CN115279402A - 对ve-ptp磷酸酶的抑制保护肾免于缺血-再灌注损伤 - Google Patents
对ve-ptp磷酸酶的抑制保护肾免于缺血-再灌注损伤 Download PDFInfo
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Abstract
本公开内容涉及抑制VE‑PTP磷酸酶以保护肾免受缺血‑再灌注损伤。本公开内容还涉及条件性敲除VE‑PTP以保护或改善缺血‑再灌注损伤中的肾功能。本公开内容将VE‑PTP鉴定为用于缺血‑再灌注损伤中的肾保护的有希望的治疗性靶物,并提出使用小分子VE‑PTP抑制剂在急性肾损伤的情况下赋予保护。
Description
发明领域
本发明涉及急性肾病和任何其他肾病,更具体地涉及VE-PTP抑制和Tie2激活保护肾脏功能和减轻急性肾损伤症状的用途。
发明背景
内皮血管生成素(ANG)-Tie2信号传导通路是血管发育、内皮稳定性维持、完整性和稳态所必需的。Ang-Tie2通路的脱调节已经与疾病联系起来,所述疾病包括静脉畸形、青光眼、血管渗漏、糖尿病肾病、脓毒症、缺血-再灌注损伤和急性肾损伤(AKI)。Tie2(TEK)受体酪氨酸激酶表达在血管内皮中重度富集。由基因PTPRB编码的内皮特异性磷酸酶VE-PTP是Tie2磷酸化和激活状态的关键负调节物。抑制VE-PTP是小鼠糖尿病肾损伤的有希望的治疗性靶物,但迄今为止尚未研究其在急性肾损伤中的作用。本发明涉及抑制VE-PTP以保护肾免于由于缺血-再灌注(IR)损伤引起的急性肾损伤,以及减缓和/或减少患者的肾脏功能障碍。
发明概述
本发明的一些实施方案包括通过施用药物组合物治疗患有急性肾损伤或疾病的患者的方法,所述药物组合物包含能够激活TIE2受体的药剂,如VE-PTP抑制剂或血管生成素重组蛋白或嵌合蛋白。
本发明还包括用于皮下递送和受控持续释放的药物组合物,其包含有效剂量量的Tie2受体激活剂,如VE-PTP抑制剂或血管生成素重组或嵌合蛋白,该药物组合物用于治疗急性肾损伤。
在本发明的实施方案中,对VE-PTP的抑制保护肾免于由于缺血-再灌注损伤引起的急性肾损伤。本发明还包括药物组合物,其包含药物活性量的TIE2受体激活剂,即VE-PTP抑制剂,该药物组合物配制用于皮下延长释放递送以治疗急性肾损伤。
本发明还包括药物组合物,其包含药物活性量的TIE2受体激活剂,即VE-PTP抑制剂,该药物组合物配制用于皮下延长释放递送以治疗急性肾损伤。
另外的实施方案也构成本公开的一部分:
1.在有此需要的受试者中治疗患有急性或慢性肾损伤或疾病(其影响肾功能)或缺血-再灌注损伤(例如,肾、肺)的患者的方法,其包括向所述受试者施用药物组合物,所述药物组合物包含一种或多种能够激活TIE2受体的药剂,如向所述受试者施用VE-PTP抑制剂或血管生成素重组蛋白或血管生成素嵌合蛋白。
2.用于皮下递送和受控持续释放的药物组合物,其包含有效剂量量的一种或多种Tie2受体激活剂,如VE-PTP抑制剂、血管生成素重组蛋白或血管生成素嵌合蛋白,所述药物组合物用于治疗急性肾损伤或疾病,或缺血-再灌注损伤,任选地其中所述组合物是水凝胶。
3.在有此需要的受试者中保护肾免于因缺血-再灌注损伤引起的急性肾损伤或疾病,或缺血-再灌注损伤的方法,所述方法包括向所述受试者施用VE-PTP抑制剂。
4.药物组合物,其包含药物活性量的TIE2受体激活剂,即VE-PTP抑制剂,所述药物组合物配制用于皮下延长释放递送以治疗急性肾损伤或疾病,或缺血-再灌注损伤。
5.在有此需要的受试者中减少/预防肾内皮活化、减少/预防促炎内皮状态、减少巨噬细胞积聚、减少损伤后的纤维化响应(例如,肾IR损伤)和/或下调/上调急性应激响应基因(例如,VCAM1(下)、E-选择素(下)、Angpt2(下)、Entpd1(上)、Cyr61(下)、内皮激活基因签名)(在受伤组织中)、下调HIF2-α的方法,所述方法包括向所述受试者施用药物组合物,所述药物组合物包含一种或多种能够激活TIE2受体的药剂,如向所述受试者施用VE-PTP抑制剂或血管生成素重组蛋白或血管生成素嵌合蛋白。
6.在有此需要的受试者中保护和/或改善肾功能并减轻急性肾损伤症状的方法,所述方法包括向所述受试者施用药物组合物,所述药物组合物包含一种或多种能够激活TIE2受体的药剂,如向所述受试者施用VE-PTP抑制剂或血管生成素重组蛋白或血管生成素嵌合蛋白。
7.根据实施方案1至6中任一项所述的方法或治疗,其中在罹患急性肾损伤或疾病,或缺血-再灌注损伤之前;在罹患急性肾损伤或疾病,或缺血-再灌注损伤期间;和/或在罹患急性肾损伤或疾病,或缺血-再灌注损伤后向所述受试者施用所述一种或多种能够激活TIE2受体的药剂,如VE-PTP抑制剂或血管生成素重组蛋白或血管生成素嵌合蛋白。
8.根据实施方案1至7中任一项所述的方法或治疗,其中在急性冠状动脉综合征、急性肾损伤、肠缺血和再灌注、中风、镰状细胞病、睡眠呼吸暂停、大手术或实体器官移植的情况下发生缺血-再灌注损伤。
9.根据实施方案1至8中任一项所述的方法或治疗,其中VE-PTP的抑制与抗炎和/或抗氧化疗法组合使用。
10.根据实施方案1至9中任一项所述的方法或治疗,其中所述药剂直接或通过抑制所述Tie2受体的负调节物VE-PTP激活Tie2受体,任选地所述药剂选自本申请第[020]段中描述的药剂。
11.根据实施方案1至10中任一项所述的方法或治疗,其中通过本领域普通技术人员已知的任何方法(白蛋白与肌酸酐比率、白蛋白尿、血清尿素、菊粉清除、放射性同位素方法、放射性造影剂、胱蛋白酶抑制剂C和/或肾小球滤过率和肾病的分期)来测量肾脏/肾功能。
12.根据实施方案1至11中任一项所述的方法或治疗,其中肾损伤/衰竭的体征和症状包括离开身体的尿液过少、尿中带血、腿部、脚踝中和/或眼睛周围肿胀、疲劳或疲倦、呼吸急促、严重情况下癫痫发作或昏迷、意识模糊、恶心、胸痛或胸闷、高血压、脱水、嗜睡、出血、发烧、皮疹、血性腹泻、严重呕吐、腹痛、皮肤苍白、水肿和/或可检测到的腹部块。
13.根据实施方案1至12中任一项所述的方法或治疗,其中肾损伤是由以下引起的:感染、脱水、近期手术、创伤、暴露于重金属或有毒溶剂、阻碍血流的病况(例如,心脏骤停)、药物、肾结石、影响流去肾/从肾流出/在肾内的血液流动的血管异常、肾小球肾炎、狼疮、输尿管阻塞、低血压、出血过多、严重腹泻、心脏病或心脏病发作、肝衰竭、非类固醇抗炎药(如阿司匹林、布洛芬、萘普生)、严重烧伤、严重过敏反应、肾内部或周围的血块、化疗、抗生素、CT扫描、MRI扫描和其他成像测试期间使用的造影染料、酗酒、药物滥用、癌症、前列腺肥大、糖尿病、病毒感染(例如冠状病毒)。
14.根据实施方案1至13中任一项所述的方法或治疗,其中所述治疗与以下组合:血液透析、腹膜透析、控制血液中维生素和矿物质(例如钾、钙)量的药物(例如钙、葡萄糖或聚苯乙烯磺酸钠(Kionex))、保持血液中正确量的流体的治疗(例如,IV流体、利尿剂)、饮食、肾移植物、类固醇、促皮质素、利妥昔单抗、环磷酰胺、吗替麦考酚酯、ACE抑制剂、血管紧张素II受体阻滞剂、环孢菌素、他克莫司、西罗莫司、liposorber LA-15及其组合。
15.VE-PTP敲除小鼠,其由包括图1的步骤的方法产生。
16.VE-PTP敲除小鼠,其中使用双转基因多西环素可诱导系统(Veptpflox/flox,Rosa26-rtTA+/+,tetO-CreTg/+)在出生后第0天,从小鼠的脉管系统中敲除所述VE-PTP基因(VE-PTPiKO)。
17.如本申请的附图和实施例中描述的任何实施方案。
附图说明
图1显示了用于生成诱导型VE-PTP敲除小鼠模型的策略。使用双转基因多西环素诱导型系统(Veptpflox/flox、Rosa26-rtTA+/+、tetO-CreTg/+)在出生后第0天,从小鼠的脉管系统中敲除VE-PTP基因(VE-PTPiKO)。
图2显示了VE-PTP在具有缺血-再灌注损伤的肾中上调。(A)成年雄性VE-PTPiKO和同窝对照小鼠接受了20分钟的双侧肾脏缺血再灌注损伤(IR)或假手术。全肾提取物的Western印迹分析显示了再灌注1天和7天后VE-PTP的水平升高。误差条显示为s.e.m和显著性,其由单向ANOVA与用于多重比较的Tukey校正确定。(B)HIF2-α的系统性过表达导致肾VE-PTP的水平升高。值是平均值±SD。****P<0.0001;**P<0.01;*P<0.05;ns,P>0.05。
图3显示了靶向VE-PTP改善幼小鼠的缺血性肾脏功能。A)野生型(对照)和VE-PTP诱导的敲除(VE-PTPiKO)雄性小鼠在3个月时的基线肌酸酐水平。(B)IR后在指定时间点的3个月龄对照和VE-PTPiKO小鼠的肌酸酐水平(双向ANOVA)。(C)IR后在24小时1年龄对照和VE-PTPiKO小鼠的肌酸酐水平。血清肌酸酐通过HPLC法测量。(D)肺组织的Western印迹和免疫沉淀(IP)分析显示VE-PTP的缺失增加了Tie2磷酸化。(E)IR后7天从小鼠肾中提取mRNA。值是平均值±SEM。***,P<0.001;*,P<0.05;ns,P>0.05。
图4显示水凝胶贮库注射后受控的VE-PTP抑制剂释放增加Tie2磷酸化。肺组织的Western印迹和免疫沉淀(IP)分析显示,以每克体重32ul的剂量皮下注射含有8mg/mlVE-PTP抑制剂的水凝胶后Tie2磷酸化增加(A),对VEGFR2磷酸化的影响可忽略不计(B)。实验至少重复一次。
图5显示肾中VE-PTP的遗传失活减少了肾脏IR损伤后的巨噬细胞积聚和纤维化响应。(A)第7天收获的肾用CD68染色以确定巨噬细胞积聚。免疫组织化学在VE-PTP敲除小鼠的肾外部髓质区域中鉴定出较少的免疫炎症性CD68阳性细胞。(B)与对照组相比,在第7天,VE-PTP缺陷肾中促纤维化基因如结缔组织生长因子(CTGF)、纤连蛋白(Fn1)和Snail1的表达显著降低。
图6显示肾中VE-PTP的遗传失活导致双侧肾脏IR损伤后较少的促炎性内皮状态。(A)转录物组分析揭示内皮活化的几个标志物基因(VCAM1、E-选择素和Angpt2)的下调,保护基因外核苷三磷酸二磷酸水解酶-1(Entpd1)的上调和富含半胱氨酸的蛋白61(Cyr61)(AKI的早期生物标志物)的下调。对于RNA分析,使用从整个肾中提取的总RNA进行整体(bulk)RNAseq。使用STAR将序列与小家鼠(Mus musculus)基因组(mm10)比对,标准化和使用DESeq2确定差异表达。(B)在接受双侧肾脏IR损伤或假手术的3个月龄的VE-PTP敲除雄性和同窝对照小鼠中,使用相对于GAPDH标准化的qPCR证实了基因表达的变化。
发明详述
除非本文另有明确规定,否则以下每个术语应具有以下阐述的含义。在整个申请中阐述了额外定义。除非另有定义,否则本文使用的所有技术和科学术语均具有本领域普通技术人员通常理解的含义。例如,Concise Dictionary of Biomedicine and MolecularBiology,Juo,Pei-Show,第2版,2002,CRC Press;The Dictionary of Cell andMolecular Biology,第3版,1999,Academic Press;和Oxford Dictionary ofBiochemistry and Molecular Biology,修订版,2000,Oxford University Press为本领域技术人员提供了具有本申请中使用的许多术语的通用词典。
单位、前缀和符号以其国际单位制(Système International de Unites,SI)接受的形式表示。数字范围包括定义范围的数字。本文提供的公开内容并不对本申请的各个方面进行限制,其可以整体参考说明书。
冠词“一个/一种”是指任何列举或枚举的组分中的“一个/种或多个/种”。
术语“约”或“基本上由……组成”是指如本领域普通技术人员所确定的某个值或组分在可接受的误差范围内的值或组成,这将部分取决于该值或组成是如何测量或确定的,即测量系统的局限性。例如,“约”或“基本上由……组成”可以表示按照本领域实践在1个或多于1个标准偏差内。或者,“约”或“基本上由……组成”可表示多达10%(即±10%)的范围。例如,约3mg可包括2.7mg至3.3mg之间的任何数字(对于10%)。对于生物系统或过程,术语可意味着高达一个数量级或高达5倍的值。当在申请和权利要求中提供某些值或组成时,除非另有说明,否则“约”或“基本上由……组成”的含义包括该值或组成的可接受误差范围。除非另有说明,否则任何浓度范围、百分比范围、比率范围或整数范围都包括所述范围内的任何整数的值,并且在适当时包括其分数(如整数的十分之一和百分之一)。
术语“和/或”指有或没有另一个的两个特定特点或组分中的每一个。因此,术语“和/或”如本文中诸如“A和/或B”的短语中所用的,旨在包括“A和B”、“A或B”、“A”(单独)和“B”(单独)。类似地,术语“和/或”如诸如“A、B和/或C”的短语中所用的,旨在涵盖以下的各个方面:A、B和C;A、B或C;A或C;A或B;B或C;A和C;A和B;B和C;A(单独);B(单独);和C(单独)。
术语“例如”和“即”仅作为示例使用,并非旨在限制,并且不应理解为仅指在说明书中明确列举的那些项。
术语“或更多”、“至少”、“多于”等,例如“至少一个”包括但不限于至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149或150、200、300、400、500、600、700、800、900、1000、2000、3000、4000、5000或大于所述值。还包括介于两者之间的任何更大的数字或分数。术语“不超过”包括小于所述值的每个值。例如,“不超过100个核苷酸”包括100、99、98、97、96、95、94、93、92、91、90、89、88、87、86、85、84、83、82、81、80、79、78、77、76、75、74、73、72、71、70、69、68、67、66、65、64、63、62、61、60、59、58、57、56、55、54、53、52、51、50、49、48、47、46、45、44、43、42、41、40、39、38、37、36、35、34、33、32、31、30、29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、1和0个核苷酸。还包括介于两者之间的任何较小的数字或分数。
术语“多个”、“至少两个”、“两个或更多”、“至少第二”等包括但不限于至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149或150、200、300、400、500、600、700、800、900、1000、2000、3000、4000、5000或更多。还包括介于两者之间的任何更大的数字或分数。
在整个说明书中,词语“包含”或变体被理解为暗示包含所述的元素、整数或步骤,或元素组、整数组或步骤组,但不排除任何其他元素、整数或步骤,或元素组、整数组或步骤组。应当理解,在本文中用语言“包括”来描述的任何方面,也提供了以“由……组成”和/或“基本上由……组成”来描述的其他类似方面。
术语“活化”、“活化的”等是指已被充分刺激以诱导可检测的细胞增殖的细胞,包括但不限于内皮细胞的状态。
术语“施用”等是指使用本领域技术人员已知的各种方法和递送系统中的任一种将药剂物理引入受试者。通过本文公开的方法制备的药物或药剂的示例性施用途径包括静脉内(i.v.或IV)、肌内、皮下、腹膜内、脊髓或其他肠胃外施用途径,例如通过注射或输注。肠胃外施用途径是指除肠内和局部施用以外的施用方式,通常通过注射,并且包括但不限于静脉内、肌内、动脉内、鞘内、淋巴管内、病灶内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、包膜下、蛛网膜下腔、脊髓内、硬膜外和胸骨内注射和输注,以及体内电穿孔。在一个实施方案中,通过本方法制备的药剂经由注射或输注施用。非肠胃外途径包括局部、表皮或粘膜施用途径,例如鼻内、阴道、直肠、舌下或局部。施用也可以是一次、两次或在一个或多个延长时间段内多次施用。在施用一种或多种治疗剂(例如细胞)的情况下,施用可以同时或序贯进行。序贯施用包括仅在另一种或多种药剂的施用完成后才施用一种药剂。
“治疗有效量”、“治疗有效剂量”等是指由本方法产生的药剂的量,当单独使用或与另一种治疗剂组合使用时,保护或治疗受试者免于疾病的发作或促进疾病的消退,如由疾病症状的严重程度降低、无疾病症状期的频率和持续时间增加、和/或预防由疾病折磨引起的损伤或残疾。促进疾病消退的能力可以使用熟练技术人员已知的多种方法来评估,如在临床试验期间的受试者中,在预测人类功效的动物模型系统中,或通过在体外测定中测定药剂的活性。除了本申请中描述的模型外,还有许多小鼠肾脏缺血再灌注损伤模型。参见例如Guan,Y.,Nakano,D.,Zhang,Y.et al.A mouse model of renal fibrosis toovercome the technical variability in ischaemia/reperfusion injury amongoperators.Sci Rep 9,10435(2019)doi:10.1038/s41598-019-46994-z,并且还有商业上可获得的定制临床前服务来研究新药剂在肾缺血/再灌注损伤中的作用。
术语细胞“增殖”等是指通过细胞分裂细胞在数目上生长的能力。在一些实施方案中,可以通过用羧基荧光素琥珀酰亚胺酯(CFSE)染色细胞来测量增殖。细胞增殖可以在体外发生,例如在内皮细胞培养期间,或在体内发生。可以通过本文所述或本领域已知的方法测量或确定细胞增殖。例如,细胞增殖可以通过活细胞密度(VCD)或总活细胞(TVC)来测量或确定。VCD或TVC可以是理论上的(在某个时间点从培养物中取出等分试样或样品以确定细胞数,然后将细胞数与研究开始时的培养体积相乘)或实际的(在某个时间点从培养物中取出等分或样品以确定细胞数,然后将细胞数与该时间点的实际培养体积相乘)。
如本文所用,“患者”包括患有疾病或病症,包括肾病的任何人。术语“受试者”和“患者”在本文中可互换使用。在一个实施方案中,患者是人。在一个实施方案中,患者是动物。
术语“减少”和“降低”在本文中可互换使用,表示小于原始的任何变化。“减少”和“降低”是相对术语,需要测量前和测量后之间的比较。“减少”和“降低”包括完全耗尽。
受试者的“治疗/处理”是指对受试者进行的任何类型的干预或过程,或向受试者施用本申请制备的一种或多种药剂或药物,目标是逆转、减轻、改善、抑制、减缓或预防与疾病相关的症状、并发症或病况或生化指标的发作、进展、发展、严重性或复发。一方面,“治疗”包括部分缓解。在另一个方面,“治疗”包括完全缓解。
术语“缺血-再灌注”是指由于最初限制给器官的血液供应,随后恢复灌注和伴随的再氧合而导致的病理状况。缺血再灌注损伤(IRI)导致多种病理,例如急性冠状动脉综合征、急性肾损伤、肠缺血和再灌注、中风、镰状细胞病、睡眠呼吸暂停和实体器官移植(例如肾移植)的发病率和死亡率。
在以下小节中进一步详细地描述了本申请的各个方面。
在一个实施方案中,本公开提供了通过施用药物组合物来治疗患有急性肾损伤或疾病的患者的方法,所述药物组合物包含一种或多种能够激活TIE2受体的药剂,如VE-PTP抑制剂或血管生成素重组蛋白或嵌合蛋白。
在一个实施方案中,药剂直接或通过抑制Tie2受体的负调节剂VE-PTP来激活Tie2受体。血管生成素-1重组或嵌合蛋白,如BowAng1和COMP-Ang1直接激活Tie2。参见,例如Davis,S.et al.Angiopoietins have distinct modular domains essential forreceptor binding,dimerization and superclustering.Nat Struct Biol.10(1):38-44(2003)doi:10.1038/nsb880和Oh,N.et al.A Designed Angiopoietin-1Variant,DimericCMP-Ang1 ActivatesTie2and Stimulates Angiogenesis and Vascular Stabilizationin N-glycan Dependent Manner.Sci Rep.5,15291(2015)doi:10.1038/srep15291。或者,还有激活Tie2的合成模拟配体和调节剂,包括Vasculotide、TSL1和AXT107。参见,例如Dekker,N.A.et al.Vasculotide,an angiopoietin-1mimetic,reduces pulmonaryvascular leakage and preserves microcirculatory perfusion duringcardiopulmonary bypass in rats.Br J Anaesth.121(5)(2018)doi:10.1016/j.bja.2018.05.049,Issa,E.et al.Development of an OrthogonalTie2LigandResistant to Inhibition by Ang2.Mol Pharm.4;15(9)(2018)doi:10.1021/acs.molpharmaceut.8b00409和Mirando,A.C.et al.A collagen IV-derived peptidedisruptsα5β1integrin and potentiates Ang2/Tie2signaling.JCI Insight.21;4(4)(2019)doi:10.1172/jci.insight.122043。还有作用为Tie2激活剂的不同类型的抗体。这些包括血管生成素-2结合和Tie2激活抗体(ABTAA)、抗Tie2受体激动抗体,以及靶向VE-PTP细胞外结构域的抗体。参见例如Kim,J.et al.Tie2activation promoteschoriocapillary regeneration for alleviating neovascular age-related maculardegeneration.Sci Adv.13;5(2)(2019)doi:10.1126/sciadv.aau6732,Hwang,B.etal.Stimulation of angiogenesis and survival of endothelial cells by humanmonoclonalTie2receptor antibody.Biomaterials 51:119-128(2015)doi:10.1016/j.biomaterials.2015.01.062,和Frye,M.et al.Interfering withVE-PTPstabilizesendothelial junctions in vivo via Tie-2in the absence of VE-cadherin.J ExpMed14;212(13)(2015)doi:10.1084/jem.20150718。还有作用为Tie2激活剂的小分子VE-PTP抑制剂,参见,例如Campochiaro,P.A.,Enhanced Benefit in Diabetic MacularEdema from AKB-9778Tie2Activation Combined with Vascular Endothelial GrowthFactor Suppression.Ophthalmology.123(8):1722-1730(2016)doi:10.1016/j.ophtha.2016.04.025。
在一个实施方案中,本公开内容提供了用于皮下递送和受控持续释放的药物组合物,其包含有效剂量量的Tie2受体激活剂,如VE-PTP抑制剂或血管生成素重组或嵌合蛋白,用于治疗急性肾损伤。在一个实施方案中,可注射水凝胶用于递送VE-PTP抑制剂并且基于腙交联的聚(低聚(乙二醇)甲基丙烯酸酯)或POEGMA。这两种组分系统-醛和酰肼,在混合后迅速形成交联的可生物降解水凝胶。PBS中的8%POEGMA可用于包囊VE-PTP小分子抑制剂以延长释放。VE-PTP抑制剂在POEGMA中的溶解度高达25mg/mL。
在本公开内容的一个实施方案中,对VE-PTP的抑制保护肾免于由于缺血-再灌注损伤引起的急性肾损伤。
在另一个实施方案中,本公开内容提供了药物组合物,其包含药物活性量的TIE2受体激活剂,即VE-PTP抑制剂,该药物组合物配制用于皮下延长释放递送以治疗急性肾损伤。
在一个实施方案中,缺血再灌注损伤发生在急性冠状动脉综合征、急性肾损伤、肠缺血和再灌注、中风、镰状细胞病、睡眠呼吸暂停、大手术或实体器官移植的情况下。
在一个实施方案中,VE-PTP的抑制与抗炎和抗氧化疗法组合使用。
实施例
实施例1
VE-PTP蛋白水平在缺血-再灌注损伤后的肾中上调(图2A)。HIF2-α的全身性转基因过表达(由含PAS结构域的内皮蛋白1(EPAS1)的上调所证实)也导致肾VE-PTP水平升高(图2B)。为了确定肾健康功能,测量了血清肌酸酐。野生型对照和VE-PTPiKO小鼠的基线肌酸酐水平在相同范围内(图3A)。虽然在对照小鼠中血清肌酸酐在IR后1天升高,但这种升高在VE-PTPiKO小鼠中没有发生(图3B)。这种效果似乎是龄期依赖性的(图3C)。
在IR损伤后,与VE-PTPiKO小鼠相比,在对照中观察到促纤维化因子和FOXO1靶基因CTGF的增加(图3E),阐释了与VE-PTP缺乏相关的对肾的保护作用。VE-PTP的遗传缺失在体内稳健地增强了肺和肾组织脉管系统中的Tie2磷酸化和激活(图3D)。通过皮下注射水凝胶进行持续释放,对VE-PTP的药理抑制在体内也稳健地增强了肺组织脉管系统中Tie2的磷酸化和激活(图4A),而对VEGFR2的磷酸化和激活的影响可忽略不计(图4B)。
VE-PTP的丧失减少了肾脏缺血再灌注(IR)损伤后的巨噬细胞聚集和纤维化响应。使用巨噬细胞谱系标志物CD68确定外部肾髓质中免疫细胞浸润的程度。IR损伤后,WT照小鼠的肾显示出巨噬细胞浸润和肾脏内定位,这到损伤后第3天可清楚地检测到(图5A)。肾中VE-PTP的遗传缺失降低了IR损伤中促纤维化基因的表达(图5B)。转录谱分析显示,IR损伤中VE-PTP的丧失导致肾脏内皮活化减少、促炎内皮状态降低和急性应激响应基因签名(signature)下调(图6)。
Claims (16)
1.在有此需要的受试者中治疗患有急性或慢性肾损伤或疾病(其影响肾功能)或缺血-再灌注损伤(例如,肾、肺)的患者的方法,所述方法包括向所述受试者施用药物组合物,所述药物组合物包含一种或多种能够激活TIE2受体的药剂,如向所述受试者施用VE-PTP抑制剂或血管生成素重组蛋白或血管生成素嵌合蛋白。
2.用于皮下递送和受控持续释放的药物组合物,其包含有效剂量量的一种或多种Tie2受体激活剂,如VE-PTP抑制剂、血管生成素重组蛋白或血管生成素嵌合蛋白,所述药物组合物用于治疗急性肾损伤或疾病,或缺血-再灌注损伤,任选地其中所述组合物是水凝胶。
3.在有此需要的受试者中保护肾免于因缺血-再灌注损伤引起的急性肾损伤或疾病,或缺血-再灌注损伤的方法,所述方法包括向所述受试者施用VE-PTP抑制剂。
4.药物组合物,其包含药物活性量的TIE2受体激活剂,即VE-PTP抑制剂,所述药物组合物配制用于皮下延长释放递送以治疗急性肾损伤或疾病,或缺血-再灌注损伤。
5.在有此需要的受试者中减少/预防肾内皮活化、减少/预防促炎内皮状态、减少巨噬细胞积聚、减少损伤后的纤维化响应(例如,肾IR损伤)和/或下调/上调急性应激响应基因(例如,VCAM1(下)、E-选择素(下)、Angpt2(下)、Entpd1(上调)、Cyr61(下)、内皮活化基因签名)(在受伤组织中)、下调HIF2-α的方法,所述方法包括向所述受试者施用药物组合物,所述药物组合物包含一种或多种能够激活TIE2受体的药剂,如向所述受试者施用VE-PTP抑制剂或血管生成素重组蛋白或血管生成素嵌合蛋白。
6.在有此需要的受试者中保护和/或改善肾功能并减轻急性肾损伤症状的方法,所述方法包括向所述受试者施用药物组合物,所述药物组合物包含一种或多种能够激活TIE2受体的药剂,如向所述受试者施用VE-PTP抑制剂或血管生成素重组蛋白或血管生成素嵌合蛋白。
7.根据权利要求1至6中任一项所述的方法或治疗,其中在罹患急性肾损伤或疾病,或缺血-再灌注损伤之前;在罹患急性肾损伤或疾病,或缺血-再灌注损伤期间;和/或在罹患急性肾损伤或疾病,或缺血-再灌注损伤后向所述受试者施用所述一种或多种能够激活TIE2受体的药剂,如VE-PTP抑制剂或血管生成素重组蛋白或血管生成素嵌合蛋白。
8.根据权利要求1至7中任一项所述的方法或治疗,其中在急性冠状动脉综合征、急性肾损伤、肠缺血和再灌注、中风、镰状细胞病、睡眠呼吸暂停、大手术或实体器官移植的情况下发生缺血-再灌注损伤。
9.根据权利要求1至8中任一项所述的方法或治疗,其中VE-PTP的抑制与抗炎和/或抗氧化疗法组合使用。
10.根据权利要求1至9中任一项所述的方法或治疗,其中所述药剂直接或通过抑制所述Tie2受体的负调节物VE-PTP激活所述Tie2受体,任选地所述药剂选自本申请第[020]段中描述的药剂。
11.根据权利要求1至10中任一项所述的方法或治疗,其中通过本领域普通技术人员已知的任何方法(白蛋白与肌酸酐比率、白蛋白尿、血清尿素、菊粉清除、放射性同位素方法、放射性造影剂、胱蛋白酶抑制剂C和/或肾小球滤过率和肾病的分期)来测量肾脏/肾功能。
12.根据权利要求1至11中任一项所述的方法或治疗,其中肾损伤/衰竭的体征和症状包括离开身体的尿液过少、尿中带血、腿部、脚踝中和/或眼睛周围肿胀、疲劳或疲倦、呼吸急促、严重情况下癫痫发作或昏迷、意识模糊、恶心、胸痛或胸闷、高血压、脱水、嗜睡、出血、发烧、皮疹、血性腹泻、严重呕吐、腹痛、皮肤苍白、水肿和/或可检测到的腹部块。
13.根据权利要求1至12中任一项所述的方法或治疗,其中肾损伤是由以下引起的:感染、脱水、近期手术、创伤、暴露于重金属或有毒溶剂、阻碍血流的病况(例如,心脏骤停)、药物、肾结石、影响流去肾/从肾流出/在肾内的血液流动的血管异常、肾小球肾炎、狼疮、输尿管阻塞、低血压、出血过多、严重腹泻、心脏病或心脏病发作、肝衰竭、非类固醇抗炎药(如阿司匹林、布洛芬、萘普生)、严重烧伤、严重过敏反应、肾内部或周围的血块、化疗、抗生素、CT扫描、MRI扫描和其他成像测试期间使用的造影染料、酗酒、药物滥用、癌症、前列腺肥大、糖尿病、病毒感染(例如冠状病毒)。
14.根据权利要求1至13中任一项所述的方法或治疗,其中所述治疗与以下组合:血液透析、腹膜透析、控制血液中维生素和矿物质(例如钾、钙)量的药物(例如钙、葡萄糖或聚苯乙烯磺酸钠(Kionex))、保持血液中正确量的流体的治疗(例如,IV流体、利尿剂)、饮食、肾移植物、类固醇、促皮质素、利妥昔单抗、环磷酰胺、吗替麦考酚酯、ACE抑制剂、血管紧张素II受体阻滞剂、环孢菌素、他克莫司、西罗莫司、liposorber LA-15及其组合。
15.VE-PTP敲除小鼠,其由包括图1的步骤的方法产生。
16.VE-PTP敲除小鼠,其中使用双转基因多西环素可诱导系统(Veptpflox/flox,Rosa26-rtTA+/+,tetO-CreTg/+)在出生后第0天,从小鼠的脉管系统中敲除所述VE-PTP基因(VE-PTPiKO)。
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