CN101010105A - 甘油支化的聚乙二醇人生长激素缀合物、其制备方法及其使用方法 - Google Patents
甘油支化的聚乙二醇人生长激素缀合物、其制备方法及其使用方法 Download PDFInfo
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Abstract
本发明涉及使用甘油支化的PEG对人生长激素(hGH)的聚乙二醇化。本发明还涉及使hGH聚乙二醇化的方法。此外,本发明涉及包括聚乙二醇化hGH的药物组合物。另一个实施方案为聚乙二醇化hGH在治疗生长和发育障碍中的应用。
Description
本申请根据标题35美国代码§119要求2004年8月31日提交的美国临时申请顺序号US60/605,945的优先权,将该文献完整地引入作为参考,如同写入本文。
发明领域
本发明涉及人生长激素(hGH)的聚乙二醇化,通过该方法可以改变hGH的化学和/或生理特性。聚乙二醇化hGH缀合物可以具有增加的血浆滞留期、降低的清除率、改善的稳定性、降低的抗原性、减少的聚乙二醇化不均匀性或其组合。本发明还涉及修饰hGH的方法。此外,本发明涉及包含经修饰的hGH的药物组合物。另一个实施方案为修饰的hGH在治疗生长和发育障碍中的应用。
发明背景
天然人生长激素(hGH)为一种蛋白质,它包括通过两个二硫桥交联的191个氨基酸的单链,并且该单体形式具有22kDa的分子量。人GH由垂体腺分泌并且还可以通过重组遗传工程产生。hGH可以在所有能够生长的身体组织中引起生长。hGH不仅在人类生长期中促进生长方面,而且还在维持正常的身体组成、合成代谢和脂质代谢方面起重要作用(K.Bameis.和U.Keller,Baillieres Clin.Endocrinlo.Metab.10:337(1996))。
重组hGH已经市售几年。目前市场上存在两种类型的治疗应用的重组hGH制品:真实的一种例如GenotropinTM或NutropinTM,和在N-末端上带有额外的甲硫氨酸残基的类似物,例如SomatonormTM。hGH用于刺激患有垂体功能减退性侏儒症(也称作生长激素缺乏(GHD))或特纳综合征的患者的直线性生长,还提示了其它适应症,包括长期治疗出生时小于胎龄(SGA)的儿童的生长不足、治疗患有帕-魏综合征(PWS)、慢性肾功能不全(CRI)、AIDS消耗和老化的患者。成人GH缺乏(aGHD)患者存在各种问题,诸如身体组成的特征性改变,包括脂肪量增加、去脂肪体重和胞外液减少以及骨矿物质密度下降、脂质代谢异常和心血管机能障碍。那些问题中的许多通过hGH替代疗法改善(J.Verhelst J和R.Abs.Drugs.;62:2399(2002)。
生长激素(GH)的主要生物学作用在于促进幼小的哺乳动物生长和维持年长哺乳动物的组织。受影响的器官系统包括骨骼、结缔组织、肌肉和内脏,诸如肝、肠和肾。生长激素通过与靶细胞膜上的特异性受体的相互作用发挥其作用。hGH为包括胎盘催乳素、催乳素和生长激素的其它遗传和种变体的同源性激素家族的成员(Nicoll,C.S.等(1986)Endocrine Reviews 7:169)。在它们中hGH不寻常的原因在于它表现出广泛的种特异性并且结合克隆的躯体原的(Leung,D.W.等[1987]Nature 330;537)或催乳素受体(Boutin,J.M.等[1988]Ce11;53:69)。已经以分泌形式在大肠埃希氏杆菌(Escherichia coli)中表达了hGH的克隆的基因(Chang,C.N.等[1987]Gene 55:189)并且已经报导了其DNA和氨基酸序列(Goeddel等[1979]Nature 281:544;Gray等[1985]Gene 39:247)。
人生长激素(hGH)参与对正常人体生长和发育的大多数调节。这种垂体激素表现出众多生物学作用,包括直线性生长(体质形成)、泌乳、巨噬细胞活化、胰岛素样和致糖尿病作用等(Chawla,R,K.(1983)Ann.Rev.Med.34,519;Edwards,C.K.等(1988)Science 239,769;Thomer,M.O.等(1988)J.CHn.Inves t.81:745)。儿童生长激素缺乏导致侏儒症,已经通过外源性给予hGH成功地治疗了该病十年以上。
在成年人和儿童中,hGH通过增加氮贮留和刺激骨骼肌生长并且通过体脂肪的动员维持正常的身体组成。内脏脂肪组织特别对hGH起反应。除强化的脂解作用外,hGH减少了甘油三酯类摄入体脂肪贮存。IGF-I(胰岛素样生长因子-I)和IGFBP3(胰岛素样生长因子结合蛋白3)的血清浓度因hGH而增加。
hGH为有效的合成代谢剂,特别是由于对氮、磷、钾和钙的贮留。使用GH治疗垂体切除的大鼠可恢复大鼠的至少一部分生长速率。Moore等Endocrinology 122:2920-2926(1988)。其在垂体功能减退(GH-缺乏)对象中最为显著的作用之一在于骨-生长板-软骨的加速直线性生长,从而导致身高增加。Kaplan,Growth Disorders inChildren and Adolescents(Springfield,IL:Charles C.Thomas,1964).
hGH在各种动物模型中产生不同的生理和代谢作用,包括直线性骨生长、泌乳、巨噬细胞活化、胰岛素样和致糖尿病作用等(R.K.Chawla等Annu.Rev.Med.34:519(1983);O.G.P.lsaksson等Annu.Rev.Physiol.47,483(1985);C.K.Edwards等Science 239,769(1988);M.O.Thomer和M.L.Vance,J.Clin.Invest.82:745(1988);J.P.Hughes和H.G.Friesen,Ann.Rev.Physiol.47:469(1985))。已经报导了尤其是在绝经后的女性中,GH分泌随年龄而下降。Millard等Neurobiol.Aging,11:229-235(1990);Takahashi等NeuroendocrinologyM,L6-137-142(1987)。另外,参见Rudman等J.CHn.Invest,67:1361-1369(1981)和Blackman,Endocrinology and Aging,16:981(1987)。此外,报告提出了某些老化的表现,包括去脂肪体重下降、脂肪组织质量膨胀和皮肤变薄,可以由每周3次用GH治疗而减轻。例如,参见Rudman等N.Eng.J.Med,323:1-6(1990)和Dr.Vance在相同一期杂志中伴随的文章(pp.52-54)。这些生物学作用来源于hGH与特异性细胞受体之间的相互作用。已经克隆了两种不同的人受体,hGH肝受体(D.W.Leung等Nature330:537(1987))和人催乳素受体(J.M.Boutin等MoI.Endocrinology.3:1455(1989))。然而,可能存在其它受体,包括人胎盘催乳激素受体(M.Freemark,M.Comer,G.Komer,和S.Handwerger,Endocrinol.120:1865(1987))。这些同源性受体含有糖基化胞外激素结合结构域、单一跨膜结构域和胞质域,其在序列和大小方面明显不同。推定一种或多种受体在对hGH的生理反应方面起决定作用。
一般观察到将生理活性蛋白给药入身体可能仅表现出较短时间期限的药理活性,这是因其在体内的高清除率所致。此外,这些蛋白质的相对疏水性可限制其稳定性和/或溶解性。
为了减小清除率、改善稳定性或消除治疗蛋白的抗原性的目的,已经提出了一些方法,其中使用水溶性聚合物对蛋白质进行化学修饰。这种类型的化学修饰可以有效阻断蛋白水解酶与蛋白质骨架自身的物理性接触,由此防止降解。某些水溶性聚合物的化学结合可以因分子的流体动力学体积增加而有效减少肾清除率。在某些情况中,额外的优点包括增加治疗蛋白的稳定性和循环时间、增加溶解度和减少免疫原性。聚环氧烷烃,特别是聚(乙二醇)(PEG)是一种这类用于制备治疗蛋白产品的化学部分(动词″聚乙二醇化″意指附加至少一个PEG分子)。已经证实聚(乙二醇)的附加可以防止蛋白水解,Sada等,J.Fermentation Bioengineering 71:137-139(1991),并且可以利用结合某些聚(乙二醇)部分的方法。参见1979年12月18日授权的美国专利US 4,179,337,Davis等,“非免疫原性多肽类”;和1977年1月11日授权的美国专利US 4,002,531,Royer,“使用聚乙二醇修饰酶及其生产的产品”。就综述而言,参见Abuchowski等,EnzymesasDrugs.(J.S.Holcerberg和J.Roberts,eds.pp.367-383(1981))。
已经使用了其它水溶性聚合物,诸如乙二醇/丙二醇共聚物、羧甲基纤维素、葡聚糖、聚(乙烯醇)、聚(乙烯吡咯烷酮)、聚(-1,3-二氧戊环)、聚(-1,3,6-三烷)、乙烯/马来酸酐共聚物、聚-氨基酸(均聚物或随机共聚物)。
就聚(乙二醇)而言,已经使用了多种方式使聚(乙二醇)分子与蛋白质结合。一般而言,聚(乙二醇)分子通过蛋白质上发现的反应基与该蛋白质连接。诸如那些在赖氨酸残基上或在N-末端的氨基对这类结合而言是便利的。例如,Royer(上述美国专利US 4,002,531)描述了将还原烷基化用于使聚(乙二醇)分子与酶结合。Chamow等BioconjugateChem.5:133-140(1994)报导了通过还原烷基化用一甲氧基聚(乙二醇)醛修饰CD4免疫粘合素。美国专利US 5,824,784中证实了在还原烷基化条件下聚乙二醇化G-CSF(包括在N-末端)。
WO 93/00109中涉及刺激哺乳动物或鸟类的GH反应性组织的方法,包括将连续有效血浆GH浓度维持3天或3天以上期限。描述了获得这类血浆浓度的一种方式在于使用与大分子物质诸如聚(乙二醇)偶联的GH。描述与大分子物质偶联可导致半衰期得到改善。WO 93/00109中报导了使用mPEG醛-5000和mPEG N-羟基琥珀酰亚胺基酯(mPEG-NHS-5000)聚乙二醇化的人生长激素以获得如所述的大于肾过滤的70K分子量截止值(Knauf,M.J等,J.Biol.Chem.263:15064-15070,1988)的流体动力学体积。mPEG-NHS的应用产生了hGH的多种聚乙二醇化形式的不均匀混合物。WO 93/00109中还披露了mPEG-马来酰亚胺在使半胱氨酸hGH变体聚乙二醇化中的应用。
WO 99/03887中披露了聚乙二醇化的半胱氨酸变体生长激素。其被命名为BT-005,据认为这种缀合物可比hGH更有效地刺激生长激素缺乏大鼠的体重增加并且具有更长的半衰期。
Clark等使用羧甲基化PEG的琥珀酰亚胺基酯也报道了聚乙二醇化的人生长激素(Journal of Biological Chemistry271:21969-21977,1996)。Clark等描述了使用选择性缀合至伯胺类的mPEG-NHS-5000而得到的增加大小的hGH衍生物。PEG修饰的水平增加减少了它对受体的亲和力并且在基于细胞的试验中将EC50增加高达1500倍。Olson等在Polymer Preprints 38:568-569,1997中披露了N-羟基琥珀酰亚胺(NHS)PEG和琥珀酰亚胺基丙酸酯(SPA)PEG在获得多种聚乙二醇化hGH种类中的应用。
WO 94/20069中预言性地披露了聚乙二醇化hGH作为肺部递送用制剂的组成部分。
US 4,179,337中披露了使酶和激素聚乙二醇化以获得生理活性的非免疫原性的水溶性多肽缀合物的方法。GH被提及作为有待聚乙二醇化的激素中的一个实例。
EP 458064 A2中披露了促生长素中引入或天然存在的半胱氨酸残基的聚乙二醇化。EP 458064 A2中进一步提及了将两个半胱氨酸残基引入野生型牛促生长素中称作ω环(据称在残基102-112处)的环中,更具体地说,EP 458064 A2中披露了分别将牛促生长素的编号为102和112的残基由Ser置换为Cys和由Tyr置换为Cys。
WO 95/11987中提示了PEG与存在于母体分子中或通过定点诱变引入的半胱氨酸残基的硫代基团结合。WO 95/11987中涉及蛋白酶-微管连接蛋白-1的聚乙二醇化,不过,也泛泛提示了hGH和其它蛋白的聚乙二醇化。
WO 99/03887中披露了例如通过用半胱氨酸残基置换25位上的丝氨酸和PEG与引入的半胱氨酸残基结合而修饰的生长激素。
WO 00/42175中涉及制备含有用于结合PEG的游离半胱氨酸残基的蛋白的方法。WO 00/42175中披露的hGH的如下突变蛋白:T3C、S144C和T148C及其半胱氨酸聚乙二醇化。
WO 97/11178(以及US 5849535、US 6004931和US 6022711)中涉及GH变体作为hGH的激动剂或拮抗剂的应用。WO 97/11178中还披露了hGH的聚乙二醇化,包括赖氨酸聚乙二醇化和赖氨酸的引入或替换(例如K168A和K172R)。WO 9711178中还披露了置换G120K。
WO 03/044056中披露了多种聚乙二醇化hGH种类,包括赖氨酸支化的40K PEG醛hGH缀合物。
US 2004/0127417中披露了赖氨酸支化的PEG丁醛hGH缀合物。
WO 04/46222、US 2005/0058620、JP 08-059818、JP 11-228685和JP 2000-001541中披露了在甘油骨架的1-位上的伯碳上带有反应基团并且在2-和3-位上带有聚亚烷基二醇链的聚亚烷基二醇衍生物。
目前每日给予rhGH需要持续长时间期限且由此较少的给药频率是非常理想的。具有较长循环半衰期的hGH分子可以减少必要的给药次数并且可能提供更为优化的治疗hGH水平且伴随增强的治疗作用。
尽管进行了研发长效形式的hGH包括聚乙二醇化hGH的大量尝试,但是对具有成为成功商品的合适特性的聚乙二醇化hGH分子的需求仍然未得到满足。本发明提供了具有主要连接在hGH的N-末端苯丙氨酸上的单一PEG的PEG-hGH缀合物,这提供了超过其它PEG-hGH缀合物的优点。WO 93/00109、Clark等(Journal of Biological Chemistry271:21969-21977,1996和Olson等(Polymer Preprints 38:568-569,1997)已经描述了使用mPEG醛-5000或mPEG N-羟基琥珀酰亚胺基酯(mPEG-NHS-5000)使多个低分子量(5Kd)PEG结合在α-或ε-氨基位点(hGH上的N-末端和9个赖氨酸)上。这产生了不均一的群体。作为说明,具有9个赖氨酸的hGH中某些分子可带有10个结合的PEG,某些带有9个,某些带有8个,某些带有7个,某些带有6个,某些带有5个,某些带有4个,某些带有3个,某些带有2个,某些带有1个且某些带有0个。此外,在带有几个的分子中,PEG可以不结合在不同分子的相同位置上。这种产生的不均匀性在研发治疗产品时存在缺陷,从而使得缀合、纯化和表征困难、成本高和高度不可再现。另一种手段(WO 00/42175)使用了含有用于结合PEG的游离半胱氨酸残基的hGH变体。然而,这种手段产生非天然的hGH变体并且也可导致带有不正确配对的二硫键的不正确折叠的蛋白质,从而产生PEG结合在某些或所有半胱氨酸上的不均匀聚乙二醇化的产品。多个PEG与多个位点结合可以导致分子具有PEG与不同位点之间不那么稳定的键,其可以以不同速率解离。这使得难以准确预测产品的药代动力学,导致定量不准确。不均匀产品在获得管理部门对治疗产品的批准方面还存在不利的问题。
因此,需要拥有具有结合在单一位点上的单一PEG的聚乙二醇化hGH分子。本发明以多种方式解决了这一需求。
发明概述
本发明涉及使用甘油支化的(branched)聚(乙二醇)部分的聚乙二醇化hGH,它可以具有至少一种改善的化学或生理特性,该特性选自但不限于降低的清除率、增加的血浆滞留期、增加的稳定性、改善的溶解性和减少的抗原性。因此,正如下文更具体地描述的,本发明具有多个涉及使用甘油支化的聚(乙二醇)部分化学修饰hGH的方面。
本发明还可以具有一种或多种与基于赖氨酸的支化的PEG人生长激素缀合物相比改善的特性,包括,但不限于:a)增加的甘油骨架稳定性;b)增加的受体结合;c)降低的成本;d)增加的N-末端结合选择性;e)增加的溶解度;f)减少的免疫原性;g)增加的缀合物稳定性;h)增加的可制造性;和i)蛋白水解减少。
本发明还涉及生产聚乙二醇化hGH的方法。特别地,本发明涉及使用甘油支化的PEG生产聚乙二醇化hGH的方法。
本发明还涉及包括单独的或与另一种治疗剂组合的聚乙二醇化hGH的组合物。本发明还涉及单独的本发明的聚乙二醇化hGH或其与另一种治疗剂的组合在预防和/或治疗在其中GH治疗有用的病症和/或疾病中的应用。
附图简述
附图1为表示TSK G4000PWXL柱上纯化的一聚乙二醇化的甘油支化的43K PEG醛hGH反应产物的洗脱谱的大小排阻HPLC示踪。
附图2为hGH和甘油支化的43K PEG醛hGH的胰蛋白酶图分析的HPLC示踪。上图为hGH的胰蛋白酶图。下图为甘油支化的43K PEG醛hGH的胰蛋白酶图。T1为N-末端胰蛋白酶片段。
附图3显示人生长激素的氨基酸序列(SEQ ID NO:1)。
附图4显示甘油支化的43K PEG醛hGH在11天大鼠体重增加试验中的功效。从Harlan实验室购得4-5周龄(85-110g)的垂体切除的雌性Sprague-Dawley大鼠。在进入动物设施时,将动物维持在80的恒定室温下。3天适应环境后,每天给大鼠称体重,持续4-10天,以便建立基础生长速率。然后从第0天开始,对照组中的大鼠(~100g)每天接受1次皮下注射~0.3mg/kg hGH(▲)或PBS载体(●)连续11天。在第0和6天时甘油支化的43K PEG醛hGH试验组(■)接受单剂量的1.8mg/kg甘油支化的43K PEG醛hGH。每组中有6只动物。绘图的值表示平均体重增加±SEM。
附图5显示对甘油支化的43K PEG醛hGH起反应的11天胫骨生长。动物为附图4中治疗的那些动物。在第11天取体重值后处死动物,给左侧胫骨拍摄X光照片并且使用测径器测量骨长度。将平均长度±SEM绘图。星号表示与对照组相比具有显著性差异(P<0.05)。每组中有6只动物。
附图6显示对甘油支化的43K PEG醛hGH起反应的11天血液尿素氮水平。从附图4中治疗的动物中取血样。制备血清并且测定尿素氮水平。将平均值±SEM绘图(每组中有6只动物)。星号表示与对照组相比具有显著性差异(P<0.05)。
附图7显示甘油支化的43K PEG醛hGH的6天剂量增加功效研究。按照与附图4中所述类似的方式进行这种生长研究,但仅在第0天给予改变的单剂量的甘油支化的43K PEG醛hGH并且将该研究进行6天。对照组每天接受1次皮下注射0.3mg/kg hGH(◆)或PBS载体(o)连续6天。甘油支化的43K PEG醛hGH试验组在第0天时接受单剂量的甘油支化的43K PEG醛hGH。甘油支化的43K PEG醛hGH剂量为1.8mg/kg(■)、0.6mg/kg(X)、0.2mg/kg(+)、0.067mg/kg(▲)。每组中有6只动物。
附图8显示6天功效研究的血清IGF-1水平。如附图7中所述治疗动物。在绘制的不同时间点取血样并且通过ELISA测定血清IGF-1水平。将组(n=6)平均值用于使用单向方差分析对测定的值计算IGF-1响应,并且对1.8、0.6、0.2和0.067mg/kg给药组分别测定了37,839、28,1292、22,958和20,040的AUC d0-6(ng/mL*24h)值。
附图9显示对垂体切除的雌性大鼠给予单剂量的甘油支化的43KPEG醛hGH后的PK/PD评价。1.8mg/kg SC的甘油支化的43K PEG醛hGH的单剂量给药对血浆药物水平(a)或血浆IGF-1响应(b)的作用。
发明详述
本发明涉及甘油支化的聚乙二醇-人生长激素缀合物。在一个具体的实施方案中,甘油支化的聚乙二醇衍生物带有醛反应基和任选存在的聚乙二醇与甘油骨架1-位上的伯碳处的反应性官能团之间的连接基并且如WO 04/46222或US 2005/0058620(引入作为参考)中所述在2-和3-位上带有聚亚烷基二醇链,以便生成hGH缀合物。对所述的连接基并没有特别的限制,只要它为共价键,但优选包括亚烷基和含有酯键、尿烷键、酰胺键、醚键、碳酸酯键或仲氨基的亚烷基。优选的亚烷基包括亚甲基、亚乙基、1,3-亚丙基、亚丙基、亚异丙基、1,4-亚丁基、亚丁基、亚异丁基、1,5-亚戊基和1,6-亚己基。
本发明的一个具体的实施方案为具有如下通式结构的人生长激素-PEG缀合物:
其中:
n为60-75的整数;
m为450-460的整数;且
R为人生长激素多肽。
在一个具体的实施方案中,n为约64-约72。
在一个具体的实施方案中,(CH2CH2O)n部分具有约2.6-约3.5Kd的平均分子量且特别是平均分子量约为3Kd。
在一个具体的实施方案中,每个(CH2CH2O)m部分具有约17.6-约22Kd的平均分子量且特别是平均分子量约为20Kd。
在一个具体的实施方案中,(CH2CH2O)n部分具有约3Kd的平均分子量且每个(CH2CH2O)m部分具有约20Kd的平均分子量。
术语″约″在与PEG部分的分子量联用时意指在聚乙二醇制品中,某些分子的重量高于、某些低于所述的分子量,并且所述的分子量意指平均分子量。应理解存在一定程度的与聚合物诸如聚(乙二醇)相关的多分散性。优选使用具有低多分散性的PEG。在一个具体的实施方案中,末端聚合物羟基端基之一被转化或被甲基封端。本文所用的术语″mPEG″意指PEG,它在一端被甲基封端。mPEG在结构上可以被表示为:
CH3O-(CH2CH2O)n-H
术语″人生长激素多肽″、″hGH多肽″或″hGH蛋白″在本文中使用时包括所有的hGH多肽类,其特征在于在生长期促进生长并且维持正常身体组成、合成代谢和脂质代谢。优选术语″hGH多肽″意指SEQ ID NO:1的hGH多肽。
可以按照任意合适的方式制备本发明的hGH多肽类。这类hGH多肽类和其片段可以使用本领域技术人员公知的技术纯化自天然来源,通过化学合成,通过重组技术产生,包括体外翻译技术或在能够表达hGH cDNA的重组细胞中表达,或这些方法的组合(例如,对用于纯化蛋白质的各种方法而言,参见″Methods in Enzymology,AcademicPress,1993″;Creighton,(1983)Proteins:Structures andMolecular Principles,W.H.Freeman&Co.2nd Ed.,T.E.,NewYork;和就化学合成蛋白质而言,参见Hunkapiller等(1984)Nature.310(5973):105-11;并且就重组技术而言,参见Davis等(1986)BasicMethods in Molecular Biology,ed.,Elsevier Press,NY,将这些文献披露的内容完整地引入作为参考)。优选以分离的形式提供本发明的多肽类并且它们可以为部分或优选基本上纯化的。
本发明的一个具体的实施方案为人生长激素-PEG缀合物,其中大于80%,更优选81%,更优选82%,更优选83%,更优选84%,更优选85%,更优选86%,更优选87%,更优选88%,更优选89%,更优选90%,更优选91%,更优选92%,更优选93%,更优选94%,更优选95%,更优选96%,更优选97%且更优选98%的聚乙二醇与SEQ ID NO:1的人生长激素的氨基-末端苯丙氨酸缀合。
本发明的另一个实施方案为任选在药物上可接受的稀释剂、载体或辅剂中的基本上均一的N-末端聚乙二醇化hGH制品,所述的制品中基本上不含在非N-末端的位点上聚乙二醇化的hGH。术语″基本上均一的制品″意指一种制品,其中大于80%,更优选81%,更优选82%,更优选83%,更优选84%,更优选85%,更优选86%,更优选87%,更优选88%,更优选89%,更优选90%,更优选91%,更优选92%,更优选93%,更优选94%,更优选95%,更优选96%,更优选97%且更优选98%为一聚乙二醇化的(monoPEGylated)。
在本发明的一个实施方案中,如Chamow等Bioconjugate Chem.5:133-140(1994)、美国专利US 4,002,531、WO 90/05534和美国专利US 5,824,784中所述,使用合适的还原剂,诸如NaCNBH3、NaBH3、吡啶硼烷等,通过还原烷基化在hGH多肽的N-末端伯α-氨基与甘油支化链PEG醛之间形成仲胺键。将甘油支化的PEG醛与hGH多肽一起温育,导致通过希夫碱形成将PEG部分添加到氨基上。通过使用还原剂还原将这些键转化成稳定的仲胺类。还原烷基化反应过程如以下方案中所示(来自Chamow等)。
称作″聚乙二醇化反应″的缀合反应在历史上在溶液中使用摩尔过量的聚合物进行并且不考虑聚合物将在何处附着到蛋白质。然而,这类一般技术通常经证实不足以在使生物活性蛋白质与非抗原性聚合物缀合的同时保留足够的生物活性。一种维持hGH生物活性的方式在于基本上避免在聚合物偶联过程中缀合那些与受体结合位点相关的hGH反应基。本发明的另一个方面在于提供使聚(乙二醇)与hGH缀合并维持高水平保留活性的方法。
可以在一般用于生物活性物质与活化的聚(乙二醇)反应的任意合适的条件下通过共价键进行化学修饰。在相对温和条件下进行缀合反应以避免使hGH失活。温和的条件包括将反应溶液的pH维持在3-10的范围并且将反应温度维持在约0℃-37℃的范围内。就hGH中的反应性氨基酸残基带有游离氨基的情况而言,上述修饰优选在4℃-37℃下和非限制性列举的合适的缓冲液(pH4-10),包括磷酸盐、MES、柠檬酸盐、乙酸盐、琥珀酸盐或HEPES中进行1-48小时。在使用试剂诸如PEG醛靶向N-末端氨基酸中,优选维持pH4-8。可以以约0.01-100倍,优选约0.01-2.5倍于hGH的游离氨基数目的摩尔量使用活化的聚(乙二醇)。
尽管本文所述的反应条件可以产生大量的未修饰的hGH,但是易于使未修饰的hGH再循环入未来批次,以便进行额外的缀合反应。本发明的方法令人意外地产生了极少,即低于约20%且更优选低于约10%的高分子量种类和每个hGH含有一条以上聚合物链的种类。这些反应条件与典型用于聚合物缀合反应的那些条件形成对比,后者中活化的聚合物以相对于靶标数倍摩尔过量存在。
本发明的缀合反应最初提供了含有一-PEG-hGH缀合物、未反应的hGH、未反应的聚合物和低于约20%高分子量种类的反应混合物或库。高分子量种类包括含有一条以上聚合物链的缀合物和/或聚合的PEG-hGH种类。在未反应的种类和高分子量种类被除去后,回收了主要含有一-聚乙二醇化的hGH缀合物的组合物。鉴于缀合物大部分包括单一的聚合物链这一事实,所以缀合物基本上为均一的。这些修饰的hGH具有与天然或未修饰的hGH相关的体外生物活性的至少约0.1%,正如使用标准FDC-P1细胞增殖试验(Clark等Journal of BiologicalChemistry 271:21969-21977,1996)、受体结合试验(US 5,057,417)或垂体切除大鼠的生长(Clark等Journal of Biological Chemistry271:21969-21977,1996)测定的。然而,在本发明的优选方面中,修饰的hGH具有约25%的体外生物活性,更优选修饰的hGH具有约50%的体外生物活性,更优选修饰的hGH具有约75%的体外生物活性,且最优选修饰的hGH具有等同或改善的体外生物活性。
本发明的方法优选包括相当有限的聚合物与hGH之比。因此,已经发现hGH缀合物主要限于仅含有一条聚合物链的种类。此外,聚合物与hGH反应基的结合的随机性显著低于使用高摩尔过量聚合物连接基的情况。在已经终止缀合反应后,可以使用离子交换或大小排阻色谱法或类似的分离技术使存在于反应收集物中的未修饰的hGH再循环入未来的反应。
可以通过用于纯化蛋白质的常规方法,诸如透析、盐析、超滤、离子交换色谱法、疏水相互作用色谱(HIC)、凝胶色谱和电泳,从反应混合物中纯化聚(乙二醇)-修饰的hGH。离子交换色谱法特别可以有效地除去未反应的聚(乙二醇)和hGH。在本发明的另一个实施方案中,从反应混合物中分离一聚乙二醇化的hGH种类以便除去高分子量种类和未修饰的hGH。通过将混合的种类置于含有约0.5-10mg/mL hGH-聚合物缀合物的缓冲溶液中进行分离。合适的溶液具有约4-约10的pH。这些溶液优选含有一种或多种缓冲盐,它们选自KCl、NaCl、K2HPO4、KH2PO4、Na2HPO4、NaH2PO4、NaHCO3、NaBO4、CH3CO2H和NaOH。
根据反应缓冲液的不同,hGH聚合物缀合物溶液可能首先必须进行缓冲液交换/超滤以便除去任何未反应的聚合物。例如,可以将PEG-hGH缀合物溶液通过低分子量截止值(10,000-30,000道尔顿)的膜超滤以便除去大部分不需要的物质,诸如未反应的聚合物、表明活性剂(如果存在)等。
优选使用离子交换色谱介质将缀合物分级分离入含有期望种类的收集物(pool)。这类介质能够通过以一定程度可预测的方式改变的电荷差异选择性结合PEG-hGH缀合物。例如,根据蛋白质表面上的可利用带电荷基团数目确定hGH的表面电荷。这些带电荷的基团一般用作聚环氧烷烃聚合物的可能附着点。因此,hGH缀合物会带有不同于其它种类的电荷以允许进行选择性分离。
强极性阴离子或阳离子交换树脂,分别诸如季铵或磺丙基树脂,用于本发明的方法。尤其优选阴离子交换树脂。包括适用于本发明的商购阳离子交换树脂的非限制性列表为SP-hitrap、SP SepharoseHP和SP Sepharosefast flow。还可以使用其它合适的阳离子交换树脂,例如S和CM树脂。适用于本发明的阴离子交换树脂包括商购阴离子交换树脂的非限制性列表为Q-hitrap、Q Sepharose HP和Qsepharosefast flow。还可以使用其它合适的阴离子交换树脂,例如DEAE树脂。
例如,优选将阴离子或阳离子交换树脂填充在柱中并且通过常规方式平衡。使用与聚合物缀合的hGH溶液具有相同的pH和同渗质量摩尔浓度的缓冲液。洗脱缓冲液优选含有一种或多种盐,它们选自KCl、NaCl、K2HPO4、KH2PO4、Na2HPO4、NaH2PO4、NaHCO3、NaBO4和(NH4)2CO3。然后使含有缀合物的溶液吸附到不阻留未反应聚合物和某些高分子量种类的柱上。在上样结束时,将具有增加的盐浓度的洗脱缓冲液梯度流上柱以便洗脱聚环氧烷烃-缀合的hGH的所需级分。在阳离子或阴离子交换分离步骤后,洗脱的收集级分优选限于均匀的聚合物缀合物。然后可以通过常规技术从柱上反洗任何未缀合的hGH种类。如果需要,可以进一步通过额外的离子交换色谱法或大小排阻色谱法将一和多聚乙二醇化的hGH种类彼此分离。
还可以使用应用增加盐浓度或pH的多等度步骤的技术。增加浓度的多等度洗脱步骤使得二-且然后是一-hGH-聚合物缀合物依次洗脱。
用于洗脱的温度范围在约4℃-约25℃。优选在约4℃-约22℃的温度下进行洗脱。例如,通过在280nm处的UV吸收检测PEG-hGH级分的洗脱。可以通过简单的时间洗脱谱图进行级分收集。
可以将表面活性剂用于使聚(乙二醇)聚合物与hGH部分缀合的方法中。合适的表面活性剂包括离子型试剂,诸如十二烷基硫酸钠(SDS)。还可以使用其它离子型表面活性剂,诸如十二烷基硫酸锂、季铵化合物、牛磺胆酸、辛酸、癸磺酸等。也可以使用非离子型表面活性剂。例如,可以使用诸如聚(氧乙烯)失水山梨糖醇类(Tweens)、聚(氧乙烯)醚类(Tritons)这类物质。另外,参见Neugebauer,A Guide to theProperties and Uses of Detergents in Biology andBiochemistry(1992)Calbiochem Corp.。对用于本发明方法中的表面活性剂的唯一限制是它们在不会导致hGH的实质性不可逆变性和不完全抑制聚合物缀合的条件和浓度下使用。表面活性剂在反应混合物中的存在量约0.01-0.5%;优选0.05-0.5%;且最优选约0.075-0.25%。还关注表面活性剂的混合物。
认为表面活性剂在聚合物缀合过程中提供暂时的可逆的保护系统。已经证实表面活性剂可以有效地选择性阻碍聚合物缀合,同时允许基于赖氨酸或基于氨基末端的缀合进行。
本发明的聚(乙二醇)-修饰的hGH具有更为持久的药理作用,这可能归因于其延长的体内半衰期。
本发明的另一个实施方案涉及用于预防和/或治疗其中使用GH优选hGH有益的疾病或病症的方法,包括对有此需要的患者给予治疗有效量的本发明聚(乙二醇)-修饰的hGH或其激动剂变体,单独的或与另一种治疗剂组合。本发明还涉及本发明聚(乙二醇)-修饰的hGH或其激动剂变体在制备用于预防和/或治疗其中使用GH优选hGH有益的疾病或病症的药物中的应用。此外,本发明还涉及用于预防和/或治疗其中使用GH优选hGH有益的疾病或病症的包含本发明聚(乙二醇)-修饰的hGH或其激动剂变体的药物组合物。
其中使用GH有益的疾病或病症包括但不限于生长激素缺乏(GHD)、成人生长激素缺乏(aGHD)、特纳综合征、出生时小于胎龄(SGA)的儿童的生长不足、帕-魏综合征(PWS)、慢性肾功能不全(CRI)、爱滋病消耗、衰老、终末期肾功能衰竭、囊性纤维化、勃起机能障碍、HIV脂肪营养障碍、纤维肌痛、骨质疏松症、记忆障碍、抑郁症、克罗恩病、骨骼发育异常、外伤性脑损伤、蛛网膜下腔出血、努南综合征、唐氏综合征、特发性身材矮小症(ISS)、终末期肾病(ESRD)、极低出生体重(VLBW)、骨髓干细胞解救、代谢综合征、糖皮质类固醇肌病、因儿童中的糖皮质类固醇治疗导致的身材矮小症和矮小早产儿的生长滞后。
在本发明一个更具体的实施方案中,本发明的聚(乙二醇)-修饰的hGH或其激动剂变体用于预防和/或治疗选自GHD、aGHD、SGA、PWS、特纳综合征和CRI组成的组的病症或疾病。
在本发明的另一个更具体的实施方案中,本发明的聚(乙二醇)-修饰的hGH或其激动剂变体用于预防和/或治疗选自特发性身材矮小症、极低出生体重、外伤性脑损伤、代谢综合征和努南综合征组成的组的病症或疾病。
本发明的另一个实施方案涉及药物组合物,其包含本发明的聚(乙二醇)-修饰的hGH,单独或与另一种治疗剂组合,以及至少一种药物上可接受的赋形剂或载体。然后可以将本发明的聚(乙二醇)-修饰的hGH配制成还含有药物上可接受的稀释剂、用于制备等渗溶液的试剂、pH-调节剂等的药剂以便对患者给药。
可以根据治疗目的的不同通过皮下、肌内、静脉内、肺部、真皮内或口服给予上述药物。剂量还可以基于所治疗患者的病症的种类和病情,对成年人而言,一般通过注射为0.1mg-5mg,口服给药为0.1mg-50mg。
本文所用的本发明聚(乙二醇)-修饰的hGH或其激动剂变体可以与另一种治疗剂联用。本文所用涉及化合物A和一种或多种其它治疗剂的术语″共同给药″、″共同施用″和″组合/联用″意指并且确指和包括如下含义:
о对有治疗需要的患者同时给予这类A和治疗剂的组合,此时将这类成分共同配制成单一剂型,该剂型以基本上同时的方式对所述的患者释放所述的成分;
о对有治疗需要的患者基本上同时给予这类A和治疗剂的组合,此时将这类成分彼此分开配制成单独的剂型,所述剂型基本上同时由所述的患者摄取,于是所述成分基本上同时释放给所述患者;
о对有治疗需要的患者依次给予这类A和治疗剂的组合,此时将这类成分彼此分开配制成单独的剂型,这些剂型由所述的患者在连续时间摄取,每次给药之间存在显著的时间间隔,于是所述的成分以基本上不同的时间释放给所述的患者;和
о对有治疗需要的患者依次给予这类A和治疗剂的组合,此时将这类成分共同配制成单一剂型,该剂型以受控方式释放所述的成分,于是它们在同时和/或不同时间时对所述的患者同时、连续和/或重叠交错给予。
可以与A、其药物上可接受的盐和/或其衍生形式联用的其它治疗剂的合适的实例包括,但不限于:芳香酶抑制剂,诸如依西美坦、福美坦、阿他美坦、法倔唑、来曲唑、伏氯唑和阿那曲唑;游离脂肪酸调节剂,包括fibric acid衍生物(诸如非诺贝特、氯贝丁酯、吉非贝齐、苯扎贝特和环丙贝特)和烟酸衍生物,诸如阿昔莫司;胰岛素敏化剂,包括但不限于双胍类,诸如二甲双胍;PPARγ胰岛素敏化剂和噻唑烷二酮类(thiazolodeniones),诸如曲格列酮和罗西格列酮:曲格列酮,5-[[4-[3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-]-苯并吡喃-2-基]甲氧基]苯基]甲基3-2,4-噻唑烷二酮V411(DIABII,Glaucanin);吡格列酮(ACTOS,AD 4833,U 72107,U 72107A,U 72107E,ZACTOS),化学名:2,4-噻唑烷二酮,5-[[4-[2-(5-乙基-2-吡啶基)乙氧基]苯基]甲基]-,一盐酸盐,(a/-);罗西格列酮(Avandia,BRL 49653,BRL49653C)化学名:2,4-噻唑烷二酮,5-[[4-[2-(甲基-2-吡啶基氨基)乙氧基]苯基]甲基];25贝沙罗汀-口服(LGD 1069口服、Targretin口服、Targretin、Targretyn口服、Targrexin口服)化学名:4-[1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)乙烯基]苯甲酸;ZD2079,(ICI D 2079)(化学名:R)-N-[2-4-(羧甲基)30苯氧基]乙基)-N-(2-羟基-2-苯乙基)铵氯化物:Netoglitazone,(Isaglitazone,MCC 555,RWJ 241947)(化学名:5-[6(2-氟苄氧基)萘-2-基甲基]噻唑烷-2,4-二酮);INS(D-手性-肌醇)(化学名:D-1,2,3,4,5,6-六羟基环己烷),ON 2344(DRF 2593);Dexlipotam,化学名:5(R)-(1,2-二硫戊环-3-基)pentaloic 35 acid;HQL 975,化学名:3-[4-[2-(5-甲基-2-苯基唑-4-基)乙氧基]苯基]-2(S)-(丙氨基)丙酸;YM 268,化学名:5,5′-亚甲基-双(1,4-亚苯基)双亚甲基双(噻唑烷-2,4-二酮)。在研发中的I PPAR激动剂包括:Reglitazar(JTT 501,PNU182716,PNU 716)(化学名:异唑烷二烯-3,5-二酮、i 4-[[4-(2-苯基-5-甲基)-1,3-唑基]乙氧基苯基-4]甲基-,(4RS));I(RP 297,化学名:10 5-(2,4-二氧代噻唑烷噻唑烷-5-基甲基)-2-甲氧基-N-[4-(三氟甲基)苄基苯甲酰胺;R 119702(C1 1037,CS 011)化学名:(/-)-5-[4-(5-甲氧基-1H苯并咪唑-2-基甲氧基)苄基]噻唑烷-2,4-二酮盐酸盐;15 DRF 2189,化学名:5-[[4-[2-(1-吲哚基)乙氧基]苯基]甲基]噻唑烷-2,4-二酮;考的松合成抑制剂,诸如酮康唑、益康唑或咪康唑;生长激素,诸如生长激素(somatropin)或生长激素(somatonorm)及其衍生物,如人生长激素融合蛋白,诸如ALBUTROPIN;聚乙二醇生长激素,诸如半胱氨酸-聚乙二醇化的生长激素、BT005(Bolder BioTechnology Inc.);生长激素促分泌素,诸如,例如SM 130686(Sumitomo)卡普瑞林(Pfizer)、美卡舍明(Fujisawa)、舍莫瑞林(Salk Institute,Bio-Technology General)、人蛋氨生长素、生长调节素(C Llorente;Pharmacia Corporation)艾沙瑞林、他莫瑞林;CP 464709(Pfizer)、LY 426410和LY 444711(Lilly);如WO2002057241中披露的8-(氨基烷氧基亚氨基)-8H-二苯并[a,e]三唑并[4,5-c][7]环庚烯类、如WO2002056873中所述的2-取代的二苯并[a,e]1,2,3-三唑并[4,5-c][7]轮烯-8-酮类、如美国专利US 4,411,890和公开文献WO 89/07110、WO 89/07111中所述的生长激素释放肽类GHRP-6和GHRP-1、如WO 93/04081中所述的B-HT920、hexarelin和GHRP-2或生长激素释放激素(GHRH,也命名为GRF)及其类似物;生长调节素,包括IGF-1和IGF-2及其衍生物,诸如Somatokine-一种胰岛素样生长因子-1与其结合蛋白BP-3的重组融合体;α-2-肾上腺素能激动剂,诸如可乐定、赛拉嗪、地托咪定和美托咪定;或5-羟色胺5HTID激动剂,诸如surnitriptan或抑制生长抑素或其释放的活性剂,诸如毒扁豆碱和吡啶斯的明、ThGRF1-44(Theratechnologies);L 165166(Merck&Company);如WO9858947中所述的二肽衍生物;二肽基肽酶IV抑制剂,诸如US6521644、WO95/15309和WO98/19998中所述的氨基-酰基吡咯烷腈;β-氨基杂环二肽基肽酶抑制剂,诸如US20030100563和WO2003082817中所述的那些抑制剂;如下列文献中所述的生长激素释放化合物:US20030055261、US20030040483、EP18072、EP83864、WO89/07110、WO89/01711、WO89/10933、WO88/9780、WO83/02272、WO91/18016、WO92/01711、WO93/04081、WO9514666、EP0923539、美国专利US5,206,235、5,283,241、5,284,841、5,310,737、5,317,017、5,374,721、5,430,144、5,434,261、5,438,136、5,494,919、5,494,920、5,492,916、5,536,716和5,578,593、WO94/13696、WO94/19367、WO95/03289、WO95/03290、WO95/09633、WO95/11029、WO95/12598、WO95/13069、WO95/14666、WO95/16675、WO95/16692、WO95/17422、WO95/17423、WO95/34311和WO96/02530;如US5804578、US5783582、WO2004007468中所述的哌啶类、吡咯烷类和六氢-1H-吖庚因类;酰氨基螺哌啶类,诸如那些WO0104119中所述的化合物;2-氨基-5-嘧啶乙酸化合物,包括如US6329383中所述的2-[(5,6-二甲基-2-苯并咪唑基)氨基]-4-羟基-6-甲基-5-嘧啶乙酸(2)和2-[(5,6-二甲基-2-苯并咪唑基)氨基]-4-羟基-6-甲基-5-嘧啶乙酸乙酯;如EP1155014中所述的苯并咪唑类;与GRF相关的类似肽基化合物和美国专利US4,411,890的肽类;促性腺激素释放激素拮抗剂,诸如那些描述在WO0170228、WO0170227、WO0170228、WO0069433、WO0004013、W0995156、WO9951595、WO9951231-4、WO9941251-2、WO9921557、WO9921553中的化合物和如WO0053602、WO0053185、WO0053181、WO0053180、WO0053179、WO0053178、US6288078中所述的6-氮杂吲哚化合物;IGF-1促分泌素;胰岛素样生长因子-2(IGF-2或生长调节素A)和IGF-2促分泌素;筒箭毒碱拮抗剂和抑制成纤维细胞生长因子受体-3(FGFR-3)酪氨酸激酶的化合物。
包括的聚合物物质还优选在室温下为水溶性的。这类聚合物的非限制性列表包括聚(环氧烷烃)均聚物诸如聚(乙二醇)或聚(丙二醇)、聚(氧乙烯化多元醇)、其共聚物及其嵌段共聚物,条件是嵌段共聚物的水溶性得以维持。
作为基于PEG的聚合物的备选,可以使用有效地非抗原性的物质,诸如葡聚糖、聚(乙烯吡咯烷酮)、聚(丙烯酰胺)、聚(乙烯醇类)、基于碳水化合物的聚合物等。实际上,可以按照与用于转化聚(环氧烷烃)类似的方式进行这些聚合物物质的α-和ε-末端基团的活化且由此对本领域技术人员而言显而易见。本领域技术人员将认识到上述列表仅为解释性的并且关注具有本文所述性质的所有聚合物物质。就本发明的目的而言,″有效地非抗原性的″意指本领域中理解为对哺乳动物无毒性并且不会引起显著的免疫原性应答的所有物质。
定义
下面是在本文中可以互换使用的缩写和相应含义的列表:
-g 克
-mg 毫克
-ml或mL 毫升
-RT 室温
-PEG 聚(乙二醇)
-将本说明书中引述的所有公开文献、专利和专利申请的全部内容引入本文作为参考,就如同将每一公开文献、专利或专利申请特别和分别各自引入作为参考一样。
尽管目的在于清楚理解已经通过解释和实例较详细描述了上述的发明,但是根据本发明的教导可以在不脱离本发明实质和范围的情况下进行改变和变型对本领域技术人员显而易见。提供下列实施例仅以例示为目的,但不意图限定上文以宽范围术语所述的本发明的范围。
在下列实施例中,hGH为SEQ ID NO:1的hGH。应理解其它hGH多肽类也可以如随后的实施例例示的类似方式被聚乙二醇化。
实施例
实施例1
甘油支化的43K PEG醛hGH
其中:
(CH2CH2O)n具有约3Kd的平均分子量且每个(CH2CH2O)m具有约20Kd的平均分子量。
(GL3-400AL2)
本实施例显示了通过还原烷基化生成N-末端一聚乙二醇化hGH。通过还原烷基化,通过利用N-末端上伯胺的相对pKa值相对于赖氨酸残基的ε-氨基位置上的伯胺类的pKa值之差,使约43,000MW的甘油支化的PEG醛试剂(GL3-400AL2 NOF公司)与hGH的N-末端偶联。使以4、7或10mg/mL溶于pH5.8的25mM MES(Sigma Chemical,St.Louis,MO)或pH7.0的20mM HEPES的hGH蛋白质与甘油支化的43K PEG醛通过添加试剂得到相对PEG:hGH摩尔比为1.5∶1、2∶1、3.4∶1、4∶1或5∶1而反应。通过添加吡啶硼烷(Sigma Chemical,St.Louis,MO)至终浓度为10mM催化反应。使反应在4℃下和暗处进行16-87小时。通过稀释入合适的缓冲液终止反应以便进行纯化。
表1显示多-聚乙二醇化的种类、一-聚乙二醇化的缀合物、未反应的hGH的百分比和在pH5.8和1.5∶1∶1摩尔比下反应63小时的甘油支化的43K PEG醛hGH的最终纯化产率。
表1甘油支化的43K PEG醛hGH缀合物合成和纯化方法
甘油支化的43K PEG醛-hGH的合成和纯化产率 | |
反应混合物中的种类: | |
甘油支化的43K PEG醛-hGH | |
多-PEG产物 | 4% |
一-PEG产物 | 68% |
未反应的hGH | 28% |
纯化产率 | 35% |
实施例2
聚乙二醇化hGH的纯化
使用单一离子交换色谱步骤从反应混合物中纯化聚乙二醇化hGH种类至>95%(SEC分析,附图1)。
阴离子交换色谱法
使用单一离子交换色谱步骤从反应混合物中纯化PEG hGH种类至>95%(SEC分析,附图1)。使用阴离子交换色谱法从未修饰的hGH和多-聚乙二醇化hGH种类中纯化一-聚乙二醇化hGH。在用25mM HEPES,pH7.3(缓冲液A)平衡的Q-Sepharose Hitrap柱(5mL)(AmershamPharmacia Biotech,Piscataway,NJ)或Q-Sepharose柱(26/20,70mL床体积)(Amersham Pharmacia Biotech,Piscataway,NJ)上纯化如上所述的典型的甘油支化的43K PEG醛hGH反应混合物(80或1500mg蛋白质)。用缓冲液A将该反应混合物稀释7X并且以2.5mL/分钟的流速上柱。用3-10个柱体积的缓冲液A洗涤柱。随后用20个柱体积的缓冲液A和0-100mM的线性NaCl梯度从柱上洗脱不同的hGH种类。根据在280nm的吸光度(A280)监测洗脱液并且收集合适大小的级分。将级分按照聚乙二醇化的程度汇集,例如一-、二-、三-等(如实施例3中评价的)。然后将收集物在Centriprep YM10浓缩器(Amicon,Technology Corporation,Northborough,MA)中或通过透析过滤浓缩至0.5-5mg/mL。通过A280,使用0.78的消光系数测定收集物的蛋白质浓度。
实施例3
生化表征
通过非还原SDS-PAGE、非变性大小排阻色谱法和肽作图表征纯化的聚乙二醇化hGH收集物。
大小排阻高效液相色谱法(SEC-HPLC)
使用非变性SEC-HPLC评价甘油支化的43K PEG醛与hGH的反应混合物、阴离子交换纯化收集物和最终纯化的产物。使用在20mM磷酸盐pH7.2、150mM NaCl中的柱TSK G4000PWXL(Tosohaas)或ShodexKW-804(Waters Corp),以0.5mL/分钟的流速(任选地Superdex 2007.8mm×30cm,Amersham Bioscience,Piscataway,NJ),进行分析型非变性SEC-HPLC。聚乙二醇化大大增加了蛋白质的流体动力学体积,导致迁移至较早的保留时间。在PEG醛hGH反应混合物中观察到了新的种类连同未修饰的hGH。使用Q-Sepharose色谱法分离这些聚乙二醇化的和非-聚乙二醇化的种类,并且随后证实所得纯化的一PEG-醛hGH种类在非变性SEC时作为单峰洗脱(>95%纯度,附图1)。Q-Sepharose色谱步骤有效从一-聚乙二醇化hGH中除去了游离的PEG、hGH和多聚乙二醇化hGH种类。
SDS-PAGE
SDS-PAGE用于评价甘油支化的43K PEG醛与hGH的反应和纯化的终产物。SDS-PAGE在1mm厚度10-NuPAGE凝胶(Invitrogen,Carlsbad,CA)上在还原和非还原条件下进行并且使用Novex ColloidalCoomassie(TM)G-250染色试剂盒(Invitrogen,Carlsbad,CA)染色。
N-末端序列
自动化埃德曼降解化学用于测定NH2-末端蛋白质序列。AppliedBiosystems Model 494 Procise测序仪(Perkin Elmer,Wellesley,MA)用于降解。通过RP-HPLC分析,按照与使用安装了PerkinElmer/Brownlee 2.1mm i.d.PTH-C18柱的Applied Biosystems Model140C PTH分析仪的联机操作方式鉴定相应的PTH-AA衍生物。
肽作图
以1mg/mL的浓度进行胰蛋白酶消化并且一般每次消化使用25ug物质。加入胰蛋白酶以使胰蛋白酶与PEG-hGH之比为1∶30(w/w)。Tris缓冲液以30mM,pH7.5存在。在室温下将样品温育16±0.5小时。通过添加50uL 1N HCl/mL消化溶液使反应猝灭。在将样品放入自动采样器前将样品稀释至终浓度为在6.25%乙腈中0.25mg/ml。首先加入乙腈(至19.8%乙腈),轻轻混合且然后加入水至终体积(4倍于起始体积)。可以除去额外的消化溶液并且在-20℃下贮存达1周。
将Waters Alliance 2695 HPLC系统用于分析,不过,其它系统应产生类似的结果。使用具有5um颗粒的AstecC-4聚合物25cm×4.6mm柱。实验在环境温度下以50ug蛋白质/样品的典型上样量进行。缓冲液A为0.1%在水中的三氟乙酸;缓冲液B为0.085%在乙腈中的三氟乙酸。以90分钟内0-45%B的线性梯度洗脱样品。
使用在210-300nm之间采集数据的Waters 996 PDA检测器检测峰。将214nm处的提取的色谱图用于样品分析。
对hGH和以2∶1的摩尔比(PEG∶hGH)反应的甘油支化的43K PEG醛进行胰蛋白酶作图(附图2)。将N-末端胰蛋白酶片段称作T-1。与未聚乙二醇化hGH相比较存在的T-1百分比提示大于99%的PEG修饰位于N-末端,而剩余部分显然与几个可能的赖氨酸残基之一连接。
表2
T-1含量比较
存在的T-1% | 与未聚乙二醇化hGH相比存在的T-1% | |
hGH | 28.0% | 100% |
甘油支化的43K PEG醛/hGH | 低于1% | 低于1% |
实施例4
体外生物学
在设计用于评估缀合物与人生长激素受体(hGHR)(28kDa胞外域)之间相互作用的试验中使用Biacore 3000仪器测试甘油支化的43KPEG醛hGH识别人受体的能力。来自表面等离子共振(SPR)实验的结果如下表3中所示。
表3.Biacore试验结果
样品 | Avg.ka×105(M-1s-1±stdev)a | Avg.kd(s-1±stdev)a | KD=kd/ka,mM | 相对于hGH的KD |
hGH(n=9) | 3.07±8.20 | 38.8±3.6 | 0.13±0.03 | 1.000 |
43K PEG-hGH(n=3) | 0.28±0.03 | 90.0±31.0 | 3.22±0.10 | 0.041 |
a在37℃下和HEP-BES缓冲液(0.01 M Hepes,pH7.4,+0.15MNaCl,3mM EDTA和0.005%表面活性剂P20)中,使用通过以ΔRU≈3000-5000的胺偶联化学在CM5芯片上标记的人生长激素结合蛋白(28kDa胞外域),以50uL/分钟的流速测定ka(on-rate)和kd(off-rate)。表示为每M每秒的ka,表示为每秒的kd,均为在1个芯片上的至少3次测定的平均值±标准偏差。数据假设测量hGH以1∶1比例结合GHBP上的高亲和力位点1。
实施例5
药效学研究
体内效力-11-天大鼠试验中的功效(体重增加、胫骨生长、血清BUN阻抑)
大鼠体重增加
将在Harlan实验室垂体切除的雌性Sprague Dawley大鼠预筛选生长率4-10天。将大鼠分成6只动物的组。从第0天开始,对照组大鼠接受每日1次皮下注射0.3mg/kg hGH或载体连续11天。试验组在第0和6天接受1.8mg/kg单一(一次/每周)剂量的甘油支化的43KPEG醛hGH。每天给动物称重。附图4显示在有代表性的研究中hGH和甘油支化的43K PEG醛hGH对体重增加的作用。
将附图4中所示研究代表的数据与来自对hGH(对照品)治疗的大鼠的历史11-天生长研究加上使用43K甘油支化的PEG醛hGH缀合物的额外的生长研究的数据合并,使用1.8mg/kg缀合物每周治疗1次的动物的平均递增体重增加为按照每日hGH给药(累积3.3mg/kg)获得的值的109%。
大鼠胫骨长度
在11-天体重增加研究中的动物在第11天时处死,取出左侧胫骨并且拍X光照片且使用测径器测量骨长度。附图5显示甘油支化的43KPEG醛hGH治疗动物的胫骨长度测量值。
大鼠BUN水平
作为hGH-治疗后代谢作用的生物标记,由第11天的血样测定血液尿素氮水平。附图6显示每日hGH和1次/每周甘油支化的43K PEG醛hGH治疗均导致血液尿素氮显著减少。
大鼠体重增加6-天剂量递增研究
用不同单剂量的甘油支化的43K PEG醛hGH治疗垂体切除的大鼠,或每天使用hGH治疗,且监测体重增加6天。附图7显示对不同治疗组获得的体重增加。在指定时间取血样并且通过ELISA测定血清IGF-1水平。将平均值±SEM绘图。将组(n=6)平均值用于使用单向方差分析对测定的值计算IGF-1响应,并且对0.067、0.2、0.6和1.8mg/kg给药组分别测定了20,040、22,958、28,129和37,839的AUCd0-6(ng-hr/mL)值。
大鼠体重增加11-天剂量递增研究
在第二项研究中,在第0天并且再次在第6天用1.8mg/kg或更高剂量即5.1mg/kg43K甘油支化的PEG醛hGH缀合物治疗动物。表4显示与每天(QD11)给予载体或每天给予hGH(以0.3mg/kg/天)后获得的值相比在第6和11天时与剂量相关的体重增加。
表4.在第6和11天时与剂量相关的体重增加
第0天(g) | 第6天(g) | 第11天(g) | |
载体(QD11) | 106.2±2.3 | 106.2±2.8(0.07±0.7) | 106.7±2.8(0.5 1±0.6) |
hGH(0.3mg/kg)(QD11) | 109.2±1.3 | 123.1±1.4*(13.9±0.5) | 136.7±1.6(27.5±0.7)* |
甘油支化的43K PEG醛hGH(1.8mg/kg)(D0,6) | 106.8±1.3 | 120.6±1.1*(13.8±0.7) | 133.6±1.0(26.7±0.8)* |
甘油支化的43K PEG醛hGH(5.1mg/kg)(D0,6) | 106.1±1.4 | 127.1±1.3*(21.0±1.0) | 142.5±1.4(36.4±1.2)* |
*与载体相比p<0.05,与hGH相比p<0.05;如从第0天测定的平均体重增加递增值(g)
BW,体重;hGH,人生长激素。
值代表平均值±SEM(平均值的标准误)。
圆括号中的值代表从第0天的改变的平均值±SEM。
IGF-1研究
使用来自6-天体重增加研究的动物。在本研究过程中的不同时间时取血样并且附图8中显示通过ELISA测定的血清IGF-1水平。用免疫测定试剂盒(Diagnostic System Laboratories)监测大鼠IGF-1水平。
实施例6
药代动力学研究
在正常插套管的Sprague-Dawley雄性大鼠中进行药代动力学研究。使用每组6只大鼠进行1.0mg/kg的静脉内单剂量注射或1.8mg/kg hGH或甘油支化的43K PEG醛hGH的单一皮下快速推注。适宜地在1-5天内取血样用于相关PK参数的评价。在每次取样时使用免疫测定法监测hGH和甘油支化的43K PEG醛hGH血液水平。表4显示甘油支化的43K PEG醛hGH的大鼠PK参数。聚乙二醇化的作用在观察到的消除半衰期方面显而易见,因为该参数对于缀合物而言超过了6小时,而来自类似研究的对hGH报导的数据据报导为1.35±0.2(Clark,文献同上),0.77-1.7(Jorgensen等″Polyethyleneglycol-conjugated proteins″,PSTT 1(8),1998年11月)或1小时(Genotropin(PNU-180307)Investigator Brochure)。
hGH免疫测定
使用hGH AutoDELFIA试剂盒荧光免疫测定法(Perkin-Elmer)测定大鼠血浆中的hGH和甘油支化的43K PEG醛hGH蛋白质浓度水平。
表5.
甘油支化的43K PEG醛hGH | ||
途径 | iv/sc | |
剂量 | mg/kg | 1.0/1.8 |
T1/2 | h | 6.44±2.38 |
AUCO-∞,,iv | μg·h/mL | 489±16 |
AUC0-∞,,sc | μg·h/mL | 97.7±2.1 |
CL总计 | mL/hr/kg | 2.05±0.07 |
Vss | mL/kg | 27.2±2.8 |
Tmax | h | 12±0 |
Cmax | μg/ml | 1.96±0.05 |
F | % | 11.1±0.2 |
*AUCO-∞,,sc对1.8mpk校正 |
另外,在对垂体切除的雌性啮齿动物皮下给予单剂量的甘油支化的43K PEG醛hGH(1.8mg/kg)后的综合研究设计中直接测定血浆药物浓度与IGF-1反应之间的相关性。
Claims (12)
2.权利要求1所述的PEG-hGH缀合物,其中所述的(CH2CH2O)n部分具有约3Kd的平均分子量且每个(CH2CH2O)m部分具有约20Kd的平均分子量。
3.权利要求1或2所述的PEG-hGH缀合物,其中所述的人生长激素包括SEQ ID NO:1的氨基酸序列。
4.权利要求3所述的PEG-hGH缀合物,其中PEG与SEQ ID NO:1的N-末端苯丙氨酸缀合。
5.权利要求4所述的PEG-hGH缀合物,其中所述的缀合物为一-聚乙二醇化的。
6.权利要求4所述的PEG-hGH缀合物,其中PEG中的至少80%与SEQ ID NO:1的N-末端苯丙氨酸的α氨基缀合。
7.权利要求5所述的PEG-hGH缀合物,其中PEG中的至少90%与SEQ ID NO:1的N-末端苯丙氨酸的α氨基缀合。
8.权利要求5所述的PEG-hGH缀合物,其中PEG中的至少95%与SEQ ID NO:1的N-末端苯丙氨酸的α氨基缀合。
9.权利要求5所述的PEG-hGH缀合物,其中PEG中的至少98%与SEQ ID NO:1的N-末端苯丙氨酸缀合。
10.治疗具有生长或发育障碍的患者的方法,包括对所述的患者给予治疗有效量的权利要求1、2、3、4、5、6、7、8或9所述的人生长激素-PEG缀合物。
11.权利要求10所述的方法,其中所述的生长或发育障碍选自生长激素缺乏(GHD)、特纳综合征、慢性肾功能不全和小于胎龄(SGA)组成的组。
12.权利要求11所述的方法,其中所述的生长或发育障碍选自勃起机能障碍、HIV脂肪营养障碍、纤维肌痛、骨质疏松症、记忆障碍、抑郁症、克罗恩病、骨骼发育不良、外伤性脑损伤、蛛网膜下腔出血、努南综合征、唐氏综合征、特发性身材矮小症(ISS)、终末期肾病(ESRD)、极低出生体重(VLBW)、骨髓干细胞解救、代谢综合征、糖皮质类固醇肌病、因儿童中的糖皮质类固醇治疗导致的身材矮小症和矮小早产儿的生长滞后。
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Cited By (4)
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CN101831067A (zh) * | 2010-05-31 | 2010-09-15 | 王二新 | 聚乙二醇脂类缀合物及其在制备药物中的应用 |
CN102367290A (zh) * | 2011-04-26 | 2012-03-07 | 刘超 | 链官能化的多级支化聚乙二醇及其合成方法 |
CN102367290B (zh) * | 2011-04-26 | 2013-05-08 | 厦门赛诺邦格生物科技有限公司 | 链官能化的多级支化聚乙二醇及其合成方法 |
WO2014110867A1 (zh) * | 2013-01-17 | 2014-07-24 | 厦门赛诺邦格生物科技有限公司 | 一种单一官能化的支化聚乙二醇及其修饰的生物相关物质 |
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