JP7476171B2 - 免疫チェックポイント阻害のための組成物および方法 - Google Patents
免疫チェックポイント阻害のための組成物および方法 Download PDFInfo
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Description
この出願は、2018年9月7日に出願された米国特許出願第62/728,459号、および2019年1月10日に出願された米国特許出願第62/790,953号の恩典を主張し、それらの特許出願の全内容は参照により本明細書に組み入れられている。
この発明は、国立衛生研究所により授与された認可番号CA163461による政府支援でなされた。政府は、本発明において一定の権利を有する。
免疫チェックポイント分子、例えば、プログラム細胞死1リガンド1(PD-L1)を標的化する阻害性核酸、例えば、siRNAに連結されたナノ粒子を用いる、癌、例えば、膵癌を処置するための治療的組成物および方法が本明細書に記載される。
約2nm~約200nmの間(例えば、約10nm~約30nmの間、約5nm~約25nmの間、約10nm~約25nmの間、約15nm~約25nmの間、約20nmから約25nmの間、約25nm~約50nmの間、約50nmから約200nmの間、約70nmから約200nmの間、約80nmから約200nmの間、約100nmから約200nmの間、約140nm~約200nm、および約150nm~約200nmの間)の直径を有し、かつポリマーコーティングと、ヒト免疫チェックポイント分子、例えば、PD-L1、PD-1、CTLA-4(細胞傷害性Tリンパ球関連タンパク質-4(Cytotoxic T-Lymphocyte-Associated Protein-4);CD152);LAG-3(リンパ球活性化遺伝子3(Lymphocyte Activation Gene 3);CD223);TIM-3(T細胞免疫グロブリンドメインおよびムチンドメイン3(T-cell Immunoglobulin domain and Mucin domain 3);HAVCR2);TIGIT(IgおよびITIMドメインを有するT細胞免疫受容体(T-cell Immunoreceptor with Ig and ITIM domains));B7-H3(CD276);VSIR(V-set免疫調節性受容体(V-set immunoregulatory receptor)、aka VISTA、B7H5、C10orf54);BTLA(Bリンパ球およびTリンパ球アテニュエータ(B- and T-Lymphocyte Attenuator)、CD272);GARP(Glycoprotein A Repetitions Predominant;PVRIG(PVR related immunoglobulin domain containing);またはVTCN1(V-set domain containing T cell activation inhibitor 1、aka B7-H4)に相補的である、配列内に少なくとも10個(例えば、11個、12個、13個、14個、15個、16個、17個、18個、19個、20個、または21個)の連続したヌクレオチドを含有する核酸とを含有する、治療用ナノ粒子が本明細書に提供される。
PD-L1は、CD274、B7-H;B7H1;PDL1;PDCD1L1;およびPDCD1LG1としても知られている。ヒトPD-L1についての例示的な配列は、表Aに示されたNCBI GenBankアクセッション番号において提供されている。
いくつかの実施形態において、本明細書に記載された治療用ナノ粒子のいずれかは、磁性材料のコアを含有することができる(例えば、治療用磁性ナノ粒子)。いくつかの実施形態において、磁性材料または粒子は、磁場に対して応答性である反磁性、常磁性、超常磁性、または強磁性材料を含有することができる。治療用磁性ナノ粒子の非限定的例は、マグネタイト、フェライト(例えば、マンガン、コバルト、およびニッケルのフェライト)、酸化Fe(II)、およびヘマタイト、ならびにそれらの金属合金の群から選択される酸化金属を含有する磁性材料のコアを含有する。磁性材料のコアは、当技術分野において知られた方法を用いて金属塩を酸化金属へ変換することにより形成することができる(例えば、Kieslich et al., Inorg. Chem. 2011)。いくつかの実施形態において、ナノ粒子は、シクロデキストリン金または量子ドットを含有する。治療用磁性ナノ粒子を作製するために用いることができる方法の非限定的例は、Medarova et al., Methods Mol. Biol. 555:1-13, 2009;および Medarova et al., Nature Protocols 1:429-431, 2006に記載されている。追加の磁性材料、および磁性材料を作製する方法は、当技術分野において知られている。本明細書に記載された方法のいくつかの実施形態において、治療用磁性ナノ粒子の場所または局在性は、対象において画像化することができる(例えば、1回または複数の用量の治療用磁性ナノ粒子の投与後、対象において画像化される)。
本明細書に記載された治療用ナノ粒子は、コアの磁性材料を覆う(例えば、磁性材料の表面を覆う)ポリマーコーティングを含有する。ポリマー材料は、1つまたは複数の生物学的作用物質(例えば、本明細書に記載された、核酸、フルオロフォア、またはターゲティングペプチドのいずれかなど)を付着し、または結合する(coupling)のに適し得る。1つまたは複数の生物学的作用物質(例えば、核酸、フルオロフォア、またはターゲティングペプチド)は、化学的結合(coupling)(共有結合)によりポリマーコーティングに固定することができる。
提供される治療用ナノ粒子は、ナノ粒子へ共有結合性に連結されている、免疫チェックポイント分子の配列、例えば、PD-L1配列、例えば、配列番号1内の少なくとも10個(例えば、少なくとも11個、12個、13個、14個、15個、16個、17個、18個、19個、20個、21個、または22個)の連続したヌクレオチドと相補的である配列を含む少なくとも1つの核酸を含有する。いくつかの実施形態において、共有結合性に連結された核酸分子は、免疫チェックポイントタンパク質(本明細書に記載された免疫チェックポイントタンパク質のいずれか)をコードするmRNAの全部または一部と相補的である配列を含有する。例えば、共有結合性に連結された核酸は、免疫チェックポイントタンパク質(本明細書に記載された免疫チェックポイントタンパク質のいずれか)をコードするヌクレオチド配列のコード鎖の非コード領域の全部または一部と相補的であり得る。非コード領域(「5’および3’非翻訳領域」)は、遺伝子においてコード領域に隣接する5’および3’配列であり、アミノ酸へ翻訳されない。いくつかの実施形態において、治療用ナノ粒子へ共有結合性に連結された核酸は、免疫チェックポイントタンパク質(本明細書に記載された免疫チェックポイントタンパク質のいずれか)の翻訳開始コドンまたはアミノ酸1~5をコードする配列と相補的である。
いくつかの実施形態において、治療用ナノ粒子はさらに、例えば国際公開第2013/016126号パンフレットに記載されているような、共有結合性に連結されたターゲティングペプチドを含有する。用語「ターゲティングペプチド」とは、標的細胞(例えば、癌細胞)の形質膜中または形質膜上に存在する分子(例えば、タンパク質、糖、もしくは脂質、またはそれらの組合せ)によって結合されるペプチドを意味する。本明細書に記載されているように、ターゲティングペプチドは、第2の分子または組成物(例えば、本明細書に記載された治療用ナノ粒子のいずれか)へ共有結合性に連結されて、その第2の分子または組成物を標的細胞(例えば、癌細胞)へ標的化することができる。いくつかの実施形態において、第2の分子または組成物(例えば、本明細書に記載された治療用ナノ粒子のいずれか)へ共有結合性に連結されているターゲティングペプチドは、標的化された細胞による第2の分子または組成物の取り込み(例えば、エンドサイトーシスまたはピノサイトーシスによる細胞取り込み)を生じる。ターゲティングペプチドの非限定的例は本明細書に記載されている。いくつかの実施形態において、ターゲティングペプチドは、RGDペプチド、EPPTペプチド、NYLHNHPYGTVG(配列番号2)、SNPFSKPYGLTV(配列番号3)、GLHESTFTQRRL(配列番号4)、YPHYSLPGSSTL(配列番号5)、SSLEPWHRTTSR(配列番号6)、LPLALPRHNASV(配列番号7)、またはβAla-(Arg)7-Cys(配列番号8)を含有する。いくつかの実施形態において、ターゲティングペプチドは、ジスルフィド結合を含有する化学的部分を通してナノ粒子へ共有結合性に連結されている。いくつかの実施形態において、治療用ナノ粒子は、磁性である。ターゲティングペプチド、およびそれらをナノ粒子に付着させるための方法の追加の例は、当技術分野において知られており、例えば、国際公開第2013/016126号パンフレットを参照されたい。
本明細書に記載されているような治療用ナノ粒子を含有する薬学的組成物もまた本明細書に提供される。本明細書に記載されたいずれかの型の治療用ナノ粒子の2つ以上(例えば、2つ、3つ、または4つ)は、任意の組合せで薬学的組成物中に存在することができる。薬学的組成物は、当技術分野において知られた任意の様式で製剤化することができる。
本明細書に記載された治療用ナノ粒子は、癌成長を減少させることが発見された。この発見を勘案して、対象において癌を処置する方法が本明細書に提供される。これらの方法の特定の実施形態および様々な態様が下に記載されている。
方法は一般的に、腫瘍、例えば、癌を有する対象を同定することを含む。本明細書で用いられる場合、用語「癌」は、自律的成長の能力を有する細胞、すなわち、急速に増殖する細胞成長により特徴づけられる異常な状態または状況、を指す。過剰増殖性および腫瘍性疾患状態は、病的、すなわち、疾患状態を特徴づけもしくは構成するものとして、分類され得、または非病的、すなわち、正常から逸脱しているが、疾患状態に関連づけられないものとして分類され得る。一般的に、癌は、1つまたは複数の腫瘍、すなわち、異常な細胞塊の存在と関連づけられる。用語「腫瘍」は、組織病理学的型や浸潤性の段階とは関係なく、全ての型の、癌性成長もしくは発癌過程、転移性組織、または悪性形質転換した細胞、組織、もしくは器官を含むことを意図される。「病的過剰増殖性」細胞は、悪性腫瘍成長により特徴づけられる疾患状態で起こる。本研究は、膵癌に、それの憂うつな予後およびそれの転移型に対する進行の欠如を理由に、焦点をおいているが、本組成物および本方法は、固形悪性腫瘍に幅広く適用できる。したがって、癌は、任意の型の固形腫瘍であり得、その固形腫瘍には、乳癌、結腸癌、腎癌、肺癌、皮膚癌、卵巣癌、膵癌、直腸癌、胃癌、甲状腺癌、または子宮癌が挙げられるが、それらに限定されない。
本明細書に記載された方法のいずれかにおいて、治療用ナノ粒子は、医療専門家(例えば、医師、医師の助手、看護師、または検査室もしくは診療所従業員)、対象(すなわち、自己投与)、または対象の友人もしくは家族メンバーによって投与することができる。投与は、臨床設定(例えば、診療所または病院)において、介護施設において、または薬局で実施することができる。
本発明者らの治療アプローチの追加の重要な利点は、それが、標的組織における薬物生物学的利用率についての知識と治療結果とを組み合わせる、臨床的に意義のある画像ガイド処置プロトコールを開発するまたとない機会を提示するという事実に由来する。この能力は、MN-siPDL1が20nm超常磁性ナノ粒子担体と合体して、そのことが、腫瘍細胞への高効率的な送達を保証し、かつ組織におけるその蓄積が、定量的非侵襲性MRIによりモニターされ得るという事実によって、可能になる。この能力は、処置の間に薬物生物学的利用率を非侵襲性に測定する可能性を示さない全ての他の利用可能な治療アプローチの状況においては、独特である。
低分子干渉RNA(siRNA)オリゴ
pd-l1に対するsiRNAオリゴ(siPDL1;MW=13,788.9g/mol)の配列は、5’-ThioMC6-D/GGUCAACGCCACAGCGAAUUU-3’(センス配列;配列番号2)および5’-PAUUCGCUGUGGCGUUGACCUU-3’(アンチセンス配列;配列番号3)からなった。スクランブルsiRNAオリゴ(siSCR;MW=13,728.8g/mol)の配列は、5’-ThioMC6-D/UGGUUUACAUGUCGACUAAUU-3’(センス配列;配列番号4)および5’-PUUAGUCGACAUGUAAACCAUU-3’(アンチセンス配列;配列番号5)であった。両方のsiRNAは、Dharmacon(Lafayette、CO)によって設計および合成された。5’-チオール修飾因子C6ジスルフィド(5’-ThioMC6)を、磁性ナノ粒子にコンジュゲートするためにセンス配列中に導入した。
MNを、以前に発表されたプロトコール20に従って合成した。簡単に述べれば、アルゴンガスを1時間、流しながら、30mlのDextan-T10(0.3g ml-1、Pharmacosmos A/S、Holbaek、Denmark)を、1mlのFeCl3・6H2O(0.65g ml-1、Sigma、Saint Louis、MO)と混合した。1mlのFeCl2・4H2O(0.4g ml-1、Sigma)を、その混合物へ加え、15mlの冷たいNH4OH(28%、Sigma)を、その撹拌される混合物へ滴下した。温度を、ナノ粒子分散の形成を開始させるために85℃まで1時間、上昇させ、その後、室温まで冷却した。磁性ナノ粒子を、Amicon超遠心ユニット(MWCO 30kDa;Millipore、Darmstadt、Germany)を用いて20mlへ濃縮した。生じたデキストランコーティング化磁性ナノ粒子を、エピクロロヒドリン(14ml、8h、Sigma)により架橋し、その後のNH4OH(28%、60ml)の添加でアミノ化した。アミノ化磁性ナノ粒子(MN)を、透析により精製し、Amicon超遠心ユニットを用いて濃縮した。MNの性質は以下の通りであった:濃度、Feとして10.94mg ml-1;MNあたりのアミン基の数、64;緩和能(R2)、82.5mM-1秒-1;MNのサイズ、20.3±0.6nm(NanoSight LM-10システムおよびナノ粒子追跡分析ソフトウェア(Ver.3.2)、Malvern、UK)。
ナノドラッグ合成を、以前に発表されたプロトコール20に従って行った。図1Aおよび図6も参照。簡単に述べれば、MNにヘテロ二官能性リンカー N-スクシンイミジル3-[2-ピリジルジチオ]-プロピオネート(SPDP、Thermoscientific Co.、Rockford、IL)をコンジュゲートし、それを、活性化siRNAオリゴの連結のために利用した。SPDPを無水DMSO中に溶解し、MNとインキュベートし、それは、siRNAオリゴとの還元不安定性ジスルフィド連結を形成するためのピリジルジチオ基を有する。siRNAオリゴの5’-ThioMC6を、ヌクレアーゼフリーのPBS中、3%TCEP(Thermoscientific Co.、Rockford、IL)処理により活性化して、チオールを遊離させた。そのsiRNAオリゴを、酢酸アンモニウム/エタノール沈殿法を用いて精製した。TCEP活性化および精製後、各オリゴ(siPDL1およびsiSCR)を水中に溶解し、SPDP修飾MNと一晩、インキュベートして、ナノドラッグ(MN-siPDL1およびMN-siSCR)を調製した。オリゴを、2つの異なる比率でMNに加えて、電気泳動分析法20により定量化した場合、MNあたり2.1±0.4(低用量)または4.8±0.7(高用量)siRNAオリゴを組み入れるナノドラッグを得た。ナノドラッグを、毎週、新鮮に調製した。最終MN-siPDL1/SCRのサイズは、23.2±0.9nmであった。
マウス膵管腺腫PAN 02細胞株(NCI、Frederick、MD)を、10%FBS(Thermoscientific、Waltham、MA)、1%抗生物質(Invitrogen、Carlsbad、CA)、および2mM L-グルタミンを追加したRPMI 1640培地(Sigma)中で、供給会社の使用説明書通り、培養した。培地を、週3回、交換し、週1回、継代培養のためにトリプシン処理した。
一次および二次抗体を、Abcam(Cambridge、MA)から購入し、それには以下が含まれた:一次抗体として、抗CD3(カタログ番号:AB16669)、抗CD8(カタログ番号:AB25478)、抗FoxP3(カタログ番号:AB75763)、Granzyme B(カタログ番号:AB4069)、抗Ki67(カタログ番号:AB16667)、および抗PDL1(カタログ番号:AB80276)、二次抗体として、ヤギ抗ラットIgG H&L(DyLight 488血清吸着済み、AB98420)およびヤギ抗ウサギIgG H&L(DyLight 488血清吸着済み、AB96899)。
MR画像化を、それぞれの毎週のMN-siPDL1/SCRでの処置の前および後に、傾斜インサートを有し、かつParaVision 5.1ソフトウェアを用いて操作されるBruker 9.4T水平ボアマグネット(Magnex Scientific)を用いて実施した。接種から2週間後、マウスは、腫瘍を形成し、腫瘍容積の定量的測定のために、緩和促進での高速収集(rapid acquisition with relaxation enhancement)(RARE)T1強調プロトコール(TE=8.5ミリ秒、TR=2500ミリ秒、平均の数=4、RAREファクター=4、FOV=4×4cm2、マトリックスサイズ=128×128ピクセル、スライスの数=50、スライス厚さ=0.5mm、およびスライス間厚さ=0.5mm)およびT2強調プロトコール(TE=8.5ミリ秒、TR=7500ミリ秒、平均の数=4、RAREファクター=16、FOV=4×4cm2、マトリックスサイズ=128×128ピクセル、スライスの数=50、スライス厚さ=0.5mm、およびスライス間厚さ=0.5mm、フリップ角=162度)を利用するMR画像化によりモニターした。マルチスライスマルチエコー(MSME)T2強調マップを、以下のパラメータを用いて収集した:TE=8、16、24、32、40、48、56、64、72、および80ミリ秒、TR=4500ミリ秒、スライスの数=5、スライス配向=軸方向、平均の数=1、RAREファクター=1、撮影視野(field of view)=4×4cm2、マトリックスサイズ=128×128ピクセル、スライス厚さ=0.5mm、スライス間厚さ=0.5mm、フリップ角=128度)。腫瘍容積の測定およびT2マップの再構築は、関心領域(ROI)選択の変動性の原因となる試料アイデンティティを知らされていない2人の独立した研究者によって実施された。腫瘍におけるT2マップおよびT2緩和時間を、ImageJソフトウェア(Ver.1.50c、NIH)を用いて計算した。緩和率R2を、緩和時間の逆数として得た。結果として、緩和率の変化(ΔR2)は、MNにおける酸化鉄の濃度に比例する。ΔR2は、以下の方程式:S=S0 Exp(TE/T2)、△R2=1/T2,1-1/T2,2=(1/TE)*ln(S1/S2)を用いて計算され、方程式:△R2=r2・△[C]に従って、MNの濃度に相関した。全てのΔR2値は、0週間目に対して計算された。
週齢6週間の雌マウス(C57Bl/6、n=12)に、マウス膵癌細胞株、Pan02細胞(0.25×106細胞)を右側腹部に移植した。細胞注射から1週間後、腫瘍サイズを、ノギス測定によりモニターした。腫瘍容積を、以下の方程式に従って計算した:容積=0.5×L×W2、式中、Lは長さ、Wは幅である。ノギスを用いて見積もられた場合、腫瘍体積が50mm3に達するとすぐに、処置を開始した。その後、腫瘍容積を、マウスを本研究に登録した時点、ならびにそれぞれの毎週の処置の前および後にMRIにより測定した。全ての動物実験は、施設内ガイドラインに従って実施され、Massachusetts General Hospitalにおける動物実験委員会(Institutional Animal Care and Use Committee)により承認された。
マウス(n=6)を、実験群(MN-siPDL1+ゲムシタビンで処置される)または対照群(MN-siSCR+ゲムシタビンで処置される)へランダムに割り当てた。実験群におけるマウスを、ゲムシタビン(333.3mg/kg)を含む溶液中低用量MN-siPDL1(鉄として10mg kg-1;520ナノモル/kg siRNA)、またはゲムシタビン(333.3mg/kg)を含む溶液中高用量MN-siPDL1(鉄として10mg kg-1;937ナノモル/kg siRNA)で処置した。対照群におけるマウスは、同じ用量でMN-siSCRおよびゲムシタビンを受けた。どちらの場合も、薬物を、ナノドラッグとゲムシタビンの混合物として尾静脈を通して(i.v.注射)週1回の頻度で投与した。7週間目の後、ゲムシタビンの同時投与を、最大耐容量を超えることを避けるために中断し、ナノドラッグのみを、研究の終わりまで投与した。全てのマウスは、最初の処置後最大12週間、または動物が瀕死状態になるまで、腫瘍容積の変化の記録をつけるために磁気共鳴画像法により毎週、モニターした。
データは、示されている場合、平均±s.d.またはs.e.m.として表された。統計比較は、両側t検定(SigmaStat 3.0;Systatソフトウェア、Richmond、CA)を用いて引き出された。P<0.05の値は、統計的に有意であると見なされた。
膵癌免疫療法のためのRNAi媒介性PD-L1阻害
MN-siPDL1は、原発性腫瘍へインビボで送達することができ、その送達は、非侵襲性MRIによりモニターすることができる。
抗腫瘍免疫応答への処置の効果を評価するために、本発明者らは、処置されたマウスの腫瘍における免疫細胞の動員および活性化の組織バイオマーカーを分析した。MN-siPDL1およびゲムシタビンでの併用処置後、PD-L1発現は有意に低下した。CD8+腫瘍浸潤リンパ球(TIL)の動員、およびグランザイムBのより高いレベルにより証明されているように、細胞媒介性細胞傷害の増加の証拠があった。免疫抑制性Foxp3+ 制御性T(Treg)細胞による腫瘍浸潤もまた、有意に低下した。最後に、腫瘍細胞増殖が阻害された(図4A~B)。興味深いことに、高用量MN-siPDL1およびゲムシタビンで処置された非応答性動物におけるこれらのバイオマーカーの発現は、対照動物と退行する実験動物との中間であり、肉眼的応答を観察するために必要とされるPD-L1阻害の臨界レベルがあることを示唆している(図4A~B)。これらの結果は、観察された治療効果が、抗腫瘍免疫応答の誘導の成功の結果であることを示唆した。
本発明は、その詳細な説明と共に記載されているが、前述の説明は、例証することを意図され、本発明の範囲を限定することを意図されず、本発明の範囲は添付の特許請求の範囲の範囲によって定義されることは、理解されているはずである。他の態様、利点、および改変は、以下の特許請求の範囲内である。
以下に、本願の当初の特許請求の範囲に記載の発明を列挙する。
[発明1]
治療用ナノ粒子であって、前記ナノ粒子が
10nm~30nmの間の直径を有し、ならびに
酸化鉄コア、ポリマーコーティング、および前記ナノ粒子へ共有結合性に連結されている、免疫チェックポイント分子を標的化する阻害性核酸を含み、
好ましくは、前記チェックポイント分子がプログラム細胞死1リガンド1(PD-L1)である、治療用ナノ粒子。
[発明2]
前記核酸が、配列番号1と相補的な少なくとも10個の連続したヌクレオチドの配列を含む、発明1に記載の治療用ナノ粒子。
[発明3]
前記核酸が、少なくとも1個の改変ヌクレオチドを含む、発明1に記載の治療用ナノ粒子。
[発明4]
前記少なくとも1個の改変ヌクレオチドがロックドヌクレオチドである、発明3に記載の治療用ナノ粒子。
[発明5]
前記ポリマーコーティングがデキストランを含む、発明1に記載の治療用ナノ粒子。
[発明6]
前記核酸が低分子干渉RNA(siRNA)である、発明1に記載の治療用ナノ粒子。
[発明7]
前記核酸が、ジスルフィド結合またはチオエーテル結合を含む化学的部分を通してナノ粒子へ共有結合性に連結されている、発明1に記載の治療用ナノ粒子。
[発明8]
前記ナノ粒子が磁性である、発明1に記載の治療用ナノ粒子。
[発明9]
発明1~8のいずれか一つに記載の治療用ナノ粒子および、任意で、化学療法剤を含む薬学的組成物。
[発明10]
治療的有効量の、発明1~8のいずれか一つに記載の治療用ナノ粒子および化学療法剤を、癌を有する対象に投与することを含む、癌を有する対象を処置するための方法。
[発明11]
対象において癌を処置することにおける使用のための、発明1~8のいずれか一つに記載の治療用ナノ粒子および化学療法剤。
[発明12]
前記癌が、乳癌、結腸癌、腎癌、肺癌、皮膚癌、卵巣癌、膵癌、前立腺癌、直腸癌、胃癌、甲状腺癌、および子宮癌からなる群から選択される、発明10に記載の方法または発明11に記載の使用。
[発明13]
対象における癌細胞の位置もしくは数、または対象における治療用ナノ粒子の位置を決定するために、対象の組織を画像化することをさらに含む、発明10に記載の方法または発明11に記載の使用。
[発明14]
前記治療用ナノ粒子が、対象に2回以上の用量で投与される、発明10に記載の方法または発明11に記載の使用。
[発明15]
前記治療用ナノ粒子が対象に少なくとも週1回、投与される、発明14に記載の方法または使用。
[発明16]
前記治療用ナノ粒子が、対象に静脈内、皮下、動脈内、筋肉内、または腹腔内投与により投与される、発明10に記載の方法または発明11に記載の使用。
[発明17]
前記対象が膵癌を有する、発明10に記載の方法または発明11に記載の使用。
[発明18]
前記化学療法剤がゲムシタビンである、発明10もしくは16に記載の方法または発明11に記載の使用。
[発明19]
前記化学療法剤がゲムシタビンである、発明9に記載の薬学的組成物。
Claims (17)
- 治療用ナノ粒子であって、前記ナノ粒子が、
10nm~30nmの間の直径を有し、ならびに
酸化鉄コア、デキストランポリマーコーティング、および、前記ナノ粒子へ共有結合性に連結されている、プログラム細胞死1リガンド1(PD-L1)を標的化する阻害性核酸を含み、かつ、
前記ナノ粒子が、ターゲティングペプチドを含まない、
前記治療用ナノ粒子。 - 前記ナノ粒子が、
10nm~30nmの間の直径を有し、ならびに
酸化鉄コア、デキストランポリマーコーティング、および、前記ナノ粒子へ共有結合性に連結されている、プログラム細胞死1リガンド1(PD-L1)を標的化する阻害性核酸からなり、かつ、
前記ナノ粒子が、ターゲティングペプチドを含まない、
請求項1に記載の治療用ナノ粒子。 - 前記核酸が、配列番号1と相補的な少なくとも10個の連続したヌクレオチドの配列を含む、請求項1又は2に記載の治療用ナノ粒子。
- 前記核酸が、少なくとも1個の改変ヌクレオチドを含む、請求項1又は2に記載の治療用ナノ粒子。
- 前記少なくとも1個の改変ヌクレオチドがロックドヌクレオチドである、請求項4に記載の治療用ナノ粒子。
- 前記核酸が低分子干渉RNA(siRNA)である、請求項1又は2に記載の治療用ナノ粒子。
- 前記核酸が、ジスルフィド結合またはチオエーテル結合を含む化学的部分を通してナノ粒子へ共有結合性に連結されている、請求項1又は2に記載の治療用ナノ粒子。
- 前記ナノ粒子が磁性である、請求項1又は2に記載の治療用ナノ粒子。
- 請求項1~8のいずれか一項に記載の治療用ナノ粒子を含む薬学的組成物。
- 癌を有する対象を処置するために用いられる、請求項9に記載の薬学的組成物。
- 対象において癌を処置する方法における使用のための、請求項1~8のいずれか一項に記載の治療用ナノ粒子。
- 前記癌が、転移性癌である、請求項10に記載の薬学的組成物または請求項11に記載の治療用ナノ粒子。
- 前記癌が、乳癌、結腸癌、腎癌、肺癌、皮膚癌、卵巣癌、膵癌、前立腺癌、直腸癌、胃癌、甲状腺癌、および子宮癌からなる群から選択される、請求項10に記載の薬学的組成物または請求項11に記載の治療用ナノ粒子。
- 前記処置する方法が、対象における癌細胞の位置もしくは数、または対象における治療用ナノ粒子の位置を決定するために、対象の組織を画像化することを含む、請求項11に記載の治療用ナノ粒子。
- 前記治療用ナノ粒子が、対象に2回以上の用量で投与されるように用いられる、請求項10に記載の薬学的組成物または請求項11に記載の治療用ナノ粒子。
- 前記治療用ナノ粒子が、対象に少なくとも週1回、投与されるように用いられる、請求項15に記載の薬学的組成物または治療用ナノ粒子。
- 前記治療用ナノ粒子が、対象に静脈内、皮下、動脈内、筋肉内、または腹腔内投与により投与されるように用いられる、請求項10に記載の薬学的組成物または請求項11に記載の治療用ナノ粒子。
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US20210332359A1 (en) | 2021-10-28 |
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CN112955155A (zh) | 2021-06-11 |
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