JP2021527072A - がん免疫治療のための組換え単純ヘルペスウイルス - Google Patents
がん免疫治療のための組換え単純ヘルペスウイルス Download PDFInfo
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Abstract
Description
本出願は、2018年6月8日に出願された米国仮特許出願第62/682,202号に対する優先権の利益を主張し、この内容は、その全体において参照により本明細書に組み込まれる。
腫瘍溶解性単純ヘルペスウイルス1(HSV−1)は、がん免疫治療にとって魅力的な薬剤である(Peters & Rabkin (2015) Mol. Ther. Oncolytics 2:15010; Chiocca & Rabkin (2014) Cancer Immunol. Res. 2:295-300)。感染すると、HSV−1は逐次的な遺伝子発現、DNA複製、組み立て、および退出を経て、腫瘍細胞破壊がもたらされる。これは、適応抗腫瘍免疫を活性化する、危険シグナルとネオ抗原の放出を伴う。一連の腫瘍溶解性HSVは、様々な開発段階にある(Peters & Rabkin (2015) Mol. Ther. Oncolytics 2:15010)。最も臨床的に進んでいる薬剤は、進行性黒色腫の処置のためにFDAによって承認されたタリモジェンラヘルパレプベック(T−VEC)である(Andtbacka, et al. (2015) J. Clin. Oncol. 33:2780-88)。腫瘍溶解性HSVの追加の例は、臨床試験を経た、または臨床試験中のG207、1716、およびΔG47である(Markert, et al. (2000) Gene Ther. 7:867-74; Rampling, et al. (2000) Gene Ther. 357:525-6; Streby, et al. (2017) Clin. Cancer Res. 23:3566-74; Fukuhara, et al. (2016) Cancer Sci. 107:1373-79)。バックボーンの設計は異なるものの、これらの腫瘍溶解性HSVウイルスは、病原性因子をコードするγ134.5遺伝子をもともと欠失している。
本発明は、治療的有効量の、野生型または無傷のγ134.5タンパク質発現を伴わずに、γ134.5タンパク質のC末端部分、例として、配列番号2からなるタンパク質のみを発現する組換え単純ヘルペスウイルス−1(HSV−1)を、対象へ投与し、それによって対象のがんを処置することによる、がんを有する対象を処置するための方法を提供する。いくつかの態様において、組換えHSV−1は、1以上の非必須遺伝子、例として、UL2、UL3、UL4、UL9.5、UL10、UL11、ULI2、UL13、ULI4、UL20、UL21、UL23、UL24、UL39、UL40、UL41、UL43、UL43.5、UL44、UL45、UL46、UL47、UL50、UL51、UL53、UL55、Us1、Us1.5、Us2、Us3、Us4、Us5、Us7、Us8、Us8.5、Us9、Us10、Us11、Us12、およびICP0、またはそのフラグメントの欠失をさらに含む。他の態様において、組換えHSV−1は、がん治療のための治療用タンパク質(例として、インターフェロンアルファ(IFN−α)、インターロイキン−2(IL−2)、および顆粒球−コロニー刺激因子(G−CSF))、酵素、抗体(例として、抗プログラム細胞死タンパク質1抗体(抗PD1)、抗チェックポイントT−リンパ球関連タンパク質4抗体(抗CTLA4)、抗OX40(抗CD134)抗体、および抗CD40抗体)または核酸を発現する1以上の遺伝子での1以上の非必須遺伝子の置換をさらに含み、ここで非必須遺伝子は、UL2、UL3、UL4、UL9.5、UL10、UL11、ULI2、UL13、ULI4、UL20、UL21、UL23、UL24、UL39、UL40、UL41、UL43、UL43.5、UL44、UL45、UL46、UL47、UL50、UL51、UL53、UL55、Us1、Us1.5、Us2、Us3、Us4、Us5、Us7、Us8、Us8.5、Us9、Us10、Us11、Us12、およびICP0から選択される。なおさらなる態様において、がんは、固形腫瘍であり、任意に、乳房、肺、肝臓、皮膚(黒色腫)、脳、および結腸がんから選択されるがんである。組換えHSV−1の投与に加えて、方法は、有効量の、がんの処置のために有用な第2の治療剤の投与をさらに含んでもよい。
ウイルス複製のための最適な細胞内環境は、細胞膜へのウイルスの付着により起こり始める事象を通じて進行する。単純ヘルペスウイルスの細胞膜受容体(単数または複数)への結合に、細胞における生化学的、生理学的、および形態学的変化に関連する事象のカスケードが続く。感受性細胞における感染に続いて、溶解的複製は、時間的に調整された一連の遺伝子転写によって調節される。ウイルスの宿主細胞膜への結合は、最初期(immediate-early)(IEまたはα)遺伝子(ICP0、ICP4、ICP22、ICP27、およびICP47)を活性化し、それは、転写される次の群の遺伝子である、初期(β)遺伝子の産生を可能にするトランス活性化因子である。最初期遺伝子産物の発現に、初期および次いで後期(γ)遺伝子によってコードされるタンパク質の発現が続く。野生型ウイルスにおける遺伝子活性化とウイルス複製のカスケード全体は約18〜24時間かかり、不可逆的に細胞死をもたらす。本発明の組換えHSV突然変異体は、γ134.5ヌルウイルスのタンパク質合成シャットオフ表現型を回避し、抗腫瘍免疫を媒介するSTING(インターフェロン刺激遺伝子)を活性化し、標的化されたγ134.5欠失を有するより堅牢なHSVバリアントを作成する。
MARRRRHRGPRRPRPPGPTGAVPTAQSQVTSTPNSEPAVRSAPAAAPPPPPASGPPPSCSLLLRQWLHVPESASDDDDDDDWPDSPPPEPAPEARPTAAAPRPRSPPPGAGPGGGANPSHPPSRPFRLPPRLALRLRVTAEHLARLRLRRAGGEGAPEPPATPATPATPATPATPARVRFSPHVRVRHLVVWASAARLARRGSWARERADRARFRRRVAEAEAVIGPCLGPEARARALARGAGPANSV(配列番号1)
を有する。
RLRRAGGEGAPEPPATPATPATPATPATPARVRFSPHVRVRHLVVWASAARLARRGSWARERADRARFRRRVAEAEAVIGPCLGPEARARALARGAGPANSV(配列番号2)
を指す。
細胞およびウイルス。Vero、HT−29、SW480、C32、A375、MDA−MB−231、4T1、HepG2およびA549細胞をAmerican Type Culture Collectionから得た。Vero、SW480、C32、A375、MDA−MB−231およびA549細胞を、10%ウシ胎児血清で補充したダルベッコ改変イーグル培地(DMEM)中で増殖させた。HT−29、4T1およびHepG2細胞を、10%ウシ胎児血清で補充したRPMI1640中で増殖させた。HSV−1(F)は、この研究(Ejercito, et al. (1968) J. Gen. Virol. 2:357-364)において用いられているプロトタイプHSV−1株である。組換えウイルスΔγ134.5において、γ134.5遺伝子のコーディング領域から1−kbフラグメントを欠失させた(Chou, et al. (1990) Science 250:1262-1266)。ΔN146においては、アミノ酸1〜146をコードするγ134.5遺伝子の配列を欠失させた(Ma, et al. (2012) J. Virol. 86:2188-2196)。EUs11においては、γ134.5遺伝子を欠失させたが、α−47プロモーターにより駆動されるUs11遺伝子を有した(Liu, et al. (2018) J. Virol. 92)。ウイルスストックの調製および感染力の力価測定を、これまでに記載されるように行った(Ma, et al. (2012) J. Virol. 86:2188-2196)。
アミノ酸147〜263のみを含むHSV γ134.5突然変異体(ΔN146)は、正常な細胞または組織中のウイルスの成長を実質的に損なわせることが示されている(Ma, et al. (2012) J. Virol. 86:2188-2196; Ma, et al (2017) Sci. Rep. 7:41461; Pan, et al (2018) J. Virol. 92:e01015-18)。悪性細胞中のこの突然変異体の活性を決定するために、ウイルスの複製を評価した。この分析は、4T1(マウス乳房癌)細胞において、野生−+型HSV−1が1x107pfu/mlまで増幅した一方で、γ134.5ヌル突然変異体(Δγ134.5)は、1x103pfu/mlにのみ達したことを示す。しかしながら、ΔN146は、1x106pfu/mlまで成長し、堅牢な複製を示した。同様の傾向は、MDA−MB−231(ヒト乳房腺癌)細胞においても観察され、ΔN146は、Δγ134.5よりも100倍増幅した。その上、これらの表現型は、ヒトHT29(結腸)、SW480(結腸)、HepG2(肝臓)、C32(黒色腫)、A375(黒色腫)およびA549(肺)を含む広範な他の腫瘍細胞において再現された。
HSV感染は、α、β、およびγ遺伝子の逐次的な発現を伴って、一時的な様式で進行する。ウイルスDNA複製の開始は、γ134.5の非存在下でタンパク質合成の停止を引き起こす(Chou & Roizman (1992) Proc. Natl. Acad. Sci. USA 89:3266-70)。代表的なタンパク質ICP27(αタンパク質)およびgC(γタンパク質)の発現はウイルスDNA複製に依存しているので、ΔN146の影響を評価するために、これらのタンパク質の発現を測定した。細胞をモック感染またはHSV−1、Δγ134.5、またはΔN146ウイルスに感染させ、感染の12時間後、試料をウェスタンブロット分析に供した。この分析は、野生型ウイルスが、感染した4T1およびMDA−MB−231細胞においてICP27とgCの両方を発現したことを示した。もっともΔγ134.5はICP27を発現したが、4T1またはMDA−MB−231細胞のいずれにおいてgCはほとんど検出できなかった。これらの同じ条件下で、ΔN146は野生型HSV−1と同等のレベルのICP27およびgCを発現し、これは、ウイルスのDNA複製によって開始される翻訳停止をブロックする能力を示す。
ウイルス感染に対する腫瘍細胞応答を評価するために、4T1細胞におけるトランスクリプトーム分析を行った。多様な細胞経路における多数の遺伝子が、モック感染およびウイルスに感染した4T1細胞において差次的に発現したことが観察された。注目すべきことに、先天性免疫経路における多くの遺伝子は、ΔN146に応答して明確に上方調節された。試験された46の遺伝子のうち、ほとんどは、モック感染または野生型ウイルスに感染した細胞において変化しないままか、わずかに発現した。しかしながら、それらは、程度は異なるものの、Δγ134.5に感染した細胞で上方調節された。注目すべきことに、遺伝子誘導はΔN146に感染した細胞でより顕著であり、これは、ΔN146が炎症応答を刺激する傾向があることを示している。
I型IFNは、腫瘍に対する免疫を準備刺激するために必要である。他方、それは抗ウイルス応答を媒介する。ΔN146がIFNによるクリアランスに不応であるかどうかを決定するために、ウイルス成長を調べた。概念を実証するものとして、IFNに対するウイルス応答は、IFN−α/β遺伝子を欠くVero細胞で最初に決定された。IFN−αによる処置はHSV−1(F)の複製にほとんど影響を与えなかったが、Δγ134.5の複製を大幅に、およそ1000倍低減させた。しかしながら、IFN−αはΔN146の複製を適度に減少させただけであった。さらにまた、4T1およびMDA−MB−231細胞で試験した場合、同様の傾向が観察された。IFN−αは一般にウイルス複製を低減させる一方で、野生型HSV−1またはΔN146への効果は小さかった。実際、ΔN146は、外因性IFN−αの存在下で、Δγ134.5よりも500〜1000倍一貫して複製した。よって、γ134.5のアミノ酸147〜263は、IFNに対するウイルス耐性を付与するのに充分である。
実施例2〜5に提示された結果に照らして、複製および炎症を活性化するΔN146の能力は、in vivoで腫瘍破壊を増大させると仮定された。これを実証するために、自発的に転移する攻撃的な4T1乳がんが選択され、プロセスはヒト乳腺腫瘍に似ていた。比較のために、Δγ134.5もまたHSV1716に類似していた(Rampling, et al. (2000) Gene Ther. 7:859-866; Streby, et al. (2017) Clin. Cancer Res. 23:3566-3574)。加えて、組換えHSV EUs11(Liu, et al. (2018) J. Virol. 92)はタリモジェンラヘルパレプベックの腫瘍溶解性バックボーンと構造的に同等であるため(Liu、et al. (2003) GeneTher. 10: 292-303)、このウイルスが含まれる。マウスの脇腹の皮下に確立された腫瘍に、1、3、および6日目にPBS、Δγ134.5、ΔN146、またはEUs11(1x107pfu)を3回注射した。次いで、腫瘍サイズをモニタリングした。図1に例証するように、PBSで処置された対照腫瘍は期間にわたり速い速度で成長した。γ134.5ヌルウイルスによる処置は、局所腫瘍成長をわずかに低減させた。しかしながら、ΔN146またはEUs11での腫瘍内接種は、腫瘍成長を著しく遅らせ、処置が進むにつれて腫瘍サイズの低減はより明らかになった。24日目に、ΔN146およびEUs11は、モック対照またはΔγ134.5と比較して腫瘍サイズをほぼ45%低減させた。ゆえに、EUs11に匹敵する一方で、ΔN146はΔγ134.5と比較した場合に原発腫瘍に対して優れた活性を示した。
ウイルスの複製を評価するために、9日目に収集された原発腫瘍中のウイルス収量を決定した。この分析は、プラークアッセイによって測定されるように、Δγ134.5が1x102pfu/g腫瘍組織の平均力価で複製されることを示した(図3)。他方、EUs11は7x103pfu/g腫瘍組織の平均力価で成長した。同様に、ΔN146は5x103pfu/g腫瘍組織の平均力価で成長した。明らかなように、EUs11と同様に、ΔN146はΔγ134.5よりも50倍多く複製された。これを踏まえると、ウイルス抗原は腫瘍床の薄片で検出され、ΔN146およびEUs11はΔγ134.5よりも広範囲に広がった。これは、腫瘍組織の壊死の程度と相関していた。
先の証拠は、γ134.5の欠失を伴う腫瘍溶解性HSVが全身性抗腫瘍免疫を活性化することを示唆している(Thomas & Fraser (2003) Mol. Ther. 8:543-51; Toda, et al. (1999) Hum. Gene Ther. 10:385-93)。腫瘍内ウイルス注射は局所腫瘍成長と転移形成の両方を低減したので、適応免疫の誘導が存在したかどうかが決定された。そのため、CD4+およびCD8+T細胞は免疫組織化学分析によって評価された。24日目に収集された原発腫瘍を薄片にし、CD4+およびCD8+T細胞の存在について染色した。モック感染腫瘍において、いくらかのCD4+またはCD8+T細胞(<4%)が検出可能であった。しかしながら、Δγ134.5で処置された腫瘍においては、CD4+T細胞は12%に、CD8+T細胞は7%に上昇した。同様に、ΔN146はCD4+細胞の15%およびCD8+T細胞の8%を占めた。EUs11は免疫細胞浸潤を引き起こしたが、観察された効果はCD4+(10%)とCD8+T細胞(5%)の両方で低減した。これらの結果は、Δγ134.5と同様に、ΔN146がT細胞浸潤を誘導するのに対し、EUs11はこのプロセスを弱めるように見えることを示す。
ΔN146とEUs11が腫瘍細胞と差次的に相互作用するかどうかを決定するために、in vitro分析を実施した。図4に示すように、ΔN146感染はIFN−α1およびcxcl9遺伝子の転写を刺激した。対照的に、EUs11は遺伝子発現を抑制した。これは、ELISAによって測定されたサイトカイン産生のレベルと一致していた。一貫して、ΔN146はIRF3のリン酸化を刺激した一方で、EUs11は刺激せず、これは、EUs11がウイルス感染時の免疫抑制を媒介することを示唆する。
Claims (11)
- がんを有する対象を処置するための方法であって、治療的有効量の、野生型または無傷のγ134.5タンパク質発現を伴わずに、γ134.5タンパク質のC末端部分のみを発現する組換え単純ヘルペスウイルス−1(HSV−1)を対象へ投与し、それによって対象のがんを処置することを含む、前記方法。
- γ134.5タンパク質のC末端部分が、配列番号2からなる、請求項1に記載の方法。
- 組換えHSV−1が、1以上の非必須の遺伝子またはそのフラグメントの欠失をさらに含む、請求項1に記載の方法。
- 非必須の遺伝子が、UL2、UL3、UL4、UL9.5、UL10、UL11、ULI2、UL13、ULI4、UL20、UL21、UL23、UL24、UL39、UL40、UL41、UL43、UL43.5、UL44、UL45、UL46、UL47、UL50、UL51、UL53、UL55、Us1、Us1.5、Us2、Us3、Us4、Us5、Us7、Us8、Us8.5、Us9、Us10、Us11、Us12、およびICP0から選択される、請求項3に記載の方法。
- 組換えHSV−1が、
がん治療のための、治療用タンパク質、酵素、抗体または核酸を発現する1以上の遺伝子での1以上の非必須の遺伝子の置換をさらに含む、請求項1に記載の方法。 - 非必須の遺伝子が、UL2、UL3、UL4、UL9.5、UL10、UL11、ULI2、UL13、ULI4、UL20、UL21、UL23、UL24、UL39、UL40、UL41、UL43、UL43.5、UL44、UL45、UL46、UL47、UL50、UL51、UL53、UL55、Us1、Us1.5、Us2、Us3、Us4、Us5、Us7、Us8、Us8.5、Us9、Us10、Us11、Us12、およびICP0から選択される、請求項5に記載の方法。
- 治療用タンパク質が、インターフェロンアルファ、インターロイキン−2、および顆粒球−コロニー刺激因子から選択される、請求項5に記載の方法。
- 抗体が、抗プログラム細胞死タンパク質1抗体、抗チェックポイントT−リンパ球関連タンパク質4抗体、抗OX40抗体、および抗CD40抗体から選択される、請求項5に記載の方法。
- がんが、固形腫瘍を含む、請求項1に記載の方法。
- がんが、乳房、肝臓、皮膚、脳、肺、および結腸がんから選択される、請求項9に記載の方法。
- 有効量の、がんの処置のために有用な第2の治療剤を投与することをさらに含む、請求項1に記載の方法。
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