JP6006183B2 - 増強された免疫刺激活性を有する疎水性T類似体を含有するCpGオリゴヌクレオチド類似体 - Google Patents
増強された免疫刺激活性を有する疎水性T類似体を含有するCpGオリゴヌクレオチド類似体 Download PDFInfo
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Description
a)ヌクレオチドの3’および/または5’末端に位置するホスホジエステルインターヌクレオチド架橋の修飾インターヌクレオチド架橋による置き換え、
b)ヌクレオチドの3’および/または5’末端に位置するホスホジエステル架橋の、デホスホ架橋による置き換え、
c)糖ホスフェート主鎖由来の糖ホスフェート単位の別の単位による置き換え、
d)β−D−リボース単位の修飾糖単位による置き換え、および、
e)天然ヌクレオチド塩基の修飾ヌクレオチド塩基による置き換えから選択されるオリゴヌクレオチドに関する。
オリゴデオキシヌクレオチド(ODN)および試薬
すべてのODNは、標準的なホスホルアミダイト化学反応プロトコルに従って合成し、Coley Pharmaceutical GmbHにより同一性および純度について制御し、Limulusアッセイ(BioWhittaker、Verviers、Belgium)により測定される検出不可能な内毒素レベル(<0.1EU/ml)を有していた。ODNを、無菌で内毒素を含まないTris−EDTA(Sigma、Deisenhofen、Germany)に懸濁し、微生物汚染と内毒素汚染の両方を予防するために無菌条件下で保存および操作した。すべての希釈は、内毒素を含まないTris−EDTAを用いて行った。
HEK293細胞を、エレクトロポレーションにより、それぞれのヒトTLRおよび6xNF−κB−ルシフェラーゼレポータープラスミドを発現するベクターでトランスフェクトした。安定なトランスフェクタント(3×104細胞/ウェル)を、加湿したインキュベーター中で37℃にて16時間にわたって指示量のODNと共にインキュベートした。各データポイントは、3回ずつ行った。細胞を溶解させ、ルシフェラーゼ遺伝子活性について(Perkin−Elmer、Zaventem、Belgium製のBriteLiteキットを用いて)アッセイした。刺激指数は、ODNを添加しない培地のレポーター遺伝子活性を参照して計算した。
健康なヒトドナー由来の末梢血液バフィーコート調製物は、the Blood Bank of the University of Dusseldolf(Germany)から入手し、PBMCは、Ficoll−Hypaque(Sigma)上の遠心分離により精製した。細胞を、5%(v/v)加熱不活性化ヒトAB血清(BioWhittaker)、または10%(v/v)加熱不活性化FCS、2mM L−グルタミン、100U/mlペニシリンおよび100μg/mlストレプトマイシン(すべてSigma製)が補充されたRPMI1640培地中37℃にて、加湿したインキュベーター中で培養した。
PBMCを、5×106細胞/mlの濃度で再懸濁し、96ウェル丸底プレート(250μl/ウェル)に加えた。PBMCを、ODNと共にインキュベートし、培養上清(SN)を、指定された時点後に集めた。すぐに使用しない場合、SNを、必要になるまで−20℃にて保存した。
雌性BALB/cマウス(6〜8週齢)を、Charles River Canada(Quebec、Canada)から購入し、Coley Pharmaceutical Group Canadaのthe Animal Care Facility内のマイクロアイソレーターに収容した。すべての研究は、the Canadian Council on Animal Careの指針の下にthe Animal Care Committee of Coley Canadaに準拠して行った。すべての動物は、CpG ODNに対してナイーブであった。
ナイーブなBALB/cマウス脾細胞(3〜5匹の動物のプールから)を、in vitroアッセイに使用した。動物をイソフルランで麻酔し、頸椎脱臼により安楽死させた。脾臓を無菌条件下で摘出し、PBS+0.2%ウシ血清アルブミン(Sigme Chemical Company)に入れた。次いで、脾臓をホモジナイズし、脾細胞を、2%正常マウス血清(Cedarlane Laboratories、Ontario、Canada)、ペニシリン−ストレプトマイシン溶液(それぞれ、最終濃度1000U/mlおよび1mg/ml;Sigma Chemical Company)、および5×10−5M b−メルカプトエタノール(Sigma Chemical Company)が補充されたRPMI1640(Life Technologies、Grand Island、NY)組織培養培地に再懸濁した。
カボキシ(Caboxy)−フロレセイン(florescein)ジアセテート、スクシミジル(succimidyl)エステル(CFSE)(Invitrogen、Eugene、Oregon、USA)染色BALB/cマウス脾細胞(4×105/ウェル)を、5日にわたって37℃にて加湿した5%CO2インキュベーター中で様々な濃度のODNと共にインキュベートした。次いで、細胞を、CD19用のPE結合抗CD19抗体(BD Pharmingen、San Diego、CA、USA)で染色し、FACSと、続いて、ModFit Software V3.0(Verity Software House Inc.、Topsham、ME、USA)による分析によりB細胞増殖を決定した。
CpGモチーフにおける構造活性相関の検討
非メチル化CpGモチーフを含有するオリゴヌクレオチドが、トール様受容体9(TLR9)経路を介して免疫応答を刺激することができることは知られている。TLR9経路を刺激する最高の能力を有するオリゴヌクレオチドを同定するために、CpGモチーフにおける包括的構造活性相関(SAR)研究を行った。結果は、ヒポキサンチンおよび6−チオグアニンによるグアニンの置換が、hTLR9アッセイにおいて類似の活性につながるが、プリン、2−アミノプリン、2,6−ジアミノプリン、8−オキソ−7,8−ジヒドログアニンおよび7−デアザグアニン置換は、hTLR9刺激において40〜80%の低下をもたらすことを示した。さらに、C5およびN4における修飾は、hTLR9経路の刺激をもたらさなかった。これらの知見から、グアニンは、フーグスティーン部位を介して認識され、一方、シトシンは、C,H−エッジにおいてTLR9受容体と結合するSARモデルが得られた(図1aを参照)。したがって、グアニンのフーグスティーン認識部位ならびにシトシンのC,H−エッジにおける無修飾は、hTLR9活性の有意な喪失なしに可能であった。ジヌクレオチドモチーフにおいて検討した塩基修飾のどれも、非修飾CpGモチーフよりも活性であった。
CpGモチーフに近い疎水性チミン塩基形類似体の効果
CpGモチーフに隣接するdT残基の影響を検討するために、2,4−ジフルオロトルエン(FF)(配列番号3〜9)、5−ブロモ−2’−デオキシウリジン(BU)および5−ヨード−2’−デオキシウリジン(JU)などのいくつかの疎水性チミン塩基形類似体をCpGモチーフの外側に組み入れた(表1および図2〜3を参照)。驚いたことに、すべての試験した疎水性チミン類似体の組入れは、hTLR9活性の異常に強い増加につながったが、ウラシル残基(メチル基を欠くチミン、図4)による置換は、hTLR9刺激の強い減少につながった。TLR9刺激の増加は、修飾がCpGモチーフの5’側にある場合に顕著であった。CpGモチーフの5’および3’の5−ヨードウラシル(JU)による二重置換は、試験したもののうちで最も強力な刺激をもたらした。対照的に、CpGモチーフにおける2,4−ジフルオロトルエンによるグアニンおよびシトシンの置換は、両方の場合に、TLR9刺激指数の強い減少につながった。
親油性塩基形置換基によるTLR9の活性化
CpGモチーフの5’側にある塩基の様々なタイプの親油性置換が、hTLR9の刺激の有意な増加を引き起こしたことから、5−クロロ−ウラシル、5−トリフルオロメチル−ウラシル、フェニル、アリールおよび置換アリール残基などの他の塩基類似体を、hTLR9を刺激するそれらの能力について検討した(表3)。様々な親油性塩基類似体で修飾されたBクラスオリゴヌクレオチドによるヒトTLR9の活性化を検討するために、BクラスODN配列番号1を、5−クロロ−2’−デオキシウリジン(CU)、5−ブロモ−2’−デオキシウリジン(BU)、5−ヨード−2’−デオキシウリジン(JU)および5−エチル−2’−デオキシウリジン(EU)で修飾した。hTLR9−NFkB−293細胞を16時間にわたって指示されたODN(図5a)と共にインキュベートした。次いで、細胞を溶解し、ルシフェラーゼ活性を決定した。CU修飾(配列番号41)、BU修飾(配列番号10)JU修飾(配列番号13)およびEU修飾(配列番号42)オリゴヌクレオチドはすべて、対照(配列番号1)よりも高いTLR9活性の刺激を示した。ウリジン修飾を有する配列番号16は、劇的に減少した活性を示した。第二の実験では、IFN−α産生を測定した(図5b)。ヒトPBMCを、24時間にわたって指示されたように修飾ODNと共にインキュベートした後、上清をELISAにより試験した。JU修飾、BU修飾、およびEU修飾ODNは、対照に対して最も高いIFN−αの増加をもたらした。これらのデータは、BクラスODN上のdUの5’置換が、TLR9活性およびIFN−α産生を増加させることを証明している。
A、B、C、P、およびTクラスのオリゴヌクレオチド上の親油性置換
ODNの様々なクラスに対する親油性塩基類似体置換の効果を検討するために、Aクラス、Bクラス、Cクラス、Pクラス、およびTクラスオリゴヌクレオチドに修飾を行った。これらのオリゴヌクレオチドの一部の実施例を表3に示す。
短い修飾オリゴヌクレオチドによるTLR9の刺激
長さが20ヌクレオチドの修飾CpG ODNが、TLR9活性化について普通でない親和性を示したため、極めて短いCpG ODNを、TLR9を活性化するそれの能力について検討した。極めて短いオリゴヌクレオチドは、細胞による取り込みやすさの増加ならびにDOTAPを使用しない潜在的可能なより簡単な製剤化のために、治療で使用するより長いオリゴヌクレオチドよりも有利であると思われる。3種の短いCpG ODN(ショートマー)すなわち、六量体CpGモチーフ六量体(配列番号38)、六量体の5’JU修飾(配列番号39)、および六量体の5’3’JU修飾(配列番号40)を検討した(表3)(表4)。ショートマーの活性を、ルシフェラーゼアッセイにおいて非修飾Bクラスオリゴヌクレオチド配列番号37と比較した。図12に示すように、配列番号40については特に、修飾ショートマーの使用は、改善された免疫療法医薬品としての高い可能性を示している。
修飾オリゴヌクレオチドによるin vivoでのTLR9経路の活性化
in vivoでの本発明の修飾ODNの有効性を決定するために、親油性T類似体を有するODNを、単離マウス脾細胞において試験した。BALB/cマウス脾細胞を単離し、修飾Bクラス(配列番号13)、非修飾Bクラス(配列番号37)、および非CpG ODN(配列番号26)と共にインキュベートした(表5)。培養上清を、6時間目(TNF−α)または24時間目(IL−6、IL−10、IL−12)に集め、サイトカイン濃度をELISAにより測定した。図13に示すように、修飾配列番号13とのインキュベーションは、試験したすべてのサイトカインの劇的に増加したレベルをもたらした。
追加修飾を有するオリゴヌクレオチド
親油性塩基類似体を有するODNを、ルシフェラーゼアッセイにおいてTLR9媒介性NF−κB活性を誘導するそれらの能力について試験した(材料および方法を参照)。図16〜23は、追加修飾を有するODNの活性を示している(表6を参照)。
修飾Pクラスオリゴヌクレオチドの活性
親油性塩基類似体を有するPクラスODNを、ルシフェラーゼアッセイにより測定されるようなTLR9を介するNF−kB経路を活性化する能力について試験した。親油性置換ヌクレオチド類似体を有するPクラスODN(配列番号58〜61)の活性を、Bクラス陽性対照(配列番号55)および非修飾PクラスODN(配列番号56)の活性と比較した。図24に示すように、すべての修飾PクラスODNは、対照に比較して増加したTLR9刺激を示した。図24aは、JU修飾PクラスODNを示し、24bは、EU修飾PクラスODNを示している。
以上に記載された明細書は、当業者が本発明を実施するのを可能にするのに十分であると見なされる。本発明が、提供される実施例により範囲を限定されないのは、実施例が、本発明の一態様の単なる例示として意図されており、他の機能的に均等な実施形態が、本発明の範囲内にあるためである。本明細書に示されかつ記載されているものの他に、本発明の様々な改変形態は、上記の説明から当業者に明らかになると思われ、添付の特許請求の範囲内に含まれる。本発明の利点および目的は、必ずしも本発明の各実施形態により包含されるわけではない。
Claims (4)
- 下記の配列のオリゴヌクレオチド
JU*C-G*T*C*G*A*C*G*A*T*C*G*G*C*G*C*G*C*G*C*C*G
(配列番号31)
T*C*G*JU*C-G*A*C*G*A*T*C*G*G*C*G*C*G*C*G*C*C*G
(配列番号32)
JU*C-G*JU*C*G*A*C*G*A*T*C*G*G*C*G*C*G*C*G*C*C*G
(配列番号33)
JU*C-G*A*C*G*T*C*G*A*T*C*G*G*C*G*C*G*C*G*C*C*G
(配列番号58)
JU*C*G*A*C*G*T*C*G*A*T*C*G*G*C*G*C*G*C*G*C*C*G
(配列番号59)
EU*C-G*A*C*G*T*C*G*A*T*C*G*G*C*G*C*G*C*G*C*C*G
(配列番号62)
[ここで、JUは5−ヨード−2´−デオキシウリジンを示し、EUは5−エチル−2´−デオキシウリジンを示し、*はホスホロチオエートインターヌクレオチド結合を示し、−はホスホジエステルインターヌクレオチド結合を示す]
から選ばれる一つからなる、オリゴヌクレオチド。 - 請求項1に記載のオリゴヌクレオチドを含む医薬組成物であって、抗原を更に含む、医薬組成物。
- 請求項1に記載のオリゴヌクレオチドを含む医薬組成物であって、薬学的に許容される担体を更に含む、医薬組成物。
- 請求項1に記載のオリゴヌクレオチドを含む医薬組成物であって、抗原および薬学的に許容される担体を更に含む、医薬組成物。
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Families Citing this family (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7935675B1 (en) | 1994-07-15 | 2011-05-03 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US6239116B1 (en) | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US20030026782A1 (en) | 1995-02-07 | 2003-02-06 | Arthur M. Krieg | Immunomodulatory oligonucleotides |
US6207646B1 (en) | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US6406705B1 (en) | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
EP1077722B1 (en) | 1998-05-22 | 2006-08-09 | Ottawa Health Research Institute | Methods and products for inducing mucosal immunity |
EP1176966B1 (en) * | 1999-04-12 | 2013-04-03 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Oligodeoxynucleotide and its use to induce an immune response |
US20030129251A1 (en) * | 2000-03-10 | 2003-07-10 | Gary Van Nest | Biodegradable immunomodulatory formulations and methods for use thereof |
EP2423335B1 (en) * | 2001-06-21 | 2014-05-14 | Dynavax Technologies Corporation | Chimeric immunomodulatory compounds and methods of using the same |
EP1446162B1 (en) | 2001-08-17 | 2008-10-15 | Coley Pharmaceutical GmbH | Combination motif immune stimulatory oligonucleotides with improved activity |
US7276489B2 (en) * | 2002-10-24 | 2007-10-02 | Idera Pharmaceuticals, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5′ ends |
IL164354A0 (en) | 2002-04-04 | 2005-12-18 | Coley Pharm Gmbh | Immunostimulatory g,u-containing oligoribonucleotides |
US20040053880A1 (en) | 2002-07-03 | 2004-03-18 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7807803B2 (en) | 2002-07-03 | 2010-10-05 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
AR040996A1 (es) | 2002-08-19 | 2005-04-27 | Coley Pharm Group Inc | Acidos nucleicos inmunoestimuladores |
JP2006515277A (ja) | 2002-10-29 | 2006-05-25 | コーリー ファーマシューティカル グループ, リミテッド | C型肝炎ウィルス感染の処置および予防に関する方法および製品 |
WO2004046331A2 (en) | 2002-11-15 | 2004-06-03 | Idenix (Cayman) Limited | 2’-branched nucleosides and flaviviridae mutation |
JP2006512927A (ja) | 2002-12-11 | 2006-04-20 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 5’cpg核酸およびその使用方法 |
US8158768B2 (en) * | 2002-12-23 | 2012-04-17 | Dynavax Technologies Corporation | Immunostimulatory sequence oligonucleotides and methods of using the same |
US7354907B2 (en) * | 2003-02-07 | 2008-04-08 | Idera Pharmaceuticals, Inc. | Short immunomodulatory oligonucleotides |
JP4989225B2 (ja) * | 2003-09-25 | 2012-08-01 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 核酸親油性接合体 |
BRPI0416079A (pt) | 2003-10-30 | 2007-01-02 | Coley Pharm Gmbh | análogos de oligonucleotìdeos de classe c com uma potência imunoestimuladora aumentada |
MY159370A (en) | 2004-10-20 | 2016-12-30 | Coley Pharm Group Inc | Semi-soft-class immunostimulatory oligonucleotides |
PT2078080E (pt) * | 2006-09-27 | 2015-09-18 | Coley Pharm Gmbh | Análogos dos oligonucleotídeos cpg que contêm análogos t hidrofóbicos com atividade imunoestimulante potenciada |
WO2009022215A1 (en) * | 2007-08-13 | 2009-02-19 | Pfizer Inc. | Combination motif immune stimulatory oligonucleotides with improved activity |
RU2010112771A (ru) * | 2007-10-09 | 2011-11-20 | Коули Фармасьютикал ГмбХ (DE) | Иммуностимулирующие аналоги олигонуклеотидов, содержащие модифицированные сахарные группировки |
US8541569B2 (en) * | 2008-09-06 | 2013-09-24 | Chemgenes Corporation | Phosphoramidites for synthetic RNA in the reverse direction, efficient RNA synthesis and convenient introduction of 3'-end ligands, chromophores and modifications of synthetic RNA |
RU2015151857A (ru) | 2008-12-02 | 2019-01-15 | Уэйв Лайф Сайенсес Джапан, Инк. | Способ синтеза модифицированных по атому фосфора нуклеиновых кислот |
KR100998365B1 (ko) * | 2009-06-29 | 2010-12-06 | 압타바이오 주식회사 | 치료 효능이 있는 변형핵산 및 구아노신을 함유하는 올리고뉴클레오티드 변형체 |
AU2010270714B2 (en) | 2009-07-06 | 2015-08-13 | Wave Life Sciences Ltd. | Novel nucleic acid prodrugs and methods use thereof |
DK2575878T3 (en) | 2010-05-28 | 2018-08-13 | Zoetis Belgium S A | VACCINES INCLUDING CHOLESTEROL AND CPG AS THE ONLY ADJUVENT CARRIER MOLECULES |
DK2620428T3 (da) | 2010-09-24 | 2019-07-01 | Wave Life Sciences Ltd | Asymmetrisk hjælpegruppe |
EP2691409B1 (en) | 2011-03-31 | 2018-02-21 | Idenix Pharmaceuticals LLC. | Compounds and pharmaceutical compositions for the treatment of viral infections |
CN107365339A (zh) | 2011-07-19 | 2017-11-21 | 波涛生命科学有限公司 | 合成官能化核酸的方法 |
TW201329096A (zh) * | 2011-09-12 | 2013-07-16 | Idenix Pharmaceuticals Inc | 經取代羰氧基甲基磷酸醯胺化合物及用於治療病毒感染之藥學組成物 |
WO2013177195A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphate prodrugs for hcv infection |
WO2013177188A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
EP2852603B1 (en) | 2012-05-22 | 2021-05-12 | Idenix Pharmaceuticals LLC | D-amino acid compounds for liver disease |
AU2013287630B2 (en) | 2012-07-13 | 2017-05-25 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant |
CA2879023C (en) | 2012-07-13 | 2017-03-28 | Wave Life Sciences Japan | Asymmetric auxiliary group |
CN104661664B (zh) | 2012-07-13 | 2020-07-03 | 波涛生命科学有限公司 | 手性控制 |
EP2900682A1 (en) | 2012-09-27 | 2015-08-05 | IDENIX Pharmaceuticals, Inc. | Esters and malonates of sate prodrugs |
CN111848711A (zh) | 2012-10-08 | 2020-10-30 | 埃迪尼克斯医药有限责任公司 | 用于hcv感染的2′-氯核苷类似物 |
CN104884618A (zh) | 2012-11-15 | 2015-09-02 | 罗氏创新中心哥本哈根有限公司 | 寡核苷酸缀合物 |
US9309275B2 (en) | 2013-03-04 | 2016-04-12 | Idenix Pharmaceuticals Llc | 3′-deoxy nucleosides for the treatment of HCV |
US20140271547A1 (en) | 2013-03-13 | 2014-09-18 | Idenix Pharmaceuticals, Inc. | Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv |
EP3542819B1 (en) * | 2013-05-14 | 2021-08-18 | Zoetis Services LLC | Novel vaccine compositions comprising immunostimulatory oligonucleotides |
WO2014197578A1 (en) | 2013-06-05 | 2014-12-11 | Idenix Pharmaceuticals, Inc. | 1',4'-thio nucleosides for the treatment of hcv |
WO2015017713A1 (en) | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
JP6586083B2 (ja) * | 2013-09-19 | 2019-10-02 | ゾエティス・サービシーズ・エルエルシー | 油性アジュバント |
CN105925583B (zh) * | 2013-11-08 | 2019-05-17 | 上海交通大学 | 被修饰的含CpG序列单元的寡聚脱氧核苷酸分子及其用途 |
BR112016012127A2 (pt) | 2013-11-26 | 2017-09-26 | Zoetis Services Llc | composições para a indução da resposta imunológica |
JPWO2015108046A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗アレルギー作用を有するキラル核酸アジュバンド及び抗アレルギー剤 |
EP3095461A4 (en) | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator |
JPWO2015108048A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
KR20230152178A (ko) | 2014-01-16 | 2023-11-02 | 웨이브 라이프 사이언시스 리미티드 | 키랄 디자인 |
WO2015161137A1 (en) | 2014-04-16 | 2015-10-22 | Idenix Pharmaceuticals, Inc. | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
LT3240801T (lt) | 2014-12-31 | 2021-02-25 | Checkmate Pharmaceuticals, Inc. | Kombinuota navikų imunoterapija |
KR20170097116A (ko) * | 2015-01-16 | 2017-08-25 | 조에티스 서비시즈 엘엘씨 | 구제역 백신 |
US10456459B2 (en) | 2015-07-20 | 2019-10-29 | Zoetis Services Llc | Liposomal adjuvant compositions |
CN108713061B (zh) * | 2016-03-09 | 2022-04-05 | 学校法人东京理科大学 | Rna杂交形成用核酸低聚物 |
AU2017274332B2 (en) | 2016-06-02 | 2024-06-27 | Zoetis Services Llc | Vaccine against infectious bronchitis |
US11013757B2 (en) * | 2016-06-03 | 2021-05-25 | Wave Life Sciences Ltd. | Oligonucleotides, compositions and methods thereof |
GB201703529D0 (en) | 2017-03-06 | 2017-04-19 | Cambridge Entpr Ltd | Vaccine composition |
KR20200006972A (ko) | 2017-04-14 | 2020-01-21 | 톨나인, 인크. | 면역조절 폴리뉴클레오티드, 이의 항체 접합체, 및 이의 사용 방법 |
CN107090009B (zh) * | 2017-04-14 | 2019-10-25 | 佛山科学技术学院 | 一种二糖核苷化合物及其制备方法 |
SG11202004773SA (en) | 2017-12-15 | 2020-06-29 | Bayer Animal Health Gmbh | Immunostimulatory compositions |
BR112020011962A2 (pt) | 2017-12-20 | 2020-11-17 | Zoetis Services Llc | vacinas contra infecção de vírus hendra e nipah |
US11639364B2 (en) | 2018-01-29 | 2023-05-02 | Stichting Radboud Universiteit | Potent sialyltransferase inhibitors |
TW202206098A (zh) | 2020-08-11 | 2022-02-16 | 美商碩騰服務公司 | 抗冠狀病毒疫苗 |
WO2024077025A1 (en) | 2022-10-04 | 2024-04-11 | Zoetis Services Llc | Poultry vaccines and methods of protecting poultry |
Family Cites Families (166)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4469863A (en) | 1980-11-12 | 1984-09-04 | Ts O Paul O P | Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof |
JP2547714B2 (ja) | 1981-10-23 | 1996-10-23 | モルキユラ− バイオシステムズ インコ−ポレテツド | オリゴヌクレオチド治療剤及びその製法 |
US5023243A (en) | 1981-10-23 | 1991-06-11 | Molecular Biosystems, Inc. | Oligonucleotide therapeutic agent and method of making same |
CA1339596C (en) | 1987-08-07 | 1997-12-23 | New England Medical Center Hospitals, Inc. | Viral expression inhibitors |
US4958013A (en) | 1989-06-06 | 1990-09-18 | Northwestern University | Cholesteryl modified oligonucleotides |
US5399676A (en) | 1989-10-23 | 1995-03-21 | Gilead Sciences | Oligonucleotides with inverted polarity |
US5177198A (en) | 1989-11-30 | 1993-01-05 | University Of N.C. At Chapel Hill | Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates |
EP0468520A3 (en) | 1990-07-27 | 1992-07-01 | Mitsui Toatsu Chemicals, Inc. | Immunostimulatory remedies containing palindromic dna sequences |
ATE154246T1 (de) | 1990-07-27 | 1997-06-15 | Isis Pharmaceuticals Inc | Nuklease resistente, pyrimidin modifizierte oligonukleotide, die die gen-expression detektieren und modulieren |
WO1992016192A1 (en) | 1991-03-15 | 1992-10-01 | Amgen Inc. | Pulmonary administration of granulocyte colony stimulating factor |
RU95104940A (ru) | 1992-07-27 | 1997-01-10 | Хайбрайдон | Способ введения в олигонуклеотид алкилфосфонотиоатной или арилфосфонотиоатной межнуклеотидной связи, способ получения олигонуклеотида, олигонуклеотиды, способ ингибирования генной экспрессии, способ лечения |
DE4321946A1 (de) | 1993-07-01 | 1995-01-12 | Hoechst Ag | Methylphosphonsäureester, Verfahren zu deren Herstellung und deren Verwendung |
US6605708B1 (en) | 1993-07-28 | 2003-08-12 | Hybridon, Inc. | Building blocks with carbamate internucleoside linkages and oligonucleotides derived therefrom |
US5859231A (en) | 1993-09-03 | 1999-01-12 | Duke University | Synthesis of oligonucleotides with boranophosphonate linkages |
DE4338704A1 (de) | 1993-11-12 | 1995-05-18 | Hoechst Ag | Stabilisierte Oligonucleotide und deren Verwendung |
US5646126A (en) | 1994-02-28 | 1997-07-08 | Epoch Pharmaceuticals | Sterol modified oligonucleotide duplexes having anticancer activity |
US5596091A (en) | 1994-03-18 | 1997-01-21 | The Regents Of The University Of California | Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides |
WO1995026204A1 (en) | 1994-03-25 | 1995-10-05 | Isis Pharmaceuticals, Inc. | Immune stimulation by phosphorothioate oligonucleotide analogs |
US6727230B1 (en) | 1994-03-25 | 2004-04-27 | Coley Pharmaceutical Group, Inc. | Immune stimulation by phosphorothioate oligonucleotide analogs |
US5451569A (en) | 1994-04-19 | 1995-09-19 | Hong Kong University Of Science And Technology R & D Corporation Limited | Pulmonary drug delivery system |
US5658738A (en) | 1994-05-31 | 1997-08-19 | Becton Dickinson And Company | Bi-directional oligonucleotides that bind thrombin |
US5696248A (en) | 1994-06-15 | 1997-12-09 | Hoechst Aktiengesellschaft | 3'-modified oligonucleotide derivatives |
US20030050263A1 (en) | 1994-07-15 | 2003-03-13 | The University Of Iowa Research Foundation | Methods and products for treating HIV infection |
US6239116B1 (en) | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US20030026782A1 (en) | 1995-02-07 | 2003-02-06 | Arthur M. Krieg | Immunomodulatory oligonucleotides |
US7935675B1 (en) | 1994-07-15 | 2011-05-03 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US6429199B1 (en) | 1994-07-15 | 2002-08-06 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules for activating dendritic cells |
ATE328890T1 (de) * | 1994-07-15 | 2006-06-15 | Univ Iowa Res Found | Immunomodulatorische oligonukleotide |
US6207646B1 (en) | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
DE19502912A1 (de) | 1995-01-31 | 1996-08-01 | Hoechst Ag | G-Cap Stabilisierte Oligonucleotide |
US5968909A (en) | 1995-08-04 | 1999-10-19 | Hybridon, Inc. | Method of modulating gene expression with reduced immunostimulatory response |
US6160109A (en) | 1995-10-20 | 2000-12-12 | Isis Pharmaceuticals, Inc. | Preparation of phosphorothioate and boranophosphate oligomers |
US6030955A (en) | 1996-03-21 | 2000-02-29 | The Trustees Of Columbia University In The City Of New York And Imclone Systems, Inc. | Methods of affecting intracellular phosphorylation of tyrosine using phosphorothioate oligonucleotides, and antiangiogenic and antiproliferative uses thereof |
US5856462A (en) | 1996-09-10 | 1999-01-05 | Hybridon Incorporated | Oligonucleotides having modified CpG dinucleosides |
EP1537877A3 (en) | 1996-10-11 | 2005-08-03 | The Regents Of The University Of California | Immunostimulatory polynucleotide/immunomodulatory molecule conjugates |
EP0855184A1 (en) | 1997-01-23 | 1998-07-29 | Grayson B. Dr. Lipford | Pharmaceutical composition comprising a polynucleotide and an antigen especially for vaccination |
EP1039935A4 (en) * | 1997-02-28 | 2005-04-27 | Univ Iowa Res Found | USE OF NUCLEIC ACIDS CONTAINING NON-METHYLATED CpG DINUCLEOTIDES IN THE TREATMENT OF LIPOPOLYSACCHARIDE-ASSOCIATED ILLNESSES |
US6406705B1 (en) | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
US6426334B1 (en) | 1997-04-30 | 2002-07-30 | Hybridon, Inc. | Oligonucleotide mediated specific cytokine induction and reduction of tumor growth in a mammal |
CA2289741A1 (en) | 1997-05-19 | 1998-11-26 | Merck & Co., Inc. | Oligonucleotide adjuvant |
US6339068B1 (en) * | 1997-05-20 | 2002-01-15 | University Of Iowa Research Foundation | Vectors and methods for immunization or therapeutic protocols |
US6589940B1 (en) | 1997-06-06 | 2003-07-08 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
US20040006034A1 (en) | 1998-06-05 | 2004-01-08 | Eyal Raz | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
WO1999001154A1 (en) | 1997-07-03 | 1999-01-14 | University Of Iowa Research Foundation | Method for inhibiting immunostimulatory dna associated responses |
DE69935507T2 (de) * | 1998-04-03 | 2007-12-06 | University Of Iowa Research Foundation | Verfahren und produkte zur stimulierung des immunsystems mittels immunotherapeutischer oligonukleotide und zytokine |
EP1077708A1 (en) | 1998-05-06 | 2001-02-28 | University Of Iowa Research Foundation | Methods for the prevention and treatment of parasitic infections and related diseases using cpg oligonucleotides |
EP1078053B1 (en) | 1998-05-14 | 2005-09-28 | Coley Pharmaceutical GmbH | METHODS FOR REGULATING HEMATOPOIESIS USING CpG-OLIGONUCLEOTIDES |
EP1077722B1 (en) | 1998-05-22 | 2006-08-09 | Ottawa Health Research Institute | Methods and products for inducing mucosal immunity |
US6562798B1 (en) | 1998-06-05 | 2003-05-13 | Dynavax Technologies Corp. | Immunostimulatory oligonucleotides with modified bases and methods of use thereof |
US20040247662A1 (en) | 1998-06-25 | 2004-12-09 | Dow Steven W. | Systemic immune activation method using nucleic acid-lipid complexes |
JP2002521489A (ja) | 1998-07-27 | 2002-07-16 | ユニバーシティ オブ アイオワ リサーチ ファウンデーション | CpGオリゴヌクレオチドの立体異性体および関連する方法 |
WO2000014217A2 (en) | 1998-09-03 | 2000-03-16 | Coley Pharmaceutical Gmbh | G-motif oligonucleotides and uses thereof |
FR2783170B1 (fr) | 1998-09-11 | 2004-07-16 | Pasteur Merieux Serums Vacc | Emulsion immunostimulante |
US6207819B1 (en) | 1999-02-12 | 2001-03-27 | Isis Pharmaceuticals, Inc. | Compounds, processes and intermediates for synthesis of mixed backbone oligomeric compounds |
WO2000054803A2 (en) | 1999-03-16 | 2000-09-21 | Panacea Pharmaceuticals, Llc | Immunostimulatory nucleic acids and antigens |
US6977245B2 (en) | 1999-04-12 | 2005-12-20 | The United States Of America As Represented By The Department Of Health And Human Services | Oligodeoxynucleotide and its use to induce an immune response |
EP1176966B1 (en) | 1999-04-12 | 2013-04-03 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Oligodeoxynucleotide and its use to induce an immune response |
US6558670B1 (en) | 1999-04-19 | 2003-05-06 | Smithkline Beechman Biologicals S.A. | Vaccine adjuvants |
AU4978100A (en) | 1999-04-29 | 2000-11-17 | Coley Pharmaceutical Gmbh | Screening for immunostimulatory dna functional modifyers |
OA11937A (en) | 1999-05-06 | 2006-04-12 | Immune Response Corp Inc | HIV immunogenic compositions and methods. |
US6479504B1 (en) | 1999-06-16 | 2002-11-12 | The University Of Iowa Research Foundation | Antagonism of immunostimulatory CpG-oligonucleotides by 4-aminoquinolines and other weak bases |
US6514948B1 (en) | 1999-07-02 | 2003-02-04 | The Regents Of The University Of California | Method for enhancing an immune response |
DK1200580T3 (da) | 1999-08-13 | 2005-04-11 | Hybridon Inc | Modulering af oligonukleotid-CpG-medieret immunstimulering ved positionel modifikation |
DK1221955T3 (da) | 1999-09-25 | 2006-01-30 | Univ Iowa Res Found | Immunstimulerende nukleinsyre |
US6949520B1 (en) | 1999-09-27 | 2005-09-27 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
JP2003510290A (ja) | 1999-09-27 | 2003-03-18 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 免疫刺激核酸誘導インターフェロンに関する方法 |
US20070031446A1 (en) | 2003-07-11 | 2007-02-08 | Intercell Ag | Hcv vaccines |
US7223398B1 (en) | 1999-11-15 | 2007-05-29 | Dynavax Technologies Corporation | Immunomodulatory compositions containing an immunostimulatory sequence linked to antigen and methods of use thereof |
WO2001045750A1 (en) | 1999-12-21 | 2001-06-28 | The Regents Of The University Of California | Method for preventing an anaphylactic reaction |
EP1311288A1 (en) | 2000-01-20 | 2003-05-21 | Ottawa Health Research Institute | Immunostimulatory nucleic acids for inducing a th2 immune response |
ATE382690T1 (de) | 2000-01-26 | 2008-01-15 | Idera Pharmaceuticals Inc | Modulierung der durch cpg-oligonukleotide verursachte immunstimulierung durch positionsbedingte veränderung von nukleosiden |
US7585847B2 (en) | 2000-02-03 | 2009-09-08 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for the treatment of asthma and allergy |
US20020156033A1 (en) | 2000-03-03 | 2002-10-24 | Bratzler Robert L. | Immunostimulatory nucleic acids and cancer medicament combination therapy for the treatment of cancer |
US20040131628A1 (en) | 2000-03-08 | 2004-07-08 | Bratzler Robert L. | Nucleic acids for the treatment of disorders associated with microorganisms |
US7129222B2 (en) * | 2000-03-10 | 2006-10-31 | Dynavax Technologies Corporation | Immunomodulatory formulations and methods for use thereof |
JP2003531915A (ja) * | 2000-05-01 | 2003-10-28 | ハイブリドン・インコーポレイテッド | ヌクレオシドの位置的修飾によるオリゴヌクレオチドCpG誘導性免疫刺激の調節 |
US20020013287A1 (en) | 2000-05-09 | 2002-01-31 | Reliable Biopharmaceuticals, Inc. St Louis Missouri | Polymeric compounds useful as prodrugs |
CA2412026A1 (en) | 2000-06-07 | 2001-12-13 | Biosynexus Incorporated | Immunostimulatory rna/dna hybrid molecules |
SI1296714T1 (sl) | 2000-06-22 | 2010-01-29 | S For Entpr University Of Iowa | Kombinacija CpG-ja in protiteles, usmerjenih proti CD19, CD20, CD22 ali CD40 za zdravljenje ali preprečevanje raka |
US20020165178A1 (en) | 2000-06-28 | 2002-11-07 | Christian Schetter | Immunostimulatory nucleic acids for the treatment of anemia, thrombocytopenia, and neutropenia |
US20020198165A1 (en) | 2000-08-01 | 2002-12-26 | Bratzler Robert L. | Nucleic acids for the prevention and treatment of gastric ulcers |
US20020091097A1 (en) | 2000-09-07 | 2002-07-11 | Bratzler Robert L. | Nucleic acids for the prevention and treatment of sexually transmitted diseases |
CA2419894A1 (en) | 2000-09-15 | 2002-03-21 | Coley Pharmaceutical Gmbh | Process for high throughput screening of cpg-based immuno-agonist/antagonist |
ATE384072T1 (de) | 2000-09-26 | 2008-02-15 | Idera Pharmaceuticals Inc | Modulation der immunostimulatorischen aktivität von immunostimulierenden oligonukleotidanaloga durch positionelle chemische veränderungen |
FR2814958B1 (fr) | 2000-10-06 | 2003-03-07 | Aventis Pasteur | Composition vaccinale |
GB0025577D0 (en) | 2000-10-18 | 2000-12-06 | Smithkline Beecham Biolog | Vaccine |
ES2307568T3 (es) | 2000-12-08 | 2008-12-01 | Coley Pharmaceutical Gmbh | Acidos nucleicos de tipo cpg y metodos de uso de los mismos. |
WO2002053141A2 (en) | 2000-12-14 | 2002-07-11 | Coley Pharmaceutical Group, Inc. | Inhibition of angiogenesis by nucleic acids |
US20030050268A1 (en) | 2001-03-29 | 2003-03-13 | Krieg Arthur M. | Immunostimulatory nucleic acid for treatment of non-allergic inflammatory diseases |
US7105495B2 (en) | 2001-04-30 | 2006-09-12 | Idera Pharmaceuticals, Inc. | Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides |
US7176296B2 (en) | 2001-04-30 | 2007-02-13 | Idera Pharmaceuticals, Inc. | Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides |
US20030129605A1 (en) | 2001-05-04 | 2003-07-10 | Dong Yu | Immunostimulatory activity of CpG oligonucleotides containing non-ionic methylphosophonate linkages |
US20040132677A1 (en) | 2001-06-21 | 2004-07-08 | Fearon Karen L. | Chimeric immunomodulatory compounds and methods of using the same-IV |
EP2423335B1 (en) | 2001-06-21 | 2014-05-14 | Dynavax Technologies Corporation | Chimeric immunomodulatory compounds and methods of using the same |
US20030148316A1 (en) | 2001-08-01 | 2003-08-07 | Lipford Grayson B. | Methods and compositions relating to plasmacytoid dendritic cells |
WO2003014316A2 (en) | 2001-08-07 | 2003-02-20 | Dynavax Technologies Corporation | Immunomodulatory compositions, formulations, and methods for use thereof |
EP1446162B1 (en) * | 2001-08-17 | 2008-10-15 | Coley Pharmaceutical GmbH | Combination motif immune stimulatory oligonucleotides with improved activity |
WO2003031573A2 (en) | 2001-10-05 | 2003-04-17 | Coley Pharmaceutical Gmbh | Toll-like receptor 3 signaling agonists and antagonists |
JP2005519990A (ja) | 2001-10-12 | 2005-07-07 | ユニバーシティ オブ アイオワ リサーチ ファウンデーション | イミダゾキノリン化合物を用いて免疫応答を増強するための方法および産物 |
US7276489B2 (en) | 2002-10-24 | 2007-10-02 | Idera Pharmaceuticals, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5′ ends |
WO2003035836A2 (en) | 2001-10-24 | 2003-05-01 | Hybridon Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5' ends |
JP2005526497A (ja) | 2002-02-04 | 2005-09-08 | ビオミラ,インコーポレーテッド | 免疫刺激性、共有結合性脂質化オリゴヌクレオチド |
IL164354A0 (en) * | 2002-04-04 | 2005-12-18 | Coley Pharm Gmbh | Immunostimulatory g,u-containing oligoribonucleotides |
AU2003219383B2 (en) | 2002-04-22 | 2010-08-26 | Bioniche Life Sciences Inc. | Oligonucleotide compositions and their use for the modulation of immune responses |
WO2003094963A2 (en) | 2002-05-10 | 2003-11-20 | Inex Pharmaceuticals Corporation | Methylated immunostimulatory oligonucleotides and methods of using the same |
CA2388049A1 (en) | 2002-05-30 | 2003-11-30 | Immunotech S.A. | Immunostimulatory oligonucleotides and uses thereof |
AU2003243409A1 (en) | 2002-06-05 | 2003-12-22 | Coley Pharmaceutical Group, Inc. | Method for treating autoimmune or inflammatory diseases with combinations of inhibitory oligonucleotides and small molecule antagonists of immunostimulatory cpg nucleic acids |
US7576066B2 (en) | 2002-07-03 | 2009-08-18 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US20040053880A1 (en) * | 2002-07-03 | 2004-03-18 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7569553B2 (en) | 2002-07-03 | 2009-08-04 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7605138B2 (en) | 2002-07-03 | 2009-10-20 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7807803B2 (en) | 2002-07-03 | 2010-10-05 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
JP2005532067A (ja) * | 2002-07-03 | 2005-10-27 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 刺激性免疫応答用の核酸組成物 |
AU2003255969A1 (en) | 2002-07-17 | 2004-02-02 | Coley Pharmaceutical Gmbh | Use of cpg nucleic acids in prion-disease |
AR040996A1 (es) * | 2002-08-19 | 2005-04-27 | Coley Pharm Group Inc | Acidos nucleicos inmunoestimuladores |
CN1688192B (zh) * | 2002-08-19 | 2012-07-18 | 科勒制药集团有限公司 | 免疫刺激核酸 |
WO2004026888A2 (en) | 2002-09-19 | 2004-04-01 | Coley Pharmaceutical Gmbh | Toll-like receptor 9 (tlr9) from various mammalian species |
JP2006515277A (ja) | 2002-10-29 | 2006-05-25 | コーリー ファーマシューティカル グループ, リミテッド | C型肝炎ウィルス感染の処置および予防に関する方法および製品 |
JP2006512927A (ja) | 2002-12-11 | 2006-04-20 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 5’cpg核酸およびその使用方法 |
US7625872B2 (en) | 2002-12-23 | 2009-12-01 | Dynavax Technologies Corporation | Branched immunomodulatory compounds and methods of using the same |
MXPA05007652A (es) | 2003-01-16 | 2006-02-22 | Hybridon Inc | Modulacion de propiedades inmunoestimulantes de compuestos basados en oligonucleotido mediante la utilizacion de dinucleotidos inmunoestimulantes modificados. |
WO2004087203A2 (en) | 2003-04-02 | 2004-10-14 | Coley Pharmaceutical Group, Ltd. | Immunostimulatory nucleic acid oil-in-water formulations for topical application |
WO2005016235A2 (en) | 2003-04-14 | 2005-02-24 | The Regents Of The University Of California | Combined use of impdh inhibitors with toll-like receptor agonists |
EP1631687A2 (en) | 2003-04-22 | 2006-03-08 | Coley Pharmaceutical GmbH | Methods and products for identification and assessment of tlr ligands |
US7569554B2 (en) | 2003-05-16 | 2009-08-04 | Idera Pharmaceuticals, Inc. | Synergistic treatment of cancer using immunomers in conjunction with therapeutic agents |
AU2004252505B2 (en) | 2003-06-11 | 2010-10-28 | Idera Pharmaceuticals, Inc. | Stabilized immunomodulatory oligonucleotides |
KR20060016817A (ko) | 2003-06-20 | 2006-02-22 | 콜리 파마슈티칼 게엠베하 | 소분자 톨-유사 수용체 (tlr) 길항제 |
US20050013812A1 (en) | 2003-07-14 | 2005-01-20 | Dow Steven W. | Vaccines using pattern recognition receptor-ligand:lipid complexes |
EP2363141A1 (en) | 2003-07-15 | 2011-09-07 | Idera Pharmaceuticals, Inc. | Compsition comprising two oligonucleotides linked directly at their 3'ends wherein at leat one oligonucleotide has an accessible 5'end and the compound further comprising IL-2 used for synergistically stimulating an immune response in a patient. |
US20070110714A1 (en) | 2003-09-08 | 2007-05-17 | Norio Hayashi | Medicinal composition for treatment of chronic hepatitis c |
JP4989225B2 (ja) | 2003-09-25 | 2012-08-01 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 核酸親油性接合体 |
US20050215501A1 (en) | 2003-10-24 | 2005-09-29 | Coley Pharmaceutical Group, Inc. | Methods and products for enhancing epitope spreading |
BRPI0416079A (pt) | 2003-10-30 | 2007-01-02 | Coley Pharm Gmbh | análogos de oligonucleotìdeos de classe c com uma potência imunoestimuladora aumentada |
US20050239733A1 (en) | 2003-10-31 | 2005-10-27 | Coley Pharmaceutical Gmbh | Sequence requirements for inhibitory oligonucleotides |
US20050100983A1 (en) | 2003-11-06 | 2005-05-12 | Coley Pharmaceutical Gmbh | Cell-free methods for identifying compounds that affect toll-like receptor 9 (TLR9) signaling |
KR101138131B1 (ko) | 2003-12-08 | 2012-04-23 | 이데라 파마슈티칼즈, 인코포레이티드 | 작은 올리고뉴클레오티드-기초 화합물에 의한 면역자극특성의 조절 |
JP2007526253A (ja) | 2004-02-19 | 2007-09-13 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 免疫刺激性ウイルスrnaオリゴヌクレオチド |
CA2557443A1 (en) | 2004-03-12 | 2005-09-29 | Hybridon, Inc. | Enhanced activity of hiv vaccine using a second generation immunomodulatory oligonucleotide |
US20060019916A1 (en) | 2004-04-02 | 2006-01-26 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for inducing IL-10 responses |
WO2006080946A2 (en) | 2004-06-08 | 2006-08-03 | Coley Pharmaceutical Gmbh | Abasic oligonucleotide as carrier platform for antigen and immunostimulatory agonist and antagonist |
EP2901856B1 (en) | 2004-06-15 | 2017-08-09 | Idera Pharmaceuticals, Inc. | Immunostimulatory oligonucleotide multimers |
AU2005333126A1 (en) | 2004-07-18 | 2006-12-21 | Csl Limited | Methods and compositions for inducing innate immune responses |
US20060287263A1 (en) | 2004-07-18 | 2006-12-21 | Csl Limited | Methods and compositions for inducing antigen-specific immune responses |
MY159370A (en) | 2004-10-20 | 2016-12-30 | Coley Pharm Group Inc | Semi-soft-class immunostimulatory oligonucleotides |
CA2598992A1 (en) | 2005-02-24 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Immunostimulatory oligonucleotides |
KR20080008350A (ko) | 2005-04-08 | 2008-01-23 | 콜레이 파마시티컬 그룹, 인코포레이티드 | 감염성 질환에 의해 악화된 천식의 치료 방법 |
AU2006241149A1 (en) | 2005-04-26 | 2006-11-02 | Coley Pharmaceutical Gmbh | Modified oligoribonucleotide analogs with enhanced immunostimulatory activity |
MX2008000379A (es) | 2005-07-07 | 2008-03-18 | Coley Pharm Group Inc | Anticuerpo anti-citla-1 y terapia de combinacio con oligodesoxinucleotido sintetico que contiene motivo cpg. |
CN101310019A (zh) | 2005-09-16 | 2008-11-19 | 科利制药公司 | 具有磷酸二酯主链的免疫刺激性单链核糖核酸 |
AU2006290435A1 (en) | 2005-09-16 | 2007-03-22 | Coley Pharmaceutical Gmbh | Modulation of immunostimulatory properties of short interfering ribonucleic acid (siRNA) by nucleotide modification |
CA2626547A1 (en) | 2005-10-21 | 2007-05-03 | Medical College Of Georgia Research Institute, Inc. | The induction of indoleamine 2,3-dioxygenase in dendritic cells by tlr ligands and uses thereof |
US20070093439A1 (en) | 2005-10-25 | 2007-04-26 | Idera Pharmaceuticals, Inc. | Short immunomodulatory oligonucleotides |
US7470674B2 (en) | 2005-11-07 | 2008-12-30 | Idera Pharmaceuticals, Inc. | Immunostimulatory properties of oligonucleotide-based compounds comprising modified immunostimulatory dinucleotides |
WO2007062107A2 (en) | 2005-11-25 | 2007-05-31 | Coley Pharmaceutical Gmbh | Immunostimulatory oligoribonucleotides |
CN101379195B (zh) | 2005-12-20 | 2012-05-09 | 艾德拉药物股份有限公司 | 含有不同长度回文片段的回文免疫调节性寡核苷酸(imotm)的免疫刺激活性 |
US20080045473A1 (en) | 2006-02-15 | 2008-02-21 | Coley Pharmaceutical Gmbh | Compositions and methods for oligonucleotide formulations |
DE102006007433A1 (de) | 2006-02-17 | 2007-08-23 | Curevac Gmbh | Adjuvanz in Form einer Lipid-modifizierten Nukleinsäure |
US8027888B2 (en) | 2006-08-31 | 2011-09-27 | Experian Interactive Innovation Center, Llc | Online credit card prescreen systems and methods |
WO2008033432A2 (en) | 2006-09-12 | 2008-03-20 | Coley Pharmaceutical Group, Inc. | Immune modulation by chemically modified ribonucleosides and oligoribonucleotides |
PT2078080E (pt) * | 2006-09-27 | 2015-09-18 | Coley Pharm Gmbh | Análogos dos oligonucleotídeos cpg que contêm análogos t hidrofóbicos com atividade imunoestimulante potenciada |
AU2007300378A1 (en) | 2006-09-27 | 2008-04-03 | Coley Pharmaceutical Gmbh | Compositions of TLR ligands and antivirals |
WO2008139262A2 (en) | 2006-10-26 | 2008-11-20 | Coley Pharmaceutical Gmbh | Oligoribonucleotides and uses thereof |
WO2008057529A2 (en) | 2006-11-06 | 2008-05-15 | Coley Pharmaceutical Group, Inc. | Peptide-based vaccine compositions to endogenous cholesteryl ester transfer protein (cetp) |
MX2009012482A (es) | 2007-05-17 | 2009-12-02 | Coley Pharm Group Inc | Oligonucleotidos de clase a con potencia inmunoestimuladora. |
RU2010112771A (ru) | 2007-10-09 | 2011-11-20 | Коули Фармасьютикал ГмбХ (DE) | Иммуностимулирующие аналоги олигонуклеотидов, содержащие модифицированные сахарные группировки |
US9968305B1 (en) | 2014-10-02 | 2018-05-15 | James S Brown | System and method of generating music from electrical activity data |
-
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