JPWO2020025642A5

JPWO2020025642A5 -

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Publication number: JPWO2020025642A5
Application number: JP2021505666A
Authority: JP
Publication date: 2022-08-08

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本開示は以下の［１］から［４８］を含む。
［１］核酸分子をカプシドで包んだチンパンジーアデノウイルス（ＣｈＡｄ）ベクターであって、上記核酸分子が、（ｉ）ＭＡＧＥがん抗原および／もしくはＮＹ－ＥＳＯ－１がん抗原、もしくはその免疫原性断片、または（ｉｉ）ＭＡＧＥがん抗原および／もしくはＬＡＧＥ１がん抗原、もしくはその免疫原性断片をコードするポリヌクレオチド配列であって、動物細胞において上記がん抗原またはその断片の翻訳、転写および／または発現を指令する発現制御配列に作動可能に連結している、上記ポリヌクレオチド配列、ならびにアデノウイルスパッケージングシグナル配列を含む、ＣｈＡｄベクター。
［２］（ａ）国際公開第２０１２／１７２２７７号パンフレットに開示されたＣｈＡｄＯｘ１；好ましくは、国際公開第２０１２／１７２２７７号パンフレットに開示された配列番号３８のポリヌクレオチドもしくはそれと少なくとも８０％の同一性を有する配列によりコードされるＣｈＡｄＯｘ１、または（ｂ）国際公開第２０１７／２２１０３１号パンフレットに開示されたＣｈＡｄＯｘ２；好ましくは、国際公開第２０１７／２２１０３１号パンフレットに開示された配列番号１０のポリヌクレオチドもしくはそれと少なくとも８０％の同一性を有する配列によりコードされるＣｈＡｄＯｘ２である、上記［１］に記載のＣｈＡｄベクター。
［３］核酸分子をカプシドで包んだ改変ワクシニアウイルスアンカラ（ＭＶＡ）ベクターであって、上記核酸分子が、（ｉ）ＭＡＧＥがん抗原および／もしくはＮＹ－ＥＳＯ－１がん抗原、もしくはその免疫原性断片、または（ｉｉ）ＭＡＧＥがん抗原および／もしくはＬＡＧＥ１がん抗原、もしくはその免疫原性断片をコードするポリヌクレオチド配列であって、動物細胞において上記がん抗原またはその断片の翻訳、転写および／または発現を指令する発現制御配列に作動可能に連結している、上記ポリヌクレオチド配列を含む、ＭＶＡベクター。
［４］国際公開第２０１１／１２８７０４号パンフレットまたは欧州特許出願公開第２０４４９４７号明細書に開示された通りのものである、上記［３］に記載のＭＶＡベクター。
［５］上記ＭＡＧＥ抗原が、配列番号１のアミノ酸配列、またはそれと少なくとも４６％、好ましくは少なくとも６９％、より好ましくは少なくとも９５％の同一性を有する配列、もしくはその任意の免疫原性断片の配列を有するＭＡＧＥ３Ａである、上記［１］～［４］のいずれか一項に記載のＣｈＡｄまたはＭＶＡベクター。
［６］上記ＮＹ－ＥＳＯ－１がん抗原が、配列番号３のアミノ酸配列、またはそれと少なくとも７５％、好ましくは少なくとも７６．７％の同一性を有する配列、もしくはその任意の免疫原性断片の配列を有する、上記［１］～［５］のいずれか一項に記載のＣｈＡｄまたはＭＶＡベクター。
［７］上記ＬＡＧＥ１がん抗原が、配列番号５のアミノ酸配列、またはそれと少なくとも７８％、好ましくは少なくとも９７％の同一性を有する配列、もしくはその任意の免疫原性断片の配列を有する、上記［１］～［５］のいずれか一項に記載のＣｈＡｄまたはＭＶＡベクター。
［８］上記ポリヌクレオチド配列が、配列番号６のアミノ酸配列、またはそれと少なくとも７９％の同一性を有する配列、もしくはその断片の配列を有するヒトＨＬＡクラスＩＩ組織適合性抗原ガンマ鎖（ｌｉ）をさらにコードし、それにより、上記がん抗原が、ｌｉとの融合物またはその断片として動物細胞中で発現され、
好ましくは、上記断片が膜貫通ドメインであり、より好ましくは、上記膜貫通ドメインが、アミノ酸残基３０～５５または３０～６１を含み、よりいっそう好ましくは、上記膜貫通ドメインが、配列番号７のアミノ酸配列を有する、上記［１］～［７］のいずれか一項に記載のＣｈＡｄまたはＭＶＡベクター。
［９］上記ポリヌクレオチド配列が、配列番号８のアミノ酸配列、またはそれと少なくとも８１％の同一性を有する配列、もしくはその断片の配列を有するｔＰＡをさらにコードし、それにより、上記がん抗原が、ｔＰＡとの融合物またはその断片として動物細胞中で発現され、好ましくは、上記断片が、２１アミノ酸のリーダー配列を含み、より好ましくは、上記２１アミノ酸のリーダー配列が配列番号９である、上記［１］～［８］のいずれか一項に記載のＣｈＡｄまたはＭＶＡベクター。
［１０］上記ポリヌクレオチド配列が、融合タンパク質として動物細胞中で発現される、（ｉ）ＭＡＧＥがん抗原もしくはその免疫原性断片およびＮＹ－ＥＳＯ－１がん抗原もしくはその免疫原性断片、または（ｉｉ）ＭＡＧＥがん抗原もしくはその免疫原性断片およびＬＡＧＥ１がん抗原もしくはその免疫原性断片をコードする、上記［１］～［９］のいずれか一項に記載のＣｈＡｄベクター。
［１１］上記ポリヌクレオチド配列が、融合タンパク質として動物細胞中で発現される、（ｉ）ＭＡＧＥがん抗原もしくはその免疫原性断片および／もしくはＮＹ－ＥＳＯ－１がん抗原もしくはその免疫原性断片、または（ｉｉ）ＭＡＧＥがん抗原もしくはその免疫原性断片および／もしくはＬＡＧＥ１がん抗原もしくはその免疫原性断片をコードし、上記ＭＡＧＥがん抗原、ＮＹ－ＥＳＯ－１がん抗原またはＬＡＧＥ１がん抗原のうちの少なくとも１つが断片である、上記［１］～［９］のいずれかに記載のＭＶＡベクター。
［１２］上記ＭＡＧＥがん抗原およびＮＹ－ＥＳＯ－１またはＭＡＧＥがん抗原およびＬＡＧＥ１が免疫原性断片である、上記［１１］に記載のＭＶＡベクター。
［１３］上記ポリヌクレオチド配列が、発現された場合に、上記ＭＡＧＥおよびＮＹ－ＥＳＯ－１もしくはＬＡＧＥ１がん抗原またはその断片をいずれかの順序において融合タンパク質として連結する、５～９アミノ酸のリンカー、好ましくは、アミノ酸配列ＧＧＧＰＧＧＧを有するリンカーをコードする、上記［１０］～［１２］のいずれかに記載のＣｈＡｄまたはＭＶＡベクター。
［１４］上記［１］～［１３］のいずれか一項に記載のＣｈＡｄまたはＭＶＡベクターを含む、免疫原性組成物。
［１５］アジュバントをさらに含む、上記［１４］に記載の組成物。
［１６］上記［１］～［１０］もしくは［１３］のいずれかに記載のＣｈＡｄベクター、または上記［３］～［９］もしくは［１１］～［１３］のいずれかに記載のＭＶＡベクターをコードする配列を含む、単離されたポリヌクレオチド。
［１７］ヒトコドン用法についてコドン最適化されている、上記［１６］に記載の単離されたポリヌクレオチド。
［１８］上記［１６］または［１７］に記載のポリヌクレオチドを含む、細菌人工染色体（ＢＡＣ）クローン。
［１９］上記［１］～［１３］のいずれかに記載のＣｈＡｄおよび／またはＭＶＡベクターを含む、単離された宿主細胞。
［２０］個体においてがんを予防または治療する方法であって、有効量の上記［１］～［１０］または［１３］のいずれかに記載のＣｈＡｄベクターを投与すること、および有効量の上記［３］～［９］または［１１］～［１３］のいずれかに記載のＭＶＡベクターを投与することを含み、それにより、上記個体の適応免疫系が刺激されて、抗がん免疫応答が提供される、方法。
［２１］上記ＣｈＡｄおよびＭＶＡベクターの上記投与が、別々に、逐次的にまたは同時に実行される、上記［２０］に記載のがんを予防または治療する方法。
［２２］有効量の１つまたは複数のチェックポイント阻害剤の投与をさらに含む、上記［２０］または［２１］に記載の方法。
［２３］上記チェックポイント阻害剤が、上記ＣｈＡｄおよびＭＶＡベクターと同時に、別々にまたは並行して投与される、上記［２０］～［２２］のいずれかに記載の方法。
［２４］上記個体が、化学療法および／または放射線療法治療を受けた、受けている、または受ける個体である、上記［２０］～［２３］のいずれかに記載の方法。
［２５］上記ＣｈＡｄベクターが最初に投与される、上記［２０］～［２４］のいずれかに記載の方法。
［２６］上記ＣｈＡｄおよびＭＶＡベクターが、それぞれ１回より多く投与される、上記［２０］～［２５］のいずれかに記載の方法。
［２７］上記ＣｈＡｄおよびＭＶＡベクターが交互に投与される、上記［２０］～［２６］のいずれかに記載の方法。
［２８］ベクターの各投与の間の期間が、５日～８週の範囲内、好ましくは１週である、上記［２０］～［２７］のいずれかに記載の方法。
［２９］上記チェックポイント阻害剤が、ＰＤ－１、ＣＴＬＡ－４またはＰＤ－Ｌ１を遮断する、上記［２２］～［２８］のいずれかに記載の方法。
［３０］上記チェックポイント阻害剤が、ニボルマブ、ペムブロリズマブ、イピリムマブ、トレメリムマブもしくはアテゾリズマブ、デュルバルマブまたはアベルマブから選択される、上記［２２］～［２８］のいずれかに記載の方法。
［３１］上記がんが、非小細胞肺がん（ＮＳＣＬＣ）、黒色腫、ホジキンリンパ腫、非ホジキンリンパ腫、尿路（尿路上皮）、膀胱、小細胞肺がん、腎臓、頭頸部、肉腫、または乳房のがんである、上記［２２］～［２８］のいずれかに記載の方法。
［３２］がんの予防または治療において使用するための、上記［１］、［２］、［５］～［１０］または［１３］のいずれかに記載のＣｈＡｄベクター。
［３３］がんの予防または治療において使用するための、上記［３］～［９］または［１１］～［１３］のいずれかに記載のＭＶＡベクター。
［３４］がんの予防または治療のための患者への別々の、逐次的なまたは同時の投与のための、上記［１］、［２］、［５］～［１０］または［１３］のいずれかに記載のＣｈＡｄベクター、および上記［３］～［９］または［１１］～［１３］のいずれかに記載のＭＶＡベクター。
［３５］がんの治療のためにＣｈＡｄおよびＭＶＡベクターと共に投与するための１つまたは複数のチェックポイント阻害剤をさらに含む、上記［３４］に記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［３６］上記チェックポイント阻害剤が、ベクターと同時に、別々にまたは並行して投与される、上記［３５］に記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［３７］患者が、化学療法を受けた、受けているまたは受ける患者である、上記［３１］～［３３］のいずれかに記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［３８］上記ＣｈＡｄベクターが最初に投与される、上記［３４］～［３６］のいずれかに記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［３９］上記ＣｈＡｄおよびＭＶＡベクターが、それぞれ１回より多く投与される、上記［３４］～［３８］のいずれかに記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［４０］上記ＣｈＡｄおよびＭＶＡベクターが交互に投与される、上記［３４］～［３９］のいずれかに記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［４１］ベクターの各投与の間の期間が、５日～８週の範囲内、好ましくは１週である、上記［３４］～［４０］のいずれかに記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［４２］上記チェックポイント阻害剤が、ＰＤ－１、ＣＴＬＡ－４またはＰＤ－Ｌ１を遮断する、上記［３５］～［４１］のいずれかに記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［４３］上記チェックポイント阻害剤が、ニボルマブ、ペムブロリズマブ、イピリムマブ、トレメリムマブもしくはアテゾリズマブ、デュルバルマブまたはアベルマブから選択される、上記［３５］～［４１］のいずれかに記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［４４］上記がんが、非小細胞肺がん（ＮＳＣＬＣ）、黒色腫、ホジキンリンパ腫、非ホジキンリンパ腫、尿路（尿路上皮）、膀胱、小細胞肺がん、腎臓、頭頸部、肉腫または乳房のがんである、上記［３５］～［４１］のいずれかに記載のがんの予防または治療において使用するためのＣｈＡｄおよびＭＶＡベクター。
［４５］がんの予防または治療のための患者への別々の、逐次的なまたは同時の投与のための、上記［１］、［２］、［５］～［１０］または［１３］のいずれかに記載のＣｈＡｄベクター、上記［３］～［９］または［１１］～［１３］のいずれかに記載のＭＶＡベクター、化学療法剤、およびチェックポイント阻害剤。
［４６］上記化学療法剤が、（ｂ）パクリタキセル、ドセタキセル、ビノレルビン、ゲムシタビン、エトポシドまたはペメトレキセドのうちの１つと組み合わせた（ａ）カルボプラチンまたはシスプラチンから選択される、上記［４５］に記載のＣｈＡｄベクター、ＭＶＡベクター、化学療法剤およびチェックポイント阻害剤。
［４７］上記チェックポイント阻害剤がＰＤ－１である、上記［４５］または［４６］に記載のＣｈＡｄベクター、ＭＶＡベクター、化学療法剤およびチェックポイント阻害剤。
［４８］上記がんが、非小細胞肺がん（ＮＳＣＬＣ）もしくは小細胞肺がん（ＳＣＬＣ）、黒色腫、ホジキンリンパ腫、非ホジキンリンパ腫、尿路（尿路上皮）、膀胱、小細胞肺がん、腎臓、頭頸部、肉腫または乳がんから選択されるがんである、上記［４５］～［４７］のいずれかに記載のＣｈＡｄベクター、ＭＶＡベクター、化学療法剤およびチェックポイント阻害剤。
本発明によれば、核酸分子をカプシドで包んだチンパンジーアデノウイルス（ＣｈＡｄ
）ベクターであって、核酸分子が、（ｉ）ＭＡＧＥがん抗原および／もしくはＮＹ－ＥＳ
Ｏ－１がん抗原、もしくはその免疫原性断片、または（ｉｉ）ＭＡＧＥがん抗原および／
もしくはＬＡＧＥ１がん抗原、もしくはその免疫原性断片をコードするポリヌクレオチド
配列であって、動物細胞においてがん抗原またはその断片の翻訳、転写および／または発
現を指令する発現制御配列に作動可能に連結している、前記ポリヌクレオチド配列、なら
びにアデノウイルスパッケージングシグナル配列を含む、ＣｈＡｄベクターが提供される
。有利には、そのようなＣｈＡｄウイルスベクターは、安定かつ十分に研究されており、
ヒトアデノウイルスに対する抗体により中和されず、かつ複製欠損性となるように操作さ
れている。それらは、挿入される目的の抗原のために高容量を有し、アデノウイルスＥ１
遺伝子を含有するＨＥＫ２９３細胞中で製造することができる。
This disclosure includes the following [1] to [48].
[1] A chimpanzee adenovirus (ChAd) vector encapsidating a nucleic acid molecule, wherein the nucleic acid molecule is (i) the MAGE cancer antigen and/or the NY-ESO-1 cancer antigen, or immunogenicity thereof fragment, or (ii) a MAGE cancer antigen and/or LAGE1 cancer antigen, or an immunogenic fragment thereof, wherein translation, transcription and/or of said cancer antigen or fragment thereof in animal cells; or a ChAd vector comprising the above polynucleotide sequence, operably linked to expression control sequences that direct expression, and an adenovirus packaging signal sequence.
[2] (a) ChAdOx1 disclosed in WO2012/172277; preferably, the polynucleotide of SEQ ID NO: 38 disclosed in WO2012/172277 or having at least 80% identity thereto or (b) ChAdOx2 as disclosed in WO2017/221031; preferably the polynucleotide of SEQ ID NO: 10 disclosed in WO2017/221031 or at least The ChAd vector of [1] above, which is ChAdOx2 encoded by a sequence with 80% identity.
[3] A modified vaccinia virus Ankara (MVA) vector encapsidating a nucleic acid molecule, wherein the nucleic acid molecule is (i) the MAGE cancer antigen and/or the NY-ESO-1 cancer antigen, or an immunogen thereof or (ii) a MAGE cancer antigen and/or a LAGE1 cancer antigen, or an immunogenic fragment thereof, wherein translation, transcription and translation of said cancer antigen or fragment thereof in animal cells; /or an MVA vector comprising the above polynucleotide sequence operably linked to expression control sequences that direct expression.
[4] The MVA vector according to [3] above, which is as disclosed in WO2011/128704 or EP2044947.
[5] the MAGE antigen is the amino acid sequence of SEQ ID NO: 1 or a sequence having at least 46%, preferably at least 69%, more preferably at least 95% identity therewith, or any immunogenic fragment thereof; The ChAd or MVA vector according to any one of [1] to [4] above, which is MAGE 3A having
[6] the NY-ESO-1 cancer antigen is the amino acid sequence of SEQ ID NO: 3, or a sequence having at least 75%, preferably at least 76.7% identity therewith, or any immunogenic fragment thereof; The ChAd or MVA vector according to any one of [1] to [5] above, which has the sequence.
[7] The above [ 1] to the ChAd or MVA vector according to any one of [5].
[8] further human HLA class II histocompatibility antigen gamma chain (li), wherein the polynucleotide sequence has the amino acid sequence of SEQ ID NO: 6, or a sequence having at least 79% identity thereto, or a fragment thereof; encoding, whereby said cancer antigen is expressed in animal cells as a fusion with li or a fragment thereof;
Preferably, said fragment is a transmembrane domain, more preferably said transmembrane domain comprises amino acid residues 30-55 or 30-61, even more preferably said transmembrane domain comprises The ChAd or MVA vector according to any one of [1] to [7] above, which has an amino acid sequence.
[9] The polynucleotide sequence further encodes tPA having the amino acid sequence of SEQ ID NO: 8, or a sequence having at least 81% identity thereto, or a fragment thereof, whereby the cancer antigen is The above [ 1] to the ChAd or MVA vector according to any one of [8].
[10] the polynucleotide sequences are expressed in animal cells as fusion proteins, (i) MAGE cancer antigen or immunogenic fragment thereof and NY-ESO-1 cancer antigen or immunogenic fragment thereof, or (ii) the ChAd vector of any one of [1] to [9] above, which encodes a MAGE cancer antigen or an immunogenic fragment thereof and a LAGE1 cancer antigen or an immunogenic fragment thereof;
[11] The polynucleotide sequence is expressed in animal cells as a fusion protein, (i) MAGE cancer antigen or immunogenic fragment thereof and/or NY-ESO-1 cancer antigen or immunogenic fragment thereof or (ii) encoding a MAGE cancer antigen or an immunogenic fragment thereof and/or a LAGE1 cancer antigen or an immunogenic fragment thereof, wherein said MAGE cancer antigen, NY-ESO-1 cancer antigen or LAGE1 cancer antigen The MVA vector according to any one of [1] to [9] above, wherein at least one of the antigens is a fragment.
[12] The MVA vector of [11] above, wherein the MAGE cancer antigen and NY-ESO-1 or the MAGE cancer antigen and LAGE1 are immunogenic fragments.
[13] a linker of 5-9 amino acids, which, when said polynucleotide sequence is expressed, links said MAGE and NY-ESO-1 or LAGE1 cancer antigens or fragments thereof in either order as a fusion protein; Preferably, the ChAd or MVA vector according to any one of [10] to [12] above, which encodes a linker having the amino acid sequence GGGPGGG.
[14] An immunogenic composition comprising the ChAd or MVA vector of any one of [1] to [13] above.
[15] The composition of [14] above, further comprising an adjuvant.
[16] The ChAd vector according to any one of [1] to [10] or [13] above, or the MVA vector according to any one of [3] to [9] or [11] to [13] above An isolated polynucleotide comprising a coding sequence.
[17] The isolated polynucleotide of [16] above, which is codon-optimized for human codon usage.
[18] A bacterial artificial chromosome (BAC) clone comprising the polynucleotide of [16] or [17] above.
[19] An isolated host cell containing the ChAd and/or MVA vector according to any one of [1] to [13] above.
[20] A method for preventing or treating cancer in an individual, comprising administering an effective amount of the ChAd vector according to any one of [1] to [10] or [13] above, and an effective amount of the above administering the MVA vector according to any one of [3] to [9] or [11] to [13], thereby stimulating the adaptive immune system of the individual and producing an anticancer immune response; method provided.
[21] The method of preventing or treating cancer according to [20] above, wherein the administration of the ChAd and the MVA vector is performed separately, sequentially or simultaneously.
[22] The method of [20] or [21] above, further comprising administration of an effective amount of one or more checkpoint inhibitors.
[23] The method of any of [20]-[22] above, wherein the checkpoint inhibitor is administered simultaneously, separately or in parallel with the ChAd and MVA vector.
[24] The method of any of [20] to [23] above, wherein the individual has undergone, is undergoing, or is undergoing chemotherapy and/or radiotherapy treatment.
[25] The method of any one of [20] to [24] above, wherein the ChAd vector is administered first.
[26] The method of any one of [20] to [25] above, wherein the ChAd and MVA vector are each administered more than once.
[27] The method of any one of [20] to [26] above, wherein the ChAd and the MVA vector are administered alternately.
[28] The method of any of [20] to [27] above, wherein the period between administrations of the vector is in the range of 5 days to 8 weeks, preferably 1 week.
[29] The method of any one of [22] to [28] above, wherein the checkpoint inhibitor blocks PD-1, CTLA-4 or PD-L1.
[30] The method of any one of [22] to [28] above, wherein the checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, tremelimumab or atezolizumab, durvalumab or avelumab.
[31] the cancer is non-small cell lung cancer (NSCLC), melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, urinary tract (urothelial), bladder, small cell lung cancer, renal, head and neck, sarcoma, or breast The method according to any one of [22] to [28] above, which is cancer.
[32] The ChAd vector of any one of [1], [2], [5]-[10] or [13] above for use in the prevention or treatment of cancer.
[33] The MVA vector of any one of [3] to [9] or [11] to [13] above for use in the prevention or treatment of cancer.
[34] the above [1], [2], [5] to [10] or [13] for separate, sequential or simultaneous administration to a patient for the prevention or treatment of cancer The ChAd vector according to any of the above, and the MVA vector according to any of [3] to [9] or [11] to [13] above.
[35] for use in the prevention or treatment of cancer according to [34] above, further comprising one or more checkpoint inhibitors for administration with the ChAd and MVA vector for the treatment of cancer ChAd and MVA vectors.
[36] ChAd and MVA vectors for use in the prevention or treatment of cancer according to [35] above, wherein the checkpoint inhibitor is administered simultaneously, separately or in parallel with the vector.
[37] ChAd and MVA vectors for use in the prevention or treatment of cancer according to any of [31] to [33] above, wherein the patient has undergone, is undergoing, or is undergoing chemotherapy .
[38] A ChAd and MVA vector for use in the prevention or treatment of cancer according to any of [34] to [36] above, wherein the ChAd vector is administered first.
[39] The ChAd and MVA vectors for use in the prevention or treatment of cancer according to any one of [34] to [38] above, wherein the ChAd and MVA vectors are each administered more than once.
[40] The ChAd and MVA vectors for use in the prevention or treatment of cancer according to any one of [34] to [39] above, wherein the ChAd and MVA vectors are administered alternately.
[41] In the prevention or treatment of cancer according to any one of [34] to [40] above, wherein the period between administrations of the vector is in the range of 5 days to 8 weeks, preferably 1 week. ChAd and MVA vectors for use.
[42] For use in the prevention or treatment of cancer according to any one of [35] to [41] above, wherein the checkpoint inhibitor blocks PD-1, CTLA-4 or PD-L1 ChAd and MVA vectors.
[43] Use in the prevention or treatment of cancer according to any one of [35] to [41] above, wherein the checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, tremelimumab or atezolizumab, durvalumab or avelumab ChAd and MVA vectors for
[44] the cancer is non-small cell lung cancer (NSCLC), melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, urinary tract (urothelium), bladder, small cell lung cancer, renal, head and neck, sarcoma or breast ChAd and MVA vectors for use in the prevention or treatment of cancer according to any of [35]-[41] above.
[45] the above [1], [2], [5] to [10] or [13] for separate, sequential or simultaneous administration to a patient for the prevention or treatment of cancer The ChAd vector according to any one, the MVA vector according to any one of [3] to [9] or [11] to [13] above, a chemotherapeutic agent, and a checkpoint inhibitor.
[46] The ChAd vector of [45] above, wherein the chemotherapeutic agent is selected from (a) carboplatin or cisplatin in combination with (b) one of paclitaxel, docetaxel, vinorelbine, gemcitabine, etoposide or pemetrexed , MVA vectors, chemotherapeutic agents and checkpoint inhibitors.
[47] The ChAd vector, MVA vector, chemotherapeutic agent and checkpoint inhibitor of [45] or [46] above, wherein the checkpoint inhibitor is PD-1.
[48] The cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, urinary tract (urothelium), bladder, small cell lung cancer, kidney, head and neck The ChAd vector, MVA vector, chemotherapeutic agent and checkpoint inhibitor according to any one of [45] to [47] above, which is a cancer selected from cancer, sarcoma or breast cancer.
According to the present invention, a chimpanzee adenovirus encapsidating a nucleic acid molecule (ChAd
) vector, wherein the nucleic acid molecule comprises (i) MAGE cancer antigen and/or NY-ES
O-1 cancer antigen, or an immunogenic fragment thereof, or (ii) MAGE cancer antigen and/or
or a polynucleotide sequence encoding a LAGE1 cancer antigen, or an immunogenic fragment thereof, operably linked to expression control sequences that direct translation, transcription and/or expression of the cancer antigen or fragment thereof in animal cells A ChAd vector is provided comprising said polynucleotide sequence, as well as an adenovirus packaging signal sequence. Advantageously, such ChAd viral vectors are stable and well-studied,
It is engineered to be non-neutralized by antibodies against human adenovirus and to be replication-deficient. They have a high capacity for antigens of interest to be inserted, adenovirus E1
It can be produced in HEK293 cells containing the gene.

Claims

A chimpanzee adenoviral (ChAd) vector encapsidating a nucleic acid molecule, wherein the nucleic acid molecule comprises (i) an immunogenic fragment of the MAGE cancer antigen; (ii) the NY-ESO-1 cancer antigen or an immunogenic (iii) MAGE cancer antigen or immunogenic fragment thereof, and NY-ESO-1 cancer antigen or immunogenic fragment thereof , ( iv ) LAGE1 cancer antigen or an immunogenic fragment thereof, or (v) a polynucleotide sequence encoding a cancer antigen(s) comprising a MAGE cancer antigen or an immunogenic fragment thereof and a LAGE1 cancer antigen or an immunogenic fragment thereof , wherein said polynucleotide sequence, wherein said cancer antigen (s) is operably linked to expression control sequences that direct translation, transcription and/or expression of said cancer antigen( s) in animal cells; and A ChAd vector containing an adenoviral packaging signal sequence.

(a) ChAdOx1 disclosed in WO2012/172277; preferably by the polynucleotide of SEQ ID NO: 38 disclosed in WO2012/172277 or a sequence having at least 80% identity thereto (b) ChAdOx2 as disclosed in WO2017/221031; preferably the polynucleotide of SEQ ID NO: 10 as disclosed in WO2017/221031 or at least 80% thereof 2. The ChAd vector of claim 1, which is ChAdOx2 encoded by sequences of identity.

A modified vaccinia virus Ankara (MVA) vector encapsidating a nucleic acid molecule, wherein the nucleic acid molecule comprises (i) an immunogenic fragment of the MAGE cancer antigen, (ii) the NY-ESO-1 cancer antigen or its an immunogenic fragment, (iii) an immunogenic fragment of the MAGE cancer antigen and an immunogenic fragment of the NY-ESO-1 cancer antigen , (iv ) the LAGE1 cancer antigen or its an immunogenic fragment , or (v) a polynucleotide sequence encoding a cancer antigen(s) comprising a MAGE cancer antigen or an immunogenic fragment thereof and a LAGE1 cancer antigen or an immunogenic fragment thereof , said An MVA vector , wherein cancer antigen(s) is operably linked to expression control sequences that direct translation, transcription and/or expression of said cancer antigen or fragment thereof in animal cells.

4. The MVA vector of claim 3, as disclosed in WO2011/128704 or EP2044947.

(a) said MAGE antigen is the amino acid sequence of SEQ ID NO: 1 or a sequence having at least 46%, preferably at least 69%, more preferably at least 95% identity therewith, or any immunogenic fragment thereof; and/or
(b) said NY-ESO-1 cancer antigen is of the amino acid sequence of SEQ ID NO: 3 or a sequence having at least 75%, preferably at least 76.7% identity therewith, or any immunogenic fragment thereof; have an array and/or
(c) said LAGE1 cancer antigen has the amino acid sequence of SEQ ID NO: 5 or a sequence having at least 78%, preferably at least 97% identity therewith, or any immunogenic fragment thereof. A ChAd or MVA vector according to any one of 1-4 .

said polynucleotide sequence further encodes a human HLA class II histocompatibility antigen gamma chain (li) having the amino acid sequence of SEQ ID NO: 6, or a sequence having at least 79% identity thereto, or a fragment thereof; whereby said cancer antigen is expressed in animal cells as a fusion with li or a fragment thereof;
Preferably, said fragment is a transmembrane domain, more preferably said transmembrane domain comprises amino acid residues 30-55 or 30-61, even more preferably said transmembrane domain comprises A ChAd or MVA vector according to any one of claims 1 to 5 , having an amino acid sequence.

The polynucleotide sequence further encodes tPA having the amino acid sequence of SEQ ID NO: 8, or a sequence having at least 81% identity thereto, or a fragment thereof, whereby the cancer antigen is Claims 1-6 , expressed in animal cells as a fusion or a fragment thereof, preferably said fragment comprises a 21 amino acid leader sequence, more preferably said 21 amino acid leader sequence is SEQ ID NO:9. A ChAd or MVA vector according to any one of .

(i) the MAGE cancer antigen or immunogenic fragment thereof and the NY-ESO-1 cancer antigen or immunogenic fragment thereof, or (ii) wherein said polynucleotide sequences are expressed in animal cells as a fusion protein; A ChAd vector according to any one of claims 1 to 7 , encoding a MAGE cancer antigen or an immunogenic fragment thereof and a LAGE1 cancer antigen or an immunogenic fragment thereof.

(i) an immunogenic fragment of the MAGE cancer antigen and/or an immunogenic fragment of the NY-ESO-1 cancer antigen , or ( ii) encoding a MAGE cancer antigen or an immunogenic fragment thereof and/or a LAGE1 cancer antigen or an immunogenic fragment thereof, wherein said MAGE cancer antigen, NY-ESO-1 cancer antigen or LAGE1 cancer antigen 8. Any of claims 1-7, wherein at least one of which is a fragment and optionally said MAGE cancer antigen and NY-ESO-1 or MAGE cancer antigen and LAGE1 is an immunogenic fragment. of the MVA vector.

said MAGE cancer antigen and NY-ESO-1 or MAGE cancer antigen and LAGE1 is an immunogenic fragment ;
preferably a linker of 5-9 amino acids, which, when said polynucleotide sequence is expressed, links said MAGE and NY-ESO-1 or LAGE1 cancer antigens or fragments thereof in either order as a fusion protein; ChAd or MVA vector according to claim 8 or 9 , preferably encoding a linker with the amino acid sequence GGGPGGGG .

An immunogenic composition comprising a ChAd or MVA vector according to any one of claims 1-10 , optionally further comprising an adjuvant .

comprising a sequence encoding a ChAd vector according to any of claims 1-8 or 10 , or an MVA vector according to any of claims 3-7 or 9 or 10 , optionally for human codon usage An isolated polynucleotide that is codon optimized .

(a) (i) MAGE cancer antigen and/or NY-ESO-1 cancer antigen or immunogenic fragments thereof, or (ii) MAGE cancer antigen and/or LAGE1 cancer antigen or immunogenicity thereof a polynucleotide sequence encoding a fragment, said polynucleotide sequence being operably linked to an expression control sequence that directs translation, transcription and/or expression of said cancer antigen or fragment thereof in an animal cell; and a ChAd vector encapsidating a nucleic acid molecule comprising an adenovirus packaging signal sequence, or
(b) (i) MAGE cancer antigen and/or NY-ESO-1 cancer antigen or immunogenic fragment thereof, or (ii) MAGE cancer antigen and/or LAGE1 cancer antigen or immunogenic fragment thereof operably linked to an expression control sequence that directs translation, transcription and/or expression of said cancer antigen or fragment thereof in an animal cell MVA vector encapsidating a nucleic acid molecule
A bacterial artificial chromosome (BAC) clone comprising a polynucleotide comprising a sequence encoding

(a) the ChAd vector is according to any one of claims 2-8 or 10; or (b) the MVA vector is according to any one of claims 3-7, 9 or 10. 14. The BAC clone of claim 13, optionally wherein said polynucleotide sequence is optimized for human codon usage.

An isolated host cell comprising a ChAd and/or MVA vector according to any one of claims 1-10 .

Use of the ChAd vector according to any one of claims 1 , 2, 5-8, or 10 for the manufacture of a medicament for preventing or treating cancer .

Use of the MVA vector according to any one of claims 3-7, 9 or 10 for the manufacture of a medicament for preventing or treating cancer .

Use of a ChAd vector and an MVA vector for the manufacture of a medicament for the prevention or treatment of cancer , wherein said ChAd vector and MVA vector are administered separately, sequentially or simultaneously to a patient in need thereof administered ,
(a) said ChAd vector is characterized by: (i) MAGE cancer antigen and/or NY-ESO-1 cancer antigen or immunogenic fragments thereof; or (ii) MAGE cancer antigen and/or LAGE1 cancer antigen; polynucleotide sequences encoding immunogenic fragments thereof, operably linked to expression control sequences that direct translation, transcription, and/or expression of said cancer antigens or fragments thereof in animal cells; encapsidating a nucleic acid molecule comprising said polynucleotide sequence and an adenovirus packaging signal sequence, or
(b) said MVA vector is characterized by: (i) MAGE cancer antigen and/or NY-ESO-1 cancer antigen or immunogenic fragments thereof; or (ii) MAGE cancer antigen and/or LAGE1 cancer antigen or operably linked to expression control sequences that direct translation, transcription, and/or expression of said cancer antigen or fragment thereof in animal cells. The use of encapsidating a nucleic acid molecule comprising a polynucleotide sequence .

further comprising administration of one or more checkpoint inhibitors with said ChAd or MVA vector for the treatment of cancer , optionally wherein said checkpoint inhibitors are administered simultaneously, separately or in parallel with the vector 19. Use according to claim 18 , administered as

Use according to any of claims 16 to 18 , wherein said patient has undergone, is undergoing or is about to undergo chemotherapy and/or radiotherapy treatment.

(a) said ChAd vector is administered first, and/or
(b) said ChAd and MVA vectors are each administered more than once, and/or
(c) said ChAd and MVA vectors are administered alternately, and/or
( d) Use according to any of claims 18-20 , wherein the period between each administration of vector is in the range of 5 days to 8 weeks, preferably 3 weeks .

(a) the checkpoint inhibitor blocks PD-1, CTLA-4 or PD-L1, or
(b) the checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, tremelimumab or atezolizumab, durvalumab or avelumab.

The cancer is non-small cell lung cancer (NSCLC), melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, urinary tract (urothelium), bladder, small cell lung cancer, kidney, head and neck, sarcoma, or breast cancer The use according to any one of claims 19-21 .

Use of a ChAd vector, an MVA vector, a chemotherapeutic agent, and a checkpoint inhibitor in the manufacture of a medicament for the prevention or treatment of cancer, said ChAd vector, MVA vector, chemotherapeutic agent, and checkpoint inhibitor the inhibitor is for separate, sequential or simultaneous administration to a patient in need thereof ;
(a) said ChAd vector is characterized by: (i) MAGE cancer antigen and/or NY-ESO-1 cancer antigen or immunogenic fragments thereof; or (ii) MAGE cancer antigen and/or LAGE1 cancer antigen; polynucleotide sequences encoding immunogenic fragments thereof, operably linked to expression control sequences that direct translation, transcription, and/or expression of said cancer antigens or fragments thereof in animal cells; encapsidating a nucleic acid molecule comprising said polynucleotide sequence and an adenovirus packaging signal sequence, or
(b) said MVA vector is characterized by: (i) MAGE cancer antigen and/or NY-ESO-1 cancer antigen or immunogenic fragments thereof; or (ii) MAGE cancer antigen and/or LAGE1 cancer antigen or operably linked to expression control sequences that direct translation, transcription, and/or expression of said cancer antigen or fragment thereof in animal cells. The use of encapsidating a nucleic acid molecule comprising a polynucleotide sequence .

said chemotherapeutic agent is selected from (a) carboplatin or cisplatin in combination with (b) one of paclitaxel, docetaxel, vinorelbine, gemcitabine, etoposide or pemetrexed ;
(i) the checkpoint inhibitor is PD-1, and /or
(ii) the cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, urinary tract (urothelium), bladder, small cell lung cancer, kidney, head and neck 25. Use according to claim 24 , wherein the cancer is selected from cancer, sarcoma or breast cancer.