JP6772065B2 - 免疫賦活プラスミド - Google Patents
免疫賦活プラスミド Download PDFInfo
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- JP6772065B2 JP6772065B2 JP2016554261A JP2016554261A JP6772065B2 JP 6772065 B2 JP6772065 B2 JP 6772065B2 JP 2016554261 A JP2016554261 A JP 2016554261A JP 2016554261 A JP2016554261 A JP 2016554261A JP 6772065 B2 JP6772065 B2 JP 6772065B2
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- C12N2710/16011—Herpesviridae
- C12N2710/16711—Varicellovirus, e.g. human herpesvirus 3, Varicella Zoster, pseudorabies
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- C—CHEMISTRY; METALLURGY
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- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16711—Varicellovirus, e.g. human herpesvirus 3, Varicella Zoster, pseudorabies
- C12N2710/16771—Demonstrated in vivo effect
Description
本明細書中に記載のものなど、本発明において有用な組成物は、一般に、感染性疾患に対する、予防的治療、メタフィラキシス的な(metaphylactic)治療または処置的治療として使用することができる。このような組成物は、本明細書中で免疫調節物質組成物と呼ぶ。本免疫調節物質組成物は、少なくとも、受容対象において免疫反応を誘発可能な免疫賦活プラスミドまたは免疫賦活DNA配列を含む。いくつかの態様において、本免疫調節物質組成物は、リポソーム送達ビヒクルも含み得る。
いくつかの態様において、本発明は、感染性疾患を引き起こす病原体の処置または予防に有用な核酸分子に関する。本明細書中に記載の核酸分子は、直鎖状2本鎖または1本鎖DNA、アミノ酸配列、リボ核酸(RNA)またはそれらの組み合わせとして、免疫賦活プラスミドに含まれ得る。いくつかの態様において、本発明は、本免疫賦活プラスミドまたは免疫賦活DNA配列を含有する、核酸分子、ベクターおよび宿主細胞(インビトロ、インビボまたはエクスビボ)に関する。
本明細書中に記載の免疫賦活プラスミドとの使用に対する適切な免疫調節物質組成物は、米国特許出願公開第2012/0064151号明細書(鳥類)および同第2013/0295167号明細書(ウシ亜科)に記載されており、この両方の内容はそれらの全体において参照により本明細書によって組み込まれる。
本明細書中に記載の免疫調節物質組成物の何れも、リポソーム送達ビヒクルおよび本明細書中に記載のプラスミドの少なくとも1つに加えて、少なくとも1つの生物学的製剤をさらに含み得る。
本発明の目的は、非感染対象に対する防御免疫、感染対象に対する防御免疫、非感染対象に対する免疫向上、感染対象に対する免疫向上、感染対象に対する治療的免疫またはそれらの組み合わせを誘発する、免疫調節物質組成物、免疫賦活プラスミド(またはDNA配列)および方法を提供することである。このように、本発明の組成物は、対象において予防的に免疫付与するために使用され得るか、または対象を処置するために使用され得る。本明細書中に記載の方法には、本明細書中に記載の免疫賦活プラスミドまたはDNA配列を対象に投与することが含まれる。
本発明は、受容対象において免疫反応を誘発する方法に関する。本方法は、免疫反応を誘発するために有効量の免疫調節物質組成物を対象に投与することを含む。いくつかの態様において、免疫調節物質組成物は、単独で有効である非抗原特異的な免疫反応を誘発する。いくつかの態様において、本免疫調節物質組成物は、ワクチンなどの少なくとも1つの生物学的製剤の作用を、このようなワクチンの前に投与された場合に、ワクチンと同時投与された場合に、ワクチン接種後に投与された場合に、またはワクチンと混合して投与された場合に、促進する。いくつかの態様において、本方法は、感染性疾患から受容対象を防御し、感染性疾患を有する集団を処置するための新しい処置ストラテジーを提供する。いくつかの態様において、本方法は、ワクチンと組み合わせて本免疫調節物質を使用する場合に、本免疫調節物質組成物なしでワクチンを使用する場合と比較して、疾患に対する、より迅速で、より長く、より良好な防御を提供する。
本発明の方法は、対象が、免疫反応の誘発に適している疾患から防御されるように、対象において免疫反応を誘発する。本明細書中で使用される場合、「疾患から防御される」という句は、疾患の症状を軽減すること;疾患の発症率を低下させること;疾患の臨床または病理的な重症度を低下させること;または疾患を引き起こす病原体の脱粒(shedding)を減少させることを指す。対象を防御することは、本発明の治療用組成物が、対象に投与された場合に、疾患の発症を予防する、疾患症状、臨床徴候、病態または原因を治癒させる、および/または改善するかまたは軽減する能力を指し得る。例えば、非限定で、ウシ呼吸器疾患(BRD)の臨床徴候としては、肺損傷、体温上昇、抑うつ(例えば食欲不振、外的刺激に対する反応性低下、垂れ耳)、鼻汁および呼吸特性(例えば呼吸数、呼吸努力)が挙げられる。本明細書中に記載の免疫調節物質組成物は、BRDの上記臨床徴候を予防するかまたはその重症度を低下させるために、BRDに曝露されている疑いがあるウシに投与し得る。さらなる例として、非限定で、鳥類対象におけるマレック病の臨床徴候としては、孵化率および鳥類生存率の低下が挙げられる。本明細書中に記載の免疫調節物質組成物は、マレック病の上記の臨床徴候を予防するかまたはその重症度を低下させるためにマレック病ウイルスに曝露されている疑いがある鳥類対象に投与し得る。
様々な投与経路を利用可能である。選択される特定の方式は、当然ではあるが、選択される特定の生物学的製剤、対象の年齢および総体的健康状態、処置されている特定の状態および治療的有効性のために必要とされる投与量に依存する。本発明の方法は、臨床的に許容できない悪影響を引き起こすことなく免疫反応の有効レベルを生じさせる何れかの投与方式を用いて実施され得る。本組成物は都合よく、単位剤形で与えられ得、当技術分野で周知の方法の何れかにより調製され得る。
「有効量」という用語は、所望の生物学的効果を実現するのに必要であるかまたは十分である量を指す。例えば、感染性疾患を処置または予防するための免疫調節物質の有効量は、病原菌に曝露された際に免疫反応の発現を引き起こす、したがって対象内の病原菌の量の減少および好ましくは病原菌の根絶を引き起こすのに必要な量である。何らかの特定の適用のための有効量は、処置されている疾患もしくは状態、対象の体格または疾患もしくは状態の重症度といった要因に依存して変動し得る。当業者は、過度の実験を必要とすることなく、免疫調節物質の有効量を経験的に決定することができる。
次の非限定例は、本発明をさらに例示するために提供される。
pGCMB75.6のマップは図2で示す。pGCMB75.6において、pMB75.6のカナマイシン耐性遺伝子(図1参照)は、E.コリ(E.coli)K−12から非コード配列により置き換えられている。pGCMB75.6プラスミドを作製するために、カナマイシン耐性遺伝子の5’部位でpMB75.6にAscIシングルカッター(single cutter)制限部位を導入して、pMB75.6_AscI(配列番号3)を作製した。AscI制限部位を導入するために、pGCMB75.6の配列に存在するアデニンをグアニンに突然変異させ、それによってpGCMB75.6プラスミド中の配列AGCGCGCCをGGCGCGCCに変化させた。増幅中のライゲーションによる突然変異誘発に基づくアプローチを用いて、この修飾を完遂した。その中間でAscI制限部位を保有した単一プライマーを使用した。
pLacZMB75.6プラスミド(図3;配列番号4)を作製するために、1307nt XhoI(CTCGAG)/DraI(TTTAAA)断片をLife Technologies GmbH(Darmstadt,Germany)により合成させた。この1307nt断片は、lacZ遺伝子(265nt)の一部を含有した。したがって、pGCMB75.6にライゲーションした場合、この断片は、XhoI制限部位の上流に位置する短縮型LacZ遺伝子を伸長させ、LacZ遺伝子を発現できるようにする(図2および図3を比較)。さらに、新たに導入されたLacZ遺伝子領域との配列相同性を削除し、組み換えを回避するために、91ntの多重クローニング部位をE.コリ(E.coli)非コード配列で置き換えた。さらに、プラスミドpGCMB75.6と同じサイズのプラスミドを作製するために、CMVプロモーターの5’領域を欠失させた(265nt)。
本免疫調節物質は、陽イオン性脂質および本明細書中に記載の非コードDNA配列を含む組成物である。直径およそ200nmのリポソームを作製するために、合成免疫調節物質脂質成分[1−[2−[9−(Z)−オクタデセノイルオキシ]]−2−[8](Z)−ヘプタデセニル]−3−[ヒドロキシエチル]イミダゾリニウムクロリド(DOTIM)および合成中性脂質コレステロールを処方する(米国特許第6,693,086号明細書参照)。DNA成分は、pGCMB75.6またはpLacZMB75.6である。負に荷電しているので、プラスミドDNAは正に荷電した(陽イオン)リポソームと会合する(米国特許第6,693,086号明細書参照)。
Claims (42)
- 核酸分子を含む免疫賦活化のための組成物であって、該核酸分子が配列番号1の配列と少なくとも89%の配列相同性を有し、少なくとも200のCpGジヌクレオチドを含み、該核酸分子は抗生物質耐性遺伝子を含まず、免疫原をコードしないことを特徴とする、前記組成物。
- 前記核酸分子が、91%、92%、93%、94%、95%、96%、97%、98%および99%からなる群から選択される、配列番号1の配列との配列相同性を有する核酸配列を含む、請求項1に記載の組成物。
- 前記核酸分子が配列番号1を含む、請求項1に記載の組成物。
- 医薬的に許容可能な担体をさらに含む、請求項1に記載の組成物。
- 配列番号4の配列と少なくとも84%の配列相同性を有し、少なくとも200のCpGジヌクレオチドを含む核酸分子を含み、該核酸分子は抗生物質耐性遺伝子を含まず、免疫原をコードしないことを特徴とする、免疫賦活化のための組成物。
- 前記核酸分子が、配列番号4の配列と少なくとも85%の配列相同性を含む、請求項5に記載の組成物。
- 前記核酸分子が、配列番号4の配列と少なくとも86%の配列相同性を含む、請求項5に記載の組成物。
- 前記核酸分子が、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%および99%からなる群から選択される、配列番号4の配列との配列相同性を有する核酸配列を含む、請求項5に記載の組成物。
- 前記核酸分子が配列番号4を含む、請求項5に記載の組成物。
- 医薬的に許容可能な担体をさらに含む、請求項5に記載の組成物。
- a.配列番号1の配列と少なくとも89%の配列相同性を有し、少なくとも200のCpGジヌクレオチドを含む核酸分子と;
b.リポソーム送達ビヒクルと、
を含み、前記核酸分子は抗生物質耐性遺伝子を含まず、免疫原をコードしないことを特徴とする、免疫賦活化のための組成物。 - 前記核酸分子が、91%、92%、93%、94%、95%、96%、97%、98%および99%からなる群から選択される、配列番号1の配列との配列相同性を有する核酸配列を含む、請求項11に記載の組成物。
- 前記核酸分子が配列番号1を含む、請求項11に記載の組成物。
- 前記リポソーム送達ビヒクルが、N−[1−(2,3−ジオレイルオキシ)プロピル]−N,N,N−トリメチルアンモニウムクロリド(DOTMA)およびコレステロール;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(DOTAP)およびコレステロール;1−[2−(オレオイルオキシ)エチル]−2−オレイル−3−(2−ヒドロキシエチル)イミダゾリニウムクロリド(DOTIM)およびコレステロール;ならびにジメチルジオクタデシルアンモニウムブロミド(DDAB)およびコレステロールからなる群から選択される脂質ペアを含む、請求項11に記載の組成物。
- 医薬的に許容可能な担体をさらに含む、請求項11に記載の組成物。
- a.配列番号4の配列と少なくとも84%の配列相同性を有し、少なくとも200のCpGジヌクレオチドを含む核酸分子と、
b.リポソーム送達ビヒクルと、
を含み、前記核酸分子は抗生物質耐性遺伝子を含まず、免疫原をコードしないことを特徴とする、免疫賦活化のための組成物。 - 前記核酸分子が、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%および99%からなる群から選択される、配列番号4の配列との配列相同性を有する核酸配列を含む、請求項16に記載の組成物。
- 前記核酸分子が配列番号4を含む、請求項16に記載の組成物。
- 前記リポソーム送達ビヒクルが、N−[1−(2,3−ジオレイルオキシ)プロピル]−N,N,N−トリメチルアンモニウムクロリド(DOTMA)およびコレステロール;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(DOTAP)およびコレステロール;1−[2−(オレオイルオキシ)エチル]−2−オレイル−3−(2−ヒドロキシエチル)イミダゾリニウムクロリド(DOTIM)およびコレステロール;ならびにジメチルジオクタデシルアンモニウムブロミド(DDAB)およびコレステロールからなる群から選択される脂質ペアを含む、請求項16に記載の組成物。
- 医薬的に許容可能な担体をさらに含む、請求項16に記載の組成物。
- 組成物を対象に投与することを含む、対象において免疫反応を刺激する方法に用いるための該組成物であって、配列番号1の配列と少なくとも89%の配列相同性を有し、少なくとも200のCpGジヌクレオチドを含む核酸配列と、リポソーム送達ビヒクルと、を含み、前記核酸配列は抗生物質耐性遺伝子を含まず、免疫原をコードしないことを特徴とする、組成物。
- 前記リポソーム送達ビヒクルが、多重膜小胞脂質および押出脂質からなる群から選択される脂質を含む、請求項21に記載の組成物。
- 前記リポソーム送達ビヒクルが、N−[1−(2,3−ジオレイルオキシ)プロピル]−N,N,N−トリメチルアンモニウムクロリド(DOTMA)およびコレステロール;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(DOTAP)およびコレステロール;1−[2−(オレオイルオキシ)エチル]−2−オレイル−3−(2−ヒドロキシエチル)イミダゾリニウムクロリド(DOTIM)およびコレステロール;ならびにジメチルジオクタデシルアンモニウムブロミド(DDAB)およびコレステロールからなる群から選択される脂質ペアを含む、請求項21に記載の組成物。
- 投与が、静脈内、筋肉内、皮内、腹腔内、皮下、噴霧によるもの、エアロゾルによるもの、胚内、経口、眼内、気管内および鼻腔内からなる群から選択される、請求項21に記載の組成物。
- 生物学的製剤をさらに含む、請求項21に記載の組成物。
- 前記生物学的製剤が、免疫促進物質タンパク質、免疫原、ワクチン、抗菌剤およびそれらのいずれかの組み合わせからなる群から選択される、請求項25に記載の組成物。
- 前記投与が感染性病原体への曝露前である、請求項21に記載の組成物。
- 前記投与が感染性病原体への曝露後である、請求項21に記載の組成物。
- 前記刺激される免疫反応が、非抗原特異的免疫反応、抗原特異的免疫反応、自然免疫反応、適応免疫反応、液性免疫反応、細胞性免疫反応またはそれらの組み合わせからなる群から選択される、請求項21に記載の組成物。
- 前記対象が、哺乳類、水産養殖物類および鳥類からなる群から選択される、請求項21に記載の組成物。
- 医薬的に許容可能な担体をさらに含む、請求項21に記載の組成物。
- 組成物を対象に投与することを含む、対象において免疫反応を刺激する方法に用いるための該組成物であって、配列番号4の配列と少なくとも84%の配列相同性を有し、少なくとも200のCpGジヌクレオチドを含む核酸配列と、リポソーム送達ビヒクルと、を含み、前記核酸配列は抗生物質耐性遺伝子を含まず、免疫原をコードしないことを特徴とする、組成物。
- 前記リポソーム送達ビヒクルが、多重膜小胞脂質および押出脂質からなる群から選択される脂質を含む、請求項32に記載の組成物。
- 前記リポソーム送達ビヒクルが、N−[1−(2,3−ジオレイルオキシ)プロピル]−N,N,N−トリメチルアンモニウムクロリド(DOTMA)およびコレステロール;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(DOTAP)およびコレステロール;1−[2−(オレオイルオキシ)エチル]−2−オレイル−3−(2−ヒドロキシエチル)イミダゾリニウムクロリド(DOTIM)およびコレステロール;ならびにジメチルジオクタデシルアンモニウムブロミド(DDAB)およびコレステロールからなる群から選択される脂質ペアを含む、請求項32に記載の組成物。
- 投与が、静脈内、筋肉内、皮内、腹腔内、皮下、噴霧によるもの、エアロゾルによるもの、胚内、経口、眼内、気管内および鼻腔内からなる群から選択される、請求項32に記載の組成物。
- 生物学的製剤をさらに含む、請求項32に記載の組成物。
- 前記生物学的製剤が、免疫促進物質タンパク質、免疫原、ワクチン、抗菌剤およびそれらのいずれかの組み合わせからなる群から選択される、請求項36に記載の組成物。
- 前記投与が感染性病原体への曝露前である、請求項32に記載の組成物。
- 前記投与が感染性病原体への曝露後である、請求項32に記載の組成物。
- 前記刺激される免疫反応が、非抗原特異的免疫反応、抗原特異的免疫反応、自然免疫反応、適応免疫反応、液性免疫反応、細胞性免疫反応またはそれらの組み合わせからなる群から選択される、請求項32に記載の組成物。
- 前記対象が、哺乳類、水産養殖物類および鳥類からなる群から選択される、請求項32に記載の組成物。
- 医薬的に許容可能な担体をさらに含む、請求項32に記載の組成物。
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