CN111116735A - 包含分泌-样免疫球蛋白的组合物 - Google Patents
包含分泌-样免疫球蛋白的组合物 Download PDFInfo
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- CN111116735A CN111116735A CN201911079922.5A CN201911079922A CN111116735A CN 111116735 A CN111116735 A CN 111116735A CN 201911079922 A CN201911079922 A CN 201911079922A CN 111116735 A CN111116735 A CN 111116735A
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Abstract
本发明涉及包含分泌‑样免疫球蛋白的组合物，及体外产生包含分泌‑样免疫球蛋白，尤其是分泌‑样IgA和/或分泌‑样IgM的组合物的方法，所述方法包括以下步骤：(a)获得包含非‑纯化的形式的含有J链的免疫球蛋白的源于血的蛋白组合物，及(b)使步骤(a)中的组合物与分泌组分混合。通过本发明，无需首先纯化含有J链的免疫球蛋白而将含有源于血浆的J链的免疫球蛋白(尤其是IgA和/或IgM)与分泌组分组合是可能的。本发明开启了可用于医学，例如用于预防和治疗受试者，尤其是人受试者中粘膜表面上的感染的分泌‑样IgA和/或IgM的大规模生产的大门。
Description
本申请是2013年3月8日提交的同名发明专利申请201380013073.8的分案申请。
【技术领域】
本发明涉及制备包含分泌-样免疫球蛋白，尤其是分泌-样IgA和/或分泌-样IgM的组合物的方法，及可由该方法获得的组合物。
【背景技术】
IgA是在人血浆中在IgG之后第2最丰富的Ig类，其在血浆中以0.88～4.10g/L存在。有2种IgA亚类，IgA1和IgA2(图1)(Zuercher AW等人，Plasma derivedimmunoglobulins.Principles of Immunopharmacology.3rd ed.
2011:p.271-301)，它们不同在于，它们的连接重和轻链的二硫键，以及它们的由于分子的铰链区中的显著差异而致的抗原性多样性。2种亚类的糖基化模式不同：两种亚类的重链是N-糖基化的；相反，由于IgA2的截短的铰链区，O-糖基化见于IgA1但不IgA2。
人IgA见于2种主要形式：在血/血浆中循环，或分泌到粘膜表面。在血浆中，IgA是主要作为单体存在(80～90％)，及由骨髓浆细胞产生；血浆中的主要亚类是IgA1。
术语多聚体IgA(pIgA)描述由接合(J)链在它们的“尾部”共价接合的二聚，偶尔四聚体IgA(图1)。
IgM分子占总血清Ig含量的10％。它们被主要限制在血管内库，且是初次，抗原-特异性，体液免疫应答的部分；系统发生地和个体发生地，它们是最早的抗体(Ab)分子。IgM主要作为由J链接合的及排列为平面结构的五聚体存在；偶尔，IgM也可见于缺少J链的六聚体形式(Zuercher AW等人，Plasma derived immunoglobulins.Principles ofImmunopharmacology.3rd ed.
2011:p.271-301)。
消化道，呼吸道和泌尿生殖道，以及外分泌腺管的粘膜表面下衬有形成分隔身体的内部隔室与外部环境的紧密屏障的上皮细胞层。在人中，这些巨大表面覆盖400m2，永久暴露于外源病原体的面积(Corthésy,B.(2010)Future Microbiol.5:817-829)。先天性和诱导性细胞和分子机理的组合确保保护免于微生物定居和进入/侵入。在健康个体中，分泌性IgA(SIgA)是在粘膜表面的腔侧上实现免疫排除功能的最丰富的抗体(Ab)(Macpherson,A.J.et al.(2008)Mucosal Immunol.1:11-22)，然而在IgA-缺陷型患者中，分泌性IgM Ab取而代之。SIgA由肠固有层，上呼吸道或尿-生殖道的粘膜浆细胞合成。SIgA由pIgA二聚体，及大致75kDa的高度糖基化的分泌组分(SC)(图1)组成；类似地，与SC结合的五聚体的、含有J链的IgM构成SIgM。SC表示聚合物Ig受体(pIgR)的细胞外部分。pIgA或五聚体IgM自产生位点到粘膜表面的跨上皮运输需要pIgR，其中pIgR-pIgA/pIgR-IgM复合物由酶促切割转化为SIgA/SIgM(Zuercher AW等人，Plasma derived immunoglobulins.Principles ofImmunopharmacology.3rd ed.
2011:p.1-31)。与SC结合保护IgA或IgM免于蛋白水解降解。SIgA是浆液粘液性分泌诸如唾液，气管-支气管分泌，初乳，乳，泪，肠分泌和尿-生殖分泌中的主要Ig。其是在粘膜衬(由此在人身体中)产生的最显著的Ig；大致3～5g的SIgA每天分泌进肠腔。由此，SIgA对于免疫排除及对于维持上皮完整性是必要的。SIgM以更低水平存在，但与SIgA实现相同的免疫排除功能。
对于少数病原体诸如脊髓灰质炎病毒，沙门氏菌属(Salmonella)或流感，针对粘膜感染的保护可用许可的疫苗的活性粘膜免疫被诱导。但是，对于大多数粘膜病原体而言，无可利用的活性粘膜疫苗。或者，可将保护性水平的Abs由被动免疫直接递送到粘膜表面。在自然界，此许多哺乳动物物种由母源抗体经乳转移到它们的后代而生理学地发生(Brandtzaeg,P(2003)Vaccine 21:3382-3388)。使用被动粘膜免疫的人和动物研究展示，由口腔，鼻内，子宫内或肺滴注施用的pIgA和SIgA抗体分子可预防，减少或治愈细菌和病毒感染(Corthésy,B(2003)Curr.Pharm.Biotechnol.4:51-67)。但是，在粘膜表面天然地发现的分泌形式的IgA罕被使用，及至今SIgA的大规模生产还不可能。用生物技术方法构建SIgA是挑战，但该分子可具有重要临床应用(Corthésy,B。(2002)Trends Biotechnol.20:65-71)。其也应用于含有分泌组分的IgM。
【发明概述】
发明人意外地发现，无需首先纯化含有J链的免疫球蛋白而将含有源于血浆的J链的免疫球蛋白(尤其是IgA和/或IgM)与分泌组分组合是可能的。本发明开启了可用于医学，例如用于预防和治疗受试者，尤其是人受试者中粘膜表面上的感染的分泌-样IgA和/或IgM的大规模生产的大门。
本发明的一方面是体外产生包含分泌-样免疫球蛋白(尤其是IgA和/或IgM)的组合物的方法，包括以下步骤：
(a)获得源于血的蛋白组合物，其包含非-纯化的形式的含有J链的免疫球蛋白(尤其是IgA和/或IgM)；以及
(b)使步骤(a)中的组合物与分泌组分混合。
优选地，分泌-样免疫球蛋白是分泌-样IgA。优选地，步骤(a)中的组合物含有至少5％含有J链的IgA，更优选至少10％，更优选至少20％，甚至更优选至少30％，最优选其会含有至少50％含有J链的IgA。优选地，步骤(a)中的组合物源于人血，例如就IgA或甚至含有J链的IgA富集的人血浆或其级分，但无需含有J链的IgA的纯化。
优选地，分泌-样免疫球蛋白是分泌-样IgM。优选地，步骤(a)中的组合物含有至少5％含有J链的IgM，更优选至少10％，更优选至少20％，甚至更优选至少30％，最优选其会含有至少50％含有J链的IgM。优选地，步骤(a)中的组合物源于人血，例如就IgM或甚至含有J链的IgM富集的人血浆或其级分，但无需含有J链的IgM的纯化。
步骤(b)中使用的分泌组分优选是重组体分泌组分，更优选人重组体分泌组分，优选由哺乳动物细胞系产生的。但是，也可使用来自天然的源的分泌组分，诸如自乳，唾液，粘液或类似源纯化的分泌组分。
在步骤(a)的组合物中IgA二聚体/多聚体或IgM五聚体之内分泌组分和J链之间的摩尔比介于1:10和10:1之间，优选在1:5和5:1之间，更优选在1:2和2:1之间。
在本发明的另一方面，步骤(a)的组合物之中分泌组分和J链之间的摩尔比介于1:10和10:1之间，优选在1:5和5:1之间，更优选在1:2和2:1之间。
本发明的另一方面是组合物，其包含分泌-样IgA和/或分泌-样IgM或其组合，其可由本发明的方法获得。组合物可还包含药学可接受的载体或赋形剂。
本发明的再一方面是上述组合物，其用于医疗用途。
【发明详述】
如以上已提及，发明人意外地发现，无需首先纯化含有J链的免疫球蛋白而将含有源于血浆的J链的免疫球蛋白(尤其是含有J链的IgA和/或含有J链的IgM)与分泌组分组合是可能的。本发明开启了可用于医学，例如用于预防和治疗受试者，尤其是人受试者中粘膜表面上的感染的分泌-样IgA和/或分泌-样IgM的大规模生产的大门。
本发明的一方面是体外产生包含分泌-样免疫球蛋白(尤其是分泌-样IgA或分泌-样IgM)的组合物的方法，包括以下步骤：
(a)获得源于血的蛋白组合物，其包含非-纯化的形式的含有J链的IgA或含有J链的IgM，
(b)将步骤(a)中的组合物与分泌组分混合或组合。
优选地，步骤(a)中的组合物含有至少5％(w/w)含有J链的IgA，更优选至少10％，更优选至少20％，甚至更优选至少30％，更优选至少50％，最优选其会含有至少70％含有J链的IgA。优选地，步骤(a)中的组合物源于人血，例如就IgA或甚至含有J链的IgA富集的人血浆或其级分，但无需含有J链的IgA二聚体或聚合物的特定纯化步骤。因此，含有J链的IgA会在也包含其他蛋白诸如单体IgA，IgM或IgG的组合物中。例如，组合物可包含多于10％单体IgA，和/或多于10％IgG，和/或多于10％IgM。尽管就含有J链的二聚IgA富集可作为用于血浆蛋白诸如IgG，白蛋白，α-1抗胰蛋白酶及凝血因子的纯化的加工人血浆级分的部分而发生，对于获得步骤(a)中的组合物无需被特别设计用来分离含有J链的二聚IgA或聚合物与其他蛋白的纯化步骤，如亲和层析或尺寸排阻和关联分子质量的级分的选择。
在另一优选的本发明的方面，步骤(a)中的组合物含有至少5％(w/w)含有J链的IgM，更优选至少10％，更优选至少20％，甚至更优选至少30％，更优选至少50％，最优选其会含有至少70％含有J链的IgM。优选地，步骤(a)中的组合物源于人血，例如就IgM或甚至含有J链的IgM富集的人血浆或其级分，但无需含有J链的IgM的特定纯化步骤。因此，含有J链的IgM会在也包含其他蛋白诸如IgA或IgG的组合物中。例如，组合物可包含多于10％IgA，和/或多于10％IgG。尽管就含有J链的IgM的富集可作为用于纯化血浆蛋白诸如IgG，白蛋白，α-1抗胰蛋白酶及凝血因子的加工人血浆级分的部分发生，对于获得步骤(a)中的组合物无需被特别设计用来分离含有J链的IgM与其他蛋白的纯化步骤，如亲和层析或尺寸排阻和关联分子质量的级分的选择。
本文所用的术语“分泌组分”指称特异性结合于含有J-链的免疫球蛋白的蛋白，及涉及或可源于或相同于多聚体免疫球蛋白受体(pIgR)，优选哺乳动物pIgR，更优选灵长类动物pIgR，最优选人pIgR的细胞外部分。优选地，分泌组分赋予含有J-链的免疫球蛋白增加的稳定性。在组合物中包含的分泌组分可为重组体分泌组分，优选哺乳动物细胞系中产生的分泌组分。分泌组分以其传统，狭义(在本文被称为“天然的分泌组分”)是多聚体免疫球蛋白受体(pIgR)的细胞外部分，其通常在分泌期间与包含J链的二聚体或多聚体IgA或五聚体IgM结合。含有J链的IgA/IgM在上皮细胞的基底外侧表面结合于多聚体免疫球蛋白受体及由胞吞转运被摄入细胞。此受体复合物然后在运输到上皮细胞的腔表面之前通过细胞隔室运输。胞吞转运的IgA/IgM-pIgR复合物然后通过蛋白水解释放，及多聚体免疫球蛋白受体(pIgR)的部分(被称为天然的分泌组分)保持与含有J链的IgA/IgM结合，释放分泌IgA/IgM。但是，有证据表明，IgA的反向胞吞转运(即从腔表面到基底外侧表面)也可发生。
人pIgR被克隆及测序，其序列作为SwissProt登录号P01833可利用，及显示于SEQID NO:1。人pIgR是具有764个氨基酸残基的糖蛋白，其含有信号肽(残基1～18)，细胞外部分(残基19～638)，跨膜区(残基639～661)，及细胞质区(残基662～764)。残基19～603被认为结合于上述含有J链的IgA，及此糖蛋白的此部分通常被称为分泌组分(在本文被称为“天然的分泌组分”)。
在本发明的组合物中使用的分泌组分可包含任何能与含有J链的IgA结合的细胞外pIgR序列。例如，分泌组分可包含来自哺乳动物源，例如来自灵长类动物，牛，马，猫，狗，兔，豚鼠，大鼠或小鼠的pIgR的细胞外结构域，或其变体。也涵盖来自几种哺乳动物物种的细胞外结构域或其变体的功能杂交体以在本发明中使用，例如通过将来自不同物种的免疫球蛋白-样结构域融合进分泌组分-样蛋白而制备的。功能分泌组分也可通过融合一系列正常存在的免疫球蛋白-样结构域而形成，例如兔分泌组分是仅由结构域1，4和5组成的有功能的组分。但是，优选使用人分泌组分或其功能变体。
因此在本发明的组合物中使用的分泌组分优选包含SEQ ID NO:1的残基19～603或其功能变体。功能变体可包括缺失，插入和/或取代，优选取代是保守性取代，例如碱性氨基酸残基用另一碱性氨基酸代替，疏水氨基酸用另一疏水氨基酸代替，等。变体分泌组分在序列上与SEQ ID NO:1的残基19～603具有至少50％同一性，优选与SEQ ID NO:1的残基19～603具有至少55％，60％，65％，70％，75％，80％，更优选至少85％或甚至90％，甚至更优选至少92％，94％，95％，97％，98％或甚至99％同一性。优选地，分泌组分包含pIgR的细胞外部分，更优选人pIgR的细胞外部分，最优选分泌组分包含SEQ ID NO:1的残基19～603或甚至由SEQ ID NO:1的残基19～603组成。
本领域技术人员熟知如何由重组技术产生分泌组分。CHO细胞中人分泌组分的表达的一例已被Phalipon等人(Phalipon A等人(2002)Immunity 17:107-115)描述，但本发明不限于由此系统产生的分泌组分。例如，期望的cDNA序列可合成产生或使用从表达pIgR的细胞或组织分离的RNA作为模板经RT-PCR克隆。然后可将cDNA插入哺乳动物表达载体诸如pcDNA3-许多替代性的表达载体是可利用的。然后会将重组表达载体导入适合的宿主细胞系，诸如CHO，Cos，HEK293或BHK。其他细胞系是可利用的和也可使用。将该载体导入细胞系的方法包括脂转染，电穿孔和本领域技术人员熟知的其他技术。通常然后选择及克隆带有表达载体及表达目标蛋白的细胞。也可使用病毒表达系统，例如，痘苗病毒可用于在哺乳动物细胞中以高水平表达蛋白，杆状病毒表达系统可用于在昆虫细胞中以高水平表达蛋白。也可采用酵母或细菌表达系统，及该表达系统已由本领域技术人员所知。同样，也可采用植物表达系统，及该系统已由本领域技术人员所知。
在本发明的组合物中使用的分泌组分或其变体也可包含标签，诸如六-组氨酸标签，其可辅助纯化得到的蛋白。如果该标签经可切割的接头附接，标签可在本发明中使用之前切割下。类似地，分泌组分可作为融合蛋白产生。再次，可使用可切割的接头，从而融合偶体可在本发明中使用之前自分泌组分切割下。
本领域技术人员然后可用标准方法纯化表达的蛋白。重组体分泌组分可用适合的方法，例如尺寸排阻和/或离子交换层析纯化至高纯度。优选重组体分泌组分的最终制备物会是基本上无混杂物，特别宿主细胞蛋白。但是，分泌组分也可特异性结合未纯化的形式的含有J-链的免疫球蛋白，由此在与含有J-链的免疫球蛋白结合之前的纯化不是必要的。
分泌组分也可从天然的源，优选从乳，唾液或粘液得到。优选分泌组分具有人来源，但来自其他物种的分泌组分也可在本发明中使用。
在步骤(a)的组合物中IgA二聚体/多聚体或IgM五聚体之内的分泌组分和J链之间的摩尔比介于1:10和10:1之间，优选在1:5和5:1之间，更优选在1:2和2:1之间。
步骤(a)的组合物之中分泌组分和J链之间的摩尔比在1:10和10:1之间，优选在1:5和5:1之间，更优选在1:2和2:1之间。
步骤(b)中使用的分泌组分的量可为在步骤(a)的组合物中至少1份(以重量计)的分泌组分比50份(以重量计)的蛋白，优选至少1份比40，30，20，15，10份，最优选在步骤(a)的组合物中至少1份的分泌组分比5份的蛋白。
本发明的另一方面是包含分泌-样IgA的组合物，其可由本发明的方法获得。本发明的仍另一方面是包含分泌-样IgM的组合物，其可由本发明的方法获得。仍再一方面是例如以10:1和1:10之间，优选5:1和1:5之间，更优选2:1和1:2之间的摩尔比包含分泌-样IgA和分泌-样IgM的组合物，其可由本发明的方法获得。在本发明的另一方面，在组合物中IgA和IgM的组合的含量超过50％，优选60％，更优选70％，甚至更优选80％，甚至更优选90％，最优选其是100％。
本发明的再一方面是上述组合物，其用于医疗用途。例如，本发明的组合物可有利地用来治疗坏死小肠结肠炎，及通常在粘膜表面的感染。
组合物可还包含一种或更多药学可接受的载体或赋形剂，和/或稳定剂。组合物可以液体形式，配制为糖浆，洗液，软膏，可在施用之前用液体溶液化的粉，胶囊，丸剂，凝胶，霜剂，胶冻剂，受控释放制剂，或适合于旨在的医疗用途的任何其他制剂。例如，为治疗GI疾病，组合物可用在GI段的期望的区中溶解而释放组合物的保护性包衣配制。组合物可经口摄取，局部，肠内，通过吸入施用，或用于旨在的用途的任何其他适合的途径。为口腔应用，可共施用酸泵抑制物。
在组合物中的蛋白可在配制之前，例如使用透析过滤/超滤或其他标准方法浓缩。此外，组合物可冷冻干燥，然后在使用之前用适合的溶液重建。
【定义】
术语“分泌-样IgA”或“分泌-样血浆IgA”旨在包括与作为分泌组分或其功能变体的蛋白组合的含有J链的(血浆)IgA，其用于提供一些免于蛋白水解消化的保护。一般而言，含有J链的IgA会包含2个或4个，或甚至更多IgA单体。一般而言，含有J链的IgA会与分泌组分或其变体体外混合，即分泌组分和含有J链的IgA之间的结合体外发生，而非在胞吞转运期间。
术语“分泌-样IgM”旨在包括与分泌组分或其功能变体体外组合的含有J链的(血浆)IgM。优选地，含有J链的IgM会是五聚体IgM。
“含有J链的IgA二聚体或多聚体的特定纯化步骤”涉及会包括在为分离含有J链的IgA二聚体或多聚体与其他蛋白，诸如单体IgA，其他免疫球蛋白和其他血浆蛋白特别设计的纯化过程中的纯化步骤。该特定纯化步骤可，例如，包括用特异性结合J链的配体的亲和层析，或选择含有对应于含有J链的IgA二聚体的分子量的蛋白的级分的尺寸排阻层析。尽管自血浆制备组合物的过程可包括导致IgA或甚至含有J链的IgA富集的方法，诸如离子交换层析，含有J链的IgA未被特别纯化。由此，“非-纯化的形式的含有J链的IgA”指称含有少于80％含有J链的IgA，一般少于70％，60％或50％含有J链的IgA的组合物，其可甚至含有少于40％，30％，25％，20％，15％或甚至10％含有J链的IgA。
“含有J链的IgM的特定纯化步骤”涉及会包括在为分离含有J链的IgM与其他蛋白，诸如其他免疫球蛋白，及其他血浆蛋白而特别设计的纯化过程中的纯化步骤。该特定纯化步骤可，例如，包括用特异性结合IgM或J链的配体的亲和层析，或选择含有对应于含有J链的IgM五聚体的分子量的蛋白的级分的尺寸排阻层析。尽管自血浆制备组合物的过程可包括导致含有J链的IgM富集的方法，诸如离子交换层析，含有J链的IgM未被特别纯化。由此，“非-纯化的形式的含有J链的IgM”指称含有少于80％含有J链的IgM，一般少于70％，60％或50％含有J链的IgM的组合物，其可甚至含有少于40％，30％，25％，20％，15％或甚至10％含有J链的IgM。
本文所用的术语“分泌组分”指称特异性结合于含有J-链的免疫球蛋白的蛋白，及涉及或可源于或相同于多聚体免疫球蛋白受体(pIgR)，优选哺乳动物pIgR，更优选灵长类动物pIgR，最优选人pIgR的细胞外部分。优选地，分泌组分赋予含有J-链的免疫球蛋白增加的稳定性。如以上详述，最优选的分泌组分是人分泌组分，例如对应于SEQ ID NO:1的残基19～603。但是，可包括氨基酸缺失，插入，取代，只要它们导致有功能的蛋白，即仍能与含有J链的IgA结合和优选赋予保护免于对其的蛋白水解消化的蛋白。也包括来自其他哺乳动物物种的同源物，如包含来自不同物种的部分的嵌合蛋白。
术语“％[百分率]”当用来描述组合物/制备物中免疫球蛋白的含量时，是指重量/重量蛋白。
【附图说明】
本发明会由以下非限制性例，参照以下图和序列表例证：
图1显示单体，二聚体和含有J链的分泌IgA的结构的图。
图2显示用不同抗体显影的不同IgA制备物的蛋白印迹：
图2A显示用抗-α链，抗-J链或抗-分泌组分抗体显影的不同IgA制备物的蛋白印迹。
图2B显示用抗-分泌组分抗体显影的不同分泌-样和分泌IgA制备物的蛋白印迹。
图2C显示用针对分泌组分，α链和J链的抗体显影的分泌-样IgAF5的不同尺寸排阻层析级分的蛋白印迹。
图2D显示分泌-样IgAF5的尺寸排阻层析运行的层析谱。
图3显示使用固定的分泌组分的点印迹：
图3A显示如何启动测定的流程图
图3B显示捕获含有J链的IgA的SC
图3C显示捕获含有J链的IgM的SC
图4显示与肠洗涤物温育的不同IgA制备物(A)或IgM制备物(B)的时间进程实验的蛋白印迹。印迹通过使用抗-重链抗体显影。
图5显示由不同IgA制备物针对被志贺菌属(Shigella)感染的保护：
图5A显示在极化的Caco-2单层上由志贺菌属(Shigella)经上皮抗性的减小，及保护免于该由抗-志贺菌属(Shigella)SIgA(见Phalipon A等人(1995)J.Exp.Med.182:769-778)，IgAF5和SIgAF5的TER减小。
图5B显示由抗-志贺菌属(Shigella)SIgA，IgAF5和SIgAF5的结合的及内化的细菌的减少。
图6显示在与抗-志贺菌属(Shigella)SIgA(SIgAC5)(用作阳性对照)，及源于血浆的多聚体IgAF5，SIgAF5，单体IgAF5和IgG温育之后获得的志贺菌属(Shigella)免疫复合物的图像。
图7显示由暴露于志贺菌属(Shigella)(单独或以与各种Abs的复合物)的极化的Caco-2上皮单层细胞的细胞因子TNF-α和趋化因子CXCL8和CCL3的分泌。
图8显示由五聚体IgM和SIgM制备物的针对被志贺菌属(Shigella)感染的保护。
图8显示极化的Caco-2单层上由志贺菌属(Shigella)经上皮抗性的减小，及由抗-志贺菌属(Shigella)SIgA(见Phalipon A等人(1995)J.Exp.Med.182:769-778)，IgM和SIgM保护免于该TER的减小。
SEQ ID NO:1显示人pIgR的蛋白序列。
【实施例】
【实施例1：与重组体分泌组分混合的来自血浆的IgA制备物的蛋白印迹】
【材料和方法】
【1.1.由亲和层析和/或由MPHQ柱的连续洗脱来自血浆的IgA制备物】
由亲和层析，使用CaptureSelect人IgA树脂(Bioaffinity公司BAC,Naarden,Netherlands)，根据树脂生产商的流程，使用3种不同血浆IgA源作为原材料，即冷冻-耗尽的血浆，再溶解的冷的乙醇分级分离膏，或来自通过清洗所述柱获得的阴离子交换(AIEX)层析柱的条级分，根据商业上应用的CSL Behring AG的IgG纯化过程(Berne,Switzerland)纯化人血浆IgA。简言之，将冷冻-耗尽的合并血浆，再溶解的膏或AIEX条级分稀释于磷酸盐缓冲液(PBS)至大致1mg/mL的IgA浓度，后装载到PBS-平衡的CaptureSelect人IgA柱上，不超过柱的IgA结合容量。在装载之后，将柱用PBS洗涤，及将IgA用pH3的甘氨酸缓冲剂洗脱。将洗出液用0.5M Tris(pH8)调整到pH4.5，及在PBS中浓缩达16mG/mL蛋白。自人乳的SIgA由相同的方法纯化。
自CSL Behring AG(Berne,Switzerland)的IVIg制备过程的AIEX层析步骤，在将Macro-Prep High Q(Bio-Rad,Hercule,CA)柱用pH6.5的10mM磷酸盐/30mM乙酸盐后洗涤之后，通过用pH7.6的55mM酒石酸盐/5mM乙酸盐洗脱来获得级分F4。然后，用pH5.0的50mM磷酸盐/25mM柠檬酸盐洗脱级分F5。使F4和F5在PBS中由超/渗滤达到大致1mG/mL，然后由亲和层析，使用IgSelect树脂(GE Healthcare,Glattbrugg,Switzerland)耗尽IgG。在F4负荷的IgSelect层析的流通物中直接收获IgAF4。为了获得IgAF5，由亲和层析，使用CaptureSelect人IgM树脂(Bioaffinity Company BAC)使F5负荷的IgSelect流通物耗尽IgM。使IgAF4和IgAF5由超/渗滤达到终浓度。
【1.2.自血浆由亲和层析的IgM制备】
由亲和层析，使用CaptureSelect人IgM树脂(Bioaffinity Company BAC,Naarden,Netherlands)，根据树脂生产商的流程，使用相同的3个不同源作为原材料(如描述于关于IgA的1.1部分)，即冷冻-耗尽的血浆，再溶解的冷乙醇分级分离膏，或来自通过清洗所述柱获得的阴离子交换(AIEX)层析柱的条级分，根据商业上应用的CSL Behring AG的IgG纯化过程(Berne,Switzerland)来纯化人血浆IgM。简言之，将冷冻-耗尽的合并血浆，再溶解的膏或AIEX条级分稀释于磷酸盐缓冲液(PBS)至大致1mg/mL的IgM浓度，然后装载在PBS-平衡的CaptureSelect人IgM柱上，不超过柱的IgM结合容量。在装载之后，将柱用PBS洗涤，及将IgM用pH3的甘氨酸缓冲剂洗脱。将洗出液用0.5M Tris(pH8)调整至pH4.5，及在PBS中浓缩达10mG/mL蛋白。
【1.3.蛋白印迹】
使用来自Invitrogen的Mini-Cell系统(Carlsbad,CA)，根据生产商的流程实施SDS-PAGE及电转移到硝酸纤维素(NC)膜。简言之，将样品在样品缓冲剂中，分别在还原或非-还原性条件下变性，和在预浇铸的梯度凝胶，NuPAGE Novex Bis-Tris 4～12％1.0mm10孔上，使用NuPAGE MOPS电泳缓冲剂(Invitrogen)电泳分离。湿转移到NC膜(0.2μm)用XCell II Blot模块(Invitrogen)和NuPAGE Transfer缓冲剂实施。然后将膜在含有4％Rapilait脱脂乳粉(Migros,Switzerland)的PBS-0.5％吐温20溶液(PBS-T)中阻断30min。为免疫印迹，使用多克隆兔抗体：(1)兔抗-人α链(Dako,缀合了辣根过氧化物酶(HRP)的：1/5,000稀释)；(2)兔抗-人J链(BioGenex,Fremont,CA；1/300稀释)，之后是缀合了第二抗-兔HRP的抗血清(Sigma；1/10,000稀释)；(3)兔抗-人SC(Dako；1/5000稀释)，之后是缀合了第二抗-兔HRP的抗血清(Sigma；1/10,000稀释)。于环境温度，在含有4％乳粉的PBS-T中实施全部温育1～2小时。在最终用PBS-T之后洗涤，由化学发光揭示和在ImageQuant LAS 4000系统(GE Healthcare Lifesciences)中数字地记录在膜上的免疫检测。
【1.4.血浆来源的IgA与重组体分泌组分的结合】
通过体外组合100mg的IgAF5与4mg的重组人分泌组分(recSC)获得分泌-样IgA。如之前描述，于室温，在PBS中实施结合30min(Crottet,P.,and Corthésy,B.(1998)J.Immunol.161:5445-5453)。
【1.5.尺寸排阻层析(SEC)分级分离】
将包含分泌-样IgA(与recSC体外结合)的IgAF5以200μG/20μL注射进AgilentTechnologies 1050HPLC系统，用于以1.5mL/min的流速，在TSK凝胶G3000SWXL 7.8mm ID×30cm柱(Tosoh Bioscience)上进行尺寸排阻层析。在8.0和13.5min之间的滞留时间，以30s的间隔收集0.75mL的级分。
【结果】
结果显示于图2。图2A展示自血浆由亲和层析纯化的，自再溶解的膏纯化的及自AIEX条级分纯化的或为获得IgAF5由连续洗脱纯化的IgA(如描述于1.1)与来自人乳的SIgA的比较。分泌组分见于来自乳的SIgA，但不见于任何自人血浆纯化的IgA级分。全部制备物含有相同的量的IgA重链/α-链。如所预期，来自乳的SIgA含有最高量的J链，由于基本上全部IgA分子被预期作为含有J链的二聚体存在。自血浆纯化的IgA中J链和由此含有J链的IgA二聚体量低。这被预期为，仅小部分的血浆IgA以二聚形式存在。从自再溶解的膏纯化的IgA中观察到近似含量的J链。意外地，增加的IgA级分在柱带级分中作为含有J链的二聚体存在，如由增加的J链量证明。意外地，此还在IgAF5中增加。此蓄积无需应用用于富集的特定过程步骤而发生。
图2B显示，IgAF5中不存在含有IgA的分泌-组分。在与recSC结合之后，发现游离的recSC(75kDa)和二聚IgA与recSC结合。的确，分泌-样血浆IgA呈现出类似于来自乳的SIgA。估计在显示的实验中使用的IgAF5的制备物中，含有J链的IgAF5的含量是约20％。的确，泳道2中观察到的信号强度与1:5-稀释的人乳SIgA的信号相当。
图2C显示由分泌-样IgAF5的尺寸排阻层析获得的级分中SC，IgAα链和J链的含量。在对应于高分子量形式的IgA(可能多聚和二聚形式)的早期级分中观察到recSC。SC的呈现与J链的呈现重合，指示IgAF5的含有SC的级分的确是二聚的，含有J链的级分。此外，在更小分子量的级分(可能包含IgAF5的单体级分)中检测到IgAα-链；这些级分缺乏SC和J链。这些数据展示，与含有单体和二聚形式的IgA的源于血浆的IgA混合的recSC与二聚的，含有J链的形式的IgA特别结合。
图2D显示了SEC层析谱，期间收集8.0min和13.5min之间的滞留时间的级分。显示了表示IgA多聚体，二聚体和单体的峰。
【实施例2：点印迹重结合测定(DORA)】
点-印迹重结合测定用于显示固定的分泌组分与源于血浆的IgA或IgM体外结合。简言之，如显示于图3A，分泌组分点斑在印迹膜上；阻断非特异性结合位点。然后将自血浆由亲和层析(泳道4)获得的，自再溶解的膏获得的(泳道5)或自AIEX条级分获得的(如描述于1.1和1.2获得的)(泳道6)血浆来源的IgA(图3B)或IgM(图3C)应用于膜。在洗下未结合的IgA或IgM之后，如以下简述检测结合的IgA/IgM。
基本上如描述实施DORA(Rindisbacher,L.等人(1995)J.Biol.Chem.270:14220-14228)，进行了以下修饰：印迹膜由聚偏氟乙烯(PVDF)聚合物组成，封闭溶液是含有1％牛血清白蛋白(BSA)的磷酸盐缓冲液-0.05％吐温-20(PBS-T)，使用富集IgA的粗制备物覆盖200μl的含有0.1％BSA的PBS-T中温育，及将检测抗体直接偶联于HRP。
IgA的结果显示于图3B。固定的分泌组分能捕获源于血浆的IgA。类似于图2C中显示的，此展示，recSC与源于血浆的IgA二聚体结合。
IgM的结果显示于图3C。固定的分泌组分能捕获源于血浆的IgM。此展示，recSC与源于血浆的IgM结合。
【实施例3：用肠洗涤消化分泌-样IgA和分泌-样IgM】
为了证明纯化的分泌组分分别与含有J链的IgA和IgM结合的功能优势，如描述于段落1.1和1.2制备IgA和IgM。通过使用尺寸排阻层析富集含有J链的IgA，并将其10μg与2.5μg的重组人分泌组分(hSCrec)体外组合来获得分泌-样IgA。通过使用尺寸排阻层析富集五聚体IgM，并将其25μg与2.5μg的重组人分泌组分(hSCrec)体外组合来获得分泌-样IgM。如之前描述，于室温在PBS中实施结合30min(Crottet,P.,and Corthésy,B.(1998)J.Immunol.161:5445-5453)。由SDS-PAGE，在非-还原和还原性条件下检查分子可能集成和适当的组装为共价复合物，之后是用特异于hSC的抗血清进行蛋白印迹和免疫检测，如以上显示。
根据公开的方法自BALB/c小鼠(4～6周龄)收集肠洗涤物(Crottet,P.,and Corthésy,B.(1998)J.Immunol.161:5445-5453)。为体外消化，将120ng的纯化的含有J链的IgA及重建的分泌-样IgA在20μl的PBS的最终体积中与1或2μl的肠洗涤物混合(或不)，及于37℃温育各时间，如显示于图4(T＝以小时计的时间)。为IgM的体外消化，将250ng纯化的IgM和分泌-样IgM与4μl的肠洗涤物混合。通过添加2μl的CompleteTM蛋白酶抑制物混合物(RocheApplied Science,Rotkreuz,Switzerland)停止反应，及保持冷冻，直到由检测还原型的抗体重链的蛋白印迹分析。
结果显示于图4A和B。将来自再溶解的膏及来自柱带的IgA(如描述于1.1获得的)及来自柱带的IgM(如描述于1.2)原样或在与recSC结合而形成分泌-样IgA(图4A)或分泌-样IgM(图4B)之后使用。对于IgA，在4小时的用肠酶消化之后，非-结合的IgA的信号开始减小，指示蛋白水解消化；在6小时之后效应更强，及在过夜消化之后，由蛋白印迹检测不到完整IgAα-链。相反，分泌-样IgA对于由肠蛋白酶的消化欠敏感得多，和甚至在过夜暴露之后，分泌-样IgA之内的IgAα-链的重要部分保持完整。
对于IgM(图4B)，显示了在24h和48h的消化之后IgM和新鲜结合的分泌-样IgM(SIgM)与相同的制备物的比较。相比SIgM，对于IgM而言，降解的μ-链片段的出现更快速和更广泛地发生，类似于IgA，对于IgM确认，与recSC结合提供改善的结构稳定性。
总之，此展示，与recSC的特异性结合提供改善的结构稳定性，且会使消化-倾向血浆IgA分子适合于粘膜应用，例如经口腔途径。
【实施例4：弗氏志贺菌(Shigella flexneri)】
如描述将人结肠腺癌上皮Caco-2细胞系(American Type Tissue Collection)接种在聚酯Snapwell滤器(直径,12mm；孔径,0.4μm；Corning Costar)上(Crottet,S.,Corthésy-Theulaz,I.,Spertini,F.,and Corthésy,B.(2002)J.Biol.Chem.277:33978-33986)。通过使用Millicell-ERS装置(Millipore)测量经上皮电阻(TER)来检查极化的Caco-2单层细胞的完整性。良好分化的单层的TER值跨450～550Ω×cm2之间。
将2×107细菌(Phalipon A.et al(1995)J.Exp.Med.182:769-778)在500μl的无血清DMEM(P-DMEM：补充10mM HEPES,20μg/ml转铁蛋白,2mM谷氨酰胺,1％非-必要的氨基酸,1mM丙酮酸钠的DMEM)的最终体积中与100μg的IgA，125μg的分泌-样IgA，275μg IgM或300μg SIgM混合，及在轻轻搅拌下于室温温育1h。使混合物重悬浮于P-DMEM，以感染极化的Caco-2单层细胞。
在使用极化的Caco-2单层细胞之前1h，在顶部和底部外侧隔室中将C-DMEM用P-DMEM取代。然后将顶部培养基由500μl的细菌悬浮液(2×107细菌)原样或组合抗体取代。自感染开始，在选择的时间-点测量TER值。
为了定量粘附及感染了细胞的细菌，将滤器中的Caco-2细胞用PBS洗涤3次，将细胞在500μl的冷裂解缓冲剂[10mM Tris-HCl(pH7)，0.2％Nonidet P-40，50mM NaCl，2mMEDTA(pH8)]中在冰上温育5min，和由上下移液裂解。将细胞裂解物的系列稀释物(10-2～10-6)应用到LB琼脂板，及在37℃24h的温育之后，通过两份板的肉眼计数测定集落-形成单位(CFU)
为了检查Caco-2单层细胞的完整性，在用5ml的4％多聚甲醛，于4℃固定过夜之前，将Snapwells用PBS洗涤。在用PBS洗涤之后，将滤器渗透化，及通过使用含有5％FCS和0.2％Triton X-100的PBS(PBS-Tr)于室温阻断非特异性结合位点30min。将全部抗体稀释于PBS-Tr。将滤器于室温与兔抗-人ZO-1(1/200,Invitrogen)温育2h，在PBS中洗涤，之后是于室温与缀合了Alexa 
647(1/100,Invitrogen)的山羊抗-兔IgG温育90min。为了可视化细胞，将滤器最终在PBS(Invitrogen)中与100ng/ml的4',6-二脒基-2-苯基吲哚(DAPI)温育30min。将滤器从它们的支架切出，及在Vectashield溶液中包埋，以用于使用装备10×或40×物镜的Zeiss LSM 710Meta共聚焦显微镜(Carl Zeiss,德国)观察。图像通过使用Zeiss ZEN 2009光软件处理。
为了检查志贺菌属(Shigella)-IgA复合物，使用组成性表达绿荧光蛋白的细菌，及在于室温，在轻轻搅拌下与生物素化的小鼠抗-人IgA1/IgA2(1/10,BD)温育30min，之后是于室温，在轻轻搅拌下与缀合了花青苷5的链霉亲和素(1/400,GE HealthCare)温育30min之后确证免疫复合物的形成。在各步骤之间实施用PBS的3次洗涤，和将全部抗体稀释于PBS/5％FCS。将标记的免疫复合物搁在玻璃载玻片(Thermo Scientific)上，包埋及通过使用装备63×物镜的Zeiss LSM 710Meta共聚焦显微镜(Carl Zeiss,德国)立即可视化。将图像用Zeiss ZEN 2009光软件处理。
由ELISA，用商业试剂盒(分别BD Biosciences和R&D Systems)定量极化的Caco-2单层细胞的基底外侧隔室中的人CXCL8(IL-8)，TNF-α和CCL3(MIP-3α)。
【结果】
极化的肠上皮单层细胞暴露于志贺菌属(Shigella)导致单层的完整性的破坏(由TER的减小(图5A)证明)，大量侵入(由发现与上皮细胞结合的细菌计数增加(图5B)，及由明显受损的单层细胞(如由激光扫描共聚焦显微镜检观察到的)证明)。由TER减小的显著抑制(图5A)，由结合上皮细胞的细菌数的减小(图5B)，及由通过共聚焦显微镜检分析中更保存的单层细胞完整性指示，分泌-样IgA的添加延迟及部分抑制单层的破坏。
与仅包被细菌的单体IgA和IgG(图6)相反，志贺菌属(Shigella)-特异性单克隆SIgA SIgAC5，多聚体IgA和分泌-样IgA的结合导致多个细菌的免疫聚集物的形成(图6)。由源于特异性mAb和血浆的pIgA和分泌-样IgA的细菌聚集贡献于图5B中观察的细菌粘接于Caco-2细胞减少是可能的。相同的3个抗体制备物显著地减少由Caco-2细胞促-炎性细胞因子/趋化因子的产生，而单体IgAF4和IgG无(TNF-α和CCL3)或具有弱(CXCL8)效应(图7)。此指示，由分泌和多聚体IgA的志贺菌属(Shigella)中和减小Caco-2细胞的应答，最终贡献于IgA的总体抗-炎性性质。
用IgM和分泌-样IgM类似地达到保护极化的Caco-2单层细胞免于被志贺菌属(Shigella)感染至当使用特定SIgAC5时恢复的至少近似水平(图8)。TER维持至少12h30指示，IgM同种型具有保护Caco-2单层免于由暴露于志贺菌属(Shigella)诱导的损伤的中和性质。
【实施例5：防止难辨梭菌(Clostridium difficile)感染(CDI)复发】
本发明的组合物用于难辨梭菌(Clostridium difficile)感染的小鼠模型。
如之前描述，将C57BL/6小鼠用口腔抗生素的混合物(卡那霉素,庆大霉素,多粘菌素,甲硝唑和万古霉素)处理3天(Chen X,等人，Gastroenterology 2008December；135(6):1984-92)。2天后，给它们施用肠胃外磷酸克林霉素(10mg/kg皮下)[第-1天]。1天后[第0天]通过强饲0.5×105cfu的产毒难辨梭菌(C.difficile)株10465攻击它们。在施用难辨梭菌(C.difficile)之后1～5天发生中等至爆发性结肠炎。在未处理的大多数动物中，此快速发展为严重的和致死的结肠炎。为治疗原发感染，在难辨梭菌(C.difficile)攻击之后5天，动物接收万古霉素，及监测动物死亡率，以及伴随腹泻的严重的CDI的存在或缺失。由单次注射戊巴比妥钠无痛处死被判断在垂死状态的动物。为了研究CDI的复发，保持对在初次难辨梭菌(C.difficile)攻击中存活的动物的观察直到第28天。第7～28天每周给动物称重3次。在停止万古霉素处理之后，在最后万古霉素剂量之后一日起，动物接收IgA或分泌-样IgA(400mg/kg体重，经口腔途径)5天。
【结果】
用万古霉素处理的动物在用难辨梭菌(C.difficile)原发感染中生存。但是，显著比例(达70％)的动物在万古霉素处理终止之后3～4天之内屈服于难辨梭菌(C.difficile)感染复发。相反，如果将动物用分泌-样IgA经口腔途径处理，则防止感染复发。血浆IgA单独在防止难辨梭菌(C.difficile)感染复发中不如分泌-样IgA有效(或至少不那么有效)。
或者，类似于Watkins等人(Oral Dis 2010,16:655-660)描述，在口腔粘膜炎模型中使用所述组合物。
给叙利亚金色仓鼠每天3次预防性地施用(例如起始于第-3天)适当配制的IgA制备物(或对照是媒质溶液)经研究的整个持续时间达第28天。在急性放射-诱导的粘膜炎模型中，在第0天照射(40Gy)一个外翻的颊囊，另一颊囊保持未处理用于对照。或者，在分次的放射-诱导的粘膜炎模型中，应用60Gy的累积剂量，分为7.5Gy的8个部分，如描述于(Watkins,Oral Dis 2010,16:655-660)。在组合的顺铂和急性放射-诱导的粘膜炎的仍另一模型中，通过在第0天组合顺铂(5mg/kg)和35Gy放射来诱导疾病。从第6天起始直到研究结束(一般在第28天)每天进行口腔粘膜炎的临床评估及体重监测。评分系统描述于(Watkins Oral Dis,2010 16:655-660)。此外，收集组织和血浆样品及贯穿组织分析的研究，测定血浆中的炎性标志物及为各种组织的基因表达研究而适当加工。
【结果】
未处理的/媒质处理的动物发展口腔粘膜炎，疾病峰约第16～18天，自发治愈，通过粘膜炎消退证明，约第18～20天起始。用IgA治疗的动物和尤其是用分泌-样IgA治疗的动物相比对照动物具有显著地更低粘膜炎分值及体重减轻更少，并行欠严重的组织发现及减少的炎性标志物(包括但不限于炎性细胞因子和趋化因子)水平。由基因-表达分析技术在mRNA表达水平确认了发炎减小和促进创伤-治愈。
序列表
<110> CSL Behring AG
<120> 包含分泌-样免疫球蛋白的组合物
<130> A192
<150> EP2012158931.1
<151> 2012-03-09
<150> EP2012168343
<151> 2012-05-16
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 764
<212> PRT
<213> 智人（Homo sapiens）
<400> 1
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Leu Asp Ile Gln Gly Thr Gly Gln Leu Leu Phe Ser Val Val Ile Asn
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Gln Leu Arg Leu Ser Asp Ala Gly Gln Tyr Leu Cys Gln Ala Gly Asp
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Asp Ser Asn Ser Asn Lys Lys Asn Ala Asp Leu Gln Val Leu Lys Pro
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Glu Pro Glu Leu Val Tyr Glu Asp Leu Arg Gly Ser Val Thr Phe His
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Cys Ala Leu Gly Pro Glu Val Ala Asn Val Ala Lys Phe Leu Cys Arg
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Gln Ser Ser Gly Glu Asn Cys Asp Val Val Val Asn Thr Leu Gly Lys
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Arg Ala Pro Ala Phe Glu Gly Arg Ile Leu Leu Asn Pro Gln Asp Lys
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Asp Gly Ser Phe Ser Val Val Ile Thr Gly Leu Arg Lys Glu Asp Ala
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Gly Arg Tyr Leu Cys Gly Ala His Ser Asp Gly Gln Leu Gln Glu Gly
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Ser Pro Ile Gln Ala Trp Gln Leu Phe Val Asn Glu Glu Ser Thr Ile
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Ser Ile Arg Ser Tyr Arg Thr Asp Ile Ser Met Ser Asp Phe Glu Asn
675 680 685
Ser Arg Glu Phe Gly Ala Asn Asp Asn Met Gly Ala Ser Ser Ile Thr
690 695 700
Gln Glu Thr Ser Leu Gly Gly Lys Glu Glu Phe Val Ala Thr Thr Glu
705 710 715 720
Ser Thr Thr Glu Thr Lys Glu Pro Lys Lys Ala Lys Arg Ser Ser Lys
725 730 735
Glu Glu Ala Glu Met Ala Tyr Lys Asp Phe Leu Leu Gln Ser Ser Thr
740 745 750
Val Ala Ala Glu Ala Gln Asp Gly Pro Gln Glu Ala
755 760
Claims (18)
1.体外产生包含分泌-样免疫球蛋白的组合物的方法，包括以下步骤：
(a)获得包含非-纯化的形式的含有J链的免疫球蛋白的源于血的蛋白组合物，
(b)使步骤(a)中的组合物与分泌组分混合。
2.权利要求1的方法，其中分泌-样免疫球蛋白是分泌-样IgA和/或分泌-样IgM。
3.权利要求1或权利要求2的方法，其中步骤(a)中的组合物含有至少5％J链-连接的IgA。
4.权利要求3的方法，其中步骤(a)中的组合物含有至少10％J链-连接的IgA。
5.权利要求3的方法，其中步骤(a)中的组合物含有至少20％J链-连接的IgA。
6.权利要求3的方法，其中步骤(a)中的组合物含有至少30％J链-连接的IgA。
7.权利要求3的方法，其中步骤(a)中的组合物含有至少50％J链-连接的IgA。
8.前述权利要求之任一项的方法，其中步骤(a)中的组合物源于人血。
9.前述权利要求之任一项的方法，其中步骤(b)中的分泌组分是重组体分泌组分。
10.前述权利要求之任一项的方法，其中分泌组分是人分泌组分。
11.前述权利要求之任一项的方法，其中分泌组分在哺乳动物细胞系中产生。
12.前述权利要求之任一项的方法，其中分泌组分是多聚体免疫球蛋白受体pIgR的细胞外部分。
13.前述权利要求之任一项的方法，其中在步骤(b)中，添加的分泌组分和IgA二聚体/多聚体之内的J链之间的摩尔比介于1:10和10:1之间。
14.权利要求13的方法，其中所述比介于约1:5和5:1之间。
15.权利要求14的方法，其中所述比介于约1:2和2:1之间。
16.组合物，其包含分泌-样IgA和/或分泌-样IgM或其组合，所述组合物可由权利要求1～15之任一项的方法获得。
17.权利要求16的组合物，其还包含药学可接受的载体或赋形剂。
18.权利要求16或权利要求17的组合物，其用于医疗用途。
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| EP12158931.1 | 2012-03-09 | ||
| EP12168343.7 | 2012-05-16 | ||
| EP12168343 | 2012-05-16 | ||
| CN201380013073.8A CN104254542A (zh) | 2012-03-09 | 2013-03-08 | 包含分泌-样免疫球蛋白的组合物 |
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| CN201380013073.8A Division CN104254542A (zh) | 2012-03-09 | 2013-03-08 | 包含分泌-样免疫球蛋白的组合物 |
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| CN201911079922.5A Pending CN111116735A (zh) | 2012-03-09 | 2013-03-08 | 包含分泌-样免疫球蛋白的组合物 |
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| US9458230B2 (en) | 2013-01-04 | 2016-10-04 | Wisconsin Alumni Research Foundation | Secretory IGA compositions, methods of making and methods of use thereof |
| US9468674B2 (en) * | 2013-09-24 | 2016-10-18 | Wisconsin Alumni Research Foundation | Methods of use of secretory IgA |
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| EP3429622B1 (en) | 2016-03-14 | 2021-04-21 | Biotest AG | Treatment of severe community acquired pneumonia |
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| CN110724176B (zh) * | 2018-07-16 | 2021-10-26 | 北京豪思生物科技有限公司 | 一种治疗阿尔茨海默症的血浆蛋白分离物及其制备方法和应用 |
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Also Published As
| Publication number | Publication date |
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| US20190256577A1 (en) | 2019-08-22 |
| EP2822967B1 (en) | 2019-08-07 |
| BR112014022240A2 (pt) | 2017-08-01 |
| KR102142261B1 (ko) | 2020-08-11 |
| HK1204628A1 (zh) | 2015-11-27 |
| US10221233B2 (en) | 2019-03-05 |
| US20140371431A1 (en) | 2014-12-18 |
| JP2019038834A (ja) | 2019-03-14 |
| RU2644240C2 (ru) | 2018-02-08 |
| AU2013201393A1 (en) | 2013-09-26 |
| RU2014140744A (ru) | 2016-04-27 |
| EP2822967A1 (en) | 2015-01-14 |
| US11623948B2 (en) | 2023-04-11 |
| CA2866634C (en) | 2022-07-19 |
| US20170058018A2 (en) | 2017-03-02 |
| SG11201404958SA (en) | 2014-11-27 |
| NZ629072A (en) | 2016-03-31 |
| MX2014010754A (es) | 2014-12-05 |
| CA2866634A1 (en) | 2013-09-12 |
| ES2751976T3 (es) | 2020-04-02 |
| DK2822967T3 (da) | 2019-10-07 |
| US10385117B2 (en) | 2019-08-20 |
| CN104254542A (zh) | 2014-12-31 |
| AU2013201393B2 (en) | 2015-08-27 |
| KR20140132770A (ko) | 2014-11-18 |
| JP2015510875A (ja) | 2015-04-13 |
| PL2822967T3 (pl) | 2020-01-31 |
| MX360245B (es) | 2018-10-26 |
| US20150056180A1 (en) | 2015-02-26 |
| IL234449B (en) | 2018-07-31 |
| JP2021038246A (ja) | 2021-03-11 |
| WO2013132052A1 (en) | 2013-09-12 |
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