CN113993538A - 包含从鞭毛蛋白衍生的tlr5激动剂作为有效成分的用于预防或治疗移植物抗宿主病的组合物 - Google Patents
包含从鞭毛蛋白衍生的tlr5激动剂作为有效成分的用于预防或治疗移植物抗宿主病的组合物 Download PDFInfo
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Abstract
本发明涉及一种包含从鞭毛蛋白衍生的TLR5激动剂作为有效成分的用于预防或治疗移植物抗宿主病(GVHD)的组合物。本发明的从鞭毛蛋白衍生的TLR5激动剂对移植物抗宿主病表现出优异的治疗效果,因此可以开发为用于治疗、预防或改善移植物抗宿主病的组合物的活性成分。
Description
技术领域
本发明涉及一种包含从鞭毛蛋白衍生的TLR5激动剂作为有效成分的用于预防或治疗移植物抗宿主病的组合物。
背景技术
TLR5(Toll样受体5(Toll-like receptor 5))是一种由人类TLR5基因编码的蛋白质(PNAS.95(2):588–93),是TLR(Toll样受体(Toll-like receptor))家族的一员。众所周知,TLR5可以识别入侵的运动细菌的鞭毛蛋白(flagellin)(Seminars inImmunopathology.29(3):275–88)。已知TLR5参与包括炎症性肠病在内的各种疾病的发生(Journal of Physiology and Pharmacology.60Suppl 4:71–5)。
鞭毛蛋白(Flagellin)是构成作为运动细胞小器官的细菌鞭毛细丝的主要结构蛋白。数万个鞭毛蛋白分子以螺旋形聚合而形成长鞭状鞭毛细丝。鞭毛蛋白包含D0结构域(domain)、D1结构域、D2结构域及D3结构域,其中,D0结构域和D1结构域是细丝组装所必需的。鞭毛蛋白的D0及D1结构域在各种细胞物种中在结构及序列上高度保守,起到具有鞭毛的细菌公分子模式的作用,即通知宿主细菌感染。已知鞭毛蛋白被TLR5识别,并且通过激活NF-κB信号传导机制来诱导先天免疫刺激、细胞保护及辐射抗性。
移植物抗宿主病(Graft-Versus-Host disease,GVHD)发生在为治疗白血病、骨髓瘤、淋巴瘤及再生障碍性贫血等血癌而移植同种异体造血干细胞的过程中,其通过移植或输血输注的淋巴细胞攻击免疫功能下降的宿主而引起。输注的淋巴细胞一般会被宿主的免疫机制破坏,当宿主的免疫功能下降时,宿主的免疫体系无法执行这种功能,从而发送移植物抗宿主病。另一方面,宿主的免疫抑制程度越高,发生移植物抗宿主病的可能性就越大,移植物抗宿主病与移植物抗肿瘤(graft-versus-tumor,GVT)效应密切相关,若移植后提高免疫抑制强度,则移植物抗宿主病的发生率减少,但移植物抗肿瘤效应也随之减弱,因而最终增加白血病的复发率。因此,迫切需要开发一种能够在抑制移植物抗宿主病的同时最大化移植物抗肿瘤效应的新型治疗剂。
本说明书中提及的专利文献及参考文献以与每种文献通过引用单独且明确特定的情况相同的程度通过引用并入本说明书中。
发明内容
技术问题
本发明人力求努力研发一种能够在对移植物抗宿主病(GVHD)有效的同时最大化移植物抗肿瘤(Graft-versus-tumor,GVT)效应的治疗剂物质。最终,开发了一种从鞭毛蛋白衍生的新型TLR5(Toll-like receptor 5)肽激动剂(agonist),并通过实验确认该TLR5激动剂有效抑制移植物抗宿主病,从而完成了本发明。
因此,本发明的目的在于,提供一种用于治疗或预防移植物抗宿主病的药学组合物,其包含:治疗有效量的从鞭毛蛋白衍生的TLR5激动剂;以及药学上可接受的载体。
并且,本发明的另一目的在于,提供一种用于改善移植物抗宿主病的功能性食品组合物,其包含上述从鞭毛蛋白衍生的TLR5激动剂作为有效成分。
本发明的其他目的及技术特征将通过以下具体实施方式、权利要求书及附图来更具体地阐述。
解决问题的方案
根据本发明的一方面,提供一种用于治疗或预防移植物抗宿主病的药学组合物,其包含:(i)治疗有效量的从鞭毛蛋白衍生的TLR5激动剂(agonist);以及(ⅱ)药学上可接受的载体。
本发明中使用的术语“从鞭毛蛋白衍生的TLR5激动剂”是源自或修饰自细菌的鞭毛蛋白,具有激活TLR5(Toll-like receptor 5)信号传导活性的蛋白质或多肽的含义。
本发明中使用的术语“鞭毛蛋白(flagellin)”是指构成细菌鞭毛细丝的主要蛋白质。鞭毛蛋白包含D0结构域(domain)、D1结构域、D2结构域及D3结构域。已知鞭毛蛋白被TLR5识别,并且通过激活NF-κB信号传导机制来诱导先天免疫刺激、细胞保护及辐射抗性。
根据本发明的一实例,作为上述“从鞭毛蛋白衍生的TLR5激动剂”的肽物质,可以包含鞭毛蛋白的D0结构域及鞭毛蛋白的D1结构域。
根据本发明的再一实例,上述“从鞭毛蛋白衍生的TLR5激动剂”可以包含鞭毛蛋白的D0结构域、鞭毛蛋白的D1结构域及连接肽。
根据本发明的另一实例,上述连接肽可以包含于D1结构域内部。
根据本发明的还有一实例,上述连接肽可以包含SEQ ID NO:1的氨基酸序列。
根据本发明的又一实例,上述“从鞭毛蛋白衍生的TLR5激动剂”包含SEQ ID NO:2的氨基酸序列。
在本发明中,作为待治疗的疾病,“移植物抗宿主病(Graft-Versus-Hostdisease,GVHD)”是一种当输注的淋巴细胞攻击免疫功能下降的宿主时发生的全身性疾病,供者(donor)的T细胞会损害宿主(host)的肝脏、小肠、大肠、皮肤等器官。输注的淋巴细胞通常会被宿主的免疫机制破坏,当宿主的免疫功能下降时,宿主的免疫体系无法执行这种功能,从而发生移植物抗宿主病。免疫抑制程度越高,因输血而发生移植物抗宿主病的可能性就越高。这发生在因恶性血癌(急性白血病或霍奇金病等)或先天性免疫缺乏症而不可避免地需要造血干细胞移植的患者中,并发症免疫抑制程度越高,发生移植物抗宿主病(GVHD)的可能性就越高。骨髓移植后发生的移植物抗宿主病有急性和慢性两种,输血后发生的移植物抗宿主病以急性形式发生。其症状包括发烧、皮疹、瘙痒、黄疸、肝功能障碍、腹泻、出血、全血细胞减少症(白细胞、红细胞、血小板均减少的状态)等,这些症状发生在输血后4~30天之间。
另一方面,移植物抗肿瘤(graft-versus-tumor)是由存在于移植的骨髓或组织中的供者的免疫细胞针对受者所具有的癌组织引起的免疫反应。在骨髓移植等中,若供者与受者的相容性不合适,则移植的白细胞会攻击受者正常体细胞,由此导致移植物抗宿主病。尽管给药免疫抑制剂以抑制免疫异常的移植物抗宿主病(GVHD),但这不可避免地降低攻击癌细胞的移植物抗肿瘤效应(GVT效应),从而可能导致白血病复发。因此,可以说移植物抗宿主病与移植物抗肿瘤(graft-versus-tumor,GVT)效应密切相关。
通过本说明书的实施例中的实验结果证实,本发明的从鞭毛蛋白衍生的TLR5激动剂在移植物抗宿主病诱导的动物模型中表现出优异的移植物抗宿主病治疗效果。
并且,通过本说明书的实施例中的另一实验结果证实,本发明的从鞭毛蛋白衍生的TLR5激动剂表现出促进宿主来源的IL(interleukin)-22及IL-23的产生的效果。因此,本发明的从鞭毛蛋白衍生的TLR5激动剂通过促进上述宿主来源的IL-22及IL-23的产生,可以抑制患有移植物抗宿主病的宿主中的肠道干细胞(intestinal stem cell)的减少。
通过本说明书的实施例中的实验结果证实,本发明的从鞭毛蛋白衍生的TLR5激动剂在移植物抗宿主病及移植物抗肿瘤诱导的动物模型中表现出优异的增加移植物抗肿瘤效应。
本发明的组合物能够以药学组合物的形式提供,上述药学组合物包含:(i)治疗有效量的从鞭毛蛋白衍生的TLR5激动剂;以及(ⅱ)药学上可接受的载体。
在本说明书中,术语“治疗有效量”是指通过向对象患者给药有效成分“从鞭毛蛋白衍生的TLR5激动剂”而适合于治疗或预防移植物抗宿主病的量,具体地,上述“治疗有效量”是指足以一定程度缓解所治疗的疾病或状态的一种以上症状的药剂或化合物的给药量。
上述药学组合物的优选给药量可以适当调节。基于日给药量,上述组合物的给药量可优选为25ug/kg至100ug/kg,上述药学组合物包含:(i)治疗有效量的从鞭毛蛋白衍生的TLR5激动剂;以及(ⅱ)药学上可接受的载体。
本发明的药学组合物除有效成分“从鞭毛蛋白衍生的TLR5激动剂”之外,还可包含药学上可接受的载体,这种载体通常用于制剂中,包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、氢化羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、薄荷醇及矿物油等,但不限于此。
本发明的药学组合物除上述成分之外,还可包含润滑剂、润湿剂、甜味剂、香味剂、乳化剂、悬浮剂、防腐剂等。合适的药学上可接受的载体及制剂在Remington'sPharmaceutical Sciences(19th ed.,1995)中有详细描述。
本发明的药学组合物的合适给药量可根据制剂方法、给药方式、患者的年龄、体重、性别、病理状况、食物、给药时间、给药途径、排泄速度和反应敏感性等因素开出各种处方。
本发明的药学组合物可以口服给药,也可以非口服给药,当非口服给药时,可以通过静脉注射、皮下注射、肌肉注射、腹腔注射、经皮给药等方式给药。
另一方面,考虑到本发明的药学组合物用于治疗或预防移植物抗宿主病,本发明的药学组合物的给药可以通过多种途径给药,例如口服或非口服给药。
本发明的药学组合物中包含的有效成分的浓度可通过考虑治疗目的、患者状态、所需时间等来确定,并且不限于特定范围内的浓度。
本发明的药学组合物通过使用药学上可接受的载体和/或赋形剂且根据本发明所属技术领域的普通技术人员容易实施的方法配制而制成单位剂量形式,或者可以通过将其倒入多剂量容器中来制备。在此情况下,剂型可以是在油或水性介质中的溶液、悬浮液或乳液的形式,或者也可以是浸膏剂、粉末剂、颗粒剂、片剂或胶囊剂形式,并且可以进一步包含分散剂或稳定剂。
根据本发明的另一方面,本发明提供一种包含从鞭毛蛋白衍生的TLR5激动剂作为有效成分的用于改善移植物抗宿主病的功能性食品组合物。
本发明的功能性食品组合物包含食品制造中通常添加的成分,例如,包含蛋白质、碳水化合物、脂肪、营养素及调味剂。例如,除了作为有效成分的从鞭毛蛋白衍生的TLR5激动剂之外,还可以包含香味剂或天然碳水化合物作为附加成分。例如,天然碳水化合物包括单糖(例如,葡萄糖、果糖等);二糖(例如,麦芽糖、蔗糖等);寡糖;多糖(例如糊精、环糊精等);以及糖醇(例如,木糖醇、山梨糖醇、赤藓糖醇等)。作为香味剂,可以使用天然香味剂(例如,索马甜、甜菊提取物等)以及合成调味剂(例如,糖精、阿斯巴甜等)。
本发明的优点概括如下:
(i)本发明的从鞭毛蛋白衍生的TLR5激动剂对移植物抗宿主病(GVHD)表现出优异的治疗效果。
(ii)本发明的从鞭毛蛋白衍生的TLR5激动剂可以开发为用于治疗、预防或改善移植物抗宿主病的组合物的活性成分。
发明的效果
本发明涉及一种包含从鞭毛蛋白衍生的TLR5激动剂作为有效成分的用于预防或治疗移植物抗宿主病的组合物。本发明的从鞭毛蛋白衍生的TLR5激动剂对移植物抗宿主病(GVHD)表现出优异的治疗效果,因此可以开发为用于治疗、预防或改善移植物抗宿主病的组合物的活性成分。
附图说明
图1是示出在移植物抗宿主病小鼠动物模型中,通过给药作为SEQ ID NO:2的氨基酸序列多肽的TLR5激动剂(下文中,将SEQ ID NO:2的TLR5激动剂记载为“KMRC011”)而产生的移植物抗宿主病抑制效果的实验结果照片。移植物抗宿主病小鼠动物模型是使用不同MHC类别(class)的C57BL/6(H-2kb)小鼠(供者)和BALB/c(H-2kd)小鼠(受者)将供者的骨髓细胞和脾细胞移植到受者的静脉来得到的。
图2是示出在移植物抗宿主病小鼠动物模型中,KMRC011对移植物抗宿主病的抑制效果的实验结果。图表中示出对移植物抗宿主病小鼠模型的存活率、体重及移植物抗宿主病临床评价指标的测量结果。
图3是示出在移植物抗宿主病小鼠模型中,通过给药KMRC011而产生的移植物抗宿主病抑制效果的结果,是示出通过免疫组织化学染色而出现的组织学差异的照片。
图4是示出在移植物抗宿主病小鼠模型中,KMRC011对移植物抗宿主病的抑制效果的结果,示出通过给药KMRC011而产生的IL-22和IL-23的表达增加及对肠道干细胞(intestinal stem cells)的保护效果。
图5是在通过TLR5基因的转染产生的HEK-Dual细胞中,对KMRC011和鞭毛蛋白(flagellin)的生物学活性的测量结果,示出了通过光度计(luminometer)确认IL-8反应的结果。
图6是在通过TLR5基因的转染产生的HEK-Dual细胞中,对KMRC011和鞭毛蛋白的生物学活性的测量结果,示出了通过碱性磷酸酶活性(alkaline phosphatase activity,AP)反应测量方法确认NF-κB反应的结果。
图7是示出在移植物抗宿主病及移植物抗肿瘤小鼠模型中,通过给药KMRC011而产生的移植物抗宿主病抑制效果的结果。
图8是示出在移植物抗宿主病及移植物抗肿瘤小鼠模型中,通过给药KMRC011而产生的移植物抗肿瘤协同效应的结果,是使用活体荧光光谱仪(IVIS Lumina XRMS)跟踪、观察肿瘤的结果。
具体实施方式
本说明书中所描述的具体实施例代表本发明的优选实例或例示,而本发明的范围不限于此。本发明所属技术领域的普通技术人员可以明确理解,本发明的变形和其他用途不脱离本说明书的发明要求保护范围中记载的发明范围。
实施例
实验方法
1.建立小鼠模型
(1)移植物抗宿主病小鼠模型
使用不同MHC类别(class)的6-8周龄的C57BL/6(H-2kb)和BALB/c(H-2kd)小鼠,向受者小鼠BALB/c(H-2kd)全身照射800cGy的放射线,在24小时内分离供者小鼠C57BL/6(H-2kb)的骨髓细胞(5×106个细胞)和脾细胞(5×106个细胞)并将其植入到同种异体受者小鼠的静脉来诱导了移植物抗宿主病动物模型。接着,根据移植物抗宿主病临床评价标准(参照下表1),每周2次对移植物抗宿主病小鼠进行观察及评价,上述移植物抗宿主病临床评价标准的总分设置为10分,其中,体重、姿势、活动性、毛状态及皮肤密度各占2分。下表1中记载了移植物抗宿主病小鼠模型的体重、姿势、活动性、毛状态及皮肤密度的临床评价标准。
表1
(2)移植物抗宿主病及移植物抗肿瘤小鼠模型
为了通过引入分子成像技术确认KMRC011对肿瘤细胞的移动路径、存活率、增殖率及移植物抗肿瘤效应的作用影响,并同时验证以肿瘤患者为对象的移植物抗宿主病治疗剂的有效性,通过向患有肿瘤小鼠移植同种异体造血干细胞来建立了移植物抗宿主病及移植物抗肿瘤共诱导模型。
将能够通过分子标记进行肿瘤跟踪的癌细胞株(A20 1×106)静脉注射到小鼠中,并在7天后进行放射线照射(8Gy)以及同种异体移植来建立了移植物抗肿瘤模型。使用活体荧光光谱仪(IVIS Lumina XRMS)对注入荧光素(luciferin)的动物全身(whole body)进行活体成像,并进行了移植物抗宿主病评价。
2.免疫组织化学染色(Immunohistochemistry)
从被石蜡包埋的组织取4μm连续切片,用二甲苯(xylene)处理3次来去除石蜡,并在95%、90%、70%乙醇(ethanol)中逐步水解后,用0.5%过氧化氢(hydrogen peroxide)去除内源性过氧化物酶(endogenous peroxidase),然后用正常山羊血清(goat serum)处理30分钟,并用含有3%牛血清白蛋白(BSA,bovine serum albumin)的磷酸盐缓冲液(PBS)根据制造商的指示对一抗进行稀释并反应1小时。对于表现出表达差异的基因,在与表达蛋白发生一抗反应后,用Tris-缓冲盐水(TBS)洗涤3次,并与稀释于3%BSA的5μg/ml生物素化抗鼠/抗兔IgG(biotinylated anti-mouse/anti-rabbit IgG)反应30分钟,用Tris-缓冲盐水洗涤3次之后,将其在3μg/ml辣根过氧化物酶链霉亲和素(horseradish peroxidasestreptavidin)中放置30分钟,用二氨基联苯胺(DAB)和过氧化氢着色之后,用Meyer’s苏木精(hematoxylin)或1%甲基绿(methyl green)进行了复染。
3.HEK-DualTMhTLR5(NF/IL8)细胞培养
作为TLR5激动剂,使用了SEQ ID NO:2的氨基酸序列的多肽(“KMRC011”)。为了比较本发明的KMRC011和鞭毛蛋白(Flagellin)对TLR5反应的生物学活性,使用了HEK-DualTMhTLR5(NF/IL8)细胞。HEK-DualTM细胞是一种通过稳定转染人类TLR5(hTLR5)基因并敲除(knockout)TLR3及TNFR,可以仅研究hTLR5信号而不受其他TLR及细胞因子TNF-α干扰的细胞,它是从InvivoGen购买来使用的。该细胞稳定地表达能够通过TLR5信号诱导NF-κB/AP-1的分泌型胚胎碱性磷酸酶(SEAP,secreted embryonic alkaline phosphatase)报告结构,并表达在内源性IL-8启动子的控制下的荧光素酶(Lucia luciferase)。使用含有10%胎牛血清(FBS)、50U/ml青霉素(penicillin)、50μg/ml链霉素(streptomycin)、100μg/ml NormocinTM、100μg/ml潮霉素(Hygromycin)B Gold、50μg/ml博来霉素(Zeocin)TM的DMEM培养基(Life Technologies),在5%CO2及37℃的条件下培养细胞。将本发明的TLR5激动剂(KMRC011)和鞭毛蛋白在平底96孔板(flat-bottom96-well plate)中稀释至100ng/ml、10ng/ml、1ng/ml、0.1ng/ml、0.01ng/ml,并在每孔(well)中分别加入20μl。向另一孔(well)中加入20μl无菌水作为阴性对照组。准备HEK-DualTMhTLR5(NF/IL8)细胞悬浮液之后,向平底96孔板(flat-bottom 96-well plate)的每孔(well)中分别加入180μl(10000cells)细胞悬浮液,并在5%CO2及37℃条件下培养20~24小时。
4.检测HEK-DualTMhTLR5细胞中的IL-8反应
QUANTI-LucTM是一种分析试剂,其包含荧光素酶反应所需的稳定底物等所有组分,因而可以定量测量荧光素酶(Lucia luciferase)的活性。荧光素酶反应产生的发光(luminescence)可以使用光度计(luminometer)进行定量化。向平底96孔板的每孔(well)分别接种10μl的HEK-DualTMhTLR5(NF-κB/IL8)细胞培养上清液之后,加入50μl的QUANTI-LucTM,并立即使用光度计测量发光。
5.检测HEK-DualTMhTLR5细胞中的NF-κB反应
QUANTI-BlueTM是一种为了测量诸如细胞培养上清液之类的生物学样品中的碱性磷酸酶活性(alkaline phosphatase activity,AP)而开发的比色酶分析试剂,在AP存在下,其从粉红色变为紫蓝色。在向平底96孔板的每孔(well)分别接种180μl的QUANTI-BlueTM(InvivoGen)之后,分别加入20μl的诱导的HEK-DualTMhTLR5(NF-κB/IL8)细胞培养上清液,然后在常温下反应5-30分钟后使用分光光度计在620-655nm处测量SEAP水平。
实验结果
1.验证在移植物抗宿主病小鼠模型中TLR5激动剂对移植物抗宿主病的抑制效果
诱导移植物抗宿主病小鼠模型后,观察本发明的TLR5激动剂(”KMRC011”)对移植物抗宿主病的抑制效果。药物的详细给药方法如下:用KMRC011 25μg/kg(▽)、KMRC011 50μg/kg(◇)、KMRC011100μg/kg(△)、载体(vehicle)(对照组;■)对受者小鼠进行预处理以及按照2天的间隔共5次腹腔注射。
通过标记耳朵,每周2次评价每组小鼠的体重、姿势、活动性、毛状态及皮肤密度。评价实验结果,如图1及图2所示,在移植物抗宿主病小鼠模型中,载体组体重减少、背部驼背、活动性减弱、毛的形态和皮肤强度发生了变化。相反,KMRC011给药组中上述症状显著减少。并且,与载体组相比,KMRC011给药组中存活率显著延长,在移植物抗宿主病临床评价指标中确认到症状显著减轻。
2.在移植物抗宿主病小鼠模型中给药TLR5激动剂后的组织学评价
将KMRC011给于移植物抗宿主病小鼠模型后,取动物模型的肠道、肝脏、皮肤、肺组织并固定于4%甲醛(formaldehyde)中,然后制造石蜡块并通过H&E染色分析组织学结果。其结果,如图3所示,载体组的肠道中,绒毛和粘膜被破坏,在肝脏和皮肤中,出现炎症细胞的浸润,而在KMRC011给药组中,表现出与正常组织学结果类似的结果。
3.在移植物抗宿主病小鼠模型中通过给药TLR5激动剂而引起的增加IL-22和IL-23的表达以及对肠道干细胞(intestinal stem cell)的保护效果
将KMRC011给药于移植物抗宿主病小鼠模型后,评价IL-22及IL-23的表达水平和对肠道干细胞(intestinal stem cell)的保护效果。如图4所示,TLR5在小肠(smallintestine)中的表达高于脾脏(spleen)和皮肤,当在移植物抗宿主病小鼠模型中给药KMRC011时,肠道(intestine)中IL-22和IL-23的表达显著提高。并且,在移植物抗宿主病动物模型中,观察到肠Lgr5+干细胞(intestinal Lgr5+stem cell)减少,但在移植物抗宿主病动物模型中给药KMRC01的组中,观察到Lgr5+干细胞得到有效有效保护(参照图4)。
4.本发明的TLR5激动剂与鞭毛蛋白的TLR5反应活性比较结果
比较了KMRC011和鞭毛蛋白在通过TLR5基因的转染产生的HEK-Dual细胞中的TLR5激活功效。应用HEK-293报告细胞且通过光度计(luminometer)确认了IL-8反应。结果,如图5所示,在低浓度下(0.001~0.01ng/ml)下,KMRC011的激活反应显著高于鞭毛蛋白。相反,当用作为阴性对照组(negative control)的LPS处理时,未观察到TLR5的生物学活性(图5)。并且,在相同条件下,通过碱性磷酸酶活性(alkaline phosphatase activity,AP)反应测量方法确认了NF-κB反应。结果,如图6所示,确认到KMRC011的反应性从0.01nm/ml的浓度开始高于鞭毛蛋白的反应性。
5.验证移植物抗宿主病及移植物抗肿瘤小鼠模型中通过TLR5激动剂产生的移植物抗宿主病抑制及移植物抗肿瘤协同效应
验证了通过KMRC011给药而产生的在抑制移植物抗宿主病的同时最大化移植物抗肿瘤协同效应的效果。在向作为患有肿瘤动物模型的移植物抗宿主病及移植物抗肿瘤小鼠模型照射放射线3小时前,向腹腔内注射一次KMRC011(50ug/kg)。可以确认到在未给药KMRC011的组(Allogeneic BMT组)中,由于体重减少、背部驼背、活动性减弱、毛的形态和皮肤强度发生了变化而发送移植物抗宿主病,相反,给药KMRC011的组(Allogeneic BMT+KMRC011组)中,上述症状显著减少(参照图7)。
进一步地,使用活体荧光光谱仪(IVIS Lumina XRMS)来跟踪并观察了肿瘤。在Allogeneic BMT组中确认到一些肿瘤,相反,Allogeneic BMT+KMRC011组中未确认到肿瘤。从而证实KMRC011是能够抑制移植物抗宿主病的同时增强移植物抗肿瘤效应的突破性的治疗剂(参照图8)。
产业上的可利用性
本发明涉及一种包含从鞭毛蛋白衍生的TLR5激动剂作为有效成分的用于预防或治疗移植物抗宿主病的组合物,本发明的从鞭毛蛋白衍生的TLR5激动剂对移植物抗宿主病(GVHD)表现出优异的治疗效果。
序列表
<110> 加图立大学校产学协力团
<120> 包含从鞭毛蛋白衍生的TLR5激动剂作为有效成分的用于预防或治疗移植物抗宿主病的组合物
<130> DPB192042
<140> PCT/KR2020/004146
<141> 2020-03-26
<150> KR 10-2019-0035521
<151> 2019-03-28
<160> 2
<170> KoPatentIn 3.0
<210> 1
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 连接肽
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<213> 沙门氏菌(Salmonella enterica)
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Claims (12)
1.一种用于治疗或预防移植物抗宿主病的药学组合物,包含:
(i)治疗有效量的从鞭毛蛋白衍生的TLR5激动剂;以及
(ⅱ)药学上可接受的载体。
2.根据权利要求1所述的用于治疗或预防移植物抗宿主病的药学组合物,其特征在于,上述从鞭毛蛋白衍生的TLR5激动剂包含鞭毛蛋白的D0结构域及D1结构域。
3.根据权利要求1所述的用于治疗或预防移植物抗宿主病的药学组合物,其特征在于,上述从鞭毛蛋白衍生的TLR5激动剂在D1结构域内部包含由SEQ ID NO:1所示的氨基酸序列的连接肽。
4.根据权利要求1所述的用于治疗或预防移植物抗宿主病的药学组合物,其特征在于,上述从鞭毛蛋白衍生的TLR5激动剂包含由SEQ ID NO:2所示的氨基酸序列。
5.根据权利要求1所述的用于治疗或预防移植物抗宿主病的药学组合物,其特征在于,上述从鞭毛蛋白衍生的TLR5激动剂促进宿主来源的IL-22及IL-23的产生。
6.根据权利要求1所述的用于治疗或预防移植物抗宿主病的药学组合物,其特征在于,上述从鞭毛蛋白衍生的TLR5激动剂抑制宿主的肠道干细胞的减少。
7.根据权利要求1所述的用于治疗或预防移植物抗宿主病的药学组合物,其特征在于,上述组合物增加移植物抗肿瘤效应。
8.一种用于改善移植物抗宿主病的功能性食品组合物,包含上述从鞭毛蛋白衍生的TLR5激动剂作为有效成分。
9.根据权利要求8所述的用于改善移植物抗宿主病的功能性食品组合物,其特征在于,上述从鞭毛蛋白衍生的TLR5激动剂包含鞭毛蛋白的D0结构域及D1结构域。
10.根据权利要求8所述的用于改善移植物抗宿主病的功能性食品组合物,其特征在于,上述从鞭毛蛋白衍生的TLR5激动剂包含由SEQ ID NO:1所示的氨基酸序列的连接肽。
11.根据权利要求8所述的用于改善移植物抗宿主病的功能性食品组合物,其特征在于,上述从鞭毛蛋白衍生的TLR5激动剂包含由SEQ ID NO:2所示的氨基酸序列。
12.根据权利要求8所述的用于改善移植物抗宿主病的功能性食品组合物,其特征在于,上述组合物增加移植物抗肿瘤效应。
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