CN101889022A - 三聚IL-1Ra - Google Patents
三聚IL-1Ra Download PDFInfo
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- CN101889022A CN101889022A CN2008801197414A CN200880119741A CN101889022A CN 101889022 A CN101889022 A CN 101889022A CN 2008801197414 A CN2008801197414 A CN 2008801197414A CN 200880119741 A CN200880119741 A CN 200880119741A CN 101889022 A CN101889022 A CN 101889022A
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Abstract
本发明包括融合蛋白的白介素-1受体拮抗剂(IL-1Ra),所述融合蛋白包含三聚域和IL-1Ra多肽序列。所述融合蛋白是三聚复合物的一部分,所述复合物可用在治疗由IL-1介导的疾病的药物组合物中。本发明描述了对炎症性疾病如风湿性关节炎和糖尿病的有效治疗。
Description
对相关申请的交叉引用
本申请要求2008年10月8日提交的美国临时专利申请No.60/978,254的权利,其通过引用全部并入本文。
技术领域
本发明涉及由白介素1介导的疾病的治疗。更具体地,本发明涉及可用于治疗这些疾病的白介素1受体拮抗剂(IL-1Ra)。
背景技术
IL-1家族是先天免疫系统的重要部分,其是适应免疫系统的调节剂。局部组织中IL-1和IL-1Ra之间的平衡影响炎症性疾病可能的发展,并导致结构损伤。在存在过量IL-1时,炎症性和自免疫疾病可以在关节、肺、胃肠道、中枢神经系统(CNS)或血管中发展。已经通过注射重组IL-1Ra或通过基因疗法途径用IL-1Ra进行人类疾病的治疗。已经证明用重组IL-1Ra可以治疗风湿性关节炎(RA),并且正在进行对于骨关节炎(OA)的二期研究。
过去的10年间,已经描述了IL-1在很多人类疾病中重要的促炎作用。已经在多种动物疾病模型中深入研究了IL-1和IL-1Ra之间的平衡,包括风湿性关节炎(RA)、骨关节炎(OA)、炎症性肠病(IBD)、肉芽肿和纤维化肺疾病、肾疾病、肝脏和胰脏疾病、移植物抗宿主疾病(GVHD)、白血病、癌症、骨质疏松症、糖尿病、中枢神经系统疾病、传染性疾病和动脉疾病。在每种疾病中,局部过量产生IL-1和/或过少产生IL-1Ra使受试对象容易患上疾病。IL-1Ra的治疗已经表明可有效预防组织损失(参见W.P.Arend,Cytokine & Growth Factor Reviews,13(2002)pp.323-240)。
IL-1家族由下述组成:两种激动剂,IL-1α和IL-1β;特异性受体拮抗剂IL-1Ra;和三种不同的受体,I型IL-1R(IL-1RI)、II型IL-1R(IL-1RII)和IL-1受体辅助蛋白(IL-1RAcP)。IL-1R1是包括215个残基的长胞质域的80kDa蛋白质。生物惰性的IL-1RII是包括29个残基的短胞质域的60kDa蛋白质。在将IL-1α或IL-1β结合至单链IL-1R1后,将IL-1R AcP募集至复合物。由接近的IL-1R1和IL-1R AcP的胞质域活化的信号传导通路包括NF-κB、JNK/AP-1和p38MAP激酶途径。IL-1RII作为诱杀受体,在质膜上结合IL-1,并且作为流体相中的可溶受体,从而防止IL-1与具有功能的IL-1RI相互作用。
IL-1家族中的第三种配体,IL-1Ra,是IL-1的结构变体,其可结合IL-1R,但是不能活化细胞。IL-1Ra是与IL-1α有18%氨基酸同源性并与IL-1β有26%同源性的17kDa蛋白质。IL-1Ra最早描述的同工型分泌自单核细胞、巨噬细胞、中性细胞和其它细胞,并且现在称为sIL-1Ra。至今为止已经描述了IL-1Ra的三个其它细胞内同工型。IL-1Ra的18kDa型,由可选的转录拼接机制从上游外显子产生,称为icIL-1Ra1,并且在角化细胞和其它上皮细胞、单核细胞、组织巨噬细胞、纤维原细胞和内皮细胞中发现。克隆自人白血球的IL-1Ra cDNA包含额外的63bp序列,作为cDNA的5’区域的插入序列。在单核细胞、巨噬细胞、中性细胞和肝细胞中发现了IL-1Ra的15kDa同工型,称为icIL-1Ra3,并且其可以通过可选的转录拼接以及通过可选的翻译起始而产生。
可溶的IL-1Ra和icIL-1Ra1同样很好地与IL-1R结合,但是icIL-1Ra3表现出弱的受体结合。IL-1Ra通过结合IL-1R1但是防止IL-1R AcP与IL-1RI关联而作为特异性的受体拮抗剂,其导致不能启动信号传导通路。
诱杀受体IL-1RII结合质膜上并作为流体相中可溶受体的IL-1,防止IL-1与具有功能的IL-1RI相互作用。因此,可溶的IL-1RII和IL-1Ra能共同抑制IL-1。可溶的IL-R1能与IL-1以及IL-1Ra结合,但是由于IL-1和IL-1Ra之间的平衡,可溶的IL-1RI似乎作为促炎剂而作用。
KINERET是来自Amgen的由大肠杆菌产生的IL-1Ra,其已经表明对于活动性风湿关节炎的患者有益。KINERET需皮下注射,一日一次。皮下给药时,KINERET的半衰期从4至6小时;对于i.v.给药,半衰期约为2.5小时。通过肾清除而清除IL-1Ra。KINERET是IL-1的特异性受体拮抗剂,其通过存在的甲硫氨酸基团与天然发生的IL-1受体拮抗剂相区别。在单独使用或与甲氨蝶呤组合使用时,由于临床征兆和症状的改善、放射学进展的减缓和患者功能、疼痛与疲劳的改善,KINERET已经表明对于患者有益。如临床试验所证明的,KINERET具有相当安全的特性。
已经进行了几种尝试来改善IL-1Ra较差的药物动力学。已经开发了仅靶向IL-1β的抗体。然而,与IL-1ra相反,这些只阻断IL-1β,但是不能阻断IL-1α的作用。
因此,本发明人发现了本领域中对于传递IL1-Ra的改善方法的需要,所述方法可提供分子更长的半衰期,并提供相当安全的特性。
附图说明
图1表示四连蛋白家族的三聚结构元件的氨基酸序列比对。对应于残基V17至K52的氨基酸序列(单字母编码)包含外显子2和人四连蛋白的外显子3的第一个三残基(SEQ ID NO:59);鼠科动物四连蛋白(SEQ ID NO:60);分离自礁鲨软骨的四连蛋白同源蛋白质(SEQ IDNO:61)和分离自牛软骨的四连蛋白同源蛋白质(SEQ ID NO:62)。七重复序列中a和d位置的残基用黑体列出。列出的四连蛋白家族三聚结构元件的保守序列包括七重复序列中a和d位置的残基,除了区域中其它保守残基之外,图中还表示出所述七重复序列。“hy”表示脂肪族疏水残基。
图2表示通过透析重折叠CII-H6-GrB-TripK-IL-1Ra的结果。
图3显示在NiNTA上捕捉CII-H6-GrB-TripK-IL-1Ra。
图4是表示GG-TripV-IL-1Ra(trip V-IL-1Ra)、GG-TripK-IL-1Ra(trip K-IL-1Ra)、GG-TripT-IL-1Ra(trip T-IL-1Ra)和GG-TripT-IL-1Ra(trip T-IL-1Ra)抑制U937细胞中IL8的IL-1诱导的能力的图。
图6是表示PK研究中使用的TripT-IL-1Ra、I10-TripT-IL-1Ra和V17-TripT-IL-1Ra抑制U937细胞中IL-8的IL-1诱导的能力的图。
图7是表示在大鼠中i.v.注射100mg/kg后TripT-IL-1Ra、I10-TripT-IL-1Ra和V17-TripT-IL-1Ra的血浓度的图。
图8表示对于多批次Met-I10-TrpT-IL-1Ra(LM022和LM023)和GG-V17-TrpT-IL-1Ra(CF019和CF020)蛋白质产量的SDS-PAGE分析。
图9表示Met-I10-TrpT-IL-1Ra和GG-V17-TrpT-IL-1Ra蛋白质产量的分析SEC结果。
图10表示大鼠CIA研究的结果。在用载体(10mM磷酸缓冲液pH7.4)处理,或施用等摩尔数量的IL-1ra(或者是单聚IL-1ra(100mg/kg KINERET),或者是三聚IL 1ra(120mg/kg Met-I10-TripT-IL1ra,或120mg/kg GG-V17-TripT-IL 1ra))之后,测量患有II类胶原关节炎的雌性Lewis大鼠的脚踝直径。
发明内容
本发明提供包含三聚域和可抑制IL-1活性的IL-1Ra多肽序列的融合蛋白。在一个实施方案中,融合蛋白包括IL-1Ra序列,其包含可抑制IL-1活性的SEQ ID NO:38的变体或片段。在另一个实施方案中,融合蛋白包括与SEQ ID NO:38至少85%相同的IL-1Ra多肽序列。融合蛋白可以包括聚乙二醇。融合蛋白的三聚域可以源自四连蛋白。
本发明还提供包含本发明的三个融合蛋白的三聚复合物。在一个实施方案中,三聚复合物包括三聚域,其为四连蛋白三聚结构元件(TTSE)。在一个实施方案中,三聚复合物包括与SEQ ID NO:1至少66%相同的三聚域。在另一个实施方案中,三聚复合物包括至少一个选自下组的融合蛋白:TripK-IL-1ra(SEQ ID NO:39);TripV-IL-1ra(SEQ IDNO:40);TripT-IL-1ra(SEQ ID NO:41);TripQ-IL-1ra(SEQ ID NO:42);I10-TripK-IL-1ra(SEQ ID NO:43);I10-TripV-IL-1ra(SEQ ID NO:44);I10-TripT-IL-1ra(SEQ ID NO:45);I10-TripQ-IL-1ra(SEQ ID NO:46);V17-TripT-IL1Ra(SEQ ID NO:55);V17-TripK-IL-1Ra(SEQ ID NO:56);V17-TripV-IL-1RA(SEQ ID NO:57)和V17-TripQ-IL1RA(SEQ IDNO:58)。
在进一步的实施方案中,本发明提供包含三聚体和至少一个可药用的赋形剂的药物组合物。
甚至更进一步地,本发明涉及治疗由白介素1介导的疾病的方法。所述方法包括对有需要的患者施用本发明的药物组合物。疾病可以是炎症性疾病如风湿性关节炎或糖尿病。方法还包括对患者同时或顺序施用抗炎剂。
本发明还提供融合蛋白,其进一步包括与融合蛋白共价连接的抗炎剂。
本发明的这些和其它方面在下文中进一步详细描述。
具体实施方式
本发明涉及用于治疗由IL-1介导的疾病的化合物和方法。在一个方面,本发明涉及IL-1Ra多肽序列与三聚或多聚域融合而成的融合蛋白。三个或更多的融合蛋白可以三聚或多聚,从而提供比单独的IL-1Ra稳定性更强、药物动力学性质更好的组合物,并且提供相当安全的特性。
在其他方面,本发明提供核酸,其编码任一个上述多肽,以及在允许特异性表达和回收的条件下制备这些多肽的方法。
本发明的多肽可以能够用于制备药物组合物,所述药物组合物用于治疗具有由IL-1介导的病理学的受试对象,比如通过对受试对象施用有效量的药物组合物而治疗炎症性疾病的方法。
如本文所使用的,如果自发或实验疾病或身体状况与体液或组织中IL-1水平升高有关,或者取自身体的细胞或组织在培养基中产生的IL-1水平升高,则认为疾病或身体状况是“白介素-1介导疾病”或“由白介素-1介导的疾病”。在很多情况下,这些白介素-1介导的疾病还通过下述另外两个条件识别:(1)与疾病或身体状况相关的病理学发现能通过施用IL-1而在动物中通过实验模拟;和(2)在疾病或身体状况的实验动物模型中诱导的病理学能通过用可抑制IL-1作用的药剂治疗而抑制或消除。在大多数IL-1介导的疾病中,至少符合三个条件中的两个,并且在很多IL-1介导的疾病中,符合全部三个条件。急性和慢性IL-1介导的炎症性疾病的非独占性列表包括但不限于下述:痛风;急性胰腺炎;ALS;老年痴呆症;恶病质/厌食;哮喘;动脉硬化;急性疲劳综合症;发烧;糖尿病(例如,胰岛素糖尿病);血管球性肾炎;移植物抗宿主排斥;出血性休克;痛觉过敏、炎性肠道疾病;关节炎症,包括骨关节炎、牛皮癣关节炎、幼年型关节炎和风湿性关节炎;缺血性损伤,包括脑缺血(例如,外伤、癫痫、出血或中风引起的脑部损伤,均可引起神经退行性疾病);肺部疾病(例如,ARDS);多发性骨髓瘤;多发性硬化;骨髓性(例如,AML和CML)和其它白血病;肌肉疾病(例如,肌蛋白代谢,特别是败血症);骨质疏松症;帕金森病;疼痛;早产;牛皮癣;再灌注损伤;感染性休克;放射疗法的副作用、暂时颚关节疾病、肿瘤转移;或者由于拉伤、扭伤、软骨损伤、外伤、矫形外科、感染或其它疾病过程和与cryopyrin相关的周期综合症,包括Muckle-Wells综合征、家族感冒自发炎症综合征和新生儿多系统炎症性疾病。
如本文所使用的,术语“多聚域”表示包含功能性(functionality)的氨基酸序列,所述功能性可以与两个或多个其它氨基酸序列关联,形成三聚或其它多聚复合物。在一个实例中,融合蛋白包含氨基酸序列-三聚域-其与两个其它三聚域形成三聚复合物。三聚域能与相同氨基酸序列的其它三聚域(同三聚体),或不同氨基酸序列的三聚域(异三聚体)关联。这种相互作用可以由三聚域组分之间的共价键以及通过氢键力、疏水力、范德华力和盐桥而引起。在本发明的多个实施方案中,多聚域是二聚域、三聚域、四聚域、五聚域等。这些域能形成本发明的两个、三个、四个、五个或多个融合蛋白的多肽复合物。
本发明的融合蛋白的三聚域可以来自如美国专利申请No.2007/0154901(‘901申请)所述的四连蛋白,所述文献通过引用全部并入本文。本文以SEQ ID NO:63提供全长人四连蛋白多肽序列。四连蛋白三聚域的实例包括氨基酸SEQ ID NO:63的17至49、17至50、17至51和17-52,其代表由人四连蛋白基因的外显子2编码的氨基酸,和可选地由所述基因的外显子3编码的第一个单、双或三氨基酸。其它实例包括氨基酸1至49,1至50,1至51和1至52,其代表全部的外显子1和2,和可选地由所述基于的外显子3编码的第一个单、双或三氨基酸。或者,三聚域中包括外显子1编码的部分氨基酸序列。具体地,三聚域的N末端可以在SEQ ID NO:63的残基1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16和17中的任何一个开始。在具体的实施方案中,N末端是I10或V17,并且C末端是Q47、T48、V49、C(S)50、L51或K52(根据SEQ ID NO:63编号)。
在本发明的一个方面,三聚域是包含SEQ ID NO:1的氨基酸序列的四连蛋白三聚结构元件(“TTSE”),所述序列是四连蛋白家族三聚结构元件的保守性序列,如US 2007/00154901中更加完整地描述的。如图1所示,TTSE包含蛋白质的四连蛋白家族中天然发生的成员的变体,并且具体为已经在氨基酸序列中进行修饰的变体,其实质上未对TTSE形成α螺旋卷轴螺旋三聚体的能力产生负面影响。在本发明的各个方面中,根据本发明的三聚多肽包括作为三聚域的TTSE,其与SEQ IDNO:1的保守性序列具有至少66%的氨基酸序列同一性;例如与SEQ IDNO:1的保守性序列具有至少73%,至少80%,至少86%或至少92%的序列同一性(仅计算确定(而不是Xaa)的残基)。即,SEQ ID NO:1中确定氨基酸的至少一个,至少两个,至少三个,至少四个,或者至少五个可以被取代。
在一个具体的实施方案中,SEQ ID NO:63的位置50的半胱氨酸(C50)可以有利地突变成丝氨酸、苏氨酸、甲硫氨酸或任何其它氨基酸残基,以避免形成不理想的链间二硫桥,所述链间二硫桥能导致不理想的多聚合。其它已知的变体包括选自氨基酸残基6、21、22、24、25、27、28、31、32、35、39、41和42(根据SEQ ID NO:63编号)的至少一个氨基酸残基,其可由任何非螺旋断裂氨基酸残基取代。这些残基已经表现出不直接参与分子间的相互作用,所述作用可稳定天然四连蛋白单体的TTSE之间的三聚复合物。在图1所示的一个方面,TTSE包括重复的七残基,其式为a-b-c-d-e-f-g(N至C),其中残基a和d(即,位置26、33、37、40、44、47和51)可以是任何疏水氨基酸(根据权利要求63编号)。
在进一步的实施方案中,TTSE三聚域可以通过掺入聚组氨酸序列和/或蛋白酶分解位点如血凝因子Xa或颗粒酶B(参见US2005/0199251,其通过引用并入本文),并且包括C末端KG或KGS序列而进行修饰。此外,为了帮助纯化,位置2的脯氨酸可以用甘氨酸取代以帮助纯化。
TTSE截短和变体的具体非限定性实例如下面的表1所示。
表1
TTSE变体 | |
SEQ ID NO:2 | EPPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLK |
SEQ ID NO:3 | EPPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSL |
SEQ ID NO:4 | EPPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVS |
SEQ ID NO:5 | EPPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTV |
SEQ ID NO:6 | PPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:7 | PTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
TTSE变体 | |
SEQ ID NO:8 | TQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:9 | QKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:10 | KPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:11 | PKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:12 | KKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:13 | KIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:14 | IVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:15 | VNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:16 | NAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:17 | AKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:18 | KKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:19 | KDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:20 | VVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:21 | VVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:22 | VVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLK |
SEQ ID NO:23 | VVNTKMFEELKSRLDTLAQEVALLKEQQALQTV |
SEQ ID NO:24 | VVNTKMFEELKSRLDTLAQEVALLKEQQALQT |
SEQ ID NO:25 | VNTKMFEELKSRLDTLAQEVALLKEQQALQ |
SEQ ID NO:26 | NTKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:27 | TKMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
TTSE变体 | |
SEQ ID NO:28 | KMFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:29 | MFEELKSRLDTLAQEVALLKEQQALQTVSLKG |
SEQ ID NO:30 | EGPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLK |
SEQ ID NO:31 | EGPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTV |
SEQ ID NO:32 | EGPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQT |
SEQ ID NO:33 | EGPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQ |
SEQ ID NO:34 | IVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLK |
SEQ ID NO:35 | IVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTV |
SEQ ID NO:36 | IVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQT |
SEQ ID NO:37 | IVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQ |
US 6,190,886(全部并入本文)中公开了三聚域的另一个实例,其描述了包括胶原凝集素颈区的多肽。然后可以在合适的条件下,用包含胶原凝集素颈区氨基酸序列的三个多肽产生三聚物。
三聚域的另一个实例是MBP三聚域,如本发明的代理人于2007年9月7日提交的美国临时专利申请No.60/996,288中所述,其通过引用全部并入本文。这个三聚域甚至能进一步低聚,并产生更高阶的多聚复合物。
本发明的IL-1Ra多肽可以连接至三聚域的N或C末端氨基酸残基。可选地,可以在代表IL-1Ra的多肽和三聚域之间,并且共价连接,放置灵活的分子接头(linker)。优选地,接头是约1至20,2至10,或3至7个氨基酸残基的多肽序列。在进一步的实施方案中,接头是不产生免疫性的,不易由蛋白水解作用分解,并且不包含已知可与其它残基相互作用的氨基酸残基(例如半胱氨酸残基)。
如本文所使用的,“IL-1Ra”指包含如下所示的氨基酸序列的多肽:
RPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQG
PNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDET
RLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAAC
PGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE
(SEQ ID NO:38)
“IL-1Ra”定义中还包括SEQ ID NO:38的变体和片段,其可提供与IL-1R的IL-1Ra结合,并且优选提供IL-1R抑制活性。与全长天然IL-1Ra蛋白质相比,这些片段可以在IL-1Ra的N末端或C末端截短,或者可以缺少内部残基。某些片段可以缺少根据本发明对于三聚IL-1Ra蛋白质的理想生物活性不是必需的氨基酸残基。例如,Evans等人(J.Biol.Chem.1995,19:11477-11483)通过定点突变证明只有Trp16、Gln20、Tyr34、Gln36和Tyr147对于与IL-1R的结合是关键的,并且其它氨基酸位置可以改变,同时仍能保持功能性分子。此外,如Dahlen等人所示(J.Immunotoxicology 5:189-199(2008)),通过将结合区域之外的氨基酸突变,增加IL-1Ra预期受体的环状相互作用,可以改善IL-1Ra与其受体之间的亲和性。这可以通过突变IL-1Ra受体结合区域之外的氨基酸而完成,并且特别地,例如突变:D47N、E52R、E90Y、P38Y、H54R、Q129L和M136N。同上。此外,存在天然的IL-1Ra变体,可以使用任何这类变体。将IL-1Ra的18kDa形式称作icIL-1Ra1,其通过来自上游外显子的另一种转录拼接机制产生,并且发现存在于角化细胞和其它上皮细胞中。由人白血球克隆的IL-1Ra cDNA包含额外的63bp作为cDNA的5’区域中的插入序列。在单核细胞、巨噬细胞、中性细胞和肝细胞中发现了名为icIL-1Ra3的IL-1Ra的15kDa同工型,并且其可以通过另一种转录拼接以及可选的翻译起始产生。
可用作本发明的融合蛋白的IL-1Ra肽包括与SEQ ID NO:38至少65%、至少70%、至少75%、至少80%、至少85%、至少90%或者至少95%相同的多肽。在具体的实施方案中,融合蛋白包括与SEQ ID NO:3885%相同,并且具有IL-1R结合活性,和优选地具有IL-1Ra抑制活性的IL-1Ra肽序列。在另一个具体的实施方案中,融合蛋白包括与SEQID NO:3890%相同,并且具有IL-1R结合活性,和优选地具有IL-1Ra抑制活性的IL-1Ra肽序列。在这些实施方案中,多肽包含Trp16、Gln20、Tyr34、Gln36和Tyr147,所述编号根据SEQ ID NO:38的编号。这些多肽可以进一步包括一个或多个氨基酸取代D47N、E52R、E90Y、P38Y、H54R、Q129L和M136N(根据SEQ ID NO:38编号)。此外,IL-1Ra多肽的变体可以通过用具有相似结构或化学性质的另一个氨基酸取代一个或多个氨基酸例如保守氨基酸取代而完成。
在进一步的实施方案中,根据本发明的融合蛋白选自IL-1受体拮抗剂,其选自下述:
TRipQ-IL-1raMVRANKRNEALRIESALLNKIAMLGTEKTAEGGSHHHHHHGSIEPDGGEGPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLK EQQALQ (SEQ ID NO:42)
其中标下划线的部分表示三聚单元,并且黑体部分表示IL-1Ra部分。
融合蛋白的产生
本发明的三聚IL-1Ra可以化学合成或在任何合适的标准蛋白表达系统中表达。优选地,蛋白表达系统是易于从中分离期望蛋白并体外重折叠的系统。优选原核表达系统,因为可以获得较高的蛋白产量,并且具备有效的纯化和重折叠策略。也可以使用真核表达系统。因此,技术人员能判断如何选择合适的表达系统。相似地,一旦选择了本发明融合蛋白的一级氨基酸序列,考虑这些因素如所选宿主中的密码子偏好性,宿主中分泌信号序列的需要,信号序列中蛋白酶分解位点的引入等,本领域的普通技术人员能轻松地设计合适的编码期望蛋白的重组DNA构建体。可以将这些重组DNA构建体框内插入任何数量的对所选宿主合适的表达载体中。优选地,表达载体将包括强启动子来驱动重组构建体的表达。
本发明的融合蛋白可以通过在使融合蛋白表达的条件下培养用编码融合蛋白的载体转化的宿主,在任何合适的标准蛋白表达系统中表达。优选地,表达系统是是易于从中分离期望蛋白并体外重折叠的系统。通常地,优选原核表达系统,因为可以获得较高的蛋白产量,并且具备有效的纯化和重折叠策略。因此,本领域的技术人员能选择合适的表达系统(包括载体和细胞类型)。相似地,一旦选择了本发明融合蛋白的一级氨基酸序列,考虑这些因素如所选宿主中的密码子偏好性,宿主中分泌信号序列的需要,信号序列中蛋白酶分解位点的引入等,本领域的普通技术人员能轻松地设计合适的编码期望蛋白的重组DNA构建体。可以将这些重组DNA构建体框内插入任何数量的对所选宿主合适的表达载体中。
在一个实施方案中,分离的多核苷酸编码本发明的融合蛋白。在其它实施方案中,IL-1Ra多肽和三聚域由不连续的多核苷酸序列编码。因此,在一些实施方案中,分别表达、分离并纯化IL-1Ra多肽,并融合在一起形成本发明的融合蛋白。
这些重组DNA构建体可以框内插入任何对于所选宿主合适的多个表达载体中。在某些实施方案中,表达系统包含控制重组融合蛋白构建体表达的强启动子。当使用重组表达策略产生本发明的融合蛋白时,可以使用本领域公知的合适的标准过程分离并纯化得到的融合蛋白,并且可选地对融合蛋白进行进一步的处理如冻干。
可以使用标准技术进行重组DNA分子、蛋白质和融合蛋白的生产,以及用于组织培养和细胞转化。参见,例如Sambrook等人(下文)或Current Protocols in Molecular Biology(Ausubel et al.,eds.,GreenPublishers Inc.and Wiley and Sons 1994)。通常根据生产商的说明进行纯化技术,或者如本领域中通常使用常规技术如Sambrook等人(MolecularCloning:A Laboratory Manual.Cold Spring Harbor Laboratory Press,ColdSpring Harbor,NY(1989)所提出的或如本文所述而完成。除非特别说明,否则与实验室过程相连使用的术语,和本文所述涉及分子生物学、生物化学、分析化学和药物/制剂化学的技术是本领域中公知和常用的。可以使用标准技术进行生物化学合成,生物化学分析,药物制备、配制和传递,和患者的治疗。
应了解的是,弹性分子接头可选地可以放置于IL-1Ra多肽和三聚域之间,并将两者共价连接。在某些实施方案中,接头是约1-20个氨基酸残基的多肽序列。接头可以少于10个氨基酸,最优选地,五个、四个、三个、两个或一个氨基酸。在某些情况下,九个、八个、七个或六个氨基酸是合适的。在有用的实施方案中,接头基本不产生免疫性,不容易由蛋白质分解作用所分解,并且不包括已知可以与其它残基反应的氨基酸残基(例如半胱氨酸残基)。
下文的描述还涉及产生融合蛋白和共价附着(下文称作“共轭结合”)于一个或多个化学基团上的三聚复合物的方法。适用于这些共轭物的化学基团优选没有显著的毒性或产生免疫性。可选地选择化学基团,以产生能在适于保存的条件下保存并使用的共轭物。本领域中已知能与多肽共轭结合的各种示例性化学基团,包括例如碳水化合物,比如天然存在于糖蛋白上的那些碳水化合物、聚谷氨酸,和不含蛋白的聚合物,比如多元醇(参见,例如美国专利No.6,245,901)。
例如,多元醇可以与本发明的融合蛋白在一个或多个氨基酸残基共轭结合,包括赖氨酸残基,如WO 93/00109,见上文中所公开的。使用的多元醇可以是任何可溶于水的聚烯化氧聚合物,并且包含直链或支链。合适的多元醇包括那些在一个或多个羟基位置用化学基团取代的多元醇,比如用具有一个和四个碳之间的烷基基团取代。通常地,多元醇是聚烯化氧,比如聚乙二醇(PEG),并且因此,为了方便描述,讨论的其余部分涉及示例性实施方案,其中使用的多元醇是PEG,并且将多元醇与多肽共轭结合的过程称作“聚乙二醇化”。然而,本领域的技术人员可以认识到能使用本文所述针对PEG的用于共轭结合的技术,使用其它多元醇,比如,例如,聚丙二醇和聚乙二醇-聚丙二醇共聚物
IL-1Ra的聚乙二醇化中使用的PEG的平均分子量可以变化,并且通常在从约500至约30,000道尔顿的范围内变化。优选地,PEG的平均分子量从约1,000至约25,000D,并且更优选地从约1,000至约5,000D。在一个实施方案中,用平均分子量为约1,000D的PEG进行聚乙二醇化。可选地,PEG均聚物未取代,但是也可以在一个末端用烷基基团取代。优选地,烷基基团是C1-C4烷基基团,并且最优选地为甲基基团。PEG制备物可以由商业提供,并且通常地,适用于本发明中的那些PEG制备物是根据平均分子量销售的非均一制备物。例如,商业提供的PEG(5000)制备物通常包含的分子在分子量上略有不同,经常相差±500D。本发明的融合蛋白可以使用本领域已知的技术进一步修饰,比如,与小分子化合物共轭结合(例如,化学疗法);与信号分子(例如,荧光团)共轭结合;与特异性结合对(例如,生物素/链霉亲和素,抗体/抗原)的分子共轭结合;或者通过糖基化、PEG化而稳定,或者进一步融合至稳定域(例如,Fc域)。
本领域已知多种将蛋白质聚乙二醇化的方法。产生与PEG结合的蛋白质的具体方法包括美国专利No.4,179,337、4,935,465和5,849,535中所述的方法。通常地,通过蛋白质的一个或多个氨基酸残基将蛋白质与聚合物上的末端反应活性基团共价结合,主要依赖于反应条件、聚合物的分子量等。在本文中具有反应活性基团的聚合物称作活化聚合物。反应活性基团选择性地与蛋白质上的自由氨基或其它反应活性基团反应。PEG聚合物可以以随机或定点方式偶联至氨基或其它反应活性基团。然而,应理解的是,为获得最优结果而所选择的反应活性基团的类型和量,以及使用的聚合物的类型,将取决于使用的具体蛋白质或蛋白变体,以避免反应活性基团与蛋白质上过多活性基团反应。因为不可能完全避免,所以建议通常使用从约0.1-1000摩尔,优选2-200摩尔的活化聚合物每摩尔蛋白质,依赖于蛋白质浓度。最终的每摩尔蛋白质的活化聚合物的量是一个平衡,保持最优活性,同时尽可能优化蛋白质的循环半衰期。
在用于本文时,术语“多元醇“广义地表示多羟基醇化合物。多元醇可以是任何水溶性的例如聚烯化氧聚合物,并且能包含直链或支链。优选的多元醇包括那些用化学基团在一个或多个羟基位置取代的多元醇,比如用一和四碳之间的烷基取代。通常地,多元醇是聚烷基二醇,优选聚乙二醇(PEG)。然而,本领域的技术人员可以认识到能用本文所述针对PEG的结合技术而使用的其它多元醇,比如,例如,聚丙二醇和聚乙二醇-聚丙二醇共聚物。本发明的多元醇包括本领域中公知和公开提供如从商业提供来源提供的那些。
此外,可以将其它可延长半衰期的分子附着于三聚域的N或C末端,包括血清白蛋白结合肽、FcRn-结合肽或IgG结合肽。
在一个实施方案中,在原核宿主细胞如大肠杆菌中表达本发明的三聚IL-1Ra蛋白质,并可选地将其连接至第三个多肽即第三个融合伴侣上。因此,可以通过向本发明的三聚IL-1Ra蛋白加入这种第三个融合伴侣,获得高产量的三聚IL-1Ra蛋白。第三个融合伴侣可以是任何合适的肽、寡肽、多肽或蛋白,包括二肽、三肽、四肽、五肽或六肽。在某些情况下,融合伴侣可以是单个氨基酸。可以选择融合伴侣,使其赋予融合蛋白对蛋白降解更强的耐受性,促进融合蛋白的表达和分泌增强,提高溶解度,和/或允许之后亲和纯化融合蛋白。
在一个实施方案中,本发明的融合蛋白(即IL-1Ra部分和三聚域)和第三个融合蛋白伴侣如泛素之间的交界区域,包括颗粒酶B蛋白酶分解位点,比如US 2005/0199251中所述的人颗粒酶B(E.C.3.4.21.79)。
在进一步的实施方案中,第三个融合伴侣可以偶联亲和标签。这种亲和标签可以是允许融合蛋白在亲和树脂上纯化的亲和域。亲和标签可以是聚组氨酸标签如六组氨酸标签、聚精氨酸标签、FLAG标签、Strep标签、c-myc标签、S标签、钙调蛋白结合肽、纤维素结合肽、几丁质结合域、谷胱甘肽S-转移酶标签,或麦芽糖结合蛋白。
本发明的方法可以在分离步骤中用于分离三聚IL-1Ra蛋白,其由将已通过使用上述亲和标签系统而固定化的融合蛋白酶解而形成。这个分离步骤可以通过本领域任何已知用于蛋白质分离的合适方法进行,包括使用离子交换和根据尺度分级分离,方法的选择依赖于融合蛋白的性质。在一个实施方案中,第三个融合伴侣和包含三聚域与IL-1Ra的区域之间的区域与人丝氨酸蛋白酶颗粒酶B接触,在颗粒酶B蛋白酶分解位点分解融合蛋白,获得本发明的融合蛋白。
本发明还提供包含至少一种上述核酸的质粒、载体、转录或表达盒。可以选择或构建包含适当的调控序列的合适载体,所述序列包括启动子序列、终止子序列、聚腺苷酸化序列、增强子序列、标记基因和合适的其它序列。载体可以是质粒、病毒、噬菌体或噬菌粒(MolecularCloning:a Laboratory Manual:2nd edition,Sambrook et al.,1989,ColdSpring Harbor Laboratory Press)。
本发明还提供包含至少一个或多个本发明构建体的重组宿主细胞。合适的宿主细胞包括细菌、哺乳动物细胞、酵母和杆状病毒系统。可用于表达异源多肽的哺乳动物细胞系包括中国仓鼠卵巢细胞、HeLa细胞、仓鼠幼鼠肾细胞、NSO小鼠黑素瘤细胞和很多其它细胞。优选的细菌宿主是大肠杆菌(E.coli)。
药物组合物
在另一个方面,本发明涉及药物组合物,其包含治疗有效量的本发明融合蛋白和可药用的载体或赋形剂。如本文所使用的,“可药用的载体”或“可药用的赋形剂”包括任何和所有生理相容的溶剂,分散介质,涂层剂、抗细菌剂和抗真菌剂,等压和吸附延迟剂,等等。可药用的载体或赋形剂的实例包括一种或多种水、盐、磷酸缓冲盐、右旋糖、甘油、乙醇等,以及它们的组合。在很多情况下,组合物中优选包括等压剂,例如,糖,多元醇如甘露醇、山梨醇,或氯化钠。也可以包括可药用的物质如润湿剂或最少量的辅助物质如润湿或乳化剂、防腐剂或缓冲液,其可以延长抗体或抗体部分的保存期或者增强其效果。可选地,可以包括崩解剂,比如交联的聚乙烯吡咯烷、琼脂、海藻酸或其盐,比如海藻酸钠等。除了赋形剂,药物组合物可以包括下述一个或多个成分:载体蛋白如血清白蛋白、缓冲液、结合剂、甜味剂和其它增味剂;着色剂和聚乙二醇。
组合物可以是多种形式,包括,例如,液体、半固体和固体剂型,比如液体溶液(例如可注射和可输注的溶液)、分散剂或悬浮剂、片剂、丸剂、粉剂、脂质体和栓剂。优选形式依赖于意欲施用的途径和治疗应用。在实施方案中,组合物的形式为可注射或可输注的溶液,比如与人用抗体被动免疫所使用的组合物相似。在一个实施方案中,施用模式为肠胃外(例如,静脉内、皮下、腹膜内、肌肉内)。在一个实施方案中,通过静脉内输液或注射施用融合蛋白(或三聚复合物)。在另一个实施方案中,通过肌肉内或皮下施用融合蛋白或三聚复合物。
对于药物组合物的其它合适的施用途径包括,但不限于,口服、直肠、经皮、阴道、粘膜或肠给药。
在生产和保存条件下,治疗组合物通常无菌并且稳定。组合物可以配制成溶液、微乳液、分散剂、脂质体,或其它适合高药物浓度的有序结构。可以如下制备无菌注射溶液:通过将需要量的活性化合物(即融合蛋白或三聚复合物)掺入合适的包含上文列举的一个组分或组分组合的溶剂中,然后过滤除菌。通常,通过将活性混合物掺入包含基本分散介质和上文列举的其它必需成分的无菌载体而制备分散剂。对于无菌粉剂,对于无菌注射溶液的制备,制备的优选方法是真空干燥和冷冻干燥,从先前过滤除菌的溶液中获得活性成分加任何其它期望成分的粉末。可以保持溶液的正确流动性,例如,通过使用涂层如卵磷脂,对于分散剂则通过保持所需的粒度,并且通过使用表面活性剂。通过在组合物中包括可延迟吸附的试剂,例如,单硬脂酸盐和明胶,使注射组合物的吸附延迟。
生产物质如包含治疗本文所述疾病中有用的治疗剂的试剂盒包括至少一个容器和标记。适当的容器包括,例如,瓶、小瓶、注射剂和试管。容器可以由多种材料形成,比如玻璃或塑料。容器上或与其相关的标记表明使用制剂治疗所选择的病症。生产物质可以进一步包括包含可药用的缓冲液的容器,所述缓冲液如磷酸缓冲盐、Ringer溶液和右旋糖溶液。可以进一步包括从商业和使用者角度期望的其它材料,包括其它缓冲液、稀释液、过滤器、针、注射器和包含使用说明的包装说明书。生产物质还可以包括包含上述另一个活性剂的容器。
通常地,制剂中使用适量的可药用的盐赋予制剂等压性。可药用的盐的实例包括盐、Ringer溶液和右旋糖溶液。制剂的pH优选从约6至约9,并且更优选从约7至约7.5。对于本领域技术人员显而易见的是,某些载体可以更优选,依赖于,例如,施用途径和治疗剂的浓度。
可以通过将具有适当纯度的期望分子与可选的可药用的载体、赋形剂或稳定剂混合(Remington′s Pharmaceutical Sciences,16th edition,Osol,A.ed.(1980)),以冻干制剂、含水溶液或含水悬浮液的形式制备治疗组合物。可接受的载体、赋形剂或稳定剂使用的剂量和浓度优选对接受者无毒,并且包括缓冲液如Tris、HEPES、PIPES、磷酸、柠檬酸和其它有机酸;包括抗坏血酸和甲硫氨酸的抗氧化剂;防腐剂(比如十八烷基二甲基苄基氯化铵;氯化六烃季铵;苯扎氯铵、苄索氯铵、苯酚、丁醇或苄醇;烷基苯甲酸酯如甲基或丙基苯甲酸酯;苯邻二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(小于约10个残基)多肽;蛋白质,比如血清白蛋白、明胶或免疫球蛋白;疏水性聚合物如聚乙烯吡咯烷;氨基酸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物,包括葡萄糖、甘露糖或糊精;糖如蔗糖、甘露糖醇、海藻糖或山梨糖醇;可形成盐的抗衡离子如钠;和/或无毒表面活性剂如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
这种载体的其它实例包括离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢二钾、氯化钠、硅胶、三硅酸镁、聚乙烯吡咯烷和基于纤维素的物质。用于局部或基于凝胶形式的载体包括多糖如羧甲基纤维素钠或甲基纤维素、聚乙烯吡咯烷、聚丙烯酸酯、聚氧化乙烯-聚氧化丙烯-嵌段聚合物、聚乙二醇和木蜡醇。对于所有施用,适当使用常规库存形式。这些形式包括,例如,微胶囊、纳米胶囊、脂质体、石膏、吸入剂形式、鼻腔喷雾、舌下片和缓释制剂。
用于体内施用的制剂应无菌。这可以通过在冻干和重构之前或之后由无菌过滤膜过滤而很容易地实现。制剂可以以冻干形式保存,或者如果全身用药,可以以溶液形式保存。如果以冻干形式,通常与其它成分组合配制,用于在使用时与合适的稀释剂重构。液体制剂的实例是填充在用于皮下注射的单剂量小瓶中的无菌、澄清、无色的无防腐剂溶液。
治疗制剂通常放在具有无菌入口的容器内,例如,静脉注射溶液袋或具有可由皮下注射针刺穿的塞子的小瓶。制剂优选以重复进行的静脉(i.v.)、皮下(s.c.)、肌肉内(i.m.)注射或输液的方式施用,或者以适于鼻内或肺内传递的喷雾形式施用(对于肺内传递,参见,例如,EP 257,956)。
本文公开的分子也可以以缓释制剂的形式施用。缓释制剂的合适的实例包括包含蛋白质的固体疏水聚合物的半渗透性基质,所述基质是成型材质的形式,例如,薄膜或微胶囊。缓释基质的实例包括聚酯、水凝胶(例如,如Langer等人,J.Biomed.Mater.Res.,15:167-277(1981)和Langer,Chem.Tech.,12:98-105(1982)所述的聚(2-羟基乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚乳酸(美国专利No.3,773,919,EP 58,481)、L-谷氨酸和γ乙基-L-谷氨酸的共聚物(Sidman等人,Biopolymers,22:547-556(1983))、不可降解的乙烯-醋酸乙烯酯(Langer,等人,见上文)、可降解的乳酸-乙醇酸共聚物如Lupron Depot(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林组成的可注射微球),和聚-D-(-)-3-羟基丁酸(EP133,988)。
治疗方法
本发明的另一个方面涉及治疗由IL-1Ra介导的疾病的方法。方法包括用治疗有效量的本发明的药物组合物治疗受此类疾病困扰的受试对象。
本发明的另一个方面涉及组合疗法。通过本发明还提供包含治疗剂的制剂。人们相信这种制剂特别适合保存以及治疗施用。制剂可以通过已知技术制备。例如,制剂可以通过凝胶过滤柱上的缓冲液交换而制备。
药物组合物可以按照已知方法施用,比如作为大丸剂静脉用药或通过肌肉内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、口服、局部或吸入途径,历时一段时间连续输液。可选地,可以使用多种商业提供的设备,通过微型泵输液而进行施用。
可以根据经验确定施用三聚IL-1Ra的有效剂量和计划,并使确定的方案在本领域技术内。可以使用单一或多种剂量。目前相信单独使用的三聚IL-1Ra的有效剂量或量可以从每天约1μg/kg至100mg/kg体重或更多。剂量的种间放大可以以本领域已知的方式,例如,如Mordenti等人,Pharmaceut.Res.,8:1351(1991)所公开的进行。
在体内施用IL-1Ra融合蛋白时,正常剂量可以从约10ng/kg至高达100mg/kg哺乳动物体重或更多每天不等,优选约1μg/kg/天-50mg/kg/天,依赖于施用途径。文献中以具体剂量和传递方法提供了指导(参见,例如,美国专利No.4,657,760;5,206,344;或5,225,212)。一名技术人员应了解的是,不同剂量将对不同治疗化合物和不同疾病有效,例如,用药靶向的一种组织或器官可以使传递方式不同于另一种组织或器官。本领域的那些技术人员将理解,必须施用的三聚IL-1Ra的剂量依赖于,例如,接受三聚IL-1Ra的哺乳动物、施用途径,和待用于所述哺乳动物的其它药物或疗法而不同。
可以同时或顺序施用三聚复合物和其它治疗剂(和一种或多种其它疗法)。在具体的实施方案中,同时施用融合蛋白或三聚复合物和治疗剂。在另一个实施方案中,在施用治疗剂前施用融合蛋白或三聚复合物。在另一个实施方案中,在施用融合蛋白或三聚复合物之前使用治疗剂。施用后,可以分析体外治疗的细胞。在进行体内治疗时,可以通过技术人员已知的多种方法检测治疗的哺乳动物。例如,可以分析血清细胞因子响应。
本文所述IL-1Ra融合蛋白可以与用于治疗或预防本文所述疾病和病症的任何一种或多种TNF抑制剂组合使用(治疗前、治疗后或治疗同时),所述抑制剂比如但不限于,所有形式的可溶TNF受体,包括依那西普(比如ENBREL),以及所有形式的单体或多聚体的p75和/或p55TNF受体分子及其片段;抗-人TNF抗体,比如但不限于,因福利美(比如REMICADE),和D2E7(比如HUMIRA),等等。这种TNF抑制剂包括可以阻断TNF的体内合成或细胞外释放的化合物和蛋白质。在特定的实施方案中,本发明涉及IL-17RA IL-1Ra融合蛋白与任何一种或多种下述TNF抑制剂组合使用(治疗前、治疗后或治疗同时):TNF结合蛋白(可溶TNF I类受体和可溶TNF II类受体(“sTNFR”),如本文所定义的),抗-TNF抗体,粒性白细胞菌落刺激因子;萨力多胺;BN 50730;替尼达普;E 5531;替帕芬特(tiapafant)PCA4248;尼美舒利;帕拉威尔;咯利普兰;RP 73401;肽T;MDL 201,449A;(1R,3S)-顺式-1-[9-(2,6-二氨基嘌呤基)]-3-羟基-4-环戊烯氢氯化物;(1R,3R)-反式-1-(9-(2,6-二氨基)嘌呤)-3-乙酰氧基环戊烯;(1R,3R)-反式-1-[9-腺嘌呤基]-3-叠氮基环戊烯氢氯化物和(1R,3R)-反式-1-(6-羟基-嘌呤-9-基)-3-叠氮基环戊烯。TNF结合蛋白在本领域中公开(EP 308378、EP 422 339、GB 2 218 101、EP 393 438、WO 90/13575、EP 398 327、EP 412 486、WO 91/03553、EP 418 014、JP 127,800/1991、EP 433 900、美国专利No.5,136,021、GB 2 246 569、EP 464 533、WO 92/01002、WO 92/13095、WO 92/16221、EP 512 528、EP 526 905、WO 93/07863、EP 568 928、WO 93/21946、WO 93/19777、EP 417 563、WO 94/06476、和PCT国际申请No.PCT/US97/12244)。
例如,EP 393438和EP 422339教导可溶TNF I类受体(也称作“sTNFR-1”或“30kDa TNF抑制剂”和可溶TNF II类受体(也称作“sTNFR-II”或“40kDa TNF抑制剂”)(统称为“sTNFR”)的氨基酸和核酸序列,以及其修饰形式(例如,片段、功能衍生物和变体)。EP393438和EP 422339还公开了用于分离负责编码抑制剂的基因,在合适的载体和细胞类型中克隆基因并表达基因产生抑制剂的方法。此外,还公开了sTNFR-1和sTNFR-II的多价形式(即,包含不止一个活性部分的分子)。在一个实施方案中,可以通过将至少一个TNF抑制剂和另一个部分与任何临床可接受的接头,例如聚乙二醇(WO 92/16221和WO 95/34326)化学偶联,通过肽接头(Neve等人(1996),Cytokine,8(5):365-370),通过化学偶联至生物素然后结合至亲和素(WO91/03553)并且,最后,通过合并嵌合的抗体分子(美国专利No.5,116,964,WO 89/09622,WO 89/09622,WO 91/16437和EP 315062)而构建多价形式。
抗-TNF抗体包括MAK 195F抗体(Holler等人(1993),1stInternational Symposium on Cytokines in Bone Marrow Transplantation,147);CDP 571抗-TNF单克隆抗体(Rankin等人(1995),British Journalof Rheumatology,34:334-342);BAY X 1351鼠抗-肿瘤凋亡因子单克隆抗体(Kieft等人(1995),7th European Congress of Clinical Microbiologyand Infectious Diseases,第9页);CenTNF cA2抗-TNF单克隆抗体(Elliott等人(1994),Lancet,344:1125-1127and Elliott et al.(1994),Lancet,344:1105-1110)。
本文所述IL-1Ra融合蛋白可以与所有形式的IL-17抑制剂(例如抗-IL17受体抗体,Amgen;抗-IL-17A,抗-IL17F)、RORc抑制剂组合使用。
本文所述IL-1Ra融合蛋白可以与所有形式的IL-6和/或IL-6受体抑制剂组合使用,比如但不限于,托珠单抗(Tocilizumab)(例如ACTEMRA)。
本文所述IL-1Ra融合蛋白可以与所有形式的抗-IL-18化合物如IL-18BP或衍生物,IL-18trap、抗-IL-18、抗-IL-18R1或抗-IL-18-RAcP组合使用。
本文所述IL-1Ra融合蛋白可以与所有形式的抗-IL22如抗-IL22或抗IL22R组合使用。
本文所述IL-1Ra融合蛋白额可以与所有形式的抗-IL-23和或IL-12如抗-p19、抗-p40(乌特津单抗(Ustekinumab))、抗-IL-23R组合使用。
本文所述IL-1Ra融合蛋白可以与所有形式的抗-IL21如抗-IL21或抗-IL21R组合使用。
本文所述IL-1Ra融合蛋白可以与所有形式的抗-TGF-β组合使用。
IL-1Ra融合蛋白可以与一种或多种细胞因子、淋巴因子、成血因子和/或抗炎剂组合使用。
本文所述疾病和病症的治疗可以包括使用用于控制疼痛和炎症的一线药物和用一种或多种本文提供的IL-1Ra融合蛋白治疗的组合(治疗前、治疗后或治疗同时)。这些药物被划分为非甾体抗炎药物(NSAID)。二级治疗包括皮质类固醇、慢作用抗风湿药物(SAARD),或病症改善(DM)药物。关于下述化合物的信息可以在The Merck Manualof Diagnosis and Therapy,Sixteenth Edition,Merck,Sharp & DohmeResearch Laboratories,Merck & Co.,Rahway,N.J.(1992)和Pharmaprojects,PJB Publications Ltd中找到。
本文所述IL-1Ra融合蛋白可以与用于治疗本文所述疾病和病症的一种或多种NSAID组合使用。NSAID至少进行部分抗炎作用,抑制前列腺素合成(Goodman and Gilman in″The Pharmacological Basis ofTherapeutics,″MacMillan 7th Edition(1985))。NSAID可以分为至少九组:(1)水杨酸衍生物;(2)丙酸衍生物;(3)乙酸衍生物;(4)芬那酸衍生物;(5)羧酸衍生物;(6)丁酸衍生物;(7)昔康类(oxicam);(8)吡唑和(9)吡唑啉酮。
本文所述IL-1Ra融合蛋白可以与任何一种或多种水杨酸衍生物、前药酯或其可药用的盐组合使用(治疗前、治疗后或治疗同时)。这些水杨酸衍生物、前药酯或其可药用的盐包括:醋氨沙洛、阿洛普令、阿司匹林、扑炎痛、溴水杨醇、乙酰水杨酸钙、三水杨酸胆碱镁、水杨酸镁、水杨酸胆碱、二氟尼柳(diflusinal)、伊特柳酯、芬度柳、龙胆酸、水杨酸乙二醇酯、水杨酸咪唑、赖氨酸乙酰水杨酸、氨水杨酸、水杨酸吗啉、1-萘基水杨酸、奥沙拉秦、帕沙米特、苯基乙酰水杨酸、苯基水杨酸、醋水杨胺、邻氨甲酰基苯氧乙酸、双水杨酯、水杨酸钠和柳氮磺胺吡啶。结构相关、具有相似的止痛和抗炎性质的水杨酸衍生物也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一个或多个丙酸衍生物、前药酯或其可药用的盐组合(治疗前、治疗后或治疗同时)的用途。丙酸衍生物、前药酯和其可药用的盐包括:阿洛明芬、苯恶洛芬、布氯酸、卡洛芬、右吲哚洛芬、非诺洛芬、氟诺洛芬、氟洛芬、氟比洛芬、呋洛芬、布洛芬、布洛芬铝、异丁普生、吲哚洛芬、异洛芬、酮洛芬、氯索洛芬、咪洛芬、萘普生、萘普生钠、奥沙普秦、吡酮洛芬、吡啶洛芬(pimeprofen)、吡咯洛芬、普拉洛芬、丙替嗪酸、吡哆洛芬(pyridoxiprofen)、舒洛芬、噻洛芬酸和硫恶洛芬。具有相似镇痛和抗炎性质的结构相关丙酸衍生物也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra与任何一个或多个乙酸衍生物、前药酯或其可药用的盐的组合用途(治疗前、治疗后或治疗同时)。乙酸衍生物、前药酯,和其可药用的盐包括:阿西美辛、阿氯芬酸、氨芬酸、丁苯羟酸、桂美辛、氯吡酸、地美辛、双氯芬酸钠、依托度酸、联苯乙酸、芬氯酸、苯克洛酸、芬克洛酸、芬替酸、呋罗芬酸、葡美辛、异丁芬酸、消炎痛、三苯唑酸、伊索克酸、氯那唑酸、甲嗪酸、奥沙美辛、奥克品那(oxpinac)、吡美辛、丙谷美辛、苏灵大、他美辛、噻拉米特、硫平酸、甲苯酰吡啶乙酸、甲苯酰吡啶乙酸钠、齐多美辛和佐美酸。具有相似镇痛和抗炎性质的结构相关乙酸衍生物也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一个或多个芬那酸衍生物、前药酯或其可药用的盐的组合用途(治疗前、治疗后或治疗同时)。芬那酸衍生物、前药酯和其可药用的盐包括:因法来酸、依托芬那酯、氟芬那酸、异尼克辛、甲氯芬那酸、甲氯芬那酸钠、medofenamic acid、甲灭酸、尼氟酸、他尼氟酯、特罗氨酯、邻甲氯灭酸和乌芬那酯。具有相似镇痛和抗炎性质的结构相关芬那酸衍生物也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一个或多个羧酸衍生物、前药酯或其可药用的盐的组合用途(治疗前、治疗后或治疗同时)。羧酸衍生物、前药酯和其可药用的盐包括:环氯茚酸、二氟尼柳、氟苯柳、因诺立定(inoridine)、酮咯酸和替诺立定。具有相似镇痛和抗炎性质的结构相关羧酸衍生物也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一个或多个丁酸衍生物、前药酯或其可药用的盐的组合用途(治疗前、治疗后或治疗同时)丁酸衍生物、前药酯和其可药用的盐包括:布地马宗、布替布芬、芬布芬和联苯丁酸。具有相似镇痛和抗炎性质的结构相关丁酸衍生物也意欲包括在这组中。
在另一个实施方案中,本发明涉及IL-1Ra融合蛋白与任何一个或多个昔康、前药酯或其可药用的盐的组合用途(治疗前、治疗后或治疗同时)。昔康、前药酯和其可药用的盐包括:屈恶昔康、依诺利康、伊索昔康、吡罗昔康、舒多昔康、替诺昔康和4-羟基-1,2-苯并噻嗪1,1-二氧-4-(N-苯基)-酰胺。具有相似镇痛和抗炎性质的结构相关昔康也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一个或多个吡唑、前药酯或其可药用的盐的组合用途(治疗前、治疗后或治疗同时)。可以使用的吡唑、前药酯或其可药用的盐包括:二苯咪唑和依匹唑。具有相似镇痛和抗炎性质的结构相关吡唑也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一个或多个吡唑啉酮、前药酯或其可药用的盐的组合用途(治疗前、治疗后或治疗同时)。可以使用的吡唑啉酮、前药酯和其可药用的盐包括:阿扎丙宗、阿扎丙酮、苄哌立隆(benzpiperylon)、非普拉宗、莫非保松、玛拉宗、羟基得泰松、苯基丁氮酮、哌保松、丙基安替比林(propylphenazone)、雷米那酮、琥保松和噻唑保泰松(thiazolinobutazone)。具有相似镇痛和抗炎性质的结构相关吡唑啉酮也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一个或多个下述NSAID组合的用途(治疗前、治疗后或治疗同时):ζ-乙酰氨基己酸、S-腺苷-甲硫氨酸、3-氨基-4-羟基丁酸、阿米西群、阿尼扎芬、安曲非宁、苄达酸、苄达酸赖氨酸酯、苄达明、比普钦(beprozin)、溴哌莫、布可隆、丁苯唑酸、环丙喹宗、氯可昔酯(cloximate)、达奇胺、地波沙美、地托咪定、联苯吡胺(difenpiramide)、联苯吡胺(difenpyramide)、difisalamine、地他唑、依莫法宗、甲磺酸法奈替唑、吩氟咪唑、氟喹氨苯酯、氟咪唑、氟尼辛、氟丙喹宗、伏哌托宁、磷柳酸、胍美柳、guaiazolene、isonixirn、盐酸利非他明、来氟米特、洛非咪唑、氯替法唑、lysin clonixinate、美西拉宗、萘丁美酮、尼克吲哚、尼美舒立、奥古蛋白、奥帕诺辛、奥沙西罗、奥沙帕朵、瑞尼托林、派立索唑、柠檬酸派立索唑、派福肟、萘普生哌嗪酸、吡拉唑酸、吡非尼酮、普罗喹宗、普罗沙唑、thielavin B、替氟咪唑、替美加定、托美丁、托帕朵、tryptamid和那些由公司代码号如480156S、AA861、AD1590、AFP802、AFP860、AI77B、AP504、AU8001、BPPC、BW540C、CHINOIN 121、CN100、EB382、EL508、F1044、FK-506、GV3658、ITF182、KCNTEI6090、KME4、LA2851、MR714、MR897、MY309、ONO3144、PR823、PV102、PV108、R830、RS2131、SCR152、SH440、SIR133、SPAS510、SQ27239、ST281、SY6001、TA60、TAI-901(4-苯甲酰-1-茚酸)、TVX2706、U60257、UR2301和WY41770命名的那些。具有与NSAID相似镇痛和抗炎性质的结构相关NSAID也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一种或多种皮质类固醇、前药酯或其可药用的盐的组合用于治疗本文所述疾病和病症的用途(治疗前、治疗后或治疗同时),所述疾病或病症包括急性和慢性炎症如风湿性疾病、移植物抗宿主疾病和多发性硬化。皮质类固醇、前药酯和其可药用的盐包括氢化可的松和源自氢化可的松的化合物,比如21-醋酸基娠烯醇酮、alclomerasone、阿尔孕酮、安西奈德、倍氯米松、倍他米松、戊酸倍他米松、布地奈德、氯泼尼松、氯倍他索、丙酸氯倍他索、氯倍他松、丁酸氯倍他松、氯可托龙、氯泼尼醇、皮质酯酮、可的松、可的伐唑、deflazacon、羟泼尼缩松、desoximerasone、地塞米松、二氟拉松、二氟可龙、二氟泼尼酯、甘草次酸、氟扎可特、氟氯奈德、氟米松、三甲基乙酸氟米松、丙酮化氟新龙、氟尼缩松、氟轻松醋酸酯、丁基氟可丁、氟可龙、己酸氟可龙、戊酸氟可龙、氟甲龙、乙酸氟培龙、乙酸氟泼尼定、氟泼尼龙、flurandenolide、福莫可他、哈西缩松、卤米松、乙酸卤泼尼松、hydro-cortamate、氢化可的松、乙酸氢化可的松、丁酸氢化可的松、磷酸氢化可的松、氢化可的松21-琥珀酸钠、氢化可的松叔丁乙酯、马泼尼酮、甲羟松、甲泼尼松、甲强龙、糠酸莫米他松、帕拉米松、泼尼卡酯、强的松龙、强的松龙21-diedryaminoacetate、强的松龙21-磷酸钠、强的松龙21-琥珀酸钠、强的松龙21-间磺苯甲酸钠、强的松龙21-硬脂酰甘醇酸钠、强的松龙叔丁乙酯、三甲基乙酸强的松龙21、强的松、强的松龙戊酸酯、泼尼立定、泼尼立定21-二乙胺乙酸酯、替可的松、去炎松、曲安奈德、苯曲安缩松和己曲安缩松。具有与相似镇痛和抗炎性质的结构相关皮质类固醇也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一种或多种慢作用抗风湿药物(SAARD)或病情缓解抗风湿药物(DMARD)、前药酯或其可药用的盐组合用于治疗本文所述疾病和病症的用途(治疗前、治疗后或治疗同时),所述疾病包括急性和慢性炎症如风湿性疾病、移植物抗宿主疾病和多发性硬化。SAARD或DMARDS、前药酯和其可药用的盐包括:阿洛酮钠、金诺芬、金硫葡糖、金硫醋苯胺、咪唑硫嘌呤、布喹那钠、布西拉明、3-金硫-2-丙醇-1-磺酸钙、苯丁酸氮芥、氯喹、氯丁扎利、铜克索林、环磷酰胺、环孢素、氨苯砜、15-脱氧格埃林、双醋瑞因、葡萄糖胺、金盐(例如、环喹金盐、硫代苹果酸金钠、硫代硫酸金钠)、羟基氯喹、硫酸羟基氯喹、羟基脲、酮保泰松、左旋咪唑、氯苯扎利、蜂毒素、6-巯嘌呤、甲氨蝶呤、咪唑立宾、霉酚酸酯、myoral、氮芥、D-青霉胺、pyridinolimidazole如SKNF86002和SB203580、雷帕霉素、硫醇、促胸腺生成素和长春新碱。具有与相似镇痛和抗炎性质的结构相关SAARD或DMARD也意欲包括在这组中。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一种或多种COX2抑制剂、前药酯或其可药用的盐组合用于本文所述疾病和病症的治疗的用途(治疗前、治疗后或治疗同时),所述疾病和病症包括急性和慢性炎症。COX2抑制剂、前药酯或其可药用的盐的实例包括,例如,赛来昔布。具有相似镇痛和抗炎性质的结构相关COX2也意欲包括在这组中。COX-2选择性抑制剂的实例包括但不限于依托考昔、伐地昔布、赛来昔布、立克飞龙、罗美昔布(lumiracoxib)、罗非昔布等等。
在另一个具体的实施方案中,本发明涉及IL-1Ra融合蛋白与任何一种或多种抗细菌剂、前药酯或其可药用的盐组合用于治疗本文所述基本和病症的用途(治疗前、治疗后或治疗同时),所述疾病或病症包括急性和慢性炎症。抗细菌剂包括,例如,各种类型的青霉素,头孢菌素和其它β-内酰胺,氨基糖苷,唑类,喹诺酮。青霉素包括,但不限于青霉素G、青霉素V、甲氧西林、萘夫西林、新青二、氯洒西林、双氯青霉素、氟氯青霉素、氨苄青霉素、氨苄青霉素/舒巴坦、阿莫西林、阿莫西林/克拉维酸、海他西林、环青霉素、氨苄青霉素甲戊酯、羧苄青霉素、羧茚青霉素、羧基噻吩青霉素、羧基噻吩青霉素/克拉维酸、阿洛西林、meziocillin、哌拉西林和美西林。头孢菌素和其它β-内酰胺包括,但不限于先锋霉素、头孢匹林、头孢氨苄、头孢拉啶、头孢唑啉、头孢羟氨苄、头孢克洛、头孢羟唑、头孢替坦、头孢西丁、ceruroxime、头孢尼西、ceforadine、头孢克肟、头孢噻肟、拉氧头孢、头孢唑肟、头孢曲松、cephoperazone、头孢他啶、亚胺培南和氨曲南。氨基糖苷包括,但不限于氯霉素、庆大霉素、妥布霉素、丁胺卡那霉素、奈替米星、卡那霉素和新霉素。唑类包括,但不限于氟康唑。喹诺酮包括,但不限于萘啶酮酸、诺氟沙星、依诺沙星、环丙沙星、氧氟沙星、司帕沙星和替马沙星。大环内酯包括,但不限于红霉素、螺旋霉素和阿奇霉素。利福霉素包括,但不限于利福平。四环素包括,但不限于spicycline、氯四环素、氯莫环素、地美环素、去氧土霉素、胍甲环素、赖甲环素、甲氯环素、甲烯土霉素、二甲胺四环素、氧四环素、青哌环素、匹哌环素、罗利环素、山环素、senociclin和四环素。磺胺包括,但不限于磺胺、新诺明、磺胺醋酰、磺胺嘧啶、磺胺异噁唑和复方磺胺甲噁唑(甲氧苄胺嘧啶/新诺明)。林可胺包括,但不限于氯林肯霉素和林肯霉素。多粘菌素(多肽)包括,但不限于多粘菌素B和粘菌素。
应注意的是,本文使用的小节标题仅用于组织,不应理解为以任何方式限定所述主题。本文引用的所有参考文献通过引用全部并入本文。
下述实施例仅是对本发明某些实施方案的阐述,不应视为对本发明的限制,本发明由所附的权利要求所限定。
实施例
实施例1:三聚IL-1Ra的形式、产生和纯化
先前已经显示,IL-1Ra能作为大肠杆菌中的重组蛋白而产生(Steinkasserer等人1992.FEBS 310:63-65)。蛋白非常稳定并且有效地重折叠。也已经描述了在N-末端具有其它氨基酸的IL-1Ra的同工型(Haskill等人1991,PNAS 88:3681-3685;Muzio等人1995,JEM 182,623-628)。这些分子结合IL-1R以及成熟分泌形式,表明可能将多余的肽与拮抗剂的N-末端融合,而不影响与受体的结合。对与IL-1R相互反应的IL-1Ra的晶体进行的结构分析也支持N-末端变化不影响与IL1R的相互作用(Schreuder等人1997,Nature 386:190-194)。从源自骨髓和/或人胎盘的人cDNA文库克隆IL-1Ra。
三聚IL-1Ra经过设计,与Trip-三聚单元进行C-末端融合。设计了八个不同的融合蛋白,四个具有全长三聚单元(Trip),四个具有三聚单元的九个氨基酸的截短型(I10Trip)。然后使用四个不同的C-末端融合,将IL-1ra与任一个三聚单元融合。名为Trip V、Trip T、Trip Q和Trip K的C-末端变体允许在三聚域上唯一呈现CTLD。Trip K变体是最长的构建体,并且在CTLD和三聚域之间包含最长并且最灵活的连接头。Trip V、Trip T、Trip Q代表直接位于三聚模块上而没有任何结构灵活性的CTLD分子的融合体,而且将三分之一的CTLD分子从TripV到Trip T,并从Trip T到Trip Q。这是由于这些氨基酸中的每个都为α-螺旋旋转,并且完整旋转需要3.2aa。
以BL21AI细菌中的颗粒酶B可分裂融合蛋白的形式产生下述蛋白。带下划线的部分表示三聚单元,并且黑体字部分表示IL-1Ra部分:
CII-H6-GrB-GG-TripK-IL-1ra:
MVRANKRNEALRIESALLNKIAMLGTEKTAEGGSHHHHHHGSIEPDGGEGPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQ QALQTVSLK (SEQ ID NO:47);
CII-H6-GrB-GG-TripV-IL-1ra:MVRANKRNEALRIESALLNKIAMLGTEKTAEGGSHHHHHHGSIEPDGGEGPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQ QALQTV (SEQ ID NO:48);
CII-H6-GrB-GG-TripT-IL-1ra:MVRANKRNEALRIESALLNKIAMLGTEKTAEGGSHHHHHHGSIEPDGGEGPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQ QALQT (SEQ ID NO:49);
CII-H6-GrB-GG-TripQ-IL-1ra:MVRANKRNEALRIESALLNKIAMLGTEKTAEGGSHHHHHHGSIEPDGGEGPTQKPKKIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQ QALQ (SEQ ID NO:50);
CII-H6-GrB-I10-TripK-IL-1raMVRANKRNEALRIESALLNKIAMLGTEKTAEGGSHHHHHHGSIEPDIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTVSLK (SEQ ID NO:51);
CII-H6-GrB-I10-TripV-IL-1raMVRANKRNEALRIESALLNKIAMLGTEKTAEGGSHHHHHHGSIEPDIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQTV (SEQ ID NO:52);
CII-H6-GrB-I10-TripT-IL-1ra:MVRANKRNEALRIESALLNKIAMLGTEKTAEGGSHHHHHHGSIEPDIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQT (SEQ ID NO:53);和
CII-H6-GrB-I10-TripQ-IL-1ra:MVRANKRNEALRIESALLNKIAMLGTEKTAEGGSHHHHHHGSIEPDIVNAKKDVVNTKMFEELKSRLDTLAQEVALLKEQQALQ (SEQ ID NO:54)
在NiNTA Superflow(Qiagen)上捕捉所有构建体,重折叠并进一步在SP-Sepharose FF(GE Heathcare)上纯化。根据摇瓶中的表达或三聚IL1-Ra的发酵结果,纯化包涵体。将密实的细胞团在裂解缓冲液(50mMTris-HCl,pH8.0,25w/v%蔗糖,1mM EDTA)中通过超声均质化(50g湿细胞团每100mL裂解缓冲液)。然后加入100mg溶菌酶每100mL裂解缓冲液并混合,之后将样品在室温放置15分钟。然后将样品和其中的混合物一起超声2-5分钟。加入清洁缓冲液(0.2M NaCl、1w/v%脱氧胆酸盐、Na盐、1w/v%Nonidet P40、20mM Tris-HCl、pH7.5,2mM EDTA)并与样品混合,之后再次超声。通过在8000rpm,4℃离心25分钟而回收包涵体。在4℃保存上清并将细胞团重悬于100mLTRITONX-100缓冲液(0.5w/v%TRITONX-100、1mM EDTA,pH8)每50g初始细胞团中。通过在8000rpm,4℃离心25分钟而回收包涵体,并在4℃保存上清。再重复一次TRITONX-100缓冲液洗涤,并通过在12000rpm,4℃离心5分钟而回收包涵体。
将包涵体在28℃在30mL变性缓冲液/克初始细胞糊(6M尿素、10mM EDTA、20mM Tris/HCl和20mMβ-巯基乙醇,pH8.0)中重悬2小时。在7500g将悬浮液离心15分钟,去除不溶物。然后加入CaCl2至终浓度20mM,并将溶液应用于100mL Ni-NTA Superflow柱,其在NTA缓冲液(8M尿素;1000mM NaCl;50mM Tris HCl pH8.0;5mMβ-巯基乙醇)中平衡并洗涤,直至获得稳定基线。用250mL盐酸胍、50mMTris-HCl pH8.0、5mMβ-巯基乙醇进一步洗涤,然后用100mL缓冲液NTA洗涤。
已经使用了两种重折叠的方法,透析重折叠和柱上重折叠都获得了纯的可溶蛋白。对于透析重折叠,重悬的包涵体可直接用于过夜透析进入包含3M尿素、1mM EDTA的1×PBS,pH7.2。透析次日继续透析进入包含0M尿素、1mM EDTA的1×PBS,pH7.2。
对于柱上重折叠,洗涤已结合蛋白的Ni-NTA Superflow柱,用包含3M尿素的4CV ml 1×PBS,pH7.2洗涤树脂,之后运行线性梯度,其为包含3M尿素的10CV 1×PBS,pH7.2和包含0M尿素的10CV1×PBS,pH7.2。为了回收重折叠的三聚IL-1ra,用1×PBS,10mMEDTA,pH6.0洗脱柱并收集各部分。
重折叠后,如下进行用重组人颗粒酶B的分裂:通过用NaOH将洗脱液中的pH调至7.5,然后以1∶400的比例(颗粒酶/蛋白)加入颗粒酶B,并在25℃过夜孵育。之后进行SDS-PAGE。
最后,使用SP-Sepharose FF(GE Healthcare)阴离子交换步骤纯化分裂的蛋白质。填充约50mL SP-Sepharose FF,并在缓冲液A(1xPBS,1mM EDTA pH5,5)中平衡直至获得稳定基线。用缓冲液A 1∶3稀释分裂反应物,并载入柱上,然后用缓冲液A洗涤直至监测到稳定基线。建立从10CV缓冲液A到10CV缓冲液B(1×PBS、1mM EDTA+0.5M NaCl pH5.5)的梯度,并收集各部分5mL。在合并蛋白产物前在SDS-PAGE上分析包含各部分的蛋白。
或者,使用来自上述包涵体制备物的上清纯化蛋白。在用缓冲液A(20mM TrisHCL,50mM NaCl pH8.0)平衡的Ni-NTA Superflow(Qiagen)柱上纯化上清中的可溶三聚IL1-ra。合并包涵体纯化的洗涤液,并在10000rpm离心10分钟,然后加入CaCl2至5mM,并加入Tris-HCl至20mM,并用HCl/NaOH将pH调至6.0。将合并物载入柱上并用缓冲液A洗涤,直至获得稳定基序。在缓冲液A+1M NaCl洗涤直至基线稳定后,用缓冲液A+20mM EDTA洗脱已结合蛋白,并收集各部分。此后用颗粒酶B分裂蛋白合并物,并如上所述在SP-Sepharose FF柱上精制。来自3L表达培养物的CII-H6-GrB-GG-TripK-IL-1ra的可溶部分的最终产量为95mg TripK-IL-1Ra(在捕捉Ni-NTA Superflow(Qiagen)后约250mg CII-H6-GrB-TripK-IL-1Ra)。因为来自可溶部分的蛋白产量和纯度显著优于重折叠,所以选择这种方法进行初始构建体测试。
在Biacore 300(Biacore,Uppsala,Sweden)上分析重折叠蛋白与IL-1受体1结合的能力,其中小鼠IL1-RI/Fc与CM5传感器芯片偶联,并且测定可溶TripK-IL-1ra与IL-1RI蛋白的结合。通过透析重折叠未分裂CII-H6-GrB-TripK-IL-1ra的结果示于图2,并且未分裂CII-H6-GrB-TripK-IL-1ra柱上NiNTA重折叠示于图3。分裂和纯化分析方法产生SEQ ID NO:47-54的三聚IL-1Ra化合物。
实施例2:三聚IL-1Ra化合物在U937细胞中抑制IL-8的IL-1诱
导的能力
进一步分析GG-TripV-IL-1ra(trip V-IL1Ra)、GG-TripK-IL-1ra(tripK-IL1Ra)、GG-TripT-IL-1ra(trip T-IL1Ra)和CII-H6-GrB-GG-TripT-IL-1ra(trip Q-IL1Ra)在U937细胞中抑制IL-8的IL-1诱导的能力。结果示于图4中。
化合物对于阻断响应基本同样有效,并且全部表现为和KINERET(在w/w上比较)一样有效。由于在实验中的缓冲作用,在使用的最高蛋白浓度(100g/mL),IL-8的产生增加而不是继续下降。根据几种体外效果检测实验以及Biacore检测,根据阻断和结合效率以及产量,确定TripT IL1Ra是最佳的化合物。
实施例3:聚乙二醇三聚IL-1Ra化合物
因为体内半衰期是KINERET效率中的关键参数(KINERET在人体中的半衰期只有4-6小时,并且因此可每天用一次),所以测试通过N-末端聚乙二醇化将TripT IL1Ra聚乙二醇化的能力。在N末端将三聚IL1-Ra聚乙二醇化。使用上述纯化过程最后一步后的三聚IL1-Ra拮抗剂蛋白作为聚乙二醇化的起点。将缓冲液换成PBS缓冲液pH6.0,进行聚乙二醇化反应。反应物中的蛋白浓度为0.5-3.5mg/ml,并且使用补加20mM氰硼氢钠的过量5-10摩尔的mPeg5K-乙醛或mPeg20K-乙醛(Nektar)。在20℃进行16小时反应。反应后,将混合物用于Source15S柱(GE Healtcare),纯化单聚乙二醇化形式。如图5所示,与未聚乙二醇化蛋白相比,聚乙二醇化形式蛋白的拮抗活性下降。然而,聚乙二醇化蛋白仍然具有好的IL1阻断效果。
实施例4:i.v.注射后雄性Lewis大鼠中三聚IL1Ra蛋白的药代动
力学分析
选择前面实施例中描述的三种三聚IL1Ra多肽进行药代动力学分析。构建体中的差异在三聚域的N-末端:全长(FL)、前九个氨基酸截短(I10)和前16个氨基酸截短(V17)。I10构建体代表三聚域天然发生缺失的变体,并且缺少在Thr 4的O-糖苷化。V17衍生物代表缺失编码三聚域的第一个外显子,并且缺少肝素结合位点。这个位点在I10构建体中也部分去除。如图6所示,在U937细胞分析中确认了IL-1Ra分子的体外效果。
在静脉内(i.v.)注射后,分析Lewis大鼠中这三种构建体多肽的药代动力学谱。获得的谱与同样实验中KINERET的药代动力学谱相比较。使用四只雄性Lewis大鼠每组进行药代动力学研究,并且使用的构建体为FL IL-1Ra、I10IL-1Ra、V17IL-1Ra和KINERET对动物每次i.v.剂量为100mg/kg。测试化合物溶于载体(4.4mM柠檬酸钠,pH6.5,93.8mM NaCl,0.33mM EDTA,0.7g TWEEN-80)中,并通过尾部静脉(骶正中静脉)或后爪静脉(隐静脉)施用。
然后在基线(0小时)和用药后0.5、1、2、4、8、12、24、48、72小时的每个时间点从四只动物收集血液。在MicrotainersTM中,从尾尖收集约100μl的血液样本。收集血浆并转移到聚丙烯管中。然后在-70℃储存血浆样本,直至进行测量。然后通过吸入CO2而杀死动物,并弃去尸体而不进行病原检查。然后通过ELISA测定血浆中的IL-1Ra化合物水平和KINERET水平。
每只大鼠的平均体重为250克。假设大鼠平均血体积为16.5mL,在i.v.注射后,计算得到化合物的理论最大初始浓度为1500000ng/mL。这些浓度示于图7中。使用这一起始水平为分析的起始值。在动物体中未观察到副作用或变化。
在上述时间点取血液样本后,使用ELISA方法测定血液样本中注射的蛋白质。根据这些ELISA结果,使用曲线下面积(AUC)作为药物暴露的量度,并使用标准软件计算血浆半衰期。曲线下面积示于表2中,并且蛋白质的血浆半衰期示于表3中。
表2
表3
这些i.v.数据表明,与KINERET相比,三聚化合物的血浆半衰期更长。KINERET的半衰期约为1.2分钟,同时V17IL1Ra三聚化合物在i.v.注射后的半衰期约为69分钟。依赖于分析中所使用的标准,AUC的相对增加在两倍(FL IL1Ra三聚物)和五倍(V17 IL1Ra三聚物)之间,表明与KINERET相比,使用三聚变体的药物暴露得到充分改善。
实施例5:Met-I10-TripT-IL1ra和GG-V17-TripT-IL1ra和大鼠CIA
模型的产生
两种分子均由BL21AI细菌在10L发酵罐中使用2×TY培养基(Met-I10-TripT-IL-1ra)或化学合成最小培养基(GG-V17-TripT-IL-1ra)产生。通过以5887×g离心20分钟而获得细胞团,然后重悬于10mMNa2HPO4 pH6中。对于Met-I10-TripT-IL-1ra,通过高压均质化(2×17.000psi)而获得包括目的蛋白的可溶细胞部分,然后以10.000×g离心10分钟。用10mM Na2HPO4 pH7.4稀释上清,并在SP-Sepharose FF柱(阳离子交换,GE Healthcare)上跑样,然后使用AKTA fPLC在Q-Sepharose FF(阴离子交换,GE Healthcare)上跑样。在最后一步,使蛋白通过Mustang E过滤器(Pall)以去除内毒素,然后通过缓冲液交换进入PBS pH7.4中,并浓缩至50mg/mL。以包括N-末端加强域、噬菌体CII蛋白的融合蛋白之后加入人颗粒酶B分裂位点的形式表达GG-V17-TripT-IL-1Ra蛋白。通过在包含裂解酶的裂解缓冲液中均质化,然后以8000rpm离心25分钟而从发酵细胞团中纯化GG-V17-TripT-IL-1Ra。然后使上清通过FractogelEMD Chelate(M)柱(EMD Chemicals Inc.),并将洗脱液通过缓冲液交换进入20mM Tris pH7.5,150mM NaCl。然后用重组人颗粒酶B(产自小鼠,参照专利)消化蛋白部分。在用PBS pH6稀释后,使用SP Sepharose FF纯化蛋白,然后用Mustang E过滤和FractogelEMD Chelate(M)柱,以流动模式去除融合标签和人颗粒酶B。最后,将蛋白通过缓冲液交换进入PBS pH7.4,并浓缩至50mg/mL。Met-I10-TripT-IL-1ra和GG-V17-TripT-IL-1ra蛋白的得率均为3-5g/L,纯度>95%,如由SDS-PAGE(图8)、RP-HPLC和MS所确定的。内毒素水平<3EU/mg,如使用LAL分析(Lonza)所确定的。聚集物<0.5%,如由分析SEC所确定的(图9),并且宿主细胞蛋白<6ng/mL。上述分析中测试了两批(LM022,LM023)Met-I10-TripT-IL-1ra和两批(CF019,CF020)GG-V17-TripT-IL-1ra。
对已形成4天II类胶原关节炎的雌性Lewis大鼠在患关节炎后第1-3天,每天(QD)用载体(10mM磷酸缓冲液pH7.4)或等摩尔量的IL-1ra进行皮下(SC)处理,其中IL-1ra可以使用单体IL-1ra(100mg/kgKINERET),或三局IL1ra(120mg/kg Met-I10-TripT-IL1ra,或120mg/kgGG-V17-TripT-IL1ra)。为了只设一组对照,QD组中的所有大鼠在第二次和第三次施用是分别施用载体(10mM磷酸缓冲液pH7.4,或对于KINERET是柠檬酸钠缓冲液pH6.5),以保持操作恒定。在关节炎第4天结束动物实验。根据脚踝卡尺测量结果进行效果评价,用曲线下面积(AUC)、后爪末端重量和体重表示(Bendele等人2000,Arthritis+Rheumatism 43:2648-2659)。所有动物均存活至研究结束。用KINERET或其载体(CSEP)注射的大鼠在注射过程中发出叫声,从而表示发生皮下刺激。任何其它注射没有发出声音。
将动物(关节炎组:8/组,正常组:4/组),4只/笼,用异氟烷麻醉,并用包含2mg/ml牛II类胶原(弹性蛋白产品,Owensville,Missouri)的300μl Freund不完全佐剂(Difco,Detroit,MI)在尾巴根部和背部两处,在第0天和第6天皮下/皮肤内(SC/ID)注射。通过皮下途径施用(每隔24小时QD)在关节炎第1天开始,并持续至第3天。实验组示于表4中。
表4
在关节炎的第0-4天为大鼠称重,并从关节炎第0天(第9个研究日)开始每天进行脚踝的卡尺测量。在最后一次体重测量后,使动物无痛死亡,并在内踝和外踝水平横切后爪,并称重(两次)。与用载体处理的疾病对照动物相比,在用100mg/kg KINERETQD(d3-4)、120mg/kg Met-I10-TripT-IL1ra QD(d2-4)或120mg/kgGG-V17-TripT-IL1ra QD(d3-4)处理的大鼠中见到脚踝直径的明显减小。与用载体处理的疾病对照动物相比,用100mg/kg KINERETQD(34%)、120mg/kg Met-I10-TripT-IL1ra QD(54%)或120mg/kgGG-V17-TripT-IL1ra QD(49%)处理的大鼠中脚踝直径AUC的减小非常明显。与KINERETQD处理相比,Met-I10-TripT-IL1ra QD处理使脚踝直径AUC显著减小(研究结束时p<0.035)。此外,与KINERETQD处理相比,研究结束时GG-V17-TripT-IL1ra QD处理使脚踝直径AUC显著减小(p<0.001)。(图10)
与用载体处理的疾病对照动物相比,用100mg/kg KINERETQD(61%)、120mg/kg Met-I10-TripT-IL1ra QD(79%)或120mg/kgGG-V17-TripT-IL1ra QD(91%)处理的大鼠中后爪重量的减小非常明显。与KINERETQD处理相比,GG-V17-TripT-IL1ra QD处理使后爪重量显著降低(图11)。
与用载体处理的疾病对照动物相比,用100mg/kg KINERETQD(54%)、120mg/kg Met-I10-TripT-IL1ra QD(49%)或120mg/kgGG-V17-TripT-IL1ra QD(65%)处理的大鼠体重的变化显著朝正常情况增加。
实施例6:链脲菌素(STZ)诱导糖尿病模型
对禁食C57BL/6J雄性小鼠,以50mg/kg i.p.每日施用一次STZ(SigmaAldrich),连续五天。从第一天到第四天,小鼠逐渐发展出较高水平的血糖浓度。在STZ诱导期间,血糖水平从6.9nmol/L升至13.1nmol/L。在最后一次施用STZ后五天(第四天),将小鼠随机分成10个处理组,每组包含正常状况的10只小鼠。从这天起在糖尿病发作前开始处理,并继续进行至病发。处理组示于表5中。
表5
研究时间为28天,并且在处理期间,将小鼠每周称重一次。在研究期间,每隔一天测定血糖水平,以监控糖尿病的发展。通过尾静脉学收集一滴全血,并放在Ascensia ELITE血糖测试条上,并用AscensiaELITE血糖仪(Bayer)分析。记录数值,并计算与处理初期的水平相比任何指定组中增加的倍数。每天观察临床症状,或者在出现副作用症状时进行适当观察。
如图12所示,在以100和30mg/kg的剂量,每天i.p.施用I10-TripT-IL1-Ra或KINERET后,均观察到血糖水平显著下降。此外,每周施用两次100mg/kg I10-TripT-IL1Ra和每日施用100mg/kgKINERET同样有效。这些数据证明三聚IL-1Ra是实验诱导糖尿病的有效治疗手段。
上述实验仅用于阐述目的,不意味着本发明所有可能实施方案、应用或修改的穷尽式列表。因此,在不背离本发明的范围和精神的情况下,本发明上述方法和系统的各种修改和变动对于本领域的技术人员是显而易见的。尽管已经于具体的实施方案一起描述了本发明,但是可以理解的是,如所要求的权利,本发明不应过度限定为这些具体的实施方案。事实上,进行本发明的所述模式的各种修改,其对于分子生物学、免疫学、化学、生物化学或相关领域的技术人员是显而易见的,意欲落入所附权利要求的范围中。
可以理解的是,本发明不限定于本文所述的特定方法、方案和试剂等,因为这些变化可以由技术人员识别。还可以理解的是,本文所使用的术语仅用于描述特定的实施方案,不意欲限定本发明的范围。还应注意的是,如本文和所附权利要求中所使用的,单数形式包括复数,除非明确指出。因此,例如,对于“接头”的描述指一个或多个接头,和本领域技术人员已知的等同物。
除非特别定义,本文使用的所有技术和科学术语与本发明所属领域普通技术人员通常理解的意义相同。本发明的实施方案及其各种特色和优势细节参照非限定性实施方案和/或附图所述及下文所详细指出的,更全面地进行解释。应注意的是,附图所阐述的特点不需要按比例绘制,并且一个实施方案的特点可以如技术人员所识别的用于其它实施方案,即使本文未明确说明。
本文引用的任何数值包括从较小值到较大值的以一个单位递增的全部数值,只要任何较小值和较大值之间有至少两个单位的间隔。作为实例,如果说明组分的浓度或过程变量的数值如,例如,尺寸、角度大小、压力、时间等,为,例如,1-90,具体为20-80,更具体为30-70,其意欲在这种规格中列举数值如15-85,22-68,43-51,30-32等。对于小于一的数值,适当时认为一个单位是0.0001、0.001、0.01或0.1。这些仅是具体意欲表示的实例,并且最小值和最大值之间的数值的全部组合认为以相似方式在本申请中表示。
描述了具体的方法、设备和材料,尽管于本文所述相似或等同的任何方法和材料可以在本发明的实践或测试中使用。对于上文引用的所有参考文献和出版物的公开通过引用全部并入本文,与各自单独并入本文的程度相同。
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<110>阿纳福公司
<120>三聚IL-1Ra
<130>08-354-WO
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Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val
1 5 10 15
Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu
20 25 30
Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val
35 40 45
Ser Leu Lys Gly
50
<210>7
<211>51
<212>PRT
<213>人工序列
<220>
<223>合成
<400>7
Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val
1 5 10 15
Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala
20 25 30
Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser
35 40 45
Leu Lys Gly
50
<210>8
<211>50
<212>PRT
<213>人工序列
<220>
<223>合成
<400>8
Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn
1 5 10 15
Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln
20 25 30
Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu
35 40 45
Lys Gly
50
<210>9
<211>49
<212>PRT
<213>人工序列
<220>
<223>合成
<400>9
Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr
1 5 10 15
Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu
20 25 30
Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys
35 40 45
Gly
<210>10
<211>48
<212>PRT
<213>人工序列
<220>
<223>合成
<400>10
Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys
1 5 10 15
Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val
20 25 30
Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly
35 40 45
<210>11
<211>47
<212>PRT
<213>人工序列
<220>
<223>合成
<400>11
Pro Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met
1 5 10 15
Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala
20 25 30
Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly
35 40 45
<210>12
<211>46
<212>PRT
<213>人工序列
<220>
<223>合成
<400>12
Lys Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe
1 5 10 15
Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu
20 25 30
Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly
35 40 45
<210>13
<211>45
<212>PRT
<213>人工序列
<220>
<223>合成
<400>13
Lys Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu
1 5 10 15
Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu
20 25 30
Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly
35 40 45
<210>14
<211>44
<212>PRT
<213>人工序列
<220>
<223>合成
<400>14
Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu
1 5 10 15
Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys
20 25 30
Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly
35 40
<210>15
<211>43
<212>PRT
<213>人工序列
<220>
<223>合成
<400>15
Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu
1 5 10 15
Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu
20 25 30
Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly
35 40
<210>16
<211>42
<212>PRT
<213>人工序列
<220>
<223>合成
<400>16
Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys
1 5 10 15
Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln
20 25 30
Gln Ala Leu Gln Thr Val Ser Leu Lys Gly
35 40
<210>17
<211>41
<212>PRT
<213>人工序列
<220>
<223>合成
<400>17
Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser
1 5 10 15
Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln
20 25 30
Ala Leu Gln Thr Val Ser Leu Lys Gly
35 40
<210>18
<211>40
<212>PRT
<213>人工序列
<220>
<223>合成
<400>18
Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg
1 5 10 15
Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala
20 25 30
Leu Gln Thr Val Ser Leu Lys Gly
35 40
<210>19
<211>39
<212>PRT
<213>人工序列
<220>
<223>合成
<400>19
Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu
1 5 10 15
Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu
20 25 30
Gln Thr Val Ser Leu Lys Gly
35
<210>20
<211>37
<212>PRT
<213>人工序列
<220>
<223>合成
<400>20
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
20 25 30
Val Ser Leu Lys Gly
35
<210>21
<211>37
<212>PRT
<213>人工序列
<220>
<223>合成
<400>21
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
20 25 30
Val Ser Leu Lys Gly
35
<210>22
<211>36
<212>PRT
<213>人工序列
<220>
<223>合成
<400>22
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
20 25 30
Val Ser Leu Lys
35
<210>23
<211>33
<212>PRT
<213>人工序列
<220>
<223>合成
<400>23
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
20 25 30
Val
<210>24
<211>32
<212>PRT
<213>人工序列
<220>
<223>合成
<400>24
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
20 25 30
<210>25
<211>30
<212>PRT
<213>人工序列
<220>
<223>合成
<400>25
Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu
1 5 10 15
Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln
20 25 30
<210>26
<211>35
<212>PRT
<213>人工序列
<220>
<223>合成
<400>26
Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala
1 5 10 15
Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser
20 25 30
Leu Lys Gly
35
<210>27
<211>34
<212>PRT
<213>人工序列
<220>
<223>合成
<400>27
Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln
1 5 10 15
Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu
20 25 30
Lys Gly
<210>28
<211>33
<212>PRT
<213>人工序列
<220>
<223>合成
<400>28
Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu
1 5 10 15
Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys
20 25 30
Gly
<210>29
<211>32
<212>PRT
<213>人工序列
<220>
<223>合成
<400>29
Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val
1 5 10 15
Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Gly
20 25 30
<210>30
<211>52
<212>PRT
<213>人工序列
<220>
<223>合成
<400>30
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
1 5 10 15
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
20 2 530
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
35 40 45
Val Ser Leu Lys
50
<210>31
<211>49
<212>PRT
<213>人工序列
<220>
<223>合成
<400>31
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
1 5 10 15
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
20 25 30
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
35 40 45
Val
<210>32
<211>48
<212>PRT
<213>人工序列
<220>
<223>合成
<400>32
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
1 5 10 15
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
20 25 30
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
35 40 45
<210>33
<211>47
<212>PRT
<213>人工序列
<220>
<223>合成
<400>33
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
1 5 10 15
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
20 25 30
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln
35 40 45
<210>34
<211>43
<212>PRT
<213>人工序列
<220>
<223>合成
<400>34
Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu
1 5 10 15
Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys
20 25 30
Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys
35 40
<210>35
<211>40
<212>PRT
<213>人工序列
<220>
<223>合成
<400>35
Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu
1 5 10 15
Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys
20 25 30
Glu Gln Gln Ala Leu Gln Thr Val
35 40
<210>36
<211>39
<212>PRT
<213>人工序列
<220>
<223>合成
<400>36
Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu
1 5 10 15
Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys
20 25 30
Glu Gln Gln Ala Leu Gln Thr
35
<210>37
<211>38
<212>PRT
<213>人工序列
<220>
<223>合成
<400>37
Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu
1 5 10 15
Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys
20 25 30
Glu Gln Gln Ala Leu Gln
35
<210>38
<211>152
<212>PRT
<213>智人
<400>38
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210>39
<211>204
<212>PRT
<213>人工序列
<220>
<223>合成
<400>39
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
1 5 10 15
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
20 25 30
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
35 40 45
Val Ser Leu Lys Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala
50 55 60
Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn
65 70 75 80
Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu
85 90 95
Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile
100 105 110
His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr
115 120 125
Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg
130 135 140
Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr
145 150 155 160
Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala
165 170 175
Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly
180 185 190
Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
195 200
<210>40
<211>200
<212>PRT
<213>人工序列
<220>
<223>合成
<400>40
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
1 5 10 15
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
20 25 30
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
35 40 45
Val Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
50 55 60
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
65 70 75 80
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
85 90 95
Val Val Pro Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
100 105 110
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
115 120 125
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
130 135 140
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
145 150 155 160
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
165 170 175
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
180 185 190
Lys Phe Tyr Phe Gln Glu Asp Glu
195 200
<210>41
<211>200
<212>PRT
<213>人工序列
<220>
<223>合成
<400>41
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
1 5 10 15
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
20 25 30
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
35 40 45
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
50 55 60
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
65 70 75 80
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
85 90 95
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
100 105 110
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
115 120 125
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
130 135 140
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
145 150 155 160
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
165 170 175
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
180 185 190
Lys Phe Tyr Phe Gln Glu Asp Glu
195 200
<210>42
<211>247
<212>PRT
<213>人工序列
<220>
<223>合成
<400>42
Met Val Arg Ala Asn Lys Arg Asn Glu Ala Leu Arg Ile Glu Ser Ala
1 5 10 15
Leu Leu Asn Lys Ile Ala Met Leu Gly Thr Glu Lys Thr Ala Glu Gly
20 25 30
Gly Ser His His His His His His Gly Ser Ile Glu Pro Asp Gly Gly
35 40 45
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
50 55 60
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
65 70 75 80
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Arg
85 90 95
Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp Asp
100 105 110
Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly
115 120 125
Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val Val
130 135 140
Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys Met
145 150 155 160
Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu
165 170 175
Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg
180 185 190
Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser
195 200 205
Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp Gln
210 215 220
Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr Lys
225 230 235 240
Phe Tyr Phe Gln Glu Asp Glu
245
<210>43
<211>195
<212>PRT
<213>人工序列
<220>
<223>合成
<400>43
Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu
1 5 10 15
Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys
20 25 30
Glu Gln Gln Ala Leu Gln Thr Val Ser Leu Lys Arg Pro Ser Gly Arg
35 40 45
Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys
50 55 60
Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly
65 70 75 80
Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro
85 90 95
His Ala Leu Phe Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys
100 105 110
Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile
115 120 125
Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile
130 135 140
Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro
145 150 155 160
Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu
165 170 175
Thr Asn Met Pro Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln
180 185 190
Glu Asp Glu
195
<210>44
<211>192
<212>PRT
<213>人工序列
<220>
<223>合成
<400>44
Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu
1 5 10 15
Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys
20 25 30
Glu Gln Gln Ala Leu Gln Thr Val Arg Pro Ser Gly Arg Lys Ser Ser
35 40 45
Lys Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr
50 55 60
Leu Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val
65 70 75 80
Asn Leu Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu
85 90 95
Phe Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser
100 105 110
Gly Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu
115 120 125
Ser Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp
130 135 140
Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe
145 150 155 160
Leu Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met
165 170 175
Pro Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
180 185 190
<210>45
<211>191
<212>PRT
<213>人工序列
<220>
<223>合成
<400>45
Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu
1 5 10 15
Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys
20 25 30
Glu Gln Gln Ala Leu Gln Thr Arg Pro Ser Gly Arg Lys Ser Ser Lys
35 40 45
Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu
50 55 60
Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn
65 70 75 80
Leu Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe
85 90 95
Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly
100 105 110
Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser
115 120 125
Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser
130 135 140
Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu
145 150 155 160
Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro
165 170 175
Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
180 185 190
<210>46
<211>190
<212>PRT
<213>人工序列
<220>
<223>合成
<400>46
Ile Val Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu
1 5 10 15
Leu Lys Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys
20 25 30
Glu Gln Gln Ala Leu Gln Arg Pro Ser Gly Arg Lys Ser Ser Lys Met
35 40 45
Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg
50 55 60
Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu
65 70 75 80
Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu
85 90 95
Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp
100 105 110
Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu
115 120 125
Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly
130 135 140
Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys
145 150 155 160
Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp
165 170 175
Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
180 185 190
<210>47
<211>252
<212>PRT
<213>人工序列
<220>
<223>合成
<400>47
Met Val Arg Ala Asn Lys Arg Asn Glu Ala Leu Arg Ile Glu Ser Ala
1 5 10 15
Leu Leu Asn Lys Ile Ala Met Leu Gly Thr Glu Lys Thr Ala Glu Gly
20 25 30
Gly Ser His His His His His His Gly Ser Ile Glu Pro Asp Gly Gly
35 40 45
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
50 55 60
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
65 70 75 80
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
85 90 95
Val Ser Leu Lys Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala
100 105 110
Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn
115 120 125
Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu
130 135 140
Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile
145 150 155 160
His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr
165 170 175
Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg
180 185 190
Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr
195 200 205
Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala
210 215 220
Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly
225 230 235 240
Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
245 250
<210>48
<211>249
<212>PRT
<213>人工序列
<220>
<223>合成
<400>48
Met Val Arg Ala Asn Lys Arg Asn Glu Ala Leu Arg Ile Glu Ser Ala
1 5 10 15
Leu Leu Asn Lys Ile Ala Met Leu Gly Thr Glu Lys Thr Ala Glu Gly
20 25 30
Gly Ser His His His His His His Gly Ser Ile Glu Pro Asp Gly Gly
35 40 45
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
50 55 60
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
65 70 75 80
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
85 90 95
Val Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
100 105 110
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
115 120 125
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
130 135 140
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
145 150 155 160
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
165 170 175
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
180 185 190
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
195 200 205
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
210 215 220
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
225 230 235 240
Thr Lys Phe Tyr Phe Gln Glu Asp Glu
245
<210>49
<211>248
<212>PRT
<213>人工序列
<220>
<223>合成
<400>49
Met Val Arg Ala Asn Lys Arg Asn Glu Ala Leu Arg Ile Glu Ser Ala
1 5 10 15
Leu Leu Asn Lys Ile Ala Met Leu Gly Thr Glu Lys Thr Ala Glu Gly
20 25 30
Gly Ser His His His His His His Gly Ser Ile Glu Pro Asp Gly Gly
35 40 45
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
50 55 60
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
65 70 75 80
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
85 90 95
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
100 105 110
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
115 120 125
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
130 135 140
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
145 150 155 160
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
165 170 175
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
180 185 190
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
195 200 205
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
210 215 220
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
225 230 235 240
Lys Phe Tyr Phe Gln Glu Asp Glu
245
<210>50
<211>247
<212>PRT
<213>人工序列
<220>
<223>合成
<400>50
Met Val Arg Ala Asn Lys Arg Asn Glu Ala Leu Arg Ile Glu Ser Ala
1 5 10 15
Leu Leu Asn Lys Ile Ala Met Leu Gly Thr Glu Lys Thr Ala Glu Gly
20 25 30
Gly Ser His His His His His His Gly Ser Ile Glu Pro Asp Gly Gly
35 40 45
Glu Gly Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
50 55 60
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
65 70 75 80
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Arg
85 90 95
Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp Asp
100 105 110
Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly
115 120 125
Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val Val
130 135 140
Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys Met
145 150 155 160
Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu
165 170 175
Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg
180 185 190
Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser
195 200 205
Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp Gln
210 215 220
Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr Lys
225 230 235 240
Phe Tyr Phe Gln Glu Asp Glu
245
<210>51
<211>241
<212>PRT
<213>人工序列
<220>
<223>合成
<400>51
Met Val Arg Ala Asn Lys Arg Asn Glu Ala Leu Arg Ile Glu Ser Ala
1 5 10 15
Leu Leu Asn Lys Ile Ala Met Leu Gly Thr Glu Lys Thr Ala Glu Gly
20 25 30
Gly Ser His His His His His His Gly Ser Ile Glu Pro Asp Ile Val
35 40 45
Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys
50 55 60
Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln
65 70 75 80
Gln Ala Leu Gln Thr Val Ser Leu Lys Arg Pro Ser Gly Arg Lys Ser
85 90 95
Ser Lys Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe
100 105 110
Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn
115 120 125
Val Asn Leu Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala
130 135 140
Leu Phe Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys
145 150 155 160
Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp
165 170 175
Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser
180 185 190
Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp
195 200 205
Phe Leu Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn
210 215 220
Met Pro Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp
225 230 235 240
Glu
<210>52
<211>238
<212>PRT
<213>人工序列
<220>
<223>合成
<400>52
Met Val Arg Ala Asn Lys Arg Asn Glu Ala Leu Arg Ile Glu Ser Ala
1 5 10 15
Leu Leu Asn Lys Ile Ala Met Leu Gly Thr Glu Lys Thr Ala Glu Gly
20 25 30
Gly Ser His His His His His His Gly Ser Ile Glu Pro Asp Ile Val
35 40 45
Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys
50 55 60
Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln
65 70 75 80
Gln Ala Leu Gln Thr Val Arg Pro Ser Gly Arg Lys Ser Ser Lys Met
85 90 95
Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg
100 105 110
Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu
115 120 125
Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu
130 135 140
Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp
145 150 155 160
Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu
165 170 175
Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly
180 185 190
Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys
195 200 205
Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp
210 215 220
Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
225 230 235
<210>53
<211>237
<212>PRT
<213>人工序列
<220>
<223>合成
<400>53
Met Val Arg Ala Asn Lys Arg Asn Glu Ala Leu Arg Ile Glu Ser Ala
1 5 10 15
Leu Leu Asn Lys Ile Ala Met Leu Gly Thr Glu Lys Thr Ala Glu Gly
20 25 30
Gly Ser His His His His His His Gly Ser Ile Glu Pro Asp Ile Val
35 40 45
Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys
50 55 60
Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln
65 70 75 80
Gln Ala Leu Gln Thr Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln
85 90 95
Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn
100 105 110
Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu
115 120 125
Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly
130 135 140
Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu
145 150 155 160
Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn
165 170 175
Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro
180 185 190
Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr
195 200 205
Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu
210 215 220
Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
225 230 235
<210>54
<211>236
<212>PRT
<213>人工序列
<220>
<223>合成
<400>54
Met Val Arg Ala Asn Lys Arg Asn Glu Ala Leu Arg Ile Glu Ser Ala
1 5 10 15
Leu Leu Asn Lys Ile Ala Met Leu Gly Thr Glu Lys Thr Ala Glu Gly
20 25 30
Gly Ser His His His His His His Gly Ser Ile Glu Pro Asp Ile Val
35 40 45
Asn Ala Lys Lys Asp Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys
50 55 60
Ser Arg Leu Asp Thr Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln
65 70 75 80
Gln Ala Leu Gln Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala
85 90 95
Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn
100 105 110
Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu
115 120 125
Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile
130 135 140
His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr
145 150 155 160
Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg
165 170 175
Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr
180 185 190
Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala
195 200 205
Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly
210 215 220
Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
225 230 235
<210>55
<211>188
<212>PRT
<213>人工序列
<220>
<223>合成
<400>55
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
20 25 30
Val Ser Leu Lys Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala
35 40 45
Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn
50 55 60
Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu
65 70 75 80
Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile
85 90 95
His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr
100 105 110
Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg
115 120 125
Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr
130 135 140
Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala
145 150 155 160
Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly
165 170 175
Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
180 185
<210>56
<211>185
<212>PRT
<213>人工序列
<220>
<223>合成
<400>56
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
20 25 30
Val Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
35 40 45
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
50 55 60
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
65 70 75 80
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
85 90 95
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
100 105 110
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
115 120 125
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
130 135 140
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
145 150 155 160
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
165 170 175
Thr Lys Phe Tyr Phe Gln Glu Asp Glu
180 185
<210>57
<211>184
<212>PRT
<213>人工序列
<220>
<223>合成
<400>57
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
20 25 30
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
35 40 45
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
50 55 60
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
65 70 75 80
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
85 90 95
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
100 105 110
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
115 120 125
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
130 135 140
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
145 150 155 160
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
165 170 175
Lys Phe Tyr Phe Gln Glu Asp Glu
180
<210>58
<211>183
<212>PRT
<213>人工序列
<220>
<223>合成
<400>58
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Arg
20 25 30
Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp Asp
35 40 45
Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly
50 55 60
Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val Val
65 70 75 80
Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys Met
85 90 95
Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu
100 105 110
Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg
115 120 125
Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser
130 135 140
Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp Gln
145 150 155 160
Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr Lys
165 170 175
Phe Tyr Phe Gln Glu Asp Glu
180
<210>59
<211>36
<212>PRT
<213>智人
<400>59
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
1 5 10 15
Gly Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
20 25 30
Val Cys Leu Lys
35
<210>60
<211>36
<212>PRT
<213>小家鼠
<400>60
Leu Val Ser Ser Lys Met Phe Glu Glu Leu Lys Asn Arg Met Asp Val
1 5 10 15
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Lys Gln Ala Leu Gln Thr
20 25 30
Val Cys Leu Lys
35
<210>61
<211>36
<212>PRT
<213>牛
<400>61
Arg Arg Val Lys Glu Lys Asp Gly Asp Leu Lys Thr Gln Val Glu Lys
1 5 10 15
Leu Trp Arg Glu Val Asn Ala Leu Lys Glu Met Gln Ala Leu Gln Thr
20 25 30
Val Cys Leu Arg
35
<210>62
<211>36
<212>PRT
<213>大白鲨
<400>62
Ser Lys Ser Gly Lys Gly Lys Asp Asp Leu Arg Asn Glu Ile Asp Lys
1 5 10 15
Leu Trp Arg Glu Val Asn Ser Leu Lys Glu Met Gln Ala Leu Gln Thr
20 25 30
Val Cys Leu Lys
35
<210>63
<211>181
<212>PRT
<213>智人
<400>63
Glu Pro Pro Thr Gln Lys Pro Lys Lys Ile Val Asn Ala Lys Lys Asp
1 5 10 15
Val Val Asn Thr Lys Met Phe Glu Glu Leu Lys Ser Arg Leu Asp Thr
20 25 30
Leu Ala Gln Glu Val Ala Leu Leu Lys Glu Gln Gln Ala Leu Gln Thr
35 40 45
Val Cys Leu Lys Gly Thr Lys Val His Met Lys Cys Phe Leu Ala Phe
50 55 60
Thr Gln Thr Lys Thr Phe His Glu Ala Ser Glu Asp Cys Ile Ser Arg
65 70 75 80
Gly Gly Thr Leu Ser Thr Pro Gln Thr Gly Ser Glu Asp Asp Ala Leu
85 90 95
Thr Glu Thr Leu Arg Gln Ser Val Gly Asn Glu Ala Glu Ile Trp Leu
100 105 110
Gly Leu Asp Asp Met Ala Ala Glu Gly Thr Trp Val Asp Met Thr Gly
115 120 125
Ala Arg Ile Ala Thr Lys Asn Trp Glu Thr Glu Ile Thr Ala Gln Pro
130 135 140
Asp Gly Gly Lys Thr Glu Asp Cys Ala Val Leu Ser Gly Ala Ala Asn
145 150 155 160
Gly Lys Trp Phe Asp Lys Arg Cys Arg Asp Gln Leu Pro Thr Ile Cys
165 170 175
Gln Phe Gly Ile Val
180
Claims (26)
1.融合蛋白,其包含三聚域和可抑制IL-1活性的IL-1Ra多肽。
2.权利要求1的融合蛋白,其中由于保守氨基酸取代,IL-1Ra多肽与SEQID NO:38至少85%相同,并且包含Trp16、Gln20、Tyr34、Gln36和Tyr147。
3.权利要求1的融合蛋白,其中IL-1Ra多肽与SEQ ID NO:38至少95%相同。
4.权利要求2的融合蛋白,其还包含选自下组的至少一个突变:D47N、E52R、E90Y、P38Y、H54R、Q129L和M136N。
5.权利要求1的融合蛋白,其中所述三聚域源自人四连蛋白。
6.权利要求1的融合蛋白,其中所述三聚域是四连蛋白三聚结构元件。
7.权利要求1的融合蛋白,其中所述三聚域与SEQ ID NO:1至少66%相同。
8.包含三个权利要求5的融合蛋白的三聚复合物,其中所述融合蛋白相同或不同。
9.包含三个权利要求6的融合蛋白的三聚复合物,其中所述融合蛋白相同或不同。
10.权利要求1的融合蛋白,其还包括聚乙二醇。
11.权利要求1的融合蛋白,其还包括IL-1Ra多肽和三聚域之间的接头。
12.包含三个融合蛋白的三聚复合物,其中每个融合蛋白包含权利要求1的融合蛋白,并且其中至少一个融合蛋白选自下组:TripK-IL-1ra(SEQ ID NO:39);TripV-IL-1ra(SEQ ID NO:40);TripT-IL-1ra(SEQ ID NO:41);TripQ-IL-1ra(SEQ ID NO:42);I10-TripK-IL-1ra(SEQ ID NO:43);I10-TripV-IL-1ra(SEQ IDNO:44);I10-TripT-IL-1ra(SEQ ID NO:45);I10-TripQ-IL-1ra(SEQ ID NO:46);V17-TripT-IL1Ra(SEQ ID NO:55);V17-TripK-IL-1Ra(SEQ ID NO:56);V17-TripV-IL-1RA(SEQ ID NO:57)和V17-TripQ-IL1RA(SEQ ID NO:58)。
13.编码权利要求1的多肽的分离的多核苷酸。
14.包含权利要求13的多核苷酸的载体。
15.包含权利要求14的载体的宿主细胞。
16.包含权利要求1的融合蛋白和至少一种可药用的赋形剂的药物组合物。
17.包含权利要求7的三聚复合物和至少一种可药用的赋形剂的药物组合物。
18.治疗由白介素1介导的疾病的方法,包括对有需要的患者施用权利要求17的药物组合物。
19.权利要求18的方法,其中所述疾病是炎症性疾病。
20.权利要求19的方法,其中所述炎症性疾病是风湿性关节炎。
21.权利要求19的方法,其中所述炎症性疾病是糖尿病。
22.权利要求19的方法,其还包括同时或顺序向患者施用抗炎剂。
23.权利要求1的融合蛋白,其还包含与融合蛋白共价连接的抗炎剂。
24.权利要求19的方法,其中至少一个融合蛋白与抗炎剂共价连接。
25.包含至少两个权利要求1的融合蛋白的多肽复合物。
26.权利要求25的多肽复合物,其包含至少四个所述融合蛋白。
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US97825407P | 2007-10-08 | 2007-10-08 | |
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PCT/US2008/079216 WO2009048961A1 (en) | 2007-10-08 | 2008-10-08 | Trimeric il-1ra |
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WO2013170636A1 (zh) * | 2012-05-18 | 2013-11-21 | 爱德迪安(北京)生物技术有限公司 | 用于糖尿病治疗的蛋白、蛋白缀合物及其应用 |
CN104587457A (zh) * | 2015-01-13 | 2015-05-06 | 广东海大畜牧兽医研究院有限公司 | 一种利用难溶或不溶蛋白、多肽抗原制备纳米微粒疫苗的方法 |
CN105367663A (zh) * | 2014-08-31 | 2016-03-02 | 复旦大学 | 一种长效白细胞介素-1受体拮抗剂重组融合蛋白及其制备方法和用途 |
CN111875694A (zh) * | 2020-05-25 | 2020-11-03 | 北京伟德杰生物科技有限公司 | 一种白细胞介素-1受体拮抗剂以及包含其的融合蛋白 |
CN114457086A (zh) * | 2022-03-02 | 2022-05-10 | 上海勉亦生物科技有限公司 | 白介素1受体拮抗蛋白的表达盒以及基于aav的基因递送系统 |
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BR0115257A (pt) * | 2000-11-10 | 2003-08-12 | Proteopharma Aps | Análogos de apolipoproteìna |
JP2005528107A (ja) * | 2002-05-31 | 2005-09-22 | シェジェン ピーティーワイ リミテッド | 膜転位置配列由来の自己合体または自己凝集キメラタンパク質 |
WO2004039841A2 (en) * | 2002-10-29 | 2004-05-13 | Borean Pharma A/S | Trimeric binding proteins for trimeric cytokines |
EP1720899A2 (en) * | 2004-02-23 | 2006-11-15 | Borean Pharma A/S | Multimerised hiv fusion inhibitors |
EP2769990A3 (en) * | 2004-12-02 | 2015-02-25 | Domantis Limited | Bispecific domain antibodies targeting serum albumin and GLP-1 or PYY |
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- 2008-10-08 AU AU2008310902A patent/AU2008310902A1/en not_active Abandoned
- 2008-10-08 JP JP2010529006A patent/JP2010539995A/ja not_active Withdrawn
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WO2013170636A1 (zh) * | 2012-05-18 | 2013-11-21 | 爱德迪安(北京)生物技术有限公司 | 用于糖尿病治疗的蛋白、蛋白缀合物及其应用 |
US9745359B2 (en) | 2012-05-18 | 2017-08-29 | Adda Biotech Inc. | Protein and protein conjugate for diabetes treatment, and applications thereof |
US10472404B2 (en) | 2012-05-18 | 2019-11-12 | Adda Biotech Inc. | Protein and protein conjugate for diabetes treatment, and applications thereof |
US11208451B2 (en) | 2012-05-18 | 2021-12-28 | Adda Biotech Inc. | Protein and protein conjugate for diabetes treatment, and applications thereof |
CN105367663A (zh) * | 2014-08-31 | 2016-03-02 | 复旦大学 | 一种长效白细胞介素-1受体拮抗剂重组融合蛋白及其制备方法和用途 |
CN104587457A (zh) * | 2015-01-13 | 2015-05-06 | 广东海大畜牧兽医研究院有限公司 | 一种利用难溶或不溶蛋白、多肽抗原制备纳米微粒疫苗的方法 |
CN104587457B (zh) * | 2015-01-13 | 2017-03-22 | 广东海大畜牧兽医研究院有限公司 | 一种利用难溶或不溶蛋白、多肽抗原制备纳米微粒疫苗的方法 |
CN111875694A (zh) * | 2020-05-25 | 2020-11-03 | 北京伟德杰生物科技有限公司 | 一种白细胞介素-1受体拮抗剂以及包含其的融合蛋白 |
CN114457086A (zh) * | 2022-03-02 | 2022-05-10 | 上海勉亦生物科技有限公司 | 白介素1受体拮抗蛋白的表达盒以及基于aav的基因递送系统 |
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CA2701705A1 (en) | 2009-04-16 |
JP2010539995A (ja) | 2010-12-24 |
AU2008310902A1 (en) | 2009-04-16 |
EP2195337A1 (en) | 2010-06-16 |
WO2009048961A1 (en) | 2009-04-16 |
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