CN112566653A - Igfbp-2的肝素结合域在治疗代谢紊乱中的作用 - Google Patents
Igfbp-2的肝素结合域在治疗代谢紊乱中的作用 Download PDFInfo
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Abstract
本技术通常涉及化合物,特别是涉及用于调节代谢紊乱的肽,其包含胰岛素样生长因子结合蛋白‑2(IGFBP‑2)的肝素结合域(HBD)。本技术通常还涉及此类化合物在预防和/或治疗代谢紊乱的方法中的用途以及在用于此类用途的组合物和制剂中的用途。
Description
相关申请的交叉引用
本申请要求于2018年5月24日提交的美国临时专利申请62/676,087的优先权及其权益,通过引用其全部公开内容合并于此。
技术领域
本技术通常涉及化合物,特别是涉及用于预防和/或治疗代谢紊乱的肽,其包含胰岛素样生长因子结合蛋白-2(IGFBP-2)的肝素结合域(HBD)。本技术通常还涉及此类化合物在预防或治疗代谢紊乱的方法中的用途以及涉及用于此类用途的组合物和制剂。
背景技术
胰岛素样生长因子结合蛋白-2(IGFBP-2)是一种36,000道尔顿的蛋白,其为IGFBP家族的成员。高亲和力IGF结合蛋白有六(6)种形式。除了结合胰岛素样生长因子I和II并作为转运蛋白(尤其是在血液中)外,这些蛋白还具有一些与它们结合IGF的能力无关的直接的组织作用。
IGFBP-2是血清中第二丰富的结合蛋白。在人体内,它在健康受试者中以100-600ng/ml的浓度进行循环。在胎儿期和出生时,该蛋白质的浓度很高,而在儿童期和青春期时逐渐下降。在60-80岁之间,其浓度大约会增加25%。IGFBP-2的血清浓度受激素和营养物质的调节。空腹会导致IGFBP-2显著增加,而进食(尤其是进食蛋白质)可使其浓度恢复正常。
除了作为胰岛素样生长因子的载体蛋白的作用外,IGFBP-2还能够调节骨量、脂肪代谢和葡萄糖代谢。IGFBP-2基因敲除的小鼠(IGFBP-2-/-)的骨量会减少,并且脂肪量会增加(DeMambro,Endocrinology,2008)。相反地,小鼠中IGFBP-2的过表达会导致对饮食诱导的肥胖症的敏感性降低,而对胰岛素的敏感性提高(Wheatcroft,Diabetes,2007;Hedbacker,Cell Metab,2010)。在体外,IGFBP-2直接刺激小鼠和人成骨细胞的分化(Xi,JBMR,2014),相反地抑制前脂肪细胞的分化(Wheatcroft,Diabetes,2007)。对于其他IGFBP,IGFBP-2的N末端区域包含一个IGF-1结合位点,而C末端区域能够促进与IGF-1的结合,彰显了其与细胞外基质结合的能力。
IGFBP-2还包含两个肝素结合域(HBD),其赋予结合IGF的独立功能。HBD1是位于接头区域的独特HBD,而HBD2位于C末端区域。尽管HBD1和HBD2都负责IGFBP-2抑制脂肪形成的能力(Xi,Endocrinology,2013),但只有HBD1介导了骨量的获取和成骨细胞分化的特性(Kawai,JBC,2011;Xi,JBMR,2014)。
先前的研究已经公开了一些包含HBD的肽。例如,WO 2005/014635公开了与HBD1具有氨基酸序列相似性的心血管疾病血浆多肽(CPP),并暗示了这类CPP的潜在诊断功能。美国专利NO.9,220,746公开了一类HBD1肽,其保留了IGFBP-2的造骨新生(osteoblastogenesis)活性,并提出了这些肽在治疗骨相关病症中的作用。最近,WO 2018/145006提出了多种HBD片段,其在体内可以诱导骨形成。
迄今为止,可获得的实验数据表明,IGFBP-2的生物学效应,即刺激成骨细胞分化和抑制脂肪细胞分化,至少部分地由该分子的HBD介导(Xi,2013;Kawai,2013)。这些特性为被衍生并描述于美国专利No.9,220,746和WO 2018/145006中的各种HBD肽片段和类似物所共有。由于成骨细胞和脂肪细胞均起源于间充质干细胞(MSC),这表明了较分化为脂肪细胞而言,IGBP-2的HBD更有利于MSC分化为成骨细胞。
IGFBP-2的另一种生物学作用是对葡萄糖的控制。在各种瘦素缺乏症动物模型和其他肥胖症和糖尿病模型中,IGFBP-2的过表达可改善对葡萄糖的控制(Weathcroft,2007;Hedbacker,Cell Metab,2010)。这种作用似乎至少部分应归因于对胰岛素敏感性的提高(Hedbacker,Cell Metab,2010)。此外,IGFBP-2还显示在体外可增加脂肪细胞和肌肉细胞对葡萄糖的摄取(Assefa,2018;Yau,2013),并通过胰岛素和胰岛素样生长因子-1(IGF1)所利用的信号通路来实现,以及通过胰岛素和IGF1独立机制来实现。有趣的是,瘦素刺激了IGFBP-2基因的表达,并且IGFBP-2被认为是瘦素代谢作用的介质(Hedbacker,2010)。
尽管已经证明IGFBP-2在葡萄糖控制方面的生物学作用,但是仍不清楚HBD结构域是否参与了这些生物学作用。在一个显示HBD1和HBD2降低小鼠体重和脂肪堆积的文献中,显示出HBD1和HBD2对葡萄糖耐量没有影响,因此表明HBD不参与葡萄糖的代谢(Xi,2013)。
因此,研究具有调节葡萄糖代谢潜力例如改善受试者的葡萄糖控制的具有治疗性的肽将会非常有趣。
发明概述
根据各个方面,本技术涉及一种用于调节受试者的代谢紊乱(metabolicdisorder)的方法,所述方法包括:向所述受试者施用治疗有效量的肽,其由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中所示的任意一种肽的药学上可接受的盐。
根据各个方面,本技术涉及一种分离的肽,其由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐,所述肽用于在患有代谢疾病的受试者中调节代谢紊乱。
根据各个方面,本技术涉及一种试剂盒,其包含:a)药物组合物,其包含:治疗有效量的肽,所述肽由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐;以及一种或多种药学上可接受的载体;b)用于所述药物组合物的一个或多个容器;c)其应用在调节代谢紊乱中的使用说明。
根据各个方面,本技术涉及一种用于改善受试者的葡萄糖控制的方法,该方法包括:向受试者施用治疗有效量的肽,所述肽由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐。
根据各个方面,本技术涉及一种用于改善受试者的血糖控制的分离的肽,其由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐。
根据各个方面,本技术涉及一种用于改善受试者的胰岛素敏感性的方法,所述方法包括:向所述受试者施用治疗有效量的肽,所述肽由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐。
根据各个方面,本技术涉及一种用于恢复受试者的葡萄糖稳态的方法,该方法包括:向受试者施用治疗有效量的肽,所述肽由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐。在某些情况下,可以独立于胰岛素和胰岛素样生长因子-1(IGF1)来实现恢复葡萄糖稳态的方法。
根据各个方面,本技术涉及一种分离的肽,其由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐,所述肽用于改善受试者的胰岛素敏感性。
通过结合附图阅读以下对特定实施例的描述,本技术的其他方面和特征对于本领域普通技术人员应当是显而易见的。
附图说明
在本公开中描述的实施例的所有特征不是互相排斥的,并且可以彼此组合。例如,一个实施方案的元件可以在其他实施方案中使用,而无需进一步提及。在下文中参考附图提供了特定实施方案的详细描述,其中:
图1是显示本技术的一个实施方案的HBD1片段改善了ob/ob小鼠的葡萄糖耐受性,ob/ob小鼠经过两周的酰化HBD1(3-11)片段处理。显示的数据是腹膜内葡萄糖耐量测试(IPGTT)后45分钟的血糖水平(平均值±SEM)。(每组n=5;***:p值<0.001)。
图2A-2C显示了表明本技术的一个实施方案的HBD1片段改善了葡萄糖遥测的ob/ob小鼠(具有瘦素缺乏导致胰岛素抗性的小鼠模型)中的葡萄糖耐受性的图。图2A:酰化HBD1(3-11)片段处理28天后的3小时腹膜内葡萄糖耐量测试曲线。(每组n=5-8;两种剂量vs VHL,p值<0.0001),双向方差分析,多重比较,****p<0.0001;图2B:酰化HBD1(3-11)片段治疗28天后的空腹血糖水平(IPGTT之前10分钟内的平均值)。(每组n=5-8;3mg/kg剂量vsVHL,p值<0.005),未配对双尾t检验vs VHL,***p<0.005;图2C:酰化HBD1(3-11)片段处理28天后3小时腹膜内葡萄糖耐量测试曲线的面积。(每组n=5-8),未配对双尾t检验vs VHL,*p<0.05,****p<0.0001。
图3A-3B显示了表明本技术的一个实施方案的HBD1片段改善了葡萄糖遥测的ob/ob小鼠中的葡萄糖不耐受,该小鼠具有瘦素缺乏导致的胰岛素抗性。图3A:酰化HBD1(3-11)片段治疗前(第-1天)和27天后的16小时平均血糖水平。(每组n=5-8;3mg/kg剂量vsVHL,**p值<0.001);图3B:酰化HBD1(3-11)片段治疗27天后16小时平均血糖水平相对于基线的变化。(每组n=5-8;3mg/kg剂量vs VHL,**p值<0.01)。
图4显示了表明本技术的一些实施方案,用HBD1片段处理的完全分化的3T3脂肪细胞增加的葡萄糖摄取的图。在测试[3H]-2-脱氧葡萄糖摄取之前,将细胞以3μg/ml的浓度暴露于测试化合物24小时。所有测试的HBD1肽均刺激3T3-LI脂肪细胞增加葡萄糖摄取。
图5A-5C显示了说明本技术的一些实施方案中用HBD1片段治疗时,完全分化的C2C12小鼠骨骼肌肌管的葡萄糖摄取的剂量依赖性(图5A)和时间依赖性(图5B)增加的图。特别是:0.8μM,1.5μM和2.3μM的HBD1 SEQ ID NO:73(C18:0-HLGLEEPKK);或者在测试葡萄糖摄取之前的2、4和16小时内,使用1.5μM的SEQ ID NO:73(C18:0-HLGLEEPKK)。此外,添加与胰岛素结合的HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)产生葡萄糖摄取的累积增加(图5C)。
图6显示了说明本技术的一个实施方案,当用HBD1片段治疗时,完全分化的C2C12小鼠骨骼肌肌管对Akt途径的剂量依赖性磷酸化(激活)的图。特别是:HBD1 SEQ ID NO:73(C18:0-HLGLEEPKK)。胰岛素和IGF1均利用Akt途径最终诱导GLUT4向细胞膜转运,从而促进葡萄糖的摄取和代谢。通过用抗纤连蛋白抗体治疗,可防止HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)对Akt的激活,该抗纤连蛋白抗体已被证明可防止IGFBP2与RPTPβ受体结合并激活Akt途径。
图7显示了本技术的一个实施方案的图,其说明了当用HBD1片段治疗时,完全分化的C2C12小鼠骨骼肌肌管对AMPK途径的剂量依赖性磷酸化(激活)。特别是:HBD1SEQ ID NO:73(C18:0-HLGLEEPKK)。AMPK途径既不依赖胰岛素也不依赖IGF1,但最终起到诱导GLUT4向细胞膜转运的作用,从而促进葡萄糖的摄取和代谢。通过抗纤连蛋白抗体和AMPK特异性抑制剂化合物C(CC)的两种处理均阻止了HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)对AMPK的激活,所述抗纤连蛋白抗体已被证明可以防止IGFBP2与RPTPβ受体结合并且激活Akt途径。
图8显示了说明本技术的一个实施方案,当用HBD1片段治疗时,完全分化的C2C12小鼠骨骼肌肌管对葡萄糖摄取增加的图。特别是:1.5μM SEQ ID NO:73(C18:0-HLGLEEPKK),单独或以与胰岛素的共同添加的方式使用。通过抗纤连蛋白抗体和AMPK特异性抑制剂化合物C(CC)的两种处理均阻止了HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)增加的葡萄糖摄取,所述抗纤连蛋白抗体已被证明可以防止IGFBP2与RPTPβ受体结合。
发明详述
本技术的当前描述并非旨在成为可实施本技术的所有不同方式或可添加至本技术的所有特征的详细目录。例如,关于一个实施例示出的特征可以被并入其他实施例中,并且关于特定实施例示出的特征可以从该实施例中删除。另外,根据不背离本技术的本公开,对本文提出的各种实施例的多种变化和添加对于本领域技术人员应当是显而易见的。因此,以下说明书旨在说明本技术的一些特定实施例,而非穷举地指定其所有排列、组合和变形。除非另有定义,否则本文中使用的所有技术和科学术语具有与本技术所属领域的技术人员通常所理解的含义相同的含义。
除非上下文另外明确指出,否则本文所用的单数形式的“一个”、“一种”和“所述”包括复数指代物。
本文通过端点对数值范围的叙述旨在包括该范围内包含的所有数字(例如1-5的描述包括1、1.5、2、2.75、3、3.80、4、4.32和5)。
术语“约”在本文中被明确地使用或不明确地使用,本文中给出的每个量是指实际的给定值,并且还意味着是指基于本领域普通技术人员合理地推断出的该给定值的近似值,包括由于这种给定值的实验和/或测量条件而引起的等效值和近似值。例如,在给定值或范围的上下文中,术语“约”是指在在给定值或范围的20%以内,优选在15%以内,更优选在10%以内,更优选在9%以内,更优选在8%以内,更优选在7%以内,更优选在6%以内,更优选在5%以内的值或范围。
本文中使用的表述“和/或”应被理解为两个指定的特征或组分中的每个具有或不具有另一个的具体公开。例如,“A和/或B”将被视为(i)A、(ii)B和(iii)A和B中的每一个的具体公开,就如同每一个在本文中分别列出一样。
本公开源于本发明人对IGFBP-2的肽片段的研究,特别是对IGFBP-2的肝素结合域(HBD)的肽片段的研究,以及对这些肽片段如何能被用于调节受试者代谢紊乱的方法的研究,例如预防和/或治疗代谢紊乱的方法。特别地,发明人发现,IGFBP-2的肝素结合域1(HBD1)的肽片段被证明可改善对胰岛素有抵抗力的动物模型的整体葡萄糖耐受性而可用于调节受试者的葡萄糖代谢。
A.化合物、肽、其片段和类似物
如本文所用,表述和术语“肝素结合域”和“HBD”是指IGFBP-2的肝素结合域,而术语“HBD2”是指IGFBP-2的肝素结合域2。HBD1意图是指具有如SEQ ID NO:1所示的氨基酸序列的肽,即:1-KHHLGLEEPKKLR-13,其中“1”是指在该HBD1肽的5'-末端或在N-末端处的氨基酸残基。“13”是指该HBD1肽的3'-末端或C-末端的氨基酸残基。因此,HBD1的氨基酸占据以下位置:
1KH2H3L4G5L6E7E8P9K10K11L12R13
本领域中公认的缩写将用于描述氨基酸,包括左旋氨基酸(L-氨基酸或L或L-形式)和右旋氨基酸(D-氨基酸或D或D-形式),丙氨酸(Ala或A),精氨酸(Arg或R),天冬酰胺(Asn或N),天冬氨酸(Asp或D),半胱氨酸(Cys或C),谷氨酸(Glu或E),谷氨酰胺(Gln或Q),甘氨酸(Gly或G),组氨酸(His或H),异亮氨酸(Ile或I),亮氨酸(Leu或L),赖氨酸(Lys或K),蛋氨酸(Met或M),苯丙氨酸(Phe或F),脯氨酸(Pro或P),丝氨酸(Ser或S),苏氨酸(Thr或T),色氨酸(Trp或W),酪氨酸(Tyr或Y)和缬氨酸(Val或V)。天然肽序列中的L-氨基酸残基可以被改变为蛋白质中通常发现的20个L-氨基酸中的任何一种或相应的D-氨基酸,稀有氨基酸中的任何一种,例如但不限于,4-羟脯氨酸或羟赖氨酸,或非蛋白质氨基酸,例如P-丙氨酸或高丝氨酸。除非另有说明,本文命名的氨基酸是指L-形式。
本文所定义的肽的天然存在的变体是可以包含具有一种或多种氨基酸的取代、添加或缺失的那些变体,这些取代、添加或缺失是由于编码基因或其等位基因的核苷酸序列的离散变化或转录的RNA的可变剪接所致。应当理解,这些变化基本上不影响肽的变体的性质、药理和生物学特性。
本公开的肽可以是盐的形式。特别地,分子的酸性功能可以被其盐衍生物代替,例如但不限于三氟乙酸盐。
“肽”、“多肽”或“蛋白质”是指任何氨基酸链,无论其长度或翻译后修饰(例如糖基化或磷酸化)、化学修饰、或包含非天然或异常氨基酸的氨基酸,例如D-酪氨酸,鸟氨酸,氨基己二酸。
在一些实施方案中,本公开的肽包含HBD1的片段。在一些实施方案中,该肽的长度为13个氨基酸。在一些实施方案中,该肽的长度为12个氨基酸。在一些实施方案中,该肽的长度为11个氨基酸。在一些实施方案中,该肽的长度为10个氨基酸。在一些实施方案中,该肽的长度为9个氨基酸。在一些其他实施方案中,该肽的长度为8个氨基酸。在一些其他实施方案中,该肽的长度为7个氨基酸。在一些其他实施方案中,该肽的长度为6个氨基酸。在一些实施方案中,该肽的长度为5个氨基酸。在一些实施方案中,该肽的长度为4个氨基酸。
如本文所用,术语和表述“片段”或“其片段”是指例如IGFBP-2或IGFBP-2的HBD或IGFBP-2的HBD1等肽的氨基酸片段。HBD1的片段少于13个氨基酸残基。因此,HBD1的片段的长度可以是12、11、10、9、8、7、6、5或4个氨基酸残基。在一些实施方案中,HBD1的片段的长度为12个氨基酸。在一些实施方案中,HBD1的片段的长度为11个氨基酸。在一些实施方案中,HBD1的片段的长度为10个氨基酸。在一些实施方案中,HBD1的片段的长度为9个氨基酸。在一些其他实施方案中,HBD1的片段的长度为8个氨基酸。在一些其他实施方案中,HBD1的片段的长度为7个氨基酸。在一些其他实施方案中,HBD1的片段的长度为6个氨基酸。在一些其他实施方案中,HBD1的片段的长度为5个氨基酸。在一些其他实施方案中,HBD1的片段的长度为4个氨基酸。
在一个实施方案中,本公开提供了具有如表1中所描述的氨基酸序列的肽。HBD1(1-13)代表全长HBD1。表1中呈现的其余的肽是HBD1(1-13)的片段,其中在N-末端、或在C端、或同时在N-末端和C-末端均不存在氨基酸残基。
表1:HBD1肽的实例
在一些实施方案中,本公开的肽是“纯化的”、“分离的”或“基本上纯的”。当肽与天然伴随的组分分离时,它们是“纯化的”、“分离的”或“基本上纯的”。通常,当化合物为样品中总物质的至少约60%,至少约65%,至少约70%,至少约75%,至少约80%,至少约85%,至少约90%,至少约91%,至少约92%,至少约93%,至少约94%,至少约95%,至少约96%,至少约97%,至少约98%,或至少约99%(重量)时,其是基本上纯的。纯化或分离肽的技术是本领域公知的并且是本领域技术人员已知的。
在一些其他实施方案中,本发明的某些肽也可以呈环化形式,使得N末端或C-末端直接头尾相连或通过插入接头部分头尾相连。这样的部分本身通常包含一个或多个氨基酸残基,这些氨基酸残基以避免相对于非环化形式改变肽的三维结构的方式连接主链。相对于未环化的肽而言,这样的肽衍生物可以具有改善的稳定性和生物利用度。
用于使肽环化的方法是本领域众所周知的。可以通过在两个侧链官能团之间形成二硫键,在一个侧链官能团和主链α-氨基或羧基官能团之间形成酰胺键或酯键,在两个侧链官能团之间形成酰胺键或酯键,或在主链α-氨基和羧基官能团之间形成酰胺键来实现环化。这些环化反应传统上是在溶液的高稀释度下进行的。环化通常是在肽连接到树脂上时完成的。在固相支持物上合成环肽的最常见方法之一是将氨基酸的侧链连接到树脂上。使用适当的保护策略,在链组装后,可以对C-末端和N-末端进行选择性脱保护并在树脂上环化。这种策略被广泛使用,并且与叔丁氧羰基(Boc)或9-芴基甲氧羰基(Fmoc)的方案兼容。然而,它仅限于含有适当的侧链官能团以附着于固相支持物的肽。可以使用多种方法来实现环状肽的有效合成。合成环状肽的一种方法是基于环化的同时从树脂上切割。在通过固相合成将合适的肽序列组装到树脂上或者将线性序列附加到树脂上之后,脱保护的氨基基团可以与其锚定活性键反应以产生受保护的环肽。通常,需要最终的脱保护步骤以产生靶标环肽。合成环肽的方法是本领域众所周知的。
在其他实施方案中,本公开提供了本文所定义的肽的类似物。如本文所用,术语“类似物”是指具有其亲本化合物的生理活性并且包含一个或多个(例如,两个,三个,四个,五个或六个或更多个)不同于天然存在的亲本肽的氨基酸序列的氨基酸。这样的类似物优选具有至少约40%,至少约45%,至少约50%,至少约55%,至少约60%,至少约65%,至少约70%,至少约75%,至少约80%,至少约85%,至少约90%,至少约95%,至少约96%,至少约07%,至少约98%或至少约99%亲本肽的生理活性。
在一些其他实施方案中,类似物可以具有与亲本一样的生理活性(即,具有亲本肽的生理活性的100%)或可以具有比亲本肽大于约100%,大于约110%,大于约120%,大于约130%,大于约140%,大于约150%,大于约160%,大于约170%,大于约180%,大于约190%,大于约200%,或多大于约300%的生理活性。
在一些其他实施方案中,类似物的生理活性可能低于亲本(例如为亲本肽的生理活性的95%),但仍可以呈现与某些治疗应用相关和/或所期望的活性水平。
此类不同氨基酸可以是添加、取代、缺失或其组合,包括添加非天然侧链基团和主链连接。肽修饰以产生其类似物是已知的。参见例如美国专利No.7,323,543、7,482,171、7,459,152和7,393,919,其通过全部引用并入本文。例如,包含HBD1的肽的类似物或HBD1的片段的类似物是指HBD1的:i)结构类似物;或ii)功能类似物;或iii)结构和功能类似物,其尤其能够替代HBD1以调节葡萄糖的代谢,例如预防和/或治疗与葡萄糖代谢受损和/或胰岛素代谢受损有关的代谢异常。
本公开的肽的类似物其全长与本文描述的氨基酸序列具有至少约50%,至少约55%,至少约60%,至少约65%,至少约70%,至少约75%,与氨基的序列同源性至少约80%,至少约85%,至少约90%,至少约95%,至少约96%,至少约97%,至少约98%或至少99%序列同源性,并共享HBD1的代谢作用或生物活性中的至少一种。本领域技术人员将容易地鉴定出HBD1的类似序列或HBD1的片段的类似序列。例如,HBD1的类似物包括但不限于具有如SEQ ID NO:1所示氨基酸序列的肽(KHHLGLEEPKKLR),其中1、2或3位的K或H被R或K取代,第4或6位的L被I或V取代,第10或11位的K被H或R取代,第12位的L被I或V取代,和/或第13位的R被K或H取代。
HBD1的类似物或HBD1的片段的类似物是例如通过丙氨酸扫描或通过氨基酸取代获得的类似物。在一些情况下,HBD1的类似物或其片段的类似物可以包含非天然编码的氨基酸,其中非天然编码的氨基酸是指不是常见氨基酸或吡咯赖氨酸或硒代半胱氨酸之一的氨基酸,或通过修饰(例如翻译后修饰)天然编码的氨基酸(包括但不限于20个常见氨基酸或吡咯赖氨酸和硒代半胱氨酸)而出现的氨基酸,但自身并未通过翻译复合物并入生长中的多肽链中。这种非天然存在的氨基酸的实例包括但不限于N-乙酰氨基葡萄糖基-L-丝氨酸,N-乙酰氨基葡萄糖基-L-苏氨酸和O-磷酸酪氨酸。表2给出了在不同氨基酸位置具有丙氨酸取代的HBD1(3-11)类似物的实例。
表2:在不同位置具有丙氨酸取代的HBD1(3-11)片段
SEQ ID NOs | 氨基酸序列 |
SEQ ID NO:17 | <u>A</u>LGLEEPKK |
SEQ ID NO:18 | H<u>A</u>GLEEPKK |
SEQ ID NO:19 | HL<u>A</u>LEEPKK |
SEQ ID NO:20 | HLG<u>A</u>EEPKK |
SEQ ID NO:21 | HLGL<u>A</u>EPKK |
SEQ ID NO:22 | HLGLE<u>A</u>PKK |
SEQ ID NO:23 | HLGLEE<u>A</u>KK |
SEQ ID NO:24 | HLGLEEP<u>A</u>K |
SEQ ID NO:25 | HLGLEEPK<u>A</u> |
表3显示了HBD1片段类似物的其他实例,其在HBD1(3-11)的不同氨基酸位置处包含氨基酸的取代。
表3:在不同位置具有氨基酸取代的HBD1(3-11)片段类似物
在一些情况下,HBD1的类似物或其片段的序列与HBD1的序列可以相差1、2、3、4、5、6、7、8或9个氨基酸的取代、缺失或添加或其组合。在某些情况下,氨基酸取代是保守氨基酸取代。如本文所用,表述“保守氨基酸取代”是指用另一个相似特征取代残基的取代。典型的保守氨基酸取代包括Gly(G),Ala(A),Val(V),Leu(L)和Ile(I)中的那些;Ser(S),Cys(C),Met(M)和Thr(T)中的那些;酸性残基Asp(D)和Glu(E)中的那些;Asn(N)和Gln(Q)中的那些;碱性残基His(H),Lys(K)和Arg(R)中的那些;以及芳香族残基Phe(F),Try(W)和Tyr(Y)中的那些。在一些实施方案中,本技术提供了一种分离的肽,其具有如SEQ ID NO:1所示的HBD1片段。在一些情况下,该片段的长度为6至10个氨基酸,并且包含HBD1的3至10个残基,即:如SEQ ID NO:7所示的HLGLEEPK或其类似物。具有氨基酸序列HLGLEEPK的肽的类似物的实例包括但不限于如表4中显示的肽。
表4:在不同位置具有氨基酸取代的HBD1(3-10)片段类似物
SEQ ID NO: | 氨基酸序列 |
SEQ ID NO:112 | HLGLEEP<u>R</u> |
SEQ ID NO:113 | HLGLEEP<u>H</u> |
在一些实施方案中,本技术提供了一种分离的肽,其具有如SEQ ID NO:1所示的HBD1片段。在一些情况下,该片段的长度为6至10个氨基酸,并且包含HBD1的5至10个残基,即:如SEQ ID NO:14所示的GLEEPK或其类似物。在一些其他实施方案中,该片段的长度为6至9个氨基酸,并且包含HBD1的5至10个残基,即:如SEQ ID NO:14所示的GLEEPK或其类似物。具有氨基酸序列GLEEPK的肽的类似物的实例包括但不限于表5中显示的肽。
表5:在不同位置具有氨基酸取代的HBD1(5-10)片段的类似物
SEQ ID NO: | 氨基酸序列 |
SEQ ID NO:79 | GLEEP<u>L</u> |
SEQ ID NO:80 | GLEEP<u>R</u> |
SEQ ID NO:81 | GLDEPK |
SEQ ID NO:82 | GLE<u>D</u>PK |
SEQ ID NO:83 | G<u>G</u>EEPK |
SEQ ID NO:84 | G<u>V</u>EEPK |
SEQ ID NO:85 | G<u>I</u>EEPK |
SEQ ID NO:86 | <u>V</u>LEEPK |
SEQ ID NO:87 | <u>L</u>LEEPK |
SEQ ID NO:88 | <u>I</u>LEEPK |
在一些其他实施方案中,可以修饰本公开的肽。如本文所用,术语“修饰的”当用于鉴定肽时,是指对肽进行的任何改变,例如肽的长度、氨基酸序列、化学结构、共翻译修饰或肽的翻译后修饰的改变。在一些情况下,本发明的肽包含一个或多个被修饰的氨基酸残基。
如本文所用,表述“翻译后修饰”是指天然或非天然氨基酸在被掺入肽链后在该氨基酸上发生的任何修饰。仅举例来说,该术语包括体内共翻译修饰、体外共翻译修饰(例如在无细胞翻译系统中)、体内翻译后修饰和体外翻译后修饰。翻译后修饰的实例为但不限于本公开的肽的糖基化、聚乙二醇化、乙酰化、酰化、酰胺化、甲基化、羧化、磷酸化、添加盐、酰胺或酯(特别是添加C-末端酯)和N-酰基衍生物。这些类型的翻译后修饰是本领域众所周知的。
在一些实施方案中,本公开的肽包括一个或多个分子量为约10,000至约40,000的聚(乙二醇)(或“PEG”)部分,其偶联至所述肽的N-或C-末端。“聚亚烷基二醇”是指直链或支链的聚亚烷基二醇聚合物,包括但不限于聚乙二醇(PEG)、聚丙二醇(PPG)和聚丁二醇(PBG),以及PEG,PPG和PBG的任意组合的共聚物,并且包括聚亚烷基二醇的单烷基醚。因此,在本技术的各种实施方案中,本发明的肽中的聚亚烷基二醇可以是但不限于聚乙二醇、聚丙二醇、聚丁二醇及其任意组合。在某些实施方案中,聚亚烷基二醇是聚乙二醇或“PEG”。术语“PEG亚单元”是指单个聚乙二醇单元,即-(CH2CH2O)-。
在一些实施方案中,聚亚烷基二醇(例如,PEG)可以是非多分散的、单分散的、基本上单分散的、纯单分散的或基本上纯的单分散的。“单分散的”用于描述化合物的混合物,其中混合物中约100%的化合物具有相同的分子量。“基本上单分散的”用于描述化合物的混合物,其中混合物中至少约95%的化合物具有相同的分子量。“纯单分散的”用于描述化合物的混合物,其中混合物中约100%的化合物具有相同的分子量和相同的分子结构。因此,纯单分散混合物是单分散混合物,但是单分散混合物不一定是纯单分散混合物。“基本上纯单分散的”用于描述化合物的混合物,其中混合物中至少约95%的化合物具有相同的分子量和相同的分子结构。因此,基本上纯单分散的混合物是基本上单分散的混合物,但是基本上单分散的混合物不一定是基本上纯单分散的混合物。表6给出了通过聚乙二醇化修饰的本公开的肽的实例。
表6:PEG化的HBD1片段
SEQ ID NOs | 氨基酸序列 |
SEQ ID NO:63 | <u>PEG20-C</u>-KHHLGLEEPKKLR |
SEQ ID NO:64 | KHHLGLEEPKKLR-<u>C-PEG20</u> |
SEQ ID NO:65 | <u>PEG20-C</u>-HHLGLEEPKK |
SEQ ID NO:66 | HHLGLEEPKK-<u>C-PEG20</u> |
SEQ ID NO:67 | <u>PEG20-C</u>-HLGLEEPKK |
在一些其他情况下,本公开的肽包括偶联至该肽的任何氨基酸的一个或多个酰基。在一些情况下,一个或多个酰基与N-末端氨基酸或C-末端氨基酸或同时与两者偶联。在一些情况下,本公开的肽的酰化是脂肪酰化,通过该脂肪酰化将脂肪酸添加到该肽的一个或多个特定氨基酸中。脂肪酰化的实例包括将月桂酸(C12:0),十三环酸(C13:0),肉豆蔻酸(C14:0),十五环酸(C15:0),棕榈酸(C16:0),玛格酸(margaric acid,C17:0),硬脂酸(C18:0),十九环酸(C19:0),花生四烯酸(C20:0),二十一酸(C21:0),二十二酸(C22:0),二十三酸(C23:0),或二十四酸(C24:0),或其混合物添加到本发明肽的一个或多个氨基酸。
在一些变体中,待添加的脂肪酸可以是不饱和的(例如,单不饱和或多不饱和)。不饱和脂肪酸的实例包括但不限于:i)单不饱和脂肪酸:巴豆酸,肉豆蔻酸,棕榈油酸,烯酸(sapienic acid),油酸,反油酸,异油酸,鳕油酸,二十碳烯酸,芥酸,神经氨酸;ii)二不饱和脂肪酸:亚油酸,二十碳二烯酸,二十二碳二烯酸;iii)三不饱和脂肪酸:亚麻酸,松油酸,桐酸,米德酸,二高-γ-亚麻酸,二十碳三烯酸;iv)四不饱和脂肪酸:硬脂酸,花生四烯酸,二十碳四烯酸,肾上腺酸;v)五不饱和脂肪酸:波司戊戊烯酸(bosseopentaenoic acid),二十碳五烯酸,奥兹坐酸(ozubondo acid),沙丁鱼酸,二十四碳五烯酸(tetracosanolpentaenoic acid);vi)六不饱和脂肪酸:二十二碳六烯酸和鲱鱼酸。在一些实施方案中,本公开的肽可以与包含一个或多个羧基官能团(-COOH)的脂肪酸偶联。进行肽的酰化的方法是本领域众所周知的。表7给出了通过酰化修饰的本公开的肽的实例。
表7:酰化的HBD1(2-11)片段
SEQ ID NOs | 氨基酸序列 |
SEQ ID NO:68 | <u>C16:0</u>-HHLGLEEPKK |
SEQ ID NO:69 | <u>C18:0</u>-HHLGLEEPKK |
SEQ ID NO:70 | <u>C20:0</u>-HHLGLEEPKK |
SEQ ID NO:71 | <u>C14:0</u>-HLGLEEPKK |
SEQ ID NO:72 | <u>C16:0</u>-HLGLEEPKK |
SEQ ID NO:73 | <u>C18:0</u>-HLGLEEPKK |
SEQ ID NO:74 | <u>C20:0</u>-HLGLEEPKK |
SEQ ID NO:75 | <u>C16:0-diacid</u>-HLGLEEPKK |
SEQ ID NO:76 | HLGLEEPKK-<u>C16:0</u> |
SEQ ID NO:78 | <u>C16:0</u>-KHHLGLEEPKKLR |
在一些另外的实施方案中,本公开的肽可以偶联至接头或接头基团(例如,接头部分)。如本文所用,表述“接头”或“连接基团”包括例如本领域已知的(参见例如美国专利No.7,468,418;7,402,652;和7,351,797,其全部内容通过引用并入本文)那些非氨基酸连接基团,活着对于本领域技术人员来说是显而易见的它们的变体。
在一些实施方案中,本公开的肽可包含一种以上的修饰(例如,可包含PEG基团和酰基)。
在一些其他实施方案中,本公开的肽可以偶联至自身被修饰的修饰基团。例如,本公开的肽可以与自身被修饰的脂肪酸偶联。所述修饰的脂肪酸可以例如与接头或连接基团偶联,并且所述接头或连接基团本身可以与另一修饰基团,例如PEG基团或一个或多个羧基官能团(-COOH)连接。各种修改的组合以及用于实现它们的方法将被本领域技术人员认识和理解。
本技术的某些方面使用多核苷酸。这些多核苷酸包括编码本文定义的HBD1肽,片段和类似物的分离的多核苷酸。
如本文所用,术语“多核苷酸”是指由多个脱氧核糖核苷酸或核苷亚基组成的分子。核苷亚基之间的连接可以通过磷酸酯、膦酸酯、氨基磷酸酯、硫代磷酸酯等来提供,或者通过本领域已知的非磷酸酯基团来提供,例如用于肽核酸(PNA)中的类肽型连接。连接基团可以是手性的或非手性的。寡核苷酸或多核苷酸的长度范围可以从2个核苷亚基到数百或数千个核苷亚基。尽管寡核苷酸的长度优选为5至100个亚基,更优选为5至60个亚基,但是多核苷酸的长度可以更大(例如,最多100个)。多核苷酸可以是DNA和RNA中的任何一种。DNA可以是任何形式的基因组DNA,基因组DNA文库,衍生自细胞或组织的cDNA和合成DNA。此外,在某些方面,本发明可以使用包括噬菌体,质粒,粘粒或噬菌粒的载体。
可通过本领域已知的任何合适方式来制备可用于本技术的多肽。这样的多肽包括分离的天然存在的多肽,重组产生的多肽,合成产生的多肽或通过这些方法的组合产生的多肽。制备此类多肽的手段和方法是本领域众所周知的。
B.治疗措施
如本文所用,术语“治疗”指赋予受疾病折磨的患者有益的任何类型的治疗,包括改善患者的状况(例如,出现一种或多种症状),疾病进展延迟等。
如本文所用,术语“调节”是指响应的上调(即,激活或刺激)和下调(即,抑制或压制),或两者的结合或分开。
如本文所用,术语“受试者”或“患者”通常涉及哺乳动物或非哺乳动物的动物,包括例如但不限于人、大鼠、小鼠或农场动物。提及受试者不一定指示其存在疾病或病症。术语“受试者”包括,例如,给哺乳动物或非哺乳动物动物施用本技术的肽作为实验的一部分,治疗哺乳动物或非哺乳动物动物以帮助减轻疾病或病症,和预防性治疗哺乳动物或非哺乳动物以延缓或预防疾病或病症的发作。哺乳动物受试者可以是任何年龄的人类对象,例如婴儿、儿童、成人或老年人。
在一些实施方案中,本公开的肽可用于控制、调控、调节、预防、改善、减轻和/或治疗代谢紊乱。如本文所用,表述“代谢紊乱”是指但不限于与异常或受损的代谢过程相关的疾病。代谢紊乱的例子包括但不限于与酸碱失衡有关的紊乱,与钙代谢受损有关的紊乱,与葡萄糖代谢受损有关的紊乱,与碳水化合物代谢受损有关的紊乱,与铁代谢受损有关的紊乱,与脂质代谢受损有关的紊乱,吸收不良综合征,代谢综合征,与瘦素代谢受损有关的疾病,与胰岛素代谢受损有关的疾病以及与胰岛素样生长因子代谢受损有关的疾病。
在一些实施方案中,本公开的肽可用于调节葡萄糖代谢。在这些实施方案的一些实施方式中,本技术的肽可用于调节患有与葡萄糖代谢受损有关的病症的受试者中的葡萄糖代谢。在这些实施方案的一些其他实施方式中,本技术的肽可用于控制、调控、调节、预防、改善、减轻和/或治疗与受试者葡萄糖代谢受损有关的病症。
如本文所用,表述“与葡萄糖代谢受损有关的病症”是指其中血浆葡萄糖不能维持在正常范围内的病症。与葡萄糖代谢受损有关的疾病的实例包括但不限于:低血糖、高血糖、碳水化合物不耐受、葡萄糖不耐受、空腹血糖受损、葡萄糖耐量受损、碳水化合物-脂质代谢紊乱、高胰岛素血症、IV型高脂蛋白血症、胰岛素抗性、I型糖尿病、II型糖尿病、肥胖症、β细胞功能受损、肢端肥大症、与黑皮质素4(MC4)信号通路受损相关的疾病、与瘦素受体(LEPR)缺乏相关的疾病、与LEPR突变相关的疾病、瘦素受体相关的单基因型肥胖、极度胰岛素抵抗综合征、阿黑皮素原(proopiomelanocortin,POMC)缺乏症、POMC杂合症、综合征、Bardet-Biedl综合征(BBS)、Donohue综合征(妖精貌综合征,leprechaunism)、Rabson-Mendenhall综合征、A型极度胰岛素抵抗综合征、B型极度胰岛素抵抗综合征、C型极度胰岛素抵抗综合征、HAIR-AN综合征、多囊卵巢综合征(PCOS)、先天性脂肪营养不良综合征、Beradinelli-Seip综合征、获得性脂肪营养不良综合征、全身性脂肪营养不良和部分脂肪营养不良综合征。
在某些情况下,代谢紊乱是与胰岛素代谢受损有关的疾病。如本文所用,表述“与胰岛素代谢受损有关的疾病”是指与以下之一有关的疾病:胰岛素的合成、循环和降解,以及与胰腺功能受损有关的疾病。与胰岛素代谢受损有关的疾病的实例包括但不限于代谢综合症,血脂异常,动脉粥样硬化,高血压,肥胖,高胰岛素血症,葡萄糖不耐量,高血压,外周动脉疾病,A型综合征,B型综合征,内皮功能障碍,糖尿病,微量白蛋白尿和纤维蛋白溶解受损。
如本文所用,表述“代谢综合征”是指由伴随异常脂肪沉积和功能的胰岛素抵抗引起的多重危险因素。它由冠心病,糖尿病,脂肪肝和几种癌症的风险因素组合而成。代谢综合征的临床表现包括:高血压,高血糖,高甘油三酸酯血症,高密度脂蛋白胆固醇(HDL-C)降低,腹部肥胖,胸痛或呼吸急促:提示心血管疾病和其他并发症,黑棘皮病,多毛症,周围神经病变,视网膜病变,黄瘤和睑黄瘤的增加。
在一些实施方案中,本公开的肽可用于降低受试者的血浆葡萄糖水平,和/或用于改善受试者对葡萄糖的总体耐受性和/或抗性。在这些实施方案的一些实施方式中,本公开的肽可以用于控制受试者的糖尿病。在这些实施方案的一些实施方式中,本公开的肽可用于预防受试者的糖尿病。在这些实施方案的一些实施方式中,本公开的肽可用于治疗受试者的糖尿病。在这些实施方案的一些实施方式中,糖尿病为I型糖尿病。在这些实施方式的一些其他实施方式中,糖尿病为II型糖尿病。
在一些实施方案中,本公开的肽可用于调节胰岛素代谢。例如,本公开的肽可用于增加胰岛素分泌,增加胰岛素敏感性,降低胰岛素抗性和/或克服胰岛素缺乏。
在一些实施方案中,本技术的肽可用于控制、调控、调节、预防、改善、减轻和/或治疗低血糖、高血糖、碳水化合物不耐受、葡萄糖不耐受、空腹血糖受损、葡萄糖耐量受损、碳水化合物-脂质代谢紊乱、高胰岛素血症、IV型高脂蛋白血症、胰岛素抗性、I型糖尿病、II型糖尿病、肥胖症、β细胞功能受损、肢端肥大症、与黑皮质素4(MC4)信号通路受损相关的疾病、与瘦素受体(LEPR)缺乏相关的疾病、与LEPR突变相关的疾病、瘦素受体相关的单基因型肥胖、极度胰岛素抵抗综合征、阿黑皮素原(POMC)缺乏症、POMC杂合症、综合征、Bardet-Biedl综合征(BBS)、Donohue综合征(妖精貌综合征,leprechaunism)、Rabson-Mendenhall综合征、A型极度胰岛素抵抗综合征、B型极度胰岛素抵抗综合征、C型极度胰岛素抵抗综合征、HAIR-AN综合征、多囊卵巢综合征(PCOS)、先天性脂肪营养不良综合征、Beradinelli-Seip综合征、获得性脂肪营养不良综合征、全身性脂肪营养不良和部分脂肪营养不良综合征。
在一些实施方案中,本文定义的用途和方法包括向受试者施用治疗有效量的本文定义的肽以实现本文讨论的效果。如本文所用,表述“治疗有效量”是指以适用于任何医学治疗的合理的受益/风险比有效产生本文所定义的某些期望的治疗效果时的本发明的肽的量。
本公开内容的任何特定肽的治疗有效量将在肽之间、受试者之间以及患者之间有所变化,并且除其他因素外,将取决于要达到的效果或结果、患者和递送途径。在一些实施方案中,剂量为约0.01μg/kg至约100mg/kg,约0.01μg/kg至约50mg/kg,约0.01μg/kg至约10mg/kg,约0.01μg/kg至约5mg/kg,约0.1μg/kg至约100mg/kg,约0.1μg/kg至约50mg/kg,约0.1μg/kg至约10mg/kg,约0.1μg/kg至约5mg/kg,约1μg/kg至约100mg/kg,约1μg/kg至约50mg/kg,约1μg/kg至约10mg/kg,约1μg/kg至约5mg/kg,约10μg/kg至约100mg/kg,约10μg/kg至约50mg/kg,约10μg/kg至约10mg/kg,约10μg/kg至约5mg/kg,约100μg/kg至约100mg/kg,约100μg/kg至约50mg/kg,约100μg/kg至约10mg/kg,约100μg/kg至约5mg/kg。
在一些情况下,剂量为从约0.001mg/kg,约0.05mg/kg,约0.1mg/kg,约0.2mg/kg,约0.3mg/kg,约0.4mg/kg,约0.5mg/kg,约0.6mg/kg,约0.7mg/kg,约0.8mg/kg,约0.9mg/kg或约1.0mg/kg,直至约30mg/kg,或约40mg/kg。在一些情况下,使用的剂量为约1mg/kg,约2mg/kg,约3mg/kg,约4mg/kg,约5mg/kg,约6mg/kg,约7mg/kg,约8mg/kg,约9mg/kg,约10mg/kg,约11mg/kg,约12mg/kg,约13mg/kg,约14mg/kg,约15mg/kg,约16mg/kg,约17mg/kg,约18mg/kg,约19mg/kg,约20mg/kg,约21mg/kg,约22mg/kg,约23mg/kg,约24mg/kg,约25mg/kg,约26mg/kg,约27mg/kg,约28mg/kg,约29mg/kg,约30mg/kg,约31mg/kg,约32mg/kg,约33mg/kg,约34mg/kg,约35mg/kg,约36mg/kg,约37mg/kg,约38mg/kg,约39mg/kg,约40mg/kg,约41mg/kg,约42mg/kg,约43mg/kg,约44mg/kg,约45mg/kg,约46mg/kg,约47mg/kg,约48mg/kg,约49mg/kg,或约50mg/kg或更多。治疗有效剂量的其他实例包括:约1和约50mg/kg/96hr之间,约1和约50mg/kg/48hr之间,约1和约50mg/kg/36hr之间,约1和约50mg/kg/24hr之间,约1和约50mg/kg/12hr之间,约1和约25mg/kg/96hr之间,约1和约25mg/kg/48hr之间,约1和约25mg/kg/36hr之间,约1和约25mg/kg/24hr之间,约1和约25mg/kg/12hr之间,约1和约10mg/kg/96hr之间,约1和约10mg/kg/48hr之间,约1和约10mg/kg/36hr之间,约1和约10mg/kg/24hr之间,约1和约10mg/kg/12hr之间,约1和约5mg/kg/96hr之间,约1和约5mg/kg/48hr之间,约1和约5mg/kg/36hr之间,约1和约5mg/kg/24hr之间,约1和约5mg/kg/12hr之间,约0.001和约1mg/kg/96hr之间,约0.001和约1mg/kg/48hr之间,约0.001和约1mg/kg/36hr之间,约0.001和约1mg/kg/24hr之间,以及约0.001和约1mg/kg/12hr之间。
如本文所用,“同时施用”是指两种或多种肽、化合物或组合物在时间上足够紧密地施用以产生联合作用(即,可以同时地共同进行,或者可以是在彼此之前或之后的较短时间段内(例如按顺序)发生的两个或多个事件。同时进行共同给药可以通过例如在给药前混合化合物,或通过在相同时间但在不同解剖部位和/或通过使用不同的给药途径来进行。
C.药物组合物
如本文所用,表达“活性剂”是指如本文所定义的肽。
表述“治疗上可接受的”,“治疗上合适的”,“药学上可接受的”和“药学上合适的”在本文中可互换使用,并且是指适于施用于受试者以实现本文所述的效果的肽、化合物或组合物,所述的效果例如本文所定义的治疗,鉴于疾病的严重程度和治疗的必要性,没有过度有害的副作用。
可以根据已知技术配制上述肽以在药物载体中进行施用。参见例如雷明顿,《药学技术与实践》(1995年第9版)。在根据本发明的药物组合物的制造中,通常将肽(包括其生理上可接受的盐)与可接受的载体混合。在与组合物中的任何其他成分相容的意义上,载体当然必须是可接受的,并且对患者无害。载体可以是固体或液体,或两者均可,并且优选与肽一起配制为单位剂量制剂,例如片剂,其可以包含约0.01或约0.5%至约95%或约99%重量的肽。可以将一种或多种活性化合物掺入本发明的组合物中,其可以通过任何众所周知的药学技术制备,包括混合组分,任选地包括一种或多种辅助成分。
本公开的组合物包括适用于口服,直肠,局部,口腔(例如舌下),阴道,肠胃外(例如皮下,肌内,皮内或静脉内),局部(即皮肤和粘膜表面,包括气道表面)和经皮给药,在任何给定情况下最合适的途径将取决于所治疗疾病的性质和严重程度以及所用特定肽的性质。
适用于口服的组合物可以离散单位存在,例如胶囊,扁囊剂,锭剂或片剂,每个均包含预定量的肽;作为粉末或颗粒;作为在水性或非水性液体中的溶液或悬浮液;或作为水包油或油包水乳液。这样的组合物可以通过任何合适的药学方法制备,包括将肽和合适的载体(其可以包含一种或多种如上所述的辅助成分)结合的步骤。通常,本公开的组合物是通过将肽与液体或细分的固体载体或两者均匀且紧密地混合,然后,如果需要,可以将所得混合物成形来制备。例如,可以通过压缩或模制含有肽的粉末或颗粒来制备片剂,所述粉末或颗粒任选地与一种或多种辅助成分一起。压制的片剂可以通过在合适的机器中压制自由流动形式的化合物来制备,例如任选与粘合剂、润滑剂、惰性稀释剂和/或表面活性/分散剂混合的粉末或颗粒。模制片剂可以通过在合适的机器中模制用惰性液体粘合剂润湿的粉状化合物来制备。
适用于口腔(舌下)给药的组合物包括锭剂,所述锭剂包含在调味基质中的肽,通常是蔗糖和阿拉伯胶或黄蓍胶;包括在惰性基质中的肽的锭剂,例如明胶和甘油或蔗糖和阿拉伯胶。
适用于肠胃外给药的本公开的组合物包含所述肽的无菌水性和非水性注射溶液,所述制剂优选与预期受体的血液等渗。这些制剂可以包含抗氧化剂,缓冲剂,抑菌剂和溶质,它们使组合物与预期接受者的血液等渗。水性和非水性无菌悬浮液可包括悬浮剂和增稠剂。所述组合物可以存在于单位剂量或多剂量容器中,例如密封的安瓿瓶和小瓶,并且可以在冻干(冻干)条件下储存,其仅需要在使用前立即加入无菌液体载体例如盐水或注射用水。临时注射溶液和悬浮液可以由前述类型的无菌粉末、颗粒和片剂制备。例如,在本公开的一个方面提供了在密封容器中的单位剂型的包含本文定义的肽或其盐的可注射的、稳定的、无菌的组合物。肽或盐以冻干物的形式提供,该冻干物能够用合适的药学上可接受的载体重构,以形成适于将其注射到受试者体内的液体组合物。单位剂型通常包含约10mg至约10g的肽或盐。当肽或盐基本上不溶于水时,可以使用足够量的生理上可接受的乳化剂,以将化合物或盐乳化在含水载体中。一种这样的有用的乳化剂是磷脂酰胆碱。
适用于直肠给药的组合物优选以单位剂量栓剂的形式存在。这些可以通过将如本文定义的肽与一种或多种常规固体载体例如可可脂混合,然后使所得混合物成形来制备。
适用于局部施用于皮肤的组合物优选采取软膏,乳膏,洗剂,糊剂,凝胶,喷雾剂,气雾剂或油的形式。可以使用的载体包括凡士林,羊毛脂,聚乙二醇,醇,透皮增强剂及其两种或更多种的组合。
适合于透皮施用的组合物可以呈离散贴片形式存在,所述离散贴片适合于与接受者的表皮保持紧密接触一段延长的时间。适合于透皮给药的组合物也可以通过离子电渗疗法递送(参见例如Pharmaceutical Research 3(6):318(1986)),并且通常采取本文定义的肽的任选缓冲水溶液的形式。合适的组合物包含柠檬酸盐或bis\tris缓冲液(pH 6)或乙醇/水,并含有0.1M至0.2M的活性成分。
此外,本公开提供了本文公开的肽及其盐的脂质体制剂。形成脂质体悬浮液的技术是本领域众所周知的。当本文所定义的肽或其盐是水溶性盐时,使用常规脂质体技术,可以将其掺入脂质囊泡中。在这种情况下,由于肽或盐的水溶性,肽或盐将基本上被夹带在脂质体的亲水中心或核心内。所使用的脂质层可以具有任何常规组成,并且可以包含胆固醇或可以不含胆固醇。当靶标肽或盐是水不溶性的时,再次采用常规脂质体形成技术,该盐可基本上夹带在形成脂质体结构的疏水脂质双层中。在任一种情况下,通过使用标准的超声处理和均质化技术,可以减小所产生的脂质体的尺寸。
可以冻干含有本文公开的活性剂或其盐的脂质体制剂以产生冻干物,其可以用药学上可接受的载体例如水重构以再生脂质体悬浮液。
其他药物组合物可以由本文公开的水不溶性活性剂或其盐例如水性基础乳液制备。在这种情况下,组合物将包含足够量的药学上可接受的乳化剂,以乳化所需量的活性剂或其盐。特别有用的乳化剂包括磷脂酰胆碱和卵磷脂。
在一些实施方案中,可以使用医疗装置,特别是使用整形外科医疗装置将本公开的肽递送至需要其的受试者。可用于递送本公开的肽的医疗装置的实例包括但不限于海绵(例如,胶原海绵,明胶海绵等),敷料,量具,支架,笼子(例如,椎间笼,融合笼等),骨水泥,骨混合器,骨替代物,大头钉,锚固件,纽扣,假体,螺钉(例如,小平面螺钉,椎弓根螺钉系统,骨螺钉等),垫片,髓内钉,杆(例如,髋杆等),定制植入物,板(例如,肱骨板,腕关节板,桡骨板,颈椎板,腰椎板等)和创伤产品。在这些实施方案中,本公开的肽可以掺入用于制造医疗装置的材料中,或者可以施加到用于制造医疗装置的材料上或施加在医疗装置本身上。
在一些其他实施方案中,可以使用递送装置例如颗粒(例如,纳米颗粒或微粒)或包囊系统(例如,微胶囊,微球)将本公开的肽递送给需要其的受试者。在一些情况下,本公开的肽可以分散在形成递送系统的材料中,例如聚合物链,或者可以位于形成于递送系统中的孔或腔中。在某些情况下,可以控制肽从此类递送系统中的释放(即,缓慢释放、持续释放或受控释放)。可用于递送本公开的肽的颗粒以及包封系统的实例是本领域众所周知的。
除一种或多种活性化合物外,药物组合物还可包含其他添加剂,例如pH调节添加剂。特别地,有用的pH调节剂包括酸,例如盐酸,碱或缓冲剂,例如乳酸钠,乙酸钠,磷酸钠,柠檬酸钠,硼酸钠或葡萄糖酸钠。此外,所述组合物可以包含微生物防腐剂。有用的微生物防腐剂包括对羟基苯甲酸甲酯,对羟基苯甲酸丙酯和苯甲醇。当将制剂置于设计用于多剂量用途的小瓶中时,通常使用微生物防腐剂。
在一些实施方案中,本技术提供了一种试剂盒,其包含本文定义的一种或多种肽,以及根据本文定义的应用的试剂盒的使用说明。
等同肽、化合物、组合物、方法、用途和试剂盒的鉴定完全在普通技术人员的技术范围内,并且根据本公开的教导,仅需要常规实验即可。从下面的实施例中将更加全面地理解本公开的实践,在此给出的这些实施例仅用于说明,并且不应以任何方式解释为限制本公开。
具体实施方式
给出以下实施例以便说明本技术的各种实施方案的实践。它们无意于限制或定义该技术的整个范围。应当理解,该技术不限于本文描述和示出的特定实施例,而是包括落入如所附实施例所限定的本公开范围内的所有修改和变化。
实施例1:HBD1肽改善体内葡萄糖耐量
在适应实验室条件7天后,九周大的雄性B6.V-Lepob/J.小鼠(Charles River)皮下注射3mg/kg媒介物(vehicle)(NaCl 0.9%)或如SEQ ID NO:73(C18:0-HLGLEEPKK)中列出的肽(每组n=5只动物),每天2次,注射15天。在第15天,给禁食(过夜)的小鼠腹膜内注射1g/kg的葡萄糖。葡萄糖注射后45分钟记录血浆血糖(以mmol/L表示)。结果显示在图1中。结果显示,施用HBD1肽降低了IP葡萄糖耐量试验的血浆葡萄糖水平,从而表明HBD1肽在血糖控制中的作用。这些结果支持将HBD1肽用于治疗与葡萄糖不耐受或胰岛素抵抗相关的临床病症,例如但不限于2型糖尿病、瘦素缺乏症、瘦素受体缺乏症和极端胰岛素抵抗综合症。
实施例2:HBD1肽对瘦素缺乏症小鼠的葡萄糖耐量的影响
为了进一步评估HBD1肽对葡萄糖和胰岛素代谢的影响,在每日两次施用HBD肽、连续28天后,在葡萄糖遥测肥胖ob/ob小鼠中评估基础血糖和对腹膜内葡萄糖耐量测试(IPGTT)的葡萄糖反应。葡萄糖遥测装置(HD-XG,数据科学国际)的植入根据已知方案进行。
在每日两次给药之间,以8小时±1小时的间隔,每日给药两次一定剂量的如SEQID NO:73的HBD肽片段(C18:0-HLGLEEPKK)。对24只V-Lepob/J(Ob/Ob)雄性小鼠(TheJackson Laboratory,Farmington,CT USA)皮下注射vehicle(NaCl 0.9%)(对照组)或以1mg/kg和3mg/kg的肽皮下给药(测试组)(每组n=5-8只动物)每天两次,共28天。给药的第一天被指定为第一天。使用无菌注射器进行小块注射,并将针头插入皮下,轮流使用2-4个注射部位。在第一次注射之前修剪注射区域的动物毛发,然后在治疗期间根据需要进行修剪。给药体积为5mL/kg/次。使用最新体重计算个体剂量。在第27天,在正常进食条件下评估16小时平均血糖水平。在第28天,给禁食(4小时)的小鼠腹膜内注射1g/kg的葡萄糖。注射葡萄糖后,每分钟记录一次血浆葡萄糖曲线(以mg/dL表示)直至3小时。
腹膜内葡萄糖耐量测试(IPGTT)-在IGPTT日的早晨(第28天),用vehicle或HBD片段治疗禁食2小时的动物。给药后2小时±15分钟施用葡萄糖溶液(vehicle或如SEQ ID NO:73所示肽(C18:0-HLGLEEPKK),监测从禁食前10分钟(禁食状态)至葡萄糖激发后3小时的血糖。葡萄糖激发后4小时重新施用食物,食物重新施用后2小时进行当天的第二次处理(HBD片段或vehicle)。
显示在图2和图3A-3B中的结果表明,在葡萄糖遥测的ob/ob小鼠中,HBD1片段SEQID NO:73以剂量依赖的方式改善了葡萄糖不耐受,该小鼠是瘦素缺乏症导致胰岛素抵抗和葡萄糖耐受不良的小鼠模型。图2显示,在施用4周后,测试肽降低了空腹血糖水平和IPGTT后的葡萄糖波动。在3mg/kg的剂量下观察到显著效果。图3A-3B还显示了对葡萄糖控制的积极作用,因为测试肽能够显著降低这些在基线时表现出严重高血糖的小鼠的16小时平均血糖水平。
实施例3:HBD1肽对体外脂肪细胞摄取葡萄糖的影响
为了进一步测试HBD1肽对葡萄糖代谢的影响,检测了HBD1肽增加培养的、完全分化的3T3-LI脂肪细胞的葡萄糖摄取的能力。3T3-LI细胞是一种小鼠成纤维细胞系,在特定条件下培养时会分化为脂肪细胞。
使用以下方案实现3T3-LI细胞向脂肪细胞的分化。将3T3-L1细胞接种在24孔板中,并在3T3-L1维持培养基(含10%胎牛血清,4mM L-谷氨酰胺,1mM丙酮酸钠的DMEM)中培养直至细胞100%汇合。然后向细胞中加入3T3-L1维持培养基,再培养48小时。为了开始分化为脂肪细胞,将培养基更换为分化培养基1(含有10%胎牛血清,4mM L-谷氨酰胺,1mM丙酮酸钠,0.5mM IBMX,0.25mM地塞米松1mg/ml胰岛素的DMEM),并继续培养2天。然后将培养基换成分化培养基2(含有10%胎牛血清,4mM L-谷氨酰胺,1mM丙酮酸钠,1mg/ml胰岛素的DMEM),并继续培养2天。然后将培养基换成脂肪细胞维持培养基(含有10%胎牛血清,4mML-谷氨酰胺,1mM丙酮酸钠的DMEM),并继续培养7天。在此期间,培养基每隔一天更换一次。现在完全分化的脂肪细胞用于葡萄糖摄取实验(从分化开始的第11天)。待测试的HBD1肽的储备溶液是通过在无菌条件下在层流柜中用0.9%NaCl溶液稀释至1mg/ml的浓度(基于净肽含量)来制备的。通过轻轻倒置将溶液均质化。从储备溶液中制备测试溶液,将剩余的储备溶液等分并保存在-20℃下,无需重复进行冻融循环即可使用。
使用以下方案进行葡萄糖摄取实验。在开始实验之前,先加入100ml克雷布斯林格碳酸氢盐缓冲液(Krebs Ringer bicarbonate buffer,KRBB)(25mM Hepes pH 7.4、118mMNaCl,5mM NaHCO3、4.7mM KCl,1.2mM KH2PO4、1.2mM MgSO4、2.5mM CaCl2、0.2%BSA-使用0.2-M过滤器过滤)和100ml孵育培养基(含有4mM L-谷氨酰胺,1mM丙酮酸钠,1%青霉素-链霉素,0.2%BSA的DMEM-使用0.2M-过滤器过滤)预热至37℃,将500毫升KRBB在冰上冷却。在预热的孵育培养基和预热的KRBB中将测试化合物的储备溶液稀释至终浓度为3μ浓度为化。预先在无菌0.9%NaCl中按1:1000稀释的胰岛素(阳性对照)在10ml的培养基和缓冲液中进一步稀释至终浓度为1nM。使用细尖小心地从细胞中除去所有痕量培养基。将包含检测化合物或vehicle的1ml孵育培养基添加到适当的孔中。此时未添加胰岛素。将该板在37℃孵育24小时。孵育期结束后,从孔中取出培养基,并用300孵育含有适当测试物质或vehicle的预热KRBB洗涤适当孔中的细胞。然后从适当的孔的细胞中除去洗涤缓冲液,并用270除去的预热KRBB替代,其中包含测试物质、vehicle或胰岛素,并在37℃下继续孵育20分钟。在孵育期间,如下制备10x 2-脱氧葡萄糖的混合物:985μ8KRBB,10μl10 mM 2-脱氧葡萄糖,5μ氧[3H]-2-脱氧葡萄糖(1mCi/ml)。在20分钟的孵育期结束时,将30的孵的10×2-脱氧葡萄糖混合物添加到所有孔中,并在37℃下再孵育10分钟。从孔中除去缓冲溶液,并用1ml冰冷的KRBB将细胞洗涤3次。向所有孔中添加100μ0的0.5N NaOH,并在室温下孵育30分钟。将50μ0所得细胞裂解物转移至白色96孔板。向所有孔中加入200μ0Microscint 20,盖上盖玻片,在室温下振摇30分钟。通过闪烁计数确定每个孔的[3H]-2-脱氧葡萄糖含量的定量。
所述测定中测试了以下HBD1肽:SEQ ID NO:1(KHHLGLEEPKKLR),SEQ ID NO:10(HLGLEEPKK),SEQ ID NO:16(HHLGLEEPKK)和SEQ ID NO:73(C18:0-HLGLEEPKK),以确定对3T3-LI脂肪细胞摄取葡萄糖的影响。HBD1肽孵育分化的3T3-LI脂肪细胞后摄取葡萄糖的结果如图4所示。总而言之,所有测试的HBD1肽均刺激3T3-LI脂肪细胞摄取葡萄糖的增加。
实施例4:证明HBD1肽在体外对骨骼肌细胞摄取葡萄糖的作用,并证明HBD1肽利用与IGFBP2相同的受体和机制来增加葡萄糖摄取
先前的研究表明,胰岛素样生长因子2(IGFBP2)通过细胞表面受体,受体型蛋白酪氨酸磷酸酶-β(RPTPβ)来激活Akt和AMPK途径,从而增加葡萄糖的摄取(Assefa etal.2017)。进行以下研究以确定HBD1肽是否利用相同的受体和转导途径来增加葡萄糖摄取。使用培养的、完全分化的C2C12小鼠骨骼肌肌管进行研究。通过在24孔板中使用含25mM葡萄糖和10%胎牛血清的DMEM将C2C12细胞培养至汇合密度来制备细胞。此时,将培养基更换为分化培养基(含25mM葡萄糖和2%马血清的DMEM)培养6天,每三天更换一次培养基。将各种处理物在无血清培养基中稀释,并在用无血清培养基洗涤细胞后,将其加入细胞中,并孵育2小时或其他时间,具体取决于处理方法。在孵育期结束时,除去培养基并加入含有相同处理的1.0ml无葡萄糖克雷布斯林格碳酸氢盐缓冲液(pH 7.4),并继续孵育10分钟。在10分钟的孵育期结束时,将3H-2-脱氧葡萄糖(0.5mCi/孔)(比活度=8Ci/mmole)直接添加到所有孔中,并继续孵育10分钟。然后用冰冷的磷酸盐缓冲盐水冲洗孔3次,用0.5N NaOH提取细胞,并通过闪烁计数定量细胞裂解液的3H-2-脱氧葡萄糖含量。
除了使用6孔板外,以相同的方式制备细胞以用于信号研究。在分化培养基中孵育6天后,将细胞用无血清培养基洗涤。然后将各种处理添加到含有0.1%BSA的无血清培养基中。加入HBD1肽并孵育8小时。当利用IGF-1时,在加入IGF-1后孵育15分钟。孵育后,将细胞在RIPA缓冲液中裂解并超声处理。离心细胞裂解物,并通过使用10%凝胶的SDS PAGE分析上清液中的Akt或AMPK,然后用适当的抗体进行免疫印迹。
当测试通过完全分化的C2C12小鼠骨骼肌肌管增加葡萄糖摄取的能力时,与vehicle治疗的对照相比,HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)以剂量依赖性和时间依赖性的方式均刺激了葡萄糖摄取增加(图5A-5B)。此外,添加与胰岛素结合的HBD1肽SEQ IDNO:73(C18:0-HLGLEEPKK)产生了葡萄糖摄取的累积增加(图5C)。
为了检测由HBD1肽利用的细胞内转导途径,在用HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)处理后,通过SDS PAGE分离细胞裂解物蛋白,并用抗Akt pS473抗体进行免疫印迹。观察到,HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)诱导了磷酸化的Akt的剂量相关性增加(图6)。磷酸化Akt的检测通过抗纤连蛋白抗体(FN3)的处理而被完全废除,该抗体已被证明可以阻止与RPTPβ受体的相互作用,并且先前已被证明可以阻断IGFBP2与RPTPβ的相互作用(Shen et al.2012)。
为了进一步检测由HBD1肽利用的细胞内转导途径,在用HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)处理后,通过SDS PAGE分离细胞裂解物蛋白,并用抗pAMPK T172进行免疫印迹。观察到用HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)的处理导致磷酸化AMPK的剂量依赖性增加(图7)。通过使用抗纤连蛋白抗体(FN3)或与化合物C(一种AMPK活化的特异性抑制剂)的处理完全消除了磷酸化AMPK的检测,前者已被证明可以阻止与RPTPβ受体的相互作用,并且先前已被证明可以阻断IGFBP2与RPTPβ的相互作用(Shen et al.2012),后者也已被证明能阻断IGFBP2刺激培养的脂肪细胞摄取葡萄糖(Assefa et al.2017)。
在单独的实验中,再次证明了用HBD1肽SEQ ID NO:73(C18:0-HLGLEEPKK)进行治疗可增加完全分化的小鼠骨骼肌肌管对葡萄糖的摄取,以及与胰岛素的加和作用(图8)。为了与观察到的细胞内转导途径的影响保持一致,可使用抗纤连蛋白抗体(FN3)或化合物C(AMPK活化的特异性抑制剂)进行治疗,前者已被证明能阻止与RPTPβ受体的相互作用,并且先前已被证明可阻断IGFBP2与RPTPβ的相互作用(Shen et al.2012),后者也已被证明能阻断IGFBP2刺激的培养脂肪细胞摄取葡萄糖(Assefa et al.2017),完全消除了HBD1肽SEQID NO:73(C18:0-HLGLEEPKK)增加葡萄糖摄取的能力,无论是单独使用还是与胰岛素共同使用。
总体而言,本文呈现的数据建立了HBD1、HBD1片段及其类似物在调节葡萄糖代谢、胰岛素代谢以及瘦素代谢中的潜力。HBD1对成骨细胞分化和葡萄糖摄取的作用机制相似,因为它们共享相同的受体(RPTPβ)和相同的细胞内途径(Akt)。因此可以预见,在成骨细胞分化中显示出效力的HBD1类似物(根据先前在例如WO 2018/145006中报道的成骨细胞分化测定)也将对葡萄糖代谢有效。
应当理解,在本说明书中报告的数据仅是为了说明本公开而给出的,并且不被视为构成对其的限制。
尽管已经结合本公开的特定实施例描述了本公开,但是应该理解,本公开能够进行进一步的修改,并且本申请一般旨在覆盖本公开的任何变化、使用或修改,这些变化、使用或修改通常遵循本公开的原理,并且包括与本公开的偏离,这些偏离属于本公开所属技术领域内的已知或惯例,并且可以应用于上文阐述的基本特征,并且在所附权利要求书的范围内。
通过引用合并
在本说明书中引用的所有参考文献及其参考文献,通过引用其整体并入本文,以在适当的情况下用于教导附加的或替代的细节、特征和/或技术背景。
等价替代
尽管已经参考特定实施例具体示出和描述了本公开,但是应当理解,上述公开的和附加特征和功能的变化或其替代可以预期地组合到许多其他不同的系统或应用中。而且,本领域技术人员可以随后做出其中各种目前无法预料或无法预料的替代、修改、变化或改进,这些也意在被以下实施例所涵盖。
参考文献
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-U.S.Pat.No.9,220,746;
-PCT/US2018/16869
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-Wheatcroft SB,Kearney MT,Shah AM,Ezzat VA,Miell JR,Modo M,WilliamsSC,Cawthorn WP,Medina-Gomez G,Vidal-Puig A,Sethi JK,Crossey PA.IGF-bindingprotein-2protects against the development of obesity and insulinresistance.Diabetes.2007;56(2):285–294.
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SEQUENCE LISTING
<110> 阿莫利特制药公司
<120> IGFBP-2的肝素结合域在治疗代谢紊乱中的作用
<130> P20116213WP
<150> US 62/676,087
<151> 2018-05-24
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<400> 37
His Leu Gly Leu Glu Glu Pro Pro Lys
1 5
<210> 38
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 38
His Leu Gly Leu Glu Glu Pro Ser Lys
1 5
<210> 39
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 39
His Leu Gly Leu Glu Glu Pro Asp Lys
1 5
<210> 40
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 40
His Leu Gly Leu Glu Glu Pro Lys Phe
1 5
<210> 41
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 41
His Leu Gly Leu Glu Glu Pro Lys Ile
1 5
<210> 42
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 42
His Leu Gly Leu Glu Glu Pro Lys Pro
1 5
<210> 43
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 43
His Leu Gly Leu Glu Glu Pro Lys Ser
1 5
<210> 44
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 44
His Leu Gly Leu Glu Glu Pro Lys Asp
1 5
<210> 45
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 45
His Leu Gly Leu Glu Glu Pro Ile Lys
1 5
<210> 46
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 46
His Leu Gly Leu Glu Glu Pro Val Lys
1 5
<210> 47
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 47
His Leu Gly Leu Glu Glu Pro Gln Lys
1 5
<210> 48
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 48
His Leu Gly Leu Glu Glu Pro Thr Lys
1 5
<210> 49
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 49
His Leu Gly Leu Glu Glu Pro Glu Lys
1 5
<210> 50
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 50
His Leu Gly Leu Glu Glu Pro Lys His
1 5
<210> 51
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 51
His Leu Gly Leu Glu Glu Pro Lys Arg
1 5
<210> 52
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 52
His Leu Gly Leu Glu Glu Pro Lys Leu
1 5
<210> 53
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 53
His Leu Gly Leu Glu Glu Pro Lys Met
1 5
<210> 54
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 54
His Leu Gly Leu Glu Glu Pro Lys Trp
1 5
<210> 55
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 55
His Leu Gly Leu Glu Glu Pro Lys Val
1 5
<210> 56
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 56
His Leu Gly Leu Glu Glu Pro Lys Gln
1 5
<210> 57
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 57
His Leu Gly Leu Glu Glu Pro Lys Asn
1 5
<210> 58
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 58
His Leu Gly Leu Glu Glu Pro Lys Tyr
1 5
<210> 59
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 59
His Leu Gly Leu Glu Glu Pro Lys Thr
1 5
<210> 60
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 60
His Leu Gly Leu Glu Glu Pro Lys Glu
1 5
<210> 61
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 61
His Leu Gly Leu Glu Glu Pro Ser Pro
1 5
<210> 62
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 62
His Leu Gly Leu Glu Glu Pro Ser Ser
1 5
<210> 63
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 聚乙二醇化
<400> 63
Lys His His Leu Gly Leu Glu Glu Pro Lys Lys Leu Arg
1 5 10
<210> 64
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (13)..(13)
<223> 聚乙二醇化
<400> 64
Lys His His Leu Gly Leu Glu Glu Pro Lys Lys Leu Arg
1 5 10
<210> 65
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 聚乙二醇化
<400> 65
His His Leu Gly Leu Glu Glu Pro Lys Lys
1 5 10
<210> 66
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (10)..(10)
<223> 聚乙二醇化
<400> 66
His His Leu Gly Leu Glu Glu Pro Lys Lys
1 5 10
<210> 67
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 聚乙二醇化
<400> 67
His Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 68
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 与C16:0酰化
<400> 68
His His Leu Gly Leu Glu Glu Pro Lys Lys
1 5 10
<210> 69
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 与C18:0酰化
<400> 69
His His Leu Gly Leu Glu Glu Pro Lys Lys
1 5 10
<210> 70
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 与C20:0酰化
<400> 70
His His Leu Gly Leu Glu Glu Pro Lys Lys
1 5 10
<210> 71
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 与C14:0酰化
<400> 71
His Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 72
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 与C16:0酰化
<400> 72
His Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 73
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 与C18:0酰化
<400> 73
His Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 74
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 与C20:0酰化
<400> 74
His Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 75
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 与C16:0二酰化
<400> 75
His Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 76
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (9)..(9)
<223> 与C16:0酰化
<400> 76
His Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 77
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MISC_FEATURE
<222> (1)..(9)
<223> 环肽
<400> 77
His Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 78
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 与C16:0酰化
<400> 78
Lys His His Leu Gly Leu Glu Glu Pro Lys Lys Leu Arg
1 5 10
<210> 79
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 79
Gly Leu Glu Glu Pro Leu
1 5
<210> 80
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 80
Gly Leu Glu Glu Pro Arg
1 5
<210> 81
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 81
Gly Leu Asp Glu Pro Lys
1 5
<210> 82
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 82
Gly Leu Glu Asp Pro Lys
1 5
<210> 83
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 83
Gly Gly Glu Glu Pro Lys
1 5
<210> 84
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 84
Gly Val Glu Glu Pro Lys
1 5
<210> 85
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 85
Gly Ile Glu Glu Pro Lys
1 5
<210> 86
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 86
Val Leu Glu Glu Pro Lys
1 5
<210> 87
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 87
Leu Leu Glu Glu Pro Lys
1 5
<210> 88
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 88
Ile Leu Glu Glu Pro Lys
1 5
<210> 89
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 89
Lys Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 90
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 90
His Val Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 91
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 91
His Leu Pro Leu Glu Glu Pro Lys Lys
1 5
<210> 92
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 92
His Leu Gly Ile Glu Glu Pro Lys Lys
1 5
<210> 93
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 93
Asn Leu Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 94
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 94
His Thr Gly Leu Glu Glu Pro Lys Lys
1 5
<210> 95
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 95
His Leu Lys Leu Glu Glu Pro Lys Lys
1 5
<210> 96
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 96
His Leu Gly Ser Glu Glu Pro Lys Lys
1 5
<210> 97
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 97
His Leu Gly Leu Glu Glu Pro Tyr Lys
1 5
<210> 98
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 98
His Leu Gly Leu Glu Glu Pro Gln Lys
1 5
<210> 99
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 99
His Leu Gly Leu Glu Glu Pro Asn Lys
1 5
<210> 100
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 100
His Leu Gly Leu Glu Glu Pro Ser Phe
1 5
<210> 101
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 101
His Leu Gly Leu Glu Glu Pro Ser Val
1 5
<210> 102
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 102
His Leu Gly Leu Glu Glu Pro Leu Met
1 5
<210> 103
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 103
His Leu Gly Leu Glu Glu Pro Leu Tyr
1 5
<210> 104
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 104
His Leu Gly Leu Glu Glu Pro Leu Asn
1 5
<210> 105
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 105
His Leu Gly Leu Glu Glu Pro Leu Gln
1 5
<210> 106
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 106
His Leu Gly Leu Glu Glu Pro Phe Val
1 5
<210> 107
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 107
His Leu Gly Leu Glu Glu Pro Phe Gln
1 5
<210> 108
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 108
His Leu Gly Leu Glu Glu Pro Phe Asn
1 5
<210> 109
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 109
His Leu Gly Leu Glu Glu Pro Val Met
1 5
<210> 110
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 110
His Leu Gly Leu Glu Glu Pro Val Asn
1 5
<210> 111
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 111
His Leu Gly Leu Glu Glu Pro Met Lys
1 5
<210> 112
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 112
His Leu Gly Leu Glu Glu Pro Arg
1 5
<210> 113
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 113
His Leu Gly Leu Glu Glu Pro His
1 5
Claims (30)
1.一种用于调节受试者的代谢紊乱的方法,所述方法包括:向所述受试者施用治疗有效量的肽,所述肽由:
i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中所示的任意一种肽的药学上可接受的盐
组成。
2.如权利要求1所述的方法,其特征在于,所述代谢紊乱为与葡萄糖代谢受损相关的紊乱。
3.如权利要求1或2所述的方法,其特征在于,所述代谢紊乱进一步与胰岛素代谢受损相关。
4.如权利要求1-3任一项所述的方法,其特征在于,所述代谢紊乱进一步与瘦素代谢受损相关。
5.如权利要求1所述的方法,其特征在于,所述代谢紊乱为罕见的遗传性肥胖症。
6.如权利要求1所述的方法,其特征在于,所述代谢紊乱为综合征性肥胖症。
7.如权利要求1所述的方法,其特征在于,所述代谢紊乱为与瘦素受体(LEPR)缺乏或瘦素缺乏有关的紊乱。
8.如权利要求1所述的方法,其特征在于,所述代谢紊乱为以下一种或多种:低血糖、高血糖、碳水化合物不耐受、葡萄糖不耐受、空腹血糖受损、葡萄糖耐量受损、碳水化合物-脂质代谢紊乱、高胰岛素血症、IV型高脂蛋白血症、胰岛素抗性、I型糖尿病、II型糖尿病、肥胖症、β细胞功能受损、肢端肥大症、与黑皮质素4(MC4)信号通路受损相关的疾病、与瘦素受体(LEPR)缺乏相关的疾病、与LEPR突变相关的疾病、瘦素受体相关的单基因型肥胖、极度胰岛素抵抗综合征、阿黑皮素原(POMC)缺乏症、POMC杂合症、综合征、Bardet-Biedl综合征(BBS)、Donohue综合征(妖精貌综合征)、Rabson-Mendenhall综合征、A型极度胰岛素抵抗综合征、B型极度胰岛素抵抗综合征、C型极度胰岛素抵抗综合征、HAIR-AN综合征、多囊卵巢综合征(PCOS)、先天性脂肪营养不良综合征、Beradinelli-Seip综合征、获得性脂肪营养不良综合征、全身性脂肪营养不良和部分脂肪营养不良综合征。
9.如权利要求1-7任一项所述的方法,其特征在于,所述HBD为HBD1。
10.如权利要求1-8任一项所述的方法,其特征在于,所述肽被聚乙二醇化。
11.如权利要求1-8任一项所述的方法,其特征在于,所述肽被酰化。
12.如权利要求1-11任一项所述的方法,其特征在于,所述肽为环状。
13.如权利要求1-12任一项所述的方法,其特征在于,所述其类似物为其保守的类似物。
14.如权利要求1-13任一项所述的方法,其特征在于,所述其类似物为其结构类似物、其功能类似物或两者均有。
15.如权利要求1-9任一项所述的方法,其特征在于,所述肽如SEQ ID NO:73或其类似物所示。
16.如权利要求1-9任一项所述的方法,其特征在于,所述肽如下所示:SEQ ID NO:6,SEQ ID NO:7,SEQ ID NO:8,SEQ ID NO:10,SEQ ID NO:11,SEQ ID NO:12,SEQ ID NO:13,SEQ ID NO:14,SEQ ID NO:17,SEQ ID NO:22,SEQ ID NO:23,SEQ ID NO:24,SEQ ID NO:25,SEQ ID NO:26,SEQ ID NO:27,SEQ ID NO:28,SEQ ID NO:29,SEQ ID NO:30,SEQ IDNO:31,SEQ ID NO:32,SEQ ID NO:33,SEQ ID NO:34,SEQ ID NO:35,SEQ ID NO:36,SEQ IDNO:37,SEQ ID NO:38,SEQ ID NO:39,SEQ ID NO:40,SEQ ID NO:41,SEQ ID NO:42,SEQ IDNO:43,SEQ ID NO:44,SEQ ID NO:45,SEQ ID NO:46,SEQ ID NO:47,SEQ ID NO:48,SEQ IDNO:49,SEQ ID NO:50,SEQ ID NO:51,SEQ ID NO:52,SEQ ID NO:53,SEQ ID NO:54,SEQ IDNO:55,SEQ ID NO:56,SEQ ID NO:57,SEQ ID NO:58,SEQ ID NO:59,SEQ ID NO:60,SEQ IDNO:61,SEQ ID NO:62,SEQ ID NO:63,SEQ ID NO:64,SEQ ID NO:65,SEQ ID NO:66,SEQ IDNO:67,SEQ ID NO:68,SEQ ID NO:69,SEQ ID NO:70,SEQ ID NO:71,SEQ ID NO:72,SEQ IDNO:73,SEQ ID NO:74,SEQ ID NO:75,SEQ ID NO:76,SEQ ID NO:77,SEQ ID NO:78,SEQ IDNO:89,SEQ ID NO:90,SEQ ID NO:91,SEQ ID NO:92,SEQ ID NO:93,SEQ ID NO:94,SEQ IDNO:95,SEQ ID NO:96,SEQ ID NO:97,SEQ ID NO:98,SEQ ID NO:99,SEQ ID NO:100,SEQID NO:101,SEQ ID NO:102,SEQ ID NO:103,SEQ ID NO:106,SEQ ID NO:107,SEQ ID NO:108,SEQ ID NO:109,SEQ ID NO:110,SEQ ID NO:111,SEQ ID NO:112,SEQ ID NO:113或任何其类似物。
17.如权利要求1-16任一项所述的方法,其特征在于,所述施用为鞘内施用、皮下施用、经皮肤施用、口服施用、静脉内施用、鼻内施用、腹腔施用、肌内施用、通过植入物施用、通过基质施用、通过凝胶施用,或其任意组合。
18.如权利要求1-17任一项所述的方法,其特征在于,所述治疗有效量为约0.01μg/kg至约100mg/kg。
19.如权利要求1-17任一项所述的方法,其特征在于,所述治疗有效量为约0.3mg/kg至约3mg/kg。
20.如权利要求1-19任一项所述的方法,其特征在于,所述施用为每天一次、两次或三次。
21.如权利要求1-19任一项的方法,其特征在于,所述施用为每周进行一次、两次或三次。
22.如权利要求1-21任一项所述的方法,其特征在于,所述施用持续至少约1周或约28周的时间。
23.如权利要求1-21任一项所述的方法,其特征在于,所述施用持续超过约28周的时间。
24.一种恢复受试者体内葡萄糖稳态的方法,所述方法包括:i)向所述受试者施用治疗有效量的肽,所述肽由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐。
25.如权利要求24所述的方法,其特征在于,所述葡萄糖稳态的恢复独立于胰岛素或胰岛素样生长因子-1(IGF1)或独立于两者而实现。
26.一种试剂盒,其包括:
a)药物组合物,其包含:治疗有效量的肽,所述肽由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐;以及一种或多种药学上可接受的载体;和
b)一个或多个用于所述药物组合物的容器;和
c)其应用在调节代谢紊乱中的使用说明。
27.一种用于改善受试者的葡萄糖控制的方法,所述方法包括:向所述受试者施用治疗有效量的肽,所述肽由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中所示的任意一种肽的药学上可接受的盐。
28.一种用于改善受试者的血糖控制的分离的肽,其由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐。
29.一种用于改善受试者的胰岛素敏感性的方法,所述方法包括:向所述受试者施用治疗有效量的肽,所述肽由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐。
30.一种用于改善受试者的胰岛素敏感性的分离的肽,其由以下组成:i)如SEQ ID NO:1所示的肝素结合域(HBD)或其类似物;ii)如i)中所示肽的片段;或iii)如i)和ii)中列出的任意一种肽的药学上可接受的盐。
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PCT/IB2019/054302 WO2019224786A1 (en) | 2018-05-24 | 2019-05-23 | Heparin-binding domain of igfbp-2 in the treatment of metabolic disorders |
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WO2019224786A1 (en) | 2019-11-28 |
US11192932B2 (en) | 2021-12-07 |
US20190359676A1 (en) | 2019-11-28 |
EP3801591A4 (en) | 2022-03-09 |
JP2021525261A (ja) | 2021-09-24 |
US20210196789A1 (en) | 2021-07-01 |
CA3100665A1 (en) | 2019-11-28 |
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