JP2017517253A - ペプチド担体上の多重オリゴヌクレオチド部分 - Google Patents
ペプチド担体上の多重オリゴヌクレオチド部分 Download PDFInfo
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Abstract
Description
本出願は、米国仮特許出願第62/002,296号(2014年5月23日出願、これはその全体として参照により本明細書に加入される)に対して優先権の利益を主張する。
発明の分野
本開示は、限定されないが、ホスホロジアミデートモルホリノオリゴヌクレオチド(PMO)のようなアンチセンスオリゴヌクレオチド(AON)に関する。本開示はさらに、目的の組織、例えば骨格筋細胞及び心筋細胞へのPMOの取り込みを増強するための、カチオン性膜透過性ペプチド(CPP)への多重PMOの結合に関する。本開示は、上記結合体、さらには、例えば遺伝子発現を調節するためにそれらを使用することを含むそれらの使用方法を包含する。本開示はさらに、それを必要とするヒト又は動物に、上記多重PMO-CPP結合体を投与することにより様々な疾患状態を処置する方法を含む。
AONは、例えばDuchenne型筋ジストロフィー(DMD)を含む様々な疾患状態においてインビトロ及びインビボの両方で首尾よく遺伝子発現を調節することが示されてきた。特に、インフレームエクソン23を標的とし除去するように設計されたPMOは、DMDのmdxマウスモデルにおいてジストロフィン機能の回復において成功を収めた。
上述のように、標的細胞への結合体の取り込みを低下させることなく、単一PMO-CPP結合体の安全プロフィールを改善することが本開示の1つの目的である。有効用量と無有害作用レベル(NOAEL)との間に少なくとも10倍の安全マージンを有することが一般に好ましい。上記のmdx/エクソン23実験において、有効用量は30mg/kgであることが見出され、そしてまたNOAELは30mg/kgであった。結果として、安全マージンは殆ど無いか全く無かった。本開示の少なくとも1つの実施態様において、多重PMO-CPP結合体は、上記のmdx/エクソン23実験よりも良好な、例えば2倍より良好、5倍より良好、6倍より良好、10倍より良好な安全マージンを有する。10倍の安全マージンは、有効用量がNOAELより10倍低いということを意味する。従って、適切なモデルで試験された場合、本開示に従う多重PMO-CPP結合体は、対応する単一PMO-CPP結合体よりも2倍良好な安全マージンを有し得る。本発明は、単一CPPに結合された多重AON(PMO AONを含む)を含む。
の15〜30のサブユニットを含むPMO化合物を含む。
の15〜30のサブユニットを含むPMO化合物を含む。
の15〜30のサブユニットを含むホスホラミデート化合物を含む。
の15〜30のサブユニットを含むMMI化合物を含む。
の15〜30のサブユニットを含む2-OMe化合物を含む。
の15〜30のサブユニットを含む2MOE化合物を含む。
合物であり得、式中、可変配列はAc-R(O)nRであり、ここでn≧7であり;Oは、R、X、及びZから選択される残基の配列であり;ここでRはL-アルギニンであり、Xは3-cis-アミノシクロヘキサンであり、そしてZはcis-2-アミノシクロペンタン-1-カルボニルであり;そしてここで可変配列は、化合物を核に標的化させる。
合物であり得、式中、可変配列はAc-R(O)nRであり、ここでn≧7であり;Oは、R、X、及びZから選択される残基の配列であり;ここでRはL-アルギニンであり、Xは3-cis-アミノシクロヘキサンであり、そしてZはcis-2-アミノシクロペンタン-1-カルボニルであり;そしてここで、リンカーはFSQを含む。
Ranin Symphony自動化ペプチド合成機を使用して、予め組み込まれたCLEAR(架橋エトキシル化アクリレート樹脂)(Peptides International, Louisville, KY)で標準的Fmoc化学を使用してペプチドを合成した。アミノ酸(EMD Biosciences, San Diego, CA又はAnaspec, San Jose, CA)を、tertブトキシカルボニル(BOC)、tert-ブチル(tBu) 2,2,4,6,7-ペンタメチルジヒドロ-ベンゾフラン-5-スルホニル(Pbf)、又はトリチル(Trt)基で直交性に(orthogonally)保護した。5/5/10/1のアミノ酸/HCTU/N-メチルモルホリン/樹脂モル割当(molar ration)を使用してカップリングを行った。DMF中の20%ピペリジン、2% 1,8-ジアザビシクロ[5.4.0]-ウンデカ-7-エン(DBU)を使用して、各サイクルの間にアミン末端からFmocを除去した。N-末端アセチル化を、30/8/1のモル比でDMF中の無水酢酸/NMM/樹脂を使用する樹脂で行った。樹脂からの脱保護/切断を、2.5%水/2.5% TIS/5%アニソール/90% TFA 体積/体積比の15ml/0.1mM樹脂の混合物を3時間使用して行った。上清をジエチルエーテル(-80℃)中で沈殿させ、そして3000rpmで10分間ペレット化した。エーテルをデカンテーションし、そしてペレットを再び洗浄した。粗製ペプチドを凍結乾燥し、そして半分取逆相HPLC(XBridge C18、10x250mm、5μm粒径)を使用して精製した。99%緩衝液-A(水、0.1% TFA)及び1%緩衝液-B(アセトニトリル、0.1% TFA)(グラジエント勾配、0.3% B/分)のロードグラジエントを用いて5ml/分で精製を行った。ペプチド純度>95%を、逆相分析HPLC及びMALDI-TOF(Waters Synapt)により評価した。フラクションをプールし、凍結乾燥し、そして適切な結合緩衝液に再溶解した。(全ての溶媒は、EMD Biosciences, San Diego, Ca or Sigma Aldrich, St. Louis, MOから購入されたHPLC等級のものであった)
5’-末端第一級アミンを有するPMOを注文し、そしてペプチドを上記のように合成した。単一PMO-CPP結合体において、ペプチドをPMOと比較して2倍モル過剰で使用し、そして多重PMO-CPP結合体において、PMOのモル数を、以下の式を使用して計算した: (1.2倍) x (結合体数) x (ペプチドのモル数)。PMOをDMSO(5mM)に溶解して取っておいた。ペプチドをDMF(50mM)に溶解し、そしてモル当量のアミニウムベースのカップリング試薬2-(6-クロロ-1-H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルアミニウム ヘキサフルオロホスフェートと混合した。2モル当量の4-メチルモルホリン(NMM)をペプチド混合物に加え、そしてすぐにPMO溶液に加えた。反応を1.5時間37℃にて進め、そして4体積当量の水を使用して止めた。この混合物をCMセファロース(Sigma Aldrich, St. Louis, MO)カラムに加え、そして10カラム体積で洗浄して未結合PMO及び反応物を除去した。ペプチドCPP-PMO結合体を1Mグアニジウム-HCL、1M NaClでカラムから溶出し、そして100mM NH4HCO3に対して3回の緩衝液交換で透析して塩及び未結合ペプチドを除去した。透析された物質を凍結乾燥し、そして分析HPLCで分析した。
・ No. 1215: Ac-(RXRRBR)2XFKEG-OH (配列番号55)
・ No. 1216: Ac-(RXRRBR)2XFD(d-Glu)EG-OH (配列番号56)
・ No. 1217: Ac-E(RXRRBR)2XFKG-アミド (配列番号57)
・ No. 1218: Ac-E(RXRRBR)2XFKG-OH (配列番号58)
・ No. 1219: Ac-E(RXRRBR)2XFKEG-OH (配列番号59)
・ No. 1220: Ac-E(RXRRBR)2XFK(d-Glu)EG-OH (配列番号60)
・ No. 1221: Ac-(d-Glu)E(RXRRBR)2xFKG-アミド (配列番号61)
・ No. 1222: Ac-(dGlu)E(RXRRBR)2XFKG-OH (配列番号62)
・ No. 1223: Ac-(d-Glu)E(RXRRBR)2XFKEG-OH (配列番号63)
・ No. 1224: Ac-(d-Glu)E(RXRRBR)2XFK((d-Glu)EG-OH (配列番号64)
・ No. 1225-B: Biot-(RXRRBR)2XFKG-OH (配列番号65)
・ No. 1225-F: FITC-(RXRRBR)2XFKG-OH (配列番号66)
・ No. 1226-B: Ac-(RXRRBR)2XFK(Biot)G-OH (配列番号67)
・ No. 1226-F: Ac-(RXRRBR)2XFK(FITC)G-OH (配列番号68)
ここで、Acはアセチルであり、RはD-アルギニンであり、Xは6-アミノヘキサン酸であり、Bはβ-アラニンであり、FKはカテプシン切断部位であり、Eはグルタミン酸であり、Gはグリシンであり、Biotはビオチンであり、そしてFITCはフルオレセインイソチオシアネートである。
・ No. 1215: Ac-(RXRRBR)2XFKE(PMO)G(PMO) (配列番号69)
・ No. 1216: Ac-(RXRRBR)2XFD(d-Glu)(PMO)E(PMO)G(PMO) (配列番号70)
・ No. 1217: Ac-E(PMO)(RXRRBR)2XFKG (配列番号71)
・ No. 1218: Ac-E(PMO)(RXRRBR)2XFKG(PMO) (配列番号72)
・ No. 1219: Ac-E(PMO)(RXRRBR)2XFKE(PMO)G(PMO) (配列番号73)
・ No. 1220: Ac-E(PMO)(RXRRBR)2XFK(d-Glu)(PMO)E(PMO)G(PMO) (配列番号74)
・ No. 1221: Ac-(d-Glu)(PMO)E(PMO)(RXRRBR)2XFKG (配列番号75)
・ No. 1222: Ac-(dGlu)(PMO)E(PMO)(RXRRBR)2XFKG(PMO) (配列番号76)
・ No. 1223: Ac-(d-Glu)(PMO)E(PMO)(RXRRBR)2XFKE(PMO)G(PMO) (配列番号77)
・ No. 1224: Ac-(d-Glu)(PMO)E(PMO)(RXRRBR)2XFK(d-Glu)(PMO)E(PMO)G(PMO) (配列番号78)
・ No. 1225-B: Biot-(RXRRBR)2XFKG(PMO) (配列番号79)
・ No. 1226-B: Ac-(RXRRBR)2XFK(Biot)G(PMO) (配列番号80)
上で言及されたCPP-PMO結合体に加えてNo.1120 (Ac-(RXR)4XFKE-((PEG)2-PMO)G-(PMO))
(配列番号81)及び(Ac-(RXRRBR)2XBA-PMO) (配列番号82)を、2.84μM/kgの用量で野生型マウスに静脈内投与した。
K系(PMOはPMO23である):
・ No. 1118: Ac-(RXR)4XEG-(PMO) (配列番号86)
・ No. 1119: Ac-(RXR)4XE-((PEG)2-PMO)G-(PMO) (配列番号87)
・ No. 1120: Ac-(RXR)4XFKE-((PEG)2-PMO)G-(PMO) (配列番号81)
・ No. 970-S: ステアリル-(RXR)4XA-PMO (配列番号88)
B系(PMOはPMO23である):
・ No. 1204: Ac-(RXRRBR)2XBA-PMO (配列番号82)
・ E(PMO)(RXRRBR)2XFKG、「n-末端PPMO-B」 (配列番号89)
・ No. 1239: Ac-(RXRRBR)2XE(PMO)G(PMO) (配列番号90)
・ Ac-(RXRRBR)2FKEG-(PMO)2、「Di-PMO-B + FK」 (配列番号91)
ここでAcはアセチルであり、RはD-アルギニンであり、Xは6-アミノヘキサン酸であり、Bはβ-アラニンであり、FKはカテプシン切断部位であり、Eはグルタミン酸であり、そしてGはグリシンである。
Claims (2)
- 式(I)、(II)、(III)、(IV)、(V)、又は(VI):
[式中、Bは、C、G、A、又はTから選択される天然に存在するプリン又はピリミジンヌクレオチド塩基である]
の15〜30のサブユニットを含む少なくとも2つのAON化合物を含む、ペプチド結合AON化合物であって;
ここで、該少なくとも2つのAON化合物は、標的プレ−mRNA又はmRNAの塩基の少なくとも75%に相補的であるヌクレオチド塩基配列を有し;
該少なくとも2つのAON化合物は、BがGである0〜3個の反復サブユニットを有し;
該少なくとも2つのAON化合物は、BがC又はGである該サブユニットを60%未満有し;
該少なくとも2つのAON化合物は、非自己相補性配列を有し;かつ
該少なくとも2つのAON化合物は、ポリカチオン性ペプチドに結合している、上記ペプチド結合AON化合物。 - 式(I):
ここで、該少なくとも2つのホスホロジアミデートモルホリノ化合物は、標的プレ−mRNA又はmRNAの少なくとも8個の隣接した塩基に対して相補的であるヌクレオチド塩基配列を有し;
該少なくとも2つのホスホロジアミデートモルホリノ化合物は、BがGである0〜3個の反復サブユニットを有し;
該少なくとも2つのホスホロジアミデートモルホリノ化合物は、BがC又はGである該サブユニットを60%未満有し;
該少なくとも2つのホスホロジアミデートモルホリノ化合物は、非自己相補性配列を有し;そして
該少なくとも2つのホスホロジアミデートモルホリノ化合物は、ポリカチオン性ペプチドに結合されている、上記ペプチド結合ホスホロジアミデートモルホリノ化合物。
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US20190388547A1 (en) | 2019-12-26 |
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MX2016015156A (es) | 2017-03-27 |
CN106459975A (zh) | 2017-02-22 |
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TW201617373A (zh) | 2016-05-16 |
JP2021063128A (ja) | 2021-04-22 |
KR20170005118A (ko) | 2017-01-11 |
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EP3151841A1 (en) | 2017-04-12 |
WO2015179742A1 (en) | 2015-11-26 |
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AU2015263963B2 (en) | 2021-02-18 |
CA2949104A1 (en) | 2015-11-26 |
TWI726844B (zh) | 2021-05-11 |
KR102487942B1 (ko) | 2023-01-11 |
US11103587B2 (en) | 2021-08-31 |
AU2015263963A1 (en) | 2016-12-01 |
JP6825914B2 (ja) | 2021-02-03 |
CN106459975B (zh) | 2020-03-27 |
SG11201608880VA (en) | 2016-11-29 |
RU2739987C2 (ru) | 2020-12-30 |
SG10202004611SA (en) | 2020-06-29 |
RU2016150629A3 (ja) | 2018-12-24 |
US20170182171A1 (en) | 2017-06-29 |
BR112016027236A2 (pt) | 2017-10-17 |
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RU2020142530A (ru) | 2021-04-26 |
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