JP7391831B2 - Car t細胞標的を発現する腫瘍溶解性ウイルス、及びその使用 - Google Patents
Car t細胞標的を発現する腫瘍溶解性ウイルス、及びその使用 Download PDFInfo
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Description
[0045] 一態様では、配列番号1、又は配列番号2と、少なくとも70%(75%、80%、85%、90%、92%、94%、96%、98%、又は99%)の配列同一性があるヌクレオチド配列、及び細胞表面に発現しうる、ヒトCD19、又はその部分、をコードするヌクレオチド配列、を含むキメラポックスウイルスが提供される。いくつかの実施形態では、配列番号1、又は配列番号2と、少なくとも70%同一性がある配列としては、牛痘ウイルスBrighton株、アライグマポックスウイルスHerman株、ウサギポックスウイルスUtrecht株、ワクシニアウイルスWR株、ワクシニアウイルスIHD株、ワクシニアウイルスElstree株、ワクシニアウイルスCL株、ワクシニアウイルスLederle-Chorioallantoic株、ワクシニアウイルスAS株、羊痘ウイルスNZ2株、及び偽牛痘ウイルスTJS株を含む群から選択される、少なくとも2つのポックスウイルス株由来のヌクレオチド配列(「核酸断片」)があげられる。
(又は、少なくとも当該配列番号と、95%、97%、98%、又は99%同一の配列)を含む。ある場合には、当該CD19tは、配列番号Cのアミノ酸22~323を含むか、又はからなる。配列番号3のアミノ酸1~21は、シグナル伝達ドメインであり、異なるシグナル伝達ドメインで、置換できる。すなわち、当該腫瘍崩壊ウイルスは、発現制御配列(例えば、初期プロモーター)に作動可能に連結された、切断型ヒトCD19をコードするヌクレオチド配列、を含む配列を含む。
[0056] これまで、米国特許第7,446,179号、及びPark et al. 2016 Blood 128:4035を含む、様々なCD19 CARの報告があり、それらに記載されているものを用いることができる。CD19 CARとしては、CD19と結合するscFv、例えば、FMC63(Zola et al. 1991 Immunol Cell Biol 69:411)、又はSJ25C1(Bejcek et al. 1995 Cancer Research 55:2346)をあげることができ、これらはいずれも商業的に利用可能である。
)、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体;CD4膜貫通ドメイン、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体、CD8膜貫通ドメイン、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体、CD28膜貫通ドメイン、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体、CD3ゼータ膜貫通ドメイン、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体、から選択される膜貫通ドメイン;共刺激ドメイン、例えば、CD28共刺激ドメイン、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体;4-1BB共刺激ドメイン、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体;又は、CD28共刺激ドメイン、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体、及び4-1BB共刺激ドメイン、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体;並びに、CD3ゼータシグナル伝達ドメイン、又は1~5(例えば、1、又は2)のアミノ酸が改変(例えば、置換)された、その変異体、を含む。
表1:スペーサーの例
Proteins of Immunological Interest, 5th Ed., United States Public Health
Service, National Institutes of Health, Bethesda)。当該EUインデックス、又はKabatの文献に記載されるEUインデックス、又はEU番号付けスキームは、EU抗体の番号付けをいう(Edelman et al. 1969 Proc Natl Acad
Sci USA 63:78-85)。
[0069] 以下に、組換えウイルスに感染した細胞で、ヒトCD19を発現する、組換えキメラポックスウイルスの調製に用いうる、腫瘍溶解性アンカーである、キメラポックスウイルスを記載する。当該組換えウイルスはがん細胞に感染し、CD19を発現させるからである。当該感染細胞は、CD19指向性のCARにより、標的化されることができる。
牛痘ウイルスBrighton株、アライグマポックスウイルスHerman株、ウサギポックスウイルスUtrecht株、ワクシニアウイルスIHD株、ワクシニアウイルスElstree株、CL、Lederle-Chorioallantoic株、及びワクシニアウイルスAS株を、各ウイルスの感染多重度(MOI)を0.01で、CV-1細胞に共感染させて、キメラオルソポックスウイルスのプールを作製した。MDBK細胞を羊痘ウイルスNZ2株、及び偽牛痘ウイルスTJS株に、MOIを0.1で共感染させて、キメラパラポックスウイルスのプールを作製した。本出願人のパイロット実験では、CV-1細胞は、本実験で用いた全てのオルソポックスウイルスに感受性であり、羊痘ウイルス、及び偽牛痘ウイルスは、ともにMDBK細胞に感染して、プラークを形成することを示す。
キメラオルソポックスウイルス200株、及びキメラパラポックスウイルス200株、並びに親ウイルス株11株、及び対照腫瘍溶解性ウイルス2株(GLV-1h68、及びOncoVEX GFP)の腫瘍細胞殺傷活性を評価し、NCI-60細胞株のパネルで比較した(表4)。GLV-1h68は、最もよく研究されている腫瘍溶解性ワクシニアウイルスの1つであり、現在臨床開発中である。OncoVEX GFPは、腫瘍溶解性単純ヘルペスウイルス1型であり、かつ、FDAが承認した最初の腫瘍溶解性ウイルスである、T-VECと骨格が同じである。各細胞株を、各ウイルスにMOIを0.01で感染させた。感染96時間後の細胞生存率を、MTSアッセイを用いて、測定した。このハイスループットスクリーニング実験で用いたウイルス量(MOI 0.01)を意図的に低くして、強力な新規ウイルス分離株が目立つように最適化して、接着細胞株(NCI-60パネルの細胞株の大部分は接着細胞である)における細胞殺傷能を比較した。しかしながら、懸濁細胞株で、有意かつ一貫した細胞殺傷能を観察するには、このウイルス量は低すぎた。そこで、6つの白血病細胞株からの結果は、ウイルス比較分析には含めなかった。
[0075] 100の新規キメラオルソポックスウイルス分離株のうち、分離株#17(配列番号3)、及び#33(配列番号1)の細胞殺傷能は、NCI-60固形腫瘍細胞株において、親のオルソポックスウイルス株9株、及び対照ウイルス2株よりも、有意に優れていた(図1)。新規パラポックスウイルス分離株100株のうち、分離株#189(配列番号2)の細胞殺傷能は顕著であり、2つの親パラポックスウイルス株、及び対照ウイルスの細胞殺傷能よりも、有意に良好であった(図2)。3つの新規キメラウイルス分離株(#17、#33、#189)はいずれも、MOIが0.01という低値でも、大多数のNCI-60固形がん細胞株で、有意な細胞死を惹起した。一般に、オルソポックスウイルス株、及びキメラオルソポックスウイルス株は、MOIが0.01という低レベルで、パラポックスウイルス株、及びキメラパラポックスウイルス株よりも、がん細胞の殺傷効果が強かった。
[0083] NCI-60がん細胞株は、8つの異なる臓器由来の固形がんしか含まない(表4参照)。NCI-60がん細胞株から得られた結果が、他の臓器の固形がんで再現されることを検討するため、6種類の膵がん細胞株(BxPC3、FG、MIA PaCa-2、Capan-2、PANC-1、及びSU.86.86)に、NCI-60がん細胞株のハイスループットスクリーニングで用いたウイルスと同じウイルスを、MOIを0.1で、感染させた。MTSアッセイを用いて、感染96時間後の細胞生存率を再度測定した。全てのキメラオルソポックスウイルス分離株のうち、キメラオルソポックスウイルス分離株#17、及び#33の細胞殺傷能が最良であり、全てのキメラパラポックスウイルス分離株のうち、キメラパラポックスウイルス分離株#189の細胞殺傷能が最良であった。表5、図3、及び図4に示すように、それらは、各親ウイルス株、並びに対照ウイルスGLV-1h68、及びOncoVEX GFPの膵臓がん細胞株の殺傷能よりも、すべて良好であった。すなわち、NCI-60がん細胞株で得られた結果の、膵臓がん細胞株のパネルにおける再現性は、極めて良好であった。
表5:膵がん細胞の生存
[0084] NCI-60がん細胞株、及び膵がん細胞株パネルのハイスループットスクリーニングの結果に基づき、新たなキメラオルソポックスウイルス分離株#33、及びキメラパラポックスウイルス分離株#189を選択して、さらなる特徴付けに供した。分離株#33、及び#189の腫瘍細胞殺傷活性を、3つの胃がん細胞株でさらに検討した。MKN-45、OCUM-2M、及びKATO-3細胞を、MOIを0.01、0.1、及び1で、#33、#189、GLV-1h68、及びOncoVEX GFPで感染させた。MTSアッセイを用いて、細胞生存率を、4日間毎日モニターした。MKN-45、及びOCUM-2M細胞株は、#33株に対して最も感受性が高く、OncoVEX GFPに対する感受性は中程度であり、GLV-1h68に対する感受性は最も低かった。一方、KATO-3は、0.01の低MOIで、OncoVEX GFPに対して最も感受性が高かったが、#33、#189、及びOncoVEX GFPは、高MOI(0.1、及び1)では、KATO-3細胞を等しく殺傷した。KATO‐3細胞は、GLV-1h68に対して最も感受性が低かった。全体として、#33は、最も効率的に胃がん細胞株を殺傷させた一方で、GLV-1h68の胃がん細胞株の殺傷能は、最低であった(図5A~C)。
外来遺伝子発現カセットを#33キメラポックスウイルスゲノムへ挿入するシャトルベクターの構築
[0087] チミジンキナーゼ(TK)シャトルベクターを構築するために、Q5 High-Fidelity 2X Master Mix(New England Biolabs,Ipswich,MA)、及び以下のプライマー:
を用いて、#33ゲノムDNA由来の#33キメラポックスウイルスの7XT遺伝子の左右の隣接配列を、PCRで増幅した。2つの断片を、オーバーラッピング伸長による遺伝子スプライシング法を用いて、連結した。得られた断片をNdel、及びEcoRIで消化し、同一切断型プラスミドpGPTにクローニングして、p33NC-TKを得た。シャトルベクター中のTKの隣接配列を、配列決定により確認した。p33NC-TKは、Sacl、Sail、BamHI、Nhel、及びNotlで分離したTKの左右の隣接配列、並びに一過性優性選択マーカーとしての、ワクシニアウイルス(VACV)初期プロモーターp7.5Eにより駆動される大腸菌グアニンホスホリボシルトランスフェラーゼ(gpt)遺伝子を含む。
[0089] 以下の実験では、2つの乳がん細胞株、MDA-MB-468wt(トリプルネガティブ乳がん細胞株)、親株、及びシグナル伝達ドメイン(MDA-MB-468-CD19t)欠損切断型ヒトCD19を発現するように改変されたMDA-MB-468の変異体を、用いた。図6に示すように、MDA-MB-468-CD19tはCD19tを発現する。CD19を標的とするCARを発現するように改変されたT細胞(以下により詳細に記載)も用いた。これらのT細胞によって発現されるCARは、図7に模式的に示されるが、CD19を標的とするscFv、及びIgG4スペーサー、CD28膜貫通ドメイン、CD28共刺激ドメイン、及びCD3ゼータを含む。このCAR、及び切断EGFRをコードする配列を、レンチウイルスベクターに挿入し、この組換えベクターを用いて、PBMCを形質導入した。切断型EGFRは、CARの発現のマーカーとして、用いることができる。図8に示すように、Mock形質転換PBMC、及びCD19 CARを発現する組換えレンチウイルスで形質転換されたPBMCによる、EGFR発現を、切断型EGFRと比較すると、当該形質転換細胞は、導入遺伝子を効果的に発現することが示される。
[0095] 図13に示すように、腫瘍溶解性ウイルスは、CD19tを固形腫瘍に効果的に送達し、in vitroでCD19-CAR T細胞を活性化させることができる。図13パネルAは、ワクシニア腫瘍溶解性ウイルス[CF33-(SE)hCD19t]の概略図であり、J2R遺伝子座に、チミジンキナーゼ遺伝子を置換して、挿入された合成初期プロモーター(PSE)の制御下での、切断型ヒトCD19(CD19t)の取り込みを示す。図13パネルBは、OV19tを、MOIを0.025(左)、及びMOIを1(中央)で、24時間感染させたMDAMB-468細胞、又はレンチウイルスを形質導入してCD19tを安定発現させた細胞(右)の、免疫蛍光顕微鏡検査を示す。画像の倍率は10x、挿入画像の倍率は40xである。図13パネルCは、MOIを増加させた、OV19t感染24時間後のフローサイトメトリーで測定した、MDA-MB468腫瘍細胞上のCD19tの細胞表面発現、及びワクシニアウイルスの細胞内発現を示す、FACSプロットのセットである。図13パネルDは、OV19tを、示されたMOIで共培養してから、24、48、及び72時間後の、MDA-MB-468腫瘍細胞のCD19t(左)、ワクシニア(中央)、及び生存率(右)の定量を示す。パネルEは、Mock (非形質導入)、又はCD19-CAR T細胞を、エフェクター:腫瘍(E:T)比率1:2で、OV19tの示したMOIでの処理の有無により、腫瘍細胞と共培養してから24時間後の、CD25(左)、及びCD137(右)発現の定量を示す。
Claims (14)
- 機能的シグナル伝達ドメインが欠損した、切断型ヒトCD19をコードするヌクレオチド配列を含む、組換え腫瘍溶解性ウイルスであって、前記切断型ヒトCD19をコードするヌクレオチド配列が、プロモーターに作動可能に連結され、かつ、ここで、前記組換え腫瘍溶解性ウイルスは、配列番号1又は配列番号2と少なくとも90%同一であるヌクレオチド配列を含むがチミジンキナーゼをコードする配列は欠損している、組換え腫瘍溶解性ウイルス。
- 配列番号1又は配列番号2と少なくとも95%同一であるヌクレオチド配列を含むがチミジンキナーゼをコードする配列は欠損している、請求項1に記載の、組換え腫瘍溶解性ウイルス。
- 配列番号1又は配列番号2と少なくとも98%同一であるヌクレオチド配列を含むがチミジンキナーゼをコードする配列は欠損している、請求項1に記載の、組換え腫瘍溶解性ウイルス。
- ウイルスがキメラポックスウイルスであり、前記キメラポックスウイルスが、牛痘ウイルス(cowpox virus)Brighton株、アライグマポックスウイルス(raccoonpox virus)Herman株、ウサギポックスウイルス(rabbitpox virus)Utrecht株、ワクシニアウイルスWR株、ワクシニアウイルスIHD株、ワクシニアウイルスElstree株、ワクシニアウイルスCL株、ワクシニアウイルスLederle-Chorioallantoic株、ワクシニアウイルスAS株、羊痘ウイルス(orf virus)NZ2株、及び偽牛痘ウイルス(pseudocowpox virus)TJS株からなる群から選択される、少なくとも2つのポックスウイルス株の、少なくとも100個の連続したヌクレオチドを含む、請求項1に記載の、組換え腫瘍溶解性ウイルス。
- プロモーターが、ウイルス初期プロモーターである、請求項1に記載の、組換え腫瘍溶解性ウイルス。
- プロモーターがポックスウイルス初期プロモーターである、請求項1に記載の、組換え腫瘍溶解性ウイルス。
- 機能的シグナル伝達ドメインが欠損した、切断型ヒトCD19は、以下の:
MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCVPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKR
で表されるアミノ酸配列を含む、請求項1に記載の、組換え腫瘍溶解性ウイルス。 - がん患者を治療するための請求項1~7のいずれか一項に記載された組換え腫瘍溶解性ウイルスを含む医薬組成物であって、ここで、同時に、又はその後、ヒトCD19を標的とする、キメラ抗原レセプター(CAR)を発現するT細胞集団を患者に投与するための、医薬組成物。
- T細胞集団が、CARをコードするレンチウイルスベクターで形質導入された、T細胞を含む、請求項8に記載の、医薬組成物。
- T細胞集団が、CARをコードするRNA分子で形質転換された、T細胞を含む、請求項9に記載の、医薬組成物。
- T細胞集団が、組換え腫瘍溶解性ウイルスの投与後、1~20日、投与される、請求項9に記載の、医薬組成物。
- T細胞集団が、組換え腫瘍溶解性ウイルスの投与後、5~100日、投与される、請求項9に記載の、医薬組成物。
- がんが、固形腫瘍である、請求項8に記載の、医薬組成物。
- 固形腫瘍が、卵巣がん、又は膵がんである、請求項13に記載の、医薬組成物。
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US20210077554A1 (en) * | 2019-09-13 | 2021-03-18 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of Neoplasm Treatment Utilizing Complementary Oncolytic Viruses and CAR T-Cells |
US11110165B2 (en) | 2019-10-10 | 2021-09-07 | Ricardo Rosales Ledezma | Therapeutic vaccine for the treatment of papillomavirus lesions |
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CN112143711B (zh) * | 2020-09-29 | 2021-07-23 | 杭州荣谷生物科技有限公司 | 重组痘瘤病毒、药物组合物及其构建方法和应用 |
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CA3216079A1 (en) * | 2021-04-05 | 2022-10-13 | Bionoxx Inc. | Chimeric antigen receptor targeting oncolytic virus-derived protein, immunocyte expressing same, and uses of both |
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WO2016009017A1 (en) | 2014-07-16 | 2016-01-21 | Institut Gustave-Roussy | Combination of oncolytic virus with immune checkpoint modulators |
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