CN112424347A - 治疗酸性鞘磷脂酶缺乏症的药物组合物 - Google Patents
治疗酸性鞘磷脂酶缺乏症的药物组合物 Download PDFInfo
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- CN112424347A CN112424347A CN201980048133.7A CN201980048133A CN112424347A CN 112424347 A CN112424347 A CN 112424347A CN 201980048133 A CN201980048133 A CN 201980048133A CN 112424347 A CN112424347 A CN 112424347A
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Abstract
本发明提供了包含重组人酸性鞘磷脂酶的组合物,如水性液体组合物和冻干组合物。还提供了使用所述组合物治疗酸性鞘磷脂酶缺乏的患者的方法。
Description
背景技术
酸性鞘磷脂酶缺乏症(ASMD)是一种罕见的威胁生命的溶酶体贮积障碍。它是一种常染色体隐性遗传疾病,是由编码溶酶体酶酸性鞘磷脂酶(ASM)的SMPD1基因突变引起的(Schuchman等人,Mol.Genet.Metab.120(1-2):27-33(2017))。ASMD患者无法代谢鞘磷脂,结果其在多个器官的溶酶体中积累,在严重的情况下导致内脏疾病和神经退化。ASMD患者的脾、肝、肺和骨髓中的胆固醇和其他脂质增加。
婴幼儿脑脊髓交感神经系统ASMD(也称为A型尼曼-皮克病或NPD A)是最严重的疾病表型,并且其特征在于早发和急性神经病形式。NPD A导致无法茁壮成长、肝脾肿大和快速进行性神经退化。患者在儿童早期死亡(McGovern等人,Neurology 66(2):228-232(2006))。
患有慢性内脏ASMD(NPD B)和慢性脑脊髓交感神经系统A SMD(NPD A/B)的患者的发作从婴幼儿期到成年期不等(Wasserstein等人,Pediatrics 114(6):e672-677(2004);Wasserstein等人,J.Pediatr.149(4):554-559(2006))。NPD B患者通常在儿童期、典型地在两岁以后被诊断出。大多数NPD B患者活到成年。将NPD A/B患者分类为具有表现为可能发展为神经退行性疾病的儿童神经系统症状的中间形式。肝、肺和血液病的发病在患有慢性ASMD的所有患者中均有发生,并且包括肝脾肿大、肝功能障碍、浸润性肺病和血小板减少症(McGovern等人,Genet.Med.15(8):618-623(2013);McGovern等人,Orphanet J.RareDis.12(1):41(2017))。儿童时期的生长受限和骨障碍(如低骨密度)也是慢性ASMD的常见特征(Wasserstein等人,J.Pediatr.142(4):424-428(2003))。肺病和肝病是这些患者的主要死因(McGovern等人,Pediatrics 122(2):e341-349(2008);Cassiman等人,Mol.Genet.Metab.118(3):206-213(2016))。
由于ASMD的高发病率和死亡率,迫切需要这种遗传疾病的有效治疗。
发明内容
本发明提供了用于治疗ASMD的重组人ASM(rhASM)的组合物。在一些实施方案中,所述组合物包含rhASM、磷酸钠、甲硫氨酸和蔗糖(或海藻糖)。在某些实施方案中,所述rhASM是奥利普酶α(olipudase alfa)(SEQ ID NO:2)。
在一些实施方案中,所述组合物是冻干的。本发明的冻干组合物可以包含例如:
4%-7%w/w奥利普酶α,
3%-7%w/w磷酸钠,
15%-25%w/w L-甲硫氨酸,和
65%-75%w/w蔗糖。
在某些实施方案中,本发明的冻干组合物可以包含:
5.5%w/w奥利普酶α,
2.3%w/w磷酸氢二钠七水合物,
2.6%w/w磷酸二氢钠一水合物,
20.5%w/w L-甲硫氨酸,和
68.6%w/w蔗糖。
在一些实施方案中,所述组合物是水性液体组合物。所述水性液体组合物可以包含例如:
1-10mg/mL奥利普酶α,
10-50mM磷酸钠,
70-150mM L-甲硫氨酸,和
1%-10%w/v蔗糖,
其中所述组合物具有5-8的pH。
在某些实施方案中,本发明的水性液体组合物可以包含:
3-5mg/mL奥利普酶α,
10-30mM磷酸钠,
80-120mM L-甲硫氨酸,和
4%-6%w/v蔗糖,
其中所述组合物具有6-7的pH。
在具体的实施方案中,本发明的水性液体组合物可以包含:
4mg/mL奥利普酶α,
20mM磷酸钠,
100mM L-甲硫氨酸,和
5%w/v蔗糖,
其中所述组合物具有6.5的pH。
在一些实施方案中,本发明的水性液体组合物可以还包含0.005%w/v聚山梨醇酯80。
本发明进一步提供了一种通过将本文所述的水性液体组合物干燥(例如,冻干或喷雾干燥)而获得的组合物。本发明还提供了一种用于制造冻干组合物的方法,所述方法包括将本文所述的水性液体组合物冻干。
在一些实施方案中,本发明提供了一种含有本文所述的冻干组合物的小瓶。在某些实施方案中,所述小瓶中的冻干组合物包含以下或基本上由以下组成:
21.2mg奥利普酶α,
9.0mg磷酸氢二钠七水合物,
10.0mg磷酸二氢钠一水合物,
79mg L-甲硫氨酸,和
265mg蔗糖。
在一些实施方案中,在5.1mL无菌水中重构所述冻干组合物,以获得水性液体组合物。
在某些实施方案中,所述小瓶中的冻干组合物包含以下或基本上由以下组成:
4.8mg奥利普酶α,
2.0mg磷酸氢二钠七水合物,
2.3mg磷酸二氢钠一水合物,
17.9mg L-甲硫氨酸,和
60mg蔗糖。
在一些实施方案中,在1.1mL无菌水中重构所述冻干组合物,以获得水性液体组合物。
本发明进一步提供了一种制品,所述制品包含1)含有本文所述的冻干组合物的小瓶,和2)含有例如用于重构所述冻干组合物的无菌水、0.9%氯化钠或磷酸盐缓冲盐水的小瓶。
本发明进一步提供了一种治疗人类患者的ASMD的方法,所述方法包括向所述患者给予本文所述的组合物,其中如果所述组合物是冻干组合物,则在给予前将其重构为液体形式。
本发明进一步提供了一种本文所述的组合物,其用于治疗人类患者的ASMD。
本发明进一步提供了本文所述的组合物用于制造治疗人类患者的ASMD用的药物的用途。
在一些实施方案中,如本文所述的ASMD的治疗是针对A/B型或B型尼曼-皮克病或针对ASMD的非神经学表现。
附图说明
图1A示出了如通过在各种pH下在琥珀酸盐、柠檬酸盐、柠檬酸盐/磷酸盐或磷酸盐缓冲液中在30℃下储存两周后的比(酶)活度测量的rhASM的稳定性。
图1B示出了如通过在各种pH下在琥珀酸盐、柠檬酸盐、柠檬酸盐/磷酸盐或磷酸盐缓冲液中在30℃下储存一周后的高分子量物质的百分比(%HMWS)测量的rhASM的稳定性。通过尺寸排阻色谱法(SEC)确定HMWS。
图1C示出了如通过在各种pH下在柠檬酸盐/磷酸盐或磷酸盐缓冲液中的热稳定性测量的rhASM的稳定性。通过差示扫描量热法确定热稳定性。
图2A示出了在30℃下在6.5的pH的10mM、20mM、50mM或100mM磷酸盐缓冲液中rhASM随时间的比活性。
图2B示出了如通过在30℃下在6.5的pH的10mM、20mM、50mM或100mM磷酸盐缓冲液中的%HMWS测量的rhASM随时间的物理稳定性。
图3A示出了冻干之前(液体)和冻干之后(lyo)5%w/v甘露糖醇、蔗糖或海藻糖对4mg/mL rhASM的比(酶)活度的影响。
图3B示出了如通过冻干之前(液体)和冻干之后(lyo)的%HMWS测量的5%w/v甘露糖醇、蔗糖和海藻糖对4mg/mL rhASM的物理稳定性的影响。
图4A示出了在5℃下rhASM随时间的比活性。从含有5%甘露糖醇、5%蔗糖或3%甘露糖醇和2%蔗糖的溶液中冻干rhASM(全部都是w/v浓度)。
图4B示出了如通过%HMWS测量的在5℃下rhASM随时间的物理稳定性。从含有5%甘露糖醇、5%蔗糖或3%甘露糖醇和2%蔗糖的溶液中冻干rhASM(全部都是w/v浓度)。
图5A示出了在5℃下rhASM随时间的比活性。从有或没有100mM甲硫氨酸的含有5%蔗糖的溶液中冻干rhASM(全部都是w/v浓度)。
图5B示出了如通过%HMWS测量的在5℃下rhASM随时间的物理稳定性。从有或没有100mM甲硫氨酸的含有5%w/v蔗糖的溶液中冻干rhASM。
图6示出了在2℃-8℃下在液体rhASM组合物中pH、蛋白质浓度、甲硫氨酸浓度和蔗糖浓度随时间对二聚体百分比的影响。
图7示出了在2℃-8℃下在液体组合物中pH、蛋白质浓度、甲硫氨酸浓度和蔗糖浓度随时间对rhASM比活性的影响。
图8示出了在具有不同pH、蛋白质浓度、甲硫氨酸浓度和蔗糖浓度的液体rhASM组合物中在2℃-8℃下随时间的%HMWS。在图的右侧指示了配制品编号。
图9示出了在具有不同pH、蛋白质浓度、甲硫氨酸浓度和蔗糖浓度的液体rhASM组合物中在2℃-8℃下随时间的%聚集。在图的右侧指示了配制品编号。
图10示出了在各种pH下在液体rhASM组合物中在25℃下的%二聚体、%聚集和比活性。
具体实施方式
本发明提供了包含重组人ASM例如奥利普酶α和一种或多种药学上可接受的赋形剂的组合物。与其他组合物相比,本发明的组合物具有改善的稳定性和保质期。在一些实施方案中,本发明的组合物是药物组合物,即呈这样的形式或可以制备以变成这样的形式的组合物,以允许活性成分的生物活性有效,同时不含有在患者体内具有明显的毒性或以其他方式引起与活性成分无关的有害的副作用的另外的成分。术语“药物组合物”和“药物制剂”在本文中可互换使用。如下文进一步描述,本发明的药物组合物可用于治疗患有ASM缺乏症的患者。
重组人酸性鞘磷脂酶
ASM是一种催化鞘磷脂分解为神经酰胺和磷酸胆碱的酶。“重组人ASM”是指通过重组的方式制备的相对于野生型序列有或没有某些氨基酸修饰的人ASM。例如,重组人ASM可以在培养的哺乳动物宿主细胞(例如,COS、CHO、HeLa、3T3、293T、NS0、SP2/0或HuT78细胞等)中或在对人ASM编码序列为转基因的动物中表达。
在一些实施方案中,所述重组人ASM是奥利普酶α。奥利普酶α是在CHO细胞中产生的人ASM(EC-3.1.4.12)的糖型α。成熟的奥利普酶α是一种570个氨基酸的多肽,其保留了天然人蛋白质的酶促和溶酶体靶向活性。奥利普酶α的氨基酸序列(包括其前导序列(残基1-57))在下文显示为SEQ ID NO:1,其中前导序列是斜体并且加粗。成熟的奥利普酶α序列(SEQ ID NO:2,其跨越SEQ ID NO:1的残基58-627)没有前导序列。
在其他实施方案中,可用于本发明的人ASM与奥利普酶α在氨基酸序列方面是99%、98%、97%、96%或95%相同的。例如,所述组合物中的人ASM可以具有美国专利6,541,218中所示的序列,将其公开内容以其整体并入本文。该序列(SEQ ID NO:3)在下文示出,前导序列(残基1-59)是斜体并且加粗,其中成熟蛋白质(SEQ ID NO:4,其跨越SEQ IDNO:3的残基60-629)没有前导序列。
所述组合物中的人ASM与在UNIPROT数据库中公开为序列P17405-1的人ASM或其多态性变体在氨基酸序列方面也可以相同。P17405-1序列在下文示出(SEQ ID NO:5),前导序列(残基1-59)是斜体并且加粗,其中成熟蛋白质(SEQ ID NO:6,其跨越SEQ ID NO:5的残基60-629)没有前导序列。
重组人酸性鞘磷脂酶组合物
本发明的组合物含有重组人ASM,并且相对于酶表现出优异的稳定性。“稳定的”或“稳定性”是指组合物中的活性成分在储存期间和/或当经受物理或化学应力时保持其物理稳定性、化学稳定性和/或生物活性的能力。稳定性可以在选定的温度的背景下,例如在冷藏条件下(例如,2℃-8℃)或在室温下(例如,23℃-25℃),持续选定的时间段,例如16周、24周、36周、四个月、六个月、一年、两年、三年或更长时间。蛋白质的稳定性可以在这样的测定中测量,所述测定在较短的时间内进行,但是所述测定的结果指示临床环境中的稳定性。此类测定包括冷冻/解冻测定,其中使蛋白质组合物经受一个或多个冻融循环;或搅拌测定,其中使蛋白质组合物在预定的时间段内经受机械搅拌处理。可以通过这样的方式确定蛋白质稳定性:将蛋白质组合物在指定的储存温度(如2℃-8℃)下储存选定的时间段,并且分析其结构和功能属性,如二聚化或聚集程度(例如,如通过尺寸排阻HPLC或蛋白质凝胶测量的)、蛋白质降解(例如,如通过尺寸排阻HPLC或蛋白质凝胶测量的)、组合物的颜色变化、液体组合物的透明度、酶活性、聚糖含量和组成、受体结合亲和力、甲硫氨酸残留氧化和组合物的生物活性。
本发明的组合物含有一种或多种药学上可接受的赋形剂。“赋形剂”是指用作药物的一种或多种活性成分的稀释剂、媒介物、载体、防腐剂、粘结剂或稳定剂的惰性物质。例如,所述组合物可以含有缓冲剂、等渗剂和/或稳定剂(如抗氧化剂)。在一些情况下,一种试剂可以用于不止一个的这些目的。在一些实施方案中,本发明的组合物含有重组人ASM(如奥利普酶α)、缓冲剂(如磷酸钠或柠檬酸钠)、稳定剂(如L-甲硫氨酸)和非还原糖(如蔗糖或海藻糖)。由于所述组合物中的特定组成,人ASM具有改善的稳定性。本发明的组合物可以是水性液体溶液或冻干制剂。
液体组合物
在一些实施方案中,所述组合物是水性液体组合物,其包含1-10mg/mL(例如,3-5mg/mL)rhASM(例如,奥利普酶α);10-50mM(例如,10-30mM)磷酸钠;70-150mM(例如,80-120mM)甲硫氨酸(例如,L-甲硫氨酸);和1%-10%(例如,4%-6%)w/v蔗糖或海藻糖。所述水性液体组合物的pH可以是5-8(例如,6-7)。
在一些实施方案中,所述水性液体组合物不包含可检测量的甘露糖醇(最容易使用的结晶赋形剂),因为它可以在冻干本文所述的水性液体组合物期间或之后显著增加人ASM的聚集。
在一些实施方案中,所述水性液体组合物包含0.004%-0.008%、0.005%-0.007%或0.005%w/v的一种或多种表面活性剂。示例性的表面活性剂包括非离子型去污剂,如聚山梨醇酯(例如,聚山梨醇酯20和80)和泊洛沙姆(例如,泊洛沙姆188)。在具体的实施方案中,所述水性液体组合物包含0.005%聚山梨醇酯80。在一些情况下,一种或多种表面活性剂的存在可以帮助降低液体组合物中的浊度。
在一些实施方案中,所述水性液体组合物包含不超过0.05、0.01或0.005mM的一种或多种螯合剂,如EDTA和EGTA;在示例性实施方案中,所述水性液体组合物不包含可检测量的一种或多种螯合剂。在一些情况下,尤其是在延长的储存时间段(例如,12-16周)之后或在非冷藏条件下(例如,在25℃下),螯合剂以高于例如0.05mM或0.1mM的浓度存在可能增加人ASM的聚集并且降低其稳定性。
在一些实施方案中,所述水性液体组合物可以含有0-50ppm(例如15-30ppm)锌,其可以例如从制造过程中携带或从外部添加。
在具体的实施方案中,所述水性液体组合物包含4mg/mL奥利普酶α、20mM磷酸钠、100mM甲硫氨酸和5%(w/v)蔗糖或基本上由其组成并且具有6.5的pH。术语“基本上由……组成”意指组合物不含有可检测量的其他成分,或可以仅含有痕量的某些材料,所述材料是从蛋白质制造过程中衍生出来的,其中此类材料在人类患者中不会影响酶的生物活性或引起伤害。
在一些实施方案中,所述组合物是水性液体组合物,其包含1-20mg/mL(例如,10mg/mL)rhASM(例如,奥利普酶α)和10-50mM(例如,20mM)磷酸钠。在某些实施方案中,所述水性液体组合物还包含甲硫氨酸(例如,L-甲硫氨酸)和蔗糖或海藻糖。在某些实施方案中,所述水性液体组合物还包含80-120mM(例如,100mM)甲硫氨酸和4%-6%(例如,5%)(w/v)蔗糖。在具体的实施方案中,所述水性液体组合物具有6.5的pH。
在一些实施方案中,所述组合物是水性液体组合物,其包含1-50mg/mL(例如,3.8、18或49mg/mL)rhASM(例如,奥利普酶α)和10-50mM(例如,20mM)磷酸钠。在某些实施方案中,所述水性液体组合物还包含1%-15%(例如,5%、6%、7%或8%)蔗糖或海藻糖。在某些实施方案中,所述水性液体组合物还包含80-120mM(例如,100mM)甲硫氨酸。在具体的实施方案中,所述水性液体组合物具有6.5的pH。所述组合物可以包含例如3.8mg/mL rhASM、20mM磷酸钠和5%蔗糖;18mg/mL rhASM、20mM磷酸钠和5%蔗糖;或49mg/mL rhASM、20mM磷酸盐和8%蔗糖。
所述水性液体组合物可以通过这样的方式制备:将通过重组技术产生并且随后从宿主细胞纯化的人ASM与本文所述的赋形剂在水中混合,并且将所得的混合物调节至所需pH。例如,可以将人ASM和所需赋形剂添加到或缓冲液交换到具有所需的磷酸钠浓度和pH的磷酸钠缓冲液中。
在一些实施方案中,所述水性液体组合物可以通过下文进一步详细描述的重构本发明的冻干组合物来制备。可以用药学上可接受的液体(如无菌水、盐水(例如,0.9%氯化钠)或磷酸盐缓冲盐水)来完成重构。
冻干组合物
本发明还提供了冻干组合物。此类组合物可以通过冻干本文所述的水性液体组合物来制备。冻干组合物适合于长期储存。可以根据本领域已知的方法进行冻干。例如,可以将液体组合物冷却至允许冷冻的低于零度(摄氏度)温度(例如,-5℃至-80℃),然后将其置于低压(部分真空)室内以允许发生升华(初步干燥);如果需要,可以在干燥的第二阶段(二次干燥)中使组合物的温度升高,以进一步除去不需要的水分子。在一些实施方案中,在冻干过程完成之后,可以在密封容器之前将惰性气体(如氮气)引入组合物的容器(例如,玻璃小瓶)中。
在一些实施方案中,本发明提供了粉末状组合物,其可以例如通过喷雾干燥本文所述的水性液体组合物来制备。喷雾干燥组合物适合于长期储存。可以根据本领域已知的方法进行喷雾干燥。例如,可以迫使液体组合物通过雾化器或喷嘴,以将其作为受控尺寸的小液滴分散到室内的热气流中,从而使液体组合物快速干燥成粉末。然后可以将干燥的粉末收集在干燥室的底部。也考虑了用于制备粉末状组合物的其他干燥方法。
诸位发明人出乎意料地发现,在冻干期间以本文所述的量存在的蔗糖(或海藻糖)和甲硫氨酸提供了优异的结果;冻干产品形成优雅的饼,同时在储存期间保持人ASM的稳定性。在冷藏条件下(例如,在0℃-10℃、2℃-8℃或4℃下),本发明的冻干组合物中的人ASM可以保持无聚集和有生物学活性至少4个月(例如,至少6个月或至少12个月)。
在一些实施方案中,本发明的组合物是冻干药物组合物,其包含4%-50%奥利普酶α、3%-7%磷酸钠和45%-90%蔗糖(全部都是w/w百分比)。在某些实施方案中,所述冻干组合物包含5.5%奥利普酶α、20.6%L-甲硫氨酸、2.3%磷酸氢二钠七水合物、2.6%磷酸二氢钠一水合物和69.0%蔗糖(全部都是w/w百分比)。在某些实施方案中,所述冻干组合物包含6.6%奥利普酶α、3.0%磷酸氢二钠七水合物、3.3%磷酸二氢钠一水合物和87.1%蔗糖(全部都是w/w百分比)。在某些实施方案中,所述冻干组合物包含25.2%奥利普酶α、2.4%磷酸氢二钠七水合物、2.6%磷酸二氢钠一水合物和69.9%蔗糖(全部都是w/w百分比)。在某些实施方案中,所述冻干组合物包含47.8%奥利普酶α、1.7%磷酸氢二钠七水合物、1.8%磷酸二氢钠一水合物和48.8%蔗糖(全部都是w/w百分比)。
在一些实施方案中,本发明的组合物是冻干药物组合物,其包含4%-7%奥利普酶α、15-25%L-甲硫氨酸、3%-7%磷酸钠和65%-75%蔗糖(全部都是w/w百分比)。在具体的实施方案中,所述冻干组合物包含5.5%奥利普酶α、20.5%L-甲硫氨酸、2.3%磷酸氢二钠七水合物、2.6%磷酸二氢钠一水合物和68.6%蔗糖(全部都是w/w百分比)。在某些实施方案中,所述冻干组合物还可以包含例如0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%或1.0%水分。
在一些实施方案中,本发明提供了含有冻干药物组合物的小瓶,所述冻干药物组合物包含15-25mg奥利普酶α、75-85mg L-甲硫氨酸、15-25mg磷酸钠和250-300mg蔗糖。在使用之前,可以在4-6mL的无菌水中重构所述组合物。
在一些实施方案中,所述小瓶含有冻干药物组合物,所述冻干药物组合物包含21.2mg、20.1mg、95.4mg或259.7mg奥利普酶α;9.0mg磷酸氢二钠七水合物;10.0mg磷酸二氢钠一水合物;和265mg蔗糖或由其组成。所述冻干组合物可以任选地包含79.1mg L-甲硫氨酸。所述冻干药物组合物可以任选地包含0-0.3mg(例如,0.08-0.16mg)锌,其可以例如从制造过程中携带或从外部添加。在某些实施方案中,所述小瓶可以具有内部无菌的氮气填充气氛。在具体的实施方案中,可以在5.1mL的无菌水中重构所述冻干组合物以分别产生约4.0mg/mL、3.8mg/mL、18mg/mL或49mg/mL的奥利普酶α浓度。基于待给予的剂量,所述重构的组合物可以进一步在0.9%氯化钠溶液中稀释至特定的体积。
在具体的实施方案中,所述小瓶含有冻干药物组合物,所述冻干药物组合物包含21.2mg奥利普酶α、79mg L-甲硫氨酸、9.0mg磷酸氢二钠七水合物、10.0mg磷酸二氢钠一水合物和265mg蔗糖或由其组成。所述冻干药物组合物可以任选地包含0-0.3mg(例如,0.08-0.16mg)锌,其可以例如从制造过程中携带或从外部添加。在某些实施方案中,所述冻干药物组合物呈饼或冻干粉末的形式。在某些实施方案中,所述小瓶可以具有内部无菌的氮气填充气氛。在具体的实施方案中,可以在5.1mL的无菌水中重构所述冻干组合物以产生约4.0mg/mL的奥利普酶α浓度。基于待给予的剂量,所述重构的组合物可以进一步在0.9%氯化钠溶液中稀释至特定的体积。
在一些实施方案中,本发明提供了含有冻干药物组合物的小瓶,所述冻干药物组合物包含3-5mg奥利普酶α、15-17mg L-甲硫氨酸、3-5mg磷酸钠和50-60mg蔗糖。在使用之前,可以在0.8-1.2mL的无菌水中重构所述组合物。
在具体的实施方案中,所述小瓶含有冻干药物组合物,所述冻干药物组合物包含4.8mg奥利普酶α、17.9mg L-甲硫氨酸、2.0mg磷酸氢二钠七水合物、2.3mg磷酸二氢钠一水合物和60mg蔗糖或由其组成。在某些实施方案中,所述冻干药物组合物呈饼或冻干粉末的形式。所述冻干组合物可以任选地包含0-0.06mg锌,其可以例如从制造过程中携带或从外部添加。在某些实施方案中,所述小瓶可以具有内部无菌的氮气填充气氛。在具体的实施方案中,可以在1.1mL的无菌水中重构所述冻干组合物以产生约4.0mg/mL的奥利普酶α浓度。基于待给予的剂量,所述重构的组合物可以进一步在0.9%氯化钠溶液中稀释至特定的体积。
制品
本发明的组合物可以在制品(例如,试剂盒)中提供,所述制品包括使用说明书和任选地用于治疗ASM障碍的其他治疗剂。所述制品中的药物活性成分(例如,rhASM)能以按照本文所述的给药方案容易给予的量提供。例如,“入门试剂盒(starter kit)”可以包括用于剂量递增方案的不同量的rhASM的多个小瓶。
例如,所述制品可以包括含有15-25mg奥利普酶α、75-85mg L-甲硫氨酸、15-25mg磷酸钠和250-300mg蔗糖的小瓶。在具体的实施方案中,所述制品提供了冻干组合物,其包含21.2mg奥利普酶α、79mg甲硫氨酸、9.0mg磷酸氢二钠七水合物、10.0mg磷酸二氢钠一水合物和265mg蔗糖。
举另一个例子,所述制品可以包括含有3-5mg奥利普酶α、15-17mg L-甲硫氨酸、3-5mg磷酸钠和50-60mg蔗糖的小瓶。在具体的实施方案中,所述制品提供了冻干组合物,其包含4.8mg奥利普酶α、17.9mg L-甲硫氨酸、2.0mg磷酸氢二钠七水合物、2.3mg磷酸二氢钠一水合物和60mg蔗糖。
在一些实施方案中,所述制品可以还包括溶液(例如无菌水、0.9%氯化钠和/或磷酸盐缓冲盐水),用于在向患者给予之前重构冻干组合物和/或进一步稀释重构的组合物。
酸性鞘磷脂酶组合物的用途
本发明的药物组合物可以作为酶替代疗法向有需要的患者肠胃外给予。“肠胃外给予”是指除经肠和局部给予以外的给予方式,通常通过注射。肠胃外给予包括但不限于静脉内输注或注射以及肌内、皮内、腹膜内和皮下注射。在具体的实施方案中,经由静脉内输注给予所述药物组合物。
本文所述药物组合物的适当的剂量水平可以基于多种因素确定,包括患者的年龄、体重、疾病状况、总体健康状况和病史;以及药物给予的途径和频率;药物中ASM活性成分的药效学和药代动力学;和患者可能同时服用的任何其他药物。在一些实施方案中,可以根据例如美国专利9,655,954(Schuchman等人)中所述的剂量方案给予本文所述的药物组合物。例如,取决于患者的年龄和状况,所述患者可以接受递增剂量的人ASM,剂量强度起始于例如0.1mg/kg或更低,结束于3mg/kg(维持剂量)或更低。在一些实施方案中,对于儿科患者可以按0.03mg/kg或0.1mg/kg或对于成人患者按0.1mg/kg的剂量强度给予一个或两个第一剂量;在患者以0.03和/或0.1mg/kg接受一个或两个剂量后,然后向患者给予0.3mg/kg、0.3mg/kg、0.6mg/kg、0.6mg/kg、1.0mg/kg、2.0mg/kg和3.0mg/kg的后续顺序剂量。在某些实施方案中,可以重复任何所述剂量(例如,1.0mg/kg和2.0mg/kg的剂量)。对于一些患者,3.0mg/kg的剂量强度适合于维持剂量,而对于其他患者,较低的剂量强度可能足以维持。如临床医生确定是适当的,连续剂量之间的间隔可以是两周或短于或长于两周。
本发明提供了使用本文所述的药物组合物治疗有需要的患者的ASMD的方法、用于治疗有需要的患者的ASMD的本文所述的药物组合物以及本文所述的药物组合物用于制造治疗有需要的患者的ASMD用的药物的用途。在一些实施方案中,所述药物组合物可以是冻干组合物,其可以在药学上可接受的液体(如无菌水、0.9%氯化钠溶液或磷酸盐缓冲盐水)中重构。
所述患者可以是成人(例如,18岁或以上的患者,包括65岁或以上的老年患者)。所述患者可以是儿科患者(小于18岁的患者,例如新生儿至6岁、6至12岁或12至18岁的患者)。在一些实施方案中,所述患者可以患有NPD A/B或NPD B。在一些实施方案中,所述患者可以患有NPD A。在具体的实施方案中,所述药物组合物用于治疗患有慢性内脏ASMD(NPD B)的成人或儿科患者。在具体的实施方案中,所述药物组合物用于治疗成人或儿科患者的ASMD的非神经学表现。
示例性实施方案
本发明的其他具体的实施方案描述如下。
1.一种组合物,其包含重组人酸性鞘磷脂酶、磷酸钠、甲硫氨酸和蔗糖。
2.根据实施方案1所述的组合物,其中所述组合物是冻干组合物,其包含:
4%-7%w/w奥利普酶α(SEQ ID NO:2),
3%-7%w/w磷酸钠,
15%-25%w/w L-甲硫氨酸,和
65%-75%w/w蔗糖。
3.根据实施方案2所述的组合物,其基本上由以下组成:
5.5%w/w奥利普酶α,
2.3%w/w磷酸氢二钠七水合物,
2.6%w/w磷酸二氢钠一水合物,
20.5%w/w L-甲硫氨酸,和
68.6%w/w蔗糖。
4.根据实施方案1所述的组合物,其中所述组合物是水性液体组合物,其包含:
1-10mg/mL奥利普酶α,
10-50mM磷酸钠,
70-150mM L-甲硫氨酸,和
1%-10%w/v蔗糖,
其中所述组合物具有5-8的pH。
5.根据实施方案4所述的组合物,其中所述组合物是水性液体组合物,其包含:
3-5mg/mL奥利普酶α,
10-30mM磷酸钠,
80-120mM L-甲硫氨酸,和
4%-6%w/v蔗糖,
其中所述组合物具有6-7的pH。
6.根据实施方案4所述的组合物,其基本上由以下组成:
4mg/mL奥利普酶α,
20mM磷酸钠,
100mM L-甲硫氨酸,和
5%w/v蔗糖,
其中所述组合物具有6.5的pH。
7.根据实施方案4-6中任一项所述的组合物,其还包含0.005%w/v聚山梨醇酯80。
8.一种组合物,其通过将根据实施方案4-7中任一项所述的水性液体组合物冻干而获得。
9.一种用于制造冻干组合物的方法,其包括:
获得根据实施方案4-7中任一项所述的水性液体组合物,以及
冻干所述水性液体组合物。
10.一种含有冻干组合物的小瓶,所述冻干组合物基本上由以下组成:
21.2mg奥利普酶α,
9.0mg磷酸氢二钠七水合物,
10.0mg磷酸二氢钠一水合物,
79mg L-甲硫氨酸,和
265mg蔗糖。
11.一种水性液体组合物,其通过在5.1mL的无菌水中重构基本上由以下组成的冻干组合物而获得:
21.2mg奥利普酶α,
9.0mg磷酸氢二钠七水合物,
10.0mg磷酸二氢钠一水合物,
79mg L-甲硫氨酸,和
265mg蔗糖。
12.一种含有冻干组合物的小瓶,所述冻干组合物基本上由以下组成:
4.8mg奥利普酶α,
2.0mg磷酸氢二钠七水合物,
2.3mg磷酸二氢钠一水合物,
17.9mg L-甲硫氨酸,和
60mg蔗糖。
13.一种水性液体组合物,其通过在1.1mL的无菌水中重构基本上由以下组成的冻干组合物而获得:
4.8mg奥利普酶α,
2.0mg磷酸氢二钠七水合物,
2.3mg磷酸二氢钠一水合物,
17.9mg L-甲硫氨酸,和
60mg蔗糖。
14.一种制品,其包含根据实施方案10或12所述的小瓶和含有用于重构冻干组合物的无菌水、0.9%氯化钠或磷酸盐缓冲盐水的小瓶。
15.一种治疗人类患者的酸性鞘磷脂酶缺乏症(ASMD)的方法,所述方法包括向所述患者给予根据实施方案1-8、11和13中任一项所述的组合物,其中如果所述组合物是冻干组合物,则在给予前将其重构为液体形式。
16.根据实施方案1-8、11和13中任一项所述的组合物,其用于治疗人类患者的ASMD。
17.根据实施方案1-8、11和13中任一项所述的组合物用于制造治疗人类患者的ASMD用的药物的用途。
18.根据实施方案15所述的方法、根据实施方案16所述的用于所述用途的组合物或根据实施方案17所述的用途,其中所述ASMD是A/B型或B型尼曼-皮克病。
19.根据实施方案18所述的方法、用于所述用途的组合物或用途,其中所述治疗是针对ASMD的非神经学表现。
本文提及的所有出版物和其他参考文献都通过引用以其整体并入。尽管本文引用了许多文件,但是此引用并不意味着承认这些文件中的任何文件构成了本领域公知常识的一部分。除非本文另有定义,否则结合本发明所用的科学和技术术语应当具有本领域普通技术人员通常理解的含义。尽管与本文所述的那些类似或等同的方法和材料也可以用于本发明的实践或测试,但是下文描述了示例性方法和材料。在矛盾的情况下,将以包括定义在内的本说明书为准。通常,结合本文所述的细胞和组织培养、分子生物学、微生物学、遗传学、分析化学、合成有机化学、药物和药物化学以及蛋白质和核酸化学所用的术语及其技术是本领域熟知并且常用的那些。酶反应和纯化技术是根据制造商的说明书来进行的,如本领域通常完成的或如本文所述的。此外,除非上下文另有要求,否则单数术语应当包括复数,并且复数术语应当包括单数。在整个本说明书和实施方案中,词语“具有”(have)和“包含”(comprise)或变体如“具有”(has)、“具有”(having)、“包含”(comprises)或“包含”(comprising)将被理解为暗示包括所述整数或整数组,但是不排除任何其他整数或整数组。
为了可以更好地理解本发明,列出了以下实施例。这些实施例仅用于说明目的,并且不被解释为以任何方式限制本发明的范围。
实施例
实施例1:重组人酸性鞘磷脂酶配制品
此实施例描述了评估各种奥利普酶α水性液体和冻干组合物的稳定性的研究。
材料和方法
溶液浊度
通过光谱浊度测定评估溶液乳光。基于在特定NTU值下的欧洲药典参考悬浮液,使用340-360nm范围内的光密度设置先前建立的乳光类别的范围。在SpectraMax Plus 384微孔板分光光度计(Molecular Devices,加利福尼亚州森尼韦尔)上进行分析。
聚集
通过SEC进行聚集和二聚体分析。在装入HPLC小瓶之前,通过五个温和的移液循环混合每个样品。在配备有TSK凝胶G3000SWXL(Tosoh Bioscience,日本东京)分析柱和匹配保护柱的1100/1200系列HPLC(Agilent,加利福尼亚州圣克拉拉)上进行SEC分析。所使用的流动相是pH6的20mM磷酸钠、200mM氯化钠,设置的流速为0.5mL min-1,持续35分钟。每个样品进行三次大约80μg的进样。通过在280nm处的UV吸光度进行检测。
使用在非还原条件下的SDS-PAGE,然后用考马斯亮蓝染色,确定奥利普酶α相关的高分子量物质(HMWS)的水平。每个凝胶上均包括奥利普酶α对照标准品。将奥利普酶α样品与样品缓冲液混合,并且与分子量标志物一起上样到4%-20%Tris-甘氨酸梯度凝胶上。在125V的目标电压下电泳大约2小时后,将凝胶用考马斯蓝染色,并且在甲醇、乙酸和HPLC级水中脱色。进行光密度分析以提供相对于所有观察到的条带HMWS条带的百分比的定量结果。
酶活性
在1.2mL库管中将rhASM样品以2000:1稀释。在此程序中测量由rhASM催化的2-(N-十六酰基氨基)-4-硝基苯基磷酸胆碱(HDA-PC)在37℃下的水解速率。使用SpectraMaxPlus 384微孔板分光光度计通过在415nm处的吸光度测量释放的发色团。rhASM活性的一个单位定义为在指定的测定条件下每分钟从HDA-PC产生1μmol的2-(N-十六酰基氨基)-4-硝基苯酚的酶量。
蛋白质浓度
通过在280nm处的吸光度确定rhASM样品的蛋白质浓度。使用匹配缓冲液将样品一式两份地稀释至1:10和1:20。在SpectraMax Plus 384微孔板分光光度计上确定280nm处的吸光度。
pH
在Thermo Electron Microprobe pH计(Thermo Scientific,马萨诸塞州贝弗莉)上进行样品pH分析。使用Thermo Orion 8203BN PerHecT Ross Semi微玻璃探针(ThermoScientific)。
差示扫描量热仪
使用CAP-VP-DSC微量热仪(MicroCal-GE Healthcare,马萨诸塞州北安普顿)进行差示扫描量热仪(DSC)分析。用匹配缓冲液将样品稀释至0.4mg/mL。从15℃-100℃以200℃/hr的扫描速率运行样品。在配备有DSC分析附件(MicroCal-GE Healthcare)的Origin 7.0(OriginLab Corp.,马萨诸塞州北安普顿)中进行数据分析。
结果
缓冲液和pH评价
评价了各种缓冲液pH和缓冲液种类对rhASM稳定性的影响。通过在30℃下在20mM缓冲液中将4mg/ml奥利普酶α孵育两周并且评估所述酶的物理和功能稳定性来进行测定(图1A-1C)。
在低于pH 6.0的奥利普酶α中,观察到显著的不稳定性(物理的和功能的)。在低于pH 6.0时酶活性急剧降低,但是在pH 6.0及以上时,酶活性保持相对恒定(图1A)。聚集倾向在pH 5.5与6.5之间最小。在低于pH 5.5时观察到聚集快速增加,并且在高于pH 6.5时看到聚集逐渐增加(图1B)。在可比较的pH值下,与柠檬酸盐/磷酸盐缓冲液相比,磷酸盐缓冲液中的稳定性更高。这些稳定性趋势与从在冷藏温度下储存的样品获得的数据一致。通过DSC分析证实了在高于pH 6.5时观察到的逐渐增加的聚集速率,其在磷酸盐缓冲液中在较高pH下显示出降低的热稳定性(图1C)。基于这些数据,将约6.5的pH的磷酸钠缓冲液鉴定为rhASM配制品的合适的缓冲系统。
接下来,通过将磷酸钠浓度从10mM改变为100mM,研究了离子强度或缓冲液浓度对稳定性的影响。如图2A和2B所示,低缓冲液浓度(10mM、20mM或50mM)下的离子强度对奥利普酶α的酶活性和物理稳定性几乎没有影响。对于50mM及以下的缓冲液浓度,奥利普酶α在磷酸钠(pH6.5)中的稳定性相对一致。然而,当磷酸钠的浓度增加到100mM时,稳定性显著降低。这样的浓度导致聚集体种类的快速增加和伴随的活性降低(图2A和2B)。在30℃下的数据与在冷藏条件下储存奥利普酶α期间观察到的那些一致。选择20mM的磷酸钠浓度作为缓冲液浓度,所述浓度虽然较低,但是仍确保足够的缓冲能力。
赋形剂评价
评价了各种药学上可接受的赋形剂对液体和冻干组合物中的奥利普酶α的稳定性的影响。首先研究了已知的通过优先排除机制起作用的稳定剂对液体稳定性的影响(参见例如,Timasheff,Proc Nat Acad Sci USA.99:9721-9726(2002);和Lee等人,J.Biol.Chem.256:7193-7201(1981))。将蔗糖、海藻糖和丙二醇添加到20mM磷酸钠、0.005%PS80、pH 6.5的基础配制品中,并且评估它们对4mg/mL奥利普酶α的酶活性和物理稳定性的影响。数据显示,这些优先排除稳定剂中的任何一种的存在均不提高在5℃或30℃下在液体状态下奥利普酶α的稳定性(数据未显示)。虽然在所有研究的条件下酶活性和物理稳定性均损失,但是蔗糖似乎比海藻糖和丙二醇稍微更有利。
接下来,研究了蔗糖和海藻糖对冷冻干燥期间奥利普酶α的稳定性的影响。还研究了甘露糖醇,因为它是冷冻干燥中常用的填充剂(图3A和3B)。将这三种多元醇以5%w/v包括在液体组合物中,随后将所述液体组合物冻干。图3A中的数据显示,甘露糖醇的添加降低了冷冻干燥后奥利普酶α的酶活性。图3B中的数据显示,甘露糖醇的添加导致冷冻干燥后蛋白质聚集的大量增加。在蔗糖和海藻糖的存在下聚集的增加是最小的。选择蔗糖作为在液体组合物中的5%w/v的浓度的冷冻保护剂,然后可以将所述液体组合物冻干。
还研究了在甘露糖醇的存在下冻干的奥利普酶α配制品随时间的稳定性。从含有20mM磷酸钠缓冲液(pH 6.5)、0.005%PS80和(i)5%w/v甘露糖醇、(ii)5%w/v蔗糖或(iii)3%甘露糖醇和2%蔗糖的液体组合物中冷冻干燥奥利普酶α。数据显示,当单独使用时,甘露糖醇不仅在冷冻干燥期间导致蛋白质聚集的即刻以及连续增加,而且当在六个月的时间内与蔗糖组合使用时,甘露糖醇也导致蛋白质聚集的即刻以及连续增加(图3B和4B)。在甘露糖醇存在的情况下六个月时的酶活性也比不存在甘露糖醇的情况下低(图4B)。因此,对于冻干的rhASM配制品,认为甘露糖醇是不合适的填充剂。
由于证明在冷冻干燥期间甘露糖醇对rhASM稳定性有害,因此将甲硫氨酸作为潜在的填充剂来评价。评估了在L-甲硫氨酸的存在下奥利普酶α的液体储存期间的酶活性和物理稳定性,并且发现100mM L-甲硫氨酸的添加既不会改善在5℃下奥利普酶α的液体稳定性,也不会对其产生负面影响。如图5A和5B所示,从含有100mM L-甲硫氨酸的液体组合物制备的冻干组合物产生了奥利普酶α的稳定的冻干构造。在5℃下储存六个月的过程中未观察到活性或聚集的变化。另外,与仅用蔗糖冻干的那些相比,通过在甲硫氨酸和蔗糖的存在下冷冻干燥奥利普酶α而获得的饼具有改善的外观。
通过从含有20mM磷酸钠(pH 6.5)、5%w/v蔗糖和渐增量的L-甲硫氨酸的液体组合物冻干的奥利普酶α饼的X射线衍射(XRD)进行用于冻干的适当量的甲硫氨酸的鉴定(数据未显示)。不含有甲硫氨酸的样品是完全无定形的。在含有33mM甲硫氨酸的样品中有一些结晶度的证据,并且在含有66mM和100mM甲硫氨酸的样品中有更多的结晶度的证据。在甲硫氨酸水平低于100mM(例如,10mM和33mM)时,奥利普酶α的冻干产生出现凹陷和塌陷(收缩)的小瓶。因此,选择100mM甲硫氨酸作为冻干rhASM配制品的填充剂。
实施例2:奥利普酶α组合物的稳健性
为了评估含有奥利普酶α、蔗糖和L-甲硫氨酸的组合物的稳健性,在20mM磷酸钠缓冲液中,将这些组分中的每一种相对于对照设置在五个不同的水平下-低、中低、中(对照)、中高和高(表1)。
表1用于评价奥利普酶α配制品稳健性的赋形剂水平
组分 | 对照 | 低 | 中低 | 中 | 中高 | 高 |
蔗糖(%w/v) | 5 | 4 | 4.33 | 5 | 5.67 | 6 |
L-甲硫氨酸(mM) | 100 | 80 | 86.51 | 100 | 113.49 | 120 |
奥利普酶(mg/mL) | 4 | 3 | 3.33 | 4 | 4.67 | 5 |
pH | 6.5 | 6 | 6.16 | 6.5 | 6.84 | 7 |
总共产生了26种液体配制品变体(表2)。配制品2和7代表对照配制品或中心点。剩余24种配制品变体代表围绕中心点的各种条件。所有26种变体均在2℃-8℃(24周或长达12个月)和25℃(16周)下储存以监测其稳定性。
表2用于稳健性评价的奥利普酶α配制品
在测试阶段结束时,以下参数将指示组合物的稳定性:(1)透明无色的外观;(2)pH6.0-7.0;(3)不超过3.0%的聚集体;(4)3.5-4.5mg/mL蛋白质;(5)不超过15%的HMWS;以及(6)11-42U/mg的比活性。图6-8分别示出了在2℃-8℃下储存24周后在26种配制品变体中不同因素对%二聚体、比活性和%HMWS的影响。数据显示,关于%二聚体、比活性或%HMWS,变体之间无显著差异,并且因此所有24种变体以及两种对照配制品均在2℃-8℃下稳定持续了24周。
一直到36周,对于一些变体,还观察到不同pH值和成分浓度对%二聚体和比活性缺乏显著影响。图9显示,所有变体在36周时具有可比较的聚集。
在25℃的加速温度下,在测试的范围内,在16周内赋形剂对稳定性也几乎没有影响。在具有不同pH的变体中观察到最明显的作用(图10)。在较高的pH(6.8至7.0)下,奥利普酶α的稳定性更高,并且在较低的pH(6.5或更低)下,聚集和二聚体更多。
此研究显示,在2℃-8℃下的变体配制品在选定的组分范围内是稳健并且稳定的。
序列表
<110> 建新公司
<120> 治疗酸性鞘磷脂酶缺乏症的药物组合物
<130> 022548.WO048
<150> 62/676,525
<151> 2018-05-25
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<170> PatentIn version 3.5
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530 535 540
Pro Ala Leu Cys Arg His Leu Met Pro Asp Gly Ser Leu Pro Glu Ala
545 550 555 560
Gln Ser Leu Trp Pro Arg Pro Leu Phe Cys
565 570
<210> 5
<211> 629
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Met Pro Arg Tyr Gly Ala Ser Leu Arg Gln Ser Cys Pro Arg Ser Gly
1 5 10 15
Arg Glu Gln Gly Gln Asp Gly Thr Ala Gly Ala Pro Gly Leu Leu Trp
20 25 30
Met Gly Leu Val Leu Ala Leu Ala Leu Ala Leu Ala Leu Ala Leu Ser
35 40 45
Asp Ser Arg Val Leu Trp Ala Pro Ala Glu Ala His Pro Leu Ser Pro
50 55 60
Gln Gly His Pro Ala Arg Leu His Arg Ile Val Pro Arg Leu Arg Asp
65 70 75 80
Val Phe Gly Trp Gly Asn Leu Thr Cys Pro Ile Cys Lys Gly Leu Phe
85 90 95
Thr Ala Ile Asn Leu Gly Leu Lys Lys Glu Pro Asn Val Ala Arg Val
100 105 110
Gly Ser Val Ala Ile Lys Leu Cys Asn Leu Leu Lys Ile Ala Pro Pro
115 120 125
Ala Val Cys Gln Ser Ile Val His Leu Phe Glu Asp Asp Met Val Glu
130 135 140
Val Trp Arg Arg Ser Val Leu Ser Pro Ser Glu Ala Cys Gly Leu Leu
145 150 155 160
Leu Gly Ser Thr Cys Gly His Trp Asp Ile Phe Ser Ser Trp Asn Ile
165 170 175
Ser Leu Pro Thr Val Pro Lys Pro Pro Pro Lys Pro Pro Ser Pro Pro
180 185 190
Ala Pro Gly Ala Pro Val Ser Arg Ile Leu Phe Leu Thr Asp Leu His
195 200 205
Trp Asp His Asp Tyr Leu Glu Gly Thr Asp Pro Asp Cys Ala Asp Pro
210 215 220
Leu Cys Cys Arg Arg Gly Ser Gly Leu Pro Pro Ala Ser Arg Pro Gly
225 230 235 240
Ala Gly Tyr Trp Gly Glu Tyr Ser Lys Cys Asp Leu Pro Leu Arg Thr
245 250 255
Leu Glu Ser Leu Leu Ser Gly Leu Gly Pro Ala Gly Pro Phe Asp Met
260 265 270
Val Tyr Trp Thr Gly Asp Ile Pro Ala His Asp Val Trp His Gln Thr
275 280 285
Arg Gln Asp Gln Leu Arg Ala Leu Thr Thr Val Thr Ala Leu Val Arg
290 295 300
Lys Phe Leu Gly Pro Val Pro Val Tyr Pro Ala Val Gly Asn His Glu
305 310 315 320
Ser Thr Pro Val Asn Ser Phe Pro Pro Pro Phe Ile Glu Gly Asn His
325 330 335
Ser Ser Arg Trp Leu Tyr Glu Ala Met Ala Lys Ala Trp Glu Pro Trp
340 345 350
Leu Pro Ala Glu Ala Leu Arg Thr Leu Arg Ile Gly Gly Phe Tyr Ala
355 360 365
Leu Ser Pro Tyr Pro Gly Leu Arg Leu Ile Ser Leu Asn Met Asn Phe
370 375 380
Cys Ser Arg Glu Asn Phe Trp Leu Leu Ile Asn Ser Thr Asp Pro Ala
385 390 395 400
Gly Gln Leu Gln Trp Leu Val Gly Glu Leu Gln Ala Ala Glu Asp Arg
405 410 415
Gly Asp Lys Val His Ile Ile Gly His Ile Pro Pro Gly His Cys Leu
420 425 430
Lys Ser Trp Ser Trp Asn Tyr Tyr Arg Ile Val Ala Arg Tyr Glu Asn
435 440 445
Thr Leu Ala Ala Gln Phe Phe Gly His Thr His Val Asp Glu Phe Glu
450 455 460
Val Phe Tyr Asp Glu Glu Thr Leu Ser Arg Pro Leu Ala Val Ala Phe
465 470 475 480
Leu Ala Pro Ser Ala Thr Thr Tyr Ile Gly Leu Asn Pro Gly Tyr Arg
485 490 495
Val Tyr Gln Ile Asp Gly Asn Tyr Ser Gly Ser Ser His Val Val Leu
500 505 510
Asp His Glu Thr Tyr Ile Leu Asn Leu Thr Gln Ala Asn Ile Pro Gly
515 520 525
Ala Ile Pro His Trp Gln Leu Leu Tyr Arg Ala Arg Glu Thr Tyr Gly
530 535 540
Leu Pro Asn Thr Leu Pro Thr Ala Trp His Asn Leu Val Tyr Arg Met
545 550 555 560
Arg Gly Asp Met Gln Leu Phe Gln Thr Phe Trp Phe Leu Tyr His Lys
565 570 575
Gly His Pro Pro Ser Glu Pro Cys Gly Thr Pro Cys Arg Leu Ala Thr
580 585 590
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610 615 620
Arg Pro Leu Phe Cys
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<210> 6
<211> 570
<212> PRT
<213> 智人(Homo sapiens)
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His Pro Leu Ser Pro Gln Gly His Pro Ala Arg Leu His Arg Ile Val
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Pro Arg Leu Arg Asp Val Phe Gly Trp Gly Asn Leu Thr Cys Pro Ile
20 25 30
Cys Lys Gly Leu Phe Thr Ala Ile Asn Leu Gly Leu Lys Lys Glu Pro
35 40 45
Asn Val Ala Arg Val Gly Ser Val Ala Ile Lys Leu Cys Asn Leu Leu
50 55 60
Lys Ile Ala Pro Pro Ala Val Cys Gln Ser Ile Val His Leu Phe Glu
65 70 75 80
Asp Asp Met Val Glu Val Trp Arg Arg Ser Val Leu Ser Pro Ser Glu
85 90 95
Ala Cys Gly Leu Leu Leu Gly Ser Thr Cys Gly His Trp Asp Ile Phe
100 105 110
Ser Ser Trp Asn Ile Ser Leu Pro Thr Val Pro Lys Pro Pro Pro Lys
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Pro Pro Ser Pro Pro Ala Pro Gly Ala Pro Val Ser Arg Ile Leu Phe
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Leu Thr Asp Leu His Trp Asp His Asp Tyr Leu Glu Gly Thr Asp Pro
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Asp Cys Ala Asp Pro Leu Cys Cys Arg Arg Gly Ser Gly Leu Pro Pro
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Ala Ser Arg Pro Gly Ala Gly Tyr Trp Gly Glu Tyr Ser Lys Cys Asp
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Leu Pro Leu Arg Thr Leu Glu Ser Leu Leu Ser Gly Leu Gly Pro Ala
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Gly Pro Phe Asp Met Val Tyr Trp Thr Gly Asp Ile Pro Ala His Asp
210 215 220
Val Trp His Gln Thr Arg Gln Asp Gln Leu Arg Ala Leu Thr Thr Val
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Thr Ala Leu Val Arg Lys Phe Leu Gly Pro Val Pro Val Tyr Pro Ala
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Val Gly Asn His Glu Ser Thr Pro Val Asn Ser Phe Pro Pro Pro Phe
260 265 270
Ile Glu Gly Asn His Ser Ser Arg Trp Leu Tyr Glu Ala Met Ala Lys
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Ala Trp Glu Pro Trp Leu Pro Ala Glu Ala Leu Arg Thr Leu Arg Ile
290 295 300
Gly Gly Phe Tyr Ala Leu Ser Pro Tyr Pro Gly Leu Arg Leu Ile Ser
305 310 315 320
Leu Asn Met Asn Phe Cys Ser Arg Glu Asn Phe Trp Leu Leu Ile Asn
325 330 335
Ser Thr Asp Pro Ala Gly Gln Leu Gln Trp Leu Val Gly Glu Leu Gln
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Ala Ala Glu Asp Arg Gly Asp Lys Val His Ile Ile Gly His Ile Pro
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Pro Gly His Cys Leu Lys Ser Trp Ser Trp Asn Tyr Tyr Arg Ile Val
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Ala Arg Tyr Glu Asn Thr Leu Ala Ala Gln Phe Phe Gly His Thr His
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Val Asp Glu Phe Glu Val Phe Tyr Asp Glu Glu Thr Leu Ser Arg Pro
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Leu Ala Val Ala Phe Leu Ala Pro Ser Ala Thr Thr Tyr Ile Gly Leu
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Asn Pro Gly Tyr Arg Val Tyr Gln Ile Asp Gly Asn Tyr Ser Gly Ser
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Ser His Val Val Leu Asp His Glu Thr Tyr Ile Leu Asn Leu Thr Gln
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Ala Asn Ile Pro Gly Ala Ile Pro His Trp Gln Leu Leu Tyr Arg Ala
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Arg Glu Thr Tyr Gly Leu Pro Asn Thr Leu Pro Thr Ala Trp His Asn
485 490 495
Leu Val Tyr Arg Met Arg Gly Asp Met Gln Leu Phe Gln Thr Phe Trp
500 505 510
Phe Leu Tyr His Lys Gly His Pro Pro Ser Glu Pro Cys Gly Thr Pro
515 520 525
Cys Arg Leu Ala Thr Leu Cys Ala Gln Leu Ser Ala Arg Ala Asp Ser
530 535 540
Pro Ala Leu Cys Arg His Leu Met Pro Asp Gly Ser Leu Pro Glu Ala
545 550 555 560
Gln Ser Leu Trp Pro Arg Pro Leu Phe Cys
565 570
Claims (19)
1.一种组合物,其包含重组人酸性鞘磷脂酶、磷酸钠、甲硫氨酸和蔗糖。
2.根据权利要求1所述的组合物,其中所述组合物是冻干组合物,其包含:
4%-7%w/w奥利普酶α(SEQ ID NO:2),
3%-7%w/w磷酸钠,
15%-25%w/w L-甲硫氨酸,和
65%-75%w/w蔗糖。
3.根据权利要求2所述的组合物,其基本上由以下组成:
5.5%w/w奥利普酶α,
2.3%w/w磷酸氢二钠七水合物,
2.6%w/w磷酸二氢钠一水合物,
20.5%w/w L-甲硫氨酸,和
68.6%w/w蔗糖。
4.根据权利要求1所述的组合物,其中所述组合物是水性液体组合物,其包含:
1-10mg/mL奥利普酶α,
10-50mM磷酸钠,
70-150mM L-甲硫氨酸,和
1%-10%w/v蔗糖,
其中所述组合物具有5-8的pH。
5.根据权利要求4所述的组合物,其中所述组合物是水性液体组合物,其包含:
3-5mg/mL奥利普酶α,
10-30mM磷酸钠,
80-120mM L-甲硫氨酸,和
4%-6%w/v蔗糖,
其中所述组合物具有6-7的pH。
6.根据权利要求4所述的组合物,其基本上由以下组成:
4mg/mL奥利普酶α,
20mM磷酸钠,
100mM L-甲硫氨酸,和
5%w/v蔗糖,
其中所述组合物具有6.5的pH。
7.根据权利要求4-6中任一项所述的组合物,其还包含0.005%w/v聚山梨醇酯80。
8.一种组合物,其通过将根据权利要求4-7中任一项所述的水性液体组合物冻干而获得。
9.一种用于制造冻干组合物的方法,其包括:
获得根据权利要求4-7中任一项所述的水性液体组合物,以及
冻干所述水性液体组合物。
10.一种含有冻干组合物的小瓶,所述冻干组合物基本上由以下组成:
21.2mg奥利普酶α,
9.0mg磷酸氢二钠七水合物,
10.0mg磷酸二氢钠一水合物,
79mg L-甲硫氨酸,和
265mg蔗糖。
11.一种水性液体组合物,其通过在5.1mL的无菌水中重构基本上由以下组成的冻干组合物而获得:
21.2mg奥利普酶α,
9.0mg磷酸氢二钠七水合物,
10.0mg磷酸二氢钠一水合物,
79mg L-甲硫氨酸,和
265mg蔗糖。
12.一种含有冻干组合物的小瓶,所述冻干组合物基本上由以下组成:
4.8mg奥利普酶α,
2.0mg磷酸氢二钠七水合物,
2.3mg磷酸二氢钠一水合物,
17.9mg L-甲硫氨酸,和
60mg蔗糖。
13.一种水性液体组合物,其通过在1.1mL的无菌水中重构基本上由以下组成的冻干组合物而获得:
4.8mg奥利普酶α,
2.0mg磷酸氢二钠七水合物,
2.3mg磷酸二氢钠一水合物,
17.9mg L-甲硫氨酸,和
60mg蔗糖。
14.一种制品,其包含根据权利要求10或12所述的小瓶和含有用于重构冻干组合物的无菌水、0.9%氯化钠或磷酸盐缓冲盐水的小瓶。
15.一种治疗人类患者的酸性鞘磷脂酶缺乏症(ASMD)的方法,所述方法包括向所述患者给予根据权利要求1-8、11和13中任一项所述的组合物,其中如果所述组合物是冻干组合物,则在给予前将其重构为液体形式。
16.根据权利要求1-8、11和13中任一项所述的组合物,其用于治疗人类患者的ASMD。
17.根据权利要求1-8、11和13中任一项所述的组合物用于制造治疗人类患者的ASMD用的药物的用途。
18.根据权利要求15所述的方法、根据权利要求16所述的用于所述用途的组合物或根据权利要求17所述的用途,其中所述ASMD是A/B型或B型尼曼-皮克病。
19.根据权利要求18所述的方法、用于所述用途的组合物或用途,其中所述治疗是针对ASMD的非神经学表现。
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US201862676525P | 2018-05-25 | 2018-05-25 | |
US62/676,525 | 2018-05-25 | ||
PCT/US2019/033983 WO2019227029A1 (en) | 2018-05-25 | 2019-05-24 | Pharmaceutical compositions for treating acid sphingomyelinase deficiency |
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JP2024069459A (ja) | 2024-05-21 |
EP3802805A1 (en) | 2021-04-14 |
MX2020012700A (es) | 2021-04-28 |
US20210145941A1 (en) | 2021-05-20 |
JP2021525083A (ja) | 2021-09-24 |
WO2019227029A1 (en) | 2019-11-28 |
KR20210015903A (ko) | 2021-02-10 |
CA3101688A1 (en) | 2019-11-28 |
CO2020014399A2 (es) | 2020-12-10 |
IL278964A (en) | 2021-01-31 |
UY38238A (es) | 2019-12-31 |
SG11202011488WA (en) | 2020-12-30 |
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