かつ、その標的遺伝子の転写を絶えず駆り立てる。場合によっては、罹患した細胞の以前の上皮の表現型を侵襲性の間葉のような型に変えるベータ-カテニンの可能性が転移形成に寄与する。
ヒポキサンチン-グアニンホスホリボシルトランスフェラーゼ(HGPRT)は、イノシン一リン酸に対するヒポキサンチンの転換とグアノシン一リン酸に対するグアニンの転換を触媒するトランスフェラーゼである。HGPRTはヒポキサンチンホスホリボシルトランスフェラーゼ1(HPRT1)遺伝子によってコードされる。
いくつかの実施形態において、ポリ核酸分子は、表1、4、7、8、あるいは10で例証された標的配列にハイブリダイズする配列を含む。いくつかの例では、ポリ核酸分子はBである。いくつかの例では、ポリ核酸分子Bは、表1で例証された標的配列(KRAS標的配列)にハイブリダイズする配列を含む。いくつかの例では、ポリ核酸分子Bは、表4で例証された標的配列(EGFR標的配列)にハイブリダイズする配列を含む。場合によっては、ポリ核酸分子Bは、表7で例証された標的配列(AR標的配列)にハイブリダイズする配列を含む。場合によっては、ポリ核酸分子Bは、表8で例証された標的配列(β-カテニン標的配列)にハイブリダイズする配列を含む。さらなる例では、ポリ核酸分子Bは、表10で例証された標的配列(PIK3CAとPIK3CBの標的配列)にハイブリダイズする配列を含む。
いくつかの実施形態において、本明細書に記載されたポリ核酸分子はRNAまたはDNAを含む。場合によっては、ポリ核酸分子はRNAを含む。いくつかの例では、RNAは低分子干渉RNA(siRNA)、低分子ヘアピン型RNA(shRNA)、マイクロRNA(miRNA)、二本鎖RNA(dsRNA)、転移RNA(tRNA)、リボソームRNA(rRNA)、あるいはヘテロ核RNA(hnRNA)を含む。いくつかの例では、RNAはshRNAを含む。いくつかの例では、RNAはmiRNAを含む。いくつかの例では、RNAはdsRNAを含む。いくつかの例では、RNAはtRNAを含む。いくつかの例では、RNAはrRNAを含む。いくつかの例では、RNAはhnRNAを含む。いくつかの実施形態において、RNAはsiRNAを含む。いくつかの例では、ポリ核酸分子はsiRNAを含む。場合によっては、BはsiRNAを含む。
いくつかの実施形態において、ポリ核酸分子は結合部分に抱合する。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、炭水化物、ポリエチレングリコールおよびポリプロピレングリコールなどのポリマー、同様に、これらのクラスのすべての物質のアナログまたは誘導体を含む。結合部分のさらなる例としては、限定されないが、コレステロールなどのステロイド、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、不飽和の、飽和した、あるいは置換を含む)、酵素基質、ビオチン、ジゴキシゲニン、および多糖類を含む。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、さらにポリマーと、随意にエンドソーム溶解性部分と抱合する。
いくつかの実施形態において、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、マウス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、一価のFab’、二価のFab2、F(ab)’3フラグメント、単鎖可変フラグメント(scFv)、ビス-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(triabody)、テトラボディ(tetrabody)、ジスルフィド安定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、あるいはその化学修飾された誘導体を含む。
いくつかの実施形態において、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に、本明細書に記載される結合部分に、あるいはこれらの組み合わせで抱合する。いくつかの例では、ポリマー部分Cはポリ核酸分子に抱合する。場合によっては、ポリマー部分Cは結合部分に抱合する。他の場合には、ポリマー部分Cはポリ核酸分子-結合部分分子に抱合する。さらなる場合には、図1に例証されるように、および治療分子プラットフォームの段落で議論されるように、ポリマー部分Cは抱合する。
いくつかの実施形態では、式(I):A-X-B-Y-Cの分子はさらに、追加の抱合部分を含む。いくつかの例では、追加の抱合部分はエンドソーム溶解性部分である。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、リソソーム、小胞体(ER)、ゴルジ体、微小管、ペルオキシソーム、あるいは細胞を含む他の小胞性本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などの細胞区画の放出成分である。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、あるい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。他の場合には、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。
いくつかの実施形態では、式(I):A-X-B-Y-Cの分子はさらに、エンドソーム溶解性ポリペプチドと抱合する。場合によっては、エンドソーム溶解性ポリペプチドは、pH依存性の膜活性なペプチドである。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性である。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、メイシン(meucin)、あるいはこれらの誘導体を含む。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メイシン(meucin)またはその誘導体を含む。
いくつかの実施形態では、式(I):A-X-B-Y-Cの分子はさらに、エンドソーム溶解性ポリマーと抱合する。本明細書で使用されるように、エンドソーム溶解性ポリマーは、線形、分岐ネットワーク、星形、櫛形、あるいははしご型のタイプのポリマーを含む。いくつかの例では、エンドソーム溶解性ポリマーは2つ以上の異なるタイプのモノマーを含む、ホモポリマーまたはコポリマーである。場合によっては、エンドソーム溶解性ポリマーはポリカチオンポリマーである。他の場合には、エンドソーム溶解性ポリマーはポリアニオンポリマーである。
いくつかの実施形態において、エンドソーム溶解性部分は脂質(例えば、膜融合脂質)である。いくつかの実施形態、式(I):A-X-B-Y-Cの分子はさらに、エンドソーム溶解性脂質(例えば、膜融合脂質)と抱合する。典型的な膜融合脂質としては、1,2-ジレオイル-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(DLink-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)が挙げられる。
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(I):A-X-B-Y-Cの分子はさらに、エンドソーム溶解性小分子と抱合する。エンドソーム溶解性部分として適切な典型的な少分子は、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(amopyroquines)、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、あるいはこれらの組み合わせを含む。いくつかの例では、キノリンエンドソーム溶解性部分は、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;リン酸ヒドロキシクロロキン;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-メトキシキノリン二塩酸塩;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-アルファ,アルファ’-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-アルファ,アルファ’-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-アルファ,アルファ’-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’-ペンタメチレンジキノリニウム(diquinoleinium)ジヨウ化物;8-キノリノール硫酸塩およびアミノ、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、ならびにビニルの誘導体またはそのアナログを含む。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)と米国特許第5,736,557において記載される小分子である。
いくつかの実施形態において、1つ以上のエンドソーム溶解性部分は、少なくとも1つの結合部分、少なくとも1つのポリヌクレオチド、少なくとも1つのポリマー、あるいはその任意の組み合わせを含む分子に抱合する。いくつかの例では、エンドソーム溶解性部分は式(II)にしたがって抱合し、
Bはポリヌクレオチドであり;
Cはポリマーであり;
Xは単結合または第1のリンカーであり;
Yは単結合または第2のリンカーであり;
Lは単結合または第3のリンカーであり;
Dはエンドソーム溶解性部分であり;
および、cは1という整数であり;
および、ここで、ポリヌクレオチドは、少なくとも1つの2’修飾ヌクレオチド、少なくとも1つの修飾ヌクレオチド間の結合、または、少なくとも1つの逆位の脱塩基部分を含む。
Bはポリヌクレオチドであり;
Xは単結合または第1のリンカーであり;
Lは単結合または第3のリンカーであり;
および、Dはエンドソーム溶解性部分であり;
および、ここで、ポリヌクレオチドは、少なくとも1つの2’修飾ヌクレオチド、少なくとも1つの修飾ヌクレオチド間の結合、または、少なくとも1つの逆位の脱塩基部分を含む。
Bはポリヌクレオチドであり;
Cはポリマーであり;
Xは単結合または第1のリンカーであり;
Yは単結合または第2のリンカーであり;
Lは単結合または第3のリンカーであり;
Dはエンドソーム溶解性部分であり;
および、cは1という整数であり;
および、ここで、ポリヌクレオチドは、少なくとも1つの2’修飾ヌクレオチド、少なくとも1つの修飾ヌクレオチド間の結合、または、少なくとも1つの逆位の脱塩基部分を含む。
Bはポリヌクレオチドであり;
Cはポリマーであり;
Xは単結合または第1のリンカーであり;
Yは単結合または第2のリンカーであり;
Lは単結合または第3のリンカーであり;
Dはエンドソーム溶解性部分であり;
および、cは1という整数であり;
および、ここで、ポリヌクレオチドは、少なくとも1つの2’修飾ヌクレオチド、少なくとも1つの修飾ヌクレオチド間の結合、または、少なくとも1つの逆位の脱塩基部分を含む。
いくつかの実施形態では、本明細書に記述された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、リンカーはペプチドリンカーである。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、ホモ二官能性クロスリンカー、ヘテロ二官能性クロスリンカーなどを含んでいる。いくつかの例では、リンカーは痕跡のないリンカー(traceless linker)(またはゼロレングスリンカー(zero-length linker))である。いくつかの例では、リンカーは、非ポリマー性リンカーである。いくつかの場合には、リンカーは、非ペプチドリンカー、または、アミノ酸残基を包含していないリンカーである。
いくつかの実施形態では、ポリ核酸分子およびポリマーに結合された結合部分を含む本明細書に記載の組成物または医薬製剤は、疾患または障害の処置のために使用される。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、本明細書に記載の組成物または医薬製剤は、疾患または障害の処置のために免疫療法として使用される。いくつかの例では、免疫療法は免疫腫瘍治療である。
いくつかの実施形態では、本明細書に記述された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、癌は血液系腫瘍である。いくつかの例では、癌は再発性癌または難治性癌、または転移性癌である。いくつかの例では、固形腫瘍は再発性固形腫瘍または難治性固形腫瘍、または転移性固形腫瘍である。いくつかの場合には、血液系腫瘍は、再発血液系腫瘍または難治性血液系腫瘍、または転移性である。
いくつかの実施形態では、本明細書に記載の組成物または医薬製剤は、疾患または障害の処置のために免疫療法として使用される。いくつかの例では、免疫療法は免疫腫瘍治療である。いくつかの例では、免疫腫瘍治療は、能動型、受動型または併用型の(能動型および受動型)方法に分類される。能動型の免疫腫瘍治療の方法では、例えば、腫瘍関連抗原(TAA)が免疫系に提示され、これらのTAAを提示する癌細胞に対する攻撃を引き起こす。いくつかの例では、能動型の免疫腫瘍治療の方法は、腫瘍標的化剤および/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、インサイチュワクチン接種および/または細胞系または非細胞系の(例えば、樹状細胞系、腫瘍細胞系、抗原、抗イディオタイプ、DNA、またはベクター系)ワクチンなどのワクチン、を含む。いくつかの例では、細胞系のワクチンは、次いで患者自身の癌によって活性化される、患者自身の免疫系から得られた活性化免疫細胞を用いて生成されるワクチンである。いくつかの例では、能動型の免疫腫瘍治療は、さらに、非特異的能動免疫療法および特異的能動免疫療法に細分される。いくつかの例では、非特異的能動免疫療法は、サイトカイン、および/または、一般的な免疫系応答を誘導する他の細胞シグナル伝達構成要素、を利用する。いくつかの場合には、特異的能動免疫療法は、特異的なTAAを利用して免疫応答を誘発する。
いくつかの実施形態では、本明細書に記載された医薬製剤は、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、局所、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被験体に投与される。いくつかの例では、本明細書に記載の医薬組成物は、非経口(例えば、静脈内、皮下、筋肉内)投与のために製剤される。他の例では、本明細書に記載の医薬組成物は、経口投与のために製剤される。いくつかの実施形態では、本明細書に記載の医薬組成物は、直腸内投与のために処方される。
いくつかの実施形態では、本明細書に記載の医薬組成物は、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、またはそれより多く、投与される。医薬組成物は、日常的に、毎日、隔日、週5日、週1回、隔週、月2週間、月3週間、月1回、月2回、月3回、またはそれより多く、投与される。医薬組成物は、少なくとも1か月間、2か月間、3か月間、4か月間、5か月間、6か月間、7か月間、8か月間、9か月間、10か月間、11か月間、12か月間、18か月間、2年間、3年間、またはそれより長く、投与される。
本明細書に開示されるのは、特定の実施形態では、本明細書に記載の組成物および方法の1つ以上との使用のためのキットおよび製品である。このようなキットは、バイアル、チューブなどの1つ以上の容器を受け容れるために仕切られている運搬装置(carrier)、包装または容器を含み、この容器の各々は、本明細書に記載の方法で使用される、個別の要素のうちの1つを含む。適切な容器には、例えば、ボトル、バイアル、シリンジ、および試験管が含まれる。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。
これらの実施例は、説明の目的でのみ提供され、本明細書に提供される特許請求の範囲を限定するものではない。
表1、4、7、8および10は、本明細書に記載の標的配列を示す。表2、3、5、6、9、12は、本明細書に記載のポリ核酸分子配列を示す。
● 大文字(N)=2’-OH(リボ);
● 小文字(n)=2’-O-Me(メチル);
● dN=2’-H(デオキシ);
● Nf=2’-F(フルオロ);
● s=ホスホロチオエート骨格修飾;
● iB=逆位脱塩基性(inverted abasic)
パニツムマブは、同じ細胞株においてインビトロ及びインビボで細胞増殖を阻害するとも示された。
相補性の19の塩基及び3’ジヌクレオチドオーバーハングを持つ21量体の二本鎖を、ヒトEGFRに対して設計した。ガイド/アンチセンス鎖の配列は、EGFRのヒトmRNAの転写のための塩基位置333で始まる遺伝子配列に相補的であった(ACUCGUGCCUUGGCAAACUUU;SEQ ID NO:2082)。塩基、糖、及びリン酸塩の修飾を使用して、二本鎖の潜在能を最適化し且つ免疫原性を減らした。siRNA一本鎖を全て、標準のホスホロアミダイト化学を使用して固相上で完全に組み立てて、HPLC上で精製した。精製された一本鎖を二重にし、二本鎖siRNAを得た。パッセンジャー鎖は、2つの抱合ハンドル、5’末端にC6-NH2及び3’末端にC6-SHを含んでいた。両方の抱合ハンドルを、ホスホロチオエートで逆位脱塩基のホスホロチオエートリンカーを介してsiRNAパッセンジャー鎖に接続した。化学構造は実施例9を参照されたい。
相補性の19の塩基及び3’ジヌクレオチドオーバーハングを持つ21量体の二本鎖を、ヒトEGFRに対して設計した。ガイド/アンチセンス鎖の配列は、EGFRのヒトmRNAの転写のための塩基位置333で始まる遺伝子配列に相補的であった(ACUCGUGCCUUGGCAAACUUU;SEQ ID NO:2082)。塩基、糖、及びリン酸塩の修飾を使用して、二本鎖の潜在能を最適化し且つ免疫原性を減らした。siRNA一本鎖を全て、標準のホスホロアミダイト化学を使用して固相上で完全に組み立てて、HPLC上で精製した。精製された一本鎖を二重にし、二本鎖siRNAを得た。パッセンジャー鎖は、2つの抱合ハンドル、5’末端にC6-NH2及び3’末端にC6-SHを含んでいた。両方の抱合ハンドルを、ホスホロチオエートで逆位脱塩基のホスホロチオエートリンカーを介してsiRNAパッセンジャー鎖に接続した。化学構造は実施例9を参照されたい。
上の図72Aに例示されるように、切断可能なジスルフィドリンカー(leaker)がより安定したSMCCのリンカーの代わりに使用された時、siRNAの腫瘍組織蓄積が減少した。図72Bに例示されるように、両方のリンカー戦略が、スクランブルされた対照に比べてHCC827腫瘍細胞においてEGFR mRNAノックダウンを産生することが可能であった。
野生型のメスのCD-1マウスの群(n=4)を、siRNA抱合体の1回の静脈内(i.v.)尾静脈注射で処置した。処置群は0.5mg/kgを受け(siRNAの重量に基づく)、全ての群は5.0mL/kgの用量を投与された。表43は研究設計をより詳細に例示している。非終末期の血液サンプルを、眼窩後方の網状組織の穿刺を介して投与の5、30、及び180分後に集め、遠心分離して、PK分析のために血漿を生成した。投与の24、96、又は168時間後にCO2窒息によってマウスを屠殺した。終末期の血液サンプルを、心臓の穿刺を介して集め、処理することで、PK分析のために血漿を生成した。血漿siRNA濃度の定量化を、実施例2に記載されるようなステム-ループqPCRアッセイを使用して判定した。siRNAのアンチセンス鎖を、配列に特異的なステム-ループRTプライマーを用いるTaqMan MicroRNA逆転写キットを使用して、逆転写した。その後、RT工程からのcDNAをリアルタイムPCRのために利用し、Ct値を、標準曲線に由来する一次方程式を使用して血漿又は組織濃度に転換させた。抗体の血漿濃度を、ELISAアッセイを使用して判定した。
その後、RT工程からのcDNAをリアルタイムPCRのために利用し、Ct値を、標準曲線に由来する一次方程式を使用して血漿又は組織濃度に転換させた。
相補性の19の塩基及び3’ジヌクレオチドオーバーハングを持つ21量体の二本鎖を、ヒトEGFRに対して設計した。ガイド/アンチセンス鎖の配列は、EGFRのヒトmRNAの転写のための塩基位置333で始まる遺伝子配列に相補的であった(ACUCGUGCCUUGGCAAACUUU;SEQ ID NO:2082)。塩基、糖、及びリン酸塩の修飾を使用して、二本鎖の潜在能を最適化し且つ免疫原性を減らした。siRNA一本鎖を全て、標準のホスホロアミダイト化学を使用して固相上で完全に組み立てて、HPLC上で精製した。精製された一本鎖を二重にし、二本鎖siRNAを得た。パッセンジャー鎖は、2つの抱合ハンドル、5’末端にC6-NH2及び3’末端にC6-SHを含んでいた。両方の抱合ハンドルを、ホスホロチオエートで逆位脱塩基のホスホロチオエートリンカーを介してsiRNAパッセンジャー鎖に接続した。化学構造は実施例9を参照されたい。
100-350mm3の体積の側腹部HCC827腫瘍を皮下に持つメスのNCr nu/nuマウスの群(n=3)をsiRNA抱合体の1回の静脈内(i.v.)尾静脈注射で処置し、同じマウスの対照群(n=4)はビヒクル対照としてPBSの1回のi.v.注射を受けた。コレステロール-siRNA抱合体を受けた処置群に、5mg/kgで投与した(siRNAの重量に基づく)。幾つかの処置群は、特定されたペプチド:siRNAのモル比でコレステロール-ペプチドの抱合体を受け、そこではchol-siRNA及びchol-ペプチドの抱合体は全て溶液中に共に混合し、同時に注入された。全ての群(処置及び対照)に、5mL/kgの用量を投与した。表58は研究設計をより詳細に示しており、抱合体の合成及び特徴付けに対する相互参照を提供する。投与の24、72、又は144時間後にCO2窒息によってマウスを屠殺した。50mg片の腫瘍、肝臓、腎臓、及び肺を集め、液体窒素中で急速凍結した。mRNAノックダウンの分析及びsiRNAの定量化を、実施例2-7に記載されるように実行した。
100-350mm5の体積の側腹部HCC827腫瘍を皮下に持つメスのNCr nu/nuマウスの群(n=3)を、48時間毎に分割されるsiRNA抱合体の3回の静脈内(i.v.)尾静脈注射で処置し、同じマウスの対照群(n=5)は、同じ投薬スケジュールでビヒクル対照としてPBSの3回のi.v.注射を受けた。コレステロール-siRNA抱合体を受けた処置群に、5mg/kgで投与した(siRNAの重量に基づく)。幾つかの処置群は、特定されたペプチド:siRNAのモル比でコレステロール-ペプチドの抱合体を受け、そこではchol-siRNA及びchol-ペプチドの抱合体は全て溶液中に共に混合し、同時に注入された。全ての群(処置及び対照)に、5mL/kgの用量を投与した。表59は研究設計をより詳細に記載しており、抱合体の合成及び特徴付けに対する相互参照を提供する。投与後24又は96時間で、CO2窒息によってマウスを屠殺した。50mg片の腫瘍、肝臓、腎臓、及び肺を集め、液体窒素中で急速凍結した。mRNAノックダウンの分析及びsiRNAの定量化を、実施例2-7に記載されるように実行した。
100-350mm5の体積の側腹部HCC827腫瘍を皮下に持つメスのNCr nu/nuマウスの群(n=5)をsiRNA抱合体の1回の静脈内(i.v.)尾静脈注射で処置し、同じマウスの対照群(n=5)はビヒクル対照としてPBSの1回のi.v.注射を受けた。EGFR抗体-siRNA-PEGの抱合体を受けた処置群に、0.5mg/kgで投与し(siRNAの重量に基づく)、EGFR抗体-メリチンも受けた群は、EGFR抗体-siRNAとEGFR抗体-メリチンとの間で一致したEGFR-Abの用量を受けた。全ての群(処置及び対照)に、5mL/kgの用量を投与した。表60は研究設計をより詳細に記載しており、抱合体の合成及び特徴付けに対する相互参照を提供する。投与後96時間で、CO2窒息によってマウスを屠殺した。50mg片の腫瘍、腎臓、及び肺を集め、液体窒素中で急速凍結した。mRNAノックダウンの分析及びsiRNAの定量化を、実施例2-7に記載されるように実行した。
摂取の1週間後にHep3B腫瘍を肝臓内に持つメスのNCr nu/nuマウスの群(n=11)を、コレステロール-siRNAの抱合体の9回の静脈内(i.v.)又は皮下(s.c.)の注射(TIW)で処置し、同じマウスの対照群(n=11)は、ビヒクル対照としてPBSの9回のi.v.尾部静脈注射を受けた(TIWでも投与)。chol-CTNNB1を受けた処置群に、5mg/kgで投与した。全ての群(処置及び対照)に、6.25mL/kgの用量を投与した。表61は研究設計をより詳細に記載しており、抱合体の合成及び特徴付けに対する相互参照を提供する。非終末期の血液サンプルを、眼窩後方の網状組織の穿刺を介して週に1回集められ、処理することで、アルファ-胎児タンパク(AFP)測定のための血清を生成した。最後の投与後24時間で、CO2窒息によってマウスを屠殺した。50mg片の腫瘍を持つ肝臓を集め、液体窒素中で急速凍結した。mRNAノックダウン分析を上述のように実行した。メーカーの指示に従い、ヒトアルファ-胎児タンパクDuoSet ELISAキット(R&D Systems)を使用してAFPを定量化した。
Claims (51)
- 少なくとも1つの2’修飾されたヌクレオチドは、2’-O-メチル、2’-O-メトキシエチル(2’-O-MOE)、2’-O-アミノプロピル、2’-デオキシ、T-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)、T-O-ジメチルアミノエチルオキシエチル(2’-O-DMAEOE)、あるいは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を含む、請求項1に記載の分子。
- 少なくとも1つの2’修飾されたヌクレオチドはロックド核酸(LNA)あるいはエチレン核酸(ENA)を含む、請求項1または2に記載の分子。
- 少なくとも1つの修飾されたヌクレオチド間結合は、ホスホロチオエート結合あるいはホスホロジチオエート結合を含む、請求項1-3のいずれか1つに記載の分子。
- 少なくとも1つの逆位脱塩基部分は少なくとも1つの末端にある、請求項1に記載の分子。
- ポリヌクレオチドは一本鎖を含む、請求項1-5のいずれか1つに記載の分子。
- ポリヌクレオチドは、二重らせん構造のポリ核酸分子を形成するために、第1のポリヌクレオチドと、第1のポリヌクレオチドにハイブリダイズされた第2のポリヌクレオチドとを含む、請求項1-5のいずれか1つに記載の分子。
- 第2のポリヌクレオチドは少なくとも1つの修飾を含む、請求項7に記載の分子。
- 第1のポリヌクレオチドと第2のポリヌクレオチドはRNA分子である、請求項1-8のいずれか1つに記載の分子。
- 第1のポリヌクレオチドは、SEQ ID NO:16-75、452-1955、1956-1962、1967-2002、2013-2032、あるいは2082-2109、または2117に対して少なくとも80%、85%、90%、95%、96%、97%、98%、99%、あるいは100%の配列同一性を有する配列を含む、請求項1-9のいずれか1つに記載の分子。
- 第2のポリヌクレオチドは、SEQ ID NO:16-75、452-1955、1956-1962、1967-2002、2013-2032、あるいは2117に対して少なくとも80%、85%、90%、95%、96%、97%、98%、99%、あるいは100%の配列同一性を有する配列を含む、請求項1-10のいずれか1つに記載の分子。
- Yは非ポリマー性リンカー基である、請求項1-11のいずれか1つに記載の分子。
- Xは単結合である、請求項1-12のいずれか1つに記載の分子。
- XはC1-C6アルキル基である、請求項1-12のいずれか1つに記載の分子。
- YはC1-C6アルキル基である、請求項1-14のいずれか1つに記載の分子。
- Xは、C1-C6アルキル基に随意に抱合した、ホモ二官能性リンカーあるいはヘテロ二官能性リンカーである、請求項1-14のいずれか1つに記載の分子。
- Yはホモ二官能性リンカーまたはヘテロ二官能性リンカーである、請求項1-14のいずれか1つに記載の分子。
- 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、単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)、あるいはラクダ科抗体またはその結合フラグメントを含む、請求項1-17のいずれか1つに記載の分子。
- Cはポリエチレングリコールである、請求項1-18のいずれか1つに記載の分子。
- Cは約1000Da、2000Da、あるいは5000Daの分子量を有する、請求項1-19のいずれか1つに記載の分子。
- A-XはBの5’末端へ抱合し、Y-CはBの3’末端に抱合する、請求項1-20のいずれか1つに記載の分子。
- Y-CはBの5’末端へ結合し、A-XはBの3’末端へ抱合する、請求項1-20のいずれか1つに記載の分子。
- Dをさらに含む、請求項1-22のいずれか1つに記載の分子。
- DはCまたはAに抱合する、請求項23に記載の分子。
- Dは式(II)に従って式(I)の分子に抱合し、
Aは抗体あるいはその結合フラグメントであり、
Bはポリヌクレオチドであり、
Cはポリマーであり、
Xは単結合または第1の非ポリマー性リンカーであり、
Yは単結合または第2のリンカーであり、
Lは単結合または第3のリンカーであり、
Dはエンドソーム溶解性部分であり、
および、cは0から1までの整数であり、
ここで、ポリヌクレオチドは、少なくとも1つの2’修飾されたヌクレオチド、少なくとも1つの修飾されたヌクレオチド間結合、あるいは少なくとも1つの逆位脱塩基部分を含み、
ここで、AとCは同じ末端ではBに結合せず、
および、ここで、DはAまたはCの任意の場所に、あるいはBの末端に抱合する、請求項23または24に記載の分子。 - DはINF7またはメリチンである、請求項23-25のいずれか1つに記載の分子。
- Dはエンドソーム溶解性ポリマーである、請求項23-25のいずれか1つに記載の分子。
- LはC1-C6アルキル基である、請求項25に記載の分子。
- Lはホモ二官能性リンカーまたはヘテロ二官能性リンカーである、請求項25に記載の分子。
- 少なくとも第2の結合部分をさらに含む、請求項1-29のいずれか1つに記載の分子。
- 少なくとも第2の結合部分はAに、Bに、あるいはCに抱合する、請求項30に記載の分子。
- 少なくとも第2の結合部分はコレステロールである、請求項30または31に記載の分子。
- 少なくとも追加のポリヌクレオチドBをさらに含む、請求項1-32のいずれか1つに記載の分子。
- 少なくとも追加のポリヌクレオチドBはAに、Bに、あるいはCに抱合する、請求項33に記載の分子。
- さらに少なくとも追加のポリマーCを含む、請求項1-34のいずれか1つに記載の分子。
- 少なくとも追加のポリマーCはAに、Bに、あるいはCに抱合する、請求項35に記載の分子。
- 請求項1-36に記載された分子と
薬学的に許容可能な賦形剤とを含む、医薬組成物。 - 医薬組成物はナノ粒子製剤として製剤される、請求項37に記載の医薬組成物。
- 医薬組成物は、非経口、経口、鼻腔内、バッカル、直腸、または経皮的な投与のために製剤される、請求項37または38に記載の医薬組成物。
- 請求項1-36に記載の分子を含む組成物を患者に投与する工程を含む、患者の疾患または障害を処置する方法。
- 疾患または障害は癌である、請求項40に記載の方法。
- 癌は固形腫瘍である、請求項41に記載の方法。
- 癌は血液悪性腫瘍である、請求項41に記載の方法。
- 癌は、KRASに関連する癌、EGFRに関連する癌、ARに関連する癌、(β)-カテニンに関連する癌、PIK3Cに関連する癌、あるいはMYCに関連する癌を含む、請求項40-43のいずれか1つに記載の方法。
- 癌は、膀胱癌、乳癌、大腸癌、子宮内膜癌、食道癌、多形膠芽腫、頭頚部癌、腎癌、肺癌、卵巣癌、膵癌、前立腺癌、あるいは甲状腺癌を含む、請求項40-44のいずれか1つに記載の方法。
- 癌は急性骨髄性白血病、CLL、DLBCL、あるいは多発性骨髄腫を含む、請求項40-44のいずれか1つに記載の方法。
- 方法は免疫腫瘍治療である、請求項40に記載の方法。
- 患者の初代細胞中の標的遺伝子の発現を阻害する方法であって、請求項1-36に記載の分子を初代細胞に投与する工程を含む、方法。
- 前記方法がインビボの方法である、請求項48に記載の方法。
- 患者はヒトである、請求項40-49に記載の方法。
- 患者の疾患または障害の処置のための、請求項1-36に記載の分子を含む免疫腫瘍治療。
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