CN116648255A - 用于治疗covid-19的dsg2组合物和方法 - Google Patents
用于治疗covid-19的dsg2组合物和方法 Download PDFInfo
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Abstract
本发明整体涉及治疗COVID‑19的组合物和通过施用本文公开的组合物来治疗COVID‑19的方法。这些方法还包括使用本公开中描述的组合物治疗COVID‑19后综合征和心肌病。
Description
相关申请的交叉引用
本申请要求2020年12月15日提交的题为治疗COVID-19的DSG2组合物和方法(DSG2COMPOSITIONS AND METHODS FOR THE TREATMENT OF COVID-19)的63/125,583和2021年11月2日提交的题为治疗COVID-19的DSG2组合物和方法(DSG2 COMPOSITIONS AND METHODSFOR THE TREATMENT OF COVID-19)的63/274,715的优先权,其各自的内容通过引用整体并入本文。
序列表
本申请与电子格式的序列表一起提交。序列表文件的标题为2198_1001PCT_SL.txt,创建于2021年12月10日,大小为44,002字节。序列表的电子格式的信息通过引用整体并入本文。
技术领域
本公开整体涉及通过施用本文公开的组合物治疗COVID-19的基于DSG2的方法。所述方法还包括治疗与COVID-19的长期效应(例如但不限于COVID-19后综合征(post COVID-19syndrome)或COVID-19后心脏综合征(post COVID-19cardiac syndrome))相关的治疗性适应症,包括心肌炎症和/或射血分数降低/心力衰竭/心肌病,以及治疗与DSG2自身抗体相关的疾病,例如致心律失常性右心室心肌病(arrhythmogenic right ventricularcardiomyopathy,ARVC)、结节病。
背景技术
从2019年开始,严重急性呼吸综合征冠状病毒2(SARS-CoV-2)引起了流行病,使数百万人类感染了冠状病毒病(称为COVID-19)(Wu等,2020Nature 579,265-269),这导致全世界超过一百万人死亡。感染SARS-CoV-2的患者可经历一系列临床表现,范围从无症状到危重疾病。新兴的研究表明,在一些情况下,个体,甚至那些具有轻微形式的疾病的个体,有时可能在他们最初恢复后继续经历症状。这种情况被称为COVID-19后综合征(post-COVID-19syndrome)或“长COVID-19(long COVID-19)”。此外,患者也可能发生射血分数(ejectionfraction)降低或心肌病,即使在急性COVID-19感染已经解决之后。COVID-19后心脏病征和症状可能与对其它器官系统的影响同时存在,但也可能单独存在。患有COVID后心肌病的患者从无症状的患者到暴发性心力衰竭、心律失常和/或心源性猝死的患者。
COVID-19病毒,即SARS-CoV-2影响多个器官系统,尤其是肺和心脏。在COVID-19感染的患者中通常观察到心脏生物标志物,特别是高敏感性肌钙蛋白和/或肌酸激酶MB的升高。Bavishi等进行的临床分析综述发现20%的COVID-19感染患者发生心肌损伤(ProgCardiovasc Dis.2020September-October;63(5):682-689)。与COVID-19相关的心肌损伤的可能机制包括但不限于1)由病理性T细胞和单核细胞介导的过度炎症和细胞因子风暴导致心肌炎,2)呼吸衰竭和血氧过少导致心肌细胞损伤,3)心肌细胞中ACE2表达和随后的保护性信号传导途径的下调,4)高凝性和冠状微血管血栓的形成,5)弥漫性内皮损伤,和/或,6)炎症和/或应激产生冠状动脉斑块破裂或供应需求错配导致心肌缺血/梗塞。
COVID-19后综合征也与包括心血管损伤在内的多器官损伤有关。COVID-19恢复后数月进行的成像测试显示出对心肌的持续损伤,即使是在仅有轻微COVID-19症状的人中。COVID-19后综合征还似乎与具有心律失常风险增加的心肌炎和/或心肌病有关。
目前,缺乏治疗和/或控制COVID-19和COVID-19后综合征的治疗策略。由于这些患者需要大量的资源和潜在的特别护理支持,COVID-19的心脏损害使已经遭受重创的健康护理系统处于相当大的压力下。特别地,迫切需要开发用于抑制炎性反应的治疗方式以降低与COVID-19和COVID-19后综合征相关性心肌损伤相关的发病率和死亡率。本公开提供了基于DSG2融合多肽的组合物和方法,用于治疗疾病,例如但不限于COVID-19、COVID-19后综合征和/或COVID-19后心脏综合征。
发明内容
本公开提供了包含分离的多肽的组合物。本公开的多肽可包括DSG2蛋白的全部或部分。在一些实施方案中,分离的多肽是桥粒黏蛋白2(Desmoglein2,DSG2)融合多肽。DSG2融合多肽可包括(a)DSG2蛋白(SEQ ID NO:1)的全部或部分;和/或(b)免疫球蛋白的全部或部分。在一个实施方案中,DSG2多肽可包括DSG2蛋白的部分。DSG2蛋白的部分可包括DSG2蛋白的胞外区。在一些方面,DSG2的整个胞外区可包括在融合多肽中。在一个实施方案中,DSG2的整个胞外区包括SEQ ID NO:3的氨基酸序列。本公开的实施方案还可包括DSG2的胞外区的部分。例如,胞外区的部分可以是胞外钙粘着蛋白(cadherin)结构域1(EC1)、胞外钙粘着蛋白结构域2(EC2)、胞外钙粘着蛋白结构域3(EC3)、胞外钙粘着蛋白结构域4(EC4)和/或胞外锚定结构域(EA)。在一些方面,DSG2融合多肽包括胞外区的2个结构域。例如,所述两个结构域可以是EC4EA、EC1EC2、EC2EC3、EC3EC4、EC1EA、EC1EC3、EC2EC4和/或EC3EA。在一些方面,DSG2融合多肽包括胞外区的三个结构域。例如,所述三个结构域可以是EC1EC3EA、EC1EC4EA、EC1EC3EA、EC3EC4EA、EC1EC2EC3、EC2EC3EC4和/或EC2EC4EA。在一些方面,DSG2融合多肽可包括胞外区的四个结构域。例如,所述三个结构域可以是EC1EC2EC4EA、EC2EC3EC4EA、EC1EC2EC3EC4EA、EC1EC2EC3EC4和/或EC1EC2EC3EA。
DSG2融合多肽可包括免疫球蛋白的部分。所述部分可以是Fc区、Fab区、重链可变(VH)结构域、重链恒定结构域、轻链可变(VL)结构域和/或轻链恒定结构域。在一个方面,免疫球蛋白的部分可以是Fc区。免疫球蛋白可以是IgG、IgM、IgA、IgD和/或IgE。作为非限制性实例,免疫球蛋白可以是IgG。组合物可以包含IgG,例如IgG1、IgG2、IgG3和/或IgG4。可用于本公开的免疫球蛋白的部分的非限制性实例包括IgG1 Fc区(SEQ ID NO:5)、IgG2 Fc区(SEQ ID NO:7)、IgG3 Fc区(SEQ ID NO:9)、IgG4 Fc区(SEQ ID NO:11)、IgG1重链恒定结构域(SEQ ID NO:4)、IgG2重链恒定结构域(SEQ ID NO:6)、IgG3重链恒定结构域(SEQ ID NO:8)、IgG4或重链恒定结构域(SEQ ID NO:10)。
本公开的多肽可进一步包括接头和/或信号序列。接头的长度可以是约5个氨基酸至约50个氨基酸。在一个实施方案中,接头可以是GGGGS(SEQ ID NO:12)。在另一个方面,接头可以是EAAAK(SEQ ID NO:13)。
本公开还提供了使用本文所述的组合物的治疗方法。在一些实施方案中,本公开提供了治疗COVID-19后综合征的方法。此类方法可包括i)使受试者与本公开的分离的多肽接触,和(ii)测量一种或多种与COVID-19后综合征相关的症状,其选自心律失常、心肌炎、心力衰竭、呼吸短促、疲劳、水肿、端坐呼吸、活动限制(limitations to exertion)、认知能力受损、心悸、眩晕、晕厥和/或头晕。用本公开的多肽治疗可有效改善一种或多种与COVID-19后心脏综合征相关的症状。在一些方面,患有COVID-19后病症(post-COVID-19)的受试者先前已用本领域已知的方法诊断患有COVID-19。在一个方面,受试者的血清具有可检测水平的抗SARS-CoV-2抗体。在一些实施方案中,受试者的血清不具有可检测水平的抗SARS-CoV-2抗体。本文还提供了通过施用本文所述组合物治疗患有COVID-19的受试者的方法。在一些实施方案中,患有COVID-19或COVID-19后病症的受试者的血清可具有抗DSG2抗体。
本公开还提供了治疗与血清DSG2自身抗体相关的病症的方法。此类方法可包括向受试者施用本文所述的组合物或表达本文所述的组合物的细胞。在一些实施方案中,所述病症可以是心肌病。在一些方面,所述病症可以是自身免疫性疾病。
本公开提供了治疗受试者的心肌病的方法。此类方法可包括使受试者与本公开的分离的多肽或细胞接触,随后测量与心肌病相关的一种或多种症状,如心律失常、心悸、心肌炎、心力衰竭、心输出量(cardiac output)差和/或射血分数降低。作为非限制性实例,心肌病可以是致心律失常性右心室心肌病(ARVC)。心肌病也可以由病毒(例如SARS-CoV2、腺病毒、肝炎病毒、丙型肝炎病毒、细小病毒、单纯疱疹病毒、艾柯病毒(echovirus)、爱泼斯坦-巴尔(Epstein-Barr)病毒、风疹病毒、巨细胞病毒或HIV)、细菌(葡萄球菌、链球菌或疏螺旋体(Borrelia))、寄生虫(锥虫或弓形虫)或真菌(念珠菌、曲霉或组织胞浆菌)引起。在一些实施方案中,受试者在其血清中可具有可检测水平的抗DSG2抗体。
附图说明
本公开的具体实施方案的前述和其它目的、特征和优点将根据以下描述和附图说明而变得明显。附图不一定是按比例的;而是将重点放在说明本公开的各种实施方案的原理上。
图1是显示健康对照(N=152)、COVID-19后病症(N=300)和致心律失常性右心室心肌病样品(N=5)中抗DSG2抗体信号的比较水平的图。HC,健康对照;PC,COVID-19后病症;ARVC,致心律失常性右心室心肌病;S/NC,信号/阴性对照;各个菱形表示每个单独的血清样品;盒和箱须限分别代表第25-75和第10-90百分位数。P值基于非参数秩Wilcoxon-Mann-Whitney双边检验。
图2A为条形图,显示了所有样品中在6个月和9个月时的抗DSG2抗体信号,其通过COVID-19感染后的月份收集来分析(N=300)。
图2B为条形图,显示了配对样品中在6个月和9个月时的抗DSG2抗体信号,其通过COVID-19感染后的月份收集来分析(N=17)。
具体实施方式
I.介绍
COVID-19的最新爆发在人类中引起严重的呼吸系统疾病,并在世界范围内威胁人类健康。引起COVID-19的新病毒已被国际病毒分类委员会(ICTV)命名为严重急性呼吸综合征冠状病毒2(SARS-CoV-2),因为SARS-CoV-2与SARS病毒紧密相关。
SARS-CoV-2颗粒利用特殊的表面糖蛋白(刺突蛋白)与血管紧张素转化酶2(ACE2)结合,后者在肺的II型肺泡细胞中含量最丰富,并因此进入宿主细胞。然后冠状病毒的基因组在宿主细胞中复制。每种组织中ACE2受体的密度与该组织中COVID-19疾病的严重程度相关。ACE2受体也在动脉、心脏、肾脏和肠道中的细胞的外表面上表达。因此,COVID-19在非常严重的情况下可能引起多器官衰竭。
COVID-19的症状范围从轻度(例如,发热、咳嗽、呼吸短促)到重度(例如肺炎和急性呼吸窘迫综合征(ARDS)、脓毒症和脓毒性休克、多器官衰竭,包括急性肾损伤和心脏损伤)。尽管呼吸系统疾病是COVID-19感染的主要临床表现,但也可能发生多器官衰竭。在一项分析COVID-19的致命病例的多中心研究中,观察到心肌损伤是40%的病例的死亡原因(Ruan Q.等Intensive Care Med.2020;46(5):846–848)。有多种心脏并发症与活性COVID-19感染有关,包括心律失常、心肌炎和急性心肌损伤。全身性炎症、心肌细胞的直接损伤、细胞因子风暴和缺氧是所提出的多因子病理生理学机制中的其中一些。与COVID-19相关的心律失常也可归因于用阿奇霉素、羟氯喹和一些可引起QT延长的抗病毒剂进行的治疗。COVID-19中的急性心肌损伤的范围可以从心脏肌钙蛋白的无症状升高到暴发性心肌炎和循环性休克(circulatory shock)。心肌损伤可单独出现,或者可与心律失常组合出现(基于感染的临床进程)。
COVID-19中的促炎环境和增加的交感神经刺激可进一步增加心血管并发症的风险,例如心律失常、现有心力衰竭(HF)的恶化或新发作HF的发展。在患有严重疾病的患者中,缺氧和电解质紊乱可进一步加重心律失常的风险。
在某些情况下,在患者样品中检测到病毒颗粒后数周、数月或数年,患者可能出现症状(本文称为COVID-19后综合征或“长COVID-19”或病毒后综合征)。COVID-19后综合征还可与心脏症状有关,在此称为COVID-19后心脏综合征。许多从COVID-19恢复的患者通过MRI测量在心肌中显示持续的炎症。在一项研究中,高达60%的有症状和无症状COVID-19患者具有正在发生的心肌炎症的MRI证据,平均是从COVID-19急性期恢复后71天((Puntmann等JAMA Cardiol.2020;5(11):1265-1273,其内容通过引用整体并入本文)。在一项较小的研究中,15%的运动员在从COVID-19恢复后具有心肌炎的证据((Metzel等2020,HSSJournal,第16卷,第102-107页)。相当比例的COVID-19后综合征患者随后发展为心脏功能受损,最显著的是射血分数降低,具有或不具有明显的心力衰竭症状。为了清楚起见,具有COVID-19后心脏表现的患者在本文中可以称为COVID-19后心脏综合征。患有COVID-19后综合征的患者还经历慢性疲劳综合征,这可能是由未确诊的心输出量减少所驱动的。症状可包括呼吸短促、疲劳、水肿、端坐呼吸、由于心输出量差导致的活动限制和认知能力受损(“脑雾”)、心律失常、心悸、眩晕、晕厥、头晕、心力衰竭、由于心力衰竭和/或心律失常导致的住院治疗。在一些情况下,死亡可由于心力衰竭和/或心律失常而发生。在一些实施方案中,COVID-19后综合征可能与心脏表现不相关。
包括心律失常在内的心脏症状与其它疾病有关,例如但不限于致心律失常性右心室心肌病(ARVC)。与ARVC类似,患有COVID-19和/或COVID-19后综合征的患者在体力活动时也表现出恶化的心脏功能。在ARVC的情况下,Chatterjee等人鉴定了针对心脏桥粒黏蛋白2(DSG2)的自身抗体作为ARVC患者的血清中的通常特征(Chatterjee D,等,Eur HeartJ.2018;39(44):3932-3944,其内容通过引用整体并入本文)。这些自身抗体对ARVC是特异性的,因为它们在两个独立组的对照血清和来自患有其它形式的遗传性心肌病的受试者的血清中基本上不存在。DSG2抗体也可在结节病的一些病例中发现,结节病是一种导致器官例如但不限于心脏中肉芽瘤的全身性炎性疾病。抗DSG2抗体也见于心脏受累的类肉瘤患者(Suna等2020,Eur.Heart Journal,Volume 41,Issue Supplement_2,November 2020,ehaa946.2127;其内容通过引用整体并入本文)。诊断为扩张性心肌病的患者可能在与ARVC相关的相同桥粒蛋白中具有突变。这些观察结果表明,一些扩张性心肌病患者可能实际上患有由DSG2抗体介导的ARVC样疾病,但已被诊断为扩张性心肌病,因为它们与ARVC相关的典型年龄和/或表现不匹配。抗DSG2自身抗体被认为在心脏细胞损伤和激活的免疫系统的组合存在时产生—通常在已知直接影响心肌的感染的情况下。从发病机理的观点来看,病毒感染如COVID-19通常引发对病毒清除至关重要的强烈的免疫应答,以及涉及先天性和适应性免疫臂(innate and adaptive immune arms)的级联事件。COVID-19感染也引起直接和间接的心肌损伤,使得心脏蛋白暴露于激活的免疫系统。在患有COVID-19病症的患者中也观察到了免疫学改变。这些改变的范围从适应不良的免疫应答(maladaptive immuneresponse)和异常的细胞因子/趋化因子产生,到T细胞的超活化和活化的单核细胞、巨噬细胞和嗜中性粒细胞的数量增加(Chang,S.E.,等Nature Communications 2021;12:5417;Liu,Y.,等Curr.Opin.Rheumatol.2021;33:155-162;Lee,C.C.E.,等Diseases 2021;9:47;其内容通过引用整体并入本文)。
COVID-19已经在全世界感染了至少2亿人,迄今为止有约450万人死于COVID 19疾病。人们越来越认识到COVID-19感染可以引起多种长期后遗症,其中心脏受累可能是最不被认识到的,因为其症状可能归于其它器官系统。
COVID-19感染与早就进入恢复的心肌受累和心律失常的MRI证据有关,与先前存在的病症、急性疾病的严重程度和总进程以及距最初诊断的时间无关。尽管在COVID-19后病症患者中描述了Frank心肌病,但随后将发生射血分数降低的患者的百分比目前还不是很清楚。
在致心律失常性右心室心肌病(ARVC)中也观察到心肌病和心律失常倾向性增加的结果。已显示针对桥粒蛋白桥粒黏蛋白-2(DSG2)的抗体存在于ARVC患者中(DiptenduChatterjee D.,等EHJ 2018(39)3932-3944,其内容通过引用整体并入本文)。抗DSG2抗体的浓度与心律失常负荷正相关,并且这些抗体在临界ARVC病例中的存在预测了爆发性ARVC的发展。iPSC衍生的心肌细胞暴露于抗DSG2抗体会导致间隙连接功能降低,这可反映直接心脏毒性。总之,这些数据表明抗DSG2抗体可在心脏病理学中起作用。本公开还提供了证据表明,甚至在诊断后6-9个月,COVID-19患者中的抗DSG2抗体水平仍升高。
病毒感染,包括COVID-19,已经被假设是导致自身免疫应答的原因,例如,通过将损伤细胞上先前隐藏的隐蔽表位暴露于激活的免疫系统(Ehrenfeld M.,等AutoimmunityReviews 2020 102597;其内容通过引用整体并入本文)。在COVID-19感染中观察到的心脏受累的高发病率表明,抗DSG2自身抗体可能作为结果而产生。
心律失常的存在以及免疫系统在COVID-19、COVID-19后综合征和ARVC的进展中的作用共同提示了DSG2自身抗体参与这些疾病的发病。因此,针对抗DSG2抗体(例如DSG2自身抗体)的策略可有益于治疗COVID-19、COVID-19后综合征和/或ARVC。
本公开提供了涉及用于靶向抗DSG2抗体的DSG2融合多肽的组合物和方法。因此,本公开的DSG2融合多肽可以是治疗COVID-19、COVID-19后心脏综合征和/或ARVC的可行治疗策略。DSG2融合多肽还可用于治疗与心脏细胞损伤相关的其它疾病,例如但不限于致心律失常性心肌病(AC)、结节病、具有抗DSG2自身抗体的扩张性心肌病和病毒感染,包括但不限于由柯萨奇病毒、腺病毒、艾柯病毒、细小病毒、风疹病毒和/或巨细胞病毒引起的那些病毒感染。
II.组合物
在一些实施方案中,本公开提供了包括DSG2融合多肽的组合物。本文所述的组合物能够结合抗DSG2抗体或与抗DSG2抗体相互作用。在一个实施方案中,本公开的组合物可调节抗DSG2抗体的活性。在一个实施方案中,本公开的组合物可抑制抗DSG2抗体的活性。
在一些实施方案中,本公开包括DSG2蛋白。在一些方面,DSG2蛋白可以是完整的DSG2蛋白或DSG2蛋白的部分。在一些实施方案中,DSG2蛋白可与任何其它蛋白或蛋白的片段融合。
本公开的DSG2融合多肽可包括DSG2蛋白的全部或部分和免疫球蛋白的全部或部分。在一些实施方案中,DSG2融合多肽可进一步包括接头和/或信号肽。在一些实施方案中,DSG2蛋白的全部或部分可与不是免疫球蛋白的蛋白融合。DSG2蛋白可与能够在体外或体内改善DSG2蛋白表达的蛋白或蛋白的片段融合。
心脏细胞中闰盘内的DSG2突变与心脏病有关,包括心律失常、扩张性心肌病且尤其是ARVC(致心律失常性右心室心肌病)。Chatterjee等人鉴定了针对心脏DSG2蛋白的自身抗体是ARVC患者血清中的通常特征((Chatterjee D,等,Eur Heart J.2018;39(44):3932-3944,其内容通过引用整体并入本文)。这些自身抗体对ARVC是特异性的,因为它们在两个独立组的对照血清和来自患有其它形式的遗传性心肌病的受试者的血清中基本上不存在。Chatterjee等鉴定的DSG2自身抗体的存在表明,靶向DSG2抗体可能代表了治疗与诸如但不限于ARVC和/或COVID-19的疾病相关的心肌病的治疗策略。本公开提供了DSG2融合多肽作为针对DSG2自身抗体的治疗策略。在一些实施方案中,本公开的DSG2融合多肽可结合DSG2自身抗体。在一些实施方案中,本公开的DSG2融合多肽与DSG2自身抗体的结合妨碍了受试者中自身抗体与内源性DSG2的结合。在本公开的这一方面,DSG2融合多肽发挥诱饵蛋白(decoy protein)或配体陷阱(ligand trap)的作用。
Chatterjee等人提出,DSG2蛋白可包括暴露或释放到细胞间隙和/或循环中的表位,这是DSG2突变的结果。这些表位的非掩蔽状态也可因任何心脏损伤(例如但不限于感染性心肌炎和/或心脏创伤)而发生。在一些实施方案中,本公开的组合物可以不包括任何突变。这种释放的DSG2蛋白可与抗原呈递细胞连接以刺激T细胞应答,产生观察到的自身抗体。通过基因突变使隐蔽表位处于非掩蔽状态可能有助于其它形式的自身免疫。在一些实施方案中,本公开的DSG2融合多肽可包括在DSG2中含有一个或多个突变的表位。
DSG2融合多肽可以是可溶的和/或重组的多肽。可优化DSG2融合多肽中组分的配置,以实现合适的蛋白质表达和/或期望的治疗效果。在一些实施方案中,DSG2融合多肽可包括本文描述的形式。本文提供的形式包括从N端到C端的组分,组分之间用“;”标示。DSG2融合多肽形式的非限制性实例包括(i)DSG2蛋白的全部或部分;Fc区,(ii)Fc区;DSG2蛋白的全部或部分,(iii)信号序列;DSG2蛋白的全部或部分;Fc区,(iv)信号序列;Fc区;DSG2蛋白的全部或部分,(v)DSG2蛋白的全部或部分;接头;Fc区,(vi)Fc区;接头;DSG2蛋白的全部或部分,(vii)信号序列;DSG2蛋白的全部或部分;接头;Fc区,(viii)信号序列;Fc区;接头;DSG2蛋白的全部或部分。
DSG2蛋白
在一些实施方案中,本公开的DSG2融合多肽可包括完整的DSG2蛋白。桥粒钙粘附蛋白桥粒黏蛋白-2(DSG2)是广泛表达于上皮和非上皮组织(例如心脏、肠道和表皮)中的跨膜细胞粘附蛋白。DSG2已显示调节包括增殖和凋亡在内的许多细胞过程。在上皮细胞和肌细胞中,DSG2是细胞-细胞粘附结构的组分,其胞质尾区与一系列直接接触细胞粘附的蛋白和细胞间连接/细胞类型调节剂相互作用。在一些实施方案中,DSG2蛋白是由1,118个氨基酸组成的人DSG2蛋白(UniProt ID:Q14126;ENSEMBL Protein ID:ENSP00000261590.8),并包括SEQ ID NO:1的氨基酸序列。在一个实施方案中,DSG2蛋白可由SEQ ID NO:2的核酸序列(NCBI参考序列:NM_001943.5;ENSMBL ID:ENST00000261590.13)编码。
在一些实施方案中,本公开的DSG2融合多肽可以是完全加工的DSG2蛋白,其包含SEQ ID NO:1的氨基酸50-1118。
DSG2蛋白还可包括相对于SEQ ID NO:1的序列的一个或多个突变。在一些实施方案中,DSG2蛋白突变可以是与疾病状态相关的突变。在一个实施方案中,疾病状态可以是致心律失常性右心室活动障碍/心肌病。在一些实施方案中,本公开的DSG2融合多肽可包括在DSG2中含有一个或多个突变的表位。作为非限制性实例,DSG2融合多肽可包括在SEQ IDNO:1的氨基酸485-531和/或氨基酸586-610的区域中的一个或多个突变。
DSG2属于细胞粘附蛋白的钙粘附蛋白超家族,其通常以三个不同的区域为特征:胞外区、跨膜结构域和胞内信号传导区。在一些实施方案中,DSG2的胞外区可包括SEQ IDNO:3的氨基酸序列,其是SEQ ID NO:1的氨基酸50-609。钙粘附蛋白家族蛋白的胞外区含有不同数目的钙结合基序重复,称为钙粘附蛋白基序或EC结构域。DSG2含有四个EC结构域,本文称为EC1、EC2、EC3和EC4。DSG2还包括接近膜的细胞外锚定(EA)结构域。在一些实施方案中,本公开的DSG2融合多肽可包括DSG2的整个胞外区。在一些方面,DSG2融合多肽可包括至少一个结构域,例如但不限于EC1、EC2、EC3、EC4和/或EA。在一些实施方案中,EC1结构域可以是SEQ ID NO:1的氨基酸50-155。在一些实施方案中,EC2结构域可以是SEQ ID NO:1的氨基酸151-268。在一些实施方案中,EC3结构域可以是SEQ ID NO:1的氨基酸264-384。在一些实施方案中,EC4结构域可以是SEQ ID NO:1的氨基酸382-495。在一些实施方案中,EA结构域可以是SEQ ID NO:1的氨基酸491-608。表1提供了DSG2蛋白的氨基酸序列以及DSG2的胞外区的氨基酸序列。在一些实施方案中,本公开的DSG2蛋白可与表1中的任何序列或表1中的序列的片段具有至少50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、99%或100%同一性。
表1.DSG2蛋白和DSG2细胞外结构域的序列
本公开的DSG2融合多肽可以包括DSG2胞外区的一个或多个结构域。DSG2胞外区的结构域可以包括一个或多个EC结构域或EA结构域以串联或混合顺序重复。例如,DSG2融合多肽可以包括EC1、EC2、EC3、EC4或EA结构域的2个、3个或更多个重复。当存在DSG2胞外区的多于一个结构域和/或结构域的多于一个重复时,这些结构域可以通过本文所述的接头有效地连接。
在一些实施方案中,DSG2融合多肽可以包括DSG2胞外区的两个结构域。本公开的融合多肽中存在的DSG2胞外区的结构域的非限制性实例包括EC1EC2、EC1EC3、EC1EC4、EC1EA、EC2EC1、EC2EC3、EC2EC4、EC2EA、EC3EC1、EC3EC2、EC3EC4、EC3EA、EC4EC1、EC4EC2、EC4EC3、EC4EA、EAEC1、EAEC2、EAEC3和/或EAEC4。
在一些实施方案中,DSG2融合多肽可以包括DSG2胞外区的三个结构域。本公开的融合多肽中存在的DSG2胞外区的结构域的非限制性实例包括EC1EC2EC3、EC1EC2EC4、EC1EC2EA、EC1EC3EC2、EC1EC3EC4、EC1EC3EA、EC1EC4EC2、EC1EC4EC3、EC1EC4EA、EC1EAEC2、EC1EAEC3、EC1EAEC4、EC2EC1EC3、EC2EC1EC4、EC2EC1EA、EC2EC3EC1、EC2EC3EC4、EC2EC3EA、EC2EC4EC1、EC2EC4EC3、EC2EC4EA、EC2EAEC1、EC2EAEC3、EC2EAEC4、EC3EC1EC2、EC3EC1EC4、EC3EC1EA、EC3EC2EC1、EC3EC2EC4、EC3EC2EA、EC3EC4EC1、EC3EC4EC2、EC3EC4EA、EC3EAEC1、EC3EAEC2、EC3EAEC4、EC4EC1EC2、EC4EC1EC3、EC4EC1EA、EC4EC2EC1、EC4EC2EC3、EC4EC2EA、EC4EC3EC1、EC4EC3EC2、EC4EC3EA、EC4EAEC1、EC4EAEC2、EC4EAEC3、EAEC1EC2、EAEC1EC3、EAEC1EC4、EAEC2EC1、EAEC2EC3、EAEC2EC4、EAEC3EC1、EAEC3EC2、EAEC3EC4、EAEC4EC1、EAEC4EC2和/或EAEC4EC3。
在一些实施方案中,DSG2融合多肽可以包括DSG2胞外区的四个结构域。本公开的融合多肽中存在的DSG2胞外区的结构域的非限制性实例包括EC1EC2EC3EC4、EC1EC2EC3EA、EC1EC2EC4EC3、EC1EC2EC4EA、EC1EC2EAEC3、EC1EC2EAEC4、EC1EC3EC2EC4、EC1EC3EC2EA、EC1EC3EC4EC2、EC1EC3EC4EA、EC1EC3EAEC2、EC1EC3EAEC4、EC1EC4EC2EC3、EC1EC4EC2EA、EC1EC4EC3EC2、EC1EC4EC3EA、EC1EC4EAEC2、EC1EC4EAEC3、EC1EAEC2EC3、EC1EAEC2EC4、EC1EAEC3EC2、EC1EAEC3EC4、EC1EAEC4EC2、EC1EAEC4EC3、EC2EC1EC3EC4、EC2EC1EC3EA、EC2EC1EC4EC3、EC2EC1EC4EA、EC2EC1EAEC3、EC2EC1EAEC4、EC2EC3EC1EC4、EC2EC3EC1EA、EC2EC3EC4EC1、EC2EC3EC4EA、EC2EC3EAEC1、EC2EC3EAEC4、EC2EC4EC1EC3、EC2EC4EC1EA、EC2EC4EC3EC1、EC2EC4EC3EA、EC2EC4EAEC1、EC2EC4EAEC3、EC2EAEC1EC3、EC2EAEC1EC4、EC2EAEC3EC1、EC2EAEC3EC4、EC2EAEC4EC1、EC2EAEC4EC3、EC3EC1EC2EC4、EC3EC1EC2EA、EC3EC1EC4EC2、EC3EC1EC4EA、EC3EC1EAEC2、EC3EC1EAEC4、EC3EC2EC1EC4、EC3EC2EC1EA、EC3EC2EC4EC1、EC3EC2EC4EA、EC3EC2EAEC1、EC3EC2EAEC4、EC3EC4EC1EC2、EC3EC4EC1EA、EC3EC4EC2EC1、EC3EC4EC2EA、EC3EC4EAEC1、EC3EC4EAEC2、EC3EAEC1EC2、EC3EAEC1EC4、EC3EAEC2EC1、EC3EAEC2EC4、EC3EAEC4EC1、EC3EAEC4EC2、EC4EC1EC2EC3、EC4EC1EC2EA、EC4EC1EC3EC2、EC4EC1EC3EA、EC4EC1EAEC2、EC4EC1EAEC3、EC4EC2EC1EC3、EC4EC2EC1EA、EC4EC2EC3EC1、EC4EC2EC3EA、EC4EC2EAEC1、EC4EC2EAEC3、EC4EC3EC1EC2、EC4EC3EC1EA、EC4EC3EC2EC1、EC4EC3EC2EA、EC4EC3EAEC1、EC4EC3EAEC2、EC4EAEC1EC2、EC4EAEC1EC3、EC4EAEC2EC1、EC4EAEC2EC3、EC4EAEC3EC1、EC4EAEC3EC2、EAEC1EC2EC3、EAEC1EC2EC4、EAEC1EC3EC2、EAEC1EC3EC4、EAEC1EC4EC2、EAEC1EC4EC3、EAEC2EC1EC3、EAEC2EC1EC4、EAEC2EC3EC1、EAEC2EC3EC4、EAEC2EC4EC1、EAEC2EC4EC3、EAEC3EC1EC2、EAEC3EC1EC4、EAEC3EC2EC1、EAEC3EC2EC4、EAEC3EC4EC1、EAEC3EC4EC2、EAEC4EC1EC2、EAEC4EC1EC3、EAEC4EC2EC1、EAEC4EC2EC3、EAEC4EC3EC1和/或EAEC4EC3EC2。
在一些实施方案中,DSG2融合多肽可以包括DSG2胞外区的五个结构域。本公开的融合多肽中存在的DSG2胞外区的结构域的非限制性实例包括EC1EC2EC3EC4EA、EC1EC2EC3EAEC4、EC1EC2EC4EC3EA、EC1EC2EC4EAEC3、EC1EC2EAEC3EC4、EC1EC2EAEC4EC3、EC1EC3EC2EC4EA、EC1EC3EC2EAEC4、EC1EC3EC4EC2EA、EC1EC3EC4EAEC2、EC1EC3EAEC2EC4、EC1EC3EAEC4EC2、EC1EC4EC2EC3EA、EC1EC4EC2EAEC3、EC1EC4EC3EC2EA、EC1EC4EC3EAEC2、EC1EC4EAEC2EC3、EC1EC4EAEC3EC2、EC1EAEC2EC3EC4、EC1EAEC2EC4EC3、EC1EAEC3EC2EC4、EC1EAEC3EC4EC2、EC1EAEC4EC2EC3、EC1EAEC4EC3EC2、EC2EC1EC3EC4EA、EC2EC1EC3EAEC4、EC2EC1EC4EC3EA、EC2EC1EC4EAEC3、EC2EC1EAEC3EC4、EC2EC1EAEC4EC3、EC2EC3EC1EC4EA、EC2EC3EC1EAEC4、EC2EC3EC4EC1EA、EC2EC3EC4EAEC1、EC2EC3EAEC1EC4、EC2EC3EAEC4EC1、EC2EC4EC1EC3EA、EC2EC4EC1EAEC3、EC2EC4EC3EC1EA、EC2EC4EC3EAEC1、EC2EC4EAEC1EC3、EC2EC4EAEC3EC1、EC2EAEC1EC3EC4、EC2EAEC1EC4EC3、EC2EAEC3EC1EC4、EC2EAEC3EC4EC1、EC2EAEC4EC1EC3、EC2EAEC4EC3EC1、EC3EC1EC2EC4EA、EC3EC1EC2EAEC4、EC3EC1EC4EC2EA、EC3EC1EC4EAEC2、EC3EC1EAEC2EC4、EC3EC1EAEC4EC2、EC3EC2EC1EC4EA、EC3EC2EC1EAEC4、EC3EC2EC4EC1EA、EC3EC2EC4EAEC1、EC3EC2EAEC1EC4、EC3EC2EAEC4EC1、EC3EC4EC1EC2EA、EC3EC4EC1EAEC2、EC3EC4EC2EC1EA、EC3EC4EC2EAEC1、EC3EC4EAEC1EC2、EC3EC4EAEC2EC1、EC3EAEC1EC2EC4、EC3EAEC1EC4EC2、EC3EAEC2EC1EC4、EC3EAEC2EC4EC1、EC3EAEC4EC1EC2、EC3EAEC4EC2EC1、EC4EC1EC2EC3EA、EC4EC1EC2EAEC3、EC4EC1EC3EC2EA、EC4EC1EC3EAEC2、EC4EC1EAEC2EC3、EC4EC1EAEC3EC2、EC4EC2EC1EC3EA、EC4EC2EC1EAEC3、EC4EC2EC3EC1EA、EC4EC2EC3EAEC1、EC4EC2EAEC1EC3、EC4EC2EAEC3EC1、EC4EC3EC1EC2EA、EC4EC3EC1EAEC2、EC4EC3EC2EC1EA、EC4EC3EC2EAEC1、EC4EC3EAEC1EC2、EC4EC3EAEC2EC1、EC4EAEC1EC2EC3、EC4EAEC1EC3EC2、EC4EAEC2EC1EC3、EC4EAEC2EC3EC1、EC4EAEC3EC1EC2、EC4EAEC3EC2EC1、EAEC1EC2EC3EC4、EAEC1EC2EC4EC3、EAEC1EC3EC2EC4、EAEC1EC3EC4EC2、EAEC1EC4EC2EC3、EAEC1EC4EC3EC2、EAEC2EC1EC3EC4、EAEC2EC1EC4EC3、EAEC2EC3EC1EC4、EAEC2EC3EC4EC1、EAEC2EC4EC1EC3、EAEC2EC4EC3EC1、EAEC3EC1EC2EC4、EAEC3EC1EC4EC2、EAEC3EC2EC1EC4、EAEC3EC2EC4EC1、EAEC3EC4EC1EC2、EAEC3EC4EC2EC1、EAEC4EC1EC2EC3、EAEC4EC1EC3EC2、EAEC4EC2EC1EC3、EAEC4EC2EC3EC1、EAEC4EC3EC1EC2和/或EAEC4EC3EC2EC1。
表2中提供了DSG2蛋白的部分以及DSG2融合多肽中存在的可能构型的非限制性实例。表2中所述的任何DSG2结构域都可使用本文提供的任何接头或本领域已知的任何接头与融合多肽内的另一个结构域或与另一个DSG2结构域有效地连接。本公开的组合物可包括表2中所描述的任何结构域的部分或片段。本公开的多肽中包含的SEQ ID NO:1或SEQ IDNO:3的结构域或结构域的组合可以在表2中定义的结构域的上游或下游延伸1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、30、40或50个氨基酸。在一些实施方案中,本公开的多肽中包含的SEQ ID NO:1或SEQ ID NO:3的结构域或结构域的组合可以在表2中定义的结构域的N末端或C末端截短1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、30、40或50个氨基酸。作为非限制性实例,DSG2蛋白的胞外区可从跨SEQ ID NO:1的50-610的氨基酸延伸。
表2.DSG2胞外区的DSG2结构域组合
免疫球蛋白
在一些实施方案中,本公开的DSG2融合多肽可包括免疫球蛋白的全部或部分。免疫球蛋白可以是IgG、IgM、IgA、IgD和IgE。在一个实施方案中,免疫球蛋白可以是IgG。IgG的非限制性实例可以是IgG1、IgG2、IgG3和/或IgG4。DSG2融合多肽可包括免疫球蛋白的区域或部分。免疫球蛋白的区域的非限制性实例,例如Fc区、Fab区、重链可变(VH)结构域、重链恒定结构域、轻链可变(VL)结构域和/或轻链恒定结构域。
DSG2融合多肽可包括免疫球蛋白的一个或多个Fc区。在一些实施方案中,Fc区可以包括第一恒定区免疫球蛋白结构域(例如CH1)或其部分和(在一些情况下)铰链的部分。在其它方面,Fc区不包括第一恒定区免疫球蛋白结构域。因此,Fc可以指IgA、IgD和IgG的最后两个恒定区免疫球蛋白结构域(例如CH2和CH3),IgE和IgM的最后三个恒定区免疫球蛋白结构域,和这些结构域N端的柔性铰链。对于IgA和IgM,Fc可以包括J链。对于IgG,Fc结构域包含免疫球蛋白结构域Cγ2和Cγ3(Cγ2和Cγ3)以及Cγ1(Cγ1)和Cγ2(Cγ2)之间的下铰链区(lower hinge region)。在一些实施方案中,Fc是指截短的免疫球蛋白CH1结构域、CH2和CH3。尽管Fc区的边界可以变化,但是人IgG重链Fc区通常被定义为包括残基E216或C226或P230至其羧基末端,其中编号是根据如Kabat抗体编号序列中的EU索引。
在一些实施方案中,免疫球蛋白可以包括另外的细胞靶向模块(并且在本文中可以称为细胞靶向抗体CTAB)。
表3提供了免疫球蛋白的部分的序列的非限制性实例。在一些实施方案中,DSG2融合多肽可包括与表3中任何序列或表3中序列的片段具有至少50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、99%或100%同一性的免疫球蛋白或其部分。
表3.免疫球蛋白区域的序列
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信号序列
信号序列(有时称为信号肽、靶向信号、靶肽、定位序列、转运肽、前导序列或前导肽)将蛋白质(例如,本公开的多肽)引导至其指定的细胞位置和/或细胞外位置。信号序列可以是存在于大多数新合成的蛋白质的N末端的短(约5-50个氨基酸长)肽,其指向特定位置。信号序列可被信号识别颗粒(SRP)识别并用I型和II型信号肽肽酶切割。来源于人蛋白的信号序列可作为本公开的DSG2融合多肽并入,以将本公开的多肽引导向特定的细胞和/或细胞外位置。这些信号序列经实验证实并可被切割(Zhang等,Protein Sci.2004,13:2819-2824)。
在一些实施方案中,信号序列可位于本公开的多肽的N末端或C末端。并且可以(但不是必须)从多肽上切割下来以产生“成熟”多肽,如本文所讨论。
在一些实例中,信号序列可以是源自天然分泌蛋白的分泌信号序列及其变体。
在一些情况下,可以使用将本公开的多肽引导至靶细胞的膜表面的信号序列。本公开的多肽在靶细胞表面上的表达可以用于限制本公开的多肽扩散至体内非靶标环境,由此潜在地改善本公开的多肽的安全性特征。另外,本公开的多肽的膜呈递可允许生理性和定性信号传导以及多肽的稳定和再循环,以获得更长的半衰期。
信号序列可以是来自其它生物体如病毒、酵母和细菌的异源信号序列,其可以将本公开的多肽引导向特定的细胞位点,如细胞核(例如EP 1209450)。其它实例可包括来自木霉属(Trichoderma)的天冬氨酸蛋白酶(NSP24)信号序列,其可增加融合蛋白例如酶的分泌(例如Cervin和Kim的美国专利号8,093,016),细菌脂蛋白信号序列(例如Lau和Rioux的PCT公开号1991/09952),大肠杆菌肠毒素II信号肽(例如Kwon等人的美国专利号6,605,697),大肠杆菌分泌信号序列(例如Malley等人的美国专利公开号2016/090404),来自甲基营养型酵母的脂肪酶信号序列(例如美国专利号8,975,041)和来自棒状细菌(Corynejbnnbacteria)的DNase的信号肽(例如美国专利号4,965,197),其每一个的内容均通过引用整体并入本文。
接头
在一些实施方案中,本公开的DSG2融合多肽可包括至少一个接头。接头可以位于本公开的多肽的一个或多个区域之间。在一个实施方案中,接头可位于DSG2蛋白的全部或部分和免疫球蛋白的全部或部分之间。在一个方面,接头可位于DSG2蛋白的一个或多个结构域之间。
在一些实施方案中,接头可以是多肽。在一些实施方案中,接头可以包含氨基酸残基的组合。在一些实施方案中,接头可包含约1-50个氨基酸残基。在一些实施方案中,接头可以包含约1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45或50个氨基酸残基。
本公开的接头的长度可以是约1至100个氨基酸,其将效应器模块(effectormodule)的任何结构域/区域连接在一起(也称为肽接头)。接头的长度可以是1-40个氨基酸,或2-30个氨基酸,或20-80个氨基酸,或50-100个氨基酸。接头长度也可以根据多肽的构型类型和基于多肽的晶体结构进行优化。在一些情况下,可以优选选择较短的接头长度。在一些方面,肽接头可以由通过肽键连接在一起的氨基酸组成,优选地由通过肽键连接的1至20个氨基酸组成,其中氨基酸选自20种天然存在的氨基酸:甘氨酸(G)、丙氨酸(A)、缬氨酸(V)、亮氨酸(L)、异亮氨酸(I)、丝氨酸(S)、半胱氨酸(C)、苏氨酸(T)、甲硫氨酸(M)、脯氨酸(P)、苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W)、组氨酸(H)、赖氨酸(K)、精氨酸(R)、天冬氨酸(D)、谷氨酸(E)、天冬酰胺(N)和谷氨酰胺(Q)。如本领域技术人员所理解的,这些氨基酸中的一个或多个可以被糖基化。在一些方面,肽接头的氨基酸可以选自丙氨酸(A)、甘氨酸(G)、脯氨酸(P)、天冬酰胺(R)、丝氨酸(S)、谷氨酰胺(Q)和赖氨酸(K)。
在一些实施方案中,接头可以是柔性接头或刚性接头。柔性接头可以由小的非极性(例如Gly)或极性(例如Ser或Thr)氨基酸组成。这些氨基酸的小尺寸提供了柔性,并允许连接功能结构域的活动性。最常用的柔性接头具有主要由Gly和Ser残基的片段组成的序列(“GS”接头)。最广泛使用的柔性接头的实例具有序列(Gly-Gly-Gly-Gly-Ser)n。通过调节拷贝数“n”,可以优化该GS接头的长度以实现功能结构域的适当分离,或维持必需的结构域间相互作用。在一些实施方案中,接头可以包括额外的氨基酸如Thr和Ala以维持柔性,以及极性氨基酸如Lys和Glu以改善溶解度。在一些实施方案中,DSG2融合多肽可包括柔性接头,如(Gly)8(SEQ ID NO:14),其仅由甘氨酸残基组成。接头序列避免了大的疏水残基,以保持在水性溶液中的良好溶解性。
在一些实施方案中,接头可以是刚性接头。刚性接头的非限制性实例包括具有序列(EAAAK)n(n=2-5)(SEQ ID NO:15)的接头。在一些实施方案中,刚性接头可以具有富含脯氨酸的序列(XP)n,其中X表示任何氨基酸,优选Ala、Lys或Glu。
在一些实施方案中,接头可以是GGGGS(SEQ ID NO:12)。在一些实施方案中,接头可以是GGGGGS(SEQ ID NO:16)和EAAAK(SEQ ID NO:13)。
多核苷酸
在一些实施方案中,本公开的多肽由本文所述的多核苷酸或其变体编码。示例性核酸或多核苷酸包括但不限于核糖核酸(RNA)、脱氧核糖核酸(DNA)、苏糖核酸(TNA)、乙二醇核酸(GNA)、肽核酸(PNA)、锁核酸(LNA,包括具有β-D-核糖构型的LNA、具有α-L-核糖构型的α-LNA(LNA的非对映异构体)、具有2'-氨基官能化的2'-氨基-LNA和具有2'-氨基官能化的2'-氨基-α-LNA)、乙烯核酸(ENA)、环己烯基核酸(CeNA)或其杂合体或组合。
因此,本文公开了编码相对于参考序列,特别是多肽序列含有取代、插入和/或添加、缺失和共价修饰的肽或多肽的多核苷酸。例如,序列标签或氨基酸,如一个或多个赖氨酸,可以被添加到本文所述的肽序列中(例如,在N-末端或C-末端)。序列标签可用于肽纯化或定位。赖氨酸可用于增加肽的溶解度或允许生物素化。或者,位于肽或蛋白质的氨基酸序列的羧基和氨基末端区域的氨基酸残基可以任选地缺失,以提供截短的序列。根据序列的用途,例如,作为可溶的更大序列的一部分的序列的表达或连接到固体支持物,某些氨基酸(例如C-末端或N-末端残基)可以选择性地缺失。
一旦任何特征已被鉴定或定义为由本文所述多核苷酸编码的多肽的所需组分,则可通过移动、交换(swapping)、倒置、删除、随机化或复制来进行这些特征的若干操作和/或修饰中的任何一种。此外,应理解,特征的操纵可导致与对本文所述分子的修饰相同的结果。例如,涉及删除结构域的操作将导致分子长度的改变,就像修饰核酸以编码小于全长的分子一样。
III.药物组合物和递送
本文所述的融合多肽可用作治疗剂。在一些实施方案中,本公开提供了包含至少一种药学上可接受的载体和融合多肽的药物组合物。
在一些实施方案中,将组合物施用于人、人患者或受试者。尽管本文提供的药物组合物的描述主要涉及适于向人施用的药物组合物,但本领域技术人员将理解,这样的组合物通常适于施用给任何其它动物,例如非人动物,例如非人哺乳动物。为了使组合物适于施用给各种动物而对适于施用给人的药物组合物进行的修饰是公知的,并且普通技术的兽医学药理学家可以仅用普通的实验(如果有的话)设计和/或进行这样的修饰。涉及施用药物组合物的受试者包括但不限于人和/或其它灵长类动物;哺乳动物,包括商业相关的哺乳动物,例如狗、牛、猪、马、绵羊、猫、小鼠和/或大鼠;和/或鸟类,包括商业相关鸟类,例如家禽、鸡、鸭、鹅和/或火鸡。作为非限制性实例,本公开的组合物可以施用给狗以治疗ARVC。
本文提供了融合多肽及其药物组合物,其可以与一种或多种药学上可接受的赋形剂组合使用。
在一些实施方案中,药学上可接受的赋形剂包括但不限于任何和所有溶剂、分散介质、稀释剂或其它液体媒介物、分散或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂、调味剂、稳定剂、抗氧化剂、渗透摩尔量(osmolality)调节剂、pH调节剂等,只要适合于所需的特定剂型。用于配制药物组合物的各种赋形剂和用于制备组合物的技术是本领域已知的(参见Remington:The Science and Practice ofPharmacy,21"Edition,A.R.Gennaro(Lippincott,Williams&Wilkins,Baltimore,Md.,2006,通过引用全部并入本文)。常规赋形剂介质的使用可以包括在本公开的范围内,除非任何常规赋形剂介质与物质或其衍生物不相容,例如通过产生任何不希望的生物效应或以有害方式与药物组合物的任何其它组分相互作用,其使用被认为在本公开的范围内。
在一些实施方案中,药学上可接受的赋形剂可以是至少95%、至少96%、至少97%、至少98%、至少99%或100%纯的。在一些实施方案中,赋形剂被批准用于人类和兽医用途。在一些实施方案中,赋形剂可以被美国食品和药品管理局批准。在一些实施方案中,赋形剂可以是药物级的。在一些实施方案中,赋形剂可满足美国药典(USP)、欧洲药典(EP)、英国药典和/或国际药典的标准。
用于制备药物组合物的药学上可接受的赋形剂包括但不限于惰性稀释剂、分散剂和/或成粒剂、表面活性剂和/或乳化剂、崩解剂、粘合剂、防腐剂、缓冲剂、润滑剂和/或油。这些赋形剂可任选地包括在药物组合物中。所述组合物还可包括赋形剂如可可脂和栓剂蜡、着色剂、包衣剂、甜味剂、调味剂和/或芳香剂。
示例性稀释剂包括但不限于碳酸钙、碳酸钠、磷酸钙、磷酸二钙、硫酸钙、磷酸氢钙、磷酸钠乳糖、蔗糖、纤维素、微晶纤维素、高岭土、甘露醇、山梨醇、肌醇、氯化钠、干淀粉、玉米淀粉、糖粉等和/或其组合。
示例性的成粒剂和/或分散剂包括但不限于马铃薯淀粉、玉米淀粉、木薯淀粉、淀粉乙醇酸钠、粘土、藻酸、瓜尔胶、柑橘浆(citrus pulp)、琼脂、膨润土、纤维素和木材产物、天然海绵、阳离子交换树脂、碳酸钙、硅酸盐、碳酸钠、交联聚乙烯吡咯烷酮(交聚维酮)、羧甲基淀粉钠(淀粉乙醇酸钠)、羧甲基纤维素、交联羧甲基纤维素钠(交联羧甲基纤维素(croscarmellose))、甲基纤维素、预胶化淀粉(淀粉1500)、微晶淀粉、水不溶性淀粉、羧甲基纤维素钙、硅酸镁铝十二烷基硫酸钠、季铵化合物等,和/或其组合。
示例性的表面活性剂和/或乳化剂包括但不限于天然乳化剂(例如阿拉伯胶、琼脂、藻酸、藻酸钠、黄蓍胶、chon-drux、胆固醇、黄原胶、果胶、明胶、蛋黄、酪蛋白、羊毛脂、胆固醇、蜡和卵磷脂),胶体粘土(例如膨润土(硅酸铝)和(硅酸镁铝),长链氨基酸衍生物,高分子量醇(例如硬脂醇、鲸蜡醇、油醇、甘油三乙酸酯单硬脂酸酯(triacetinmonostearate)、乙二醇二硬脂酸酯、甘油单硬脂酸酯和丙二醇单硬脂酸酯、聚乙烯醇),卡波姆(例如羧基聚亚甲基、聚丙烯酸、丙烯酸聚合物和羧基乙烯基聚合物),角叉菜胶(carrageenan),纤维素衍生物(例如羧甲基纤维素钠、粉状纤维素、羟甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素),脱水山梨醇脂肪酸酯(例如聚氧乙烯脱水山梨醇单月桂酸酯(/>20)、聚氧乙烯脱水山梨醇(/>60)、聚氧乙烯脱水山梨醇单油酸酯(/>80)、脱水山梨醇单棕榈酸酯(/>40)、脱水山梨醇单硬脂酸酯(60)、脱水山梨醇三硬脂酸酯(/>65)、甘油单油酸酯、脱水山梨醇单油酸酯(80)、聚氧乙烯酯(例如聚氧乙烯单硬脂酸酯(/>45)、聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、聚氧亚甲基硬脂酸酯和/>)、蔗糖脂肪酸酯、聚乙二醇脂肪酸酯(例如/>)、聚氧乙烯醚(例如聚氧乙烯月桂基醚(/>30)、聚(乙烯基吡咯烷酮)、二甘醇单月桂酸酯、三乙醇胺油酸酯、油酸钠、油酸钾、油酸乙酯、油酸、月桂酸乙酯、月桂基硫酸钠、/>F 68、/>188、西曲溴铵、西吡氯铵、苯扎氯铵、多库酯钠(docusate sodium)等和/或其组合。
示例性的粘合剂包括但不限于淀粉(例如玉米淀粉和淀粉糊);明胶;糖(例如蔗糖、葡萄糖、右旋糖、糊精、糖蜜、乳糖、乳糖醇、甘露醇);氨基酸(例如,甘氨酸);天然和合成树胶(例如阿拉伯胶、海藻酸钠、爱尔兰藓提取物、潘瓦尔胶(panwar gum)、盖提胶(ghattigum)、苎麻胶(mucilage of isapol husks)、羧甲基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、微晶纤维素、醋酸纤维素、聚(乙烯基吡咯烷酮)、硅酸镁铝和落叶松阿拉伯半乳聚糖(larch arabogalactan));藻酸盐;聚环氧乙烷;聚乙二醇;无机钙盐;硅酸;聚甲基丙烯酸酯;蜡;水;醇;等等;以及它们的组合。
示例性防腐剂可以包括但不限于抗氧化剂、螯合剂、抗微生物防腐剂、抗真菌防腐剂、醇防腐剂、酸性防腐剂和/或其他防腐剂。氧化是mRNA的潜在降解途径,尤其是对于液体mRNA制剂。为了防止氧化,可以将抗氧化剂添加到制剂中。示例性的抗氧化剂包括但不限于α生育酚、抗坏血酸、抗坏血酸棕榈酸酯(acorbyl palmitate)、苯甲醇、丁基化羟基茴香醚、EDTA、间-甲酚、甲硫氨酸、丁基化羟基甲苯、一硫代甘油、焦亚硫酸钾、丙酸、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代甘油和/或亚硫酸钠。示例性螯合剂包括乙二胺四乙酸(EDTA)、柠檬酸一水合物、依地酸二钠、依地酸二钾、依地酸(edetic acid)、富马酸、苹果酸、磷酸、依地酸钠、酒石酸和/或依地酸三钠。示例性的抗微生物防腐剂包括但不限于苯扎氯铵、苄索氯铵、苄醇、溴硝丙二醇、溴棕三甲铵、西吡氯铵、氯己定、氯丁醇、氯甲酚、氯二甲苯酚、甲酚、乙醇、甘油、海克替啶(hexetidine)、咪脲、苯酚、苯氧基乙醇、苯乙醇、硝酸苯汞、丙二醇和/或硫柳汞。示例性抗真菌防腐剂包括但不限于对羟基苯甲酸丁酯、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、苯甲酸、羟基苯甲酸、苯甲酸钾、山梨酸钾、苯甲酸钠、丙酸钠和/或山梨酸。示例性的醇防腐剂包括但不限于乙醇、聚乙二醇、苯酚、酚类化合物、双酚、氯丁醇、羟基苯甲酸酯和/或苯乙醇。示例性的酸性防腐剂包括但不限于维生素A、维生素C、维生素E、β-胡萝卜素、柠檬酸、乙酸、脱氢乙酸、抗坏血酸、山梨酸和/或植酸。其它防腐剂包括但不限于生育酚、生育酚乙酸酯、乙肟甲磺酸酯、西曲溴胺、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、乙二胺、月桂基硫酸钠(SLS)、月桂基醚硫酸钠(SLES)、亚硫酸氢钠、偏亚硫酸氢钠、亚硫酸钾、偏亚硫酸氢钾、GLYDANT 对羟基苯甲酸甲酯、/>115、/>NEOLONETM、KATHONTM和/或/>/>
在一些实施方案中,药物溶液的pH保持在pH 5和pH 8之间,以改善稳定性。控制pH的示例性缓冲液可包括但不限于磷酸钠、柠檬酸钠、琥珀酸钠、组氨酸(或组氨酸-HCl)、碳酸钠和/或苹果酸钠。在另一个实施方案中,上面列出的示例性缓冲剂可与另外的单价抗衡离子(包括但不限于钾)一起使用。二价阳离子也可用作缓冲抗衡离子;然而,由于复合物形成和/或mRNA降解,这些不是优选的。
示例性缓冲剂还可包括但不限于柠檬酸盐缓冲溶液、乙酸盐缓冲溶液、磷酸盐缓冲溶液、氯化铵、碳酸钙、氯化钙、柠檬酸钙、葡乳醛酸钙、葡庚糖酸钙、葡萄糖酸钙、D-葡萄糖酸、甘油磷酸钙、乳酸钙、丙酸、乙酰丙酸钙、戊酸、磷酸氢钙、磷酸、三代磷酸钙、氢氧化磷酸钙、乙酸钾、氯化钾、葡萄糖酸钾、钾混合物、磷酸氢二钾、磷酸二氢钾、磷酸钾混合物、乙酸钠、碳酸氢钠、氯化钠、柠檬酸钠、乳酸钠、磷酸氢二钠、磷酸二氢钠、磷酸钠混合物、氨基丁三醇(tromelhamine)、氢氧化镁、氢氧化铝、海藻酸、无热原水、等渗盐水、林格氏溶液、乙醇等和/或其组合。
示例性润滑剂包括但不限于硬脂酸镁、硬脂酸钙、硬脂酸、二氧化硅、滑石、麦芽、山嵛酸甘油酯、氢化植物油、聚乙二醇、苯甲酸钠、乙酸钠、氯化钠、亮氨酸、月桂基硫酸镁、月桂基硫酸钠等,及其组合。
示例性油包括但不限于扁桃仁(almond)、杏仁(apricot kernel)、鳄梨、巴巴苏、佛手柑、黑加仑籽、琉璃苣、杜松子(cade)、甘菊、油菜(canola)、香菜、巴西棕榈(carnauba)、蓖麻、肉桂、可可油、椰子、鳕鱼肝、咖啡、玉米、棉籽、鸸鹋(emu)、桉树、月见草、鱼、亚麻子、香叶醇、葫芦、葡萄籽、榛子、海索草(hyssop)、肉豆蔻酸异丙酯、霍霍巴、库奎果(kukui nut)、杂熏衣草(lavandin)、薰衣草、柠檬、山苍子、澳洲坚果、锦葵、芒果籽、白芒花籽(meadowfoam seed)、貂(mink)、肉豆蔻、橄榄、橙(orange)、橙连鳍鲑(orange roughy)、棕榈、棕榈仁、桃仁、花生、罂粟籽、南瓜籽、油菜籽、米糠、迷迭香、红花、檀香、sasquana、savoury、沙棘、芝麻、乳木果油、硅酮、大豆、向日葵、茶树、蓟、lsubaki、松草(vetiver)、胡桃和小麦胚芽油。示例性油包括但不限于硬脂酸丁酯、辛酸甘油三酯、癸酸甘油三酯、环甲基硅酮、癸二酸二乙酯、二甲基硅油360、肉豆蔻酸异丙酯、矿物油、辛基十二烷醇、油醇、硅油和/或它们的组合。
赋形剂如可可脂和栓剂蜡、着色剂、包衣剂、甜味剂、调味剂和/或芳香剂可以根据配制者的判断存在于组合物中。
示例性的添加剂包括生理上生物相容的缓冲剂(例如,三甲胺盐酸盐),添加螯合剂(例如,DTPA或DTPA-双酰胺)或钙螯合物复合物(例如,DTPA钙、CaNaDTPA-双酰胺),或任选地,添加钙或钠盐(例如,氯化钙、抗坏血酸钙、葡萄糖酸钙或乳酸钙)。此外,可以使用抗氧化剂和悬浮剂。
在一些实施方案中,本公开的组合物可以通过产生治疗有效结果的任何途径施用。这些包括但不限于经肠(进入肠)、经胃肠道、经硬膜(进入硬膜质)、经口(通过口)、透皮、硬膜外、脑内(进入大脑)、脑室内(进入脑室)、表皮上(施用于皮肤)、皮内(进入皮肤本身)、皮下(皮肤下)、经鼻施用(通过鼻)、静脉内(进入静脉)、静脉内推注(bolus)、静脉内滴注、动脉内(进入动脉)、肌内(进入肌肉)、心内(进入心脏)、骨内输注(进入骨髓)、鞘内(进入椎管)、腹膜内(输注或注射至腹膜内)、膀胱内输注、玻璃体内(通过眼睛)、阴茎海绵体内(intracavernous)注射(进入病理腔)、腔内(进入阴茎基部)、阴道内施用、子宫内、羊膜外施用、透皮(扩散通过完整皮肤以全身分布)、经黏膜(通过黏膜扩散)、经阴道、喷入(鼻吸)、舌下、唇下、灌肠、滴眼液(在结膜上)、滴耳液、经耳壳(在耳朵中或通过耳朵)、经颊(针对脸颊)、经结膜、经皮肤、经牙齿(至牙齿)、电渗透、子宫颈内、窦内(endosinusial)、气管内、体外、血液透析、浸润、经间质、腹腔内、羊膜内、关节内、胆内、支气管内、滑囊内、软骨内(在软骨内)、尾部内(脊髓尾内)、脑池内(在小脑延髓池内)、角膜内(在角膜内)、牙膜内、冠状动脉内(在冠状动脉内)、海绵体内(在阴茎海绵体的可扩张空间内)、椎间盘内(在椎间盘内)、导管内(在腺体导管内)、十二指肠内(在十二指肠内)、硬膜内(在硬膜内或硬膜下方)、表皮内(至表皮)、食道内(至食道)、胃内(在胃内)、牙龈内(在牙龈内)、回肠内(在小肠远端部分内)、病灶内(在局部病灶内或直接引入局部病灶)、血管腔内(在管腔内)、淋巴内(在淋巴内)、髓内(在骨髓腔内)、脑膜内(在脑膜内)、眼内(在眼内)、卵巢内(在卵巢内)、心包内(在心包膜内)、胸膜内(在胸膜内)、前列腺内(在前列腺内)、肺内(在肺或其支气管内)、窦内(在鼻或眶周窦内)、脊柱内(在脊柱内)、滑膜内(在关节滑膜腔内)、腱内(在肌腱内)、睾丸内(在睾丸内)、鞘内(在脑脊髓轴线任何水平的脑脊液内)、胸腔内(在胸腔内)、管内(在器官的管内)、肿瘤内(在肿瘤内)、鼓室内(在中耳内)、血管内(在一个或多个血管内)、心室内(在心室内)、离子电渗(通过电流的手段,其中可溶性盐离子迁移到身体组织中)、冲洗(浸泡或冲刷开放性伤口或体腔)、喉部(直接在喉部)、鼻饲(通过鼻子并进入胃部)、封闭性敷料技术、经眼(至外眼)、经口咽(直接进入口腔和咽部)、肠胃外、皮周、关节周、硬膜周、神经周、牙周、经直肠、经呼吸道(在呼吸道内通过口腔或鼻腔吸入以局部或全身作用)、眼球后(脑桥后面或眼球后面)、心肌内(进入心肌)、软组织、蜘蛛膜下、结膜下、黏膜下、经胎盘(穿过或透过胎盘)、经气管(穿过气管壁)、经鼓膜(穿过或透过鼓室)、经输尿管(至输尿管)、经尿道(至尿道)、经阴道、尾椎神经阻断(caudal block)、诊断性、神经阻滞、胆灌注、心脏灌注、光分离置换术或脊柱。在具体的实施方案中,组合物可以以允许它们穿过血脑屏障、血管屏障或其他上皮屏障的方式施用。
治疗有效剂量将由本领域技术人员容易地确定,并且将取决于疾病的严重程度和进程、患者的健康和对治疗的反应、以及治疗医师的判断。
IV.使用方法
本文提供了使用本公开DSG2融合多肽组合物的方法。在一些实施方案中,本公开的DSG2融合多肽可用于治疗受试者中本文所述的一种或多种疾病或病症。此类方法可包括使受试者与DSG2融合多肽接触。在一些实施方案中,与受试者接触可包括向受试者施用DSG2融合多肽。在一些实施方案中,与受试者接触可包括用本公开的DSG2融合多肽治疗受试者。在一个实施方案中,本公开的组合物可用于治疗与DSG2自身抗体相关的疾病。在一个实施方案中,本公开的组合物减轻与DSG2抗体相关的心脏毒性。
在一些实施方案中,可以用本文所述的DSG2融合多肽治疗与心肌炎症相关的任何治疗性疾病。此类适应症的非限制性实例包括致心律失常性右心室心肌病(ARVC)、结节病、扩张性心肌病、感染后心肌病、心脏功能受损、射血分数降低、心力衰竭、心律失常和心肌炎。
疾病治疗或改善的功效可以例如通过测量疾病进展、疾病缓解、症状严重程度、疼痛减轻、生活质量、维持治疗效果所需的药物剂量、疾病标志物的水平或适合于所治疗的或所靶向预防的给定疾病的任何其它可测量参数来评估。通过测量这些参数中的任一项或这些参数的任意组合来监测治疗或预防的功效,这完全在本领域技术人员的能力范围内。与融合多肽或其药物组合物的施用相关,“有效对抗”疾病或病症表明以临床上适当的方式施用导致对至少一部分患者的有益效果,例如症状的改善、治愈、疾病负荷的降低、寿命的延长、生活质量的改善、输血需求的减少或其他通常被熟悉治疗特定类型的疾病或病症的医师认为是积极的效果。
当疾病状态的一个或多个参数有显著改善,通常是统计学上的显著改善时,或者当所预期的恶化或症状发展没有发生时,治疗或预防效果是明显的。例如,疾病的可测量参数有至少10%的有利变化,优选至少20%、30%、40%、50%或更多,可以表明是有效的治疗。给定化合物或组合物的功效也可使用本领域已知的给定疾病的实验动物模型来判断。当使用实验动物模型时,当观察到标志物或症状有统计学上的显著调节时,即证明了治疗的功效。
COVID-19
可施用本文所述的DSG2融合多肽或含有该融合多肽的组合物,以治疗COVID-19或COVID-19的长期效应。
在一些实施方案中,本公开的组合物可用于治疗COVID-19和/或感染SARS-CoV-2的个体。被感染的人可以是有症状的(symptomatic)、症状前的(pre-symptomatic)和无症状的(asymptomatic)。根据世界卫生组织(WHO),COVID-19传播可以发生自有症状、症状前和无症状的感染SARS-CoV-2的人。有症状的传播可以指在人经历症状之前发生的传播。症状前传播可以指在COVID-19症状发作之前发生的传播。
COVID-19可能与一种或多种症状有关,例如但不限于发热或寒战、咳嗽、呼吸短促或呼吸困难、疲劳、肌肉或身体疼痛、头痛、新的味觉或嗅觉丧失、咽喉痛、充血或流鼻涕、恶心或呕吐、腹泻、呼吸费力(trouble breathing)、持续性胸痛或胸压。
DSG2融合多肽可用于治疗COVID-19疾病的一个或多个阶段。通常,感染SARS-CoV-2的成人可以被分组为以下疾病严重程度类别。然而,每个类别的标准可能在临床指南和临床试验中重叠或不同,并且患者的临床状态可能随时间而改变(COVID-19TreatmentGuidelines Panel.Coronavirus Disease 2019(COVID-19)TreatmentGuidelines.National Institutes of Health,可获自www.covid19treatmentguidelines.nih.gov/,2020年11月12日起可访问)。在一些实施方案中,本公开的组合物可用于治疗无症状或症状前的感染,其可包括使用病毒学检测(即核酸扩增检测或抗原检测)检测SARS-CoV-2阳性但没有与COVID-19一致的症状的个体。在一些实施方案中,本公开的组合物可用于治疗轻度疾病,其包括具有COVID-19的任何的各种体征和症状(例如,发热、咳嗽、喉咙痛、不适、头痛、肌肉疼痛、恶心、呕吐、腹泻、味觉和嗅觉丧失)但没有呼吸短促、呼吸困难或胸部成像异常的个体。在一些实施方案中,本公开的组合物可用于治疗中度疾病,其可包括在临床评估或成像期间显示下呼吸道疾病证据的个体和在海平面室内空气中具有≥94%的氧饱和度(SpO2)的个体。在一些实施方案中,本公开的组合物可用于治疗严重疾病,其包括在海平面室内空气中SpO2<94%、动脉氧分压与吸入氧气分数的比率(PaO2/FiO2)<300mmHg、呼吸频率>30次呼吸/分钟或肺浸润>50%的个体。在一些实施方案中,本公开的组合物可以用于治疗危重疾病,其包括具有呼吸衰竭、肺炎、急性呼吸窘迫综合征(ARDS)、败血症、败血性休克、多器官功能障碍和/或多器官衰竭(包括急性肾损伤和心脏损伤)的个体。
本文还提供了预防与COVID-19相关的一种或多种病症的方法。在一个实施方案中,本公开的组合物可以在症状发作之前但在暴露于病毒之后提供给受试者,因为在暴露于病毒和症状发作之间存在潜伏期(incubation period)。新型冠状病毒SARS-CoV-2的潜伏期通常在2到14天之间,平均为五天(Lombardi等,J.Hosp.Infect.2020doi:10.1016/j.jhin.2020.03.003,其内容通过引用整体并入本文)。
本发明的组合物还可与一种或多种推荐用于治疗COVID-19的治疗剂组合施用。在一些实施方案中,本文所述的DSG2融合多肽可与一种或多种治疗剂组合使用,所述治疗剂例如但不限于瑞德西韦、氯喹、羟氯喹、髓袢利尿剂(loop diuretics)、阿奇霉素、洛匹那韦、利托那韦、伊维菌素(ivermectin)、白介素抑制剂、干扰素、激酶抑制剂、糖皮质类固醇和/或SARS CoV-2单克隆抗体(例如,巴马尼维单抗(Bamlanivimab)、卡西维单抗(Casirivimab)、利维单抗(Imdevimab))。
COVID-19后综合征
在一些实施方案中,本公开的组合物可用于治疗COVID-19后综合征。已经有越来越多的患者报告,这些患者在从急性COVID-19恢复后经历持续的症状(在本文中称为“COVID-19后综合征”),并且患有这些症状的个体通常称为“长期搬运工(long hauler)”。在一些实施方案中,如果患者在SARS CoV-2感染后遭受长达一个月、长达两个月、长达三个月、长达四个月、长达五个月、长达六个月、长达七个月、长达八个月、长达九个月、长达十个月、长达十一个月、长达一年或更久的一种或多种症状,则可以认为他们患有COVID-19后综合征。在一些实施方案中,受试者在SARS CoV-2感染后可能没有症状。在一些实施方案中,受试者可能没有已知的COVID-19或SARS CoV2感染,但可具有血清抗DSG2抗体。
本公开的组合物可用于治疗与COVID-19后综合征的心血管系统(即,COVID-19后心脏综合征)相关的一种或多种症状。一项包括最近从COVID-19恢复的100名患者的研究中,心脏磁共振成像显示78名患者(78%)具有心脏受累,60名患者(60%)有进行性心肌炎症,这与预先存在的病况、急性疾病的严重程度和总进程以及距最初诊断的时间无关(Puntmann等JAMA Cardiol.2020;5(11):1265-1273)。在一项较小的研究中,15%的运动员具有在从急性COVID-19恢复后患有心肌炎的证据。在一个实施方案中,DSG2融合多肽可用于治疗患有COVID-19后综合征的受试者中的心肌炎。
在一些实施方案中,本文所述的组合物可用于治疗与任何心脏适应症无关的COVID-19后综合征。
在一些实施方案中,本公开的组合物可用于治疗在初始诊断COVID-19后显示COVID-19症状长达数周、数月和/或数年的受试者。在一些实施方案中,在初始诊断COVID-19后,COVID-19后综合征患者可表现症状长达1周、2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、12个月、1年、2年、3年、4年、5年或更长时间,或在1周、2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、12个月、1年、2年、3年、4年、5年或更长时间之后表现症状。可以使用本领域已知的方法(例如,逆转录聚合酶链反应和/或抗体测试)来建立COVID-19的诊断。在一些实施方案中,患有COVID-19后综合征的受试者可以用本公开的组合物治疗长达1周、长达1个月和/或长达一年。
在一些实施方案中,本公开的组合物可用于治疗患有或发展为心脏功能受损、最显著的是射血分数降低、具有或不具有明显的心力衰竭症状的COVID-19患者。在一些实施方案中,本公开的组合物可以用于治疗心律失常。
本公开的组合物可改善一种或多种与COVID-19后综合征有关的症状。在一些实施方案中,COVID-19后综合征的症状可以与急性COVID-19相同。在一些方面,与COVID-19后综合征相关的症状可以是呼吸短促、疲劳、水肿、端坐呼吸、活动限制、认知能力受损、心悸、眩晕、晕厥、头晕、心力衰竭和/或心律失常。
在一些实施方案中,本公开的组合物可用于治疗COV1D-19后综合征,其症状与重症监护后综合征(post-intensive care syndrome)重叠,后者也在没有COV1D-19的患者中描述。
在一些实施方案中,本公开的组合物可用于治疗患有COVID-19后综合征的受试者,所述受试者可能具有一种或多种与心血管系统(例如,心肌炎症)、呼吸系统(肺功能异常)、肾系统(急性肾损伤)、皮肤(皮疹、脱发)、神经并发症(气味和味道问题、睡眠问题、注意力困难、记忆问题)和/或精神病问题(抑郁、焦虑、情绪变化)相关的长期并发症。
在一些实施方案中,本公开的组合物可用于治疗COVID-19后综合征的受试者,所述受试者可能具有一种、两种或更多种相关的共病。共病的非限制性实例包括但不限于高血压、甲状腺疾病、免疫病症、COPD(慢性阻塞性肺病)、高血压、肥胖症、心理健康状况和糖尿病。
与COVID-19相关的自身免疫
从发病机理的观点来看,病毒感染如COVID-19通常引发对病毒清除至关重要的强烈的免疫应答,以及涉及先天性和适应性免疫臂的级联事件。COVID-19感染也引起直接和间接的心肌损伤,使得心脏蛋白暴露于激活的免疫系统。在患有COVID-19病症的患者中也观察到了免疫学改变。这些改变的范围从适应不良的免疫应答和异常的细胞因子/趋化因子产生,到T细胞的超活化和活化的单核细胞、巨噬细胞和嗜中性粒细胞的数量增加。
已在COVID-19患者中检测到已知在许多自身免疫疾病中出现的自身抗体。因为COVID-19感染可以破坏免疫耐受性并触发自身免疫应答,所以它也有可能诱导临床自身免疫。在患有COVID-19的患者中检测到的自身抗体包括抗核抗体(ANA)、抗磷脂(APL)、狼疮抗凝剂、冷凝集素、抗Ro/综合征A(SSA)抗体、抗Caspr2抗体、抗GD1b抗体、抗髓鞘少突胶质细胞糖蛋白(MOG)抗体和红细胞结合抗体(Liu,Y.,等Curr.Opin.Rheumatol.2021;33:155-162,其内容通过引用整体并入本文)。在一些实施方案中,本公开的组合物可用于阻断在COVID-19或SARS CoV2感染期间产生的自身抗体。
在一项研究中,装配了三种蛋白阵列来测定147名住院COVID-19患者血清中与结缔组织疾病相关的IgG自身抗体、抗细胞因子抗体和抗病毒抗体应答。在大约50%的患者中鉴定出自身抗体,但在小于15%的健康对照中鉴定出自身抗体。发现自身抗体主要靶向与罕见疾病如肌炎、系统性硬化症和重叠综合征相关的自身抗原。然而,靶向传统自身抗原或细胞因子的自身抗体的子组是在COVID-19感染后重新产生的(Chang,S.E.,等NatureCommunications 2021;12:5417,其内容通过引用整体并入本文)。在一些实施方案中,本公开的组合物可用于阻断在COVID-19感染后产生的自身抗体。
在重度和危重病例中,已经应用了靶向促炎细胞因子的免疫调节药物和生物制剂,以包含COVID-19中的稳健免疫应答。皮质类固醇、JAK抑制剂、IL-1阻断剂和IL-6受体拮抗剂已经用于治疗COVID-19患者。在一些实施方案中,本公开的组合物可与靶向促炎细胞因子的免疫调节药物和生物制剂组合使用。在一些实施方案中,本公开的组合物可以与皮质类固醇、JAK抑制剂、IL-1阻断剂和IL-6受体拮抗剂组合使用。
已有报道在ChAdOx1 nCov-19(AstraZeneca)疫苗接种和可能在Ad26.COV2.S(Johnson&Johnson)疫苗接种后发生血栓栓塞事件。尽管很少见,但观察到血栓形成发生在异常部位,例如脑静脉和内脏静脉。基于观察到血小板减少症和产生了针对血小板因子4-聚阴离子复合物的抗体,已经提出这是免疫介导的反应(Lee,C.C.E.,等Diseases 2021;9:47,其内容通过引用整体并入本文)。
在一项研究中,实施了一种称为快速细胞外抗原分析(REAP)的高通量自身抗体发现方法,以在194名感染COVID-19的个体的组(包括172名患有COVID-19的患者和22名患有轻度疾病或无症状感染的医护人员)中筛选抗2,770种细胞外和分泌蛋白(外蛋白质组(exoproteome)成员)的自身抗体。在筛选患者样品后,鉴定和验证跨广范围组织的许多蛋白质靶标以及免疫和生理功能。这些自身抗体具有强效的功能活性,可直接与COVID-19患者样品中的各种病毒学、免疫学和临床参数在体内相关。分析表明这些自身抗体中的一些可能在时间上早于感染,而其它的则在感染后诱导。此外,这些自身抗体的小鼠替代物导致在COVID-19感染的小鼠模型中疾病严重程度增加。这些结果提供了证据表明,自身抗体能够通过干扰对SARS-CoV2的免疫应答和组织稳态来改变COVID-19的进程(Wang,E.Y.,等Nature 2021;595:283,其内容通过引用整体并入本文)。在一些实施方案中,本公开的组合物可用于阻断在时间上早于COVID-19感染的自身抗体。在一些实施方案中,本公开的组合物可用于阻断可在COVID-19感染后被诱导的自身抗体。
心肌病
在一些实施方案中,本公开的组合物可用于治疗心肌病。心肌病是指心室肌肉壁结构和功能的进行性损伤。本公开的组合物可用于治疗一种或多种类型的心肌病,例如但不限于扩张性心肌病、肥厚型心肌病和/或限制型心肌病。在一个实施方案中,心肌病患者在其血清中可表现血清DSG2自身抗体。
在一个实施方案中,本公开的组合物可用于治疗致心律失常性右心室心肌病(ARVC)。致心律失常性右心室心肌病/发育异常(ARVC/ARVD)是与室性心律失常、心力衰竭和猝死相关的心肌疾病。ARVC是一种退行性心脏病,其特征在于进行性心室功能丧失和心律失常。除了心肌细胞桥粒的结构蛋白和信号传导蛋白的基因突变外,还已知患者免疫系统在ARVC疾病病理学中也起作用。DSG2蛋白中的突变与ARVC相关,在患有该疾病的患者中已经鉴定了靶向DSG2的自身抗体。大约50%的ARVC患者没有已知的桥粒突变;然而,这些患者表达DSG2抗体。在一些实施方案中,DSG2融合蛋白可用于治疗在DSG2蛋白中具有一个或多个突变的ARVC患者。在一些方面,DSG2融合蛋白可用于治疗在DSG2蛋白中没有已知突变的ARVC患者。在一些实施方案中,本公开的DSG2融合多肽可靶向与ARVC相关的DSG2自身抗体。
心肌病可与炎症相关,并且在本文中称为心肌炎。在一些实施方案中,心肌炎可由病毒、细菌、寄生虫和/或真菌引起。在一些实施方案中,本公开的组合物可用于治疗和/或预防与病毒相关的心肌炎。与心肌炎相关的病毒的非限制性实例包括,引起普通感冒的腺病毒,COVID-19;乙型肝炎和丙型肝炎;细小病毒,其引起轻度皮疹,通常在儿童中(第五种疾病);和/或单纯疱疹病毒、引起胃肠道感染的艾柯病毒、引起单核细胞增多症的爱泼斯坦-巴尔病毒、风疹、巨细胞病毒和HIV。
心血管并发症经常与COVID-19关联发生,甚至在感染后数月。这些心血管并发症包括心肌损伤和心肌炎、急性冠状动脉综合征、心力衰竭、心律失常和血栓栓塞事件。此外,在初始感染后数周至数月,在患者中已经观察到心脏症状、心悸、胸痛和呼吸困难。(Lee,C.C.E.,等Diseases 2021;9:47,其内容通过引用整体并入本文)。在一些实施方案中,本公开的组合物可用于治疗心血管并发症如心肌损伤和心肌炎、急性冠状动脉综合征、心力衰竭、心律失常和血栓栓塞事件。
在一些实施方案中,本公开的组合物可用于治疗和/或预防由细菌引起的心肌炎。与心肌炎相关的细菌的非限制性实例包括葡萄球菌、链球菌和/或疏螺旋体。在一些实施方案中,本公开的组合物可用于治疗和/或预防由寄生虫引起的心肌炎。与心肌炎相关的寄生虫的非限制性实例包括克氏锥虫(Trypanosoma cruzi)和弓形虫,包括通过昆虫传播并且可引起称为Chagas病的病症的一些寄生虫。在一些实施方案中,本公开的组合物可用于治疗和/或预防由真菌引起的心肌炎。与心肌炎相关的真菌的非限制性实例包括念珠菌属、曲霉属以及其他真菌,如组织胞浆菌。
V.定义
结构域(domain):如本文所用,当提及多肽时,术语“结构域”是指具有一个或多个可鉴定的结构或功能特征或特性(例如,结合能力、充当蛋白质-蛋白质相互作用的位点)的多肽的基序。
表达载体(expression vector):如本文所用,术语“表达载体”指含有编码能够被转录的基因产物的至少一部分的核酸序列的载体。表达载体可以含有多种控制序列,其指有效连接的编码序列在特定宿主生物中转录和可能的翻译所必需的核酸序列。除了管控转录和翻译的控制序列之外,载体和表达载体还可以含有发挥其它功能的核酸序列。该术语还包括重组质粒或病毒,其包含在体外或体内待被递送至宿主细胞中的多核苷酸。在一些实施方案中,宿主细胞是瞬时细胞系或稳定细胞系。在一些实施方案中,它选自CHO、HEK293和NSO。
特征(feature):“特征”当指多肽时,定义为分子的独特的基于氨基酸序列的组分。由本文所述多核苷酸编码的多肽的特征包括局部构象形状、折叠、环、半环、结构域、半结构域、位点、末端或其任何组合。
融合蛋白(fusion protein):如本文所用,术语“融合蛋白”或嵌合蛋白指包含两个或更多个氨基酸序列或其活性片段的蛋白质或多肽,所述两个或更多个氨基酸序列或其活性片段不天然存在于相同多肽中。在一些实施方案中,两个或更多个单独的多肽有效地共价连接,例如化学连接,或通过肽键融合在一起。重组融合多肽是通过重组DNA技术人工产生的。
半结构域(half-domain):如本文所用,当提及多肽时,术语“半结构域”是指具有其源自的结构域的至少一半氨基酸残基数目的经鉴定的结构域的一部分。应理解,结构域可不总是含有偶数的氨基酸残基。因此,在结构域含有或经鉴定包含奇数氨基酸的情况下,该奇数结构域的半结构域将包含结构域的整数部分或下一个整数部分(结构域的氨基酸数目/2+/-0.5个氨基酸)。例如,鉴定为7个氨基酸的结构域的结构域可以产生3个氨基酸或4个氨基酸的半结构域(7/2=3.5+/-0.5是3或4)。还应理解,亚结构域可在结构域或半结构域内鉴定,这些亚结构域具有的结构或功能特性小于在它们所源自的结构域或半结构域中鉴定的全部结构或功能特性。还应理解,包含本文任何结构域类型的氨基酸不需要沿多肽主链是连续的(即,不相邻的氨基酸可以在结构上折叠以产生结构域、半结构域或亚结构域)。
免疫应答(immune response):如本文所用,术语“免疫应答”是指与炎症、创伤、免疫病症或感染性或遗传性疾病相关的病症。这些病症的特征在于表达各种因子,例如细胞因子、趋化因子和其它信号转导分子,它们可影响细胞和全身防御系统。
接头(linker):如本文所用,“接头”是指其中共价键连接两个或更多个多肽的官能团(例如,化学物质或多肽)。如本文所用,“肽接头”是用于将两种蛋白质彼此结合的两个或更多个氨基酸。
调节(modulation):如本文所用,术语“调节”是本领域已知的,并且指反应的上调(即激活或刺激)、下调(即抑制或阻抑)或两者的组合或分开。
多核苷酸(polynucleotide):如本文所用,术语“多核苷酸”是指通过磷酸二酯键连接的核苷酸序列。多核苷酸在本文以从5'到3'方向的方向呈现。多核苷酸可以是脱氧核糖核酸(DNA)分子或核糖核酸(RNA)分子。当多核苷酸是DNA分子时,该分子可以是基因或cDNA分子。核苷酸碱基在本文中由单字母代码表示:腺嘌呤(A)、鸟嘌呤(G)、胸腺嘧啶(T)、胞嘧啶(C)、肌苷(I)和尿嘧啶(U)。多核苷酸可以使用本领域技术人员熟知的标准技术制备。
多肽(polypeptide):在一些实施方案中,本公开的组合物是多肽或蛋白质或其变体。根据本公开,任何基于氨基酸的分子(天然或非天然)都可以被称为“多肽”,并且该术语涵盖“肽”、“肽模拟物”和“蛋白质”。“如本文所用,“多肽”是指最通常通过肽键连接在一起的氨基酸残基(天然或非天然)的聚合物。如本文所用,该术语是指任何大小、结构或功能的蛋白质、多肽和肽。“肽模拟物”或“多肽模拟物”是其中分子含有天然多肽(即,仅由20个蛋白源性氨基酸组成的多肽)中不存在的结构元件的多肽。在一些实施方案中,肽模拟物能够重演或模拟天然肽的生物学作用。
多肽变体(polypeptide variant):术语“多肽变体”是指其氨基酸序列与天然或参考序列不同的分子。与天然或参考序列相比,氨基酸序列变体可在氨基酸序列内的某些位置处具有取代、缺失和/或插入。通常,变体将与天然或参考序列具有至少约50%的同一性(同源性),优选地,它们将与天然或参考序列具有至少约80%,更优选地至少约90%的同一性(同源性)。
重组(recombinant):如本文所用,术语“重组”是指与通常在自然界中发现的遗传实体不同的遗传实体。当应用于多核苷酸或基因时,这意味着多核苷酸是克隆、限制和/或连接步骤以及导致产生不同于自然界中发现的多核苷酸的构建体的其它步骤的各种组合的产物。
样品(sample):如本文所用,术语“样品”是指取自某来源和/或用于分析或处理而提供的等分试样或部分。在一些实施方案中,样品来自生物来源,例如组织、细胞或组成部分(例如体液,包括但不限于血液、粘液、淋巴液、滑液、脑脊液、唾液、羊水、羊膜血、尿液、阴道液和精液)。在一些实施方案中,样品可以是或包括从完整生物体或其组织、细胞或组成部分的子集或其级分或部分(包括但不限于例如血浆,血清,脊髓液,淋巴液,皮肤、呼吸道、肠道和泌尿生殖道的外部切片(external section),泪液,唾液,乳汁,血细胞,肿瘤或器官)制备的匀浆、裂解物或提取物。在一些实施方案中,样品是或包括培养基,例如营养肉汤或凝胶,其可以含有细胞组分,例如蛋白质。在一些实施方案中,“初级(primary)”样品是来源的等分试样。在一些实施方案中,使初级样品经历一个或多个处理(例如,分离、纯化等)步骤以制备用于分析或其他用途的样品。
基本上(substantially):如本文所用,术语“基本上”是指表现出所关注的特性或性质的全部或接近全部程度或度的定性条件。生物领域的普通技术人员将理解,生物和化学现象极少(如果有的话)达到完全和/或进行到完全或达到或避免绝对结果。因此,术语“基本上”在本文中用于体现许多生物和化学现象中固有的潜在的完全性缺乏。
末端(terminus):如本文所用,术语“末端”在指多肽时是指肽或多肽的端点。这种末端不仅限于肽或多肽的第一或最后位点,而且可以包括在末端区的额外氨基酸。本文所述的基于多肽的分子的特征可在于具有N-末端(以具有游离氨基(NH2)的氨基酸为终止)和C-末端(以具有游离羧基(COOH)的氨基酸为终止)两者。在一些情况下,本文所述的蛋白质由通过二硫键或非共价力结合在一起的多个多肽链组成(多聚体、寡聚体)。这些种类的蛋白质将具有多个N-和C-末端。或者,多肽的末端可以被修饰,使得它们根据情况以非基于多肽的部分(例如有机缀合物)开始或结束。
治疗有效量(therapeutically effective amount):如本文所用,术语“治疗有效量”是指在向患有或易患有疾病、病症和/或病况的受试者施用时足够改善疾病、病症和/或病况的症状,诊断、预防疾病、病症和/或病况和/或延迟其发作的待递送的药剂的量。
治疗(treating):如本文所用,术语“治疗”是指针对特定疾病、病症和/或病况的一种或多种症状或特征实现部分或完全缓解、改进、改善、缓解、延迟其发作、抑制其进展、降低其严重程度和/或降低其发生率。为了降低与疾病、病症和/或病况相关的病理发展的风险,可以对不显示疾病、病症和/或病况的体征的受试者和/或仅显示疾病、病症和/或病况的早期体征的受试者施用治疗。
治疗(treatment):如本文所用,术语“治疗”等是指减轻或缓解病理过程。在本公开的上下文中,其涉及本文以下所述的任何其它病症,术语“治疗”等意指缓解或减轻与这种病症相关的至少一种症状,或减缓或逆转这种病症的进展或预期进展。
治疗剂量(treatment dose):如本文所用,“治疗剂量”是指在解决或减轻治疗性适应症的过程中施用的治疗剂的一个或多个剂量。可以调节治疗剂量以在体液或生物系统中维持所需的治疗剂浓度或活性水平。
VI.等同和范围
尽管在本公开中已经具体示出和描述了本公开的各种实施方式,但是本领域技术人员理解,可以进行形式和细节上的各种改变,而不脱离本文公开的和所附权利要求中阐述的实施方案的精神和范围。
本领域技术人员使用常规实验会认识到或能够确定本文所述的具体实施方案的许多等同方案。本公开的范围不旨在被限制于以上说明书,而是如所附权利要求中所阐述的。
在权利要求中,除非相反地指示或从上下文中明显可见,否则诸如“一”、“该”和“所述”的冠词可以表示一个或多于一个。如果一个、多于一个或所有的组成员存在于、用于给定的产品或方法中或以其它方式与给定的产品或方法相关,则认为满足在一个或多个组成员之间包括“或”的权利要求或描述,除非相反地指出或以其它方式从上下文显而易见。本公开包括其中组中的正好一个成员存在于、用于给定产品或方法中或以其它方式与给定产品或方法相关的实施方案。本公开包括其中多于一个或所有的组成员存在于、用于给定产品或方法中或以其他方式与给定产品或方法相关的实施方案。
还应注意,术语“包含”旨在是开放的,并且允许但不要求包括附加的元件或步骤。当术语“包含”在本文中使用时,术语“由……组成”和“或包括”因此也被涵盖和公开。
在给出范围的情况下,包括端点。此外,应理解,除非另外指明或从上下文和本领域普通技术人员的理解中显而易见,否则表示为范围的值可在本公开的不同实施方案中采用所述范围内的任何具体值或子范围,直至范围下限单位的十分之一,除非上下文另外清楚地指明。
此外,应当理解,落入现有技术范围内的本公开的任何特定实施方案可以明确地从权利要求中的任何一个或多个中排除。由于这些实施方案被认为是本领域普通技术人员已知的,因此即使在此没有明确地阐述排除,也可以将它们排除在外。出于任何原因,本文公开的组合物的任何具体实施方案可从任何一个或多个权利要求中排除,无论是否与现有技术的存在相关。
所有引用的来源,例如本文引用的参考文献、出版物、数据库、数据库条目和技术都通过引用并入本申请,即使在引用时没有明确陈述。在引用来源和本申请的陈述冲突的情况下,应以本申请中的陈述为准。
章节和表格标题不旨在是限制性的。
实施例
实施例1.DSG2融合多肽的合成方法
本文所述的DSG2融合多肽通过合成编码所需多肽的DNA的重组DNA技术产生。一旦合成或分离了所需多肽的编码序列,就将它们克隆到任何合适的载体中用于表达。
通过转化、转导和/或转染将表达载体插入合适的宿主细胞中。可优化DSG2融合多肽的序列以在宿主细胞中产生最大表达。宿主细胞是本领域已知用于表达重组蛋白的任何宿主细胞。许多哺乳动物细胞系都是本领域已知的,包括可从美国典型培养物保藏中心(ATCC)获得的永生化细胞系,例如但不限于中国仓鼠卵巢(CHO)细胞、HeLa细胞、HEK293、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人肝细胞癌细胞(例如Hep G2)、Madin-Darby牛肾(“MDBK”)细胞、源自癌细胞如肉瘤的NOS细胞以及其它细胞。细菌物种也可用作宿主细胞。非限制性实例包括大肠杆菌(Escherichia coli)、枯草芽孢杆菌(Bacillus subtilis)和链球菌(Streptococcus)。可用于本公开的酵母宿主细胞的非限制性实例尤其包括酿酒酵母(Saccharomyces cerevisiae)、白色念珠菌(Candida albicans)、麦芽假丝酵母(Candida maltosa)、多形汉逊酵母(Hansenula polymorpha)、脆壁克鲁维酵母(Kluyveromyces fragilis)、乳酸克鲁维酵母(Kluyveromyces lactis)、季也蒙毕赤酵母(Pichia guillerimondii)、巴斯德毕赤酵母(Pichia pastoris)、粟酒裂殖酵母(Schizosaccharomyces pombe)和解脂耶氏酵母(Yarrowia lipolytica)。
根据所选择的表达系统和宿主,通过在表达目的蛋白质的条件下培养表达载体的宿主细胞来产生本公开的融合多肽。然后从宿主细胞中分离蛋白质并纯化。
或者,本公开的融合多肽可通过本领域已知的常规技术合成,例如通过化学合成如固相肽合成。
实施例2.COVID-19后(post COVID-19)血清样品中的抗DSG2抗体
已经假设了包括COVID-19在内的病毒感染促成自身免疫应答,例如,通过将损伤细胞上先前隐藏的隐蔽表位暴露于激活的免疫系统(Ehrenfeld M,等,AutoimmunityReviews 2020;102597,其内容通过引用整体并入本文)。考虑到在COVID-19感染中观察到的心脏受累的高发病率,假设抗DSG2自身抗体可能作为结果而产生。
从一组COVID-19后感染患者中获得300个恢复期血清样品,所述患者来自2020年10月至2021年2月的东亚人群。研究人群的平均年龄为37岁(范围为21-65岁)。在COVID-19感染后6个月取154个样品,在COVID感染后9个月取146个样品。在6个月和9个月(症状状态未知)从同一患者获得17个样品。阴性对照组血清获自商业来源的自称健康的个体。阳性对照ARVC血清根据国际协调委员会(ICH)指南获得。抗药物抗体(ADA)形式测定用于检测抗DSG2抗体。如图1所示,在COVID-19后样品中的抗DSG2抗体的平均信号强度显著高于健康对照群体(在COVID-19后样品中为19±83.2,在健康对照群体中为2.1±6.8,p值<0.001)。值得注意的是,29.3%的COVID-19后感染样品显示高于对照群体的第90个百分位数的信号,8.7%具有的信号高于ARVC患者中发现的中值。在COVID-19感染后6-9个月获得的样品中存在抗DSG2抗体则表明,该抗体不是急性期反应物。结果也示于表4和表5中。
表4.抗DSG2抗体水平的分析
表5.抗DSG2抗体水平的分析
6个月和9个月样品之间的信号强度彼此没有显著差异(p=0.529)。在所有非同时期评估的6个月和9个月样品(N=300;图2A)以及在COVID-19感染后月份收集来分析的成对的6个月和9个月样品(N=17;图2B)中,也观察到这一点。
总之,恢复的COVID-19患者与健康对照群体相比表现出显著更高和持续的抗DSG2自身抗体水平,并且与诊断的ARVC组相当。值得注意的是,这些血清在急性COVID-19感染后获得,表明这些抗体可以长期持续。
序列表
<110> 阿瓦达治疗公司(ARVADA THERAPEUTICS, INC.)
<120> 用于治疗COVID-19的DSG2组合物和方法
<130> 2198.1001PCT
<140> PCT/US2021/XXXXXX
<141> 2021-12-15
<150> 63/274,715
<151> 2021-11-02
<150> 63/125,583
<151> 2020-12-15
<160> 16
<170> PatentIn version 3.5
<210> 1
<211> 1118
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Met Ala Arg Ser Pro Gly Arg Ala Tyr Ala Leu Leu Leu Leu Leu Ile
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Cys Phe Asn Val Gly Ser Gly Leu His Leu Gln Val Leu Ser Thr Arg
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Asn Glu Asn Lys Leu Leu Pro Lys His Pro His Leu Val Arg Gln Lys
35 40 45
Arg Ala Trp Ile Thr Ala Pro Val Ala Leu Arg Glu Gly Glu Asp Leu
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Ser Lys Lys Asn Pro Ile Ala Lys Ile His Ser Asp Leu Ala Glu Glu
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Arg Gly Leu Lys Ile Thr Tyr Lys Tyr Thr Gly Lys Gly Ile Thr Glu
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Pro Pro Phe Gly Ile Phe Val Phe Asn Lys Asp Thr Gly Glu Leu Asn
100 105 110
Val Thr Ser Ile Leu Asp Arg Glu Glu Thr Pro Phe Phe Leu Leu Thr
115 120 125
Gly Tyr Ala Leu Asp Ala Arg Gly Asn Asn Val Glu Lys Pro Leu Glu
130 135 140
Leu Arg Ile Lys Val Leu Asp Ile Asn Asp Asn Glu Pro Val Phe Thr
145 150 155 160
Gln Asp Val Phe Val Gly Ser Val Glu Glu Leu Ser Ala Ala His Thr
165 170 175
Leu Val Met Lys Ile Asn Ala Thr Asp Ala Asp Glu Pro Asn Thr Leu
180 185 190
Asn Ser Lys Ile Ser Tyr Arg Ile Val Ser Leu Glu Pro Ala Tyr Pro
195 200 205
Pro Val Phe Tyr Leu Asn Lys Asp Thr Gly Glu Ile Tyr Thr Thr Ser
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Val Thr Leu Asp Arg Glu Glu His Ser Ser Tyr Thr Leu Thr Val Glu
225 230 235 240
Ala Arg Asp Gly Asn Gly Glu Val Thr Asp Lys Pro Val Lys Gln Ala
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Gln Val Gln Ile Arg Ile Leu Asp Val Asn Asp Asn Ile Pro Val Val
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Glu Asn Lys Val Leu Glu Gly Met Val Glu Glu Asn Gln Val Asn Val
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Glu Val Thr Arg Ile Lys Val Phe Asp Ala Asp Glu Ile Gly Ser Asp
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Asn Trp Leu Ala Asn Phe Thr Phe Ala Ser Gly Asn Glu Gly Gly Tyr
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Phe His Ile Glu Thr Asp Ala Gln Thr Asn Glu Gly Ile Val Thr Leu
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Ile Lys Glu Val Asp Tyr Glu Glu Met Lys Asn Leu Asp Phe Ser Val
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Ile Val Ala Asn Lys Ala Ala Phe His Lys Ser Ile Arg Ser Lys Tyr
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Lys Pro Thr Pro Ile Pro Ile Lys Val Lys Val Lys Asn Val Lys Glu
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Gly Ile His Phe Lys Ser Ser Val Ile Ser Ile Tyr Val Ser Glu Ser
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Met Asp Arg Ser Ser Lys Gly Gln Ile Ile Gly Asn Phe Gln Ala Phe
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Asp Glu Asp Thr Gly Leu Pro Ala His Ala Arg Tyr Val Lys Leu Glu
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Asp Arg Asp Asn Trp Ile Ser Val Asp Ser Val Thr Ser Glu Ile Lys
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Leu Ala Lys Leu Pro Asp Phe Glu Ser Arg Tyr Val Gln Asn Gly Thr
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Tyr Thr Val Lys Ile Val Ala Ile Ser Glu Asp Tyr Pro Arg Lys Thr
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Ile Thr Gly Thr Val Leu Ile Asn Val Glu Asp Ile Asn Asp Asn Cys
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Pro Thr Leu Ile Glu Pro Val Gln Thr Ile Cys His Asp Ala Glu Tyr
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Val Asn Val Thr Ala Glu Asp Leu Asp Gly His Pro Asn Ser Gly Pro
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Phe Ser Phe Ser Val Ile Asp Lys Pro Pro Gly Met Ala Glu Lys Trp
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Lys Ile Ala Arg Gln Glu Ser Thr Ser Val Leu Leu Gln Gln Ser Glu
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Lys Lys Leu Gly Arg Ser Glu Ile Gln Phe Leu Ile Ser Asp Asn Gln
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Gly Phe Ser Cys Pro Glu Lys Gln Val Leu Thr Leu Thr Val Cys Glu
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Cys Leu His Gly Ser Gly Cys Arg Glu Ala Gln His Asp Ser Tyr Val
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Leu Leu Leu Val Pro Leu Leu Leu Leu Met Cys His Cys Gly Lys Gly
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Ala Lys Gly Phe Thr Pro Ile Pro Gly Thr Ile Glu Met Leu His Pro
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Trp Asn Asn Glu Gly Ala Pro Pro Glu Asp Lys Val Val Pro Ser Phe
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Gly Met Ala Lys Glu Ala Thr Met Lys Gly Ser Ser Ser Ala Ser Ile
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Val Lys Gly Gln His Glu Met Ser Glu Met Asp Gly Arg Trp Glu Glu
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His Arg Ser Leu Leu Ser Gly Arg Ala Thr Gln Phe Thr Gly Ala Thr
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Gly Ala Ile Met Thr Thr Glu Thr Thr Lys Thr Ala Arg Ala Thr Gly
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Ala Ser Arg Asp Met Ala Gly Ala Gln Ala Ala Ala Val Ala Leu Asn
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Glu Glu Phe Leu Arg Asn Tyr Phe Thr Asp Lys Ala Ala Ser Tyr Thr
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Glu Glu Asp Glu Asn His Thr Ala Lys Asp Cys Leu Leu Val Tyr Ser
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<210> 2
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<212> DNA
<213> 智人(Homo sapiens)
<400> 2
gaggagccga gtgcgcgctc ggggcaggcg gcggcgcgga gcggtgcggc ggcgggaggc 60
ggaggcgagg gtgcgatggc gcggagcccg ggacgcgcgt acgccctgct gcttctcctg 120
atctgcttta acgttggaag tggacttcac ttacaggtct taagcacaag aaatgaaaat 180
aagctgcttc ctaaacatcc tcatttagtg cggcaaaagc gcgcctggat caccgccccc 240
gtggctcttc gggagggaga ggatctgtcc aagaagaatc caattgccaa gatacattct 300
gatcttgcag aagaaagagg actcaaaatt acttacaaat acactggaaa agggattaca 360
gagccacctt ttggtatatt tgtctttaac aaagatactg gagaactgaa tgttaccagc 420
attcttgatc gagaagaaac accatttttt ctgctaacag gttacgcttt ggatgcaaga 480
ggaaacaatg tagagaaacc cttagagcta cgcattaagg ttcttgatat caatgacaac 540
gaaccagtgt tcacacagga tgtctttgtt gggtctgttg aagagttgag tgcagcacat 600
actcttgtga tgaaaatcaa tgcaacagat gcagatgagc ccaataccct gaattcgaaa 660
atttcctata gaatcgtatc tctggagcct gcttatcctc cagtgttcta cctaaataaa 720
gatacaggag agatttatac aaccagtgtt accttggaca gagaggaaca cagcagctac 780
actttgacag tagaagcaag agatggcaat ggagaagtta cagacaaacc tgtaaaacaa 840
gctcaagttc agattcgtat tttggatgtc aatgacaata tacctgtagt agaaaataaa 900
gtgcttgaag ggatggttga agaaaatcaa gtcaacgtag aagttacgcg cataaaagtg 960
ttcgatgcag atgaaatagg ttctgataat tggctggcaa attttacatt tgcatcagga 1020
aatgaaggag gttatttcca catagaaaca gatgctcaaa ctaacgaagg aattgtgacc 1080
cttattaagg aagtagatta tgaagaaatg aagaatcttg acttcagtgt tattgtcgct 1140
aataaagcag cttttcacaa gtcgattagg agtaaataca agcctacacc cattcccatc 1200
aaggtcaaag tgaaaaatgt gaaagaaggc attcatttta aaagcagcgt catctcaatt 1260
tatgttagcg agagcatgga tagatcaagc aaaggccaaa taattggaaa ttttcaagct 1320
tttgatgagg acactggact accagcccat gcaagatatg taaaattaga agatagagat 1380
aattggatct ctgtggattc tgtcacatct gaaattaaac ttgcaaaact tcctgatttt 1440
gaatctagat atgttcaaaa tggcacatac actgtaaaga ttgtggccat atcagaagat 1500
tatcctagaa aaaccatcac tggcacagtc cttatcaatg ttgaagacat caacgacaac 1560
tgtcccacac tgatagagcc tgtgcagaca atctgtcacg atgcagagta tgtgaatgtt 1620
actgcagagg acctggatgg acacccaaac agtggccctt tcagtttctc cgtcattgac 1680
aaaccacctg gcatggcaga aaaatggaaa atagcacgcc aagaaagtac cagtgtgctg 1740
ctgcaacaaa gtgagaaaaa gcttgggaga agtgaaattc agttcctgat ttcagacaat 1800
cagggtttta gttgtcctga aaagcaggtc cttacactca cagtttgtga gtgtctgcat 1860
ggcagcggct gcagggaagc acagcatgac tcctatgtgg gcctgggacc cgcagcaatt 1920
gcgctcatga ttttggcctt tctgctcctg ctattggtac cacttttact gctgatgtgc 1980
cattgcggaa agggcgccaa aggctttacc cccatacctg gcaccataga gatgctgcat 2040
ccttggaata atgaaggagc accacctgaa gacaaggtgg tgccatcatt tctgccagtg 2100
gatcaagggg gcagtctagt aggaagaaat ggagtaggag gtatggccaa ggaagccacg 2160
atgaaaggaa gtagctctgc ttccattgtc aaagggcaac atgagatgtc cgagatggat 2220
ggaaggtggg aagaacacag aagcctgctt tctggtagag ctacccagtt tacaggggcc 2280
acaggcgcta tcatgaccac tgaaaccacg aagaccgcaa gggccacagg ggcttccaga 2340
gacatggccg gagctcaggc agctgctgtt gcactgaacg aagaattctt aagaaattat 2400
ttcactgata aagcggcctc ttacactgag gaagatgaaa atcacacagc caaagattgc 2460
cttctggttt attctcagga agaaactgaa tcgctgaatg cttctattgg ttgttgcagt 2520
tttattgaag gagagctaga tgaccgcttc ttagatgatt tgggacttaa attcaagaca 2580
ctagctgaag tttgcctggg tcaaaaaata gatataaata aggaaattga gcagagacaa 2640
aaacctgcca cagaaacaag tatgaacaca gcttcacatt cactctgtga gcaaactatg 2700
gttaattcag agaataccta ctcctctggc agtagcttcc cagttccaaa atctttgcaa 2760
gaagccaatg cagagaaagt aactcaggaa atagtcactg aaagatctgt gtcttctagg 2820
caggcgcaaa aggtagctac acctcttcct gacccaatgg cttctagaaa tgtgatagca 2880
acagaaactt cctatgtcac agggtccact atgccaccaa ccactgtgat cctgggtcct 2940
agccagccac agagccttat tgtgacagag agggtgtatg ctccagcttc taccttggta 3000
gatcagcctt atgctaatga aggtacagtt gtggtcactg aaagagtaat acagcctcat 3060
gggggtggat cgaatcctct ggaaggcact cagcatcttc aagatgtacc ttacgtcatg 3120
gtgagggaaa gagagagctt ccttgccccc agctcaggtg tgcagcctac tctggccatg 3180
cctaatatag cagtaggaca gaatgtgaca gtgacagaaa gagttctagc acctgcttcc 3240
actctgcaat ccagttacca gattcccact gaaaattcta tgacggctag gaacaccacg 3300
gtgtctggag ctggagtccc tggccctctg ccagattttg gtttagagga atctggtcat 3360
tctaattcta ccataaccac atcttccacc agagttacca agcatagcac tgtacagcat 3420
tcttactcct aaacagcagt cagccacaaa ctgacccaga gtttaattag cagtgactaa 3480
tttcatgttt ccaatgtacc tgatttttca tgagccttac agacacacag agacacatac 3540
acattgatct taaaattttt ctcagtcact gatatgcaaa ggaccacact gtctctgctt 3600
ccaggagtat tttagaaatg ttccacaatt tactgaagac atagagatga tgctgctgct 3660
taggtgcctt ttagcaagct atgcaaacaa tcctgataaa acaagataca tagagagtca 3720
atctggcttc tgagaattta ccaagtgaac agagtaccta gttcatcagc cgtccagtaa 3780
agcaacccag gaaactgact gggtctcttt gcctaccgta ttaacattaa acattgatgt 3840
tctgtattct gtactttact gcacccagca gactttcaac aactcattga tccaaagata 3900
catgcacagt ctgagcacca gctatggtgc tcataacttc tttaagactt gaaccctttc 3960
aatctgtgtg attcattaaa ttggaccatt gatgataaga atacacattg tatgtttctg 4020
tgcacatgac agtgtgtgtg tgtgcacgta catactgtat agtcttaaaa atagcattat 4080
actggccagg ggtggtggct aacgcctgta atcccagcac tttgggaggc cgaggcgggt 4140
ggatcaactg tggtcaggag tttgagatca gccaggccaa cctggtgaaa ccccgtctct 4200
actaaaaata caaaaattag ctgggcgtga tggtgggcgc ctgtaatccc agctacttgg 4260
gaggctgagg caggagaatc acttgaaccc gggaggcgga ggttgcagtg agccgagatc 4320
gcaccattgc actccagtct gggcaacaga gtgagattcc gtctcaaaaa aaaaaagaaa 4380
aggaaaaaaa aatagcatta tacctcttcc ttgtctcaac cgccatgaaa attctgaaca 4440
ctccaaattc agttgaataa tccaaaacaa aatttataag tataaaataa ttttacttct 4500
tatagtaata gtatacttta aaaagcctca gggtatatta tcttctaaac agctacaatt 4560
cagtgcagct acattaacca actatgttct ctagttgaga acaactaggc ctatttcact 4620
gctgtgtagc ctcagtgcct aacatgggtg ccaaataaat attcgtagaa ttacactgaa 4680
ttgtaaaaac cattcgtttt tgtttacaat tgccaaaaat ctcaaaaggc cctgtattta 4740
tgtaattctt tgaaattatt attttatttt gatttctcag ttattgactg gctgggtgtg 4800
acttagtaca taagtactca atattataaa aacctcaaat aattgacttg attttacaca 4860
acatccttcc cttttctaca agttaatttt tttacaaatc atttgggtta tctcctaaat 4920
aggttatatt ttattgcttc tagaaacaat gtttcaaaat atatgtgcat tatcagtaat 4980
aatttgtata aatatttccc acaacaattt tcataatttt caaagactaa tttcttgact 5040
gaagatattt tgctagggaa gtgaaacttt aaaattttgt agattttaaa aaatattgtt 5100
gaatggtgtc atgcaaagga tttatatagt gtgctcccac taactgtaca gatcaggaca 5160
catattttta gacatctaag tctgtagctt aaatggaggt tactcttcca tcatctagaa 5220
ttgtttactt agtaattgtt gtttctttta ttattataga cttactatca gttttatttt 5280
gccaagtatg caacaggtat atcactagta tatgaaaatg taaatatcac ttgtgtactc 5340
aaacaaaagt tggtcttaag cttccacctt gagcagcctt ggaaacctaa cctgcctctt 5400
ttagcataat cacattttct aaatgatttt ctttgttcct gaaaaagtga tttgtattag 5460
ttttacattt gttttttgga agattatatt tgtatatgta tcatcataaa atatttaaat 5520
aaaaagtatc tttagagtga ccctttcccc atagattttt atttctctat tatattttac 5580
aaggaatata actcagtttg ttagggagag tgccttaaag gcaggtgttt cttggacttt 5640
gttatttaat tagatctgct tgcaataaaa aaagttgtcg gttatctaaa attcaaa 5697
<210> 3
<211> 560
<212> PRT
<213> 智人(Homo sapiens)
<400> 3
Ala Trp Ile Thr Ala Pro Val Ala Leu Arg Glu Gly Glu Asp Leu Ser
1 5 10 15
Lys Lys Asn Pro Ile Ala Lys Ile His Ser Asp Leu Ala Glu Glu Arg
20 25 30
Gly Leu Lys Ile Thr Tyr Lys Tyr Thr Gly Lys Gly Ile Thr Glu Pro
35 40 45
Pro Phe Gly Ile Phe Val Phe Asn Lys Asp Thr Gly Glu Leu Asn Val
50 55 60
Thr Ser Ile Leu Asp Arg Glu Glu Thr Pro Phe Phe Leu Leu Thr Gly
65 70 75 80
Tyr Ala Leu Asp Ala Arg Gly Asn Asn Val Glu Lys Pro Leu Glu Leu
85 90 95
Arg Ile Lys Val Leu Asp Ile Asn Asp Asn Glu Pro Val Phe Thr Gln
100 105 110
Asp Val Phe Val Gly Ser Val Glu Glu Leu Ser Ala Ala His Thr Leu
115 120 125
Val Met Lys Ile Asn Ala Thr Asp Ala Asp Glu Pro Asn Thr Leu Asn
130 135 140
Ser Lys Ile Ser Tyr Arg Ile Val Ser Leu Glu Pro Ala Tyr Pro Pro
145 150 155 160
Val Phe Tyr Leu Asn Lys Asp Thr Gly Glu Ile Tyr Thr Thr Ser Val
165 170 175
Thr Leu Asp Arg Glu Glu His Ser Ser Tyr Thr Leu Thr Val Glu Ala
180 185 190
Arg Asp Gly Asn Gly Glu Val Thr Asp Lys Pro Val Lys Gln Ala Gln
195 200 205
Val Gln Ile Arg Ile Leu Asp Val Asn Asp Asn Ile Pro Val Val Glu
210 215 220
Asn Lys Val Leu Glu Gly Met Val Glu Glu Asn Gln Val Asn Val Glu
225 230 235 240
Val Thr Arg Ile Lys Val Phe Asp Ala Asp Glu Ile Gly Ser Asp Asn
245 250 255
Trp Leu Ala Asn Phe Thr Phe Ala Ser Gly Asn Glu Gly Gly Tyr Phe
260 265 270
His Ile Glu Thr Asp Ala Gln Thr Asn Glu Gly Ile Val Thr Leu Ile
275 280 285
Lys Glu Val Asp Tyr Glu Glu Met Lys Asn Leu Asp Phe Ser Val Ile
290 295 300
Val Ala Asn Lys Ala Ala Phe His Lys Ser Ile Arg Ser Lys Tyr Lys
305 310 315 320
Pro Thr Pro Ile Pro Ile Lys Val Lys Val Lys Asn Val Lys Glu Gly
325 330 335
Ile His Phe Lys Ser Ser Val Ile Ser Ile Tyr Val Ser Glu Ser Met
340 345 350
Asp Arg Ser Ser Lys Gly Gln Ile Ile Gly Asn Phe Gln Ala Phe Asp
355 360 365
Glu Asp Thr Gly Leu Pro Ala His Ala Arg Tyr Val Lys Leu Glu Asp
370 375 380
Arg Asp Asn Trp Ile Ser Val Asp Ser Val Thr Ser Glu Ile Lys Leu
385 390 395 400
Ala Lys Leu Pro Asp Phe Glu Ser Arg Tyr Val Gln Asn Gly Thr Tyr
405 410 415
Thr Val Lys Ile Val Ala Ile Ser Glu Asp Tyr Pro Arg Lys Thr Ile
420 425 430
Thr Gly Thr Val Leu Ile Asn Val Glu Asp Ile Asn Asp Asn Cys Pro
435 440 445
Thr Leu Ile Glu Pro Val Gln Thr Ile Cys His Asp Ala Glu Tyr Val
450 455 460
Asn Val Thr Ala Glu Asp Leu Asp Gly His Pro Asn Ser Gly Pro Phe
465 470 475 480
Ser Phe Ser Val Ile Asp Lys Pro Pro Gly Met Ala Glu Lys Trp Lys
485 490 495
Ile Ala Arg Gln Glu Ser Thr Ser Val Leu Leu Gln Gln Ser Glu Lys
500 505 510
Lys Leu Gly Arg Ser Glu Ile Gln Phe Leu Ile Ser Asp Asn Gln Gly
515 520 525
Phe Ser Cys Pro Glu Lys Gln Val Leu Thr Leu Thr Val Cys Glu Cys
530 535 540
Leu His Gly Ser Gly Cys Arg Glu Ala Gln His Asp Ser Tyr Val Gly
545 550 555 560
<210> 4
<211> 330
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 5
<211> 227
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 6
<211> 326
<212> PRT
<213> 智人(Homo sapiens)
<400> 6
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ser Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 7
<211> 228
<212> PRT
<213> 智人(Homo sapiens)
<400> 7
Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val
1 5 10 15
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro
100 105 110
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ser Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
180 185 190
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Pro Gly Lys
225
<210> 8
<211> 377
<212> PRT
<213> 智人(Homo sapiens)
<400> 8
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro
100 105 110
Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg
115 120 125
Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys
130 135 140
Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
145 150 155 160
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
165 170 175
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
180 185 190
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr
195 200 205
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
210 215 220
Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His
225 230 235 240
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
245 250 255
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
260 265 270
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
275 280 285
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
290 295 300
Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn
305 310 315 320
Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
325 330 335
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile
340 345 350
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln
355 360 365
Lys Ser Leu Ser Leu Ser Pro Gly Lys
370 375
<210> 9
<211> 279
<212> PRT
<213> 智人(Homo sapiens)
<400> 9
Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro Arg Cys
1 5 10 15
Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
20 25 30
Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu
35 40 45
Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Ala Pro
50 55 60
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
65 70 75 80
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
85 90 95
Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr Val Asp
100 105 110
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
115 120 125
Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
130 135 140
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
145 150 155 160
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg
165 170 175
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
180 185 190
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
195 200 205
Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn Tyr Asn
210 215 220
Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
225 230 235 240
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile Phe Ser
245 250 255
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
260 265 270
Leu Ser Leu Ser Pro Gly Lys
275
<210> 10
<211> 327
<212> PRT
<213> 智人(Homo sapiens)
<400> 10
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 11
<211> 229
<212> PRT
<213> 智人(Homo sapiens)
<400> 11
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 12
<211> 5
<212> PRT
<213> 人工序列
<220>
<221> source
<223> /note="人工序列的描述: 合成接头序列"
<400> 12
Gly Gly Gly Gly Ser
1 5
<210> 13
<211> 5
<212> PRT
<213> 人工序列
<220>
<221> source
<223> /note="人工序列的描述: 合成接头序列"
<400> 13
Glu Ala Ala Ala Lys
1 5
<210> 14
<211> 8
<212> PRT
<213> 人工序列
<220>
<221> source
<223> /note="人工序列的描述: 合成接头序列"
<400> 14
Gly Gly Gly Gly Gly Gly Gly Gly
1 5
<210> 15
<211> 25
<212> PRT
<213> 人工序列
<220>
<221> source
<223> /note="人工序列的描述: 合成接头序列"
<220>
<221> SITE
<222> (1)..(25)
<223> /note="该序列可包含2-5 'Glu Ala Ala Ala Lys'重复单元"
<400> 15
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
1 5 10 15
Ala Ala Ala Lys Glu Ala Ala Ala Lys
20 25
<210> 16
<211> 6
<212> PRT
<213> 人工序列
<220>
<221> source
<223> /note="人工序列的描述: 合成接头序列"
<400> 16
Gly Gly Gly Gly Gly Ser
1 5
Claims (45)
1.分离的多肽,其包含桥粒黏蛋白2(DSG2)融合多肽,其中所述DSG2融合多肽包含:
a.DSG2蛋白(SEQ ID NO:1)的全部或部分;以及
b.免疫球蛋白的全部或部分。
2.根据权利要求1所述的分离的多肽,其中所述DSG2融合多肽包含所述DSG2蛋白的部分。
3.根据权利要求2所述的分离的多肽,其中所述DSG2蛋白的部分是DSG2蛋白的胞外区的全部或部分。
4.根据权利要求3所述的分离的多肽,其中所述DSG2蛋白的部分是DSG2蛋白的胞外区的全部。
5.根据权利要求4所述的分离的多肽,其中DSG2蛋白的胞外区的全部包含SEQ ID NO:3的氨基酸序列。
6.根据权利要求3所述的分离的多肽,其中所述DSG2蛋白的部分是所述DSG2蛋白的胞外区的部分。
7.根据权利要求6所述的分离的多肽,其中所述DSG2蛋白的胞外区的部分包含至少一个结构域,其中所述至少一个结构域是胞外钙粘着蛋白结构域1(EC1)、胞外钙粘着蛋白结构域2(EC2)、胞外钙粘着蛋白结构域3(EC3)、胞外钙粘着蛋白结构域4(EC4)或胞外锚定结构域(EA)。
8.根据权利要求7所述的分离的多肽,其中所述DSG2蛋白的胞外区的部分包含两个结构域。
9.根据权利要求8所述的分离的多肽,其中所述DSG2蛋白的胞外区的部分是EC4EA、EC1EC2、EC2EC3、EC3EC4、EC1EA、EC1EC3、EC2EC4或EC3EA。
10.根据权利要求7所述的分离的多肽,其中所述DSG2蛋白的胞外区的部分包含三个结构域。
11.根据权利要求10所述的分离的多肽,其中所述DSG2蛋白的胞外区的部分为EC1EC3EA、EC1EC4EA、EC1EC3EA、EC3EC4EA、EC1EC2EC3、EC2EC3EC4或EC2EC4EA。
12.根据权利要求7所述的分离的多肽,其中所述DSG2蛋白的胞外区的部分包含四个结构域。
13.根据权利要求12所述的分离的多肽,其中所述DSG2蛋白的胞外区的部分为EC1EC2EC4EA、EC2EC3EC4EA、EC1EC2EC3EC4EA、EC1EC2EC3EC4或EC1EC2EC3EA。
14.根据权利要求1所述的分离的多肽,其中所述DSG2融合多肽包括免疫球蛋白的部分。
15.根据权利要求1或权利要求14所述的分离的多肽,其中所述免疫球蛋白是IgG、IgM、IgA、IgD或IgE。
16.根据权利要求15所述的分离的多肽,其中所述免疫球蛋白是IgG。
17.根据权利要求16所述的分离的多肽,其中所述IgG为IgG1、IgG2、IgG3和IgG4。
18.根据权利要求14所述的分离的多肽,其中所述免疫球蛋白的部分是Fc区、Fab区、重链可变(VH)结构域、重链恒定结构域、轻链可变(VL)结构域或轻链恒定结构域。
19.根据权利要求18所述的分离的多肽,其中所述免疫球蛋白的部分是Fc区。
20.根据权利要求19所述的分离的多肽,其中所述Fc区是IgG1 Fc区(SEQ ID NO:5)、IgG2 Fc区(SEQ ID NO:7)、IgG3 Fc区(SEQ ID NO:9)或IgG4 Fc区(SEQ ID NO:11)。
21.根据权利要求18所述的分离的多肽,其中所述免疫球蛋白的部分是重链恒定结构域。
22.根据权利要求21所述的分离的多肽,其中所述重链恒定结构域是IgG1重链恒定结构域(SEQ ID NO:4)、IgG2重链恒定结构域(SEQ ID NO:6)、IgG3重链恒定结构域(SEQ IDNO:8)或IgG4重链恒定结构域(SEQ ID NO:10)。
23.根据权利要求1至22中任一项所述的分离的多肽,其中所述DSG2融合多肽还包含接头。
24.根据权利要求23所述的分离的多肽,其中所述接头的长度为约5个氨基酸至约50个氨基酸。
25.根据权利要求24所述的分离的多肽,其中所述接头是GGGGS(SEQ ID NO:12)。
26.根据权利要求24所述的分离的多肽,其中所述接头是EAAAK(SEQ ID NO:13)。
27.根据权利要求1至26中任一项所述的分离的多肽,其中所述DSG2融合多肽还包含信号序列。
28.细胞,其表达权利要求1至27中任一项所述的分离的多肽。
29.一种治疗与血清抗DSG2自身抗体相关的病症的方法,所述方法包括使受试者与权利要求1至27中任一项所述的分离的多肽或权利要求28所述的细胞接触。
30.根据权利要求29所述的方法,其中所述病症是心肌病。
31.根据权利要求29或30中任一项所述的方法,其中所述病症是自身免疫疾病。
32.一种治疗受试者的COVID-19后综合征的方法,所述方法包括:
(i)使所述受试者与权利要求1至27中任一项所述的分离的多肽或权利要求28所述的细胞接触;以及
(ii)评估一种或多种与COVID-19后综合征相关的症状,所述症状选自心律失常、心肌炎、心力衰竭、呼吸短促、疲劳、水肿、端坐呼吸、活动限制、认知能力受损、心悸、眩晕、晕厥和头晕,
其中所述治疗有效改善所述一种或多种与COVID-19后综合征相关的症状。
33.根据权利要求32所述的方法,其中所述受试者的血清包含抗DSG2抗体。
34.根据权利要求32所述的方法,其中所述受试者先前被诊断患有COVID-19。
35.根据权利要求34所述的方法,其中所述受试者的血清包含抗SARS-CoV-2抗体。
36.根据权利要求34所述的方法,其中所述受试者的血清不包含抗SARS-CoV-2抗体。
37.一种治疗受试者的COVID-19的方法,所述方法包括:
(i)使所述受试者与权利要求1至27中任一项所述的分离的多肽或权利要求28所述的细胞接触;以及
(ii)评估一种或多种与COVID-19相关的症状,所述症状选自发热或寒战、咳嗽、呼吸短促或呼吸困难、疲劳、肌肉或身体疼痛、头痛、新的味觉或嗅觉丧失、咽喉痛、充血或流鼻涕、恶心或呕吐、腹泻、呼吸费力、持续性胸痛或胸压,
其中所述治疗有效改善所述一种或多种与COVID-19相关的症状。
38.一种治疗受试者的心肌病的方法,所述方法包括:
(i)使所述受试者与权利要求1至27中任一项所述的分离的多肽或权利要求28所述的细胞接触,和
(ii)测量一种或多种与心肌病相关的症状,所述症状选自心律失常、心悸、心肌炎、心力衰竭、心输出量差和射血分数降低。
39.根据权利要求38所述的方法,其中所述心肌病是致心律失常性右心室心肌病。
40.根据权利要求38所述的方法,其中所述心肌病由病毒、细菌、寄生虫或真菌引起。
41.根据权利要求40所述的方法,其中所述心肌病由病毒引起,其中所述病毒为SARS-CoV2、腺病毒、肝炎病毒、细小病毒、单纯疱疹病毒、艾柯病毒、爱泼斯坦-巴尔病毒、风疹病毒、巨细胞病毒或HIV。
42.根据权利要求40所述的方法,其中所述心肌病由细菌引起,其中所述细菌是葡萄球菌、链球菌或疏螺旋体。
43.根据权利要求40所述的方法,其中所述心肌病由寄生虫引起,其中所述寄生虫是锥虫或弓形虫。
44.根据权利要求40所述的方法,其中所述心肌病由真菌引起,其中所述真菌为念珠菌、曲霉或组织胞浆菌。
45.根据权利要求38所述的方法,其中所述受试者的血清包含抗DSG2抗体。
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