JP2020521447A - 天然キラー細胞による殺傷に対する腫瘍細胞の感受性を高めるための新規な腫瘍溶解性ウイルス - Google Patents
天然キラー細胞による殺傷に対する腫瘍細胞の感受性を高めるための新規な腫瘍溶解性ウイルス Download PDFInfo
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Abstract
Description
明細書および添付の特許請求の範囲で使用されているように、単数形「a」、「an」、および「the」は、文脈がそうでないことを明確に示さない限り、複数の指示対象を含む。したがって、例えば、「医薬担体」への言及には、2つ以上のそのような担体の混合物などが含まれる。
開示される組成物を調製するために使用される成分、ならびに本明細書に開示される方法内で使用される組成物自体が開示される。これらの資料およびその他の資料は、本書で開示され、これらの材料の組み合わせ、サブセット、相互作用、グループなどが開示されている場合、これらの化合物のさまざまな個々のおよび集合的な組み合わせおよび順列の具体的な参照は明示的に開示されていない可能性があるが、それぞれが本明細書で特に企図され、説明されていることが理解される。例えば、特定の腫瘍溶解性ウイルスまたは融合タンパク質が開示および議論され、腫瘍溶解性ウイルスおよび/または融合タンパク質を含む多数の分子に対して行うことができる多数の修飾が議論されている場合、特に意図されるのは、腫瘍溶解性ウイルスおよび/または融合タンパク質のありとあらゆる組み合わせおよび順列、および特に反対の指示がない限り可能な修飾である。したがって、分子のクラスA、B、およびCが開示されている場合、分子のクラスD、E、およびFと組み合わせ分子の例が開示されている場合、A−Dが開示され、その場合、それぞれが個別に列挙されていなくても、それぞれが個々におよび集合的に意味の組み合わせを意図している場合でも、A−E、A−F、B−D、B−E、B−F、C−D、C−E、およびC−Fは開示されているとみなされる。同様に、これらのサブセットまたは組み合わせも開示されている。したがって、例えば、A−E、B−F、およびC−Eのサブグループは開示されていると見なされる。この概念は、開示された組成物を作成および使用する方法のステップを含むがこれに限定されない、本出願のすべての態様に適用される。したがって、実行可能なさまざまな追加のステップがある場合、これらの追加のステップのそれぞれは、開示された方法の特定の実施形態または実施形態の組み合わせで実行できることが理解される。
上述のように、組成物は、薬学的に許容される担体とともにin vivoで投与することもできる。「薬学的に許容される」とは、望ましくない生物学的効果を引き起こすことがなく、有害な態様でそれが含まれる医薬組成物の他の成分と相互作用することのない、生物学的ではなく、またはその他の点で望ましくない点はない材料を意味する。すなわち、材料は、核酸またはベクターとともに対象に投与されてもよい。担体は、当業者によく知られているように、当然のことながら、活性成分の分解を最小限に抑え、対象における有害な副作用を最小限に抑えるように選択される。
抗体を含む組成物は、薬学的に許容される担体と組み合わせて治療的に使用することができる。したがって、一態様において、本明細書に開示されるのは、1つまたは複数の操作された腫瘍溶解性ウイルスおよび薬学的に許容される担体を含む医薬組成物であり、腫瘍溶解性ウイルスは、例えば、細胞内に面するアミノ末端に対して逆向きになるように改変された免疫グロブリンFcドメイン(例えば、IgG1、IgG2、IgG3、および/またはIgG4 Fcドメイン);から選択される外因性膜結合免疫細胞標的化リガンド;非切断シグナルアンカードメイン(例えば、ノイラミニダーゼ膜貫通セグメント)を含むNKG2Dリガンド(例えば、RAET1、RAET1E、RAET1G、RAET1H、RAET1L、RAET1N、MICA、および/またはMICB)および/またはCD19)を発現する。
組成物を投与するための有効な投与量およびスケジュールは経験的に決定することができ、そのような決定を行うことは当業者の範囲内である。
一態様では、本明細書に開示される腫瘍溶解性ウイルス(または当該ウイルスを含む組成物)は、養子移入されたNK細胞の投与の前に投与することができる。例えば、腫瘍溶解性ウイルスは、NK細胞の養子移入の1、2、3、4、5、6、7、8、9、10、11、12、18時間前、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、20、25、または30日前に投与し得、NK細胞が投与される前に、宿主免疫系が本明細書に開示される腫瘍溶解性ウイルスに応答することを可能にする。別の態様では、腫瘍溶解性ウイルスおよび養子移入されたNK細胞は、同じまたは異なる部位に同時に、または同時に投与することができる。別の態様では、NK細胞は、本明細書に開示される腫瘍溶解性ウイルスまたは当該ウイルスを含む任意の組成物の投与の1、2、3、4、5、6、7、8、9、10、11、12、18時間、1、2、3、4、5、6、7、8、9、10、11、12、13、14、21、28、または30日前に投与され得る。腫瘍溶解性ウイルスの前または後に投与する場合、NK細胞は同じ部位または異なる部位に投与することができる。
腫瘍溶解性ウイルスは、癌の治療のための効果的な治療薬であることが当技術分野で示されている。ウイルスは、出口で感染した癌細胞を溶解し、癌細胞の感染も宿主の免疫応答を刺激して感染細胞を殺す。開示された操作されたウイルスおよび/または融合ペプチド、ポリペプチド、またはタンパク質は同様に癌の治療に有用であり、そのような腫瘍溶解性ウイルスの効力を改善してNK細胞を感染癌細胞に補充することが理解され、本明細書で企図される。したがって、一態様では、膜結合免疫細胞標的化リガンド(例えば、免疫グロブリンFcドメイン(例えば、細胞内に面したアミノ末端に対して逆方向を有するIgG1、IgG2、IgG3、および/またはIgG4 Fcドメイン)を含む1つまたは複数のペプチド、ポリペプチド、またはタンパク質を発現する開示された腫瘍溶解性ウイルス;NKG2Dリガンド(例えば、RAET1、RAET1E、RAET1G、RAET1H、RAET1L、RAET1N、MICA、および/またはMICB)、および/またはCD19)および非切断シグナルアンカードメインおよび/または融合ペプチド、ポリペプチド、または膜結合免疫細胞標的化リガンドと非切断シグナルアンカードメインを含むタンパク質が、癌の治療に使用できる。一態様において、操作された腫瘍溶解性ウイルスは、融合ペプチド、ポリペプチド、またはタンパク質を含むように改変され得る。1つまたは複数の外因性膜結合免疫細胞標的化リガンドが免疫グロブリンFcドメインである場合、Fcドメインは、そのN末端側が細胞膜の表面近くの膜アンカーペプチドに付着した状態で、細胞表面の細胞外側に発現するように改変できることが理解される。
以下の実施例は、本明細書で特許請求される化合物、組成物、物品、デバイスおよび/または方法の完全な開示および説明を当業者に提供するために提示されるものであり、また、純粋に例示的なものであり、本開示を限定するものではありません。数値(例えば、量、温度など)に関して正確性を確保するための努力がなされてきたが、いくつかの誤差と偏差は考慮されるべきである。特に指定のない限り、部は重量部であり、温度は℃または周囲温度であり、圧力は大気圧または大気圧に近い。
Claims (47)
- 非切断シグナルアンカーを含む1つまたは複数の外因性膜結合免疫細胞標的化リガンドを発現する、操作された腫瘍溶解性ウイルス。
- 前記腫瘍溶解性ウイルスが融合性の腫瘍溶解性ウイルスである、請求項1に記載の操作された腫瘍溶解性ウイルス。
- 前記融合性の腫瘍溶解性ウイルスが改変または操作されたパラインフルエンザウイルス5型である、請求項2に記載の操作された腫瘍溶解性ウイルス。
- 前記融合性の腫瘍溶解性ウイルスが腫瘍細胞の融合を可能にする高融合性特性を可能にするペプチドをコードする遺伝子を含む、請求項2に記載の操作された腫瘍溶解性ウイルス。
- 前記非切断シグナルアンカーがノイラミニダーゼ膜貫通セグメントである、請求項1に記載の操作された腫瘍溶解性ウイルス。
- 前記1つまたは複数の外因性膜結合免疫細胞標的化リガンドが操作された免疫グロブリンFcドメインを含み、
前記免疫グロブリンFcドメインは、細胞内に面するアミノ末端に対して逆向きになるように改変されている、請求項1に記載の操作された腫瘍溶解性ウイルス。 - 前記免疫グロブリンFcドメインがIgG1 Fcドメインを含む、請求項6に記載の操作された腫瘍溶解性ウイルス。
- 前記IgG1 FcドメインがFcR結合またはADCCを増加させるための変更をさらに含む、請求項6に記載の操作された腫瘍溶解性ウイルス。
- 前記1つまたは複数の外因性膜結合免疫細胞標的化リガンドは、NK細胞受容体NKG2Dのタンパク質アゴニストを含む、請求項1に記載の操作された腫瘍溶解性ウイルス。
- 前記1つまたは複数の外因性膜結合免疫細胞標的化リガンドは、抗CD19に反応性のタンパク質エピトープ領域を含む、請求項1に記載の操作された腫瘍溶解性ウイルス。
- 前記1つまたは複数の外因性膜結合免疫細胞標的化リガンドがCD19またはCD20である、請求項1に記載の操作された腫瘍溶解性ウイルス。
- 前記腫瘍溶解性ウイルスが、IL−12、IL−21またはIL−15のうちの1つまたは複数を発現するように操作されている、請求項1に記載の操作された腫瘍溶解性ウイルス。
- 請求項1に記載の操作された腫瘍溶解性ウイルスおよび薬学的に許容される担体を含む医薬組成物。
- 請求項1に記載の操作された腫瘍溶解性ウイルスを対象に投与することを含む、癌の治療方法。
- 前記対象に、ナチュラルキラー(NK)細胞、前記1つまたは複数の外因性膜結合免疫細胞標的化リガンドの1つもしくは複数を標的とする抗体、または、前記1つまたは複数の外因性膜結合免疫細胞の1つもしくは複数を標的とするように設計されたCAR T細胞を養子移入することをさらに含む、請求項14に記載の方法。
- 対象に、操作された腫瘍溶解性ウイルスを投与することを含む、癌の治療方法であって、
前記腫瘍溶解性ウイルスが非切断シグナルアンカーを含む1つまたは複数の外因性膜結合免疫細胞標的化リガンドを発現する、方法。 - 前記1つまたは複数の膜結合免疫細胞標的化リガンドは、操作された免疫グロブリンFcドメインを含み、
前記免疫グロブリンFcドメインが、細胞内に面するアミノ末端に対して逆向きになるように改変されている、請求項16に記載の方法。 - 前記1つまたは複数の膜結合免疫細胞標的化リガンドは、NK細胞受容体NKG2Dのタンパク質アゴニストを含む、請求項16に記載の方法。
- 前記方法が免疫細胞を養子移入することをさらに含む、請求項16に記載の方法。
- 前記養子移入された免疫細胞がナチュラルキラー(NK)細胞である、請求項19に記載の方法。
- 前記NK細胞は、1つまたは複数のNK細胞刺激剤で刺激および増殖される、請求項20に記載の方法。
- 前記1つまたは複数のNK細胞刺激剤は、サイトカイン、成長因子、合成リガンド、NK細胞刺激粒子、NK細胞刺激エキソソーム、またはNK細胞刺激フィーダー細胞である、請求項21に記載の方法。
- 前記1つまたは複数のNK細胞刺激剤は、NK細胞刺激粒子、NK細胞刺激エキソソーム、またはNK細胞刺激フィーダー細胞であり、
前記1つまたは複数の剤は、IL−21、4−1BBL、またはその断片を含む、請求項22に記載の方法。 - 前記1つまたは複数のNK細胞刺激剤は、IL−2、IL−12、IL−18、IL−15またはそれらの組み合わせからなる群から選択される少なくとも1つのサイトカインを含む、請求項22記載の方法。
- 前記NK細胞が、CD19標的化抗CD19キメラ抗原受容体またはCD20標的化抗CD20キメラ抗原受容体を発現するように操作される、請求項20に記載の方法。
- 前記免疫細胞が、操作されたCD19標的化抗CD19 CAR−T細胞または操作されたCD20標的化抗CD20 CAR−T細胞である、請求項19に記載の方法。
- 前記免疫細胞が、前記1つまたは複数の外因性膜結合免疫細胞標的化リガンドに特異的な抗体である、請求項19に記載の方法。
- 前記癌は、白血病、リンパ腫、骨髄腫、黒色腫、結腸直腸癌、乳癌、卵巣癌、腎細胞癌、悪性黒色腫、悪性神経膠腫、神経芽細胞腫、非小細胞肺癌、腎細胞癌、メルケル細胞癌、皮膚癌、脳癌、膵臓腺癌、悪性中皮腫、肺腺癌、肺小細胞癌、肺扁平上皮癌、甲状腺未分化癌、または頭頸部扁平上皮癌からなる群から選択される、請求項16に記載の方法。
- 前記NK細胞が遺伝子改変されている、請求項20に記載の方法。
- 細胞質尾部領域、膜貫通領域、および細胞外ストーク領域;並びに前記細胞外ストーク領域のC末端に融合したN末端を含む免疫細胞標的化リガンド、を含む非切断シグナルアンカードメインを含む、融合タンパク質。
- 前記免疫細胞標的化リガンドは、NK細胞、B細胞、T細胞およびCAR−T細胞からなる群から選択される免疫細胞に結合することができる、請求項30に記載の融合タンパク質。
- 前記免疫細胞標的化リガンドが、アミノ酸修飾を含む免疫グロブリンFcドメインを含み、前記Fcドメインの前記N末端が前記細胞外ストークドメインの前記C末端に融合する、請求項30に記載の融合タンパク質。
- 前記免疫細胞標的化リガンドが、IgG1、IgG2、IgG3、およびIgG4からなる群より選択される免疫グロブリンFcドメインを含む、請求項30に記載の融合タンパク質。
- 前記Fcドメインが、256A/K290A/S298A/E333A/K334AまたはL235V/F243L/R292P/Y300L/P396Lからなる群より選択される少なくとも1つのアミノ酸修飾をさらに含む、請求項33に記載の融合タンパク質。
- 前記非切断シグナルアンカードメインは、ノイラミニダーゼ、パラインフルエンザウイルス血球凝集素−ノイラミニダーゼ、トランスフェリン受容体、MHCクラスII不変鎖、P糖タンパク質、アシアロ糖タンパク質受容体、および中性エンドペプチダーゼのシグナルアンカードメインから選択されるシグナルアンカードメインを含む、請求項30に記載の融合タンパク質。
- 前記非切断シグナルアンカードメインがノイラミニダーゼシグナルアンカードメインを含む、請求項30に記載の融合タンパク質。
- 前記標的化リガンドが、免疫グロブリンFcドメイン、NK2GDリガンド、および抗リガンドドメインからなる群から選択される、請求項30に記載の融合タンパク質。
- 前記標的化リガンドが、RAET1、RAET1E、RAET1G、RAET1H、RAET1L、RAET1N、MICA、およびMICBから選択されるNK2GDリガンドである、請求項30に記載の融合タンパク質。
- 前記標的化リガンドが、CD19およびCD20から選択される抗リガンドドメインである、請求項30に記載の融合タンパク質。
- 配列番号1のアミノ酸配列と少なくとも95%の配列同一性を有するアミノ酸配列を含む、請求項30に記載の融合タンパク質。
- 請求項40に記載の融合タンパク質をコードするポリヌクレオチド配列。
- 請求項40に記載のポリヌクレオチドを含む改変ウイルスゲノムを含む宿主ウイルス。
- 前記宿主ウイルスが腫瘍溶解性ウイルスである、請求項42に記載の宿主ウイルス。
- 前記宿主ウイルスが、パラインフルエンザウイルス5型、CPIパラインフルエンザ、野生型パラインフルエンザ、CPIおよびWTパラインフルエンザ由来のP/Vをコードするウイルス骨格を有するCPI−WTパラインフルエンザキメラウイルス、アデノウイルス、アデノ随伴ウイルス、ヘルペスウイルス、ポックスウイルス、レオウイルス、ピコルナウイルス、トガウイルス、コロナウイルス、フラビウイルス、フィロウイルス、アレナウイルス、ブンヤウイルス、パラミクソウイルス、ラブドウイルス、ニューモウイルス、オルソミクソウイルス、デルタウイルス、レトロウイルス、ヘパドナウイルス、オルソヘペウイルス、ヒトパピローマウイルス、ポリオーマウイルス、HSV−1腫瘍溶解性ウイルスHSV1716、タリモジーン・ラハーパレプベック、アデノウイルス腫瘍溶解性ウイルスH101、ポリオウイルス腫瘍溶解性ウイルスPVSRIPO、レオウイルス腫瘍崩壊性ウイルスレオシリン、セネカバレーウイルスSVV−001、コクサッキーウイルス腫瘍溶解性ウイルスコクサッキーウイルスA21、エンテロウイルス腫瘍溶解性ウイルスリガウイルス、およびワクシニアウイルス腫瘍溶解性ウイルスGL−ONC1、またはJX−594、から選択される、請求項42に記載の宿主ウイルス。
- 前記宿主ウイルスが細胞融合性の腫瘍溶解性ウイルスである、請求項42に記載の宿主ウイルス。
- 癌免疫療法のために免疫細胞を癌細胞に標的化する方法であって、請求項41のポリヌクレオチドを含む改変腫瘍溶解性ウイルスを得て、前記細胞を前記改変腫瘍溶解性ウイルスと接触させることを含む、方法。
- 請求項41のポリヌクレオチドをウイルスゲノムに挿入することにより前記腫瘍溶解性ウイルスを改変することをさらに含む、請求項46に記載の方法。
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