CN109312000A - 重组静脉内免疫球蛋白(rIVIG)组合物及其生产和使用方法 - Google Patents
重组静脉内免疫球蛋白(rIVIG)组合物及其生产和使用方法 Download PDFInfo
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Abstract
重组静脉内免疫球蛋白(rIVIG)蛋白的组合物和用于纯化和使用rIVIG蛋白的方法。所述组合物包含寡聚Fc分子,其以高亲合力结合Fc受体。所述rIVIG蛋白可用作免疫调节分子以治疗免疫障碍,包括自身免疫疾病,如难治性免疫性血小板减少症、慢性炎性脱髓鞘性多发性神经病、多发性硬化症、狼疮、格雷夫斯病、川崎病、皮肌炎、重症肌无力、格林‑巴利综合征、自身免疫性溶血性贫血、以及其他免疫和炎症性病症。所述rIVIG蛋白也可用作患者的免疫调节剂,以降低器官移植、干细胞移植和骨髓移植的免疫排斥。另外,本发明提供了非人来源的rIVIG蛋白,以用于在兽医学免疫障碍中使用,如犬用rIVIG蛋白以用于治疗患有自身免疫性溶血性贫血、免疫性血小板减少性紫癜、类风湿性关节炎或其他犬免疫障碍的犬。
Description
相关申请声明
本申请是2016年3月30日提交的美国临时专利申请序列号62/315,483的部分继续申请,并要求其优先权,特此将其全部内容并入本文。
技术领域
本发明涉及用于生产重组蛋白的组合物和方法,所述重组蛋白可用作当前使用的人IVIG制剂(静脉内免疫球蛋白的首字母缩写词)的替代物。本发明还涉及使用此类组合物以治疗免疫障碍以及其他障碍和疾病的方法。
背景技术
免疫球蛋白作为治疗剂的临床应用可以追溯到一百多年前,当时Emil Behring及其同事发现免疫血清可以改善毒素介导的疾病(1)。六十二年之后,Ogden Bruton静脉输注人免疫球蛋白以进行无丙种球蛋白血症患者中的免疫球蛋白替代(2)。在那之前,只有有限剂量的免疫球蛋白可以肌内注射,由于这些制剂含有纯化的免疫球蛋白聚集体,其给药会导致局部疼痛刺激以及由于通过补体级联激活免疫应答引起的不良全身反应(3,4)。
在20世纪60年代和20世纪70年代开发出的新的纯化方法可以去除聚集体,从而使得制备出适合以更大剂量静脉给药的组合物成为可能(3-7)。即使此类制剂也可以通过其他方式给药,例如皮下给药,首字母缩略词“IVIG”仍然是此类制剂的常用术语。IVIG制剂的主要适应症仍主要是免疫缺陷患者的替代疗法(8-10)。
1981年,在治疗由于广泛的免疫抑制治疗而患有继发性免疫缺陷同时还患有难治性免疫性血小板减少症(ITP)的儿童时,Paul Imbach发现,患者接受IVIG治疗后血小板计数出乎意料地增加(11)。在没有免疫缺陷的ITP患者中再现了IVIG治疗增加血小板计数的效果,并为IVIG的用于其免疫调节作用的用途铺平了道路(12-15)。
目前,IVIG是许多不同疾病的治疗选择,并且被推荐作为第一线药物用作许多自身免疫障碍的免疫调节剂。事实上,虽然在免疫缺陷综合征中使用IVIG作为替代的免疫球蛋白仍然是一种重要的指征,但IVIG越来越多地用于治疗自身免疫障碍。
尽管IVIG制剂在临床治疗中有效,但是与当前实践相关的许多问题可能对其可持续性产生巨大影响。首先,在IVIG给药后经常观察到不良反应,包括过敏反应、肾病、血栓性并发症和糖尿病病症。为解决这些问题所做的努力包括针对IgA缺乏预先筛查患者,以及密切监测IgA、XI因子、葡萄糖和钠的浓度。然而,这些步骤中的每一步都会产生限制供应能力、并增加商品成本以及管理成本的影响。此外,尽管做出了这些努力,但IVIG的使用继续因不利影响而处于不利地位,而这种影响尚未完全改善。
此外,与大多数生物制剂相比,IVIG通常以非常高的剂量给药,通常范围为约0.5g至4g/kg体重。从功效所需的剂量来判断,显现IVIG的一种或多种治疗活性组分仅占制剂的非常小的一部分。随着由商品成本的不断上升所呈现的重大挑战和提高IVIG制剂质量的需求,非常需要改进替代组合物和/或方法来解决这些问题中的一个或多个:
IVIG治疗所呈现的问题部分源于尚未明确确定IVIG作用机制以及其效果可能因适应症而异的事实。
发明内容
如上所述,非常需要改进采用IVIG的治疗,包括能够消除或减少不良反应、可以以更一致的质量生产、在保持功效的同时允许更低剂量、和/或降低商品成本的一种或多种替代方案。发明人假设免疫球蛋白的重组工程将允许产生更明确的分子,所述分子可以以一致的质量生产,在保持功效的同时允许更低剂量,并降低产品的成本。
虽然IVIG的作用机制尚不完全清楚,但诸位发明人假设有可能将至少一些适应症与IVIG在这些适应症中的治疗功效所需的抗体结构元件相关联。例如,在免疫缺陷的治疗中,IVIG补充血清Ig的水平并且提供对抗感染因子和/或其毒素的挽救生命性保护。因此,可以设想,汇集的免疫球蛋白的可变区内包含的抗原特异性的大的多样性负责这些适应症的治疗功效。相比之下,研究支持免疫球蛋白Fc区负责IVIG在急性和慢性自身免疫障碍治疗中的免疫调节作用的观点。
观察到完整的IVIG及其Fc片段在ITP的治疗和动物模型中具有等同的抗炎活性(16)。这将支持Fc区在抗炎功能中的作用。此外,在小鼠ITP模型中观察到IVIG的免疫调节作用是通过Fc受体介导的,并且依赖于树突细胞(DC)-巨噬细胞交叉作用,并且FcγRIIIa对于活化期以及FcγRIIb对于效应期是至关重要的(17)。最后,观察到在小鼠ITP模型中,采用含有高含量Ig二聚体的IVIG进行的治疗比正常单体免疫球蛋白更有效地逆转血小板耗竭(18)。因此,诸位发明人推测,通常对Fc区具有低亲和力结合的树突状DC表面FcγRIIIa和FcγRIIb可以通过亲合力(多重相互作用)结合与IVIG制剂中存在的少量寡聚抗体有效地相互作用,寡聚Fc提供所述亲合力结合,可进一步用于改善IVIG制剂的免疫调节作用。
本发明提供了完全或部分解决上述问题的方法和材料。因此,在其广义方面,本发明包括重组静脉内免疫球蛋白(rIVIG)多肽,其包含(a)含有两个或更多个Fc肽结构域的单链Fc肽;和(b)寡聚化肽结构域。在本发明的具体方面,寡聚化肽结构域是三聚化肽结构域。在具体实施方案中,本发明的rIVIG多肽(也称为Pan受体相互作用分子,或“PRIM”)包含(a)含有两个Fc肽结构域的单链Fc肽和(b)寡聚化肽结构域,特别是三聚化肽结构域。本发明的rIVIG多肽中的各个Fc肽结构域可以通过柔性接头连接。在本发明的具体实施方案中,柔性接头包含氨基酸序列G-G-G-G-S(序列ID号9)的五个重复;即,G-G-G-G-S-G-G-G-S-G-G-G-G-S-G-G-G-G-S-G-G-G-G-S(序列ID号10)。在本发明的其他具体实施方案中,寡聚化肽结构域包含序列ID号4的712至768号氨基酸,或序列ID号6的1至79号氨基酸。在某些实施方案中,本发明的rIVIG多肽包含选自下组的氨基酸序列,所述组由序列ID号2、序列ID号3、序列ID号4、序列ID号5、序列ID号6、序列ID号7、和序列ID号8组成。
在其他实施方案中,本发明包括编码重组静脉内免疫球蛋白(rIVIG)多肽的核苷酸分子,所述多肽包含(a)含有两个或更多个Fc肽结构域的单链Fc肽;和(b)寡聚化肽结构域。在本发明的具体方面,核苷酸分子编码三聚化肽结构域。在具体实施方案中,本发明的核苷酸分子编码rIVIG多肽,所述多肽包含(a)两个Fc肽结构域和(b)一个三聚化肽结构域。在具体实施方案中,本发明包括编码rIVIG多肽的核苷酸分子,所述rIVIG多肽包含选自下组的氨基酸序列,所述组由序列ID号2、序列ID号3、序列ID号4、序列ID号5、序列ID号6、序列ID号7和序列ID号8组成。
另一方面,本发明提供用于治疗免疫障碍的组合物,所述组合物包含重组免疫球蛋白(rIVIG)蛋白,其中所述rIVIG蛋白包含寡聚化肽结构域,所述寡聚化肽结构域提供用于将三个单链Fc结构域(scFc)聚集在一起的支架。在具体实施方案中,寡聚化肽结构域包含选自下组的氨基酸序列,所述组包含序列ID号6的1至79号氨基酸和序列ID号4的712至768号氨基酸。在本发明的具体方面,组合物主要包含含有三个单链Fc肽的单一蛋白质种类。所述单链Fc肽的各个Fc结构域可以在分子内相互作用以形成功能性单链Fc肽。在具体实施方案中,本发明提供了主要包含rIVIG蛋白的组合物,所述rIVIG蛋白包含选自下组的氨基酸序列,所述组由序列ID号2、序列ID号3、序列ID号4、序列ID号5、序列ID号6、序列ID号7和序列ID号8组成。
另一方面,本发明提供了一种治疗患有自身免疫障碍的患者的方法,所述方法包括向所述患者给予有效量的主要包含重组免疫球蛋白(rIVIG)蛋白的组合物,其中所述rIVIG蛋白包含寡聚化肽结构域,所述寡聚化肽结构域提供形成单链Fc肽三聚体的支架。在具体实施方案中,患者患有选自以下项的免疫障碍:难治性免疫性血小板减少症、免疫性血小板减少性紫癜(ITP)、慢性炎性脱髓鞘性多发性神经病(CIDP)、多发性硬化症(MS)、***性红斑狼疮(SLE或狼疮)、格雷夫斯病、川崎病、皮肌炎、重症肌无力、格林-巴利综合征、重症肌无力、自身免疫性溶血性贫血(IMHA)、恶性贫血、溶血性贫血、再生障碍性贫血、阵发性睡眠性血红蛋白尿症(PNH)、阿狄森氏病、桥本氏病(慢性甲状腺炎)、桥本氏脑病、自身免疫性嗜中性粒细胞减少症、血小板减少症、类风湿性关节炎和反应性关节炎、炎症性肠病(IBD)、溃疡性结肠炎、克罗恩病、干燥综合征CREST综合征、***(PID)、强直性脊柱炎、贝切特病、血管炎、莱姆病(慢性或晚期)和I型糖尿病。
另一方面,本发明提供了一种降低已接受器官移植、骨髓移植、输血或干细胞移植的患者的免疫排斥反应的方法,所述方法包括向所述患者给予有效量的包含重组免疫球蛋白(rIVIG)蛋白的组合物,其中所述rIVIG蛋白包含寡聚化肽结构域,所述寡聚化肽结构域提供主要包含单链Fc肽三聚体的组合物。
另一方面,本发明提供了一种治疗患有自身免疫障碍的非人哺乳动物的方法,所述方法包括向所述非人哺乳动物给予有效量的包含重组静脉内免疫球蛋白(rIVIG)蛋白的组合物,其中所述rIVIG蛋白包含寡聚化肽结构域,所述寡聚化肽结构域提供主要包含单链Fc肽三聚体的组合物,并且其中所述rIVIG蛋白包含源自相同物种的非人哺乳动物的氨基酸序列。在具体实施方案中,非人哺乳动物患有选自下组的自身免疫障碍,所述组由自身免疫性溶血性贫血(AIHA)、免疫性血小板减少性紫癜(ITP)或类风湿性关节炎组成。例如,患有AIHA的犬可以用主要包含含有犬源氨基酸序列的三聚体rIVIG蛋白的组合物治疗,所述犬源氨基酸序列例如是序列ID号7和序列ID号8的氨基酸序列。
附图说明
图1展示了本发明某些实施方案的构建体的组成。P7005H是使用CD40配体的细胞外结构域的固有三聚能力产生寡聚功能性Fc结构域的设计的原型。最小的功能性寡聚体由六条多肽链构成,其在N-末端组装成三个二聚体Fc结构域,并且在C-末端组装成两个三聚化的CD40L ECD。根据P7005H的复杂SEC谱(图2),产生了P8001Z,其中使用scFc形式产生功能性Fc结构域,并且CD40L ECD被胶原蛋白三聚化结构域替代。虽然SEC谱(图2)优于P7005H的SEC谱,但P8001Z仍含有大量高级寡聚体。作为类似的构建体,具有额外的人IgG1重链铰链区(H)的P8004Z也展现出不太理想的SEC谱,显现单独包含铰链区不能解决折叠问题。有趣的是,当引入额外的恒定区(CL和CH1)时,P8003Z和P8020Z蛋白均折叠得更高效并且主要展现为正确折叠的三聚体。(图2)。(图2)。P8020Z构建体使用三聚化支架,其使得可以将寡聚Fc定位于融合蛋白的C-末端。预期C-末端Fc形式与用于和Fc受体相互作用的常规抗体的取向非常相似。重要的是,与P7005H、P8001Z、P8002Z或P8004Z不同,从P8003Z和P8020Z的表达成功获得了三聚体种类的同源组合物(参见图5)。
图2展示了在尺寸排阻色谱(SEC)分析模型中本发明组合物的作用。通过蛋白A亲和色谱纯化本发明的rIVIG分子,并且经缓冲液交换到pH 7.2的磷酸盐缓冲盐水中。通过使用Superdex 200 10/30 SEC柱(GE Healthcare)以0.5ml/min的速度注射约100ul的rIVIG样品来进行每个SEC分析。箭头表示正确折叠的三聚体分子被洗脱的位置。图2显示,发现少于约1/3的P7005H、P8001Z、P8002Z和P8004Z处于正确折叠的三聚体形式。相比之下,超过至少2/3的P8003Z和P8020Z被正确折叠成三聚体。这些结果表明CL和CH1结构域的引入可以大大增强三聚体形式的折叠。
图3展示了在FcγR结合模型中本发明组合物的作用。将与GST融合的个体人Fc受体包被在ELISA板上。在阻断未占据区域后,以连续稀释的浓度将人IgG1、P8003Z1、P8003Z3(P8003Z的非岩藻糖基变体,由缺乏α-1,6岩藻糖基转移酶基因的细胞系(FUT8-/-)产生)或P8020Z1加入板中。通过山羊抗人抗体的荧光标记的F(ab)'2片段定量结合的人IgG1和rIVIG变体。图3的上图显示了人IgG1和rIVIG与人FcγRIIA(H131)的亲和力测量的实施例。曲线拟合(SoftMax Pro 5.1,Molecular Devices,Sunnyvale,CA)允许估计rIVIG对重组可溶性Fc受体的KD。下表显示了这些计算的KD。显然,与人IgG1相比,本发明的三聚体rIVIG展现出结合亲和力的显著增加;除了人FcγRI,对其人IgG1已经展现出亚nM亲和力,而rIVIG只展现出略高的亲和力。这些结果证实,具有亲合力优势的本发明的三聚体rIVIG能够以更高的表观亲和力结合Fc受体。
图4展示了本发明组合物在胶原蛋白诱导的关节炎(CIA)模型中的治疗效果。在第1天用CFA中的牛II型胶原蛋白对小鼠进行初免,在第18天用P8020Z(50mg/kg体重)处理,并在第21天用IFA中的相同胶原蛋白加强免疫。每隔一天测量每只爪的临床得分,为1至4,4为最严重。在每组中加入临床得分并通过小鼠数量来归一化。与经常以约2-3g/kg体重使用并在研究过程中多次给药的传统人IVIG制剂比较,将P8020Z1以50mg/kg的剂量给药一次,这表示剂量减少了40至60倍。
图5展示了本发明的组合物在由抗胶原蛋白抗体被动转移诱导的自身免疫障碍中的治疗效果。用抗胶原蛋白抗体处理小鼠,3天后用脂多糖处理,并且在第6天以所示剂量单次注射血浆衍生的IVIG(pd.IVIG)或重组IVIG(rIVIG或PRIM)分子(PM 02,也称为非岩藻糖基P8003Z3)。pd.IVIG 1K的给药量为1gm/kg体重;对于pd.IVIG 2K,剂量为2gm/kg体重。PM02 15为15mg/kg体重;PM 0250为50mg/kg体重;并且PM 02 150为150mg/kg体重。pd.IVIG1K和pd.IVIG 2K二者在第9天与第13天之间稍微更有效。PM 02 15展现出与两种浓度的pd.IVIG可比的治疗功效。PM 02 50和PM02 150二者均展现出比任一pd.IVIG给药更好的功效。因此,证明PM 02能够治疗由抗胶原蛋白抗体的被动转移诱导的自身免疫障碍。
图6展示了P8003Z1和P8020Z1的尺寸排阻色谱图。代表本发明的三聚体rIVIG蛋白的峰证明了本发明的rIVIG肽可以以均一形式制备。
具体实施方式
在以下描述中,出于解释的目的,阐述了许多具体细节以便提供对本发明的透彻理解。然而,对于本领域普通技术人员清楚的是,可以在没有这些具体细节的情况下实践本发明,并且可以在不脱离本发明的更宽范围的情况下对其进行各种修改和改变。
将本文引用的所有公开物特此通过引用明确地并入本公开内容中,以传授引用它们所传授的内容。
如本文所用,术语“受试者”是指哺乳动物和非哺乳动物。哺乳动物是指哺乳动物类的任何成员,包括但不限于人;非人灵长类动物,如黑猩猩和其他猿猴和猴子物种;农场动物,如牛、马、绵羊、山羊和猪;家畜,如兔子、犬和猫;实验动物包括啮齿动物,如大鼠、小鼠和豚鼠;等等。非哺乳动物的实例包括但不限于鸟、鱼等。
本发明涉及重组静脉内免疫球蛋白(rIVIG)蛋白,包含此类rIVIG的组合物,以及用于治疗各种免疫障碍和病症的rIVIG组合物的生产、纯化和使用的方法。
在本发明中,重组免疫球蛋白(rIVIG)的设计集中于改造含有以下项的核酸和蛋白质分子:多个拷贝的人IgG1Fc结构域以及增强寡聚rIVIG分子形成的结构域。虽然不希望受任何理论束缚,但预期本发明的rIVIG分子不仅能够结合高亲和力FcγRI,还能够结合低亲和力Fc受体,即FcγRII和FcγRIII受体。增强的与低亲和力受体的结合很可能是由于寡聚Fc与细胞表面上存在的Fc受体的亲合力相互作用。
生物化学上,本发明提供了这样的方法和材料,其被设计为用于将Fc结构域和寡聚化蛋白质支架聚集在一起,以产生正确折叠的并展现出用于用作治疗产品的所需特征的融合蛋白。在治疗上,本发明的rIVIG蛋白可用于治疗许多免疫病症,并可用作许多自身免疫障碍的免疫调节剂。此外,考虑到各种补体蛋白参与许多自身免疫障碍,本发明可任选地包括另外的结构元件,例如能够沿补体激活级联清除组分的元件。
诸位发明人使用多种蛋白质支架设计并表达了许多rIVIG分子,以使Fc构建体的变体寡聚化。在某些优选的实施方案中,本发明的rIVIG分子包含寡聚支架结构域,其优先将三个单链Fc肽或三个Fc二聚体聚集在一起以形成三个功能性Fc结构域。
本发明的方法和材料可用于治疗免疫障碍,包括但不限于自身免疫疾病,或任何需要免疫调节的障碍、疾病或综合征。可以使用本发明的适应症包括但不限于免疫性血小板减少性紫癜(ITP)、慢性炎性脱髓鞘性多发性神经病(CIDP)、多发性硬化症(MS)、***性红斑狼疮(SLE或狼疮)、格雷夫斯病、川崎病、阿狄森氏病、乳糜泻-口炎性腹泻、皮肌炎、重症肌无力、皮炎、桥本氏病(慢性甲状腺炎)、桥本氏脑病、格林-巴利综合征、重症肌无力、自身免疫性溶血性贫血(IMHA)、恶性贫血、溶血性贫血、再生障碍性贫血、阵发性睡眠性血红蛋白尿症(PNH)、自身免疫性嗜中性粒细胞减少症、血小板减少症、类风湿性关节炎和反应性关节炎、炎症性肠病(IBD)、溃疡性结肠炎、克罗恩病、干燥综合征、CREST综合征、***(PID)、强直性脊柱炎、贝切特病、血管炎、莱姆病(慢性或晚期)和I型糖尿病。
本发明的方法和材料也可用于治疗由自身抗体引起的障碍,以及器官特异性自身免疫障碍,包括心肌炎、心肌梗塞后综合征肾炎、古德帕斯彻氏综合征(Goodpasturesyndrome)、间质性膀胱炎、自身免疫性肝炎、原发性胆汁性肝硬化和原发性硬化性胆管炎(PSC)、抗合成酶综合征;斑秃、自身免疫性血管性水肿、皮炎、银屑病、***性硬皮病、淋巴增生综合征、抗磷脂综合征、自身免疫视网膜病、葡萄膜炎和梅尼埃尔氏病。
本发明的方法和材料也可用于预防、减少和/或治疗免疫或抗体介导的反应到程序,包括器官移植、骨髓移植;输血、或干细胞移植。
本发明的方法和材料也可用于其中已经使用任何可商购的静脉内免疫球蛋白(IVIG)的任何自身免疫适应症。可商购的IVIG包括:GammakedTM、Gammaplex、-C、和已经批准使用可商购的IVIG的特定用途和自身免疫适应症包括以下:慢性炎性脱髓鞘性多发性神经病(CIDP);慢性免疫性血小板减少性紫癜(ITP);多灶性运动神经病(MMN);控制ITP中的出血;儿科患者中与川崎综合征相关联的冠状动脉瘤的预防。
本发明包括重组IVIG(rIVIG)蛋白,其可以作为含有三个功能性scFc结构域的均一物质表达和纯化。由于亲合力(多价)相互作用,此三聚Fc寡聚体可以结合高亲和力和低亲和力Fc受体二者。这些增强的对各种Fc受体的亲和力使人想起归因于人IVIG的免疫调节作用,人IVIG制剂中存在少量寡聚抗体。由于其与Fc受体的增强相互作用的模拟,预期本发明的rIVIG将替代传统的IVIG用于其免疫调节应用而不是其被动免疫保护应用。
免疫球蛋白
Fc片段
本发明利用CH2-CH3结构域,所述CH2-CH3结构域包含IgG(优选IgG1)的人重链恒定区2(CH2)和恒定区3(CH3)(CH2-CH3)。当使用两个或更多个Fc片段,例如CH2-CH3结构域时,它们通常以单链Fc肽的形式合成或表达,其中CH2-CH3结构域使用柔性肽接头例如(GGGGS)5(=GGGGSGGGGSGGGGSGGGGSGGGGS(序列ID号10))连接,所述柔性肽接头有利于单链Fc肽的分开的CH2-CH3结构域之间的分子内相互作用,允许对单链Fc肽呈现一种优化生物功能的三维构象。来自人IgG(优选IgG1)的铰链区(H)也可以存在于每个CH2区的N-末端,以促进适当的构象以优化生物活性。
在某些实施方案中,本发明的rIVIG蛋白包括Fc分子的其他区域。例如,rIVIG可包括IgG(优选IgG1)的一个或多个恒定区1(CH1)结构域,以及一个或多个Igκ或轻链恒定区(CL)结构域。可以使用短接头序列(例如(GGGGS)2)将CL结构域的C-末端连接至CH1结构域的N-末端。在此构建体中,CH1结构域可以通过分子内二硫键与CL结构域相互作用,所述分子内二硫键在热力学上比分子间二硫键更有利。此外,CL/CH1结构域在清除补体成分中起作用,其可以进一步改善许多自身免疫障碍中存在的补体免疫应答。
人抗体同种型
已知存在几种不同的抗体同种型,其具有不同的结合模式,导致在体内发挥不同的功能作用。每种同种型的结合亲和力通常是已知的(Gillis等人(2014)FrontierImmunology 5:1-13),并显示在下表1中。每种抗体同种型的Fc与Fc受体不同地结合。例如,人IgG3与FcγRIIIA(0.1微摩尔(uM)KD)的结合亲和力比人IgG1对相同受体(5-10uM KD)的结合亲和力高至少50倍。类似地,人IgG1与FcγRIIA的结合比人IgG4强15倍。因此,尽管本文的实施例使用的是衍生自IgG1的Fc片段,来自每种同种型的Fc片段均可用于本发明。例如,预期携带IgG2、IgG3或IgG4同种型恒定区的P8003Z或P8020Z的变体展现出与携带IgG1同种型恒定区的亲本P8003Z或P8020Z的亲和力不同的亲和力。由于许多自身免疫障碍与Fc受体的差异组合表达相关,因此衍生自每种同种型变体的本发明的rIVIG可提供不同的治疗益处。
表1:人抗体同种型对Fc受体的亲和力
非人哺乳动物抗体亚类
已知某些非人哺乳动物物种具有与人抗体同种型类似的抗体亚类。例如,犬免疫球蛋白有四种已知的亚类:分别为亚类A、亚类B、亚类C和亚类D。这些亚类与四种人IgG同种型共享功能特性。据报道,犬亚类A和D出现效应子功能阴性,而亚类B和C结合犬Fcγ受体并且ADCC呈阳性。进一步报道了除C亚类外,所有犬亚类都与新生儿Fc受体结合(22)。
免疫球蛋白Fc结构域的糖基化以及非岩藻糖基抗体与FcγRIII(人)和FcγRIV的增强的相互作用。
除了同种型差异之外,还已知单个糖基化位点(Asn-297)处的差异糖基化在Fc-Fc受体相互作用中起关键作用。事实上,很明显Asn-297残基处的糖型改变发生在生理和病理条件下(23)。此外,据报道差异唾液酸化会影响IgG的炎症特性,并且已经提出差异唾液酸化作为分子开关诱导抗炎性病症的机制(24)。此外,去除聚糖完全损害了Fc与除新生儿Fc受体(FcRn)之外的所有Fc受体相互作用的能力(25)。最有趣的是,已经发现消除N-聚糖复合物中的核心岩藻糖导致Fc对FcγRIII相互作用的选择性增强高达100倍(26)。非岩藻糖基化形式的抗体可以通过在缺乏α-1,6岩藻糖基转移酶基因的宿主细胞系(FUT8-/-)中表达非常相同的抗体来产生。P8003Z1和P8003Z3的核心岩藻糖基糖不同之处在于P8003Z1在FUT8感受态细胞中产生,而P8003Z3在FUT8缺陷细胞中产生。如所预期的,非岩藻糖基化的P8003Z3展现出与人FcγRIII和鼠FcγRIV的增强的结合(参见图3中的KD表)。
因此,对于熟练技术人员清楚的是,具有修饰的糖基化的rIVIG蛋白、产生具有修饰的糖基化的rIVIG蛋白的细胞系和培养基可以用于本发明,并且所述细胞系和培养基用于生产rIVIG的用途和具有修饰的糖基化的rIVIG蛋白在免疫障碍治疗中的用途形成本发明的一部分。
寡聚化支架结构域
如本文所用,术语“寡聚化结构域”“寡聚化支架结构域”和“寡聚化蛋白质支架”可互换使用,以指示指定的序列起到形成寡聚结构的作用。可用于本发明的寡聚支架结构域包括将诱导其融合配偶体(例如单链Fc肽)三聚化形成三聚体rIVIG分子的那些,其中每个rIVIG分子包含两个H-CH2-CH3 Fc结构域(铰链区-重链恒定区2-重链恒定区3)。在某些实施方案中,例如P8020Z(序列ID号6)所例示,寡聚化支架结构域可位于构建体的N-末端,在这种情况下,寡聚化支架结构域的C-末端可以直接地或通过短接头序列如GGGGS间接地连接到第一铰链区(H)或CH2区或CL结构域的N-末端。在其他实施方案中,例如P8003Z(序列ID号4)所例示,寡聚化支架结构域可以位于构建体的C-末端,在这种情况下,寡聚化支架结构域的N-末端可以直接地或通过短接头序列如GGGGS(序列ID号9)间接地连接到最后的CH3结构域的C-末端。
接头和柔性接头
可用于本发明的接头和柔性接头包括富含甘氨酸和/或丝氨酸的肽接头,其具有多个甘氨酸或丝氨酸残基并限定长度足以跨越第一结构域的C-末端与第二结构域的N-末端之间的距离的多肽。术语“柔性接头”用于定义多肽序列,其具有足够长度以允许在水溶液中形成本质上不含二级结构的柔性非结构化多肽构型,并且所述接头提供连接两个蛋白质结构域的方式,使得嵌合或融合蛋白可以作为来自单个核酸构建体的单个多肽分子产生。
接头的长度可以变化,从而允许以允许在分开的区域之间的分子内相互作用的方式,从而允许形成优化生物功能的三维构象。如本文所用,术语“柔性接头”通常适用于长度为十个或更多个氨基酸的接头。合适的柔性接头通常具有至少10个氨基酸残基的长度,并且包括具有约10个多至三十六个氨基酸残基的接头多肽。优选的柔性接头是具有多于至少约50%的甘氨酸残基并且长度为约10至约30个氨基酸、更优选长度为约12至25个氨基酸、或长度为约15至25个氨基酸的那些。可用于本发明的柔性接头包括,例如,(GGGGS)n的氨基酸序列;其中n是2到7。术语“G4S”可互换使用,指序列GGGGS(序列ID号9)。优选的柔性接头包括(GGGGS)n的氨基酸序列;其中n是2到6;并且更优选地n为3至5。这种富含甘氨酸和/或富含丝氨酸的肽接头是众所周知的,并且已经用于连接抗体结构域以形成单链Fv(sFv)蛋白,其将完整的抗体结合位点整合到单个多肽链中。富含丝氨酸和/或富含甘氨酸的少于十二个氨基酸残基的肽接头也可用作连接肽结构域的接头,但通常不能提供足够的灵活性以允许相邻融合肽结构域可在分子内相互作用的构象。可用于本发明的特定柔性接头包含氨基酸序列(GGGGS)5(序列ID号9)。可用于本发明的较短接头(不需要柔性接头的情况下)包括含有氨基酸GGGGS和(GGGGS)2的接头。通常,接头可包含具有非反应性侧链的其他氨基酸残基,例如丙氨酸和苏氨酸。然而,接头通常应不含带电荷的氨基酸残基并且不含可以形成二硫键的半胱氨酸残基。合适的柔性肽接头和可用于其制备的DNA构建体描述于美国专利5,258,498、美国专利5,482,858和美国专利5,525,491中。
纯化:
本发明还涉及主要包含一种或多种本发明的rIVIG蛋白的组合物。如本文所用,当关于组合物的重量使用时,术语“主要包含”一种或多种rIVIG蛋白意指以组合物总重量的重量计,组合物包含至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%或至少95%的指定rIVIG蛋白。当相对于组合物中的蛋白质的量使用时,术语“主要包含”一种或多种rIVIG蛋白意指以组合物中存在的总蛋白质的摩尔百分比计(以摩尔百分比计),组合物包含以摩尔百分比计至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%或至少95%的指定rIVIG蛋白。
主要包含一种或多种本发明的rIVIG蛋白的组合物可以使用传统的IgG纯化方法获得,所述纯化方法使用结合IgG的Fc部分的蛋白质A-琼脂糖或优先结合IgG的Fc部分但也可以结合IgG的Fab区(使其可用于纯化F(ab’)2)的蛋白质G-琼脂糖。根据本发明,本领域已知的其他纯化方法可用于进一步纯化根据本发明的rIVIG蛋白的组合物,包括尺寸排阻色谱(SEC)和疏水相互作用色谱(HIC)。参见http://www.kpl.com/docs/techdocs/purifigg.pdf(2016年3月23日访问)以及其中引用的参考文献;Surolia等人(1982)TrendsBiochem.Sci.7:74-76;Harlow和Lane编(1988)Antibodies,A Laboratory Manual(ColdSpring Harbor Laboratory,NY),第617-618页;Langone(1982)J.Immunological Methods55:277-296;Lindmark等人(1983)J.Immunological Methods 62:1-13;以及Thruston和Henley(1988)于Walker,编Methods in Molecular Biology,第3卷–New ProteinTechniques(Humana Press:Clifton,NJ)第149-158页。
组合物
本发明还涉及已与药学上可接受的佐剂或载体组合的rIVIG蛋白的组合物。如所使用的,术语“药学上可接受的”意指用于药学领域是可接受的,即不具有不可接受的毒性,或者在其他方面并非不适合给予哺乳动物。药学上可接受的佐剂的例子包括但不限于稀释剂、赋形剂等。可以参考“Remington's:The Science and Practice of Pharmacy”,第21版,Lippincott Williams&Wilkins,2005,一般用于药物配制品的指导。
药物组合物可进一步包含其他成分,例如防腐剂、缓冲剂、张力剂、抗氧化剂和稳定剂、非离子润湿剂或澄清剂、增粘剂等。
用于在溶液中使用的合适防腐剂可包括聚季铵盐-1、苯扎氯铵、硫柳汞、氯丁醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯乙醇、EDTA二钠、山梨酸、苄索氯铵等。通常(但不是必须)此类防腐剂的用量为0.001%-1.0%(按重量计)。
通常(但不一定)使用缓冲液以使配制品保持在生理pH或接近生理pH。合适的缓冲剂包括硼酸、碳酸氢钠和碳酸氢钾、硼酸钠和硼酸钾、碳酸钠和碳酸钾、乙酸钠、二磷酸钠等,其量足以将pH保持在约pH 6与pH 8之间,优选在约pH 7与pH 7.5之间。
合适的张力剂包括葡聚糖40、葡聚糖70、右旋糖、甘油、氯化钾、丙二醇、氯化钠等,使得可注射溶液的氯化钠当量在0.9%±0.2%的范围内。
合适的抗氧化剂和稳定剂包括亚硫酸氢钠、焦亚硫酸钠、硫代亚硫酸钠、硫脲等。合适的润湿剂和澄清剂包括聚山梨醇酯80、聚山梨醇酯20、泊洛沙姆282和泰洛沙泊。合适的增粘剂包括葡聚糖40、葡聚糖70、明胶、甘油、羟乙基纤维素、羟甲基丙基纤维素、羊毛脂、甲基纤维素、凡士林、聚乙二醇、聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素等。
佐剂的选择取决于组合物的预期给药方式,并且还可以考虑预期的适应症和患者。在本发明的一个实施方案中,将化合物配制成通过输注给药,或通过皮下或静脉注射给药,因此可以以无菌和无热原形式作为水溶液使用,并任选地经缓冲或制成等渗溶液。因此,化合物可以在蒸馏水中给予,或者更理想地在盐水、磷酸盐缓冲盐水或5%右旋糖溶液中给予。除上述之外,本发明的配制品还可包含其他活性成分和/或非活性成分,包括溶剂、稀释剂、悬浮助剂、增稠剂或乳化剂、粘合剂、稳定剂、润滑剂等,以适合于特定的剂量和给药方式。除非任何常规载体介质与本发明的成分不相容,例如通过产生任何不期望的效果或另外以有害的方式与配制品的任何其他一种或多种成分相互作用,否则其用途被认为在本发明的范围内。
给药方法:
药物组合物可适用于本文所述的各种给药方式,包括例如全身给药或局部给药。药物组合物可以是可注射溶液的形式或适于口服给药的形式。本文所述的药物组合物可以按单一单位剂量或多剂量形式包装。在某些实施方案中,药物组合物适于通过本文所述的任何给药途径给予个体、脊椎动物、哺乳动物或人,包括口服给药或静脉注射。
本文所述的组合物可通过任何途径给予个体,包括但不限于静脉(例如,通过输注泵)、腹膜内、眼内、动脉内、肺内、口服、吸入、囊内、肌肉、气管内、皮下、眼内、鞘内、经皮、经胸腔、动脉内、局部、吸入(例如,作为喷雾的雾气)、粘膜(如经由鼻粘膜)、皮下、经皮、胃肠、关节内、脑池内、室内(intraventricular)、直肠(即经由栓剂)、***(即经由子宫托)、颅内、尿道内、肝内和肿瘤内。在一些实施方案中,组合物被全身给予(例如通过静脉注射)。在一些实施方案中,组合物被局部给予(例如通过动脉内或眼内注射)。
在一些实施方案中,组合物通过血管内给予,例如静脉内或动脉内给予。在一些实施方案中(例如用于治疗肾病),将组合物直接给予于动脉(例如肾动脉)中。在优选的实施方案中,组合物被皮下给予。
在一些实施方案中,可以将组合物直接给予眼睛或眼组织。在一些实施方案中,将组合物局部给予眼睛,例如以滴眼剂形式。在一些实施方案中,通过注射给眼睛(眼内注射)或与眼睛相关的组织来给予组合物。所述组合物可以例如通过眼内注射、眼周注射、视网膜下注射、玻璃体内注射、经中隔注射、巩膜下注射、脉络膜内注射、前房内注射、subconjectval injection、结膜下注射、筋膜下注射、球后注射、球周注射、或后巩膜递送来给予。这些方法在本领域中是已知的。例如,对于视网膜药物递送的示例性球周途径的描述,参见Periocular routes for retinal drug delivery,Raghava等人(2004),ExpertOpin.Drug Deliv.1(1):99-114。所述组合物可以给予于例如玻璃体、房水、巩膜、结膜、巩膜和结膜之间的区域、视网膜脉络膜组织、黄斑或个体眼睛中或附近的其他区域。
组合物也可以作为植入物给予个体。优选的植入物是生物相容的和/或可生物降解的持续释放配制品,其经一段时间逐渐释放化合物。用于药物递送的眼部植入物在本领域中是众所周知的。参见,例如US 5,501,856、5,476,511和6,331,313。还可以使用离子电渗法将组合物给予个体,包括但不限于US 4,454,151和US 2003/0181531和2004/0058313中描述的离子电渗方法。
剂量:
组合物的最佳有效量可以凭经验确定,并且取决于疾病的类型和严重程度、给药途径、疾病进展、以及个体的健康、体重和体表面积。此类确定在本领域技术人员的技能范围内。有效量也可以基于体外测定来确定。可用于本文所述方法的组合物的剂量的例子包括但不限于在约0.01ug/kg至约300mg/kg、或约0.1ug/kg至约40mg/kg内、或约1ug/kg至约至约20mg/kg、或约1ug/kg至约10mg/kg内的任何剂量范围内的有效量。例如,当皮下给药时,组合物可以在低微克范围给予,包括例如约0.1ug/kg或更低、约0.05ug/kg或更低、或0.01ug/kg或更低。在一些实施方案中,给予至个体的组合物的量为每剂约10ug至约500mg,包括例如每剂约10ug至约50ug、约50ug至约100ug、约100ug至约200ug、约200ug至约300ug、约300ug至约500ug、约500ug至约1mg、约1mg至约10mg、约10mg至约50mg、约50mg至约100mg、约100mg至约200mg、约200mg至约300mg、约300mg至约400mg、或约400mg至约500mg中的任一个。
组合物可以以单个日剂量给予,或者总日剂量可以按每日两次、三次或四次的分剂量给药。所述组合物也可以比每日给予频率更少,例如,一周六次、一周五次、一周四次、一周三次、一周两次、一周一次、每两周一次、每三周一次、每月一次、每两个月一次、每三个月一次、或每六个月一次。所述组合物还可以以例如在植入物中的持续释放配制品给予,这样的配制品逐渐释放所述组合物以便经一段时间使用,并且可以减少组合物的给予频率,例如每月一次、每2-6个月一次、每年一次、甚至单次给药。持续释放装置(例如丸粒、纳米颗粒、微粒、纳米球、微球等)可以通过注射给予或手术植入体内的不同位置。
共同给药
本发明提供了改善免疫障碍或疾病治疗的方法,包括将本发明的rIVIG组合物与一种或多种具有预防或治疗活性、或已被批准用作治疗这种免疫障碍或疾病的其他活性剂共同给予。在这些方法中,可以在给予另外的活性剂之前、同时或之后给予rIVIG组合物。例如,在类风湿性关节炎(RA)的治疗中,本发明的rIVIG组合物可与包含(adilimumab,AbbVie Inc.)(一种批准用于RA的治疗性抗体)的组合物共同给予。预期rIVIG组合物将为患有RA的患者提供额外的缓解,并且rIVIG组合物的作用可能与的作用协同。
本发明提供了对接受器官移植或其他程序如干细胞移植或输血的患者改善治疗的方法,包括在这种移植或其他程序之前、同时或之后给予本发明的rIVIG组合物。根据本发明的这种治疗提供了预防或减少针对移植器官的抗体介导的免疫应答(即免疫排斥)的方法。rIVIG组合物可以与一种或多种另外的活性剂共同给予,所述一种或多种另外的活性剂具有针对这种抗体介导的免疫应答或移植器官排斥的预防或治疗活性。
例如,在肾移植受者的治疗中,本发明的rIVIG组合物可与包含免疫抑制药物如环孢菌素的组合物共同给予。可以与本发明的组合物共同给予的其他免疫抑制药物包括钙调磷酸酶抑制剂,如他克莫司;mTOR抑制剂,如西罗莫司;抗增殖剂,如霉酚酸酯和硫唑嘌呤;以及类固醇,如***。预计rIVIG组合物将为患有免疫排斥的患者提供额外的缓解,并且rIVIG组合物的作用可以与免疫抑制剂的作用协同。另外,根据本发明的这种治疗可以允许减少此类免疫抑制剂的量。
编码核苷酸分子、重组载体和重组细胞系
合成编码本发明rIVIG蛋白的核苷酸分子的方法在本领域中是已知的。使用遗传密码,本发明的rIVIG蛋白的氨基酸序列可以简单地使用在线工具进行回译和密码子优化(27);并且编码核苷酸分子可以使用诸如Kim等人描述的基因合成的分级方法(28)的策略来合成。
对于本发明的rIVIG蛋白的表达,已知编码核苷酸序列可以使用重组载体在宿主细胞中表达,其中编码rIVIG蛋白的核酸序列在合适的启动子的控制下,所述合适的启动子将驱动rIVIG蛋白在宿主细胞中表达。合适的宿主细胞包括例如哺乳动物CHO细胞、293T细胞(29)。
基因治疗
还可以通过体内融合蛋白的表达来递送分子,这通常称为“基因疗法”。例如,可以离体用编码融合蛋白的多核苷酸(DNA或RNA)改造细胞,然后将工程化细胞提供给待用融合蛋白治疗的个体。这些方法在本领域中是众所周知的。例如,可以通过本领域已知的程序,通过使用含有编码本发明融合蛋白的RNA的逆转录病毒颗粒来改造细胞。使用基因疗法局部递送本发明的rIVIG蛋白可以将治疗剂提供给局部靶区域。
基因递送方法在本领域中是已知的。这些方法包括但不限于直接DNA转移,参见例如Wolff等人(1990)Science 247:1465-1468;2)脂质体介导的DNA转移,参见例如Caplen等人(1995)Nature Med.3:39-46;Crystal(1995)Nature Med.1:15-17;Gao和Huang(1991)Biochem.Biophys.Res.Comm.179:280-285;3)逆转录病毒介导的DNA转移,参见例如Kay等人(1993)Science 262:117-119;Anderson(1992)Science 256:808-813;4)DNA病毒介导的DNA转移。此类DNA病毒包括腺病毒(优选基于Ad2或Ad5的载体)、疱疹病毒(优选基于单纯疱疹病毒的载体)和细小病毒(优选“有缺陷的”或非自主的基于细小病毒的载体,更优选基于腺相关病毒的载体,大多数优选基于AAV-2的载体)。参见,例如,Ali等人(1994)GeneTherapy 1:367-384;美国专利号4,797,368(通过引用并入本文)和美国专利号5,139,941。
可以衍生上文所述的逆转录病毒质粒载体的逆转录病毒包括但不限于莫洛尼小鼠白血病病毒、脾坏死病毒、逆转录病毒如劳氏肉瘤病毒、哈维肉瘤病毒、禽白血病病毒、长臂猿白血病病毒、人类免疫缺陷病毒、腺病毒、骨髓增生性肉瘤病毒和乳腺瘤病毒。在一个实施方案中,逆转录病毒质粒载体衍生自莫洛尼小鼠白血病病毒。
腺病毒的优势在于它们具有广泛的宿主范围,可以感染静止或终末分化的细胞,如神经元或肝细胞,并且显现基本上是非致癌的。参见,例如,Ali等人(1994),同上,第367页。腺病毒显现不整合到宿主基因组中。因为它们存在于染色体外,所以***突变的风险大大降低。Ali等人(1994),同上,第373页。
腺相关病毒展现出与基于腺病毒的载体相似的优势。然而,AAV在人19号染色体上展现位点特异性整合(Ali等人(1994),同上,第377页)。
基因治疗载体可包括一种或多种启动子。在一些实施方案中,载体具有驱动多种细胞类型表达的启动子。在一些实施方案中,载体具有驱动特定细胞类型(例如视网膜细胞或肾细胞)表达的启动子。可以使用的合适的启动子包括但不限于逆转录病毒LTR;SV40启动子;和Miller等人描述的人巨细胞病毒(CVM)启动子(Miller等人(1989)Biotechniques7(9):980-990),或任何其他启动子(例如,细胞启动子如真核细胞启动子,包括但不限于组蛋白、pol III和β-肌动蛋白启动子)。可以使用的其他病毒启动子包括但不限于腺病毒启动子、胸苷激酶(TK)启动子和B19细小病毒启动子。根据本文所包含的传授,选择合适的启动子对于本领域技术人员而言是清楚的。
编码rIVIG蛋白的核酸序列优选在合适的启动子的控制下。可以使用的合适启动子包括但不限于腺病毒启动子,例如腺病毒主要晚期启动子;或异源启动子,如巨细胞病毒(CMV)启动子;呼吸道合胞病毒(RSV)启动子;诱导型启动子,如MMT启动子、金属硫蛋白启动子;热激启动子;白蛋白启动子;ApoA1启动子;人珠蛋白启动子;病毒胸苷激酶启动子,如单纯疱疹胸苷激酶启动子;逆转录病毒LTR(包括上文所述的修饰的逆转录病毒LTR);β-肌动蛋白启动子;和人生长激素启动子。
逆转录病毒质粒载体可用于转导包装细胞系以形成生产细胞系。可以被转染的包装细胞的例子描述于Miller(1990)Human Gene Therapy 1:5-14中。载体可以通过本领域已知的任何手段转导包装细胞。此类手段包括但不限于电穿孔、脂质体的使用和CaPO4沉淀。在一个替代方案中,逆转录病毒质粒载体可以包封在脂质体中,或与脂质偶联,然后给予宿主。生产细胞系产生感染性逆转录病毒载体颗粒,其包括编码多肽的一个或多个核酸序列。然后可以使用此类逆转录病毒载体颗粒,以在体外或体内转导真核细胞。转导的真核细胞将表达编码多肽的一个或多个核酸序列。可被转导的真核细胞包括但不限于胚胎干细胞、胚胎癌细胞、以及造血干细胞、肝细胞、成纤维细胞、成肌细胞、角化细胞、内皮细胞和支气管上皮细胞。
离体给药
在一些实施方案中,rIVIG蛋白的免疫调节作用可以通过在允许分子发挥功能以调节免疫应答的条件下使体液与包含所述分子的组合物离体接触来实现。合适的体液包括可以返回个体的体液,例如血液、血浆或淋巴液。亲和吸附单采血液成分术总体上描述于Nilsson等人(1988)Blood 58(1):38-44;Christie等人(1993)Transfusion 33:234-242;Richter等人(1997)ASAIO J.43(1):53-59;Suzuki等人(1994)Autoimmunity 19:105-112;美国专利号5,733,254;Richter等人(1993)Metabol.Clin.Exp.42:888-894;以及Wallukat等人(1996)Int'l J.Card.54:1910195中。
因此,本发明包括在个体中治疗本文所述的一种或多种疾病的方法,所述方法包括在允许分子发挥功能以调节免疫应答的条件下用包含分子的组合物在体外(即,体外或离体)处理个体血液,并将血液返回个体。
单位剂量、制品和试剂盒
还提供了组合物的单位剂型,每个剂量含有约0.01mg至约50mg,包括例如约0.1mg至约50mg、约1mg至约50mg、约5mg至约40mg、约10mg至约20mg、或约15mg分子中的任一者。在一些实施方案中,分子组合物的单位剂型包含约0.01mg-0.1mg、0.1mg-0.2mg、0.2mg-0.25mg、0.25mg-0.3mg、0.3mg-0.35mg、0.35mg-0.4mg、0.4mg-0.5mg、0.5mg-1.0mg、10mg-20mg、20mg-50mg、50mg-80mg、80mg-100mg、100mg-150mg、150mg-200mg、200mg-250mg、250mg-300mg、300mg-400mg、或400mg-500mg分子中的任一者。在一些实施方案中,单位剂型包含约0.25mg分子。术语“单位剂型”是指适合作为个体的单位剂量的物理上离散的单位,每个单位含有预定量的活性物质,经计算所述预定量的活性物质可产生所需的治疗效果并与合适的药物载体、稀释剂或赋形剂结合使用。这些单位剂型可以以单个或多个单位剂量储存在合适的包装中,并且也可以进一步灭菌和密封。
还提供了在合适包装中的包含本文所述组合物的制品。本文所述的用于组合物(例如眼用组合物)的合适包装在本领域中是已知的,并且包括例如小瓶(例如密封小瓶)、容器、安瓿、瓶子、广口瓶、柔性包装(例如,密封的聚酯薄膜或塑料袋)等。这些制品可进一步灭菌和/或密封。
本发明还提供了包含本文所述的组合物(或单位剂量形式和/或制品)的试剂盒,并且可以进一步包括关于使用所述组合物的方法(例如本文所述的用途)的一个或多个说明。本文所述的试剂盒可以进一步包括从商业和用户角度所需的其他材料,包括其他缓冲剂、稀释剂、过滤器、针头、注射器和具有用于实施本文所述任何方法的说明的包装说明书。
本发明的组合物和配制品可用于治疗与免疫应答调节相关联的病症。
兽医学用途
除上述之外,本发明还提供了可用于兽医学适应症(包括治疗非人哺乳动物的免疫障碍和疾病)的方法和材料。在具体实施方案中,可用于兽医学用途的本发明方法和材料包括源自与兽医学宿主/患者相同物种的肽结构域。非人哺乳动物可能患有任何免疫障碍或疾病,包括自身免疫性溶血性贫血(AIHA)、免疫性血小板减少性紫癜(ITP)、类风湿性关节炎或反应性关节炎。虽然非人哺乳动物可以是任何物种,但已知某些品种的犬对自身免疫障碍特别敏感。例如,对于犬的治疗,可以使用一种或多种Fc肽结构域和一种寡聚化肽结构域,其中每一种都是犬源。具体而言,已知犬易患免疫障碍,例如自身免疫性溶血性贫血(AIHA),其中犬自身的免疫***与犬的红细胞结合并破坏其血红细胞。在患有AIHA或免疫性血小板减少性紫癜(ITP)的对常规疗法无反应的犬中或在严重ITP(其中致命性出血的风险被认为显著)中,人来源的IVIG已被用于治疗。参见例如Kellerman等人(1997)J Vet IntMed,11:327-332。然而,用人IVIG治疗的犬始终产生犬抗人抗体(DAHA),其可以在重复使用人IVIG时触发过敏反应。因此,用目前可用的IVIG组合物治疗兽医学患者受到严格限制。因此,本发明的方法和材料提供了犬源的rIVIG组合物,以及治疗展现犬免疫障碍如AIHA和ITP的犬的方法。
在兽医学适应症中,本发明包括rIVIG多肽,其包含源自与兽医学宿主/患者相同物种的肽结构域。因此,对于犬的治疗,本发明包括rIVIG多肽,其包含一个或多个犬Fc肽结构域和犬寡聚化肽结构域。如在人类治疗中,本发明的优选实施方案包含通过用以允许分子内相互作用的柔性接头连接的两个或更多个Fc部分,以及一个三聚化肽结构域。包含犬源的寡聚化肽结构域的rIVIG多肽可用于治疗展现出犬免疫障碍的犬。
重组免疫球蛋白融合蛋白
P7005H是由包含人IgG1重链CH2和CH3区的人Fc部分以及人CD40L的细胞外结构域(ECD)组成的融合蛋白。人Fc部分可以二聚化,CD40L ECD可以三聚化。因此,预期融合蛋白将形成含有三个二聚体Fc和两个三聚体CD40L的六聚体。成熟的P7005H包含含有人IgG1重链CH2和CH3区的三个二聚体Fc部分,并且预期展现出优异的IVIG模拟活性。然而,因为每个功能性Fc结构域位于单独的肽链上,所以二聚体Fc的形成不是均一的。此外,表达的肽链之间的二硫键可以显著变化,并且分子间相互作用也可以发生在分子内,导致“拉链”寡聚体比六聚体大得多。因此,由P7005H形成的组合物明显不如所需的均一,并且包括不适当折叠并因此不具有活性的聚集蛋白质。因此,为了使含有P7005H的蛋白质组合物更可接受,需要进一步的纯化步骤以分离预期最具活性的六聚体。对这种纯化的需要使得P7005H在商业上不太可行,因为制备均一组合物需要进一步的纯化步骤。
为了解决本发明的rIVIG组合物的均一性问题,诸位发明人开发了一系列单链人Fc融合肽。
P8001Z是包含单链人Fc以及源自人胶原蛋白21的GXY三联体重复和NC1结构域的融合蛋白,所述单链人Fc包含两个串联的人CH2-CH3 Fc结构域,每个CH2-CH3 Fc结构域包含人IgG1重链CH2和CH3区。单链Fc肽包括在两个CH2-CH3 Fc结构域之间的柔性接头(GGGGS)5,其允许热力学上有利的分子内相互作用并促进单链中功能性Fc肽的形成。预期这种分子内相互作用使分子间二硫键的形成最小化并使单一种类的功能性单链Fc肽的形成最大化。GXY三联体重复序列负责胶原蛋白的三聚化,并且预期将三个Fc区聚集在一起,在每个Fc区中,通过柔性接头连接的两个串联CH2-CH3 Fc结构域可以相互作用。因此预期P8001Z的产物比P7005H构建体的产物更均一。
P8003Z是融合蛋白,其包含单链人IgGκ或轻链恒定区(CL)、包含完整IgG恒定区(CH1、CH2和CH3)的第一Fc结构域和第二Fc结构域(包含CH2和CH3),所述第二Fc结构域通过柔性接头串联连接至第一Fc区的C-末端,所述柔性接头优选为(G4S)5接头。柔性接头允许构建体呈现构象,其中第一和第二Fc结构域可以在分子内相互作用。第二Fc结构域的C-末端串联连接至胶原蛋白GXY三联体重复和NC1结构域(三聚化结构域)。与P8001Z类似,胶原蛋白GXY重复和NC1结构域展现出内在的三聚化活性以使三个单链Fc肽聚集在一起,每个单链Fc肽包含通过柔性接头连接至第二CH2-CH3 Fc结构域的第一CH2-CH3 Fc结构域,处于其中第一和第二CH2-CH3 Fc结构域可以相互作用的构象。还应提及的是CL结构域与CH1结构域发生异二聚体化。CL/CH1结构域在清除补体成分中起作用,这可进一步减轻许多自身免疫障碍中存在的补体免疫应答。
P8020Z是由N-末端部分人甘露糖结合蛋白(MBP)和单链Fc肽(类似于P8003Z的)组成的融合蛋白,按照从N-末端到C-末端方向的顺序为:CL-CH1-CH2-CH3-柔性接头-CH2-CH3。人MBP的N-末端部分具有内在的三聚化能力并且负责融合蛋白的寡聚化。与P8003Z的设计相反,P8020Z的寡聚化结构域位于融合蛋白的N-末端,而Ig Fc区位于C-末端,如在天然免疫球蛋白分子中发现的。具有位于融合蛋白C-末端的单链Fc肽的P8020Z的结构被预期与常规抗体与Fc受体相互作用的取向非常接近。
上述重组rIVIG构建体已经制备和表达于293T细胞中,并且可以使用本领域已知的纯化技术纯化产生的蛋白。
为了确定rIVIG蛋白是否已正确折叠,使得它们主要包含六聚体Fc结构,通过尺寸排阻色谱(SEC)分析来分析纯化的蛋白。图2示出每种蛋白产物的SEC谱。
分析这些rIVIG蛋白的FcγR结合活性,并将其与纯化的单体人IgG1抗体的FcγR结合活性进行比较(图3)。
还使用小鼠胶原蛋白诱导的关节炎模型测试了P8003Z和P8020Z构建体的治疗效果。
用具有完全弗氏佐剂(CFA)的牛II型胶原蛋白对小鼠进行初免,并且在第21天,用具有不完全弗氏佐剂(IFA)的相同胶原蛋白进行加强免疫。第18天,腹膜内给予P8020Z。从第26天开始对发炎的爪子评分。图4示出与用PBS处理的对照小鼠相比,用P8020处理的小鼠显示炎症减弱许多。
尽管以下实施例说明了在各种实施方案中本发明的实践,但实施例不应解释为限制本发明的范围。考虑到说明书和实施例,其他实施方案对于本领域技术人员而言是清楚的。
实施例
实施例1:
P7005H的构建
P7005H蛋白由哺乳动物表达质粒pMEhFcN1-7005表达,所述质粒在巨细胞病毒(CMV)即时早期基因启动子的控制下编码395个氨基酸的蛋白质。从N-末端起,编码的产物由以下组成:人IgG1铰链,CH2和CH3区,连接至人CD40L的细胞外结构域。以下是从生产***中产生的成熟蛋白质产物(375个氨基酸)的编码序列(序列ID号1)。
P7005H的蛋白质序列(375个氨基酸)(序列ID号1):
表2
实施例2:
P8001Z的构建
P8001Z蛋白由哺乳动物表达质粒pHCM-rIVIG V1表达,所述质粒在巨细胞病毒(CMV)即时早期基因启动子的控制下编码539个氨基酸的蛋白质。从N-末端起,编码产物由以下组成:包含人IgG1重链CH2和CH3区的第一CH2-CH3 Fc结构域;随后是包含五个重复的G4S接头(GGGGS)5的柔性接头;随后是包含人IgG1重链CH2和CH3区的第二CH2-CH3 Fc结构域;随后是来自人胶原蛋白21 A1的十一个拷贝的GXY三联体和NC1结构域((GXY)11-NC1)。以下是从生产***中产生的成熟蛋白质产物(519个氨基酸)的编码序列(序列ID号2)。
P8001Z的蛋白质序列(519个氨基酸)(序列ID号2):
表3
实施例3:
P8002Z的构建
P8002Z蛋白由哺乳动物表达质粒pHCM-rIVIG V2表达,所述质粒在巨细胞病毒(CMV)即时早期基因启动子的控制下编码529个氨基酸的蛋白质。从N-末端起,编码产物由以下组成:包含人IgG1重链CH2和CH3区的第一CH2-CH3 Fc结构域;随后是三个重复的G4S接头(GGGGS)3;随后是由人IgG1重链CH2和CH3区构成的第二CH2-CH3 Fc结构域;随后是GGGGS接头;随后是来自人胶原蛋白21 A1的十一个拷贝的GXY三联体和NC1结构域((GXY)11-NC1)。以下是从生产***中产生的成熟蛋白质产物(509个氨基酸)的编码序列(序列ID号3)。
P8002Z的蛋白质序列(509个氨基酸)(序列ID号3):
表4
实施例4:
P8003Z的构建
P8003Z蛋白由哺乳动物表达质粒pHCM-rIVIG V3表达,所述质粒在巨细胞病毒(CMV)即时早期基因启动子的控制下编码788个氨基酸的蛋白质。从N-末端起,编码产物由以下组成:人κ轻链恒定区(CL);随后是两个重复的G4S接头(G4S)2;随后是包含人IgG1重链恒定区的CH1-铰链-CH2-CH3 Fc结构域(CH1-铰链-CH2-CH3);随后是包含G4S接头的五个重复(GGGGS)5的柔性接头;随后是包含人IgG1重链铰链、CH2和CH3区的铰链-CH2-CH3 Fc结构域;随后是来自人胶原蛋白21 A1的十一个拷贝的GXY三联体和NC1结构域((GXY)11-NC1)。以下是从生产***中产生的成熟蛋白质产物(768个氨基酸)的序列(序列ID号4)。
P8003Z的蛋白质序列(768个氨基酸)(序列ID号4):
表5
实施例5:
P8004Z的构建
P8004Z蛋白由哺乳动物表达质粒pHCM-rIVIG V4表达,所述质粒在巨细胞病毒(CMV)即时早期基因启动子的控制下编码569个氨基酸的蛋白质。从N-末端起,编码产物由以下组成:包含人IgG1重链铰链、CH2和CH3区的第一铰链-CH2-CH3 Fc结构域(铰链-CH2-CH3);随后是柔性接头(GGGGS)5;随后是包含人IgG1重链铰链、CH2和CH3区的第二铰链-CH2-CH3 Fc结构域;随后是来自人胶原蛋白21 A1的十一个拷贝的GXY三联体和NC1结构域(GXY11-NC1)。以下是从生产***中产生的成熟蛋白质产物(549个氨基酸)的编码序列(序列ID号5)。
P8004Z的蛋白质序列(549个氨基酸)(序列ID号5):
表6
实施例6:
P8020Z的构建
P8020Z蛋白由哺乳动物表达质粒pHCM-rIVIG V20表达,所述质粒在巨细胞病毒(CMV)即时早期基因启动子的控制下编码816个氨基酸的蛋白质。从N-末端起,编码产物由以下组成:人甘露糖结合蛋白(hMBP)N-末端肽-hMBP胶原蛋白三螺旋结构域;随后是三个重复的G4S接头(GGGGS)3;随后是人κ轻链恒定区(CL);随后是两个重复的G4S接头(G4S)2;随后是包含人IgG1重链恒定区的第一CH1-铰链-CH2-CH3 Fc结构域(CH1-铰链-CH2-CH3);随后是包含五个重复的GGGGS接头(GGGGS)5的柔性接头;随后是包含人IgG1重链铰链、CH2和CH3区的铰链-CH2-CH3 Fc结构域。以下是从生产***产生的成熟蛋白质产物(796个氨基酸)的序列:
P8020Z的蛋白质序列(796个氨基酸)(序列ID号6):
表7
实施例7:
K8020Z的构建
K8020Z蛋白由哺乳动物表达质粒pHCM-rIVIG V40表达,所述质粒在巨细胞病毒(CMV)即时早期基因启动子的控制下编码822个氨基酸的蛋白质。从N-末端起,编码产物由以下组成:犬甘露糖结合蛋白(MBP)N-末端肽-犬MBP胶原蛋白三螺旋结构域;随后是三个重复的G4S接头(GGGGS)3;随后是犬κ轻链恒定区(CL);随后是两个重复的G4S接头(GGGGS)2;随后是包含IgG亚类B重链恒定区的犬CH1-铰链-CH2-CH3 Fc结构域(CH1-铰链-CH2-CH3);随后是包含五个重复的G4S(GGGGS)5的柔性接头;随后是包含犬IgG亚类B重链铰链、CH2和CH3区的犬铰链-CH2-CH3 Fc结构域。以下是从生产***中产生的成熟蛋白质产物(802个氨基酸)的编码序列(序列ID号7)。
K8020Z的蛋白质序列(802个氨基酸)(序列ID号7):
表8
实施例8:
K8003Z的构建
K8003Z蛋白由哺乳动物表达质粒pHCM-rIVIG V42表达,所述质粒在巨细胞病毒(CMV)即时早期基因启动子的控制下编码779个氨基酸的蛋白质。从N-末端起,编码产物由以下组成:犬κ轻链恒定区(CL);随后是两个重复的G4S接头(GGGGS)2;随后是包含IgG亚类B重链恒定区的犬CH1-铰链-CH2-CH3 Fc结构域(CH1-铰链-CH2-CH3);随后是包含五个重复的G4S(GGGGS)5的柔性接头;随后是包含犬IgG亚类B重链铰链、CH2和CH3区的犬铰链-CH2-CH3 Fc结构域;随后是来自犬胶原蛋白21 A1的十一个拷贝的GXY三联体和NC1结构域((GXY)11-NC1)。以下是从生产***中产生的成熟蛋白质产物(779个氨基酸)的序列(序列ID号8)。
K8003Z的蛋白质序列(779个氨基酸)(序列ID号8):
表9
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<110> AB生物科学有限公司(AB Biosciences, Inc.)
许衍明(Hsu, Yen-Ming)
<120> 重组静脉内免疫球蛋白(rIVIG)组合物及其生产和使用方法
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<141> 2016-03-30
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Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
115 120 125
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
130 135 140
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly
210 215 220
Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
435 440 445
Gly Gly Gly Ser Gly Pro Pro Gly Ile Ser Gly Pro Pro Gly Asp Pro
450 455 460
Gly Leu Pro Gly Lys Asp Gly Asp His Gly Lys Pro Gly Ile Gln Gly
465 470 475 480
Gln Pro Gly Pro Pro Gly Ile Cys Asp Pro Ser Leu Cys Phe Ser Val
485 490 495
Ile Ala Arg Arg Asp Pro Phe Arg Lys Gly Pro Asn Tyr
500 505
<210> 4
<211> 768
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 4
Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
1 5 10 15
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
20 25 30
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
35 40 45
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
50 55 60
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
65 70 75 80
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
85 90 95
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys
465 470 475 480
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
485 490 495
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
500 505 510
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
515 520 525
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
530 535 540
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
545 550 555 560
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
565 570 575
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
580 585 590
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
595 600 605
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
610 615 620
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
625 630 635 640
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
645 650 655
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
660 665 670
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
675 680 685
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
690 695 700
Pro Gly Gly Gly Gly Gly Ser Gly Pro Pro Gly Ile Ser Gly Pro Pro
705 710 715 720
Gly Asp Pro Gly Leu Pro Gly Lys Asp Gly Asp His Gly Lys Pro Gly
725 730 735
Ile Gln Gly Gln Pro Gly Pro Pro Gly Ile Cys Asp Pro Ser Leu Cys
740 745 750
Phe Ser Val Ile Ala Arg Arg Asp Pro Phe Arg Lys Gly Pro Asn Tyr
755 760 765
<210> 5
<211> 549
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 5
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
260 265 270
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
275 280 285
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
290 295 300
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
305 310 315 320
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
325 330 335
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
340 345 350
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
355 360 365
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
370 375 380
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
385 390 395 400
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
405 410 415
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
420 425 430
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
435 440 445
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
450 455 460
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
465 470 475 480
Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Pro Pro Gly
485 490 495
Ile Ser Gly Pro Pro Gly Asp Pro Gly Leu Pro Gly Lys Asp Gly Asp
500 505 510
His Gly Lys Pro Gly Ile Gln Gly Gln Pro Gly Pro Pro Gly Ile Cys
515 520 525
Asp Pro Ser Leu Cys Phe Ser Val Ile Ala Arg Arg Asp Pro Phe Arg
530 535 540
Lys Gly Pro Asn Tyr
545
<210> 6
<211> 796
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 6
Glu Thr Val Thr Cys Glu Asp Ala Gln Lys Thr Cys Pro Ala Val Ile
1 5 10 15
Ala Cys Ser Ser Pro Gly Ile Asn Gly Phe Pro Gly Lys Asp Gly Arg
20 25 30
Asp Gly Thr Lys Gly Glu Lys Gly Glu Pro Gly Gln Gly Leu Arg Gly
35 40 45
Leu Gln Gly Pro Pro Gly Lys Leu Gly Pro Pro Gly Asn Pro Gly Pro
50 55 60
Ser Gly Ser Pro Gly Pro Lys Gly Gln Lys Gly Asp Pro Gly Lys Gly
65 70 75 80
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Thr
85 90 95
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
100 105 110
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
115 120 125
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
130 135 140
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
145 150 155 160
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
165 170 175
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
180 185 190
Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly
195 200 205
Gly Gly Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
210 215 220
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
225 230 235 240
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
245 250 255
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
260 265 270
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
275 280 285
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
290 295 300
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
305 310 315 320
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
325 330 335
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
340 345 350
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
355 360 365
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
370 375 380
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
385 390 395 400
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
405 410 415
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
420 425 430
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
435 440 445
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
450 455 460
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
465 470 475 480
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
485 490 495
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
500 505 510
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
515 520 525
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly
530 535 540
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
545 550 555 560
Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
565 570 575
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
580 585 590
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
595 600 605
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
610 615 620
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
625 630 635 640
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
645 650 655
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
660 665 670
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
675 680 685
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
690 695 700
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
705 710 715 720
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
725 730 735
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
740 745 750
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
755 760 765
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
770 775 780
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
785 790 795
<210> 7
<211> 802
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 7
Asp Lys Glu Ala Leu Ser Glu Ala Gln Arg Thr Cys Pro Val Val Thr
1 5 10 15
Cys Ala Leu Pro Gly Arg Asp Gly Arg Asp Gly Leu Lys Gly Glu Lys
20 25 30
Gly Glu Pro Gly Gln Gly Leu Arg Gly Leu Gln Gly Pro Pro Gly Lys
35 40 45
Val Gly Pro Pro Gly Asn Thr Gly Ala Pro Gly Ala Pro Gly Leu Lys
50 55 60
Gly His Lys Gly Asp Arg Gly Asp Gly Gly Gly Gly Ser Gly Gly Gly
65 70 75 80
Gly Ser Gly Gly Gly Gly Ser Arg Asn Asp Ala Gln Pro Ala Val Tyr
85 90 95
Leu Phe Gln Pro Ser Pro Asp Gln Leu His Thr Gly Ser Ala Ser Val
100 105 110
Val Cys Leu Leu Asn Ser Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp
115 120 125
Lys Val Asp Gly Val Ile Gln Asp Thr Gly Ile Gln Glu Ser Val Thr
130 135 140
Glu Gln Asp Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Met
145 150 155 160
Ser Ser Thr Glu Tyr Leu Ser His Glu Leu Tyr Ser Cys Glu Ile Thr
165 170 175
His Lys Ser Leu Pro Ser Thr Leu Ile Lys Ser Phe Gln Arg Ser Glu
180 185 190
Cys Gln Arg Val Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala
195 200 205
Ser Thr Thr Ala Pro Ser Val Phe Pro Leu Ala Pro Ser Cys Gly Ser
210 215 220
Thr Ser Gly Ser Thr Val Ala Leu Ala Cys Leu Val Ser Gly Tyr Phe
225 230 235 240
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ser Leu Thr Ser Gly
245 250 255
Val His Thr Phe Pro Ser Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
260 265 270
Ser Ser Met Val Thr Val Pro Ser Ser Arg Trp Pro Ser Glu Thr Phe
275 280 285
Thr Cys Asn Val Ala His Pro Ala Ser Lys Thr Lys Val Asp Lys Pro
290 295 300
Val Pro Lys Arg Glu Asn Gly Arg Val Pro Arg Pro Pro Asp Cys Pro
305 310 315 320
Lys Cys Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe
325 330 335
Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val
340 345 350
Thr Cys Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile
355 360 365
Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro
370 375 380
Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro
385 390 395 400
Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val
405 410 415
Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala
420 425 430
Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg
435 440 445
Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp
450 455 460
Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln
465 470 475 480
Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp
485 490 495
Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp
500 505 510
Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His
515 520 525
Asn His Tyr Thr Gln Lys Ser Leu Ser His Ser Pro Gly Gly Gly Gly
530 535 540
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
545 550 555 560
Ser Gly Gly Gly Gly Ser Pro Lys Arg Glu Asn Gly Arg Val Pro Arg
565 570 575
Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Met Leu Gly Gly Pro
580 585 590
Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala
595 600 605
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Asp Pro Glu Asp
610 615 620
Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr
625 630 635 640
Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val
645 650 655
Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln
660 665 670
Phe Thr Cys Lys Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg
675 680 685
Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val
690 695 700
Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr
705 710 715 720
Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln
725 730 735
Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro
740 745 750
Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val
755 760 765
Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met
770 775 780
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser His Ser
785 790 795 800
Pro Gly
<210> 8
<211> 779
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 8
Arg Asn Asp Ala Gln Pro Ala Val Tyr Leu Phe Gln Pro Ser Pro Asp
1 5 10 15
Gln Leu His Thr Gly Ser Ala Ser Val Val Cys Leu Leu Asn Ser Phe
20 25 30
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Val Asp Gly Val Ile Gln
35 40 45
Asp Thr Gly Ile Gln Glu Ser Val Thr Glu Gln Asp Lys Asp Ser Thr
50 55 60
Tyr Ser Leu Ser Ser Thr Leu Thr Met Ser Ser Thr Glu Tyr Leu Ser
65 70 75 80
His Glu Leu Tyr Ser Cys Glu Ile Thr His Lys Ser Leu Pro Ser Thr
85 90 95
Leu Ile Lys Ser Phe Gln Arg Ser Glu Cys Gln Arg Val Asp Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser Thr Thr Ala Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Cys Gly Ser Thr Ser Gly Ser Thr Val Ala
130 135 140
Leu Ala Cys Leu Val Ser Gly Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ser Leu Thr Ser Gly Val His Thr Phe Pro Ser Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro
180 185 190
Ser Ser Arg Trp Pro Ser Glu Thr Phe Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Lys Thr Lys Val Asp Lys Pro Val Pro Lys Arg Glu Asn Gly
210 215 220
Arg Val Pro Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Met
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu
260 265 270
Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys
275 280 285
Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu
305 310 315 320
Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn Lys Ala Leu Pro Ser
325 330 335
Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro
340 345 350
Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr
355 360 365
Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp
370 375 380
Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg
385 390 395 400
Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser
405 410 415
Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile
420 425 430
Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser His Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Pro
465 470 475 480
Lys Arg Glu Asn Gly Arg Val Pro Arg Pro Pro Asp Cys Pro Lys Cys
485 490 495
Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro
500 505 510
Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys
515 520 525
Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp
530 535 540
Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu
545 550 555 560
Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly
565 570 575
His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn
580 585 590
Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly
595 600 605
Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu Glu
610 615 620
Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe Phe
625 630 635 640
Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro
645 650 655
Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser
660 665 670
Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Arg
675 680 685
Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn His
690 695 700
Tyr Thr Gln Lys Ser Leu Ser His Ser Pro Gly Gly Gly Gly Gly Ser
705 710 715 720
Gly Pro Pro Gly Ile Ser Lys Glu Gly Pro Pro Gly Asp Pro Gly Leu
725 730 735
Pro Gly Lys Asp Gly Asp His Gly Lys Pro Gly Ile Gln Gly Gln Pro
740 745 750
Gly Pro Pro Gly Ile Cys Asp Pro Ser Leu Cys Phe Ser Val Ile Val
755 760 765
Gly Arg Asp Pro Phe Arg Lys Gly Pro Asn Tyr
770 775
<210> 9
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 9
Gly Gly Gly Gly Ser
1 5
<210> 10
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 在La合成
<400> 10
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
Claims (36)
1.一种重组静脉内免疫球蛋白(rIVIG)多肽,其包含(a)含有两个CH2-CH3 Fc结构域的单链Fc肽;以及(b)寡聚化肽结构域。
2.如权利要求1所述的rIVIG多肽,其中所述寡聚化肽结构域是三聚化结构域。
3.如权利要求2所述的rIVIG多肽,其中所述两个CH2-CH3 Fc结构域通过柔性接头连接。
4.如权利要求3所述的rIVIG多肽,其中所述柔性接头包含氨基酸序列G-G-G-G-S(序列ID号8)的二至六个重复。
5.如权利要求3所述的rIVIG多肽,其中所述柔性接头包含氨基酸序列G-G-G-G-S(序列ID号8)的五个重复。
6.如权利要求5所述的rIVIG多肽,其中所述三聚化结构域的C-末端与所述单链Fc肽的N-末端连接。
7.如权利要求6所述的rIVIG多肽,其中所述寡聚化肽结构域包含序列ID号6的1至79号氨基酸。
8.如权利要求5所述的rIVIG多肽,其中所述三聚化结构域的N-末端与所述单链Fc肽的C-末端连接。
9.如权利要求8所述的rIVIG多肽,其中所述寡聚化肽结构域包含序列ID号4的712至768号氨基酸。
10.一种编码如权利要求3-9所述的rIVIG多肽的核苷酸分子。
11.一种包含如权利要求10所述的核苷酸序列的重组载体。
12.一种包含如权利要求11所述的重组载体的重组细胞。
13.如权利要求12所述的重组细胞,其中所述细胞系缺乏α-1,6岩藻糖基转移酶基因(FUT8-/-)。
14.一种用于治疗免疫障碍的组合物,其包含重组免疫球蛋白(rIVIG)蛋白,其中所述rIVIG蛋白包含寡聚化肽结构域,所述寡聚化肽结构域提供主要包含三聚单链Fc肽的组合物。
15.如权利要求14所述的组合物,其中所述寡聚化肽结构域包含序列ID:6的1至79号氨基酸。
16.如权利要求14所述的组合物,其中所述寡聚化肽结构域包含序列ID号4的712至768号氨基酸。
17.如权利要求14所述的组合物,其中所述组合物主要包含同三聚Fc二聚体。
18.如权利要求14所述的组合物,其中所述rIVIG蛋白具有序列ID号6的氨基酸组成。
19.如权利要求14所述的组合物,其中所述rIVIG蛋白具有序列ID号4的氨基酸组成。
20.如权利要求14至19所述的组合物,其中所述rIVIG蛋白包含选自下组的同种型的Fc区,所述组由IgG1、IgG2、IgG3和IgG4组成。
21.如权利要求14至20所述的组合物,其中所述rIVIG蛋白主要是非岩藻糖基化的。
22.一种治疗患有自身免疫障碍的患者的方法,所述方法包括向所述患者给予有效量的包含重组静脉内免疫球蛋白(rIVIG)蛋白的组合物,其中所述rIVIG蛋白包含寡聚化肽结构域,所述寡聚化肽结构域提供主要包含三聚单链Fc分子的组合物。
23.一种降低已接受器官移植的患者的免疫排斥反应的方法,所述方法包括向所述患者给予有效量的包含重组免疫球蛋白(rIVIG)蛋白的组合物,其中所述rIVIG蛋白包含寡聚化肽结构域,所述寡聚化肽结构域提供主要包含三聚单链Fc分子的组合物。
24.如权利要求22所述的方法,其中所述患者患有难治性免疫性血小板减少症。
25.如权利要求22至24中任一项所述的方法,其中所述rIVIG蛋白包含选自下组的氨基酸序列,所述组由序列ID号4和序列ID号6组成。
26.如权利要求6所述的rIVIG多肽,其中所述寡聚化肽结构域包含序列ID号7的1至72号氨基酸或序列ID:8的721至779号氨基酸。
27.一种编码如权利要求26所述的rIVIG多肽的核苷酸分子。
28.一种包含如权利要求27所述的核苷酸序列的重组载体。
29.一种包含如权利要求28所述的重组载体的重组细胞。
30.如权利要求29所述的重组细胞,其中所述细胞系缺乏α-1,6岩藻糖基转移酶基因(FUT8-/-)。
31.如权利要求13所述的组合物,其中所述寡聚化肽结构域包含序列ID:7的1至72号氨基酸或序列ID:8的721至779号氨基酸。
32.如权利要求31所述的组合物,其中所述rIVIG蛋白包含选自下组的同种型的Fc区,所述组由IgG A、IgG B、IgG C和IgG D组成。
33.如权利要求31或32所述的组合物,其中所述rIVIG蛋白主要是非岩藻糖基化的。
34.一种治疗患有自身免疫障碍的非人哺乳动物的方法,所述方法包括向所述非人哺乳动物给予有效量的包含重组静脉内免疫球蛋白(rIVIG)蛋白的组合物,其中所述rIVIG蛋白包含寡聚化肽结构域,所述寡聚化肽结构域提供主要包含三聚单链Fc分子的组合物,并且其中所述rIVIG蛋白包含源自相同物种的非人哺乳动物的氨基酸序列。
35.如权利要求34所述的方法,其中所述非人哺乳动物是犬,并且所述rIVIG蛋白包含选自下组的氨基酸序列,所述组由序列ID号7和序列ID号8组成。
36.如权利要求34所述的组合物,其中所述非人哺乳动物是犬,并且所述寡聚化肽结构域包含序列ID:7的1至72号氨基酸或序列ID:8的721至779号氨基酸。
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