CN107406824B - 纯化生物组合物的方法及用于其的制品 - Google Patents
纯化生物组合物的方法及用于其的制品 Download PDFInfo
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- CN107406824B CN107406824B CN201680017205.8A CN201680017205A CN107406824B CN 107406824 B CN107406824 B CN 107406824B CN 201680017205 A CN201680017205 A CN 201680017205A CN 107406824 B CN107406824 B CN 107406824B
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Abstract
本发明公开了一种纯化生物组合物的方法,所述方法包括:将松散的阳离子配体官能化短纤维和生物组合物设置在容器的混合容积内;搅拌所述生物组合物和所述松散的阳离子配体官能化短纤维,同时使它们在所述混合容积内彼此紧密接触,以提供改性纤维和纯化的生物组合物;以及将所述纯化的生物组合物中的至少一部分与其所接触的改性纤维和任何松散的阳离子配体官能化短纤维分离。所述松散的阳离子配体官能化短纤维具有包含接枝丙烯酸类聚合物的改性表面层,所述接枝丙烯酸类聚合物包含10至100重量%的可阳离子化的单体单元。本发明还公开了一种用于纯化生物组合物的制品,所述制品包括:其中设置有混合容积的容器;以及设置在所述混合容积内的松散的阳离子配体官能化短纤维。
Description
技术领域
本公开广义描述使用松散的官能化短纤维用于纯化生物组合物的方法和制品。
背景技术
靶标生物材料,诸如病毒和生物大分子(例如,包括活细胞的组分或产物,例如蛋白质、碳水化合物、脂质、和核酸)的检测、定量、分离和纯化一直以来都是研究人员的目标。从诊断上来讲,检测和定量是重要的,例如,作为各种生理条件(诸如疾病)的指示。对于治疗和在生物医学研究中,生物大分子的分离和纯化是重要的。生物大分子诸如酶(它们是能够催化化学反应的特殊种类蛋白质)在工业上也是可用的;酶已被分离、纯化,并且随后被用于甜味剂、抗生素和多种有机化合物,诸如乙醇、乙酸、赖氨酸、天冬氨酸和生物可用的产品,诸如抗体和类固醇的生产。
在它们的天然状态下(即,体内),这些生物大分子的结构和相应的生物活性一般保持在相当窄的pH和离子强度范围内。因此,任何分离和纯化操作必须考虑这些因素以得到具有效能的处理后的生物大分子。
基于在流动相(其可为气体或液体)和固定相之间的溶质的交换,可对生物产物混合物进行色谱分离和纯化操作。该溶液混合物中各种溶质实现分离,是由于改变了每种溶质与固定相的结合相互作用;当受到移动相的离解或置换作用时,与相互作用不太强的溶质相比,较强的结合相互作用一般导致较长的保持时间,并且以这种方式可以实现分离和纯化。柱层析已被用于纯化生物组合物;然而,这种技术一般受到低吞吐率、柱填料沟流、和/或高成本问题的困扰。
已知聚合物树脂广泛用于多种靶标化合物的分离和纯化。例如,基于离子基团的存在、基于靶标化合物的大小、基于疏水相互作用、基于亲和相互作用或基于共价键的形成而将聚合物树脂用于纯化或分离靶标化合物。近来,已经开发出在基底上具有此种聚合物涂层的配体官能化基底以帮助纯化生物组合物;例如,如美国专利8,377,672B2(Rasmussen等人)和8,435,776B2(Rasmussen等人)所公开的。
发明内容
虽然上述两个Rasmussen等人的专利描述了可经由过滤过程,使用配体官能化织物用于生物组合物的纯化,该过程可能由于细胞碎片等造成织物中孔的积聚和阻塞而减慢。
优选地,本发明人已经发现了一种简单的更快速的纯化方法,该方法使用松散的配体官能化短纤维代替配体官能化织物。
在一个方面,本公开提供一种纯化生物组合物的方法,该方法包括:
a)将松散的阳离子配体官能化短纤维和生物组合物设置在容器的混合容积内,其中松散的阳离子配体官能化短纤维具有包含接枝丙烯酸类聚合物的改性表面层,所述接枝丙烯酸类聚合物包含10至100重量%的可阳离子化的单体单元;
b)搅拌生物组合物和松散的阳离子配体官能化短纤维,同时使它们在混合容积内彼此紧密接触,以提供改性纤维和纯化的生物组合物;以及
c)将纯化的生物组合物中的至少一部分与其所接触的改性纤维和任何松散的阳离子配体官能化短纤维分离。
在另一方面,本公开提供一种用于纯化生物组合物的制品。
该制品包括其中设置有混合容积的样本收集容器;以及设置在混合容积内的松散的阳离子配体官能化短纤维,其中松散的阳离子配体官能化短纤维具有包含接枝丙烯酸类聚合物的改性表面层,所述接枝丙烯酸类聚合物包含10至100重量%的至少一种可阳离子化的单体单元;
优选地并且意料不到地是,根据本公开使用松散的阳离子配体官能化短纤维纯化生物组合物的方法以及利用该方法的制品,与涉及相似官能化基底的现有方法相比能够显著缩短用于去除/分离生物组合物的组分的纯化时间。
以下定义适用于整个说明书和权利要求书。
术语“丙烯酸类聚合物”是指包含至少10重量%(优选至少20,至少30,至少40,至少50,至少60,至少70或甚至至少80重量%)的单体单元的聚合物,该单体单元独立地由以下式表示:
其中
R表示H或具有1至4个碳原子、优选一个碳原子的烷基基团;并且
X表示醇或胺残基。
术语“生物组合物”是指包含生物来源的大分子的任何组合物。该组合物不需要是单一的生物来源。示例包括抗体、细胞、碳水化合物、RNA、DNA、和病毒。
术语“阳离子配体官能化”是指具有附接(例如,间接地或直接地共价键合)至其上的官能团,其中官能团可以是例如在季铵(离子)基团情况下的永久性阳离子,或者该基团具有足够的碱性,使其在pH为5.0-8.0的水中基本上质子化。例如,合适的此类碱性基团包括它们在水中的质子化阳离子形式具有至少9,优选至少10,还更优选至少12.5的pKa的基团。
术语“可阳离子化的”是指能够通过离解在水中形成有机阳离子(例如,在鎓盐的情况下)和/或通过水发生质子化(例如,在胺或胍的情况下)。
术语“可离子化的”是指能够在水中自发结合一个质子以形成阳离子物质(例如,在标准温度和压力下)。
术语“(甲基)丙烯酰基”是指“丙烯酰基和/或甲基丙烯酰基”。因此,甲基(甲基)丙烯酸酯是指丙烯酸甲酯和/或甲基丙烯酸甲酯。
术语“纯化”是指提高纯度,但是不一定以纯化形式分离,除非另外指明。
在考虑具体实施方式及所附权利要求书之后,将进一步理解本公开的特征和优点。
附图说明
图1为根据本公开的示例性制品100的示意性侧视图。
图2为根据本公开的方法的示例性实施方案的示意性工艺流程图。
应当理解,本领域的技术人员可设计出落入本公开原理的范围和实质内的许多其它的修改和实施方案。附图可不按比例绘制。
具体实施方式
本公开涉及纯化生物组合物的方法,该方法利用设置在容器的混合容积内的与生物组合物紧密接触的松散的阳离子配体官能化短纤维。根据本公开的方法和制品尤其适用于高离子强度介质,用于从生物组合物中去除和/或分离近中性或带负电的生物材料,诸如宿主细胞蛋白、DNA、RNA、病毒、以及其它微生物。一旦结合到阳离子配体官能化短纤维上,就能够通过简单的分离技术去除带负电的生物组合物的组分,诸如在多孔稀松布或其它基底上纤维的收集。
松散的阳离子配体官能化短纤维首先是短纤维;即,它们是不连续纤维。优选地,松散的阳离子配体官能化短纤维具有0.1mm至2cm,优选0.3mm至5mm,还更优选0.5mm至3mm的长度;然而,也可使用其它长度。松散的阳离子配体官能化短纤维可为例如卷曲的或不卷曲的和/或原纤化的。
如本文所用,当应用于短纤维时,术语“松散的”是指该纤维不形成纸材、织物、或加捻的丝束(例如,线、纱、或绳)。然而,纤维可能团聚在一起,但这通常是次优选的。
松散的阳离子配体官能化短纤维可根据已知的方法通过将丙烯酸类聚合物接枝至纤维来制备。丙烯酸类聚合物可通过至少一个丙烯酸类单体任选地与至少一个可自由基聚合的单体(它不是丙烯酸类单体)的聚合来制备。也可包括可自由基聚合的多官能单体(例如,具有两个或更多个可自由基聚合的基团)。多官能单体可为具有至少两个可自由基聚合的基团的单体,或者这些多官能单体可具有单个可自由基聚合的基团和另一个可聚合的基团(例如,环氧基),其能够在聚合后的后续步骤中发生反应。
可自由基聚合的丙烯酸类单体的示例包括(甲基)丙烯酸己酯、(甲基)丙烯酸2-乙基己酯、(甲基)丙烯酸异壬酯、(甲基)丙烯酸异冰片酯、(甲基)丙烯酸苯氧乙酯、(甲基)丙烯酸2-羟基乙酯、(甲基)丙烯酸十二烷酯、(甲基)丙烯酸甲酯、(甲基)丙烯酸乙酯、(甲基)丙烯酸正丙酯、(甲基)丙烯酸正丁酯、(甲基)丙烯酸正辛酯、(甲基)丙烯酸四氢糠酯、(甲基)丙烯酸异丁酯、(甲基)丙烯酸环己酯、(甲基)丙烯酸十八烷酯、(甲基)丙烯酰胺、二甲基(甲基)丙烯酰胺、2-羟乙基(甲基)丙烯酰胺,和N-乙烯基化合物,诸如N-乙烯基甲酰胺、N-乙烯基吡咯烷酮、和N-乙烯基己内酰胺。也可使用酸性单体诸如丙烯酸、甲基丙烯酸、和(甲基)丙烯酰胺基丙磺酸,但是这些单体可趋于妨碍松散的阳离子配体官能化短纤维的性能和/或引起纤维团聚,并且如果使用的话,通常应谨慎使用,尽管这不是一个要求。较亲水的或水溶性的那些单体在一些实施方案中可为优选的,这是由于它们与包含丙烯酸类单体的可阳离子化的基团的相容性或溶解度特性。
不是丙烯酸类单体的可自由基聚合的单体的示例包括烯烃,其包括卤代烯烃,诸如乙烯、丙烯、异丁烯、己烯、异辛烯、苯乙烯、氟乙烯、六氟丙烯、四氟乙烯、偏二氟乙烯、氯氟乙烯、三氟氯乙烯、和二氟乙烯。也可使用烯丙基单体。示例包括烯丙基醚(例如,烯丙基乙基醚和烯丙基丁基醚)、N-烯丙胺(例如,N-烯丙基乙酰胺和N-烯丙基甲酰胺)、和烯丙酯(例如,乙酸烯丙酯、苯甲酸烯丙酯、和丙酸烯丙酯)。
在一个实施方案中,可用的可自由基聚合的非丙烯酸类单体可包含可阳离子化的基团。在此类情况下,具有可阳离子化基团的非丙烯酸类单体需要形成接枝丙烯酸类聚合物。
示例性的此类可自由基聚合的非丙烯酸类单体包括由以下式表示的那些:
其中R1为H或具有1至4个碳原子的烷基基团(例如,甲基、乙基、丙基、异丙基、丁基),并且Z-为非干扰性阴离子(例如,将不引起阳离子配体官能化短纤维附聚的阴离子或牢固结合四价氮原子的阴离子,或者对于生物组合物为氧化性的阴离子),其优选地具有-1、-2、或-3的电荷,更优选-1的电荷。优选的非干扰性阴离子包括氯和溴。
可自由基聚合的多官能单体的示例包括(甲基)丙烯酸缩水甘油酯、亚甲基二(甲基)丙烯酰胺、二(甲基)丙烯酰哌嗪、二(甲基)丙烯酸-1,3-丁二醇酯、二(甲基)丙烯酸-1,4-丁二醇酯、二(甲基)丙烯酸-1,6-己二醇酯、二(甲基)丙烯酸乙二醇酯、烷氧基化的脂肪族二(甲基)丙烯酸酯、烷氧基化的环己烷二甲醇二(甲基)丙烯酸酯、烷氧基化的己二醇二(甲基)丙烯酸酯、烷氧基化的新戊二醇二(甲基)丙烯酸酯、己内酯改性的新戊二醇羟基特戊酸酯二(甲基)丙烯酸酯、己内酯改性的新戊二醇羟基特戊酸酯二(甲基)丙烯酸酯、环己烷二甲醇二(甲基)丙烯酸酯、二乙二醇二(甲基)丙烯酸酯、二丙二醇二(甲基)丙烯酸酯、乙氧基化的(10)双酚A二(甲基)丙烯酸酯、乙氧基化的(3)双酚A二(甲基)丙烯酸酯、乙氧基化的(30)双酚A二(甲基)丙烯酸酯、乙氧基化的(4)双酚A二(甲基)丙烯酸酯、羟基特戊醛改性的三羟甲基丙烷二(甲基)丙烯酸酯、新戊二醇二(甲基)丙烯酸酯、聚乙二醇(200)二(甲基)丙烯酸酯、聚乙二醇(400)二(甲基)丙烯酸酯、聚乙二醇(600)二(甲基)丙烯酸酯、丙氧基化的新戊二醇二(甲基)丙烯酸酯、四乙二醇二(甲基)丙烯酸酯、三环癸烷二甲醇二(甲基)丙烯酸酯、三乙二醇二(甲基)丙烯酸酯、三丙二醇二(甲基)丙烯酸酯;三(甲基)(甲基)丙烯酸酯,诸如甘油三(甲基)丙烯酸酯、三羟甲基丙烷三(甲基)丙烯酸酯、乙氧基化的三(甲基)丙烯酸酯(例如,乙氧基化的(3)三羟甲基丙烷三(甲基)丙烯酸酯、乙氧基化的(6)三羟甲基丙烷三(甲基)丙烯酸酯、乙氧基化的(9)三羟甲基丙烷三(甲基)丙烯酸酯、乙氧基化的(20)三羟甲基丙烷三(甲基)丙烯酸酯)、季戊四醇三(甲基)丙烯酸酯、丙氧基化的三(甲基)丙烯酸酯(例如,丙氧基化的(3)甘油基三(甲基)丙烯酸酯、丙氧基化的(5.5)甘油基三(甲基)丙烯酸酯、丙氧基化的(3)三羟甲基丙烷三(甲基)丙烯酸酯、丙氧基化的(6)三羟甲基丙烷三(甲基)丙烯酸酯)、三羟甲基丙烷三(甲基)丙烯酸酯、三(2-羟乙基)异氰脲酸酯三(甲基)丙烯酸酯;以及较高官能度的包含(甲基)丙烯基的化合物:诸如双三羟甲基丙烷四(甲基)丙烯酸酯、二季戊四醇五(甲基)丙烯酸酯、乙氧基化的(4)季戊四醇四(甲基)丙烯酸酯、季戊四醇四(甲基)丙烯酸酯、己内酯改性的二季戊四醇六(甲基)丙烯酸、以及它们的组合。同样,由于相容性或溶解度原因,亲水性或水溶性多官能单体是优选的。
如果包括的话,多官能单体的量通常为小于5重量%的可自由基聚合的单体(其用于制备接枝丙烯酸类聚合物),优选地为小于2重量%,还更优选地为小于1重量%;然而,这不是一个要求。
合适的纤维包括包含合成聚合物的纤维,该合成聚合物诸如聚烯烃(例如,聚乙烯、聚丙烯、苯乙烯-丁二烯共聚物、聚苯乙烯、和聚异丁烯、以及它们的组合);氟化聚合物(例如,偏二氟乙烯、乙烯基氟化物、四氟乙烯、三氟氯乙烯、它们的组合的均聚物和共聚物,以及前述化合物与聚乙烯和/或聚丙烯的共聚物);氯化聚合物(例如,聚偏二氯乙烯、聚氯丁二烯、和聚氯乙烯);聚酯(例如,聚己内酯和聚对苯二甲酸乙二醇酯);聚酰胺(例如,尼龙-6,6和尼龙6);乙酸乙烯酯均聚物和共聚物(例如,与乙烯)、以及它们的水解衍生物(例如,聚(乙烯醇));聚醚砜;和聚酰亚胺。一种优选的合成纤维是原纤化的高密度聚乙烯(HDPE);例如以SHORT STUFF FIBRILLATED HDPE(例如,等级ESS2F、ESS5F、ESS50F、E380F、E505F、E780F、E990F)购自田纳西州约翰逊市的微纤维公司(MiniFibers,Inc.,JohnsonCity,Tennessee)的原纤化HDPE纤维。可用的天然纤维包括人造丝、纤维素、棉、亚麻布、脱乙酰壳多糖、和淀粉。
纤维通过接枝包含10至100重量%的可阳离子化的单体单元的丙烯酸类聚合物至它的表面进行表面改性。用于接枝丙烯酸类聚合物的技术可涉及使纤维经受电离辐射(例如,γ辐射或电子束辐射)并且随后接触可自由基聚合的单体,包括丙烯酸类单体,其中整个过程在无氧环境下进行。在多个专利中详述了如何进行此类过程。示例包括美国专利8,377,672(Rasmussen等人)、8,652,582(Bothof等人)、8,551,894(Seshadri等人)、8,328,023(Weiss等人)、和8,329,034(Waller,Jr.等人)。丙烯酸类单体的接枝可涉及在存在II型光引发剂的情况下的紫外线辐照,例如如WO 2013/184366A1(Bothof等人)所述
松散的阳离子配体官能化短纤维具有包含接枝丙烯酸类聚合物的改性表面层。接枝丙烯酸类聚合物包含10至100重量%的可阳离子化的单体单元。例如,接枝丙烯酸类聚合物可包含至少10重量%,至少20重量%,至少30重量%,至少40重量%,或至少50重量%多至60重量%,70重量%,80重量%,90重量%,95重量%,或甚至100重量%的可阳离子化的单体单元。可使用任何可阳离子化的单体单元。优选的示例包括由以下式(A)至(C)中的任一项表示的二价单体单元:
R1表示H或具有1至4个碳原子的烷基基团(例如,甲基、乙基、丙基、异丙基、丁基)。优选地,R1为H或甲基。
R2表示任选地被悬链羰氧基、羰基氨基、氧羰基氨基或亚脲基二价连接基团取代的二价亚烷基基团。优选地,R2具有2至12个碳原子,更优选地具有2至6个碳原子,并且还更优选地具有2至4个碳原子。
每个R3独立地表示H或具有1至4个碳原子的烷基基团(例如,甲基、乙基、丙基、异丙基、丁基)。优选地,R3为H、甲基、或乙基。
R4表示H、具有1至4个碳原子的烷基基团(例如,甲基、乙基、丙基、异丙基、丁基)、或-N(R3)2,其中R3如上文所定义。优选地,R4为H、甲基、或乙基。
X1表示-O-或-NR3-,其中R3如上文所定义。
优选的示例也包括由以下式(D)或(E)表示的二价单体单元:
其中
R5为H、C1-C12烷基、或C5-C12(杂)芳基;
每个R7独立地为H、-OH、C1-C12烷基、或C5-C12(杂)芳基,优选H或C1-C4烷基;
R8为H、C1-C12烷基、C5-C12(杂)芳基、或-N(R7)2,优选H或C1-C4烷基
R9为C2-C12亚烷基或C5-C12(杂)亚芳基;
X2为-O-或-NR7-;
R10为C2-C12亚烷基;并且
R11为H或甲基。
涉及二价单体单元及其制备方法的另外细节可见于美国专利8,377,672(Rasmussen)中。
单体单元(A)和(B)可通过对应单体的聚合、或通过例如活性侧基诸如前体聚合物的二氢唑酮基团(例如,由包括链烯吖内酯的单体制成的聚合物)例如与伯或仲氨基烷基官能化的胍或胍丁胺化合物的反应便利地生成。适于生成单体单元(A)和(B)的单体和方法描述于例如美国专利8,377,672(Rasmussen等人)、8,652,582(Bothof等人)、和WO 2014/204763A1(Rasmussen等人)。
用于生成单体单元(C)的合适单体的示例包括N-(3-三甲基氨基丙基)丙烯酰胺;甲基丙烯酸2-三甲基氨基乙酯;2-三甲基氨基乙基丙烯酸酯;N-(3-三甲基氨基丙基)甲基丙烯酰胺;N-(6-三甲基氨基己基)丙烯酰胺;和N-(3-三甲基氨基丙基)丙烯酰胺的盐(例如,氯盐或溴盐)。适于生成单体单元(C)的单体和方法可见于例如美国专利6,007,803(Mandeville,III等人)和PCT国际专利申请US2014/057388中,该专利申请提交于2014年9月25日。阳离子单体单元(C)优选地与如前文所定义的非干扰性阴离子Z-成对。
可阳离子化的单体单元可通过例如具有可阳离子化基团的对应单体的自由基聚合(例如,均聚或共聚)产生,或者通过在后续反应中用可阳离子化的基团官能化的前体单体的聚合(例如,均聚或共聚)产生。
接枝丙烯酸类聚合物还可包含0.1至90重量%的至少一种不可离子化的亲水单体单元,或者它可一点都不包含。例如接枝丙烯酸类聚合物可包含至少1重量%,至少5重量%,至少10重量%,至少15重量%,或至少25重量%多至30重量%,40重量%,50重量%,75重量%,或90重量%的至少一种不可离子化的亲水单体单元。在一些实施方案中,不可离子化的亲水单体单元包括具有如下所示的5至7个碳原子的N-乙烯基内酰胺的二价残基,其中n=1、2、或3。
可通过在经聚合以制备接枝丙烯酸类聚合物的单体中包括N-乙烯基吡咯烷酮、N-乙烯基戊内酰胺、和/或N-乙烯基己内酰胺将此类单体单元容易地引入。
在一些实施方案中,不可离子化的亲水单体单元包括聚醚(甲基)丙烯酸酯的二价残基,如下所示,其中R1和R3如前文所定义,并且w为≥2的整数。
可通过在经聚合以制备接枝丙烯酸类聚合物的单体中包括聚醚(甲基)丙烯酸酯将此类单体单元容易地引入。制备此类单体的方法是本领域熟知的,并且许多可商购获得。示例包括丙烯酸2-(2-乙氧基乙氧基)乙酯、甲氧基聚乙二醇(350)单丙烯酸酯、甲氧基聚乙二醇(350)单甲基丙烯酸酯、甲氧基聚乙二醇(550)单丙烯酸酯、和甲氧基聚乙二醇(550)单甲基丙烯酸酯,它们全部可购自宾夕法尼亚州埃克斯顿的沙多玛公司(Sartomer Co.,Exton,Pennsylvania)。
任选地,生物组合物可用水溶性聚合物絮凝剂预处理,该水溶性聚合物絮凝剂在与松散的阳离子配体官能化短纤维结合之前(或同时)絮凝一部分生物组合物的组分。合适的絮凝剂的示例包括合成的阳离子配体官能化聚合物,例如如美国专利8,377,672(Rasmussen等人)和8,435,776(Rasmussen等人)所公开的。
合适的容器包括至少一个混合容积(例如,一个腔室)。示例性容器包括样本收集管和袋(优选密封的样本收集管和袋)、带有排出装置的混合容器、烧瓶、烧杯、筒、袋、槽、管式流反应器、静态混合器、和罐。在一些实施方案中,容器是密闭和/或密封的(例如,用橡胶隔膜/塞子或盖密封)。合适的容器可为例如一次性的或可重复使用的。搅拌装置(例如,桨状物、搅拌器、叶片、或搅拌棒)可与混合容器一起使用以便于搅拌。
静态混合器(例如,如示意图2所示)可从不同供应商商购获得,例如伊利诺斯州卡里的考弗洛公司(Koflo Corp.,Cary,Illinois)和纽约州霍波格的查尔斯·罗斯父子公司(Charles Ross and Son Co.,Hauppauge,New York)。在一些实施方案中,容器配有一个排出装置,其可通过打开和关闭阀门(例如,龙头)进行操作。这尤其可用于不能容易地用手操纵的较大容器。
现在参见图1,纯化生物组合物的示例性制品100包括其中设置有混合容积115的容器110。根据本公开的松散的阳离子配体官能化短纤维120设置在混合容积115内。任选的覆盖件130(例如,橡胶隔膜、塑料压接顶部、或螺旋盖),连同容器100一起封闭混合容积115。任选地,合成的聚合物絮凝剂颗粒180也可存在。
在使用时,将生物组合物(未示出)设置在混合容积内,同时搅拌纤维120和生物组合物使它们紧密接触。可打开任选的阀门150,允许纯化的生物组合物通过多孔基底140排出并流经任选的出口端口160。
用于进行根据本公开的方法的一个示例性实施方案如图2所示。现在参见图2,松散的阳离子配体官能化短纤维120悬浮在流体225(例如,盐水或水)中,其任选地包含溶解的合成聚合物絮凝剂,它与生物组合物210结合并通过静态混合器220。通过多孔过滤器230去除粒状和纤维材料,并且纯化的生物组合物240通过多孔过滤器230而被收集。
松散的阳离子配体官能化短纤维可在将生物组合物设置在容器的混合腔室内之前、之后、或与其同时设置在混合腔室内。
一旦在混合容器中混合,就搅拌生物组合物和松散的阳离子配体官能化短纤维,同时使它们在混合腔室内彼此紧密接触,以提供改性纤维(即,具有一些来自结合到其上的生物组合物的材料)和纯化的生物组合物。合适的混合方法包括例如手摇、实验室搅拌器、机械和/或磁力搅拌器、以及通过静态混合器。搅拌可进行任何足以有效结合生物化合物与纤维的时间长度。在一些实施方案中,搅拌优选地少于60秒,少于45秒,或甚至少于30秒。在其它实施方案中,搅拌可例如长达20分钟或更长。
纯化的生物组合物与改性纤维的分离可通过任何合适的方法实现,包括例如离心、滗析、过滤、和筛分。在一个尤其优选的实施方案中,混合腔室的内容物在搅拌后被传送通过多孔基底(例如,多孔稀松布、多孔薄膜、多孔非织造织物、或网片),由此纤维不通过多孔基底并形成位于基底上游的多孔纤维团,并且其可用于机械去除在纯化的生物组合物中的粒状碎片剩余物。例如聚丙烯、聚乙烯、金属、和玻璃可用作多孔基底的材料。
通常多孔基底具有约0.5mm至约0.5cm的开口/孔,用于实现改性纤维的有效收集,并且不过度阻碍通过多孔基底的流体流,但也可使用其它大小的开口/孔。
在一些实施方案中,纯化的目的在于从流体中移除生物物质。例如,重组蛋白或酶可以在细胞培养物中制备,可以添加松散的阳离子配体官能化短纤维以絮凝蛋白或酶,并且该沉淀可以作为蛋白或酶的纯化过程中的第一步骤被分离。又如,作为浓缩、计数和/或鉴别微生物的过程中的第一步骤,可使用松散的阳离子配体官能化短纤维来从流体中捕集微生物。
在其它实施方案中,从流体中移除的生物物质是必须在针对流体附加处理步骤之前移除的污染物。
因此,松散的阳离子配体官能化短纤维可用于结合来自生物组合物(诸如细胞培养物或发酵液)的细胞和细胞碎片并促进它们的去除。它可以用于从溶液中沉淀出所需或污染蛋白或核酸。显著地是,松散的阳离子配体官能化短纤维在高盐浓度或高离子强度条件下可用。
本公开的选择实施方案
在第一实施方案中,本公开提供了一种纯化生物组合物的方法,该方法包括:
a)将松散的阳离子配体官能化短纤维和生物组合物设置在容器的混合容积内,其中松散的阳离子配体官能化短纤维具有包含接枝丙烯酸类聚合物的改性表面层,所述接枝丙烯酸类聚合物包含10至100重量%的可阳离子化的单体单元;
b)搅拌生物组合物和松散的阳离子配体官能化短纤维,同时使它们在混合容积内彼此紧密接触,以提供改性纤维和纯化的生物组合物;以及
c)将纯化的生物组合物中的至少一部分与其所接触的改性纤维和任何松散的阳离子配体官能化短纤维分离。
在第二实施方案中,本公开提供根据第一实施方案所述的方法,其中在将生物组合物设置在混合容积内之前将松散的阳离子配体官能化短纤维设置在混合容积内。
在第三实施方案中,本公开提供根据第一或第二实施方案所述的方法,其中步骤b)是使用静态混合器来至少部分地实现的。
在第四实施方案中,本公开提供根据第一至第三实施方案中任一项所述的方法,其中松散的阳离子配体官能化短纤维中的至少一部分为原纤化的。
在第五实施方案中,本公开提供根据第一至第四实施方案中任一项所述的方法,其中生物组合物包含合成的聚合物絮凝剂。
在第六实施方案中,本公开提供根据第五实施方案所述的方法,其中接枝丙烯酸类聚合物还包含多官能单体单元。
在第七实施方案中,本公开提供根据第一至第六实施方案中任一项所述的方法,其中接枝丙烯酸类聚合物还包含0.1至90重量%的至少一种不可离子化的亲水单体单元。
在第八实施方案中,本公开提供根据第七实施方案所述的方法,其中不可离子化的亲水单体单元包括具有4至6个碳原子的N-乙烯基内酰胺。
在第九实施方案中,本公开提供根据第一至第八实施方案中任一项所述的方法,其中可阳离子化的单体单元为由以下式表示的二价单体单元:
其中:
R1为H或具有1至4个碳原子的烷基基团;
R2为任选地被悬链羰氧基、羰基氨基、氧羰基氨基或亚脲基二价连接基团取代的二价亚烷基基团;
每个R3独立地为H或具有1至4个碳原子的烷基基团;
R4为H或具有1至4个碳原子的烷基基团或-N(R3)2;并且
X1为-O-或-NR3-。
在第十实施方案中,本公开提供根据第一至第八实施方案中任一项所述的方法,其中可阳离子化的单体单元包括由以下式表示的二价单体单元:
其中:
R1为H或具有1至4个碳原子的烷基基团;
R2为任选地被悬链羰氧基、羰基氨基、氧羰基氨基或亚脲基二价连接基团取代的二价亚烷基基团;并且
每个R3独立地为H或具有1至4个碳原子的烷基基团;R4为H或具有1至4个碳原子的烷基基团或-N(R3)2;并且
X1为-O-或-NR3-。
在第十一实施方案中,本公开提供根据第一至第十实施方案中任一项所述的方法,其中容器包括任选密封的样本收集袋或管。
在第十二实施方案中,本公开提供根据第一至第十一实施方案中任一项所述的方法,其中步骤c)包括将改性纤维和任何松散的阳离子配体官能化短纤维中的至少一部分沉积在多孔基底上。
在第十三实施方案中,本公开提供了一种用于纯化生物组合物的制品,该制品包括:
其中设置有混合容积的容器;以及
设置在混合容积内的松散的阳离子配体官能化短纤维,其中松散的阳离子配体官能化短纤维具有包含接枝丙烯酸类聚合物的改性表面层,所述接枝丙烯酸类聚合物包含10至100重量%的至少一种可阳离子化的丙烯酸类单体单元。
在第十四实施方案中,本公开提供根据第十三实施方案所述的制品,其中接枝丙烯酸类聚合物包含多官能单体单元。
在第十五实施方案中,本公开提供根据第十三或第十四实施方案所述的制品,其中接枝丙烯酸类聚合物还包含0.1至90重量%的至少一种不可离子化的亲水单体单元。
在第十六实施方案中,本公开提供根据第十五实施方案所述的方法,其中不可离子化的亲水单体单元包括具有4至6个碳原子的N-乙烯基内酰胺。
在第十七实施方案中,本公开提供根据第十三至第十六实施方案中任一项所述的制品,其中可阳离子化的丙烯酸类单体单元由以下式表示:
其中:
R1为H或具有1至4个碳原子的烷基基团;
R2为任选地被悬链羰氧基、羰基氨基、氧羰基氨基或亚脲基二价连接基团取代的二价亚烷基基团;
每个R3独立地为H或具有1至4个碳原子的烷基基团;
R4为H或具有1至4个碳原子的烷基基团或-N(R3)2;并且
X1为-O-或-NR3-。
在第十八实施方案中,本公开提供根据第十三至第十六实施方案中任一项所述的制品,其中可阳离子化的单体单元包括由以下式表示的二价单体单元:
其中:
R1为H或具有1至4个碳原子的烷基基团;
R2为任选地被悬链羰氧基、羰基氨基、氧羰基氨基或亚脲基二价连接基团取代的二价亚烷基基团;并且
每个R3独立地为H或具有1至4个碳原子的烷基基团。
在第十九实施方案中,本公开提供根据第十三至第十八实施方案中任一项所述的制品,其中松散的阳离子配体官能化短纤维中的至少一部分为原纤化的。
在第二十实施方案中,本公开提供根据第十三至第十九实施方案中任一项所述的制品,其中生物组合物包含合成的聚合物絮凝剂。
通过以下非限制性实施例,进一步说明了本公开的目的和优点,但是这些实施例中引用的具体材料及其量以及其它条件和细节不应视为对本公开的不当限制。
实施例:
除非另外指明,否则在实施例及本说明书的其余部分中的所有份数、百分比(%)、比率等均是按重量计的。除非另外指明,用于实施例的材料购自标准化学供应商(例如诸如密苏里州圣路易斯的西格玛奥德里奇公司(Sigma-Aldrich Co.,Saint Louis,Missouri))和/或根据已知方法制备。用在实施例中的材料缩写列于表1中。
表1:
制备例1(PE 1)
十克聚乙烯(PE)纤维(SHORT STUFF E380F,长~.7mm并且直径为0.015mm,获取自田纳西州约翰逊市的微纤维公司(MiniFibers,Inc.,Johnson City,Tennessee))在贫氧(<50ppm氧)手套箱中用氮气吹扫。纤维密封在塑料袋中并从手套箱中移除。纤维在10Mrad和300kV下通过来自爱荷华州达文波特的PCT工程化系统(PCT Engineered Systems,Davenport,Iowa)的BROADBEAM EP电子束装置进行照射。该袋随后翻过来并在10Mrad和300kV下再次通过电子束。该袋随后放回氮气吹扫的手套箱中。
将照射过的纤维转移到玻璃广口瓶中并涂覆有223g包含单体的涂覆溶液,该溶液包含11.1重量%的NVP、6.7重量%的IEM-Ag、5重量%的GMA和77.2重量%的去离子水。使纤维和单体在氮气吹扫的手套箱中反应过夜。
反应后的纤维用14mM的氯化钠水溶液洗涤三次,使得盐水通过筛网片排出,同时保留纤维。纤维随后转移到大的铝盘中并使之干燥。干燥纤维称重以测定最终接枝产量。洗涤后的纤维称重为41.9g,指示31.9g的接枝聚合物已经被加到10g纤维中。
制备例2和3(PE2和PE3)
实施例1的方法用于制备官能化纤维,不同的是PE纤维是SHORT STUFF E780F,长1.3-2mm,直径为0.025mm,并且单个组分的量不同,如表2所记录。该纤维用于实施例2和3。
实施例5-6和比较例A-C
中国仓鼠卵巢细胞(CHO)培养物(以CHO-S购自纽约州格兰德艾兰的生命技术公司(Life Technologies,Grand Island,New York))在37℃下,在按体积计含5%CO2的空气的潮湿大气环境中,在带有合适补充剂的CD CHO培养基(购自生命技术公司(LifeTechnologies))中生长。将十五毫升培养物加到15mL锥形管中,其包含320mg实施例1的IEM-胍丁胺官能化纤维,并且随后在旋转器上手动混合10秒或10分钟。在混合后,样品立即在18-20英寸汞柱(61-68kPa)的最大压力下,通过使用25mm玻璃真空过滤器保持器(密理博(Millipore))的聚丙烯吹塑微纤维非织造过滤器(基重=107g/m2,5.9%的密实度,和37.8微米的有效纤维直径),进行真空过滤(Model 2522B-01真空泵,伊利诺斯州奈尔斯的威尔奇-伊尔姆(Welch-Ilmvac,Niles,Illinois))。作为比较,通过与pH 7.4的10mL磷酸盐缓冲溶液(购自生命技术公司(Life Technologies))混合并在基础基底上真空过滤以预封装相同量的纤维。在封装纤维团后,加入CHO培养物(15ml)并真空过滤。对于所有样品,样品过滤时间确定为从当启动真空泵时启动跑表至当溶液通过并且干燥纤维团剩下时停止泵的时间。测定每个样品的接触时间,并且接触时间是指纤维接触生物溶液的总时间。它被预计为从将生物溶液加入纤维时、混合、注入过滤漏斗、并且通过基础基底过滤的时间。收集滤液用于进一步分析(浊度、DNA浓度、宿主细胞蛋白浓度)。
滤液的浊度通过使用Hach 2100AN浊度计(科罗拉多州拉夫兰的哈希公司(HachCo.,Loveland,Colorado))测量滤液来测定。样品滤液的1-mL等分试样在14000rpm下离心5分钟以去除不可溶的物质。来自离心产物的总蛋白、DNA和CHO宿主细胞蛋白(CHOP)浓度分别使用Coomassie Plus蛋白分析(购自生命技术公司(Life Technologies))、QUANT ITPICOGREEN DSDNA分析试剂盒(生命技术公司(Life Technologies))、和CHO HCP ELISA试剂盒(北卡罗莱纳州绍斯波特的赛纳斯科技公司(Cygnus Technologies,Southport,NorthCarolina)),按照制造商的规程进行测定。样品一式三份,除了起始培养物不同(n=1),用于显示代表性的起始基线,并且结果记录在下表3中,其中“NA”是指“不适用”。
实施例7-10和比较例D-G
实施例7-10和比较例D-G类似于上文实施例5-6和比较例A-C进行,具有以下修改:i)使用新的CHO培养物;ii)纤维和生物溶液在50mL锥形管中,而非15mL管中混合;以及iii)改变混合时间以匹配在游离纤维样品和预封装纤维介质之间的接触时间。
样品一式三份,除了起始培养物不同(n=1),用于显示代表性的起始基线,并且结果记录在下表4中。
以上获得专利证书的申请中所有引用的参考文献、专利和专利申请以一致的方式全文以引用方式并入本文中。在并入的参考文献部分与本申请之间存在不一致或矛盾的情况下,应以前述说明中的信息为准。为了使本领域的普通技术人员能够实践受权利要求书保护的本公开而给出的前述说明不应理解为是对本公开范围的限制,本公开的范围由权利要求书及其所有等同形式限定。
Claims (18)
1.一种纯化生物组合物的方法,所述方法包括:
a)将松散的阳离子配体官能化短纤维和生物组合物设置在容器的混合容积内,其中所述松散的阳离子配体官能化短纤维具有包含接枝丙烯酸类聚合物的改性表面层,所述接枝丙烯酸类聚合物包含10至100重量%的可阳离子化的单体单元,和其中所述松散的阳离子配体官能化短纤维中的至少一部分为原纤化的高密度聚乙烯纤维;
b)搅拌所述生物组合物和所述松散的阳离子配体官能化短纤维,同时使它们在所述混合容积内彼此紧密接触,以提供改性纤维和纯化的生物组合物;以及
c)将所述纯化的生物组合物中的至少一部分与其所接触的所述改性纤维和任何松散的阳离子配体官能化短纤维分离。
2.根据权利要求1所述的方法,其中在将所述生物组合物设置在所述混合容积内之前将所述松散的阳离子配体官能化短纤维设置在所述混合容积内。
3.根据权利要求1所述的方法,其中步骤b)是使用静态混合器来至少部分地实现的。
4.根据权利要求1所述的方法,其中所述生物组合物包含合成的聚合物絮凝剂。
5.根据权利要求1所述的方法,其中所述接枝丙烯酸类聚合物还包含多官能单体单元。
6.根据权利要求1所述的方法,其中所述接枝丙烯酸类聚合物还包含0.1至90重量%的至少一种不可离子化的亲水单体单元。
7.根据权利要求6所述的方法,其中所述不可离子化的亲水单体单元包括具有4至6个碳原子的N-乙烯基内酰胺。
10.根据权利要求1所述的方法,其中所述容器包括密封的样本袋。
11.根据权利要求1所述的方法,其中步骤c)包括将所述改性纤维和任何松散的阳离子配体官能化短纤维中的至少一部分沉积在多孔基底上。
12.一种用于纯化生物组合物的制品,所述制品包括:
其中设置有混合容积的容器;以及
设置在所述混合容积内的松散的阳离子配体官能化短纤维,其中所述松散的阳离子配体官能化短纤维具有包含接枝丙烯酸类聚合物的改性表面层,所述接枝丙烯酸类聚合物包含10至100重量%的至少一种可阳离子化的丙烯酸类单体单元,和其中所述松散的阳离子配体官能化短纤维中的至少一部分为原纤化的高密度聚乙烯纤维。
13.根据权利要求12中任一项所述的制品,其中所述接枝丙烯酸类聚合物包含多官能单体单元。
14.根据权利要求13所述的制品,其中所述接枝丙烯酸类聚合物还包含0.1至90重量%的至少一种不可离子化的亲水单体单元。
15.根据权利要求14所述的制品,其中所述不可离子化的亲水单体单元包括具有4至6个碳原子的N-乙烯基内酰胺。
18.根据权利要求12所述的制品,其中所述生物组合物包含合成的聚合物絮凝剂。
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