JP5759671B2 - 結合方法 - Google Patents
結合方法 Download PDFInfo
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- JP5759671B2 JP5759671B2 JP2009502102A JP2009502102A JP5759671B2 JP 5759671 B2 JP5759671 B2 JP 5759671B2 JP 2009502102 A JP2009502102 A JP 2009502102A JP 2009502102 A JP2009502102 A JP 2009502102A JP 5759671 B2 JP5759671 B2 JP 5759671B2
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- JP
- Japan
- Prior art keywords
- pnag
- carrier protein
- sulfo
- protein
- spdp
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960000814 tetanus toxoid Drugs 0.000 claims description 14
- PVGATNRYUYNBHO-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(2,5-dioxopyrrol-1-yl)butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCN1C(=O)C=CC1=O PVGATNRYUYNBHO-UHFFFAOYSA-N 0.000 claims description 12
- GKSPIZSKQWTXQG-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[1-(pyridin-2-yldisulfanyl)ethyl]benzoate Chemical compound C=1C=C(C(=O)ON2C(CCC2=O)=O)C=CC=1C(C)SSC1=CC=CC=N1 GKSPIZSKQWTXQG-UHFFFAOYSA-N 0.000 claims description 11
- ULARYIUTHAWJMU-UHFFFAOYSA-M sodium;1-[4-(2,5-dioxopyrrol-1-yl)butanoyloxy]-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)CCCN1C(=O)C=CC1=O ULARYIUTHAWJMU-UHFFFAOYSA-M 0.000 claims description 7
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- PMJWDPGOWBRILU-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCC(C=C1)=CC=C1N1C(=O)C=CC1=O PMJWDPGOWBRILU-UHFFFAOYSA-N 0.000 claims description 3
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Landscapes
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Description
(a)マレイミド基を含むリンカーを添加することによりPNAGを活性化して、活性化PNAGを生成するステップ;
(b)スルフィドリル基を含むリンカーを添加することによりキャリアタンパク質を活性化して、活性化キャリアタンパク質を生成するステップ;及び
(c)上記活性化PNAGと上記活性化キャリアタンパク質とを反応させて、PNAG−キャリアタンパク質複合体を生成するステップ;
を含む、あるいは
(a)スルフィドリル基を含むリンカーを添加することによりPNAGを活性化して、活性化PNAGを生成するステップ;
(b)マレイミド基を含むリンカーを添加することによりキャリアタンパク質を活性化して、活性化キャリアタンパク質を生成するステップ;及び
(c)上記活性化PNAGと上記活性化キャリアタンパク質とを反応させて、PNAG−キャリアタンパク質複合体を生成するステップ;
を含む、あるいは
(a)スルフィドリル基を含むリンカーを添加することによりPNAGを活性化して、活性化PNAGを生成するステップ;
(b)スルフィドリル基を含むリンカーを添加することによりキャリアタンパク質を活性化して、活性化キャリアタンパク質を生成するステップ;及び
(c)上記活性化PNAGと上記活性化キャリアタンパク質とを反応させて、PNAG−キャリアタンパク質複合体を生成するステップ
を含む方法を提供する。
(a)マレイミド基を含むリンカーを添加することによりPNAGを活性化して、活性化PNAGを生成するステップ;
(b)スルフィドリル基を含むリンカーを添加することによりキャリアタンパク質を活性化して、活性化キャリアタンパク質を生成するステップ;及び
(c)上記活性化PNAGと上記活性化キャリアタンパク質とを反応させて、PNAG−キャリアタンパク質複合体を生成するステップ
を含む方法を記載する。
(a)マレイミド基を含むリンカーを添加することによりキャリアタンパク質を活性化して、活性化キャリアタンパク質を生成するステップ;
(b)スルフィドリル基を含むリンカーを添加することによりPNAGを活性化して、活性化PNAGを生成するステップ;及び
(c)上記活性化PNAGと上記活性化キャリアタンパク質とを反応させて、PNAG−キャリアタンパク質複合体を生成するステップ;
を含む方法を記載する。
(a)スルフィドリル基を含むリンカーを添加することによりキャリアタンパク質を活性化して、活性化キャリアタンパク質を生成するステップ;
(b)スルフィドリル基を含むリンカーを添加することによりPNAGを活性化して、活性化PNAGを生成するステップ;及び
(c)上記活性化PNAGと上記活性化キャリアタンパク質とを反応させて、PNAG−キャリアタンパク質複合体を生成するステップ
を含む方法を記載する。
5型
→4)-β-D-ManNAcA-(1→4)-α-L-FucNAc(3OAc)-(1→3)-β-D-FucNAc-(1→
8型
→3)-β-D-ManNAcA(4OAc)-(1→3)-α-L-FucNAc(1→3)-α-D-FucNAc(1→
dPNAGをWO04/43405号に記載のように調製した。dPNAGをさらにSuperose6カラムで精製した。
dPNAG(12mg)を、300μlの5M HCl+300μlの5M NaOH+1700μlの1×PBS(pH7.0)に溶解し、pH7.0に調整した。サンプルを0.22μmフィルターを通してろ過し、再度pHを7.0に調整した。12mgのGMBSを200μlのDMSOに溶解し、サンプルを暗所で室温にて2時間ゆっくりと攪拌した。0.5M NaOHを用いてpHを7.0に維持した。1×PBS、10mM EDTA(pH7.0)バッファーで平衡化した脱塩カラム(PD10カラム)を用いて過剰のGMBSを除き、Centricon10KDa MWCO濃縮デバイスを用いてサンプルを0.6mlになるまで濃縮した。
破傷風トキソイド(TT)(6.5mg;195μl原液)を1105μlの1×PBS含有10mM EDTA(pH8.0)に添加した。130μlのSPDP(DMSO中6.2mg/ml)をタンパク質溶液に添加し、暗所で室温にて1時間ゆっくりと攪拌した。0.5M NaOHを用いてpHを8.0に維持した。1×PBS、10mM EDTA(pH8.0)バッファーで平衡化した脱塩カラム(PD10カラム)を用いて過剰のSPDPを除き、Centricon10KDa MWCOを用いてサンプルを1.3mlになるまで濃縮した。0.65mlのDTT(1×PBS、10mM EDTA(pH8.0)バッファー中23mg/ml)を1.3mlのSPDP活性化TTに添加した。サンプルを暗所で室温にて30分間インキュベートした。0.5M NaOHを用いてpHを8.0に維持した。1×PBS、10mM EDTA(pH7.0)バッファーで平衡化した脱塩カラム(PD10カラム)を用いて過剰のDTTを除き、Centricon10KDa MWCO濃縮デバイスを用いてサンプルを0.6mlになるまで濃縮した。
dPNAG:153.37μg/ml (46.3%)
TT: 178.06μg/ml (53.7%)
dPNAG−TT複合体
本明細書の以下に記載する手法を用いて、下記の複合体を生成した:
dPNAG−TT010:dPNAG−S−GMBS+DTT処理TT−LC−SPDP
dPNAG−TT011:dPNAG−S−GMBS+DTT処理TT−LC−SPDP
dPNAG−TT012:dPNAG−S−GMBS+DTT処理TT−SPDP
dPNAG−TT014:dPNAG−SPDP+DTT処理TT−SPDP
dPNAG−TT017:DTT処理dPNAG−SPDP+TT−LC−SPDP
dPNAG−TT019:dPNAG−S−GMBS+DTT処理TT−SPDP
dPNAG−TT020:dPNAG−S−GMBS+DTT処理TT−SPDP
1gのPNAGを20mg/mlの濃度で5N HClに溶解し、1時間インキュベートした。続いて5N NaOHを用いて中和した。この溶液を5μm膜において清澄化し、Sephacryl S400HRにおいて精製した。目的の画分、すなわち「中間の分子サイズ」(Infection and Immunity, 70: 4433-4440 (2002)を参照)に相当するものをプールし、濃縮したあと、脱N−アセチル化処理を行った。
S−GMBS(N−(γ−マレイミドブチリルオキシ)スルホスクシンイミド、Pierce)を0.2M NaCl中のdPNAGに添加し(比S−GMBS/PS(w/w):1/1)、pH7.0(1M NaOHを用いてpH調節)にて室温で2時間にわたりインキュベートした。ToyopearlHW−40FにおいてPBS、10mM EDTA、50mM NaCl(pH7.2)を溶出バッファーとして60ml/時の一定の流速で用いて精製することにより過剰のGMBSと副産物を除去した。溶出プールを光学密度(UV=206nm)の関数で選択し、続いてVivaspin管3,000MWCO又はAmiconUltra 10,000MWCOにおいて濃縮した。
GMBS活性化dPNAG及びDTT還元(reduced)TT−SPDPを混合し、室温で攪拌した。使用した条件に応じて、システイン(リン酸ナトリウムバッファーpH8.0中4mg/ml)を30分かけて添加することにより20〜120分後に反応を停止させた。複合体を5μmフィルターを用いて清澄化し、精製のためにSephacryl S300HR樹脂(XK16/100)に注入した。200mM NaClを用いて30ml/時の一定の流速で溶出を行った。溶出画分をヘキソサミンにより及びタンパク質用量により分析した。目的の画分をプールし、0.22μm Sterivexにおいてろ過した。最終的な複合体は、多糖(ヘキソサミン用量)及びタンパク質組成(ローリー用量)について試験した。
DMSO(ジメチルスルホキシド,Merck)に溶解した5倍モル過剰のSPDP(N−スクシンイミジル−3−(2−ピリジルジチオ)プロピオネート,MW:312.4,Pierce)を、100mMリン酸ナトリウム(pH7.2)中5mg/mlのdPNAG100mgに添加し、室温で1時間インキュベートした。反応混合物をAmiconUltra 10,000MWCO(3000rpmで28分間の遠心)で±6mlにまで濃縮した後、Sephacryl S100HR(XK16/40)で精製を行った。リン酸バッファー(pH7.4)を用いて60ml/時の一定の流速で溶出を行った。目的の画分(206nmで読み取り)をプールし、AmiconUltra 10,000MWCO(3000rpmで30分間の遠心)において1.1mlになるまで濃縮した。
DMSO(ジメチルスルホキシド,Merck)に溶解した15倍モル過剰のSPDP(Pierce)を、100mMリン酸ナトリウム(pH7.2)中のTT(50/ml)1gに添加し、室温で80分間インキュベートした。続いて、生成物をSephacryl S100HR(XK16/40)に注入し、100mM酢酸ナトリウム(pH5.6),100mM NaCl,1mM EDTAを60ml/時の一定の流速で用いて溶出した。溶出プールを光学密度(UV=280nm)の関数で選択し、続いてAmiconUltra 10,000MWCO(3000rpmで75分間の遠心)において19.6mlになるまで濃縮した。
DTTをTT−SPDP又はTT−LC−SPDPにDTT/TT比(mg/mg)が0.7/1となるよう添加した。室温で2時間後、ピリジン−2−チオンが放出されて、その特徴的な吸収が343nmとなった。ゲルろ過(PD−10,Amersham)によりチオール化タンパク質を過剰のDTTから精製した。AmiconUltra 10,000MWCOにおいて濃縮した後、タンパク質含量をローリー用量により評価した。
カップリングは、連続的に攪拌しながら、初期TT/PS比(w/w)2/1で、室温にて実施した。
11.6mgのDTT(1,4−ジチオトレイトール,Boerhinger Mannheim,MW:154.24)を16.5mgのdPNAG−SPDPに添加した。室温で2時間後、ピリジン−2−チオンが放出されて、その特徴的な吸収が343nmとなった。ゲルろ過(Toyopearl HW40F)によりチオール化PSを過剰のDTTから精製し、続いてAmiconUltra 10,000MWCOにおいて860μlになるまで濃縮した。
カップリングは、連続的に攪拌しながら、初期TT/PS比(w/w)1.7/1で、室温にて実施した。
30匹のマウスの群に、黄色ブドウ球菌dPNAG−TT複合体(糖用量0.3μg)をアジュバント無添加で又は3D−MPLアジュバントと組み合わせて皮下接種した。マウスには、0日、14日及び28日目に3回の接種を行った。41日目にマウスから血清を採取し、各血清サンプルをELISAで試験して、PNAGに対する免疫応答を評価した。10匹のマウスの群を対照群として使用し、生理食塩水を接種した。
精製PNAG(2.5μg/ml)をリン酸緩衝生理食塩水(PBS)で希釈したメチル化HSA(2.5μg/ml)と混合し、高結合マイクロタイタープレート(Nunc Maxisorp)に4℃で一晩かけてコーティングした。
Claims (9)
- 40%未満がN−アセチル化されているブドウ球菌PNAGとキャリアタンパク質とを結合する方法であって、
(a)BMPS、EMCS、GMBS、MBS、LC−SMCC、SMCC、SMPB、SMPH、スルホ−EMCS、スルホ−MBS、スルホ−SMCC、スルホ−GMBS及びスルホ−SMPBからなる群より選択されるマレイミド基を含むリンカーを添加することによりブドウ球菌PNAGを活性化して、活性化ブドウ球菌PNAGを生成するステップ;
(b)10〜25オングストロームのスペーサー長を有するスルフィドリル基を含むリンカーを添加することによりキャリアタンパク質を活性化して、活性化キャリアタンパク質を生成するステップ;及び
(c)上記活性化ブドウ球菌PNAGと上記活性化キャリアタンパク質とを反応させて、ブドウ球菌PNAG−キャリアタンパク質複合体を生成するステップ
を含む方法。 - マレイミド基を含むリンカーが、ステップ(a)においてPNAGのアミン基に付加される、請求項1記載の方法。
- スルフィドリル基を含むリンカーが、ステップ(b)においてキャリアタンパク質のアミン基に付加される、請求項1又は2記載の方法。
- スルフィドリル基を含むリンカーが、LC−SPDP、SMPT、LC−SMPT、スルホ−SMPT、スルホ−LC−SMPT及びスルホ−LC−SPDPからなる群より選択される、請求項1〜3のいずれか1項に記載の方法。
- キャリアタンパク質が、破傷風トキソイド、ジフテリアトキソイド、CRM197、rEPA及びプロテインDからなる群より選択される、請求項1〜4のいずれか1項に記載の方法。
- 請求項1〜5のいずれか1項に記載の方法を実施するステップ、及びPNAG−キャリアタンパク質複合体と薬学的に許容される賦形剤とを混合するさらなるステップを含む、ワクチンの製造方法。
- PNAG−キャリアタンパク質複合体とさらなる抗原(複数でもよい)とを混合するさらなるステップを含む、請求項6記載の方法。
- 請求項1〜5のいずれか1項に記載の方法により得られるPNAG−キャリアタンパク質複合体。
- ブドウ球菌疾患の治療又は予防に使用するための、請求項8に記載のPNAG−キャリアタンパク質複合体。
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US4902506A (en) * | 1983-07-05 | 1990-02-20 | The University Of Rochester | Immunogenic conjugates |
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CA2647455C (en) | 2014-07-15 |
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