JP6895374B2 - 免疫チェックポイントモジュレーターの発現用腫瘍溶解性ウイルス - Google Patents
免疫チェックポイントモジュレーターの発現用腫瘍溶解性ウイルス Download PDFInfo
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Description
癌の進展を開始または促進させるために共にまたは別々に作用するかもしれない決定的な因子が多いため、癌は、何年も深刻で世界的な健康への脅威であり続けると予想される。さらに、悪性および特に転移性腫瘍は、しばしば、従来の療法に対して耐性であり、幾つかの癌の顕著な死亡率を裏付けている。
本願全体で使用される用語「1つ(a)」および「1つ(an)」は、本文が明確に他を指示していない限り、言及された構成要素またはステップの「少なくとも1つ」、「少なくとも第一」、「1つ以上」または「複数」を意味するという意義で使用される。例えば、用語「1つの細胞(a cell)」は、それらの混合物を含む、複数の細胞が包含される。
本発明において使用される腫瘍溶解性ウイルスは、現在同定されている任意のウイルスメンバーから得ることができるが、ただし、それらは、非分裂細胞と比べて分裂細胞を選択的に複製および破壊するその傾向によって腫瘍溶解性である。それは、生来的に腫瘍溶解性である天然ウイルスでもよく、または、腫瘍選択性および/または分裂細胞中での選択的複製を増大させるために、DNA複製、核酸代謝、宿主向性、表面付着、病原性、溶解、および伝播に関与するもの等の1つ以上のウイルス遺伝子を改変することによって操作されたものでもよい(例えば、Kirn et al., 2001, Nat. Med. 7: 781; Wong et al., 2010, Viruses 2: 78-106を参照)。1つ以上のウイルス遺伝子を、イベントの制御または組織特異的調節因子(例えば、プロモーター)下で配置することを想定してもよい。
一つの態様において、本発明の腫瘍溶解性ウイルスは、ウイルスゲノム内に挿入された、少なくとも1つの治療遺伝子をさらに発現する。「治療遺伝子」は、対象へ適切に投与された際に、抗腫瘍効果を強化するかまたはウイルスの腫瘍溶解性特性を強化することのいずれかによって、治療される病態の過程または症状に対して有益な効果を引き起こすと期待される、生物学的活性を提供できる生成物をコードする。本発明の文脈において、治療遺伝子は、哺乳類(例えば、ヒト、マウス、ウサギ等)由来であっても、そうでなくても(例えば、細菌性、酵母またはウイルス由来)よい。
用語「自殺遺伝子」とは、薬剤の前駆体を細胞傷害性化合物に転換できるタンパク質をコードする遺伝子を意味する。自殺遺伝子は、限定されることなく、シトシンデアミナーゼ活性、チミジンキナーゼ活性、ウラシルホスホリボシルトランスフェラーゼ活性、プリンヌクレオシドホスホリラーゼ活性およびチミジレートキナーゼ活性を有するタンパク質をコードする遺伝子を含んでなる。自殺遺伝子の例および1つの核酸塩基部分を含んでなる薬剤の対応する前駆体は、下記の表において開示されている。
本明細書で使用される場合、用語「免疫刺激性タンパク質」とは、特異的または非特異的様式で、免疫系を刺激する能力を有するタンパク質を意味する。当技術分野において、多数のタンパク質が、その免疫刺激効果を発揮する能力で公知である。本発明の文脈において好適な免疫刺激性タンパク質の例としては、限定されることなく、サイトカインが挙げられ、特に好ましくはインターロイキン(例えば、IL−2、IL−6、IL−12、IL−15、IL−24)、ケモカイン(例えば、CXCL10、CXCL9、CXCL11)、インターフェロン(例えば、IFNg、IFNα)、腫瘍壊死因子(TNF)、コロニー刺激因子(例えば、GM−CSF、C−CSF、M−CSF等)、APC(抗原提示細胞)暴露タンパク質(例えば、B7.1、B7.2等)、増殖因子(形質転換増殖因子TGF、線維芽細胞増殖因子FGF、血管内皮増殖因子VEGF等)、クラスIまたはIIのMHC抗原、アポトーシス誘発因子または阻害因子(例えば、Bax、Bcl2、BclX等)、細胞増殖抑制剤(p21、p16、Rb等)、抗毒素、抗原性ポリペプチド(抗原性ポリペプチド、エピトープ等)およびマーカー(β−ガラクトシダーゼ、ルシフェラーゼ等)である。好ましくは、免疫刺激性タンパク質は、インターロイキンまたはコロニー刺激因子、特に好ましくはGM−CSFである。
免疫チェックポイントおよびそれらのモジュレーター、同様にそのような化合物を用いた方法は、文献に記載されている。本発明によれば、1つ以上の免疫チェックポイントモジュレーターは、アンタゴニスト機能(即ち、免疫チェックポイント媒介阻害シグナルと拮抗することができること)またはアゴニスト機能(即ち、免疫チェックポイント媒介刺激性シグナルを高めることができること)を発揮するために、独立して、標的免疫チェックポイントを結合でき、かつ/またはリガンドの当該標的免疫チェックポイントへの結合を阻害することができるドメインを含んでなるポリペプチドであってもよい。そのような1つ以上の免疫チェックポイントモジュレーターは、ペプチド(例えば、ペプチドリガンド)、天然受容体の可溶性ドメイン、RNAi、アンチセンス分子、抗体およびタンパク質の骨組からなる群から独立して選択され得る。
i)VL、VH、CLおよびCH1ドメインからなる一価断片で表されるFab断片;
ii)ヒンジ領域で少なくとも1つのジスルフィド架橋によって結合された2つのFab断片を含んでなる二価断片で表されるF(ab’)2断片;
iii)VHおよびCH1ドメインからなるFd断片;
iv)抗体の単一アームのVLおよびVHドメインからなるFv断片、
v)単一ドメイン可変断片(VHまたはVLドメイン)からなるdAb断片;
vi)Fv断片の2つのドメインと、融合され、最終的に一本鎖タンパク質を形成するためにリンカーを有するVLおよびVHとを含んでなる一本鎖Fv(scFv)(例えば、Bird et al., 1988, Science 242: 423-6; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85: 5879-83; US4,946,778; US5,258,498を参照);および
vii)任意の他の人工抗体
が挙げられる。
免疫チェックポイントモジュレーターをコードする核酸分子および治療遺伝子は、当技術分野において入手可能な配列データおよび本明細書で提供された情報を用いて、標準的な分子生物学技法(例えば、PCR増幅、cDNAクローニング、化学合成)によって容易に得ることができる。抗体、それらの断片および類似体をクローニングする方法は、当技術分野において公知である(例えば、Harlow and Lane, 1988, Antibodies - A laboratory manual; Cold Spring Harbor Laboratory, Cold Spring Harbor NYを参照)。例えば、抗体の軽鎖および重鎖、またはそれらのCDRをコードする核酸分子(例えば、cDNA)は、産生ハイブリドーマ(例えば、Kohler and Milstein, 1975, Nature 256: 495-7; Cote et al., 1983, Proc. Natl. Acad. Sci. USA 80: 2026-30; Cole et al. in Monoclonal antibodies and Cancer Therapy; Alan Liss pp77- 20 96を参照)、免疫グロブリン遺伝子ライブラリー、または任意の入手可能な材料(source)から分離してもよく、またはヌクレオチド配列は、化学合成によって生成させてもよい。類似体および断片は、分子生物学の標準的な技法を用いて発生させてもよい。
一つの態様において、本発明の文脈において、腫瘍溶解性ウイルスを、組換え手段によってそれがコードする1つ以上の免疫チェックポイントモジュレーターを生成するために利用してもよい。宿主細胞内の免疫チェックポイントモジュレーターをコードする核酸分子の維持、増殖または発現を可能にする1つ以上の追加的因子を含むことが有利であり得る。そのような追加的因子は、(例えば、細胞の栄養要求性の相補性または抗生物質抵抗性によって)生成宿主細胞の同定および分離を容易にするためのマーカー遺伝子を含んでなる。好適なマーカー遺伝子は、限定されることなく、メトトレキサートへの耐性を付与するジヒドロ葉酸還元酵素(dhfr)(Wigler et al., 1980, Proc. Natl. Acad. Sci. USA 77: 3567、 O'Hare et al., 1981, Proc. Natl. Acad. Sci. USA 78: 1527)、ミコフェノール酸への耐性を付与するgpt(Mulligan and Berg, 1981, Proc. Natl. Acad. Sci. USA 78: 2072)、アミノグリコシドG−418への耐性を付与するneo(Colberre-Garapin et al., 1981, J. Mol. Biol. 150: 1)、ゼオマイシン(zeomycin)への耐性を付与するzeo、カナマイシンへの耐性を付与するkana、ハイグロマイシンへの耐性を付与するhygro(Santerre et al., 1984, Gene 30: 147)を含む。機能的TKを欠失している組換えウイルス(例えば、免疫チェックポイントモジュレーターをコードする核酸分子のTK遺伝子座への挿入に起因する)を、ブロモデオキシウリジン(BrdU)を含有する培地と選択してもよい。実際に、TKウイルスは、BrdU剤に対して感度が低い一方で、該薬剤は、TK+ウイルス内でのDNA合成を妨げる。例えば、GFP(緑色蛍光タンパク質)、ルシフェラーゼおよびベータガラクトシダーゼに基づく、レポーター発光システムまたは比色システムに依存してもよい。
本発明は、場合により薬学的に許容可能な賦形剤を含む、本発明の腫瘍溶解性ウイルスの治療的有効量を含んでなる組成物も提供する。そのような組成物は、1回または数回、および同一または異なる経路を介して投与されてもよい。
本発明の腫瘍溶解性ウイルスまたは組成物は、単回投与(例えば、ボーラス注射)または複数回投与で投与してもよい。複数回投与の場合、投与は同一または異なる経路によって行ってもよく、同一の部位または異なる部位に行ってもよい。投与は、休息期間後に、繰り返し、連続的サイクルで投与することによって進めることも可能である。各投与の間隔は、数時間から1年であり得る(例えば、24時間、48時間、72時間、毎週、隔週、毎月または毎年)。間隔は、不規則であってもよい(例えば、腫瘍進行の後)。用量は、上記の範囲内で、それぞれの投与について変化させてもよい。
・例えば、マイトマイシンC、シクロホスファミド、ブスルファン、イホスファミド、イソファミド、メルファラン、ヘキサメチルメラミン、チオテパ、クロラムブシルまたはダカルバジン等のアルキル化剤;
・例えば、ゲムシタビン、カペシタビン、5−フルオロウラシル、シタラビン、2−フルオロデオキシシチジン、メトトレキサート、イダトレキサート、トムデックスまたはトリメトレキサート等の代謝拮抗物質;
・例えば、ドキソルビシン、エピルビシン、エトポシド、テニポシドまたはミトキサントロン等のトポイソメラーゼII阻害剤;
・例えば、イリノテカン(CPT−11)、7−エチル−10−ヒドロキシ−カンプトセシン(SN−38)またはトポテカン等のトポイソメラーゼI阻害剤;
・例えば、パクリタキセル、ドセタキセル、ビンブラスチン、ビンクリスチンまたはビノレルビン等の細胞分裂抑制薬;
・例えば、シスプラチン、オキサリプラチン、スピロプラチナム(spiroplatinum)またはカルボプラチナム(carboplatinum)等の白金誘導体;
・スニチニブ(Pfizer)およびソラフェニブ(Bayer)等のチロシンキナーゼ受容体の阻害剤;
・抗腫瘍抗体、具体的には、トラスツズマブ、セツキシマブ、パニツムマブ、ザルツムマブ、ニモツズマブ、マツズマブ、ベバシズマブおよびラニビズマブ等の細胞表面受容体の調節に影響する抗体;
・ゲフィチニブ、エルロチニブおよびラパチニブ等のEGFR(上皮成長因子受容体)阻害剤;ならびに
・例えば、α、βまたはγインターフェロン、インターロイキン(具体的には、IL-2、IL-6、IL-10またはIL-12)または腫瘍壊死因子等の免疫調節剤
である。
J43の重鎖は、抗CD79b IgGの重鎖と高い相同性を示した。従って、重鎖のクローン化用に保持されていた配列は、J43の可変鎖および抗CD79Bの定常鎖であった。J43の軽鎖を、抗CD79b抗体の軽鎖のシグナル配列とクローン化した。重鎖および軽鎖を、若干異なる強度を持つ、ウイルスプロモーターpH5Rまたはp7.5Kの制御下に置いた。「全」抗体コンストラクトに加えて、誘導体、それぞれHisタグ抗原結合断片(Fab)コンストラクト、同様に、Hisタグ一本鎖抗体(scFv)コンストラクトを生成した。それぞれのプロモーター下に置かれた軽鎖または重鎖の部位に依存して、Fabに対して、2つのコンストラクトフォーマットも生成した。全ての5つのコンストラクトを、TK、RR欠失WR VVの骨格に挿入した。コンストラクトは、下記のとおりまとめられる:
pH5R−HC−p7.5K−LCに対応するWRTG18618(または、mAb1)
pH5R−LC−p7.5K−HCに対応するWRTG18619(または、mAb2)
pH5R−(VH−CH1−6His)−p7.5K−LCに対応するWRTG18621(または、Fab1)
pH5R−LC−p7.5K−(VH−CH1−6His)に対応するWRTG18620(または、Fab2)
pH5R−VH−gs−VL−6His)に対応するWRTG18616(scFv)。
合成的方法(Geneart:レーゲンスブルク、ドイツ)により、p7.5Kプロモーターに続くHCを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18614を得た。合成的方法により、LCを含有する断片を産生し、NsiIおよびSalIによって制限されたpTG18614中にクローン化し、pTG18618を得た。
合成的方法により、p7.5Kプロモーターに続くLCを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18615を得た。合成的方法により、HCを含有する断片を産生し、NsiIおよびMluIによって制限されたpTG18615中にクローン化し、pTG18619を得た。
合成的方法により、p7.5Kプロモーターに続くVH−CH1−6Hisを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18617を得た。合成的方法により、LCを含有する断片を産生し、NsiIおよびSalIによって制限されたpTG18617中にクローン化し、pTG18621を得た。
合成的方法により、p7.5Kプロモーターに続くLCを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18615を得た。合成的方法により、VH−CH1−6Hisを含有する断片を産生し、NsiIおよびMluIによって制限されたpTG18615中にクローン化し、pTG18620を得た。
合成的方法により、VH−gs−VL−6Hisを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18616を得た。
上述の組換え腫瘍溶解性ベクターを、コードされた抗mPD−1分子の産生を評価するために試験した。これに、初代許容細胞または細胞株を感染させ、上清を集菌した。抗mPD−1分子の存在は、SDS−PAGE、ウエスタンブロット分析、質量分析、ELISAおよび機能的アッセイによって決定できる。市販の抗mPD−1抗体をコントロールとして用いた。
CEFを、F175フラスコ内で培養し、2.7×108pfuの抗PD−1発現ウイルスを感染させた。48〜72時間後、培養上清を採取し、0.2μmのろ過器で濾過した。mAb1を、Hitrap protein A(GE Healthcare)によって精製し、次いでSuperdex 200 ゲル濾過(GE Healthcare)する一方で、Fab1およびscFvを、HIS-Trap(GE Healthcare)によって精製し、次いでSuperdex 75ゲル濾過(GE Healthcare)した。scFvは、ゲル濾過により2つのピークとして溶出され、一つ目のピークは二量体、2つ目のピークは単量体に対応していた。図1において示されているように、相当量のmAb、FabおよびscFVが産生された。収量は、抗体型によって、上清1mlあたり0.5〜2μgであった。
ヒトLoVo癌細胞株を、トランス遺伝子のないTK−RR欠失WRワクシニアウイルス(WRTG18011)によって、および異なる抗mPD−1分子を発現するTK−RR欠失WRワクシニアウイルス(WRTG18616、WRTG18618およびWRTG8621)によって、0.001および0.0001のMOIの懸濁液に形質導入した。合計3×105細胞/ウェルを、6ウェル培養皿に、10%のFCSを補充した2mlの培地中に置いた。次いで、細胞を37℃で培養し、細胞生存を、5日後にトリパンブルー除去によって決定した。図3に示されているように、異なるウイルスの腫瘍溶解性活性は、それぞれ0.0001および0.001のMOIで、生存細胞数の75〜95%および99%の減少をもたらした。トランス遺伝子のないTK−RR欠失WRウイルスおよび異なる抗mPD−1分子を発現するTK−RR欠失WRウイルスは、細胞傷害活性において差異を示さなかった。従って、異なる抗mPD−1分子の発現は、ワクシニアウイルスの腫瘍溶解性活性に影響しなかった。
組換え腫瘍溶解性ベクターを、発現レベルおよび分泌された抗体の集合を評価するための免疫ブロットによって試験した。免疫ブロット分析を、CEFと上記のmAbおよびFabコンストラクトとを感染させてから24時間後に回収した細胞培養上清において行った。上清を、16000gで5分間遠心分離機にかけ、25μlを、還元剤を含まないLaemmli緩衝液中に調製し、PrecastGel4〜15%ポリアクリルアミドゲル(Biorad)にロードした。市販のモノクローナルJ43(BioXcell)を、参照分子として用いた。各分子を1μgゲル上にロードした。ゲル電気泳動を、非還元条件下で行い、軽鎖および重鎖の集合を保存して、最適な検出を可能にした(即ち、検出に用いられたポリクローナル抗体は、還元されたIgG鎖およびFab鎖を認識しなかった)。次いで、タンパク質を、予備プログラム化されたプロトコル(高分子量:10分、2.5A一定、最大25V)によるTransblot Turboシステム(Transblot Turbo Transfer pack Biorad)を用いて、PVDF膜に移した。膜を、ブロッキング液(0.05% Tween20、無脂肪粉ミルクBiorad5%を添加した、8mM NaPO4、2mM KPO4、154mM NaCl pH7.2(PBS))中で、4℃で一晩飽和させた。希釈緩衝液(PBS、0.05% Tween20、無脂肪粉ミルク5%)中の西洋ワサビペルオキシダーゼ(HRP)接合ヤギ抗アルメニアハムスターIgG(Jackson Immunoresearch)80ng/mLを、抗体免疫検出のために用いた。Amersham ECL Prime ウェスタンブロッティング検出試薬を用いて現像し、化学発光を捕らえるためにMolecular Imager ChemiDOCTMXRSを用いた。
ベクター化抗PD−1J43mAbの発現を、皮下移植したB16F10腫瘍を持つマウスおよび持たないマウスにおいてin vivoで評価した。WRTG18618(mAb1コンストラクト)を、腫瘍内または皮下のいずれかで注射し、市販のJ43(腫瘍内注射)と比較した。
より詳細には、3×105のB16F10細胞(マウス黒色腫)を6週齢雌C57BL/6マウスの右横腹に皮下(S.C.)注射した。0日目(D0)、腫瘍体積が、100〜200mm3に到達した際に、100μLの、WRTG18618(107pfu)または市販のJ43(1μgまたは10μg、BioXcell)のいずれかを腫瘍内(I.T.)に注射した。
J43濃度を、血清および腫瘍ホモジネートの両方において評価した。より具体的には、96ウェルプレート(Nunc immune plate Maxisorp)を、1ウェルあたり100μLの、コート溶液(0.05M炭酸ナトリウム pH9.6、Sigma)中の0.8μg/mLのヤギ抗ハムスターIgG(Southern Biotech)とともに、4℃で一晩培養した。プレートを、洗浄緩衝液(PBS、Tween20 0.05%、1ウェルあたり300μL)で3回洗浄し、1ウェルあたり200μLのブロッキング溶液(PBS、Tween20 0.05%、無脂肪粉ミルク5%)で、室温で1時間培養した。プレートを、洗浄緩衝液で3回洗浄した。2倍連続希釈法によって、1000〜0.488ng/mLのJ43(BioXcell)の標準範囲を、100%マウス血清(Sigma)中に調製した。次いで、各標準液を、ブロッキング溶液でさらに2倍希釈し(最終J43濃度は500〜0.244ng/mL)、血清の最終濃度を50%とした。1ウェルあたり100μLの各標準液を、プレートに二重に添加した。血清試料を、ブロッキング緩衝液で少なくとも2倍に希釈し、必要に応じて、ブロッキング緩衝液/血清の1体積/1体積混合物でさらに希釈し、プレートに100μLを添加した。プレートを、37℃で2時間インキュベートした。洗浄緩衝液で3回洗浄した後、1ウェルあたり100μLで、80ng/mLのHRP接合ヤギ抗アルメニアハムスターIgG(Jackson Immunoresearch)を添加し、プレートを、37℃で1時間インキュベートした。3回洗浄後、1ウェルあたり100μLの3,3’,5,5’−テトラメチルベンジジン(TMB、Sigma)を添加し、プレートを、室温で30分間インキュベートした。反応を、1ウェルあたり100μLの2M H2SO4で停止し、プレートリーダー(TECAN Infinite M200 PRO)により450nmの吸光を測定した。得られたOD値を、GraphPadPrismソフトウェアに転送し、試料濃度を、5つのパラメーターに適合した標準カーブを用いて逆算出した。
上記の多様な抗PD−1発現ワクシニアウイルスの抗腫瘍活性は、従来の前臨床的モデルにおいて、腫瘍の移植に続くコンストラクトの注射後に試験されてもよい。例えば、マウス癌細胞を、免疫競合性マウスの横腹中に皮下注射する。腫瘍が、50〜70mm3の体積に達したら、盲検下でランダム化し、1×107PFUの用量で指示されたワクシニアウイルスで処理した。ベクターまたはコントロール賦形剤(ウイルスを再懸濁するために使用される緩衝液)を、腫瘍移植後、10日目、12日目および14日目に腫瘍内へ直接注射した。キャリパーを用いて、1週間に2回、腫瘍サイズを計測した。具体的には、ベクター化したscFvおよびmAB1抗体は、腫瘍増殖を遅延させ、かつ生存率を増大させるために、少なくともWRベクターと市販のJ43の共投与と同じくらい効率的であった。
Claims (28)
- ゲノム内に挿入された、1つ以上の免疫チェックポイントモジュレーターをコードする核酸分子を含んでなる腫瘍溶解性ウイルスであって、前記腫瘍溶解性ウイルスが、J2Rウイルス性遺伝子中の不活性化突然変異に起因するチミジンキナーゼ(TK)の欠損を有するワクシニアウイルスであり、かつ、前記腫瘍溶解性ウイルスが、ウイルス性I4L遺伝子および/またはF4L遺伝子中の不活性化突然変異に起因するリボヌクレオチドレダクターゼ(RR)の欠損を有するワクシニアウイルスであり、かつ、前記1つ以上の免疫チェックポイントモジュレーターが、PD−1およびCTLA4のいずれかに特異的に結合するモノクローナル抗体から選択される、前記腫瘍溶解性ウイルス。
- 前記1つ以上の免疫チェックポイントモジュレーターが、PD−1に特異的に結合するモノクローナル抗体を含んでなる、請求項1に記載の腫瘍溶解性ウイルス。
- 前記腫瘍溶解性ウイルスが、ウイルス性ゲノム内に挿入された少なくとも1つの治療遺伝子をさらに含んでなる、請求項1または2に記載の腫瘍溶解性ウイルス。
- 前記治療遺伝子が、自殺遺伝子産物をコードする遺伝子および免疫刺激性タンパク質をコードする遺伝子からなる群から選択される、請求項3に記載の腫瘍溶解性ウイルス。
- 前記自殺遺伝子が、シトシンデアミナーゼ(CDase)活性、チミジンキナーゼ活性、ウラシルホスホリボシルトランスフェラーゼ(UPRTase)活性、プリンヌクレオシドホスホリラーゼ活性、チミジレートキナーゼ活性、ならびにCDaseおよびUPRTase活性の両方を有するタンパク質をコードする遺伝子からなる群から選択される、請求項4に記載の腫瘍溶解性ウイルス。
- 前記自殺遺伝子産物が、codA::upp、FCY1::FUR1およびFCY1::FUR1[デルタ]105(FCU1)およびFCU1〜8ポリペプチドからなる群から選択される、請求項5に記載の腫瘍溶解性ウイルス。
- 前記腫瘍溶解性ワクシニアウイルスが、TK活性およびRR活性の両方を欠損しているワクシニアウイルスであって、かつそのゲノム内に挿入された治療用FCU1自殺遺伝子を含んでなる、請求項5または6に記載の腫瘍溶解性ウイルス。
- 前記免疫刺激性タンパク質が、インターロイキンまたはコロニー刺激性因子である、請求項4に記載の腫瘍溶解性ウイルス。
- 前記腫瘍溶解性ワクシニアウイルスが、TK活性を欠損しているワクシニアウイルスであって、かつそのゲノム内に挿入された治療用ヒトGM−CSFを含んでなる、請求項8に記載の腫瘍溶解性ウイルス。
- 前記1つ以上の免疫チェックポイントモジュレーターが、ヒトPD−1に特異的に結合する抗体を含んでなる、請求項1〜9のいずれか一項に記載の腫瘍溶解性ウイルス。
- 前記ヒトPD−1に特異的に結合する抗体が、ニボルマブ(Nivolumab)、ペンブロリズマブ(Pembrolizumab)およびピディリズマブ(Pidilizumab)からなる群から選択される、請求項10に記載の腫瘍溶解性ウイルス。
- 前記1つ以上の免疫チェックポイントモジュレーターが、ヒトPD−L1に特異的に結合する抗体を含んでなる、請求項1〜9のいずれか一項に記載の腫瘍溶解性ウイルス。
- 前記ヒトPD−L1に特異的に結合する抗体が、MPDL3280AおよびBMS−936559からなる群から選択される、請求項12に記載の腫瘍溶解性ウイルス。
- 前記1つ以上の免疫チェックポイントモジュレーターが、ヒトCTLA−4に特異的に結合する抗体を含んでなる、請求項1〜9のいずれか一項に記載の腫瘍溶解性ウイルス。
- 前記ヒトCTLA−4に特異的に結合する抗体が、イピリムマブ(Ipilimumab)、トレメリムマブ(Tremelimumab)および一本鎖抗CTLA4抗体からなる群から選択される、請求項14に記載の腫瘍溶解性ウイルス。
- 前記抗体の重鎖またはその断片が、前記抗体の軽鎖またはその断片の発現に用いられるものより強いプロモーターの制御下に置かれる、請求項1〜15のいずれか一項に記載の腫瘍溶解性ウイルス。
- 前記重鎖の発現に用いられるプロモーターが、前記軽鎖の発現と比べて、少なくとも10%多く生成物を提供する、請求項16に記載の腫瘍溶解性ウイルス。
- ・前記重鎖の発現に用いられるプロモーターが、CMV、RSVおよびワクシニアウイルスpH5Rおよびp11K7.5プロモーターから選択され、かつ/または、
・前記軽鎖の発現に用いられるプロモーターが、PGK、β−アクチンおよびワクシニアウイルスp7.5KおよびpA35Rプロモーターから選択される、
請求項16または17に記載の腫瘍溶解性ウイルス。 - 請求項1〜18のいずれか一項に記載の腫瘍溶解性ウイルスの有効量および薬学的に許容可能な賦形剤を含んでなる、医薬組成物。
- 107pfu〜5×109pfuの前記腫瘍溶解性ウイルスを含んでなる、請求項19に記載の医薬組成物。
- 非経口投与用に製剤化された、請求項19または20に記載の医薬組成物。
- 増殖性疾患の治療のための、請求項19〜21のいずれか一項に記載の医薬組成物。
- 前記増殖性疾患が癌である、請求項22に記載の医薬組成物。
- 前記癌が、黒色腫、腎臓癌、前立腺癌、乳癌、大腸癌、肺癌および肝臓癌からなる群から選択される、請求項23に記載の医薬組成物。
- 前記腫瘍溶解性ウイルスが、静脈内または腫瘍内の経路によって投与される、請求項22〜24のいずれか一項に記載の医薬組成物。
- 1または2週間間隔で、108または109pfuの腫瘍溶解性ウイルスを2〜5回静脈内投与または腫瘍内投与することを含んでなる、請求項25に記載の医薬組成物。
- プロドラッグおよび/または抗癌治療において効果的な物質の投与をさらに含んでなる、請求項22〜26のいずれか一項に記載の医薬組成物。
- 増殖性疾患の治療のための医薬組成物を製造するための、請求項1〜18のいずれか一項に記載の腫瘍溶解性ウイルスの使用。
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