JP2016513710A - mRNAによってコードされる抗体を送達するための方法及び組成物 - Google Patents
mRNAによってコードされる抗体を送達するための方法及び組成物 Download PDFInfo
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Abstract
Description
本願は、2013年3月14日出願の米国仮特許出願第61/784,903号及び2013年12月23日出願の米国仮特許出願第61/920,165号の優先権を主張し、それらの内容は全体が参照により本明細書に援用される。
遺伝子治療及びDNAワクチン接種とも言われる遺伝子ワクチン接種は、生体内で大量の抗体を送達するための代替的方法を提供する。しかしながら、遺伝子治療における薬剤としてのDNAの使用及び遺伝的ワクチン接種は、安全上の懸念事項をいくつか生じさせることがある。例えば、DNAは血流でゆっくりと分解される。抗DNA抗体の形成が起こることがある(Gilkeson et al.,J.Clin.Invest.1995,95:1398−1402)。生体において(外来性)DNAが残存する可能性があり、そうして、免疫系の活性化過剰につながる可能性があり、これはマウスに脾腫を生じさせることが知られていた(Montheith et al.,Anticancer Drug Res.1997,12(5):421−432)。さらに、DNAの組込みは、無傷遺伝子に妨害を行うことによって宿主ゲノムに突然変異を生じさせる可能性がある。
本発明がより容易に理解されるように、まず所定の用語を下に定義する。次の用語及び他の用語に対する追加的定義も本明細書全体を通じて明記する。
本発明は、mRNA送達技術に基づいて、生体内で抗体を送達するための方法と組成物をとりわけ、提供する。いくつかの実施形態では、本発明は、抗体の重鎖及び軽鎖をコードする1つまたは複数のmRNAを、抗体の送達を必要とする対象に投与することによって抗体を送達する方法を提供する。いくつかの実施形態では、抗体の重鎖及び軽鎖は別々のmRNAによって送達される。いくつかの実施形態では、抗体の重鎖及び軽鎖は同じmRNAによって送達される。mRNAは、包装された粒子(例えば、リポソーム若しくはポリマー系賦形剤に被包)または包装されていない(即ち、裸の)粒子として、送達してもよい。mRNAがコードする抗体は、対象内で局所的(例えば、組織特異的方法で)または系統的に発現させてもよい。
mRNAがコードする抗体
重鎖及び軽鎖をコードするmRNA
シグナルペプチド
5’ヒト成長ホルモン(hGH)配列(配列番号9):
AUGGCCACUGGAUCAAGAACCUCACUGCUGCUCGCUUUUGGACUGCUUUGCCUGCCCUGGUUGCAAGAAGGAUCGGCUUUCCCGACCAUCCCACUCUCC
代替的5’ヒト成長ホルモン(hGH)配列(配列番号10):
AUGGCAACUGGAUCAAGAACCUCCCUCCUGCUCGCAUUCGGCCUGCUCUGUCUCCCAUGGCUCCAAGAAGGAAGCGCGUUCCCCACUAUCCCCCUCUCG
mRNAの合成
抗CCL2の重鎖及び軽鎖をコードする例示的mRNA
5’及び3’UTRのない抗CCL2重鎖(HC−αCCL2)mRNA(配列番号1):
AUGGAAUUCGGCCUGAGCUGGCUGUUCCUGGUGGCCAUCCUGAAGGGCGUGCAGUGCCAGGUCCAGCUGGUGCAGUCUGGCGCCGAAGUGAAGAAACCCGGCUCCUCCGUGAAGGUGUCCUGCAAGGCCUCCGGCGGCACCUUCUCCAGCUACGGCAUCUCCUGGGUCCGACAGGCCCCAGGCCAGGGCCUGGAAUGGAUGGGCGGCAUCAUCCCCAUCUUCGGCACCGCCAACUACGCCCAGAAAUUCCAGGGCAGAGUGACCAUCACCGCCGACGAGUCCACCUCCACCGCCUACAUGGAACUGUCCUCCCUGCGGAGCGAGGACACCGCCGUGUACUACUGCGCCAGAUACGACGGCAUCUACGGCGAGCUGGACUUCUGGGGCCAGGGCACCCUGGUCACCGUGUCCUCUGCCAAGACCACCCCCCCCUCCGUGUACCCUCUGGCCCCUGGCUCUGCCGCCCAGACCAACUCUAUGGUCACCCUGGGCUGCCUGGUCAAGGGCUACUUCCCCGAGCCCGUGACCGUGACCUGGAACUCCGGCUCCCUGUCCUCCGGCGUGCACACCUUCCCUGCCGUGCUGCAGUCCGACCUCUACACCCUGUCCAGCAGCGUGACCGUGCCCUCCUCCACCUGGCCCUCCGAGACAGUGACCUGCAACGUGGCCCACCCCGCCUCCAGCACCAAGGUGGACAAGAAAAUCGUGCCCCGGGACUGCGGCUGCAAGCCCUGCAUCUGUACCGUGCCCGAGGUGUCCUCCGUGUUCAUCUUCCCACCCAAGCCCAAGGACGUGCUGACCAUCACACUGACCCCCAAAGUGACCUGCGUGGUGGUGGACAUCUCCAAGGACGACCCCGAGGUGCAGUUCAGUUGGUUCGUGGACGACGUGGAAGUGCACACCGCUCAGACCCAGCCCAGAGAGGAACAGUUCAACUCCACCUUCAGAUCCGUGUCCGAGCUGCCCAUCAUGCACCAGGACUGGCUGAACGGCAAAGAAUUCAAGUGCAGAGUGAACUCCGCCGCCUUCCCAGCCCCCAUCGAAAAGACCAUCUCCAAGACCAAGGGCAGACCCAAGGCCCCCCAGGUCUACACCAUCCCCCCACCCAAAGAACAGAUGGCCAAGGACAAGGUGUCCCUGACCUGCAUGAUCACCGAUUUCUUCCCAGAGGACAUCACCGUGGAAUGGCAGUGGAACGGCCAGCCCGCCGAGAACUACAAGAACACCCAGCCCAUCAUGGACACCGACGGCUCCUACUUCGUGUACUCCAAGCUGAACGUGCAGAAGUCCAACUGGGAGGCCGGCAACACCUUCACCUGUAGCGUGCUGCACGAGGGCCUGCACAACCACCACACCGAGAAGUCCCUGUCCCACUCCCCCGGCAAGUGA
5’及び3’UTRのある抗CCL2重鎖(HC−αCCL2)mRNA(配列番号2):
(5’及び3’UTRの配列には下線あり)
GGACAGAUCGCCUGGAGACGCCAUCCACGCUGUUUUGACCUCCAUAGAAGACACCGGGACCGAUCCAGCCUCCGCGGCCGGGAACGGUGCAUUGGAACGCGGAUUCCCCGUGCCAAGAGUGACUCACCGUCCUUGACACGAUGGAAUUCGGCCUGAGCUGGCUGUUCCUGGUGGCCAUCCUGAAGGGCGUGCAGUGCCAGGUCCAGCUGGUGCAGUCUGGCGCCGAAGUGAAGAAACCCGGCUCCUCCGUGAAGGUGUCCUGCAAGGCCUCCGGCGGCACCUUCUCCAGCUACGGCAUCUCCUGGGUCCGACAGGCCCCAGGCCAGGGCCUGGAAUGGAUGGGCGGCAUCAUCCCCAUCUUCGGCACCGCCAACUACGCCCAGAAAUUCCAGGGCAGAGUGACCAUCACCGCCGACGAGUCCACCUCCACCGCCUACAUGGAACUGUCCUCCCUGCGGAGCGAGGACACCGCCGUGUACUACUGCGCCAGAUACGACGGCAUCUACGGCGAGCUGGACUUCUGGGGCCAGGGCACCCUGGUCACCGUGUCCUCUGCCAAGACCACCCCCCCCUCCGUGUACCCUCUGGCCCCUGGCUCUGCCGCCCAGACCAACUCUAUGGUCACCCUGGGCUGCCUGGUCAAGGGCUACUUCCCCGAGCCCGUGACCGUGACCUGGAACUCCGGCUCCCUGUCCUCCGGCGUGCACACCUUCCCUGCCGUGCUGCAGUCCGACCUCUACACCCUGUCCAGCAGCGUGACCGUGCCCUCCUCCACCUGGCCCUCCGAGACAGUGACCUGCAACGUGGCCCACCCCGCCUCCAGCACCAAGGUGGACAAGAAAAUCGUGCCCCGGGACUGCGGCUGCAAGCCCUGCAUCUGUACCGUGCCCGAGGUGUCCUCCGUGUUCAUCUUCCCACCCAAGCCCAAGGACGUGCUGACCAUCACACUGACCCCCAAAGUGACCUGCGUGGUGGUGGACAUCUCCAAGGACGACCCCGAGGUGCAGUUCAGUUGGUUCGUGGACGACGUGGAAGUGCACACCGCUCAGACCCAGCCCAGAGAGGAACAGUUCAACUCCACCUUCAGAUCCGUGUCCGAGCUGCCCAUCAUGCACCAGGACUGGCUGAACGGCAAAGAAUUCAAGUGCAGAGUGAACUCCGCCGCCUUCCCAGCCCCCAUCGAAAAGACCAUCUCCAAGACCAAGGGCAGACCCAAGGCCCCCCAGGUCUACACCAUCCCCCCACCCAAAGAACAGAUGGCCAAGGACAAGGUGUCCCUGACCUGCAUGAUCACCGAUUUCUUCCCAGAGGACAUCACCGUGGAAUGGCAGUGGAACGGCCAGCCCGCCGAGAACUACAAGAACACCCAGCCCAUCAUGGACACCGACGGCUCCUACUUCGUGUACUCCAAGCUGAACGUGCAGAAGUCCAACUGGGAGGCCGGCAACACCUUCACCUGUAGCGUGCUGCACGAGGGCCUGCACAACCACCACACCGAGAAGUCCCUGUCCCACUCCCCCGGCAAGUGACGGGUGGCAUCCCUGUGACCCCUCCCCAGUGCCUCUCCUGGCCCUGGAAGUUGCCACUCCAGUGCCCACCAGCCUUGUCCUAAUAAAAUUAAGUUGCAUCAAGCU
5’及び3’UTRのない抗CCL2軽鎖(LC−αCCL2)mRNA(配列番号3):
AUGGAAACCCCUGCCCAGCUGCUGUUCCUGCUGCUGCUGUGGCUGCCUGAUACCACCGGCGAAAUCGUGCUGACCCAGUCCCCCGCCACCCUGUCUCUGAGCCCUGGCGAGAGAGCCACCCUGAGCUGCAGAGCCUCCCAGUCCGUGUCCGACGCCUACCUGGCCUGGUAUCAGCAGAAGCCCGGCCAGGCCCCUCGGCUGCUGAUCUACGACGCCUCCUCUAGAGCCACCGGCGUGCCCGCCAGAUUCUCCGGCUCUGGCUCUGGCACCGACUUCACCCUGACCAUCUCCAGCCUGGAACCCGAGGACUUCGCCGUGUACUACUGCCACCAGUACAUCCAGCUGCACAGCUUCACCUUCGGCCAGGGCACCAAGGUGGAAAUCAAGGCCGAUGCCGCCCCUACCGUGUCCAUCUUCCCACCCUCCAGCGAGCAGCUGACCUCUGGCGGCGCUUCCGUCGUGUGCUUCCUGAACAACUUCUACCCCAAGGACAUCAACGUGAAGUGGAAGAUCGACGGCUCCGAGCGGCAGAACGGCGUGCUGAACUCCUGGACCGACCAGGACUCCAAGGACAGCACCUACUCCAUGUCCUCCACCCUGACCCUGACCAAGGACGAGUACGAGCGGCACAACUCCUAUACCUGCGAGGCCACCCACAAGACCUCCACCUCCCCCAUCGUGAAGUCCUUCAACCGGAACGAGUGCUGA
5’及び3’UTRのある抗CCL2軽鎖(LC−αCCL2)mRNA(配列番号4):
(5’及び3’UTRの配列には下線あり)
GGACAGAUCGCCUGGAGACGCCAUCCACGCUGUUUUGACCUCCAUAGAAGACACCGGGACCGAUCCAGCCUCCGCGGCCGGGAACGGUGCAUUGGAACGCGGAUUCCCCGUGCCAAGAGUGACUCACCGUCCUUGACACGAUGGAAACCCCUGCCCAGCUGCUGUUCCUGCUGCUGCUGUGGCUGCCUGAUACCACCGGCGAAAUCGUGCUGACCCAGUCCCCCGCCACCCUGUCUCUGAGCCCUGGCGAGAGAGCCACCCUGAGCUGCAGAGCCUCCCAGUCCGUGUCCGACGCCUACCUGGCCUGGUAUCAGCAGAAGCCCGGCCAGGCCCCUCGGCUGCUGAUCUACGACGCCUCCUCUAGAGCCACCGGCGUGCCCGCCAGAUUCUCCGGCUCUGGCUCUGGCACCGACUUCACCCUGACCAUCUCCAGCCUGGAACCCGAGGACUUCGCCGUGUACUACUGCCACCAGUACAUCCAGCUGCACAGCUUCACCUUCGGCCAGGGCACCAAGGUGGAAAUCAAGGCCGAUGCCGCCCCUACCGUGUCCAUCUUCCCACCCUCCAGCGAGCAGCUGACCUCUGGCGGCGCUUCCGUCGUGUGCUUCCUGAACAACUUCUACCCCAAGGACAUCAACGUGAAGUGGAAGAUCGACGGCUCCGAGCGGCAGAACGGCGUGCUGAACUCCUGGACCGACCAGGACUCCAAGGACAGCACCUACUCCAUGUCCUCCACCCUGACCCUGACCAAGGACGAGUACGAGCGGCACAACUCCUAUACCUGCGAGGCCACCCACAAGACCUCCACCUCCCCCAUCGUGAAGUCCUUCAACCGGAACGAGUGCUGACGGGUGGCAUCCCUGUGACCCCUCCCCAGUGCCUCUCCUGGCCCUGGAAGUUGCCACUCCAGUGCCCACCAGCCUUGUCCUAAUAAAAUUAAGUUGCAUCAAGCU
抗VEGFの重鎖及び軽鎖をコードする例示的なmRNA
5’及び3’UTRのない抗VEGF重鎖(HC−αVEGF)mRNA(配列番号5):
AUGGCAACUGGAUCAAGAACCUCCCUCCUGCUCGCAUUCGGCCUGCUCUGUCUCCCAUGGCUCCAAGAAGGAAGCGCGUUCCCCACUAUCCCCCUCUCGGAGGUUCAGCUGGUCGAAAGCGGGGGCGGCCUCGUCCAGCCAGGUGGAUCCCUCCGCCUGAGCUGCGCCGCGUCCGGAUACACUUUCACCAACUACGGCAUGAACUGGGUCCGCCAGGCGCCGGGAAAGGGACUGGAAUGGGUCGGCUGGAUCAAUACCUACACUGGAGAGCCUACCUACGCCGCUGACUUUAAGAGGCGGUUCACUUUCUCACUGGAUACUUCCAAGUCAACCGCUUACCUUCAGAUGAAUUCCCUGCGCGCCGAGGAUACCGCAGUGUAUUACUGCGCCAAAUACCCGCAUUACUACGGCUCCAGCCACUGGUACUUUGACGUGUGGGGUCAAGGAACCCUGGUGACUGUGUCGUCCGCUUCCACCAAGGGACCAAGCGUGUUUCCACUCGCCCCGAGCUCAAAAUCGACGUCGGGAGGUACUGCCGCACUGGGGUGCUUGGUCAAGGACUACUUUCCAGAGCCGGUGACUGUUUCCUGGAACAGCGGAGCGCUCACCUCGGGCGUGCACACCUUCCCUGCGGUGUUGCAGUCAUCUGGACUGUACUCGCUGUCCAGCGUGGUCACGGUCCCGAGCUCGUCGCUCGGGACCCAAACCUACAUUUGCAAUGUCAACCACAAGCCAUCGAACACCAAAGUCGACAAGAAGGUGGAACCGAAGUCGUGCGACAAGACUCAUACGUGCCCACCGUGUCCGGCUCCGGAACUGUUGGGGGGCCCCUCCGUGUUCCUUUUCCCGCCAAAGCCUAAGGACACUCUCAUGAUCUCACGGACGCCAGAAGUGACCUGUGUGGUCGUGGAUGUGUCACAUGAGGAUCCGGAAGUCAAAUUCAACUGGUAUGUGGACGGGGUGGAAGUGCAUAAUGCCAAAACCAAACCUCGCGAGGAGCAGUACAACUCAACCUACCGGGUGGUGUCCGUGCUGACUGUGCUGCACCAGGACUGGCUGAAUGGAAAGGAGUACAAAUGCAAGGUCAGCAACAAGGCCCUUCCCGCCCCAAUCGAAAAGACGAUCUCGAAGGCCAAAGGUCAGCCGCGAGAGCCUCAAGUGUACACUCUGCCGCCGUCAAGAGAAGAAAUGACUAAGAACCAAGUUUCCCUCACUUGCCUGGUGAAGGGCUUCUACCCCAGCGACAUCGCAGUGGAAUGGGAGAGCAACGGACAGCCGGAAAACAACUAUAAGACCACCCCUCCUGUGUUGGACUCGGAUGGUUCCUUCUUCCUUUACAGCAAGCUGACCGUGGAUAAAUCGCGGUGGCAGCAAGGAAAUGUGUUUUCAUGCUCAGUCAUGCACGAGGCGCUGCACAAUCACUACACUCAGAAGUCCCUGUCGCUGUCGCCAGGAAAAUAA
5’及び3’UTRのある抗VEGF重鎖(HC−αVEGF)mRNA(配列番号6):
(5’及び3’UTR配列には下線があり、シグナルペプチド配列はイタリック体、太字である。)
AUGGCCACUGGAUCAAGAACCUCACUGCUGCUCGCUUUUGGACUGCUUUGCCUGCCCUGGUUGCAAGAAGGAUCGGCUUUCCCGACCAUCCCACUCUCCGACAUUCAAAUGACGCAGUCCCCAUCGAGCCUCUCAGCAUCAGUGGGGGAUCGCGUGACUAUCACUUGCUCGGCGAGCCAGGAUAUCAGCAAUUACCUGAACUGGUAUCAGCAAAAGCCUGGAAAGGCACCGAAGGUGCUGAUCUACUUCACCUCAAGCCUCCAUUCGGGUGUCCCGUCCCGCUUCAGCGGCUCCGGCUCAGGCACUGACUUCACCCUGACUAUCUCCUCGCUGCAACCGGAAGAUUUCGCCACUUACUACUGUCAGCAGUACUCCACCGUGCCUUGGACGUUCGGACAGGGAACCAAAGUUGAGAUUAAGCGGACGGUCGCGGCCCCCUCCGUGUUUAUCUUUCCGCCUUCGGACGAGCAGCUGAAGUCGGGAACCGCCUCUGUCGUGUGCCUCCUGAACAACUUCUACCCGCGGGAAGCCAAGGUGCAGUGGAAAGUGGAUAACGCGCUUCAGAGCGGCAAUUCGCAAGAGUCCGUGACCGAAGAGGACUCGAAGGACUCAACCUACUCCCUCAGCUCAACCCUCACUUUGUCGAAGGCCGACUACGAGAAGCACAAAGUCUACGCAUGCGAAGUCACCCACCAGGGUCUGUCGAGCCCAGUGACUAAAUCCUUCAAUAGGGGGGAAUGUUAA
5’及び3’UTRのある抗VEGF軽鎖(HC−αVEGF)mRNA(配列番号8):
(5’及び3’UTR配列には下線があり、シグナルペプチド配列はイタリック体、太字である。)
送達賦形剤
リポソーム性送達賦形剤
式中、各R2は独立して水素またはC1〜3アルキルであり;
各qは独立して2〜6であり;
各R’は独立して水素またはC1〜3アルキルであり;
各RLは独立してC8〜12アルキルである。
RNAにコードされる抗体の生体内での発現
医薬組成物及び投与
RNAによってコードされる抗体の生体外での発現
抗ケモカイン(C−Cモチーフ)リガンド2の重鎖(HC−αCCL2、配列番号1)及び抗CCL2の軽鎖(LC−αCCL2、配列番号2)を、遺伝子をコードするプラスミドDNA鋳型から生体外転写することによって合成し、続いて、既知の方法(Fechter,P.;Brownlee,G.G.“Recognition of mRNA cap structures by viral and cellular proteins”J.Gen.Virology 2005,86,1239−1249を参照のこと)に従って5’キャップ構造(Cap1)を付加し、さらに、長さがゲル電気泳動で測定して約200ヌクレオチドの3’ポリ(A)尾部を付加した。HC−αCCL2及びLC−αCCL2に対する配列は下に示す通りであり、各mRNA産生物に存在する5’及び3’非翻訳領域は、それぞれX及びYとして表し、下に定義する:
抗CCL2(HC−αCCL2)重鎖mRNA:
X1=
GGACAGAUCGCCUGGAGACGCCAUCCACGCUGUUUUGACCUCCAUAGAAGACACCGGGACCGAUCCAGCCUCCGCGGCCGGGAACGGUGCAUUGGAACGCGGAUUCCCCGUGCCAAGAGUGACUCACCGUCCUUGACACG
Y1=
CGGGUGGCAUCCCUGUGACCCCUCCCCAGUGCCUCUCCUGGCCCUGGAAGUUGCCACUCCAGUGCCCACCAGCCUUGUCCUAAUAAAAUUAAGUUGCAUCAAGCU
実施例2 生体外mRNAトランスフェクション材料及び条件
A.例示的脂質材料
B.実験的製剤
実施例3 生体外mRNAトランスフェクション後の抗体の検出
A.ELISAによる
B.ウエスタンブロットによる
実施例4 HC−αCCL2及びLC−αCCL2のトランスフェクションから産生されたαCCL2抗体の生体外分析
実施例5 静脈内投与したmRNA挿入ナノ粒子から産生されたαCCL2抗体の生体内分析
実施例6 生体内α−VEGF抗体産生
抗VEGF(HC−αVEGF)重鎖mRNA:
X1(5’UTR配列)=
GGACAGAUCGCCUGGAGACGCCAUCCACGCUGUUUUGACCUCCAUAGAAGACACCGGGACCGAUCCAGCCUCCGCGGCCGGGAACGGUGCAUUGGAACGCGGAUUCCCCGUGCCAAGAGUGACUCACCGUCCUUGACACG
Y1(3’UTR配列)=
CGGGUGGCAUCCCUGUGACCCCUCCCCAGUGCCUCUCCUGGCCCUGGAAGUUGCCACUCCAGUGCCCACCAGCCUUGUCCUAAUAAAAUUAAGUUGCAUCAAGCU
同等事物及び範囲
Claims (51)
- 生体内における抗体の送達方法であって、前記方法は抗体の重鎖及び軽鎖をコードする1つまたは複数のmRNAを、送達を必要とする対象に投与することを含み、前記抗体が前記対象内に全身的に発現される、前記方法。
- 前記1つまたは複数のmRNAが、前記抗体の前記重鎖をコードする第1のmRNAと前記抗体の前記軽鎖をコードする第2のmRNAとを含む、請求項1に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約10:1〜1:10の範囲の比で存在する、請求項2に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約4:1〜1:4の範囲の比で存在する、請求項3に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約4:1の比で存在する、請求項4に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが1より大きい比で存在する、請求項2〜5のいずれか一項に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約1:1の比で存在する、請求項4に記載の方法。
- 前記1つまたは複数のmRNAが、前記抗体の前記重鎖及び前記軽鎖の両方をコードする単一のmRNAを含む、請求項1または2に記載の方法。
- 前記抗体の前記重鎖及び前記軽鎖をコードする前記1つまたは複数のmRNAが1つまたは複数のリポソームに被包される、請求項1〜8のいずれか一項に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが別々のリポソームに被包される、請求項9に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが同じリポソームに被包される、請求項10に記載の方法。
- 前記1つまたは複数のリポソームは、カチオン性脂質、中性脂質、コレステロール系脂質、及びPEG修飾された脂質の1つまたは複数を含む、請求項9〜11のいずれか一項に記載の方法。
- 前記1つまたは複数のリポソームは約150nm以下の大きさを有する、請求項9〜12のいずれか一項に記載の方法。
- 前記1つまたは複数のリポソームは約100nm以下の大きさを有する、請求項9〜13のいずれか一項に記載の方法。
- 前記1つまたは複数のリポソームは約75nm以下の大きさを有する、請求項9〜13のいずれか一項に記載の方法。
- 前記1つまたは複数のmRNAが、安定性を高めるように修飾されている、請求項1〜15のいずれか一項に記載の方法。
- 前記1つまたは複数のmRNAが、修飾ヌクレオチド、キャップ構造、ポリA尾部、5’非翻訳領域、及び/または3’非翻訳領域を含むように修飾されている、請求項16に記載の方法。
- 前記1つまたは複数のmRNAが無修飾である、請求項1〜15のいずれか一項に記載の方法。
- 前記1つまたは複数のmRNAが静脈内投与される、請求項1〜18のいずれか一項に記載の方法。
- 前記1つまたは複数のmRNAが腹腔内投与される、請求項1〜18のいずれか一項に記載の方法。
- 前記抗体の前記全身的発現が、投与後少なくとも約6時間、12時間、24時間、36時間、48時間、72時間、96時間、または120時間で検出可能である、請求項1〜20のいずれか一項に記載の方法。
- 前記抗体が無傷免疫グロブリン、(Fab)2、(Fab’)2、Fab、Fab’、またはscFvである、請求項1〜21のいずれか一項に記載の方法。
- 前記抗体がIgGである、請求項22に記載の方法。
- 前記抗体が抗CCL2、抗リシルオキシダーゼ様−2(LOXL2)、抗Flt−1、抗TNF−α、抗インターロイキン−2Rα受容体(CD25)、抗TGFβ、抗B−細胞活性化因子、抗アルファ−4インテグリン、抗BAGE、抗β−カテニン/m、抗Bcr−abl、抗C5、抗CA125、抗CAMEL、抗CAP−1、抗CASP−8、抗CD4、抗CD19、抗CD20、抗CD22、抗CD25、抗CDC27/m、抗CD30、抗CD33、抗CD52、抗CD56、抗CD80、抗CDK4/m、抗CEA、抗CT、抗CTL4、抗Cyp−B、抗DAM、抗EGFR、抗ErbB3、抗ELF2M、抗EMMPRIN、抗EpCam、抗ETV6−AML1、抗HER2、抗G250、抗GAGE、抗GnT−V、抗Gp100、抗HAGE、抗HER−2/neu、抗HLA−A*0201−R170I、抗IGF−1R、抗IL−2R、抗IL−5、抗MC1R、抗ミオシン/m、抗MUC1、抗MUM−1、−2、−3、抗プロテイナーゼ−3、抗p190マイナーbcr−abl、抗Pml/RARα、抗PRAMS、抗PSA、抗PSM、抗PSMA、抗RAGE、抗RANKL、抗RU1またはRU2、抗SAGE、抗SART−1または抗SART−3、抗サバイビン、抗TEL/AML1、抗TPI/m、抗TRP−1、抗TRP−2、抗TRP−2/INT2、抗VEGF、及び抗VEGF受容体からなる群より選択される、請求項1〜23のいずれか一項に記載の方法。
- 抗体の産生方法であって、前記方法は抗体の重鎖をコードする第1のmRNAと抗体の軽鎖をコードする第2のmRNAとを細胞に投与することを含み、前記抗体が前記細胞によって産生される、前記方法。
- 前記細胞が哺乳動物細胞である、請求項25に記載の方法。
- 前記細胞がヒト細胞である、請求項25または26に記載の方法。
- 前記細胞が培養細胞である、請求項25〜27のいずれか一項に記載の方法。
- 前記細胞が生体内の細胞である、請求項25〜27のいずれか一項に記載の方法。
- 前記抗体が細胞内に発現される、請求項25〜29のいずれか一項に記載の方法。
- 前記抗体が前記細胞によって分泌される、請求項25〜30のいずれか一項に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約10:1〜1:10の範囲の比で存在する、請求項25〜31のいずれか一項に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約4:1〜1:4の範囲の比で存在する、請求項32に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約4:1の比で存在する、請求項33に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが1より大きい比で存在する、請求項25〜34のいずれか一項に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約1:1の比で存在する、請求項25〜34のいずれか一項に記載の方法。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが1つまたは複数のリポソームに被包される、請求項25〜36のいずれか一項に記載の方法。
- 前記第1のmRNAと前記第2のmRNAとが別々のリポソームに被包される、請求項37に記載の方法。
- 前記第1のmRNAと前記第2のmRNAとが同じリポソームに被包される、請求項37に記載の方法。
- 前記1つまたは複数のリポソームは、カチオン性脂質、中性脂質、コレステロール系脂質、及びPEG修飾脂質の1つまたは複数を含む、請求項37〜39のいずれか一項に記載の方法。
- 抗体の重鎖をコードする第1のmRNAと軽鎖をコードする第2のmRNAとを含み、前記第1のmRNAと前記第2のmRNAとが1つまたは複数のリポソームに被包される、組成物。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約10:1〜1:10の範囲の比で存在する、請求項41に記載の組成物。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約4:1〜1:4の範囲の比で存在する、請求項42に記載の組成物。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約4:1の比で存在する、請求項43に記載の組成物。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが1より大きい比で存在する、請求項41〜44のいずれか一項に記載の組成物。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが約1:1の比で存在する、請求項41〜44のいずれか一項に記載の組成物。
- 前記重鎖をコードする前記第1のmRNAと前記軽鎖をコードする前記第2のmRNAとが1つまたは複数のリポソームに被包される、請求項41〜46のいずれか一項に記載の組成物。
- 前記第1のmRNAと前記第2のmRNAとが別々のリポソームに被包される、請求項47に記載の組成物。
- 前記第1のmRNAと前記第2のmRNAとが同じリポソームに被包される、請求項47に記載の組成物。
- 前記1つまたは複数のリポソームは、カチオン性脂質、中性脂質、コレステロール系脂質、及びPEG修飾脂質の1つまたは複数を含む、請求項41〜49のいずれか一項に記載の組成物。
- 前記1つまたは複数のリポソームが約250nm、225nm、200nm、175nm、150nm、125nm、100nm、75nm、または50nm以下の大きさを有する、請求項41〜50のいずれか一項に記載の組成物。
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