JP2018115220A - 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
【解決手段】一態様では、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をその抗体を必要とする対象に投与することによる生体内抗体送達方法であって、抗体が対象において全身的に発現されるものである方法を提供する。いくつかの実施形態では、上記1つまたは複数のmRNAは抗体の重鎖をコードする第1のmRNA及び軽鎖をコードする第2のmRNAを含む。いくつかの実施形態では、上記1つまたは複数のmRNAは抗体の重鎖と軽鎖の両方をコードする単一のmRNAを含む。
【選択図】なし
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。
本発明は、いずれの種類の抗体を送達するように用いてもよい。本明細書で使用される場合、用語「抗体」とは、無傷抗体及び抗体断片の両方を包含する。典型的に、無傷「抗体」は、特定の抗原に特異的に結合する免疫グロブリンである。抗体は、いずれの免疫グロブリン・クラスの中のひとつであってもよく、例えば、ヒト・クラス:IgG、IgM、IgE、IgA、及びIgDのいずれもが挙げられる。典型的には、無傷抗体は四量体である。各四量体は、2つの同一のポリペプチド鎖対から構成され、各対は、1つの「軽」鎖(約25kD)及び1つの「重」鎖(約50kD〜約70kD)を有する。各鎖のN末端は、抗原認識を主に担う、約100〜110またはそれより多くのアミノ酸からなる可変領域を特徴づける。用語「可変軽鎖」(VL)及び「可変重鎖」(VH)とは、それぞれ、軽鎖及び重鎖上でそれらの対応する領域を指す。各可変領域はさらに、超可変(HV)領域及びフレームワーク(FR)領域に下位区分されることができる。超可変領域は、相補性決定領域(CDR1、CDR2、及びCDR3)と呼ばれる3つの超可変配列領域を含み、これは、4つのフレームワーク領域(FR1、FR2、FR2、及びFR4)によって分けられ、フレームワーク領域は、βシート構造を形成し、HV領域を所定の位置に保持する足場材料として働く。各重鎖及び軽鎖のC末端は、軽鎖(CL)としての1つの領域と重鎖(CH1、CH2、及びCH3)としての3つの領域とからなる定常領域を特徴づける。免疫グロブリンの軽鎖はさらに、カッパ及びラムダのアイソタイプに区別できる。
本発明によれば、抗体(例えば、無傷抗体及び抗体断片)は、細胞及び生体内での外因性mRNA翻訳を通して細胞または生体内で産生させてもよい。特に、本発明によれば、完全に構築された多連鎖抗体の産生は、抗体の重鎖及び軽鎖をコードする外因性mRNAを送達することによって、細胞または生体内で達成することができる。いくつかの実施形態では、2つの重鎖及び2つの軽鎖を含有する四量体が産生される。
いくつかの実施形態では、重鎖及び/または軽鎖をコードするmRNAはシグナルペプチドをコードするヌクレオチド配列を組み込む。本明細書で使用される場合、用語「シグナルペプチド」とは、新しく合成されたタンパク質に存在し、そのタンパク質を分泌経路に向かわせることができるペプチドを指す。典型的には、シグナルペプチドは、mRNAの翻訳に続いて、小胞体へ移行した後、切断される。シグナルペプチドは、シグナル配列、リーダー配列、またはリーダーペプチドとも称される。典型的には、シグナルペプチドは、短い(例えば、5〜30、5〜25、5〜20、5〜15、または5〜10アミノ酸長)ペプチドである。シグナルペプチドは、新しく合成されたタンパク質のN末端に存在していてもよい。いずれの特定の理論によっても拘束されることを望むのもではないが、重鎖及び/または軽鎖をコードするmRNA上に、シグナルペプチドをコードする配列を組み込むことにより、生体内でmRNAから産生される抗体の分泌及び/または産生が促進されることがある。
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
本発明によるmRNAは、種々の既知の方法のいずれによって合成してもよい。例えば、本発明によるmRNAは、生体外転写(IVT)によって合成してもよい。手短に言えば、IVTは典型的に、プロモーターを含有する線状または環状のDNA鋳型、リボヌクレオチド三リン酸のプール、DTT及びマグネシウムイオンを含んでいてもよい緩衝系と、適切なRNAポリメラーゼ(例えば、T3、T7、またはSP6RNAポリメラーゼ)、デオキシリボヌクレアーゼI、ピロホスファターゼ、及び/またはリボヌクレアーゼ阻害剤とで実行する。正確な条件は具体的な用途によって異なる。
非限定的な例として、抗CCL2抗体の重鎖及び軽鎖をコードするmRNAが実施例1で説明される。重鎖をコードするmRNAの配列を、5’及び3’UTRのない場合とある場合とで、それぞれ配列番号1及び配列番号2として下に示す。軽鎖をコードするmRNAの配列を、5’及び3’UTRのない場合とある場合とで、それぞれ配列番号3及び配列番号4として下に示す。
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。)
本発明によれば、本明細書に記載の抗体をコードするmRNA(例えば、重鎖及び軽鎖をコードするmRNA)は、裸のRNAとして(包装せず)または送達賦形剤によって送達してもよい。本明細書で使用される場合、用語「送達賦形剤」、「転移賦形剤」、または文法的相当語句は、互換的に使用される。
いくつかの実施形態では、適切な送達賦形剤はリポソーム性送達賦形剤、例えば、脂質ナノ粒子である。本明細書で使用される場合、リポソーム性送達賦形剤、例えば、脂質ナノ粒子は通常、外側の媒体から1つまたは複数の二重層の膜によって隔離された内部水分空間を有する微小な小胞とみなされる。リポソームの二重層膜は典型的に、空間的に隔てられた親水性領域と疎水性領域を含む合成または天然由来の脂質等、両親媒性分子によって形成される(Lasic,Trends Biotechnol.,16:307−321,1998)。リポソームの二重層膜は、両染性ポリマー及び界面活性剤(例えば、ポリマーソーム(polymerosome)、ニオソーム等)によって形成することもできる。本発明との関連においては、リポソーム性送達賦形剤は典型的に、所望のmRNAを標的細胞または組織に輸送するよう働く。所望のmRNAをリポソームに組み込む過程はしばしば「挿入」と称される。例示的な方法がLasic,et al.,FEBS Lett.,312:255−258,1992に記載されており、これは参照により本明細書に援用される。リポソームに組み込んだ核酸は、リポソームの内部空間内に位置していても、リポソームの二重層膜内に完全または部分的に位置していても、リポソーム膜の外側表面に会合していてもよい。リポソームの中への核酸の組込みは、本明細書では「被包」とも称され、それは、核酸が全体的にリポソームの内部空間内に含有されることをいう。mRNAを転移賦形剤、例えば、リポソームに組み込む目的はしばしば、核酸を分解させる酵素若しくは化学薬品、及び/または核酸の迅速な排出を引き起こす系若しくは受容体を含有することがある環境から核酸を保護することである。したがって、いくつかの実施形態では、適切な送達賦形剤は、そこに含有されるmRNAの安定性を高め、標的細胞または組織へのmRNAの送達を促進することができる。
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。
本発明によれば、本明細書に記載される、抗体をコードするmRNA(例えば、重鎖及び軽鎖をコードするmRNA)は、完全に構築された所望の抗体が生体内で発現されるように、送達を必要とする対象に、送達賦形剤を用いても用いなくても、送達してよい。
生体内で抗体の発現を促進するために、抗体をコードするmRNA(例えば、重鎖及び軽鎖をコードするmRNA)及び送達賦形剤は、1つまたは複数の追加的核酸、担体、ターゲティングリガンド、若しくは安定化試薬と組み合わせて、または薬理学的組成物中で適切な賦形剤と混合して、製剤化することができる。薬物の製剤化及び投与の技術は、“Remington’s Pharmaceutical Sciences,”Mack Publishing Co.,Easton,Pa.,最新版、に見ることができる。
いくつかの実施形態では、抗体をコードするmRNA(例えば、重鎖及び軽鎖をコードするmRNA)は、生体外で抗体を産生するために用いてもよい。例えば、細胞を、抗体をコードするmRNA(例えば、重鎖及び軽鎖をコードするmRNA)によってトランスフェクトし、細胞による抗体の産生を可能とする細胞培養条件下で培養してもよい。いくつかの実施形態では、抗体は細胞内で発現される。他の実施形態では、抗体は、それが上清から採取されるように、細胞によって分泌される。
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
A.例示的脂質材料
本明細書の実施例においてトランスフェクションに用いられる脂質製剤は、1つ若しくは複数の脂質からか、または、種々の核酸系材料を被包するよう設計された1つ若しくは複数のカチオン性脂質、ヘルパー脂質、及びペグ化脂質を種々の比で用いた多成分脂質混合物からなるものであった。カチオン性脂質としては(他を排除しないが)、DOTAP(1,2−ジオレイル−3−トリメチルアンモニウムプロパン)、DODAP(1,2−ジオレイル−3−ジメチルアンモニウムプロパン)、DOTMA(1,2−ジ−O−オクタデセニル−3−トリメチルアンモニウムプロパン)、DLinDMA(Heyes,J.;Palmer,L.;Bremner,K.;MacLachlan,I.“Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids”J.Contr.Rel.2005,107,276−287を参照のこと)、DLin−KC2−DMA(Semple,S.C.et al.“Rational Design of Cationic Lipids for siRNA Delivery”Nature Biotech.2010,28,172−176を参照のこと)、C12−200(Love,K.T.et al.“Lipid−like materials for low−dose in vivo gene silencing”PNAS 2010,107,1864−1869)、HGT4003、ICE、ジアルキルアミノ−系、イミダゾール系、グアニジウム系等が挙げられる。ヘルパー脂質としては(他を排除しないが)、DSPC(1,2−ジステアロイル−sn−グリセロ−3−ホスホコリン)、DPPC(1,2−ジパルミトイル−sn−グリセロ−3−ホスホコリン)、DOPE(1,2−ジオレイル−sn−グリセロ−3−ホスホエタノールアミン)、DPPE(1,2−ジパルミトイル−sn−グリセロ−3−ホスホエタノールアミン)、DMPE(1,2−ジミリストイル−sn−グリセロ−3−ホスホエタノールアミン)、DOPG(2−ジオレオイル−sn−グリセロ−3−ホスホ−(1’−rac−グリセロール))、コレステロール等が挙げられる。ペグ化脂質は(他を排除しないが)、C6〜C20の長さのアルキル鎖をもった脂質に共有結合した、長さが最大5kDaのポリ(エチレン)グリコール鎖を含むことができる。
これらの実験において、C12−200、DOPE、コレステロール、及びDMG−PEG2Kの50mg/mLエタノール溶液のアリコートを混合させ、エタノールで希釈して最終体積3mLとした。別途、HC−αCCL2のmRNA及びLC−αCCL2のmRNA(重量:重量で1:1)mRNAの水性緩衝液(10mMのクエン酸/150mMのNaCl、pH4.5)を、500マイクログラムの各構築物を1mg/mLの原液から添加することによって調製した。脂質溶液を水性mRNA溶液に素早く注入して振盪すると、20%エタノール中最終懸濁液が得られた。得られたナノ粒子懸濁液をろ過し、1×PBS(pH7.4)でダイアフィルトレーション(diafiltrate)し、濃縮し、2〜8℃で保管した。最終濃度=1.35mg/mL αCCL2 mRNA(被包)。Zave=89.2nm(Dv(50)=64.0nm;Dv(90)=115nm)。
A.ELISAによる
この実施例では、F96 MaxiSorp Nunc−Immuno Platesに、pH9.6の炭酸ナトリウム緩衝液中1μg/mlのヤギ抗マウスIgG1(Invitrogen A10538)100μlをコーティングし、37℃で1時間インキュベートした。洗浄緩衝液(1×PBS、0.05%トウィーン20)で3回洗浄した後、37℃で1時間、ウェルをブロッキング緩衝液(1×PBS、0.05%トウィーン20、2%BSA)320μlでブロッキングした。モノクローナルIgG標準物質の系列希釈物を、250〜0ng/mlの範囲でブロッキング緩衝液中に調製した。試料の系列希釈物を、標準曲線(1:100〜1:10,000)の範囲に入るようブロッキング緩衝液中に調製した。試料と標準の両方を37℃で1時間インキュベートした。洗浄緩衝液で3回洗浄した後、ヤギ抗マウスIgG Fc HRP接合2次抗体(Pierce 31439)を1:40,000の希釈で用い、37℃で1時間インキュベートした。洗浄緩衝液で3回洗浄した後、TMB EIA基質試薬を、製造者の指示に従って調製した。37℃で15分間インキュベーションした後、2N H2SO4を加えて反応を停止し、プレートを450nmで読み取った。
この実施例では、トランスフェクト293T細胞または電気穿孔HCL2細胞からの馴化培地をSDS−PAGEによって分画し、製造者(Invitrogen)の指示に従い転写装置を用いてポリフッ化ビニリデン膜に転写した。TBST(10mMトリス、pH8.0、150mM NaCl、0.5%トウィーン20)中5%脱脂粉乳で1時間インキュベーションした後、膜をPBSTで3回洗浄し、室温で1時間、ヤギ抗マウスIgG1(Invitrogen A10538)でインキュベートした。膜をPBST中3回洗浄し、西洋わさびペルオキシダーゼ接合抗マウス二次抗体(Promega W4021)の1:5000の希釈物で、室温で1時間インキュベートした。ブロットをPBSTでさらに3回洗浄し、製造者の指示に従ってECLシステム(Amersham Bioscience)で現像した。
HC−αCCL2とLC−αCCL2の両方のmRNAを実施例1に上述した通り産生させた。続いて、実施例2A及びBに従って、HC−αCCL2及びLC−αCCL2のmRNAを、既知の方法に従って、種々の比(重量:重量)でHCL1(即ち、ヒト細胞株1)細胞またはHCL2細胞にトランスフェクトした。
この実施例では、完全に処理された抗体の産生を外因性メッセンジャーRNAの送達によって生体内で達成し、詳しくは、α−CCL2重鎖及び軽鎖それぞれのmRNA構築物(HC−αCCL2のmRNA:LC−αCCL2のmRNAが1:1(重量:重量))を実施例2Aに記載の通りにカチオン性脂質ナノ粒子に被包して、単回ボーラス静脈内注射としてマウスに送達した。
この実施例では、完全に処理されたα−VEGF抗体の産生を、外因性メッセンジャーRNAの送達によって生体内で達成した。
X1(5’UTR配列)=
GGACAGAUCGCCUGGAGACGCCAUCCACGCUGUUUUGACCUCCAUAGAAGACACCGGGACCGAUCCAGCCUCCGCGGCCGGGAACGGUGCAUUGGAACGCGGAUUCCCCGUGCCAAGAGUGACUCACCGUCCUUGACACG
Y1(3’UTR配列)=
CGGGUGGCAUCCCUGUGACCCCUCCCCAGUGCCUCUCCUGGCCCUGGAAGUUGCCACUCCAGUGCCCACCAGCCUUGUCCUAAUAAAAUUAAGUUGCAUCAAGCU
当業者は、本明細書に記載する発明の具体的な実施形態の多くの同等事物を認識し、単に日常的実験を用いてそれを確認することができるものである。本発明の範囲は、上記明細書に限定されることを意図されておらず、より正確には次の特許請求の範囲に明記する通りである。
例えば、本発明の特定の実施形態では、以下の項目が提供される。
(項目1)
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。
(項目2)
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、項目1に記載の方法。
(項目3)
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、項目2に記載の方法。
(項目4)
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、項目3に記載の方法。
(項目5)
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、項目4に記載の方法。
(項目6)
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、項目2〜5のいずれか一項に記載の方法。
(項目7)
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、項目4に記載の方法。
(項目8)
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、項目1または2に記載の方法。
(項目9)
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、項目1〜8のいずれか一項に記載の方法。
(項目10)
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、項目9に記載の方法。
(項目11)
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、項目10に記載の方法。
(項目12)
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、項目9〜11のいずれか一項に記載の方法。
(項目13)
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、項目9〜12のいずれか一項に記載の方法。
(項目14)
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、項目9〜13のいずれか一項に記載の方法。
(項目15)
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、項目9〜13のいずれか一項に記載の方法。
(項目16)
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、項目1〜15のいずれか一項に記載の方法。
(項目17)
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、項目16に記載の方法。
(項目18)
前記1つまたは複数のmRNAが無修飾である、項目1〜15のいずれか一項に記載の方法。
(項目19)
前記1つまたは複数のmRNAが静脈内投与される、項目1〜18のいずれか一項に記載の方法。
(項目20)
前記1つまたは複数のmRNAが腹腔内投与される、項目1〜18のいずれか一項に記載の方法。
(項目21)
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、項目1〜20のいずれか一項に記載の方法。
(項目22)
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、項目1〜21のいずれか一項に記載の方法。
(項目23)
前記抗体がIgGである、項目22に記載の方法。
(項目24)
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、項目1〜23のいずれか一項に記載の方法。
(項目25)
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。
(項目26)
前記細胞が哺乳動物細胞である、項目25に記載の方法。
(項目27)
前記細胞がヒト細胞である、項目25または26に記載の方法。
(項目28)
前記細胞が培養細胞である、項目25〜27のいずれか一項に記載の方法。
(項目29)
前記細胞が生体内の細胞である、項目25〜27のいずれか一項に記載の方法。
(項目30)
前記抗体が細胞内に発現される、項目25〜29のいずれか一項に記載の方法。
(項目31)
前記抗体が前記細胞によって分泌される、項目25〜30のいずれか一項に記載の方法。
(項目32)
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、項目25〜31のいずれか一項に記載の方法。
(項目33)
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、項目32に記載の方法。
(項目34)
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、項目33に記載の方法。
(項目35)
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、項目25〜34のいずれか一項に記載の方法。
(項目36)
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、項目25〜34のいずれか一項に記載の方法。
(項目37)
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、項目25〜36のいずれか一項に記載の方法。
(項目38)
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、項目37に記載の方法。
(項目39)
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、項目37に記載の方法。
(項目40)
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、項目37〜39のいずれか一項に記載の方法。
(項目41)
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。
(項目42)
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、項目41に記載の組成物。
(項目43)
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、項目42に記載の組成物。
(項目44)
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、項目43に記載の組成物。
(項目45)
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、項目41〜44のいずれか一項に記載の組成物。
(項目46)
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、項目41〜44のいずれか一項に記載の組成物。
(項目47)
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、項目41〜46のいずれか一項に記載の組成物。
(項目48)
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、項目47に記載の組成物。
(項目49)
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、項目47に記載の組成物。
(項目50)
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、項目41〜49のいずれか一項に記載の組成物。
(項目51)
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、項目41〜50のいずれか一項に記載の組成物。
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- 明細書に記載の発明。
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