CN109069643A - 药物组合物 - Google Patents
药物组合物 Download PDFInfo
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- CN109069643A CN109069643A CN201780028404.3A CN201780028404A CN109069643A CN 109069643 A CN109069643 A CN 109069643A CN 201780028404 A CN201780028404 A CN 201780028404A CN 109069643 A CN109069643 A CN 109069643A
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及包含适于冷冻干燥(即冻干)的抗体或其片段的药物组合物。所述药物组合物包含抗体或其抗原结合片段;1%至20%w/v的蔗糖;氨基酸或氨基酸的混合物;和表面活性剂;所述药物组合物被提供作为用于冷冻干燥的药物组合物;作为可以在使用时在溶剂中重构的冷冻干燥的(即冻干的)组合物,或作为准备用于施用的重构液体制剂。
Description
发明领域
本发明属于药物制剂领域。更具体地,本发明涉及液体或冷冻干燥的药物组合物,其包含抗体、蔗糖、氨基酸或氨基酸的混合物和表面活性剂。
发明背景
治疗性抗体的工业制造是一项复杂的任务。它需要从在实验室中开发以毫克数量生产抗体的工艺扩大规模至数千克的数量。尽管抗体是相当稳定的分子,但是当在一段时间内以高浓度储存时,它们可能遭受化学和物理不稳定性。典型的化学不稳定性可导致脱酰胺、水解、氧化、β-消除、二硫化物交换或还原。物理不稳定性可导致变性、聚集或沉淀。
虽然液体制剂能够以最少的制剂施用,但它们具有随时间变得不稳定的缺点。液体水基制剂是特别复杂的;水充当反应物或促进反应物的转移,导致化学降解和蛋白质不稳定性。液体制剂中蛋白质的稳定化以避免或最小化聚集、沉淀或降解仍然是特别的挑战。聚集(形成不溶性物质或沉淀物)是一个特别的问题。这可能引起各种问题,例如聚集体的形成,这可能导致施用后的免疫反应和/或难以进行药物制剂的适当施用,例如,通过导致输送装置的堵塞。
抗体可以配制成冷冻干燥的(即冻干)形式,用于在施用前不久在溶剂中重构。冷冻干燥的抗体制剂往往比液体水基制剂更稳定。冷冻干燥有助于在最终制剂中获得高浓度的抗体,因此减少了注射体积以及注射时间。
此外,冷冻干燥(冻干)是单克隆抗体的长期储存稳定化的选择方法,否则单克隆抗体在液体形式中不稳定。在较低温度下冷冻干燥抗体减少对产品的损害并有助于保持分子完整性。它延长了保质期,降低了运输的温度要求,并保留了抗体的化学和生物学特性。
与其他蛋白质一样,抗体在不存在稳定剂的情况下在冷冻干燥时经历变性。通常将不同的稳定剂如糖或多元醇加入到制剂中以保护抗体免于在冷冻干燥和储存期间降解。糖或多元醇提供的稳定化水平通常取决于它们的浓度。将糖/多元醇浓度增加到一定水平可能最终达到稳定化的极限或甚至使蛋白质在冷冻干燥过程中不稳定,因此冷冻干燥抗体的储存稳定性需要稳定剂与蛋白质的特定浓度(Chang L等人J Pharm Sci.2005;94:1445-55)。在冷冻干燥过程中用于保护的稳定剂的水平取决于稳定剂的制剂组成、浓度和物理性质,以及其与抗体的相容性。干燥过程中稳定化的机理是稳定剂充当水替代物。水和蛋白质之间的相互作用对蛋白质的构象稳定性至关重要。当在干燥期间除去水时,稳定剂能够如水分子那样与蛋白质形成氢键,从而在冻干过程中保留天然蛋白质结构(Chang L等人,JPharm Sci.2005;94:1445-55)。
尽管冻干是实现抗体所需长期储存的良好选择,但在配制抗体方面没有简单的通用方案。在冻干过程和/或长期储存期间,抗体可能变得不稳定,在重构时可能形成聚集体,或者冻干的糕状物可能花费太长时间来重构。高浓度的稳定剂可影响最终制剂的物理化学性质(即粘度)。
鉴于上述情况,本领域仍需要提供进一步改进的适用于冷冻干燥的抗体药物组合物。
发明概述
本发明通过提供包含适于冷冻干燥(即冻干)的抗体或其片段的药物组合物解决了上述需要。得到的药物组合物能够被提供作为在使用时在溶剂中重构的冷冻干燥的(即冻干的)组合物,或作为准备用于施用的重构液体制剂。减少体积的重构允许以低水平的聚集和递送时间实现具有高浓度的抗体或其片段的制剂。
以下文中的编号描述了以下具体实施方案:
1.一种药物组合物,其包含:
a.抗体或其抗原结合片段;
b.1%至20%w/v的蔗糖;
c.氨基酸或氨基酸的混合物;和
d.表面活性剂。
2.根据实施方案1的药物组合物,其具有4.0至7.5的pH。
3.根据实施方案1或实施方案2的药物组合物,其中所述抗体或其抗原结合片段的浓度为1至200mg/mL,优选50至150mg/mL,更优选80至140mg/mL。
4.根据前述实施方案中任一项的药物组合物,其中所述组合物包含5%至13%w/v的蔗糖,优选7%至10%w/v的蔗糖,更优选7%w/v的蔗糖。
5.根据前述实施方案中任一项的药物组合物,其中:
a.氨基酸是组氨酸或脯氨酸;或
b.氨基酸的混合物包含组氨酸和脯氨酸。
6.根据前述实施方案中任一项的药物组合物,其中所述组合物包含0.01至1.0%w/v,优选0.01%至0.5%w/v的表面活性剂。
7.根据实施方案6的药物组合物,其中所述表面活性剂是聚山梨醇酯80。
8.根据前述实施方案中任一项的药物组合物,其中所述抗体或其抗原结合片段特异性结合人FcRn。
9.根据前述实施方案中任一项的药物组合物,其中所述抗体是人或人源化抗体。
10.根据前述实施方案中任一项的药物组合物,其中所述抗体或其抗原结合片段包含如SEQ ID NO:7中定义的轻链可变区和如SEQ ID NO:8中定义的重链可变区。
11.根据前述实施方案中任一项的药物组合物,其中所述组合物包含1mg/mL至200mg/mL的抗体或其抗原结合片段,10mM至50mM组氨酸,10至300mM脯氨酸,1%至20%w/v的蔗糖,0.01%至1.0%w/v的聚山梨醇酯80,pH为5.6;优选地,所述组合物包含50mg/mL至150mg/mL的抗体或其抗原结合片段,20mM至40mM组氨酸,50至280mM脯氨酸,5%至13%w/v的蔗糖,0.01%至0.5%w/v的聚山梨醇酯80,pH为5.6;更优选地,所述组合物包含80mg/mL至140mg/mL的抗体或其抗原结合片段,30mM组氨酸,180mM脯氨酸,7%w/v的蔗糖,0.03%w/v的聚山梨醇酯80,pH为5.6;并且甚至更优选地,所述组合物包含100mg/mL的抗体或其抗原结合片段,30mM组氨酸,180mM脯氨酸,7%w/v的蔗糖,0.03%w/v的聚山梨醇酯80,pH为5.6。
12.根据前述实施方案中任一项的药物组合物,其中所述组合物还包含甘露醇和/或精氨酸和/或甘氨酸。
13.一种冷冻干燥药物组合物,其包含抗体或其抗原结合片段、蔗糖、氨基酸或氨基酸的混合物和任选表面活性剂。
14.根据实施方案13的冷冻干燥制剂,其中所述制剂包含10%至40%w/w的蔗糖,优选20%至40%w/w的蔗糖。
15.一种冷冻干燥制剂,其包含抗体和10%至40%w/w的蔗糖,所述抗体包含如SEQID NO:7中定义的轻链可变区和如SEQ ID NO:8中定义的重链可变区。
16.一种液体药物制剂,其包含根据实施方案13-15中任一项的药物组合物和溶剂。
17.根据实施方案16的液体药物制剂,其中所述溶剂是水。
18.一种容器,其包含根据实施方案13-15中任一项的冷冻干燥制剂或根据实施方案16或17中任一项的液体药物制剂。
19.根据实施方案1至12中任一项的药物组合物、根据实施方案13至15中任一项所述的冷冻干燥制剂或根据实施方案16至17中任一项所述的液体药物制剂,其用于治疗。
20.根据实施方案1至12中任一项的药物组合物、根据实施方案13至15中任一项所述的冷冻干燥制剂或根据实施方案16至17中任一项所述的液体药物制剂,其用于治疗选自以下的炎性或自身免疫疾病:重症肌无力,寻常型天疱疮,视神经脊髓炎,吉兰-巴雷综合征,狼疮和血栓性血小板减少性紫癜,特发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)及其组合。
21.一种治疗哺乳动物受试者的炎性或自身免疫疾病的方法,包括施用根据实施方案1至12中任一项的药物组合物、根据实施方案13至15中任一项的冷冻干燥制剂或根据实施方案16至17中任一项的液体药物制剂;其中所述炎性或自身免疫疾病选自重症肌无力,寻常型天疱疮,视神经脊髓炎,吉兰-巴雷综合征,狼疮和血栓性血小板减少性紫癜,特发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)及其组合。
22.一种用于制备包含抗-FcRn抗体的药物组合物的方法,其中所述方法包括以下步骤:
(i)制备包含抗-FcRn抗体的组合物;和
(ii)加入1%至20%w/v的蔗糖。
23.根据实施方案22的方法,其中由步骤(ii)得到的药物组合物是根据实施方案1至12中任一项的药物组合物。
24.根据实施方案22或实施方案23的方法,其中所述方法还包括冷冻干燥由步骤(ii)得到的药物组合物的步骤。
25.通过根据实施方案24的方法获得的药物组合物。
26.通过添加溶剂重构根据实施方案13、14、15、24或25中任一项的药物组合物的方法,其中所述溶剂优选为水。
27.通过实施方案26的方法获得的液体药物制剂。
附图的简要说明
图1.冻干后的重构时间。表2的每种制剂(x轴)的重构时间(重构时间)以分钟显示在y轴上。
图2.通过SEC测量的聚集体形成。表2的每种制剂(x轴)的总聚集体(以%面积表示)显示y轴上。
图3.通过DLS测量的HMW聚集体形成。表2的每种制剂(x轴)的强度(以%表示)绘制y轴上。
图4.电荷变体。表2的每种制剂(x轴)的酸性(A)和碱性(B)变体的形成作为%面积(y轴)的函数作图。
图5.粘度。表2的每种制剂(x轴)的粘度(cP)显示在y轴上。
图6.重量摩尔渗透压浓度。表2的每种制剂(x轴)的重量摩尔渗透压浓度(mOsm/kg)显示在y轴上。
图7.冻干后的重构时间。表5的每种制剂(x轴)的重构时间(重构时间)以分钟显示在y轴上。
图8.通过SEC测量的聚集体形成。表5的每种制剂(x轴)的总聚集体(以%面积表示)显示y轴上。
图9.通过DLS测量的HMW聚集体形成。表5的每种制剂(x轴)的质量(以%表示)绘制y轴上。
图10.电荷变体。表5的包含100mg/mL的抗-FcRn抗体的每种制剂(x轴)的酸性(A)和碱性(B)变体的形成作为%面积(y轴)的函数作图。
图11.电荷变体。表5的包含140mg/mL的抗-FcRn抗体的每种制剂(x轴)的酸性(A)和碱性(B)变体的形成作为%面积(y轴)的函数作图。
图12.粘度。表5的每种制剂(x轴)的粘度(cP)显示在y轴上。
图13.重量摩尔渗透压浓度。表5的每种制剂(x轴)的重量摩尔渗透压浓度(mOsm/kg)显示在y轴上。
发明详述
根据本发明的药物组合物包含抗体或其抗原结合片段;1%至20%w/v的蔗糖;氨基酸或氨基酸的混合物;和表面活性剂。
药物组合物中抗体或其抗原结合片段的浓度可以是1-200mg/mL,优选50-200mg/mL,更优选80-140mg/mL。
优选地,根据本发明的药物组合物中包含的抗体或其抗原结合片段特异性结合人FcRn。
本文所用的术语“特异性结合人FcRn(specifically binds to human FcRn)”、“特异性结合至人FcRn(specifically binding to human FcRn)”和等同物意指抗体将以足够的亲和力和特异性结合人FcRn,以实现具有生物学意义的效果。选择的抗体通常会对人FcRn具有结合亲和力,例如,抗体可以以100nM至1pM的Kd值结合人FcRn。抗体亲和力可以通过例如以下的测定法来测定:基于表面等离子体共振的测定法,例如BIAcore测定法;酶联免疫吸附测定法(ELISA);和竞争测定法(例如RIA竞争测定法)。在本发明的含义内,特异性结合人FcRn的抗体或其抗原结合片段也可以结合另一种分子,例如,食蟹猴FcRn或例如作为非限制性实例在双特异性抗体的情况下。
FcRn是膜蛋白FcRnα链和β2微球蛋白(β2M)的非共价复合物。在成年哺乳动物中,FcRn通过充当结合并挽救IgG同种型抗体的受体而在维持血清抗体水平中起关键作用。IgG分子被内皮细胞内吞,并且如果它们与FcRn结合,则被再循环转胞吞到例如循环中。相反,不与FcRn结合的IgG分子进入细胞并靶向溶酶体途径,在那里它们被降解。其中His435突变为丙氨酸的变体IgG1导致FcRn结合的选择性丧失和血清半衰期显著降低(Firan等人,2001,International Immunology 13:993)。
特异性结合人FcRn的抗体或其抗原结合片段优选还中和人FcRn。
如本文所用的术语“中和”是指抗体抑制或基本上降低其特异性结合的分子的生物学效应。因此,表述“抗体中和人FcRn”是指抗体特异性结合人FcRn并抑制或基本上降低其生物学效应,例如通过阻断FcRn与IgG的结合。
如本文所用的术语“抗体”是指单克隆或多克隆抗体,并且不限于通过本领域已知的重组技术产生的重组抗体。
优选地,包含在根据本发明的药物组合物中的抗体是特异性结合人FcRn的单克隆抗体。
“抗体”包括任何物种的抗体,特别是哺乳动物物种的抗体,具有两条基本上完整的重链和两条基本上完整的轻链,任何同种型的人抗体,包括IgA1,IgA2,IgD,IgG1,IgG2a,IgG2b,IgG3,IgG4IgE和IgM及其修饰变体,非人灵长类抗体,例如,来自黑猩猩、狒狒、恒河猴或食蟹猴,啮齿动物抗体,例如来自小鼠、大鼠或兔子;山羊或马抗体,及其衍生物,或鸟类物种的抗体例如鸡抗体或鱼类物种的抗体例如鲨鱼抗体。术语“抗体”还指“嵌合”抗体,其中至少一个重链和/或轻链抗体序列的第一部分来自第一物种并且该重链和/或轻链抗体序列的第二部分来自第二物种。本文的目标嵌合抗体包括“灵长类化”抗体,其包含衍生自非人灵长类动物(例如,旧世界猴,例如狒狒、恒河猴或食蟹猴)的可变结构域抗原结合序列和人恒定区序列。“人源化”抗体是嵌合抗体,其含有衍生自非人抗体的序列。在大多数情况下,人源化抗体是人抗体(受者抗体),其中来自受者的高变区的残基被来自非人物种(例如小鼠、大鼠、兔、鸡或非人灵长类动物)(供体抗体)的具有所需的特异性、亲和力和活性的高变区或互补决定区(CDR)的残基取代。在大多数情况下,CDR外(即,在框架区(FR)中)的人(受者)抗体残基另外被相应的非人残基取代。此外,人源化抗体可包含在受者抗体或供体抗体中未发现的残基。进行这些修饰以进一步改善抗体性能。人源化降低了人体内非人抗体的免疫原性,从而促进了抗体在人类疾病治疗中的应用。人源化抗体和产生它们的几种不同技术是本领域熟知的。术语“抗体”也指人抗体,其可以作为人源化的替代物产生。例如,有可能产生转基因动物(例如小鼠),其在免疫后能够在不产生内源性鼠抗体的情况下产生完整的人抗体库。例如,已经描述了嵌合和种系突变小鼠中抗体重链连接区(JH)基因的纯合缺失导致内源性抗体产生的完全抑制。在这种种系突变小鼠中转移人种系免疫球蛋白基因阵列将导致在用特定抗原免疫携带人种系免疫球蛋白基因的转基因动物后产生对所述抗原具有特异性的人抗体。用于产生此类转基因动物的技术和用于从这些转基因动物分离和产生人抗体的技术是本领域已知的。或者,在转基因动物中;例如在小鼠中,只有编码小鼠抗体可变区的免疫球蛋白基因被相应的人可变免疫球蛋白基因序列取代。编码抗体恒定区的小鼠种系免疫球蛋白基因保持不变。以这种方式,抗体效应子在转基因小鼠的免疫系统中起作用,因此B细胞发育基本上不变,这可以在体内抗原攻击后导致改善的抗体应答。一旦从这些转基因动物中分离出编码特定目标抗体的基因,就可以用人恒定区基因替换编码恒定区的基因,以获得完全人抗体。如本文所用的术语“抗体”也指非糖基化抗体。
如本文所用的术语“其抗原结合片段”或其语法变体是指抗体片段。抗体的片段包含至少一个本领域已知的重链或轻链免疫球蛋白结构域,并与一种或多种抗原结合。根据本发明的抗体片段的实例包括Fab,Fab',F(ab')2,以及Fv和scFv片段;以及双抗体,三抗体,四抗体,微抗体,结构域抗体(dAb),例如sdAb,VHH或骆驼科抗体(例如来自骆驼或美洲驼,例如NanobodiesTM)和VNAR片段,单链抗体,由抗体片段或抗体形成的双特异性、三特异性、四特异性或多特异性抗体,包括但不限于Fab-Fv或Fab-Fv-Fv构建体。如上定义的抗体片段是本领域已知的。
包含在根据本发明的药物组合物中的抗体或其抗原结合片段可以是人或人源化抗体,优选特异性结合人FcRn的人源化单克隆抗体。
更优选地,根据本发明的药物组合物包含(表1):
1)抗体或其抗原结合片段,其
a.包含具有SEQ ID NO:1中定义的序列的CDR-H1;具有SEQ ID NO:2中定义的序列的CDR-H2;具有SEQ ID NO:3中定义的序列的CDR-H3;具有SEQ ID NO:4中定义的序列的CDR-L1;具有SEQ ID NO:5中定义的序列的CDR-L2,具有SEQ ID NO:6中定义的序列的CDR-L3;或
b.包含具有SEQ ID NO:7中定义序列的轻链可变区和具有SEQ ID NO:8中定义序列的重链可变区;或
c.包含与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:8中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链可变区;
d.包含具有SEQ ID NO:7中定义的序列的轻链可变区和具有SEQ ID NO:11中定义的序列的重链;或
e.包含与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:11中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链;或
2)抗体,其包含具有SEQ ID NO:9中定义的序列的轻链和具有SEQ ID NO:10中定义的序列的重链;或
3)抗体,其包含与SEQ ID NO:9中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链和与SEQ ID NO:10中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链。
在整个说明书中,根据Kabat定义来定义互补决定区(“CDR”)。Kabat定义是编号抗体中残基的标准,并且它通常用于鉴定CDR区(Kabat等,(1991),第5版,NIH公开号91-3242)。
表1
示例的抗体或其抗原结合片段进一步详细描述于WO2014019727(通过引用并入本文)。
抗体分子通常可以通过在适于导致从编码本发明的抗体分子的DNA表达蛋白质的条件下培养含有编码抗体序列的载体的宿主细胞,并分离抗体分子来产生。
抗体分子可仅包含重链或轻链多肽,在这种情况下,仅需要使用重链或轻链多肽编码序列来转染宿主细胞。为了产生包含重链和轻链的产物,可以用两种载体转染细胞系,第一载体编码轻链多肽,第二载体编码重链多肽。或者,可以使用单一载体,该载体包括编码轻链和重链多肽的序列。
可以通过培养用一种或多种编码重组抗体片段的表达载体转染的真核宿主细胞来产生可以根据工业规模制备的抗体或其抗原结合片段。真核宿主细胞优选是哺乳动物细胞,更优选是中国仓鼠卵巢(CHO)细胞。
哺乳动物细胞可以在任何支持其生长和重组蛋白表达的培养基中培养,优选培养基是化学成分确定的培养基,其不含动物来源的产品,例如动物血清和蛋白胨。本领域技术人员可获得不同的细胞培养基,其包含以适当的浓度存在以实现细胞生长和蛋白质生产的维生素、氨基酸、激素、生长因子、离子、缓冲液、核苷、葡萄糖或等效能源的不同组合。另外的细胞培养基组分可以在细胞培养周期的不同时间以适当的浓度包含在细胞培养基中,这是本领域技术人员已知的。
哺乳动物细胞培养可以在任何合适的容器中进行,例如摇瓶或生物反应器,其可以或可以不以补料分批模式操作,这取决于所需的生产规模。这些生物反应器可以是搅拌罐或气升式反应器。可提供各种大规模生物反应器,其容量超过1,000L至50,000L,优选5,000L至20,000L,或至10,000L。或者,也可使用较小规模的生物反应器,例如2L至100L的生物反应器来制备抗体或抗体片段。
抗体或其抗原结合片段通常存在于哺乳动物宿主细胞培养物(通常是CHO细胞培养物)的上清液中。对于其中目标蛋白质如抗体或其抗原结合片段分泌在上清液中的CHO培养过程,通过本领域已知的方法,通常通过离心收集所述上清液。
因此,抗体或其抗原结合片段的制备方法包括细胞培养后和蛋白质纯化前的离心和上清液回收步骤。在另一个具体实施方案中,所述离心是连续离心。为避免疑义,上清液表示位于由细胞培养物的离心产生的沉降细胞上方的液体。
或者,宿主细胞是原核细胞,优选革兰氏阴性细菌。更优选地,宿主细胞是大肠杆菌细胞。用于蛋白质表达的原核宿主细胞是本领域熟知的(Terpe,K.Appl MicrobiolBiotechnol 72,211-222(2006))。宿主细胞是已经过基因工程改造以产生目的蛋白质例如抗体的抗原结合片段的重组细胞。重组大肠杆菌宿主细胞可以衍生自任何合适的大肠杆菌菌株,包括MC4100,TG1,TG2,DHB4,DH5α,DH1,BL21,K12,XL1Blue和JM109。一个实例是大肠杆菌菌株W3110(ATCC27,325),其是用于重组蛋白质发酵的常用宿主菌株。也可以通过培养修饰的大肠杆菌菌株,例如代谢突变体或蛋白酶缺陷的大肠杆菌菌株来产生抗体片段。
抗体片段通常存在于大肠杆菌宿主细胞的周质中或宿主细胞培养上清液中,这取决于蛋白质的性质、生产规模和所用的大肠杆菌菌株。将蛋白质靶向这些区室的方法是本领域熟知的(Makrides,S.C.;Microbiol Rev 60,512-538(1996))。将蛋白质导向大肠杆菌周质的合适信号序列的实例包括大肠杆菌PhoA,OmpA,OmpT,LamB和OmpF信号序列。蛋白质可以通过依赖天然分泌途径或通过诱导外膜的有限渗漏以引起蛋白质分泌(其实例是使用pelB前导序列、蛋白A前导序列、共表达细菌素释放蛋白、丝裂霉素诱导的细菌素释放蛋白连同向培养基中添加甘氨酸和用于膜透化的kil基因的共表达)来被靶向至上清液。最优选地,重组蛋白在宿主大肠杆菌的周质中表达。
重组蛋白在大肠杆菌宿主细胞中的表达也可以在诱导型系统的控制下,由此重组抗体在大肠杆菌中的表达处于诱导型启动子的控制之下。适用于大肠杆菌的许多诱导型启动子是本领域熟知的,并且取决于启动子,重组蛋白的表达可以通过改变因素例如温度或生长培养基中特定物质的浓度来诱导。诱导型启动子的实例包括可用乳糖或不可水解的乳糖类似物异丙基-b-D-1-硫代吡喃半乳糖苷(IPTG)诱导的大肠杆菌lac、tac和trc启动子,和分别由磷酸盐、色氨酸和L-阿拉伯糖诱导的phoA、trp和araBAD启动子。表达可以通过例如诱导物的添加或在诱导是温度依赖性的情况下温度的变化诱导。当通过向培养物中添加诱导物来实现重组蛋白表达的诱导的情况下,可以通过任何合适的方法添加诱导物,这取决于发酵系统和诱导物,例如,通过单次或多次注射(shot)添加或通过进料逐渐添加诱导物。应当理解,在诱导物的添加和蛋白质表达的实际诱导之间可能存在延迟,例如在诱导物是乳糖的情况下,由于在乳糖之前消耗任何预先存在的碳源,在诱导蛋白质表达发生之前可能存在延迟。
大肠杆菌宿主细胞培养物(发酵物)可以在任何支持大肠杆菌生长和重组蛋白表达的培养基中培养。培养基可以是任何化学成分确定的培养基,例如如Durany O等人(2004),Studies on the expression of recombinant fuculose-1-phosphate aldolasein Escherichia coli.Process Biochem 39,1677-1684中所描述的。
大肠杆菌宿主细胞的培养可以在任何合适的容器中进行,例如摇瓶或发酵罐,这取决于所需的生产规模。可提供各种大型发酵罐,容量超过1,000升至约100,000升。优选使用1,000至50,000升的发酵罐,更优选1,000至25,000、20,000、15,000、12,000或10,000升。也可以使用容量为0.5至1,000升的较小规模的发酵罐。
大肠杆菌的发酵可以在任何合适的系统中进行,例如连续、分批或补料分批模式,这取决于蛋白质和所需的产量。可以在需要时用注射添加的营养物或诱导物使用分批模式。或者,可以使用补料分批培养,并且在诱导前培养物在分批模式下以最大比生长速率生长,其可以使用最初存在于发酵罐中的营养物和用于控制生长速率的一种或多种营养物进料方案来维持直到发酵完成。也可以在诱导前使用补料分批模式来控制大肠杆菌宿主细胞的代谢并允许达到更高的细胞密度。
如果需要,可以从发酵培养基中收集宿主细胞,例如,可通过离心、过滤或浓缩从样品中收集宿主细胞。在这种情况下,该方法通常包括在提取蛋白质之前离心和细胞回收的步骤。
对于其中目标蛋白质如抗体或抗体的抗原结合片段在宿主细胞的周质空间中发现的大肠杆菌发酵过程,需要从宿主细胞释放蛋白质。释放可以通过任何合适的方法实现,例如通过机械或压力处理的细胞裂解、冻融处理、渗透压休克、提取剂或热处理。此类蛋白质释放的提取方法是本领域熟知的。因此,在特定实施方案中,生产方法包括在蛋白质纯化之前的另外的蛋白质提取步骤。
用于体外获得人抗体的抗原结合片段的其他方法基于展示技术,例如噬菌体展示或核糖体展示技术,其中使用至少部分人工产生或来自供体的免疫球蛋白可变(V)结构域基因库的重组DNA文库。用于产生人抗体的噬菌体和核糖体展示技术是本领域熟知的。还可以从分离的人B细胞产生人抗体,所述人B细胞用目标抗原离体免疫,随后融合以产生杂交瘤,其随后可以就最佳人抗体进行筛选。
根据本发明的药物组合物可具有4.0至7.5,优选4.0至6.0,更优选4.5至6.0,更优选5.5至5.8或最优选约5.6的pH。
药物组合物含有缓冲剂以维持pH恒定。存在用于液体药物制剂领域的许多缓冲剂,例如但不限于柠檬酸盐,磷酸盐,乳酸盐,组氨酸,谷氨酸盐,马来酸盐,酒石酸盐或琥珀酸盐。优选的缓冲物质通常选自具有与最佳蛋白质稳定性所优选的pH接近(+/-1pH单位)以保持高缓冲能力并且与当置于一系列不同的缓冲物质中时特定蛋白质所观察到的最大所示稳定性相关的pKa的那些。制剂的适当pH范围通常选自与当置于一系列不同pH制剂中时特定蛋白质所观察到的最大所示稳定性相关的那些。
根据本发明的药物组合物包含作为缓冲剂的氨基酸或氨基酸的混合物,优选浓度为10mM至100mM,10mM至80mM,10mM至60mM,25mM至60mM,优选30mM至50mM,或30mM。
合适的氨基酸是精氨酸,赖氨酸,组氨酸,甲硫氨酸,鸟氨酸,异亮氨酸,亮氨酸,丙氨酸,甘氨酸,谷氨酸或天冬氨酸。优选包含碱性氨基酸,即精氨酸、赖氨酸和/或组氨酸。氨基酸可以以其D-和/或L-形式存在,但L-形式是典型的。氨基酸可以作为任何合适的盐存在,例如盐酸盐,如精氨酸-HCl。
优选地,氨基酸是组氨酸,更优选地浓度是30mM。
根据本发明的药物组合物还可以包含氨基酸的混合物,例如组氨酸和脯氨酸,组氨酸、脯氨酸和甘氨酸,组氨酸、脯氨酸和精氨酸,组氨酸、脯氨酸、精氨酸和甘氨酸的混合物。优选地,根据本发明的药物组合物包含组氨酸和另一种氨基酸,优选浓度为10mM至300mM,50mM至280mM,100mM至280mM或180mM至250mM的脯氨酸。优选地,根据本发明的药物组合物包含30mM组氨酸和180mM至250mM脯氨酸。
根据本发明的药物组合物另外包含表面活性剂。可用于根据本发明的药物组合物的表面活性剂包括但不限于非离子表面活性剂、离子表面活性剂和两性离子表面活性剂。用于与本发明使用的典型表面活性剂包括但不限于,山梨糖醇脂肪酸酯(例如脱水山梨醇单辛酸酯,脱水山梨醇单月桂酸酯,脱水山梨醇单棕榈酸酯),脱水山梨醇三油酸酯,甘油脂肪酸酯(例如甘油单辛酸酯,甘油单肉豆蔻酸酯,甘油单硬脂酸酯),聚甘油脂肪酸酯(例如十聚甘油单硬脂酸酯,十聚甘油二硬脂酸酯,十聚甘油单亚油酸),聚氧乙烯脱水山梨醇脂肪酸酯(例如聚氧乙烯山梨糖醇单月桂酸酯,聚氧乙烯脱水山梨糖醇单油酸酯,聚氧乙烯山梨糖醇单硬脂酸酯,聚氧乙烯山梨糖醇单棕榈酸酯,聚氧乙烯山梨糖醇三油酸酯,聚氧乙烯山梨糖醇三硬脂酸酯),聚氧乙烯山梨糖醇脂肪酸酯(例如聚氧乙烯山梨糖醇四硬脂酸酯,聚氧乙烯山梨糖醇四油酸酯),聚氧乙烯甘油脂肪酸酯(例如聚氧乙烯甘油单硬脂酸酯),聚乙二醇脂肪酸酯(例如聚乙二醇二硬脂酸酯),聚氧乙烯烷基醚(例如,聚氧乙烯月桂基醚),聚氧乙烯聚氧丙烯烷基醚(例如聚氧乙烯聚氧丙烯二醇,聚氧乙烯丙基醚,聚氧乙烯聚氧丙烯十六烷基醚),聚氧乙烯烷基苯基醚(例如,聚氧乙烯壬基苯基醚),聚氧乙烯氢化蓖麻油(例如聚氧乙烯蓖麻油,聚氧乙烯氢化蓖麻油),聚氧乙烯蜂蜡衍生物(例如聚氧乙烯山梨糖醇蜂蜡),聚氧乙烯羊毛脂衍生物(例如聚氧乙烯羊毛脂)和聚氧乙烯脂肪酸酰胺(例如聚氧乙烯硬脂酸酰胺);C10-C18烷基硫酸盐(例如十六烷基硫酸钠,十二烷基硫酸钠,油基硫酸钠),聚氧乙烯C10-C18烷基醚硫酸盐,平均加入2至4摩尔环氧乙烷单元(例如聚氧乙烯十二烷基硫酸钠),和C1-C18烷基磺基琥珀酸酯盐(例如月桂基磺基琥珀酸钠);天然表面活性剂如卵磷脂,甘油磷脂,神经鞘氨醇磷脂(例如鞘磷脂)和C12-C18脂肪酸的蔗糖酯。该组合物可包括一种或多种这些表面活性剂。优选的表面活性剂是聚氧乙烯脱水山梨糖醇脂肪酸酯,例如聚山梨醇酯20、40、60或80。优选地,根据本发明的药物组合物包含聚山梨醇酯80。
本发明的药物组合物可包含0.01%至10%w/v的表面活性剂,0.01%至1.0%w/v的表面活性剂,0.01%至0.5%w/v的表面活性剂或0.03%w/v的表面活性剂,例如聚山梨醇酯。优选地,本发明的药物组合物包含0.03%w/v的聚山梨醇酯80。
根据本发明的药物组合物包含1至20%w/v,或5%至13%w/v或7%至10%w/v或7%的蔗糖作为稳定剂(即冷冻保护剂)。
本发明还提供了制备包含抗-FcRn抗体或其抗原结合片段的药物组合物的方法,其中该方法包括制备包含抗-FcRn抗体的组合物,例如包含80mg/mL至140mg/mL的包含含有SEQ ID NO:7的轻可变链和含有SEQ ID NO:8的重可变链的抗-FcRn抗体或其抗原结合片段、30mM组氨酸、250mM脯氨酸、0.03%w/v的聚山梨醇酯80、pH为5.6的组合物,并加入1%至25%w/v的蔗糖。
优选地,该方法包括制备包含80mg/mL至140mg/mL的包含含有SEQ ID NO:7的轻可变链和含有SEQ ID NO:8的重可变链的抗-FcRn抗体、30mM组氨酸、250mM脯氨酸、0.03%w/v的聚山梨醇酯80、pH为5.6的组合物,并加入包含30mM的组氨酸、0.03%w/v的聚山梨醇酯80、17.5%至24.5%w/v的蔗糖、pH为5.6的组合物。
本文描述和实施的药物组合物可以是冷冻干燥(即冻干)的药物组合物的形式。
因此,根据本发明的制备药物组合物的方法可以进一步包括冷冻干燥(即冻干)的步骤。
用于冷冻干燥抗体的技术是本领域熟知的(John F.Carpenter and MichaelJ.Pikal,1997Pharm.Res.14,969-975);类似地,存在作为冷冻干燥物提供的现有单克隆抗体产品,例如SYNAGISTM,REMICADETM,RAPTIVATM,SIMULECTTM,XOLAIRTM和HERCEPTINTM。将这些抗体重构成各种终浓度,例如:将SIMULECTTM重构至4mg/ml抗体的浓度,将REMICADETM重构至10mg/ml的浓度,HERCEPTINTM重构至21mg/ml,SYNAGISTM和RAPTIVATM重构至100mg/ml,以及XOLAIRTM重构至125mg/ml。
冷冻干燥技术将在本文的实施例部分中进一步讨论。
因此,本发明提供了一种冷冻干燥制剂,其包含抗体或其抗原结合片段、蔗糖、氨基酸或氨基酸的混合物和任选表面活性剂。优选地,冷冻干燥制剂包含10%至40%w/w的蔗糖,更优选20%至40%w/w的蔗糖。
在本发明的一个优选实施方案中,包含10%至40%w/w的蔗糖的冷冻干燥制剂还包含抗-FcRn抗体或其抗原结合片段,其中所述抗体或其片段包含含有SEQ ID NO:7的轻可变链和含有SEQ ID NO:8的重可变链。
在另一个优选的实施方案中,冷冻干燥制剂包含约50.8%w/w的抗体或其抗原结合片段、约35.5%w/w蔗糖、约3.0%w/w组氨酸、约10.5%w/w脯氨酸和0.2%w/w聚山梨醇酯80;其中所述抗体或其片段包含含有SEQ ID NO:7的轻可变链和含有SEQ ID NO:8的重可变链。
在根据本发明的药物组合物中使用的其他赋形剂包括但不限于粘度增强剂,填充剂,增溶剂如单糖,例如果糖,麦芽糖,半乳糖,葡萄糖,D-甘露糖,山梨糖等;二糖,例如乳糖,海藻糖,纤维二糖等;多糖,例如棉子糖,松三糖,麦芽糖糊精,葡聚糖,淀粉等;和多元醇,例如甘露醇,木糖醇,麦芽糖醇,乳糖醇,木糖醇山梨糖醇(葡萄糖醇)等;聚乙二醇(例如PEG100,PEG300,PEG600,PEG1500,PEG2000,PEG3000,PEG3350,PEG4000,PEG6000,PEG8000或PEG20000),聚乙烯吡咯烷酮,三甲胺N-氧化物,三甲基甘氨酸或其组合。
在可以将冷冻干燥(即冻干)的药物组合物施用至患者之前,其需要用溶剂重构。在本发明中,优选的溶剂是水性溶剂,更优选水性溶剂是水。
用于重构的溶剂的体积决定了所得液体药物制剂中抗体或其抗原结合片段的浓度。用比冻干前体积更小体积的溶剂重构提供了比冻干前更浓缩的制剂,反之亦然。
因此,本发明提供了通过添加溶剂重构根据本发明的冷冻干燥的药物组合物的方法,其中溶剂优选为水。
重构比例(冻干前的药物组合物相对于用于重构冷冻干燥的药物组合物的溶剂的体积)可以在0.5:1至1:10变化。在优选的实施方案中,施加约1:1的比例,使得重构的液体药物制剂的所得体积为约4.4mL。
根据本发明的优选的冻干前的药物组合物和/或重构的液体药物制剂包含:
A.1mg/mL至200mg/mL的抗体或其抗原结合片段(其包含含有SEQ ID NO:7的轻可变链和含有SEQ ID NO:8的重可变链)、10mM至50mM组氨酸、10至300mM脯氨酸、1%至20%w/v的蔗糖、0.01%至1.0%w/v的聚山梨醇酯80,pH为5.6;
B.50mg/mL至150mg/mL的抗体或其抗原结合片段(其包含含有SEQ ID NO:7的轻可变链和含有SEQ ID NO:8的重可变链)、20mM至40mM组氨酸、50至280mM脯氨酸、5%至13%w/v的蔗糖、0.01%至0.5%w/v的聚山梨醇酯80,pH为5.6;
C.80mg/mL至140mg/mL的抗体或其抗原结合片段(其包含含有SEQ ID NO:7的轻可变链和含有SEQ ID NO:8的重可变链)、30mM组氨酸、250mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80,pH为5.6;
D.50mg/mL至150mg/mL的抗体或其抗原结合片段(其包含含有SEQ ID NO:7的轻可变链和含有SEQ ID NO:8的重可变链或含有SEQ ID NO:11的重链)、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80,pH为5.6;
E.80mg/mL至140mg/mL,优选100mg/ml的抗体或其抗原结合片段(其包含重可变链和轻可变链,其中重可变链包含SEQ ID NO:1的CDR-H1、SEQ ID NO:2的CDR-H2和SEQ IDNO:3的CDR-H3和轻可变链包含SEQ ID NO:4的CDR-L1、SEQ ID NO:5的CDR-L2和SEQ ID NO:6的CDR-L3)、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80,pH为5.6;
F.80mg/mL至140mg/mL,优选100mg/ml的抗体(其包含含有SEQ ID NO:10的重链和含有SEQ ID NO:9的轻链)、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80,pH为5.6,以及至少i)或i)和ii)或i)、ii)和iii):
i)100mM至250mM的甘露醇;
ii)80mM至200mM的L-精氨酸HCl;
iii)100mM至280mM的甘氨酸;
G.80mg/mL至140mg/mL,优选100mg/ml的抗体或其抗原结合片段(其包含含有SEQID NO:7的轻可变链和含有SEQ ID NO:8的重可变链或含有SEQ ID NO:11的重链)、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80,pH为5.6,以及至少i)或i)和ii)或i)、ii)和iii):
i)100mM至250mM的甘露醇;
ii)80mM至200mM的L-精氨酸HCl;
iii)100mM至280mM的甘氨酸;
H.80mg/mL至140mg/mL,优选100mg/ml的抗体或其抗原结合片段(其包含重可变链和轻可变链,其中重可变链包含SEQ ID NO:1的CDR-H1、SEQ ID NO:2的CDR-H2和SEQ IDNO:3的CDR-H3和轻可变链包含SEQ ID NO:4的CDR-L1、SEQ ID NO:5的CDR-L2和SEQ ID NO:6的CDR-L3)、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80,pH为5.6,以及至少i)或i)和ii)或i)、ii)和iii):
i)100mM至250mM的甘露醇;
ii)80mM至200mM的L-精氨酸HCl;
iii)100mM至280mM的甘氨酸;
I.80mg/mL至140mg/mL,优选100mg/ml的抗体(其包含含有SEQ ID NO:10的重链和含有SEQ ID NO:9的轻链)、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80、pH为5.6,以及至少i)或i)和ii)或i)、ii)和iii):
i)100mM至250mM的甘露醇;
ii)80mM至200mM的L-精氨酸HCl;
iii)100mM至280mM的甘氨酸;
本发明还提供了一种容器,其包含根据本发明的冷冻干燥的药物组合物或重构的液体药物制剂。特别地,容器可以是包含待重构的冷冻干燥的药物组合物的小瓶。
容器可以是包含一个或多个容器的多组件试剂盒(kit-of-parts)的一部分,所述容器包含根据本发明的冷冻干燥的药物组合物、用于重构冷冻干燥的药物组合物的合适溶剂、递送装置如注射器和使用说明书。
根据本发明的药物组合物或液体药物制剂用于治疗。
在优选的实施方案中,用于治疗的重构液体药物制剂包含80mg/mL至140mg/mL优选100mg/ml的抗体或其抗原结合片段、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80、pH为5.6、任选地i)或i)和ii)或i)、ii)和iii),其中:
i)100mM至250mM的甘露醇;
ii)80mM至200mM的L-精氨酸HCl;
iii)100mM至280mM的甘氨酸;
其中抗体或其抗原结合片段(如果适用)包含:
1)包含SEQ ID NO:7的轻可变链和包含SEQ ID NO:8的重可变链或包含SEQ IDNO:11的重链;或
2)与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:8中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链可变区;
3)与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:11中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链;
4)包含SEQ ID NO:9的轻链和包含SEQ ID NO:10的重链;或
5)与SEQ ID NO:9中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链和与SEQ ID NO:10所定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链;
6)重可变链和轻可变链,其中重可变链包含SEQ ID NO:1的CDR-H1、SEQ ID NO:2的CDR-H2和SEQ ID NO:3的CDR-H3和轻可变链包含SEQ ID NO:4的CDR-L1、SEQ ID NO:5的CDR-L2和SEQ ID NO:6的CDR-L3。
根据本发明的药物组合物或液体药物制剂还用于治疗选自重症肌无力、寻常天疱疮、视神经脊髓炎、吉兰-巴雷综合征、狼疮和血栓性血小板减少性紫癜、特发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)及其组合的炎性或自身免疫疾病。
在另一个优选的实施方案中,用于治疗选自重症肌无力、寻常型天疱疮、视神经脊髓炎、吉兰-巴雷综合征、狼疮和血栓性血小板减少性紫癜、特发性血小板减少性紫癜(ITP)、慢性炎性脱髓鞘多发性神经病(CIDP)及其组合的炎性或自身免疫疾病的重构液体药物制剂包含80mg/mL至140mg/mL,优选100mg/ml的抗体或其抗原结合片段、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80、pH为5.6、任选i)或i)和ii)或i)、ii)和iii),其中:
i)100mM至250mM的甘露醇;
ii)80mM至200mM的L-精氨酸HCl;
iii)100mM至280mM的甘氨酸;
其中抗体或其抗原结合片段(如果适用)包含:
1)包含SEQ ID NO:7的轻可变链和包含SEQ ID NO:8的重可变链或包含SEQ IDNO:11的重链;或
2)与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:8中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链可变区;
3)与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:11中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链;
4)包含SEQ ID NO:9的轻链和包含SEQ ID NO:10的重链;或
5)与SEQ ID NO:9中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链和与SEQ ID NO:10所定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链;
6)重可变链和轻可变链,其中重可变链包含SEQ ID NO:1的CDR-H1、SEQ ID NO:2的CDR-H2和SEQ ID NO:3的CDR-H3和轻可变链包含SEQ ID NO:4的CDR-L1、SEQ ID NO:5的CDR-L2和SEQ ID NO:6的CDR-L3。
本发明还提供了治疗哺乳动物受试者的炎性或自身免疫疾病的方法,包括施用本发明的药物组合物或液体药物制剂;其中炎性或自身免疫疾病选自重症肌无力,寻常型天疱疮,视神经脊髓炎,吉兰-巴雷综合征,狼疮和血栓性血小板减少性紫癜,特发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)及其组合。
哺乳动物受试者可选自啮齿动物、猫、狗、马、牛、羊、非人灵长类动物和人受试者。优选地,哺乳动物受试者是人受试者。
在另一个优选的实施方案中,治疗哺乳动物受试者的炎性或自身免疫疾病的方法包括施用重构的液体药物制剂,其包含80mg/mL至140mg/mL,优选100mg/ml的抗体或其抗原结合片段、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80、pH为5.6、任选i)或i)和ii)或i)、ii)和iii),其中:
i)100mM至250mM的甘露醇;
ii)80mM至200mM的L-精氨酸HCl;
iii)100mM至280mM的甘氨酸;
其中抗体或其抗原结合片段(如果适用)包括:
1)包含SEQ ID NO:7的轻可变链和包含SEQ ID NO:8的重可变链或包含SEQ IDNO:11的重链;或
2)与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:8中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链可变区;
3)与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:11中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链;
4)包含SEQ ID NO:9的轻链和包含SEQ ID NO:10的重链;或
5)与SEQ ID NO:9中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链和与SEQ ID NO:10所定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链;
6)重可变链和轻可变链,其中重可变链包含SEQ ID NO:1的CDR-H1、SEQ ID NO:2的CDR-H2和SEQ ID NO:3的CDR-H3和轻可变链包含SEQ ID NO:4的CDR-L1、SEQ ID NO:5的CDR-L2和SEQ ID NO:6的CDR-L3,
其中炎性或自身免疫疾病选自重症肌无力,寻常型天疱疮,视神经脊髓炎,吉兰-巴雷综合征,狼疮和血栓性血小板减少性紫癜,特发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)及其组合。
此外,根据本发明的药物组合物或液体药物制剂可以用于制备用于治疗选自重症肌无力、寻常型天疱疮、视神经脊髓炎、吉兰-巴雷综合征、狼疮和血栓性血小板减少性紫癜、特发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)及其组合的炎性或自身免疫疾病的药物。
在另一个优选的实施方案中,重构的液体药物制剂可以用于制备用于治疗选自重症肌无力、寻常型天疱疮、视神经脊髓炎、吉兰-巴雷综合征、狼疮和血栓性血小板减少性紫癜、特发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)及其组合的炎性或自身免疫疾病的药物,其包含80mg/mL至140mg/mL,优选100mg/ml的抗体或其抗原结合片段、30mM组氨酸、180mM脯氨酸、7%w/v的蔗糖、0.03%w/v的聚山梨醇酯80、pH为5.6、任选i)或i)和ii)或i)、ii)和iii),其中:
i)100mM至250mM的甘露醇;
ii)80mM至200mM的L-精氨酸HCl;
iii)100mM至280mM的甘氨酸;
其中抗体或其抗原结合片段(如果适用)包括:
1)包含SEQ ID NO:7的轻可变链和包含SEQ ID NO:8的重可变链或包含SEQ IDNO:11的重链;或
2)与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:8中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链可变区;
3)与SEQ ID NO:7中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链可变区和与SEQ ID NO:11中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链;
4)包含SEQ ID NO:9的轻链和包含SEQ ID NO:10的重链;或
5)与SEQ ID NO:9中定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的轻链和与SEQ ID NO:10所定义的序列具有至少80%同一性或相似性,优选90%同一性或相似性的重链;
6)重可变链和轻可变链,其中重可变链包含SEQ ID NO:1的CDR-H1、SEQ ID NO:2的CDR-H2和SEQ ID NO:3的CDR-H3和轻可变链包含SEQ ID NO:4的CDR-L1、SEQ ID NO:5的CDR-L2和SEQ ID NO:6的CDR-L3。
根据本发明的重构的液体药物制剂以治疗有效量施用。如本文所用的术语“治疗有效量”是指治疗、改善或预防靶向疾病、病症或病况或表现出可检测的治疗性、药理性或预防性效果所需的治疗剂(即抗体)的量。对于任何抗体或其抗原结合片段,最初可以在细胞培养测定中或在动物模型中(通常在啮齿动物、兔、狗、猪或灵长类动物中)估计治疗有效量。动物模型也可用于确定合适的浓度范围和施用途径。然后,这些信息可用于确定人体施用的有用剂量和途径。
对人类受试者的精确治疗有效量将取决于疾病状态的严重程度、受试者的一般健康状况、受试者的年龄、体重和性别、饮食、施用的时间和频率、药物组合、反应敏感性和对治疗的耐受性/应答。该量可以通过常规实验确定,并且在临床医生的判断范围内。通常,抗体的治疗有效量为0.01mg/kg至500mg/kg,例如0.1mg/kg至200mg/kg,例如100mg/kg。
对于上述疾病和/或病症的治疗,适当的剂量将根据例如待使用的特定抗体、治疗的受试者、施用方式和所治疗病症的性质和严重程度而变化。在一个具体实施方案中,本发明的重构液体药物制剂通过静脉内或皮下途径施用。当通过静脉内注射施用时,它可以作为推注或连续输注施用。根据本发明任何实施方案的重构液体药物制剂也可以通过肌内注射施用。可以使用注射器、注射装置如自动注射器、无针装置、植入物和贴剂注射重构的液体药物制剂。
在本发明的一个具体实施方案中,通过施用4mL包含100mg/mL抗-FcRn抗体或其抗原结合片段的1:1重构液体药物制剂来实现400mg的剂量。
本发明的液体药物制剂适合于一次或在一系列治疗中施用至患者,并且可以在诊断之后的任何时间施用至患者;它可以作为唯一的治疗施用,或与其他用于治疗前述病症的药物或疗法联合施用。
抗体或其抗原结合片段可以是液体药物制剂中的唯一活性成分。或者,抗体或其抗原结合片段可以与一种或多种其他治疗活性成分组合施用,例如,同时、依次或分开施用。如本文所用的活性成分是指在相关剂量下具有药理学作用(例如治疗效果)的成分。在一些实施方案中,液体药物制剂中的抗体或其抗原结合片段可以伴有其他活性成分,包括其他抗体或非抗体成分。当根据本发明的液体药物制剂中的抗体是抗-FcRn抗体时,可以向受试者施用另外的活性成分以治疗炎性或自身免疫疾病。在一个实施方案中,所述受试者同时或依次(之前和/或之后)施用其他抗体成分或非抗体成分如类固醇或其他药物分子,特别是其半衰期独立于FcRn结合的药物分子。
现在将参考附图中所示的实施方案以示例的方式进一步描述本发明
实施例
缩略语
DLS(动态光散射);Arg(L-精氨酸);iCE(成像毛细管电泳);Mal(麦芽糖醇);Pro(L-脯氨酸);PS80(聚山梨醇酯80);Raf(棉子糖);SE-UPLC(尺寸排阻超高效液相色谱);Sor(山梨糖醇);Suc(蔗糖);Gly(甘氨酸);Man(甘露醇);Met(L-甲硫氨酸);Tre(海藻糖)。
材料
D-(-)-山梨糖醇(VWR GPR RectopurTM);聚山梨醇酯80(Tween80TM,MerckTM);如WO2014019727(SEQ ID NO:9和10)中所述的在30mM组氨酸、250mM脯氨酸、0.03%PS80、pH5.6(UCB Celltech ltd)中的140mg/mL抗-FcRn抗体;甘露醇(RoquetteTM);以下所有来自(SigmaTM):D-(+)-五水棉子糖,L-精氨酸单盐酸盐,L-组氨酸,L-脯氨酸,麦芽糖醇,甘氨酸,蔗糖,L-甲硫氨酸和脱水海藻糖。
实施例1
冷冻干燥制剂制备
包含100mg/mL和80mg/mL如WO2014019727(SEQ ID NO:9和10)中所述的抗-FcRn抗体的冷冻干燥制剂通过在pH5.6的30mM组氨酸、250mM脯氨酸、0.03%PS80(参照制剂)中掺入包含140mg/mL所述抗体的组合物来制备,其中溶液A-I如下表2所示。
表2
用1mL冷冻干燥制剂填充约3mL小瓶(透明的Schott Topline FiolaxTM)。用Martin-Christ Epsilon 2-6DTM冷冻干燥器进行冷冻干燥。冻干循环包括在-40℃冷冻,在-10℃退火,在-20℃升华,和在25℃二次干燥(表3)。在冷冻干燥循环结束时,用约400mbar的N2填充小瓶,并用单通道塞子(WestarTM,West PharmaceuticalsTM)封闭。将冻干物储存在2-8℃直至分析或开始稳定性研究。
表3
在这些实验中进行的稳定性研究包括在30℃进行3个月和6个月的加速稳定性研究,并且在40℃进行4周和3个月的应力稳定性研究。
1.重构
用0.9mL Milli-Q水重构冻干物至浓度分别为80或100mg/mL。记录滤饼完全溶解成澄清溶液(可能在顶部有泡沫边缘)的时间。目视评估冻干物和重构溶液的外观。
重构时间显示在图1中。表2的每种制剂的重构时间以分钟显示在y轴上。测量执行于冻干后立即重构的制剂(无储存;t0);在30℃储存3个月后(t3m,30℃);在30℃6个月后(t6m,30℃);在40℃4周后(t4w,40℃)和在40℃3个月后(t3m,40℃)重构冻干的药物组合物之后。
对于含有蔗糖的制剂和含有180mM L-精氨酸的制剂,重构时间在10分钟内(图1)。包含80mg/mL抗-FcRn抗体的制剂比包含100mg/mL的制剂显著更快地重构。包含7%蔗糖或180mM L-精氨酸中的100mg/mL抗-FcRn抗体的制剂在稳定性研究的所有时间点显示小于10分钟的可接受的重构时间。
聚集
使用连接到Cary50TM紫外-可见分光光度计(VarianTM)的SoloVPETM(CETechnologiesTM)扩展在未稀释的情况下,或使用SpectramaxTM M5读板仪(MolecularDevicesTM),ε=1.34mL.mg-1.cm-1在于水中稀释至1mg/mL后,通过280nm处的UV吸光度测定抗-FcRn抗体浓度。
蛋白质聚集的量通过尺寸排阻UPLC(SE-UPLC)使用两个AcquityTM BEH200SEC(Waters)1.7μm、4.6x150mm串联柱和0.1M磷酸钠、0.3M NaCl、pH7.0运行缓冲液(0.3mL/min)测定。通过荧光(ex 280nm,em 345nm)进行检测和定量。
还使用DynaPro Plate ReaderTM(WyattTM)通过动态光散射(DLS)评估蛋白质聚集。测量在pH5.6的30mM组氨酸中稀释至10mg/mL的样品等分试样(10次5秒的采集)。使用适用于多峰粒子分布的DynamicsTM 7.1.4正则化(WyattTM)分析数据。
数据显示在图2中,作为每种制剂的SE UPLC测定的聚集体的总百分比。还研究了参照制剂(在30mM组氨酸pH5.6、250mM脯氨酸、0.03%PS80中的140mg/mL抗-FcRn抗体;未冻干)(参见图2)。测量执行于冻干后立即重构的制剂(无储存;t0);在30℃储存3个月后(t3m,30℃);在30℃6个月后(t6m,30℃);在40℃4周后(t4w,40℃)和在40℃3个月后(t3m,40℃)重构冻干的药物组合物之后。
除脯氨酸制剂(100-Pro250)外,所有制剂与参照制剂相比均显示出增加的针对聚集的稳定性(图2)。特别是含有≥7%蔗糖的制剂显示出良好的针对聚集的稳定性,不仅在每次稳定性研究的绝对聚集体形成方面,也在30℃和40℃进行的研究期间聚集体形成速率方面。在30mM组氨酸pH5.6、180mM脯氨酸、7%蔗糖、0.03%PS80中包含100mg/mL抗-FcRn抗体的制剂显示在30℃仅0.2%/月和在40℃0.4%/月的聚集体增加(表4)。
表4
麦芽糖醇也显示出可接受的聚集体形成,与用≥7%蔗糖观察到的一致。虽然精氨酸和麦芽糖醇分别在重构时间和聚集体形成中显示出合理的结果,但它们没有在两个试验中均提供可接受的结果,这不同于≥7%蔗糖,其提供低重构时间、低聚集体形成和形成速率。
通过DLS研究未通过SE UPLC检测到的聚集体。显示了在冻干之前和在冻干后立即重构的制剂(无储存;t0);在30℃储存3个月后(t3m,30℃);在30℃6个月后(t6m,30℃);在40℃4周后(t4w,40℃)和在40℃3个月后(t3m,40℃)重构冻干的药物组合物之后,每个冻干组合物的使用百分比强度大小分布通过DSL确定的聚集体百分比。
还研究了参照制剂(在30mM组氨酸pH5.6、250mM脯氨酸、0.03%PS80中的140mg/mL抗-FcRn抗体;未冻干)。参照(Ref)和冷冻干燥制剂均未显示出显著量的HMW聚集体。通过DLS未观察到大聚集体或HMW聚集体在稳定性方面的显著变化(图3),因为测量的强度变化并不显著且是测量技术所固有的。
电荷变体
通过成像毛细管电泳(iCE与iCE3(Protein SimpleTM))测定电荷变体。测量执行于冻干后立即重构的制剂(无储存;t0);在30℃储存3个月后(t3m,30℃);在30℃6个月后(t6m,30℃);在40℃4周后(t4w,40℃)和在40℃3个月后(t3m,40℃)重构冻干的药物组合物之后。
对于参照制剂(在30mM组氨酸pH5.6、250mM脯氨酸、0.03%PS80中的140mg/mL抗-FcRn抗体;未冻干)观察到酸性物质的增加(图4A)。含有250mM脯氨酸的制剂显示出酸性物质的减少,但它还显示出碱性物质的显著增加(图4B)。包含4%山梨糖醇的制剂也显示出碱性物质的显著增加。剩余的冷冻干燥制剂确实显示碱性物质的仅略微增加并且酸性物质没有显著变化(图4A和4B)。包含≥7%蔗糖的制剂未显示任何显著的电荷变体变化。
粘度
用ViscoPro2000TM粘度计(Cambridge Viscosity)测量重构产物的粘度。在22+/-1℃对冻干后立即重构(无储存)的制剂进行测量。
粘度随着糖/糖醇浓度的增加或糖/糖醇分子量的增加而增加(图5)。在冷冻干燥制剂中包含80和100mg/mL蔗糖的制剂的粘度都是可接受的。包含与180mM L-精氨酸组合的100mg/mL抗-FcRn抗体的制剂也显示出可接受的粘度。精氨酸是公认的赋形剂,其通常添加到药物组合物中以降低粘度。其效果与包含蔗糖的制剂相当。
重量摩尔渗透压浓度
用VaproTM 5520蒸气压渗透压计(WescorTM)测量重构制剂的重量摩尔渗透压浓度。对冻干后立即重构(无储存)的制剂进行测量。
大多数制剂显示出约500mOsm/kg的重量摩尔渗透压浓度(图6)。在180mM L-精氨酸制剂中包含100mg/mL抗-FcRn抗体的制剂显示出最高的重量摩尔渗透压浓度(570mOsm/kg),而在250mM脯氨酸制剂中包含100mg/mL抗-FcRn抗体的制剂显示出最低的重量摩尔渗透压浓度(330mOsm/kg)。包含蔗糖的制剂显示出可接受的重量摩尔渗透压浓度。
实施例2
使用AmiconTM Ultra-15 30K(MilliporeTM)离心过滤器/浓缩装置从30mM组氨酸、250mM山梨糖醇、pH5.6中的60mg/mL抗-FcRn抗体针对高达15mL的体积通过缓冲液交换(使用至少4个稀释/浓缩循环,使用的总透析体积为原始样品体积的至少7倍)制备冷冻干燥制剂(表5),参照制剂除外,从而获得表5中的pH5.6的最终组合物。在缓冲液交换后,从过滤的3%PS20储备溶液中加入聚山梨醇酯20(PS20)至终浓度为0.03%。选择实施例1的制剂B(100mg/ml抗-FcRn抗体、7%蔗糖、30mM组氨酸、180mM脯氨酸和0.03%PS80,pH为5.6)作为实施例2的实验的参照制剂。
用1mL包含100mg/mL或140mg/mL抗-FcRn抗体的制剂(由*表示的是在100mg/ml和140mg/ml两者的浓度下测试的制剂)填充小瓶(3mL;Topline Fiolac clear,SchottTM)(表5)。如实施例1进行冷冻干燥。
表5
重构
按照实施例1进行重构。测量执行于冻干后立即重构的制剂(无储存;t0);在30℃储存3个月后(t3m,30℃);在30℃储存6个月后(t6m,30℃);在40℃储存4周后(t4w,40℃)和在40℃储存3个月后(t3m,40℃)重构冻干的药物组合物之后。对于蔗糖、蔗糖-甘氨酸和蔗糖-精氨酸制剂,在100mg/mL和140mg/mL的抗-FcRn抗体中都实现了相对快速的重构(图7A,图7B)。蔗糖-甘露醇制剂没有相对快速地重构,而甲硫氨酸制剂和海藻糖制剂需要长时间重构(参见图7A中的不同y轴标度)。10%蔗糖和10%海藻糖制剂之间的差异是令人惊讶的,并且表明蔗糖和抗FcRn抗体之间的特异性相互作用有助于重构。甲硫氨酸对重构的负面影响可能是由于冻干饼的结构发生变化,也可能是由于抗-FcRn抗体的分子变化(在下面的聚集分析中更明显)。
聚集
根据实施例1的方法研究聚集。测量执行于冻干后立即重构的制剂(无储存;t0);在30℃储存3个月后(t3m,30℃);在30℃储存6个月后(t6m,30℃);在40℃储存4周后(t4w,40℃)和在40℃储存3个月后(t3m,40℃)重构冻干的药物组合物之后。除了含有甲硫氨酸的制剂之外,两种浓度(100mg/ml和140mg/mL)抗-FcRn抗体的所有制剂显示出良好的针对聚集的稳定性(图8A和8B)。显示出最高的针对聚集的稳定性的制剂包括10%和13%蔗糖制剂、6%蔗糖-3%甘露醇和7%蔗糖-2%甘露醇制剂、所有含精氨酸的制剂以及参照制剂(含有7%蔗糖和脯氨酸)。含有140mg/mL抗-FcRn抗体的制剂的聚集水平与含有100mg/mL的聚集水平相似。含有甲硫氨酸的制剂在两种浓度的抗-FcRn抗体中显示出高程度的聚集体形成。
还研究了高分子量(HMW)聚集体。显示了在冻干之前和在冻干后立即重构的制剂(无储存;t0);在30℃储存3个月后(t3m,30℃);在30℃储存6个月后(t6m,30℃);在40℃储存4周后(t4w,40℃)和在40℃储存3个月后(t3m,40℃)重构冻干的药物组合物之后,每个冷冻干燥制剂的使用百分比质量大小分布通过DSL确定的聚集体百分比。结果显示在图9A和9B中。除含甲硫氨酸的制剂外,未观察到通过DLS测量的高分子量(HMW)聚集体的显著增加。甲硫氨酸制剂的HMW聚集体的增加与SE-UPLC数据很好地相关。聚集似乎是由热应力引起的,而不是通过冷冻干燥引起的。
电荷变体
按照实施例1进行电荷变体分析。测量执行于冻干后立即重构的制剂(无储存;t0);在30℃储存3个月后(t3m,30℃);在30℃储存6个月后(t6m,30℃);在40℃储存4周后(t4w,40℃)和在40℃储存3个月后(t3m,40℃)重构冻干的药物组合物之后。对于包含100mg/mL抗-FcRn抗体的制剂,在30℃和40℃储存后,对于甲硫氨酸制剂观察到酸性物质的减少和碱性物质的增加(图10A和10B)。对于包含140mg/mL抗-FcRn抗体和甲硫氨酸的制剂,证实了类似的行为(图11A和11B)。这表明了由于甲硫氨酸的存在,抗-FcRn抗体中的热诱导的化学变化,这也可能是抗-FcRn抗体聚集行为的原因。对于所有其他制剂,未观察到电荷变体的显著变化。
粘度
用ViscoPro2000TM粘度计(Cambridge ViscosityTM)测量重构产物的粘度。对冻干后立即重构(无储存)的制剂进行测量。含精氨酸的制剂的粘度非常低(<6cP),即使在140mg/mL时也是如此(图12)。对于所有其他制剂,粘度高于>8cP。
重量摩尔渗透压浓度
用VaproTM 5520蒸气压渗透压计(WescorTM)测量重构制剂的重量摩尔渗透压浓度。对冻干后立即重构(无储存)的制剂进行测量。具有良好稳定性和重构特性的所有制剂,例如包含≥7%蔗糖的制剂显示出可接受的重量摩尔渗透压浓度。值得注意的是,含甲硫氨酸的制剂显示出非常低的重量摩尔渗透压浓度。
序列表
<110> UCB生物制药私人有限公司
<120> 药物组合物
<130> PF0076-WO
<150> GB1608323.0
<151> 2016-05-12
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Claims (27)
1.一种药物组合物,其包含:
a.抗体或其抗原结合片段;
b.1%至20%w/v的蔗糖;
c.氨基酸或氨基酸的混合物;和
d.表面活性剂。
2.根据权利要求1的药物组合物,其具有4.0至7.5的pH。
3.根据权利要求1或2的药物组合物,其中所述抗体或其抗原结合片段的浓度为1至200mg/mL,优选50至150mg/mL,更优选80至140mg/mL。
4.根据前述权利要求中任一项的药物组合物,其中所述组合物包含5%至13%w/v的蔗糖,优选7%至10%w/v的蔗糖,更优选7%w/v的蔗糖。
5.根据前述权利要求中任一项的药物组合物,其中:
a.氨基酸是组氨酸或脯氨酸;或
b.氨基酸的混合物包含组氨酸和脯氨酸。
6.根据前述权利要求中任一项的药物组合物,其中所述组合物包含0.01至1.0%w/v,优选0.01%至0.5%w/v的表面活性剂。
7.根据权利要求6的药物组合物,其中所述表面活性剂是聚山梨醇酯80。
8.根据前述权利要求中任一项的药物组合物,其中所述抗体或其抗原结合片段特异性结合人FcRn。
9.根据前述权利要求中任一项的药物组合物,其中所述抗体是人或人源化抗体。
10.根据前述权利要求中任一项的药物组合物,其中所述抗体或其抗原结合片段包含SEQ ID NO:7中定义的轻链可变区和SEQ ID NO:8中定义的重链可变区。
11.根据前述权利要求中任一项的药物组合物,其中所述组合物包含1mg/mL至200mg/mL的抗体或其抗原结合片段,10mM至50mM组氨酸,10至300mM脯氨酸,1%至20%w/v的蔗糖,0.01%至1.0%w/v的聚山梨醇酯80,pH为5.6;优选地,所述组合物包含50mg/mL至150mg/mL的抗体或其抗原结合片段,20mM至40mM组氨酸,50至280mM脯氨酸,5%至13%w/v的蔗糖,0.01%至0.5%w/v的聚山梨醇酯80,pH为5.6;更优选地,所述组合物包含80mg/mL至140mg/mL的抗体或其抗原结合片段,30mM组氨酸,180mM脯氨酸,7%w/v的蔗糖,0.03%w/v的聚山梨醇酯80,pH为5.6;以及甚至更优选地,所述组合物包含100mg/mL的抗体或其抗原结合片段,30mM组氨酸,180mM脯氨酸,7%w/v的蔗糖,0.03%w/v的聚山梨醇酯80,pH为5.6。
12.根据前述权利要求中任一项的药物组合物,其中所述组合物还包含甘露醇和/或精氨酸和/或甘氨酸。
13.一种冷冻干燥制剂,其包含抗体或其抗原结合片段、蔗糖、氨基酸或氨基酸的混合物和任选表面活性剂。
14.根据权利要求13的冷冻干燥制剂,其中所述制剂包含10%至40%w/w的蔗糖,优选20%至40%w/w的蔗糖。
15.一种冷冻干燥制剂,其包含抗体和10%至40%w/w的蔗糖,所述抗体包含SEQ IDNO:7中定义的轻链可变区和SEQ ID NO:8中定义的重链可变区。
16.一种液体药物制剂,其包含根据权利要求13-15中任一项的冷冻干燥制剂和溶剂。
17.根据权利要求16的液体药物制剂,其中所述溶剂是水。
18.一种容器,其包含根据权利要求13-15中任一项的冷冻干燥制剂或根据权利要求16或17中任一项的液体药物制剂。
19.根据权利要求1至12中任一项的药物组合物、根据权利要求13至15中任一项所述的冷冻干燥制剂或根据权利要求16至17中任一项所述的液体药物制剂,其用于治疗。
20.根据权利要求1至12中任一项的药物组合物、根据权利要求13至15中任一项所述的冷冻干燥制剂或根据权利要求16至17中任一项所述的液体药物制剂,其用于治疗选自以下的炎性或自身免疫疾病:重症肌无力,寻常型天疱疮,视神经脊髓炎,吉兰-巴雷综合征,狼疮和血栓性血小板减少性紫癜,特发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)及其组合。
21.一种治疗哺乳动物受试者的炎性或自身免疫疾病的方法,包括施用根据权利要求1至12中任一项的药物组合物、根据权利要求13至15中任一项的冷冻干燥制剂或根据权利要求16至17中任一项的液体药物制剂;其中所述炎性或自身免疫疾病选自重症肌无力,寻常型天疱疮,视神经脊髓炎,吉兰-巴雷综合征,狼疮和血栓性血小板减少性紫癜,特发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)及其组合。
22.一种用于制备包含抗-FcRn抗体的药物组合物的方法,其中所述方法包括以下步骤:
(i)制备包含抗-FcRn抗体的组合物;和
(ii)加入1%至20%w/v的蔗糖。
23.根据权利要求22的方法,其中由步骤(ii)得到的药物组合物是根据权利要求1至12中任一项的药物组合物。
24.根据权利要求22或权利要求23的方法,其中所述方法还包括冷冻干燥由步骤(ii)得到的药物组合物的步骤。
25.通过根据权利要求24的方法获得的药物组合物。
26.通过添加溶剂重构根据权利要求13、14、15、24或25中任一项的药物组合物的方法,其中所述溶剂优选为水。
27.通过权利要求26的方法获得的液体药物制剂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GB1608323.0 | 2016-05-12 | ||
GBGB1608323.0A GB201608323D0 (en) | 2016-05-12 | 2016-05-12 | Pharmaceutical compositions |
PCT/EP2017/061261 WO2017194646A1 (en) | 2016-05-12 | 2017-05-11 | Pharmaceutical composition |
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CN109069643A true CN109069643A (zh) | 2018-12-21 |
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CN201780028404.3A Pending CN109069643A (zh) | 2016-05-12 | 2017-05-11 | 药物组合物 |
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CN (1) | CN109069643A (zh) |
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BR (1) | BR112018072264A2 (zh) |
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Cited By (1)
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CN115484931A (zh) * | 2020-03-11 | 2022-12-16 | 西莱克塔生物科技公司 | 与合成纳米载体相关的方法和组合物 |
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CN112004827A (zh) * | 2018-03-23 | 2020-11-27 | 艾伯维德国有限责任两合公司 | 稳定的水性抗tau抗体调配物 |
WO2020172002A1 (en) | 2019-02-18 | 2020-08-27 | Eli Lilly And Company | Therapeutic antibody formulation |
BR112022026780A2 (pt) * | 2020-06-29 | 2023-01-17 | Hanall Biopharma Co Ltd | Formulação para anticorpo anti-fcrn |
WO2022241148A1 (en) * | 2021-05-12 | 2022-11-17 | Anaptysbio, Inc. | Antibody composition |
WO2023099607A1 (en) | 2021-12-01 | 2023-06-08 | UCB Biopharma SRL | Formulations comprising fab-peg |
WO2023224112A1 (ja) * | 2022-05-20 | 2023-11-23 | 株式会社ダイセル | 液状医薬組成物 |
US11926669B2 (en) | 2022-05-30 | 2024-03-12 | Hanall Biopharma Co., Ltd. | Anti-FcRn antibody or antigen binding fragment thereof with improved stability |
WO2024184444A1 (en) * | 2023-03-08 | 2024-09-12 | Immunovant Sciences Gmbh | High concentration protein formulations with polysorbate excipients and methods of making the same |
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2017
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- 2017-05-11 US US16/300,522 patent/US11407835B2/en active Active
- 2017-05-11 JP JP2018559221A patent/JP7126454B2/ja active Active
- 2017-05-11 KR KR1020187036132A patent/KR102436694B1/ko active IP Right Grant
- 2017-05-11 AR ARP170101248A patent/AR108449A1/es unknown
- 2017-05-11 EA EA201892446A patent/EA201892446A1/ru unknown
- 2017-05-11 CN CN201780028404.3A patent/CN109069643A/zh active Pending
- 2017-05-11 CA CA3022124A patent/CA3022124A1/en active Pending
- 2017-05-11 BR BR112018072264-2A patent/BR112018072264A2/pt not_active IP Right Cessation
- 2017-05-11 AU AU2017264553A patent/AU2017264553A1/en not_active Abandoned
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US11407835B2 (en) | 2022-08-09 |
SG11201809229VA (en) | 2018-11-29 |
US20200048346A1 (en) | 2020-02-13 |
KR20190008320A (ko) | 2019-01-23 |
GB201608323D0 (en) | 2016-06-29 |
EP3454899C0 (en) | 2024-03-20 |
EP3454899B1 (en) | 2024-03-20 |
EP3454899A1 (en) | 2019-03-20 |
CO2018011733A2 (es) | 2019-02-08 |
WO2017194646A1 (en) | 2017-11-16 |
JP2019514998A (ja) | 2019-06-06 |
JP7126454B2 (ja) | 2022-08-26 |
AR108449A1 (es) | 2018-08-22 |
CA3022124A1 (en) | 2017-11-16 |
BR112018072264A2 (pt) | 2019-02-12 |
RU2018141591A (ru) | 2020-06-15 |
CL2018003178A1 (es) | 2019-02-01 |
AU2017264553A1 (en) | 2018-12-13 |
KR102436694B1 (ko) | 2022-08-25 |
RU2018141591A3 (zh) | 2021-01-13 |
MX2018013215A (es) | 2019-02-21 |
ES2977545T3 (es) | 2024-08-26 |
IL262654A (en) | 2018-12-31 |
EA201892446A1 (ru) | 2019-04-30 |
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