JP2017515806A - 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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- JP2017515806A JP2017515806A JP2016561850A JP2016561850A JP2017515806A JP 2017515806 A JP2017515806 A JP 2017515806A JP 2016561850 A JP2016561850 A JP 2016561850A JP 2016561850 A JP2016561850 A JP 2016561850A JP 2017515806 A JP2017515806 A JP 2017515806A
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Abstract
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.)。
抗腫瘍効果を達成するためには、高用量のポックスウイルスを注射することが必要であり、毒性の問題が提起された。大多数の有害事象は軽症であり、ワクシニアウイルスに通常関係する有害反応は自己限定性であり、発熱、頭痛、疲労、筋痛、悪寒、局所的皮膚反応、非特異性発疹、多形性紅斑、リンパ節症、および予防接種部位の疼痛が挙げられる。他の反応は、追加的な治療(例えば、VIG、一次治療、およびシドホビル(cidofovir)、二次治療)を必要とする場合がある。更なる評価または治療を必要とする可能性がある有害反応には、偶発性接種、汎発性種痘疹(GV)、種痘性湿疹(EV)、進行性痘疹(PV)、種痘後の中枢神経系疾患、および胎児ワクシニア症が挙げられる(CONO, et al. Smallpox vaccination and adverse reactions. Guidance for clinicians. MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 2003, vol.52, no.RR-4, p.1-28.)。
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.)。
NC_005309、NC_004105、NC_001132である)。
(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。
5FCプロドラッグの存在下および非存在でのヒト膵臓癌MiaPaca2細胞株(ATCC(商標)番号:CRL−1420(商標))において、イリノテカンと組合せたVVTK−I4L−/FCU1治療の治療効果をin vivoで評価した。更に詳細には、ヌードマウス(1グループあたりn=12マウス)の皮下に5×106個のMiaPaca2細胞を注射した。腫瘍が、100〜200mm3であった際、腫瘍移植後24日、28日および30日目に1×106PFUでVVTK−I4L−/FCU1を皮下に注射した。イリノテカンを28日、31日、35日、38日、42日、45日目に、33mg/kg/日で皮静脈内投与した。腫瘍移植後31日目に開始して、経口の胃管栄養法により1日2回で3週間、100mg/kgの5−FCを付与した。腫瘍サイズは、カリパスを使用して測定した。腫瘍体積は、式(π/6)(長さ×幅2)を使用して、mm3で計算した。マウスは、腫瘍体積が4000mm3を超えた際に屠殺した。グループ間の腫瘍体積差を決定するために、マンホイットニーU検定を用いた。P−値<0.05が、有意であるとみなした。
5FCプロドラッグの存在下および非存在での結腸直腸癌LoVo細胞株において、オキサリプラチンと組合せたVVTK−I4L−/FCU1治療の治療効果をin vivoで評価した。これらの条件において5FUも検査した。
統計分析は、ノンパラメトリックのマンホイットニーU検定およびSTATISTICA 7.1ソフトウェア(スタットソフト(StatSoft, Inc.)社製)を用いて実施した。P<0.05は、統計学的に有意であるとみなした。
Claims (21)
- 抗癌治療において効果的な1種以上の物質と組合せて使用するための、NYVACではない欠損I4Lおよび/またはF4L遺伝子を含んでなるポックスウイルスを含んでなる、組成物。
- 前記ポックスウイルスが、欠損J2R遺伝子を更に含んでなる、請求項1に記載の組成物。
- 抗癌治療において効果的な1種以上の物質がトポイソメラーゼI阻害剤および抗有糸分裂薬からなる群から選択される、請求項1または2に記載の組成物。
- 前記組成物および前記1種以上の物質が、全身経路を経由してかまたは腫瘍内に、好ましくは静脈内に投与される、請求項3に記載の組成物。
- 前記トポイソメラーゼI阻害剤がイリノテカン、7−エチル−10−ヒドロキシカンプトテシン、およびトポテカンからなる群から選択される、請求項3または4に記載の組成物。
- 前記トポイソメラーゼI阻害剤がイリノテカンである、請求項5に記載の組成物。
- イリノテカンの用量が5〜100mg/kg/日を含んでなり、かつポックスウイルスの用量が1x106〜1x109pfuを含んでなる、請求項6に記載の組成物。
- 前記ポックスウイルスが静脈内に1〜3回、およびイリノテカンが前記ポックスウイルスの初回投与後の3〜10日目に注射される、請求項6または7に記載の組成物。
- 前記抗有糸分裂薬がパクリタキセル、ドセタセル、ビンブラスチン、ビンクリスチン、ビノレルビンおよび白金誘導体からなる群から選択され、白金誘導体がシスプラチン、オキサリプラチン、スピロプラチナム、またはカルボプラチナムなどである、請求項3または4に記載の組成物。
- 前記抗有糸分裂薬がオキサリプラチンである、請求項9に記載の組成物。
- オキサリプラチンが静脈内にまたは腹腔内に投与され、およびポックスウイルスが静脈内に投与される、請求項10に記載の組成物。
- オキサリプラチンの用量が0.5〜10mg/kg/日を含んでなり、かつポックスウイルスの用量が1x106〜1x109pfuを含んでなる、請求項11に記載の組成物。
- 前記ポックスウイルスが静脈内に1〜3回、およびオキサリプラチンが1以上のサイクルで2週間ごとに注射される、請求項11または12に記載の組成物。
- 前記オキサリプラチンが、前記ポックスウイルス組成物の初回投与後3〜10日目に投与される、請求項13に記載の組成物。
- 前記ポックスウイルスが自殺遺伝子を更に含んでなる、請求項1〜14のいずれか一項に記載の組成物。
- 前記自殺遺伝子が、配列番号1または配列番号3における配列に表されるアミノ酸配列を実質的に含んでなるポリペプチドをコードする、請求項15に記載の組成物。
- 前記使用が、薬学上許容可能な量のプロドラッグを更に含んでなる、請求項15または16に記載の組成物。
- 前記プロドラッグが、5−フルオロシトシンである、請求項17に記載の組成物。
- 前記プロドラッグが、前記ポックスウイルス組成物の投与後、好ましくは少なくとも3日目、より好ましくは少なくとも4日目、および更により好ましくは少なくとも5日目に投与される、請求項18に記載の癌の治療における使用のための組成物。
- 癌の治療に使用するための、請求項1〜19のいずれか一項に記載の組成物。
- 前記癌が、乳癌、子宮癌、前立腺癌、肺癌、膀胱癌、肝臓癌、結腸癌、膵臓癌、胃癌、食道癌、喉頭癌、中枢神経系の癌(例えば、神経膠芽腫)、および血液の癌、好ましくは膵臓癌および結腸直腸癌からなる群から選択される、請求項20に記載の癌の治療における使用のための組成物。
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