CN100536910C - 胸腺素α1肽/聚合物结合物 - Google Patents

胸腺素α1肽/聚合物结合物 Download PDF

Info

Publication number
CN100536910C
CN100536910C CNB028218728A CN02821872A CN100536910C CN 100536910 C CN100536910 C CN 100536910C CN B028218728 A CNB028218728 A CN B028218728A CN 02821872 A CN02821872 A CN 02821872A CN 100536910 C CN100536910 C CN 100536910C
Authority
CN
China
Prior art keywords
peptide
thymosin
peg
conjugate
patient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CNB028218728A
Other languages
English (en)
Other versions
CN1582162A (zh
Inventor
阿尔佛雷德·R·鲁道夫
辛西娅·W·塔特希尔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Saisheng Pharmaceutical Co ltd
Original Assignee
Sciclone Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sciclone Pharmaceuticals LLC filed Critical Sciclone Pharmaceuticals LLC
Publication of CN1582162A publication Critical patent/CN1582162A/zh
Application granted granted Critical
Publication of CN100536910C publication Critical patent/CN100536910C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/62—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 the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/56—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 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Abstract

一种药物组合物，包括一有生理活性的结合物，该结合物含有与一材料结合的胸腺素α1(TA1)肽，当将所述结合物给药于患者时，该材料增加TA1肽在患者血浆中的半衰期。该材料可以是一基本上非抗原的聚合物。在本发明的方法中，将基本上非抗原的聚合物与一TA1肽连接。将本发明的组合物给药于需要免疫刺激的患者。

Description

胸腺素α1肽/聚合物结合物
发明背景
1、发明领域
本发明涉及胸腺素α1肽。
2、背景技术描述
胸腺素α1(有时被称之为TA1)是一个具有免疫调节功能的28个氨基酸的胸腺肽，与最初从小牛胸腺的胸腺素分部5分离的天然产物类似。其生物学功效包括增进T淋巴细胞功能并包括调控白细胞介素-2(IL-2)、刺激干扰素-γ产生、诱导T淋巴细胞和NK细胞活性，以及刺激胸腺生成作用。胸腺素α1还显示出上调MHC族I表达的作用。
在本领域中一直需要改进含有TA1和相关肽的组合物。
发明概述
按照本发明的药物组合物包括一有生理活性的结合物，该结合物含有与一物质结合的胸腺素α1(TA1)肽，当将所述结合物给药于患者时，该物质可增加TA1肽在患者血浆中的半衰期。该物质可以是一基本上非抗原的聚合物。根据本发明的方法，将一基本上非抗原的聚合物与一TA1肽连接。将按照本发明的组合物给药于需要免疫刺激的患者。
发明详述
本发明使用的TA1肽包括天然产生的TA1和合成TA1以及具有天然产生的TA1的氨基酸序列、与其实质上相同的氨基酸序列、或其简并的序列类型的重组TA1，以及具有取代的、缺失的、延长的、置换的、或甚至修饰的序列的类似物，这些类似物具有与TA1实质上相同的生物活性，例如具有与TA1足够的氨基酸同源性的TA肽，以至于其以与TA1具有实质上相同活性的实质上相同的方式发挥作用。
按照本发明的药物组合物包括含有与一物质结合的TA1肽的有生理活性的结合物，当将所述结合物给药于患者时，所述的物质可增加TA1肽在患者血浆中的半衰期。该物质可以是一基本上非抗原的聚合物。合适的聚合物具有范围约为200～300,000的分子量，优选为约在1,000～100,000范围内，更优选为约在5,000～35,000范围内，而最优选为约10,000～30,000范围内，分子量约为20,000是特别好的。
其中包括的聚合的物质也最好是室温下水溶性的。这种聚合物的一个非限制的实例包括例如聚乙二醇(PEG)或聚丙二醇的聚烷撑氧均聚物、聚氧乙烯基多元醇、其共聚物或其嵌段共聚物(维持该嵌段共聚物的水溶性的条件下)。在基本上非抗原的聚合物中，单一有活性的烷基封端的聚烷撑氧(PAO)，例如单甲基封端的聚乙二醇(mPEG)是预期可选用的。除了mPEG外，也可以使用C1-4烷基封端的聚合物。
作为基于PAO的聚合物的另一种选择，也可以使用例如右旋糖酐、聚乙烯基砒络烷酮、聚丙烯酰胺、聚乙烯醇、碳水化合物基的聚合物等等有效的非抗原材料。本领域技术人员应当认识到前述的列举仅仅为了说明，具有这里描述的性质的所有聚合物材料都是预期可选用的。用于本发明的目的，“有效的非抗原”意为在本领域中所理解的所有被认为无毒性的并且不会在哺乳动物中引起明显的致免疫反应的材料。
该聚合物可以是直链的或分支的。聚乙二醇(PEG)是特别优选的聚合物。
可以通过任何适当的方式将聚合物与TA1肽连接。用于连接聚合物与肽的典型的方法在美国专利No.4,179,337、4,766,106、4,917,888、5,122,614和6,177,074，以及PCT国际公开WO95/13090中公开，这里通过引用结合进来。胸腺素α1具有5个用于聚合物的氨基结合的独立的位点，并且聚合物(多个聚合物)可以在一个或多个位点结合。按照一个实施方案，将20,000分子量的PEG与TA1的N末端结合形成PEG-TA1。如本领域技术人员所知，用适当的侧链保护基团，可以通过在不溶的聚合体支持珠(polymeric support beads)的TA1的固相肽合成形成PEG-TA1。在珠(beads)上完全合成TA1肽后，将被保护的TA1从珠上劈离留下具有自由氨基的N末端，再与20,000分子量的PEG反应。然后除去侧链保护基团，形成按照本发明实施方案的结合物。
按照本发明的组合物可以用于需要免疫刺激的患者的治疗。这类患者可以包括癌症病人、包括乙型肝炎或丙型肝炎病毒感染的肝炎病人、HIV病人等。方法涉及给药于患者免疫刺激有效量的有生理活性的本发明结合物。
TA1肽的分离、特性和用途已在例如美国专利No.4,079,127、美国专利No.4,353,821、美国专利No.4,148,788和美国专利No.4,116,951中描述。免疫刺激有效量的TA1肽可以通过常规剂量滴定实验来确定。已发现当以高至16mg/kg体重/天的剂量给药时，TA1对于人类是安全的。TA1肽的优选剂量是在0.001mg/kg体重/天至10mg/kg体重/天的范围内，典型的剂量是大约0.02mg/kg体重/天。按照一个实施方案，免疫刺激有效量是包括TA1肽总计在大约0.1-10mg范围内的剂量。优选的剂量包括TA1肽总计在大约1-5mg范围内。上述剂量仅反映存在于组合物中的TA1肽，不反映与其结合的聚合物的重量。
在优选的实施方案中，TA1肽存在于药学上可接受的液体载体中，例如注射用水、生理浓度的盐水或类似的液体中。
皮下注射的TA1的血浆半衰期仅约2小时。然而，本发明聚合物与TA1肽的结合物实质上增加了该肽的血浆半衰期。
通过以下的实施例进一步说明但并无意限制本发明。
【实施例1】
用5-氟尿嘧啶(5-FU)注射大鼠引起免疫抑制，然后用胸腺素α1(200μg/kg)或PEG基结合的(pegylated)胸腺素α1(20,000MW PEG-胸腺素α1)(等量于摩尔基的200μg/kg的胸腺素分子)注射处理大鼠以确定在免疫参数上的效力。发现：(1)与用胸腺素α1相比，用PEG-胸腺素o1注射在动物中NK活性的恢复(被5-FU降低后)更多；(2)与用胸腺素α1相比，用PEG-胸腺素α1注射在动物中有活性T细胞、CD25+的恢复(被5-FU降低后)更多。
在下面的实施例中，并不打算限制，在一个具有使用外科手术灌输的渗透微型真空泵的癌症治疗模型中评价了TA1的连续注入，该模型以一恒定的流速输送液体5天。给药于大鼠5—氟尿嘧啶(5-FU)以引起免疫抑制，然后8天后(使用5-FU后白细胞计数的最低点)用注射的或注入的TA1治疗。每组8只大鼠，治疗分组是：对照(微型真空泵使用盐水)；低剂量TA1(0.2mg/kgsc注射；空微型真空泵)；高剂量TA1(3.5mg/kg sc注射；空微型真空泵)；以及高剂量注入的TA1(3.5mg/kg用微型真空泵注入)。在基线和5-FU处理8天后(TA1治疗的1天)，以及TA1治疗的5天、12天、20天和27天后测定免疫参数。
【实施例2】
10周龄大鼠，重250—300g，给予100mg/kg5—氟尿嘧啶(5-FU)进行免疫抑制。
5-FU处理8天后，将大鼠随机分入下面的组(n＝8)：
对照(微型真空泵使用盐水)
低剂量TA1，0.2mg/kg s.c.注射；(用空微型真空泵)
高剂量TA1，3.5mg/kg s.c.注射；(用空微型真空泵)
连续注入TA1，通过微型真空泵以3.5mg/kg/5天提供
在基线和5-FU处理8天后(TA1治疗的1天)，以及TA1治疗的5天、12天、20天和27天后测定免疫参数。
评价包括NK活性(暴露于PBMC4小时后从YAC-1细胞中释放的LDH)、总白细胞数(在通过单克隆抗体进行特异性检查后，通过身体的流式细胞计数参数来判断)、总淋巴细胞数(流式细胞术测定CD3+)、以及有活性的淋巴细胞(流式细胞术测定CD25+CD3+)。
在基线的NK活性为42±5％，而5-FU处理后下降至9±2％。低剂量的TA1在12天后导致NK活性的明显恢复，而高剂量的TA1使NK活性仅在5天中就获得了明显恢复。然而，连续注入TA1在5天时能双倍该效应，达到32±4％(相对于高剂量注射组的16±2％，低剂量注射组的12±3％和对照组的11±1％)。只有通过连续注入TA1治疗的动物的NK活性恢复到基线水平。
由形态学测定的总白细胞计数，在用5-FU处理后从14,590±2,071细胞/mm3下降至2597±582细胞/mm3。与未治疗的动物相比，采用注射的低或高剂量TA1治疗组在恢复上倾向于较快的增加。而连续注入TA1的组仅在5天后就令人满意地、明显地并且完全地恢复至基线水平。
5-FU处理后有活性的淋巴细胞(CD3+CD25+)没有明显降低(从65±21细胞/mm3至37±10细胞/mm3)，然而，在高剂量TA1治疗12和20天后，有活性的淋巴细胞明显地增加(分别为297±136细胞/mm3和321±75对166±70和212±77细胞/mm3)。由连续注入提供的TA1导致有活性的淋巴细胞更多的增加，达到422±105和446±73细胞/mm3。
【实施例3】
10周龄大鼠，重250—300g，给予100μg/kg 5—氟尿嘧啶(5-FU)进行免疫抑制。
5-FU处理8天后，将大鼠随机分入下面的组(n＝15)：
对照(微型真空泵使用盐水)
高剂量TA1，3.5mg/kg s.c.注射；(用空微型真空泵)
连续注入TA1，通过微型真空泵以3.5mg/kg/5天提供
在基线和5-FU处理8天后(TA1治疗的1天)，以及TA1治疗的5天和14后测定免疫参数。
评价包括总白细胞数(在通过单克隆抗体进行特异性检查后，通过身体的流式细胞计数参数来判断)、粒细胞(用FITC抗大鼠粒细胞HIS—48进行流式细胞测定)、总淋巴细胞数(流式细胞术测定CD3+)、辅助性T淋巴细胞(流式细胞术测定CD4+)、有活性的淋巴细胞(流式细胞术测定CD25+CD3+)和血浆中的细胞因子表达(通过ELISA测定IL-2和IFN-γ)。
在实施例2中测定了与皮下注射相比通过连续注入提供的TA1对于白细胞总数有明显影响后，人们对于测定哪种类型的白细胞带来了这种增长感兴趣。显示出通过连续注入提供的TA1影响最明显的白细胞种类是粒细胞。在5-FU作用后，粒细胞数从4,485±1,116降至1,249±432。用TA1治疗后导致5天内粒细胞数增至14,652±2,463(与注射TA1的9,924±3,218和无TA1的6,954±1,519比较)，并且这个数目在14天后仍然是最高的。
有趣的是，在该研究中有一只动物既通过注射(3.5mg/kg)又通过连续注入(另外的3.5mg/kg)提供TA1。这只动物不仅健康和精力旺盛，没有明显的不利的反应，而且TA1对测定的免疫参数的影响甚至比其他的那些动物更大。对于粒细胞，与其他采用注入方式治疗的动物的平均14,652±2,463相比，这只研究的动物在5天后具有非常高的19,376细胞/mm3的水平。
5-FU处理后，总淋巴细胞数(CD3+)显著下降(从10,904±1,973细胞/mm3降至1,740±560)。用TA1治疗使得总淋巴细胞数恢复至基线水平，这发生在用连续注入方式提供TA1后仅5天，而用注射方式提供TA1则直至14天都未见这种恢复。
通过注射和注入二种方式提供TA1的那只动物具有与其他动物差不多的淋巴细胞水平(与平均的9,644±961细胞/mm3相比，其为9,765细胞/mm3)，但是在这些淋巴细胞中有活性的淋巴细胞的百分数大大增多(从通过注入方式提供TA1的动物中有活性的淋巴细胞数428±89，或淋巴细胞的4％，增至通过以高剂量注射接着注入TA1的动物中有活性的淋巴细胞数为976，或淋巴细胞的10％)。
用5-FU处理后辅助性T淋巴细胞(CD3+CD4+)也降低，从5，411±1,084细胞/mm3降至1,710±449细胞/mm3。不用TA1治疗的实验这个降低的T细胞水平14天中没有增加。在粒细胞测定中，对于细胞数目恢复的效果，以连续注入方式提供TA1优于注射方式，与粒细胞测定中所见到的结果相反，用这两种输送方式提供TA1都足以将辅助性T细胞的水平恢复至基线。
由于通过注射或通过连续注入提供TA1都可导致CD4+辅助性T淋巴细胞增多，人们对于测定这种增多是归于辅助性T细胞的Th1还是Th2种类影响感兴趣。先前在体外和体内的数据已证明TA1增加T细胞的Th1种类，并且在本研究中也观察到相同的结果。通过连续注入的方式提供TA1比通过皮下注射方式提供TA1导致在血浆水平的Th1细胞因子IL—2更多增加(在连续注入后14天为42±7pg/ml，与之相比，对于采用注射的TA1为21±16pg/ml，而对照动物为10±16pg/ml)。
用TA1治疗导致Th1细胞因子IL-2的增加，并且TA1可使另一Th1细胞因子IFN—γ增加。虽然其水平较低，治疗后5天，皮下注射TA1导致较高的血浆水平的IFN—γ。在用连续注入提供TA1治疗动物14天时，具有最高的血浆水平的IFN—γ(14±5pg/ml，与之相比，对于采用注射的TA1组为10±1pg/ml，而对照组为8±8pg/ml)。
接受注射和连续注入TA1的动物具有更高的2种测定的Th1细胞因子，特别是IFN—γ，治疗14天后为45pg/ml，与之相比，其他动物为14±5pg/ml。
结论：
●在循环系统中维持恒定水平的TA1数天可增加测定的免疫效应。
●这种剂量制度在粒细胞数上导致未预料到的正效果，并且在注射TA1中在单核细胞中观察到正效果。
●未观察到不利事件，甚至在比常规用量高15倍的TA1剂量下使用也未观察到不利事件(并且在一只动物中以超过常规用量的30倍剂量使用)。

Claims (18)

1、一种药物组合物，包括一有生理活性的结合物，该结合物含有与PEG结合的胸腺素α1肽，所述PEG在将所述结合物给药于患者时可增加胸腺素α1肽在患者血浆中的半衰期，并且其中所述结合物和胸腺素α1肽在所述患者中具有比未与该物质结合的胸腺素α1肽高的活性。
2、权利要求1的组合物，其中所述PEG具有约200—3000,000范围内的分子量。
3、权利要求2的组合物，其中所述分子量为约5,000—35,000。
4、权利要求3的组合物，其中所述分子量为约20,000。
5、权利要求1的组合物，其中所述PEG连接于胸腺素α1肽的N—末端部分。
6、权利要求1所述的组合物，其中所述胸腺素α1肽为胸腺素α1。
7、形成权利要求1的组合物的方法，包括将PEG与一胸腺素α1肽结合。
8、权利要求7的方法，其中所述PEG结合于胸腺素α1的N-末端部分。
9、权利要求7的方法，其中所述PEG具有约200-300,000范围的分子量。
10、权利要求9的方法，其中所述分子量为约5,000—35,000。
11、权利要求10的方法，其中所述分子量为约20,000。
12、权利要求7的方法，其中所述胸腺素α1肽为胸腺素α1。
13、权利要求1组合物的在制备药物上的用途，所述药物组合物包括一有生理活性的结合物，该结合物含有与PEG结合的胸腺素α1肽，所述PEG在将所述结合物给药于患者时可增加胸腺素α1肽在患者血浆中的半衰期，并且其中所述胸腺素α1肽和所述结合物在所述患者中具有比未与该物质结合的胸腺素α1肽高的活性。
14、权利要求13的用途，其中所述PEG具有约200—3000,000范围内的分子量。
15、权利要求14的用途，其中所述分子量为约5,000—35,000。
16、权利要求15的用途，其中所述分子量为约20,000。
17、权利要求13的用途，其中所述PEG连接于胸腺素α1肽的N—末端部分。
18、权利要求13所述的用途，其中所述胸腺素α1肽为胸腺素α1。
CNB028218728A 2001-11-01 2002-11-01 胸腺素α1肽/聚合物结合物 Expired - Lifetime CN100536910C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33087001P 2001-11-01 2001-11-01
US60/330,870 2001-11-01

Publications (2)

Publication Number Publication Date
CN1582162A CN1582162A (zh) 2005-02-16
CN100536910C true CN100536910C (zh) 2009-09-09

Family

ID=23291654

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB028218728A Expired - Lifetime CN100536910C (zh) 2001-11-01 2002-11-01 胸腺素α1肽/聚合物结合物

Country Status (17)

Country Link
US (2) US7297676B2 (zh)
EP (1) EP1455766B1 (zh)
JP (1) JP2005511553A (zh)
KR (1) KR20050042230A (zh)
CN (1) CN100536910C (zh)
AT (1) ATE549036T1 (zh)
AU (1) AU2002353964B2 (zh)
BR (1) BR0213821A (zh)
CA (1) CA2465874A1 (zh)
EA (1) EA008703B1 (zh)
IL (1) IL161670A0 (zh)
MX (1) MXPA04004188A (zh)
NO (1) NO20042055L (zh)
NZ (1) NZ532719A (zh)
PL (1) PL373795A1 (zh)
UA (1) UA78726C2 (zh)
WO (1) WO2003037272A2 (zh)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897567B2 (en) 2002-11-25 2011-03-01 Sciclone Pharmaceuticals, Inc. Methods of protecting against radiation damage using alpha thymosin
CN1820024B (zh) * 2003-05-12 2011-06-22 阿费麦克斯公司 新的聚(乙二醇)修饰的化合物及其用途
PT1639011E (pt) * 2003-06-30 2009-01-20 Domantis Ltd Anticorpos (dab) de domínio único peguilados
CN100355786C (zh) * 2004-04-28 2007-12-19 江苏豪森药业股份有限公司 聚乙二醇修饰的胸腺肽1衍生物
CN1314708C (zh) * 2004-05-24 2007-05-09 华东师范大学 一种人α1－胸腺肽的复合物及其制备方法
CN100500844C (zh) * 2005-03-07 2009-06-17 上海普洛康裕药物研究院有限公司 重组胸腺素α1在大肠杆菌中的高分泌表达和分离纯化
CN100577685C (zh) * 2005-11-10 2010-01-06 中国人民解放军军事医学科学院毒物药物研究所 长效胸腺素α1的聚乙二醇化修饰物
CN101062950B (zh) * 2006-04-25 2010-04-21 江苏豪森药业股份有限公司 聚乙二醇修饰的胸腺肽1衍生物
US8017129B2 (en) * 2006-06-15 2011-09-13 SciClone Pharmaceuticals International Ltd Use of thymosin alpha 1 for preparing a medicament for the treatment of stage IV malignant melanoma
US20080300166A1 (en) * 2007-06-01 2008-12-04 Sciclone Pharmaceuticals, Inc. Treatment of Melanoma with Alpha Thymosin Peptides
WO2010033240A2 (en) 2008-09-19 2010-03-25 Nektar Therapeutics Carbohydrate-based drug delivery polymers and conjugates thereof
EP2344199A1 (en) * 2008-09-19 2011-07-20 Nektar Therapeutics Polymer conjugates of thymosin alpha 1 peptides
WO2010129947A2 (en) * 2009-05-08 2010-11-11 Sciclone Pharmaceuticals, Inc. Alpha thymosin peptides as vaccine enhancers
ES2873844T3 (es) 2012-05-18 2021-11-04 Replicor Inc Composiciones de complejo de quelato de oligonucleótido y polipéptido y métodos

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4079127A (en) * 1976-10-28 1978-03-14 Board Of Regents Of The University Of Texas Thymosin alpha 1
US4179337A (en) * 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4353821A (en) * 1979-05-15 1982-10-12 Max Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Method of preparing thymosin α1 and derivatives thereof

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4116951A (en) 1977-04-22 1978-09-26 Hoffmann-La Roche Inc. [Asn2 ]-thymosin α1 and analogs thereof
US4148788A (en) 1978-01-23 1979-04-10 Hoffmann-La Roche Inc. Synthesis of thymosin α1
US4917888A (en) 1985-06-26 1990-04-17 Cetus Corporation Solubilization of immunotoxins for pharmaceutical compositions using polymer conjugation
US4766106A (en) * 1985-06-26 1988-08-23 Cetus Corporation Solubilization of proteins for pharmaceutical compositions using polymer conjugation
US5122614A (en) 1989-04-19 1992-06-16 Enzon, Inc. Active carbonates of polyalkylene oxides for modification of polypeptides
US5595732A (en) 1991-03-25 1997-01-21 Hoffmann-La Roche Inc. Polyethylene-protein conjugates
WO1994004193A1 (en) * 1992-08-21 1994-03-03 Enzon, Inc. Novel attachment of polyalkylene oxides to bio-effecting substances
CN1094310A (zh) * 1992-12-15 1994-11-02 托马斯·C·梅里根 人体免疫缺陷性病毒感染用组合式化学疗法
NZ276943A (en) 1993-11-10 1998-02-26 Schering Corp Substituted For Alpha-interferon conjugated to a non-antigenic polymer (preferably a polyalkylene oxide) and its preparation
US5632983A (en) 1994-11-17 1997-05-27 University Of South Florida Method for treating secondary immunodeficiency
US5908621A (en) 1995-11-02 1999-06-01 Schering Corporation Polyethylene glycol modified interferon therapy
EP1121424A1 (en) * 1998-10-13 2001-08-08 Novozymes A/S A modified polypeptide with reduced immune response
US6309633B1 (en) * 1999-06-19 2001-10-30 Nobex Corporation Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same
WO2001074399A1 (fr) * 2000-03-30 2001-10-11 Ajinomoto Co., Inc. Medicaments a long temps de conservation dans un tissu
EP1353701B1 (en) * 2000-10-31 2011-12-21 PR Pharmaceuticals, Inc. Methods for producing compositions for enhanced delivery of bioactive molecules
US7610156B2 (en) 2003-03-31 2009-10-27 Xencor, Inc. Methods for rational pegylation of proteins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179337A (en) * 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4079127A (en) * 1976-10-28 1978-03-14 Board Of Regents Of The University Of Texas Thymosin alpha 1
US4353821A (en) * 1979-05-15 1982-10-12 Max Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Method of preparing thymosin α1 and derivatives thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
胸腺素a1治疗病毒性肝炎的临床应用与前景. 范公忍等.国外医学病毒学分册，第7卷第6期. 2000
胸腺素a1治疗病毒性肝炎的临床应用与前景. 范公忍等.国外医学病毒学分册，第7卷第6期. 2000 *

Also Published As

Publication number Publication date
WO2003037272A2 (en) 2003-05-08
JP2005511553A (ja) 2005-04-28
EA200400592A1 (ru) 2004-12-30
IL161670A0 (en) 2004-09-27
WO2003037272A3 (en) 2003-11-20
US20040248792A1 (en) 2004-12-09
EP1455766B1 (en) 2012-03-14
NO20042055L (no) 2004-05-18
US7297676B2 (en) 2007-11-20
CN1582162A (zh) 2005-02-16
ATE549036T1 (de) 2012-03-15
BR0213821A (pt) 2004-08-31
PL373795A1 (en) 2005-09-19
MXPA04004188A (es) 2004-07-08
EP1455766A4 (en) 2008-11-05
EP1455766A2 (en) 2004-09-15
UA78726C2 (en) 2007-04-25
NZ532719A (en) 2005-11-25
EA008703B1 (ru) 2007-06-29
US20080152668A1 (en) 2008-06-26
AU2002353964B2 (en) 2006-08-03
KR20050042230A (ko) 2005-05-06
CA2465874A1 (en) 2003-05-08

Similar Documents

Publication Publication Date Title
US20080152668A1 (en) Thymosin Alpha 1 Peptide/Polymer Conjugates
Winkelhake et al. Synergistic effects of combination therapy with human recombinant interleukin-2 and tumor necrosis factor in murine tumor models
KR20040007413A (ko) 단기 및 장기 약물 약량측정 방법
US20100221274A1 (en) Method of administering a thymosin alpha 1 peptide
AU707019B2 (en) Use of IL-10 to stimulate peripheral blood mononuclear cell cytolytic activity
CA2466228A1 (en) Method for treating diseases with omega interferon
AU2002353964A1 (en) Thymosin alpha 1 peptide/polymer conjugates
Bui et al. Differential disposition of soluble and liposome-formulated human recombinant interleukin-7: effects on blood lymphocyte population in guinea pigs
AU2002363248A1 (en) Method of administering a Thymosin alpha 1 peptide
EP1570269B1 (en) Methods of protecting against radiation damage using alpha thymosin
EA009945B1 (ru) Способ лечения или профилактики респираторной коронавирусной инфекции с использованием пептидов альфа-тимозина
CA2188871C (en) Method for treating psoriasis
RU7872U1 (ru) Препарат "беталейкин"
AU2008200190A1 (en) Method of Administering a Thymosin Alpha 1 Peptide

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C56 Change in the name or address of the patentee

Owner name: SAISHENG PHARMACEUTICAL CO.,LTD.

Free format text: FORMER NAME: SCICLONE PHARMACEUTICALS INC.

CP01 Change in the name or title of a patent holder

Address after: California, USA

Patentee after: SCICLONE PHARMACEUTICALS, Inc.

Address before: California, USA

Patentee before: SCICLONE PHARMACEUTICALS, Inc.

PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Thymosin alpha 1 peptide/polymer conjugates

Effective date of registration: 20180628

Granted publication date: 20090909

Pledgee: China Minsheng Banking Corp Hongkong branch

Pledgor: SciClone Pharmaceuticals, Inc.

Registration number: 2018990000502

PE01 Entry into force of the registration of the contract for pledge of patent right
CP01 Change in the name or title of a patent holder

Address after: California, USA

Patentee after: Saisheng Pharmaceutical Co.,Ltd.

Address before: California, USA

Patentee before: SciClone Pharmaceuticals, Inc.

CP01 Change in the name or title of a patent holder
CP01 Change in the name or title of a patent holder

Address after: California, USA

Patentee after: SCICLONE PHARMACEUTICALS, Inc.

Address before: California, USA

Patentee before: Saisheng Pharmaceutical Co.,Ltd.

CP01 Change in the name or title of a patent holder
PC01 Cancellation of the registration of the contract for pledge of patent right
PC01 Cancellation of the registration of the contract for pledge of patent right

Date of cancellation: 20200401

Granted publication date: 20090909

Pledgee: China Minsheng Banking Corp Hongkong branch

Pledgor: SCICLONE PHARMACEUTICALS, Inc.

Registration number: 2018990000502

PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Thymosin alpha 1 peptide/polymer conjugates

Effective date of registration: 20200402

Granted publication date: 20090909

Pledgee: China Minsheng Banking Corp Hongkong branch

Pledgor: SCICLONE PHARMACEUTICALS, Inc.

Registration number: Y2020990000265

PE01 Entry into force of the registration of the contract for pledge of patent right
PC01 Cancellation of the registration of the contract for pledge of patent right

Date of cancellation: 20200925

Granted publication date: 20090909

Pledgee: China Minsheng Banking Corp Hongkong branch

Pledgor: SCICLONE PHARMACEUTICALS, Inc.

Registration number: Y2020990000265

PC01 Cancellation of the registration of the contract for pledge of patent right
TR01 Transfer of patent right

Effective date of registration: 20201125

Address after: Greater Cayman, Cayman Islands

Patentee after: Saisheng Pharmaceutical Co.,Ltd.

Address before: California, USA

Patentee before: SCICLONE PHARMACEUTICALS, Inc.

TR01 Transfer of patent right
PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Thymosin a 1 peptide / polymer conjugate

Effective date of registration: 20210119

Granted publication date: 20090909

Pledgee: China Minsheng Banking Corp Hongkong branch

Pledgor: Saisheng Pharmaceutical Co.,Ltd.

Registration number: Y2021990000080

PE01 Entry into force of the registration of the contract for pledge of patent right
CX01 Expiry of patent term

Granted publication date: 20090909

CX01 Expiry of patent term
PC01 Cancellation of the registration of the contract for pledge of patent right
PC01 Cancellation of the registration of the contract for pledge of patent right

Granted publication date: 20090909

Pledgee: China Minsheng Banking Corp Hongkong branch

Pledgor: Saisheng Pharmaceutical Co.,Ltd.

Registration number: Y2021990000080