JP7229222B2 - 核酸薬物複合体およびその用途 - Google Patents
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Description
本出願は、2019年12月31日に出願された米国仮特許出願第62/955,690号の利益を主張し、その全体が参照することにより本明細書に組み込まれる。
本開示は核酸薬物複合体に関し、特に抗PD-L1アプタマーの核酸薬物複合体およびその用途に関する。
プログラム死-1(programmed death-1,PD-1)はT細胞発現を活性化する共刺激分子であり、免疫システムにおいて負の調節(negative regulation)を行って、T細胞の活性化および増殖を阻害することができる。PD-L1はPD-1のリガンド(ligand)であり、免疫抑制性を備え、いくつかの非リンパ組織の血管内皮系の抗原発現細胞、例えば樹状細胞(dendritic cell,DC)、マクロファージ(macrophage)およびB細胞に発現し得る。さらに、PD-L1は多くの腫瘍細胞、間質細胞および免疫細胞にも発現するため、PD-1とPD-L1との結合をブロックすると免疫反応が有効に強化され、かつ抗腫瘍効果が生じる。抗PD-1抗体と抗PD-L1抗体により調節される免疫チェックポイント阻害療法(checkpoint blockade immunotherapy)はすでに臨床治療において応用されている。
核酸薬物複合体であって、
PD-L1に結合する抗PD-L1アプタマーの核酸配列と、
TLR9レセプターに結合してTLR9を活性化するCpGオリゴヌクレオチド配列と、を含み、
前記CpGオリゴヌクレオチド配列が第1のフラグメントおよび第2のフラグメントからなり、前記抗PD-L1アプタマーの核酸配列が前記CpGオリゴヌクレオチド配列の前記第1のフラグメントと前記第2のフラグメントとの間に挿入されている、核酸薬物複合体。
[本発明1002]
前記CpGオリゴヌクレオチド配列と配列番号:10から23のうちの任意の1つで示される核酸配列とが少なくとも85%の類似性を有する、本発明1001の核酸薬物複合体。
[本発明1003]
前記CpGオリゴヌクレオチド配列が配列番号:10から23のうちの任意の1つからなる、本発明1002の核酸薬物複合体。
[本発明1004]
前記CpGオリゴヌクレオチド配列の前記第1のフラグメントの長さと前記CpGオリゴヌクレオチド配列の前記第2のフラグメントの長さとの比の範囲が1:15から15:1である、本発明1001の核酸薬物複合体。
[本発明1005]
前記第1のフラグメントの長さと前記第2のフラグメントの長さとの比の範囲が1:10から10:1である、本発明1004の核酸薬物複合体。
[本発明1006]
前記CpGオリゴヌクレオチド配列の長さが、15個のヌクレオチドから40個のヌクレオチドである、本発明1001の核酸薬物複合体。
[本発明1007]
前記CpGオリゴヌクレオチド配列がホスホロチオエート結合(phosphorothioate bond)を含む、本発明1001の核酸薬物複合体。
[本発明1008]
前記ホスホロチオエート結合の数が前記CpGオリゴヌクレオチド配列のホスホジエステル結合の数の70%から100%を占める、本発明1007の核酸薬物複合体。
[本発明1009]
前記ホスホロチオエート結合の数が前記CpGオリゴヌクレオチド配列のホスホジエステル結合の数の80%から100%を占める、本発明1008の核酸薬物複合体。
[本発明1010]
配列番号:29から34のうちの任意の1つで示される核酸配列からなる、本発明1001の核酸薬物複合体。
[本発明1011]
本発明1001から1010のうちいずれかの核酸薬物複合体の用途であって、がんを治療する薬剤を作製するのに用いる用途。
[本発明1012]
前記がんには、結腸がん、乳がん、肺がん、すい臓がん、肝臓がん、胃がん、食道がん、頭頸部扁平上皮がん、前立腺がん、膀胱がん、リンパ腫、胆嚢がん、腎臓がん、血液がん、大腸がん、多発性骨髄腫、卵巣がん、子宮頸がんまたは神経膠腫が含まれる、本発明1011の用途。
[本発明1013]
本発明1001から1010のうちいずれかの核酸薬物複合体および医薬上許容されるキャリアを含む医薬組成物。
[本発明1014]
がんを治療するのに用いられ、かつ静脈内(intravenous)注射、腫瘍内注射(intratumoral)または皮下注射(subcutaneous)により投薬される、本発明1013の医薬組成物。
[本発明1015]
本発明1013または1014の医薬組成物を含むキット。
本開示の特徴、または利点がより明瞭かつ分かり易くなるよう、以下に好ましい実施形態を挙げると共に、添付の図面を対応させて、詳細に説明していく。
Claims (12)
- 核酸薬物複合体であって、
PD-L1に結合する抗PD-L1アプタマーの核酸配列と、
TLR9レセプターに結合してTLR9を活性化するCpGオリゴヌクレオチド配列と、を含み、
前記CpGオリゴヌクレオチド配列が第1のフラグメントおよび第2のフラグメントからなり、前記抗PD-L1アプタマーの核酸配列が前記CpGオリゴヌクレオチド配列の前記第1のフラグメントと前記第2のフラグメントとの間に挿入されており、
前記CpGオリゴヌクレオチド配列の前記第1のフラグメントの長さと前記CpGオリゴヌクレオチド配列の前記第2のフラグメントの長さとの比が1:10から10:1の範囲にあり、かつ
前記第1のフラグメントと前記第2のフラグメントの長さの合計が、15個のヌクレオチドから40個のヌクレオチドである、核酸薬物複合体。 - 前記CpGオリゴヌクレオチド配列と配列番号:10から23のうちの任意の1つで示される核酸配列とが少なくとも96%の同一性を有する、請求項1に記載の核酸薬物複合体。
- 前記CpGオリゴヌクレオチド配列が配列番号:10から23のうちの任意の1つからなる、請求項2に記載の核酸薬物複合体。
- 前記CpGオリゴヌクレオチド配列がホスホロチオエート結合(phosphorothioate bond)を含む、請求項1に記載の核酸薬物複合体。
- 前記ホスホロチオエート結合の数が前記CpGオリゴヌクレオチド配列のホスホジエステル結合の数の70%から100%を占める、請求項4に記載の核酸薬物複合体。
- 前記ホスホロチオエート結合の数が前記CpGオリゴヌクレオチド配列のホスホジエステル結合の数の80%から100%を占める、請求項5に記載の核酸薬物複合体。
- 配列番号:29から34のうちの任意の1つで示される核酸配列からなる、請求項1に記載の核酸薬物複合体。
- 請求項1から7のうちいずれか1項に記載の核酸薬物複合体を含む、がんを治療するための医薬組成物。
- 前記がんには、結腸がん、乳がん、肺がん、すい臓がん、肝臓がん、胃がん、食道がん、頭頸部扁平上皮がん、前立腺がん、膀胱がん、リンパ腫、胆嚢がん、腎臓がん、血液がん、大腸がん、多発性骨髄腫、卵巣がん、子宮頸がんまたは神経膠腫が含まれる、請求項8に記載の医薬組成物。
- 請求項1から7のうちいずれか1項に記載の核酸薬物複合体および医薬上許容されるキャリアを含む医薬組成物。
- がんを治療するのに用いられ、かつ静脈内(intravenous)注射、腫瘍内注射(intratumoral)または皮下注射(subcutaneous)により投薬される、請求項10に記載の医薬組成物。
- 請求項10または11に記載の医薬組成物を含むキット。
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JP2007525177A (ja) | 2003-04-21 | 2007-09-06 | アーケミックス コーポレイション | 血小板由来増殖因子に対する安定化アプタマーおよび腫瘍治療剤としてのそれらの使用 |
JP2018502120A (ja) | 2014-12-31 | 2018-01-25 | チェックメイト ファーマシューティカルズ, インコーポレイテッド | 組合せ腫瘍免疫療法 |
WO2018095697A1 (en) | 2016-11-23 | 2018-05-31 | Berlin Cures Holding Ag | Aptamers for use in inhibition and/or suppression of tlr9 activation |
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US20210230600A1 (en) | 2021-07-29 |
EP3845649A1 (en) | 2021-07-07 |
TW202126811A (zh) | 2021-07-16 |
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US11613755B2 (en) | 2023-03-28 |
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