JP2016020342A - 低酸素誘導因子(hif)関連状態の治療方法 - Google Patents
低酸素誘導因子(hif)関連状態の治療方法 Download PDFInfo
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Abstract
【解決手段】本発明は、低酸素誘導因子(HIF)関連状態の治療方法に関し、特に、トランスフェリンを含む組成物の投与を含むHIF関連状態の治療方法に関する。
【選択図】なし
Description
(a)A1PIを含む精製された溶液を得るために沈殿によって水溶液から夾雑タンパク質の部分を取り除く工程;
(b)精製された溶液をアニオン交換樹脂に通し、それによりA1PIがアニオン交換樹脂に結合する工程;
(c)アニオン交換樹脂からA1PIを溶出して、A1PIを含む溶出された溶液を得る工程;
(d)溶出された溶液をカチオン交換樹脂に通す工程;
(e)A1PIを含むカチオン交換樹脂からフロースルー画分を収集する工程;及び
(f)工程(c)の溶出された溶液又は工程(e)のフロースルー画分を少なくとも1つのHIC媒質の疎水性吸着剤と接触させる工程。
大部分がApoTfのトランスフェリンを含む組成物及び大部分がHoloTfのトランスフェリンを含む組成物は、正常酸素及び低酸素条件下における6時間の処理後にHIF-1αタンパク質を誘導する。
大部分がApoTfのトランスフェリンを含む組成物及び大部分がHoloTfのトランスフェリンを含む組成物は、正常酸素条件下における24時間の処理後にHIF-1αタンパク質を誘導する。
ApoTf及びHoloTfの混合物は、6時間の処理後にHIF-1αタンパク質を誘導する。
HSA、アポトランスフェリン又はホロトランスフェリンの存在下、正常酸素及び低酸素条件におけるGlut1及びVEGFのmRNA発現量。
ApoTf及びHoloTfの混合物は、インビトロ又はインビボにおいて毒性を示さない。
スコア0:明白な神経学的異常なし;
スコア1:体のねじれあり;
スコア2:体のねじれ、右側の脱力;
スコア3:体のねじれ、右側の脱力、旋回行動;及び
スコア4:発作活動。
スコア1:元気/活動的/反応を示す;ラットは自発的に動き、ケージを見て回る、外的刺激に反応する、ケージの上部を見て回る;
スコア2:静か/警戒/反応を示す;行動は控えめであるが外的刺激には反応する、後ろ足で立ったり、ケージの上部を見て回ったりすることはほとんどない;
スコア3:元気のない行動:つつかれない限りほとんど動かない、傾眠状態にすぐに戻る、外的刺激への関心がほとんどないから全くない;
スコア4:無反応:つつかれた際にも横たわった姿勢のまま;及び
スコア5:安楽死が必要な発作活動。
インビボにおけるトランスフェリンによる細胞保護。
ApoTf及びHoloTfはAβ 1-42の毒性からSH-SY5Yを保護する。
小分子HIF活性化物質及びApoTf/HoloTf混合物に関する相乗効果。
大部分がアポトランスフェリンのトランスフェリン及びDFO又はIOX2の組み合わせに反応したGlut1及びVEGFのmRNA発現量。
大部分がApoTfのトランスフェリンの組成物及び大部分がHoloTfのトランスフェリンの組成物がヒト初代腎細胞においてHIF-1αタンパク質を誘導する。
大部分がApoTfのトランスフェリン又はDFOの存在下におけるヒト初代腎細胞内のカスパーゼ3/7の活性化を伴う、トランスフェリン又はDFOの存在下におけるヒト初代腎細胞の生存率。
ヒト初代肝細胞又は肺細胞株NCI-H1650では、HIFのアップレギュレーションは観察されなかった。
トランスフェリンの存在下におけるNCI-H1650及びヒト初代肝細胞の生存率。
ヒト神経細胞株SH-SY5Yで行われた実験から、血漿由来のアポトランスフェリン及びホロトランスフェリンの両方が細胞のHIF-1αの量を増加させることが示された。正常酸素及び低酸素両条件下においてHIF-1α量が増加した。正常な酸素条件においてアポトランスフェリンを細胞へ投与すると、細胞が低酸素環境に曝露された場合に見られる量と同様のレベルにまでHIF-1αの量が引き上げられた。正常酸素条件においてSH-SY5Y細胞をアポトランスフェリンに長期間曝露すると、HIF-1αの量が短時間の場合よりも大幅に増加した。陰性対照のヒト血清アルブミンは、HIF-1α量に何の影響ももたらさなかった。
1 MRLAVGALLV CAVLGLCLAV PDKTVRWCAV SEHEATKCQS FRDHMKSVIP SDGPSVACVK
61 KASYLDCIRA IAANEADAVT LDAGLVYDAY LAPNNLKPVV AEFYGSKEDP QTFYYAVAVV
121 KKDSGFQMNQ LRGKKSCHTG LGRSAGWNIP IGLLYCDLPE PRKPLEKAVA NFFSGSCAPC
181 ADGTDFPQLC QLCPGCGCST LNQYFGYSGA FKCLKDGAGD VAFVKHSTIF ENLANKADRD
241 QYELLCLDNT RKPVDEYKDC HLAQVPSHTV VARSMGGKED LIWELLNQAQ EHFGKDKSKE
301 FQLFSSPHGK DLLFKDSAHG FLKVPPRMDA KMYLGYEYVT AIRNLREGTC PEAPTDECKP
361 VKWCALSHHE RLKCDEWSVN SVGKIECVSA ETTEDCIAKI MNGEADAMSL DGGFVYIAGK
421 CGLVPVLAEN YNKSDNCEDT PEAGYFAVAV VKKSASDLTW DNLKGKKSCH TAVGRTAGWN
481 IPMGLLYNKI NHCRFDEFFS EGCAPGSKKD SSLCKLCMGS GLNLCEPNNK EGYYGYTGAF
541 RCLVEKGDVA FVKHQTVPQN TGGKNPDPWA KNLNEKDYEL LCLDGTRKPV EEYANCHLAR
601 APNHAVVTRK DKEACVHKIL RQQQHLFGSN VTDCSGNFCL FRSETKDLLF RDDTVCLAKL
661 HDRNTYEKYL GEEYVKAVGN LRKCSTSSLL EACTFRRP
Sequence Reference:
GENBANK ACCESSION AAB22049
AUTHORS Hershberger,C.L., Larson,J.L., Arnold,B., Rosteck,P.R. Jr.,
Williams,P., DeHoff,B., Dunn,P., O'Neal,K.L., Riemen,M.W.,
Tice,P.A. et al.
TITLE A cloned gene for human transferrin
JOURNAL Ann. N. Y. Acad. Sci. 646, 140-154 (1991)
Claims (21)
- HIF関連の病的状態を治療する方法であって、
a.それを必要とする患者のHIF関連の病的状態を診断する工程、及び
b.前記患者に治療有効量のトランスフェリンを含む組成物を投与する工程
を含む、方法。 - 前記組成物は、治療的有効量のトランスフェリン及び鉄キレーター又はPHD2酵素阻害物質のいずれかを含む、請求項1に記載の方法。
- 前記HIF関連の病的状態は、移植レシピエントの臓器移植と関連づけられる、請求項1に記載の方法。
- 前記臓器は、前記レシピエントへの移植に備えて、トランスフェリンを含む組成物により処置されている、請求項3に記載の方法。
- 前記臓器は、前記レシピエントへの移植に備えて、トランスフェリンを含む組成物及び鉄キレーター又はPHD2酵素阻害物質により処置されている、請求項4に記載の方法。
- 前記状態は、手術前の患者の虚血又は酸素欠乏と関連づけられる、請求項1に記載の方法。
- 前記状態は、心停止、血栓塊又は外傷に起因する虚血である、請求項1に記載の方法。
- 外科的処置の間に血流の遮断が起こる、請求項1に記載の方法。
- 前記状態は、アルツハイマー病、パーキンソン病、ハンチントン病及び筋萎縮性側索硬化症からなる群から選択される神経変性疾患に起因する、請求項1に記載の方法。
- 前記トランスフェリンは組換え型である、請求項1に記載の方法。
- 前記トランスフェリンは、ペグ化、グリコシル化、ポリシアリル化又は免疫グロブリンのFcドメイン、アルブミン、グルカゴン様ペプチド-1、エキセンディン-4、XTEN等、血中半減期を延長するドメインとの共有結合融合(covalent fusion)を含む、前記トランスフェリンの血漿半減期を延長するためのその他の物理的修飾によって修飾される、請求項1に記載の方法。
- 前記トランスフェリンは、完全長型トランスフェリン又はトランスフェリンのフラグメントと任意のその他のタンパク質、タンパク質フラグメント又はペプチドとのタンパク質コンジュゲートである、請求項1に記載の方法。
- 前記トランスフェリンは、金属結合親和性を高めるように修飾される、請求項1に記載の方法。
- 前記トランスフェリンは、50%を超える類似性を含むトランスフェリンの誘導体である、請求項1に記載の方法。
- 前記トランスフェリンは、ホロトランスフェリン単独である、請求項1に記載の方法。
- 前記トランスフェリンは、アポトランスフェリン単独である、請求項1に記載の方法。
- 前記トランスフェリンは、99% Apo-Tf:1% Holo-Tfから30% Apo-Tf:70% Holo-Tfの比率又は生体液から得られた若しくは精製された画分と最も類似した割合のアポトランスフェリン及びホロトランスフェリンの混合物である、請求項1に記載の方法。
- 前記組成物は、鉄キレーターを更に含む、請求項1に記載の方法。
- 前記鉄キレーターは、M30、デフェロキサミン(DFO)、デフェラシロクス、デフェリプロン、デフェリトリン、L1NAll、CP363、CP502又はエチレンジアミン四酢酸(EDTA)である、請求項1に記載の方法。
- 前記PHD2酵素阻害物質は、IOX2、IOX3、ジメチルオキサリルグリシン又はその他の2-オキソグルタレート結合部位分子である、請求項1に記載の方法。
- 血液濃度が少なくとも25uM及び最大250uM、最も好ましくは175uMに達するトランスフェリン及び500〜6000mg、最も好ましくは1000mgのデフェロキサミン(DFO)を含む医薬組成物。
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CN107831315B (zh) * | 2017-10-31 | 2019-11-05 | 中国科学院昆明动物研究所 | 转铁蛋白标志物及其应用 |
AU2021306631A1 (en) * | 2020-07-08 | 2023-02-02 | Grifols Worldwide Operations Limited | Compositions having neuroregenerative applications |
KR20230038194A (ko) * | 2020-07-08 | 2023-03-17 | 그리폴즈 월드와이드 오퍼레이션스 리미티드 | 신경재생 응용성을 가진 조성물 |
RU2747653C1 (ru) * | 2021-01-11 | 2021-05-11 | Государственное бюджетное учреждение Санкт-Петербургский научно-исследовательский институт скорой помощи им. И.И. Джанелидзе | Способ диагностики нарушения обмена железа при тяжелых формах covid-19 |
EP4052723A1 (en) | 2021-03-02 | 2022-09-07 | Grifols Worldwide Operations Limited | Alpha-1 antitrypsin dosing regimen |
EP4311556A1 (en) | 2022-07-28 | 2024-01-31 | Grifols Worldwide Operations Limited | Antithrombin in stroke |
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