KR100808089B1 - 인간 과립구콜로니자극인자 변이체 및 이의 화학적 접합물 - Google Patents
인간 과립구콜로니자극인자 변이체 및 이의 화학적 접합물 Download PDFInfo
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- KR100808089B1 KR100808089B1 KR1020070045393A KR20070045393A KR100808089B1 KR 100808089 B1 KR100808089 B1 KR 100808089B1 KR 1020070045393 A KR1020070045393 A KR 1020070045393A KR 20070045393 A KR20070045393 A KR 20070045393A KR 100808089 B1 KR100808089 B1 KR 100808089B1
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/53—Colony-stimulating factor [CSF]
- C07K14/535—Granulocyte CSF; Granulocyte-macrophage CSF
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- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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Abstract
Description
변이체 | |||
실시예 | 변이위치 | 변이체 회수율(%) | maleimide-PEG 접합율(%) |
1 | Ala 128 Cys | 0.01 | 0 |
2 | Ala 130 Cys | 8 | 3 |
3 | Leu 131 Cys | 30 | 3 |
4 | Gln 132 Cys | 50 | 35 |
5 | Thr 134 Cys | 50 | 70 |
6 | Gln 135 Cys | 40 | 70 |
7 | Gly 136 Cys | 18 | 0.01 |
8 | Ala 137 Cys | 62 | 30 |
9 | Met 138 Cys | 34 | 0.01 |
10 | Ala 140 Cys | 0.01 | 0 |
11 | Ala 142 Cys | 0.01 | 0 |
변이체 | |||
실시예 | 변이위치 | 변이체 회수율(%) | maleimide-PEG 접합율(%) |
12 | Ala 128 Cys, Cys 18 Ser | 0.5 | 0 |
13 | Ala 130 Cys, Cys 18 Ser | 10 | 10 |
14 | Leu 131 Cys, Cys 18 Ser | 30 | 5 |
15 | Gln 132 Cys, Cys 18 Ser | 45 | 30 |
16 | Thr 134 Cys, Cys 18 Ser | 55 | 75 |
17 | Gln 135 Cys, Cys 18 Ser | 43 | 65 |
18 | Gly 136 Cys, Cys 18 Ser | 15 | 0.01 |
19 | Ala 137 Cys, Cys 18 Ser | 64 | 35 |
20 | Met 138 Cys, Cys 18 Ser | 30 | 0.01 |
21 | Ala 140 Cys, Cys 18 Ser | 0.01 | 0 |
22 | Ala 142 Cys, Cys 18 Ser | 0.01 | 0 |
변이체 | |||
실시예 | 변이위치 | 변이체 회수율(%) | maleimide-PEG 접합율(%) |
23 | 130 Cys 131 | 45 | 45 |
24 | 131 Cys 132 | 40 | 20 |
25 | 134 Cys 135 | 45 | 0.01 |
26 | 135 Cys 136 | 50 | 37 |
27 | 136 Cys 137 | 75 | 85 |
28 | 137 Cys 138 | 25 | 15 |
변이체 | |||
실시예 | 변이위치 | 변이체 회수율(%) | maleimide-PEG 접합율(%) |
29 | 130 Cys 131, Cys 18 Ser | 50 | 40 |
30 | 131 Cys 132, Cys 18 Ser | 45 | 15 |
31 | 134 Cys 135, Cys 18 Ser | 55 | 0.01 |
32 | 135 Cys 136, Cys 18 Ser | 40 | 43 |
33 | 136 Cys 137, Cys 18 Ser | 85 | 70 |
34 | 137 Cys 138, Cys 18 Ser | 23 | 20 |
변이체 | ||||
실시예 | 변이위치 | 변이체 회수율(%) | maleimide-PEG 접합율(%) | PEG 접합물의 NFS 60 활성화(%)[Filgrastim 100% 기준] |
1 | Ala 128 Cys | 0.01 | 0 | - |
2 | Ala 130 Cys | 8 | 3 | 21 |
3 | Leu 131 Cys | 30 | 3 | 2 |
4 | Gln 132 Cys | 50 | 35 | 40 |
5 | Thr 134 Cys | 50 | 70 | 210 |
6 | Gln 135 Cys | 40 | 70 | 30 |
7 | Gly 136 Cys | 18 | 0.01 | - |
8 | Ala 137 Cys | 62 | 30 | 40 |
9 | Met 138 Cys | 34 | 0.01 | - |
10 | Ala 140 Cys | 0.01 | 0 | - |
11 | Ala 142 Cys | 0.01 | 0 | - |
12 | Ala 128 Cys, Cys 18 Ser | 0.5 | 0 | - |
13 | Ala 130 Cys, Cys 18 Ser | 10 | 10 | 21 |
14 | Leu 131 Cys, Cys 18 Ser | 30 | 5 | 5 |
15 | Gln 132 Cys, Cys 18 Ser | 45 | 30 | 45 |
16 | Thr 134 Cys, Cys 18 Ser | 55 | 75 | 230 |
17 | Gln 135 Cys, Cys 18 Ser | 43 | 65 | 45 |
18 | Gly 136 Cys, Cys 18 Ser | 15 | 0.01 | - |
19 | Ala 137 Cys, Cys 18 Ser | 64 | 35 | 55 |
20 | Met 138 Cys, Cys 18 Ser | 30 | 0.01 | - |
21 | Ala 140 Cys, Cys 18 Ser | 0.01 | 0 | - |
22 | Ala 142 Cys, Cys 18 Ser | 0.01 | 0 | - |
23 | 130 Cys 131 | 45 | 45 | 48 |
24 | 131 Cys 132 | 40 | 20 | 60 |
25 | 134 Cys 135 | 45 | 0.01 | - |
26 | 135 Cys 136 | 50 | 37 | 43 |
27 | 136 Cys 137 | 75 | 85 | 270 |
28 | 137 Cys 138 | 25 | 15 | 65 |
29 | 130 Cys 131, Cys 18 Ser | 50 | 40 | 60 |
30 | 131 Cys 132, Cys 18 Ser | 45 | 15 | 70 |
31 | 134 Cys 135, Cys 18 Ser | 55 | 0.01 | - |
32 | 135 Cys 136, Cys 18 Ser | 40 | 43 | 50 |
33 | 136 Cys 137, Cys 18 Ser | 85 | 70 | 350 |
34 | 137 Cys 138, Cys 18 Ser | 23 | 20 | 70 |
대조구 | 실시예 | 실시예 | 실시예 | 실시예 | |
필그라스팀 | 20kDa PEG-M1 | 20kDa PEG-M1_S | 20kDa PEG-M2 | 20kDa PEG-M2_S | |
혈중반감기 (T1 /2, hr) | 1.9 | 7.9 | 8.2 | 8.9 | 9.7 |
Claims (5)
- 서열번호 1의 아미노산 서열을 포함하는 인간 과립구콜로니자극인자(G-CSF)의 133번 위치의 트레오닌(Thr)잔기가 시스테인(Cys)잔기로 치환되어 있는 서열번호 3의 인간 과립구콜로니자극인자 변이체의 상기 치환된 시스테인(Cys)잔기에 생체적합성고분자(biocompatible polymer)가 수식된 것인 인간 과립구콜로니자극인자 변이체의 접합체.
- 제1항에 있어서, 인간 과립구콜로니자극인자(G-CSF) 변이체의 17번 시스테인(Cys)잔기가 세린(Ser)잔기로 치환된 서열번호 4의 인간 과립구콜로니자극인자 변이체의 접합체.
- 제1항 또는 제2항에 있어서, 상기 생체적합성고분자는 폴리에틸렌글리콜(PEG), 폴리비닐알코올(PVA), 폴리카르복실산 및 폴리비닐피롤리돈으로 이루어진 군에서 선택된 1종 이상과 말레이미드(maleimide), 비닐설폰(vinyl sulfone), 이오도아세트아미드(iodacetamide) 및 오르토피리딜 디설파이드(orthopyridyl disulfide)로 이루어진 군에서 선택된 1종이 상호 결합한 것인 인간 과립구콜로니자극인자 변이체의 접합체.
- 제1항 또는 제2항에 있어서, 상기 생체적합성고분자가 2 내지 100 kDa의 분 자량을 가지는 것인 인간 과립구콜로니자극인자 변이체의 접합체.
- 제3항에 있어서, 상기 폴리에틸렌글리콜(PEG)이 5 내지 100 kDa의 분자량을 가지는 것인 인간 과립구콜로니자극인자 변이체의 접합체.
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