JP6802275B2 - 癌の治療に用いる腫瘍溶解性単純ヘルペスウイルス(oHSV)偏性ベクター及びその構築体の構築 - Google Patents
癌の治療に用いる腫瘍溶解性単純ヘルペスウイルス(oHSV)偏性ベクター及びその構築体の構築 Download PDFInfo
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Description
本明細書における「一」又は「1つ」の実体という用語は、当該実体のうちの1つ又は複数を指す。例えば、「組み換え腫瘍溶解性HSV−1」は、1つ又は複数の組み換え腫瘍溶解性HSV−1ウイルスを表すものと理解される。よって、「1つ」、「1つ又は複数」及び「少なくとも1つ」といった用語は、本明細書で相互に置き換えて用いることができる。
本発明の一態様として、改変されたHSV−1ゲノムを含むHSV−1ウイルスを提供し、HSV−1偏性ベクターとも呼ばれる。HSV−1ゲノムは共有結合する2つの成分(LとSと称する)からなる。各成分はユニーク配列(L成分はUL、S成分はUS)からなり、両側は逆方向反復配列である。L成分の逆方向反復配列はabとb’a’と呼ばれ、S成分の逆方向反復配列はa’c’とcaと呼ばれる。逆方向反復領域には2コピーの転写単位が含まれている。本分野では、少なくとも5つの2コピーを有するオープンリーディングフレームが知られており、これらのタンパク質はそれぞれICP0、ICP4、ICP34.5、ORF P及びORF Oと名づけられる。逆方向反復配列b’a’とa’c’(b’a’−a’c’)が結合して内部逆方向反復領域を形成する。そして、逆方向反復配列abとcaは本明細書で外部反復領域と呼ばれる。
少なくとも5種のタンパク質(ICP0、ICP4、ICP34.5、ORF−O及びORF−P)をコードする転写単位の1つのコピー(ただし残りすべてのオープンリーディングフレームが保持される)(a)、
b’a’−a’c’配列内に全体で包含される転写単位(b)、及び
ユニーク領域から始まり、欠失された領域まで延伸する転写単位(c)を含む。
外来DNA配列を野生型ウイルスに挿入すると、DNAをビリオンにパッケージすることが干渉されるため、その挿入量に制限がある。所定の領域における正確な欠失により、外来DNA配列を挿入するのに好適なスペースが与えられる。本発明の一実施形態によれば、前記欠失により、腫瘍溶解性ウイルスベクターから少なくとも15Kbpが除去され、これにより相当量の外来DNA配列を受け入れることができる。また他の関連研究によると、野生型ゲノムは7KBのDNAをさらに受け入れることができる。
いくつかの実施形態では、本発明によるoHSV−1は、サイトカイン(例えばIL−2、IL4、IL−12、GM−CSF、IFNγ)、ケモカイン(例えばMIP−1、MCP−1、IL−8)及び成長因子(例えばFLT3リガンド)を含む1種又は複数種の免疫刺激剤(免疫刺激分子とも呼ばれる)をコードする。
本発明の一態様として、抗PD−1剤及び/又は抗CTLA−4剤をコードする外来核酸を含む腫瘍溶解性ウイルスを提供する。いくつかの実施形態では、抗PD−1剤又は抗CTLA−4剤には、PD−1又はCTLA−4エピトープに特異的結合する抗体可変領域が含まれている。抗体可変領域は、例えば完全抗体、抗体フラグメント及び抗体又は抗体フラグメントの組み換え誘導体に存在してもよい。「抗体」という用語は、天然、一部合成又は全体合成の免疫グロブリンを指すものである。よって、本発明の抗PD−1剤又は抗CTLA−4剤は、PD−1又はCTLA−4エピトープに特異的結合する結合ドメインを有するあらゆるポリペプチド又はタンパク質を含む。
腫瘍溶解性ウイルスは、適切な薬学的に許容可能な担体又は賦形剤の中で製造することができる。通常の保管と使用条件では、これらの製剤には微生物の成長を防止する防腐剤が含まれている。注射用に好適な投与剤型は、無菌水溶液や、分散液又は無菌注射溶液や分散液の仮調製に用いる無菌粉末(米国特許登録第5,466,468号)を含む。あらゆる場合において、製剤は無菌でなくてはならず、且つ注射を容易にするために流体としなければならない。製造と保管の条件において安定する状態を保たなければならず、且つ細菌と真菌などの微生物による汚染も防止しなければならない。
本発明のもう一つの態様は、治療を必要とする被験者に組み換え腫瘍溶解性HSV−1ウイルス又は上記組み換え腫瘍溶解性HSV−1ウイルスを含む医薬組成物の有効量の投与を含む、癌を治療又は寛解する方法を提供する。また本発明は、上記の癌を治療又は寛解する方法に用いる腫瘍溶解性HSV−1ウイルスを合わせて提供する。
細菌人工染色体(BAC)技術による偏性ベクター−IMMV201の生成において、3つの終止(STOP)コドンを生成するCMVプロモーターカセットであるATGCAGGTGCAGTAATAGTAAカセットをT−Easyベクターの中に挿入した。プロトタイプ(P)配置のHSV−1を用いられる。それぞれ2セットのプライマー(GAAGATCTAATATTTTTATTGCAACTCCCTG、CTAGCTAGCTTATAAAAGGCGCGTCCCGTGG)と(GCTCTAGATTGCGACGCCCCGGCTC、CCTTAATTAAGGTTACCACCCTGTAGCCCCGATGT)によってHSV−1ウイルスゲノムから、上流側がヌクレオチド117005に連結され、下流側がヌクレオチド132096に連結される遺伝子カセットをPCR増幅させ、上記CMVと3つの終止コドンを含むプラスミドの中に挿入し、そして当該遺伝子置き換えプラスミドをpKO5の中に構築することにより、pKO−CMV−STOPを得た。pKO−CMV−STOPを電気穿孔法によってBAC HSVを担持する大腸菌RecA +の中に導入することによりIMMV201を得た。
OptiMEM agency(Life Technologies社)を用いて説明書に従って、上記のように構築されたBAC−IMMV201の2〜3μgを70%コンフルエント状態のVero細胞の中にトランスフェクトした。37℃、5%CO2のインキュベーターの中で4時間インキュベーション。インキュベーション後、新鮮な完全成長培地(5%新生仔ウシ血清/DMEM)4mLで置換。3〜4日以内にウイルスのプラークが認められなかった。実験を3回繰り返すところ、ウイルスのプラークが認められなかった。
pKO遺伝子カセットを電気穿孔法によってIMMV201を担持する大腸菌RecA +の中に導入することにより、免疫刺激遺伝子(マウスIL12、ヒトIL12)又は免疫治療遺伝子(ヒトPD−1 scFV(配列番号1又は3)、ヒトCTLA−4 scFV(配列番号5)を駆動するCMVプロモーター遺伝子カセットを得た(図1参照)。
免疫刺激遺伝子(IL12)と免疫治療遺伝子(PD−1 scFV、CTLA−4 scFV)を駆動するCMVプロモーターカセットを、さらに、IMMV202、203、303、403ベクターにおけるUL3とUL4遺伝子の間に挿入することにより免疫刺激遺伝子(IL12)と免疫治療遺伝子の組み合わせを発現する組み換えoHSVを生成した(図2参照)。
IMMV503ベクター(図2参照)におけるUL37とUL38遺伝子の間にCTLA−4 scFVを挿入することにより、ヒトIL12、PD−1 scFVとCTLA−4 scFVをコードする3種の免疫刺激cDNA及び免疫治療cDNAを発現するIMMV603を構築した。
本明細書に記載の一連の実験では、モック又はプラスミドでトランスフェクトされる2×106個のH293T細胞は、CMVプロモーターにより駆動されHisタグscFV−抗−PD−1をコードするcDNA及び各種自然源に由来するシグナルペプチドコーディング領域を含む。トランスフェクト46時間後、細胞溶解物と上澄み液を収集し、SDS−PAGEを行って抗His抗体によってウェスタンブロッティングを行った。上澄み液2mLから40μL、細胞溶解物200μLから30μLを取り出して12%のPAGEゲルにロードした。細胞培養の上澄み液の中に蓄積されるPD−1 scFVの量(図3参照)は異なるシグナルペプチドの効率を反映している。
モック又はプラスミドでトランスフェクトされる2×106個のH293T細胞はCMVプロモーターにより駆動されHisタグscFV−抗PD−1をコードするcDNA及びHMM38シグナルペプチドを含む。トランスフェクト46時間後、上澄み液を収集し、そしてELISAアッセイを行い、抗His抗体を用いて検出した(図4参照)。分泌されたPD−1 scFVは用量依存的にPD−1と結合する。
モック(陰性対照)又はIMMV507(PD−1抗体及びCTLA−4抗体を発現するoHSV−1)を用いて、それぞれ各細胞に対する0.01、0.1、1、10、100の倍率のPFUで、96ウェルプレートに接種した5×103個の次に示すヒト腫瘍細胞を感染した。CCK−8キットを用いて、成長の細胞生存性を、96時間が経過するまで24時間ごとに測定した(図5参照)。マイクロプレートリーダー(BiotekEpoch社)を用いて450nmでの吸光度を測定した。
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Claims (25)
- 単純ヘルペスウイルスI型(HSV−1)ベクターであって、
野生型HSV−1ゲノムのU L 成分における最後の遺伝子のプロモーターからU S 成分における第1遺伝子のプロモーターまでの欠失を有する改変型HSV−1ゲノムを含み、前記ベクターは、(i)野生型HSV−1ゲノムのすべての2コピー遺伝子の1コピーのみ、(ii)野生型HSV−1ゲノムの重複するノンコーディング配列の1コピーのみ、及び、(iii)野生型HSV−1ゲノムのすべてのシングルコピーのオープンリーディングフレーム(ORF)の発現のために必要な配列、を含み、
ここで、HSV−1ベクターは、野生型HSV−1に感受性のある哺乳動物細胞において複製できないが、追加の細胞又はウイルスDNA配列の挿入後に複製できるようになる、ことを特徴とするHSV−1ベクター。 - 前記2コピー遺伝子は、ICP0、ICP4、ICP34.5、ORF P及びORF Oをコードする遺伝子を含むことを特徴とする請求項1に記載のHSV−1ベクター。
- 前記HSV−1は、プロトタイプ(P)のゲノム異性体を備えることを特徴とする請求項1に記載のHSV−1ベクター。
- 前記HSV−1は、F株、KOS株、及び、17株からなるグループから選択されることを特徴とする請求項1に記載のHSV−1ベクター。
- 前記欠失により、F株のゲノムにおけるヌクレオチド位置117005から132096が除去されることを特徴とする請求項4に記載のHSV−1ベクター。
- 前記U L 成分における最後の既知遺伝子は、U L 56である請求項1に記載のHSV−1ベクター。
- 前記U S 成分における第1の既知遺伝子は、U S 1である請求項1に記載のHSV−1ベクター。
- 前記重複するノンコーディング配列は、LATドメイン及び「a」配列を含む請求項1に記載のHSV−1ベクター。
- 組み換え腫瘍溶解性単純ヘルペスウイルスI型(HSV−1)であって、
請求項1記載のHSV−1ベクター、及び
請求項1に記載のHSV−1ベクターの欠失された領域に安定的に導入され、免疫刺激剤及び/又は免疫治療剤をコードする外来核酸配列、とを含むことを特徴とする組み換え腫瘍溶解性HSV−1。 - 前記免疫刺激剤は、GM−CSF、IL 2、IL 12、IL 15、IL 24及びIL 27からなるグループから選択されることを特徴とする請求項9に記載の組み換え腫瘍溶解性HSV−1。
- 前記免疫治療剤は、抗PD−1剤及び/又は抗CTLA−4剤であることを特徴とする請求項9に記載の組み換え腫瘍溶解性HSV−1。
- 前記外来核酸配列は、IL−12、抗PD−1剤、及び/又は抗CTLA−4剤をコードすることを特徴とする請求項9に記載の組み換え腫瘍溶解性HSV−1。
- IL−12をコードする第1の外来核酸配列及び抗PD−1剤又は抗CTL−4剤をコードする第2の外来核酸配列を含むことを特徴とする請求項9に記載の組み換え腫瘍溶解性HSV−1。
- 抗PD−1剤をコードする第1の外来核酸配列及び抗CTLA−4剤をコードする第2の外来核酸配列を含むことを特徴とする請求項9に記載の組み換え腫瘍溶解性HSV−1。
- IL−12をコードする第1の外来核酸配列、抗PD−1剤をコードする第2の外来核酸配列及び抗CTLA−4剤をコードする第3の外来核酸配列を含むことを特徴とする請求項9に記載の組み換え腫瘍溶解性HSV−1。
- 前記外来核酸配列に作動可能に連結されるプロモーター配列をさらに含むことを特徴とする請求項9に記載の組み換え腫瘍溶解性HSV−1。
- 前記第1の外来核酸配列が前記改変されたHSV−1ゲノムの欠失された領域に挿入されており、且つ前記第2の外来核酸配列が前記改変されたHSV−1ゲノムにおけるUL成分のUL3とUL4遺伝子の間に挿入されていることを特徴とする請求項13又は14に記載の組み換え腫瘍溶解性HSV−1。
- 前記第1の外来核酸配列が前記改変されたHSV−1ゲノムの欠失された領域に挿入されており、前記第2の外来核酸配列が前記改変されたHSV−1ゲノムにおけるUL成分のUL3とUL4遺伝子の間に挿入されており、且つ第3の外来核酸配列が前記改変されたHSV−1ゲノムにおけるUL成分のUL37とUL38遺伝子の間に挿入されていることを特徴とする請求項15に記載の組み換え腫瘍溶解性HSV−1。
- 前記第1の外来核酸配列が前記改変されたHSV−1ゲノムの欠失された領域に挿入されており、前記第2の外来核酸配列が前記改変されたHSV−1ゲノムにおけるUL成分のUL37とUL38遺伝子の間に挿入されており、且つ第3の外来核酸配列が前記改変されたHSV−1ゲノムにおけるUL成分のUL3とUL4遺伝子の間に挿入されていることを特徴とする請求項15に記載の組み換え腫瘍溶解性HSV−1。
- 前記プロモーター配列は、CMVプロモーター又はEgr−1プロモーターであることを特徴とする請求項16に記載の組み換え腫瘍溶解性HSV−1。
- 前記免疫刺激剤及び/又は免疫治療剤は、ヒト化されていることを特徴とする請求項9に記載の組み換え腫瘍溶解性HSV−1。
- 前記抗PD−1剤又は前記抗CTLA−4剤は、それぞれPD−1又はCTLA−4エピトープに特異的結合するための抗体の可変領域を含むことを特徴とする請求項11に記載の組み換え腫瘍溶解性HSV−1。
- 前記抗体は、完全抗体、抗体フラグメント、又は前記抗体もしくは前記抗体フラグメントの組み換え誘導体であることを特徴とする請求項22に記載の組み換え腫瘍溶解性HSV−1。
- 医薬組成物であって、
有効量の請求項9〜23のいずれか一項に記載の組み換え腫瘍溶解性HSV−1及び薬学的に許容可能な担体を含むことを特徴とする医薬組成物。 - 前記医薬組成物は腫瘍−内投与用として調製されることを特徴とする請求項24に記載の医薬組成物。
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JP2021027842A (ja) * | 2020-11-26 | 2021-02-25 | イムヴィラ・カンパニー・リミテッドImmvira Co., Limited | 癌の治療に用いる腫瘍溶解性単純ヘルペスウイルス(oHSV)偏性ベクター及びその構築体の構築 |
JP7235334B2 (ja) | 2020-11-26 | 2023-03-08 | イムヴィラ・カンパニー・リミテッド | 癌の治療に用いる腫瘍溶解性単純ヘルペスウイルス(oHSV)偏性ベクター及びその構築体の構築 |
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KR20210013366A (ko) | 2021-02-03 |
US10821140B2 (en) | 2020-11-03 |
RU2751236C2 (ru) | 2021-07-12 |
NZ746916A (en) | 2020-08-28 |
AU2020204209A1 (en) | 2020-07-16 |
IL262385A (en) | 2018-11-29 |
KR102323872B1 (ko) | 2021-11-08 |
IL262385B2 (en) | 2024-01-01 |
CN108350468B (zh) | 2020-10-30 |
EP3380621A4 (en) | 2019-05-08 |
CN112575036A (zh) | 2021-03-30 |
WO2017181420A1 (en) | 2017-10-26 |
KR102211838B1 (ko) | 2021-02-03 |
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