JP2022510856A - Vsvキメラベクター - Google Patents
Vsvキメラベクター Download PDFInfo
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- JP2022510856A JP2022510856A JP2021529121A JP2021529121A JP2022510856A JP 2022510856 A JP2022510856 A JP 2022510856A JP 2021529121 A JP2021529121 A JP 2021529121A JP 2021529121 A JP2021529121 A JP 2021529121A JP 2022510856 A JP2022510856 A JP 2022510856A
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Abstract
Description
癌療法におけるウイルスの使用は、過去10年間に集中的に研究されている。腫瘍溶解性ウイルス(OV)は、癌治療における重要な薬剤であると考えられる。腫瘍溶解性ウイルスは、免疫刺激と腫瘍-特異性細胞溶解の魅力的な治療の組合せをもたらす。更に、OVは、腫瘍選択性の最適化及び増強された免疫刺激のために遺伝的に改変されることができ、且つチェックポイント阻害抗体分子などの他の薬剤及び他の免疫療法と容易に組合せることができる。OVの有効性は、多くの前臨床試験において、最近はヒトにおいて明らかにされており、腫瘍溶解性ヘルペスウイルスであるタリモジェンラヘルパレペベクが米食品医薬品局(FDA)により承認された[1, 2]。
本発明は、ベクターが、ダンデノングウイルス(DANDV)又はモペイアウイルス(MOPV)の糖タンパク質GPをコードしている遺伝子又はそれらの機能性断片もしくはバリアントを含み、且つVSVのエンベロープタンパク質Gをコードしている機能性遺伝子を欠いていることを特徴とする、VSVキメラベクターを提供する。本発明において、VSVのエンベロープタンパク質Gが、DANDVもしくはMOPVのGP又はそれらの機能性断片もしくはバリアントにより置き換えられることは好ましい。代わりの本発明の実施態様において、ベクターが、イッピイウイルス(IPPYV)、ラティーノウイルス(LATV)もしくはオリベロウイルス(OLIVV)の糖タンパク質GPをコードしている遺伝子又はそれらの機能性断片もしくはバリアントを含み、且つVSVのエンベロープタンパク質Gをコードしている機能性遺伝子を欠いていることを特徴とする、VSVキメラベクターが、提供される。
先に説明したように、本発明は、概して、キメラVSVベクターの提供に関し、ここでこのVSVベクターは、VSVのエンベロープタンパク質GPをコードしている機能性遺伝子を欠き、且つ代わりに、アレナウイルス、特にダンデノングウイルス又はモペイアウイルス(MOPV)の糖タンパク質GPをコードしている遺伝子を含む。或いはこれらのベクターは、イッピイウイルス、ラティーノウイルス又はオリベロウイルスのGPを含んでよい。当業者が公知のように、糖タンパク質GPは、ビリオンの表面上に存在するエンベロープタンパク質であり、これはビリオンと宿主生物の細胞の間の結合に寄与している。従って、このエンベロープタンパク質は、ビリオンのトロピズムを決定する。VSVのトロピズムを変更することにより、医薬における使用に適しているキメラVSVベクターを調製することができる。そのようなキメラベクター/ビリオンは、先行技術において、例えばWO2010/040526において、提供されている。しかし、更により効率的な治療選択肢及び医薬用途に関して更により良い適性を提供する更に改善されたキメラベクターの必要性が存在する。この必要性は、本発明により満たされる。
(i) VSVベクターは、腫瘍溶解性であり、且つ他の腫瘍溶解性ウイルスベクターと比べ、特に高い腫瘍溶解性活性を有する。
(ii) VSVベクターは、腫瘍細胞において優先的に複製し、且つ他の腫瘍溶解性ウイルスベクターと比べ、特に高い複製能を有する。
(iii) VSVベクターは、活発な分裂細胞に加え、静止細胞に感染する。
(iv) VSVベクターは、強力な先天性の体液性及び細胞性免疫応答を誘導する。
(v) VSVベクターは、純粋に細胞質性で、すなわちRNAウイルスとして、複製し、これらは、宿主細胞ゲノムへ組込むか、又は複製-コンピテントなウイルスを組換えることができない。
(vi) VSVベクターは、容易にパッケージングされる。
(vii) VSV糖タンパク質は、外来エンベロープタンパク質と互換性がある。先にVSVエンベロープへ取り込まれている糖タンパク質の例は:HIVgp160[19]、HCVE1/E2[20]、SARS S[21]、Lassa GP[22]、又はLCMVのGPである。しかし本発明のベクターは、先行技術、及び特にLCMVのGPによりシュードタイプ化されたVSVにまさる追加の利点を有する。
(1) 疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2) 中性親水性:Cys、Ser、Thr、Asn、Gln;
(3) 酸性:Asp、Glu;
(4) 塩基性:His、Lys、Arg;
(5) 鎖配向に影響を及ぼす残基:Gly、Pro;
(6) 芳香族:Trp、Tyr、Phe。
実施例1:アレナウイルスGP配列アラインメント
SセグメントのアレナウイルスRNA配列を、以下の遺伝子バンクフラットファイルフォーマットにおけるNCBIヌクレオチドライブラリーから検索した:LCMV-GP WE-HPI(寄託番号:AJ297484)、MOPV-GP(寄託番号:JN561684)、DANDV-GP(寄託番号:EU136038)、IPPYV-GP(寄託番号:DQ328877)、OLIVV-GP(寄託番号:U34248)及びLATV(寄託番号:AF485259)。GPC糖タンパク質配列は、SセグメントによりコードされたGPCオープンリーディングフレームの翻訳により得た。旧世界及び新世界クレードCアレナウイルスGPC配列は、ヌクレオチド及びタンパク質のレベルで、Geneiousソフトウェアパッケージバージョン11.0.5(Biomatters Ltd.)を使用し、比較した。
DANDV、MOPV、並びにLATV及びOLIVVのGP糖タンパク質は、VSV*MQΔGウイルスをtrans-補完(trans-complement)することができた。得られるVSVシュードタイプは、後続の継代においてBHK21Cl.13細胞を感染することができ、且つ偽対照と比べた場合、異なる希釈で、増大したGFPシグナルを示した(図4A)。IPPYV-GP-補完したVSV*MQΔGウイルスの上清により感染されたBHK21Cl.13細胞において認めることができたGFPグナルは、偽対照及び投入したVSV*MQΔGウイルスの結果と同等であった。これらの結果を確認するために、LCMV-GPを安定して発現するBHK-566細胞を、シュードタイプ化されたVSV*MQΔGウイルスにより感染させた。DANDV-GP、LATV-GP、MOPV-GP又はOLIVV-GPによりtrans-補完されたウイルスは、高い希釈であっても、細胞培養物内で拡散することができ、これは感染48時間後の遍在性のGFP発現につながった(図4B)。DANDV、MOPVV、IPPYV、OLIVV及びLATVのGPによりtrans-補完されたVSV*McpΔGウイルスの細胞変性効果(CPE)は、対応するVSV*MQΔGシュードタイプにより得られた結果を確認し、且つ図5にまとめた。
WO2010/040526に説明されたようなVSVベクター骨格並びにDANDV、MOPV、OLIVV及びLATVのGPを含むVSV-キメラベクターを、クローニングした。得られたキメラVSV-G(x)-DANDV、-MOPV、-OLIVV及びLATVベクターのGPを、残りのVSVベクター骨格にはいかなる変化も伴わずに、LCMVのGPと置き換えた。VSV-G(x)-DANDV及び-MOPVの複製動態にはわずかな差異が存在したが(VSV-G(x)-LATV及び-OLIVVは試験しなかった)、両方のウイルスは、30hpi後に、1×107TCID50/ml(図6A)又は1×109ゲノムコピー/ml(図6B)よりも高い力価まで複製した。それらの複製能力に関して、VSV-G(x)-DANDV及び-MOPVは、特にOV癌療法に適しているであろう。
細胞株
ヒトCalu6肺癌細胞は、Dr. Edith Lorenz, OncoTyrol (Department of Internal Medicine, Hematology and Oncology, AG Zwierzina, Innsbruck)から得た。細胞を、10%ウシ胎仔血清、2mM L-グルタミン及び1%ペニシリン/ストレプトマイシン(Pen/Strep)を含むDMEM培地において増殖した。これらの細胞を、EDTA-トリプシン0.05%を用い2~3日毎に継代培養し、その時これらは、集密度80%に達していた。ヒト前立腺癌由来の22Rv1細胞は、Prof. Z. Culig (Department of Urology, Medical University of Innsbruck)のご厚意により提供された。細胞を、10%FCS、2mMグルタミン、10mM HEPES、1mMピルビン酸ナトリウム及び1%Pen/Strepを含有するRPMI1640中で、1週間に2回継代培養した。接着性のマウス扁平上皮癌細胞(SCCVII)は、Dr. Lukas Mach (Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna)から得た。細胞を、10%FCS、2mMグルタミン、0.1mM非必須アミノ酸(NEAA)、1mMピルビン酸ナトリウム及び1%Pen/Strepを含有するDMEMにおいて増殖させた。SCCVII細胞は、EDTA-トリプシン0.05%を使用し、1:10の比で、1週間に3回継代培養した。IFN-I抗ウイルス反応を破壊するLacZカセットが安定して形質導入されたBalb/c由来のCT26Cl.25マウス結腸癌細胞は、ATCCから入手した(#CRL-2639)。細胞を、10%FCS、2%グルタミン、10mM HEPES、0.1mM NEAA、1mMピルビン酸ナトリウム、1%P/S及び400μg/ml G418を含有するRPMI1640中、1:10の比で、1週間に2回継代培養した。LLC1細胞は、原発性Lewis肺癌の移植後に、肺腫瘍を有するC57BL/6マウスから、確立した。これらの細胞は、ATCCから入手し(#CRL-1642)、且つ10%FCS、4mMグルタミン及び1%P/Sを含有するDMEM中で培養した。集密な細胞培養物を、緩く接着した細胞の再浮遊により、3~4日毎に、1:6~1:10で継代培養した。
細胞を、96-ウェルプレートに播種し、10、100、500及び1000単位のユニバーサルタイプ-1 IFN(PBL, Piscataway, NJ, USA)と共に、容積100μl/ウェルで、一晩プレインキュベーションした。翌朝、細胞を、MOIが0.1、1、又は10のVSV-GP、VSV-G(x)DANDV、VSV-G(x)MOPV又はVSV-G(x)OLIVVにより、最終容積120μl/ウェルで、感染させた。各条件に関して、4つ組試料で行った。陽性として、死滅対照細胞を、最終濃度6.67mMのH2O2と共にインキュベーションした。感染の3日後、細胞を、製造業者の推奨に従い、MTT(3-(4,5-ジメチルチアゾール-2-イル)-2,5-ジフェニルテトラゾリウムブロミド)-ベースのインビトロ細胞毒性アッセイ(Sigma-Aldrich, Saint Louis, MI, USA)を用いて、生存度について分析した。プレートを、常用のマイクロプレートリーダーにおいて、550nmで測定し、細胞を含まないウェルのブランク値を減算した。値は、インターフェロン(IFN)で前処理しなかった偽感染した細胞に対し規準化し、生存細胞の割合(%)として表した。
本試験は、VSV G(x)バリアントは、健康な無腫瘍のニュージーランドホワイト(NZW)ウサギにおける3回静脈内(i.v.)投与後に、のVSV-GPと比べ、中和抗体(nAb)を誘導しないか、又はnAbをより低いレベルで誘導するかどうかを評価することを試みた。NZWウサギは、VSV-GP又は様々なVSV-G(x)候補の1×109TCID50により、14日間間を開けて3回i.v.処置した。nAb誘導、並びに体重及び体温、ウイルス血症、全血球カウント及び血液化学を、図9に図示したように処置後一定の間隔でモニタリングした。この試験の主要目的は、各投与後10日間、nAbレベルを測定することにより、nAb誘導をモニタリングすることであった。nAbアッセイは、先にKakuら[29]、J. Virol Methods (2012) 179(1):226-32に公開された研究を基にしている。このnAbアッセイにおいて使用したVSVΔG SEAPウイルスは、エンベロープ糖タンパク質Gの代わりに分泌型胚性アルカリホスファターゼ(SEAP)を発現する。このウイルスは、LCMV-GP、又はこのプロデューサー細胞の細胞表面上に異所性に発現された他のアレナウイルス糖タンパク質の各々により、補完された。これらのtrans-補完されたウイルスは次に、収集したウサギによる中和について試験した(図10)。
必要とされるウイルスストックの容積[μl]=3.5×104感染粒子(MOI=1)/ウイルスストック力価[TCID50/ml]×ウェル数
及び
cGMEMの容積[μl]=(175μl×ウェル数)-必要とされるウイルスストックの容積[μl]
レシピエントマウス:8週齢の雌のNMRI-ヌードマウスを、Janvier(仏国)から購入した。動物を、8匹の動物群で、換気した檻中で、個別に飼育した。同定を目的に、マウスの耳にクリップを付けた。腫瘍生着(engraftment)前に、マウスは、少なくとも1週間馴化させた。
野生型VSV感染症は、そのウイルスが脳へのアクセスを獲得した場合に、神経症状を引き起こし得る。これらの神経学的合併症は、感染した対象の死亡に繋がり得る重度の脳炎を含む。キメラVSV-GPを使用する利点は、神経学的感染症は、ほぼ完全に存在しないことが示され、VSV-骨格を安全な腫瘍溶解性薬剤とすることである。弱毒化された表現型の理由は、ウイルスエンベロープ糖タンパク質を介して促進された変更されたウイルストロピズムのためであると考えられる。GP糖タンパク質の変更又は修飾は、VSV-GPのトロピズムプロファイルに影響を及ぼし、その結果VSV-G(x)DANV及びVSV-G(x)MOPVの神経毒性評価が行われた。VSV-G(x)DANDV及びVSV-G(x)MOPVの両方は、Swiss CD1マウスの頭蓋内への直接注射後に、VSV-LCMV-GPについて示されたような、神経毒性のいかなる徴候も示さなかった(図13)。VSV-G DsRedを受け取った全ての対照マウスは、感染後最初の1週間以内に死亡した。
8週齢の雌のSwiss CD-1マウスを、Janvier(仏国)から購入した。動物を、5匹の動物群で、換気した檻中で、個別に飼育した。同定を目的に、マウスの耳にクリップを付けた。動物は、実験開始前に、少なくとも1週間馴化させた。
各実験群に関して、指定されたウイルスストックを、氷上で解凍した。これらのウイルスを、PBS中1×106TCID50/3μlに希釈した。全体の容積は、100μlであった。ウイルス浮遊液80μlを、マウスの1群(n=5)の定位注射に使用した。残存する20μlは、標準手順に従い力価決定に使用した。この試料の連続1/2対数希釈は、1×105~1×1010TCID50/mlの範囲をカバーしていた。ウイルス力価決定は、定位注射のためのウイルス希釈液の調製後、1時間以内に行った。
処置後、1週間又は全てのVSV-G動物が屠殺されるまで、動物を、1日2回試験した。その後、処置後40日まで、動物を毎日モニタリングした。スコア化したパラメータは、体重、運動性、外観及び身体状態、並びに神経毒性の臨床的及び誘発された行動徴候を含む(図12)。累積毒性スコアは、特定のスコアの足し算により計算した。安楽死は、規定されたエンドポイント基準に従い適用された。
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Claims (22)
- VSVキメラベクターであって、前記ベクターが、ダンデノングウイルス(Dandenong virus)又はモペイアウイルス(Mopeia virus)の糖タンパク質GPをコードしている遺伝子を含み、且つVSVのエンベロープタンパク質Gをコードしている機能性遺伝子を欠いていることを特徴とする、VSVキメラベクター。
- 前記ベクターが、同一条件下で、LCMVのGPによりシュードタイプ化(pseudotyped)されたVSVベクターと比べ、腫瘍細胞の増大した死滅及び中和抗体の減少した誘導を示す、請求項1に記載のベクター。
- 前記VSVのエンベロープタンパク質Gが、ダンデノングウイルス又はモペイアウイルスのGPにより置き換えられることを特徴とする、請求項1又は2に記載のベクター。
- 前記ベクターが更に、少なくとも1つの導入遺伝子を含むことを特徴とする、請求項1~3のいずれか一項に記載のベクター。
- システムが、少なくとも2つの補完的複製(complementary replicating)するVSVベクターを含むことを特徴とする、VSVキメラベクターシステムであって、ここで該システムが、VSVのタンパク質N、L、P及びMをコードしている遺伝子n、l、p及びm、ダンデノング-GP又はモペイア-GPをコードしている遺伝子gpを含み、且つVSVのGタンパク質をコードしている機能性遺伝子を欠いており、ここで該システムの各ベクターが、遺伝子n、l、p、m及びgpの一つを欠いており、並びにここでこの欠けている遺伝子が、該システムの任意の他のベクター上に存在する、VSVキメラベクターシステム。
- キメラVSVビリオンであって、前記ビリオンが、エンベロープタンパク質としてダンデノング又はモペイアウイルスのGPタンパク質を含むことを特徴とする、キメラVSVビリオン。
- ウイルス産生細胞であって、前記細胞が、請求項6に記載のキメラVSVビリオンを産生することを特徴とする、ウイルス産生細胞。
- 前記細胞が、哺乳動物細胞であることを特徴とする、請求項7に記載のウイルス産生細胞。
- 前記哺乳動物細胞が、多能性成体前駆細胞(MAPC)、神経幹細胞(NSC)、間葉系幹細胞(MSC)、HeLa細胞、任意のHEK293細胞、Vero細胞又は骨髄由来の腫瘍浸潤細胞(BM-TIC)であることを特徴とする、請求項8に記載のウイルス産生細胞。
- 前記細胞が、VSVのタンパク質N、L、P及びMをコードしている遺伝子n、l、p及びm、並びにダンデノング又はモペイアGP糖タンパク質をコードしている遺伝子gpからなる群から選択される少なくとも1種の遺伝子の発現のための1又は複数の発現カセットを含むことを特徴とする、請求項7~9のいずれか一項に記載のウイルス産生細胞。
- 前記細胞が、ダンデノング又はモペイアウイルスのGPによりシュードタイプ化されたVSVビリオンへのパッケージングのための遺伝子導入ベクターを含み、ここで該遺伝子導入ベクターが、導入遺伝子を含むことを特徴とする、請求項7~10のいずれか一項に記載のウイルス産生細胞。
- インビトロにおいて細胞へ導入遺伝子を導入する方法であって、前記細胞が、請求項6に記載のキメラビリオンにより形質導入され、ここで該ビリオンが、導入遺伝子を含むことを特徴とする、方法。
- インビトロにおいて細胞へ導入遺伝子を導入する方法であって、前記細胞が、請求項7~11のいずれか一項に記載のウイルス産生細胞と接触させられることを特徴とする、方法。
- 前記細胞が、腫瘍細胞であることを特徴とする、請求項12又は13に記載の方法。
- 請求項1~4のいずれか一項に記載のVSVキメラベクター、請求項5に記載のVSVキメラベクターシステム、請求項6に記載のキメラVSVビリオン、又は請求項7~11のいずれか一項に記載のウイルス産生細胞を含有することを特徴とする、医薬組成物。
- 医薬品として使用するための、請求項1~4のいずれか一項に記載のVSVキメラベクター、請求項5に記載のVSVキメラベクターシステム、請求項6に記載のキメラVSVビリオン、請求項7~11のいずれか一項に記載のウイルス産生細胞、又は請求項15に記載の医薬組成物。
- 癌の治療に使用するための、請求項1~4のいずれか一項に記載のVSVキメラベクター、請求項5に記載のVSVキメラベクターシステム、請求項6に記載のシュードタイプ化されたVSVビリオン、請求項7~11のいずれか一項に記載のウイルス産生細胞、又は請求項15に記載の医薬組成物。
- 前記癌が、固形癌である、請求項17に記載の使用のためのVSVキメラベクター、VSVキメラベクターシステム、キメラVSVビリオン、ウイルス産生細胞又は医薬組成物。
- 前記固形癌が、脳癌、結腸直腸癌、中咽頭扁平上皮癌、胃癌、胃食道接合部腺癌、食道癌、肝細胞癌、膵臓腺癌、胆管癌、膀胱尿路上皮癌、転移性黒色腫、前立腺癌、乳癌、膠芽細胞腫、非小細胞肺癌、脳腫瘍又は小細胞肺癌であることを特徴とする、請求項18に記載の使用のためのVSVキメラベクター、VSVキメラベクターシステム、キメラVSVビリオン、ウイルス産生細胞又は医薬組成物。
- 前記VSVキメラベクター、VSVキメラベクターシステム、キメラVSVビリオン、ウイルス産生細胞又は医薬組成物が、PD-1又はPD-L1アンタゴニストと組合せられている、請求項16~19のいずれか一項に記載の使用のためのVSVキメラベクター、VSVキメラベクターシステム、キメラVSVビリオン、ウイルス産生細胞又は医薬組成物。
- 前記VSVキメラベクター、VSVキメラベクターシステム、キメラVSVビリオン、ウイルス産生細胞又は医薬組成物が、腫瘍内又は静脈内に投与されることになる、請求項16~20のいずれか一項に記載の使用のためのVSVキメラベクター、VSVキメラベクターシステム、キメラVSVビリオン、ウイルス産生細胞又は医薬組成物。
- 前記VSVキメラベクター、VSVキメラベクターシステム、キメラVSVビリオン、ウイルス産生細胞又は医薬組成物が、腫瘍内に、続いて静脈内に投与される、請求項21に記載の使用のためのVSVキメラベクター、VSVキメラベクターシステム、キメラVSVビリオン、ウイルス産生細胞又は医薬組成物。
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