JP2011518170A - カチオン性脂質の鏡像異性体による免疫応答の刺激 - Google Patents
カチオン性脂質の鏡像異性体による免疫応答の刺激 Download PDFInfo
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Abstract
【選択図】 図1A
Description
an, C, and Anderson, D. E. Immune regulation in tumor-bearing hosts. Curr Opin Immunol 18:214 (2006)〕。
本出願は、Elizabeth Vasievich、Weihsu Chen、Kenya Toney、Gregory Conn、Frank Bedu-Addo及びLeaf Huangにより2008年4月17日に出願され、表題が“Stimulation of an Immune Response by Enantiomers of Cationic Lipids”の米国仮出願第61/045,837号の利益を請求し、この開示はその全体が参照として本明細書に組み込まれる。
本発明のキラルカチオン性脂質複合体は、場合により抗原と混合されてもよいリポソームを形成することができ、キラルカチオン性脂質のみ、又は中性脂質と組み合わせたキラルカチオン性脂質を含有することができる。適切なキラルカチオン性脂質種としては、以下に挙げるもののR及びS鏡像異性体が含まれるが、但しこれらに限定されない:3−β〔4N−(1N,8−ジグアニジノスペルミジン)−カルバモイル〕コレステロール(BGSC);3−β〔N,N−ジグアニジノエチル−アミノエタン)−カルバモイル〕コレステロール(BGTC);N,N1N2N3テトラ−メチルテトラパルミチルスペルミン(セルフェクチン);N−t−ブチル−N′−テトラデシル−3−テトラデシル−アミノプロピオン−アミジン(CLONフェクチン);ジメチルジオクタデシルアンモニウムブロミド(DDAB);1,2−ジミリスチルオキシプロピル−3−ジメチル−ヒドロキシエチルアンモニウムブロミド(DMRIE);2,3−ジオレオイルオキシ−N−〔2−(スペルミンカルボキシアミド)エチル〕−N,N−ジメチル−1−プロパンアミニウムトリフルオロアセテート)(DOSPA);1,3−ジオレオイルオキシ−2−(6−カルボキシスペルミル)−プロピルアミド(DOSPER);4−(2,3−ビス−パルミトイルオキシ−プロピル)−1−メチル−1H−イミダゾール(DPIM);N,N,N′,N′−テトラメチル−N,N′−ビス(2−ヒドロキシエチル)−2,3−ジオレオイルオキシ−1,4−ブタンジアンモニウムヨージド)(Tfx−50);N−1−(2,3−ジオレオイルオキシ)プロピル−N,N,N−トリメチルアンモニウムクロリド(DOTMA)又は他のN−(N,N−1−ジアルコキシ)−アルキル−N,N,N−三置換アンモニウム界面活性剤;1,2−ジオレオイル−3−(4′−トリメチルアンモニオ)ブタノール−sn−グリセロール(DOBT)又はトリメチルアンモニウム基がブタノールスペーサーアームを介して二重鎖(DOTB)若しくはコレステリル基(ChOTB)に連結しているコレステリル(4′−トリメチルアンモニア)ブタノエート(ChOTB);DORI(DL−1,2−ジオレオイル−3−ジメチルアミノプロピル−β−ヒドロキシエチルアンモニウム)若しくはDORIE(DL−1,2−O−ジオレオイル−3−ジメチルアミノプロピル−β−ヒドロキシエチルアンモニウム)(DORIE)又はWO93/03709に開示されているこれらの類似体;1,2−ジオレオイル−3−スクシニル−sn−グリセロールコリンエステル(DOSC);コレステリルヘミスクシネートエステル(ChOSC);ジオクタデシルアミドグルシルスペルミン(DOGS)及びジパルミトイルホスファチジルエタノールアミンスペルミン(DPPES)又は米国特許第5,283,185号に開示されているカチオン性脂質、コレステリル−3β−カルボキシル−アミド−エチレントリメチルアンモニウムヨージド、1−ジメチルアミノ−3−トリメチルアンモニオ−DL−2−プロピル−コレステリルカルボキシレートヨージド、コレステリル−3−O−カルボキシアミドエチレンアミン、コレステリル−3−β−オキシスクシンアミド−エチレントリメチルアンモニウムヨージド、1−ジメチルアミノ−3−トリメチルアンモニオ−DL−2−プロピル−コレステリル−3−β−オキシスクシネートヨージド、2−(2−トリメチルアンモニオ)−エチルメチルアミノエチル−コレステリル−3−β−オキシスクシネートヨージド、3−β−N−(N′,N′−ジメチルアミノエタン)カルバモイルコレステロール(DC−chol)及び3−β−N−(ポリエチレンイミン)−カルバモイルコレステロールのようなリポポリアミン;O,O′−ジミリスチル−N−リシルアスパルテート(DMKE);O,O′−ジミリスチル−N−リシル−グルタメート(DMKD);1,2−ジミリスチルオキシプロピル−3−ジメチル−ヒドロキシエチルアンモニウムブロミド(DMRIE);1,2−ジラウロリル−sn−グレセロ−3−エチルホスホコリン(DLEPC);1,2−ジミリストイル−sn−グリセロ−3−エチルホスホコリン(DMEPC);1,2−ジオレオイル−sn−グリセロ−3−エチルホスホコリン(DOEPC);1,2−ジパルミトイル−sn−グリセロ−3−エチルホスホコリン(DPEPC);1,2−ジステアロイル−sn−グリセロ−3−エチルホスホコリン(DSEPC);1,2−ジオレオイル−3−トリメチルアンモニウムプロパン(DOTAP);ジオレオイルジメチルアミノプロパン(DODAP);1,2−パルミトイル−3−トリメチルアンモニウムプロパン(DPTAP);1,2−ジステアロイル−3−トリメチルアンモニウムプロパン(DSTAP);1,2−ミリストイル−3−トリメチルアンモニウムプロパン(DMTAP);並びにナトリウムドデシルスルフェート(SDS)。本発明は、本明細書に開示されているカチオン性脂質の構造変異体及び誘導体の使用を考慮する。
一つの実施態様において、キラルカチオン性脂質は、他の免疫調節物質の産生を含む多様な免疫応答を上げる又は下げるため、及び疾患と闘う免疫応答を増進するため、任意の追加の作用物質を用いることなく投与される。別の実施態様において、キラルカチオン性脂質は、1つの抗原又は複数の抗原と組み合わせて投与される。この場合、目的は、カチオン性脂質と組み合わせて送達される抗原に特異的な免疫応答を生じさせることである。生じる応答には、特定の細胞毒性T細胞、記憶T細胞、又は抗原に関連する特定の疾患の予防若しくは治療応答をもたらすB細胞を含めることができる。抗原は、任意の腫瘍関連抗原若しくは微生物抗原又は当業者に既知の他の任意の抗原であることができる。
<カチオン性脂質の鏡像異性体による免疫系の効果的な刺激>
1.細胞株及びペプチド
TC−1細胞は、HPV16 E6及びE7腫瘍遺伝子と活性化H−rasでで形質転換された、C57BL/6マウス肺内皮細胞である。細胞を、10%ウシ胎児血清及び100U/mlのペニシリン及び100mg/mlのストレプトマイシンを補充したRPMI培地(Carlsbad, CAのInvitrogenにより販売)において増殖させた。HPV16 E7タンパク質(アミノ酸11〜20、YMLDLQPETT〔配列番号1〕)のMHCクラスI拘束性ペプチドを、Pittsburgh Peptide Synthesis Facilityにおいて、Advanced ChemTech200型ペプチド合成機を使用した固相合成により合成し、HPLCにより精製した。
DOTAPの鏡像異性体は、Merck AG(EPROVA), Switzerlandから供給された。他の脂質は、全て、Avanti Polar Lipids(Alabaster, AL)から購入した。小型単層DOTAPリポソームは、薄膜水和、続く押出しにより調製した。クロロホルム中の脂質を、ガラス管の中で窒素流により薄層として乾燥した。薄膜を2〜3時間真空乾燥し、次に、細胞培養等級水(Walkersville, MDのCambrexにより販売)、又はE7ペプチドを含有する緩衝液(そのような緩衝液は当業者に周知である)によって、1mLあたり0.7mgの脂質及び0.1mgのE7(モル比=11:1)の最終濃度になるように再水和した。脂質分散体を、孔径0.4、0.2及び0.1μmのポリカーボネート膜を通して連続的に押し出した。閉じ込められていないペプチドは除去されなかった。リポソームを、使用するまで4℃で保存した。E7ペプチドのリポソームとの会合は、リポソームと結合したペプチドの率を測定することにより決定した。簡潔には、R−DOTAP/E7、S−DOTAP/E7又はRS−DOTAP/E7複合体の非結合E7ペプチドを、Microcon(登録商標)遠心分離濾過装置(Millipore, Bedford, MA)により分離し、非結合ペプチドの濃度を、Micro BCA(商標)Protein Assay Kit(Pierce, Rockford, IL)により測定した。ペプチド会合の効率を、非結合ペプチド百分率として決定した。当業者に周知の一般的なリポソーム調製に使用される他の方法を使用することもできる。
データは、少なくとも3つの独立した実験の平均±SDとして表される。両側スチューデントt検定を使用して、平均における統計的に有意な差を評価した。有意性は、p<0.05に設定した。
カチオン性リポソームを上記に記載されたように調製した。製剤に使用されるE7抗原は、HLA−A*0201で拘束された同定済みヒトE7ペプチドである〔HPV−16 E7、アミノ酸11〜20、YMLDLQPETT(配列番号1)〕。ペプチドは、University of Pittsburgh, Molecular Medicine Institute, Pittsburgh, PAにおいて合成された。ヒトHLA−A2ヒト樹状細胞は、Lonza(Walkersville, MD)から得た。凍結クリオバイアルを融解し、樹状細胞を、12ウエル組織培養皿において、50マイクログラム/mlのIL−4及びGM−CSFを補充したLGM−3培地(Walkersville, MDのLonzaにより市販されている)により、培地2mlに125,000細胞/cm2の初期平板培養密度で、37℃・5%CO2にて培養した。細胞を培養で3日間増殖させると、顕微鏡検査では、接着した細胞及び円形になった細胞の混合物が認められた。
ヒトHLA−A2樹状細胞(Lonza, Walkersville, MD)を上記に記載したように試験し、培養で増殖させた。3日目に、40マイクロモルのDOTAP/E7複合体により、又は強力な免疫刺激物質であるリポ多糖(LPS)の50マイクロモル濃度(陽性対照)により、細胞を処理した。アッセイウエルから培地を取り出し、微量遠心管により1300rpmで5分間遠心分離して、非結合樹状細胞をペレット化した。上澄みを取り出し、1mlあたり10マイクロリットルのCalbiochem(La Jolla, CA)のプロテアーゼインヒビターカクテルセットI(カタログ番号539131)で処理し、分析するまで凍結保存した。試料を、Searchlight Protein Array Multiplex ELISAアッセイ〔Pierce Biotechnology(Woburn, MA)〕によりケモカイン及びサイトカイン発現について分析した。
図12では、0日目に、HP−V陽性腫瘍の増殖を誘発するために、マウスにTC−1細胞を皮下注射した。DOTAP/E7組成物は、DOTAPのラセミ混合物を含んでいた。6日目に、10μgのE7ペプチドを含有するDOTAP/E7組成物をマウスの腹部の両側の皮下に与えた。複合体中のDOTAP脂質濃度は、3〜600nmolの範囲で異なる値(3、15、30、75、150、300及び600nmol)にした。23日目において、低用量のDOTAP(15nmol)は、未処理対照と比較して部分的な腫瘍阻害効果を示し(P<0.05)、一方、30、150又は300nmolのDOTAPは、増強された効力を示した(P<0.01)。75nmolのDOTAPは、最も有意な腫瘍退縮効果を示した(P<0.001)。ここでも、高用量のDOTAP(600nmol)を与えたマウスは抗腫瘍活性を示さず、高用量のDOTAPリポソームが免疫応答に負の調節を誘導したかもしれないことが確認された。加えて、100nmol用量のDOTAPを有するがE7ペプチドを有さないリポソームは、腫瘍増殖の有意な阻害を示さず、抗腫瘍効果が抗原特異的であることを示した。更に、アニオン性脂質である1,2−ジオレオイル−sn−グリセロ−3−ホスホグリセロール(DOPG)のリポソームは、抗原と共に150nmolで投与されるても腫瘍増殖を有意に阻害できなかった。
図13及び14では、0日目に、HPV陽性腫瘍の増殖を誘発するために、マウスにTC−1細胞を皮下注射した。6日目に、20μgのE7ペプチドを含有するR及びS−DOTAP/E7組成物を、マウスの腹部の両側の皮下に与えた。複合体中のR又はS−DOTAP脂質濃度は、3〜600nmolの範囲で異なる値(3、15、30、75、100、125、150、300及び600nmol)にした。DOTAPのラセミ混合物(図12)と異なり、S−DOTAP複合体は、腫瘍増殖を阻害する能力を示さず、腫瘍退縮は観察されなかった(図13)。しかし、用量応答効果は観察され、23日目には、S−DOTAP用量の600nmolは、未処理対照と比較して最も遅い腫瘍増殖を誘導した(P<0.05)。図14を参照すると、R−DOTAP及び抗原を含有する複合体の抗腫瘍効果は、ラセミ混合物(図12)において観察された効果と同様であった。23日目には、75〜150nmol用量のR−DOTAPは、未処理対照と比較して部分的な腫瘍阻害効果を示し(P<0.001)、一方、300nmolのR−DOTAPは、最も有意な腫瘍退縮効力を示した(P<0.0001)。ここでも、高用量のR−DOTAP(600nmol)を与えたマウスは有意な抗腫瘍活性を示さず、高用量のR−DOTAPリポソームが免疫応答に負の調節を誘導したかもしれないことが確認された。E7ペプチドのみは、腫瘍増殖の阻害を何も示さなかった(図示されず)。図15は、多様なカチオン性脂質/E7抗原複合体、DOTAP、S−DOTAP3、及びR−DOTAPと20μgの抗原、並びにDOTAPと10μgの抗原、の腫瘍退縮効力の脂質用量応答曲線を示す。
本出願者たちは以前に、米国仮出願第60/983,799号(本出願の譲渡人に譲渡された)において、DOTAP/E7がヒトTリンパ球と直接相互作用して、クローン増殖及びT細胞活性化をもたらすことを示した。これらの研究は、DOTAPのラセミ混合物がT細胞のクローン増殖を刺激する能力を検査した。これらの研究において、HLA−A2+の健康な提供者から得た濃縮ヒトリンパ球を、媒質、DOTAPのみ、ペプチドのみ、又はDOTAP/E7で、直接刺激した。刺激を7日の間隔を置いて3回繰り返した。第3刺激の3日後、DOTAP又はDOTAP/E7で処理したリンパ球は、クローン増殖がなかった培地対照とは対照的に、培養液中においてT細胞コロニーの広範な増殖を示した。増殖したT細胞は、有意なCTL活性も示した。
米国特許第7,303,881号に記載されているように、広範な部類のカチオン性脂質は、抗原と共に強力な免疫刺激物質として作用して、疾患の治療において抗原特異的免疫応答を生じることができる。例えば、米国特許第7,303,881号は、DC2.4樹状細胞上での同時刺激分子CD80/CD86の発現がカチオン性脂質によって刺激されることによって示されているように、カチオン性脂質から構成されるリポソームが樹状細胞を活性化することを開示する(図14A及びA4B)。米国特許第7,303,881号の図14Aに示されているように、異なるカチオン性リポソームによる、DC2.4細胞のCD80/CD86の発現を刺激する能力は、大きく異なる。ポリカチオン性脂質である2,3−ジオレオイルオキシ−N−〔2−(スペルミンカルボキシアミド)エチル〕−N,N−ジメチル−1−プロパンアミニウムトリフルオロアセテート(DOSPA)と中性脂質であるジオレオイルホスファチジルエタノールアミン(DOPE)との3:1(w/w)リポソーム製剤であるリポフェクタミン(登録商標)、並びに、O,O′−ジミリスチル−N−リシルアスパラテート(DMKE)及びO,O′−ジミリスチル−N−リシルグルタメート(DMKD)から調製されるリポソームは、DC2.4細胞によるCD80/CD86の発現を強く刺激する。
Claims (16)
- エキソビボにおいて免疫系の細胞を活性化するのに十分な用量の、又は被験者の免疫系を活性化して対象における免疫応答を誘発するのに十分な用量の、少なくとも1つのキラルカチオン性脂質を含む、組成物。
- キラルカチオン性脂質が、下記式:
により表される構造を有する非ステロイド性のカチオン性脂質を含む、請求項1記載の組成物。 - キラルカチオン性脂質が、DOTAP、DOTMA、DOEPC、及びこれらの組み合わせから選択される、請求項2記載の組成物。
- カチオン性脂質/抗原複合体を形成する少なくとも1つの抗原を更に含み、該カチオン性脂質/抗原複合体が、抗原特異的効果又は免疫応答を刺激する、請求項1記載の組成物
- 少なくとも1つの抗原が、腫瘍関連抗原、ウイルス抗原、微生物抗原、及びこれらの組み合わせから選択される、請求項4記載の組成物。
- 少なくとも1つの抗原が、脂質付加抗原、又は疎水性を増加するように修飾されている抗原を含み、該抗原と付加された疎水性基との間にアミノ酸リンカー配列を含有することができる、請求項4記載の組成物。
- 少なくとも1つの抗原が、リポタンパク質、リポペプチド、増加した疎水性を有するアミノ酸配列で修飾されているタンパク質又はペプチド、及びこれらの組み合わせから選択される、請求項6記載の組成物。
- 少なくとも1つの抗原が、母体タンパク質に存在する配列と異なるアミノ酸配列を有するように該抗原を導くアミノ酸配列に共有結合している少なくとも1つの抗原を含む、請求項4記載の組成物。
- エキソビボで免疫細胞を活性化する、又は被験者における免疫応答を誘発する方法であって、該細胞を活性化するのに十分な用量の、又は被験者における免疫応答を誘発するのに十分な用量の、少なくとも1つのキラルカチオン性脂質を被験者に投与することを含む、方法。
- カチオン性脂質が、下記式:
により表される構造を有する非ステロイド性のカチオン性脂質を含む、請求項9記載の方法。 - キラルカチオン性脂質が、DOTAP、DOTMA、DOEPC、及びこれらの組み合わせから選択される、請求項10記載の方法。
- カチオン性脂質/抗原複合体を形成する少なくとも1つの抗原を更に含み、該カチオン性脂質/抗原複合体が、抗原特異的免疫応答を刺激する、請求項9記載の方法。
- 少なくとも1つの抗原が、腫瘍関連抗原、ウイルス抗原、微生物抗原、及びこれらの組み合わせから選択される、請求項12記載の方法。
- 少なくとも1つの抗原が、脂質付加抗原、又は疎水性を増加するように修飾されている抗原を含み、該抗原と付加された疎水性基との間にアミノ酸リンカー配列を含有することができる、請求項12記載の方法。
- 少なくとも1つの抗原が、リポタンパク質、リポペプチド、増加した疎水性を有するアミノ酸配列で修飾されているタンパク質又はペプチド、及びこれらの組み合わせから選択される、請求項12記載の方法。
- T細胞をキラルカチオン性脂質又はカチオン性脂質/抗原複合体で処理することによって、T細胞の増殖を誘発する方法であって、該カチオン性脂質がキラル脂質又はキラル脂質の混合物から構成される、方法。
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014527965A (ja) * | 2011-09-12 | 2014-10-23 | ピーディーエス バイオテクノロジー コーポレイションPds Biotechnology Corporation | 粒子状ワクチン製剤 |
JP2015521601A (ja) * | 2012-06-15 | 2015-07-30 | ピーディーエス バイオテクノロジー コーポレイションPds Biotechnology Corporation | カチオン性脂質ワクチン組成物および使用方法 |
JP2015530413A (ja) * | 2012-09-21 | 2015-10-15 | ベデュ−アッド,フランク | 改良されたワクチン組成物および使用方法 |
JP2017501172A (ja) * | 2013-12-16 | 2017-01-12 | メルク パテント ゲーエムベーハー | サバイビン指向性癌ワクチン治療 |
JP2019500021A (ja) * | 2015-11-13 | 2019-01-10 | ピーディーエス バイオテクノロジー コーポレイションPds Biotechnology Corporation | 樹状細胞療法においてex vivoでの抗原のプロセシングと提示を亢進させるための合成ベクターとしての脂質 |
JP2021505606A (ja) * | 2017-12-05 | 2021-02-18 | ピーディーエス バイオテクノロジー コーポレイションPds Biotechnology Corporation | I型インターフェロン遺伝子を刺激するための方法及びカチオン性脂質を含む組成物 |
US11612652B2 (en) | 2015-11-13 | 2023-03-28 | Pds Biotechnology Corporation | Lipids as synthetic vectors to enhance antigen processing and presentation ex-vivo in dendritic cell therapy |
US11801257B2 (en) | 2008-04-17 | 2023-10-31 | Pds Biotechnology Corporation | Stimulation of an immune response by enantiomers of cationic lipids |
US11911359B2 (en) | 2007-03-22 | 2024-02-27 | Pds Biotechnology Corporation | Stimulation of an immune response by cationic lipids |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10347710B4 (de) | 2003-10-14 | 2006-03-30 | Johannes-Gutenberg-Universität Mainz | Rekombinante Impfstoffe und deren Verwendung |
DE102005046490A1 (de) | 2005-09-28 | 2007-03-29 | Johannes-Gutenberg-Universität Mainz | Modifikationen von RNA, die zu einer erhöhten Transkriptstabilität und Translationseffizienz führen |
WO2011109294A1 (en) * | 2010-03-01 | 2011-09-09 | Dicerna Pharmaceuticals, Inc. | Lipid delivery formulations |
JP2011184344A (ja) * | 2010-03-08 | 2011-09-22 | Kao Corp | p21発現促進剤 |
EP3449910A1 (en) | 2010-07-06 | 2019-03-06 | GlaxoSmithKline Biologicals S.A. | Cationic oil-in-water emulsions |
WO2012159754A2 (en) | 2011-05-24 | 2012-11-29 | Biontech Ag | Individualized vaccines for cancer |
EP3456316A1 (en) | 2011-07-06 | 2019-03-20 | GlaxoSmithKline Biologicals S.A. | Cationic oil-in-water emulsions |
MX350198B (es) | 2011-07-06 | 2017-08-30 | Novartis Ag | Emulsiones aceite en agua que contienen acidos nucleicos. |
WO2013143555A1 (en) | 2012-03-26 | 2013-10-03 | Biontech Ag | Rna formulation for immunotherapy |
EP2925348B1 (en) | 2012-11-28 | 2019-03-06 | BioNTech RNA Pharmaceuticals GmbH | Individualized vaccines for cancer |
WO2014180490A1 (en) | 2013-05-10 | 2014-11-13 | Biontech Ag | Predicting immunogenicity of t cell epitopes |
WO2016045732A1 (en) | 2014-09-25 | 2016-03-31 | Biontech Rna Pharmaceuticals Gmbh | Stable formulations of lipids and liposomes |
WO2016128060A1 (en) | 2015-02-12 | 2016-08-18 | Biontech Ag | Predicting t cell epitopes useful for vaccination |
WO2017059902A1 (en) | 2015-10-07 | 2017-04-13 | Biontech Rna Pharmaceuticals Gmbh | 3' utr sequences for stabilization of rna |
WO2018067822A1 (en) * | 2016-10-05 | 2018-04-12 | Pds Biotechnology Corporation | Methods to alter the tumor microenvironment for effective cancer immunotherapy |
WO2018080253A1 (ko) * | 2016-10-31 | 2018-05-03 | 아이진 주식회사 | 면역반응 조절물질 및 양이온성 리포좀을 포함하는 면역증강용 조성물 및 이의 용도 |
US20220160867A1 (en) * | 2020-11-20 | 2022-05-26 | Pds Biotechnology Corporation | Methods and compositions comprising cationic lipids for immunotherapy by direct tumor injection |
WO2024086290A2 (en) * | 2022-10-19 | 2024-04-25 | Pds Biotechnology Corporation | Novel t cell activating immunotherapeutic for treatment of mucin 1 protein expressing human cancers |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06510051A (ja) * | 1991-08-26 | 1994-11-10 | エピミューン,インコーポレイティド | Hla−制限型b型肝炎ウィルスのctlエピトープ |
US20060008472A1 (en) * | 2004-04-30 | 2006-01-12 | Leaf Huang | Antigen delivery compositions and methods of use |
JP2008521757A (ja) * | 2004-11-26 | 2008-06-26 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Dotap塩化物の安定な結晶変態 |
Family Cites Families (120)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2167480A (en) | 1927-11-02 | 1939-07-25 | Rca Corp | Signaling |
US4703004A (en) | 1984-01-24 | 1987-10-27 | Immunex Corporation | Synthesis of protein with an identification peptide |
JPS6440808A (en) | 1987-08-05 | 1989-02-13 | Canon Kk | Zoom lens |
US6214804B1 (en) | 1989-03-21 | 2001-04-10 | Vical Incorporated | Induction of a protective immune response in a mammal by injecting a DNA sequence |
US5703055A (en) | 1989-03-21 | 1997-12-30 | Wisconsin Alumni Research Foundation | Generation of antibodies through lipid mediated DNA delivery |
US5264618A (en) | 1990-04-19 | 1993-11-23 | Vical, Inc. | Cationic lipids for intracellular delivery of biologically active molecules |
US6183745B1 (en) | 1990-12-12 | 2001-02-06 | The University Of Queensland | Subunit papilloma virus vaccine and peptides for use therein |
AU2143992A (en) | 1991-08-16 | 1993-03-16 | Vical, Inc. | Composition and method for treating cystic fibrosis |
US6419931B1 (en) * | 1991-08-26 | 2002-07-16 | Epimmune Inc. | Compositions and methods for eliciting CTL immunity |
US5283185A (en) | 1991-08-28 | 1994-02-01 | University Of Tennessee Research Corporation | Method for delivering nucleic acids into cells |
IL105554A (en) | 1992-05-05 | 1999-08-17 | Univ Leiden | Peptides of human papillomavirus for use in preparations elicit a human T cell response |
WO1993024640A2 (en) | 1992-06-04 | 1993-12-09 | The Regents Of The University Of California | Methods and compositions for in vivo gene therapy |
US7105574B1 (en) | 1999-03-26 | 2006-09-12 | Vical Incorporated | Adjuvant compositions and methods for enhancing immune responses to polynucleotide-based vaccines |
US5334761A (en) | 1992-08-28 | 1994-08-02 | Life Technologies, Inc. | Cationic lipids |
US9266930B1 (en) | 1993-03-05 | 2016-02-23 | Epimmune Inc. | Inducing cellular immune responses to Plasmodium falciparum using peptide and nucleic acid compositions |
WO1995004542A1 (en) | 1993-08-06 | 1995-02-16 | Cytel Corporation | Cloning and characterization of the complete mage-1 gene |
AUPM500494A0 (en) | 1994-04-12 | 1994-05-05 | Minister For Agriculture & Rural Affairs For The State Of New South Wales, The | Composition for use in increasing mucosal immunity |
FR2726764B1 (fr) | 1994-11-14 | 1997-01-31 | Pasteur Merieux Serums Vacc | Adjuvant pour composition vaccinale |
US6008202A (en) | 1995-01-23 | 1999-12-28 | University Of Pittsburgh | Stable lipid-comprising drug delivery complexes and methods for their production |
FR2732895B1 (fr) | 1995-04-11 | 1997-05-16 | Pasteur Merieux Serums Vacc | Utilisation d'un compose amphipathique cationique comme agent de transfection, comme adjuvant de vaccin, ou comme medicament |
JPH11510046A (ja) | 1995-07-21 | 1999-09-07 | ローヌ−プーラン ローラー ファーマシューティカルズ インコーポレイテッド | アデノ関連ウイルスリポソーム及び樹状細胞をトランスフェクトして特異性免疫を刺激することにおけるそれらの使用 |
EP0910343A1 (en) | 1996-07-03 | 1999-04-28 | University Of Pittsburgh | Emulsion formulations for hydrophilic active agents |
US7001614B2 (en) | 1996-08-19 | 2006-02-21 | The United States Of America As Represented By The Department Of Health And Human Services | Liposome complexes for increased systemic delivery |
US7288266B2 (en) | 1996-08-19 | 2007-10-30 | United States Of America As Represented By The Secretary, Department Of Health And Human Services | Liposome complexes for increased systemic delivery |
US20030229040A1 (en) | 1997-03-21 | 2003-12-11 | Georgetown University | Cationic liposomal delivery system and therapeutic use thereof |
US6977074B2 (en) | 1997-07-10 | 2005-12-20 | Mannkind Corporation | Method of inducing a CTL response |
US20030022854A1 (en) | 1998-06-25 | 2003-01-30 | Dow Steven W. | Vaccines using nucleic acid-lipid complexes |
US6693086B1 (en) | 1998-06-25 | 2004-02-17 | National Jewish Medical And Research Center | Systemic immune activation method using nucleic acid-lipid complexes |
JP2002536344A (ja) | 1999-02-05 | 2002-10-29 | ジエンザイム コーポレイション | 抗腫瘍免疫を発生させるためのカチオン性脂質の使用 |
US8206749B1 (en) | 1999-02-26 | 2012-06-26 | Novartis Vaccines And Diagnostics, Inc. | Microemulsions with adsorbed macromolecules and microparticles |
ES2308069T3 (es) | 1999-03-26 | 2008-12-01 | Vical Incorporated | Composiciones adyuvantes para realzar inmunorespuestas a las vacunas polinucleotido-basadas. |
US6852334B1 (en) | 1999-04-20 | 2005-02-08 | The University Of British Columbia | Cationic peg-lipids and methods of use |
CA2370690A1 (en) | 1999-04-20 | 2000-10-26 | The University Of British Columbia | Cationic peg-lipids and methods of use |
US6649170B1 (en) | 1999-05-12 | 2003-11-18 | Statens Serum Institut | Adjuvant combinations for immunization composition and vaccines |
FR2794370B1 (fr) | 1999-06-03 | 2003-10-17 | Biovector Therapeutics | Fragments proteiques polyepitopiques, leur obtention et leurs utilisations notamment en vaccination |
PL210451B1 (pl) | 1999-06-10 | 2012-01-31 | Merial Sas | Szczepionka DNA przeciwko wirusowi nosówki psów (CDV) |
CA2309313A1 (en) | 1999-08-05 | 2001-02-05 | Board Of Trustees Of The University Of Arkansas | Stimulation of the immune response by human dendritic cell manipulation |
ES2330078T3 (es) | 1999-09-16 | 2009-12-04 | Eisai Corporation Of North America | Acidos nucleicos que codifican polipeptidos poliepitope. |
US20030008813A1 (en) | 1999-12-17 | 2003-01-09 | Felgner Philip L. | Intracellular protein delivery compositions and methods of use |
WO2001051617A1 (en) | 2000-01-11 | 2001-07-19 | Maxygen, Inc. | Monocyte-derived dendritic cell subsets |
WO2001057068A1 (en) * | 2000-02-01 | 2001-08-09 | The Austin Research Institute | Mucin-1 derived antigens and their use in immunotherapy |
WO2001080900A2 (en) | 2000-04-20 | 2001-11-01 | The University Of British Columbia | Enhanced stabilised plasmid-lipid particle-mediated transfection using endosomal membrane |
AU2001297693A1 (en) | 2000-12-08 | 2002-09-12 | Coley Pharmaceutical Gmbh | Cpg-like nucleic acids and methods of use thereof |
JP2004537501A (ja) | 2001-02-01 | 2004-12-16 | ボード オブ リージェンツ, ザ ユニバーシティ オブ テキサス システム | 肺への遺伝子送達のための安定化ポリマーエアロゾル |
EP1425039A4 (en) | 2001-03-23 | 2005-02-02 | Us Gov Health & Human Serv | PEPTIDES THAT GIVE AN IMMUNE REACTION WITH THE HUMAN PAPILLOMA VIRUS |
FR2824326B1 (fr) | 2001-05-04 | 2004-03-19 | Commissariat Energie Atomique | Melange de peptides issus des proteines e6 et/ou e7 de papillomavirus et leurs applications |
KR100904954B1 (ko) * | 2001-05-30 | 2009-06-26 | 더 스크립스 리서치 인스티튜트 | 핵산용 전달 시스템 |
EP1409009A1 (en) * | 2001-06-15 | 2004-04-21 | Nordic Vaccine Technology A/S | Therapeutical vaccination |
CN1320923C (zh) | 2001-06-29 | 2007-06-13 | 中外制药株式会社 | 含有基于癌抑制基因wt1的产物的癌抗原和阳离子脂质体的癌疫苗 |
EP2263465A1 (en) * | 2001-07-06 | 2010-12-22 | Sloan-Kettering Institute for Cancer Research | Polyvalent conjugate vaccine for cancer |
GB0118517D0 (en) | 2001-07-30 | 2001-09-19 | Mitsubishi Tokyo Pharm Inc | Compound |
MXPA04005382A (es) | 2001-11-07 | 2005-02-24 | Mannkind Corp | Vectores de expresion que codifican epitopes de antigenos asociados al objetivo y metodos para su diseno. |
US7598421B2 (en) | 2002-05-08 | 2009-10-06 | Ucl Biomedica Plc | Materials for the delivery of biologically-active material to cells |
RU2311911C2 (ru) | 2002-07-05 | 2007-12-10 | Липоксен Текнолоджиз Лимитед | Способ усиления иммунного ответа при вакцинации нуклеиновой кислотой |
CN1688605B (zh) | 2002-08-12 | 2011-01-12 | 昆士兰医学研究所理事会 | 包含辅助t细胞和细胞毒性t淋巴细胞(ctl)表位的新免疫原性脂肽 |
US20050031587A1 (en) | 2002-10-04 | 2005-02-10 | Yamanouchi Pharmaceutical Co., Ltd. | Immune response induction method |
US20060247190A1 (en) | 2002-10-21 | 2006-11-02 | Kathleen Beach | Compositions and methods for treating human papillomavirus mediated disease |
SE0301109D0 (sv) | 2003-04-14 | 2003-04-14 | Mallen Huang | Nucleotide vaccine composition |
KR20060015265A (ko) | 2003-05-30 | 2006-02-16 | 알자 코포레이션 | 제제의 폐 투여 방법 |
WO2005000889A1 (en) | 2003-06-05 | 2005-01-06 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Immunogenic peptides for the treatment of prostate and breast cancer |
US7906122B2 (en) | 2003-06-18 | 2011-03-15 | Yissum Research Development Company Of The Hebrew University Of Jersusalem | Sphingoid polyalkylamine conjugates for Hepatitis B virus vaccination |
WO2004110980A1 (en) | 2003-06-18 | 2004-12-23 | Biolab Ltd. | Sphingolipids' polyalkylamines conjugates |
US8592197B2 (en) | 2003-07-11 | 2013-11-26 | Novavax, Inc. | Functional influenza virus-like particles (VLPs) |
US20060182793A1 (en) | 2003-07-22 | 2006-08-17 | Cytos Biotechnology Ag | Cpg-packaged liposomes |
WO2005037190A2 (en) | 2003-09-03 | 2005-04-28 | Dendritherapeutics, Inc. | Multiplex vaccines |
CN1609617B (zh) * | 2003-09-29 | 2012-02-15 | 香港中文大学 | 诊断与预防严重急性呼吸道综合症(sars)的组合物和方法 |
AU2004298991A1 (en) | 2003-12-10 | 2005-06-30 | Canji, Inc | Methods and compositions for treatment of interferon-resistant tumors |
CN1559607A (zh) | 2004-02-20 | 2005-01-05 | �й�ũҵ��ѧ | 一种核酸物质与蛋白质类组合物及其生产方法和在免疫调节中的应用 |
KR20090051129A (ko) | 2004-04-05 | 2009-05-20 | 화이자 프로덕츠 인코포레이티드 | 미세유체화된 수중유 유화액 및 백신 조성물 |
GB0716992D0 (en) | 2007-08-31 | 2007-10-10 | Immune Targeting Systems Its L | Influenza antigen delivery vectors and constructs |
US7745651B2 (en) | 2004-06-07 | 2010-06-29 | Protiva Biotherapeutics, Inc. | Cationic lipids and methods of use |
RU2007103343A (ru) * | 2004-06-30 | 2008-08-10 | АйДи БАЙОМЕДИКАЛ КОРПОРЕЙШН ОФ КВЕБЕК (CA) | Вакцинная композиция и способы лечения коронавирусной инфекции |
US20060051405A1 (en) | 2004-07-19 | 2006-03-09 | Protiva Biotherapeutics, Inc. | Compositions for the delivery of therapeutic agents and uses thereof |
WO2006063382A1 (en) | 2004-12-13 | 2006-06-22 | Peplin Research Pty Ltd | Treatment of solid cancers |
WO2006065960A2 (en) * | 2004-12-14 | 2006-06-22 | Applera Corporation | Cationic liposomes comprising a charge neutral compound and a cationic phospholipid |
CA2595704A1 (en) | 2005-01-21 | 2006-07-27 | Introgen Therapeutics, Inc. | Topical administration permitting prolonged exposure of target cells to therapeutic and prophylactic nucleic acids |
AU2006339072A1 (en) | 2005-03-14 | 2007-10-25 | Board Of Regents Of The University Of Texas System | Bioactive FUS1 peptides and nanoparticle-polypeptide complexes |
JP4516147B2 (ja) | 2005-03-18 | 2010-08-04 | ヴェーデクス・アクティーセルスカプ | 補聴器用遠隔制御システム |
KR20150032915A (ko) | 2005-04-08 | 2015-03-30 | 아르고스 쎄라퓨틱스 인코포레이티드 | 수지상 세포 조성물 및 방법 |
AU2006236910B2 (en) | 2005-04-11 | 2012-06-07 | Purdue Research Foundation | Vaccine against pandemic strains of influenza viruses |
US20060275777A1 (en) | 2005-06-03 | 2006-12-07 | Waelti Ernst R | Novel strategies for protein vaccines |
WO2007022152A2 (en) | 2005-08-15 | 2007-02-22 | The Research Foundation Of State University Of New York | Lipid nano particulates containing antigens as cancer vaccines |
US20110305713A1 (en) | 2005-10-21 | 2011-12-15 | Medical College Of Georgia Research Institute, Inc | Methods and compositions to enhance vaccine efficacy by reprogramming regulatory t cells |
ES2514316T3 (es) | 2005-11-22 | 2014-10-28 | Novartis Vaccines And Diagnostics, Inc. | Partículas similares a virus (VLPs) de Norovirus y Sapovirus |
WO2007106073A2 (en) * | 2006-03-02 | 2007-09-20 | University Of Massachusetts | Modified pathogens for use as vaccines |
JP2007238559A (ja) | 2006-03-10 | 2007-09-20 | Nagoya City Univ | 未成熟樹状細胞活性化剤及びその使用 |
EP2013230A2 (en) | 2006-04-21 | 2009-01-14 | Transgene S.A. | Hpv-16-based papillomavirus vaccine |
US20080014251A1 (en) | 2006-07-14 | 2008-01-17 | Advanced Vascular Dynamics | Hemostatic compound and its use |
EP1894941A1 (en) | 2006-09-01 | 2008-03-05 | Institut Pasteur | Treatment of cervical carcinoma with a recombinant adenylate cyclase carrying HPV antigens |
WO2008039874A2 (en) | 2006-09-26 | 2008-04-03 | Cedars-Sinai Medical Center | Cancer stem cell antigen vaccines and methods |
WO2008048976A2 (en) | 2006-10-18 | 2008-04-24 | The Government Of The United States Of America As Represented By The Secretary Of The Deparment Of Health And Human Services, Centers For Disease Control And Prevention | Enhancing disease resistance against rna viral infections with intracytoplasmic pathogen sensors |
KR100817024B1 (ko) | 2006-11-09 | 2008-03-26 | 재단법인 목암생명공학연구소 | 핵산 또는 약물을 간에 특이적으로 전달하는 복합체 및이를 포함하는 약학적 조성물 |
US8877206B2 (en) | 2007-03-22 | 2014-11-04 | Pds Biotechnology Corporation | Stimulation of an immune response by cationic lipids |
EP2167480A2 (en) | 2007-05-23 | 2010-03-31 | Vical Incorporated | Cationic lipids compositions and methods for enhancing immune responses to vaccines |
US7832751B2 (en) * | 2007-06-29 | 2010-11-16 | Harley-Davidson Motor Company Group, Inc. | Rear fender assembly |
CA2704455C (en) | 2007-11-02 | 2020-09-01 | Richard B. S. Roden | Multitype hpv peptide compositions and methods for treatment or prevention of human papillomavirus infection |
BRPI0910464B1 (pt) | 2008-04-17 | 2021-08-10 | Pds Biotechnology Corporation | Uso de uso de um lipídio catiônico quiral consistindo de r-dotap a preparação de composição farmacêutica |
CA2724408A1 (en) | 2008-05-19 | 2009-11-26 | The University Of North Carolina At Chapel Hill | Methods and compositions comprising novel cationic lipids |
WO2010033863A2 (en) | 2008-09-18 | 2010-03-25 | Juvaris Biotherapeutics, Inc. | Vaccine compositions of m2e, ha0 and bm2 multiple antigenic peptides |
JP2012519484A (ja) | 2009-03-06 | 2012-08-30 | マウント・シナイ・スクール・オヴ・メディシン | マイクロrna応答要素を含む弱毒化生インフルエンザウイルスワクチン |
JP5797190B2 (ja) | 2009-05-15 | 2015-10-21 | アイ アール エックス セーラピューティクス, インコーポレイテッド | ワクチン免疫療法 |
WO2011109294A1 (en) | 2010-03-01 | 2011-09-09 | Dicerna Pharmaceuticals, Inc. | Lipid delivery formulations |
CA2792537A1 (en) | 2010-03-30 | 2011-10-06 | Mount Sinai School Of Medicine | Influenza virus vaccines and uses thereof |
JP5902616B2 (ja) | 2010-04-28 | 2016-04-13 | 協和発酵キリン株式会社 | カチオン性脂質 |
JP2014521657A (ja) | 2011-07-27 | 2014-08-28 | ベイラー リサーチ インスティテュート | 膵臓がんに対する樹状細胞(dc)ワクチン療法 |
TWI673062B (zh) | 2011-09-12 | 2019-10-01 | 美商Pds生技公司 | 粒狀疫苗調配物 |
EP2638896A1 (en) | 2012-03-14 | 2013-09-18 | Bioneer A/S | Cationic liposomal drug delivery system for specific targeting of human cd14+ monocytes in whole blood |
EP2639299A1 (en) | 2012-03-16 | 2013-09-18 | Invectys | Universal cancer peptides derived from telomerase |
EP3632464A1 (en) | 2012-06-15 | 2020-04-08 | PDS Biotechnology Corporation | Cationic lipid vaccine compositions and methods of use |
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SG10201801429VA (en) | 2013-08-21 | 2018-03-28 | Curevac Ag | Composition and vaccine for treating lung cancer |
WO2015061416A2 (en) | 2013-10-23 | 2015-04-30 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Hla-a24 agonist epitopes of muc1-c oncoprotein and compositions and methods of use |
CN104189897A (zh) | 2014-05-21 | 2014-12-10 | 深圳先进技术研究院 | 一种树突状细胞高效负载抗原的制备方法 |
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EP3522908A4 (en) | 2016-10-05 | 2020-06-24 | PDS Biotechnology Corporation | NOVEL T-CELL VACCINES NOT RESTRICTED TO HPV16 HLAs, COMPOSITIONS AND METHODS OF USE THEREOF |
WO2018067822A1 (en) | 2016-10-05 | 2018-04-12 | Pds Biotechnology Corporation | Methods to alter the tumor microenvironment for effective cancer immunotherapy |
CN111655238A (zh) | 2017-12-05 | 2020-09-11 | Pds生物科技公司 | 用于刺激i型干扰素基因的包括阳离子脂质的方法和组合物 |
CN111217918B (zh) * | 2020-03-04 | 2020-11-10 | 中山大学 | 一种基于2,4-二氧四氢喋啶合酶的新型冠状病毒s蛋白双区域亚单位纳米疫苗 |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06510051A (ja) * | 1991-08-26 | 1994-11-10 | エピミューン,インコーポレイティド | Hla−制限型b型肝炎ウィルスのctlエピトープ |
US20060008472A1 (en) * | 2004-04-30 | 2006-01-12 | Leaf Huang | Antigen delivery compositions and methods of use |
JP2008521757A (ja) * | 2004-11-26 | 2008-06-26 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Dotap塩化物の安定な結晶変態 |
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US11801257B2 (en) | 2008-04-17 | 2023-10-31 | Pds Biotechnology Corporation | Stimulation of an immune response by enantiomers of cationic lipids |
JP2014527965A (ja) * | 2011-09-12 | 2014-10-23 | ピーディーエス バイオテクノロジー コーポレイションPds Biotechnology Corporation | 粒子状ワクチン製剤 |
JP2018065821A (ja) * | 2011-09-12 | 2018-04-26 | ピーディーエス バイオテクノロジー コーポレイションPds Biotechnology Corporation | 粒子状ワクチン製剤 |
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US20210308157A1 (en) | 2021-10-07 |
BRPI0910464A2 (pt) | 2018-03-27 |
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AU2009236306B2 (en) | 2015-04-02 |
IL208713A0 (en) | 2010-12-30 |
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CA2721366A1 (en) | 2009-10-22 |
BRPI0910464B1 (pt) | 2021-08-10 |
RU2010146655A (ru) | 2012-05-27 |
CN102137675A (zh) | 2011-07-27 |
US20110110972A1 (en) | 2011-05-12 |
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US10702541B2 (en) | 2020-07-07 |
AU2009236306A1 (en) | 2009-10-22 |
RU2530555C2 (ru) | 2014-10-10 |
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PL2276495T3 (pl) | 2019-05-31 |
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US11801257B2 (en) | 2023-10-31 |
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