CN111093687A - 作为自身免疫疾病及骨病治疗剂的肽的用途 - Google Patents
作为自身免疫疾病及骨病治疗剂的肽的用途 Download PDFInfo
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Abstract
本发明涉及作为治疗剂的肽的用途，本发明的肽显著抑制与自身免疫疾病相关的T细胞的活性及Th17细胞分化，减少炎症性细胞因子白细胞介素6的分泌，在关节炎动物模型中，具有显著的治疗及改善关节炎的效果，因此，上述肽可用作如骨病、炎症性疾病或类风湿性关节炎的各种自身免疫疾病治疗剂的有效成分。
Description
技术领域
本发明涉及作为骨病及自身免疫疾病治疗剂的肽的用途，更具体地，涉及本发明的由以通式1记载的氨基酸序列构成的肽及上述肽的对于包括骨质疏松症等骨病、包括炎症性疾病或类风湿性关节炎等自身免疫疾病的治疗用途。
背景技术
骨组织由如胶原蛋白、糖蛋白的细胞外基质(extracellular substance)和成骨细胞(osteoblast)、破骨细胞(osteoclast)、骨细胞等多种细胞构成。尤其，成骨细胞与破骨细胞的相互均衡对于健康骨骼系统的形成至关重要。即，在骨代谢(bone metabolism)和骨重建(bone remodeling)中，形成骨基质(bone matrix)的成骨细胞(osteoblasts)与吸收骨的破骨细胞(osteoclasts)之间的平衡活动对于维持骨内稳态非常重要。
骨组织由如胶原蛋白、糖蛋白的细胞外基质和成骨细胞、破骨细胞、骨细胞等多种细胞构成。并且，作为通过破骨细胞的骨吸收和通过成骨细胞的新的骨基质形成及无机化过程反复发生的代谢器官，通过成骨细胞活动的骨形成多于通过破骨细胞活动的骨吸收。骨重建为去除停止生长的旧骨，并以新骨代替旧骨的过程，通过如甲状旁腺激素(PTH)、降钙素、雌激素等的激素和如在胰岛素样生长因子Ⅰ(IGFI，insulin-like growth factor I)等的骨组织分泌的各种生长因子、肿瘤坏死因子α(TNF-α，tumor necrosis factor-α)等的细胞因子(cytokines)调节成骨细胞与破骨细胞的活性平衡，来维持体内平衡。在这种成骨细胞与破骨细胞的平衡被打破的情况下，诱发如骨质疏松症或关节炎的疾病。
尤其，若成骨细胞与破骨细胞的平衡被打破，则破骨细胞将导致过多的骨质破坏，从而导致如骨质疏松症的疾病。这种破骨细胞为在骨代谢过程中负责骨吸收的专门细胞，通过分化程序从作为前体细胞的单核细胞(monocyte)或巨噬细胞(macrophage)形成。并且，破骨细胞通过αvβ3整合素(integrin)等与骨结合，并形成酸性环境，同时，通过分泌各种胶原酶(collagenase)及蛋白酶(protease)来导致骨吸收(bone resorption)，因此，这种抑制破骨细胞可成为治疗骨疾病的有效方法。
并且，自身免疫疾病为人体免疫系统异常而自身细胞攻击自身细胞。人体免疫系统基本上将侵入人体的微生物及癌细胞产生等识别为外部抗原，具有攻击并去除其的能力，但由于自身容忍性，不攻击自身细胞。将这种现象称为人体的自我容忍(self-tolerance)现象。但是，在免疫系统的自我容忍被破坏的情况下，在人体中，使对自身细胞(或自身抗原)反应的自身反应T细胞活化并生成自身抗体(autoantibody)，持续破坏自身细胞并引起炎症及免疫反应。
在免疫系统中与抗原特异性反应的细胞有T细胞和B细胞。当T细胞与通过抗原递呈细胞(antigen presenting cell)递呈的特定抗原相遇时，根据其抗原作出反应，若将在抗原递呈细胞中递呈的抗原识别为“非自身(non-self)”，则作出所要去除其的免疫反应，若识别为“自身(self)”，则呈现无视免疫反应的容忍性。若T细胞对于抗原活化，则大部分的B细胞接连活化，B细胞转变为原生质细胞(plasma cell)，并生成对于所识别的特定抗原特异性反应的抗体。因此，在人体的容忍性被破坏且产生自身免疫的情况下，T细胞非正常地识别自身抗原并活化，B细胞也活化，来生成与自身抗原反应的自身抗体，在人体中，产生攻击自身细胞的免疫反应。
并且，同样，在器官移植患者中，在器官移植后，若免疫系统将所移植的组织识别为“非自身”，则产生攻击并去除移植的器官的器官移植排斥反应。为了抑制上述现象，使用用于抑制免疫细胞的活化且抑制免疫细胞向所移植的器官移动等的各种免疫抑制剂，持续使用免疫抑制剂将导致各种副作用。
另一方面，最近发现，CD4+T细胞系统的Th17细胞在自身免疫疾病的炎症诱发和发展过程中起到核心作用，并且发现在此细胞分泌的白细胞介素17(IL-17)与自身免疫疾病直接相关，因此，这种Th17细胞的重要性提高。
并且，Th17细胞诱导作为骨破坏的主要原因的破骨细胞分化因子(RANKL)及各种炎症性细胞因子(Chabaud and Miossec，2001；Connell and McInnes，2006)，由此，使炎症及关节破坏机制进一步活化。因此，Th17细胞被认为是包括类风湿性关节炎在内的自身免疫疾病、与骨病相关的信号传递过程中的核心病因细胞，从而需要发现有效抑制Th17细胞分化的候选物质。
并且，白细胞介素6(IL-6，interleukin-6)为不仅参与炎症和感染反应的细胞因子，还为参与代谢、再生及神经过程的细胞因子，最近，主要在类风湿性关节炎、克罗恩病等的自身免疫疾病等中研究，参与Th17细胞的分化来作用于Th17/Treg细胞的平衡。
并且，众所周知，白细胞介素6将作为破骨前体细胞(osteoclast precursor)的骨髓巨噬细胞(bone marrow macrophage)引导至炎症部位，刺激分化为破骨细胞，使分化的破骨细胞活化来吸收周围的骨，因此，认为是研发自身免疫疾病及骨病治疗剂的主要靶点。
同时，类风湿性关节炎为以多发性关节炎为特征的炎症性疾病，主要发病机制为自身免疫现象。症状如下，即，在关节滑膜(synovial membrane)组织产生炎症，巨噬细胞、树突状细胞及T淋巴细胞、B淋巴细胞等向滑膜组织移动，结果，关节液增加，使关节肿胀并疼痛。若这种炎症持续而使炎症性滑膜组织增生(hyperplasia)，则破坏骨与软骨，来使关节结构变形，并产生运动障碍。并且，根据各种研究结果，在类风湿性关节炎患者中，炎症性细胞因子在滑膜纤维细胞和软骨细胞中生成胶原蛋白分解酶及中性蛋白酶，所生成的这些酶破坏胶原蛋白和蛋白聚糖(proteoglycan)来破坏关节软骨。
因此，为了研发使治疗剂的副作用最小化且具有有效的治疗效果的新骨病及自身免疫疾病治疗剂而努力的结果，本发明人发现在本发明中制备的肽可有效治疗包括骨质疏松症在内的骨病或包括炎症性疾病及类风湿性关节炎在内的自身免疫疾病，从而完成本发明。
发明内容
技术问题
本发明的目的在于，提供用于预防及治疗骨病(bone disease)、炎症性疾病及自身免疫疾病(autoimmune disease)的肽。
解决问题的手段
为了实现上述目的，本发明提供由以下述序列1记载的通式1的氨基酸序列构成的肽、包含上述肽作为有效成分的用于预防及治疗骨病、炎症性疾病或自身免疫疾病的药学组合物或用于预防及改善骨病、炎症性疾病或自身免疫疾病的健康食品。
通式1：(X1-X2-X3)n
在上述式中，X1为选自由精氨酸(Arginine；R)、组氨酸(Histidine；H)及赖氨酸(Lysine；K)组成的组中的一种，X2为天冬氨酸(Aspartic acid；D)或谷氨酸(Glutamicacid；E)，X3为选自由甘氨酸(Glycine；G)、丙氨酸(Alanine；A)、缬氨酸(Valine；V)、蛋氨酸(Methionine；M)、异亮氨酸(Isoleucine；I)及亮氨酸(Leucine；L)组成的组中的一种，n为1至10的整数，但上述通式1的氨基酸序列包括以序列2记载的RDG，同时，排除n＝1或2的情况。
发明的效果
本发明的肽显著抑制与自身免疫疾病相关的T细胞(T cell)的活性及Th17细胞分化，显著抑制白细胞介素6的分泌，在关节炎动物模型中，具有治疗及改善关节炎的效果，因此，上述肽可用作如骨病、炎症性疾病或类风湿性关节炎的各种自身免疫疾病治疗剂的有效成分。
附图说明
图1为示出通过本发明合成肽的活性T细胞种群(％)的图。
图2为示出通过本发明合成肽的T细胞活化抑制率(％)的图
图3为示出本发明合成肽的Th17细胞分化抑制功效的图。
图4为确认本发明合成肽减少作为炎症性细胞因子的白细胞介素6的效果的图。
图5为简要示出胶原蛋白诱导关节炎小鼠模型的制备过程及本发明的肽的给药时间的示意图。
图6为示出本发明的Pep1肽的关节炎改善效果的图。
图7为示出本发明的Pep4肽的关节炎改善效果的图。
图8为示出本发明的Pep6肽的关节炎改善效果的图。
图9为示出本发明的Pep7肽的关节炎改善效果的图。
图10为示出本发明的Pep8肽的关节炎改善效果的图。
图11为比较本发明的肽的关节炎改善效果的图。
具体实施方式
以下，定义本发明的术语。
在本发明中，不仅使用与天然氨基酸有关的常规1个及3个字母代码，还使用如Aib(α-氨基异丁酸)、Sar(肌胺酸(N-methylglycine))等的普遍接受其他氨基酸的3个字母代码。并且，在本说明书中以缩写提及的氨基酸遵循IUPAC-IUB命名法。
本发明的“肽(peptide)”为由通过酰胺键(或肽键)相连接的2个以上的氨基酸形成的聚合物，就本发明而言，意味着具有治疗骨病、炎症性疾病、自身免疫疾病的效果的肽。
在本发明中，“稳定性”不仅意味着从生物体内蛋白质裂解酶的攻击保护本发明的肽的体内稳定性，还意味着储存稳定性(例如，常温储存稳定性)。
在本发明中，“预防”意味着通过给药本发明的药学组合物来抑制疾病或延迟发病的所有行动。
在本发明中，“治疗”意味着通过给药本发明的药学组合物来使与疾病有关的症状好转或有利地改变疾病的所有行动。
在本发明中，“对象”意味着需要治疗疾病的对象，更具体地，意味着人或作为非人的灵长类、小鼠(mouse)、狗、猫、马及牛等的哺乳类。
在本发明中，“改善”意味着与治疗状态相关的参数，如减少症状程度的所有行动。
以下，更加详细地说明本发明。
本发明提供由以下述序列1记载的通式1的氨基酸序列构成的肽及包含上述肽作为有效成分的用于预防及治疗骨病、炎症性疾病或自身免疫疾病的药学组合物。
通式1：(X1-X2-X3)n
在上述式中，X1为选自由作为正电荷氨基酸(positive charged amino acid)的精氨酸、组氨酸及赖氨酸组成的组中的一种，X2为作为负电荷氨基酸(negative chargedamino acid)的天冬氨酸或谷氨酸，X3为选自由甘氨酸、丙氨酸、缬氨酸、蛋氨酸、异亮氨酸及亮氨酸组成的组中的一种，n为1至10的整数，但上述通式1的氨基酸序列包括以序列2记载的RDG，同时，排除n＝1或2的情况。
上述肽可利用上述通式1制备各种肽，这些均包括于本发明。并且，优选地，上述X1为精氨酸或组氨酸，上述X3为甘氨酸或丙氨酸，但并不限定于此。
并且，优选地，上述n为1至6的整数，更优选地，上述n为1至3。
可通过本领域公知的多种方法获取上述本发明的肽。如一例，可利用多核苷酸重组和蛋白表达系统制备或以通过如肽合成的化学合成在试验管内合成的方法及无细胞蛋白质合成法等制备。
并且，为了获取更好的化学稳定性、加强的药理特性(半衰期、吸收性、效价、功效等)、变更的特异性(例如，广泛的生物活性谱)、减少的抗原性，肽的N-或C-末端可与保护基相结合。优选地，上述保护基可以为乙酰基、芴甲氧羰基、甲酸基、棕榈酰基、肉豆蔻基、硬脂酰基或聚乙二醇(PEG)，但只要是可使肽改性，尤其，提高肽的稳定性的成分，就可无限制地包括。
优选地，上述骨病选自由关节炎、骨质疏松症、骨转移癌(bone metastaticcancer)、实体癌骨转移、实体癌骨转移引起的肌肉骨骼并发症、恶性肿瘤引起的高钙血症、多发性骨髓瘤、原发性(primary)骨肿瘤、牙周病、炎症性牙槽骨吸收疾病、炎症性骨吸收疾病及佩吉特氏病(Paget's disease)组成的组中的一种以上，但并不限定于此。
优选地，上述炎症性疾病选自由特应性皮炎、银屑病、皮肤炎、过敏、关节炎、鼻炎、中耳炎、咽喉炎、扁桃体炎、膀胱炎、肾炎、盆腔炎、克罗恩病、溃疡性结肠炎、强直性脊柱炎、全身性红斑狼疮(systemic lupus erythematodes，SLE)、哮喘、浮肿、迟发性过敏(IV型过敏)、移植排斥反应、移植物抗宿主病、自身免疫性脑脊髓炎、多发性硬化症、炎症性肠病、囊肿性纤维化、糖尿病视网膜病变、肺缺血再灌注损伤、血管再狭窄、肾小球肾炎及胃肠道过敏组成的组中，但并不限定于此。
优选地，上述自身免疫疾病选自由类风湿性关节炎(rheumatoid arthritis)、干燥综合症(Sjogren's syndrome)、系统性硬化症(systemic sclerosis)、多肌炎(polymyositis)、系统性脉管炎(systemic angitis)、混合性结蒂组织病(mixedconnective tissue disease)、克罗恩病(Crohn's disease)、慢性甲状腺炎(Hashimoto'sdisease)、格雷夫斯病(Grave's disease)、肺出血肾炎综合症(Goodpasture's sydrome)、格林-巴利综合征(Guillain-Barre syndrom)、特发性血小板减少性紫癜、肠易激综合征、重症肌无力、嗜睡症、寻常天疱疮、恶性贫血、原发性胆汁性肝硬化、溃疡性结肠炎、血管炎、韦格纳肉芽肿(Wegener's granulomatosis)及银屑病(Psoriasis)组成的组中，但并不限定于此。
并且，即使使用对本发明的肽进行编码的多聚核苷酸，也具有相同的治疗效果，因此，对本发明的肽进行编码的多聚核苷酸也包括于本发明，这是显而易见的。
在本发明的具体实施例中，本发明人利用上述通式1[(X1-X2-X3)n]来制备各种肽(参照表1)。
并且，本发明人确认上述肽的T细胞活性抑制效果的结果，表1的肽将T细胞活性显著降低至平均8％为止，其中，在图1至图2示出任一筛选的肽的T细胞活性抑制效果(参照图1至图2)。
并且，本发明人确认在上述实施例1中制备的合成肽抑制Th17细胞分化的功效的结果，本发明的肽显著抑制Th17细胞分化(参照图3)。
并且，本发明人确认上述肽的白细胞介素6分泌抑制效果的结果，与阳性对照组相似地，本发明的肽显著抑制白细胞介素6的分泌(参照图4)。
同时，本发明人在制备类风湿性关节炎动物模型后(参照图5)确认本发明的肽的治疗效果的结果，示出显著的关节炎改善效果，尤其，相比于阳性对照组MTX，示出相似的功效(参照图6至图11)。
因此，本发明的肽显著抑制与自身免疫疾病相关的T细胞的活性及Th17细胞(Thelper 17cell)分化，与阳性对照组相似地，抑制白细胞介素6分泌，在关节炎动物模型中，具有显著地治疗及改善关节炎的效果，因此，上述肽可用作如骨病、炎症性疾病或类风湿性关节炎的各种自身免疫疾病治疗剂的有效成分。
另一方面，本发明的肽或对其进行编码的多聚核苷酸可递送至如胶体悬浮液、粉末、盐水、脂质、脂质体、微球体(microspheres)或纳米球形粒子的医药上可接受的载体。这些可形成递送单元和复合物或与此相关，可使用如脂质、脂质体、微粒、金、纳米粒子、聚合物、聚合反应剂、多糖类、多胺基酸、树状聚合物、皂甙、吸附增强物质或脂肪酸的本领域公知的递送系统递送至生物体内。
此外，医药上可接受的载体可包括制剂时通常所利用的乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、橡胶、磷酸钙、海藻酸、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、羟基苯甲酸甲酯、丙基羟苯酸酯、滑石、硬脂酸镁及矿物油等，但并不限定于此。并且，除上述成分之外，还可包括润滑剂、湿润剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。
本发明的药学组合物可根据所需方法口服给药或肠外给药(例如，适用于肌肉、静脉、腹腔、皮下、皮内或局部)，给药量根据患者的状态及体重、疾病的程度、药物形态、给药路径及时间不同，普通技术人员可适当地选择。
本发明的药学组合物以药物有效量给药。在本发明中，“药物有效量”为以可适用于医学治疗的合理效益/风险比例治疗疾病的量，有效剂量水平可根据包括患者的疾病种类、严重程度、药物活性、药物敏感性、给药时间、给药路径及排出比例、治疗时间、同时使用的药物在内的要素及其他医学领域所公知的要素确定。本发明的药学组合物可作为单独治疗剂给药或与其他骨病、炎症性疾病或自身免疫疾病治疗剂同时给药，可与以往的骨病、炎症性疾病或自身免疫疾病治疗剂同时、单独或依次给药，能够以单剂量或多剂量给药。重要的是，考虑所有上述要素，并以无副作用且最小的量获取最大效果的量给药，普通技术人员可容易确定上述量。
具体地，本发明的药学组合物的有效量可根据患者年龄、性别、状态、体重、体内活性成分的吸收率、非活性率、排泄速度、疾病种类、并用的药物不同，可根据给药路径、肥胖的重症度、性别、体重、年龄等增加或减少。
同时，本发明提供包含本发明的肽或对其进行编码的多聚核苷酸作为有效成分的用于预防及改善骨病、炎症性疾病或自身免疫疾病的健康食品。
为了预防或改善疾病，上述健康食品可在相应疾病的发病之外或发病之后，与用于治疗的药剂同时使用或单独使用。
在本发明的健康食品中，可向食品直接添加有效成分，或可与其他食品或食品成分同时使用，可根据常规方法适当地使用。可根据其使用目的(预防或改善)适当地确定有效成分的混合量。通常，当制备食品或饮料时，相对于原料，优选地，添加15重量百分比以下的本发明的组合物，优选地，添加10重量百分比以下的本发明的组合物。但是，在以健康及卫生为目的或健康调节为目的长时间摄取的情况下，上述量可以为上述范围以下。
除包含上述有效成分之外，本发明的健康食品可不受特殊限制地将其他成分作为必要成分来包含。例如，如普通饮料，可将各种调味剂或天然碳水化合物等作为追加成分来包含。上述天然碳水化合物的例可以为单糖，如葡萄糖、果糖等；二糖，如麦芽糖、蔗糖等；以及多糖，如糊精、环糊精的常规糖，如木糖醇、山梨醇、赤藓糖醇等的糖醇。作为除上述之外的调味剂，可有利地适用天然调味剂(索马甜、甜叶菊提取物(例如，莱苞迪甙A、甘草甜素等))及合成调味剂(糖精、阿斯巴甜等)。可根据普通技术人员的选择适当地确定上述天然碳水化合物的比例。
除上述内容之外，本发明的健康食品可包含各种营养剂、微生物、矿物质(电解质)、合成香料及天然香料等的香料、着色剂及增强剂(奶酪、巧克力等)、果胶酸及其盐、褐藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇、用于碳酸饮料的碳酸化剂等。这种成分可单独使用或组合使用，普通技术人员可适当地选择这种添加剂的比例。
以下，通过实施例及实验例详细说明本发明。
但，下述实施例及实验例仅用于例示本发明，本发明的内容并不局限于下述实施例及实验例。
实施例1：制备肽
根据下述通式1制备了各种肽。之后，利用高性能液相色谱仪(SHIMADZUProminence HPLC)纯分离各个合成肽，柱利用资生堂液相色谱柱(Shiseido capcell pakC18 Column)(4.6×50mm)。并且，利用质谱仪(HP 1100series LC/MSD)确认各个合成肽的重量。
通式1：(X1-X2-X3)n
在上述式中，X1为选自由精氨酸、组氨酸及赖氨酸组成的组中的一种，X2为天冬氨酸或谷氨酸，X3为选自由甘氨酸、丙氨酸、缬氨酸、蛋氨酸、异亮氨酸及亮氨酸组成的组中的一种，n为1至10的整数，但上述通式1的氨基酸序列包括以序列2记载的RDG，同时，排除n＝1或2的情况。
同时，在下述表1罗列一部分的通过上述方法合成的肽。
表1
实验例1：确认T细胞活性抑制效果
为了确认在上述实施例1中制备的合成肽的T细胞活性抑制功效，通过使用从小鼠的淋巴结提取的T细胞执行体外(ex vivo)活性抑制实验。
具体地，首先，为了诱导T细胞的活化，向96孔板(96well plate)涂敷(coating)CD3抗体，在4℃的温度条件下培养(incubation)一夜(overnight)，从而制备粘附有CD3抗体的96孔板。之后，以1×105/well向96孔板插入(seeding)从小鼠提取的初始(naive)T细胞，对在上述实施例1中制备的各个合成肽进行处理并培养18小时后，通过流式细胞术(flow cytometry)确认活性T细胞的种群。为此，在所培养的各个组中收集(collection)相同数字的细胞，并利用磷酸盐缓冲液(PBS)清洗(wash)，之后，通过使用作为辅助(helper)T细胞标记的兔抗小鼠(rabbit anti-mouse)CD4和作为T细胞的活化标记的兔抗小鼠CD69抗体执行染色(staining)过程。利用磷酸盐缓冲液清洗之后，分析CD4+CD69+T细胞种群。
结果，经确认，在上述实施例1中合成的肽将T细胞活性显著抑制到平均8％为止。
并且，在图1至图2示出在上述实施例1合成的肽中的表2示出的肽的T细胞活性抑制效果。
具体地，相比于未诱导活化的组(1.6％)，在利用CD3抗体进行活化的组中，活性T细胞增加至85.2％，在对各个合成肽进行处理的组中，减少至77～82％为止。并且，与在实施例1中合成的肽相同地，各个合成肽的活性T细胞抑制率约为8％。
因此，本申请的合成肽显著抑制T细胞活性，可用于治疗自身免疫疾病(图1至图2)。
表2
实验例2：确认Th17细胞分化抑制效果
为了确认在上述实施例1中制备的合成肽抑制Th17细胞分化的功效，在从小鼠的淋巴结提取的初始CD4+T细胞中，与T细胞抗原受体(TCR)激活(activation)一同处理20ng/ml的白细胞介素6和5ng/ml的转化生长因子β(TGF-beta)来诱导分化为Th17细胞。
同时，以10～1000ng/ml的浓度分别处理在上述实验例1的表2揭示的3种肽(Pep1、Pep6、Pep8)。之后，培养3日，并分析CD4+白细胞介素17+T细胞种群。
结果，如图3所示，相比于未诱导分化为Th17细胞的组(1.2％)，在诱导Th17分化的组中，呈现增加约2.5倍的倾向(3.14％)，与未诱导分化的组相似地，在分别处理Pep1、Pep6、Pep8肽的组中，Th17细胞的比例减少(图3)。
实验例3：确认炎症性细胞因子——白细胞介素6减少效果
为了确认在上述实施例1中制备的合成肽抑制作为炎症性细胞因子的白细胞介素6分泌的功效，利用50ng/ml的丙二醇甲醚醋酸酯(PMA)对THP-1单核细胞系(THP-1monocytic cell line)进行48小时的处理，来分化为M1巨噬细胞(M1 macrophage)。在分化的M1巨噬细胞处理10ng/ml的脂多糖(LPS)和20ng/ml的干扰素(IFN-gamma)后，分别以100ng/ml的浓度对作为阳性对照组的MTX或本发明的合成肽进行混合处理(co-treatment)。之后，培养24小时后，通过使用cultured sup来实施白细胞介素6酶联免疫吸附试验(ELISA)。
结果，如图4所示，与阳性对照组相似地，白细胞介素6通过本发明的Pep2、Pep3、Pep5、Pep7、Pep8肽显著减少(图4)。
实验例4：确认利用胶原诱导关节炎(CIA)小鼠模型(Collagen-inducedarthritis(CIA)mouse model)的类风湿性关节炎治疗效果
4-1：制备类风湿性关节炎小鼠模型
为了确认在上述实施例1中制备的肽的类风湿性关节炎改善效果，参照公知文献(Nat Protoc.2007；2(5)：1269-75.)来制备类风湿性关节炎小鼠模型。
具体地，胶原诱导关节炎小鼠模型为具有与人的类风湿性关节炎相似特征的自身免疫疾病关节炎模型，为在类风湿性关节炎动物实验中最常使用的小鼠模型。在胶原诱导关节炎小鼠模型中，首先，以1：1混合牛的第2型胶原蛋白(Bovine type II collagen，Chondrex，USA)与弗氏完全佐剂(Freund’s complete adjuvant，Chondrex，USA)并乳化后，向6周龄的DBA/1J小鼠尾部皮内注射50ul的乳化的胶原蛋白溶液，来进行第一次免疫(immunization)。在第一次免疫后，在第2周以1：1混合牛的第2型胶原蛋白和弗氏不完全佐剂(Freund’s incomplete adjuvant，Chondrex，USA)并乳化后，向小鼠尾部皮内注射50ul的乳化的胶原蛋白溶液，来诱导第二次免疫(boosting)。在第二次免疫后，从次日开始以1周3次的频率腹腔给药各个肽，来观察肽的类风湿性关节炎治疗效果。所选择的给药肽为在表2揭示的5种肽(Pep1、Pep4、Pep6、Pep7、Pep8)(图5)。
4-2：确认利用类风湿性关节炎小鼠模型的治疗效果
为了观察基于本发明的肽处理的类风湿性关节炎的进展，以类风湿性关节炎进展指数评价并测定随着时间推移的类风湿性关节炎的严重程度。
对于具体实验条件，不知情的两名观察人员以一周三次的频率评价关节炎进展程度。在此情况下，关节炎进展指数根据下述表2的Rossoliniec等的关节炎进展评价基准，以每条腿0分至4分进行评价并以总分0分至16分(四条腿的合计)示出，之后，计算两名观察人员评价的结果的平均值来使关节炎的重症度数值化。
表3
| 分数 | 症状 |
| 0分 | 没有浮肿或肿胀 |
| 1分 | 观察到足部或踝关节的轻度浮肿和红肿 |
| 2分 | 观察到踝关节至跗骨的轻度浮肿和红肿 |
| 3分 | 观察到踝关节至跗骨的重度浮肿和红肿 |
| 4分 | 观察到脚踝至整个腿部的浮肿和红肿并伴有关节僵硬 |
结果，如图6至图11所示，可知，相比于正常小鼠(normal)组，在诱发胶原诱导关节炎的小鼠(载体控制(Vehicle control)；磷酸盐缓冲液(PBS))中，关节炎分注显著增加，在分别腹腔给药5种肽(Pep1、Pep4、Pep6、Pep7、Pep8)的组中，呈现关节炎改善功效。并且，呈现与阳性对照组MTX相似的功效(图6至图11)。
因此，经确认，本发明的肽可用作包括关节炎在内的各种骨病、自身免疫疾病治疗剂。
SEQUENCE LISTING
<110> 凯恩塞恩斯株式会社
<120> 作为自身免疫疾病及骨病治疗剂的肽的用途
<130> OPB2020-004CN
<150> KR 10-2017-0118950
<151> 2017-09-15
<150> KR 10-2017-0118952
<151> 2017-09-15
<150> KR 10-2018-0110481
<151> 2018-09-14
<150> KR 10-2018-0110485
<151> 2018-09-14
<150> PCT/KR2018/010874
<151> 2018-09-14
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> MISC_FEATURE
<222> (1)
<223> Xaa是精氨酸，组氨酸或赖氨酸
<220>
<221> MISC_FEATURE
<222> (2)
<223> Xaa是天冬氨酸或谷氨酸
<220>
<221> MISC_FEATURE
<222> (3)
<223> Xaa是甘氨酸，丙氨酸，缬氨酸，蛋氨酸，异亮氨酸或亮氨酸
<400> 1
Xaa Xaa Xaa
1
<210> 2
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 2
Arg Asp Gly
1
Claims (15)
1.一种肽，由以下述序列1记载的通式1的氨基酸序列构成，其特征在于，
通式1：(X1-X2-X3)n
在上述式中，X1为选自由精氨酸、组氨酸及赖氨酸组成的组中的一种，X2为天冬氨酸或谷氨酸，X3为选自由甘氨酸、丙氨酸、缬氨酸、蛋氨酸、异亮氨酸及亮氨酸组成的组中的一种，n为1至10的整数，但上述通式1的氨基酸序列包括以序列2记载的RDG，同时，排除n＝1或2的情况。
2.根据权利要求1所述的肽，其特征在于，上述X1为精氨酸或组氨酸。
3.根据权利要求1所述的肽，其特征在于，上述X3为甘氨酸或丙氨酸。
4.根据权利要求1所述的肽，其特征在于，上述n为1至6的整数。
5.根据权利要求1所述的肽，其特征在于，上述n为1至3的整数。
6.根据权利要求1所述的肽，其特征在于，上述肽的N-或C-末端与选自由乙酰基、芴甲氧羰基、甲酸基、棕榈酰基、肉豆蔻基、硬脂酰基及聚乙二醇组成的组中的保护基结合。
7.一种药学组合物，包含由以下述序列1记载的通式1的氨基酸序列构成的肽作为有效成分，用于预防及治疗骨病、炎症性疾病或自身免疫疾病，其特征在于，
通式1：(X1-X2-X3)n
在上述式中，X1为选自由精氨酸、组氨酸及赖氨酸组成的组中的一种，X2为天冬氨酸或谷氨酸，X3为选自由甘氨酸、丙氨酸、缬氨酸、蛋氨酸、异亮氨酸及亮氨酸组成的组中的一种，n为1至10的整数，但上述通式1的氨基酸序列包括以序列2记载的RDG，同时，排除n＝1或2的情况。
8.根据权利要求7所述的药学组合物，其特征在于，上述骨病为选自由关节炎、骨质疏松症、骨转移癌、实体癌骨转移、实体癌骨转移引起的肌肉骨骼并发症、恶性肿瘤引起的高钙血症、多发性骨髓瘤、原发性骨肿瘤、牙周病、炎症性牙槽骨吸收疾病、炎症性骨吸收疾病及佩吉特氏病组成的组中的一种以上。
9.根据权利要求7所述的药学组合物，其特征在于，上述炎症性疾病为选自由特应性皮炎、银屑病、皮肤炎、过敏、关节炎、鼻炎、中耳炎、咽喉炎、扁桃体炎、膀胱炎、肾炎、盆腔炎、克罗恩病、溃疡性结肠炎、强直性脊柱炎、全身性红斑狼疮、哮喘、浮肿、迟发性过敏(IV型过敏)、移植排斥反应、移植物抗宿主病、自身免疫性脑脊髓炎、多发性硬化症、炎症性肠病、囊肿性纤维化、糖尿病视网膜病变、肺缺血再灌注损伤、血管再狭窄、肾小球肾炎及胃肠道过敏组成的组中的一种。
10.根据权利要求7所述的药学组合物，其特征在于，上述自身免疫疾病为选自由类风湿性关节炎、干燥综合症、系统性硬化症、多肌炎、系统性脉管炎、混合性结蒂组织病、克罗恩病、慢性甲状腺炎、格雷夫斯病、肺出血肾炎综合症、格林-巴利综合征、特发性血小板减少性紫癜、肠易激综合征、重症肌无力、嗜睡症、寻常天疱疮、恶性贫血、原发性胆汁性肝硬化、溃疡性结肠炎、血管炎、韦格纳肉芽肿及银屑病组成的组中的一种。
11.一种健康食品，包含由以下述序列1记载的通式1的氨基酸序列构成的肽作为有效成分，用于预防及改善骨病、炎症性疾病或自身免疫疾病，其特征在于，
通式1：(X1-X2-X3)n
在上述式中，X1为选自由精氨酸、组氨酸及赖氨酸组成的组中的一种，X2为天冬氨酸或谷氨酸，X3为选自由甘氨酸、丙氨酸、缬氨酸、蛋氨酸、异亮氨酸及亮氨酸组成的组中的一种，n为1至10的整数，但上述通式1的氨基酸序列包括以序列2记载的RDG，同时，排除n＝1或2的情况。
12.一种骨病、炎症性疾病或自身免疫疾病的治疗方法，其特征在于，向患有骨病、炎症性疾病或自身免疫疾病的对象给药药物有效量的权利要求1所述的肽。
13.一种骨病、炎症性疾病或自身免疫疾病的预防方法，其特征在于，向对象给药药物有效量的权利要求1所述的肽。
14.一种肽的用途，其特征在于，将权利要求1所述的肽用作预防及治疗骨病、炎症性疾病或自身免疫疾病的药学组合物。
15.一种肽的用途，其特征在于，将权利要求1所述的肽用作预防及改善骨病、炎症性疾病或自身免疫疾病的健康食品。
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