CN116583598A - 纯化腺病毒的方法 - Google Patents
纯化腺病毒的方法 Download PDFInfo
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- CN116583598A CN116583598A CN202180082506.XA CN202180082506A CN116583598A CN 116583598 A CN116583598 A CN 116583598A CN 202180082506 A CN202180082506 A CN 202180082506A CN 116583598 A CN116583598 A CN 116583598A
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Abstract
披露了可以大规模进行的纯化腺病毒的方法。这些方法通过以下步骤从包含或源自宿主细胞群的含腺病毒的样品中纯化腺病毒:澄清样品,其中澄清包括深层过滤然后微滤;通过阴离子交换层析处理澄清的样品;和通过切向流过滤(TFF)处理阴离子交换产物以提供TFF产物。
Description
技术领域
本发明涉及纯化腺病毒的方法。更具体地,本发明涉及纯化腺病毒的方法,其可以大规模地进行。
背景技术
腺病毒是双链DNA病毒,其具有大约为26-46kb的基因组。腺病毒具有物种特异性并且已从多种哺乳动物物种中分离出不同的血清型。人腺病毒无处不在,大多数人都已感染了一种或多种血清型,导致终身免疫。
修饰的腺病毒可用作载体来递送编码外源抗原的DNA。复制缺陷型腺病毒载体已广泛用于疫苗,因为它们会诱导对由载体编码的异源基因的强烈的体液和T细胞应答。
腺病毒载体的生产工艺包括用腺病毒感染宿主细胞并培养该宿主细胞以提高病毒滴度。然后在下游纯化处理之前裂解细胞以除去杂质(包括细胞和细胞碎片)。
目前用于纯化腺病毒的方法不经济且缺乏可扩大性(scalability)。因此,需要开发用于纯化宿主细胞培养系统内产生的腺病毒的大规模工艺。
发明内容
本发明至少部分地涉及开发改进的腺病毒纯化方法,这些方法可有效地从宿主细胞培养物中纯化腺病毒并且与替代的纯化方法相比具有减少的处理时间。与替代的纯化方法相比,本发明的这些纯化方法还可以降低对某些可能供应不足的原材料的依赖性。因此,本发明的方法在需要大量腺病毒载体的情况(例如用于为流行病和大流行病提供基于腺病毒的疫苗)下具有特别的用途。
因此,在一方面,提供了一种从含腺病毒的样品中纯化腺病毒的方法,该样品包含或源自具有至少约4x106个细胞/mL的细胞密度的宿主细胞群,该方法包括:
(a)澄清该样品以提供澄清的样品,其中澄清包括深层过滤然后微滤;
(b)通过阴离子交换层析处理澄清的样品以提供阴离子交换产物;以及
通过切向流过滤(TFF)处理该阴离子交换产物以提供TFF产物,其中TFF包括超滤和渗滤。
在另一方面,提供了纯化腺病毒的方法,如图2所述。
在又另一方面中,提供了纯化腺病毒的方法,如实例2所述。
在又另一方面中,提供了一种纯化的腺病毒,其是通过本发明的方法可获得的或通过本发明的方法获得的。
在又另一方面中,提供了原料药,其是通过本发明的方法可获得的或通过本发明的方法获得的。
在所附权利要求中陈述了本发明的多个方面和实施例。本文还描述了本发明的这些和其他的方面和实施例。
附图说明
图1示出了示例性腺病毒纯化工艺,其包括生物反应器产物的细胞裂解和核酸酶消化、澄清、第一切向流过滤、阴离子交换层析、第二切向流过滤和无菌过滤的步骤。
图2示出了根据本发明所述的示例性腺病毒纯化工艺,其包括起始材料的细胞裂解和核酸酶消化、澄清、阴离子交换层析、切向流过滤、配制和无菌过滤的步骤。
图3示出了根据本发明所述的示例性腺病毒纯化工艺的变化形式,其包括混合模式尺寸排阻层析的另外步骤。
序列表说明
具体实施方式
含腺病毒的样品
本发明的方法能够从含腺病毒的样品中大规模纯化腺病毒。例如,本发明的方法能够处理多达约5000升,例如从约3升至约3000升,优选地约200升直至约2000升的范围的体积。
含腺病毒的样品可以含有至少一种宿主细胞蛋白(HCP)。如本文所用,术语“HCP”是指由宿主细胞群产生或编码的蛋白质。
含腺病毒的样品可以具有至少约20,000ng/mL、至少约30,000ng/mL、至少约40,000ng/mL、至少约50,000ng/mL、至少约60,000ng/mL、至少约70,000ng/mL、至少约80,000ng/mL、至少约90,000ng/mL或至少约100,000ng/mL的HCP浓度。在优选的实施例中,该含腺病毒的样品具有至少约50,000ng/mL的HCP浓度。
含腺病毒的样品可以具有多达约100,000ng/mL、多达约90,000ng/mL、多达约80,000ng/mL、多达约70,000ng/mL、多达约60,000ng/mL、多达约50,000ng/mL、多达约40,000ng/mL、多达约30,000ng/mL、或多达约20,000ng/mL的HCP浓度。
含腺病毒的样品可以具有约20,000ng/mL和约100,000ng/mL之间、约30,000ng/mL和约90,000ng/mL之间或约50,000ng/mL和约80,000ng/mL之间的HCP浓度。
可适于宿主细胞(例如,哺乳动物宿主细胞)的大规模细胞培养的本领域已知的任何上游病毒生产工艺可用于产生用于本发明的方法的起始材料。
在优选的实施例中,含腺病毒的样品包含宿主细胞群或由宿主细胞群组成。宿主细胞群可以在细胞培养容器中培养。如本文所用,“细胞培养容器”是指适合用于培养细胞的容器。优选地,细胞培养容器是生物反应器。如本文所用,“生物反应器”意指适于大规模工艺的细胞培养容器。例如,在一些实施例中,生物反应器具有至少约1L、优选至少约1.2L、约3L、约50L、约1000L、约2000L、约3000L、或约5000L、最优选至少约2000L的容量。在一些实施例中,生物反应器具有至少约7x109个活T-RExTM细胞、优选至少约2.1x1010个活T-RExTM细胞、至少约3.5x1011个活T-RExTM细胞、至少约5x1012个活T-RExTM细胞或至少约3x1013个活T-RExTM细胞、最优选至少约5x1012个活T-RExTM细胞的容量。
在收获时,宿主细胞群可以具有至少约5x106个细胞/mL、至少约6x106个细胞/mL、至少约7x106个细胞/mL、至少约8x106个细胞/mL、至少约9x106个细胞/mL或至少约1x107个细胞/mL的细胞密度(例如活细胞密度)。在优选的实施例中,在收获时,宿主细胞群具有至少约4x106个细胞/mL的细胞密度(例如活细胞密度)。
在收获时,宿主细胞群可以具有高达约1x109个细胞/mL、高达约1x108个细胞/mL、高达约8x107个细胞/mL、高达约6x107个细胞/mL、高达约4x107个细胞/mL、高达约2x107个细胞/mL、高达约1x107个细胞/mL、高达约8x106个细胞/mL或高达约6x106个细胞/mL的细胞密度(例如活细胞密度)。在一些实施例中,在收获时,宿主细胞群具有高达约8x106个细胞/mL的细胞密度(例如活细胞密度)。在优选的实施例中,在收获时,宿主细胞群具有多达约1x107个细胞/mL的细胞密度(例如活细胞密度)。
在收获时,宿主细胞群可以具有约4x106个细胞/mL和约1x109个细胞/mL之间、约4x106个细胞/mL和约1x108个细胞/mL之间或约4x106个细胞/mL和约1x107个细胞/mL之间的细胞密度(例如活细胞密度)。
在优选的实施例中,本发明的方法能够处理如下的宿主细胞培养物(其具有如本文所披露的体积,即,大于200升(例如约2000升))并具有如本文所披露的收获时(例如至少约4x106个细胞/mL的)的细胞密度(例如活细胞密度)。
在优选的实施例中,本发明的方法能够处理具有如上所述的收获时细胞密度(例如活细胞密度)和如上所述的HCP浓度的宿主细胞群。例如,宿主细胞群可以具有至少约4x106个细胞/mL的细胞密度和至少约50,000ng/mL的HCP浓度。
细胞裂解和核酸酶处理
在培养含腺病毒的宿主细胞群之后,将宿主细胞裂解以释放细胞内腺病毒。裂解步骤还可以提供灭活潜在外源因子(特别是包膜病毒,例如疱疹病毒或逆转录病毒)的潜力,这些外源因子可以假设地以低水平污染细胞培养物。
因此,在一些实施例中,本发明的方法包括细胞裂解步骤。可用于细胞裂解的方法是本领域已知的并且包括非机械裂解方法(例如洗涤剂裂解、酶处理、高渗裂解和/或低渗裂解)和机械方法(例如冻融、固体剪切、液体剪切、超声处理和高压挤出)二者。
在优选的实施例中,使用细胞裂解剂(例如洗涤剂)裂解宿主细胞。使用洗涤剂进行细胞裂解具有以下优点:即,易于实施,并且易于扩大。可用于细胞裂解的洗涤剂是本领域已知的。在本发明的方法中用于细胞裂解的洗涤剂可以包括但不限于阴离子洗涤剂、阳离子洗涤剂、两性离子洗涤剂和非离子洗涤剂。在优选的实施例中,洗涤剂是非离子洗涤剂。合适的非离子洗涤剂的实例包括聚山梨醇酯(例如聚山梨醇酯-20或聚山梨醇酯-80)和Triton(例如Triton-X)。在一个实施例中,非离子洗涤剂是聚山梨醇酯-20。用于裂解宿主细胞群的非离子洗涤剂的最佳浓度可以例如在约0.005-0.025kg洗涤剂/kg容器、约0.01-0.02kg洗涤剂/kg细胞培养容器、或约0.011-0.016kg洗涤剂/kg细胞培养容器的范围内变化。如本文所用,“kg细胞培养容器”意指细胞培养容器中宿主细胞群和细胞培养基的总质量。在优选的实施例中,用于裂解宿主细胞群的非离子洗涤剂(例如,聚山梨醇酯-20)的浓度是约0.013kg洗涤剂/kg细胞培养容器。宿主细胞可以与非离子洗涤剂(例如聚山梨醇酯-20)一起孵育足够的时间以使宿主细胞群中的所有或基本上所有细胞被裂解。在实施例中,在核酸酶处理步骤之前,宿主细胞与非离子洗涤剂(例如聚山梨醇酯-20)一起孵育至少约15分钟。在实施例中,在核酸酶处理步骤之前,宿主细胞与非离子洗涤剂(例如聚山梨醇酯-20)一起孵育最多30分钟。在实施例中,在核酸酶处理步骤之前,宿主细胞与非离子洗涤剂(例如聚山梨醇酯-20)一起孵育不超过30分钟。
在实施例中,洗涤剂(例如聚山梨醇酯-20)形成裂解缓冲液的一部分。因此,在一些实施例中,使用包含至少一种洗涤剂(例如聚山梨醇酯-20)的裂解缓冲液裂解宿主细胞。可以在本发明的方法中使用的示例性裂解缓冲液包括约500mM tris、约20mM MgCl2、约50%(w/v)蔗糖和约10%(v/v)聚山梨醇酯20,并且具有约8的pH。用于裂解细胞群的裂解缓冲液的最佳浓度可以例如在约0.05-0.25kg裂解缓冲液/kg细胞培养容器、约0.10-0.20kg裂解缓冲液/kg细胞培养容器、或约0.11-0.16kg裂解缓冲液/kg细胞培养容器的范围内变化。在优选的实施例中,裂解缓冲液的浓度是约0.13kg裂解缓冲液/kg细胞培养容器。
被宿主细胞中的腺病毒感染的宿主细胞的自溶也可以提供细胞内腺病毒的大量释放并且可以用于本发明的方法中。
虽然细胞裂解步骤显著地提高了宿主细胞群中腺病毒的产率,但它也会导致污染物(如细胞内蛋白质和细胞基因组核酸)的释放。核酸的存在对于腺病毒来说可能是一个特别关注点,因为已知DNA介导病毒颗粒聚集。
本发明的方法因此可以在细胞裂解后包括核酸酶处理步骤。可替代地,可以通过在裂解前向细胞中添加核酸酶,使核酸酶步骤和裂解同时进行。适用于在本发明的方法中使用的核酸酶包括DNA酶和RNA酶,其包括非特异性DNA和RNA核酸内切酶,例如(默克公司(Merck))。在优选的实施例中,向裂解的细胞中添加/>添加核酸酶(例如/>)可减小核酸链长度,这有助于在以后的步骤中除去核酸链,降低粘度并有助于减少核酸介导的聚集。可以以达到可接受水平的腺病毒释放和细胞基因组核酸的充分减少或处理的量添加核酸酶。例如,可以向裂解的细胞中添加以达到约5,000个单位/kg裂解物至25,000个单位/kg裂解物、约10,000个单位/kg裂解物至20,000个单位/kg裂解物、或约15,000个单位/kg裂解物的最终浓度。在优选的实施例中,/>的最终浓度是约15,000个单位/kg裂解物。
细胞裂解和核酸酶处理可以进行足够长的时间以达到可接受水平的腺病毒的释放和细胞基因组核酸的充分减少或处理。细胞裂解和核酸酶处理可以进行至少1小时、至少2小时、至少3小时、至少4小时或至少5小时。在优选的实施例中,细胞裂解和核酸酶处理进行至少2小时。
细胞裂解和核酸酶处理的最佳温度可以由本领域技术人员来确定。在优选的实施例中,在从约27℃至约40℃、优选从约31℃至约35℃、最优选约33℃的温度下,进行细胞裂解和核酸酶处理。
细胞裂解和核酸酶处理后所得的产物是核酸酶处理的细胞裂解物。
澄清
本发明的方法包括澄清步骤。该澄清步骤试图从含腺病毒的样品(例如核酸酶处理的细胞裂解物)中除去杂质(包括细胞碎片)。
核酸酶处理的细胞裂解物可以源自在收获时具有至少约4x106个细胞/mL、至少约5x106个细胞/mL、至少约6x106个细胞/mL、至少约7x106个细胞/mL、至少约8x106个细胞/mL、至少约9x106个细胞/mL或至少约1x107个细胞/mL的细胞密度(例如活细胞密度)的宿主细胞群。在优选的实施例中,核酸酶处理的细胞裂解物源自在收获时具有至少约4x106个细胞/mL的细胞密度(例如活细胞密度)的宿主细胞群。
核酸酶处理的细胞裂解物可以源自在收获时具有多达约1x109个细胞/mL、多达约1x108个细胞/mL、多达约8x107个细胞/mL、多达约6x107个细胞/mL、多达约4x107个细胞/mL、多达约2x107个细胞/mL、多达约1x107个细胞/mL、多达约8x106个细胞/mL或多达约6x106个细胞/mL的细胞密度(例如活细胞密度)的宿主细胞群。在优选的实施例中,核酸酶处理的细胞裂解物源自在收获时具有多达约8x106个细胞/mL的细胞密度(例如活细胞密度)的细胞培养物。
核酸酶处理的细胞裂解物可以源自在收获时具有约4x106个细胞/mL和约1x109个细胞/mL之间、约4x106个细胞/mL和约1x108个细胞/mL之间或约4x106个细胞/mL和约1x107个细胞/mL之间的细胞密度(例如活细胞密度)的宿主细胞群。
核酸酶处理的细胞裂解物可以具有至少约20,000ng/mL、至少约30,000ng/mL、至少约40,000ng/mL、至少约50,000ng/mL、至少约60,000ng/mL、至少约70,000ng/mL、至少约80,000ng/mL、至少约90,000ng/mL或至少约100,000ng/mL的HCP浓度。在优选的实施例中,核酸酶处理的细胞裂解物具有至少约50,000ng/mL的HCP浓度。
核酸酶处理的细胞裂解物可以具有多达约100,000ng/mL、多达约90,000ng/mL、多达约80,000ng/mL、多达约70,000ng/mL、多达约60,000ng/mL、多达约50,000ng/mL、多达约40,000ng/mL、多达约30,000ng/mL、或多达约20,000ng/mL的HCP浓度。
核酸酶处理的细胞裂解物可以具有约20,000ng/mL和约100,000ng/mL之间、约30,000ng/mL和约90,000ng/mL之间或约50,000ng/mL和约80,000ng/mL之间的HCP浓度。
在优选的实施例中,澄清步骤的输入材料是核酸酶处理的细胞裂解物,其源自在收获时具有如上所述的细胞密度(例如活细胞密度)的宿主细胞群并且该细胞裂解物具有如上所述的HCP浓度。例如,核酸酶处理的细胞裂解物可以源自具有至少约4x106个细胞/mL的细胞密度的宿主细胞群并且可以具有至少约50,000ng/mL的HCP浓度。经核酸酶处理的细胞裂解物可能如以上细胞裂解和核酸酶处理章节所述获得。
澄清步骤包括使含腺病毒的样品(例如核酸酶处理的细胞裂解物)经历深层过滤以提供过滤的样品。深层过滤是指使用一个或多个深层过滤器从溶液中除去颗粒的方法。深层过滤器包含一个三维矩阵,其创造出了迷宫般的路径,样品从该路径通过。深层过滤器的主要保留机制依赖于贯穿整个矩阵深度的随机吸附和机械截留。
在各种实施例中,深层过滤器包含过滤膜或伤口用棉、聚丙烯、人造丝纤维素、二氧化硅、纤维玻璃、烧结金属、瓷、硅藻土或其他已知的组分的片层。在优选的实施例中,深层过滤器包含聚丙烯(例如玻璃纤维增强的聚丙烯)和纤维素、以及任选地硅藻土。
适用于本发明的方法的澄清步骤的深层过滤器包括具有约9μm、约8μm、约7μm、约6μm、约5μm、约4μm约3μm、约2μm、约1μm、和/或约0.1μm的标准过滤规格的深层过滤器。在一些实施例中,深层过滤器具有约0.2μm和约2μm之间的标准过滤规格。在一些实施例中,深层过滤器具有最多约0.1μm的标准过滤规格。
用于本发明的方法的澄清步骤的合适的深层过滤器包括HC Pro Pod深层过滤器、C0SP介质,/>Pod深层过滤器、X0HC介质和/>HC Pro Pod深层过滤器、X0SP介质(所有均来自密理博公司(Millipore),通过西格玛奥德里奇奥公司(Sigma-Aldrich)可获得)。
澄清步骤可以包括使用多种不同类型的深层过滤器(例如具有不同的标准过滤规格)。在一些实施例中,使用两种或更多种不同类型的深层过滤器。在一些实施例中,使用三种或更多种不同类型的深层过滤器。深层过滤器可以串联或并联布置,优选串联布置。
本发明的诸位发明人已经观察到使用串联的两个不同类型的深层过滤器(例如具有约0.2μm至约2μm的标准过滤规格的深层过滤器,例如HC Pro Pod深层过滤器、C0SP介质,然后使用具有最多约0.1μm的标准过滤规格的深层过滤器,例如/>Pod深层过滤器、X0HC介质或/>HC Pro Pod深层过滤器、X0SP介质)可以有助于捕获杂质并且从而更好地保护该膜在后续的微滤步骤中不被污染。使用串联的两个不同的深层过滤器,如与在仅使用单一类型的深层过滤器(例如/>HC Pro Pod C0SP过滤器)时相比,还可以有助于降低所需的第一深层过滤器(例如/>HC Pro Pod C0SP过滤器)的量。
在优选的实施例中,澄清步骤包括使用串联布置的两个不同类型的深层过滤器(例如具有不同标准过滤规格的深层过滤器)。两个不同类型的深层过滤器可以是以下深层过滤器的任何组合:HC Pro Pod深层过滤器、C0SP介质;/>Pod深层过滤器、X0HC介质;和/>HC Pro Pod深层过滤器、X0SP介质。两个不同类型的深层过滤器可以按照它们的标滤准过规格进行布置,例如具有约0.2μm至约2μm的标准过滤规格的深层过滤器,然后是具有多达约0.1μm的标准过滤规格的深层过滤器。在一些实施例中,两个不同类型的深层过滤器是/>HC Pro Pod深层过滤器、C0SP介质和HC Pro Pod深层过滤器、X0SP介质。在一些实施例中,两个不同类型的深层过滤器是/>HC Pro Pod C0SP过滤器和/>Pod X0HC过滤器。在特别优选的实施例中,澄清步骤包括使用串联连接的/>HC Pro Pod C0SP过滤器和Pod X0HC过滤器。在澄清步骤包括使用串联布置的两个不同类型的深层过滤器的实施例中,深层过滤器可以以3第一深层过滤器:1第二深层过滤器,例如3/>HC Pro Pod C0SP过滤器:1/>Pod X0HC过滤器的比率进行加载。
可替代地,澄清步骤可以包括使用单一类型的深层过滤器。在使用单一类型的深层过滤器的实施例中,深层过滤器可以具有约0.2μm至约2μm的标准过滤规格,例如HC Pro Pod深层过滤器、C0SP介质。
本发明的诸位发明人已示出三种过滤器串系列:HC Pro Pod C0SP过滤器然后微滤;/>HC Pro Pod C0SP过滤器然后/>HC Pro Pod深层过滤器、X0SP介质然后微滤;和/>HC Pro Pod C0SP过滤器然后/>PodX0HC过滤器然后微滤在从随后的阴离子交换步骤获得的产物的产率和品质方面具有相当的性能。
在加载含腺病毒的样品(例如核酸酶处理的细胞裂解物)之前,深层过滤器可以用平衡缓冲液进行平衡。可以在本发明的方法中使用的示例性平衡缓冲液包括约50mM tris、约2mM MgCl2、约5%(w/v)蔗糖和约1%(v/v)聚山梨醇酯20,并且具有约为8的pH。
在平衡步骤期间的最佳体积通过量可以是至少约15L/m2、优选至少约20L/m2、至少约25L/m2或至少约30L/m2、最优选至少约25L/m2。
深层过滤后,过滤的样品经受微滤。在微滤期间,过滤的样品通过微滤膜。所选的特定微滤膜将具有足够大以使腺病毒通过但又足够小以清除杂质(例如部分裂解的细胞、细胞碎片和/或聚集体)的孔径。在一些实施例中,微滤膜具有小于约1μm、小于约0.75μm、小于约0.5μm、或约小于约0.25μm的膜孔径。在优选的实施例中,微滤膜具有约0.2μm的孔径。
适用于微滤的膜可以包括再生纤维素、聚醚砜、聚砜或其衍生物,优选聚醚砜。在优选的实施例中,微滤膜包含聚醚砜并且具有约0.2μm的孔径。适合于在本发明的方法中使用的微滤膜是密理博公司SHC 0.5/0.2μm过滤器。
加载过滤的样品后,可以向微滤膜添加追踪缓冲液(chase buffer)。可以在本发明的方法中使用的示例性追踪缓冲液包括约50mM tris、约2mM MgCl2、约5%(w/v)蔗糖和约1%(v/v)聚山梨醇酯-20,并且具有pH 8。
在追踪步骤(chase step)期间,最佳体积通过量可以是从约15L/m2至约40L/m2,优选地从约20L/m2至约40L/m2、至少约25L/m2至约40L/m2或至少约30L/m2至约40L/m2,最优选地至少约25L/m2至约40L/m2。
澄清步骤的最佳温度可以由本领域技术人员来确定。在优选的实施例中,在从约15℃至约35℃、更优选从约15℃至约27℃的温度下进行澄清步骤。
澄清后,可以测试样品的各种参数。例如,在一些实施例中,澄清的样品具有从约7至约9、优选从约7.5至约8.5的pH。在一些实施例中,澄清的样品在25℃下具有小于约35mS/cm、小于约30mS/cm、优选小于约25mS/cm的电导率。因此,在一些实施例中,澄清的样品具有从约7.5至约8.5的pH和在25℃下小于约25mS/cm的电导率。
阴离子交换层析
澄清后,本发明的方法包括阴离子交换层析步骤以从澄清的样品(例如澄清的裂解物)中除去工艺相关的杂质。在阴离子交换层析步骤期间,腺病毒颗粒与带正电的材料(例如膜、筒或柱)结合,并且随后的洗脱允许将腺病毒颗粒与杂质分离。
本领域已知的纯化方法可以在澄清之后和阴离子交换层析之前包括浓缩步骤(例如切向流过滤,TFF)以减小总体积并除去与病毒相互作用的小分子例如小蛋白质(JortVellinga,J.Patrick Smith,Agnieszka Lipiec,Dragomira Majhen,AngeliqueLemckert,Mark van Ooij,Paul Ives,Christopher Yallop,Jerome Custers和MenzoHavenga.Human Gene Therapy.[人类基因治疗]2014年4月.318-327)。
本发明的方法的特征在于:澄清的样品(例如澄清的裂解物)通过阴离子交换层析进行处理,没有任何中间的浓缩步骤,例如TFF。省去中间的浓缩步骤(例如TFF)可显著简化工艺并减少原材料消耗并消除大量的废物流。省去澄清和阴离子交换层析之间的中间浓缩步骤(例如TFF)可以极大地减少处理时间;在本发明的方法中,除去该步骤可将处理时间缩短一天。因此,本发明的方法具有改进的可扩大性和通过量,但仍提供可接受的产物品质(如实例3所示)。
阴离子交换取代基可以附着至矩阵以形成用于层析的阴离子载体。可用于本发明的方法的阴离子交换取代基的非限制性实例包括二乙氨基乙基(DEAE)、季氨乙基(QAE)和季铵(Q)基团。优选地,阴离子交换材料包含DEAE或Q阴离子交换取代基。
在优选的实施例中,阴离子交换材料包含阴离子交换膜。阴离子交换膜是带有阴离子交换取代基的合成薄膜,该阴离子交换取代基能够与至少一种所接触的在穿过该膜的流体相内的物质相互作用。膜通常在相对较小的筒中堆叠5到15层深,以产生比具有类似输出量的柱小得多的占用空间。
优选地,阴离子交换材料是阴离子交换膜。阴离子交换膜可以是微孔的或大孔的。在一些实施例中,阴离子交换膜是大孔的,任选地具有至少约1μm、至少约2μm、或至少约3μm、或至少约4μm的标准孔径。在优选的实施例中,阴离子交换膜具有至少约3μm的标准孔径。
在优选的实施例中,阴离子交换膜包含季铵(Q)基团,其优选地具有至少约3μm的标准孔径。阴离子交换膜层析产物(例如由颇尔公司(Pall)(例如系列)和赛多利斯公司(Sartorius)(例如/>系列)生产的那些)可适合用于在本发明的方法中使用。在一些实施例中,本发明的方法的阴离子交换步骤包括使用/>Q(赛多利斯公司)或/>Q(颇尔公司)阴离子交换膜。特别地,本发明的诸位发明人认识到Q膜(例如/>Q,例如/>Q 4mm或8mm)可以提供优于替代性的阴离子交换膜(例如/>Q)的改进的可扩大性。
可适用于在本发明的方法中使用的其他的阴离子膜吸收剂和树脂包括但不限于Source 15Q和Source 30Q(思拓凡(Cytiva))、Q-Sepharose XL(思拓凡(Cytiva))、TMAE(密理博公司)、Adsept/>(Natrix Separations公司)、和/>QA(BIAseparations公司)、Natrix Q(EMD密理博公司(EMD Millipore))、POROS XQ(赛默飞世尔公司(ThermoFisher))、Nuvia Q(伯乐公司(BioRad))、MacroPrep HighQ(伯乐公司(BioRad))、GigaCapQ 650M(东曹(Tosoh))和Capto Q(思拓凡(Cytiva))。
将澄清的样品(例如澄清的裂解物)加载到阴离子交换层析材料(例如阴离子交换膜)上。出人意料地,诸位发明人发现相比于现有技术腺病毒纯化方法,可以减小容量负载。因此,在阴离子交换层析材料是膜(例如Q膜)的实施例中,澄清的样品(例如澄清的裂解物)可以以多达约70L澄清的样品/L阴离子交换膜、多达约65L澄清的样品/L阴离子交换膜、多达约60L澄清的样品/L阴离子交换膜、多达约55L澄清的样品/L阴离子交换膜、多达约50L澄清的样品/L阴离子交换膜、多达约45L澄清的样品/L阴离子交换膜或多达约40L澄清的样品/L阴离子交换膜的负载来加载。在优选的实施例中,澄清的样品(例如澄清的裂解物)以约50L澄清的样品/L阴离子交换膜的负载加载。
在阴离子交换层析材料是膜(例如Q膜)的一些实施例中,澄清的样品(例如澄清的裂解物)可以以约10L和约75L之间的澄清的样品/L阴离子交换膜、约20L和约70L澄清的样品/L阴离子交换膜之间、或约50和约60澄清的样品/L阴离子交换膜之间的负载加载。
在一些实施例中,澄清的样品(例如澄清的裂解物)设定为具有约10个膜体积/min或更少、优选约7个膜体积/min或更少、最优选约5.5个膜体积/min或更少的流速。在优选的实施例中,澄清的样品(例如澄清的裂解物)设定为具有约5个膜体积/min的流速。
在加载之前,例如可以用NaCl(例如5M NaCl)调节澄清的样品(例如澄清的裂解物)以提高负载中的电导率。提高负载中的电导率可以减少与工艺相关的杂质(例如HCP)与阴离子交换材料的结合并改进结合能力。在一些实施例中,调节的澄清的样品(例如,调节的澄清的裂解物)在25℃具有从约15至约30mS/cm,例如从约15至约26mS/cm,优选从约15至约25mS/cm的电导率。在一些实施例中,将澄清的样品(例如澄清的裂解物)用从约0.020至约0.040kg 5M NaCl/kg澄清的样品、优选从约0.027至约0.033kg 5M NaCl/kg澄清的样品、最优选约0.030kg 5M NaCl/kg澄清的样品来调节。
任选地,阴离子交换步骤可以包括负载过滤步骤,在该步骤中澄清的样品(例如澄清的裂解物)在加载到阴离子交换层析膜上之前经历微滤。这种微滤可有助于减轻对阴离子交换膜的高压。所选的特定微滤膜将具有足够大以使腺病毒通过但又足够小以有效清除杂质的孔径。在一些实施例中,微滤膜具有小于约1μm、小于约0.75μm、小于约0.5μm、或约小于约0.25μm的孔径。在优选的实施例中,微滤膜孔径是约0.2μm。适用于微滤的膜可以包括再生纤维素、聚醚砜、聚砜或其衍生物,优选聚醚砜。在优选的实施例中,微滤膜包含聚醚砜并且具有约0.2μm的孔径。适合于在本发明的方法中使用的微滤膜是密理博公司SHC 0.5/0.2μm过滤器。
加载澄清的样品(例如澄清的裂解物)后,可以用一种或多种缓冲液洗涤阴离子交换材料。在一些实施例中,阴离子交换材料用缓冲液的组合(例如平衡缓冲液然后洗涤缓冲液)洗涤。
应当理解的是,平衡缓冲液和洗涤缓冲液的pH将足够高以使腺病毒结合(大于大约6.5)并且足够低以避免病毒不稳定性。可用的精确最大pH可能取决于腺病毒血清型和缓冲液组分的特定稳定性特征。例如,黑猩猩腺病毒的pH范围可能地可以是约6-10、优选约6.5-9、更优选约7.5-8.5,例如约8。
平衡缓冲液在25℃下的电导率范围可以是约1.5-3.5mS/cm、约2-3.2mS/cm、或约2.1-3.1mS/cm。在优选的实施例中,平衡缓冲液在25℃下的电导率范围是约2.1-3.1mS/cm。因此,在优选的实施例中,平衡缓冲液具有约8的pH和在25℃下约2.1-3.1mS/cm的电导率范围。在特别优选的实施例中,平衡缓冲液包含约50mM tris、约1mM MgCl2和约5%(w/v)蔗糖并且具有约8的pH。
洗涤缓冲液在25℃下的电导率范围可以是约15-30mS/cm、约18-27mS/cm、或约20-24mS/cm。在优选的实施例中,洗涤缓冲液在25℃下的电导率范围是约20-24mS/cm。从阴离子交换材料中除去未结合的材料可以通过使用NaCl或KCl,优选NaCl来辅助。因此,在优选的实施例中,洗涤缓冲液在pH 8下以多达约100mM、多达约150mM、多达约200mM、多达约250mM、或多达约300mM的浓度包含NaCl。最优选地,洗涤缓冲液在pH 8下以多达约222mM的浓度包含NaCl。因此,在优选的实施例中,洗涤缓冲液包含约222mM NaCl,具有约8的pH和在25℃下约20-24mS/cm的电导率范围。在特别优选的实施例中,洗涤缓冲液包含约50mMtris、约222mM NaCl、约1mM MgCl2和约5%(w/v)蔗糖并且具有约8的pH。
结合产物可以用洗脱缓冲液洗脱。洗脱缓冲液在25℃下的电导率范围可以是约25-50mS/cm、约30-45mS/cm、或约35-43mS/cm。在优选的实施例中,洗脱缓冲液在25℃下的电导率范围是约35-43mS/cm。洗脱缓冲液可以在pH 8下以多达约300mM、多达约350mM、多达约400mM、多达约450mM、或多达约500mM的浓度包含NaCl。最优选地,洗脱缓冲液在pH 8下以多达约444mM的浓度包含NaCl。因此,在优选的实施例中,洗脱缓冲液包含约444mM NaCl,具有约8的pH和在25℃下约35-43mS/cm的电导率范围。在特别优选的实施例中,洗脱缓冲液包含约50mM tris、约444mM NaCl、约1mM MgCl2和约5%(w/v)蔗糖并且具有约8的pH。
洗脱缓冲液可以设定为具有小于约10个膜体积/min、优选约7个膜体积/min或更少、最优选约5.5个膜体积/min或更少的流速。在优选的实施例中,洗脱缓冲液设定为具有约5个膜体积/min的流速。
洗脱后,洗脱产物可用稀释缓冲液稀释。在优选的实施例中,稀释缓冲液包含约35mM NaCl、约10mM组氨酸/组氨酸-HCl、约1mM MgCl2、约0.1mM EDTA、约7.5%(w/v)蔗糖和约0.5%(v/v)乙醇并且具有约6.6的pH。可以以1:1稀释比率向洗脱产物中添加稀释缓冲液。
应当理解,洗脱缓冲液的体积直接影响洗脱产物的体积,并且因此影响来自阴离子交换步骤的产物。在本发明的方法中,可以使用体积为从约4.5至约5.5个膜体积、优选约5个膜体积的洗脱缓冲液。在一些实施例中,使用从约3个膜体积至约7个膜体积、优选从约3.5个膜体积至约5.5个膜体积、优选约5个膜体积的稀释缓冲液体积。在优选的实施例中,使用5个膜体积的洗脱缓冲液体积和5个膜体积的稀释缓冲液体积。通过使用此类体积,这些方法可以提供减少的阴离子交换产物体积和更浓缩的工艺流。这能够减少后续TFF处理步骤所需的膜表面积,从而减少原材料消耗,省去大量的废物流并缩短处理时间。
来自阴离子交换层析步骤的所得材料是阴离子交换产物。
阴离子交换产物可以具有从7至约9,优选地从约7.5至约8.5的pH。在一些实施例中,阴离子交换产物在25℃下具有从约5mS/cm至约35mS/cm、从约10mS/cm至约30mS/cm、优选从约15mS/cm至约25mS/cm的电导率。因此,在一些实施例中,阴离子交换产物具有从约7.5至约8.5的pH和在25℃下从约15mS/cm至约25mS/cm的电导率。
阴离子交换产物可以任选地经受微滤用于微生物控制。所选的特定微滤膜将具有足够大以使腺病毒通过但又足够小以有效清除杂质的孔径。在一些实施例中,微滤膜具有小于约1μm、小于约0.75μm、小于约0.5μm、或约小于约0.25μm的孔径。在优选的实施例中,微滤膜孔径是约0.2μm。适用于微滤的膜可以包括再生纤维素、聚醚砜、聚砜或其衍生物,优选聚醚砜。在优选的实施例中,微滤膜包含聚醚砜并且具有约0.2μm的孔径。适合于在本发明的方法中使用的微滤膜是密理博公司SHC 0.5/0.2μm过滤器。
在优选的步骤中,本发明的方法在阴离子交换后包括通过混合模式尺寸排阻层析进行的进一步处理步骤,以提供混合模式尺寸排阻产物。混合模式尺寸排阻层析可以使用混合模式尺寸排阻树脂(包括但不限于Capto Core 700(思拓凡(Cytiva))、Capto Core400(思拓凡(Cytiva))和Monomix Core 60(赛分科技公司(Sepax Technologies)))进行。
切向流过滤
在阴离子交换或混合模式尺寸排阻层析之后,本发明的方法包括切向流过滤(TFF)步骤。TFF步骤包括超滤和渗滤以分别浓缩阴离子交换产物和引入缓冲液。因此,在本发明的方法中,TFF产物与TFF步骤的负载相比,体积减小并且具有更高的腺病毒浓度。
最佳进料流速可以由本领域技术人员来确定。在优选的实施例中,进料流速设定为从约1至约15升/m2/min(LMM),优选地从约2至约10LMM,最优选地从约3至约7LMM,例如5LMM。
TFF步骤的负载是阴离子交换产物或混合模式尺寸排阻产物。任选地,在TFF之前,阴离子交换产物通过深层过滤来处理。这种深层过滤步骤可以在HCP减少和提高膜寿命方面提供益处。合适的深层过滤器包括在以上澄清章节中所讨论的那些。在优选的实施例中,使用具有大于0μm和最多约0.1μm的标准过滤规格的深层过滤器,例如Pod深层过滤器、X0HC介质或/>HC Pro Pod深层过滤器、X0SP介质。在特别优选的实施例中,使用/>Pod X0HC深层过滤器。/>
根据制造商和膜类型,超滤膜的标准截留分子量(NMWCO)可以在100和1000kDa之间。膜组成可以是但不限于再生纤维素、聚醚砜、聚砜或其衍生物。这些膜可以是扁平的片层或中空纤维。促湍流网(turbulence-promoting screens)也可用于优化杂质清除率。在一些实施例中,使用具有促湍流网的300kDa或500kDa NMWCO聚醚砜平片状膜(例如2膜,300kDa MWCO,C网)。切向流过滤可以通过设置切向流和渗透通量二者以及将跨膜压力维持在等于和或低于固定压力限值来控制。
膜容量负载可以由本领域技术人员来确定。在优选的实施例中,膜容量负载是小于约100L/m2。
超滤可以浓缩阴离子交换产物或混合模式尺寸排阻产物。例如,在本发明的方法的一些实施例中,超滤将阴离子交换产物或混合模式尺寸排阻产物浓缩至从约0.03至约0.3L/L核酸酶处理的裂解物、优选约0.05L/L核酸酶处理的裂解物的体积。在一些实施例中,在浓缩步骤期间,渗透流设定为小于约1.00LMM、优选小于约0.90LMM、最优选小于约0.80LMM。在特别优选的实施例中,在浓缩步骤期间,渗透流设定为约0.67LMM。
然后将浓缩的阴离子交换产物或混合模式尺寸排阻产物用渗滤(diafiltration)缓冲液渗滤。渗滤可以使用至少9、至少10、至少11或至少12个渗滤体积(diavolume)的渗滤缓冲液进行操作。在优选的实施例中,渗滤使用至少10个渗滤体积的渗滤缓冲液进行操作。可以使用小于0.80LMM(例如0.67LMM)的渗透流。渗滤缓冲液的pH范围可以是约6-8、优选约6-7、更优选约6.5-6.7。渗滤缓冲液在25℃下的电导率范围可以是约1-8mS/cm、优选约2-6mS/cm、更优选约3-4.6mS/cm。因此,在优选的实施例中,渗滤缓冲液具有约6.5-6.7的pH和在25℃下约3-4.6mS/cm的电导率范围。在一些实施例中,渗滤缓冲液不包含聚山梨醇酯-80。在优选的实施例中,渗滤缓冲液包含约35mM NaCl、约10mM组氨酸/组氨酸-HCl、约1mMMgCl2、约0.1mM EDTA、约7.5%(w/v)蔗糖和约0.5%(v/v)乙醇并且具有约6.6的pH。
从TFF系统中回收渗滤的产物。可以通过用一定体积的渗滤缓冲液(例如至少1、至少2、至少3、至少4、或至少5个系统滞留体积的渗滤缓冲液)冲洗来回收渗滤的产物。在优选的实施例中,通过用3个系统滞留体积的渗滤缓冲液冲洗来回收渗滤的产物。优选地,使用与渗滤步骤所用的相同的渗滤缓冲液。
从TFF步骤所得材料是TFF产物。TFF产物可以具有表1中所列出的一种或多种、优选所有的特性。
表1:TFF产物的特性
特性 | 规格 |
pH | 6.1-7.1 |
电导率(在25℃下,mS/cm) | ≤5.0 |
感染性(ifu/mL) | ≥2.4x108 |
宿主细胞DNA(ng/0.5x1011vp) | ≤10 |
宿主细胞蛋白(ng/0.5x1011vp) | ≤200 |
vp-腺病毒颗粒
配制品
可以配制TFF产物以提供配制的产物。在一些实施例中,配制步骤包括向TFF产物中添加聚山梨醇酯-80。在一些实施例中,添加聚山梨醇酯-80以达到配制的产物中约0.1%(w/v)聚山梨醇酯-80的浓度。在优选的实施例中,配制的产物具有以下组成:约35mM NaCl、约10mM组氨酸/组氨酸-HCl、约1mM MgCl2、约0.1mM EDTA、约7.5%(w/v)蔗糖、约0.1%(w/v)聚山梨醇酯-80和约0.5%(v/v)乙醇并且具有约6.6的pH。
无菌过滤
配制的产物可以经受无菌过滤。无菌过滤步骤可以使用具有足够小以保留微生物且足够小以允许腺病毒通过的孔径的过滤器进行。在优选的实施例中,过滤器具有约0.2μm的孔径。过滤器可由本领域所熟知的材料(例如聚醚砜、PVDF、聚丙烯、纤维素、纤维素酯、尼龙或任何其他符合低产物结合的材料)构造。在优选的实施例中,过滤器包含亲水聚醚砜。在特别优选的实施例中,过滤器包含具有0.2μm的孔径的亲水聚醚砜膜(例如颇尔公司EKV,0.2μm)。
从过滤器中收集的产物是原料药。可以在配制缓冲液中配制原料药。在优选的实施例中,配制缓冲液包含约35mM NaCl、约10mM组氨酸/组氨酸-HCl、约1mM MgCl2、约0.1mMEDTA、约7.5%(w/v)蔗糖、约0.1%(w/v)聚山梨醇酯-80和约0.5%(v/v)乙醇并且具有约6.6的pH。这可以通过在过滤前用配制缓冲液平衡过滤器和在过滤后用配制缓冲液进行追踪来实现。
原料药
本发明的方法可导致原料药的生产。
与替代的腺病毒纯化方法(例如实例1的方法)相比,本发明的方法可以提供具有提高浓度的腺病毒(例如高至少约10倍、至少约20倍、至少约30倍的腺病毒浓度)的原料药。具有更高浓度的原料药的一个优点是它不需要那么多的储存空间,当在-80℃下储存时这可能是特别有利的。在一些实施例中,原料药具有至少约0.8x1011vp/mL、至少约1x1011 vp/mL、至少约1.2x1011 vp/mL、至少约1.4x1011vp/mL、至少约1.6x1011 vp/mL、至少约1.8x1011vp/mL、至少约2x1011vp/mL、至少约2.2x1011 vp/mL、至少约2.4x1011 vp/mL、或至少约2.6x1011 vp/mL的腺病毒病毒颗粒(在本文中也称为“病毒颗粒”)浓度。
在一些实施例中,原料药具有以下特性中的一种或多种、优选所有:与核酸酶处理的裂解物中的HCP水平相比,HCP水平降低;约6.1-7.1之间的pH;大于约265mOsm/Kg的渗透压;大于或等于约2.4x109 ifu/mL的感染性;大于约0.8x1011 vp/mL的病毒颗粒浓度;约1.1-1.6的DNA:蛋白质比率;小于或等于约500:1vp/ifu的病毒颗粒:感染性滴度比率;小于约10ng/剂量的宿主细胞DNA;小于约200ng/剂量的HCP;小于约20ng/mL 小于约10EU/mL内毒素;小于约5CFU/10mL生物负载。如本文所用,一剂量的原料药包含约5x1010个病毒颗粒。
在一些实施例中,原料药具有表2中所列出的一种或多种、优选所有的特性。例如,在一些实施例中,该原料药具有大于或等于约2.4x109 ifu/mL的感染性和/或至少约0.8x1011 vp/mL的病毒颗粒浓度,例如至少约2x1011 vp/mL的病毒颗粒浓度。在优选的实施例中,原料药具有大于或等于约2.4x109 ifu/mL的感染性和至少约0.8x1011 vp/mL的病毒颗粒浓度,例如至少约2x1011 vp/mL的病毒颗粒浓度。
本发明的方法产生含有低水平HCP的原料药。在一些实施例中,原料药包含浓度为每剂量2000ng或更少,例如每剂量1000ng或更少、每剂量500ng或更少、每剂量200ng或更少、每剂量100ng或更少、或每剂量50ng或更少的HCP。在优选的实施例中,原料药包含浓度为每剂量1000ng或更少的HCP。在一些实施例中,原料药包含浓度为每剂量100ng或更少,例如每剂量50ng或更少、每剂量25ng或更少、每剂量10ng或更少或每剂量5ng或更少的宿主细胞DNA。在优选的实施例中,原料药包含浓度为每剂量10ng或更少的宿主细胞DNA。
表2:原料药的特性。
原料药可以储存在约-90℃和-55℃之间的温度下,任选地在冷冻前在2℃-8℃保存多达5天。
在一些实施例中,原料药经过无菌过滤并稀释约20倍以形成药物产品。有利地,药物产品可以在2℃-8℃下长期储存,例如储存至少约1周、至少约2周、至少约1个月或至少约1年。
腺病毒载体
在本发明的方法的优选的实施例中,腺病毒是腺病毒载体。如本文所用,“腺病毒载体”意指腺病毒的一种形式,其已被修饰以将编码异源基因的核苷酸序列插入真核细胞中。如本文所用,“异源基因”意指源自与被比较的其余部分实体相比基因型不同的实体的基因。因此,异源基因是指任何不是分离自、源自或基于天然存在的腺病毒基因的基因。如本文所用,“天然存在的”意指在自然界中发现并且不是合成制备的或修饰的。
在本发明的方法的优选的实施例中,腺病毒载体包含编码目的蛋白(例如治疗性蛋白质或免疫原性蛋白质)的异源基因。可替代地,异源基因可以包括报告基因,其在表达时产生可检测的信号。此类报告基因包括但不限于编码以下的DNA序列:β-内酰胺酶、β-半乳糖苷酶(LacZ)、碱性磷酸酶、胸苷激酶、绿色荧光蛋白(GFP)、氯霉素乙酰转移酶(CAT)、萤光素酶、膜结合蛋白(包括例如CD2、CD4、CD8)、流感血凝素蛋白、和本领域所熟知的其他针对其存在或可以通过常规方式产生高亲和力抗体的蛋白质、以及包含与来自血凝素或Myc及其他的抗原标签结构域适宜地融合的膜结合蛋白的融合蛋白。这些编码序列,当与驱动其表达的调节元件相关联时,提供可通过常规方法检测到的信号,这些常规方法包括酶促、放射照相、比色、荧光或其他光谱测定、荧光激活细胞分选测定和免疫学测定,包括酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)和免疫组织化学。
在优选的实施例中,异源基因是编码在生物学和医学中有用的产物(例如蛋白质、RNA、酶或催化性RNA)的序列,例如治疗性基因或免疫原性基因。异源基因可用于治疗(例如治疗遗传缺陷),用作癌症治疗剂,用作疫苗,用于诱导免疫应答,并且/或者用于预防性目的。
在优选的实施例中,异源基因编码外源抗原,例如外源抗原的天然存在形式或其修饰形式。如本文所用,“外源抗原”意指诱导宿主免疫应答并且源自与被其诱导免疫应答的宿主相比基因型不同的实体的抗原。如本文所用,外源抗原的修饰形式意指外源抗原的一种形式,其诱导针对天然存在的抗原的宿主免疫应答并且与天然存在的抗原具有至少50%、至少60%、至少70%、至少80%、至少85%、至少90%、至少95%、至少98%、或至少99%序列同一性。如本文所用,免疫反应的诱导是指蛋白质诱导针对该蛋白质的T细胞和/或体液免疫应答的能力。针对外源抗原的天然存在形式或其修饰形式的宿主免疫应答的确定可以通过任何合适的方法进行评估,该方法例如以下文献中所描述的那些:Jeyanathan等人2020;Immunological considerations for COVID-19vaccine strategies[COVID-19疫苗策略的免疫学考虑];Nature Reviews Immunology[免疫学自然综述]20,615-632和Albert-Vega等人2018;Immune Functional Assays,From Custom to StandardizedTests for Precision Medicine[免疫功能测定,精准医学从定制到标准化测试];Frontiers in Immunology[免疫学前沿]9:2367。在一些实施例中,天然存在的抗原的修饰形式诱导的宿主免疫应答比由天然存在的抗原诱导的更强。在一些实施例中,天然存在的抗原的修饰形式诱导的宿主免疫应答比由天然存在的抗原诱导的更弱。
在一些实施例中,外源抗原源自SARS-CoV2,优选源自SARS-CoV2的刺突蛋白。SARS-CoV2是一种新出现的冠状病毒,其引起严重的急性呼吸道疾病COVID-19。迄今为止,还没有在全球范围内可用的疫苗来预防SARS-CoV2感染。由于该病毒利用其刺突糖蛋白与细胞受体ACE2和丝氨酸蛋白酶TMPRSS2相互作用以进入靶细胞,因此该刺突蛋白代表了疫苗治疗剂的有吸引力的靶点。因此,在优选的实施例中,异源基因编码SARS-CoV2刺突蛋白的天然存在形式或其修饰版本。SARS-CoV2刺突蛋白的RNA、DNA和氨基酸序列是本领域技术人员已知的,并且可以在许多数据库中(例如,在美国国家生物技术信息中心(NCBI)的数据库(在该数据库中其登录号为NC_045512.2)中)中发现。例如,在一些实施例中,异源基因编码SARS-CoV2刺突蛋白,其包含SEQ ID NO:1所示的氨基酸序列。在其他的示例性实施例中,异源基因编码SARS-CoV2刺突蛋白的修饰形式,其包含SEQ ID NO:2所示的氨基酸序列。如将容易地理解的,SEQ ID NO:2所示的氨基酸序列包含在N末端具有人组织纤溶酶原激活物基因(tPA)的信号肽的SARS-CoV2刺突蛋白氨基酸序列。N末端tPA序列的存在可能会增强SARS-CoV2刺突蛋白的免疫原性。
除了异源基因之外,载体还可以包括常规控制元件,这些常规控制元件以允许异源基因在被腺病毒感染的细胞中转录、翻译和/或表达的方式与异源基因可操作地连接。如本文所用,“可操作地连接”包括与目的基因邻接的表达控制序列,和在相反侧或在远端作用以控制目的基因的表达控制序列二者。
表达控制序列可以包括适宜的转录起始序列、终止序列、启动子序列和增强子序列;高效的RNA加工信号,例如剪接和聚腺苷酸化(聚A)信号;提高翻译效率的序列;增强蛋白质稳定性的序列;以及在需要时,增强编码产物分泌的序列。如本文所用,“启动子”是允许RNA聚合酶的结合并指导基因的转录的核苷酸序列。许多表达控制序列(包括内部的、天然的、组成型的、诱导型的和/或组织特异性的启动子)是本领域已知的并且可以被利用。
腺病毒载体可以源自哺乳动物腺病毒。在本发明的方法的一些实施例中,腺病毒载体源自人腺病毒。在一些实施例中,人腺病毒是血清型5人腺病毒。在一些实施例中,人腺病毒不是血清型5人腺病毒。
在优选的实施例中,腺病毒载体不源自人腺病毒。因此,腺病毒载体可以源自非人腺病毒,例如,黑猩猩腺病毒。在特别优选的实施例中,腺病毒载体源自黑猩猩腺病毒,例如,ChAdOx1(Antrobus等人2014Mol.Ther.[分子疗法]22(3):668-674)、ChAdOx2(Morris等人2016Future Virol.[未来病毒学]11(9):649-659)、ChAd3或ChAd63。在尤其优选的实施例中,腺病毒载体源自ChAdOx1。
在本发明的方法的一些实施例中,腺病毒载体用于在疫苗中使用并且源自与疫苗所针对的物种相同的物种。例如,在一些实施例中,疫苗针对在人类中发现的疾病并且腺病毒载体源自人腺病毒。然而,在优选的实施例中,腺病毒载体用于在疫苗中使用并且源自与疫苗所针对的物种不同的物种。例如,在一些实施例中,疫苗针对在人类中发现的疾病并且腺病毒载体源自非人腺病毒,例如黑猩猩腺病毒。据认为,使用源自与疫苗所针对的物种不同的物种的腺病毒载体可提供改进的疫苗,该疫苗在施用时经历较低的预先存在的抗腺病毒免疫发生率。
腺病毒载体可以被工程化使得它们在施用于宿主后不能复制。因此,在本发明的方法的一些实施例中,腺病毒载体是复制缺陷型腺病毒载体(例如,源自黑猩猩腺病毒的复制缺陷型腺病毒载体)。如本文所用,“复制缺陷型腺病毒载体”意指缺少一个或多个腺病毒复制基因、不能在宿主细胞中复制的腺病毒载体。在一些实施例中,腺病毒载体缺少E1A基因。在一些实施例中,腺病毒载体已被修饰以防止宿主免疫系统消除被腺病毒载体感染的细胞。例如,在一些实施例中,腺病毒载体缺少E1B基因和/或E3基因。在一些实施例中,腺病毒载体缺少E1B基因。在一些实施例中,腺病毒载体缺少E3基因。在一些实施例中,腺病毒载体缺少E1B基因和E3基因。在一些实施例中,腺病毒载体是极小腺病毒载体,其包含复制起点(ori)和包装序列。在一些实施例中,极小腺病毒载体进一步包含编码目的蛋白的异源基因。
宿主细胞群
在本发明的方法的优选的实施例中,宿主细胞群与添加到细胞群中的腺病毒互补。如本文所用,“与所生产的腺病毒互补的宿主细胞群”是如下的宿主细胞群,该宿主细胞群已被工程化以表达要生产的腺病毒所不表达的腺病毒因子。例如,在一些实施例中,腺病毒不表达腺病毒DNA复制因子而宿主细胞群表达腺病毒DNA复制因子。如本文所用,“腺病毒DNA复制因子”是在自然界中形成腺病毒DNA的一部分并且是腺病毒在宿主细胞中复制所必需的因子。因此,在一些实施例中,腺病毒不表达E1A蛋白、E1B蛋白和/或E4蛋白而细胞群表达E1A蛋白、E1B蛋白和/或E4蛋白。
宿主细胞群可以包含悬浮的细胞。
宿主细胞群可以是从组织中新鲜分离的原代细胞群。在一些实施例中,该组织是哺乳动物组织。
可替代地,宿主细胞群可以源自经改造用于培养的细胞系。在一些实施例中,该细胞系是永生化细胞系。在一些实施例中,该细胞系是哺乳动物细胞系。在一些实施例中,宿主细胞群包含哺乳动物细胞。例如,在一些实施例中,该宿主细胞群包含人胚肾(HEK)细胞或者是HEK细胞系。这些哺乳动物细胞可以表达腺病毒复制因子。例如,在一些实施例中,该宿主细胞群表达E1A蛋白、E1B蛋白和/或E4蛋白。在一些实施例中,该宿主细胞群表达四环素阻遏蛋白。在优选的实施例中,宿主细胞群包含T-RExTM细胞。在一些实施例中,宿主细胞群由T-RExTM细胞组成。
除非另外定义,本文所使用的所有技术和科学术语具有与本披露所属领域的技术人员通常所理解的相同的意义。Singleton等人,DICTIONARY OF MICROBIOLOGY ANDMOLECULAR BIOLOGY[微生物学和分子生物学词典],第20版,John Wiley and Sons[约翰威利父子公司],纽约(1994),以及Hale和Marham,THE HARPER COLLINS DICTIONARY OFBIOLOGY[哈珀柯林斯生物学词典],Harper Perennial[哈珀永久出版社],纽约州(1991)为技术人员提供了本披露中所使用的许多术语的通用词典。
本披露并不受本文披露的示例性方法和材料的限制,并且与本文所述的那些方法和材料相似或等同的任何方法和材料都可以用于本披露的实施例的实践或测试。
除非另有说明,否则任何核酸序列以5'至3'方向从左至右书写;氨基酸序列分别以氨基至羧基的方向从左至右书写。
本文提供的标题不是对本披露的各个方面或实施例的限制。此外,将理解本文所述的任何实施例适用于本文所述的任何方面。
浓度、量、体积、百分比和其他数值能以范围格式来呈现。数值范围包括限定该范围的数字。在提供数值范围的情况中,应理解,该范围的上限和下限之间的每个中间值(至下限的个位的十分之一,除非上下文另有清楚规定)也被具体披露。在所陈述的范围中的任何规定值或中间值与所陈述的范围中的任何其他规定值或中间值之间的每个较小范围,被涵盖在本披露内。这些较小范围的上限和下限可独立地被包括或排除在该范围中,而且其中任一个、没有一个或两个极限值被包括在较小范围中的每个范围也被涵盖在本披露中,但依据所陈述的范围中的任何被具体排除的极限值而定。在所陈述的范围包含极限值的一个或两个的情况下,将那些所包含的极限值的一个或两个排除在外的范围也包含在本披露中。还应理解的是,此类范围格式仅仅是为了方便和简洁而使用,并且应该被灵活地解释为不仅包括明确列举为范围的限值的数值而且包括包含在该范围内的所有单独的数值或子范围,就像每个数值和子范围被明确地列举一样。
必须注意的是,如本文和所附权利要求所用,单数形式“一个/种(a/an)”和“该(the)”包括复数指示物,除非上下文另有明确规定。因此,例如,提及“一种药剂”包括多种这样的药剂并且提及“该药剂”包括提及本领域技术人员已知的一种或多种药剂及其等效物,等等。
“约”通常可意味着在给定测量值的性质或精度的情况下测量的量的可接受的误差程度。示例性误差程度在给定值或值范围的20%内,通常在10%内,更通常在5%内。优选地,术语“约”在本文中应被理解为使用的数字的数值的正或负(±)5%,优选±4%、±3%、±2%、±1%、±0.5%、±0.1%。
本文描述为“包括/包含(comprising)”一个或多个特征的实施例也可以被认为是“主要由此类特征组成”或“由此类特征组成”的相应实施例的披露。
上述实施例被理解为说明性实例。设想了另外的实施例。应当理解的是,关于任何一个实施例描述的任何特征可以单独使用,或者与所描述的其他特征结合使用,并且还可以与任何其他实施例的一个或多个特征,或者任何其他实施例的任何组合结合使用。此外,在不脱离由所附权利要求限定的本发明的范围的情况下,也可以采用上面未描述的等效物和修改。
本文引用的所有文献各自通过引用以其全文并入本文,包括引用文献中呈现的所有数据、表、附图和文本。
实例
实例1:使用工艺A进行腺病毒纯化
使用工艺A进行腺病毒纯化描绘于图1中。下文提供了另外的细节。
细胞裂解和消化
将10x裂解缓冲液(500mM tris、20mM MgCl2、50%(w/v)蔗糖、10%(v/v)聚山梨醇酯(PS)20,pH 8.0)添加到生物反应器中至1x裂解缓冲液的最终浓度来裂解培养物中的细胞。在细胞裂解的30分钟内,将储备溶液与细胞培养基混合并添加到生物反应器中至15个单位/mL裂解物的最终浓度。在收获开始之前,使细胞裂解和/>处理继续进行最少两小时。
在这一单元操作期间,维持生物反应器的细胞培养阶段的37℃的生物反应器温度和60RPM的搅动速率,同时关闭pH控制和溶解氧。
澄清
从生物反应器中收获处理的裂解物并使用深层过滤将该裂解物澄清。
在初始加载之前,首先用注射用水冲洗深层过滤器(HC Pro Pod深层过滤器、C0SP介质),然后用平衡缓冲液(50mM tris,2mM MgCl2、5%(w/v)蔗糖、1%(v/v)PS 20,pH 8.0)进行平衡。然后将/>处理的裂解物加载到深层过滤器上。加载后,将追踪缓冲液(50mM tris、2mM MgCl2、5%(w/v)蔗糖、1%(v/v)PS 20,pH 8.0)添加至深层过滤器中。在75%的过滤器滞留体积转为废物后开始产物收集以减少产物稀释,并在追踪结束时结束产物收集。
在这一单元操作,期间维持裂解和消化步骤的生物反应器搅动速率,同时关闭温度控制。
切向流过滤和生物负载除去过滤1
在阴离子交换层析之前,使澄清的裂解物经历切向流过滤然后0.2μm过滤以除去杂质。首先将澄清的裂解物使用300kDa超滤膜(Pellicon 2PES膜,300kDa MWCO,C网)通过超滤浓缩。然后在经历进一步的浓缩步骤和用渗滤缓冲液的渗滤步骤之前,将浓缩的产物用渗滤缓冲液(59mM bis-tris、100mM NaCl、1mM MgCl2、5%(w/v)蔗糖、0.1%(v/v)PS 20,pH 7.0)进行渗滤。
将切向流过滤1产物使用平衡缓冲液(59mM bis-tris、100mM NaCl、1mM MgCl2、5%(w/v)蔗糖、0.1%(v/v)PS 20,pH 7.0)进行平衡。然后将平衡的产物过滤(使用颇尔公司Supor EKV,0.2μm)并使用追踪缓冲液(59mM bis-tris、100mM NaCl、1mM MgCl2、5%(w/v)蔗糖、0.1%(v/v)PS 20,pH 7.0)追踪至中间储存容器。
阴离子交换层析
阴离子交换层析步骤设计用于结合产物并除去工艺相关的杂质。阴离子交换层析使用Q系统进行。因此,首先将阴离子交换层析膜/>用1M NaCl冲洗,接着用20个膜体积的消毒缓冲液(1N NaOH)消毒,然后用调节缓冲液(1M NaOH)调节。
在开始加载之前,将阴离子交换层析膜用预平衡缓冲液(50mM bis-tris、100mMNaCl、1mM MgCl2、5%(w/v)蔗糖、0.1%(v/v)PS 20,pH 7.0)预平衡,接着用30个膜体积的活化缓冲液(59mM bis-tris、444mM NaCl、1mM MgCl2、5%(w/v)蔗糖,pH 7.0)活化并用40个膜体积的平衡缓冲液(59mM bis-tris、100mM NaCl、1mM MgCl2、5%(w/v)蔗糖、0.1%(v/v)PS 20,pH 7.0)平衡。
将来自切向流过滤和生物负载除去过滤1步骤的过滤产物加载到阴离子交换层析膜上。加载后,将阴离子交换层析膜用40个膜体积的洗涤缓冲液(59mM bis-tris、222mMNaCl、1mM MgCl2、5%(w/v)蔗糖,pH 7.0)洗涤。将产物用25个膜体积的洗脱缓冲液(59mMbis-tris、444mM NaCl、1mM MgCl2、5%(w/v)蔗糖,pH 7.0)从阴离子交换层析膜上洗脱,立即用AEX稀释缓冲液(35mM NaCl、10mM组氨酸、1mM MgCl2、0.1mM EDTA、7.5%(w/v)蔗糖、0.1%(v/v)PS 80、0.5%(v/v)乙醇,pH 6.6)稀释至约一半的初始细胞裂解物体积(相当于约25个膜体积或更多)。
切向流过滤和生物负载除去过滤2
将阴离子交换产物使用300kDa超滤膜(Omega PES膜,300kDa)通过超滤浓缩。然后将浓缩的产物使用渗滤缓冲液(35mM NaCl、10mM组氨酸、1mM MgCl2、0.1mM EDTA、7.5%(w/v)蔗糖、0.1%(v/v)PS 80、0.5%(v/v)乙醇,pH 6.6)渗滤。通过用渗滤缓冲液冲洗,从TFF系统中回收渗滤的产物。
将生物负载减少过滤器(颇尔公司Supor EKV,0.2μm)用平衡缓冲液(35mM NaCl、10mM组氨酸、1mM MgCl2、0.1mM EDTA、7.5%(w/v)蔗糖、0.1%(w/v)PS 80、0.5%(v/v)乙醇,pH 6.6)平衡。然后将渗滤的产物过滤(颇尔公司Supor EKV,0.2μm)并且使用追踪缓冲液(35mM NaCl、10mM组氨酸、1mM MgCl2、0.1mM EDTA、7.5%(w/v)蔗糖、0.1%(w/v)PS 80、0.5%(v/v)乙醇,pH 6.6)追踪至中间储存容器,随后可将其在2℃-8℃储存多达7天,接着在≤-65℃下冷冻。
实例2:使用工艺B进行腺病毒纯化
使用工艺B进行腺病毒纯化描绘于图2中。下文提供了另外的细节。
细胞裂解和消化
起始材料是T-REx细胞,其细胞密度为至少4x106个细胞/mL。将裂解缓冲液(500mMtris、20mM MgCl2、50%(w/v)蔗糖、10%(v/v)聚山梨醇酯(PS)20,pH 8.0)添加到生物反应器中至1x裂解缓冲液的最终浓度来裂解培养物中的细胞。在细胞裂解的30分钟内,将储备溶液与细胞培养基混合并添加到生物反应器中以达到15,000个单位/kg裂解物的最终浓度。在收获开始之前,使细胞裂解和/>处理继续进行最少两小时。
在这一单元操作,期间维持生物反应器的细胞培养阶段的33℃的生物反应器温度、15-70W/m3的搅动速率和覆盖物,同时关闭pH控制和溶解氧。
澄清
从生物反应器中收获处理的裂解物并使用深层过滤然后是串联的0.2μm过滤,将该裂解物澄清。在初始加载之前,首先用注射用水冲洗深层过滤器(HC Pro Pod深层过滤器、C0SP介质),然后用平衡缓冲液(50mM tris,2mMMgCl2、5%(w/v)蔗糖、1%(v/v)PS 20,pH 8.0)进行平衡。深层过滤后,将/>处理的裂解物加载到0.2μm过滤膜(密理博/>SHC 0.2μm过滤器)上。加载后,将追踪缓冲液(50mM tris、2mM MgCl2、5%(w/v)蔗糖、1%(v/v)PS 20,pH 8.0)添加至0.2μm过滤膜。在75%的过滤器滞留体积转为废物后开始产物收集以减少产物稀释,并在追踪结束时结束产物收集。
在这一单元操作,期间维持裂解和消化步骤的生物反应器搅拌速率和覆盖物,同时关闭pH控制和溶解氧。在开始澄清之前,将温度控制设定点降低至20℃,但是在15℃-35℃下用负载材料进行该单元操作。
阴离子交换层析
阴离子交换层析步骤设计用于结合产物并除去工艺相关的杂质。在这一步骤中使用Q阴离子交换层析系统。首先将阴离子交换层析膜(Sartobind />8mm)用30个膜体积的消毒缓冲液(1N NaOH或0.5N NaOH)消毒,然后用10个膜体积的活化缓冲液(1MNaOH)活化。
接下来,在开始加载之前,将阴离子交换层析膜用20个膜体积的平衡缓冲液(50mMtris、1mM MgCl2、5%(w/v)蔗糖)平衡。将澄清的裂解物用5M NaCl调节,然后以50L澄清的裂解物/L膜加载到膜上。加载后,将膜首先用10个膜体积的平衡缓冲液(50mM tris、1mMMgCl2、5%(w/v)蔗糖)洗涤,然后用30个膜体积的洗涤缓冲液(50mM tris、222mM NaCl、1mMMgCl2、5%(w/v)蔗糖,pH 8.0)洗涤。
将产物用5个膜体积的洗脱缓冲液(50mM tris、444mM NaCl、1mM MgCl2、5%(w/v)蔗糖,pH 8.0)从阴离子交换层析膜上洗脱并且立即用5个膜体积的AEX稀释缓冲液(35mMNaCl、10mM组氨酸/组氨酸-HCl、1mM MgCl2、0.1mM EDTA、7.5%(w/v)蔗糖、0.5%(v/v)乙醇,pH 6.6)以1:1稀释比率稀释。通过使用这些体积的洗脱缓冲液和稀释缓冲液,与工艺A相比,阴离子交换产物体积降低了约5倍或更多倍。减少的阴离子交换产物体积能够减少后续TFF处理步骤所需的膜表面积,从而减少原材料消耗,省去大量的废物流并缩短处理时间。
产物收集后,将膜用活化缓冲液和消毒缓冲液冲洗。
切向流过滤
将阴离子交换产物使用超滤膜(Pellicon 2PES膜,300kDa MWCO,C网)通过超滤浓缩至最终体积,即得0.03-0.3L/L核酸酶处理的裂解物。然后将浓缩的产物使用10个渗滤体积的渗滤缓冲液(35mM NaCl,10mM组氨酸/组氨酸-HCl,1mM MgCl2,0.1mM EDTA,7.5%(w/v)蔗糖,0.5%(v/v)乙醇,pH 6.6)渗滤。通过用三个系统滞留体积的渗滤缓冲液冲洗,从TFF系统中回收渗滤的产物。
配制品
通过添加10%(w/v)PS-80以达到0.1%(w/v)的最终PS 80浓度来配制TFF产物。
0.2微米整体过滤(Bulk Filtration)
将最终0.2μm原料药过滤器(颇尔公司Supor EKV,0.2μm)用配制缓冲液(35mMNaCl,10mM组氨酸/组氨酸-HCl、1mM MgCl2、0.1mM EDTA、7.5%(w/v)蔗糖、0.1%(w/v)PS80、0.5%(v/v)乙醇,pH 6.6)平衡。然后将配制的散装原料药过滤并使用追踪缓冲液(35mMNaCl、10mM组氨酸/组氨酸-HCl、1mM MgCl2、0.1mM EDTA、7.5%(w/v)蔗糖、0.1%(w/v)PS80、0.5%(v/v)乙醇,pH 6.6)追踪至中间储存容器,随后在冷冻之前,将其在2℃-8℃下储存在CryoVault容器或Allegro袋中。
将填充在最终储存容器中的材料命名为原料药。
冷冻
冷冻步骤用于在-90℃至-55℃下长期储存之前冷冻原料药。已设定长期储存范围的上限(-55℃)以避开产物的玻璃化转变温度(大约为-43℃),同时已设定该范围的下限(-90℃)以适应冰柜变化。冷冻步骤在CryoVault容器或Allegro袋最终存储容器中进行。
使用Farrar Blast冰柜或Klinge冰柜以受控方式冷冻CryoVault容器。对于Farrar Blast冰柜,温度设定为-80℃并且将容器冷冻至少14小时。对于Klinge冰柜,温度设定为-65℃并且将容器冷冻至少20小时。可替代地,可以使用设定为≤-65℃的通用实验室冰柜以被动的方式进行CryoVault容器的冷冻持续至少20小时。带有RoSS装置的Allegro袋使用设定为-80℃的RoSS.pFTU设备以受控方式冷冻至少12小时。
表3提供了以1000L运行的工艺B获得的产率,表4提供了以1000L运行的工艺B获得的品质量度。
表3:以1000L运行的工艺B产率
步骤 | 重量(kg) | 滴度(gc/mL) | 产率(%) |
总病毒收获 | 758.5 | 2.08E+11 | N/A |
裂解物 | 844.5 | 2.02E+11 | 108 |
澄清的裂解物a | 961 | 1.51E+11 | 85 |
Sartobind Q | 102 | 1.20E+12 | 92 |
未配制的散装原料药 | 35 | 3.86E+12 | 110 |
配制的散装原料药b | 34.7 | 4.32E+12 | 108 |
原料药 | 28.7 | 2.70E+12 | 75 |
a移出的100L澄清的裂解物;b移出的10L配制的散装原料药
表4:当以1000L运行时工艺B产物品质
I-感染性;VP-病毒颗粒;GC-基因拷贝;VG:I-病毒基因组:感染性;VP:I-病毒颗粒:感染性;PS-聚山梨醇酯
实例3:工艺A和工艺B的比较
如表5所示,与工艺A相比,工艺B的使用使产率提高了大约3倍,而产物品质相当。此外,如将很容易理解的,工艺B需要更少的原材料,例如由于省去了切向流过滤和生物负载除去1步骤。此外,工艺3和工艺4使用的溶液体积相当,尽管工艺4的循环次数是工艺3的2倍高。
表5:工艺A和工艺B的比较。
PS-聚山梨醇酯;VP-病毒颗粒;AEX-阴离子交换层析;ND-未定义。
实例4:腺病毒纯化-工艺B的澄清步骤
在工艺B的澄清步骤期间,在0.2μm过滤步骤之前可以使用两个深层过滤串。主要方法是使用仅具有C0SP介质(“C0SP过滤器”)的HC Pro Pod深层过滤器并且如以上实例2所述。次要方法是使用C0SP过滤器然后是串联的具有X0HC介质的/>Pod深层过滤器(“X0HC过滤器”)或具有X0SP介质的/>HC Pro Pod深层过滤器(“X0SP过滤器”)。
对于次要方法,在初始加载之前,首先用注射用水冲洗深层过滤器,然后用平衡缓冲液(50mM tris、2mM MgCl2、5%(w/v)蔗糖、1%(v/v)PS 20,pH 8.0)进行平衡。然后将处理的裂解物加载到膜上。对于最佳负载分布,加载靶向的3C0SP:1X0HC或X0SP比率。加载后,将追踪缓冲液(50mM tris、2mM MgCl2、5%(w/v)蔗糖、1%(v/v)PS 20,pH 8.0)添加至膜。在75%的过滤器滞留体积转为废物后开始产物收集以减少产物稀释,并在追踪结束时结束产物收集。
如表6所示,使用不同的过滤步骤导致相似的滤液滴度和相似的宿主细胞蛋白清除率。
表6:澄清步骤中的深层过滤器比较
HCP-宿主细胞蛋白
实例5添加混合模式尺寸排阻层析步骤-工艺B的变化形式
混合模式尺寸排阻步骤设计用于结合工艺相关的杂质,同时允许产物流过层析柱。在开始加载之前,首先将混合模式尺寸排阻柱用3个柱体积的平衡缓冲液(50mM tris、222mM NaCl、1mM MgCl2、5%(w/v)蔗糖,pH 8.0)平衡。将调节的Sartobind Q池直接加载到柱上,靶负载体积>/=60L Sartobind Q池/L树脂,靶停留时间>/=4分钟。加载后,将柱用3个柱体积的平衡缓冲液(50mM tris、222mM NaCl、1mM MgCl2、5%(w/v)蔗糖,pH 8.0)平衡。将该柱用3个柱体积的剥离缓冲液(1M NaOH、30%异丙醇)再生。最后,通过用3个柱体积的0.1N NaOH或20%乙醇洗涤来储存该柱。
使用混合模式尺寸排阻层析步骤(Capto Core 700)使宿主细胞蛋白浓度从>100ng/剂量降低至小于20ng/剂量。
混合模式尺寸排阻层析改进了切向流过滤性能并且使渗透通量的下降降低了至少29%并且使膜污染降低了62%。
序列表
<110> 阿斯利康英国有限公司(ASTRAZENECA UK LIMITED)
<120> 纯化腺病毒的方法
<130> P68096US
<160> 2
<170> PatentIn 3.5版
<210> 1
<211> 1273
<212> PRT
<213> 与严重急性呼吸道综合征相关的冠状病毒
<400> 1
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Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
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His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
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Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
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Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
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Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
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Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
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Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
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Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
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Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
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Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
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Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
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Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
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Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
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Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
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His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
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Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
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Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
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Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
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Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
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Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
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Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
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Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
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Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
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Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
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His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
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<210> 2
<211> 1304
<212> PRT
<213> 与严重急性呼吸道综合征相关的冠状病毒
<400> 2
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Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val Asn
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Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe Thr
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Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp Phe
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His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp Asn
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Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu Lys
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Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser Lys
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Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile Lys
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Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr Tyr
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His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr Ser
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Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met
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Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val
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Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro
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Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro
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Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu
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Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly
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Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg
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Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val
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Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser
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Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln
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Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro
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Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp
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Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr
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Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr
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Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val
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Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys
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Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val
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Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr
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Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu
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Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn
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Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe
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Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu
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Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys
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Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly
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Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro
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Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg
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Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly
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Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala
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Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile His
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Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn
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Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn
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Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser
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Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala Ser
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Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val
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Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser
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Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp
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Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu
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Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly
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Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val
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Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn
820 825 830
Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe
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Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe
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Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu
865 870 875 880
Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu
885 890 895
Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr
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Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro
915 920 925
Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln
930 935 940
Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser
945 950 955 960
Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu
965 970 975
Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr
980 985 990
Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu
995 1000 1005
Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
1010 1015 1020
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr
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Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala
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Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser
1055 1060 1065
Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe
1070 1075 1080
Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr
1085 1090 1095
Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys
1100 1105 1110
His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser
1115 1120 1125
Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro
1130 1135 1140
Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp
1145 1150 1155
Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln
1160 1165 1170
Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys
1175 1180 1185
Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile
1190 1195 1200
Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn
1205 1210 1215
Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu
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Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp
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Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile
1250 1255 1260
Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys
1265 1270 1275
Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu
1280 1285 1290
Pro Val Leu Lys Gly Val Lys Leu His Tyr Thr
1295 1300
Claims (66)
1.一种从含腺病毒的样品中纯化腺病毒的方法,该样品包含或源自具有至少约4x106个细胞/mL的细胞密度的宿主细胞群,该方法包括:
(a)澄清该样品以提供澄清的样品,其中澄清包括深层过滤然后微滤;
(b)通过阴离子交换层析处理该澄清的样品以提供阴离子交换产物;以及
(c)通过切向流过滤(TFF)处理该阴离子交换产物以提供TFF产物,其中TFF包括超滤和渗滤。
2.如权利要求1所述的方法,其中该阴离子交换产物在进一步的步骤中通过混合模式尺寸排阻层析处理以提供混合模式尺寸排阻产物,并且其中该混合模式排阻产物通过步骤(c)的TFF进行处理。
3.如权利要求1或2所述的方法,其中该含腺病毒的样品包含宿主细胞群。
4.如权利要求2所述的方法,其中该宿主细胞群具有至少约6x106个细胞/mL、至少约8x106个细胞/mL或至少约1x107个细胞/mL的细胞密度。
5.如权利要求1-4中任一项所述的方法,其中该方法包括在步骤(a)之前裂解该宿主细胞群以提供细胞裂解物。
6.如权利要求5所述的方法,其中该方法包括用细胞裂解剂裂解该宿主细胞群。
7.如权利要求6所述的方法,其中该裂解剂包含非离子洗涤剂,任选地其中该非离子洗涤剂是聚山梨醇酯-20。
8.如权利要求5-7中任一项所述的方法,其中该细胞裂解物包含浓度为至少约50,000ng/mL的宿主细胞蛋白。
9.如权利要求6-8中任一项所述的方法,其中该方法包括在步骤(a)之前或在步骤(a)期间,用核酸酶处理该细胞裂解物。
10.如权利要求9所述的方法,其中该核酸酶是DNA酶和/或RNA酶。
11.如权利要求9或10所述的方法,其中该核酸酶是
12.如权利要求1或2所述的方法,其中该含腺病毒的样品包含细胞裂解物。
13.如权利要求12所述的方法,其中该细胞裂解物是通过向具有至少约6x106个细胞/mL、至少约8x106个细胞/mL或至少约1x107个细胞/mL的细胞密度的宿主细胞群中添加细胞裂解剂来获得的。
14.如权利要求13所述的方法,其中该细胞裂解剂包含非离子洗涤剂,任选地其中该非离子洗涤剂是聚山梨醇酯-20。
15.如权利要求12-14中任一项所述的方法,其中该细胞裂解物包含浓度为至少约50,000ng/mL的宿主细胞蛋白。
16.如权利要求12-15中任一项所述的方法,其中该细胞裂解物已用核酸酶处理。
17.如权利要求16所述的方法,其中该核酸酶是DNA酶和/或RNA酶。
18.如权利要求9或10所述的方法,其中该核酸酶是
19.如前述权利要求中任一项所述的方法,其中步骤(a)中的深层过滤包括使用单一类型的深层过滤器。
20.如权利要求19所述的方法,其中该深层过滤器具有约0.2μm和约2μm之间的标准过滤规格,任选地其中该深层过滤器是HC Pro Pod深层过滤器、C0SP介质。
21.如权利要求1-18中任一项所述的方法,其中步骤(a)中的该深层过滤包括使用串联的至少两个不同的深层过滤器。
22.如权利要求21所述的方法,其中步骤(a)中的该深层过滤包括使用具有标准过滤规格为约0.2μm和约2μm之间的深层过滤器和具有标准过滤规格为大于0μm和最多约0.1μm的深层过滤器。
23.如权利要求21或22所述的方法,其中该至少两个不同的深层过滤器选自:HC Pro Pod深层过滤器、C0SP介质;/>Pod深层过滤器、X0HC介质;和/>HC Pro Pod深层过滤器、X0SP介质。
24.如权利要求21-23中任一项所述的方法,其中该至少两个不同的深层过滤器是:HC Pro Pod深层过滤器、C0SP介质和/>HC Pro Pod深层过滤器、X0SP介质;或/>HC Pro Pod C0SP过滤器和/>Pod X0HC过滤器。
25.如前述权利要求中任一项所述的方法,其中该微滤膜具有约0.2μm的膜孔径。
26.如权利要求24或25所述的方法,其中该微滤膜是密理博公司SHC 0.5/0.2μm过滤膜。
27.如前述权利要求中任一项所述的方法,其中步骤(b)中的该阴离子交换层析包括将该澄清的样品应用于阴离子交换膜。
28.如权利要求27所述的方法,其中该阴离子交换膜包含二乙氨基乙基(DEAE)、季氨乙基(QAE)或季铵(Q)取代基。
29.如权利要求28所述的方法,其中该阴离子交换膜包含季铵(Q)取代基。
30.如权利要求27-29中任一项所述的方法,其中该阴离子交换膜具有至少约3μm的标准孔径。
31.如权利要求27-30中任一项所述的方法,其中该阴离子交换膜是Q膜。
32.如前述权利要求中任一项所述的方法,其中步骤(b)包括在阴离子交换层析之前,通过微滤处理该澄清的样品。
33.如前述权利要求中任一项所述的方法,其中步骤(b)包括通过微滤处理阴离子交换产物。
34.如权利要求32或33所述的方法,其中在阴离子交换层析之前的微滤或阴离子交换产物的微滤包括使用具有约0.2μm的膜孔径的微滤膜。
35.如权利要求34所述的方法,其中该微滤膜是密理博公司SHC 0.5/0.2μm过滤膜。
36.如前述权利要求中任一项所述的方法,其中步骤(c)包括通过深层过滤处理来自步骤(b)的产物,任选地其中该深层过滤器具有最多约0.1μm的标准过滤规格,例如Pod深层过滤器、X0HC介质或/>HC Pro Pod深层过滤器、X0SP介质。
37.如前述权利要求中任一项所述的方法,其中步骤(c)中的该超滤包括使用具有约100和1000kDa之间、约200和700kDa之间、或约300和500kDa之间的标准截留分子量(NMWCO)的超滤膜。
38.如权利要求37所述的方法,其中该超滤膜具有300kDa的NMWCO。
39.如权利要求37或38所述的方法,其中该超滤膜是具有300kDa的NMWCO的2膜。
40.如前述权利要求中任一项所述的方法,其中步骤(c)中的该渗滤包括使用渗滤缓冲液渗滤。
41.如权利要求40所述的方法,其中该渗滤步骤包括使用至少9个渗滤体积的渗滤缓冲液。
42.如前述权利要求中任一项所述的方法,其中该TFF产物包含浓度为200ng或更少/0.5x 1011个腺病毒颗粒的宿主细胞蛋白。
43.如前述权利要求中任一项所述的方法,其中该TFF产物包含浓度为10ng或更少/0.5x 1011个腺病毒颗粒的宿主细胞DNA。
44.如前述权利要求中任一项所述的方法,其中该TFF产物具有大于或等于约2.4x106ifu/mL的感染性。
45.如前述权利要求中任一项所述的方法,其中该方法进一步包括配制该TFF产物以提供配制的产物。
46.如前述权利要求中任一项所述的方法,其中该方法进一步包括使该TFF产物或配制的产物经历无菌过滤以提供原料药。
47.如权利要求46所述的方法,其中无菌过滤包括使用具有约0.2μm的孔径的无菌过滤器。
48.如权利要求47所述的方法,其中该无菌过滤器包括亲水聚醚砜膜,任选地其中该无菌过滤器是颇尔公司(Pall)EKV,0.2μm。
49.如权利要求46-48中任一项所述的方法,其中该原料药包含浓度为200ng或更少/0.5x 1011个腺病毒颗粒的宿主细胞蛋白。
50.如权利要求46-49中任一项所述的方法,其中该原料药包含浓度为10ng或更少/0.5x 1011个腺病毒颗粒的宿主细胞DNA。
51.如权利要求46-50中任一项所述的方法,其中该原料药具有至少约0.8x1011 vp/mL的腺病毒颗粒浓度。
52.如权利要求46-51中任一项所述的方法,其中该原料药具有大于或等于约2.4x109ifu/mL的感染性。
53.如权利要求46-52中任一项所述的方法,其中该原料药用于在疫苗中使用。
54.如前述权利要求中任一项所述的方法,其中该宿主细胞群包含哺乳动物细胞。
55.如权利要求54所述的方法,其中该哺乳动物细胞表达腺病毒复制因子。
56.如前述权利要求中任一项所述的方法,其中该宿主细胞群包含HEK细胞。
57.如前述权利要求中任一项所述的方法,其中该宿主细胞群包含T-REx细胞。
58.如前述权利要求中任一项所述的方法,其中该宿主细胞群由哺乳动物细胞例如T-REx细胞组成。
59.如前述权利要求中任一项所述的方法,其中该腺病毒是复制缺陷型腺病毒。
60.如前述权利要求中任一项所述的方法,其中该腺病毒是猿腺病毒。
61.如权利要求60所述的方法,其中该猿腺病毒是复制缺陷型猿腺病毒。
62.如权利要求61所述的方法,其中该复制缺陷型猿腺病毒是ChAdOx1、ChAdOx2、ChAdOx3、或ChAd63,优选地其中该复制缺陷型猿腺病毒是ChAdOx1。
63.如前述权利要求中任一项所述的方法,其中该腺病毒不是人腺病毒。
64.如前述权利要求中任一项所述的方法,其中该腺病毒编码nCov-19刺突蛋白。
65.一种纯化的腺病毒,其是通过如权利要求1-63中任一项所述的方法可获得的或通过该方法获得的。
66.一种原料药,其是通过如权利要求46-53中任一项所述或权利要求54-64中的任一项当从属于权利要求46-53中任一项时所述的方法可获得的或通过该方法获得的。
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