CN113557034A - 包含与白蛋白结合的Slit3蛋白的LRRD2的用于预防或治疗骨相关疾病的组合物 - Google Patents
包含与白蛋白结合的Slit3蛋白的LRRD2的用于预防或治疗骨相关疾病的组合物 Download PDFInfo
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- CN113557034A CN113557034A CN202080016911.7A CN202080016911A CN113557034A CN 113557034 A CN113557034 A CN 113557034A CN 202080016911 A CN202080016911 A CN 202080016911A CN 113557034 A CN113557034 A CN 113557034A
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Abstract
本发明涉及包含与白蛋白结合的Slit3蛋白的LRRD2的用于预防或治疗骨相关疾病的组合物。
Description
技术领域
本发明涉及包含与白蛋白结合的Slit3蛋白的LRRD2的用于预防或治疗骨相关疾病的组合物。
背景技术
Slit蛋白是在神经系统的发育过程中调节神经元和轴突的运动而周知的蛋白质。Slit蛋白可与Robo受体相互作用来调节生理活性,作为在心脏、肺、肾脏、乳房组织等各种组织中起到调节各种细胞内过程的因子的作用而周知,最近,据报告,在细胞的生长、附着能力及迁移能力的调节中起到重要作用,并且,据报告,Slit蛋白可参与细胞的分化过程中的移动及癌症的产生和转移过程。
在这种背景下,本发明人揭示了如下的技术:Slit3的LRRD2在细胞及动物模型中增加骨形成,减少骨吸收,与骨质疏松症的发病率具有负相关关系,可有用地用作用于预防或治疗骨折或骨质疏松症的组合物及用于预测骨折或骨质疏松症发生风险的生物标记物(韩国授权专利第10-1617497号)。LRRD2通过注射剂向访问医院的患者给药,但体内半衰期非常短,为了发挥其药效,必须缩短给药周期,由此预测发生由于使用过多的药剂而降低功效的问题。
由此,本发明人研发了通过增强LRRD2的体内半衰期来改善其功效的HSA-Slit3LRRD2融合蛋白(HSA-Slit3 LRRD2 fusion protein),从而完成了本发明。
发明内容
技术问题
本发明的目的在于,提供改善Slit3蛋白的LRRD2的骨相关疾病的预防或治疗功效的组合物。
技术方案
为了解决如上所述的问题,本发明提供包含与白蛋白结合的Slit3蛋白的LRRD2的用于预防或治疗骨相关疾病的药学组合物。
根据本发明的优选一实施例,上述白蛋白可以为人血清白蛋白(human serumalbumin)。
根据本发明的优先再一实施例,上述人血清白蛋白可与Slit3蛋白的LRRD2的N-末端结合。
根据本发明的优选另一实施例,上述人血清白蛋白可包含SEQ ID NO:2的氨基酸序列。
根据本发明的还有一实施例,上述Slit3蛋白的LRRD2可包含SEQ ID NO:3的氨基酸序列。
根据本发明的优选又一实施例,在上述白蛋白与Slit3蛋白的LRRD2之间还可还包含连接子。
根据本发明的优选又一实施例,上述连接子为(GGGGS)n(SEQ ID NO:5),其中,n可以为1至10的整数。
根据本发明的优选又一实施例,上述药学组合物可通过注射剂给药。
根据本发明的优选又一实施例,上述骨相关疾病可以为选自由骨质疏松症(osteoporosis)、骨折、骨质流失、骨关节炎(osteoarthritis)、骨转移癌及佩吉特氏病(Paget's disease)组成的组中的一种以上。
发明的效果
本发明的与白蛋白结合的Slit3蛋白的LRRD2示出与未与白蛋白结合的Slit3蛋白的LRRD2相同的细胞学功效,与未与白蛋白结合的Slit3蛋白的LRRD2相比,体内半衰期显著增加,由此可更有效地预防或治疗骨相关疾病。
附图说明
图1示出本发明的白蛋白与Slit3 LRRD2的N-末端结合的融合蛋白的组成及其氨基酸序列。
图2示出分离纯化SP胱抑素S-HSA-Slit3 LRRD2融合蛋白后,执行十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)的结果。
图3示出各种形态的HSA-Slit3 LRRD2融合蛋白的受体结合能力的曲线图。
图4为示出确认根据处理各种形态的HSA-Slit3 LRRD2融合蛋白的成骨细胞的迁移的结果的图。
图5为示出确认根据处理各种形态的HSA-Slit3 LRRD2融合蛋白的破骨细胞的分化能力的结果的图。
图6为示出确认根据处理HSA-Slit3 LRRD2融合蛋白的成骨细胞的迁移(a)、成骨细胞的β-连环蛋白活性(b)及破骨细胞分化能力(c)的结果的图。
图7示出向禁食雄性ICR小鼠给药Slit3 LRRD2(●,“Slit3”)和HSA-Slit3LRRD2(■,“HSA-Slit3”)的IV后的Slit3 LRRD2的血浆浓度时间曲线图。
具体实施方式
如上所述,Slit3蛋白的LRRD2在细胞及动物模型中增加骨形成,减少骨吸收,由此可用于预防或治疗骨折或骨质疏松症,但体内半衰期非常短,为了发挥其药效,必须缩短给药周期,从而预测,发生由于使用过多的药剂而降低功效的问题。
由此,本发明人研发了通过增强LRRD2的体内半衰期来改善其功效的HSA-Slit3LRRD2融合蛋白,从而寻求如上所述的问题的解决方案。本发明的与白蛋白结合的Slit3蛋白的LRRD2示出与未与白蛋白结合的Slit3蛋白的LRRD2相同的细胞学功效,与未与白蛋白结合的Slit3蛋白的LRRD2相比,体内半衰期显著增加,由此可更有效地预防或治疗骨相关疾病。
以下,更详细地说明本发明。
本发明提供包含与白蛋白结合的Slit3蛋白的LRRD2的用于预防或治疗骨相关疾病的药学组合物。
在本发明的药学组合物中,“Slit3蛋白的LRRD2”是指Slit3蛋白内的第二个富亮氨酸重复结构域(leucine rich repeat domain,LRRD2)。
在本发明中,术语“Slit3 LRRD2”是指“Slit3蛋白的LRRD2”,可互换来使用。
在本发明的药学组合物中,上述白蛋白可以为人血清白蛋白、恒河猴(rhesus)血清白蛋白(RhSA)、食蟹猴(cynomolgous monkey)血清白蛋白(CySA)或者小鼠(murine)血清白蛋白(MuSA),优选为人血清白蛋白。在上述Slit3 LRRD2中,存在人血清白蛋白时的Slit3LRRD2的体内半衰期与不存在人血清白蛋白时的Slit3 LRRD2的体内半衰期相比至少长10倍。
在本发明的一具体实施例中,存在人血清白蛋白时的Slit3 LRRD2的血清半衰期与不存在人血清白蛋白时的Slit3 LRRD2相比长14倍。
在本发明的药学组合物中,人血清白蛋白和Slit3 LRRD2可按照人血清白蛋白及Slit3 LRRD2的顺序结合,或者按照其相反顺序结合。优选地,按照人血清白蛋白及Slit3LRRD2的顺序结合。例如,当人血清白蛋白与Slit3 LRRD2的N末端结合时,Slit3 LRRD2的体内半衰期及其骨相关疾病的治疗功效最优秀,当人血清白蛋白与C末端结合时,可具有程度差异,但可示出有效的功效。
在本发明的药学组合物中,上述人血清白蛋白可用作包含由609个氨基酸组成的全长或其一部分氨基酸序列的片段。人血清白蛋白的全长氨基酸序列在NCBI GenBank:AAA98797.1中公开,在本发明的一具体实施例中,使用在由609个氨基酸组成的全长人血清白蛋白中由第25个至第609个氨基酸(585个氨基酸)组成的片段的形态。在本发明的融合蛋白中,人血清白蛋白由下述SEQ ID NO:2的氨基酸序列组成。
DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL(SEQ ID NO:2)
在本发明的药学组合物中,上述Slit3 LRRD2是人源性的,可用作包含由1523个氨基酸组成的Slit3蛋白内的LRRD2的全长或其一部分氨基酸序列的片段。Slit3蛋白的全长氨基酸序列在NCBI GenBank:AAQ89243.1中公开,在本发明的一具体实施例中,Slit3LRRD2使用在由1523个氨基酸组成的全长Slit3蛋白中由第278个至第486个氨基酸(209个氨基酸)组成的片段的形态。在本发明的融合蛋白中,Slit3 LRRD2由下述SEQ ID NO:3的氨基酸序列组成。
ISCPSPCTCSNNIVDCRGKGLMEIPANLPEGIVEIRLEQNSIKAIPAGAFTQYKKLKRIDISKNQISDIAPDAFQGLKSLTSLVLYGNKITEIAKGLFDGLVSLQLLLLNANKINCLRVNTFQDLQNLNLLSLYDNKLQTISKGLFAPLQSIQTLHLAQNPFVCDCHLKWLADYLQDNPIETSGARCSSPRRLANKRISQIKSKKFRCS(SEQ ID NO:3)
在本发明的药学组合物中,“Slit3 LRRD2”可包含与SEQ ID NO:3的氨基酸序列的功能等价物。
上述“功能等价物”是指如下的蛋白质或肽:由于蛋白质或肽的氨基酸附加、取代或缺失,与本发明的SEQ ID NO:1至SEQ ID NO:4的氨基酸序列至少具有70%以上的序列同源性,优选地,具有80%以上的序列同源性,更优选地,具有90%以上的序列同源性,更加优选地,具有95%以上的序列同源性,示出与由SEQ ID NO:1至SEQ ID NO:4的氨基酸序列组成的蛋白质或肽实质上相同的生理活性。
具体地,包含在本发明的药学组合物的融合蛋白不仅可包含具有其野生型氨基酸序列的蛋白质或肽,其氨基酸序列变体也可包含在本发明的范围内。上述氨基酸序列变体是指Slit3 LRRD2的野生型氨基酸序列通过一种以上的氨基酸残基的缺失、插入、非保守或保守取代或它们的组合具有不同序列的蛋白质或肽。
可在整体上不变更分子活性的蛋白质及肽中交换氨基酸是本领域公知的(H.Neurath,R.L.Hill,The Proteins,Academic Press,New York,1979)。最常见的交换是氨基酸残基Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Thy/Phe、Ala/Pro、Lys/Arg、Asp/Asn、Leu/Ile、Leu/Val、Ala/Glu、Asp/Gly之间的交换。根据情况还可通过磷酸化(phosphorylation)、硫化(sulfation)、乙酰化(acetylation)、糖基化(glycosylation)、甲基化(methylation、法尼基化(farnesylation)等修饰(modification)。
本发明的Slit3 LRRD2或其变体从天然提取或合成(Merrifleld,J.Amer.chem.Soc.85:2149-2156,1963)或者可通过基于脱氧核糖核酸(DNA)序列的基因重组方法制备(Sambrook et al,Molecular Cloning,Cold Spring Harbour LaboratoryPress,New York,USA,第2版,1989)。
在本发明的药学组合物中,在白蛋白与Slit3蛋白的LRRD2之间还可包含连接子。优选的连接子的种类可以为(GGGGS)n(SEQ ID NO:5),其中,n可以为1至10的整数,优选地,n可以为1至5的整数。
为了增强其体内半衰期,除白蛋白融合之外,本发明的Slit3 LRRD2可执行免疫球蛋白G(IgG)的Fc蛋白融合或聚乙二醇化(PEGylation)等。
本发明的药学组合物可以为各种口服剂型或肠胃外剂型。当将上述药学组合物剂型化时,可通过使用一种以上的缓冲剂(例如,生理盐水或磷酸盐缓冲液(PBS))、抗氧化剂、抑菌剂、络合剂(例如,乙二胺四乙酸(EDTA)或谷胱甘肽)、填充剂、增量剂、结合剂、佐剂(例如,氢氧化铝)、悬浮剂、增稠剂、湿润剂、崩解剂或表面活性剂、稀释剂或赋形剂来配制。
用于口服给药的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,这种固体制剂可通过向一种以上的化合物混合一种以上的赋形剂来配制,上述赋形剂可例举淀粉(包括玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉等)、碳酸钙(calciumcarbonate)、蔗糖(sucrose)、乳糖(lactose)、右旋糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、纤维素、甲基纤维素、羧甲基纤维素钠及羟丙基甲基纤维素或明胶等。例如,将活性成分与固体赋形剂混合后粉碎其,添加适合的辅助剂后加工成颗粒混合物,由此可获取片剂或糖衣丸。
并且,除简单的赋形剂之外,还使用如硬脂酸镁、滑石粉等的润滑剂。用于口服给药的液相制剂有悬浮剂、口服溶液、乳剂或糖浆剂等,除经常使用的简单稀释剂的水、液体石蜡之外,还可包含各种赋形剂,例如湿润剂、甜味剂、芳香剂或保存剂等。并且,可根据情况添加交联聚乙烯吡咯烷酮、琼脂、海藻酸或海藻酸钠等作为崩解剂,还可包含如抗凝剂、润滑剂、湿润剂、香料、乳化剂及防腐剂等。
用于肠胃外给药的制剂包括无菌水溶液、非水溶剂、悬浮溶剂、乳剂、冻干制剂或栓剂等。可使用丙二醇(propylene glycol)、聚乙二醇、如橄榄油的植物油、如油酸乙酯的可注射的酯等作为非水溶剂及悬浮溶剂。可使用witepsol、聚乙二醇(macrogol)、吐温(tween)61、可可脂、月桂脂、甘油、明胶等作为栓剂的基质。
本发明的药学组合物可口服给药或肠胃外给药,当肠胃外给药时,可根据本领域公知的方法剂型化为如下形态:皮肤外用;腹腔内注射、直肠注射、静脉注射、肌肉注射、皮下注射、子宫内注射、硬膜注射或脑血管内注射的注射剂;透皮给药剂;或者鼻腔吸入剂。
在上述注射剂的情况下,必须进行消毒,并保护其免受如细菌及真菌的微生物的污染。在注射剂的情况下,适合的载体可例举水、乙醇、多元醇(例如,甘油、丙二醇及液体聚乙二醇等)、它们的混合物和/或包含植物油的溶剂或分散介质,但并不限定于此。更优选地,适合的载体可使用Hanks溶液、林格氏液、包含三乙醇胺的磷酸盐缓冲液(phosphatebuffered saline)或如注射用无菌水、10%乙醇、40%丙二醇及5%葡萄糖的等渗溶液等。为了保护上述注射剂免受微生物的污染,还可包含如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等的抗菌剂及抗真菌剂。并且,在大部分的情况下,上述注射剂还可包含如糖或氯化钠等的等渗剂。
在透皮给药剂的情况下,包括软膏剂、霜剂、乳剂、凝胶剂、外用溶液剂、糊剂、搽剂、气雾剂等形态。在上文中,透皮给药是指将药学组合物局部给药至皮肤来使得包含在药学组合物的有效量的活性成分传递至皮肤中。
在吸入给药剂的情况下,根据本发明使用的融合蛋白可使用适合的推进剂,例如二氯氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他适合的气体,由此可便利地从加压包或雾化器以气溶胶喷雾形态传递。在加压气溶胶的情况下,可提供传递计量的量的阀来确定给药单位。例如,用于吸入器或吹入器的明胶胶囊及药筒可剂型化为包含化合物及乳糖或如淀粉的适合的粉末基质的粉末混合物。用于肠胃外给药的剂型记载于通常在所有制药化学中公知的处方文献(Remington's Pharmaceutical Science,15th Edition,1975.Mack Publishing Company,Easton,Pennsylvania 18042,Chapter 87:Blaug,Seymour)。
本发明的药学组合物以药剂学有效量给药。在本发明中,“药剂学有效量”是指足以能够以适用于医学治疗的合理的获益/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、药物的活性、对于药物的敏感性、给药时间、给药途径及排泄率、治疗时间、同时使用的药物在内的因素及其他医学领域中周知的因素确定。本发明的药学组合物可作为单独治疗剂给药或可与其他治疗剂组合给药,可与现有的治疗剂依次给药或同时给药,可单次给药或多次给药。即,本发明组合物的总有效量能够以单剂量(singledose)给药至患者,可通过多剂量(multiple dose)长期给药的分次治疗方法(fractionated treatment protocol)给药。考虑如上所述的所有因素,重要的是以无副作用的最小量获取最大效果的量给药,普通技术人员可容易确定其。
本发明药学组合物的剂量的范围根据患者的体重、年龄、性别、健康状态、饮食、给药时间、给药方法、排泄率及疾病的严重程度不同。作为一日剂量,当肠胃外给药时,以HSA-Slit3 LRRD2为基准,优选地,每1kg的体重每天给药0.01mg至50mg,更优选地,给药0.1mg至30mg的量,并且,当口服给药时,以本发明的HSA-Slit3 LRRD2为基准,优选地,每1kg的体重每天给药0.01mg至100mg,更优选地,给药0.01mg至10mg的量,可每天给药一次或多次。但是,可根据给药途径、肥胖的严重程度、性别、体重、年龄等增减,因此,上述剂量不以任何方法限定本发明的范围。
本发明的药学组合物可单独使用,或者可与手术、放射疗法、激素疗法、化学疗法及使用生物反应调节剂的方法组合使用。
本发明的药学组合物还能够以外用剂的剂型提供。当将本发明的用于预防及治疗肌肉疾病的药学组合物用作皮肤外用剂时,还可包含脂肪物质、有机溶剂、增溶剂、增稠剂及凝胶剂、软化剂、抗氧化剂、悬浮剂、稳定剂、发泡剂(foaming agent)、芳香剂、表面活性剂、水、离子型乳化剂、非离子型乳化剂、填充剂、螯合剂、络合剂、保存剂、维生素、阻断剂、湿润剂、精油、染料、颜料、亲水活性剂、亲油活性剂或脂囊泡等如在皮肤外用剂中通常使用的任意其他成分的在皮肤科学领域中通常使用的助剂。并且,上述成分能够以在皮肤科学领域中通常使用的量引入。
在本发明的用于预防及治疗骨相关疾病的药学组合物作为皮肤外用剂提供的情况下,可以为软膏、贴剂、凝胶、霜剂或喷雾剂等的剂型,但并不局限于此。
本发明的骨相关疾病是指骨吸收增加或骨形成减少,例如,骨形成少于骨吸收而使骨量减少而诱发的疾病,更优选为选自由骨质疏松症、骨折、骨质流失、骨关节炎、骨转移癌及佩吉特氏病组成的组中的一种以上,但并不限定于此。
并且,本发明提供包含与白蛋白结合的Slit3蛋白的LRRD2的用于预防或改善骨相关疾病的保健功能食品组合物。包含在本发明的保健功能食品组合物的有效成分的组成及其效果与前述的药学组合物的说明相同,因此将省略其记载。
本发明的保健功能食品组合物可根据本领域公知的常规方法制备为各种形态。可在作为普通食品的饮料(包括酒精饮料)、水果及其加工食品(例:水果罐头、瓶装食品、酱、果酱等)、鱼类、肉类及其加工食品(例:火腿、香肠等)、面包类及面类(例:乌冬面、荞麦面、拉面、意大利面、通心粉等)、果汁、各种饮料、饼干、糖浆、乳制品(例:黄油、奶酪等)、食用植物油、人造黄油、植物蛋白、蒸煮食品、冷冻食品、各种调味料(例:大奖、酱油、调味汁等)等添加本发明的HSA-Slit3 LRRD2融合蛋白来制备,但并不限定于此。并且,作为营养补充剂可向胶囊、片剂、丸剂等添加本发明的HSA-Slit3 LRRD2融合蛋白来制备,但并不限定于此。并且,例如,作为保健功能食品可将本发明的HSA-Slit3LRRD2融合蛋白本身制备为茶、果汁及饮料的形态,来以能够饮用(健康饮料)的方式液相化、颗粒化、胶囊化及粉末化来摄取,但并不限定于此。并且,为了以食品添加剂的形态使用本发明的HSA-Slit3 LRRD2融合蛋白,能够以粉末或浓缩液形态制备来使用。并且,可将本发明的HSA-Slit3 LRRD2融合蛋白与以具有预防骨相关疾病及改善肌功能效果而周知的公知的活性成分一同混合来制备为组合物的形态。
在将本发明的HSA-Slit3 LRRD2融合蛋白用作健康饮料的情况下,如通常的饮料,上述健康饮料组合物可包含各种香味剂或天然碳水化合物等作为追加成分。如上所述的天然碳水化合物可以为如葡萄糖、果糖的单糖、如麦芽糖、蔗糖的二糖、如糊精、环糊精的多糖、如木糖醇、山梨糖醇、赤藓糖醇等的糖醇。甜味剂可使用如索马甜、甜菊苷提取物的天然甜味剂、如糖精、阿斯巴甜的合成甜味剂等。通常,每100mL的本发明的组合物的上述天然碳水化合物的比例约为0.01g~0.04g,优选为约0.02g~0.03g。
并且,本发明的HSA-Slit3 LRRD2融合蛋白可作为用于预防或改善骨相关疾病的食品组合物的有效成分包含,其量为可实现骨相关疾病的预防或改善效果的有效量,优选地,相对于整个组合物的总重量,为0.01重量百分比至100重量百分比,但并不限定于此。本发明的保健功能食品组合物可通过将HSA-Slit3 LRRD2融合蛋白与对于骨相关疾病有效而周知的其他活性成分混合来制备。
除上述之外,本发明的保健功能食品组合物可包含各种营养剂、维生素、电解质、风味剂、着色剂、果胶酸、果胶酸盐、海藻酸、海藻酸盐、有机酸、保护性胶体增稠剂、pH值调节剂、稳定剂、防腐剂、甘油、醇或碳酸化剂等。此外,本发明的健康食品可包含用于制备天然果汁、果汁饮料或蔬菜饮料的果肉。这种成分可单独使用或混合使用。虽并不重要,这种添加剂的比例如下,即,相对于100重量份的本发明的组合物,通常在0.01重量份~0.1重量份的范围内选择。
以下,通过实施例更详细地说明本发明。这些实施仅用于例示本发明,不应解释为本发明的范围局限于这些实施例,这对普通技术人员而言是显而易见的。
在下述实施例中使用的简称及其含义如下述表1所示。
表1
本发明的实施方式
实施例1
制备HSA-Slit3 LRRD2融合蛋白
在Expi293F悬浮液细胞转染1.6mg/ml的PC DNA 3.1载体SP胱抑素S-HSA-Slit3LRR D2-FLAG DNA来进行表达。在125ml的293F细胞悬浮液中,将细胞培养至4.5×106细胞/ml~5×106细胞/ml为止,仅更换新培养基后,将400μl的Expifectamine和7.5ml的Opti-mem(A样品)在常温条件下反应5分钟,将150ug的DNA、7.5ml的Opti-mem(B样品)在常温条件下反应5分钟后,将A样品和B样品相混合来在常温条件下反应20分钟并进行转染。24小时后,将增强子1和增强子2混合处理后培养7天。
对于培养7天的培养液,通过离心机在4℃的温度、8000rpm的条件下将细胞沉淀20分钟后,利用康宁(corning)公司的0.22μm的过滤器过滤上清液来使用。作为树脂,使用Sigma公司的抗-FLAG树脂来进行。树脂分别使用1.2ml,在4℃的温度、1ml/分钟的速度下进行纯化。流入树脂的20倍的利用TBS(Tris Glycine,pH值为7.4)的洗涤缓冲液。当进行洗脱时,混合200μl的Sigma公司的FLAG肽和9.8ml的TBS来使用,每馏分(fraction)为500μl,共获取8个馏分,收集蛋白质馏分并将缓冲液更换为杜尔贝科磷酸盐缓冲液(DPBS)来浓缩后,测定浓度。
图2为示出通过上述过程分离纯化融合蛋白后执行十二烷基硫酸钠-聚丙烯酰胺凝胶电泳的结果的图,确认了在本实施例中制备的图1中示出的融合蛋白的大小为75KDa。
实施例2
确认各种形态的HSA-Slit3 LRRD2融合蛋白的受体结合能力
2-1.制备各种形态的HSA-Slit3 LRRD2融合蛋白
基于实施例1的制备方法,制备了如下述表2的12种不同的HSA-Slit3 LRRD2融合蛋白。连接子使用(GGGGS)3(SEQ ID NO:6)。
表2
在表3示出上述12种HSA-Slit3 LRRD2融合蛋白的氨基酸序列。
表3
在上述表3中,通过下划线表示的序列为连接HAS与LRRD2的GS连接子,通过粗体表示的序列为连接为了以最终形态表达融合蛋白而在C-末端附加的序列的GS连接子。
2-2.确认各种形态的HSA-Slit3
LRRD2融合蛋白的受体结合能力
对于骨细胞的Slit3 LRRD2的作用通过Robo1及Robo2受体介导。因此,在本实施例中,确认了在实施例2-1中制备的12种HSA-Slit3 LRRD2融合蛋白的Robo1受体结合能力。通过使用酶联免疫吸附测定(ELISA)系统来定量12种HSA-Slit3 LRRD2融合蛋白与受体的结合能力。详细条件如下。
12种HSA-Slit3 LRRD2融合蛋白考虑分子量来在4℃的温度下向96-孔Maxisorp微量滴定板(microtiter plates)(NUNC公司)涂敷18小时,以使每孔成为0nM、1nM、10nM、100nM、1000nM。使用包含0.05%的吐温20的磷酸盐缓冲液(PBST)洗涤3次涂敷的物质。为了阻断非特异性结合,使用添加有1%的牛血清白蛋白(BSA)的磷酸盐缓冲液在室温条件下阻断2小时。为了去除阻断缓冲液,利用磷酸盐缓冲液洗涤3次。将洗涤后从作为成骨细胞的MC3T3-E1细胞株获取的30ug的蛋白(裂解缓冲液(lysis buffer):0.5%的NP40、50mM的Tris pH值为7.5、150mM的NaCl、1mM的乙二胺四乙酸、0.2mM的NaF、1mM的Na3VO4、1mM的二硫苏糖醇(DTT)、1mM的苯甲基磺酰氟(PMSF)、蛋白酶抑制剂混合物(Proteinase inhibitorcocktail))在室温条件下附着2小时。使用磷酸盐缓冲液洗涤3次后,将利用0.1%的牛血清白蛋白以1∶1000稀释的Robo1抗体(abcam:ab7279)在室温条件下附着2小时。使用磷酸盐缓冲液洗涤3次后,将利用0.1%的牛血清白蛋白以1∶2000稀释的辣根过氧化物酶(HRP)结合抗体(细胞信号传导(cell signaling):7074)在室温条件下附着2小时。利用磷酸盐缓冲液洗涤5次后,利用四甲基联苯胺(TMB)溶液在37℃的温度下反应30分钟。为了终止上述反应,使用100μl的1N H2SO4,在450nm的波长下测定吸光度。
结果如图3所示,确认了LRRD2-3与LRRD2-6的受体结合能力最为优秀。
实施例3
确认各种形态的HSA-Slit3 LRRD2融合蛋白的细胞学功效
在本实施例中,观察根据处理在实施例2-1中制备的12种HSA-Slit3 LRRD2融合蛋白的成骨细胞的迁移及破骨细胞分化能力,由此确认了其细胞学功效。
3-1.测定成骨细胞的迁移
为了测定细胞迁移,使用了Boyden腔室系统(侵袭小室(transwell),8um孔(pores))。在添加有0.2%的胎牛血清的MEM-α培养基稀释作为成骨细胞株的MC3T3-E1细胞株(1×105),在内侧腔室(inner chamber)附着6小时后,在外侧腔室(outer chamber)处理药物24小时。对于侵入的(invaded)细胞,利用包含固定液(fixing solution)的结晶紫溶液处理10分钟后,通过光学显微镜测量细胞数量。
结果如图4所示,确认了LRRD2-3的成骨细胞的迁移最为优秀。
3-2.测定破骨细胞的分化能力
从6周龄的ICR小鼠股骨和胫骨提取破骨祖细胞后,在温度为37℃的培养仪中培养18小时。仅收集漂浮的细胞,并利用30ng/ml的M-CSF和30ng/ml的RANKL处理来分化为破骨细胞。4天后,利用TRAP染色溶液(白细胞酸性磷酸酶(Leukocyte acid phosphatase))反应10分钟后,将TRAP染色的核为3个以上的多核细胞视为破骨细胞,并通过光学显微镜测量细胞数量。
结果如图5所示,确认了LRRD2-3和LRRD2-6的破骨细胞分化抑制能力与剩余10种HSA-Slit3 LRRD2融合蛋白相比更优秀。
实施例4
确认HSA-Slit3 LRRD2融合蛋白的细胞学功效
在本实施例中,基于实施例2和实施例3的结果,在细胞中选定功效最为优秀的LRRD2-3,并比较观察与未与白蛋白结合的Slit3 LRRD2的成骨细胞的迁移、成骨细胞的b-连环蛋白活性及破骨细胞的分化抑制能力。
4-1.测定成骨细胞的迁移
为了测定细胞迁移,使用了Boyden腔室系统(侵袭小室,8um孔)。在添加有0.2%的胎牛血清的MEM-α培养基稀释作为成骨细胞株的MC3T3-E1细胞株(1×105),在内侧腔室附着6小时后,在外侧腔室处理药物24小时。对于侵入的细胞,利用包含固定液的结晶紫溶液处理10分钟后,通过光学显微镜测量细胞数量。
结果如图6的(a)部分所示,LRRD2-3以与未与白蛋白结合的Slit3 LRRD2相同程度促进成骨细胞迁移。
4-2.测定成骨细胞的b-连环蛋白活性
将MC3T3-E1细胞株(2×104/孔)在24孔板培养18小时后,将100ng的8xSuperTOPFlash和10ng的Renilla报告质粒(Renilla reporter plasmid)转染至细胞。48小时后,使用双荧光素酶报告分析(Dual luciferase reporter assay)试剂盒来测定萤光素酶活性。
结果如图6的(b)部分所示,LRRD2-3以与未与白蛋白结合的Slit3 LRRD2相同程度激活成骨细胞的b-连环蛋白。
4-3.测量破骨细胞的分化能力
从6周龄的ICR小鼠股骨和胫骨提取破骨祖细胞后,在温度为37℃的培养仪中培养18小时。仅收集漂浮的细胞,并利用30ng/ml的M-CSF和30ng/ml的RANKL处理来分化为破骨细胞。4天后,利用TRAP染色溶液(白细胞酸性磷酸酶(Leukocyte acid phosphatase))反应10分钟后,将TRAP染色的核为3个以上的多核细胞视为破骨细胞,并通过光学显微镜测量细胞数量。
结果如图6的(c)部分所示,LRRD2-3以与未与白蛋白结合的Slit3 LRRD2相同的程度抑制破骨细胞的分化。
实施例5
小鼠中的Slit3 LRRD2及HSA-Slit3 LRRD2融合蛋白的药代动力研究
药代动力学研究为在新药开发过程中的一部分,通过根据时间的体内药物浓度的变化评价来获取与试验药物的吸收、分布、代谢及排泄有关的信息为目标。在本实施例中,单次静脉给药Slit3 LRRD2-3及HSA-Slit3 LRRD2融合蛋白(LRRD2-3)后,在小鼠中确认药代动力特性。
5-1.化学物质及溶剂从Sigma Aldrich公司购入在本实施例中使用的卡马西平(carbamazepine),乙腈和甲醇为HPLC级,从J.T.Baker公司购入。
5-2.动物及给药条件
在本实施例中,使用体重在30g~32.5g范围内的ICR类雄性小鼠(6周龄,Orientbio Inc.,城南,韩国)。实验前,小鼠禁食4小时,并将禁食保持至给药后4小时为止。饲养场以12小时提供明暗,并保持适当温度(20℃~25℃)及湿度(40%~60%)。
表4
药代动力试验
给药物质 | 动物数量 | 剂量 |
Slit3 LRRD2 | 4 | 10mg/kg |
HSA-Slit3 LRRD2(LRRD2-30) | 3 | 35mg/kg |
总计 | 7 | - |
将Slit3 LRRD2以1mg/mL的容量溶解于磷酸盐缓冲液来准备。在HSA-Slit3LRRD2(LRRD2-3)的情况下,考虑分子量,以3.5mg/mL的容量(作为Slit3LRRD2,1mg/mL)溶解于磷酸盐缓冲液来准备。两组剂量均为10mL/kg,通过左侧尾静脉给药。
5-3.药代动力试验
在药代动力试验的情况下,通过尾静脉向禁食的小鼠分别给药10mg/kg及35mg/kg的Slit3 LRRD2和HSA-Slit3 LRRD2(LRRD2-3)。给药后,分别在0.05小时、0.12小时、0.33小时、1小时、3小时、7小时、10小时、24小时、48小时及72小时,用手固定小鼠后,用涂有肝素的毛细管从右侧眼眶静脉丛采集70μL的血液。将采集的血液离心分离5分钟后,分离血浆并直至分析前为止在-20℃的温度下冷冻保存。
5-4.分析方法
在血浆试样中,利用HPLC/MS/MS系统定量Slit3 LRRD2的浓度。在预处理试样前,利用Ni-NTA磁珠纯化血浆试样。向纯化的Slit3 LRRD2及HSA-Slit3LRRD2(LRRD2-3)添加6M的尿素和18mM的二硫苏糖醇(DTT)并改性后,利用225mM的碘乙酰胺诱导烷基化。之后,为了获取信号肽(signature peptide),添加850ng的重组猪胰蛋白酶(V5117,Promega,Madison,WI,USA)来在设定为37℃的恒温水箱(water bath)反应24小时。向70μL的反应后生成的胰蛋白酶消化物添加50μL的溶解在MeOH的3%的甲酸后,利用旋涡混合器(vortexmixer)将混合试样悬浮10分钟,在13500rpm的条件下离心分离10分钟,取出160μL的上清液并移入分析容器后,将其中的5μL注入至HPLC/MS/MS系统来进行分析。
详细的分析条件如下。
-HPLC系统:Agilent 1100(Agilent Technologies,Santa Clara,CA)
-流动相(Mobile phase):
A:溶解在蒸馏水的0.1%的甲酸
B:乙腈
(等度洗脱)
-流速:300μL/min
-温度:在柱中为20℃,在自动进样器托盘(autosampler tray)中为10℃
-运行时间:5分钟
-幕气(curtain gas):20psi
-离子源气体1(ion source gas 1):50psi
-离子源气体2(ion source gas 2):60psi
-离子喷雾电压(ionspray voltage):5500V
-温度:600℃
-多反应监测(multiple-reaction-monitoring,MRM)模式:阳性
Silt3 LRRD2的信号肽(P6)的分子离子被23V的碰撞能量(collision energy)断裂,碰撞气体(collision gas)在设备中设置为“medium(8psi)”。在ESI阳性多反应监测模式下检测离子,在m/z 587.97→491.50的条件下定量P6。利用Analyst software version1.4.2(Applied Biosystems/MDS SCIEX)进行检测峰值的积分。血浆中的Silt3 LRRD2的可定量的范围为1μg/mL~100μg/mL,在HSA-Silt3 LRRD2(LRRD2-3)的情况下,为3μg/mL~100μg/mL。在该分析中,Slit3LRRD2示出3.29分钟的峰保留时间。
5-5.数据分析
利用在上述实施例5-4记载的LC-MS/MS分析法获取根据时间的血浆中的CNC00000的浓度,通过4.2(Pharsight Corp.,Cary,NC,USA)软件的非区划的分析法(non-compartmental analysis)计算药代动力学参数(PK parameters)。最高浓度(Cmax)和达到最高浓度的时间(Tmax)通过根据血浆药物浓度和时间的曲线随时间获取,耗散速率常数(Ke)在对数尺度(log sca le)的末期(terminal phase)通过线性回归模型计算。通过将LN2除以Ke来求得半衰期(T1/2),通过线性梯形法则(linear trapezoidal rule)和标准面积外推法(standard area extrapolation method)计算血药浓度与时间曲线下的面积(AUC0-∞)及血药时刻与时间曲线下的面积(AUMC0-∞)。通过下述式1至式3计算清除率(clearance,CL)和稳态分布容积(steady state volume of distribution,Vss)。
式1:
式2:
Vss=MRTXCL
式3:
5-6.结果
在图7及表5、表6示出根据时间的血浆内Slit3 LRRD2及HSA-Slit3 LRR D2(LRRD2-3)的浓度,在表6示出药代动力学参数。计算每个个体的相关参数和所有值后以平均示出。参照根据时间的血中浓度模式和动物实验记录,在数据分析中排除具有异常的个体组,用于数据解释的实验组至少为n=3以上。
表5
静脉内给药Slit3后的血浆浓度
*BQL:低于定量限时处理为“0”。
表6
静脉给药HSA-Slit3(LRRD2-3)后的血浆浓度
*BQL:低于定量限时处理为“0”。
如可在下述表7确认,HSA-Slit3 LRRD2融合蛋白(LRRD2-3)示出与Slit3LRRD2相比改善约14倍的半衰期。
表7
实施例6
确认HSA-Slit3 LRRD2融合蛋白的生物体功效
对于12周龄的SCID小鼠处理未与白蛋白结合的Slit3 LRRD2或HSA-Slit3 LRRD2融合蛋白(LRRD2-3),共处理4周。各药物通过静脉注射给药,每天给药一次,每周给药5次,Slit3 LRRD2每天注射10mg,HSA-Slit3 LRRD2融合蛋白(LRRD2-3)每天注射37.13mg(Slit3LRRD2相当于每天10mg)。给药前后测量小动物用骨密度,并确认其变化幅度,在下述表8示出其结果。
表8
*BMD:骨矿物质密度(one mineral density),单位面积BMC
*BMC:骨矿物质含量(bone mineral content)
*P<0.05,vs.未处理对照组
如表8所示,未与白蛋白结合的Slit3 LRRD2的BMD及BMC得以改善,但并未统计学上显著增加,HSA-Slit3 LRRD2融合蛋白(LRRD2-3)示出BMD及BMC均显著改善的效果。由此确认了,HSA-Slit3 LRRD2融合蛋白(L9RRD2-3)与未与白蛋白结合的Slit3 LRRD2相比示出更强的骨相关疾病治疗效果。
产业上的可利用性
本发明的与白蛋白结合的Slit3蛋白的LRRD2示出与未与白蛋白结合的Slit3蛋白的LRRD2相同的细胞学功效,与未与白蛋白结合的Slit3蛋白的LRRD2相比,显著增加体内半衰期,由此可更加有效地预防或治疗骨相关疾病。
支持本发明的韩国国家研究研发项目如下。
(1)支持本发明的韩国国家研究研发项目
课题唯一编号:2017-1229(HI15C0377010017)
部门名:保健福祉部
研究管理主管机构:韩国保健产业振兴院
研究项目名:疾病中心中介重点研究
研究课题名:具有骨形成促进作用的巨核细胞分泌因子发掘
贡献率:75/100
主办机构:首尔峨山医院
研究时间:2017年09月07日~2018年09月06日
(2)支持本发明的韩国国家研究研发项目
课题唯一编号:2013-2234(HI13C1634060018)
部门名:保健福祉部
研究管理主管机构:韩国保健产业振兴院
研究项目名:疾病中心中介重点研究
研究课题名:Slit3 LRRD2的药代动力学研究及利用Slit3 TG小鼠验证体内毒性
贡献率:25/100
主办机构:忠南大学产学协力团
研究时间:2013年11月01日~2019年06月30日。
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Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Leu Thr Ser
595 600 605
Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu Ile Ala Lys Gly Leu Phe
610 615 620
Asp Gly Leu Val Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile
625 630 635 640
Asn Cys Leu Arg Val Asn Thr Phe Gln Asp Leu Gln Asn Leu Asn Leu
645 650 655
Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ser Lys Gly Leu Phe
660 665 670
Ala Asp Tyr Lys Asp Asp Asp Asp Lys
675 680
<210> 8
<211> 743
<212> PRT
<213> Artificial
<220>
<223> LRRD2-2
<400> 8
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
20 25 30
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala
35 40 45
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
50 55 60
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
65 70 75 80
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
85 90 95
Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala
100 105 110
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
115 120 125
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
130 135 140
Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr
145 150 155 160
Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
165 170 175
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
180 185 190
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
195 200 205
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
210 215 220
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
225 230 235 240
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
245 250 255
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
260 265 270
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
275 280 285
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
290 295 300
Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
305 310 315 320
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys
325 330 335
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
340 345 350
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
355 360 365
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
370 375 380
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
385 390 395 400
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
405 410 415
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
420 425 430
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
435 440 445
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
450 455 460
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
465 470 475 480
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
485 490 495
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
500 505 510
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
515 520 525
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
530 535 540
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
545 550 555 560
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
565 570 575
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
580 585 590
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Ile Val Glu
595 600 605
Ile Arg Leu Glu Gln Asn Ser Ile Lys Ala Ile Pro Ala Gly Ala Phe
610 615 620
Thr Gln Tyr Lys Lys Leu Lys Arg Ile Asp Ile Ser Lys Asn Gln Ile
625 630 635 640
Ser Asp Ile Ala Pro Asp Ala Phe Gln Gly Leu Lys Ser Leu Thr Ser
645 650 655
Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu Ile Ala Lys Gly Leu Phe
660 665 670
Asp Gly Leu Val Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile
675 680 685
Asn Cys Leu Arg Val Asn Thr Phe Gln Asp Leu Gln Asn Leu Asn Leu
690 695 700
Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ser Lys Gly Leu Phe
705 710 715 720
Ala Pro Leu Gln Ser Ile Gln Thr Leu His Leu Ala Gln Asn Pro Asp
725 730 735
Tyr Lys Asp Asp Asp Asp Lys
740
<210> 9
<211> 822
<212> PRT
<213> Artificial
<220>
<223> LRRD2-3
<400> 9
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
20 25 30
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala
35 40 45
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
50 55 60
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
65 70 75 80
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
85 90 95
Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala
100 105 110
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
115 120 125
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
130 135 140
Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr
145 150 155 160
Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
165 170 175
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
180 185 190
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
195 200 205
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
210 215 220
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
225 230 235 240
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
245 250 255
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
260 265 270
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
275 280 285
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
290 295 300
Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
305 310 315 320
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys
325 330 335
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
340 345 350
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
355 360 365
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
370 375 380
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
385 390 395 400
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
405 410 415
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
420 425 430
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
435 440 445
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
450 455 460
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
465 470 475 480
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
485 490 495
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
500 505 510
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
515 520 525
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
530 535 540
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
545 550 555 560
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
565 570 575
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
580 585 590
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Ile Ser Cys
595 600 605
Pro Ser Pro Cys Thr Cys Ser Asn Asn Ile Val Asp Cys Arg Gly Lys
610 615 620
Gly Leu Met Glu Ile Pro Ala Asn Leu Pro Glu Gly Ile Val Glu Ile
625 630 635 640
Arg Leu Glu Gln Asn Ser Ile Lys Ala Ile Pro Ala Gly Ala Phe Thr
645 650 655
Gln Tyr Lys Lys Leu Lys Arg Ile Asp Ile Ser Lys Asn Gln Ile Ser
660 665 670
Asp Ile Ala Pro Asp Ala Phe Gln Gly Leu Lys Ser Leu Thr Ser Leu
675 680 685
Val Leu Tyr Gly Asn Lys Ile Thr Glu Ile Ala Lys Gly Leu Phe Asp
690 695 700
Gly Leu Val Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile Asn
705 710 715 720
Cys Leu Arg Val Asn Thr Phe Gln Asp Leu Gln Asn Leu Asn Leu Leu
725 730 735
Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ser Lys Gly Leu Phe Ala
740 745 750
Pro Leu Gln Ser Ile Gln Thr Leu His Leu Ala Gln Asn Pro Phe Val
755 760 765
Cys Asp Cys His Leu Lys Trp Leu Ala Asp Tyr Leu Gln Asp Asn Pro
770 775 780
Ile Glu Thr Ser Gly Ala Arg Cys Ser Ser Pro Arg Arg Leu Ala Asn
785 790 795 800
Lys Arg Ile Ser Gln Ile Lys Ser Lys Lys Phe Arg Cys Ser Asp Tyr
805 810 815
Lys Asp Asp Asp Asp Lys
820
<210> 10
<211> 696
<212> PRT
<213> Artificial
<220>
<223> LRRD2-4
<400> 10
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
20 25 30
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala
35 40 45
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
50 55 60
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
65 70 75 80
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
85 90 95
Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala
100 105 110
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
115 120 125
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
130 135 140
Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr
145 150 155 160
Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
165 170 175
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
180 185 190
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
195 200 205
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
210 215 220
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
225 230 235 240
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
245 250 255
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
260 265 270
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
275 280 285
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
290 295 300
Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
305 310 315 320
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys
325 330 335
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
340 345 350
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
355 360 365
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
370 375 380
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
385 390 395 400
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
405 410 415
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
420 425 430
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
435 440 445
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
450 455 460
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
465 470 475 480
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
485 490 495
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
500 505 510
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
515 520 525
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
530 535 540
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
545 550 555 560
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
565 570 575
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
580 585 590
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly
595 600 605
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Thr Ser Leu
610 615 620
Val Leu Tyr Gly Asn Lys Ile Thr Glu Ile Ala Lys Gly Leu Phe Asp
625 630 635 640
Gly Leu Val Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile Asn
645 650 655
Cys Leu Arg Val Asn Thr Phe Gln Asp Leu Gln Asn Leu Asn Leu Leu
660 665 670
Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ser Lys Gly Leu Phe Ala
675 680 685
Asp Tyr Lys Asp Asp Asp Asp Lys
690 695
<210> 11
<211> 758
<212> PRT
<213> Artificial
<220>
<223> LRRD2-5
<400> 11
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
20 25 30
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala
35 40 45
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
50 55 60
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
65 70 75 80
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
85 90 95
Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala
100 105 110
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
115 120 125
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
130 135 140
Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr
145 150 155 160
Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
165 170 175
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
180 185 190
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
195 200 205
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
210 215 220
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
225 230 235 240
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
245 250 255
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
260 265 270
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
275 280 285
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
290 295 300
Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
305 310 315 320
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys
325 330 335
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
340 345 350
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
355 360 365
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
370 375 380
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
385 390 395 400
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
405 410 415
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
420 425 430
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
435 440 445
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
450 455 460
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
465 470 475 480
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
485 490 495
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
500 505 510
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
515 520 525
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
530 535 540
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
545 550 555 560
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
565 570 575
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
580 585 590
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly
595 600 605
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Val Glu Ile
610 615 620
Arg Leu Glu Gln Asn Ser Ile Lys Ala Ile Pro Ala Gly Ala Phe Thr
625 630 635 640
Gln Tyr Lys Lys Leu Lys Arg Ile Asp Ile Ser Lys Asn Gln Ile Ser
645 650 655
Asp Ile Ala Pro Asp Ala Phe Gln Gly Leu Lys Ser Leu Thr Ser Leu
660 665 670
Val Leu Tyr Gly Asn Lys Ile Thr Glu Ile Ala Lys Gly Leu Phe Asp
675 680 685
Gly Leu Val Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile Asn
690 695 700
Cys Leu Arg Val Asn Thr Phe Gln Asp Leu Gln Asn Leu Asn Leu Leu
705 710 715 720
Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ser Lys Gly Leu Phe Ala
725 730 735
Pro Leu Gln Ser Ile Gln Thr Leu His Leu Ala Gln Asn Pro Asp Tyr
740 745 750
Lys Asp Asp Asp Asp Lys
755
<210> 12
<211> 837
<212> PRT
<213> Artificial
<220>
<223> LRRD2-6
<400> 12
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
20 25 30
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala
35 40 45
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
50 55 60
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
65 70 75 80
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
85 90 95
Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala
100 105 110
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
115 120 125
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
130 135 140
Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr
145 150 155 160
Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
165 170 175
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
180 185 190
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
195 200 205
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
210 215 220
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
225 230 235 240
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
245 250 255
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
260 265 270
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
275 280 285
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
290 295 300
Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
305 310 315 320
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys
325 330 335
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
340 345 350
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
355 360 365
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
370 375 380
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
385 390 395 400
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
405 410 415
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
420 425 430
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
435 440 445
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
450 455 460
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
465 470 475 480
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
485 490 495
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
500 505 510
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
515 520 525
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
530 535 540
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
545 550 555 560
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
565 570 575
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
580 585 590
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly
595 600 605
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Ser Cys Pro
610 615 620
Ser Pro Cys Thr Cys Ser Asn Asn Ile Val Asp Cys Arg Gly Lys Gly
625 630 635 640
Leu Met Glu Ile Pro Ala Asn Leu Pro Glu Gly Ile Val Glu Ile Arg
645 650 655
Leu Glu Gln Asn Ser Ile Lys Ala Ile Pro Ala Gly Ala Phe Thr Gln
660 665 670
Tyr Lys Lys Leu Lys Arg Ile Asp Ile Ser Lys Asn Gln Ile Ser Asp
675 680 685
Ile Ala Pro Asp Ala Phe Gln Gly Leu Lys Ser Leu Thr Ser Leu Val
690 695 700
Leu Tyr Gly Asn Lys Ile Thr Glu Ile Ala Lys Gly Leu Phe Asp Gly
705 710 715 720
Leu Val Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile Asn Cys
725 730 735
Leu Arg Val Asn Thr Phe Gln Asp Leu Gln Asn Leu Asn Leu Leu Ser
740 745 750
Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ser Lys Gly Leu Phe Ala Pro
755 760 765
Leu Gln Ser Ile Gln Thr Leu His Leu Ala Gln Asn Pro Phe Val Cys
770 775 780
Asp Cys His Leu Lys Trp Leu Ala Asp Tyr Leu Gln Asp Asn Pro Ile
785 790 795 800
Glu Thr Ser Gly Ala Arg Cys Ser Ser Pro Arg Arg Leu Ala Asn Lys
805 810 815
Arg Ile Ser Gln Ile Lys Ser Lys Lys Phe Arg Cys Ser Asp Tyr Lys
820 825 830
Asp Asp Asp Asp Lys
835
<210> 13
<211> 696
<212> PRT
<213> Artificial
<220>
<223> LRRD2-7
<400> 13
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Leu Thr Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr
20 25 30
Glu Ile Ala Lys Gly Leu Phe Asp Gly Leu Val Ser Leu Gln Leu Leu
35 40 45
Leu Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asn Thr Phe Gln
50 55 60
Asp Leu Gln Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln
65 70 75 80
Thr Ile Ser Lys Gly Leu Phe Ala Asp Ala His Lys Ser Glu Val Ala
85 90 95
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
100 105 110
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
115 120 125
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
130 135 140
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
145 150 155 160
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
165 170 175
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
180 185 190
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
195 200 205
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
210 215 220
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
225 230 235 240
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
245 250 255
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
260 265 270
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
275 280 285
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
290 295 300
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
305 310 315 320
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
325 330 335
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
340 345 350
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
355 360 365
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
370 375 380
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
385 390 395 400
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
405 410 415
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
420 425 430
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
435 440 445
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
450 455 460
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
465 470 475 480
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
485 490 495
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
500 505 510
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
515 520 525
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
530 535 540
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
545 550 555 560
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
565 570 575
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
580 585 590
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
595 600 605
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
610 615 620
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
625 630 635 640
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
645 650 655
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
660 665 670
Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
675 680 685
Asp Tyr Lys Asp Asp Asp Asp Lys
690 695
<210> 14
<211> 758
<212> PRT
<213> Artificial
<220>
<223> LRRD2-8
<400> 14
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Ile Val Glu Ile Arg Leu Glu Gln Asn Ser Ile Lys
20 25 30
Ala Ile Pro Ala Gly Ala Phe Thr Gln Tyr Lys Lys Leu Lys Arg Ile
35 40 45
Asp Ile Ser Lys Asn Gln Ile Ser Asp Ile Ala Pro Asp Ala Phe Gln
50 55 60
Gly Leu Lys Ser Leu Thr Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr
65 70 75 80
Glu Ile Ala Lys Gly Leu Phe Asp Gly Leu Val Ser Leu Gln Leu Leu
85 90 95
Leu Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asn Thr Phe Gln
100 105 110
Asp Leu Gln Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln
115 120 125
Thr Ile Ser Lys Gly Leu Phe Ala Pro Leu Gln Ser Ile Gln Thr Leu
130 135 140
His Leu Ala Gln Asn Pro Asp Ala His Lys Ser Glu Val Ala His Arg
145 150 155 160
Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala
165 170 175
Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu
180 185 190
Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser
195 200 205
Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu
210 215 220
Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys
225 230 235 240
Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
245 250 255
Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val
260 265 270
Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr
275 280 285
Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu
290 295 300
Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln
305 310 315 320
Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg
325 330 335
Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser
340 345 350
Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
355 360 365
Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu
370 375 380
Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu
385 390 395 400
Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu
405 410 415
Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro
420 425 430
Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met
435 440 445
Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp
450 455 460
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe
465 470 475 480
Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu
485 490 495
Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala
500 505 510
Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys
515 520 525
Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu
530 535 540
Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg
545 550 555 560
Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val
565 570 575
Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu
580 585 590
Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn
595 600 605
Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr
610 615 620
Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala
625 630 635 640
Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr
645 650 655
Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln
660 665 670
Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys
675 680 685
Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe
690 695 700
Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu
705 710 715 720
Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Tyr
740 745 750
Lys Asp Asp Asp Asp Lys
755
<210> 15
<211> 837
<212> PRT
<213> Artificial
<220>
<223> LRRD2-9
<400> 15
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Ile Ser Cys Pro Ser Pro Cys Thr Cys Ser Asn Asn
20 25 30
Ile Val Asp Cys Arg Gly Lys Gly Leu Met Glu Ile Pro Ala Asn Leu
35 40 45
Pro Glu Gly Ile Val Glu Ile Arg Leu Glu Gln Asn Ser Ile Lys Ala
50 55 60
Ile Pro Ala Gly Ala Phe Thr Gln Tyr Lys Lys Leu Lys Arg Ile Asp
65 70 75 80
Ile Ser Lys Asn Gln Ile Ser Asp Ile Ala Pro Asp Ala Phe Gln Gly
85 90 95
Leu Lys Ser Leu Thr Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu
100 105 110
Ile Ala Lys Gly Leu Phe Asp Gly Leu Val Ser Leu Gln Leu Leu Leu
115 120 125
Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asn Thr Phe Gln Asp
130 135 140
Leu Gln Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr
145 150 155 160
Ile Ser Lys Gly Leu Phe Ala Pro Leu Gln Ser Ile Gln Thr Leu His
165 170 175
Leu Ala Gln Asn Pro Phe Val Cys Asp Cys His Leu Lys Trp Leu Ala
180 185 190
Asp Tyr Leu Gln Asp Asn Pro Ile Glu Thr Ser Gly Ala Arg Cys Ser
195 200 205
Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Ser Gln Ile Lys Ser Lys
210 215 220
Lys Phe Arg Cys Ser Asp Ala His Lys Ser Glu Val Ala His Arg Phe
225 230 235 240
Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe
245 250 255
Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val
260 265 270
Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala
275 280 285
Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys
290 295 300
Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys
305 310 315 320
Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp
325 330 335
Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met
340 345 350
Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu
355 360 365
Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu
370 375 380
Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala
385 390 395 400
Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp
405 410 415
Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu
420 425 430
Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu
435 440 445
Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val
450 455 460
Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu
465 470 475 480
Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn
485 490 495
Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu
500 505 510
Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro
515 520 525
Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val
530 535 540
Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu
545 550 555 560
Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu
565 570 575
Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala
580 585 590
Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro
595 600 605
Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe
610 615 620
Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr
625 630 635 640
Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser
645 650 655
Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala
660 665 670
Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln
675 680 685
Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys
690 695 700
Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu
705 710 715 720
Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe
725 730 735
Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile
740 745 750
Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala
755 760 765
Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val
770 775 780
Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu
785 790 795 800
Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly
805 810 815
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Tyr Lys
820 825 830
Asp Asp Asp Asp Lys
835
<210> 16
<211> 711
<212> PRT
<213> Artificial
<220>
<223> LRRD2-10
<400> 16
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Leu Thr Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr
20 25 30
Glu Ile Ala Lys Gly Leu Phe Asp Gly Leu Val Ser Leu Gln Leu Leu
35 40 45
Leu Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asn Thr Phe Gln
50 55 60
Asp Leu Gln Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln
65 70 75 80
Thr Ile Ser Lys Gly Leu Phe Ala Gly Gly Gly Gly Ser Gly Gly Gly
85 90 95
Gly Ser Gly Gly Gly Gly Ser Asp Ala His Lys Ser Glu Val Ala His
100 105 110
Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile
115 120 125
Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys
130 135 140
Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu
145 150 155 160
Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys
165 170 175
Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp
180 185 190
Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His
195 200 205
Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp
210 215 220
Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys
225 230 235 240
Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu
245 250 255
Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys
260 265 270
Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu
275 280 285
Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala
290 295 300
Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala
305 310 315 320
Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys
325 330 335
Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp
340 345 350
Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys
355 360 365
Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys
370 375 380
Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu
385 390 395 400
Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys
405 410 415
Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met
420 425 430
Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu
435 440 445
Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys
450 455 460
Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe
465 470 475 480
Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu
485 490 495
Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val
500 505 510
Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu
515 520 525
Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro
530 535 540
Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu
545 550 555 560
Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val
565 570 575
Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser
580 585 590
Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu
595 600 605
Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg
610 615 620
Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro
625 630 635 640
Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala
645 650 655
Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala
660 665 670
Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
675 680 685
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
690 695 700
Tyr Lys Asp Asp Asp Asp Lys
705 710
<210> 17
<211> 773
<212> PRT
<213> Artificial
<220>
<223> LRRD2-11
<400> 17
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Ile Val Glu Ile Arg Leu Glu Gln Asn Ser Ile Lys
20 25 30
Ala Ile Pro Ala Gly Ala Phe Thr Gln Tyr Lys Lys Leu Lys Arg Ile
35 40 45
Asp Ile Ser Lys Asn Gln Ile Ser Asp Ile Ala Pro Asp Ala Phe Gln
50 55 60
Gly Leu Lys Ser Leu Thr Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr
65 70 75 80
Glu Ile Ala Lys Gly Leu Phe Asp Gly Leu Val Ser Leu Gln Leu Leu
85 90 95
Leu Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asn Thr Phe Gln
100 105 110
Asp Leu Gln Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln
115 120 125
Thr Ile Ser Lys Gly Leu Phe Ala Pro Leu Gln Ser Ile Gln Thr Leu
130 135 140
His Leu Ala Gln Asn Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
145 150 155 160
Gly Gly Gly Gly Ser Asp Ala His Lys Ser Glu Val Ala His Arg Phe
165 170 175
Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe
180 185 190
Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val
195 200 205
Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala
210 215 220
Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys
225 230 235 240
Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys
245 250 255
Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp
260 265 270
Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met
275 280 285
Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu
290 295 300
Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu
305 310 315 320
Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala
325 330 335
Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp
340 345 350
Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu
355 360 365
Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu
370 375 380
Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val
385 390 395 400
Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu
405 410 415
Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn
420 425 430
Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu
435 440 445
Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro
450 455 460
Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val
465 470 475 480
Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu
485 490 495
Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu
500 505 510
Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala
515 520 525
Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro
530 535 540
Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe
545 550 555 560
Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr
565 570 575
Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser
580 585 590
Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala
595 600 605
Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln
610 615 620
Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys
625 630 635 640
Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu
645 650 655
Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe
660 665 670
Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile
675 680 685
Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala
690 695 700
Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val
705 710 715 720
Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu
725 730 735
Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly
740 745 750
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Tyr Lys
755 760 765
Asp Asp Asp Asp Lys
770
<210> 18
<211> 852
<212> PRT
<213> Artificial
<220>
<223> LRRD2-12
<400> 18
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Ile Ser Cys Pro Ser Pro Cys Thr Cys Ser Asn Asn
20 25 30
Ile Val Asp Cys Arg Gly Lys Gly Leu Met Glu Ile Pro Ala Asn Leu
35 40 45
Pro Glu Gly Ile Val Glu Ile Arg Leu Glu Gln Asn Ser Ile Lys Ala
50 55 60
Ile Pro Ala Gly Ala Phe Thr Gln Tyr Lys Lys Leu Lys Arg Ile Asp
65 70 75 80
Ile Ser Lys Asn Gln Ile Ser Asp Ile Ala Pro Asp Ala Phe Gln Gly
85 90 95
Leu Lys Ser Leu Thr Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu
100 105 110
Ile Ala Lys Gly Leu Phe Asp Gly Leu Val Ser Leu Gln Leu Leu Leu
115 120 125
Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asn Thr Phe Gln Asp
130 135 140
Leu Gln Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr
145 150 155 160
Ile Ser Lys Gly Leu Phe Ala Pro Leu Gln Ser Ile Gln Thr Leu His
165 170 175
Leu Ala Gln Asn Pro Phe Val Cys Asp Cys His Leu Lys Trp Leu Ala
180 185 190
Asp Tyr Leu Gln Asp Asn Pro Ile Glu Thr Ser Gly Ala Arg Cys Ser
195 200 205
Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Ser Gln Ile Lys Ser Lys
210 215 220
Lys Phe Arg Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
225 230 235 240
Gly Gly Gly Ser Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
245 250 255
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala
260 265 270
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
275 280 285
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
290 295 300
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
305 310 315 320
Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala
325 330 335
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
340 345 350
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
355 360 365
Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr
370 375 380
Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
385 390 395 400
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
405 410 415
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
420 425 430
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
435 440 445
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
450 455 460
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
465 470 475 480
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
485 490 495
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
500 505 510
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
515 520 525
Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
530 535 540
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys
545 550 555 560
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
565 570 575
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
580 585 590
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
595 600 605
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
610 615 620
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
625 630 635 640
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
645 650 655
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
660 665 670
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
675 680 685
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
690 695 700
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
705 710 715 720
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
725 730 735
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
740 745 750
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
755 760 765
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
770 775 780
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
785 790 795 800
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
805 810 815
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly
820 825 830
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Tyr Lys Asp
835 840 845
Asp Asp Asp Lys
850
Claims (9)
1.一种用于预防或治疗骨相关疾病的药学组合物,其特征在于,包含与白蛋白结合的Slit3蛋白的LRRD2。
2.根据权利要求1所述的用于预防或治疗骨相关疾病的药学组合物,其特征在于,上述白蛋白为人血清白蛋白。
3.根据权利要求2所述的用于预防或治疗骨相关疾病的药学组合物,其特征在于,上述人血清白蛋白与Slit3蛋白的LRRD2的N-末端结合。
4.根据权利要求3所述的用于预防或治疗骨相关疾病的药学组合物,其特征在于,上述人血清白蛋白包含SEQ ID NO:2的氨基酸序列。
5.根据权利要求3所述的用于预防或治疗骨相关疾病的药学组合物,其特征在于,上述Slit3蛋白的LRRD2包含SEQ ID NO:3的氨基酸序列。
6.根据权利要求1所述的用于预防或治疗骨相关疾病的药学组合物,其特征在于,在上述白蛋白与Slit3蛋白的LRRD2之间还包含连接子。
7.根据权利要求6所述的用于预防或治疗骨相关疾病的药学组合物,其特征在于,上述连接子为(GGGGS)n,其中,n为1至10的整数。
8.根据权利要求1所述的用于预防或治疗骨相关疾病的药学组合物,其特征在于,通过注射剂给药。
9.根据权利要求1所述的用于预防或治疗骨相关疾病的药学组合物,其特征在于,上述骨相关疾病为选自由骨质疏松症、骨折、骨质流失、骨关节炎、骨转移癌及佩吉特氏病组成的组中的一种以上。
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EP3932430A1 (en) | 2022-01-05 |
KR102353524B1 (ko) | 2022-01-20 |
KR20200104830A (ko) | 2020-09-04 |
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