JP7125760B2 - 免疫系を賦活化する細胞および当該細胞を含む医薬組成物 - Google Patents
免疫系を賦活化する細胞および当該細胞を含む医薬組成物 Download PDFInfo
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Description
(1)ヒトパピローマウイルスの初期遺伝子E6タンパク質およびE7タンパク質並びにE6タンパク質とE7タンパク質との融合タンパク質から選択される少なくとも1つのタンパク質とCD1dタンパク質を発現させた哺乳動物細胞であって、CD1dリガンドによってパルスされた細胞。
(2)ヒトパピローマウイルスの初期遺伝子E6タンパク質およびE7タンパク質を別々のタンパク質として発現させた、上記(1)に記載の細胞。
(3)ヒトパピローマウイルスの初期遺伝子E6タンパク質およびE7タンパク質を融合タンパク質として発現させた、上記(2)に記載の細胞。
(4)融合タンパク質が、E7タンパク質、E6タンパク質、およびE7タンパク質をこの順番で含む融合タンパク質である、上記(3)に記載の細胞。
(5)E7タンパク質、E6タンパク質、およびE7タンパク質をこの順番で含む融合タンパク質。
(6)E7タンパク質、E6タンパク質、およびE7タンパク質をこの順番で含む融合タンパク質をコードする核酸。
(7)E7タンパク質、E6タンパク質、およびE7タンパク質をこの順番で含む融合タンパク質をコードする核酸を含む、当該融合タンパク質の発現ベクター。
(8)上記(1)~(4)のいずれかに記載の細胞、上記(5)に記載の融合タンパク質、上記(6)に記載の核酸、または上記(7)に記載のベクターを含む、医薬組成物。
(9)ヒトパピローマウイルスに感染したヒト対象に投与するための、上記(8)に記載の医薬組成物。
(10)ヒト対象が、ヒトパピローマウイルスに起因するがんを有する、上記(9)に記載の医薬組成物。
(11)ヒトパピローマウイルスに起因するがんが、子宮頸がん、肛門がん、および膣がんからなる群から選択されるがんである、上記(10)に記載の医薬組成物。
ここで、E6-E7融合タンパク質のアミノ酸配列の一例は、配列番号5~8のいずれかに示される。また、E7-E6融合タンパク質のアミノ酸配列の一例は、配列番号9~12のいずれかに示される。また、E6-E7-E6融合タンパク質のアミノ酸配列の一例は、配列番号13~20に示される。また、E7-E6-E7融合タンパク質のアミノ酸配列の一例は、配列番号21~28に示される。これらの融合タンパク質は、細胞内で発現しさえすれば、樹状細胞に貪食された際に樹状細胞内で小さなペプチドに分解され、これによりHPVに対する免疫系が誘導されると考えられる。したがって、適宜、融合タンパク質におけるタンパク質間の連結部にはリンカーが導入されていてもよい。
本発明によれば、抗原であるE6タンパク質とE7タンパク質との融合タンパク質を発現するaAVCは、NKT細胞を誘導し、抗腫瘍効果を奏する。従って、本発明によれば、E6タンパク質とE7タンパク質との融合タンパク質を発現するaAVC、当該aAVCを含む医薬組成物、および当該aAVCを含む、がんを処置することに用いるための医薬組成物が提供される。
ヒトパピローマウイルス(HPV)の各種ウイルスタンパク質を発現したHEK293株を調製し、α-GalCerを用いてパルスした。
図2のパネルAに示されるように、マウスに対して実施例1で得られた細胞を静脈内投与し、3日後に当該マウス体内における免疫応答を調べた。
本実施例では、実施例2で調製した細胞を肺転移モデル動物に移植して、その抗腫瘍効果を検討した。
B16メラノーマ細胞をPBSで3×105/200μlに調製し、マウス(C57BL/6,6~8週,雌)に尾静脈より静脈内投与した。これに対して、メラノーマ細胞の投与後3~6時間後に実施例2で調製した細胞を静脈内投与した。対照群としては、PBSを投与した。投与群1には、実施例2に準じてNIH3T3細胞を用いて調製したE6発現細胞を投与した。投与群2には、実施例2で調製したE7発現細胞を投与した。2週間後にマウスから肺を取り出し、B16の肺転移を観察した。結果は、図3に示される通りであった。
本発明では、E6とE7との融合タンパク質を調整し、HEK293細胞において発現させた。融合タンパク質は、実施例1に記載された通りにmRNAとして細胞に導入した。導入4時間後に細胞を回収し、細胞溶解物を得て、ウェスタンブロット法によってタンパク質の発現量を確認した。抗体は、図4では、抗E6抗体を用い、図5では、抗E7抗体を用いた。図1と同様に、ウェスタンブロット法で各々のタンパクを検出し、画像としてコンピュータに取り込み、画像解析ソフトImage Reader LAS-1000 proを用いて分析した。発現量は、指定された量のE6標品またはE7標品のバンドの濃さから検量線を作製し、評価したい各バンドの濃さを評価することによって求めた。結果は、各々の単独発現細胞の発現量を1とし、それに対する比として図4および5に示した。
図4および5において、#1~#6は以下細胞の溶解物に対応する。
#1:E6発現HEK293細胞
#2:E7発現HEK293細胞
#3:E6-E7発現HEK293細胞
#4:E6-E7-E6発現HEK293細胞
#5:E7-E6-E7発現HEK293細胞
#6:E7-E6発現HEK293細胞
実施例3と同様の方法を用いて、B16メラノーマ細胞(3×105細胞)を移植することによって作製した肺転移モデル動物(n=5)に実施例4で調製したE7-E6-E7発現HEK293細胞(5×105細胞)を移植して、その抗腫瘍効果を検討した。結果は図6に示される通りであった。図6に示されるように、対照群では、メラノーマ細胞の肺転移が強く観察され、肺全体がメラノーマ細胞により黒色を呈するのに対して、E7-E6-E7投与群では、メラノーマ細胞に起因する黒色がほとんど認められなかった。このことから、実施例で作製したE7-E6-E7発現細胞は、自然免疫系を賦活化して抗腫瘍効果を発揮することができることが明らかとなった。
マウスに実施例4で調製したE7-E6-E7発現HEK293細胞(5×105細胞;aAVC-E7-6-7)を投与し、7日後に脾臓からCD8単独陽性T細胞(5×105細胞)を取りだし、当該細胞をE6又はE7ペプチドを添加した樹状細胞(1×105細胞)で24時間刺激した際の細胞からのIFN-γ産生CD8T細胞数(スポット数)をELISPOTアッセイを用いて調べた。このIFN-γの産生は、通常キラーT細胞の殺傷効果機能と相関するとされ、このサイトカン産生測定が広く用いられている。結果は図7に示される通りであった。図7に示されるように、E7-E6-E7投与群では、E6特異的およびE7特異的に反応し、IFN-γを産生するCD8T細胞が検出された。このことから、E7-E6-E7を発現するaAVCは、E6及びE7特異的キラーT細胞を誘導することが明らかとなった。
Claims (10)
- ヒトパピローマウイルスの初期遺伝子E6タンパク質とE7タンパク質との融合タンパク質とCD1dタンパク質を発現する哺乳動物細胞であって、CD1dリガンドによってパルスされた細胞であり、
前記融合タンパク質が、E7タンパク質、E6タンパク質、およびE7タンパク質からなり、E7タンパク質、E6タンパク質、およびE7タンパク質をこの順番で含む融合タンパク質である、細胞。 - ヒト細胞またはヒト細胞株である、請求項1に記載の細胞。
- ヒト胎児腎細胞株である、請求項1または2に記載の細胞。
- ヒトパピローマウイルスの初期遺伝子E6タンパク質とE7タンパク質との融合タンパク質であって、E7タンパク質、E6タンパク質、およびE7タンパク質からなり、E7タンパク質、E6タンパク質、およびE7タンパク質をこの順番で含む融合タンパク質。
- ヒトパピローマウイルスの初期遺伝子E6タンパク質とE7タンパク質との融合タンパク質であって、E7タンパク質、E6タンパク質、およびE7タンパク質からなり、E7タンパク質、E6タンパク質、およびE7タンパク質をこの順番で含む融合タンパク質をコードする核酸。
- ヒトパピローマウイルスの初期遺伝子E6タンパク質とE7タンパク質との融合タンパク質であって、E7タンパク質、E6タンパク質、およびE7タンパク質からなり、E7タンパク質、E6タンパク質、およびE7タンパク質をこの順番で含む融合タンパク質をコードする核酸を含む、当該融合タンパク質の発現ベクター。
- 請求項1~3のいずれか一項に記載の細胞、請求項4に記載の融合タンパク質、請求項5に記載の核酸、または請求項6に記載のベクターを含む、医薬組成物。
- ヒトパピローマウイルスに感染したヒト対象に投与するための、請求項7に記載の医薬組成物。
- ヒト対象が、ヒトパピローマウイルスに起因するがんを有する、請求項8に記載の医薬組成物。
- ヒトパピローマウイルスに起因するがんが、子宮頸がん、肛門がん、および膣がんからなる群から選択されるがんである、請求項9に記載の医薬組成物。
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