RU2015126920A - Способ лечения состояний, связанных с фактором, индуцируемым гипоксией (hif) - Google Patents
Способ лечения состояний, связанных с фактором, индуцируемым гипоксией (hif) Download PDFInfo
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- RU2015126920A RU2015126920A RU2015126920A RU2015126920A RU2015126920A RU 2015126920 A RU2015126920 A RU 2015126920A RU 2015126920 A RU2015126920 A RU 2015126920A RU 2015126920 A RU2015126920 A RU 2015126920A RU 2015126920 A RU2015126920 A RU 2015126920A
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- Prior art keywords
- transferrin
- hif
- composition
- iron chelator
- protein
- Prior art date
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- 238000000034 method Methods 0.000 title claims 21
- 206010021143 Hypoxia Diseases 0.000 title 1
- 230000007954 hypoxia Effects 0.000 title 1
- 102000004338 Transferrin Human genes 0.000 claims 16
- 108090000901 Transferrin Proteins 0.000 claims 16
- 239000012581 transferrin Substances 0.000 claims 16
- 239000000203 mixture Substances 0.000 claims 6
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims 4
- OEUUFNIKLCFNLN-LLVKDONJSA-N chembl432481 Chemical compound OC(=O)[C@@]1(C)CSC(C=2C(=CC(O)=CC=2)O)=N1 OEUUFNIKLCFNLN-LLVKDONJSA-N 0.000 claims 4
- 229960000958 deferoxamine Drugs 0.000 claims 4
- 102000004169 proteins and genes Human genes 0.000 claims 4
- 108090000623 proteins and genes Proteins 0.000 claims 4
- 102100037249 Egl nine homolog 1 Human genes 0.000 claims 3
- 101710111663 Egl nine homolog 1 Proteins 0.000 claims 3
- 210000000056 organ Anatomy 0.000 claims 3
- 230000001575 pathological effect Effects 0.000 claims 3
- 238000002054 transplantation Methods 0.000 claims 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims 2
- 102000004190 Enzymes Human genes 0.000 claims 2
- 108090000790 Enzymes Proteins 0.000 claims 2
- 108010054176 apotransferrin Proteins 0.000 claims 2
- 239000012634 fragment Substances 0.000 claims 2
- 108010045676 holotransferrin Proteins 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 claims 2
- 208000028867 ischemia Diseases 0.000 claims 2
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 claims 2
- 238000001356 surgical procedure Methods 0.000 claims 2
- CAOSCCRYLYQBES-UHFFFAOYSA-N 2-[[[4-hydroxy-2-oxo-1-(phenylmethyl)-3-quinolinyl]-oxomethyl]amino]acetic acid Chemical group O=C1C(C(=O)NCC(=O)O)=C(O)C2=CC=CC=C2N1CC1=CC=CC=C1 CAOSCCRYLYQBES-UHFFFAOYSA-N 0.000 claims 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims 1
- 102000009027 Albumins Human genes 0.000 claims 1
- 108010088751 Albumins Proteins 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 108010011459 Exenatide Proteins 0.000 claims 1
- TZXKOCQBRNJULO-UHFFFAOYSA-N Ferriprox Chemical compound CC1=C(O)C(=O)C=CN1C TZXKOCQBRNJULO-UHFFFAOYSA-N 0.000 claims 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 claims 1
- 208000010496 Heart Arrest Diseases 0.000 claims 1
- 208000023105 Huntington disease Diseases 0.000 claims 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 claims 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 102100040918 Pro-glucagon Human genes 0.000 claims 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000013060 biological fluid Substances 0.000 claims 1
- 239000008280 blood Substances 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 230000017531 blood circulation Effects 0.000 claims 1
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 claims 1
- 229960003266 deferiprone Drugs 0.000 claims 1
- BNJOZDZCRHCODO-UHFFFAOYSA-N dimethyloxalylglycine Chemical compound COC(=O)CNC(=O)C(=O)OC BNJOZDZCRHCODO-UHFFFAOYSA-N 0.000 claims 1
- 229940125532 enzyme inhibitor Drugs 0.000 claims 1
- 239000002532 enzyme inhibitor Substances 0.000 claims 1
- 229960001519 exenatide Drugs 0.000 claims 1
- 230000004927 fusion Effects 0.000 claims 1
- 230000013595 glycosylation Effects 0.000 claims 1
- 238000006206 glycosylation reaction Methods 0.000 claims 1
- 235000003642 hunger Nutrition 0.000 claims 1
- 208000014674 injury Diseases 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 230000004048 modification Effects 0.000 claims 1
- 238000012986 modification Methods 0.000 claims 1
- 230000004770 neurodegeneration Effects 0.000 claims 1
- 208000015122 neurodegenerative disease Diseases 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 230000006320 pegylation Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000006267 polysialylation Effects 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims 1
- 230000037351 starvation Effects 0.000 claims 1
- 230000001732 thrombotic effect Effects 0.000 claims 1
- 230000008736 traumatic injury Effects 0.000 claims 1
Classifications
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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Claims (23)
1. Способ лечения патологического состояния, связанного с HIF, включающий:
а. диагностирование у пациента, нуждающегося в этом, патологического состояния, связанного с HIF, и
б. введение пациенту композиции, содержащей терапевтически эффективное количество трансферрина.
2. Способ по п. 1, отличающийся тем, что композиция содержит терапевтически эффективное количество трансферрина и либо хелатора железа, либо ингибитора фермента PHD2.
3. Способ по п. 1, отличающийся тем, что патологическое состояние, связанное с HIF, ассоциировано с трансплантацией органа реципиенту трансплантата.
4. Способ по п. 3, отличающийся тем, что орган обрабатывают с применением композиции, содержащей трансферрин, в процессе подготовки к трансплантации в организм реципиента.
5. Способ по п. 4, отличающийся тем, что орган обрабатывают с применением композиции, содержащей трансферрин и хелатор железа или ингибитор фермента PHD2, в процессе подготовки к трансплантации в организм реципиента.
6. Способ по п. 1, отличающийся тем, что состояние ассоциировано с ишемией или кислородным голоданием у пациента перед операцией.
7. Способ по п. 1, отличающийся тем, что состояние является ишемией, вызванной остановкой сердца, тромботическими сгустками или травматическим повреждением.
8. Способ по п. 1, отличающийся тем, что прерывание кровотока происходит во время хирургического вмешательства.
9. Способ по п. 1, отличающийся тем, что состояние вызвано нейродегенеративным заболеванием, выбранным из группы, состоящей из болезни Альцгеймера, болезни Паркинсона, болезни Хантингтона и амиотрофического латерального склероза.
10. Способ по п. 1, отличающийся тем, что указанный трансферрин является рекомбинантным.
11. Способ по п. 1, отличающийся тем, что указанный трансферрин модифицирован путем ПЭГилирования, гликозилирования, полисиалилирования или другой физической модификации с целью продления периода полужизни белка в плазме, включая ковалентное слияние с доменами, продляющими период полужизни в крови, такими как Fc-домен иммуноглобулина, альбумин, глюкагонподобный пептид-1, эксендин-4, XTEN и т.д.
12. Способ по п. 1, отличающийся тем, что указанный трансферрин является белковым конъюгатом полноразмерного трансферрина или фрагментов трансферрина с любым другим белком, фрагментом белка или пептидом.
13. Способ по п. 1, отличающийся тем, что указанный трансферрин модифицирован с целью повышения сродства связывания с металлом.
14. Способ по п. 1, отличающийся тем, что указанный трансферрин является производным трансферрина, обладающим более чем 50% сходством.
15. Способ по п. 1, отличающийся тем, что указанный трансферрин является исключительно голотрансферрином.
16. Способ по п. 1, отличающийся тем, что указанный трансферрин является исключительно апотрансферрином.
17. Способ по п. 1, отличающийся тем, что указанный трансферрин является смесью апотрансферрина и голотрансферрина в соотношении от 99% Apo-Tf : 1% Holo-Tf до 30% Apo-Tf : 70% Holo-Tf или в пропорции, наиболее сопоставимой с фракцией, полученной или выделенной из биологических жидкостей.
18. Способ по п. 1, отличающийся тем, что указанная композиция дополнительно содержит хелатор железа.
19. Способ по п. 1, отличающийся тем, что указанный хелатор железа является M30, дефероксамином (DFO), деферазироксом, деферипроном, деферитрином, L1NA11, СР363, СР502 или этилендиаминтетрауксусной кислотой (ЭДТА).
20. Способ по п. 1, отличающийся тем, что указанный ингибитор фермента PHD2 является IOX2, IOX3, диметилоксалилглицином или другой молекулой с сайтом связывания 2-оксоглутарата.
21. Фармацевтическая композиция, содержащая трансферрин в количестве, позволяющем достичь концентрации в крови от по меньшей мере 25 мкМ до 250 мкМ, предпочтительно 175 мкМ, и дефероксамин (DFO) в количестве 500-6000 мг, предпочтительно 1000 мг.
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| 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 |
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| EP4311556A1 (en) | 2022-07-28 | 2024-01-31 | Grifols Worldwide Operations Limited | Antithrombin in stroke |
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