JP6843736B2 - 腫瘍溶解性ウイルスと免疫チェックポイントモジュレーターとの組合せ - Google Patents
腫瘍溶解性ウイルスと免疫チェックポイントモジュレーターとの組合せ Download PDFInfo
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Description
癌の発達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、何気ない因子の多さを理由に、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かもしれない。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説明している。
本発明は、癌等の増殖性疾患の治療に用いるための、腫瘍溶解性ウイルスと1つ以上の免疫チェックポイントモジュレーターとの相乗的組合せに関する。腫瘍溶解性ウイルスは、好ましくは、レオウイルス、ニューキャッスル病ウイルス(NDV)、水胞性口炎(VSV)、麻疹ウイルス、インフルエンザウイルス、シンビス(Sinbis)ウイルス、アデノウイルス、ポックスウイルスおよびヘルペスウイルス(HSV)等からなる群から選択される。一態様において、腫瘍溶解性ウイルスは、ワクシニアウイルスである。好ましい態様において、ワクシニアウイルスは、チミジンキナーゼ(TK)活性を欠失させるために遺伝子操作される(例えば、当該VVのゲノムは、欠損TK表現型を生産するための、J2R遺伝子中に不活性化突然変異または遺伝子欠失を有する)。代替的にもしくは組合せて、ワクシニアウイルスは、リボヌクレオチドレダクターゼ(RR)活性を欠失させるために遺伝子操作される(例えば、当該VVのゲノムは、I4Lおよび/またはF4L遺伝子中で不活性化突然変異または欠損RR表現型を生産するための遺伝子欠失を有する)。
本願全体で使用されている、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、言及された成分またはステップの「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ている。例えば、用語「細胞」は、複数の細胞(それらの混合物を含む)を含む。
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殺すその傾向によって腫瘍溶解性である。それは、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、自然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/または分裂細胞中の選好的複製を増大させるために、1つ以上のウイルス遺伝子を組換え操作されてもよい(例えば、Kirn et al., 2001, Nat. Med. 7: 781; Wong et al., 2010, Viruses 2: 78-106を参照のこと)。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要素(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。
一態様において、本発明で使用される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つの治療用遺伝子をさらに発現する。「治療用遺伝子」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産物をコードする。本発明の文脈において、治療用遺伝子は、ヒト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。好ましくは、治療用遺伝子は、本明細書で記載さ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遺伝子または核酸配列ではない。
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指す。自殺遺伝子は、制限することなく、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指す。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、制限することなく、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、IFNalpha)、腫瘍壊死因子(TNF)、コロニー刺激因子(例えば、GM−CSF、C−CSF、M−CSF...)APC(抗原提示細胞の略称)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の主要組織適合複合体(MHC)抗原、アポトーシス誘発因子または阻害剤(例えば、Bax、Bcl2、BclX...)、細胞増殖抑制剤(p21、p16、Rb...)、抗毒素、抗原(抗原性ポリペプチド、エピトープ等)およびマーカー(ベータ−ガラクトシダーゼ、ルシフェラーゼ...)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。
治療用遺伝子は、クローニング、PCRまたは従来的技術による化学合成によって容易に得ることができる。また、治療用遺伝子は、特定の宿主細胞または対象内で高いレベルの発現を提供するために最適化することができる。確かに、生物のコドン使用パターンは非常に非ランダムであり、コドンの使用は異なる宿主間で著しく異なり得ると観察されてきた。治療用遺伝子は、細菌性または下等真核生物由来(例えば、自殺遺伝子)であり得るため、高等真核細胞(例えば、ヒト)における効果的な発現に不適切なコドン使用パターンを有するかもしれない。典型的には、コドンの最適化は、目的の宿主生物内で頻繁に使用されないコドンに対応する1つ以上の「天然」(例えば、細菌性または酵母)コドンを、より頻繁に使用される同一のアミノ酸をコードする1つ以上のコドンと置換することによって実行される。増大した発現は部分的置換でも達成され得るため、全ての対応する天然コドンを、頻繁に使用されていないコドンに置換する必要はない。
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、文献において記載されている。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、独立して、標的免疫チェックポイントを結合でき、および/また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、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)単一可変ドメイン断片(VHまたはVLドメイン)からなるdAb断片;
vi)融合され、最終的に一本鎖タンパク質を成すためにリンカーを有するVLおよびVHである、Fv断片の2つのドメインを含んでなる短鎖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; US 4,946,778; US 5,258,498を参照のこと);および
vii)任意の別の人工抗体。
本発明において使用される1つ以上の免疫チェックポイントモジュレーターは、好適な発現ベクターおよび宿主細胞を用いた組換え手段によって生産することができる。
腫瘍溶解性ウイルスおよび1つ以上の免疫チェックポイントモジュレーターは、単一組成物で一緒にまたは別々の組成物で同時に投与してもよく、場合により、そのような有効薬の治療的有効量に加えて、薬学的に許容可能な賦形剤を含んでなる。単一組成物は、腫瘍溶解性ウイルスおよび当該1つ以上の免疫チェックポイントモジュレーターが、一緒に混合された場合(例えば、腫瘍溶解性ウイルスと1つ以上の抗体の混合物、または腫瘍溶解性ウイルスと1つ以上の抗体の発現用の1つ以上のベクターの混合物)を含む。腫瘍溶解性ウイルスおよび当該1つ以上の免疫チェックポイントモジュレーターの別々の組成物は、同時にまたは連続的に、それぞれ1回または数回(別々にまたは分散した(interspersed)様式で)、かつ同一または異なる経路を介して、投与されてもよい。
腫瘍溶解性ウイルスおよび/または免疫チェックポイントモジュレーターは、対象に一緒にまたは別々に、かつ単回投与または複数回投与で投与してもよい。投与は、同一または異なる経路によって行ってもよく、同一の部位または代わりの部位で実行してもよい。
・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、スピロプラチン(spiroplatinum)またはカルボプラチン(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;および
・抗新生物抗体。
適切な抗体を有する免疫チェックポイント遮断剤ネズミ科PD−1(mPD−1)を標的にすることが第一に選択された。ラット抗mPD−1抗体RMP1−14(BioXcell)を、抗mPD−1として選択した。この抗体は、mPD−1とそのリガンドの相互作用を遮断することが示されていた(Yamazaki et al., 2005, J. Immunol. 175(3): 1586-92)。
抗CTLA−4抗体(市販のクローン9D9)の腫瘍溶解性ウイルスWRTG17137との組合せを、MCA205マウスモデルにおいてin vivo試験した。多様なスケジュールでの投与を実験した。
ウイルスの用量を変化させて前回と同じ実験を実施した。腫瘍移植(MCA腫瘍細胞8X105)後、6匹のマウスのグループを4つ治療した。コントロールグループは、ウイルスの代わりに製剤緩衝液、および抗体の代わりに同型コントロールを受けた。2つ目のグループは、105、106または107pfuのWRTG17137(0日目および3日目に2回のit注射)、3つ目は、抗PD−1mAb(6日目、9日目および12日目に、250μgの抗mPD1抗体RMP1−14の3回のip注射)で治療した。4つ目は、ウイルス(0日目および3日目に、105、106または107pfu)、3日後に抗体(3日毎に3回のip注射、即ち、6日目、9日目および12日目にて)両方を受けさせた。腫瘍進行を15日間観察した。
抗PD1抗体組合せ
6週令雌C57BL/6マウスに、MCA205腫瘍細胞8x105を右横腹内へ皮下(sc)注射した。0日目(D0)に、腫瘍体積が40〜60mm2へ到達すると、動物をランダム化し、11個の1グループあたりマウス6匹のグループに分けた。コントロールグループは、緩衝液(0日目および3日目に2回のit注射)を受けさせ、1つのマウスのグループは、腫瘍溶解性ウイルス(0日目および3日目にWRTG17137 1x107pfuの2回のit注射)で治療し、1つのグループは、ウイルス(0日目および3日目にて)および同型コントロール(6日目、9日目および12日目に3回のip注射)両方を受けさせ、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗PD−1mAb抗体(4日目、7日目および10日目に、250μgの抗mPD1抗体クローンRMP1−14の3回のip注射)両方で治療し、1つのマウスのグループは、ウイルス(0日目および3日目)および抗PD−1 mAb抗体(6日目、9日目および12日目に、250μgの抗mPD1抗体クローンRMP1−14の3回のip注射)両方で治療し、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗PD−1mAb抗体(8日目、11日目および14日目に、250μgの抗mPD1抗体クローンRMP1−14の3回のip注射)両方で治療し、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗PD−1 mAb抗体(10日目、13日目および16日目に、250μgの抗mPD1抗体クローンRMP1−14の3回のip注射)両方で治療し、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗PD−1 mAb抗体(4日目、7日目および10日目に、100μgの抗mPD1抗体クローンRMP1−14の3回のip注射)両方を受けさせ、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗PD−1mAb抗体(6日目、9日目および12日目に、100μgの抗mPD1抗体クローンRMP1−14の3回のip注射)の両方を受けさせ、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗PD−1mAb抗体(8日目、11日目および14日目に、100μgの抗mPD1抗体クローンRMP1−14の3回のip注射)両方を受けさせ、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗PD−1 mAb抗体(10日目、13日目および16日目に、100μgの抗mPD1抗体クローンRMP1−14の3回のip注射)両方を受けさせた。腫瘍進行および生存率を時間とともに観察した。
6週令雌C57BL/6マウスに、MCA205腫瘍細胞8x105を右横腹内へ皮下注射(sc)した。0日目(D0)に、腫瘍体積が40〜60mm2へ到達すると、動物をランダム化し、11個の1グループあたりマウス6匹のグループに分けた。コントロールグループは、緩衝液(0日目および3日目に2回のit注射)を受けさせ、1つのマウスのグループは、腫瘍溶解性ウイルス(0日目および3日目にWRTG17137 1x107pfuの2回のit注射)で治療し、1つのグループは、ウイルス(0日目および3日目にて)および同型コントロール(6日目、9日目および12日目に3回のip注射)両方を受けさせ、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗CTLA4mAb抗体(4日目、7日目および10日目に、100μgの抗mCTLA4抗体クローン9D9の3回のip注射)両方で治療し、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗CTLA4mAb抗体(6日目、9日目および12日目に、100μgの抗mCTLA4抗体クローン9D9の3回のip注射)両方で治療し、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗CTLA4mAb抗体(8日目、11日目および14日目に、100μgの抗mCTLA4抗体クローン9D9の3回のip注射)両方で治療し、1つのマウスのグループは、ウイルス(0日目および3日目)および抗CTLA4mAb抗体(10日目、13日目および16日目に、100μgの抗mCTLA4抗体クローン9D9の3回のip注射)両方で治療し、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗CTLA4mAb抗体(4日目、7日目および10日目に、50μgの抗mCTLA4抗体クローン9D9の3回のip注射)両方を受けさせ、1つのマウスのグループは、ウイルス(0日目および3日目にて)および抗CTLA4 mAb抗体(6日目、9日目および12日目に、50μgの抗mCTLA4抗体クローン9D9の3回のip注射)両方を受けさせ、1つのマウスのグループは、ウイルス(0日目および3日目)および抗CTLA4mAb抗体(8日目、11日目および14日目に、50μgの抗mCTLA4抗体クローン9D9の3回のip注射)両方を受けさせ、1つのマウスのグループは、ウイルス(0日目および3日目)および抗CTLA4 mAb抗体(10日目、13日目および16日目に、50μgの抗mCTLA4抗体クローン9D9の3回のip注射)両方を受けさせた。腫瘍進行および生存率を時間とともに観察した。
Claims (13)
- 癌の治療に用いるための、1つの腫瘍溶解性ポックスウイルスと、阻害性免疫チェックポイントの活性と少なくとも部分的に拮抗する1つ以上の免疫チェックポイントモジュレーターとを含んでなる、組合せ物であって、
a)前記腫瘍溶解性ポックスウイルスが、J2Rウイルス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)を欠損するワクシニアウイルスであり、かつ前記組合せ物が、107pfu〜5x109pfuの前記腫瘍溶解性のワクシニアウイルスを含んでなり、
b)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り、かつ前記組合せ物が、2mg/kg〜15mg/kgの前記1つ以上の免疫チェックポイントモジュレーターを含んでなり、かつ
c)前記腫瘍溶解性のワクシニアウイルスと前記1つ以上の免疫チェックポイントモジュレーターとが連続的に投与され、前記腫瘍溶解性のワクシニアウイルスが第一に投与され、かつ、前記免疫チェックポイントモジュレーターが第二に投与される、組合せ物。 - 前記ワクシニアウイルスが、ウイルスI4L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)活性をさらに欠損する、請求項1に記載の組合せ物。
- 前記腫瘍溶解性のワクシニアウイルスが、さらに、ウイルスゲノム内に挿入された少なくとも1つの治療用遺伝子を発現し、該治療用遺伝子が、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1または2に記載の組合せ物。
- 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からなる群から選択される、請求項3に記載の組合せ物。
- 前記自殺遺伝子産物が、CDaseおよびUPRTase活性を有し、かつ好ましくは、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4に記載の組合せ物。
- 前記腫瘍溶解性のワクシニアウイルスが、TKおよびRR活性の両方を欠損し、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4または5に記載の組合せ物。
- 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因子、特に好ましくはGM―CSFである、請求項3に記載の組合せ物。
- 前記腫瘍溶解性のワクシニアウイルスが、TK活性を欠損し、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7に記載の組合せ物。
- 前記抗PD−1抗体が、ニボルマブ、ランブロリズマブおよびピディリズマブからなる群から選択される、請求項1に記載の組合せ物。
- 前記免疫チェックポイントモジュレーターが、静脈内、腫瘍内または腹腔内の経路によって投与され、かつ、前記腫瘍溶解性のワクシニアウイルスが、静脈内または腫瘍内の経路によって投与される、請求項1〜9のいずれか一項に記載の組合せ物。
- 1または2週間の時間間隔で、108または109pfuの腫瘍溶解性ワクシニアウイルスの2〜5回の静脈内または腫瘍内投与、続けてまたは分散して2または3週間毎に3〜10mg/kgの1つ以上の抗免疫チェックポイント抗体の2〜5回の静脈内投与を含んでなる、請求項1〜10のいずれか一項に記載の組合せ物。
- 前記癌が、黒色腫、腎臓癌、前立腺癌、乳癌、結腸直腸癌、肺癌および肝臓癌からなる群から選択される、請求項1〜11のいずれか一項に記載の組合せ物。
- 少なくとも、請求項1〜8および10または11のいずれか一項に記載の1つの腫瘍溶解性ポックスウイルスを1つの容器に、かつ請求項1および9〜11のいずれか一項に記載の1つ以上の免疫チェックポイントモジュレーターを別の容器に、組合せて含んでなり、
a)前記腫瘍溶解性ポックスウイルスが、J2Rウイルス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)を欠損するワクシニアウイルスであり、かつ前記組合せが、107pfu〜5x109pfuの前記腫瘍溶解性のワクシニアウイルスを含んでなり、
b)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り、かつ前記組合せが、2mg/kg〜15mg/kgの前記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り、かつ、
c)前記腫瘍溶解性のワクシニアウイルスと前記1つ以上の免疫チェックポイントモジュレーターとが連続的に投与され、前記腫瘍溶解性のワクシニアウイルスが第一に投与され、かつ、前記免疫チェックポイントモジュレーターが第二に投与される、
癌の治療に用いるための、キット。
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JP2020183392A (ja) * | 2014-07-16 | 2020-11-12 | トランジェーヌTransgene | 腫瘍溶解性ウイルスと免疫チェックポイントモジュレーターとの組合せ |
JP7146852B2 (ja) | 2014-07-16 | 2022-10-04 | トランジェーヌ | 腫瘍溶解性ウイルスと免疫チェックポイントモジュレーターとの組合せ |
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IL250103B (en) | 2020-06-30 |
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CA2955084A1 (en) | 2016-01-21 |
JP7146852B2 (ja) | 2022-10-04 |
CA2955084C (en) | 2023-08-29 |
EP3169340B1 (en) | 2020-09-02 |
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US20170143780A1 (en) | 2017-05-25 |
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CN106999577A (zh) | 2017-08-01 |
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DK3169340T3 (da) | 2020-11-09 |
WO2016009017A1 (en) | 2016-01-21 |
ES2833425T3 (es) | 2021-06-15 |
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