JP5209166B2 - ポルフィロモナス・ジンジバリス(Porphyromonasgingivalis)リコンビナントタンパク質と末端切断物 - Google Patents
ポルフィロモナス・ジンジバリス(Porphyromonasgingivalis)リコンビナントタンパク質と末端切断物 Download PDFInfo
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- JP5209166B2 JP5209166B2 JP2001580954A JP2001580954A JP5209166B2 JP 5209166 B2 JP5209166 B2 JP 5209166B2 JP 2001580954 A JP2001580954 A JP 2001580954A JP 2001580954 A JP2001580954 A JP 2001580954A JP 5209166 B2 JP5209166 B2 JP 5209166B2
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- gingivalis
- polypeptide
- antibody
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- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
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Description
本発明はポルフィロモナス・ジンジバリス(Porphyromonas gingivalis)のヌクレオチド配列およびP. gingivalisのポリペプチドに関する。P. gingivalisのポリペプチドおよびヌクレオチドは、被験者のP. gingivalisに対して免疫応答を起こすのにならびに歯周病として知られる症状またはP. gingivalisによる感染に関係する他の症状の重篤度を治療または予防または軽減するのに使用する組成物において使用することができる。
歯周病は細菌に関連する歯の支持組織の炎症疾患であり、比較的穏やかな形態の歯肉炎である非特定的かつ可逆的な歯肉組織の炎症から、歯支持構造の破壊により特徴づけられるもっと攻撃的な形態の歯周病まである。歯周病は歯根膜の破壊に導く特定のグラム陰性菌のコンソーシアムの歯肉下感染に関連し、重要な公衆衛生問題である。大きな関心を呼んでいる1つの細菌はP. gingivalisであり、その理由は、この微生物の成人歯周病病変部からの回収は歯肉下の嫌気性培養可能なフローラの50%にまで達しうるが、P. gingivalisは健康部位からは稀にしかも少数しか回収されないからである。歯肉下プラーク中のP. gingivalisレベルは歯周病の重症度の増加に関連して比例的に増加し、この疾患が回復すると培養可能な歯肉下微生物集団からの該微生物は根絶される。P.gingivalisの歯肉下移植による、非ヒト霊長類の歯周病病変の進行が実証されている。動物およびヒトの両方に対するこれらの知見は、成人の歯周病発達におけるP.gingivalisの重要な役割を示唆する。
本発明者らはこのほど、全長タンパク質と比較すると溶解度の改善を示すP. gingivalisのPG32およびPG33タンパク質の断片を同定した。マウスの感染病変モデルを使って、本発明者らはこれらの可溶性断片がP. gingivalisのチャレンジに対する保護能があることを発見した。
[式中、
Yは、配列番号3の残基86〜223、配列番号3の残基191〜322、配列番号4の残基193〜310、配列番号3の残基191〜306、配列番号3の残基224〜391、配列番号4の残基213〜380、配列番号4の残基286〜380、配列番号3の残基224〜306、配列番号4の残基213〜285、配列番号3の残基281〜384および配列番号4の残基306〜372からなる群から選択されるアミノ酸配列からなる可溶性P. gingivalisの断片であり;そして
XとZは、存在するかまたは存在せず、かつP. gingivalisの断片の溶解度に実質的に悪影響を与えないアミノ酸もしくはペプチドからなる]
で表される可溶性ポリペプチドを提供する。
口腔内細菌ポルフィロモナス・ジンジバリス(Porphyromonas gingivalis)はその表面上に主要外膜タンパク質PG32およびPG33を含有する。これらのタンパク質の末端切断された可溶性断片は、全長タンパク質と比較すると、マウス膿瘍モデルにおいてP. gingivalisチャレンジに対する保護の改善を提供する。
[式中、
Yは、配列番号3の残基86〜223、配列番号3の残基191〜322、配列番号4の残基193〜310、配列番号3の残基191〜306、配列番号3の残基224〜391、配列番号4の残基213〜380、配列番号4の残基286〜380、配列番号3の残基224〜306、配列番号4の残基213〜285、配列番号3の残基281〜384および配列番号4の残基306〜372からなる群から選択されるアミノ酸配列からなる可溶性P. gingivalis断片であり;そして
XとZは、存在するかまたは存在せず、かつP. gingivalis断片の溶解度に実質的に悪影響を与えないアミノ酸もしくはペプチドからなる]
で表されるポリペプチドも提供する。
実施例1:P. gingivalisリコンビナントタンパク質PG32およびPG33ならびにこれらのタンパク質の断片または末端切断物(truncation)のクローニングと分析
(a) P. gingivalis末端切断タンパク質のクローニング
PG32(GenBank登録番号AF175714)およびP33(GenBank登録番号AF175715)は、P.gingivalis株W50の免疫反応性タンパク質としてすでに説明されている。その完全なDNA配列とタンパク質配列は、PG32についてはそれぞれ配列番号1と3に、またPG33についてはそれぞれ配列番号2と4に与えられている。
単一コロニー形質転換体を用いて、50 μg/mlカナマイシンを含有するLuria-Bertaniブロス(LB)20mlに接種して、37℃で一夜振とうした。次いでこの接種菌を用いて、テリフィック(Terrific)ブロス500ml(リン酸カリウムおよび50μg/mlカナマイシンを含有する)に接種して、37℃で吸光度(OD600)が2.0になるまで振とうした。培養物を0.1mM IPTGを用いて誘導した。30℃または37℃で1〜4時間の誘導期間後に培養物を、4℃で4000rpmにて10分間遠心分離することによって回収して、ペレットを-70℃で保存してリコンビナントタンパク質の溶解度測定に備えた。
IPTG誘導後に、r-PG32またはr-PG33タンパク質あるいはそれらの末端切断物の発現レベルと溶解度を評価した。約14mlのリコンビナント大腸菌(E.coli)細胞培養物を遠心分離によりペレット化し、そして、TE pH8.0の1.5mlに再懸濁した。次に細胞を5設定でマイクロプローブ(Virosonic Digital 475 超音波細胞破砕機、The Virtis社、NY)を使って2 X 10秒間のバーストで超音波処理した。15分間の遠心分離(13,000rpm)後に上清を回収して、これを可溶性画分とした。ペレットを洗浄し、次にTE pH8.0に再懸濁して、これを不溶性画分とした。様々な画分の分析をウェスタンブロット分析とSDS-PAGEを用いて実施した。これらの実験結果を表3に示す。複数の事例では、NOGおよびCHAPSなどの非イオン性洗剤を0.1〜1%で超音波処理プロセスに加えて、リコンビナントタンパク質の可溶化を助けた。大規模な発現および精製の目的のために、大腸菌(E.coli)培養物500mlを遠心分離によりペレット化して、1x結合バッファー(5 mMイミダゾール、500nM NaCl、 20mM Tris-HCl、 pH 7.9)40mlに再懸濁した。次いで細胞を、8の設定のマイクロプローブ(0.5")(Virosonic Digital 475超音波細胞破砕機、The Virtis社、NY)を使って、6 X 10秒バーストで超音波処理した。15分間の遠心分離(13,000rpm)後に、可溶性リコンビナントタンパク質を含有する上清を回収して、以下に概説したように精製した。
全長PG32(配列番号3;残基21-391)およびPG33(配列番号4;残基22-380)の事例のようにr-タンパク質が不溶性であるとわかると、リコンビナント大腸菌(E.coli)ペレットを氷上で解凍して結合バッファーに再懸濁し、次いで超音波処理し、20,000 x gで遠心分離して封入体を回収した。ペレットを結合バッファーに再懸濁し、超音波処理と遠心分離のプロセスを2回以上繰返してさらにタンパク質を遊離させた。次いでペレットを6M尿素を含有する結合バッファーに再懸濁し、氷上で2〜3時間攪拌しながらインキュベートして完全にタンパク質を溶解した。39,000 x g、20分間の遠心分離によって残留する不溶性物質を除去した。上清は、カラム精製の前に0.45μm膜を通して濾過した。
Ni-NTA金属アフィニティクロマトグラフィを使ってリコンビナントタンパク質をH6タグを介して精製した。簡単に説明すると、タンパク質を平衡化Ni-NTA樹脂(Qiagen)にバッチ結合させて、これを小カラム中に注いで重力下で未結合タンパク質を溶出した。次にカラムを結合バッファー10mlを用いて洗浄し、次いで洗浄バッファー(60 mMイミダゾール、500mM NaCl、20mM Tris-HCI、pH7.9)6mlによって洗浄した。次に結合したタンパク質を、1Mイミダゾール、500mM NaCl、20mM Tris-HCI、pH 7.9を含有するバッファー中に溶出した。可溶化封入体または不溶性リコンビナントタンパク質を精製する場合には、上記バッファーに6M尿素を加えた。
尿素を含有しない調製物については、Ni-NTA樹脂からの溶出タンパク質画分をプールした後、痕跡量のイミダゾールを除去するために0.5M Tris-HCl、50mM NaClに対する透析を行った。
SDS-PAGEは本質的にNovexによる推奨の通り実施した。サンプルを2 x サンプル還元バッファー(Novex)の等容積と混合し、100℃で10分間ボイルし、Tris-グリシン4〜20%ゲル(Novex)に適用した。分子量標準(SeeBlueTM)もNovexから購入した。ウェスタンブロットは、電気泳動後に、タンパク質をニトロセルロース上に1時間100ボルトでエレクトロブロッティングして調製した。メンブランを5%のスキムミルク-PBSを用いてブロッキングした後、1/5000に希釈した抗ウサギ抗体と共に、または5%のスキムミルク-PBS中に1/1000に希釈した抗ラット抗体と共にインキュベートした。メンブランをその後洗浄し、ヤギ抗ウサギ-HRPコンジュゲート(KPL)またはヤギ抗マウス-HRPコンジュゲート(KPL)と共にインキュベートし、洗浄し、そしてTMBメンブランペルオキシダーゼ基質(KPL)を用いて顕色した。
BALB/cマウスに、PG32(構築物21)組換えタンパク質20μgを含むフロイント不完全アジュバント(FIA;Sigma)を2回、3週間隔で投与することによって、精製組換えタンパク質に対するポリクローナル抗血清を産生させた。2回目の投与の1週間後にマウスから採血し、産生された抗血清を用いて、変性および還元条件下で泳動したP. gingivalis W50の全体細胞のウェスタンブロットをスクリーニングした。また、ウサギにおいても、P. gingivalis全体細胞(W50株)またはP. gingivalis細胞(W50株)のサルコシル不溶性濃縮画分(グラム陰性生物の外側膜タンパク質を濃縮する方法により)を含むFIAを、3回投与して免疫感作して、抗血清を産生させた。また、ラットにおいても、P. gingivalis W50の全体細胞を含むフロイント不完全アジュバントを用いて免疫感作して、抗血清を産生させた。次いでラットにP. gingivalis生細胞(ATCC 33277株)を経口投与してチャレンジし、6週後に採血した。これらのラットは、対照ラットと比較して、チャレンジ後の大臼歯周囲の歯槽骨の損失から守られていることを示した。
10匹の雌のBALB/cマウス(6-8週齢)からなる群を、各組換えタンパク質、PG32(0.5M尿素中に含まれる構築物1)、PG33(2M尿素中に含まれる構築物2)、PG32断片(構築物21)およびPG33断片(構築物22)を用いて、皮下へ免疫感作した(20μg/投与量)。対照マウスにはホルマリン殺菌P. gingivalis細胞(ほぼ2×109)、または大腸菌(E.coli)ライセート(20pg/投与)を、いずれも不完全フロイントアジュバント(Sigma)中に乳化して与えた。この免疫感作は、尾の基部に皮下注射して与え、P. gingivalisによるチャレンジの4週前および1週前に実施した。チャレンジの2日前に、マウスの球後神経叢(retrobulbar plexus)から採血した。BALB/cマウスにP. gingivalis 33277の7.5 x 109生細胞を腹部の腹側領域中に皮下注射してチャレンジした。チャレンジ後、7日間にわたって毎日、病変の数とサイズについてマウスを試験した。病変が注射部位周囲のマウス腹部に発生したのでその病変を毎日測定した。
PG32断片(aa224-391)のクローニング。 PG32(構築物21)を、実施例1に概説したようにして、PCR増幅して抽出した。精製したDNAは、先にEcoRIおよびNotIを用いて消化しておいた、QIAexII精製した酵母GST発現ベクターpYEX4T-1(Amrad)中にライゲートした。ライゲーション産物をカルシウムコンピテント大腸菌(E.coli)BL21 DE3 (Stratagene)中に形質転換し、50μgアンピシリンを含有するLBプレート上で選択した。組換えプラスミドを含有する大腸菌(E.coli)細胞の単一コロニーをアンピシリンを含有するテリフィック(Terrific)ブロスを含む100ml培養中に接種して一夜培養し、そしてそのプラスミドを、酵母中に形質転換する前に、QIAGEN Plasmid Maxiキットを用いて精製した。
S.セレビシエ(S. cerevisiae)DY150グリセロールストックのサンプルをYPDプレート上にストリークして、30℃で3〜4日間放置した。単一コロニーを20ml YPD培地中に接種して、30℃にて24時間振とうした。500μl容量の一夜培養物を3000rpmにて5分間、遠心分離にかけ、そのDY150ペレットを1mlのdH20で洗浄した。ペレットを10mg/ml子ウシ胸腺DNA(Sigma)に再懸濁し、それに1μgのプラスミドDNAをプレート溶液の500μlとともに加えて、その混合物を25℃にて24時間インキュベートした。細胞を3000rpmにて5分間、遠心沈降して、プレート溶液を除去した。酵母を1mlのdH20で洗浄し、YNBSプレート上にプレーティングして30℃にて4〜5日間インキュベートした。
単一コロニー形質転換体を5mlのYNBSブロスに接種し、30℃にて48時間振とうした。0.5mlの種苗を5mlの新鮮なYNBSブロスに加え、0.5mM CuS04を用いて誘導を行った。30℃にて3時間の誘導期間後に、培養物を遠心分離によって回収し、500μlブレーキングバッファー(1mM PMSFおよび10mM E-64を含有、Sigma)に再懸濁した。2.0mlスクリュー栓バイアル(Biospec)を、3/4量は0.5mmガラスビーズ(Biospec)によって満たし、残りの容積は細胞によって満たした。その混合物を、ミニ・ビーズビーター細胞破砕機(Biospec)中で30秒(5,000rpm)×8回ホモジナイズし、その各作動の間は、氷上で30秒インキュベーションした。ビーズを静置沈降させて、破砕された酵母細胞を回収した。5分間の遠心分離(3000g)の後、上清を回収し、これを可溶性画分とした。ペレットはブレーキングバッファー中に再懸濁して不溶性画分とした。画分はSDS-PAGEとウェスタンブロット分析を用いて分析した。
合成PG32末端切断型遺伝子(PG32 aa224-391に対応)を、S.セレビシエ(S. cerevisiae)の推定上のコドン使用を利用して構築し、S.セレビシエ中のP. gingivalisタンパク質の発現を改善した。表4に掲げた2本鎖DNA配列全体をカバーするオリゴヌクレオチドを、酵母中の発現用に高発現バイアスコドンを用いて設計した(Sharp,P.MおよびCowe,E.(1991)Yeast. 7, 657-678)。オリゴヌクレオチドプライマーAおよびBを、 TaqPlus precision (Stratagene) DNAポリメラーゼを使って、次の条件下でのPCRにより、dsDNA断片に変換した:変性(96℃、1分間)、アニーリング(53℃、1分間)および伸長(72℃、2分間)の20サイクルとし、かつ伸長ステップの継続時間をサイクル毎に5秒ずつ増加する(Di Donato,A., de Nigris,M., Russo,N., Di Biase,S.およびD'Alessio, G. (1993) Analytical Biochemistry. 212, 291-293)。第2のPCRランでは、コア混合物の1/20アリコートを、コアテンプレート延長に機能するオリゴヌクレオチドプライマーCおよびDと共に使用した。この操作を各プライマー対を使用して繰返し、最終的に500bp産物を作製した。このPCR産物をプロテイナーゼK (Boehringer Mannheim)処理し、QIAquick PCR精製キット(Qiagen)を用いて精製し、プライマーにより導入された制限酵素切断部位EcoRIおよびNotIで消化した。DNA断片を、1%低融点アガロースゲル(Bio-Rad)を通す電気泳動によって精製し、QIAexIIゲル抽出キット(Qiagen)を使って抽出した。精製したDNAを、先にEcoRIおよびNotIを用いて消化しておいたQIAexII精製済の酵母GST発現ベクターpYEX4T1(Amrad)中にライゲートした。ライゲーション産物をカルシウムコンピテント大腸菌(E.coli)BL21 DE3(Stratagene)中に形質転換して、50μgアンピシリンを含有するLBプレート上で選択した。コドンを置き換えたインサートが正確であることをDNA配列分析によって確認した。酵母の形質転換とPG32の発現を前に概説した通り実施した。図2は、酵母により発現された、GSTと融合した合成PG32(aa224-391)の発現および免疫反応性を示す。図2aおよび2bにおいて、レーン3は、酵母により発現された未改変P. gingivalisコドンを含有し、レーン4、5、6、7は、それらのコドンを以上概説したようにして酵母での発現に対して最適化したクローンを含有する。特にPG32に対する抗血清を用いたとき(図2b)の、ほぼ48kD(矢印を参照)のバンドにおける反応性増加によって立証されるように、コドン最適化が行われると、ある程度の発現と免疫反応性の増加があるようである。
Claims (18)
- P. gingivalisに対する免疫応答を起こすことができる、配列番号3の残基86〜223、配列番号3の残基191〜322、配列番号3の残基224〜391、配列番号4の残基213〜380、配列番号3の残基224〜306、および配列番号3の残基281〜384からなる群から選択される配列を有するポリペプチドからなる、可溶性P. gingivalisのポリペプチド。
- 請求項1に記載の可溶性ポリペプチドを含んでなるキメラ構築物。
- 請求項1に記載の可溶性ポリペプチドをコードするヌクレオチド配列を含んでなる単離されたDNA分子。
- 転写調節エレメントと機能的に連結された請求項3に記載のDNA分子を含んでなるリコンビナント発現ベクター。
- 請求項4に記載のリコンビナント発現ベクターを含んでなる細胞。
- P. gingivalisのポリペプチドを産生する方法であって、該ポリペプチドの発現を可能にする条件下で請求項5に記載の細胞を培養することを含んでなる方法。
- 被験体のP. gingivalisに対する免疫応答を起こすのに使用する組成物であって、請求項1に記載の少なくとも1つの有効量の可溶性ポリペプチド、および/または請求項3に記載の少なくとも1つの有効量のDNA分子、ならびに製薬上許容される担体を含んでなる前記組成物。
- 製薬上許容される担体がアジュバントである、請求項7に記載の組成物。
- 被験体のP. gingivalis感染の発症または重篤度を低減または予防することに使用するための請求項7または8に記載の組成物。
- 請求項1に記載の可溶性ポリペプチドに対して産生され、かつ該可溶性ポリペプチドに対する抗体。
- モノクローナル抗体である、請求項10に記載の抗体。
- ポリクローナル抗体である、請求項10に記載の抗体。
- 請求項10〜12のいずれか1項に記載の抗体および製薬上許容される担体を含んでなる組成物。
- 被験体のP. gingivalis感染を治療または予防することに使用するための請求項10〜12のいずれか1項に記載の抗体または請求項13に記載の組成物。
- 個体に由来するサンプル中のP. gingivalisのポリペプチドの存在または不存在を検出する方法であって、サンプルを請求項10〜12のいずれか1項に記載の抗体と、抗体がサンプル中のP. gingivalisのポリペプチドと免疫複合体を形成するのに十分な条件下で接触させ、そして免疫複合体の存在または不存在を検出することを含んでなる方法。
- 個体に由来するサンプル中のP. gingivalis抗体の存在または不存在を検出する方法であって、サンプルを請求項1に記載の可溶性ポリペプチドまたは請求項2に記載のキメラ構築物と、ポリペプチドの可溶性断片がサンプル中の抗体と免疫複合体を形成するのに十分な条件下で接触させ、そして免疫複合体の存在または不存在を検出することを含んでなる方法。
- 請求項1に記載の可溶性ポリペプチド、または請求項2に記載のキメラ構築物、および/または請求項10〜12のいずれか1項に記載の抗体を含んでなるキット。
- 抗体を産生するための請求項1に記載のポリペプチドの使用であって、該抗体はヒトで産生されない、前記使用。
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BRPI0917321A2 (pt) | 2008-08-29 | 2015-11-17 | Oral Health Australia Pty Ltd | prevenção, tratamento e diagnóstico de infecção por p. gingivalis |
US8140041B2 (en) * | 2009-08-27 | 2012-03-20 | Mediatek Inc. | Tunable capacitive device with linearization technique employed therein |
WO2021203132A1 (en) * | 2020-03-30 | 2021-10-07 | Colgate-Palmolive Company | Improving, maintaining, protecting and repairing tissue integrity, barrier function and immunity using a composition comprising a source of zinc ions |
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US5536497A (en) * | 1992-12-21 | 1996-07-16 | The Research Foundation Of State University Of New York | Fimbrial polypeptides useful in the prevention of periodontitis |
US5475097A (en) * | 1993-10-21 | 1995-12-12 | University Of Georgia Research Foundation, Inc. | Lysine-specific Porphyromonas gingivalis proteinase |
US5523390A (en) * | 1993-09-10 | 1996-06-04 | University Of Georgia Research Foundation, Inc. | Porphyromonas gingivalis arginine-specific proteinase |
AUPN627595A0 (en) * | 1995-10-30 | 1995-11-23 | University Of Melbourne, The | Diagnostics and treatments of periodontal disease |
EP2264176A1 (en) * | 1997-12-10 | 2010-12-22 | CSL Limited | Porphorymonas gingivalis polypeptides and polynucleotides |
AUPQ485999A0 (en) * | 1999-12-24 | 2000-02-03 | Csl Limited | P. gingivalis antigenic composition |
US20030083287A1 (en) * | 2000-11-30 | 2003-05-01 | Burgess Nicola A. | ginS |
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JP2003531634A (ja) | 2003-10-28 |
AUPQ718200A0 (en) | 2000-05-25 |
CA2407603A1 (en) | 2001-11-08 |
ES2426034T3 (es) | 2013-10-18 |
DK1276762T3 (da) | 2013-08-19 |
CA2750984A1 (en) | 2001-11-08 |
EP1276762B1 (en) | 2013-05-29 |
EP1276762A1 (en) | 2003-01-22 |
US20030215402A1 (en) | 2003-11-20 |
WO2001083530A1 (en) | 2001-11-08 |
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