JP7269909B2 - 配座異性体抗原認識抗体の生産を誘導するフラジェリンワクチン補助剤ベースのワクチンの製造およびその応用 - Google Patents
配座異性体抗原認識抗体の生産を誘導するフラジェリンワクチン補助剤ベースのワクチンの製造およびその応用 Download PDFInfo
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Description
(a)本発明は、配座異性体抗原認識抗体誘導用の神経変性疾患のワクチン組成物および感染性ウイルスワクチン組成物を提供する。
(b)本発明のワクチン組成物は、配座異性体抗原認識抗体の生成を誘導する。
(c)これらの配座異性体抗原認識抗体は、抗原に対して高い特異度を有するので、疾患の改善、予防または治療に有効に用いることができる。
実験材料
各菌株の培養および保管
本発明で使用した大腸菌菌株らは、LB(Luria Bertani)培地(Difco Co.)で培養した。使用した菌株らは、培養後、グリセロールが30%になるように添加した後-80℃超低温冷凍庫で保管した。本発明に用いられた菌株とプラスミドは、表1にまとめた。
1. タンパク質の発現と精製
a. 敗血症ビブリオ菌由来FlaB組み換えタンパク質の発現および精製
敗血症ビブリオ菌CMCP6の鞭毛構成因子FlaBの遺伝子配列(配列表の配列番号1)を用いて、flaB組み換えタンパク質を製造した。フラジェリン遺伝子flaBのN-末端またはC-末端融合用のDNA断片を得るために配列表の配列番号8および配列番号9に記載されたFlaB-NおよびFlaB-Cプライマー対を使用してN-末端融合用の、またはC-末端融合用のFlaB遺伝子が含まれている1.1kbpのDNA断片を増幅した。即ち、それぞれのプライマー対を用いたPCR反応は、95℃で5分間の初期変性させた後、95℃で30秒間変性、60℃で30秒間のアニーリング、および2℃で1分間伸長するサイクルを30回繰り返した後、最後に2℃で10分間反応させる条件で実施した。
抗原としてヒトτ(タウ)タンパク質の過剰リン酸化に対する高い関連性を有している反復ドメイン(repeated domain; RD)全体を大腸菌を用いて組み換えタンパク質を製造した。組み換えタンパク質の生産のために、その遺伝子(配列表の配列番号4)を大腸菌に対してコドン最適化および遺伝子合成を行った(配列表の配列番号5)。クローニングの容易性のために、遺伝子合成時N-末端およびC-末端にそれぞれEcoRIおよびXhoI制限酵素認識遺伝子配列を追加した。融合用のDNA断片を得るために記載されたtauRD-N(配列表の配列番号10)およびtauRD-C(配列表の配列番号11)プライマー対を使用してN-末端融合用またはC-末端融合用のtauRD遺伝子が含まれてある1.1kbpのDNA断片を増幅した。つまり、それぞれのプライマー対を用いたPCR反応は、95℃で5分間の初期変性させた後、95℃で30秒間変性、60℃で30秒間のアニーリング、および72℃で1分間伸長するサイクルを30回繰り返した後、最後に72℃で10分間反応させる条件で実施した。大腸菌株の発現のための発現システムは、NEB社のIMPACT-CNシステムを用い、当該システムのpTYB12プラスミドをEcoRIとPstIで制限酵素処理した後、増幅されたtauRD PCR産物をライゲーション処理した(pCMM11102)。ライゲーション処理したプラスミドは、E.coli ER2566発現菌株に電気的形質転換を介して形質転換させ、pTYB12プラスミドの選択マーカーであるアンピシリン含有LB寒天板上で生存した菌株のみを選び出して、配列表の配列番号10及び配列番号11のPCRプライマーを用いて、その遺伝子産物の含有可否を確認した(CMM11102)。
pCMM11101のflaB遺伝子をEcoRIとPstI制限酵素を用いて処理し、pCMM11102も同じ制限酵素処理した後、アガロースゲル電気泳動を通じて、それぞれのflaB遺伝子切片とpCMM11102プラスミドを精製した。この二つの遺伝子をライゲーションしてpTYB12::flaB-tauRD遺伝子融合プラスミドを製造した(pCMM11103)。ライゲーションしたプラスミドは、E.coli ER2566発現菌株に電気的形質転換を介して形質転換させ、pTYB12プラスミドの選択マーカーであるアンピシリン含有LB寒天板上で生存した菌株のみを選び出して、配列表の配列番号8及び配列番号11のPCRプライマーを用いて、その遺伝子産物の含有可否を確認した(pCMM11104)。
(1)組み換えFlaB-TauRDタンパク質のTLR5刺激能の確認
精製した組み換えタウ-RDペプチド自体がフラジェリンの作用点であるTLR5に対して刺激能を保持しているかどうかを確認するために、ウェル平板培養基に293-T細胞を1×105細胞ずつ分注して一夜培養した後、EFFECTENE(Effectene、QIAGEN)を用いて、NF-κ-Lucプラスミド(漢陽大学校医学部微生物学教室のKim Jeongmok教授から取得)、TLR-5遺伝子がクローニングされたp3xFlag-hTLR-5プラスミド(米国Wake Forest University School of Medicine、Department of Microbiology and ImmunologyのSteven B. Mizelから取得)およびβ-ガラクトシダーゼ(β-galactosidase)発現対照群ラスミド(Clontech)を同時に細胞内に導入させた。24時間追加培養した後、新しい培地に交換し、IMPACTシステムで分離したFlaBおよびタウ-RDペプチドを一定時間処理した後、ルシフェラーゼ(luciferase)活性を発光分析器(Luminometer、Berthold社)を用いて測定してNF-κBの転写精度を確認し、その結果を図5に示した。図5の結果から抗原として用いた遺伝子組み換えタウ-RDペプチドはTLR5刺激能を見せなかったが、FlaB-TauRD融合タンパク質は、FlaB対比の有意なTLR5刺激能を示した。
本発明によるフラジェリンタウ-RDペプチド混合ワクチンを6週齢の雌Balb/cマウス(オリエントバイオ、韓国)の鼻腔内へ1週間間隔で3回、5回および6回免疫した後、血清を得てタウ-RDペプチド特異的な抗体の形成を比較した(図6)。比較のために、組み換えフラジェリンタウ-RDタンパク質を96ウェル平板ELISAプレートにコーティングした後、免疫で得られた抗血清を2倍連続-希釈して処理して間接ELISA法を通じて確認した。
本発明で誘導された抗血清が脳の特異的抗原が自ら凝集体を形成して精製5日後に、図8のようにPHFの形態の凝集体を形成することを、電子顕微鏡を介して確認した。
タンパク質のβシート(sheet)の構造に特異的に結合するチオフラビンS(thioflavin S; Green)でタウタンパク質凝集体(精製したタウ-RDペプチドにヘパリン(heparin)を処理して凝集を誘導)を染色し、本発明品の免疫で得られた抗血清を抗-マウスIgGラビットIgGをAlexa fluor 633(Molecular probe)で染色した後、共焦点レーザー顕微鏡を用いてタウタンパク質と抗血清の結合可否および程度を比較した。
本発明で誘導された抗タウ血清のタウ凝集阻害効果を確認するために、本発明で誘導された抗血清を、組み換えタウ-RDペプチドに前処理して除去した後、ヘパリンを用いてタウペプチドの凝集を誘導し凝集体の形成程度を透過電子顕微鏡を介して確認した。
本発明で誘導された抗血清が脳の特異的抗原提示細胞である小膠細胞細胞株(BV2細胞株、全南大学校医学部のMoon Changjong教授研究室の分譲)のタウ凝集体のオプソニンの食作用(opsonic phagocytosis)の促進可否を確認する実験を行った。組み換えタウ-RDペプチドをヘパリンを用いて、3日間凝集を誘導した後、FNR 488(Green、BioActs、韓国)を用いて染色した。10秒間超音波破砕を通じてタウ凝集体を分けた後、培養したBV2細胞株に、本発明による抗タウ血清と一緒に処理した。対照群としてはPBS免疫を通じて取得した対照血清を用いた。培養30分後、培地を除去し、BV2細胞の核はDAPI(Blue)で染色し、BV2細胞の細胞膜は、麦芽凝集素(Wheat germ agglutinin; WGAは、Red)を用いて染色した後、共焦点顕微鏡を用いて破砕タウ凝集体の貪食可否および程度を比較した。
a. ノロウイルスPドメイン抗原配列及びコドン最適化
ノロウイルスワクチン製造のための抗原用のDNAは、全南大学校のCho Kyeongo教授から取得したノロウイルスPドメインがクローニングされたpGEX-4T-1::VAxxxを用いた。挿入遺伝子配列は、配列表の配列番号12と同一である。
抗原用のPd遺伝子のN-末端またはC-末端融合用のDNA断片を得るために、配列表の配列番号16及び配列番号17に記載されたPd-NおよびPd-Cプライマー対を使用して配列表の配列番号12のPdを含むプラスミドを鋳型としてPd遺伝子が含まれている1.1kbpのDNA断片を増幅した。即ち、それぞれのプライマー対を用いたPCR反応は、95℃で5分間初期変性させた後、95℃で30秒間変性、60℃で30秒間のアニーリング、および72℃で1分間伸長するサイクルを30回繰り返した後、最後に72℃で10分間反応させる条件で実施した。
pCMM11101のflaB遺伝子をEcoRIとPstI制限酵素を用いて処理し、pCMM11105も同じ制限酵素処理した後、アガロースゲル電気泳動を通じて、それぞれのflaB遺伝子切片とpCMM11104プラスミドを精製した。この二つの遺伝子をライゲーションしてpTYB12::flaB-Pd遺伝子融合プラスミドを製造した(pCMM11106)。ライゲーションしたプラスミドは、E.coli ER2566発現菌株に電気的形質転換を介して形質転換させ、pTYB12プラスミドの選択マーカーであるアンピシリン含有LB寒天板上で生存した菌株のみを選び出して、配列表の配列番号8及び配列番号17のPCRプライマーを用いて、その遺伝子産物の含有可否を確認した(pCMM1106)。
(1)組み換えflaB-Pdタンパク質のTLR5刺激能
FlaB-Pd融合タンパク質の生体効果を類推するために、24ウェル平板培養基に293-T細胞を1X105細胞ずつ分注して一夜培養した後、Effectene(QIAGEN)を用いて、NF-κB-Lucプラスミド(漢陽大学校医学部微生物学教室のKim Jeongmok教授から取得)とTLR-5遺伝子がクローニングされたp3xFlag-hTLR-5プラスミド(米国Wake Forest University School of Medicine, Department of Microbiology and ImmunologyのSteven B. Mizelから取得)β-ガラクトシダーゼ(β-galactosidase)発現対照群プラスミド(Clontech)を同時に細胞内に導入させた。24時間追加培養した後、新しい培地に交換し、上記で製造しIMPACTシステムで分離したFlaB-Pd融合タンパク質を一定時間処理した後、ルシフェラーゼ(luciferase)活性を発光分析器(Luminometer、Berthold社)を用いて測定してNF-κB転写精度を確認し、その結果を図14に示した。
製造したPdおよびFlaB-Pdタンパク質のワクチン効能を検証するためにオリエント社から購入した6週齢の雌Balb/cマウスを用いた。
組み換えノロウイルスPドメインタンパク質とFlaB-Pドメイン融合タンパク質をそれぞれ精製した後、試料らを酢酸ウラニル(uranyl acetate)で染色した後、炭素グリッド(carbon grid)に2μl落とし乾燥した後、JEOL JEM-2100F透過電子顕微鏡を用いて30kVの加速電圧で観察した。その結果、ノロウイルスPドメインの組み換えタンパクでVLP(virus like particle)構造の形成が観察された。FlaB-Pドメイン融合タンパク質の場合、VLPの形態が観察されるが、これらをサブウニット(subunit)にして、互いに凝集された構造を観察することができた(図17)。
図15の免疫スケジュールを用いて、6週齢の雌BalB/cマウスに、組み換えPドメイン抗原単独、FlaBとPドメインの混合、FlaB-Pドメイン融合タンパク質ワクチンをマウス鼻腔を介して投与した。3回の免疫後、マウスの全血(図18:血清IgG、図19の血清IgA)および糞便(図20糞便内の分泌性IgAの力価測定)を回収した後、血清を分離した後、組み換えPドメインタンパク質を抗原とする抗原特異的抗体力価をELISAを用いて確認した(2次IgG抗体; Goat Anti-Mouse IgG、Human ads-HRP Cat. No.1030-05、SouthernBiotech、Birmingham、AL 35260、USA:2次IgA抗体; Goat Anti-Mouse IgA-HRP Cat. No.1040-05, SouthernBiotech, Birmingham, AL 35260, USA利用)(図18~20)。その結果、Pドメイン単独投与群に比べてFlaB-Pドメインの混合投与およびFlaB-Pドメインの融合ワクチン投与群の両方で有意な抗原特異的抗体力価の上昇を確認することができた。
Claims (6)
- (a)タウ(τ)タンパク質のRD(repeated domain);および(b)ビブリオバルニフィカス(Vibrio vulnificus)由来のFlaBタンパク質で構成された組み換えタンパク質を有効成分として含み、
前記RDは、配列表の配列番号3のアミノ酸配列からなり、
前記FlaBタンパク質は、配列表の配列番号2のアミノ酸配列からなることを特徴とする、病的タウ(τ)タンパク質の凝集を認識する抗体誘導用の神経変性疾患のワクチン組成物。 - 前記RDは、大腸菌発現のためにコドン最適化された(codon optimized)配列表の配列番号5のヌクレオチド配列によってコードされることを特徴とする請求項1に記載のワクチン組成物。
- 前記神経変性疾患は、アルツハイマー病、タウ性病症、認知症、ハンチントン病、パーキンソン病、筋萎縮性側索硬化症、記憶力低下、重症筋無力症およびプリオン関連疾患からなる群から選択される疾患であることを特徴とする請求項1に記載のワクチン組成物。
- 神経変性疾患の診断に必要な情報を提供する方法であって、
前記方法は、対象由来の採取済の試料における抗体の生成程度を測定する段階を含み、
前記抗体が、(a)タウ(τ)タンパク質のRD(repeated domain);および(b)ビブリオバルニフィカス(Vibrio vulnificus)由来のFlaBタンパク質で構成された組み換えタンパク質を有効成分として含む組成物を前記対象に投与して生成された抗体であり、
前記RDは、配列表の配列番号3のアミノ酸配列からなり、
前記FlaBタンパク質は、配列表の配列番号2のアミノ酸配列からなる、方法。 - 前記RDは、大腸菌発現のためにコドン最適化された(codon optimized)配列表の配列番号5のヌクレオチド配列によってコードされることを特徴とする請求項4に記載の方法。
- 前記神経変性疾患は、アルツハイマー病、タウ性病症、認知症、ハンチントン病、パーキンソン病、筋萎縮性側索硬化症、記憶力低下、重症筋無力症およびプリオン関連疾患からなる群から選択される疾患であることを特徴とする請求項4に記載の方法。
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