JP6886920B2 - 新規なヒト血清アルブミン変異体 - Google Patents
新規なヒト血清アルブミン変異体 Download PDFInfo
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- JP6886920B2 JP6886920B2 JP2017539213A JP2017539213A JP6886920B2 JP 6886920 B2 JP6886920 B2 JP 6886920B2 JP 2017539213 A JP2017539213 A JP 2017539213A JP 2017539213 A JP2017539213 A JP 2017539213A JP 6886920 B2 JP6886920 B2 JP 6886920B2
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Images
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Description
1.配列番号3で示されるアミノ酸配列に対し,10個以下のアミノ酸残基が欠失し及び/又は10個以下のアミノ酸残基が置換されてなるアミノ酸配列であって,但し配列番号3で示されるアミノ酸配列のN末端から318番目のアスパラギン残基及び320番目のトレオニン残基がこれら2残基の間にプロリン以外の単一のアミノ酸残基(X)を介してペプチド結合により連結された状態で保存されているものであるアミノ酸配列を含んでなる,ヒト血清アルブミン変異体。
2.該アミノ酸残基(X)がチロシンである,上記1のヒト血清アルブミン変異体。
3.配列番号3で示されるアミノ酸配列からなるものである,請求項2のヒト血清アルブミン変異体。
4.上記1〜3の何れかのヒト血清アルブミン変異体のアミノ酸配列に対し,配列番号3で示されるアミノ酸配列のN末端から318番目〜320番目に対応する位置の配列部分以外において,10個以下のアミノ酸残基が付加されてなり,且つ配列番号2に示されるアミノ酸配列とは同一でないものである,ヒト血清アルブミン変異体。
5.上記1〜3の何れかのヒト血清アルブミン変異体のアミノ酸配列に対し,10個以下のアミノ酸残基がN末端又はC末端に付加されてなり,且つ配列番号2に示されるアミノ酸配列とは同一でないものである,ヒト血清アルブミン変異体。
6.上記1〜5の何れかのヒト血清アルブミン変異体のアミノ酸配列を含んでなる第1のポリペプチド鎖と,これに連結された他の蛋白質(A)のアミノ酸配列を含んでなる第2のポリペプチド鎖とを含んでなるものである,ヒト血清アルブミン変異体連結蛋白質(A)。
7.(a)該第1のポリペプチド鎖のN末端に該第2のポリペプチド鎖のC末端が,又は
(b)該第1のポリペプチド鎖のC末端に該第2のポリペプチド鎖のN末端が,
ペプチド結合を介して連結しているものである,上記6のヒト血清アルブミン変異体連結蛋白質(A)。
8.該ペプチド結合を介した連結が,リンカーとのペプチド結合を含むものである,上記7のヒト血清アルブミン変異体連結蛋白質。
9.該リンカーが,1〜50個のアミノ酸残基からなるものである,上記8のヒト血清アルブミン変異体連結蛋白質(A)。
10.該リンカーが,1〜6個のアミノ酸残基からなるものである,上記8のヒト血清アルブミン変異体連結蛋白質(A)。
11.該リンカーが,Gly−Ser,Gly−Gly−Ser,配列番号4,配列番号5,及び配列番号6で示されるアミノ酸配列からなる群より選択されるものである,上記8のヒト血清アルブミン変異体連結蛋白質。
12.該リンカーが,アミノ酸配列Gly−Serで示されるものである,上記8のヒト血清アルブミン変異体連結蛋白質(A)。
13.該蛋白質(A)が,生体に投与したときに生理活性を示すものである,上記6〜12の何れかのヒト血清アルブミン変異体連結蛋白質(A)。
14.該蛋白質(A)が,α−L−イズロニダーゼ,イズロン酸−2−スルファターゼ,グルコセレブロシダーゼ,β−ガラクトシダーゼ,GM2活性化蛋白質,β−ヘキソサミニダーゼA,β−ヘキソサミニダーゼB,N−アセチルグルコサミン−1−ホスフォトランスフェラーゼ,α−マンノシダーゼ,β−マンノシダーゼ,ガラクトシルセラミダーゼ,サポシンC,アリルスルファターゼA,α−L−フコシダーゼ,アスパルチルグルコサミニダーゼ,α−N−アセチルガラクトサミニダーゼ,酸性スフィンゴミエリナーゼ,α−ガラクトシダーゼ,β−グルクロニダーゼ,ヘパラン硫酸N−スルファターゼ,α−N−アセチルグルコサミニダーゼ,アセチルCoAα−グルコサミニドN−アセチルトランスフェラーゼ,N−アセチルグルコサミン−6−硫酸スルファターゼ,酸性セラミダーゼ,アミロ−1,6−グルコシダーゼ,CLN1〜10を含むリソソーム酵素,PD−1リガンド,骨形成蛋白質(BMP),インスリン,プロラクチン,モチリン,副腎皮質刺激ホルモン(ACTH),メラノサイト刺激ホルモン(MSH),甲状腺ホルモン放出ホルモン(TRH),甲状腺刺激ホルモン(TSH),黄体形成ホルモン(LH),卵胞刺激ホルモン(FSH),副甲状腺ホルモン(PTH)トロンボポエチン,幹細胞因子(SCF),レプチン,バソプレシン,オキシトシン,カルシトニン,グルカゴン,ガストリン,セクレチン,パンクレオザイミン,コレシストキニン,アンジオテンシン,アンジオスタチン,エンドスタチン,ヒト胎盤ラクトーゲン(HPL),ヒト絨毛性性腺刺激ホルモン(HCG),エンケファリン,エンドルフィン,インターフェロンα,インターフェロンβ,インターフェロンγ,インターロイキン2,サイモポイエチン,サイモスチムリン,胸腺液性因子(THF),血中胸腺因子(FTS),サイモシン,サイミックファクターX,腫瘍壊死因子(TNF),顆粒球コロニー刺激因子(G−CSF),マクロファージコロニー刺激因子(M−CSF),顆粒球マクロファージコロニー刺激因子(GM−CSF),ウロキナーゼ,組織プラスミノーゲン活性化因子(tPA),ダイノルフィン,ボンベシン,ニューロテンシン,セルレイン,ブラディキニン,アスパラギナーゼ,カリクレイン,サブスタンスP,神経成長因子(NGF),毛様体神経栄養因子(CNTF),脳由来神経栄養因子(BDNF),グリア細胞株由来神経栄養因子(GDNF),ニューロトロフィン3,ニューロトロフィン4/5,ニューロトロフィン6,ニューレグリン1,アクチビン,塩基性線維芽細胞成長因子(bFGF),線維芽細胞成長因子2(FGF2),血管内皮増殖因子(VEGF),骨形成蛋白質(BMP),巨核球増殖分化因子(MGDF),血液凝固因子VII,血液凝固因子VIII,血液凝固因子IX,スーパーオキシドジスムターゼ(SOD),塩酸リゾチーム,ポリミキシンB,コリスチン,グラミシジン,バシトラシン,胃酸分泌抑制ポリペプチド(GIP),血管作動性腸ポリペプチド(VIP),血小板由来成長因子(PDGF),成長ホルモン分泌因子(GRF),上皮細胞成長因子(EGF),エリスロポエチン,ソマトスタチン,インスリン様成長因子1(IGF−1),20K成長ホルモン,22K成長ホルモン,及びこれらの塩若しくは変異体からなる群より選択されるものである,上記6〜13の何れかのヒト血清アルブミン変異体連結蛋白質(A)。
15.該蛋白質(A)が,22K成長ホルモンである,上記6〜12の何れかのヒト血清アルブミン変異体連結蛋白質(A)。
16.該蛋白質(A)が,20K成長ホルモンである,上記6〜12の何れかのヒト血清アルブミン変異体連結蛋白質(A)。
17.配列番号11で示されるアミノ酸配列からなるものである,上記15のヒト血清アルブミン変異体連結蛋白質(A)。
18.配列番号12で示されるアミノ酸配列からなるものである,上記16のヒト血清アルブミン変異体連結蛋白質(A)。
19.上記6〜18の何れかのヒト血清アルブミン変異体連結蛋白質(A)を有効成分として含有してなる,医薬。
20.成長ホルモン分泌不全性低身長症,ターナー症候群における低身長,慢性腎不全による低身長症,プラダーウィリー症候群における低身長症,軟骨異栄養症における低身長症,及びSGA性低身長症であって,何れも骨端線閉鎖を伴わないもの,並びに成人成長ホルモン分泌不全症,AIDSによる消耗,及び拒食症による消耗からなる群より選択される疾患の治療剤である,上記19の医薬。
21.上記1〜5の何れかのヒト血清アルブミン変異体をコードする遺伝子を含んでなるDNA。
22.上記6〜18の何れかのヒト血清アルブミン変異体連結蛋白質(A)をコードする遺伝子を含んでなるDNA。
23.上記21又は22のDNAを含んでなる発現ベクター。
24.上記23のベクターで形質転換された哺乳類細胞。
25.上記24の哺乳類細胞を,無血清培地で培養することにより得られる,ヒト血清アルブミン変異体又はヒト血清アルブミン変異体連結蛋白質(A)。
pEF/myc/nucベクター(インビトロジェン社)を,制限酵素(KpnI及びNcoI)で消化し,EF-1αプロモーター及びその第一イントロンを含むDNA断片を切り出し,このDNA断片をT4 DNAポリメラーゼで平滑末端化処理した。別に,pCI-neo(インビトロジェン社)を,制限酵素(BglII及びEcoRI)で消化して,CMVのエンハンサー/プロモーター及びイントロンを含む領域を切除した後に,T4 DNAポリメラーゼで平滑末端化処理した。これに,上記のEF-1αプロモーター及びその第一イントロンを含む領域(平滑末端化処理後のもの)を挿入して,pE-neoベクターを構築した(図1)。
野生型HSA(配列番号1)のC末端と22KhGHのN末端とを融合させたものである融合蛋白質HSA−22KhGHのアミノ酸配列を,配列番号32に示す。このアミノ酸配列中,1〜585番目のアミノ酸残基が野生型の成熟HSAのアミノ酸配列(配列番号1)に相当し,586〜776番目のアミノ酸残基が22KhGHのアミノ酸配列に相当する。HSA−22KhGHをコードする遺伝子(HSA-22KhGH遺伝子)を含む配列番号33で示した塩基配列を有するDNAを化学的に合成した。この配列において,塩基11〜82がHSAのリーダーペプチドを,塩基83〜1837が成熟型HSAを,そして塩基1838〜2410が成熟型hGHを,それぞれコードする。このDNAを制限酵素(MluI及びNotI)で消化し,実施例1で作製したpE-mIRES-GS-puroのMluI部位とNotI部位の間に組み込むことにより,HSA−22KhGH発現用ベクターpE-mIRES-GS-puro(HSA-22KhGH)を構築した。
HSA(A320T)(配列番号3)のC末端と22KhGHのN末端とを融合させたものである,配列番号34で示すアミノ酸配列を有する融合蛋白質を,mHSA−22KhGHとした。配列番号34で示すアミノ酸配列中,1〜585番目のアミノ酸残基がmHSAのアミノ酸配列に相当し,586〜776番目のアミノ酸残基が22KhGHのアミノ酸配列に相当する。実施例2で作製したpE-mIRES-GS-puro(HSA-22KhGH)を鋳型として,プライマーYA082(配列番号35)及びプライマーYA083(配列番号36)を用いて,PCRによりmHSA−22KhGHをコードする遺伝子を含むDNA断片を増幅した。このDNA断片をセルフアニールさせて,mHSA−22KhGH発現用ベクターであるpE-mIRES-GS-puro(mHSA-22KhGH)を構築した。
22KhGHのC末端と野生型HSA(配列番号1)のN末端とを融合させたものである,配列番号37で示したアミノ酸配列を有する融合蛋白質を,22KhGH−HSAとした。配列番号37で示したアミノ酸配列中,1〜191番目のアミノ酸残基が22KhGHのアミノ酸配列に相当し,192〜776番目のアミノ酸残基がHSAのアミノ酸配列に相当する。22KhGH−HSAをコードする遺伝子(22KhGH-HSA遺伝子)を含む配列番号38で示した塩基配列を有するDNAを化学的に合成した。この配列において,塩基11〜88がhGHのリーダーペプチドを,塩基89〜661が成熟型hGHを,塩基662〜2416が成熟型HSAを,それぞれコードする。このDNAを制限酵素(MluI及びNotI)で消化し,実施例1で作製したpE-mIRES-GS-puroのMluI部位とNotI部位の間に組み込むことにより,HSA−22KhGH発現用ベクターであるpE-mIRES-GS-puro(22KhGH-HSA)を構築した。
22KhGHのC末端とHSA(A320T)(配列番号3)のN末端とを融合させたものである,配列番号39に示したアミノ酸配列を有する融合蛋白質を,22KhGH−mHSAとした。実施例4で作製したpE-mIRES-GS-puro(22KhGH-HSA)を鋳型として,プライマーYA082(配列番号35)及びプライマーYA083(配列番号36)を用いて,PCRにより22KhGH−mHSAをコードする遺伝子を含むDNA断片を増幅した。このDNA断片をセルフアニールさせて,22KhGH−mHSA発現用ベクターであるpE-mIRES-GS-puro(22KhGH-mHSA)を構築した。
HSA−22KhGH,mHSA−22KhGH,22KhGH−HSA,及び22KhGH−mHSAの各融合蛋白質を発現させるための細胞を次のようにして作製した。チャイニーズハムスターの卵巣に由来する細胞であるCHO−K1細胞に,Gene Pulser Xcell エレクトロポレーションシステム(Bio Rad社)を用いて,実施例2〜5で作製した,HSA−22KhGH発現用ベクターpE-mIRES-GS-puro(HSA-22KhGH),mHSA−22KhGH発現用ベクターpE-mIRES-GS-puro(mHSA-22KhGH),22KhGH−HSA発現用ベクターpE-mIRES-GS-puro(22KhGH-HSA),及び22KhGH−mHSA発現用ベクターpE-mIRES-GS-puro(22KhGH-mHSA)をそれぞれ導入した。それぞれの発現ベクターを導入した細胞を,メチオニンスルホキシミン(SIGMA社)及びピューロマイシン(SIGMA社)を含むCD OptiCHOTM培地(Thermo Fisher Scientific社)を用いて選択培養し,HSA−22KhGH発現細胞,mHSA−22KhGH発現細胞,22KhGH−HSA発現細胞,及び22KhGH−mHSA発現細胞をそれぞれ確立した。選択培養の際には,メチオニンスルホキシミン及びピューロマイシンの濃度を段階的に上昇させて,最終的にメチオニンスルホキシミンの濃度を300μM,ピューロマイシンの濃度を10μg/mLとして,より高い薬剤耐性を示す細胞を選択的に増殖させた。
HSA−22KhGH発現細胞,mHSA−22KhGH発現細胞,22KhGH−HSA発現細胞,及び22KhGH−mHSA発現細胞の培養を,次のようにして行った。CD OptiCHOTM培地(Thermo Fisher Scientific社)に,メチオニンスルホキシミンとピューロマイシンとを,それぞれ300μM及び10μg/mLの濃度となるように添加して,細胞培養用培地を調製した。実施例6で作製した各発現細胞を,それぞれ2×105 個/mLの細胞密度となるように5mLの細胞培養用培地に添加し,5%CO2存在下37℃で培養した。5日毎に,2×105 個/mLの細胞密度となるように,細胞を新しい培養用培地に移して,継代培養を行った。
HSA−22KhGH,mHSA−22KhGH,22KhGH−HSA,及び22KhGH−mHSAの精製を次のようにして行った。実施例7で継代培養した各発現細胞を,それぞれ細胞培養用培地に全量が240mLとなるように2×105個/mLの密度で懸濁した。この細胞懸濁液を30mLずつ,径15cmのシャーレ8枚に加えて,5日間,5%CO2存在下,37℃で培養した。培養終了後に培地を回収し,膜フィルター(孔径0.22μm,Millipore社)でろ過して,培養上清とした。次いで,各培養上清に,1M HEPES(pH8.0)を加えて,pHを7.0〜7.2に調整した。
ヒトGH受容体(hGHR)遺伝子をマウスBaF3細胞に導入することによりGH依存性増殖能を獲得させたBaF3/hGHR細胞を,以下の通りにして作製した。配列番号40に示した塩基配列を有するhGHR ECD人工合成遺伝子(hGHRの細胞外領域(Extra Cellular Domain)をコードするhGHR遺伝子の5’側断片)を鋳型として,プライマーYA034(配列番号41)及びプライマーYA035(配列番号42)を用いてPCRを行った。得られたPCR産物をアガロース電気泳動に供し,QIAEX II(QIAGEN社)を用いて精製した。このDNA断片をメガプライマーとした。ヒト肺由来cDNAを鋳型として,プライマーK708(配列番号43)及びプライマーK709(配列番号44)を用いてPCRを行い,hGHR遺伝子の全長を含むDNA断片を増幅した。得られたPCR産物をアガロース電気泳動に供し,QIAEX IIを用いて精製した。次いで,精製したhGHR遺伝子の全長を含むDNA断片を鋳型として,上記メガプライマー及びプライマーK709(配列番号44)を用いてPCRを行い,5’側にhGHR ECD人工合成遺伝子配列を有するhGHRの全長をコードする遺伝子を含む,配列番号45に示した塩基配列を有するDNA断片を増幅した。このDNA断片を制限酵素(MluI及びNotI)で消化し,レトロウイルスベクターであるpMX-II(Ono Y., Oncogene. 19. 3050-8(2000))のMluIとNotIの間に組み込み,これをhGHR発現用レトロウイルスベクター(hGHR/pMX-II)とした。
HSA−hGH融合蛋白質の細胞増殖活性を,実施例9に記載の方法で作製したBaF3/hGHR細胞を用いて評価した。
実施例8で精製したHSA−hGH融合蛋白質(HSA−22KhGH,mHSA−22KhGH,22KhGH−HSA及び22KhGH−mHSA)を,それぞれ,4.0mg/kgの用量で雄性カニクイザルに単回皮下投与した。なお,HSA−22KhGHの投与は3匹のカニクイザルを用いて行い,mHSA−22KhGH,22KhGH−HSA及び22KhGH−mHSAの投与については,それぞれ1匹のカニクイザルを用いて行った。
マウス抗HSAモノクローナル抗体及びマウス抗hGH抗体を,当業者に周知の手法により,HSA又はhGHで免疫したマウスの脾細胞をそれぞれミエローマ細胞と融合させて得たハイブリドーマ細胞を培養して得た。マウス抗hGHモノクローナル抗体を,0.1M NaHCO3溶液(pH9)で透析した後,溶液中の抗体濃度をNanoDropTM(Thermo Scientific社)を用いて測定した。次いで,5mg/mLの濃度でDMSOに溶解したEZ-LinkTM NHS-LC-Biotin(Thermo Fisher Scientific社)を,1mgの抗体当たり60μgのNHS-LC-Biotinの比率で抗体溶液に添加し,室温で2時間反応させた後,反応溶液をPBSで透析しビオチン化マウス抗hGHモノクローナル抗体を得た。下記の定量法において,マウス抗HSAモノクローナル抗体を一次抗体,ビオチン化マウス抗hGHモノクローナル抗体を二次抗体として使用した。
測定は,Sector Imager 6000の使用説明書に従って,概ね下記のとおり実施した。マウス抗HSAモノクローナル抗体をHigh Bind Plate(Meso Scale Diagnostics社)に添加し,1時間静置して抗HSA抗体(一次抗体)をプレートに固定した。次いで,Superblock Blocking buffer in PBS(Thermo Fisher Scientific社)をプレートに添加して1時間振盪し,プレートをブロッキングした。プレートをPBST(0.05% Tween20を含有するPBS)で洗浄した後,検体を添加して1時間振盪した。プレートをPBSTで洗浄した後,ビオチン化マウス抗hGHモノクローナル抗体(二次抗体)を添加して1時間振盪した。プレートをPBSTで洗浄した後,SULFO-Tag-Streptavidin(Meso Scale Diagnostics社)を添加して1時間振盪した。プレートをPBSTで洗浄した後,Read buffer T(Meso Scale Diagnostics社)を添加し,Sector Imager 6000(Meso Scale Diagnostics社)で波長620nmの発光を測定した。同様にして同一プレート上で既知濃度のHSA−hGHを定量して標準曲線を求め,これに検体の測定値を内挿し,血漿中のHSA−hGH融合蛋白質の濃度を求めた。
血漿中に含まれるIGF−1の定量は,Human IGF-I Quantikine ELISA kit(R&D systems)を用いて,ELISA法により行った。
(1)BaF3/hGHR細胞を用いた細胞増殖活性の測定
図5は,縦軸に490nmにおける吸光度,横軸に各検体のモル濃度(nM)をとり測定値をプロットした,BaF3/hGHR細胞を用いた細胞増殖活性の測定結果を示す図である。この図から,各検体のEC50を求めた結果を表1に示す。
図6は,縦軸にカニクイザル血清中のHSA−hGH融合蛋白質(HSA−22KhGH,mHSA−22KhGH,22KhGH−HSA及び22KhGH−mHSA)の濃度,横軸にHSA−hGH融合蛋白質を投与後の経過時間をプロットした,HSA−hGH融合蛋白質の薬物動態解析の結果を示す図である。この図から,各検体のCmax,AUC0-216h,AUC0-inf及びt1/2βを求めた結果を表2に示す。
図7は,HSA融合22KhGHの薬物動態解析の結果を示す図であり,縦軸は血漿中のIGF−1の濃度を,横軸はHSA−22KhGH融合蛋白質を投与後の経過時間を表す。IGF−1は成長ホルモンによって分泌が誘導される骨成長促進作用等の活性を有するポリペプチドであり,hGHの生理活性の一部はIGF−1を介して発揮されることが知られている。
リン酸水素二ナトリウム七水和物・・・・1.33mg
リン酸二水素ナトリウム・・・・・・・・1.57mg
ポリオキシエチレン(160)ポリオキシ
プロピレン(30)グリコール・・・・・3mg
ベンジルアルコール・・・・・・・・・13.5mg
D−マンニトール・・・・・・・・・・52.5mg
22KhGH−mHSA・・・・・・・・1mg
上記成分比率で各成分を注射用水に溶解させ,pHを6.0〜6.4に調整し,液量を1.5mLとして水性注射剤とする。
L−ヒスチジン・・・・・・・・・・・・1mg
フェノール・・・・・・・・・・・・・・4.5mg
ポリオキシエチレン(160)ポリオキシ
プロピレン(30)グリコール・・・・・4.5mg
D−マンニトール・・・・・・・・・・60mg
22KhGH−mHSA・・・・・・・・1mg
上記成分比率で各成分を注射用水に溶解させて,pHを6.0〜6.4に調整し,液量を1.5mLとして水性注射剤とする。
リン酸水素二ナトリウム七水和物・・・・2.475mg
リン酸二水素ナトリウム・・・・・・・・0.394mg
塩化ナトリウム・・・・・・・・・・・1.125mg
アミノ酢酸・・・・・・・・・・・・・11.25mg
D−マンニトール・・・・・・・・・・22.5mg
22KhGH−mHSA・・・・・・・・1mg
上記成分からなる凍結乾燥剤を,使用時に9.7mgのベンジルアルコールを含有する1mLの注射用水に溶解する。
2 mPGKプロモーター
3 配列番号7に示す塩基配列を含む野生型マウス脳心筋炎ウイルスの内部リボソーム結合部位の部分配列
3a 配列番号8に示す塩基配列を含む変異型マウス脳心筋炎ウイルスの内部リボソーム結合部位の部分配列
4 mPGKのポリアデニル化領域(mPGKpA)
5 EF−1p及び第一イントロンを含む塩基配列
6 SV40後期ポリアデニル化領域
7 SV40初期プロモーターを含む領域
8 合成ポリアデニル化領域
9 サイトメガロウイルスプロモーターを含む領域
10 グルタミン合成酵素遺伝子
配列番号4:リンカー例
配列番号5:リンカー例
配列番号6:リンカー例
配列番号8:変異型マウス脳心筋炎ウイルス由来の内部リボソーム結合部位の部分配列,合成
配列番号11:22KhGH−mHSA,成熟型
配列番号12:20KhGH−mHSA,成熟型
配列番号13:プライマーHyg-Sfi5',合成
配列番号14:プライマーHyg-BstX3',合成
配列番号15:IRES-Hygr-mPGKpA,合成
配列番号16:ハイグロマイシン耐性遺伝子に対応するアミノ酸配列
配列番号17:プライマーIRES5',合成
配列番号18:プライマーIRES3',合成
配列番号19:プライマーmPGKP5',合成
配列番号20:プライマーmPGKP3',合成
配列番号21:mPGKp,合成
配列番号22:プライマーGS5',合成
配列番号23:プライマーGS3',合成
配列番号24:プライマーpuro5',合成
配列番号25:プライマーpuro3',合成
配列番号26:ピューロマイシン耐性遺伝子を含む配列
配列番号27:ピューロマイシン耐性遺伝子に対応するアミノ酸配列
配列番号28:プライマーSV40polyA5',合成
配列番号29:プライマーSV40polyA3',合成
配列番号30:プライマーmIRES-GS5',合成
配列番号31:プライマーmIRES-GS3',合成
配列番号32:HSA−22KhGH,成熟型
配列番号33:HSA−22KhGH遺伝子を含む配列,合成
配列番号34:mHSA−22KhGH,成熟型
配列番号35:プライマーYA082,合成配列
配列番号36:プライマーYA083,合成配列
配列番号37:22KhGH−HSA,成熟型
配列番号38:22KhGH−HSA遺伝子を含む配列,合成
配列番号39:22KhGH−mHSA
配列番号40:hGHR ECDをコードする人工合成遺伝子の配列
配列番号41:プライマーYA034,合成
配列番号42:プライマーYA035,合成
配列番号43:プライマーK708,合成
配列番号44:プライマーK709,合成
配列番号45:hGHRをコードする人工合成遺伝子の塩基配列,合成
Claims (3)
- 配列番号11で示されるアミノ酸配列からなるものである,ヒト血清アルブミン変異体連結22K成長ホルモン。
- 請求項1に記載のヒト血清アルブミン変異体連結22K成長ホルモンを有効成分として含有してなる,医薬。
- 成長ホルモン分泌不全性低身長症,ターナー症候群における低身長,慢性腎不全による低身長症,プラダーウィリー症候群における低身長症,軟骨異栄養症における低身長症,及びSGA性低身長症であって,何れも骨端線閉鎖を伴わないもの,並びに成人成長ホルモン分泌不全症,AIDSによる消耗,及び拒食症による消耗からなる群より選択される疾患の治療剤である,請求項2に記載の医薬。
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CN109734816A (zh) * | 2019-03-12 | 2019-05-10 | 王大勇 | 一种基因重组人促皮质素与白蛋白的融合蛋白及表达方法 |
CN114555646A (zh) * | 2019-10-17 | 2022-05-27 | Jcr制药股份有限公司 | 血清白蛋白与生长激素的融合蛋白的制造方法 |
KR20220095204A (ko) * | 2019-10-30 | 2022-07-06 | 제이씨알 파마 가부시키가이샤 | 혈청 알부민과 성장 호르몬의 융합 단백질을 함유하는 수성 의약 조성물 |
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CN114133458B (zh) * | 2021-12-08 | 2023-11-14 | 福州大学 | 一种在人血清白蛋白内部融合多肽的方法 |
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