JP5710261B2 - ポックスウイルス腫瘍細胞崩壊性ベクター - Google Patents
ポックスウイルス腫瘍細胞崩壊性ベクター Download PDFInfo
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- JP5710261B2 JP5710261B2 JP2010533510A JP2010533510A JP5710261B2 JP 5710261 B2 JP5710261 B2 JP 5710261B2 JP 2010533510 A JP2010533510 A JP 2010533510A JP 2010533510 A JP2010533510 A JP 2010533510A JP 5710261 B2 JP5710261 B2 JP 5710261B2
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Description
腫瘍細胞崩壊性ウイルスとは、腫瘍依存性の自己永続という固有の性質を有する、癌の治療に用いられる新規な治療薬の一種である(HERMISTON. A demand for next-generation oncolytic adenoviruses. Current opinion in molecular therapeutics. 2006, vol.8, no.4, p.322-30.)。腫瘍細胞崩壊性ウイルスは、悪性細胞中において、選択的に複製が可能であり、従って従来の癌治療より潜在的にはるかに高いレベルの効力および特異性を提供する(FISHER. Striking out at disseminated metastases: the systemic delivery of oncolytic viruses. Current opinion in molecular therapeutics. 2006, vol.8, no.4, p.301-13.)。これらのウイルスを用いることにより、ウイルスが複製する際にウイルスの宿主細胞を溶解するとの利点を有する。癌細胞は、抗ウイルス性インターフェロン経路が不活性化されているか、またはウイルス複製が妨げられずに進行することを可能とする腫瘍抑制遺伝子の変異を有することから、多くのウイルスにとって理想的な宿主である(CHERNAJOVSKY, et al. Fighting cancer with oncolytic viruses. British medical journal 2006, vol.332, no.7534, p.170-2.)。
米国特許第5364773号(バイロジェネティクスコーポレーション(VIROGENETICS CORPORATION)社(トロイ、米国ニューヨーク州)15/11/1994には、修飾された組換えポックスウイルス、より詳細には組換えポックスウイルスが、病原性の弱毒化および安全性の増強を示すように、不活性化された、必須でないウイルスコード化コード遺伝子機能を有するワクシニアウイルスが記載されている。具体的には、病原性因子をコードするオープンリーディングフレームを欠失させることにより、または病原性因子をコードするオープンリーディングフレームの挿入による不活化により、遺伝子機能が不活化される。より詳細には、この特許には、J2R、B13R+B14R、A26L、A56R、C7L−K1L、およびI4Lのオープンリーディングフレームが不活化されているワクシニアウイルスが記載されている。このウイルス(NYVAC)は外来核酸用のベクターとして遺伝子操作することができ、宿主動物に免疫学的応答を誘導するためのワクチンとして使用することができる。しかしながら、NYVACは、ほとんどの哺乳類細胞中において効率的に複製することができず、腫瘍細胞崩壊性ウイルスとして使用することができない(XIANGZHI, et al. Vaccinia virus K1L protein supports viral replication in human and rabbit cells through a cell-type-specific set of its ankyrin repeat residues that are distinct from its binding site for ACAP2. Journal of virology. 2006, vol.353, no.1, p.220-233.)。
haromyces cerevisiae: cloning, structure and expression of wild-type and mutant alleles. Gene. 1990, vol.88, no.2, p.149-57に開示されているS.セレビシエFUR1遺伝子によってコードされているものは、引用することにより本明細書の開示の範囲とされる。参考として、遺伝子の配列および対応するUPRTaseの配列は、文献および専門データバンク(SWISSPROT、EMBL、Genbank、およびMedline等)に見出すことができる。
(i)本発明によるポックスウイルスを細胞へ導入する工程、
(ii)前記細胞を、前記ポックスウイルスの産生を可能にする適切な条件下において培養する工程、および
(iii)前記ポックスウイルスを細胞培養から回収する工程
を含む。
I4Lを欠失させるためのシャトルプラスミドは、チミジンキナーゼ遺伝子上で欠失され、ワクシニア合成プロモーターp11K7.5の制御下でFCU1遺伝子を発現するワクシニアウイルス株コペンハーゲン(受入番号M35027)のDNAを使用して構築された。I4LのDNA隣接領域をPCRによって増幅した。I4Lの下流隣接領域のプライマーは、5’−TCC CCC GGG TTA ACC ACT GCA TGA TGT ACA−3’(配列番号7、下線はSmaI部位)、および5’−GCC GAG CTC GAG GTA GCC GTT TGT AAT TCT−3’(配列番号8、下線はSacI部位)であった。上流領域用のプライマーは、5’−GCC TGG CCA TAA CTC CAG GCC GTT−3’(配列番号9、下線はMscI部位)、および5’−GCC CAG CTG ATC GAG CCG TAA CGA TTT TCA−3’(配列番号10、下線はPvuII部位)であった。増幅されたDNA断片を、制限酵素SmaI/SacIまたはMscI/PvuIIで消化し、PpolyIIIプラスミドの対応する部位にライゲーションした。I4Lの下流隣接領域の反復領域を、プライマー5’−GCC GCA TGC ATC CTT GAA CAC CAA TAC CGA−3’(配列番号11、下線はSphI部位)、および5’−GCT CTA GAG AGG TAG CCG TTT GTA ATC TG−3’(配列番号12、下線はXbaI部位)を用いて、PCRによって増幅し、PpolyIIIプラスミドに挿入した。反復領域は、欠失ウイルスの産生中に選択カセットを除去するために用いられる。pH5Rワクシニアプロモーターの制御下でGFP/GPT融合遺伝子に対応する選択カセットを、PpolyIIIプラスミドのSacI/SphI部位に挿入した。取得されたプラスミドは、I4L遺伝子を欠失しているためpΔI4Lと名づけられた組換えシャトルプラスミドである。
CEF細胞を、VVTK−FCU1(ワクシニアウイルス、J2Rキナーゼ遺伝子欠損、合成プロモーターp11k7.5の制御下でFCU1遺伝子を発現する)コペンハーゲン株に0.1MOIで感染させ、2時間37℃でインキュベートし、その後組換えシャトルプラスミド(0.2μg)のCaCl2共沈物で形質移入した。細胞を48時間37℃でインキュベートした。その後、出現ウイルスの希釈液を使用して、終濃度が15μg/mlのヒポキサンチン、終濃度が250μg/mlのキサンチン、および終濃度が250μg/mlのミコフェノール酸を含有する選択培地中でCEF細胞を感染させた。蛍光性(GFP)および陽性(GPT選択)プラークを単離し、GPT選択培地の存在下でCEF細胞の選択を数ラウンド行って選択した。VVTK−FCU1の存在下または非存在を、欠失領域内部のプライマーを用いた40サイクルのPCRによって決定した。親ウイルスの除去後、2重欠失ウイルスを使用して、GPT選択培地を用いずにCEFに感染させ、選択カセットを除去した。非蛍光性プラークを単離し、2サイクルでCEFを選択した。最終組換えVVウイルスをCEF中で増幅させて精製し、ウイルス株をプラークアッセイによりCEFに滴定した。
ヒト腫瘍細胞を、0.0001MOIのそれぞれの組換えVVを用いて形質導入した。合計3×105細胞/ウエルを、6ウエル培養皿上の、種々の濃度の5−FCを含有する2ml培地にプレーティングした。その後、細胞を5日間37℃で培養し、生細胞をトリパンブルー排除法によって計数した。図1、2、3、および4に記載された結果は、FCU1活性が、I4LおよびJ2R遺伝子を欠損するウイルスまたはF4LおよびJ2R遺伝子を欠損するウイルスよりも、J2R遺伝子を欠損するウイルスと等しいことを示す。
分裂細胞またはコンフルエント細胞を、6−ウエルプラーク中で、100PFUのウイルス(MOIがほぼ0.0005)に感染させた。10%FCSで補完された2mLの培地を分裂細胞に、補完されていない培地をコンフルエント細胞に添加した。細胞を、感染48時間後に回収した。細胞を−20℃で保管し、超音波処理してウイルスを放出させ、CEF細胞にプラーク滴定することによってウイルスも定量化した。分裂細胞とコンフルエント細胞との比率は、全ての細胞で類似している。両ウイルスVVTK−/FCU1、VVTK−I4L−/FCU1、およびVVTK−F4L−/FCU1は、コンフルエント細胞よりも分裂細胞においてより多く複製する。
雌Swissヌードマウスは、チャールスリバーラボラトリーズ(Charles River Laboratories)社から取得した。本研究で使用された動物は、年齢が同じ(6週齢)であり、体重は23〜26gの範囲であった。Swissヌードマウスの側腹に、5×106LoVo細胞を皮下(s.c.)注射した。腫瘍の直径が50〜70mm3に達した時、in vivo実験用に、マウスを盲検法で無作為化し、表示ベクターで処置した。
種々のウイルスの存在を、腫瘍試料および器官試料のウイルス滴定によって評価した。1×106PFUのVV−FCU1、VVTK−I4L−/FCU1、またはVVTK−F4L−/FCU1を、確立した皮下LoVo腫瘍を保持するヌードマウスの尾部静脈に注射することによって静脈内(i.v.)注射した。指示された時点でマウスを屠殺し、腫瘍および他の器官を収集および計量した。腫瘍および器官をPBS中でホモジナイズし、これまでに記述されているように、力価をCEFで決定した。ウイルス力価を、ミリグラムの組織に標準化した。ウイルス力価を、ミリグラムの組織に標準化した。表2、3、4、および5に記載された結果(ウイルス力価の範囲は、組織1mg当たりのpfuで示されている)は、14日後には、本発明によるウイルスがほとんどの腫瘍で見出されることを示す。図11および12に記載された結果は、両ウイルスVVTK−/FCU1、VVTK−I4L−/FCU1、およびVVTK−F4L−/FCU1が、VVTK−/FCU1の場合の尾部を除き、分析された他の器官より腫瘍において約1000から10000倍多いウイルスで腫瘍を標的にすることを示す。少量のVVTK−/FCU1が、肺、脾臓、腎臓、およびリンパ節(10pfu/mg未満)で検出され、6日目の皮膚、尾部、および骨髄、ならびに21日目の皮膚および尾部でより多くが検出される。対照的に、VVTK−I4L−/FCU1およびVVTK−F4L−/FCU1は両方とも、より高い腫瘍特異性を示し、6日目のリンパ節および尾部、ならびに21日目の腫瘍に少量だけ検出される。
確立した皮下LoVo腫瘍(50〜70mm3)を保持するヌードマウスを、静脈内で1回(尾部静脈により)、それぞれ1.107PFUの用量の表示ベクターで処置した。ウイルス注射後の7日目から開始し、100mg/kg(0.5mlの水中0.5%5−FC)の5−FCを、経口の胃管栄養法によって1日2回で3週間与えた。腫瘍サイズは、週2回カリパスを使用して測定した。腫瘍体積は、式(p/6)(長さ×幅2)を使用して、mm3で計算した。図5および6に記載された結果により、種々のウイルスが、腫瘍の増殖を制御することができる腫瘍崩壊活性(p<0.05)および腫瘍成長の制御を更に向上させることができる5−FC投与との併用活性(ウイルスの腫瘍崩壊およびFCU1遺伝子の治療)(p<0.01)と同様の効能を有することが示された。
ウイルス病原性を、Swissヌードマウス(図13)および免疫応答性B6D2マウス(図14)の両方に対して行なった生存研究で評価した。マウス1匹当たり100μlの緩衝液中の1.107または1.108PFUの全VVTK−/FCU1およびVVTK−I4L−/FCU1をマウスに注射した。実験期間中はマウスを毎日観察した。Swissヌードマウス(図13)においては、1×108PFUのVVTK−/FCU1を注射すると、感染3日後には動物の40%が死亡する結果となった。残りのマウスは、感染後50日目から80日目の間に死亡した。VVTK−I4L−/FCU1の投与は、それほど病原性ではなく、大多数の動物は65日目から140日目の間に死亡した(p<0.01)。毒性があるという証拠は、107pfuの両ウイルスでは観察されていない(図14(A))。108pfuのVVTK−/FCU1を静脈内注射した後、マウスは全て死亡した(図14(B))。VVTK−I4L−/FCU1処置群は、VVTK−/FCU1感染マウスと比較して、生存率が70%にまで著しく延長した(図14(B))。従って、この結果により、二重欠失ウイルスVVTK−I4L−/FCU1を用いた場合の毒性の減少が実証された。
Swissヌードマウスに、1.106(図15および16)または1.107(図17および18)PFUの各ウイルスを静脈内注射した。尾部病変を週1回計数した。図15(A)および図16(A)に示されているように、VVTK−/FCU1を注射され、感染後13日目のマウスでは平均8個の痘疹を有するマウスと比較して(p<0.001)、1.106PFUのVVTK−I4L−/FCU1またはVVTK−F4L−/FCU1を注射されたマウスは、マウス1匹当たり1個未満の痘疹を有する。結果は、図15(B)および図16(B)に示されているように、注射後34日目では類似しており、VVTK−I4L−/FCU1またはVVTK−F4L−/FCU1の場合のほぼ1個と比較して(p<0.0001)、VVTK−/FCU1では痘疹は平均4個である。感染後15日目では、平均10個の痘疹/マウスを有する1.107PFUのVVTK−/FCU1を注射されたマウスと比較して、1.107PFUのVVTK−I4L−/FCU1またはVVTK−F4L−/FCU1を注射されたマウスは、平均3個の痘疹/マウスおよび平均2個の痘疹/マウスをそれぞれ有する(図17(A)および図18(A))。感染後31日目では、平均7個の痘疹/マウスを有するVVTK−/FCU1を注射されたマウスと比較して、VVTK−I4L−/FCU1またはVVTK−F4L−/FCU1を注射されたマウスは、平均1.5個の痘疹/マウスおよび平均2個の痘疹/マウスをそれぞれ有する(図17(B)および図18(B))。VVTK−/FCU1とVVTK−l4L−/FCU1およびVVTK−F4L−/FCU1の両方との間の痘疹数の差は、統計学的に有意である(p<0.01)。痘疹形成は、尾部におけるウイルス複製と相関しており、病原性および毒性とも相関している。VVTK−I4L−/FCU1またはVVTK−F4L−/FCU1の静脈内注射は、単一欠失TKウイルスより毒性が少ない。
Claims (22)
- 欠損I4Lおよび/またはF4L遺伝子を含む腫瘍細胞崩壊性のポックスウイルスを含み、ポックスウイルスが欠損J2R遺伝子を含み、かつポックスウイルスが自殺遺伝子を含む、癌を治療するための、医薬組成物。
- 前記ポックスウイルスが、欠損F2L遺伝子を更に含んでなる、請求項1に記載の医薬組成物。
- 前記ポックスウイルスが、チョルドポックスウイルス亜科に属するものである、請求項1または2に記載の医薬組成物。
- 前記ポックスウイルスが、ワクシニアウイルス種に属するものである、請求項3に記載の医薬組成物。
- 前記ポックスウイルスが、ワクシニアウイルス株コペンハーゲンである、請求項4に記載の医薬組成物。
- 前記ポックスウイルスが、ワクシニアウイルス株WRである、請求項4に記載の医薬組成物。
- 前記自殺遺伝子が、少なくともシトシンデアミナーゼ活性を有するタンパク質をコードするものである、請求項1〜6のいずれか一項に記載の医薬組成物。
- 前記自殺遺伝子が、少なくともウラシルホスホリボシルトランスフェラーゼ活性を有するタンパク質をコードするものである、請求項1〜6のいずれか一項に記載の医薬組成物。
- 前記自殺遺伝子が、FCY1、FCA1、もしくはCodAである、請求項7に記載の医薬組成物。
- 少なくともシトシンデアミナーゼ活性を有する前記タンパク質が、配列番号2に表されているFCU1−8ポリペプチドである、請求項7に記載の医薬組成物。
- 前記自殺遺伝子が、少なくとも一つのシトシンデアミナーゼ活性と、一つのウラシルホスホリボシルトランスフェラーゼ活性とを有するタンパク質をコードするものである、請求項7または8に記載の医薬組成物。
- 前記自殺遺伝子が、配列番号3(coda::upp)、配列番号1(FCU1)、またはFCY1::FUR1のアミノ酸配列に表されるアミノ酸配列を含んでなるポリペプチドをコードするものである、請求項11に記載の医薬組成物。
- 前記ポックスウイルスが、パーミアーゼをコードする遺伝子を含む核酸配列を更に含んでなる、請求項1〜12のいずれか一項に記載の医薬組成物。
- パーミアーゼが、S.セレビシエのプリンパーミアーゼまたはシトシンパーミアーゼである、請求項13に記載の医薬組成物。
- パーミアーゼが、FCY2およびFur4を含んでなる群から選択されるものである、請求項14に記載の医薬組成物。
- 前記ポックスウイルスが、前記自殺遺伝子の発現に必要な転写プロモーターを更に含んでなる、請求項1〜12のいずれか一項に記載の医薬組成物。
- 前記ポックスウイルスが、パーミアーゼの発現に必要な転写プロモーターを更に含んでなる、請求項13〜15のいずれか一項に記載の医薬組成物。
- 薬学上許容される賦形剤を含んでなる、請求項1〜17のいずれか一項に記載の医薬組成物。
- 全身経路により投与されるものである、請求項1〜18のいずれか一項に記載の医薬組成物。
- 薬学上許容される量のプロドラッグがさらに投与され、該プロドラッグが、ガンシクロビル、ガンシクロビルエライジン酸エステル、ペンシクロビル、アシクロビル、バラシクロビル、(E)−5−(2−ブロモビニル)−2’−デオキシウリジン、ジドブジン、2’−エキソ−メタノカルバチミジン、5−フルオロシトシン、6−メチルプリンデオキシリボシド、フルダラビン、5−フルオロウラシル、およびアジドチミジンからなる群から選択されるものである、請求項1〜19のいずれか一項に記載の医薬組成物。
- 前記プロドラッグが、前記ポックスウイルス投与の少なくとも3日後に投与されるものである、請求項20に記載の医薬組成物。
- 前記プロドラッグが、前記ポックスウイルスの投与の7日後に投与されるものである、請求項20に記載の医薬組成物。
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