CN112534052A - 全新il-21前药及使用方法 - Google Patents
全新il-21前药及使用方法 Download PDFInfo
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
- C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Abstract
这里提供了IL‑21前药以及制作和使用方法,用于刺激免疫系统,或治疗癌症或传染性疾病。
Description
相关申请交叉引用
本申请要求2018年7月25日提交的美国第62/703,383号临时申请的优先权,该申请的内容在此处完整引用。
序列清单
本申请包含一个已以ASCII格式电子提交的序列清单。序列列表在此通过引用全部合并。创建于2019年7月22日的ASCII副本名为025471_WO003_SL.txt,大小为 189,683字节。
发明领域
本申请叙述在肿瘤部位可激活的新型IL-21前药。本发明包括进一步使用新前药的方法。
发明背景
白细胞介素-21(IL-21)由激活的CD4+ T细胞、T卵泡辅助细胞和自然杀伤T (NKT)细胞产生(Spolski和Leonard,Ann Rev Immunol)(2008)26:57008)。IL-21已被证明对各种淋巴样细胞的增殖、分化和细胞毒性发挥多效作用。最近,IL-21在CD4+ T细胞分化为T-helper 17(TH17)细胞中发挥了关键作用,其TH17细胞是与炎症和自身免疫性疾病发展相关的T细胞亚群(Korn et al.,Nature(2007)448(7152):484-87;Nurieva et al., Nature(2007)448(7152):480-83)。
IL-21的受体复合物由IL-21Rα独有链和γC(or Rγ)共有链组成;其他5种细胞因子IL-2、IL-4、IL-7、IL-9和IL-15(Spolski and Leonard,supra)也有相同的γ共有链。人IL-21与IL-21R具有非常高的亲和力(KD~70pM;Zhang et al.,Biochem Biophys ResCommun.(2003)300(2):291-6),而与IL-21Rγ的结合亲和力相对较低(KD~160μM)。
重组IL-21已在多个临床试验中被测试用于治疗实体肿瘤(Zarkavelis et al.,Transl Cancer Res.(2017)6(Suppl 2):S328-30)。其中一项研究中,最大耐受剂量为200μg/kg(Schmidt et al.,Clin Cancer Res.(2010)16(21):5312-19)。因此,与其他细胞因子疗法一样,全身毒性可能会严重限制IL-21的治疗剂量。此外,IL-21在体内可能会遇到“PK 沉降”,因为它与其受体IL-21Rα具有很高的亲和性(Zhang et al.,supra)。于是,IL-21很难在患者体内达到最佳的药代动力学(PK)和暴露。IL-21类似物已在美国Pat.8,211,420和 Kan et al.,J Biol Chem.(2010)285(16):12223-31上公开。然而一些类似物选择性地降低了γC的结合亲和力而作为IL-21拮抗剂。
目前仍有需要开发具有更好的肿瘤靶向性、提高PK和疗效,同时减少严重副作用的基于IL-21的癌症治疗药物。
发明综述
本公开提供了IL-21前药,包括细胞因子部分、掩蔽部分和载体部分,其中细胞因子部分是IL-21激动剂多肽,掩蔽部分与细胞因子部分结合,抑制细胞因子部分的生物活性(例如阻止细胞因子部分与靶细胞上的受体结合,或减少细胞因子部分的一个或多个生物活性,如刺激免疫细胞(如T细胞和NK细胞)分泌干扰素-γ),其中细胞因子部分与载体部分融合,掩蔽部分与细胞因子部分或通过一个可切割的连接肽与载体部分融合。在某些实施例中,所述掩蔽部分包括IL-21受体alpha(IL-21Rα)胞外结构域(ECD)或其功能类似物。
在一些实施例中,细胞因子部分是人类IL-21野生型或其突变蛋白质,例如,人IL-21激动剂多肽,而其包含了SEQ ID NO:1或一个至少90%相同于SEQ ID NO:1 的氨基酸序列(例如,至少95%,96%,97%,98%或99%)。在一些实施例中,人IL-21激动剂多肽包含从D18、Q19、E109和K117中选择的一个或多个位点突变(根据SEQ ID NO:1)。在某特定实施例中,人IL-21激动剂多肽包括一个选自SEQ ID号1,2,3,4 和5中的氨基酸序列。
在一些实施例中,所述前药的掩蔽部分包括人IL-21Rα的ECD或其功能性类似物。在进一步实施例中,掩蔽部分包括(i)经肽连接融合在一起的两个人IL-21Rα的 ECD复制体或其功能类似物,或(ii)人IL-2RβECD或其功能类似物经由肽连接融合至人 IL-21Rγ的ECD或其功能类似物。在一些实施例中,人IL-21Rγ的ECD或其功能类似物包含与SEQ IDNO:7或与SEQ ID NO:7具有至少90%(例如至少95,96,97,98或 99%)同一性的氨基酸序列。在一些特定实施例中,人IL-21Rα的ECD或其功能类似物包含SEQ ID NO:6,或与SEQ IDNO:6至少90%(例如至少95,96,97,98或99%) 相同的氨基酸序列。
在一些实施例中,前药还包括与第二个细胞因子部分结合并抑制其生物活性的第二个掩蔽部分,其中第二个掩蔽部分通过一个可切割的肽连接物与第二个细胞因子部分或载体部分融合。在具体实施例中,此第二个掩蔽部分选自IL-2受体β之ECD或其功能类似物、IL-7受体之ECD或其功能类似物以及IL-9受体之ECD或其功能类似物的。
在本前药的一些实施例中,细胞因子部分通过不可切割的肽连接物,如一选自SEQ ID NOs::q29-33之中的肽连接物,融合至载体部分。
在本前药的一些实施例中,将掩蔽部分直接或间接(例如通过细胞因子部分) 连接至载体部分的可切割肽连接物包含尿激酶型纤溶酶原激活物(uPA)、基质金属肽酶(MMP)2或MMP9的底物序列。在进一步的实施例中,该可切割连接肽包含(i)uPA偕 MMP2二者,(ii)uPA偕MMP9,或(iii)uPA、MMP2并MMP9的底物序列。在特定实施例中,可切割的连接肽包含选自SEQ ID NOs:11-26中的一个氨基酸序列。在某特定的实施例中,该可切割肽链可被位于肿瘤部位或其周围环境的一个或多个蛋白酶切割,而该切割可导致前药在肿瘤部位或周围环境中被激活。
在本前药的一些实施例中,载体部分为聚乙二醇分子、脂肪酸链、白蛋白(例如人血清白蛋白)或其片段、抗体Fc结构域、或其抗体或抗原结合片段。在特定实施例中,载体部分为IgG1抗体Fc结构域,或是包含突变L234A和L235A(“LALA”)(EU编号) 的抗体,或是包含突变S228P/L234A/L235A(PAA)的IgG4 Fc结构域。其他导致Fc功能降低的突变,如那些于Tam et al.,Antibodies(2017)6(12):1-34中所描述的,在当使用 Fc结构域或抗体的Fc作为载体部分时也可以引入。
在特定实施例中,所述载体部分为抗体Fc结构域或含有球孔突变的抗体,其中细胞因子部分和掩蔽部分融合到抗体Fc结构域的不同多肽链或抗体的不同重链上。在一些实施例中,细胞因子部分和掩蔽部分融合到Fc结构域上两不同多肽链的c端或抗体上两不同重链的c端。在其它实施例中,细胞因子部分和掩蔽部分融合到Fc结构域上两不同多肽链的N-端或抗体上两不同重链的N-端。在某特定实施例中,knobs-into-holes突变包含在Fc结构域上多肽链或抗体上重链的T366Y“knob”突变,以及在Fc结构域上其他多肽链或抗体上另一条重链的Y407T“hole”突变(EU编号)。在某特定实施方案中,knobs- into-holes突变包括“knob链”中CH3结构域的Y349C和/或T366W突变,和“hole链”中 CH3结构域的E356C,T366S,L368A和/或Y407V突变(EU编号)。
在特定实施例中,前药由两条多肽链组成,其氨基酸序列分别包含SEQ ID NOs:36和38;SEQ ID NOs:37和38;SEQ ID NOs:39和41;SEQ ID NOs:40和41;SEQ ID NOs:42和44;SEQ ID NOs:43和44;SEQ ID NOs:45和47;或SEQ ID NOs:46 和47。
在一些实施例中,载体部分是抗体或其抗原结合片段,其特异性结合一种或多种选自下述生物分子的抗原:鸟苷酸环化酶C(GCC),碳水化合物抗原19-9(CA19- 9),糖蛋白A33的抗原的抗体或其抗原结合片段(gpA33),粘蛋白1(MUC1),癌胚抗原(CEA),胰岛素样生长因子1受体(IGF1-R),人表皮生长因子受体2(HER2),人表皮生长因子受体3(HER3),δ样蛋白3(DLL3),δ样蛋白4(DLL4),表皮生长因子受体(EGFR),glypican-3(GPC3),c-MET,血管内皮生长因子受体1 (VEGFR1),血管内皮生长因子受体2(VEGFR2),Nectin-4,Liv-1,糖蛋白NMB (GPNMB),前列腺特异性膜抗原(PSMA),Trop-2,碳酸酐酶IX(CA9),内皮素B 受体(ETBR),六种跨膜上皮抗原前列腺1(STEAP1),叶酸受体α(FR-α),SLIT和 NTRK样蛋白6(SLITRK6),碳酸酐酶VI(CA6)等核苷酸焦磷酸酶/磷酸二酯酶家族成员3(ENPP3),间皮素,滋养层糖蛋白(TPBG),CD19,CD20,CD22,CD33, CD40,CD56,CD66e,CD70,CD74,CD79b,CD98,CD123,CD138,CD352, CD352,CD47,信号-调节蛋白α(SIRPα),PD1,Claudin 18.2,Claudin6、5T4, BCMA,PD-L1,PD-1,成纤维细胞活化蛋白α(FAPα),与黑素瘤相关的硫酸软骨素硫酸蛋白多糖(MCSP)和上皮细胞黏附分子(EPCAM)。在特定实施例中,载体部分是与 FAPα或5T4结合的抗体或其片段。
在特定实施例中,载体部分是由两个重链多肽组成的抗体,其氨基酸序列分别为SEQ ID NO:48和SEQ ID No:49;所述抗体包括具有SEQ ID NO:50或SEQ ID NO:51 的氨基酸序列的轻链多肽链。
在一些实施例中,前药还包含TNF配体家族成员的2或3个胞外结构域或其片段,或是4-1BB配体的2或3个胞外结构域或其片段。
在一些实施例中,该前药还包含一选自下列的第二效应多肽:(i)人IL-2激动剂多肽,由SEQ ID NO:8或与其具有至少90%(例如至少95、96、97、98或99%)同一性的氨基酸序列组成,或(ii)人IL-7激动剂多肽,或(iii)人IL-9激动剂多肽,或(iv)人IL-15 激动剂多肽,由SEQ ID NO:9或与其具有至少90%(例如至少95、96、97、98或99%) 同一性的氨基酸序列组成,或(v)人IL-15激动剂多肽和IL-15受体αsushi结构域,或(vi) CCL19多肽,其氨基酸序列与SEQ ID NO:27至少具有90%(例如,至少95、96、97、98 或99%)的同一性。
在其它实施例中,该前药还包括第二效应体多肽,如第二细胞因子激动剂多肽和视需要而定结合于该第二效应体多肽的第二掩蔽部分。此种前药的实例包含两条多肽链,其氨基酸序列分别包含SEQ ID NO:42和SEQ ID NO:44。另一实例为该种前药包含两条多肽链,其氨基酸序列分别包含SEQ ID NO:43和SEQ ID NO:44。另一实例为该种前药包含两条多肽链,其氨基酸序列分别包含SEQ ID NO:45和SEQ ID NO:47。再另一实例为该种前药包含两条多肽链,其氨基酸序列分别包含SEQ ID NO:46和SEQ ID NO:47。
另一方面,本发明提供了编码本前药的多核苷酸、由多核苷酸组成的表达载体和由表达载体组成的宿主细胞(如哺乳动物宿主细胞,如CHO、NS0细胞和293T细胞)。本发明亦提供了制备本前药、包括在允许表达前药的条件下培养哺乳动物宿主细胞,以及分离前药的方法。
本发明亦对需要其的患者(例如人类患者)提供了治疗癌症,或感染性疾病,或刺激免疫系统的方法,其包括向所述患者施用治疗有效量的IL-21前药,或是本发明的药物成分。患者可能患有例如,病毒感染(如HIV、HBV、HCV或HPV感染),或乳腺癌、肺癌、胰腺癌、食道癌、髓样甲状腺癌、卵巢癌、子宫癌、前列腺癌、睾丸癌、结直肠癌和胃癌中的任一癌症。于此亦提供了IL-21前药在本方法中用于治疗癌症或感染性疾病或刺激免疫系统的用途;IL-21前药在本方法中用于治疗癌症或感染性疾病或刺激免疫系统的药物生产上的用途;以及包含本IL-21前药的一个或多个剂量单位的制品(如试剂盒)。
本发明的其他特征,目的和优点可显见于下述的详细描述中。但应理解在说明本发明的实施例和方面时,所述详细描述仅通过举例的方式给出,但是仅仅用于说明而非限制。本发明范围内的各种变化和修改对于本领域技术人员是显而易见的。
附图简述
图1为一种异二聚体IL-21前药,其载体为Fc结构域。Fc结构域的两条链包含了球孔内突变。
图2为四聚体IL-21前药,其中载体是Fc结构域中含有突变的球孔-入孔抗体。
图3A为一种异二聚体IL-21前药,包括(i)一个IL-21多肽及其相应的掩蔽部分,(ii)一个IL-2突变蛋白质及其相应的掩蔽部分。
图3B为一种IL-21前药,包括(i)一种IL-21多肽及其相应的掩膜,(ii)一种 IL-15多肽、一种IL-15Rαsushi结构域及其相应的掩蔽部分。
图4为IL-21前药具有两个4-1BBL外胞结构域。
图5A-C显示纯化后IL-21前药A的分子排阻色谱法(SEC)HPLC分析。
图6显示的是蛋白酶基质金属蛋白酶-2(MMP2)激活前后IL-21前药的SDS- PAGE分析。前药A含有野生型IL-21多肽,前药B含有突变基因Q19K和E109R的IL- 21突变蛋白质。
图7A和7B显示IL-21前药在蛋白酶MMP2激活前和激活后的细胞生物活性测定结果。图7A为IL-21前药A的结果,其中包含野生型IL-21。图7B显示IL-21前药B 的结果,其中包括IL-21突变蛋白质。
图8显示了蛋白酶MMP2激活前后PD-1-IL-21前药的细胞生物活性测定结果。
图9显示了PD-1报告基因测试的结果,该实验评估了融合分子的抗PD-1抗体阻断pd-L1介导的PD-1信号传导的能力。
发明的具体说明
本协议及附件权利要求书中使用的单数形式“一个”、“或”和“这”包括复数所指物,除非上下文另有明确规定。
此处“关于”一个值或参数的引用包括(并描述了)该值或参数本身的变体。例如,“关于X”的描述包括“X”的描述。此外,在任何一组数字前面使用“关于”也包括在这一组所引用的数字中使用“关于”。例如,“关于X、Y或Z”的描述意在描述“关于X、关于 Y或关于Z”。
术语“抗原结合部分”是指多肽或一组相互作用的多肽,其与抗原且包括抗体但不限于抗体的特异性结合(例如,单克隆抗体、多克隆抗体、多特异性抗体、双特异性抗体、抗独特型抗体或双功能混合抗体),或其抗原结合片段(例如Fab,Fab’,F(ab’)2,Fv,二硫键连接的Fv,scFv,单域抗体(dAb)或双抗体),或单链抗体和含Fc的多肽,比如免疫粘附素。在一些实施例中,抗体可以是任何重链种型(例如,IgG,IgA,IgM, IgE或IgD)或亚型(例如,IgG1,IgG2,IgG3或IgG4)。在一些实施方案中,抗体可以是任何轻链种型(例如kappa或lambda)。抗体可以是人的,非人的(例如,来自小鼠,大鼠,兔,山羊或另种非人的动物),嵌合的(例如,具有非人可变区和人源恒定区)或人源化的(例如,具有非人CDR,人源构架和恒定区)。在一些实施例中,抗体是衍生的抗体。
“细胞因子激动剂多肽”一词是指野生型细胞因子或其类似物。野生型细胞因子的类似物与野生型细胞因子具有相同的生物学特异性(例如,结合到相同的受体并激活相同的靶细胞),尽管其活性水平可能与野生型细胞因子不同。类似物可能,例如,一个野生型细胞因子的突变蛋白质(即突变多肽),并可能相对于野生型细胞因子包括至少一个、至少两个、至少三个、至少有四个、至少5个、至少6个、至少7个、至少8个、至少九个或者至少十个突变。
“细胞因子拮抗剂”或“细胞因子掩蔽部分”是指与细胞因子结合,从而抑制细胞因子与靶细胞表面受体结合和/或在拮抗剂或掩蔽部分的作用下发挥其生物学功能的部分(如多肽)。细胞因子拮抗剂或掩蔽部分的例子,包括但不仅限于从细胞因子自然受体的细胞外区域衍生的与细胞因子作用的多肽。
术语“有效量”或“治疗有效量”是指足以治疗特定失调、状况或疾病(如改善、缓和、减轻和/或延缓一种或多种症状)的化合物或组合物的量。关于疾病如癌症,有效量可能是一个足以延缓癌症发展或进展(例如减少肿瘤的生长速度,和/或延迟或阻止肿瘤血管生成、转移、或肿瘤细胞渗透到周边器官),减少上皮样细胞,达到癌症消退(例如减少或消除肿瘤),和/或防止或延缓癌症的发生或复发。有效剂量可一次或多次给予。
“功能性类似物”是指具有与对照分子相同的生物学特异性(如与相同配体结合)和/或活性(如激活或抑制靶细胞)的分子。
关于两个多肽序列的术语“融合”,其是指两个多肽序列通过主链肽键的连接。两个多肽可以直接融合,亦可以通过一个或多个氨基酸长的连接肽融合。融合多肽可以通过重组技术,由包含着两个融合部份体的各自编码序列的一段编码序列制备,其间可具或不具连接肽的编码序列。在一些实施方案中,融合涵盖化学缀合。
“可接受药用辅料”指的是用来指一个成分组合中的一个成分,适用于给予受试者,包括人体,对受试者没有过度的有害副作用、不影响药物活性成分(API)的生物活性。
“前药”一词是指一种在体内被激活前不活跃的治疗分子。
“受试者”一词指哺乳动物,包括但不限于人类、宠物(如犬、猫)、农场动物 (如牛、马)、啮齿动物或灵长类动物。
此处使用的“治疗”或“治疗”是一种获得有益或预期临床结果的方法。有益或期望的临床结果包括但不限于以下一项或多项:减轻疾病带来的一个或多个症状,减少疾病的程度,改善疾病状态,稳定疾病(例如预防或延缓疾病的恶化或进展),预防或延迟一种疾病的传播(如转移),预防或延缓疾病的复发,实现疾病部分或全部缓解,减少治疗疾病所需的一个或多个其他药物剂量,提高患者的生活质量和/或延长生存。本公开方法思考了治疗的一个或多个方面。
应该理解,这里描述的各种实施例中的一个、一些或所有属性可以组合起来形成本发明的其他实施例。此处使用的章节标题为了组织的目的而并不应该被解释成限定本申请所描述的主题。
IL-21前药
目前公开的IL-21前药可在体内代谢成为活性的IL-21治疗药物。IL-21前药与之前的IL-21疗法相比副作用更少,体内PK更好(如更长的半衰期),靶向特异性更好,更有效。本发明的前药包含与载体部分连接,并被IL-21拮抗剂(掩蔽部分或细胞因子掩蔽)掩蔽(结合)的IL-21激动剂多肽(细胞因子部分)。此IL-21拮抗剂可以是,例如, IL-21Rα的胞外结构域,其通过可切割的连接子(比如,可切割的连接肽)与细胞因子部分或载体部分相连。而此掩蔽与细胞因子结合时会抑制细胞因子部分的生物功能。前药可在患者的靶向位点(例如,在肿瘤部位或其周围环境)被激活,其是以通过切割连接并随后从前药上释出细胞因子掩蔽,从而暴露先前被掩蔽的细胞因子部分,允许其与靶细胞上的受体结合,并在靶细胞上发挥其生物功能。在一些实施例中,IL-21前药载体是抗原结合的部分,如抗体,在靶位点与抗原结合。
在一些实施例中,现有IL-21前体药物经代谢,在载体靶向部位具有活性。在进一步实施例中,前药载体是一种针对肿瘤抗原的抗体,IL-21前药递送到病人的肿瘤部位实现局部代谢(例如,肿瘤微环境的内部或周围),通过切断将细胞因子掩蔽部分连接到载体或者细胞因子部分的接头,让细胞因子部分和其受体在靶细胞发生作用并在局部刺激靶向免疫细胞。
A.前药的细胞因子部分
一个IL-21前药可能包括一个IL-21激动剂多肽(细胞因子部分),载体(载体部分),和一个IL-21拮抗剂(掩蔽部分),其中IL-21激动多肽直接或通过接头融合到载体上(如可切割或不可切割的肽接头),IL-21拮抗剂通过可切割的肽接头连接到激动剂多肽或载体上。在目前IL-21前药中,IL-21激动剂多肽可能是野生型IL-21多肽,例如IL-21野生型(SEQ ID NOs:1),或一个IL-21突变蛋白质例如衍生于人IL-21,即包括一种从SEQ ID 号:2-5中选择的氨基酸序列。与野生型IL-21相比,IL-21突变蛋白质可能显著降低IL- 21Rα或IL-21RαRγ的亲和力。在一些实施例中,IL-21突变蛋白质对高亲和力IL-2Rα的结合亲和力,比野生型IL-21低5倍、10倍、20倍、50倍、100倍、300倍、500倍、 1000倍、10000倍。除非另有说明,这里所描述的IL-21和IL-21突变蛋白质的所有残留编号均与SEQ ID NO:1中的编号一致。
B.IL-21前药的掩蔽部分
IL-21拮抗剂,即掩蔽部分,在目前的前药中可能包括一个肽或抗体或抗体片段,其结合到前药中的细胞因子部分,保护细胞因子部分并抑制其生物学功能。
例如,IL-21拮抗剂可包括结合IL-21的多肽和抗体,干扰IL-21与受体的结合,导致被掩蔽时IL-21部分的生物活性降低。在一些实施例中,IL-21拮抗剂包括IL-21Rα或 IL-21Rγ细胞外区域或其功能类似物,如源于人IL-21Rα或人类IL-21即的衍生物(例 SEQ IDNO:6或7)。在一些实施例中,IL-21拮抗剂包括从肽库中筛选的肽。在一些实施例中,IL-21拮抗剂包括阻断IL-21或IL-21突变蛋白质与IL-21受体结合的抗体或其片段。
在一些实施例中,本前药中的IL-21拮抗剂是IL-21Rα胞外结构域(ECD)。本发明人员惊奇地发现,当IL-21R-ECD被蛋白酶切开时,IL-21激动剂多肽的细胞活性几乎完全恢复,尽管IL-21激动剂多肽对IL-2IRα-ECD具有高结合亲和力。
C.前药的载体部分
目前IL-21前药的载体部分可能是抗原结合的部分,也可能不是抗原结合的部分。载体部分可改善PK情况,如细胞因子激动剂多肽的血清半衰期,也可将细胞因子激动剂多肽靶向于体内的靶部位,如肿瘤部位。
1.抗原-结合载体部分
载体部分可以是一个抗体或其抗原结合片段,或一个免疫粘附素。在一些实施例中,抗原结合部分是一条全长抗体,具有两条重链和两条轻链、一个Fab片段、一个 Fab’片段、一个F(ab’)2片段、一个Fv片段、一个二硫键连接的Fv片段、一个单域抗体、一个纳米体或一个单链可变片段(scFv)。在一些实施例中,抗原结合部分为双特异性抗原结合部分,可与两种不同抗原或同一抗原上的两种不同表位结合。抗原结合部分可能为细胞因子激动剂多肽提供附加和潜在的协同治疗效果。
IL-21激动剂多肽及其掩蔽部分可以与抗原结合部分的轻链和/或重链的N-端或C-端融合。举例来说,IL-21激动剂多肽及其掩膜可以与抗体重链或其抗原结合片段融合,也可以与抗体轻链或其抗原结合片段融合。举例来说,IL-21激动剂多肽及其掩蔽部分可以与抗体重链或其抗原结合片段融合,也可以与抗体轻链或其抗原结合片段融合。在一些实施例中,IL-21激动剂多肽的一个末端与抗体的一个或两个重链的C端融合,IL-21掩蔽通过一个可切掉的连接肽与IL-21激动剂多肽的另一个末端融合。在一些实施例中,IL-21 受体激动剂多肽融合到抗体的一个重链的C端上,IL-21保护单位通过一个可切掉的连接肽与抗体的另一个重链的c端融合,其中两个重链包含突变,允许两个不同重链的特殊配对。
形成异二聚体的策略是众所周知的(参见,例如,Spies et al.,Mol Imm. 67(2)(A):95-106(2015))。例如,前药中的两个重链多肽可以通过“knobs-into-holes”突变形成稳定的异二聚体。进行“knobs-into-holes”突变以促进抗体重链的异二聚体的形成,并且普遍用于制造双特异性抗体(参见,例如,美国专利号8,642,745)。例如,抗体的Fc 结构域可在“knob chian”的CH3结构域中包含T366W突变,而在“hole chain”的CH3结构域中包含T366S,L368A和/或Y407V突变。还可以使用CH3域之间的另一个链间二硫桥,例如,通过将Y349C突变引入“knobs chain”的CH3域,并将E356C或S354C突变引入“hole chain”的CH3域中(参见,例如,Merchant et al.,Nature Biotech 16:677-81(1998))。在其他实施方案中,抗体部分可在两个CH3结构域之一中包含Y349C和/或T366W突变,在另一个CH3结构域中包含E356C,T366S,L368A和/或Y407V突变。在某些特定实施例中,抗体部分可在两个CH3结构域之一中包含Y349C和/或T366W突变,在另一个 CH3结构域中包含S354C(或E356C),T366S,L368A和/或Y407V突变;另外以一个 CH3结构域上额外的Y349C突变,和另一个CH3结构域上额外的E356C或S354C突变,形成一个链间二硫键(编号始终根据Kabat的EU索引编号;Kabat et al.,“Sequences of Proteins of Immunological Interest,”5th ed.,Public Health Service,National Institutes of Health, Bethesda,Md.(1991))。其他knobs-in-holes技术,比如EP1870459A1中所述的,均可以替代或附加地使用。于是,抗体部分的knobs-in-holes突变的另一个例子是在“knob chain”的CH3域中带有R409D/K370E突变,在“hole chain”的CH3域中带有D399K/E357K突变(EU编号)。
在一些实施例中,前药的抗体部分包括Fc结构域的L234A和L235A(“LALA”) 突变。LALA突变可消除补体结合和固定以及Fcγ依赖性ADCC(见Hezareh et al.J.Virol.(2001)75(24):12161-8)。在进一步实施例中,除了knobs-into-holes突变外,抗体部分还存在LALA突变。
在一些实施例中,该抗体部分包括Fc结构域的M252Y/S254T/T256E(“YTE”) 突变。YTE突变允许同时调节血清半衰期、组织分布和IgG1活性(见Dall’Acqua et al.,J BiolChem.(2006)281:23514-24;and Robbie et al.,Antimicrob Agents Chemother.(2013)57(12):6147-53)。在进一步实施例中,除了knobs-into-holes突变外,在抗体部分中还存在YTE突变。在具体实施例中,抗体部分具有YTE、LALA和knobs-into-holes突变或它们的任何组合。
抗原结合部分可与细胞表面的抗原结合,如免疫细胞,例如T细胞、NK细胞和巨噬细胞,或与细胞因子结合。例如,抗原结合部分可以与PD-1、LAG-3、TIM-3、 TIGIT、CTLA-4或TGF-beta和可能的抗体结合。该抗体可能具有激活免疫细胞并增强其抗癌活性的能力。
抗原结合部分可与肿瘤细胞表面的抗原结合。例如,抗原结合部分可与FAPα、5T4、Trop-2、PD-L1、HER-2、EGFR、Claudin 18.2、DLL-3、GCP3或癌胚抗原(CEA) 和可能的抗体结合。该抗体可能具有或不具有ADCC活性。该抗体还可以进一步偶联到细胞毒性药物上。
在一些实施例中,抗原结合部分可结合于脒基环化酶C(GCC),糖类抗原19-9(CA19-9),糖蛋白A33(gpA33),粘蛋白1(MUC1)、胰岛素样生长因子1受体(IGF1- R),人类表皮生长因子受体2(HER2),人类表皮生长因子受体3(HER3),delta-like蛋白3(DLL3),delta-like蛋白4(DLL4)、表皮生长因子受体(EGFR),蛋白多糖-3 (GPC3),c-MET,血管内皮生长因子受体1(VEGFR1),血管内皮生长因子受体2 (VEGFR2)、Nectin-4、Liv-1、糖蛋白NMB(GPNMB)、前列腺特异性膜抗原 (PSMA)、Trop-2、碳酸酐酶IX(CA9),内皮素B受体(ETBR),前列腺1的6个跨膜上皮抗原(STEAPl),叶酸受体α(FR-α),SLIT和NTRK类蛋白6(SLITRK6) 碳酸酐酶VI(CA6),磷酸二酯酶家族成员3(ENPP3),间皮素,滋养层糖蛋白 (TPBG),CD19,CD20,CD22,CD33,CD40,CD56,CD66e,CD70,CD74, CD79b,CD98,CD123,CD138,CD352,CD47,信号调节蛋白(SIRPα),Claudin 18.2, Claudin 6,BCMA或EPCAM。在一些实施例中,抗原结合部分与DLL3的表皮生长因子 (EGF)-样结构域结合。在一些实施例中,抗原结合部分与DLL3的Delta/Serrate/Lag2 (DSL)-样结构域结合。在一些实施例中,抗原结合部分与位于GPC3的第374个氨基酸后的一个表位结合。在一些实施例中,抗原结合部分与GPC3的硫酸肝素聚糖结合。在一些实施例中,抗原结合部分与Claudin 18.2结合,但不与Claudin 18.1结合。在一些实施例中,抗原结合部分与Claudin 18.1的结合亲和力,比与Claudin 18.2的结合亲和力至少弱 10倍。
典型的抗原结合部分包括曲妥珠单抗、利妥昔单抗、伯妥昔单抗、西妥昔单抗、帕尼单抗、GC33(或其人源化版本)、抗EGFR抗体mAb806(或其人源化版本)、抗 dPNAG抗体F598及其抗原结合片段。在一些实施例中,抗原结合部分至少有90%、91%、 92%、93%、94%、95%、96%、97%、98%或99%与曲妥珠单抗、利妥昔单抗、伯妥昔单抗、西妥昔单抗或帕尼单抗、GC33(或其人源化版本)、抗EGFR抗体mAb806(或其人源化版本)、抗-dPNAG抗体F598或其片段一致。在一些实施例中,抗原结合部分有一个抗体重链,其至少有90%,91%,92%,93%,94%,95%,96%,97%,98%或99%与曲妥珠单抗,利妥昔单抗,本妥昔单抗,西妥昔单抗,帕尼单抗,GC33(或其人源化版本),抗-EGFR抗体mAb806(或其人源化版本),抗-dPNAG抗体F598或片段的抗体重链一致。在一些实施例中,抗原结合部分有一个抗体轻链,其至少有90%,91%,92%, 93%,94%,95%,96%,97%,98%或99%与曲妥珠单抗抗体,利妥昔单抗,本妥昔单抗,西妥昔单抗,帕尼单抗,GC33(或其人源化版本),抗-EGFR抗体mAb806(或其人源化版本),抗-dPNAG抗体F598或片段的抗体轻链一致。抗原结合部分被融合到IL-2激动剂多肽上。在一些实施例中,抗原结合部分包括曲妥珠单抗、利妥昔单抗、本妥昔单抗、西妥昔单抗、帕尼单抗、GC33、抗EGFR抗体mAb806或抗dPNAG抗体F598的6个互补决定区(CDRs)。
许多CDR描述是本领域已知的,并且在本文中涵盖。本领域技术人员可以基于重链或轻链可变区的序列,轻易地确定所给定描述的CDR。“Kabat”CDR乃基于序列可变性且最为常用(Kabat et al.,Sequences of Proteins of Immunological Interest,5thEd.Public Health Service,National Institutes of Health,Bethesda,Md.(1991))。“Chothia”CDR是指结构环的位置(Chothia&Lesk,Canonical structures for thehypervariable regions of immunoglobulins,J.Mol.Biol.,vol.196,pp.901-917(1987))。“AbM”CDR代表了Kabat CDR和Chothia结构环之间的折衷,其亦被牛津分子(Oxford Molecular)的AbM抗体建模软件使用。“Contact”CDR为基于对可用复杂晶体结构的分析。参考常见的抗体编号方案,这些CDR的各个残基在下表1中列出。除非本文另有说明,否则抗体中的氨基酸编号是指如上文Kabat等人所述的Kabat编号方案,其包括当参照Kabat,Chothia,AbM或Contact方案进行CDR描述时。使用该编号系统,实际的线性氨基酸序列可以包含较少或额外的氨基酸,其对应于可变结构域的框架区(FR)或CDR的缩短或插入。例如,重链可变域可以包括在H2的残基52之后的单个氨基酸插入(根据Kabat的残基52a),亦包括在重链FR残基82之后的插入的残基(例如,根据Kabat的残基82a,82b和82c等)。对于所给定的抗体,通过在抗体序列同源区域与“标准”Kabat编号序列进行比对,可以确定其抗体残基的Kabat编号。
Table 1.根据各种方案的CDR描述
CDR | Kabat | AbM | Chothia | Contact |
VL-CDR1 | L24-L34 | L24-L34 | L26-L32 | L30-L36 |
VL-CDR2 | L50-L56 | L50-L56 | L50-L52 | L46-L55 |
VL-CDR3 | L89-L97 | L89-L97 | L91-L96 | L89-L96 |
VH-CDR1(Kabat nos.) | H31-H35B | H26-H35B | H26-H32 | H30-H35B |
VH-CDR1(Chothia nos.) | H31-H35 | H26-H35 | H26-H32 | H30-H35 |
VH-CDR2 | H50-H65 | H50-H58 | H53-H55 | H47-H58 |
VH-CDR3 | H95-H102 | H95-H102 | H95-H101 | H93-H101 |
在一些实施例中,CDRs是“扩展的CDRs”,包含根据不同方案开始或结束区域。例如,扩展的CDR可如下所示:L24-L36,L26-L34,或L26-L36(VL-CDR1);L46- L52,L46-L56,或L50-L55(VL-CDR2);L91-L97(VL-CDR3);H47-H55,H47- H65,H50-H55,H53-H58,或H53-H65(VH-CDR2;和/或H93-H102(VH-CDR3)。
在一些实施例中,与HER2结合的抗原结合部分,包括一条与SEQ ID NO:52 的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的轻链,和一条与SEQ ID NO:53的氨基酸序列或其片段具有至少90%, 91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:52的CDR1、CDR2和CDR3,以及SEQ ID NO:53的CDR1、 CDR2和CDR3。
在一些实施例中,与CD20结合的抗原结合部分,包括一条与SEQ ID NO:54 的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的轻链,和一条与SEQ ID NO:55的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQID NO:54的CDR1、CDR2和CDR3,以及SEQ ID NO:55的CDR1、 CDR2和CDR3。
在一些实施例中,与CD30结合的抗原结合部分,包括一条与SEQ ID NO:56 的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的轻链,和一条与SEQ ID NO:57的氨基酸序列或其片段具有至少90%, 91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:56的CDR1、CDR2和CDR3,以及SEQ ID NO:57的CDR1、 CDR2和CDR3。
在一些实施例中,与EGFR结合的抗原结合部分,包括一条与SEQ ID NO:58 的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的轻链,和一条与SEQ ID NO:59或61的氨基酸序列或其片段具有至少 90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:58和59的CDR1、CDR2和CDR3,以及SEQ ID NO:60和61的CDR1、CDR2和CDR3。
在一些实施例中,与c-MET结合的抗原结合部分,包括一条与SEQ ID NO:62 的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的轻链,和一条与SEQ ID NO:63的氨基酸序列或其片段具有至少90%, 91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:62的CDR1、CDR2和CDR3,以及SEQ ID NO:63的CDR1、 CDR2和CDR3。
在一些实施例中,与GPC3结合的抗原结合部分,包括一条与SEQ ID NO:64 的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的轻链,和一条与SEQ ID NO:65的氨基酸序列或其片段具有至少90%, 91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:64的CDR1、CDR2和CDR3,以及SEQ ID NO:65的CDR1、 CDR2和CDR3。
在一些实施例中,与Claudin 18.2结合的抗原结合部分,包括一条与SEQ ID NO:66的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%, 98%,或99%同一性的轻链,和一条与于SEQ ID NO:67的氨基酸序列或其片段具有至少 90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:66的CDR1、CDR2和CDR3,以及SEQ ID NO:67 的CDR1、CDR2和CDR3。
在一些实施例中,与FAPα结合的抗原结合部分,包括一条与SEQ ID NO:80或 81的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%, 98%,或99%同一性的轻链,和一条与SEQ ID NO:82的氨基酸序列或其片段具有至少 90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:80或81的CDR1、CDR2和CDR3,以及SEQ ID NO:82的CDR1、CDR2和CDR3。
在一些实施例中,与FAPα结合的抗原结合部分,包括一条与SEQ ID NO:83具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的氨基酸序列的轻链可变区,和一条与SEQ ID NO:84具有至少90%,91%,92%,93%,94%, 95%,96%,97%,98%,或99%同一性的氨基酸序列的重链可变区。在一些实施例中,抗原结合域包括SEQ IDNO:83的CDR1、CDR2和CDR3,以及SEQ ID NO:84的CDR1、 CDR2和CDR3。
在一些实施例中,与PDL1结合的抗原结合部分,包括一条与SEQ ID NO:89 的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的轻链,和一条与SEQ ID NO:90的氨基酸序列或其片段具有至少90%, 91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:89的CDR1、CDR2和CDR3,以及SEQ ID NO:90的CDR1、 CDR2和CDR3。
在一些实施例中,与5T4结合的抗原结合部分,包括一条与SEQ ID NO:87或 88的氨基酸序列具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或 99%同一性的轻链可变区,和一条与SEQ ID NO:85或86的氨基酸序列或其片段具有至少 90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链可变区。在一些实施例中,抗原结合域包括SEQ ID NO:87或88的CDR1、CDR2和CDR3,以及 SEQ ID NO:85或86的CDR1、CDR2和CDR3。
在一些实施例中,与Trop-2结合的抗原结合部分,包含一个轻链可变区,该可变区包含一个由KASQDVSIAVA(SEQ ID NO:68)氨基酸序列组成的CDR1,包含 SASYRYT(SEQ IDNO:69)氨基酸序列组成的CDR2,包含QQHYITPLT(SEQ ID NO: 70)氨基酸序列组成的CDR3;重链可变区,包括包含NYGMN(SEQ ID NO:71)氨基酸序列组成的CDR1、包含WINTYTGEPTYTDDFKG(SEQ ID NO:72)氨基酸序列组成的CDR2,和包含GGFGSSYWYFDV(SEQ IDNO:73)氨基酸序列的CDR3。
在一些实施例中,与间皮素结合的抗原结合部分,包含一个轻链可变区,该可变区包含一个由SASSSVSYMH(SEQ ID NO:74)氨基酸序列组成的CDR1,包含 DTSKLAS(SEQ IDNO:75)氨基酸序列组成的CDR2,包含QQWSGYPLT(SEQ ID NO: 76)氨基酸序列组成的CDR3;重链可变区,包括包含GYTMN(SEQ ID NO:77)氨基酸序列组成的CDR1、包含LITPYNGASSYNQKFRG(SEQ ID NO:78)氨基酸序列组成的 CDR2,和包含GGYDGRGFDY(SEQ IDNO:79)氨基酸序列的CDR3。
在一些实施例中,与PD-1结合的抗原结合部分,包括一条与SEQ ID NO:50的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或 99%同一性的轻链,和一条与SEQ ID NO:91的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:50的CDR1、CDR2和CDR3,以及SEQ ID NO:91的CDR1、 CDR2和CDR3。
在一些实施例中,与PD-1结合的抗原结合部分,包括一条与SEQ ID NO:92的氨基酸序列或其片段具有至少90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的轻链,和一条与SEQ ID NO:93的氨基酸序列或其片段具有至少90%, 91%,92%,93%,94%,95%,96%,97%,98%,或99%同一性的重链。在一些实施例中,抗原结合域包括SEQ ID NO:92的CDR1、CDR2和CDR3,以及SEQ ID NO:93的CDR1、 CDR2和CDR3。
在一些实施例中,抗原结合部分包括一个、两个或三个抗原结合结构域。例如,抗原结合部分是双特异性的,可与两种不同的抗原结合,这两种抗原分别来自HER2、HER3、EGFR、5T4、FAPα、Trop-2、GPC3、VEGFR2、Claudin 18.2和PD-L1。在一些实施例中,上述抗原结合的双特异性部分与HER2的两个不同表位结合。
2.其它载体部分
其他非抗原结合载体部分亦可以用于本发明的前药。例如,抗体Fc结构域(例如人IgG1,IgG2,IgG3或IgG4 Fc),聚合物(例如PEG),白蛋白(例如人白蛋白),或其片段,或纳米颗粒,均可使用。
举例来说,可以将IL-21激动剂多肽和其拮抗剂与抗体Fc结构域融合,形成Fc 融合蛋白。在一些实施例中IL-21激动剂多肽与至Fc结构域多肽链之一的C端或N端融合(直接融合或通过连接肽),而细胞因子掩蔽则通过可切割的连接肽,与另一条Fc结构域多肽链的C端或N端融合,其中两条Fc结构域多肽链包含了允许两条不同的Fc链特异性配对的突变。在一些实施例中,Fc结构域包含上述的holes-into-holes突变。在一些进一步实施方案中,Fc结构域亦可包含上述的YTE和/或LALA突变。
前药的载体部分可包含白蛋白(例如人血清白蛋白)或其片段。在一些实施例中,载体部分包括白蛋白片段(即人血清白蛋白),约10或更多,20或更多,30或更多,40 或更多,50或更多,60或更多,70或更多,80或更多,90或更多,100或更多,120或更多,140或更多,160或更多,180或更多,200或更多,250或更多,300或更多,350 或更多,400或更多长度为450或更多,500或更多或550或更多的氨基酸片段(例如,人血清白蛋白片段)。在一些实施例中,长度在约10个氨基酸与约584个氨基酸之间 (例如在约10与约20,约20与约40,约40与约80,约80与约160,约160与约250,约250和约350,约350和约450,或约450和约550个氨基酸之间)。在一些实施例中,白蛋白片段包括Sudlow I结构域或其片段,或是Sudlow II结构域或其片段。
D.前药的连接体构成
IL-21激动剂多肽可以在具有或不具有连接肽的情况下与载体部分融合。连结肽可以是不可切割的。在一些实施例中,连接肽选自SEQ ID NO:29-33。在一些特定的实施例中,连接肽包含氨基酸序列GGGGSGGGGSGGGGS(SEQ ID NO:31)。
IL-21掩蔽可以通过可切割的连结与细胞因子部分或与载体融合。可切割的连结可包含一个或多个(例如,两或三个)可切割的部分(CM)。每个CM可以是选自豆蔻蛋白酶、纤溶酶、TMPRSS-3/4、MMP-2、MMP-9、MT1-MMP、组织蛋白酶、胱天蛋白酶、人嗜中性粒细胞弹性蛋白酶、β-分泌酶、uPA和PSA的酶或蛋白酶的底物。可切割连接的实例包括但不限于那些选自SEQ ID NO:11-26的氨基酸序列。例如,一个可切割的肽连接被用来连接IL-21RγECD和IL-21Rα-亚基ECD。优选一种可切割的肽连接,可将 IL-21Rα的亚基ECD与另一个侧-α亚基ECD连接,形成二聚体。
E.附加效应多肽的IL-21前药
在具体实施例中,IL-21前药进一步包括第二效应多肽,如第二个细胞因子部分。在这种情况下,前药可进一步包括与第二效应多肽结合并抑制其生物活性的第二掩蔽部分。
举例来说,IL-21激动剂多肽及其俺蔽部分可能融合在一起,在Fc域一端分离 Fc链,而第二个细胞因子部分及其俺蔽部分可能融合,在Fc域另一端分离Fc链,其中俺蔽部分通过可切割的肽链融合到Fc链上。在某些实施例中,两个Fc域多肽链包含突变,允许对两个不同的Fc链进行特定的配对。
由两个效应多肽和两个掩蔽部分组成的前药实例,包括由两个多肽链组成的前药,其氨基酸序列分别为(i)SEQ ID NOs:42和44;(ii)SEQ ID NOs:43和44;(iii)SEQ IDNOs:45和47,或(iv)SEQ ID NOs:46和47。由IL-2激动剂多肽(第二效应多肽)及其相应的俺蔽部分组成的IL-21前药的示例结构如图3A所示。由IL-15激动剂多肽、sushi结构域及其相应的俺蔽部分组成的IL-21前药的示例结构如图3B所示。
在一些实施例中,IL-21前药还包括一个或多个(例如两个或三个)拷贝的肿瘤坏死因子(TNF)超家族成员配体的外胚间。在一些实施例中,其TNF超家族成员为4-1BB。示例IL-21前药的结构还包括两个拷贝的4-1BB配体(4-1BBL)外结构域的,如图4所示。 IL-21前药的载体可能是一种抗体,它与肿瘤中表达的抗原结合,例如FAP或5T4。
IL-21激动剂多肽,细胞因子掩蔽,载体,连结肽和前药的具体而非限制性实例,显示于以下的序列章节中。此外,本发明的前药通过众所周知的重组技术制备。例如,可将包含前药中多肽链的编码序列的一个或多个表达载体,转染至哺乳动物宿主细胞(例如, CHO细胞)中,且在允许编码序列表达并将表达的多肽组装成前药复合物的条件下培养细胞。为了使前药保持无活性,可以使用不表达或微量表达uPA,MMP-2和/或MMP-9 的宿主细胞。在一些实施例中,宿主细胞可包含这些蛋白酶基因的无效突变(敲除)。
药物成分
对包含了本发明中前药和突变蛋白(例如,活性药物成分或API)的药物成分,可藉将所需纯度的API与一或多种可选择的药学上可接受赋形剂混合来制备(参见,例如,Remington′s Pharmaceutical Sciences,16th Edition.,Osol,A.Ed.(1980))in theform of lyophilized formulations or aqueous solutions.),其形式为冻干制剂或水溶液。药学上可接受的赋形剂(或载体)通常在使用的剂量和浓度下对给予者无毒,包括但不限于:缓冲液含有例如,磷酸盐,柠檬酸盐,琥珀酸盐,组氨酸,乙酸盐或另一种无机或有机酸或其盐;抗氧化剂,包括抗坏血酸和蛋氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;六甲基氯化铵;苯扎氯铵;苄索氯铵;苯酚,丁醇或苄醇;对羟基苯甲酸烷基酯如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚;间苯二酚;间苯二酚;3-戊醇和间甲酚);低分子量(少于约10个残基)多肽;蛋白质,例如血清白蛋白,明胶或免疫球蛋白;亲水性聚合物,例如聚乙烯吡咯烷酮;氨基酸,例如甘氨酸,谷氨酰胺,天冬酰胺,组氨酸,精氨酸或赖氨酸;单糖,二糖和其他碳水化合物,包括蔗糖,葡萄糖,甘露糖或糊精;螯合剂,如EDTA;糖,例如蔗糖,甘露醇,海藻糖或山梨糖醇;成盐的抗衡离子,例如钠;金属配合物(例如锌-蛋白配合物);和/或非离子表面活性剂,例如聚乙二醇(PEG)。
缓冲液用于将pH控制在最佳的治疗效果范围内,特别是当稳定性依赖于pH时。缓冲液浓度最好在50mM到250mM之间。适用于与本发明一起使用的缓冲剂包括有机和无机酸及其盐类,如柠檬酸盐、磷酸盐、琥珀酸盐、酒石酸盐、富马酸盐、葡萄糖酸盐、草酸盐、乳酸盐和醋酸盐。此外,缓冲液可包括组氨酸和三甲胺盐,如三羟甲基氨基甲烷。
添加防腐剂以减缓微生物的生长,通常在0.2%-1.0%(w/v)范围内存在。本发明使用的适用防腐剂包括十八烷基二甲基苄基氯化铵;六甲铵氯化物;苯扎卤铵(如氯、溴、碘)、苯扎氯铵;硫柳汞、苯酚、丁基或苄醇;羟苯甲酸甲酯或羟苯甲酸丙酯;邻苯二酚;间苯二酚;环己醇,3-戊醇和间甲酚。
张度剂,有时称为“稳定剂”,是用以调节或维持成分中液体的张力。当其与带电荷的大型生物分子(如蛋白质和抗体)一起使用时,它们通常被称为“稳定剂”,因其可与氨基酸侧链的带电基团相互作用,从而降低了分子间和分子内相互作用的可能性。当考虑其他成分的相对量时,张度剂可在0.1%至25%重量比之间的任何量使用,或更优选于1%至5%重量比之间。优选的张度剂包括多元糖醇,更优选地为三元或更高级的糖醇,例如甘油,赤藓糖醇,阿拉伯糖醇,木糖醇,山梨糖醇和甘露糖醇。
非离子表面活性剂或去污剂(也称为“湿润剂”),被用以帮助溶解治疗剂,并保护治疗蛋白避免因搅动所导致的聚集,其亦允许了该制剂配方可暴露于剪切表面应力而不引起活性治疗性蛋白或抗体的变性。非离子表面活性剂的使用范围为约0.05mg/mi至约1.0mg/ml,优选地为约0.07mg/ml至约0.2mg/ml。
合适的非离子表面活性剂包括聚山梨酸酯(20、40、60、65、80等),泊咯沙姆 (184、188等),普朗尼克多元醇,曲拉通,聚氧乙烯山梨糖醇单醚(吐温-20,吐温-80 等),聚桂醇400,聚氧化烯硬脂酸酯40,聚氧乙烯氢化蓖麻油10、50和60,单硬脂酸甘油酯,蔗糖脂肪酸酯,甲基纤维素和羧甲基纤维素。可使用的阴离子去污剂包括月桂基硫酸钠,磺基琥珀酸二辛酯钠和磺酸二辛基钠。阳离子去污剂包括苯扎氯铵或苄索氯铵。
药物载体、赋形剂或稀释剂的选择可根据预定的给药途径和标准制药实践。药物组合物还可包括适合的粘合剂、润滑剂、悬浮剂、涂层剂或增溶剂。
根据不同的药物传递系统,可能需要不同的成分/制剂要求。举例来说,本发明中有用的药物成分可被配制成适用于微型泵或通过粘膜途径传递,例如,作为鼻用喷雾剂或气雾剂用于吸入或可吸收溶液,亦或配制成注射形式的成分以肠胃外地给药,其藉由例如静脉内,肌内或皮下途径传递。
在一些实施例中,本发明的药物组合是一种冻干蛋白制剂配方。在其他实施例中,所述药物组合物可以是水液配方。
治疗方法
IL-21前药可用于治疗疾病,其取决于抗原结合结构域所结合的抗原。在一些实施例中,IL-21前药前药用于治疗癌症。在一些实施方案中,IL-21前药用于治疗感染,
在一些实施例中,治疗对象疾病(例如癌症,病毒感染或细菌感染)的方法包含向对象施用有效量的IL-21前药。
在一些实施例中,癌症是实体癌。在一些实施例中,癌症是血液癌或实体瘤。可治疗的示例性癌症包括但不限于,白血病,淋巴瘤,肾癌,膀胱癌,泌尿道癌,子宫颈癌,脑癌,头颈癌,皮肤癌,子宫癌,睾丸癌,食道癌,肝癌,大肠癌,胃癌,鳞状细胞癌,前列腺癌,胰腺癌,肺癌,例如非小细胞肺癌,胆管癌,乳腺癌和卵巢癌。
在一些实施例中,IL-21前药用于治疗病毒感染。在一些实施例中,引起病毒感染的病毒是丙型肝炎病毒(HCV)、乙型肝炎病毒(HBV)、人体免疫缺陷病毒(HIV) 或人类乳头瘤病毒(HPV)。在一些实施例中,抗原结合部分与病毒抗原相结合。
在一些实施例中,IL-21前药用于治疗细菌感染,如脓毒症。在一些实施例中,引起细菌感染的细菌是耐药细菌。在一些实施例中,抗原结合部分与细菌抗原结合。
一般来说,现有药物的给药剂量和给药途径是根据受试者的情况和条件,按照标准的药学实践确定。在一些实施例中,药物成分给予是通过一个给药路径,包括口服、皮下、吸入、静脉注射、动脉内的、肌内、直接应用于伤口,应用手术部位、腹腔内、栓剂、皮下、皮内注射、经皮、雾化、胸膜腔内、脑室、关节内的、眼内、颅内或脊柱内。在一些实施例中,药物被静脉注射给受试者。
在一些实施例中,药物成分的剂量是单剂量或重复剂量。在一些实施例中,剂量为每天一次,每天两次,每天三次,或每天四次或更多次给予给药对象。在一些实施方案中,一周内给予约1次或更多(例如约2、3、4、5、6或7或更多)剂量。在一些实施例中,药物成分以每周一次,每两周一次,每三周一次,每四周一次,每周一次,三周中的两周中的每周,或四周中的三周中的每周,来实施给药。在一些实施例中,多次剂量于几天,几周,几个月或几年的过程中给予。在一些实施方案中,治疗过程为约1或更多剂量(例如约2、3、4、5、7、10、15或20或更多剂量)。
除非本文另外定义,否则与本发明相关的科学和技术术语,应具有本领域普通技术人员通常理解的含义。尽管本文描述的那些类似或等同的方法和材料亦可被用于本发明的实践或试验中,但示例性方法和材料如下所描述。如有冲突,以本规范说明,包括定义,为准。通常,本文所述相关于细胞和组织培养,分子生物学,免疫学,微生物学,遗传学,分析化学,合成有机化学,医学和药物化学,以及蛋白质和核酸化学,以及杂交混合的命名法和技术均为本领域众所周知和常用的。酶促反应和纯化技术乃根据制造商的规范说明执行,如本领域通常达成的或如本文所述。此外,除非上下文另外要求,否则单数术语应包括复数,并且复数术语应包括单数。在整个规范说明和实施方案中,词语“具有”和“包含”,或其同义、替代词及变体,将被理解为暗示着包括了所述整数或整数组,但不排除任何其他整数或整数组。应当理解,本文所述发明的方面和变化包括″由......组成″和/或″基本上由......组成″的方面和变化。尽管本文引用了许多文件,但该引用并不构成承认这些文件中的任何文件形成本领域公知常识的一部分。
示例性实施方案
本发明的其他特定实施例描述如下。这些实施方案旨在说明本发明中描述的成分和方法,而并非旨在限制本发明的范围。
1.IL-21的前药,包括IL-21激动剂多肽(A)、掩蔽部分(MM)、载体(C)和至少一个可切掉的肽连接,其中:
a)所述IL-21激动剂多肽(A)包含与SEQ ID NO:1至少95%相同的氨基酸序列,
b)所述掩蔽部分(MM)是从IL-21受体胞外结构域、其类似物以及IL-21受体胞外结构域和γ链的胞外结构域的融合蛋白中选择;
c)所述载体从白蛋白、白蛋白片段、Fc和抗体中选择;和
d)所述可切割的肽连接将所述掩蔽部分(MM)连接到载体或IL-21激动剂多肽。
2.实施例1中的前药,其中所述IL-21激动剂多肽(A)是人IL-21的类似物,氨基酸序列是 SEQ ID NO:1或其类似物;其中类似物包括在D18,E109,K117,和/或K119的一个或多个突变;而其中所述突变是参照于具有SEQ ID NO:11氨基酸序列的人IL-21的编号。
3.实施例1的前药,其中IL-21激动剂多肽(A)的氨基酸序列选择自SEQ ID NOs:2-5。
4.实施例1和3中任一例的前药,其中所述IL-21受体胞外结构域,其包含至少95%,至少 96%,至少97%,至少98%,至少95%或100%与SEQ ID NO:6相同的氨基酸序列;其中γ链具有SEQ ID NO:7所示的氨基酸。
5.本发明实施例1-4的前药,其中所述可切掉的肽连接的氨基酸序列从SEQ IDNOs:11-26 中选择。
6.实施例1-5的前药,其中所述载体(C)是白蛋白或其片段。
7.实施例1-5的前药,其中所述载体(C)是Fc片段
8.实施例7的前药,其中所述IL-21激动剂多肽选择性地通过肽接头与一个Fc片段的C末端融合,且所述掩蔽部分(MM)通过可切割的连接肽与第二Fc片段的C末端融合;其中Fc-融合蛋白经由“knob-into-hole”突变形成异源二聚体。
9.实施例7的前药,其中所述IL-21激动剂多肽选择性地通过肽接头与一个Fc片段的N末端融合,且所述掩蔽部分(MM)通过可切割的连接肽与第二Fc片段的N-端融合;其中两个Fc融合蛋白经由“knob-into-hole”突变形成异源二聚体。
10.实施例1-6的前药,其中所述载体(C)是一个抗体。
11.实施例10的前药,其中所述IL-21激动剂多肽选择性地通过肽接头与所述抗体的重链上的 N末端融合,且所述掩蔽部分(MM)通过可切割的连接肽与轻链上的N-端融合。
12.实施例10的前药,其中所述IL-21激动剂多肽选择性地通过肽接头与一个所述抗体的重链上的C-端融合,且所述掩蔽部分(MM)通过可切割的连接肽与第二重链的C-端融合;其中重链融合蛋白经由“knob-into-hole”突变形成异源二聚体。
13.实施例10的前药,其中所述IL-21激动剂多肽选择性地通过肽接头与一个所述抗体的重链上的N-端融合,且所述掩蔽部分(MM)通过可切割的连接肽与第二重链的N-端融合;其中两条重链融合蛋白经由“knob-into-hole”突变形成异源二聚体。
14.实施例10的前药,其中所述IL-21激动剂多肽选择性地通过肽接头与一个所述抗体的重链上的任一C-端融合,且所述掩蔽部分(MM)通过可切割的连接肽与IL-21激动剂多肽的 C-端融合。
15.实施例10-14的前药,其中所述抗体与癌细胞上的一个或多个抗原结合。
16.实施例10-14的前药,其中所述抗体是针对人PD-L1或CD47的抗体。
17.实施例10-14的前药,其中所述抗体从抗-CEA抗体PR1A3、人源化PR1A3和抗FAP-α抗体sibrotuzumab(BIBH1)中选择。
18.实施方案10-14中任一例的前药,其中所述抗体与一种或多种选自鸟苷酸环化酶C (GCC),碳水化合物抗原19-9(CA19-9),糖蛋白A33(gpA33),粘蛋白1 (MUC1),癌胚抗原(CEA),胰岛素样生长因子1受体(IGF1-R),人表皮生长因子受体2(HER2),人表皮生长因子受体3(HER3),δ样蛋白3(DLL3),δ样蛋白4 (DLL4),表皮生长因子受体(EGFR),蛋白多糖-3(GPC3),c-MET,血管内皮生长因子受体1(VEGFR1),血管内皮生长因子受体2(VEGFR2),Nectin-4,Liv-1,糖蛋白NMB(GPNMB),前列腺特异性膜抗原(PSMA),Trop-2,碳酸酐酶IX(CA9),内皮素B受体(ETBR),六个跨膜前列腺上皮抗原1(STEAP1),叶酸受体α(FR-α), SLIT和NTRK样蛋白6(SLITRK6),碳酸酐酶VI(CA6),外核苷酸焦磷酸酶/磷酸二酯酶家族成员3(ENPP3),间皮素,滋养层糖蛋白(TPBG),CD19,CD20,CD22, CD33,CD40,CD56,CD66e,CD70,CD74,CD79b,CD98,CD123,CD138,CD352, CD47,信号调节蛋白α(SIRPα),PD1,Claudin18.2,Claudin 6,FAP-α,BCMA, EPCAM,CD3,TGF-beta,LAG3,TIM3,TIGIT和CTLA-4的抗原结合。
19.本实施例10-18的前药,其中进一步包括与SEQ ID NO:27的氨基酸序列至少95%相同的 CCL19多肽。
20.实施例1-19的前药,其中所述可切割的连接肽可被在肿瘤部位或其周围环境中的一种或多种蛋白酶裂解。
21.实施例1-19的前药,其中所述前药在肿瘤部位被激活。
22.实施例16的前药,其中所述抗体与PD-L1结合;其中,PD-L1抗体选自阿特珠单抗、德瓦鲁单抗、阿维鲁单抗。
23.实施例10-14的前药,其中所述抗体与PD-1结合;其中,抗PD-1抗体选自纳武单抗和派姆单抗。
24.IL-21的前药,其IL-21活性在肿瘤部位或其周围区域可被激活或至少增加200%,包括:
a)与PD-L1结合的抗体,包括两条相同的轻链和第1重链和第2重链;其中所述的重链包含“knob-and-hole”突变;
b)IL-21激动剂多肽,其中IL-21激动剂多肽可选地通过与氨基酸序列(GGGGS)n的肽连接,融合到该抗体第1重链的C-端,其中n=1,2,3,4(SEQ ID NO:97);
c)掩蔽部分(MM),其中所述掩蔽部分包括IL-21受体胞外结构域的一个或两个胞外结构域;和
d)一个可切割肽连接将所述掩蔽部分(MM)连接到所述抗体第2重链C-端上,其中IL-21 激动剂多肽包含从SEQ ID NO:1-5中选择的氨基酸序列;其中IL-21β受体亚基胞外结构域的氨基酸序列为SEQ ID NO:6。
25.IL-21的前药,其IL-21活性在肿瘤部位或其周围区域可被激活或至少增加200%,包括:
a)与CD47结合的抗体,包括两条相同的轻链和第1重链和第2重链;其中所述的重链包含“knob-and-hole”突变;
b)IL-21激动剂多肽,其中IL-21激动剂多肽可选地通过与氨基酸序列(GGGGS)n的肽连接,融合到该抗体第1重链的C-端,其中n=1,2,3,4(SEQ ID NO:97)
c)掩蔽部分(MM),其中所述掩蔽部分包括IL-21受体胞外结构域的一个或两个胞外结构域;和
d)一个可切割肽连接将所述掩蔽部分(MM)连接到所述抗体第2重链C-端上,其中IL-21 激动剂多肽包含从SEQ ID NO:1-5中选择的氨基酸序列;其中IL-21β受体亚基胞外结构域的氨基酸序列为SEQ ID NO:6。
26.多核苷酸,其编码实施例1-25前药中白蛋白融合蛋白、Fc融合蛋白、轻链融合蛋白或重链融合蛋白。
27.实施例26的多核苷酸的表达载体。
28.实施例27的载体转染的宿主细胞。
29.一种实施例1-25所述前药的生产方法,包括培养实施例28的宿主细胞
30.一种药物组合物,其活性成分包括实施例1-25的前药。
31.一种治疗乳腺癌,肺癌,胰腺癌,食道癌,甲状腺髓样癌,卵巢癌,子宫癌,前列腺癌,睾丸癌,结肠癌,直肠癌或胃癌或传染病的方法,其包括对人给药对象施用实施方案30 中所述药物成分。
32.实施例31的方法,其中给药剂量为0.1-18mg/kg。
33.实施例31的方法,其中剂量从0.1mg/kg、0.2mg/kg、0.5mg/kg、1mg/kg、2mg/kg、3 mg/kg、4mg/kg、5mg/kg、6mg/kg、8mg/kg、10mg/kg、15mg/kg组中选择。
34.实施例33的方法,其中,该剂量给予是每周给药一次或两次,周期从以下组中选择,包括:(i)每周;(ii)每两周;(iii)治疗一星期,然后休息两、三或四周;(iv)治疗两周,然后休息一、二、三或四周;(v)治疗三周,然后休息一、二、三、四或五周; (vi)治疗四周,然后休息一、二、三、四或五周;(vii)治疗五周,然后休息一、二、三、四或五周;(viii)每月。
为了本发明可被更好地理解,于此阐述以下示例。这些示例仅出于说明目的,而不应以任何方式解释为限制本发明的范围。
实施例
Example 1:HEK293细胞瞬时转染IL-21前药
使用PEI(聚乙烯亚胺)将表达质粒以2.5-3μg/ml转染到3x106活细胞/ml的FreestyleHEK293细胞中。对于基于Fc的IL-21前药(A和B),Fc-IL-21融合多肽和Fc- 掩蔽部分融合多肽的比例为1∶2。对于基于抗体的IL-21前药,knob重链(包含IL-21激动剂多肽)和hole重链(包含掩蔽部分)与轻链DNA的摩尔比为2∶1∶2。转染后6天,通过在9,000rpm下离心45分钟,而后0.22μM过滤,来收获细胞培养物。
表达了两种IL-21前药(A和B)。前药A由两个多肽组成,分别为SEQ ID NOs:94和38。前药B由两个多肽组成,分别为SEQ ID NOs:95和38。它们相应的对照,没有掩蔽部分的Fc-IL-21融合分子也表达了。表2列出了序列ID号。
表2.样本序列信息。
实施例2:基于Fc的IL-21前药的蛋白质纯化
采用Protein A亲和、CaptoAdhere(流穿模式)、Capto SP ImpRes三个层析步骤对基于Fc的IL-21前药A和B的蛋白进行了纯化。简单地说,将瞬时表达细胞培养的上清液加载到Protein A柱上,上样前用25mM Tris-HCl,30mM氯化钠,pH 7.8(缓冲液A)平衡。用5柱体积的缓冲液A淋洗柱,然后用50mM乙酸(pH 3.6)洗脱结合蛋白。用1M Tris- base将洗脱蛋白的pH值调至5.2,接着加载至Capto Adhere柱子,上样前柱子用50mM醋酸,30mM氯化钠,pH值5.2(缓冲液B)平衡。收集流穿液,接着进一步加载到已用缓冲液B 平衡好的Capto SPImpRes柱子上。用5柱体积的缓冲液B淋洗柱,接着用50mM乙酸, 1M氯化钠,pH 5.2(缓冲液C)以30柱体积0%-100%的梯度线性洗脱结合蛋白,每一步的洗脱样品用HPLC-SEC分析。聚合度小于10%的Capto SP ImpRes步骤的组分被合并用于进一步分析。
实施例3:SEC-HPLC分析
SEC-HPLC的分析是在Agilent 1100系列HPLC系统上进行并配以TosohBioscience的TSKgel G3000SWXL色谱柱(7.8mmIDX 30cm,粒径5μm)。上样至多 100μl,色谱柱的流动相为200mM K3PO4、250mM KCl,pH 6.5的缓冲。,流速设定为 0.5ml/min。柱温为室温。蛋白质洗脱的检测UV为220nm和280nm。SEC-HPLC被用来分析IL-21前药A在纯化过程中的各步骤组分。图5A显示了亲和层析产物的分析结果;图5B显示了Capto Adhere阴离子层析产物的分析结果;图C5显示了Capto SP ImpRes阳离子层析产物的分析结果。数据表明ProA纯化后的前药含有一个主峰和一些聚体(图 5A)。经SEC-HPLC分析,主峰的纯度在80%左右。经过接下来的离子交换层析步骤,聚体的含量显著降低,经SEC-HPLC分析显示CaptoSP ImpRes层析后的合并产物纯度达到了超过98%(Figure 5C).
实施例4:SDS-PAGE分析
将10μl培养物上清液或10-20μg纯化后的蛋白样品与具有或不具有还原剂的BoltTM LDS样品缓冲液(Novex)混合。样品于70℃加热3分钟,然后加载到 NuPAGETM 4-12%BisTris凝胶(Invitrogen)上。该凝胶在NuPAGETM MOPS SDS运行缓冲液(Invitrogen)中以200伏特运行40分钟,然后使用考马斯染色。将纯化后的前药 A和B与蛋白酶MMP-2处理后的样品(见下文)进行SDS-PAGE分析,结果如图6所示。数据表明,前药A和前药B的掩蔽部分都被蛋白酶消化完全除去,被激活分子为预期的分子量。
实施例5:蛋白水解处理
蛋白酶,人MMP2,人MMP9,小鼠MMP2和小鼠MMP9购自,R&D systems。蛋白酶消化的步骤如下,将10μg-50μg的前药蛋白与1μg人MMP2,人MMP9,小鼠 MMP2或小鼠MMP9,加入含2mM CaCl2和10μM ZnCl2的HBS缓冲液中(20mM HEPES,150mM NaCl2,pH 7.4),在37度培养12个小时。SDS-PAGE(图6)和细胞活性检测(见下文)被用于分析消化之前和之后的前药蛋白。
实施例6:细胞活性测定
采用细胞活性测定法检测蛋白酶消化前后的前药和对照样品。简单地说,NK92 细胞在PRMI-1640培养基中生长,培养基中添加1-谷氨酰胺、10%胎牛血清、10%非必需氨基酸、10%丙酮酸钠和55μM巯基乙醇。NK92细胞不贴壁,在IL-2浓度为100ng/ml 的培养基中维持在1x105-1x106细胞/ml。一般来说,细胞每周分裂两次。对于生物测定,最好使用传代后不少于48小时的细胞。将NK92细胞以5×104个细胞/孔培养,连续稀释样品,在固定量的IL-2存在下培养2天,测定IL-21的功能活性。上层液然后用ELISA 检测干扰素-γELISA。结果如图7A和7B所示。结果表明,蛋白酶MMP2的作用显著增强了前药的生物活性。
蛋白酶处理过(或激活后)的前药显示出与对照的FC-IL-21融合蛋白相似的活性,尽管遮蔽部分,即IL-21RαECD,并没有从被蛋白酶处理过的样品中除去。令人惊讶的是,通过蛋白酶分解释放出来的遮蔽部分的存在并没有影响IL-21的生物活性,鉴于IL-21和 IL-21Rα结合的亲和力非常之高(a KD of~70pM)。
实施例7:抗-PD-1抗体-IL-21前药融合分子
用两条相同的轻链构建了基于抗PD-1抗体的IL-21前药(其氨基酸序列如SEQ IDNO:50所示)。第一条重链多肽链(氨基酸序列见SEQ ID NO:48)和第二条重链多肽链 (氨基酸序列见SEQ ID NO:49)。分子被表达和纯化。作为对照,不带掩膜的抗PD-1抗体 IL-21融合分子也得到了表达和纯化。细胞因子前药活化前后的细胞活性测定采用上述相同的方法进行。数据如图8所示。结果表明,激活前IL-21的活性极小。活化后IL-21的活性与PD-1-IL-21融合分子中IL-21的活性相似。
抗PD1抗体激活前后的活性用阻断PD1/PDL1的报告基因检测法进行检测。两种经过基因工程改造的细胞系被用来检测抗PD1抗体阻断PD-L1调节下的PD1信号传导的能力。其一是既表达人PD-L1又表达T细胞受体活化剂的CHO-K1细胞系(CHO- K1/TCRA/PD-L1,BPSBioscience cat#60536)。另一个细胞系是表达PD1和NFAT萤火虫荧光素酶报告基因的Jurkat T细胞系(PD1/NFAT,BPS Bioscience cat#60535)。CHO-K1细胞上的T细胞受体活化剂会激活Jukat细胞,导致NFTA荧光素酶报告基因的表达。尽管如此,由于CHO-K1细胞同时也表达PD-L1,通过PD-1传导的信号亦会抑制NFAT的激活。阻断PD-L1/PD-1的相互作用可以恢复NFTA的活化以及荧光素酶的活性。
实验过程如下,CHO-K1/TCRA/PD-L1细胞以35,000细胞/孔接种与含有50μL培养基(RPMI-1640,10%胎牛血清,非必须氨基酸,2-巯基乙醇和庆大霉素)的白色透明平底96 孔板。过夜培养后,去除培养基并以50μL/孔加入2倍浓度的样品和标准品。经过20分钟的培养后,每个孔加入50μL 40,000PD1/NFAT细胞。接着在37度培养6个小时。等平板冷却至室温5分钟后,加入100μL/well荧光酶试剂(Pierce Firefly Luc One-Step Glow Assay Kit,Thermo Scientific cat#16197)。继续培养15分钟后,用荧光分光光度计读取荧光数值
实验结果(图9)表明,融合分子中的抗PD-1抗体保留了其生物学功能。
实施例8:同基因肿瘤模型的体内疗效研究
给六周大Balb/c小鼠(Taconic Biosciences)皮下注射1倍浓度的106CT26/18.2细胞。七天后,用数显卡尺测量并计算肿瘤的大小(V=(ab2)p/6,其中b是测量的两边中较短的边). 小鼠被随机分组使得每组的肿瘤平均大小都大致相同(~100mm3).接着,给小鼠腹膜内注射100μl浓度为0.5-5mg/kg的安慰剂或者试药。分别在第7,9,11,13,15和18天给药。每2-3天测量肿瘤的大小,当肿瘤的体积达到2000mm3时,小鼠将被处死。
上述非限制性示例仅出于说明性目的而提供,以便于更全面地理解所公开的主题。这些示例不应被解释为限制本说明书中描述的任何实施方案,包括那些涉及抗体,药物成分,或用于治疗癌症,神经变性或感染性疾病的方法和用途的实施方案。
序列
SEQ ID NO:1-人IL-21
SEQ ID NO:2-IL-21突变蛋白A
SEQ ID NO:3-IL-21突变蛋白B
SEQ ID NO:4-IL-21突变蛋白C
SEQ ID NO:5-IL-21突变蛋白D
SEQ ID NO:6-IL-21受体ECD(source:uniprot.org/uniprot/Q9HBE5)
SEQ ID NO:7-人IL-21RγECD
SEQ ID NO:8-人IL-2
SEQ ID NO:9-人IL-15
SEQ ID NO:10-人IL-15Rαsushi结构域
SEQ ID NO:11-17-MMP2/MMP9可切割的连接肽
SEQ ID NO:18-26-尿激酶型纤溶酶原激活物(uPA)可切割的连接肽
SEQ ID NO:27-人CCL19
SEQ ID NO:28-人IL-7
SEQ ID NO:29-33连接肽
SEQ ID NO:34-IgG1 Fc
SEQ ID NO:35-IgG4 Fc
SEQ ID NO:36-Fc带有knobs突变-IL-21
其中n=0,1,2,3,4,或5.
SEQ ID NO:37-Fc带有knobs突变-IL-21突变蛋白
其中n=0,1,2,3,4,或5.
SEQ ID NO:38-Fc带有holes突变-IL-21受体ECD
SEQ ID NO:39-IL-21-Fc带有knobs突变
其中n=0,1,2,3,4,或5.
SEQ ID NO:40-IL-2突变蛋白-Fc带有knobs突变
SEQ ID NO:41-IL-21RαECD-Fc带有Hole突变
SEQ ID NO:42-IL-15-Sushi-Fc带有knobs突变-IL-21
其中n1=0,1,2,3,4,或5;n2=0,1,2,3,4,或5;和n3=0,1,2,3,4,或5.
SEQ ID NO:43-IL-2类似物-Fc带有knobs突变-IL-21突变蛋白
其中n1=0,1,2,3,4,或5;和n2=0,1,2, 3,4,或5.
SEQ ID NO:44-IL-2RβECD-Fc带有holes突变-IL-21RαECD
SEQ ID NO:45-IL-21-Fc带有knobs突变-Sushi-IL-15
其中n1=0,1,2,3,4,或5;n2=0,1,2,3,4,或5;和n3=0, 1,2,3,4,或5.
SEQ ID NO:46-IL-21突变蛋白-Fc带有knobs突变-IL-2类似物
其中n1=0,1,2,3,4,或5;和 n2=0,1,2,3,4,或5.
SEQ ID NO:47-IL-21RαECD-Fc带有holes突变-IL-2RβECD
SEQ ID NO:48-PD1-HC带有knob突变-IL-21
SEQ ID NO:49-PD1-HC带有hole突变-IL-21RαECD
SEQ ID NO:50-PD1-LC
SEQ ID NO:51-PD1-LC-IL-2基础
其中Xaa88选自N and A中一个氨基酸,and Xaa126选自Q,H,W 或A中一个氨基酸.
SEQ ID NO:52-曲妥珠单抗轻链
SEQ ID NO:53-曲妥珠单抗重链
SEQ ID NO:54-利妥昔单抗轻链
SEQ ID NO:55-利妥昔单抗重链
SEQ ID NO:56-本妥昔单抗轻链
SEQ ID NO:57-本妥昔单抗重链
SEQ ID NO:58-西妥昔单抗轻链
SEQ ID NO:59-西妥昔单抗重链
SEQ ID NO:60-帕尼单抗轻链
SEQ ID NO:61-帕尼单抗重链
SEQ ID NO:62-抗c-MET抗体轻链
SEQ ID NO:63-抗c-MET抗体重链
SEQ ID NO:64-抗-GPC3抗体轻链
SEQ ID NO:65-抗-GPC3抗体重链
SEQ ID NO:66-抗-Claudin 18.2抗体轻链
SEQ ID NO:67-抗-Claudin 18.2抗体重链
SEQ ID NO:68-抗-Trop-2抗体轻链CDR1
SEQ ID NO:69-抗-Trop-2抗体轻链CDR2
SEQ ID NO:70-抗-Trop-2抗体轻链CDR3
SEQ ID NO:71-抗-Trop-2抗体重链CDR1
SEQ ID NO:72-抗-Trop-2抗体重链CDR2
SEQ ID NO:73-抗-Trop-2抗体重链CDR3
SEQ ID NO:74-抗-间皮素抗体轻链CDR1
SEQ ID NO:75-抗-间皮素抗体轻链CDR2
SEQ ID NO:76-抗-间皮素抗体轻链CDR3
SEQ ID NO:77-抗-间皮素抗体重链CDR1
SEQ ID NO:78-抗-间皮素抗体重链CDR2
SEQ ID NO:79-抗-间皮素抗体重链CDR3
SEQ ID NO:80-抗-FAP版本1LC
SEQ ID NO:81-抗-FAP LC版本2
SEQ ID NO:82-抗-FAP VH
SEQ ID NO:83-FAPalpha抗体BIBH1的人源化轻链可变域
SEQ ID NO:84-FAPalpha抗体BIBH1的人源化重链可变域
SEQ ID NO:85-人源化H8抗-5T4版本1VH
SEQ ID NO:86-人源化H8抗-5T4 VH版本2
SEQ ID NO:87-人源化H8抗-5T4版本1VL
SEQ ID NO:88-人源化H8抗-5T4 VL版本2
SEQ ID NO:89-抗-PDL1阿特珠单抗LC
SEQ ID NO:90-抗PDL1阿特珠单抗HC
SEQ ID NO:91-抗-PD-1纳武单抗HC
SEQ ID NO:92-抗-PD-1派姆单抗LC
SEQ ID NO:93-抗-PD-1派姆单抗HC
SEQ ID NO:94-Fc带有knobs突变-IL-21
SEQ ID NO:95-Fc带有knobs突变-IL-21突变蛋白Q19K/E109R
SEQ ID NO:96-IgG1 Fc带有holes突变
SEQ ID NO:97-肽链接
序列表
<110> 奥美药业有限公司
<120> 全新 IL-21前药及使用方法
<150> 62/703,383
<151> 2018-07-25
<160> 97
<170> SIPOSequenceListing 1.0
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Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser
130
<210> 2
<211> 133
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Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Ala Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser
130
<210> 3
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Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Lys Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser
130
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Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Arg Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser
130
<210> 5
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Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Lys Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Arg Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser
130
<210> 6
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<400> 6
Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys
1 5 10 15
Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp
20 25 30
Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu
35 40 45
His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met
50 55 60
Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr
65 70 75 80
Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala
85 90 95
Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser
100 105 110
Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe
115 120 125
Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg
130 135 140
Gly Asp Pro Trp Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp
145 150 155 160
Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser
165 170 175
Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln
180 185 190
Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser
195 200 205
Glu Glu Leu Lys Glu
210
<210> 7
<211> 240
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Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly Asn Glu Asp Thr Thr Ala
1 5 10 15
Asp Phe Phe Leu Thr Thr Met Pro Thr Asp Ser Leu Ser Val Ser Thr
20 25 30
Leu Pro Leu Pro Glu Val Gln Cys Phe Val Phe Asn Val Glu Tyr Met
35 40 45
Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro Gln Pro Thr Asn Leu Thr
50 55 60
Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn Asp Lys Val Gln Lys Cys
65 70 75 80
Ser His Tyr Leu Phe Ser Glu Glu Ile Thr Ser Gly Cys Gln Leu Gln
85 90 95
Lys Lys Glu Ile His Leu Tyr Gln Thr Phe Val Val Gln Leu Gln Asp
100 105 110
Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln Met Leu Lys Leu Gln Asn
115 120 125
Leu Val Ile Pro Trp Ala Pro Glu Asn Leu Thr Leu His Lys Leu Ser
130 135 140
Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn Arg Phe Leu Asn His Cys
145 150 155 160
Leu Glu His Leu Val Gln Tyr Arg Thr Asp Trp Asp His Ser Trp Thr
165 170 175
Glu Gln Ser Val Asp Tyr Arg His Lys Phe Ser Leu Pro Ser Val Asp
180 185 190
Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg Ser Arg Phe Asn Pro Leu
195 200 205
Cys Gly Ser Ala Gln His Trp Ser Glu Trp Ser His Pro Ile His Trp
210 215 220
Gly Ser Asn Thr Ser Lys Glu Asn Pro Phe Leu Phe Ala Leu Glu Ala
225 230 235 240
<210> 8
<211> 133
<212> PRT
<213> Homo sapiens
<400> 8
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 9
<211> 113
<212> PRT
<213> Homo sapiens
<400> 9
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
1 5 10 15
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
20 25 30
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
35 40 45
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
50 55 60
Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
65 70 75 80
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
85 90 95
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
100 105 110
Thr
<210> 10
<211> 75
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<213> Homo sapiens
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Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val
1 5 10 15
Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly
20 25 30
Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn
35 40 45
Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile
50 55 60
Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala
65 70 75
<210> 11
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 11
Gly Pro Leu Gly Val Arg
1 5
<210> 12
<211> 7
<212> PRT
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<400> 12
Pro Leu Gly Met Trp Ser Arg
1 5
<210> 13
<211> 7
<212> PRT
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<400> 13
Pro Leu Gly Leu Trp Ala Arg
1 5
<210> 14
<211> 8
<212> PRT
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<400> 14
Pro Gln Gly Ile Ala Gly Gln Arg
1 5
<210> 15
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 15
Pro Leu Gly Leu Ala Gly
1 5
<210> 16
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 16
Leu Ala Leu Gly Pro Arg
1 5
<210> 17
<211> 10
<212> PRT
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<400> 17
Gly Gly Pro Leu Gly Met Leu Ser Gln Ser
1 5 10
<210> 18
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 18
Gly Gly Gly Gly Arg Arg Gly Gly Ser
1 5
<210> 19
<211> 8
<212> PRT
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<400> 19
Thr Gly Arg Gly Pro Ser Trp Val
1 5
<210> 20
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 20
Ser Ala Arg Gly Pro Ser Arg Trp
1 5
<210> 21
<211> 8
<212> PRT
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<400> 21
Thr Ala Arg Gly Pro Ser Phe Lys
1 5
<210> 22
<211> 7
<212> PRT
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<400> 22
Thr Ala Arg Gly Pro Ser Trp
1 5
<210> 23
<211> 8
<212> PRT
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<400> 23
Gly Gly Trp His Thr Gly Arg Asn
1 5
<210> 24
<211> 8
<212> PRT
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<400> 24
His Thr Gly Arg Ser Gly Ala Leu
1 5
<210> 25
<211> 8
<212> PRT
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<400> 25
Pro Leu Thr Gly Arg Ser Gly Gly
1 5
<210> 26
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 26
Leu Thr Gly Arg Ser Gly Ala
1 5
<210> 27
<211> 76
<212> PRT
<213> Homo sapiens
<400> 27
Thr Asn Asp Ala Glu Asp Cys Cys Leu Ser Val Thr Gln Lys Pro Ile
1 5 10 15
Pro Gly Tyr Ile Val Arg Asn Phe His Tyr Leu Leu Ile Lys Asp Gly
20 25 30
Cys Arg Val Pro Ala Val Val Phe Thr Thr Leu Arg Gly Arg Gln Leu
35 40 45
Cys Ala Pro Pro Asp Gln Pro Trp Val Glu Arg Ile Ile Gln Arg Leu
50 55 60
Gln Arg Thr Ser Ala Lys Met Lys Arg Arg Ser Ser
65 70 75
<210> 28
<211> 152
<212> PRT
<213> Homo sapiens
<400> 28
Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu Ser Val Leu
1 5 10 15
Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu Ile Gly Ser
20 25 30
Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His Ile Cys Asp
35 40 45
Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg Lys Leu Arg
50 55 60
Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu His Leu Leu
65 70 75 80
Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr Gly Gln Val
85 90 95
Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro Thr Lys Ser
100 105 110
Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp Leu
115 120 125
Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn Lys
130 135 140
Ile Leu Met Gly Thr Lys Glu His
145 150
<210> 29
<211> 5
<212> PRT
<213> Artificial Sequence
<400> 29
Gly Gly Gly Gly Ser
1 5
<210> 30
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 30
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 31
<211> 15
<212> PRT
<213> Artificial Sequence
<400> 31
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 32
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<221> VARIANT
<222> (10)..(10)
<223> /replace="Asn"
<220>
<221> SITE
<222> (1)..(20)
<223> /note="Variant residues given in the sequence have no preferencewith respect to those in the annotations for variant positions"
<400> 32
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ala Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 33
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<221> VARIANT
<222> (10)..(10)
<223> /replace="Ala" or "Asn"
<220>
<221> VARIANT
<222> (15)..(15)
<223> /replace="Asn"
<220>
<221> SITE
<222> (1)..(20)
<223> /note="Variant residues given in the sequence have no preferencewith respect to those in the annotations for variant positions"
<400> 33
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ala Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 34
<211> 227
<212> PRT
<213> Unknown
<400> 34
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 35
<211> 230
<212> PRT
<213> Unknown
<400> 35
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
1 5 10 15
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
20 25 30
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
35 40 45
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
50 55 60
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
65 70 75 80
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
85 90 95
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
100 105 110
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
115 120 125
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
130 135 140
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
145 150 155 160
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
165 170 175
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
180 185 190
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
195 200 205
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
210 215 220
Ser Leu Ser Leu Gly Lys
225 230
<210> 36
<211> 385
<212> PRT
<213> Artificial Sequence
<220>
<221> SITE
<222> (228)..(252)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<400> 36
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Gly Gln Asp
245 250 255
Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile Val Asp Gln Leu
260 265 270
Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu
275 280 285
Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys
290 295 300
Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn
305 310 315 320
Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly
325 330 335
Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu
340 345 350
Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln
355 360 365
Lys Met Ile His Gln His Leu Ser Ser Arg Thr His Gly Ser Glu Asp
370 375 380
Ser
385
<210> 37
<211> 385
<212> PRT
<213> Artificial Sequence
<220>
<221> SITE
<222> (228)..(252)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<400> 37
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Gly Gln Asp
245 250 255
Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile Val Asp Lys Leu
260 265 270
Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu
275 280 285
Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys
290 295 300
Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn
305 310 315 320
Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly
325 330 335
Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu
340 345 350
Lys Lys Pro Pro Lys Glu Phe Leu Arg Arg Phe Lys Ser Leu Leu Gln
355 360 365
Lys Met Ile His Gln His Leu Ser Ser Arg Thr His Gly Ser Glu Asp
370 375 380
Ser
385
<210> 38
<211> 461
<212> PRT
<213> Artificial Sequence
<400> 38
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro Leu
225 230 235 240
Gly Val Arg Gly Gly Gly Gly Ser Cys Pro Asp Leu Val Cys Tyr Thr
245 250 255
Asp Tyr Leu Gln Thr Val Ile Cys Ile Leu Glu Met Trp Asn Leu His
260 265 270
Pro Ser Thr Leu Thr Leu Thr Trp Gln Asp Gln Tyr Glu Glu Leu Lys
275 280 285
Asp Glu Ala Thr Ser Cys Ser Leu His Arg Ser Ala His Asn Ala Thr
290 295 300
His Ala Thr Tyr Thr Cys His Met Asp Val Phe His Phe Met Ala Asp
305 310 315 320
Asp Ile Phe Ser Val Asn Ile Thr Asp Gln Ser Gly Asn Tyr Ser Gln
325 330 335
Glu Cys Gly Ser Phe Leu Leu Ala Glu Ser Ile Lys Pro Ala Pro Pro
340 345 350
Phe Asn Val Thr Val Thr Phe Ser Gly Gln Tyr Asn Ile Ser Trp Arg
355 360 365
Ser Asp Tyr Glu Asp Pro Ala Phe Tyr Met Leu Lys Gly Lys Leu Gln
370 375 380
Tyr Glu Leu Gln Tyr Arg Asn Arg Gly Asp Pro Trp Ala Val Ser Pro
385 390 395 400
Arg Arg Lys Leu Ile Ser Val Asp Ser Arg Ser Val Ser Leu Leu Pro
405 410 415
Leu Glu Phe Arg Lys Asp Ser Ser Tyr Glu Leu Gln Val Arg Ala Gly
420 425 430
Pro Met Pro Gly Ser Ser Tyr Gln Gly Thr Trp Ser Glu Trp Ser Asp
435 440 445
Pro Val Ile Phe Gln Thr Gln Ser Glu Glu Leu Lys Glu
450 455 460
<210> 39
<211> 385
<212> PRT
<213> Artificial Sequence
<220>
<221> SITE
<222> (134)..(158)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<400> 39
Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys
145 150 155 160
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
165 170 175
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
180 185 190
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
195 200 205
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
210 215 220
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
225 230 235 240
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
245 250 255
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
260 265 270
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
370 375 380
Lys
385
<210> 40
<211> 385
<212> PRT
<213> Artificial Sequence
<220>
<221> SITE
<222> (134)..(158)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<400> 40
Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Lys Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Arg Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys
145 150 155 160
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
165 170 175
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
180 185 190
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
195 200 205
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
210 215 220
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
225 230 235 240
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
245 250 255
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
260 265 270
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
370 375 380
Lys
385
<210> 41
<211> 461
<212> PRT
<213> Artificial Sequence
<400> 41
Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys
1 5 10 15
Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp
20 25 30
Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu
35 40 45
His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met
50 55 60
Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr
65 70 75 80
Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala
85 90 95
Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser
100 105 110
Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe
115 120 125
Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg
130 135 140
Gly Asp Pro Trp Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp
145 150 155 160
Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser
165 170 175
Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln
180 185 190
Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser
195 200 205
Glu Glu Leu Lys Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
210 215 220
Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
225 230 235 240
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
245 250 255
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
260 265 270
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
275 280 285
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
290 295 300
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
305 310 315 320
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
325 330 335
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
340 345 350
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser
355 360 365
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys
370 375 380
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
385 390 395 400
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
405 410 415
Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
420 425 430
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
435 440 445
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 42
<211> 623
<212> PRT
<213> Artificial Sequence
<220>
<221> SITE
<222> (114)..(138)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<220>
<221> SITE
<222> (214)..(238)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<220>
<221> SITE
<222> (466)..(490)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<400> 42
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
1 5 10 15
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
20 25 30
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
35 40 45
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
50 55 60
Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
65 70 75 80
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
85 90 95
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
100 105 110
Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro
130 135 140
Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr
145 150 155 160
Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly
165 170 175
Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala
180 185 190
His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val
195 200 205
His Gln Arg Pro Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
210 215 220
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys
225 230 235 240
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Gly Gln Asp Arg His
485 490 495
Met Ile Arg Met Arg Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn
500 505 510
Tyr Val Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val
515 520 525
Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln
530 535 540
Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser
545 550 555 560
Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg
565 570 575
Gln Lys His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys
580 585 590
Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met
595 600 605
Ile His Gln His Leu Ser Ser Arg Thr His Gly Ser Glu Asp Ser
610 615 620
<210> 43
<211> 543
<212> PRT
<213> Artificial Sequence
<220>
<221> SITE
<222> (134)..(158)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<220>
<221> SITE
<222> (386)..(410)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<400> 43
Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ser Met Leu Thr Lys Lys Phe Ala Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Ala Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Thr Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys
145 150 155 160
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
165 170 175
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
180 185 190
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
195 200 205
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
210 215 220
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
225 230 235 240
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
245 250 255
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
260 265 270
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
370 375 380
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Gly Gln Asp Arg His
405 410 415
Met Ile Arg Met Arg Gln Leu Ile Asp Ile Val Asp Lys Leu Lys Asn
420 425 430
Tyr Val Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val
435 440 445
Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln
450 455 460
Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser
465 470 475 480
Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg
485 490 495
Gln Lys His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys
500 505 510
Pro Pro Lys Glu Phe Leu Arg Arg Phe Lys Ser Leu Leu Gln Lys Met
515 520 525
Ile His Gln His Leu Ser Ser Arg Thr His Gly Ser Glu Asp Ser
530 535 540
<210> 44
<211> 696
<212> PRT
<213> Artificial Sequence
<400> 44
Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala
1 5 10 15
Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser
20 25 30
Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys
35 40 45
Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu
50 55 60
Gly Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu
65 70 75 80
Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln
85 90 95
Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu
100 105 110
Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile
115 120 125
Ser Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg
130 135 140
Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu
145 150 155 160
Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr
165 170 175
Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr
180 185 190
Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala
195 200 205
Ala Leu Gly Lys Asp Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Asp Lys Thr His Thr
225 230 235 240
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
245 250 255
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
260 265 270
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
275 280 285
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
290 295 300
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
305 310 315 320
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
325 330 335
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
340 345 350
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro
355 360 365
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
370 375 380
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
385 390 395 400
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
405 410 415
Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
420 425 430
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
435 440 445
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Gly Gly
450 455 460
Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro Leu Gly Val Arg Gly Gly
465 470 475 480
Gly Gly Ser Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr
485 490 495
Val Ile Cys Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr
500 505 510
Leu Thr Trp Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser
515 520 525
Cys Ser Leu His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr
530 535 540
Cys His Met Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val
545 550 555 560
Asn Ile Thr Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe
565 570 575
Leu Leu Ala Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val
580 585 590
Thr Phe Ser Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp
595 600 605
Pro Ala Phe Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr
610 615 620
Arg Asn Arg Gly Asp Pro Trp Ala Val Ser Pro Arg Arg Lys Leu Ile
625 630 635 640
Ser Val Asp Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys
645 650 655
Asp Ser Ser Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser
660 665 670
Ser Tyr Gln Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln
675 680 685
Thr Gln Ser Glu Glu Leu Lys Glu
690 695
<210> 45
<211> 623
<212> PRT
<213> Artificial Sequence
<220>
<221> SITE
<222> (134)..(158)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<220>
<221> SITE
<222> (386)..(410)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<220>
<221> SITE
<222> (486)..(510)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<400> 45
Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys
145 150 155 160
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
165 170 175
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
180 185 190
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
195 200 205
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
210 215 220
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
225 230 235 240
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
245 250 255
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
260 265 270
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
370 375 380
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro
405 410 415
Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr
420 425 430
Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly
435 440 445
Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala
450 455 460
His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val
465 470 475 480
His Gln Arg Pro Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
485 490 495
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn Trp
500 505 510
Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile Gln Ser
515 520 525
Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His Pro Ser
530 535 540
Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln Val Ile
545 550 555 560
Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu Asn Leu
565 570 575
Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val Thr Glu
580 585 590
Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile Lys Glu
595 600 605
Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn Thr
610 615 620
<210> 46
<211> 543
<212> PRT
<213> Artificial Sequence
<220>
<221> SITE
<222> (134)..(158)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<220>
<221> SITE
<222> (386)..(410)
<223> /note="This region may encompass 0-5 'Gly Gly Gly Gly Ser'repeating units"
<400> 46
Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Lys Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Arg Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys
145 150 155 160
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
165 170 175
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
180 185 190
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
195 200 205
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
210 215 220
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
225 230 235 240
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
245 250 255
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
260 265 270
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
370 375 380
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Ser Ser Ser
405 410 415
Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln
420 425 430
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ser
435 440 445
Met Leu Thr Lys Lys Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys
450 455 460
His Leu Gln Cys Leu Glu Glu Ala Leu Lys Pro Leu Glu Glu Val Leu
465 470 475 480
Asn Leu Thr Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
485 490 495
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
500 505 510
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
515 520 525
Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr
530 535 540
<210> 47
<211> 696
<212> PRT
<213> Artificial Sequence
<400> 47
Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys
1 5 10 15
Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp
20 25 30
Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu
35 40 45
His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met
50 55 60
Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr
65 70 75 80
Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala
85 90 95
Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser
100 105 110
Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe
115 120 125
Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg
130 135 140
Gly Asp Pro Trp Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp
145 150 155 160
Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser
165 170 175
Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln
180 185 190
Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser
195 200 205
Glu Glu Leu Lys Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
210 215 220
Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
225 230 235 240
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
245 250 255
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
260 265 270
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
275 280 285
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
290 295 300
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
305 310 315 320
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
325 330 335
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
340 345 350
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser
355 360 365
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys
370 375 380
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
385 390 395 400
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
405 410 415
Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
420 425 430
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
435 440 445
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Gly Gly Gly
450 455 460
Gly Ser Gly Gly Gly Gly Ser Gly Pro Leu Gly Val Arg Gly Gly Gly
465 470 475 480
Gly Ser Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser
485 490 495
Arg Ala Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp
500 505 510
Thr Ser Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln
515 520 525
Thr Cys Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu
530 535 540
Ile Leu Gly Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val
545 550 555 560
Thr Leu Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala
565 570 575
Ile Gln Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile
580 585 590
Ser Leu Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp
595 600 605
Glu Ile Ser Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu
610 615 620
Ala Arg Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu
625 630 635 640
Thr Leu Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro
645 650 655
Asp Thr Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu
660 665 670
Phe Thr Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys
675 680 685
Pro Ala Ala Leu Gly Lys Asp Thr
690 695
<210> 48
<211> 588
<212> PRT
<213> Artificial Sequence
<400> 48
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gln Gly Gln Asp Arg His Met Ile Arg
450 455 460
Met Arg Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn
465 470 475 480
Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn
485 490 495
Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser
500 505 510
Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys
515 520 525
Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His
530 535 540
Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys
545 550 555 560
Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln
565 570 575
His Leu Ser Ser Arg Thr His Gly Ser Glu Asp Ser
580 585
<210> 49
<211> 674
<212> PRT
<213> Artificial Sequence
<400> 49
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Cys Pro Asp
450 455 460
Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys Ile Leu Glu
465 470 475 480
Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp Gln Asp Gln
485 490 495
Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu His Arg Ser
500 505 510
Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met Asp Val Phe
515 520 525
His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr Asp Gln Ser
530 535 540
Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala Glu Ser Ile
545 550 555 560
Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser Gly Gln Tyr
565 570 575
Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe Tyr Met Leu
580 585 590
Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg Gly Asp Pro
595 600 605
Trp Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp Ser Arg Ser
610 615 620
Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser Tyr Glu Leu
625 630 635 640
Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln Gly Thr Trp
645 650 655
Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser Glu Glu Leu
660 665 670
Lys Glu
<210> 50
<211> 214
<212> PRT
<213> Artificial Sequence
<400> 50
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 51
<211> 362
<212> PRT
<213> Artificial Sequence
<220>
<221> VARIANT
<222> (317)..(317)
<223> /replace="Ala"
<220>
<221> VARIANT
<222> (355)..(355)
<223> /replace="His" or "Trp" or "Ala"
<220>
<221> SITE
<222> (1)..(362)
<223> /note="Variant residues given in the sequence have no preferencewith respect to those in the annotations for variant positions"
<400> 51
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Gly Gly Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln
225 230 235 240
Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
245 250 255
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ser Met Leu Thr Ala Lys
260 265 270
Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
275 280 285
Glu Glu Ala Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
290 295 300
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val
305 310 315 320
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
325 330 335
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
340 345 350
Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr
355 360
<210> 52
<211> 214
<212> PRT
<213> Artificial Sequence
<400> 52
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 53
<211> 451
<212> PRT
<213> Artificial Sequence
<400> 53
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 54
<211> 213
<212> PRT
<213> Artificial Sequence
<400> 54
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 55
<211> 451
<212> PRT
<213> Artificial Sequence
<400> 55
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 56
<211> 218
<212> PRT
<213> Artificial Sequence
<400> 56
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Phe Asp
20 25 30
Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Val Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 57
<211> 446
<212> PRT
<213> Artificial Sequence
<400> 57
Gln Ile Gln Leu Gln Gln Ser Gly Pro Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Ile Thr Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Phe
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Asn Tyr Gly Asn Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 58
<211> 214
<212> PRT
<213> Artificial Sequence
<400> 58
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 59
<211> 449
<212> PRT
<213> Artificial Sequence
<400> 59
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 60
<211> 214
<212> PRT
<213> Artificial Sequence
<400> 60
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 61
<211> 385
<212> PRT
<213> Artificial Sequence
<400> 61
Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe Ser Leu
20 25 30
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr Cys Val
35 40 45
Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met
50 55 60
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
65 70 75 80
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
85 90 95
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
100 105 110
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
115 120 125
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
130 135 140
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
145 150 155 160
Thr Lys Val Asp Glu Arg Lys Cys Cys Val Glu Cys Pro Ala Gly Pro
165 170 175
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
180 185 190
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
195 200 205
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
210 215 220
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
225 230 235 240
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
245 250 255
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
260 265 270
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
370 375 380
Lys
385
<210> 62
<211> 219
<212> PRT
<213> Artificial Sequence
<400> 62
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Val Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Arg Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Asn
85 90 95
Leu Glu Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 63
<211> 444
<212> PRT
<213> Artificial Sequence
<400> 63
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Ser Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Asn Thr Leu Lys Asp Asp
20 25 30
His Val His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Gly Gly Arg Thr Arg Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Thr Thr Leu Thr Ala Asp Lys Pro Ser Ser Thr Val Asn
65 70 75 80
Met Leu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys
85 90 95
Thr Asn Leu Val Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 64
<211> 219
<212> PRT
<213> Artificial Sequence
<400> 64
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Ala Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Asn
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 65
<211> 445
<212> PRT
<213> Artificial Sequence
<400> 65
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Leu Asp Pro Lys Thr Gly Asp Thr Ala Tyr Ser Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Phe Tyr Ser Tyr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 66
<211> 220
<212> PRT
<213> Artificial Sequence
<400> 66
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 67
<211> 448
<212> PRT
<213> Artificial Sequence
<400> 67
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 68
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 68
Lys Ala Ser Gln Asp Val Ser Ile Ala Val Ala
1 5 10
<210> 69
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 69
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 70
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 70
Gln Gln His Tyr Ile Thr Pro Leu Thr
1 5
<210> 71
<211> 5
<212> PRT
<213> Artificial Sequence
<400> 71
Asn Tyr Gly Met Asn
1 5
<210> 72
<211> 17
<212> PRT
<213> Artificial Sequence
<400> 72
Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Thr Asp Asp Phe Lys
1 5 10 15
Gly
<210> 73
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 73
Gly Gly Phe Gly Ser Ser Tyr Trp Tyr Phe Asp Val
1 5 10
<210> 74
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 74
Ser Ala Ser Ser Ser Val Ser Tyr Met His
1 5 10
<210> 75
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 75
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 76
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 76
Gln Gln Trp Ser Gly Tyr Pro Leu Thr
1 5
<210> 77
<211> 5
<212> PRT
<213> Artificial Sequence
<400> 77
Gly Tyr Thr Met Asn
1 5
<210> 78
<211> 17
<212> PRT
<213> Artificial Sequence
<400> 78
Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe Arg
1 5 10 15
Gly
<210> 79
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 79
Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr
1 5 10
<210> 80
<211> 213
<212> PRT
<213> Artificial Sequence
<400> 80
Gln Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Gly Val Asn Phe Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Arg Leu Ile Phe
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 81
<211> 213
<212> PRT
<213> Artificial Sequence
<400> 81
Gln Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Gly Val Asn Phe Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Arg Leu Ile Phe
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 82
<211> 447
<212> PRT
<213> Artificial Sequence
<400> 82
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 83
<211> 113
<212> PRT
<213> Artificial Sequence
<400> 83
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 84
<211> 124
<212> PRT
<213> Artificial Sequence
<400> 84
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 85
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 85
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asn Pro Asn Asn Gly Val Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Met Ile Thr Asn Tyr Val Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Trp Thr Val Ser Ser
115 120
<210> 86
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 86
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Asn Gly Val Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Met Ile Thr Asn Tyr Val Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 87
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 87
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Ser Tyr Thr Ser Ser Arg Tyr Ala Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Phe Cys Gln Gln Asp Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 88
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 88
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Ser Arg Tyr Ala Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asp Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 89
<211> 214
<212> PRT
<213> Artificial Sequence
<400> 89
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 90
<211> 448
<212> PRT
<213> Artificial Sequence
<400> 90
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 91
<211> 440
<212> PRT
<213> Artificial Sequence
<400> 91
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 92
<211> 218
<212> PRT
<213> Artificial Sequence
<400> 92
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 93
<211> 447
<212> PRT
<213> Artificial Sequence
<400> 93
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
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210 215 220
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225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
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325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 94
<211> 375
<212> PRT
<213> Artificial Sequence
<400> 94
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
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Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
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Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
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Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
260 265 270
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
275 280 285
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
290 295 300
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
305 310 315 320
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
325 330 335
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
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Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
355 360 365
Thr His Gly Ser Glu Asp Ser
370 375
<210> 95
<211> 375
<212> PRT
<213> Artificial Sequence
<400> 95
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
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Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
245 250 255
Asp Ile Val Asp Lys Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
260 265 270
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
275 280 285
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
290 295 300
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
305 310 315 320
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
325 330 335
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Arg Arg
340 345 350
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
355 360 365
Thr His Gly Ser Glu Asp Ser
370 375
<210> 96
<211> 227
<212> PRT
<213> Artificial Sequence
<400> 96
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 97
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<221> SITE
<222> (1)..(20)
<223> /note="This sequence may encompass 1-4 'Gly Gly Gly Gly Ser'repeating units"
<400> 97
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
Claims (39)
1.一种前药,包括人IL-21激动剂多肽、掩蔽部分和载体部分,其中
掩蔽部分与人IL-21激动剂多肽结合,抑制人类IL-21激动剂多肽的一种生物活性,人IL-21激动剂多肽融合到载体部分,和
掩蔽部分通过可切割的的肽连接与人IL-21激动剂多肽或载体部分融合。
2.如权利要求1所述的前药,其中所述人IL-21激动剂多肽包含SEQ ID NO:1或与SEQID NO:1至少90%相同的氨基酸序列。
3.如权利要求2所述的前药,其中人IL-21激动剂多肽包含一个或多个选自D18、Q19、E109和K117(根据SEQ ID NO:1编号)位点上的突变。
4.如权利要求1所述的前药,其中IL-21激动剂多肽的氨基酸序列选自SEQ ID NO:2,3,4和5。
5.如权利要求1-4中任一项所述的前药,其中掩蔽部分包括人IL-21受体的细胞外结构域(ECD)或其功能类似物。
6.如权利要求5所述的前药,其中IL-21受体为IL-21Rα或IL-21Rγ。
7.如权利要求6所述的前药,其中IL-21受体ECD包括SEQ ID NO:6或7,或与SEQ ID NO:6或7至少90%相同的氨基酸序列。
8.如权利要求1-7中任一项所述的前药,还包括第二细胞因子部分。
9.如权利要求8所述的前药,其中第二细胞因子部分是
(i)人IL-2激动剂多肽包含SEQ ID NO:8或与SEQ ID NO:8至少90%相同的氨基酸序列;
(ii)人IL-7激动剂多肽;
(iii)人IL-9激动剂多肽;
(iv)人IL-15激动剂多肽包含SEQ ID NO:9或与SEQ ID NO:9至少90%相同的氨基酸序列;
(v)人IL-15激动剂多肽和一个人IL-15受体α-sushi结构域,或
(vi)一种包括SEQ ID NO:27的人CCL19多肽或与SEQ ID NO:27至少90%相同的氨基酸序列。
10.如权利要求8或9所述的前药,还包括第二个掩蔽部分,其结合第二个细胞因子部分,抑制一个第二个细胞因子的生物活性,其中第二个掩蔽部分通过可切割的肽连接与第二细胞因子或载体融合。
11.如权利要求10所述的前药,其中第二个掩蔽部分选自IL-2受体-β亚基ECD或其功能类似物、IL-7受体ECD或其功能类似物和IL-9受体ECD或其功能类似物。
12.前述权利要求中任一项前药,其中人IL-21激动剂多肽和/或第二细胞因子部分通过不可切割的肽连接与载体部分融合。
13.如权利要求12所述的前药,其中不可切割的肽连接包含选自SEQ IDNOs:29-33的氨基酸序列。
14.前述权利要求中任一项前药,其中可切割肽连接包含尿激酶型纤溶酶原激活物(uPA)、基质金属肽酶(MMP)2或MMP9的底物序列。
15.如权利要求14所述的前药,其中可切割肽连接包括(i)uPA和MMP2的底物序列,(ii)uPA和MMP9的底物序列,或(iii)uPA、MMP2和MMP9的底物序列。
16.如权利要求14所述的前药,其中可切割肽连接包含选自SEQ ID NOs:11-26的氨基酸序列。
17.前述权利要求中任一项前药,其中可切割肽连接可被位于肿瘤位点或其周围环境的一个或多个蛋白酶裂解,裂解导致前药在肿瘤位点或周围环境被激活。
18.前述权利要求中任一项前药,其中载体部分为PEG分子、白蛋白、白蛋白片段、抗体Fc结构域或抗体或其抗原结合片段。
19.如权利要求18所述的前药,其中所述载体部分是抗体Fc结构域或抗体,包含L234A和L235A突变(“LALA”)(EU编号)。
20.如权利要求18或19所述的前药,其中载体部分是一个抗体Fc结构域或一个包含球孔突变的抗体,其中
人IL-21激动剂多肽及其掩蔽部分被融合到抗体Fc结构域的不同多肽链或抗体的不同重链上,以及
第二个细胞因子部分和第二个掩蔽部分也被选择性地融合到抗体Fc结构域的不同多肽链或抗体的不同重链上。
21.如权利要求20所述的前药,其中人IL-21激动剂多肽及其掩蔽部分融合到Fc结构域的两个不同多肽链的C-末端或抗体的两个不同重链的C-末端。
22.如权利要求20所述的前药,其中人IL-21激动剂多肽及其掩蔽部分融合到Fc结构域的两个不同多肽链的N-末端或抗体的两个不同重链的N-末端。
23.如权利要求21或22所述的前药,其中第二个细胞因子部分和第二个屏蔽部分融合至Fc域两条不同的多肽链的与人IL-21激动剂多肽及其掩蔽部分相反的末端,或者抗体的两条不同的重链的与人IL-21激动剂多肽及其掩蔽部分相反的末端相反的末端。
24.如权利要求20-23中任一项所述的前药,其中所述knobs-into-holes突变包含Fc结构域上多肽链或者是抗体的重链的T366Y“knob”突变,以及Fc结构域上另一个多肽或者是抗体的另一重链的Y407T“hole”突变(EU编号)。
25.如权利要求20-23中任一项所述的前药,其中所述knobs-into-holes突变包括“knob chain”的CH3结构域中Y349C和/或T366W的突变,以及“hole chain”的CH3结构域中E356C,T366S,L368A和/或Y407V的突变(EU编号)。
26.如权利要求18-25中任一项所述的前药,其中所述载体部分是一个抗体或一个抗原结合片段,其特异性结合一种或多种抗原选自鸟苷酸环化酶C(GCC),碳水化合物抗原19-9(CA19-9),糖蛋白A33(gpA33),粘蛋白1(MUC1),癌胚抗原(CEA),胰岛素样生长因子1受体(IGF1-R),人表皮生长因子受体2(HER2),人表皮生长因子受体3(HER3),δ样蛋白3(DLL3),δ样蛋白4(DLL4),表皮生长因子受体(EGFR),糖蛋白-3(GPC3),c-MET,血管内皮生长因子受体1(VEGFR1),血管内皮生长因子受体2(VEGFR2),Nectin-4,Liv-1,糖蛋白NMB(GPNMB),前列腺特异性膜抗原(PSMA),Trop-2,碳酸酐酶IX(CA9),内皮素B受体(ETBR),前列腺1的六种跨膜上皮抗原(STEAP1),叶酸受体α(FR-α),SLIT和NTRK样蛋白6(SLITRK6),碳酸酐酶VI(CA6),外核苷酸焦磷酸酶/磷酸二酯酶家族成员3(ENPP3),间皮素,滋养层糖蛋白(TPBG),CD19,CD20,CD22,CD33,CD40,CD56,CD66e,CD70,CD74,CD79b,CD98,CD123,CD138,CD352,CD47,信号调节蛋白α(SIRPα),PD1,Claudin 18.2,Claudin 6、5T4,BCMA,PD-L1,PD-1,成纤维细胞活化蛋白α(FAPalpha),黑素瘤相关软骨素硫酸蛋白多糖(MCSP)和EPCAM。
27.如权利要求20所述的前药,其中所述前药包括两条多肽链,其氨基酸序列分别包含
SEQ ID NOs:36和38,
SEQ ID NOs:37和38,
SEQ ID NOs:39和41,
SEQ ID NOs:40和41,
SEQ ID NOs:42和44,
SEQ ID NOs:43和44,
SEQ ID NOs:45和47,或
SEQ ID NOs:46和47。
28.如权利要求18所述的前药,包括两个重链多肽,其氨基酸序列分别为SEQ IDNOs:48和49,轻链包括SEQ ID NO:50或51。
29.如权利要求18所述的前药,其中载体部分是抗体或其抗原结合片段,与FAPα或5T4相结合;此外,该前药还可选择性地包括肿瘤坏死因子(TNF)配体家族成员或4-1BB配体或其片段的两个或三个外域。
30.一种药物成分,其包含权利要求1-29中任一项前药,以及药学上可接受的赋形剂。
31.编码如权利要求1-29中任一项权利要求所述前药的一种或多种多核苷酸。
32.包含如权利要求31所述的多核苷酸的一个或多个表达载体。
33.包含如权利要求32所述载体的宿主细胞。
34.如权利要求33所述的宿主细胞,其中编码uPA、MMP2和/或MMP9的基因在宿主细胞中被敲除。
35.一种制备权利要求1-29中任一项前药的方法,包括
在允许前药表达的条件下,培养权利要求33或34的宿主细胞,其中所述宿主细胞是哺乳动物细胞,以及
分离前药。
36.一种于有需要的患者中治疗癌症或感染性疾病或刺激免疫系统的方法,其包括向所述患者施用治疗有效量的权利要求30的药物成分。
37.权利要求1-29中任一项所述的前药用于对有需要的患者治疗癌症或传染性疾病或刺激免疫系统。
38.权利要求1-29中任一项所述的前药用于制备对有需要的患者治疗癌症或传染性疾病或刺激免疫系统的药物。
39.如权利要求36所述的方法,用于权利要求37或用于权利要求38的前药,其中所述患者患有HIV、HBV、HCV或HPV感染,或选自乳腺癌、肺癌、胰腺癌、食道癌、甲状腺髓样癌、卵巢癌、子宫癌、前列腺癌、睾丸癌、结肠直肠癌和胃癌的癌症。
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WO2023138573A1 (zh) * | 2022-01-21 | 2023-07-27 | 广东菲鹏制药股份有限公司 | 白细胞介素21及其受体复合物 |
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