JP6843997B2 - P8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物及びそれを含む胃腸管疾患予防又は治療用薬剤学的組成物 - Google Patents
P8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物及びそれを含む胃腸管疾患予防又は治療用薬剤学的組成物 Download PDFInfo
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Description
実施例1.乳酸菌来由タンパク質過発現及び分泌のためのシステム構築
実施例1−1.過発現誘導のためのプロモーターの選別
標的タンパク質(P8タンパク質)の乳酸菌での発現のための力強いプロモーター6種(ermE、エリスロマイシン耐性遺伝子のプロモーター;PK、ピルビン酸キナーゼ;GK、グルコキナーゼ;GPFK6−ホスホフルクトキナーゼ、G6Pi、グルコース6−リン酸イソメラーゼ;L−LDH、L−乳酸脱水素酸素)をペジオコックスペントサセウスの解糖作用代謝経路から選別した。標的タンパク質の発現ホストはペジオコックスペントサセウスSL4(Pediococcus pentosaceus SL4)(受託番号:KCTC 10297BP)であり、糖の消費速度が非常に早いことを実験で確認し、また消費された糖のほぼ100%が二次代謝産物であるL−ラクテートに転換されることをHPLC分析で確認した。したがって、プロモーターのうち5種は解糖作用代謝経路から、そして1種は二次代謝産物であるラクテート生産経路から選別した。
プラスミドpCBT24−2(配列番号9)(KCCM12182P)をP8タンパク質のクローニングに使った。
MRS固体培地(agar plate)で培養された形質転換体を10ml MRS液体培地(エリスロマイシン、10mg/ml)に接種し、37℃で15時間静置培養(overnight incubation)した。この培養液1mlを10ml M9最小培地(エリスロマイシン、10mg/L)に接種した後、37℃で48時間静置培養し、培養液5mlを遠心分離して上澄み液を得た。上澄み液5mlはTCA沈澱法で総タンパク質を濃縮した。これをウエスタンブロッティング法でP8タンパク質の発現及び分泌量を比較分析した。菌体の場合、緩衝溶液で希釈し、超音波粉砕機を用いて菌体を破砕した後、細胞抽出物をウエスタンブロッティング法で発現した後、分泌されなかったP8タンパク質の量を分析した。
乳酸菌形質転換体を培養した後、培養上澄み液5mlに100%TCA(Trichloro Acetic Acid)を添加して最終濃度が20%となるようにした。混合後、氷で30分間反応し、4℃、15,000rpmで30分間遠心分離して全てのタンパク質の沈澱を誘導した。遠心分離後、上澄み液を除去し、アセトン200μlを添加し、さらに4℃、15,000rpmで10分間遠心分離して沈澱したタンパク質を洗浄した。常温で乾燥によって残ったアセトンを全く除去した後、培養上澄み液に存在する目的タンパク質分泌量を測定した。この際、分泌量のはウエスタンブロッティング法で測定し、測定結果を図4〜図7に示した。
実施例2−1.腫瘍細胞移植と腫瘍増殖
韓国細胞株銀行(Seoul、Korea)から分譲された大膓癌細胞株DLD−1は10%ウシ胎仔血清(FBS;Invitrogen、NY、USA)、ペニシリン(0.02UI/ml;Sigma、MO、USA)、ストレプトマイシン(0.02μg/ml;Sigma、MO、USA)、グルタミン(2mM:Sigma、MO、USA)、非必須アミノ酸(1%;Sigma、MO、USA)が添加されたRPMI 1640培地(Sigma、MO、USA)を使用し、37℃、5%CO2インキュベーターで継代培養して維持した。培養されたDLD−1細胞を懸濁して獲得した腫瘍細胞懸濁液を雄ヌードマウス(BALB/cAnN.Cg−Foxn1nu/CrlNarl;5週齢)の背中皮下に0.2ml(2×106cell/mouse)ずつ移植して固形腫瘍を形成した。継代群で形成された腫瘍組職を解剖するため、動物を犠牲して腫瘍塊(tumor lump)を摘出し、表面に分布した血管と脂肪層を除去した後、新鮮な腫瘍組職のみを選別し、套管針を用いて無処置動物の皮下に移植した。
腫瘍塊の移植後、個別腫瘍の容積が100〜150mm3に至れば、体重と腫瘍の大きさを測定し、無作為に群分離した。実験動物は群当たり10匹ずつ下記の表3のように陰性対照群(腫瘍移植対照群:G1)、陽性対照群(抗癌剤投与群、40mg/Kg 5−Fu;5−フルオロウラシル、Sigma、MO、USA:G2)、試験群{1×1010CFU/Head投与群(薬物伝達システム(DDS)ペジオコックスペントサセウス(Empty vector)投与群:G3;1×109CFU/Head PP−DDS(PK−P8−ChoS−oriP8):2−プロモーターシステム投与群:G4;1×1010CFU/Head PP−DDS(PK−P8−ChoS−oriP8):2−プロモーターシステム投与群:G5;1×109CFU/Head PP−DDS(PK−P8−PK−oriP8:2−プロモーターシステム)投与群:G6;1×1010CFU/Head PP−DDS(PK−P8−PK−oriP8:2−プロモーターシステム投与群:G7}に総7ヶ群に区分し、一日一1回で7週間経口投与して試験した。形質転換体はMRS培地で培養し、これを1010/200μlとなるように懸濁して経口で投与した。一日に一回ずつ総6週間投与した。
大膓癌細胞株DLD−1を移植したヌードマウス(BALB/cAnN.Cg−Foxn1nu/CrlNarl;5週齢)7群(群当たり10匹)で腫瘍の増殖を確認し、右側わき腹の皮下に移植された腫瘍の容積は移植後に5日経過時に皮下結節として現れた。
マウスに投与されたP8タンパク質を分泌/発現する薬物伝達システムであるペジオコックスペントサセウス菌株(KCCM12181P)がマウスの腸まで生きて到逹することができるかを確認するために、マウスにペジオコックスペントサセウス菌株を投与し、6週後にマウスの腸内物質を回収し、これをMRS(erythromycin、10μg/ml)プレートで培養して、ペジオコックスペントサセウス菌株がいくら存在するかを確認した。生き残ったペジオコックスペントサセウス菌株でP8タンパク質の分泌/発現量を測定した。
Claims (9)
- 外因性プロモーターに作動可能に連結された、配列番号1で表示される塩基配列を有する、P8タンパク質をコーディングするポリヌクレオチドと分泌信号ペプチドをコーディングする遺伝子を含む遺伝子コンストラクトで形質転換され、胃腸管でP8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物。
- 前記外因性プロモーターは、配列番号3〜配列番号8からなる群から選択される1種以上のプロモーターであることを特徴とする、請求項1に記載のP8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物。
- 前記微生物は、ラクトバシラス(Lactobacillus)、ラトコックス(Latococcus)、ロイコノストク(Leuconostoc)、ペジオコックス(Pediococcus)、又はビフィドバクテリアム(Bifidobacterium)属に属する菌株であることを特徴とする、請求項1に記載のP8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物。
- 前記微生物は、ラクトバシラスラムノスス、ラクトバシラスアシドフィルス、ラクトバシラスパラカセイ、ラクトバシラスプランタルム、ペジオコックスペントサセウス、又はラクトバシラスブレビス菌株であることを特徴とする、請求項3に記載のP8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物。
- 前記分泌信号ペプチドは、USP45分泌信号ペプチド、Usp45 N4又はラクトバシラスブレビスS層タンパク質信号ペプチドであることを特徴とする、請求項1に記載のP8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物。
- 前記微生物はペジオコックスペントサセウス菌株であり、前記分泌信号ペプチドはUSP45分泌信号ペプチドであることを特徴とする、請求項5に記載のP8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物。
- 前記遺伝子コンストラクトは、前記プロモーターの下流に、二番目プロモーター、二番目分泌信号ペプチド及び二番目治療ポリペプチドをコーディングする異種核酸配列をさらに含み、前記二番目プロモーターは一番目プロモーターと同一であるか異なることを特徴とする、請求項1に記載のP8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物。
- 前記胃腸管疾患は、大膓癌、大腸ポリープ、大腸炎、虚血性胃腸管疾患、赤痢、腸血管異形成症、憩室症、過敏性大腸症候群、又はクローン病であることを特徴とする、請求項1に記載のP8タンパク質を発現及び分泌する胃腸管疾患治療薬物伝達用微生物。
- 請求項1〜8のいずれか一項に記載の配列番号2で表示されるアミノ酸配列を有する、P8タンパク質を生産及び分泌する菌株を含む胃腸管疾患予防又は治療用薬剤学的組成物。
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