JP2022051769A - ウイルス動態への影響を最小限にするための治療用アデノウイルスにおける外因性遺伝子発現 - Google Patents
ウイルス動態への影響を最小限にするための治療用アデノウイルスにおける外因性遺伝子発現 Download PDFInfo
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Abstract
Description
本願は、2016年2月23日に出願された米国仮出願第62/298,653号(その全体が参照によって本明細書中に組み込まれる)の利益を主張する。
特定の実施形態では、例えば以下の項目が提供される。
(項目1)
異種オープンリーディングフレーム(ORF)および自己切断ペプチドコーディング配列を、いずれも内因性アデノウイルスORFと同じリーディングフレーム内に、それと作動可能に連結した状態で含む、組換えアデノウイルスゲノムであって、前記自己切断ペプチドコーディング配列が、前記異種ORFと前記内因性ORFとの間に位置し、かつ
前記内因性ORFが、E1B-55kであり、前記異種ORFが、E1B-55kの3’にあるか、
前記内因性ORFが、DNAポリメラーゼであり、前記異種ORFが、DNAポリメラーゼの5’にあるか、
前記内因性ORFが、DNA結合タンパク質(DBP)であり、前記異種ORFが、DBPの3’にあるか、
前記内因性ORFが、アデノウイルス死タンパク質(ADP)であり、前記異種ORFが、ADPの5’にあるか、
前記内因性ORFが、E3-14.7kであり、前記異種ORFが、E3-14.7kの3’にあるか、
前記内因性ORFが、E4-ORF2であり、前記異種ORFが、E4-ORF2の5’にあるか、または
前記内因性ORFが、ファイバーであり、前記異種ORFが、ファイバーの3’にあり、
前記異種ORFが、治療用タンパク質をコードする、組換えアデノウイルスゲノム。
(項目2)
前記治療用タンパク質が、免疫調節因子を含む、項目1に記載の組換えアデノウイルスゲノム。
(項目3)
前記自己切断ペプチドが、2Aペプチドまたはそのバリアントである、項目1または項目2に記載の組換えアデノウイルスゲノム。
(項目4)
前記2Aペプチドが、ブタテッショウウイルス-1(PTV1)2A(P2A)ペプチド、口蹄疫ウイルス(FMDV)2A(F2A)ペプチド、ウマ鼻炎Aウイルス(ERAV)2A(E2A)ペプチド、またはThosea asignaウイルス(TaV)2A(T2A)ペプチド、またはそれらのバリアントを含む、項目3に記載の組換えアデノウイルスゲノム。
(項目5)
前記自己切断ペプチドのアミノ酸配列が、配列番号14~21のうちのいずれか1つのアミノ酸配列に対して、少なくとも80%、少なくとも85%、少なくとも90%、または少なくとも95%同一である、項目4に記載の組換えアデノウイルスゲノム。
(項目6)
前記自己切断ペプチドが、配列番号14~21のうちのいずれか1つのアミノ酸配列を含む、項目4に記載の組換えアデノウイルスゲノム。
(項目7)
項目1から6のいずれか一項に記載の組換えアデノウイルスゲノムと、薬学的に許容される担体とを含む、組成物。
(項目8)
項目1から6のいずれか一項に記載の組換えアデノウイルスゲノムを含む、組換えアデノウイルス。
(項目9)
項目8に記載の組換えアデノウイルスと、薬学的に許容される担体とを含む、組成物。
(項目10)
治療用タンパク質を被験体に送達する方法であって、前記被験体に、項目1から6のいずれか一項に記載の組換えアデノウイルスゲノム、項目8に記載の組換えアデノウイルス、または項目7もしくは項目9に記載の組成物を投与することを含む、方法。
(項目11)
腫瘍細胞の生存度および/または腫瘍細胞の増殖を阻害する方法であって、前記腫瘍細胞を、項目1から6のいずれか一項に記載の組換えアデノウイルスゲノム、項目8に記載の組換えアデノウイルス、または項目7もしくは項目9に記載の組成物と接触させることを含む、方法。
(項目12)
in vitro方法である、項目11に記載の方法。
(項目13)
前記方法が、in vivo方法であり、前記腫瘍細胞を接触させることが、前記組換えアデノウイルスゲノム、組換えアデノウイルス、または組成物を、腫瘍を有する被験体に投与することを含む、項目11に記載の方法。
(項目14)
被験体における腫瘍の進行を阻害するかまたは腫瘍の体積を低減させる方法であって、前記被験体に、治療有効量の、項目1から6のいずれか一項に記載の組換えアデノウイルスゲノム、項目8に記載の組換えアデノウイルス、または項目7もしくは項目9に記載の組成物を投与し、それによって、前記被験体における腫瘍の進行を阻害するか、または腫瘍の体積を低減させることを含む、方法。
(項目15)
被験体におけるがんを処置する方法であって、前記被験体に、治療有効量の、項目1から6のいずれか一項に記載の組換えアデノウイルスゲノム、項目8に記載の組換えアデノウイルス、または項目7もしくは項目9に記載の組成物を投与し、それによって、前記被験体におけるがんを処置することを含む、方法。
(項目16)
前記被験体に、追加の治療剤を投与することをさらに含む、項目13から15のいずれか一項に記載の方法。
(項目17)
(i)項目1から6のいずれか一項に記載の組換えアデノウイルスゲノム、項目8に記載の組換えアデノウイルス、または項目7もしくは項目9に記載の組成物と、
(ii)1つもしくは複数の追加の治療剤および/または1つもしくは複数の診断剤とを含む、キット。
(項目18)
前記1つまたは複数の追加の治療剤が、化学療法薬、生物製剤、またはそれらの組合せを含む、項目17に記載のキット。
(項目19)
前記1つまたは複数の診断剤が、腫瘍マーカーに特異的な1つまたは複数の抗体を含む、項目17または18に記載のキット。
(項目20)
前記1つまたは複数の診断剤が、腫瘍マーカーに特異的な1つまたは複数の核酸分子を含む、項目17または18に記載のキット。
添付の配列表に列挙されている核酸配列およびアミノ酸配列は、37 C.F.R.1.822に定義されるように、ヌクレオチド塩基の標準的な略字およびアミノ酸の3文字コードを使用して示されている。それぞれの核酸配列の一方の鎖のみが示されているが、相補鎖は、提示された鎖に対する任意の参照により含まれると理解される。配列表は、2017年2月21日に作成された703KBのASCIIテキストファイルとして提出されており、参照により本明細書に組み込まれる。添付の配列表においては、以下の通りである。
配列番号1は、合成アデノウイルスゲノムCMBT-379(YPet-P2A-E1A)のヌクレオチド配列である。
配列番号2は、合成アデノウイルスゲノムCMBT-432(E1A-P2A-YPet)のヌクレオチド配列である。
配列番号3は、合成アデノウイルスゲノムCMBT-456(E1B-55k-P2A-YPet)のヌクレオチド配列である。
配列番号4は、合成アデノウイルスゲノムCMBT-499(E1B-55k-P2A-mCherry)のヌクレオチド配列である。
配列番号5は、合成アデノウイルスゲノムCMBT-530(YPet-P2A-(DNAポリ))のヌクレオチド配列である。
配列番号6は、合成アデノウイルスゲノムCMBT-886(DBP-P2A-YPet)のヌクレオチド配列である。
配列番号7は、合成アデノウイルスゲノムCMBT-403(YPet-P2A-ADP)のヌクレオチド配列である。
配列番号8は、合成アデノウイルスゲノムCMBT-429(ADP-P2A-YPet)のヌクレオチド配列である。
配列番号9は、合成アデノウイルスゲノムPCMN-887(E3-14.7k-P2A-YPet)のヌクレオチド配列である。
配列番号10は、合成アデノウイルスゲノムCMBT-457(YPet-P2A-E4-ORF2)のヌクレオチド配列である。
配列番号11は、合成アデノウイルスゲノムCMBT-633(mCherry-P2A-E4-ORF2)のヌクレオチド配列である。
配列番号12は、合成アデノウイルスゲノムCMBT-407(YPet-P2A-ファイバー)のヌクレオチド配列である。
配列番号13は、合成アデノウイルスゲノムCMBT-445(ファイバー-P2A-YPet)のヌクレオチド配列である。
配列番号14は、P2Aのアミノ酸配列である。
配列番号15は、F2Aのアミノ酸配列である。
配列番号16は、E2Aのアミノ酸配列である。
配列番号17は、T2Aのアミノ酸配列である。
配列番号18は、N末端にGSGを含む修飾されたP2Aのアミノ酸配列である。
配列番号19は、N末端にGSGを含む修飾されたF2Aのアミノ酸配列である。
配列番号20は、N末端にGSGを含む修飾されたE2Aのアミノ酸配列である。
配列番号21は、N末端にGSGを含む修飾されたT2Aのアミノ酸配列である。
配列番号22は、合成アデノウイルスゲノムPCMN-888(Ad9 E3-15k-P2A-YPet)のヌクレオチド配列である。
配列番号23は、合成アデノウイルスゲノムPCMN-889(Ad34 E3-14.8k-P2A-YPet)のヌクレオチド配列である。
Ad アデノウイルス
ADP アデノウイルス死タンパク質
BFP 青色蛍光タンパク質
E2A ウマ鼻炎Aウイルス2A
ELISA 酵素結合免疫吸着法
ERAV ウマ鼻炎Aウイルス
F2A 口蹄疫ウイルス2A
FACS 蛍光活性化細胞分取
FMDV 口蹄疫ウイルス(food and mouth disease virus)
GFP 緑色蛍光タンパク質
MOI 感染多重度
OD 光学密度
ORF オープンリーディングフレーム
P2A ブタテッショウウイルス-1 2A
pIX タンパク質IX
PTV1 ブタテッショウウイルス-1
RFP 赤色蛍光タンパク質
SLIC 配列およびライゲーション非依存性クローニング
T2A Thosea asignaウイルス2A
TaV Thosea asignaウイルス
YFP 黄色蛍光タンパク質
別途注記されない限り、技術用語は、従来の使用法に従って使用される。分子生物学における一般用語の定義は、Oxford University Pressによって1994年に刊行されたBenjamin Lewin、Genes V(ISBN 0-19-854287-9);Blackwell Science Ltd.によって1994年に刊行されたKendrewら(編)、The Encyclopedia of Molecular Biology(ISBN 0-632-02182-9);およびVCH Publishers, Inc.によって1995年に刊行されたRobert A. Meyers(編)、Molecular Biology and Biotechnology: a Comprehensive Desk Reference(ISBN 1-56081-569-8)に見出すことができる。
Sci. USA、85巻、2444頁、1988年;HigginsおよびSharp、Gene、73巻、237~44頁、1988年;HigginsおよびSharp、CABIOS、5巻、151~3頁、1989年;Corpetら、Nuc. Acids Res.、16巻、10881~90頁、1988年;Huangら、Computer Appls. in the Biosciences、8巻、155~65頁、1992年;ならびにPearsonら、Meth. Mol. Bio.、24巻、307~31頁、1994年。Altschulら、J. Mol. Biol.、215巻、403~10頁、1990年は、配列アラインメント方法および相同性の計算に関する詳細な考察を提示している。
異種オープンリーディングフレーム(ORF)および自己切断ペプチドコーディング配列を含む、組換えアデノウイルスゲノムが、本明細書において開示される。異種ORFは、例えば、治療用タンパク質(例えば、免疫調節因子)をコードすることができる。組換えアデノウイルスゲノムおよび開示されるゲノムによって産生される組換えアデノウイルスは、例えば、がんの処置など、様々な異なる治療的適用において使用することができる。
36kbのアデノウイルスゲノムは、小型であり、様々な遺伝子のコーディングにトップストランド(top strand)とボトムストランド(bottom strand)の両方を使用する。アデノウイルスゲノム内の多数の位置において、トップストランドとボトムストランドとの両方が、別個の遺伝子のコーディングに同時に使用される。ゲノムのサイズは、そのキャプシドへの挿入に最適となるように進化してきた。結果として、外因性遺伝子の挿入は、キャプシドのサイズ容量によって制限されるが、これは、外因性核酸の過剰な追加により、キャプシドへのゲノムローディング(genome loading)が不完全となり、ウイルス動態が低減されるためである。
E1B-55k-SC-異種ORF
異種ORF-SC-(DNAポリメラーゼ)
DBP-SC-異種ORF
異種ORF-SC-ADP
E3-14.7k-SC-異種ORF
異種ORF-SC-E4-ORF2
ファイバー-SC-異種ORF
自己切断ペプチドは、リボソームがC末端におけるペプチド結合の合成をスキップするように誘導し、そのペプチド配列と下流のポリペプチドとの分離をもたらす、ペプチドである。自己切断ペプチドの使用により、単一のORFから、自己切断ペプチドに隣接する複数のタンパク質の発現が可能となる。ウイルスによってコードされる2Aペプチドは、自己切断ペプチドの一種である。
asignaウイルス(TaV)、ウマ鼻炎Aウイルス(ERAV)、ブタテッショウウイルス-1(PTV1)、および口蹄疫ウイルス(FMDV)によってコードされる2Aペプチド、またはそれらの修飾バージョンが挙げられるが、これらに限定されない。
組換えアデノウイルスまたは組換えアデノウイルスゲノムを含む組成物が、本明細書において提供される。本組成物は、任意選択で、in vitroまたはin vivoでの製剤化および投与に好適である。任意選択で、本組成物は、提供される薬剤のうちの1つまたは複数および薬学的に許容される担体を含む。好適な担体およびそれらの製剤は、Remington:The Science and Practice of Pharmacy、第22版、Loyd V. Allenら編、Pharmaceutical Press(2012年)に記載されている。薬学的に許容される担体としては、生物学的にもそれ以外にも望ましくないことのない材料が挙げられる。すなわち、この材料は、望ましくない生物学的作用を引き起こすことも、この材料が含有されている医薬組成物中の他の構成成分と有害な様式で相互作用することもなく、被験体に投与される。被験体に投与される場合、担体は、任意選択で、活性成分の分解を最小限に抑え、被験体における有害な副作用を最小限に抑えるように選択される。
、肝内、頭蓋内、噴霧化/吸入、または気管支鏡法を介した設置によるものを含む、複数の投与経路のうちのいずれかを介して投与することができる。したがって、本組成物は、局所的処置が所望されるか全身処置が所望されるかに応じて、また処置しようとする領域に応じて、いくつかの手段で投与される。
本明細書において開示される組換えアデノウイルス、組換えアデノウイルスゲノム、および組成物は、治療的処置または予防的処置のために投与することができる。具体的には、被験体における腫瘍細胞の生存度もしくは増殖を低減もしくは阻害する方法、被験体における腫瘍の進行を低減もしくは阻害する方法、転移の数を低減させる方法、転移のサイズおよび/もしくは体積を低減させる方法、被験体における腫瘍のサイズおよび/もしくは体積を低減させる方法、ならびに/または被験体におけるがんを処置する方法が、提供される。本方法は、被験体に、治療有効量の組換えアデノウイルスまたは組換えアデノウイルスゲノム(またはその組成物)を投与することを含む。全体を通じて記載されるように、アデノウイルスまたは医薬組成物は、静脈内、血管内、髄腔内、筋肉内、皮下、腫瘍内、腹腔内、または経口を含むがこれらに限定されない、任意の多数の方法で投与される。任意選択で、本方法は、被験体に、1つまたは複数の追加の治療剤、例えば、化学療法剤、生物製剤、および/または照射を投与することをさらに含む。
腫、神経芽細胞腫、神経膠腫、骨原性肉腫、膵臓腫瘍、下垂体腫瘍、網膜芽細胞腫、横紋筋肉腫、肉腫、睾丸腫瘍、胸腺腫、またはウイルムス腫瘍である。腫瘍には、原発性固形腫瘍および転移性固形腫瘍の両方が含まれ、乳房、結腸、直腸、肺、口腔咽頭部、下咽頭、食道、胃、膵臓、肝臓、胆嚢および胆管、小腸、尿路(腎臓、膀胱、および尿路上皮を含む)、女性生殖管(子宮頸部、子宮、および卵巣、ならびに絨毛癌および妊娠性絨毛性疾患を含む)、男性生殖管(前立腺、精嚢、精巣、および生殖細胞腫瘍を含む)、内分泌腺(甲状腺、副腎、および下垂体を含む)、および皮膚の癌腫、ならびに血管腫、黒色腫、肉腫(骨および軟組織から生じるもの、ならびにカポジ肉腫を含む)、ならびに脳、神経、眼、および髄膜の腫瘍(星状細胞腫、膠腫、膠芽腫、網膜芽細胞腫、神経腫、神経芽細胞腫、神経鞘腫、および髄膜腫を含む)が含まれる。一部の態様では、白血病などの造血系悪性疾患(すなわち、緑色腫、形質細胞腫、ならびに菌状息肉腫のプラークおよび腫瘍、ならびに皮膚T細胞性リンパ腫/白血病)により生じる固形腫瘍、ならびにリンパ腫(ホジキンリンパ腫および非ホジキンリンパ腫の両方)の処置において生じる固形腫瘍が、処置され得る。加えて、処置は、本明細書において記載される腫瘍からの転移の予防に有用であり得る。
剤、酵素、トポイソメラーゼ阻害剤、抗生存剤(anti-survivalagent)、生物学的応答修飾因子、抗ホルモン剤(例えば、抗アンドロゲン剤)、抗血管新生剤、およびCDK阻害剤などが挙げられるが、これらに限定されない。他の抗がん処置としては、放射線療法およびがん細胞を特異的に標的化する他の抗体が挙げられる。
(ジエチルスチルベストロールおよびエチニルエストラジオールなど)、抗エストロゲン薬(タモキシフェンなど)、ならびにアンドロゲン(プロピオン酸テストステロンおよびフルオキシメステロンなど)が挙げられる。
)、シスプラチン(Cisplatinum)、シトキサン、ダウノルビシン、DTIC、5-FU
、フルダラビン、ハイドレア、イダルビシン、イホスファミド、メトトレキセート、ミトラマイシン、マイトマイシン、ミトキサントロン、ナイトロジェンマスタード、タキソール(または他のタキサン類、例えば、ドセタキセル)、ベルバン(Velban)、ビンクリスチン、VP-16が挙げられるが、いくつかのより新しい薬物としては、ゲムシタビン(Gemzar)、ハーセプチン、イリノテカン(Camptosar、CPT-11)、ロイスタチン、ナベルビン、リツキサンSTI-571、タキソテール、トポテカン(ハイカムチン)、ゼローダ(カペシタビン)、ゼベリン(Zevelin)、およびカルチトリオ
ールが挙げられる。
る。これらは、個別に使用してもよく、または任意の組合せで使用してもよい。
アデノウイルスゲノムは、E1、E2、E3、E4、およびL1-5とラベル付けされた複数の機能的な群に組織化される。E1領域は、すべての他のウイルス遺伝子の転写を調節するタンパク質をコードし、宿主細胞にS期を誘導する。E2領域は、ウイルスDNA複製を駆動させるタンパク質をコードする。E3領域のタンパク質は、宿主細胞の免疫応答をモジュレートし、細胞培養においては必須ではない。E4領域は、異なる機能セットの遺伝子を含有する。そしてL1-5領域は、ウイルス粒子の構造タンパク質をコードする。
この実施例では、ウイルス動態を破壊することなく、自己切断ペプチド配列とともに、外因性ORFを挿入することができる、アデノウイルスゲノム内での特異的な位置の特定について記載する。
蛍光タンパク質をアデノウイルスORFに直接的に融合したいくつかの構築物を、生成した。具体的には、以下の直接的融合体を、生成した:YPet-E1A、YPet(DNAポリメラーゼ)、およびmCherry-ADP。
図7は、6種類の異なる構築物の自然対数スロープの比較を示す:YPet-E1A、YPet-P2A-E1A、E1A-P2A-mCherry、E1B-55k-P2A-YPet、YPet-P2A-ADP、およびファイバー-P2A-YPet。上述のように、YPetのE1Aへの直接的な融合により、有意に減損された動態を有するウイルスが産生され、P2A部位をN末端(YPet-P2A-E1A)またはC末端(E1A-P2A-mCherry)のいずれかに付加することにより、ウイルス動態は改善されたが、野生型レベルには至らなかった。しかしながら、P2A部位および異種ORFを、E1B-55kのC末端(E1B-55k-P2A-YPet)またはADPのN末端(YPet-P2A-ADP)に挿入することにより、野生型ウイルス動態を有する組換えウイルスが生成された。
E1B-55k-P2A-異種ORF
異種ORF-P2A-(DNAポリメラーゼ)
DBP-SC-異種ORF
異種ORF-SC-ADP
E3-14.7k-SC-異種ORF
異種ORF-P2A-E4-ORF2
ファイバー-P2A-異種ORF
これまでに説明されているウイルス動態を測定する方法は、すべて、細胞型特異的アッセイに高度に依存し、したがって、それぞれのアデノウイルス血清型の多様な親和性に起因して、血清型特異的である。本明細書において開示されるアデノウイルス動態アッセイは、いずれか1つの細胞型に依存するものではなく、そのため、Ad5以外の血清型に拡張することが可能である。すべてのアデノウイルス血清型は、Ad5 E3-14.7kと同等のORFを含有する。したがって、Ad9(E3-15kを含有する)およびAd34(E3-14.8kを含有する)を使用して、Ad5 E3-14.7k-P2A-YPet(PCMN-887、配列番号9)と同等のウイルスを生成した:PCMN-888(Ad9 E3-15k-P2A-YPet、配列番号22)およびPCMN-889(Ad34 E3-14.8k-P2A-YPet、配列番号23)。Ad5コア、ならびにAd9またはAd34のいずれかに由来するファイバーシャフトおよびノブを含有するキメラウイルスもまた、生成した。次いで、4つの組換えウイルスを、293細胞(図9A)、A549細胞(図9B)、およびU2OS細胞(図9C)を使用して、FBVKアッセイにおいて試験した。4つすべての組換えウイルスは、高いレベルのYPet発現を呈し、外因性ORFの挿入によって生じるウイルス動態への影響は最小限であった。
組換えアデノウイルスをアセンブリするためのAdsembly方法およびAdSLIC方法は、短時間で、多数の組換えウイルスゲノムおよびウイルスを生成するための手段を提供する。しかしながら、臨床上および治療上の使用のために設計された組換えアデノウイルスの複製動態を評価する高速かつ高スループットな方法に対する必要性が存在する。この実施例では、組換えアデノウイルスのウイルス複製動態を試験するために使用することができる、蛍光に基づくウイルス動態アッセイについて説明する(図3)。このアッセイは、組換えアデノウイルスゲノムプラスミドまたは組換えアデノウイルス粒子のいずれかを出発材料として用いて、行うことができる。
対数スロープを測定するために、時間に対する蛍光強度の線形プロットを、それぞれの時点で測定した蛍光強度の自然対数を取得することによって、片対数プロットに変換する。蛍光強度は、ウイルス複製時には指数関数的増殖を呈するため、この変換は、時間に対する自然対数(蛍光強度)をプロットすると直線となる。次いで、この直線を、標準的な最小二乗法を使用して当てはめる。この当てはめにより産生された結果として得られるスロープは、時間に対する蛍光の自然対数スロープであり、したがって、時間に対するウイルス増殖の自然対数スロープである。式を、以下に示す。
両側の自然対数を取得すると:
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AU2017223589A1 (en) | 2018-08-09 |
EP3390645A1 (en) | 2018-10-24 |
KR20220163505A (ko) | 2022-12-09 |
CN117384961A (zh) | 2024-01-12 |
CA3013639A1 (en) | 2017-08-31 |
CN108699566A (zh) | 2018-10-23 |
WO2017147269A1 (en) | 2017-08-31 |
KR102471633B1 (ko) | 2022-11-25 |
US20200325492A1 (en) | 2020-10-15 |
EP4155411A1 (en) | 2023-03-29 |
JP7015551B2 (ja) | 2022-02-15 |
US20230088476A1 (en) | 2023-03-23 |
CN108699566B (zh) | 2023-06-30 |
JP2019509037A (ja) | 2019-04-04 |
AU2017223589B2 (en) | 2023-08-03 |
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