CN101291684A - 甘醇化和糖基化的禽类来源的治疗性蛋白 - Google Patents
甘醇化和糖基化的禽类来源的治疗性蛋白 Download PDFInfo
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Abstract
包含从转基因鸟禽类获得的糖基化治疗性氨基酸序列的组合物,其中,所述治疗性氨基酸序列是糖蛋白并包含共价结合的甘醇聚合物。
Description
相关申请信息
本申请要求2005年10月21日提交的美国临时专利申请第60/729,429号的优先权,该申请的内容以参见方式引入本说明书中。
发明背景
强烈地需要开发能使患者和医疗保健提供者降低蛋白治疗剂成本的蛋白递送技术。一种解决办法是开发延长蛋白治疗剂体内循环半衰期的方法。该方法也满足了患者“用户友好型”蛋白治疗剂的需要和希望,例如,不需要频繁给药(例如注射)的蛋白治疗剂。
已证明用甘醇聚合物如聚乙二醇(PEG)共价修饰蛋白质是延长蛋白体内循环半衰期的有效方法(Abuchowski等,1984;Hershfield,1987;Meyers等,1991)。甘醇聚合物与蛋白质的共价结合增加了蛋白质的有效大小并降低其体内清除速率。可购得各种大小(即分子量)的甘醇聚合物如PEG,通过使用不同大小的甘醇聚合物可根据各种适应症来调节甘醇聚合物修饰蛋白的循环半衰期。已经报道过的甘醇聚合物修饰(例如PEG修饰)的其它体内优点在于,提高蛋白溶解性、提高蛋白稳定性(可能是因为保护蛋白免于蛋白酶的作用),且降低蛋白免疫原性。例如参见Katre等,1987;Katre,1990。此外,糖基化也能提高蛋白治疗剂的有效性,例如通过增加蛋白质的有效大小并降低其免疫原性和体内清除速率。
发明概述
发现鸟禽类中产生的治疗性蛋白的甘醇酸化(例如,PEG化)与糖基化的组合具有协同作用,蛋白效力显著提高,超过仅用糖基化治疗性蛋白或仅用甘醇酸化治疗性蛋白的效果。鸟禽类系统中产生的治疗性蛋白可糖基化,而不需要像例如使用原核系统(例如大肠杆菌)产生治疗性蛋白时需要的那样进行体外糖基化。
在一个有用的方面,本发明提供了组合物,该组合物包含来自转基因鸟禽类(例如转基因鸡)的糖基化的治疗性氨基酸序列,所述治疗性氨基酸序列是与甘醇聚合物结合的糖蛋白。例如,糖蛋白可通过化学作用(例如,离子键或氢键)与甘醇聚合物结合。在一个尤其有用的实施方式中,糖蛋白与甘醇聚合物共价结合。在本发明一个尤其有用的实施方式中,治疗性氨基酸序列是外源性氨基酸序列。例如,治疗性氨基酸序列可以是人内源性氨基酸序列。
在一个有用的实施方式中,治疗性氨基酸序列是细胞因子。例如,治疗性氨基酸序列可以是粒细胞集落刺激因子、干扰素α、干扰素β、红细胞生成素或粒细胞巨噬细胞集落刺激因子。一方面,细胞因子是人内源性细胞因子。
在本发明的一方面,由转基因鸟禽类输卵管细胞提供糖基化作用。例如,输卵管细胞可以是管状腺细胞。
在一个实施方式中,本发明提供了在鸟禽类基因表达系统中通过连接键连接蛋白的糖基化作用。例如,治疗性氨基酸序列可以O-糖基化和/或治疗性氨基酸序列可以N-糖基化。
本发明考虑了任何有用的甘醇聚合物与禽类来源的糖基化治疗性蛋白的连接应用。例如,甘醇聚合物可以是聚烷撑二醇,例如聚乙二醇和聚丙二醇。本发明并不限于任何特定分子量的甘醇聚合物。例如,甘醇聚合物的分子量可以为约200-400,000,例如约200-20,000。
本发明考虑了甘醇聚合物通过本领域已知的任何有用的化学键合方法与糖基化蛋白的连接。在一个实施方式中,甘醇聚合物共价结合于治疗性氨基酸序列的氨基基团。在另一个实施例中,甘醇聚合物共价结合于治疗性氨基酸序列的羧基基团。
在一个有用的实施方式中,来自转基因鸟禽类的糖基化治疗性氨基酸序列是糖蛋白,包括甘醇聚合物与治疗性氨基酸序列糖基化部分的共价结合。本发明考虑了甘醇聚合物与治疗性氨基酸序列糖基化部分任意成分的连接。例如但不限于,本发明考虑了甘醇聚合物与n-乙酰半乳糖胺、n-乙酰葡糖胺、半乳糖和/或n-乙酰神经氨酸或糖基化部分上存在的任何其它糖结构的连接。
在一个实施方式中,本发明产生的治疗性蛋白可溶于水相或基本上可溶于水相中。与未甘醇酸化的相同糖基化治疗剂相比,本发明产生的治疗性蛋白无免疫原性或免疫原性降低。
定义与缩写
本说明书提出一些定义,用于阐述和明确描述本发明所用的各种术语的含义和范围。
术语“活性成分”和“本发明化合物”指本发明禽类来源的甘醇酸化-糖基化蛋白治疗剂。
本文所用术语“鸟禽类”是指分类学鸟类(ava)的生物体的任意物种、亚种或品种,例如但不限于鸡、火鸡、鸭、鹅、鹌鹑、野鸡、鹦鹉、雀、鹰、乌鸦、以及包括驼鸟、鸸鹋和鹤鸵等平胸类鸟(ratites)。该术语包括各种已知的原鸡品系、或鸡(例如,白莱航鸡(White Leghorn)、棕莱航鸡(Brown Leghorn)、芦花鸡、苏塞克斯鸡、新汉夏鸡、洛岛鸡、澳洲黑鸡、米诺卡鸡、Amrox、加州灰鸡),以及火鸡、野鸡、鹌鹑、鸭、驼鸟品系及其它通常商业规模饲养的禽类。还包括所有发育阶段的各种鸟禽类生物体,包括胚胎和胎儿阶段。术语“鸟禽类”还可表示“与鸟类有关”,例如“鸟禽类(鸟类)细胞”。
本文所用术语“细胞因子”指参与细胞内通信的蛋白质信号化合物。细胞因子在许多免疫、炎症和感染疾病中起主要作用。胚胎形成期间它们还参与有些发育过程。细胞因子由造血和非造血性的多种细胞类型产生,可影响附近细胞或整个生物体中的细胞,有时在很大程度上取决于其它化学物质和细胞因子的存在。细胞因子通常是较小的水溶性蛋白质,例如分子量8-30kDa的糖蛋白。
“甘醇酸化”指分子上添加甘醇聚合物,例如将甘醇聚合物添加到糖基化禽类来源的蛋白治疗剂上。“甘醇酸化的”指将甘醇聚合物加到如糖基化禽类来源的蛋白治疗剂等物质上。
本文所用“甘醇聚合物”指任何有用的烯烃、烷烃或炔烃(及其组合)聚合物甘醇。例子包括但不限于:聚丙二醇、聚乙二醇和聚丁二醇。
术语“异源性”和“外源性”通常是指诸如核酸或蛋白质等的生物分子,所述生物分子是某一细胞、组织、或者生物体所含或所产生的其他组分中所通常没有的。例如,对于卵异源性或外源性的蛋白质是指卵中通常没有的蛋白质。
术语“inf”表示干扰素。
术语“PEG”指聚乙二醇。
如本文所用,“标准蛋白质治疗剂”是指不含禽类来源的糖基化部分和甘醇聚合物的蛋白治疗剂。标准蛋白治疗剂可以是含有禽类来源的糖基化部分或甘醇聚合物的蛋白治疗剂。
“治疗性蛋白质”、“蛋白治疗剂”、“药物蛋白”、“治疗性氨基酸序列”各自表示完全或部分构成药物的氨基酸序列。在一个实施方式中,药物组合物、药物制剂或治疗性组合物包含一种或多种蛋白治疗剂、药物蛋白、治疗性氨基酸序列或治疗性蛋白。
如本文所用,“转基因鸟禽类”,如本文所定义,指任何鸟禽类,其中一种或多种鸟禽类细胞含有操作(例如,通过转基因技术)导入的异源性核酸。通过精密的基因操作将核酸导入细胞前体,可以直接或间接地将核酸导入细胞,所述精密的基因操作例如显微注射或用重组逆转录病毒感染,例如用重组复制缺陷型逆转录病毒注入鸟禽类胚胎的胚下腔内。基因操作还包括经典的杂交育种或体外受精。异源性核酸可以是人工染色体或整合到鸟禽类的染色体内,或者可以是染色体外的复制型DNA。
如本文所用,“治疗”或“处理病症”指给予药物组合物或药物制剂来预防疾病和/或治疗疾病。预防疾病是指预防性治疗尚未发病但易患病或具有感染特定疾病风险的患者。治疗疾病或用于治疗性治疗是指给予已经发病的患者治疗以缓解疾病和改善患者健康状况。因此,治疗或处理病症指出于治疗或预防目的,给予哺乳动物一种或多种甘醇酸化-糖基化禽类来源的治疗性蛋白。
缩写“g”表示克。缩写“ml”表示毫升。缩写“mg”表示毫克。缩写“PEG”表示聚乙二醇。缩写“KDa”表示千道尔顿。“℃”表示摄氏度。缩写“mM”表示毫摩尔。缩写“mU”表示毫单位。
发明详述
本发明具体地涉及鸟禽类产生的糖基化治疗性蛋白的甘醇酸化,例如PEG化,所述鸟禽类包括但不限于:鸡、火鸡、鸭、鹅、鹌鹑、野鸡、鹦鹉、雀、鹰、乌鸦、以及包括驼鸟、鸸鹋和鹤鸵等平胸鸟类。在一个尤其有用的实施方式中,本发明涉及鸡产生的糖基化治疗性蛋白的甘醇酸化,例如PEG化。
通常,宿主生物体中存在的遗传序列在蛋白质的氨基酸序列方面决定了糖基的位置和一般结构。糖基通常连接于天冬酰胺、丝氨酸或苏氨酸。产生适用于形成本文所述治疗性蛋白的糖基化治疗性蛋白的方法是本领域已知的,例如参见2003年6月17日提交的美国专利申请第10/463,980号(美国专利公告第2004/0019923号)和2005年2月28日提交的美国专利申请第11/068,155号(美国专利公告第2006/0015960号)。
一种尤其适用于本发明的甘醇聚合物是聚乙二醇(PEG)。PEG是亲水、生物相容的无毒性聚合物,通式H(OCH2CH2)nOH,其中n>4。其分子量可差异很大,例如从200到20,000道尔顿。本发明并不具体涉及将PEG分子连接到治疗性蛋白的任意具体方法或所用PEG的任意具体分子量。
许多适用于甘醇酸化蛋白质的方法是本领域已知的,本发明考虑了这些方法的具体应用。例如,本发明涉及任何适用于PEG化以形成本文所述治疗性蛋白的方法。在一个实施例中,某些已熟知的PEG化蛋白质的方法,采用化合物如N-羟基琥珀酰亚胺(NHS)-PEG来连接PEG与游离胺,通常在赖氨酸残基或N-末端氨基酸。一些方法以非位点特异性方式PEG化治疗性蛋白,在某些情况下这不是优选的。
位点特异性PEG化方法也包括在本发明范围内。一种方法采用半胱氨酸-反应性PEG将PEG连接至半胱氨酸残基。市售带有许多不同反应性基团(例如马来酰亚胺、乙烯砜)和不同PEG大小(2-40kDa)的高度特异性的半胱氨酸-反应性PEG。中性pH时,这些PEG反应试剂选择性地连接至“游离”半胱氨酸残基,即没有形成二硫键的半胱氨酸残基。通过重组DNA技术的体外诱变,可以在蛋白质上任何有用的位置引入额外的半胱氨酸残基。新增加的“游离”半胱氨酸可用作PEG分子通过半胱氨酸-反应性PEG特异性连接的位点。增加的半胱氨酸残基可以是蛋白质中现有氨基酸的取代基,增加到蛋白质氨基末端之前或在蛋白质羧基末端之后添加,或插入蛋白质两个氨基酸之间。或者,在某些治疗性蛋白中,天然二硫键中的两个半胱氨酸之一可以缺失或被另一氨基酸取代,使天然半胱氨酸(蛋白质中正常情况下将与缺失的或取代的半胱氨酸残基形成二硫键的半胱氨酸残基)游离且可用于化学修饰。在一个实施方式中,取代半胱氨酸的氨基酸可以是中性氨基酸,例如丝氨酸或丙氨酸。此外,可用碘代乙酰亚胺还原或烷基化二硫键而不损伤生物学活性,提供缺失或被另一氨基酸取代的靶点。
在一个实施方式中,制备甘醇酸化(例如PEG化)糖蛋白的方法包括以下步骤:(a)使蛋白质与聚乙二醇(例如PEG的反应性酯或醛衍生物)在一定条件下反应,由此蛋白质与一个或多个PEG基团连接;和(b)获得反应产物。通常,基于已知参数和所需结果,具体确定反应的最佳反应条件。
本领域技术人员可获得许多连接方法。例如,参见EP 0 401 384,其内容以参见方式引入本说明书中;也可参见Malik等(1992),Exp.Hematol.,20:1028-1035;Francis(1992),Focus on Growth Factors,3(2):4-10,(Mediscript出版,Mountain Court,Friern Barnet Lane,London N20 OLD,UK);EP 0 154 316;EP 0 401 384;WO 92/16221;WO 95/34326;以及本文所引用的涉及甘醇聚合物与蛋白质连接(例如PEG化)的其它出版物,其内容以参见方式引入本说明书中。
在一个实施方式中,甘醇聚合物分子如聚乙二醇聚合物分子可“活化”以便于甘醇聚合物分子与鸟禽类或禽类来源的糖基化治疗性蛋白质的偶联。制备这种活化的甘醇聚合物的例子在以下参考文献中提供,其内容以参见方式引入本说明书中:K.Yoshinaga和J.M.Harris,J.Bioact.Comp.Polym.,1,17-24(1989);K.Nilsson和K.Mosbach,Methods in Enzymology,104,56(1984);C.Delgado,G.E.Francis和D.Fisher,在“Separations Using Aqueous PhaseSystems”中,D.Fisher和I.A.Sutherland编,Plenum,London,1989,第211-213页;M.-B.Stark和J.K.Holmberg,Biotech.Bioeng.,34,942(1989);J.M.Harris和K.Yoshinaga,J.Bioact.Compat.Polym.,4,281(1989);H.Walter,D.E.Brooks和D.Fisher(编者),“Partitioning in Aqueous Two-Phase Systems”,AcademicPress,Orlando,Fla.,1985;D.Fisher和I.A.Sutherland(编者),“SeparationsUsing Aqueous Phase Systems:Applications in Cell Biology and Biotechnology”,Plenum,London,1989。
1977年1月11日公布的美国专利第4,002,531号(其内容以参见方式引入本说明书中)描述了PEG乙醛的制备以使PEG连接于酶或其它蛋白质。这些方法能使PEG连接于糖基化治疗性蛋白。
1979年12月18日公布的美国专利4,179,337(其内容以参见方式引入本说明书中)公开了一些PEG与蛋白质的连接方法,以形成可溶性PEG-蛋白质偶联物。这些方法能使PEG连接于糖基化治疗性蛋白。
甘醇酸化(例如PEG化)可通过(例如)与反应性或活化聚乙二醇聚合物分子的酰化反应或烷基化反应来实现。因此,根据本发明生产的蛋白质产品包括PEG化的蛋白质,其中,PEG基团通过酰基或烷基基团连接。这些产品可以单-PEG化或多-PEG化(例如,含有2-6个,和/或2-5个PEG基团)。PEG基团可在氨基酸的α或ε氨基处连接蛋白质,但也考虑PEG可连接于蛋白质分子上的任意基团,这些基团的反应性在合适的反应条件下足以附连于PEG基团。
通过酰化的甘醇酸化(例如PEG化)通常包括:使甘醇聚合物(例如PEG)的活性酯衍生物与蛋白质反应。对于酰化反应,所选聚合物可具有单个反应性酯基团。任何已知或随后发现的反应性PEG分子可用于实现PEG化反应。一种有用的活化PEG酯是N-羟基琥珀酰亚胺(NHS)的PEG酯。如本文所用,“酰化”包括但不限于治疗性蛋白质与甘醇聚合物(例如PEG)的下述连接类型:酰胺、氨基甲酸酯、氨基甲酸乙酯等(Chamow(1994),Bioconjugate Chem.,5(2):133-140)。反应条件可选自任意PEG化技术中已知的或随后发现的反应条件,但应避免诸如温度、溶剂和pH等使待修饰的治疗性禽类来源的蛋白质灭活的条件。
通过酰化的甘醇酸化通常将形成聚-PEG化蛋白质。在一个实施方式中,连接键是酰胺。并且,所得产物基本上仅仅(例如>95%)单、二-或三-PEG化。然而,根据所采用的具体反应条件,可形成一定量PEG化程度较高的物质。需要时,可通过标准纯化技术从混合物(尤其是未反应物质)分离纯度较高的PEG化产物,所述纯化技术包括但不限于:透析、盐析、超滤、离子交换色谱、凝胶过滤色谱和电泳。
通过烷基化的甘醇酸化(例如PEG化)包括在还原剂的存在下,使甘醇聚合物(例如PEG)的末端醛衍生物与蛋白质反应。对于还原烷基化反应,所选聚合物具有单一反应性醛基。反应性PEG醛的例子有水稳定性的聚乙二醇丙醛,或其单C1-C10烷氧基或芳氧基衍生物。例如参见1993年10月12日公布的美国专利第5,252,714号,其内容以参见方式引入本说明书中。
通过烷基化的甘醇酸化(例如PEG化)还可形成聚-PEG化蛋白质。此外,可操控反应条件从而大大有助于仅在蛋白质N-末端的α氨基处发生甘醇酸化,形成单-PEG化蛋白质。任一情况下,甘醇聚合物基团常常通过-CH2-NH-基团连接蛋白质。
还原烷基化以形成大致均一的单-聚合物/蛋白质产物包括以下步骤:
(a)在还原烷基化条件下,使禽类来源的糖基化治疗性蛋白与反应性PEG分子反应,合适的pH条件以选择性修饰蛋白质氨基末端的α氨基基团;和
(b)获得反应产物。还原烷基化以形成单PEG化产物。
该反应可在一定pH条件下进行,从而能够利用赖氨酸残基的ε氨基与蛋白质N-末端残基的α氨基间的pKa差异。通常,如果pH较低,希望聚合物含量大大超过蛋白质(即,反应性N-末端α氨基越少,就需要越多的聚合物以实现最佳条件)。如果pH较高,聚合物:蛋白质比例无需很高(即,反应性基团越多,所需的聚合物分子越少)。在一个实施方式中,pH落在3-9的范围内,例如3-6。对于还原烷基化反应,还原剂应在水溶液中稳定,优选仅能还原还原烷基化初期形成的西佛碱。合适的还原剂选自:硼氢化钠、氰基硼氢化钠、二甲胺硼烷、三甲胺硼烷和吡啶硼烷。尤其优选的还原剂是氰基硼氢化钠。根据蛋白质与水溶性聚合物衍生化方面公开的信息,可基于具体情况确定其它反应参数,例如溶剂、反应时间、温度和产物的纯化方式。
通过上述选择性衍生化反应,可以控制包含如醛基等反应性基团的甘醇聚合物与蛋白质的连接。与聚合物的偶联主要在蛋白质的N末端发生,而不会显著修饰其它反应性基团,例如赖氨酸侧链氨基。制备通常形成大于90%的单聚合物/蛋白质偶联物,或大于95%的单聚合物/蛋白质偶联物,其余观察到的分子残余部分未反应(即缺乏聚合物部分的蛋白质)。
甘醇酸化也可通过具有至少一个反应性羟基的水溶性聚合物(例如聚乙二醇)与具有反应性羰基、腈或磺基的试剂反应来实现,使羟基转化为反应性迈式受体(Michael acceptor),从而形成适用于修饰各种蛋白质的活化连接基团,提供生物活性改善的偶联物。反应性羰基、腈或磺基指键合两个碳基团的羰基、腈或磺基,羰基、腈或磺基的第二碳上具有巯基特异性偶联的反应位点。例如参见WO 92/16221,其内容以参考方式引入本说明书中。
活化连接基团可以是单功能、双功能或多功能性的。所述方法中使用的具有反应性磺基的可用的反应试剂包括但不限于:氯代砜、乙烯砜和二乙烯砜。
在一个具体的实施方式中,用迈式受体活化甘醇聚合物。WO 95/13312(其内容以参考方式引入本说明书中)描述了水溶性砜活化的PEG,高度选择性地与分子和表面上的巯基部分而不是氨基部分偶联。这些PEG衍生物在pH约11或更低的水性环境中能稳定地长时间对抗水解反应,可与分子形成连接键以形成同样水解稳定的偶联物。PEG与生物活性分子偶联的连接键包括偶联于巯基部分的砜部分,具有结构PEG-SO2-CH2-CH2--S--W,其中W代表生物活性分子,砜部分可以是乙烯砜或活性乙基砜。两种有用的同基双功能衍生物是PEG-双-氯代砜和PEG-双-乙烯砜。
在一个尤其有用的实施方式中,糖基化治疗性蛋白通过甘醇聚合物经蛋白质上存在的糖基与糖基化治疗性蛋白发生偶联而甘醇酸化(例如,PEG化)。因此,本发明包括具有偶联于糖基化治疗性蛋白的糖基化结构的甘醇聚合物(例如聚乙二醇)的糖基化蛋白治疗剂,以及制备这种糖基化-甘醇酸化蛋白治疗剂的方法。
在本发明所考虑的一个具体的实施方式中,本发明涉及糖基化大分子的甘醇酸化方法,该方法包括活化聚烷撑二醇,使活化的聚烷撑二醇与二氨基化合物反应,从而使活化的聚烷撑二醇通过二氨基化合物中的一个氨基与其偶联,氧化禽类来源的糖基化治疗性蛋白以活化至少一个糖基基团,和使偶联于二氨基化合物的聚烷撑二醇与大分子中氧化的糖基基团反应。例如,本发明包括糖基化大分子的PEG化方法,该方法包括以下步骤:
(a)使通式CH3O-(CH2CH2O)n-H的聚乙二醇与o-硝基苯基氯甲酸酯和三乙胺反应,形成通式CH3O-(CH2CH2O)n-COO-Ph-NO2的硝基化合物;
(b)使硝基化合物与通式H2N-(CH2)X-NH2的二氨基烷烃反应,形成通式CH3O-(CH2CH2O)n-CO-NH-(CH2)n-NH2的氨基化合物;
(c)氧化鸟禽类来源的糖基化治疗性蛋白上的糖基,形成带有氧化的糖残基的大分子;以及
(d)使氨基化合物与活化的大分子反应,形成PEG化分子。在一个实施方式中,聚乙二醇的分子量最高达约24,000;相应地,n为约2-500。在该实施方式中,二氨基烷烃中,通常x为约1-20。
优选方法的结果是PEG化的糖基化鸟禽类来源的糖基化治疗性蛋白,其中PEG通过糖基化反应键合于蛋白质,具体地通过通式PEG-OCO-NH-烯烃-N=CH-鸟禽类来源的糖基化治疗性蛋白的糖基化。本发明甘醇酸化糖基化治疗性蛋白的方法的其它方面参见1994年3月17日公开的WO 94/05332,其内容以参考方式引入本说明书中。
本发明还可用于产生许多所选的甘醇酸化和糖基化治疗性蛋白,例如融合蛋白、生长激素、细胞因子、结构蛋白和酶,包括人生长激素、干扰素、溶菌酶和β-酪蛋白。本发明考虑进行修饰的其它可能的蛋白质包括但不限于:白蛋白、α-1抗胰蛋白酶、抗凝血酶III、胶原、因子VIII、IX、X(等)、纤维蛋白原、透明质酸、胰岛素、乳铁蛋白、蛋白C、红细胞生成素(EPO)、粒细胞集落刺激因子(G-CSF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、组织型纤维蛋白溶酶原激活剂(tPA)、生长素和糜蛋白酶。如本文所述,也可形成修饰的免疫球蛋白和抗体,包括结合于人肿瘤细胞表面抗原并破坏其的免疫毒素。
考虑与甘醇酸化和糖基化反应组合的治疗性蛋白的其它具体例子包括但不限于:因子VIII、b-域缺失因子VIII、因子VIIa、因子IX、抗凝剂;水蛭素、阿替普酶、tpa、瑞替普酶、tpa、5域缺失的tpa-3、胰岛素、赖脯胰岛素、门冬胰岛素(insulin aspart)、甘精胰岛素、长效胰岛素类似物、hgh、胰高血糖素、tsh、促滤泡素-β、fsh、gm-csf、pdgh、ifn α2a、inf-α、inf-β1b、ifn-β1a、ifn-γ1b、il-2、il-11、hbsag、ospa、抗T淋巴细胞抗原的鼠单抗、抗tag-72的鼠单抗、肿瘤相关糖蛋白、抗血小板表面受体gpII(b)/III(a)的嵌合单抗衍生的fab片段、抗肿瘤相关抗原ca125的鼠单抗片段、抗人癌胚抗原的鼠单抗片段、cea、抗人心脏肌球蛋白的鼠单抗片段、抗肿瘤表面抗原psma的鼠单抗片段、抗hmw-maa的鼠单抗片段(fab/fab2混合物)、抗肿瘤相关抗原的鼠单抗片段(fab)、抗表面粒细胞非特异性交叉反应抗原nca 90的单抗片段(fab)、抗B淋巴细胞上发现的cd20抗原的嵌合单抗、抗il2受体α链的人源化单抗、抗il2受体α链的嵌合单抗、抗tnf-α的嵌合单抗、抗呼吸核胞体病毒表面表位的人源化单抗、抗her 2(即人表皮生长因子受体2)的人源化单抗、抗细胞角蛋白肿瘤相关抗原抗-ctla4的人单抗、抗B淋巴细胞链道酶-αDNA酶的cd20表面抗原的嵌合单抗、β葡糖脑苷脂酶、tnf-α、il-2-白喉毒素融合蛋白、tnfr-lgg片段融合蛋白粘多糖-a-L-艾杜糖醛酸水解酶(laronidase)、脱氧核糖核酸酶(dnaases)、alefacept、阿法达贝泊汀(darbepoetinalfa)(集落刺激因子)、托西莫单抗、鼠单抗、阿仑单抗、拉布立酶、半乳糖苷酶β(agalsidaseβ)、特立帕肽、甲状旁腺素衍生物、阿达木单抗(lggl)、阿那白滞素、生物学修饰因子、奈西立肽、人b-型利钠肽(hbnp)、集落刺激因子、培维索孟、人生长激素受体拮抗剂、重组活化蛋白C、奥马珠单抗(omalizumab)、免疫球蛋白E(IgE)阻滞剂、替伊莫单抗、ACTH、胰高血糖素、促生长素抑制素、促生长素、胸腺素、甲状旁腺素、色素激素、生长调节素、红细胞生成素、黄体生成素、绒毛膜促性腺激素、下丘脑释放激素、抗利尿激素、促乳素和促甲状腺激素。在一个实施方式中,本发明涉及产生禽类来源的甘醇酸化-糖基化人蛋白质,例如本文所述的蛋白质的人源化形式(即人内源性)。
本发明考虑修饰本文所述的免疫球蛋白及其它多聚体蛋白质。可用本发明方法修饰的治疗性抗体的例子包括但不限于:HERCEPTINTM(曲妥单抗)(Genentech,CA),它是人源化的抗-HER2单克隆抗体,用于治疗转移性乳腺癌患者;REOPROTM(阿昔单抗)(Centocor),它是针对血小板上的糖蛋白IIb/IIIa受体的抗体,用于防止血块形成;ZENAP AXTM(达克珠单抗)(罗氏制药,瑞士),它是免疫抑制性人源化抗-CD25单克隆抗体,用于防止急性肾同种异体移植物排斥;PANOREXTM,它是鼠抗-17-IA细胞表面抗原IgG2a抗体(GlaxoWellcome/Centocor);BEC2,它是鼠抗-个体基因型(GD3表位)IgG抗体(ImCloneSystem);IMC-C225,它是嵌合抗-EGFR IgG抗体(ImClone System);VITAXINTM,它是人源化抗-αVβ3整合素抗体(Applied Molecular Evolution/Medhnmune);Campath 1H/LDP-03,它是人源化抗CD52 IgG1抗体(Leukosite);Smart M1 95,它是人源化抗-CD33 IgG抗体(Protein Design Lab/Kanebo);RITUXANTM,它是嵌合抗-CD2O IgG1抗体(IDEC Pharm/Genentech,Roche/Zettyaku);LYMPHOCIDETM,它是人源化抗-CD22 IgG抗体(Immunomedics);ICM3,它是人源化抗-ICAM3抗体(ICOS Pharm);IDEC-114,它是灵长类抗-CD80抗体(IDEC Pharm/Mitsubishi);ZEVALINTM,它是放射标记的鼠抗-CD20抗体(IDEC/Schering AG);IDEC-131,它是人源化抗-CD40L抗体(IDEC/Eisai);IDEC-151,它是灵长类化抗-CD4抗体(IDEC);IDEC-152,它是灵长类化抗-CD23抗体(IDEC/Seikagaku);SMART抗-CD3,它是人源化抗-CD3 IgG(Protein DesignLab);5G1.1,它是人源化抗-补体因子5(CS)抗体(Alexion Pharm);D2E7,它是人源化抗-TNF-α抗体(CATIBASF);CDP870,它是人源化抗-TNF-αFab片段(Celltech);IDEC-151,它是灵长类化抗-CD4 IgG1抗体(IDEC Pharm/SmithKlineBeecham);MDX-CD4,它是人抗-CD4 IgG抗体(Medarex/Eisai/Genmab);CDP571,它是人源化抗-TNF-αIgG4抗体(Celltech);LDP-02,它是人源化抗-α4β7抗体(LeukoSite/Genentech);OrthoClone OKT4A,它是人源化抗-CD4 IgG抗体(Ortho Biotech);ANTOVATM,它是人源化抗-CD40L IgG抗体(Biogen);ANTEGRENTM,它是人源化抗-VLA-4 IgG抗体(Elan);和CAT-152,它是人抗-TGF-β2抗体(Cambridge Ab Tech)。
在一个实施方式中,本文所述考虑进行修饰的治疗性蛋白是能够选择性结合抗原的抗体,所述抗原由至少一个免疫球蛋白重链可变区和至少一个免疫球蛋白轻链可变区组合形成,例如通过至少一个二硫键交联形成。两个可变区的组合产生可采用本领域公知的抗体重建方法结合抗原的结合位点。
虽然治疗中本发明蛋白质可以原始形式给予,但优选以药物制剂的一部分的形式给予所述蛋白质。
因此,本发明还提供了一种药物制剂,该制剂包含:禽类来源的糖基化-甘醇酸化治疗性蛋白或其药学上可接受的衍生物,一种或多种药学上可接受的载体以及任选地其它治疗剂和/或预防性成分。载体必须是与制剂中其它成分相容性上“可接受的”,且对受者无害。
药物制剂包括适用于口服、直肠、鼻腔、局部(包括含服和舌下)、阴道或胃肠外(包括肌内、皮下和静脉内)给药或适用于吸入或吹入给药的形式。适当时,所述制剂可方便地以离散剂型单位的形式存在,通过任意药学领域熟知的方法制备。所有方法包括:使活性化合物与液体载体或细分固体载体或两者结合,然后在需要时,使产物成形得到所选制剂。
适用于口服给药的药物制剂可方便地以离散单位的形式存在,例如胶囊、扁胶囊或片剂,各自包含预定量的活性成分;以粉末或颗粒形式;溶液形式;混悬剂形式;或以乳剂形式存在。活性成分也可以团块、药糖或糊剂的形式存在。口服给药的片剂和胶囊可包含常规赋形剂,例如粘合剂、填充剂、润滑剂、崩解剂或润湿剂。片剂可根据本领域公知的方法进行包衣。
口服液体制剂可以是水性或油性混悬剂、溶液剂、乳剂、糖浆剂或酏剂的形式,或者可以是干产物形式在使用前与水或其它合适的运载体配制。这些液体制剂可包含常规添加剂,例如助悬剂、乳化剂、非水运载体(可包含食用油)或防腐剂。
本发明化合物也可配制用于胃肠外给药(例如,通过注射,例如推注或连续输注),可以安瓿、预填充注射器、小体积输液等单位剂量形式,或含添加的防腐剂的多剂量容器存在。组合物可以是油性或水性运载体中的混悬剂、溶液剂或乳剂形式,可包含配制成分,例如助悬剂、稳定剂和/或分散剂。或者,活性成分可以是粉末形式,其可以通过无菌固体除菌分离得到或通过溶液冻干获得,使用前与合适的运载体(例如无菌无热原的水)重新配制。
对于表皮局部给药,本发明化合物可配制成软膏、乳膏或洗剂,或经皮贴片。例如,软膏和乳膏可用水性或油性基质配制,添加合适的增稠剂和/或胶凝剂。洗剂可用水性或油性基质配制,通常还包含一种或多种乳化剂、稳定剂、分散剂、助悬剂、增稠剂或着色剂。
适用于口腔局部给药的制剂包括:锭剂,其包含在调味基质中的活性成分,调味基质通常是蔗糖和阿拉伯胶或黄蓍胶;软锭剂,其包含在惰性基质中的活性成分,惰性基质包括明胶和甘油或蔗糖和阿拉伯胶;和漱口剂,其包含在合适的液体载体中的活性成分。
适用于直肠给药的药物制剂最优选以单位剂量栓剂的形式存在,其中载体是固体。合适的载体包括可可豆脂和本领域中常用的其它材料,栓剂可通过以下过程方便地形成:活性化合物与软化或熔化载体混合,然后在模具中冷却和成形。
适用于阴道给药的制剂可以阴道栓、棉塞、乳膏、凝胶、糊剂、泡沫或喷雾的形式存在,除活性成分外,还包含本领域已知适当的载体。
对于鼻腔内给药,本发明化合物可用作液体喷雾剂或可分散的粉末或滴剂形式。
滴剂可用水性或非水基质配制,还包含一种或多种分散剂、增溶剂或助悬剂。液体喷雾剂可方便地从加压容器递送。
对于吸入给药,本发明化合物可方便地从吹入器、雾化器或加压容器或其它递送喷雾剂的方便方式递送。加压容器可包含合适的压缩气体,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。对于加压气雾剂,剂量单位由阀门确定,从而实现定量递送。
或者,对于吸入或吹入给药,本发明化合物可以是干粉末组合物的形式,例如化合物与合适的粉末基质(例如乳糖或淀粉)的粉末混合物。粉末组合物可以单位剂量形式存在,例如胶囊或药筒,或者例如明胶或发泡包装,在吸入器或吹入器的帮助下实现粉末递送。
需要时,上述制剂也可被配制成实现活性成分的持续释放。
本发明药物组合物还可包含其它活性成分,例如抗微生物剂或防腐剂。
此外,还考虑将本发明化合物与其它治疗剂联合使用。例如,禽类来源的糖基化-甘醇酸化人干扰素α(例如,干扰素α2b)可与利巴韦林和/或virimidine联合使用以治疗病毒感染如丙型肝炎。
本发明组合物或化合物可用于治疗各种病症。例如,许多病症的治疗性疗法是本领域从业人员已知的,其中采用了蛋白治疗剂。本发明考虑,可采用鸟禽类系统产生的蛋白治疗剂,形成禽类来源的糖基化模式,然后根据本发明甘醇酸化,以治疗所述疾病。即,本发明考虑治疗已知可用具有某一氨基酸序列的蛋白治疗剂进行治疗的病症,通过给予具有由鸟禽类系统产生并经糖基化和甘醇酸化的同一氨基酸序列的蛋白治疗剂。
具体地说,与采用同一蛋白治疗剂但未经鸟禽类糖基化和甘醇酸化(即标准蛋白治疗剂)治疗疾病所需的给药频率和/或剂量相比,根据本发明产生的糖基化-甘醇酸化治疗性蛋白所需的给药频率降低和/或所需的治疗性蛋白的剂量降低。例如,与采用相同蛋白治疗剂但未经鸟禽类糖基化和甘醇酸化(即标准蛋白治疗剂)治疗疾病或预防通常所采用的剂量相比,本发明糖基化-甘醇酸化治疗性蛋白的剂量为通常剂量的约10%、或约20%、或约30%、或约40%、或约50%、或约60%、或约70%、或约80%。与采用相同蛋白治疗剂但未经鸟禽类糖基化和甘醇酸化(即标准蛋白治疗剂)的给药频率相比,本发明糖基化-甘醇酸化治疗性蛋白的给药频率可降低约10%、或约20%、或约30%、或约40%、或约50%、或约60%、或约70%、或约80%。
通常,给药剂量可根据许多已知因素而改变,例如接受者的年龄、健康状况和体重,并行治疗类型,治疗频率等。通常,活性成分的剂量为约0.0001-10毫克/公斤体重。治疗性蛋白给药领域的有经验的医师能够确定精确的剂量、给药频率和治疗时间跨度。
下面的实施例是尤其适用于制备产生本发明糖基化和甘醇酸化蛋白治疗剂的方法;然而应理解,本发明并不限于本发明治疗性蛋白的任何具体制备方法,本发明包括所有本领域已知有用及尚未发明的方法。
实施例1
糖基化-PEG化禽类来源的人红细胞生成素的制备
PEG-4-羟基-6-氯代-1,3,5-三嗪(PEG-HTA)的制备
将30克PEG750(约0.04摩尔)或80克PEG 2,000(约0.04摩尔)溶解在150毫升含8克Na2CO3的无水苯中。将该溶液冷却至10℃,加入7.38克氰尿酰氯。将该溶液在10℃下搅拌过夜。加入5毫升水后,溶液在室温下保持几小时,然后40℃下加热过夜。离心除去不溶性物质,40℃旋转蒸发仪中减压除去溶剂。通过加入少量苯来降低粘度,以去除浓缩期间有时可能出现的少量沉淀物,然后离心并再浓缩。40℃下粘稠液体的PEG-3-羟基-6-氯代-1,3,5-三嗪在冷藏柜中储存。
PEG-HTA-EPO偶联物的制备
根据2004年5月4日公布的美国专利第6,730,822号所述(其内容以参考方式引入本说明书中),制备禽类来源的糖基化EPO。将10毫克EPO溶解在1毫升0.1M的硼酸盐缓冲液pH9.2中,并加入179毫克PEG-HTA 2,000。2小时后,使溶液通过Sephadex G-10柱以除去未反应的PEG-HTA。在旋转蒸发仪上浓缩PEG-HTA-EPO偶联物,冷藏柜中储存。
根据上述过程,但使用PEG-750,得到类似产物。根据上述过程,但在pH8.5和pH10下进行反应,得到类似产物。
实施例2
O-PEG-(P-重氮禽类来源的糖基化干扰素α2-b苄基)醚的制备
O-PEG-p-氨基苄基醚的形成
将3.46克p-硝基苄基氯、2.0克粉末氢氧化钠、20毫升无水四氢呋喃和0.01摩尔PEG回流3小时。将溶液过滤并减压蒸发,加入石油醚(沸点30℃-40℃)沉淀PEG-p-硝基苄基醚。在拉尼镍催化剂(约1克)的存在下,大气压下在乙醇(50毫升)中用氢气还原硝基醚。除去催化剂,蒸发滤液得到O-PEG-p-氨基苄基醚。
与干扰素α2-b偶联
0℃下,在水溶液中用硝酸重氮化O-PEG-p-氨基苄基醚。在纯化的重氮化溶液中,加入0.25%糖基化干扰素α2b的水溶液(根据2004年5月4日公布的美国专利第6,730,822号制备),将混合液在0℃下保持2小时。5-10℃下透析该溶液,得到糖基化-PEG化的干扰素α2b。
实施例3
O-PEG甲基羧基禽类来源的人GM-CSF的制备
PEG-甲基甲氧羰基醚的制备
将2.0克PEG 750溶解在30毫升液氨中,用钠处理该溶液直到蓝色保持5分钟。在干燥的氮气流上蒸发氨水。残留物用5毫升氯代乙酸甲酯处理,使混合液在室温下放置过夜,然后加热至100℃持续1小时。减压除去过量的反应试剂,得到PEG-甲基甲氧羰基醚。
PEG的活化
在含1.0克O-PEG-甲基甲氧羰基醚的10毫升水溶液中,逐滴加入含1.0克N-乙氧甲酰基-2-乙氧基1,2-二氢喹啉(EEDQ)的10毫升10%丙酮溶液。pH维持在7.0,30分钟后,用浓盐酸将pH调节至1.0,保持该pH90秒以破坏多余的EEDQ。然后将溶液的pH调节至pH8。
偶联至GM-CSF
4℃-5℃下,将50毫克根据2004年5月4日公布的美国专利第6,730,822号制备的人糖基化GM-CSF的磷酸盐缓冲液(pH 8.0)加入到活化的PEG溶液中。1/2小时后,用水透析溶液,得到糖基化-PEG化的禽类来源的GM-CSF。
实施例4
1-(禽类来源的人G-CSF-2-羟基丙氧基)-4-3”-O-PEG-2”-羟基丙氧基丁烷
的制备
PEG的环氧乙烷醚
将5.0克PEG、1毫升1,4-丁二醇二缩水甘油醚和1毫升0.6M含2毫克四氢硼酸钠的的氢氧化钠溶液在室温下搅拌8小时。中和并蒸发溶液。用丙酮萃取残留物,并加入过量石油醚以沉淀PEG醚。
偶联至G-CSF
使1.0克环氧乙烷-PEG和50毫克根据2004年5月4日公布的美国专利第6,730,822号制备的人糖基化GM-CSF的缓冲溶液(pH8.5)在室温下反应48小时。透析溶液,得到禽类来源的糖基化-PEG化的G-CSF。
实施例5
PEG化、糖基化禽类来源的人干扰素β1a的制备
甲氧基-PEG(mPEG)的活化
将2克15KDa mPEG(最终浓度0.1mM)溶解在20毫升含0.24克o-硝基苯基氯甲酸酯(1.2mM)和33毫升三乙胺(1.2mM)的乙腈中,室温下搅拌24小时。
然后用烧结玻璃漏斗过滤除去三乙基氯化铵。加入200毫升乙醚,使溶液在4℃下结晶过夜。将产物过滤,用醚洗涤除去所有黄色,乙腈-醚重结晶。然后通过ε-氨基-n-己酸(ACA)的p-硝基苯酚的释放,由分光光度法测定产物。
禽类来源的人干扰素β1a经赖氨酸基团的PEG化
将5毫克根据2004年5月4日公布的美国专利第6,730,822号制备的禽类来源的人干扰素β1a广泛透析到50mM硼酸钠缓冲液(pH8.3)中。
在2毫升透析样品中加入3毫克活化的mPEG,5摩尔过量。立即加入3毫克活化的mPEG,在室温下再震荡孵育30分钟。2小时后停止反应;通过将样品上样到NAP 25(Pharmacia)脱盐柱上并用50mM NaPO4缓冲液(pH 6.8)洗脱,最终摩尔过量为20-倍。将脱盐样品装载到Superose 6柱(1×30cm BioRadEconocolumn)上并用50mM NaPO4缓冲液(pH 6.8)洗脱。用SDS-PAGE测定Superose柱得到的峰产物并合并。
实施例6
带有PEG偶联于干扰素上存在的糖基化结构的禽类来源的人干扰素β1a
的制备
制备mPEG-μ-pNP的氨基衍生物(PEG-μ-丁胺(butamine))
将0.5克mPEG-μ-p-硝基苯基缓慢加入到5毫升50mM含44.25毫克(100mmol)1,4-氨基丁烷的硼酸钠缓冲液(pH 9.0)中。在室温下持续震荡孵育3小时。使反应液通过NAP 25脱盐柱并用水洗脱来终止反应,透析到milli-Q H2O中。将透析物质低压冻干并称重。
禽类来源的人干扰素β1a的氧化
偶联缓冲液:0.05M乙酸钠
0.1M氯化钠,pH5.0
洗涤缓冲液:0.1M乙酸钠
0.5M氯化钠,pH3.5
储存缓冲液:0.05M磷酸钠,pH6.8
用NAP-10(Pharmacia)脱盐柱将0.5毫克禽类来源的人干扰素β1a缓冲交换到偶联缓冲液中。在禽类来源的蛋白溶液中加入0.1毫升新鲜制备的100mMm-高碘酸钠(NaIO4)。轻轻混合溶液,使密封的反应容器避光,并室温下孵育30分钟。为终止反应,使样品通过NAP-10脱盐柱并用洗涤缓冲液平衡。用偶联缓冲液洗脱柱子。
氧化的禽类来源的人干扰素β1a与PEG-μ-丁胺的偶联
在脱盐、氧化的禽类来源的人干扰素β1a中加入5毫克PEG-μ-丁胺。在反应混合物上笼罩氮气并在4℃下轻轻翻滚过夜。禽类来源的人干扰素β1a与PEG-μ-丁胺的摩尔比为1∶100。然后在可选地还原禽类来源的人干扰素β1a之后将样品上样到Superose 6柱上。合并含干扰素的峰并在超滤搅拌的细胞浓集器上浓缩。
实施例7
用ST3Ga1III制备O-连接的40kDa PEG连接禽类来源的人抗体
去唾液酸化作用
在该步骤中,使禽类来源的糖基化人抗体去唾液酸化。GlcNAc-Gal连接部分用作修饰的唾液酸PEG发生转移的的接受基团。
用Tris缓冲液(20mM Tris,50mM NaCl,5mM CaCl2,0.02%NaN3,pH 7.2)缓冲交换10毫升(0.33μmol)禽类来源的糖基化人抗体溶液,得到最终体积10毫升。然后将750mU来源于产脲节杆菌(Arthrobacter Ureafaciens)的2,3,6,8-唾液酸酶加入到该溶液中。将所得混合物在32℃下震摇48小时。
O-连接的PEG化
在该步骤中,采用O-唾液酸转移酶将修饰的唾液酸-PEG部分转移到去唾液酸化禽类来源的糖基化人抗体。将CMP-唾液酸-PEG(40KDa,33mg,0.825μmol)、O-唾液酸转移酶(1.4U/ml,300mU)和0.25毫升100mM MnCl2加入到上述混合物中。然后将该混合物在32℃下震摇48小时。48小时后,超滤(MWCO5K)浓缩反应混合液至2.8毫升,然后用25mM NaOAc+0.001%Tween-80(pH 6.0)进行缓冲交换至最终体积3毫升。最终产物进行离子交换纯化。收集PEG化禽类来源的PEG化人抗体并进行超滤浓缩。
CHO-禽类来源的糖基化人抗体-Galnac-Gal-SA-PEG的完全末端唾液酸化
在该步骤中,将唾液酸加入到不具有修饰的唾液酸残基的糖基结构的末端。
将合并的PEG化禽类来源的糖基化人抗体(约2mg)进行超滤浓缩(MWCO5K),然后用tris缓冲液(0.05M Tris,0.15M NaCl,0.001M CaCl2+0.005%NaN3)进行缓冲交换至最终体积2毫升,然后加入CMP-N-乙酰基神经氨酸(CMP-NANA;1.5mg,2.4μmol),ST3Ga1III(8.9U/ml,10μl,0.098U)和50微升1100mM MnCl2。将所得混合液在32℃下震摇24小时,然后浓缩至1毫升最终体积。将该溶液直接进行Superdex 200纯化。
Claims (20)
1.一种包含从转基因鸟禽获得的糖基化治疗性氨基酸序列的组合物,其特征在于,所述治疗性氨基酸序列是糖蛋白并包含共价结合的甘醇聚合物。
2.如权利要求1所述的组合物,其特征在于,所述鸟禽是鸡。
3.如权利要求1所述的组合物,其特征在于,所述治疗性氨基酸序列是外源性氨基酸序列。
4.如权利要求1所述的组合物,其特征在于,所述治疗性氨基酸序列是人内源性氨基酸序列。
5.如权利要求1所述的组合物,其特征在于,所述治疗性氨基酸序列是细胞因子。
6.如权利要求1所述的组合物,其特征在于,所述治疗性氨基酸序列选自:粒细胞集落刺激因子、干扰素α、干扰素β、红细胞生成素和粒细胞巨噬细胞集落刺激因子。
7.如权利要求6所述的组合物,其特征在于,所述治疗性氨基酸序列是人内源性氨基酸序列。
8.如权利要求6所述的组合物,其特征在于,所述治疗性氨基酸序列是抗体。
9.如权利要求1所述的组合物,其特征在于,所述糖基化作用由转基因鸟禽的输卵管细胞提供。
10.如权利要求9所述的组合物,其特征在于,所述输卵管细胞是管状腺细胞。
11.如权利要求1所述的组合物,其特征在于,所述治疗性氨基酸序列是O-糖基化的。
12.如权利要求1所述的组合物,其特征在于,所述治疗性氨基酸序列是N-糖基化的。
13.如权利要求1所述的组合物,其特征在于,所述甘醇聚合物是聚烷撑二醇。
14.如权利要求1所述的组合物,其特征在于,所述甘醇聚合物是聚乙二醇。
15.如权利要求1所述的组合物,其特征在于,所述甘醇聚合物是聚丙二醇。
16.如权利要求1所述的组合物,其特征在于,所述甘醇聚合物的分子量为约300-200,000。
17.如权利要求1所述的组合物,其特征在于,所述甘醇聚合物共价结合于治疗性氨基酸序列的氨基基团。
18.如权利要求1所述的组合物,其特征在于,所述甘醇聚合物共价结合于治疗性氨基酸序列的羧基基团。
19.一种包含从转基因鸟禽获得的糖基化治疗性氨基酸序列的组合物,其特征在于,所述治疗性氨基酸序列是糖蛋白并包含共价结合于治疗性氨基酸序列的糖基的甘醇聚合物。
20.一种包含从转基因鸡获得的糖基化治疗性氨基酸序列的组合物,其特征在于,所述治疗性氨基酸序列是糖蛋白并包含共价结合的甘醇聚合物。
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EP (1) | EP1937294A4 (zh) |
JP (1) | JP2009514814A (zh) |
CN (1) | CN101291684A (zh) |
AU (1) | AU2006304856A1 (zh) |
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WO2010138184A2 (en) * | 2009-05-27 | 2010-12-02 | Synageva Biopharma Corp. | Avian derived antibodies |
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- 2006-10-23 US US11/584,832 patent/US20070092486A1/en not_active Abandoned
- 2006-10-23 JP JP2008536869A patent/JP2009514814A/ja not_active Withdrawn
- 2006-10-23 CA CA002622210A patent/CA2622210A1/en not_active Abandoned
- 2006-10-23 EP EP06826502A patent/EP1937294A4/en not_active Withdrawn
- 2006-10-23 WO PCT/US2006/041343 patent/WO2007048047A1/en active Application Filing
- 2006-10-23 AU AU2006304856A patent/AU2006304856A1/en not_active Abandoned
- 2006-10-23 CN CNA200680039155XA patent/CN101291684A/zh active Pending
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EP1937294A1 (en) | 2008-07-02 |
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