CN1251043A - 可从动物器官中提取的蛋白质在制备可用于治疗疾病的药物中的用途 - Google Patents

可从动物器官中提取的蛋白质在制备可用于治疗疾病的药物中的用途 Download PDF

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CN1251043A
CN1251043A CN98803626A CN98803626A CN1251043A CN 1251043 A CN1251043 A CN 1251043A CN 98803626 A CN98803626 A CN 98803626A CN 98803626 A CN98803626 A CN 98803626A CN 1251043 A CN1251043 A CN 1251043A
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A·潘尼莱
P·L·麦罗尼
A·巴托莱利
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

可利用高氯酸从哺乳动物肝脏尤其是山羊肝脏中提取出来的蛋白质可以降低血液中肿瘤坏死因子(TNF)的水平,并且可用于治疗多发性硬化症、类风湿性关节炎、败血症性休克及其它以肿瘤坏死因于过量产生为特征的疾病。

Description

可从动物器官中提取的蛋白质在 制备可用于治疗疾病的药物中的用途
本发明涉及可从动物器官中提取的蛋白质在制备可用于治疗以肿瘤坏死因子(TNF)过量产生为特征之病理状态的药物中的用途。
肿瘤坏死因子，又名恶液质，是一种促炎症反应细胞因子，它与IL-1一起，在启动可引起感染和癌症情况下的免疫反应的其它细胞因子和因子的级联反应中起着重要作用。这一反应对于使感染和肿瘤转移过程完全消退是非常重要的，但它可能以不受控制的方式发生，从而导致对宿主的损害。一般认为肿瘤坏死因子过量产生与一些病理状态相关，如败血症性休克、肿瘤恶病质、自身免疫疾病(类风湿性关节炎、多发性硬化症)、脑膜炎球菌性败血症和Chron’s disease等。
WO 92/10197公开了可利用高氯酸从哺乳动物器官中提取的蛋白质成分，以及它们作为抗肿瘤制剂的用途。在这些成分中，可鉴定出三种主要成分，它们在凝胶电泳中的分子量分别为50、14和10Kda。今后，包含这三种主要成分的纯化提取物称为UK 101。上述活性即使不是全部也主要是由14Kda蛋白质成分决定的，它的序列在WO 96/02567中得到报道，并且被证明与其他作者的发现相关(Levy-Favatirer，Eur.Biochem.1903，212(3)665-73)，该作者推断此种新鉴定的蛋白质属于一个称为伴侣蛋白的蛋白质家族，这个家族也包含热休克蛋白(HSP)。
在WO 92/10197和WO 96/02567中所描述的蛋白质(今后称为UK 114)具有以往在伴侣蛋白及其类似蛋白质中从未观察到的特性。尤其是目前发现这些蛋白质能够显著降低血液中肿瘤坏死因子的水平，因而可用于治疗以肿瘤坏死因子过量产生为特征的疾病。
本发明特别涉及纯化过的蛋白质UK 114的用途。
另外本发明包含与UK 114具有80％以上、尤其是90％或以上高同源性的蛋白质的用途。
蛋白质UK 101和UK 114的活性已在体外在外周血单核白细胞上得到了证实，在体内通过评价UK 101给药后对小鼠脾细胞产生肿瘤坏死因子的影响得到了证实，报告如下：体外实验
在UK 114(1μg/ml和10μg/ml)存在或不存在的条件下，用脂多糖(100ng/ml)体外刺激密度为106/ml的外周血单核白细胞4小时。
由ELISA方法测定肿瘤坏死因子的浓度。结果
体外加入UK 114抑制了外周血单核白细胞产生肿瘤坏死因子。
UK 114浓度为1μg/ml时，抑制效果达90％，浓度为10μg/ml时，抑制效果达70％。体内实验处理：
15天中隔天以100μg/只的剂量用UK 101处理小鼠(7次注射)
分别在第一次注射48小时后和最后一次注射后48小时测定肿瘤坏死因子的浓度。
细胞的制备和肿瘤坏死因子的测定
在有10μg/ml多克隆有丝分裂原伴刀豆球蛋白A(With-A)的存在下，将脾细胞(4×106/ml)于37℃，5％CO2培养48小时。
用免疫酶联方法(ELISA)测定产生并释放到上清中的肿瘤坏死因子的量。结果
小鼠脾细胞产生肿瘤坏死因子的量在经UK 101处理后显著下降。此效果在第一次后注射48小时已经比较显著，在第七次注射后48小时效果依然存在。TNF，pg/ml            生理盐水   UK 101第一次注射后48小时    387±72    247±30□第七次注射后48小时    366±46    264±76.1□□＝p值
因此，UK 101和UK 114能够调整以肿瘤坏死因子过量产生为特征的病理状态(如多发性硬化症、类风湿性关节炎、肿瘤形式、败血症性休克和Chron’s disease等)的进程，或对其进行抑制。
本发明的蛋白质可以以合适的形式给药，优选可注射形式。
给药方法(剂量、给药频率等)可以依据环境决定，取决于一些因素，如患者状况、疾病阶段。然而，1-100mg的日剂量将是合适的。
                        表
Met Ser Glu Asn Ser Glu Glu Pro Val Gly Glu Ala Lys Ala
1               5                   10
Pro Ala Ala Ile Gly Pro Tyr Ser Gln Ala Val Leu Val Asp
15                  20                  25
Arg Thr Ile Tyr Ile Ser Gly Gln Leu Gly Met Asp Pro Ala
    30                  35                  40
Ser Gly Gln Leu Val Pro Gly Gly Val Val Glu Glu Ala Lys
        45                  50                  55
Gln Ala Leu Thr Asn Ile Gly Glu Ile Leu Lys Ala Ala Gly
            60                  65                  70
Cys Asp Phe Thr Asn Val Val Lys Ala Thr Val Leu Leu Ala
                75                  80
Asp Ile Asn Asp Phe Ser Ala Val Asn Asp Val Tyr Lys Gln
85                  90                  95
Tyr Phe Gln Ser Ser Phe Pro Ala Arg Ala Ala Tyr Gln Val
    100                 105                 110
Ala Ala Leu Pro Lys Gly Gly Arg Val Glu Ile Glu Ala Ile
        115                 120                 125
Ala Val Gln Gly Pro Leu Thr Thr Ala Ser Val
            130                 135
                    序列表(1)一般资料(i)申请人：
(A)名称：Zetesis s.p.a
(B)街道：Galleria del Corso 2
(C)城市：Milano
(D)国家：意大利
(E)邮政编码(ZIP)：20122(ii)发明题目：可从动物器官中提取的蛋白质在制备可用于治疗疾病
          的药物中的用途(iii)序列数：1(iv)计算机可读形式：
(A)介质类型：软盘
(B)计算机：IBM PC可兼容机
(C)操作系统：PC-DOS/MS-DOS
(D)软件：PatentIn Release #1.0，Version #1.30(EPO)(2)SEQ ID NO：1的资料：(i)序列特征：
(A)长度：137个氨基酸
(B)类型：氨基酸
(C)链型：
(D)拓扑结构：线性(ii)分子类型：蛋白质(iii)假定的：无(iv)反义：无(xi)序列描述：SEQ ID NO：1Met Ser Glu Asn Ser Glu Glu Pro Val Gly Glu Ala Lys Ala1               5                   10Pro Ala Ala Ile Gly Pro Tyr Ser Gln Ala Val Leu Val Asp15                  20                  25Arg Thr Ile Tyr Ile Ser Gly Gln Leu Gly Met Asp Pro Ala
30                  35                  40Ser Gly Gln Leu Val Pro Gly Gly Val Val Glu Glu Ala Lys
    45                  50                  55Gln Ala Leu Thr Asn Ile Gly Glu Ile Leu Lys Ala Ala Gly
        60                  65                  70Cys Asp Phe Thr Asn Val Val Lys Ala Thr Val Leu Leu Ala
            75                  80Asp Ile Asn Asp Phe Ser Ala Val Asn Asp Val Tyr Lys Gln85                  90                  95Tyr Phe Gln Ser Ser Phe Pro Ala Arg Ala Ala Tyr Gln Val
100                 105                 110Ala Ala Leu Pro Lys Gly Gly Arg Val Glu Ile Glu Ala Ile
    115                 120                 125Ala Val Gln Gly Pro Leu Thr Thr Ala Ser Val
    130                     135

Claims (3)

1.可利用高氯酸从哺乳动物肝脏中提取的蛋白质在制备可用于抑制和治疗以肿瘤坏死因子过量产生为特征之病理状态的药物中的用途。
2.按照权利要求1的用途，其中所述蛋白质有如下序列：
Met Ser Glu Asn Ser Glu Glu Pro Val Gly Glu Ala Lys Ala
1               5                   10
Pro Ala Ala Ile Gly Pro Tyr Ser Gln Ala Val Leu Val Asp
15                  20                  25
Arg Thr Ile Tyr Ile Ser Gly Gln Leu Gly Met Asp Pro Ala
    30                  35                  40
Ser Gly Gln Leu Val Pro Gly Gly Val Val Glu Glu Ala Lys
        45                  50                  55
Gln Ala Leu Thr Asn Ile Gly Glu Ile Leu Lys Ala Ala Gly
            60                  65                  70
Cys Asp Phe Thr Asn Val Val Lys Ala Thr Val Leu Leu Ala
                75                  80
Asp Ile Asn Asp Phe Ser Ala Val Asn Asp Val Tyr Lys Gln
85                  90                  95
Tyr Phe Gln Ser Ser Phe Pro Ala Arg Ala Ala Tyr Gln Val
    100                 105                 110
Ala Ala Leu Pro Lys Gly Gly Arg Val Glu Ile Glu Ala Ile
        115                 120                 125
Ala Val Gln Gly Pro Leu Thr Thr Ala Ser Val
            130                 135
3.按照权利要求1的用途，其中所用的蛋白质与权利要求2中的蛋白质有至少80％的同源性。
CN98803626A 1997-03-25 1998-03-16 可从动物器官中提取的蛋白质在制备可用于治疗疾病的药物中的用途 Pending CN1251043A (zh)

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IT97MI000694A IT1290828B1 (it) 1997-03-25 1997-03-25 Uso di proteine estraibili da organi animali per la preparazione di medicamenti per il trattamento di condizioni patologiche
ITMI97A000694 1997-03-25

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AU (1) AU7207298A (zh)
BR (1) BR9808625A (zh)
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IT (1) IT1290828B1 (zh)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110087670A (zh) * 2016-12-16 2019-08-02 阿尔贝托·巴托雷利库萨尼 稳定聚合物形式的新型重组蛋白uk 114用于治疗、诊断和预防恶性实体和全身性肿瘤

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WO2001093894A2 (en) * 2000-06-08 2001-12-13 Rakepoll Holding B.V. A method of treatment of parkinson's disease with a protein extractable from mammalian organs
US20030153511A1 (en) * 2000-06-08 2003-08-14 Alberto Panerai Method of treatment of huntington's chorea with a protein extractable from mammalian organs
US20030165492A1 (en) * 2000-06-08 2003-09-04 Alberto Panerai Method of treatment of alzheimer's disease with a protein extractable from mammalian organs
CA2411428A1 (en) * 2000-06-08 2001-12-13 Rakepoll Holding B.V. A method of treatment of amyotrophic lateral sclerosis with a protein extractable from mammalian organs
ITMI20010762A1 (it) * 2001-04-10 2002-10-10 Zetesis Spa Uso della proteina uk114 o di suoi frammenti per il trattamento e la prevenzione dello shock endotossico
ITMI20021205A1 (it) * 2002-06-04 2003-12-04 Pharmaproducts Uk Ltd Uso di proteine per il trattamento della leishmaniosi

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GB2251186A (en) * 1990-12-04 1992-07-01 Randall Neal Gatz Polypeptide for use in treatment of autoimmune disease
FR2688227A1 (fr) * 1992-03-04 1993-09-10 Inst Nat Sante Rech Med Proteines formant des complexes avec des chaperones et leurs ligands, leurs fragments, leur obtention et leurs applications biologiques.
US5997873A (en) * 1994-01-13 1999-12-07 Mount Sinai School Of Medicine Of The City University Of New York Method of preparation of heat shock protein 70-peptide complexes
IT1270618B (it) 1994-07-14 1997-05-07 Zetesis Spa Proteine ad attivita' antitumorale
GB9419553D0 (en) 1994-09-27 1994-11-16 Univ Bristol Polypeptides and their use in the treatment of auto-immune disease
DK0928197T3 (da) 1996-09-18 2003-06-23 Zetesis Spa Anvendelse af proteiner som midler mod autoimmune sygdomme
US6007821A (en) * 1997-10-16 1999-12-28 Fordham University Method and compositions for the treatment of autoimmune disease using heat shock proteins

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110087670A (zh) * 2016-12-16 2019-08-02 阿尔贝托·巴托雷利库萨尼 稳定聚合物形式的新型重组蛋白uk 114用于治疗、诊断和预防恶性实体和全身性肿瘤

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PL335829A1 (en) 2000-05-22
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AU7207298A (en) 1998-10-20
IL132013A0 (en) 2001-03-19
WO1998042366A1 (en) 1998-10-01
EP0969859A1 (en) 2000-01-12
KR20010005705A (ko) 2001-01-15
IT1290828B1 (it) 1998-12-11
JP2001518107A (ja) 2001-10-09
HUP0002304A2 (hu) 2000-11-28
NZ337985A (en) 2001-02-23
TR199902331T2 (xx) 2000-01-21
ITMI970694A1 (it) 1998-09-25
NO994622D0 (no) 1999-09-23
CA2284548A1 (en) 1998-10-01
NO994622L (no) 1999-09-23
US6255283B1 (en) 2001-07-03

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