JP6854765B2 - 標的への抗癌剤の送達を増加させる方法 - Google Patents
標的への抗癌剤の送達を増加させる方法 Download PDFInfo
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- JP6854765B2 JP6854765B2 JP2017537509A JP2017537509A JP6854765B2 JP 6854765 B2 JP6854765 B2 JP 6854765B2 JP 2017537509 A JP2017537509 A JP 2017537509A JP 2017537509 A JP2017537509 A JP 2017537509A JP 6854765 B2 JP6854765 B2 JP 6854765B2
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- Medicinal Preparation (AREA)
Description
本明細書で使用される「組成物」という用語は、特定の量の特定の成分を含む製品、ならびに、特定の量の特定の成分の組合せから直接的または間接的に由来する任意の製品をも包含することが意図される。薬学的組成物または他の組成物に関するこのような用語は、一般的に、活性成分と担体を構成する不活性成分とを含む製品、ならびに、二以上の任意の成分の組み合わせ、錯体化もしくは凝集、一または複数の成分の解離、または、一または複数の成分の他の種類の反応または相互作用に直接的または間接的に由来する任意の製品をも包含することを意図する。したがって、本発明の一般的な医薬組成物または他の組成物は、本発明の化合物と薬学的に許容される担体とを混合することにより製造される任意の組成物を包含する。「薬学的に許容可能な」または「許容可能な」とは、担体、希釈剤または賦形剤は、配合物の他の成分と相溶性でなければならず、そのレシピエントにとって有害であってはならないことを意味する。
このような薬学的担体は、落花生油、大豆油、鉱油、ゴマ油等といった、石油、動物、植物、または合成由来のものを含む、水および油等の無菌液体であり得る。医薬組成物が静脈内投与される場合、水が好ましい担体である。生理食塩水およびデキストロース水溶液およびグリセロール溶液は、液体担体、特に注射可能な溶液としても使用することができる。好適な薬学的賦形剤には、デンプン、グルコース、ラクトース、スクロース、ゼラチン、麦芽、米、小麦粉、チョーク、シリカゲル、ステアリン酸ナトリウム、グリセロールモノステアレート、タルク、塩化ナトリウム、乾燥スキムミルク、グリセリン、プロピレン、グリコール、水、エタノール等が含まれる。組成物は、必要に応じて、少量の湿潤剤もしくは乳化剤、またはpH緩衝剤を含むこともできる。これらの組成物は、溶液剤、懸濁剤、乳剤、錠剤、丸剤、カプセル剤、散剤、徐放性製剤等の形態をとることができる。組成物は、伝統的な結合剤およびトリグリセリドのような担体を用いて、坐薬として処方することができる。経口製剤は、医薬品等級のマンニトール、ラクトース、澱粉、ステアリン酸マグネシウム、サッカリンナトリウム、セルロース、炭酸マグネシウム等の標準的な担体を含むことができる。適切な医薬担体の例は、E.W.Martin著の“Remington's Pharmaceutical Sciences”に記載されている。このような組成物は、患者への適切な投与のための形態を提供するために、好ましくは精製形態で、適切な量の担体と共に、治療上有効な量の抗体またはそのフラグメントを含有する。処方は、投与方法に適合させるべきである。
一実施形態によれば、本発明の組成物および方法は、癌細胞、特に固形腫瘍に関連する癌細胞への抗癌剤の送達を増加させるために使用することができ、ここで、この方法は、治療有効量の少なくとも1つのIgE抗体および少なくとも1つの抗癌剤の被験体への共投与の工程を含む。抗癌剤およびIgE抗体は、別々の、または、組み合わせた製剤のいずれかで同時に、または、異なる時間に、任意の順序で、数分、数時間、数日または数週間の間隔でよいが、何らかの方法で共同に作用して望ましい治療反応を提供するようにして、連続的に投与することができる。
抗体4H5.hIgEは、配列番号:3の核酸によってコードされる重鎖可変領域、および配列番号:4の核酸によってコードされる軽鎖可変領域を有し、これらはヒトIgカッパ軽鎖およびイプシロン重鎖に移植される。
本組成物の、注射のための希釈技術を含む、医薬組成物を投与するための実際の方法および手順は、当業者にとって周知であるか、または明らかであろう。
特定の科学的理論に限定されるものではないが、IgE抗体は、間質浸透性を増加すること、および/または腫瘍周囲の間質の枯渇することができるが、これに限定されず、腫瘍微小環境を調節することができると考えられる。間質サイズの減少および/または間質浸透性の増加は、腫瘍の治療における化学療法および/または放射線療法の有効性を増強し、それによって疾患を効果的に治療するために必要な化学療法および/または放射線の量を減少させることが示されている。いかなる理論にも限定されるものではないが、本発明の間質調節量のIgE抗体は、腫瘍間質等の腫瘍または腫瘍の近傍および腫瘍の微小環境にある抗原と結合することで過敏症反応を指令し、肥満細胞、好塩基球、マクロファージおよび好酸球を含むエフェクター細胞を腫瘍箇所にもたらし、被験体において全身性過敏症および/またはアナフィラキシーを起こすことなく、局所の細胞活性化を伴う局所アレルギー性炎症反応を誘導することができると考えられる。
当業者は、日常的な実験方法のみを用いて、本明細書に記載された本発明の特定の実施形態に対する多くの均等物を認識するか、または確認することができる。そのような均等物は、添付の特許請求の範囲によって包含されることが意図される。
以下の実施例は、本発明の特に好ましい特定の実施形態をさらに説明することを意図しており、本発明の範囲を限定するものではない。
(実施例1)
<膵臓癌の皮下腫瘍モデルにおける抗MUC1−IgE抗体の血管浸透性の検討>
ヒトMUC1遺伝子を遺伝子導入したPanc02腫瘍細胞株(hMUC1−panc02)を選択する。
panc02腫瘍はBL6マウスと同系であり、hMUC1−panc02はヒトMUC1を遺伝子導入したBL6.Tgマウスと完全に同系である。
実証実験に使用される抗体は、上記の抗MUC1−IgE抗体:3C6.hIgEである。
(実施例2)
<MUC1−PANC02腫瘍におけるマスト細胞およびニュートロフィル染色>
次に、肥満細胞による腫瘍への浸潤を、腫瘍組織においてトルイジンブルー染色を行うことによって評価する。対照的に、ヘマトキシリンおよびエオシン染色を、腫瘍組織切片における好中球(多葉核細胞)の浸潤の測定に使用した。図5は、0時間後では、マスト細胞は腫瘍組織中に観察され得ないが、注射後4時間後では、マスト細胞の出現が検出され得、これは注射後8時間にピークを示し、注射後少なくとも24時間は残存した。これらの結果は、注射後に腫瘍に動員されたマスト細胞の数が増加していることを示している。一方、図6は、注射後の腫瘍における好中球の数に著しいな変化がなかったことを示す。
(実施例3)
<抗腫瘍応答の増強能力>
[配列表]
配列番号:1
<120>3C6.HIgE 重鎖可変領域
<212>DNA
GCCGCCACCATGTACTTGGGACTGAACTGTGTATTCATAGTTTTTCTCTTAAATGGTGTCCAGAGTGAAGTGAAGCTTGAGGAGTCTGGAGGAGGCTTGGTGCAACCTGGAGGATCCATGAAACTCTCTTGTGCTGCCTCTGGATTCACTTTTAGTGACGCCTGGATGGACTGGGTCCGCCAGTCTCCAGAGAAGGGGCTTGAGTGGGTTGCTGAAATTAGAAGCAAAGCTAATAATCATGCAACATACTATGCTGAGTCTGTGAAAGGGAGGTTCACCATCTCAAGAGATGTTTCCAAAAGTAGTGTCTACCTGCAAATGAACAACTTAAGAGCTGAAGACACTGGCATTTATTACTGTACCAGGGGGGGGTACGGCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGGTAAGTG
配列番号:2
<120>3C6.hIgE 軽鎖可変領域
<212>DNA
GCCGCCACCATGAAGTTGCCTGTTAGGCTGTTGGTGCTGATGTTCTGGATTCCTGCTTCCAGCAGTGATGTTTTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCATTGTACATAGTAATGGAAACACCTATTTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGCTTTCAAGGTTCACATGTTCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAACGTAAGT
配列番号:3
<120>4H5.hIgE モノクローナル抗体重鎖可変領域
<212>DNA
GCCGCCACCATGGGATGGAGCTGTATCATGCTCTTTTTGGTAGCAACAGCAACAGGTGTCCACTCCCAGGTCCAACTGCAGCAGTCTGGGGCTGAACTGGTGAAGCCTGGGGCTTCAGTGAAGTTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAGCTACTATATGTACTGGGTGAAGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGAGAGATTAATCCTAGCAATGGTGGTACTGACTTCAATGAGAAGTTCAAGAGCAAGGCCACACTGACTGTAGACAAATCCTCCAGCACAGCATACATGCAACTCAGCAGCCTGACATCTGCGGACTCTGCGGTCTATTACTGTACAAGGGGGGGTGATTACCCCTGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGGTAAGT
配列番号:4
<120>4H5.hIgE モノクローナル抗体重鎖可変領域
<212>DNA
GCCGCCACCATGGATTCACAGGCCCAGGTTCTTATGTTACTGCTGCTATGGGTATCTGGTACCTGTGGGGACATTGTGATGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAAGGTTACTATGAGCTGCAAGTCCAGTCAGAGCCTTTTATATAGTAGCAATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGGCAGTCTCCTAAACTGCTGATTTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGAAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAATATTATAGCTATCCTCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAACGTAAGT
配列番号:5
<120>MUC1エピトープのアミノ酸配列
<212>アミノ酸
STAPPAHGVTSAPDTRPAPG
Claims (31)
- 腫瘍の間質内またはその周囲に存在する癌抗原に特異的な少なくとも1つの治療用IgE抗体の有効量を、抗癌剤の投与の前に、それを必要とする被験体における固形腫瘍周囲の間質の浸透性を増加させるための薬剤の調製のために使用する方法であって、
前記IgE抗体が、MUC1に特異的な抗体であり、
前記治療用IgE抗体を含む前記薬剤は、前記抗癌剤の投与の少なくとも4時間から2週間前に投与されるためのものであり、
前記間質周囲の浸透性の増加により、前記薬剤を投与しない場合と比較して、投与される前記抗癌剤の量の減少がもたらされる、方法。 - 前記IgE抗体が、癌抗原、腫瘍の微小環境に関連する抗原、または腫瘍間質に関連する抗原に特異的である、請求項1に記載の方法。
- 前記抗癌剤が、抗腫瘍剤、免疫療法剤、放射線、光増感剤、遺伝子治療剤およびそれらの組み合わせから選択される、請求項1に記載の方法。
- 前記腫瘍が固形腫瘍である、請求項1〜3のいずれか1項に記載の方法。
- 前記腫瘍が固形腫瘍であり、前記抗癌剤が抗腫瘍剤であり、浸透性の増加が腫瘍または腫瘍間質における異なるサイズのポリデキストランの取り込みの増加によって測定される、請求項1〜4のいずれか1項に記載の方法。
- 前記腫瘍が固形腫瘍であり、前記抗癌剤が免疫療法剤であり、浸透性の増加が腫瘍または腫瘍間質における浸潤性リンパ球の存在の増加によって測定される、請求項1〜4のいずれか1項に記載の方法。
- 前記腫瘍が固形腫瘍であり、前記抗癌剤が放射線であり、浸透性の増加が、画像診断によって測定される腫瘍の大きさの減少によって測定される、請求項1〜4のいずれか1項に記載の方法。
- 前記腫瘍が固形腫瘍であり、前記抗癌剤が遺伝子治療剤であり、浸透性の増加が、腫瘍の微小環境における腫瘍内の免疫反応の増加によって測定される、請求項1〜4のいずれか1項に記載の方法。
- MUC1に特異的な前記抗体が、配列番号:5から選択されるMUC1のエピトープに結合する、請求項1に記載の方法。
- MUC1に特異的な前記抗体の重鎖可変領域が配列番号:1を含む核酸によってコードされ、MUC1に特異的な前記抗体の軽鎖可変領域が配列番号:2を含む核酸によってコードされる、請求項1に記載の方法。
- MUC1に特異的な抗体の重鎖可変領域が配列番号:3を含む核酸によってコードされ、MUC1に特異的な抗体の軽鎖可変領域が配列番号:4を含む核酸によってコードされる、請求項1に記載の方法。
- MUC1に特異的な前記抗体が、mAb 3C6.hIgE、mAb 4H5.hIgEまたはそれらの組み合わせである、請求項1に記載の方法。
- 前記腫瘍が、膵臓癌、胃癌、結腸直腸癌、卵巣癌、乳癌または肺癌である、請求項1に記載の方法。
- 前記腫瘍がインビボまたはインビトロである、請求項1に記載の方法。
- 前記間質周囲の浸透性の増加により、a)抗癌剤の治療指数の増加;b)抗癌剤の少なくとも1つの副作用の改善;c)腫瘍間質の浸透性の増加;および、d)腫瘍間質の枯渇がもたらされる、請求項1に記載の方法。
- 抗癌剤の投与の前に、それを必要とする被験体において腫瘍周囲間質の浸透性を増加させることにより癌を治療するための医薬品であって、腫瘍の間質内またはその周囲に存在する癌抗原に特異的な少なくとも1つのIgE抗体の有効量を含む医薬品であって、
前記IgE抗体が、MUC1に特異的な抗体であり、
前記治療用IgE抗体を含む前記医薬品は、前記抗癌剤の投与の少なくとも4時間から2週間前に投与されるためのものであり、
前記間質周囲の浸透性の増加により、前記医薬品を投与しない場合と比較して、投与される前記抗癌剤の量の減少がもたらされる、医薬品。 - 薬学的に許容される賦形剤をさらに含む請求項16に記載の医薬品。
- 前記IgE抗体が、癌抗原、腫瘍の微小環境に関連する抗原または腫瘍間質に関連する抗原に特異的である、請求項16に記載の医薬品。
- 前記抗癌剤が、抗腫瘍剤、免疫療法剤、放射線、光増感剤、遺伝子治療剤およびそれらの組み合わせから選択される、請求項16〜18のいずれか1項に記載の医薬品。
- 前記腫瘍が固形腫瘍である、請求項16〜19のいずれか1項に記載の医薬品。
- 前記腫瘍が固形腫瘍であり、前記抗癌剤が抗腫瘍剤であり、浸透性の増加が腫瘍または腫瘍間質における異なるサイズのポリデキストランの取り込みの増加によって測定される、請求項16〜19のいずれか1項に記載の医薬品。
- 前記腫瘍が固形腫瘍であり、前記抗癌剤が免疫療法剤であり、浸透性の増加が腫瘍または腫瘍間質中の浸潤性リンパ球の存在の増加によって測定される、請求項16〜19のいずれか1項に記載の医薬品。
- 前記腫瘍が固形腫瘍であり、前記抗癌剤が放射線であり、浸透性の増加が、画像診断によって測定される腫瘍の大きさの減少によって測定される、請求項16〜19のいずれか1項に記載の医薬品。
- 前記腫瘍が固形腫瘍であり、前記抗癌剤が遺伝子治療剤であり、浸透性の増加が、腫瘍内の微小環境おける免疫反応の増加によって測定される、請求項16〜19のいずれか1項に記載の医薬品。
- 前記MUC1に特異的な前記抗体が、配列番号:5から選択されるMUC1のエピトープに結合する、請求項16に記載の医薬品。
- MUC1に特異的な抗体の重鎖可変領域が配列番号:1を含む核酸によってコードされ、MUC1に特異的な抗体の軽鎖可変領域が配列番号:2を含む核酸によってコードされる、請求項16に記載の医薬品。
- MUC1に特異的な抗体の重鎖可変領域が配列番号:3を含む核酸によってコードされ、MUC1に特異的な抗体の軽鎖可変領域が配列番号:4を含む核酸によってコードされる、請求項16に記載の医薬品。
- 前記MUC1に特異的な抗体が、mAb 3C6.hIgE、mAb 4H5.hIgEまたはそれらの組み合わせである、請求項16に記載の医薬品。
- 前記腫瘍が、膵臓癌、胃癌、結腸直腸癌、卵巣癌、乳癌または肺癌である、請求項16〜28のいずれか1項に記載の医薬品。
- 前記腫瘍がインビボまたはインビトロである、請求項16〜29のいずれか1項に記載の医薬品。
- 前記間質周囲の浸透性の増加により、a)抗癌剤の治療指数の増加;b)抗癌剤の少なくとも1つの副作用の改善;c)腫瘍間質の浸透性の増加;および、d)腫瘍間質の枯渇がもたらされる、請求項16に記載の医薬品。
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