CN110914307A - 改进的双特异性多肽分子 - Google Patents
改进的双特异性多肽分子 Download PDFInfo
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Abstract
本发明涉及一种双特异性多肽分子,包含第一多肽链和第二多肽链,其提供源自特定于主要组织相容性复合体(MHC)相关肽表位的T细胞受体(TCR)的结合区和源自透过特异性结合所述细胞表面抗原能够募集人免疫效应细胞的抗体的结合区域,以及制备双特异性多肽分子的方法及其用途。
Description
本发明涉及一种双特异性多肽分子,包含第一多肽链和第二多肽链,其提供源自特定于主要组织相容性复合体(MHC)相关肽表位的T细胞受体(TCR)的结合区和源自透过特异性结合所述细胞表面抗原能够募集人免疫效应细胞的抗体的结合区域,以及制备双特异性多肽分子的方法及其用途。
发明背景
随着分子克隆技术的发展和对抗体工程的深入理解,有多种双特异性抗体形式(“双特异性”)可供选择,以达到最佳的生物活性和临床目的。在癌症治疗中,已开发出了双特异性抗体,其目的是透过特定于肿瘤细胞上表位元的第一结合结构域和特定于免疫效应细胞上表位元的第二结合结构域将免疫效应细胞的活性重新定向至肿瘤部位。免疫效应细胞重新靶向作用的双特异性抗体已经以不同的形式开发,包括无可结晶片段(FC)区的形式以及具有对称或不对称设计的IgG衍生形式。除了将效应细胞重新靶向作用于癌症部位外,还确立了双特异性抗体的新应用。可开发能够同时抑制两个相关信号分子的双特异性物质以克服固有或获得性耐药并且是更有效的血管生成抑制剂。此外,双特异性抗体可用作治疗各种疾病(如:癌症)有前景的免疫刺激剂。双特异性抗体也可以透过模拟因子VIII的功能用于治疗A型血友病。双特异性抗体在骨病和感染以及中枢神经系统疾病中也具有广泛的应用前景(综述见Yang F.et al.Bispecific Antibodies as a Development Platformfor New Concepts and Treatment Strategies.Int J Mol Sci.2016 Dec 28;18(1))。
T细胞表达能够诱导抗原特异性免疫应答的T细胞受体(TCR)复合体。抗原肽/主要组织相容性复合体(MHC)I类在靶细胞上与TCR结合诱导免疫突触形成并导致透过CD3共受体(TCR信号传导复合体的组分)的信号传导。该信号传导级联透过T细胞向靶细胞释放和转移颗粒酶和穿孔素,引导对抗原表达细胞的T细胞介导性杀伤。
历史上,抗体的单链连接可变结构域的发现和产生(scFv,Bird et al.1988一文的描述)作为双特异性抗体开发的主要驱动因素。这一概念最终导致BiTE分子的产生及其临床验证,作为治疗白血病的有效药物(Baeuerle,P.A.;Reinhardt,C.Bispecific T-cellengaging antibodies for cancer therapy.Cancer Res.2009,69,4941–4944)。在癌症中,与CD3ε亚基和肿瘤细胞上的表面抗原共同结合的双特异性抗体触发T细胞介导的肿瘤细胞杀伤,同时避免了TCR和MHC I类在含抗原复合体中直接相互作用的需要。这扩展了能够识别肿瘤并充当效应细胞的T细胞库(Baeuerle,P.A.;Reinhardt,C.Bispecific T-cellengaging antibodies for cancer therapy.Cancer Res.2009,69,4941–4944)。
Stieglmaier J.等人(在:Utilizing the BiTE(bispecific T-cell engager)platform for immunotherapy of cancer.Expert Opin Biol Ther.2015;15(8):1093-9一文中)描述了目前正在研究的基于T细胞的癌症免疫治疗的各种方法,其中这些是(双特异性T细胞衔接蛋白)抗体构建体,具有独特的设计和作用机制。它们透过基因连接到单个多肽链上构建肿瘤相关表面抗原和T细胞受体相关分子CD3的单克隆抗体的最小结合结构域。靶细胞抗原和CD3的同时衔接可活化多克隆细胞毒性T细胞,导致靶细胞裂解。Blinatumomab是一种靶向作用于CD19的目前正在广泛的B细胞恶性肿瘤中进行研究,最近在美国被FDA批准用于治疗费城染色体阴性复发/难治性B-急性淋巴细胞白血病,商品名为BLINCYTOTM。平台是临床上最先进的T细胞免疫治疗选择之一。
但是,已发现小型双特异性分子(如)的缺点是产量低、纯化工艺困难、有聚集倾向以及血清半衰期非常短。为了克服这类分子的固有局限性,基于人IgG的各种双特异性形式的开发开始于二十多年前设计的重组双特异性原型免疫球蛋白(Ig)-G-样抗体的概念,当时Morrison及其同事将柔性肽接头融合至IgG重链的C末端,然后融合至具有不同结合特异性的单链可变结构域(Coloma,M.J.and Morrison,S.L.(1997)Design andproduction of novel tetravalent bispecific antibodies.Nat.Biotechnol.15,159–163)。这些分子可与“正常”抗体区分开来,因为它们具有双重功能。技术障碍最初阻碍了进一步开发,导致双特异性抗体(bsAb)仍然是在学术和生物技术环境中研发的主题。但是,快速发展的技术使得重组蛋白衍生物的工程、生产和开发成为可能,再加上制药行业重新关注,启动了bsAb研究领域。如今,许多不同的bsAb形式适合开发治疗性蛋白质(综述参见Gramer,mAbs.2013;5(6):962-973,Weidle,Cancer Genomics Proteomics.2013Nov-Dec;10(6):239-50,Brinkmann,MAbs.2017Feb/Mar;9(2):182-212.)。总之,纳入由CH2和CH3结构域组成的Fc-(可结晶片段)部分导致生产率的提高、纯化工艺的简化和稳定性的增强。此外,由于i)尺寸的增加和ii)Fc部分与人Fc受体FcRn相互作用,延长了此类基于IgG的药物的血清半衰期。
基于IgG的双特异性形式的开发由于工程化突变的出现和掺入得以进一步推动,促进两个不同CH3结构域的异二聚化,从而连接两个不同的多肽链。基本概念由RIDGWAY JB等人(在:'Knobs-into-holes'engineering of antibody CH3 domains for heavy chainheterodimerization.Protein Eng.1996Jul;9(7):617-21一文)介绍,他们将“杵臼”(Knobs-into-holes)方法进行了公开,作为抗体重链同型二聚体异二聚化工程化的一种新颖和有效的设计策略。在该方法中,首先透过用CD4-IgG免疫黏附素——T366Y的CH3结构域中的较大氨基酸替换小氨基酸来获得“杵”变体。将杵设计为插入人源化抗CD3抗体的CH3结构域的“臼”中,该抗体透过用较小的残基Y407T明智地替换大残基而产生。在这两种不同的重链与抗CD3轻链共表达后,抗CD3/CD4-IgG杂合体代表高达92%的蛋白A纯化的蛋白质库。相反,在共表达后仅回收达57%的抗CD3/CD4-IgG杂合体,其中重链含有野生型CH3结构域。因此,杵臼(Knobs-into-holes)工程有助于构建抗体/免疫黏附素杂合体和可能的其他含Fc的双功能治疗剂,包括双特异性免疫黏附素和双特异性抗体。Atwell et al,1997,J MolBiol(Stable heterodimers from remodeling the domain interface of a homodimerusing a phage display library)公开了Fc结构域的CH3结构域中杵臼突变(杵:T366W/臼:T366S+L368A+Y407V)用于改善异二聚化。这一概念透过额外引入半胱氨酸残基以在异二聚体CH3结构域之间形成稳定的二硫键而得到了进一步的改善,如Merchant etal.1998,Nature Biotechnology(An Efficient Route to Human Bispecific IgG)所述。
产生异二聚体分子的其他概念公开如下:Muda et al.2011,PEDS(Therapeuticassessment of SEED:a new engineered antibody platform designed to generatemono-and bispecific antibodies);Gunasekaran et al.2010,J Biol Chem(Enhancingantibody Fc heterodimer formation through electrostatic steering effects:applications to bispecific molecules and monovalent IgG);Moore et al.2011,MAbs(A novel bispecific antibody format enables simultaneous bivalent andmonovalent co-engagement of distinct target antigens);Von Kreudenstein etal.2013,MAbs(Improving biophysical properties of a bispecific antibodyscaffold to aid developability:quality by molecular design)。Ha et al.2016,Front Immunol(Immunoglobulin Fc Heterodimer Platform Technology:From Designto Application in Therapeutic Antibodies and Proteins)和Liu et al.2017,FrontImmunol(Fc Engineering for Developing Therapeutic Bispecific Antibodies andNovel scaffolds)总结和评述了这些概念。
透过将由铰链、CH2和CH3结构域或其部分组成的Fc部分纳入到双特异性分子中,出现了由Fc:Fc-γ受体(FcgR)相互作用诱导的这些分子的非特异性固定的问题。FcgR由不同的细胞表面分子(FcgRI、FcgRIIa、FcgRIIb、FcgRIII)组成,其与IgG分子的Fc部分显示的表位元具有不同的亲和力。由于i)对分子的药代动力学的影响和ii)对免疫效应细胞的脱靶启动,这种非特异性(即,不是由双特异性分子的两个结合结构域中的任一个诱导)固定是不利的,因此,已确定消融FcgR结合性的各种Fc变体和突变。
Morgan et al.1995,Immunology(The N-terminal end of the CH2 domain ofchimeric human IgG1 anti-HLA-DR is necessary for C1q,FcyRI and FcyRIIIbinding)公开了人IgG1的残基233-236与来自人IgG2的相应序列交换,导致消除FcgRI结合、消除C1q结合并减少FcgRIII结合。
EP1075496公开了具有Fc区变异的抗体和其他含Fc的分子(233P、234V、235A和在236位置无残基或G以及327G、330S和331S),其中重组抗体能够与靶分子结合而不引发显著的补体依赖性裂解或细胞介导的靶标破坏。
使用双亲和重新靶向(DART)分子以实现,例如:B细胞淋巴瘤的最佳重新定向的T细胞杀伤。Moore等人描述了最初的DART技术(在:Application of dual affinityretargeting molecules to achieve optimal redirected T-cell killing of B-celllymphoma,Blood.2011Apr 28;117(17):4542-51一文)。与携带相同CD19和CD3抗体Fv序列的单链双特异性抗体的比较显示DART分子在引导B细胞裂解方面更有效。DART技术的进一步发展由DART-Fc分子实现,如Root et al,2016 antibodies(Development of PF-06671008,a Highly Potent Anti-P-cadherin/Anti-CD3 Bispecific DART Moleculewith Extended Half-Life for the Treatment of Cancer)一文所述。该分子结合了DART的高效力以及其他积极特征,延长了基于Fc的分子的血清半衰期。
αβTCR(TCR)识别MHC呈递的抗原肽,并负责T细胞的特异性。TCR的α链和β链都具有可变(V)和恒定结构域。V结构域参与结合抗原肽,恒定结构域穿过T细胞膜。根据结合于肽-MHC复合体的TCR的晶体结构分析,Vα和Vβ链的互补决定区(CDR)3优选与肽相互作用,而CDR1和CDR 2与MHC相互作用。但是,也有透过CDR 1识别肽和透过CDR 3识别MHC的描述(Piepenbrink et al,The basis for limited specificity and MHC restriction in aT cell receptor interface,Nat Commun,2013;4,1948)。TCRαβ异二聚体与CD3蛋白、CD4或CD8以及其他黏附和信号转导蛋白密切相关。抗原肽与TCR V区的结合经CD3和CD4或CD8细胞质蛋白透过TCR恒定结构域的信号转导触发T细胞活化。
与用于工程、可溶性蛋白质表达和具有临床潜力的全长TCR形式相比,单链TCR(scTCR)具有显著优势。从可溶性蛋白质表达(即,制造)的角度来看,scTCR作为单一多肽生产,避免了将每个TCR链作为单独多肽生产的要求,并且允许生产更大量的与其肽MHC配体结合的正确组装的scTCR。该特征可以允许临床使用所需的产量。最后,从临床角度来看,仅由V区(scTv)组成的scTCR可以设计为类似toscFv片段的治疗剂或诊断试剂。
US 2006-0166875公开了单链T细胞受体(scTCR),其包含由与TCRα链恒定区细胞外序列的N末端融合的TCRα链可变区序列构成的α区段、由与TCRβ链恒定区细胞外序列的N末端融合的TCRβ链构成的β区段、将α区段的C末端与β区段的N末端连接的连接序列(反之亦然)、透过二硫键连接的α和β区段的恒定区细胞外序列,连接序列的长度和二硫键的位置使得α和β区段的可变区序列基本上相互定向为天然α/βT细胞受体。还公开了两种或更多种此类scTCR的复合体,以及scTCR在治疗和各种筛选应用中的用途。与US 2006-0166875中描述的scTCR相反,US2012-0252742公开了不含恒定结构域的可溶性人单链TCR,其仅由TCR的可变片段(scTv)组成,可用于多种目的,包括癌症、病毒性疾病和自身免疫性疾病的治疗。
McCormack E等人(在:Bi-specific TCR-anti CD3 redirected T-celltargeting of NY-ESO-1-and LAGE-1-positive tumors.Cancer ImmunolImmunother.2013Apr;62(4):773-85一文中)公开了NY-ESO-1和LAGE-1为癌症睾丸抗原,具有理想的肿瘤免疫治疗特征,结合了许多癌症类型的上调,在正常组织中具有高度限制性表达并共用共同的HLA-A*0201表位157-165。他们提供资料描述了双重功能ImmTAC的特异性和抗肿瘤活性,其包含对融合至抗-CD3 scFv的NY-ESO-1157-165具有特异性的可溶性高亲和力T细胞受体(TCR)。该试剂ImmTAC-NYE显示可杀灭HLA-A2、抗原阳性肿瘤细胞系和新分离的HLA-A2和LAGE-1阳性NSCLC细胞。采用体内光学成像的结果显示,萤光标记的高亲和力NYESO特异性TCR体内靶向作用于异种移植小鼠中的HLA-A2、NY-ESO-1157-165阳性肿瘤。在肿瘤模型中测试了体内ImTAC-NYE的疗效,其中人淋巴细胞稳定地共移植到携带肿瘤异种移植物的免疫缺陷NSG小鼠中;使用GFP萤光读数在肿瘤预防模型和建立的肿瘤模型中观察到了疗效。使用定量RT-PCR分析了NY-ESO-1和LAGE-1抗原在15种正常组织、5种癌细胞系、10种NSCLC和10种卵巢癌样本中的表达。总体而言,LAGE-1RNA在肿瘤样本中以比NY-ESO-1更高的频率和更高的水平表达。ImmTAC包含衍生自共价连接至TCRα或β链C-或N-末端的抗-CD3抗体UCHT-1的单链Fv。
EP1868650涉及双抗体分子及其在治疗多种疾病和病症中的用途,包括免疫病症、传染病、中毒和癌症。双抗体分子包含两条多肽链,其结合形成至少两个表位结合位点,其可识别相同或不同抗原上的相同或不同表位。另外,抗原可能来自相同或不同的分子。双抗体分子的各个多肽链可透过非肽键共价键共价结合,例如但不限于位于每条多肽链内的半胱氨酸残基的二硫键合。在特定实施方案中,双抗体分子还包含Fc区,其在本文中公开,因为其允许将抗体样特性(例如,长半衰期)设计到分子中。EP1868650要求存在免疫球蛋白的轻链或重链可变结构域的结合区,并广泛讨论了功能性Fc受体结合物。
WO 2016/184592 A1公开了双特异性分子,其中一种特异性由TCR提供,另一种特异性由针对淋巴细胞表面上抗原或表位的抗体提供,但没有公开TCR元素的特定排列以及本文公开的抗体可变区。
EP2258720A1涉及功能性T细胞受体(TCR)融合蛋白(TFP),其识别并结合至少一种MHC呈递的表位,并含有至少一种识别和结合抗原的氨基酸序列。
本发明的一个目的是提出能够靶向作用于肽-MHC复合体的改进双特异性分子,其可以容易地生产、显示出高稳定性并且当与各抗原表位结合时还提供高效力。在研究以下说明及其优选实施方案以及各实施例时,本发明的其他目的和优点将变得显而易见。
在本发明的第一方面,透过提出选自包含第一多肽链和第二多肽链的分子组的双特异性多肽分子来解决上述目的,其中:
第一多肽链包含与人免疫效应细胞的细胞表面抗原特异性结合的抗体的可变结构域(VD1)的第一结合区,和
与MHC相关肽表位特异性结合的TCR的可变结构域(VR1)的第一结合区,和连接所述结构域的第一接头(LINK1);
第二多肽链包含与MHC相关肽表位特异性结合的TCR的可变结构域(VR2)的第二结合区,和
与人免疫效应细胞的细胞表面抗原特异性结合的抗体的可变结构域(VD2)的第二结合区,和
连接所述结构域的第二接头(LINK2);
其中所述第一结合区(VD1)和所述第二结合区(VD2)结合形成结合细胞表面分子表位的第一结合位点(VD1)(VD2);
所述第一结合区(VR1)和所述第二结合区(VR2)结合形成结合所述MHC相关肽表位的第二结合位点(VR1)(VR2);其中所述两条多肽链与人IgG铰链结构域和/或人IgG Fc结构域或其二聚化部分融合;和
其中所述两条多肽链透过所述铰链结构域和/或Fc结构域之间的共价键和/或非共价键连接;和
其中所述双特异性多肽分子能够同时结合细胞表面分子和MHC相关肽表位,和双特异性多肽分子,其中多肽链中结合区的顺序选自VD1-VR1、VD1-VR2、VD2-VR1、VD2-VR2、VR1-VD1、VR1-VD2、VR2-VD1、VR2-VD2,其中结构域透过LINK1或LINK2连接。
优选的是包含第一多肽链和第二多肽链的双特异性多肽分子,其中:第一多肽链包含源自透过特异性结合所述细胞表面抗原能够募集人免疫效应细胞的抗体的可变结构域的第一结合区,和源自与MHC相关肽表位特异性结合的TCR的可变结构域(VR1)的第一结合区,和连接两个结构域的第一接头部分(LINK1);第二多肽链包含源自与MHC相关肽表位特异性结合的TCR的可变结构域(VR2)的第二结合区,和源自透过特异性结合所述细胞表面抗原能够募集人免疫效应细胞的抗体的可变结构域(VD2)的第二结合区,和连接两个结构域的第二接头部分(LINK2);其中所述第一结合区(VD1)和所述第二结合区(VD2)结合形成结合细胞表面分子表位的第一结合位点(VD1)(VD2);所述第一结合区(VR1)和所述第二结合区(VR2)结合形成结合所述MHC相关肽表位的第二结合位点(VR1)(VR2);中至少一条所述多肽链在其c-末端与衍生自人IgG的铰链区、CH2和/或CH3-结构域或其部分连接;和其中所述双特异性多肽分子能够同时结合免疫效应细胞抗原和MHC相关肽表位。
优选地,根据本发明所述的双特异性多肽分子以高特异性与免疫效应细胞抗原和作为肽-MHC复合体呈递的特异性抗原表位结合,例如,结合亲和力(KD)为约100nM或更低、约30nM或更低、约10nM或更低、约3nM或更低、约1nM或更低,透过实施例6中描述的生物层干涉测量法测量或透过流式细胞术测定。
根据本发明所述的本发明双特异性多肽分子在此透过双特异性多肽分子举例说明,其包含含有SEQ ID No.16的第一多肽链和含有SEQ ID No.17的第二多肽链。
在本发明的第二方面,透过提出编码本文公开的第一多肽链和/或第二多肽链的核酸,或包含这种核酸的表达载体,解决了上述目的。
在本发明的第三方面,透过提出包含本文定义的载体的宿主细胞解决上述目的。
在本发明的第四方面,透过提出一种产生根据本发明所述的双特异性多肽分子的方法解决上述目的,该方法包括适当表达包含宿主细胞中所公开核酸的所述表达载体以及适当纯化来自细胞和/或其培养基的分子。
在本发明的第五方面,透过提出药物组合物解决上述目的,所述药物组合物包含根据本发明所述的双特异性多肽分子、根据本发明所述的核酸或表达载体或根据本发明所述的细胞以及一种或多种药用载体或赋形剂。
在本发明的第六方面,本发明涉及根据本发明所述的双特异性多肽分子、根据本发明所述的核酸或表达载体、根据本发明所述的细胞或根据本发明所述的药物组合物用于药物中。
在本发明的第七方面,本发明涉及根据本发明所述的双特异性多肽分子、根据本发明所述的核酸或表达载体、根据本发明所述的细胞或根据本发明所述的药物组合物用于治疗本文公开的疾病或病症,特别是癌症和传染病。
在本发明的第八方面,本发明涉及治疗疾病或病症的方法,包括给予治疗有效量的根据本发明所述的双特异性多肽分子、根据本发明所述的核酸或表达载体、根据本发明所述的细胞或根据本发明所述的药物组合物。
在本发明的第九方面,本发明涉及在患者或受试者中引发免疫应答的方法,包括给予治疗有效量的根据本发明所述的双特异性多肽分子或根据本发明所述的药物组合物。
在第十方面,本发明涉及杀灭患者或受试者靶细胞的方法,包括向患者施用有效量的根据本发明所述的双特异性多肽分子。
如上所述,本发明提出了新的和改进的双特异性多肽分子。分子通常包含第一多肽链和第二多肽链,其中所述链共同提供对免疫效应细胞表面抗原表位具有特异性的抗体的可变结构域,以及对MHC相关肽表位(例如:癌症表位或因感染而呈递表位,如:HIV等病毒感染)具有特异性的TCR的可变结构域。抗体和TCR衍生可变结构域透过位于两条多肽链上的Fc部分或其所属部分之间形成的共价和非共价键来稳定。然后,双特异性多肽分子能够同时结合细胞受体和MHC相关肽表位。
在本发明的背景中,可变结构域(VD1)和(VD2)衍生自能够透过特异性结合所述效应细胞的表面抗原而募集人免疫效应细胞的抗体。在一具体实施方案中,所述抗体与人T细胞的TCR-CD3复合体的表位特异性结合,包括肽链TCRα、TCRβ、CD3γ、CD3δ、CD3ε和CD3ζ。
根据本发明所述的双特异性多肽分子包含第一多肽和第二多肽链,其透过特异性结合所述细胞的表面抗原分别提供衍生自能够募集人免疫效应细胞的抗体的可变结构域的第一(VD1)和第二(VD2)结合区。第一结合区(VD1)和所述第二结合区(VD2)结合形成结合免疫效应细胞表面抗原表位的第一结合位点(VD1)(VD2)。此外,多肽分子的第一和第二多肽链分别包含分别来自对MHC相关肽表位具有特异性的TCR的可变结构域的第一(VR1)和第二(VR2)结合区。所述第一结合区(VR1)和所述第二结合区(VR2)结合形成结合所述MHC相关肽表位的第二结合位点(VR1)(VR2)。在根据本发明所述的双特异性多肽分子的一项实施方案中,第一多肽链中的区域的顺序/方向选自VD1-LINK1-VR1和VR1-LINK1-VD1;在另一实施方案中,第二多肽链中的区域的顺序/方向选自VD2-LINK2-VR2和VR2-LINK-VD2,即,结合位点的排列可以重新排列成“左”或“右”分子(参见,例如,图5)。此外,可以切换TCR相关部分的α链和β链的构型。
在本发明的背景中,根据本发明所述的双亲和性多肽分子的实例为呈递为肽MHC复合体时结合SLYNTVATL肽(SEQ ID No.7)的构建体。然而,本发明的概念显然不限于该特定肽,并且基本上包括在有MHC分子情况下呈递的任何疾病或病症相关表位。此呈递可能与MHC I或II类相关。主要组织相容性复合体I类(MHC-I)分子存在于所有有核细胞的表面上,并显示大量肽表位元用于CD8+T细胞库的监测。CD8+T细胞应答对于控制和清除病毒感染以及消除转化和致瘤细胞是必需的。待识别的优选肽表位元的实例可在各文献中找到,尤其包括WO 2016/170139表1至5中、WO 2016/102272表1至5、WO 2016/156202表1或2、WO 2016/146751表1至4、WO 2011/113819表2、WO 2016/156230表1至4b、WO 2016/177784表1至4b、WO2016/202963表1至4、WO 2016/207164表1和表2、WO 2017/001491表1至4、WO 2017/005733表1至4、WO 2017/021527表1至8、WO 2017/036936表1至3、用于癌症治疗的PCT/EP2016/073416表1至4、美国专利公开号2016-0187351、美国专利公开号2017-0165335、美国专利公开号2017-0035807、美国专利公开号2016-0280759、美国专利公开号2016-0287687、美国专利公开号2016-0346371、美国专利公开号2016-0368965、美国专利公开号2017-0022251、美国专利公开号2017-0002055、美国专利公开号2017-0029486、美国专利公开号2017-0037089、美国专利公开号2017-0136108、美国专利公开号2017-0101473、美国专利公开号2017-0096461、美国专利公开号2017-0165337、美国公开2017-0189505、美国专利公开号2017-0173132、美国专利公开号2017-0296640、美国专利公开号2017-0253633和美国专利公开号2017-0260249中所公开的肽,这些申请中每一个申请的内容透过完整引用并入本文。另一方面,根据本发明所述的双亲和性多肽分子可识别由上述专利申请中所述的任何肽组成的肽。
一方面,根据本发明所述的双亲和性多肽分子结合或能够特异性地被识别/结合一种或多种肽,总长度为8至100个氨基酸、8至30个氨基酸、8至16个氨基酸,优选为8至14个氨基酸,即8、9、10、11、12、13、14个氨基酸,在拉长II类结合肽的情况下,长度也可以是15、16、17、18、19、20、21或22个氨基酸。另一个方面,根据本发明所述的双亲和性多肽分子结合或能够特异性地识别/结合一种或多种肽,总长度为8至12个氨基酸、8至10个氨基酸、9至15个氨基酸、9至14个氨基酸、9至13个氨基酸、9至12个氨基酸、9至11个氨基酸;10至15个氨基酸、10至14个氨基酸、10至13个氨基酸或10至12个氨基酸。
其他合适的表位元可以从资料库中确定,例如免疫表位元资料库(www.iedb.org上提供)。
术语“人免疫效应细胞”是指人免疫系统中天然细胞库中的细胞,其在被启动时能够引起靶细胞活力的变化。术语“靶细胞活力”在本发明的范围内可能指靶细胞存活、增殖和/或与其他细胞相互作用的能力。这种相互作用可以是直接的(例如:当靶细胞与另一个细胞接触时)或间接的(例如:当靶细胞分泌对另一个远端细胞功能有影响的物质时)。靶细胞可以是人天然或外来细胞。如果是人天然细胞,有利的情况是,靶细胞是经历转化成为恶性细胞的细胞。天然细胞还可以是病理学修饰的天然细胞,例如:被病毒、疟原虫或细菌等生物体感染的天然细胞。如果是人外来细胞,有利的情况是,靶细胞是入侵病原体,例如:入侵细菌或疟原虫。
优选的是根据本发明所述的双特异性多肽分子,其中所述第一和第二多肽链还包含至少一个铰链结构域和/或Fc结构域或其部分。在抗体中,“铰链”或“铰链区”或“铰链结构域”是指位于CH1结构域和CH2结构域之间重链的柔性部分。它长约25个氨基酸,分为“上铰链”、“中间铰链”或“核心铰链”和“下铰链”。“铰链子结构域”是指上铰链、中(或核心)铰链或下铰链。IgG1、IgG2、IgG3和IgG4分子鉸鏈的氨基酸序列為(EU編號指示):
IgG1:E216PKSCDKTHTCPPCPAPELLG(SEQ ID No.1)
IgG2:E216RKCCVECPPCPAPPVAGP(SEQ ID No.2)
IgG3:
ELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPE216PKSCDTPPPCPRCPAPELLG(SEQ ID No.3)
IgG4:E216SKYGPPCPSCPAPEFLG(SEQ ID No.4)
核心铰链区通常含有至少一个连接两条重链的半胱氨酸桥。此外,可以在下铰链区进行突变以改善不需要的抗体依赖性细胞介导的细胞毒性(ADCC)。
优选的是根据本发明所述的双特异性多肽分子,其包含至少一个IgG可结晶片段(Fc)结构域,即可结晶片段区(Fc区)、与Fc受体相互作用的抗体尾区和补充系统的一些蛋白质。Fc区在每条多肽链中含有两个或三个重链恒定结构域(CH结构域2、3和4)。IgG的Fc区也带有高度保守的N-糖基化位点。Fc片段的糖基化对于Fc受体介导的活性是必需的。小尺寸双特异性抗体形式,如:和DARTs(~50kD),可以快速清除并缩短半衰期。因此,为了改善药代动力学性质,scTv-细胞受体(例如CD3)双特异性多肽分子可以与(人IgG1)Fc结构域融合,从而增加分子量。位于CH2和CH3结构域之间介面的几个突变,如:T250Q/M428L和M252Y/S254T/T256E+H433K/N434F,已被证明可增加对新生儿Fc受体(FcRn)的结合亲和力和半衰期。由此,可以进一步延长含Fc分子的血清半衰期。
在本发明的双特异性多肽分子中,所述Fc结构域可包含CH2结构域,其含有至少一个效应子功能沉默突变。优选地,将这些突变引入已知与效应子功能相关的人IgG1(残基233-238)或其他同种型的相应残基的ELLGGP(SEQ ID No.50)序列中。原则上,将对应于衍生自IgG2和/或IgG4残基的一个或多个突变引入IgG1 Fc。优选为:E233P、L234V、L235A和在位置236无残基或G。另一种突变为P331S。EP1075496公开了包含嵌合结构域的重组抗体,所述嵌合结构域衍生自两个或更多个人免疫球蛋白重链CH2结构域,其选自IgG1、IgG2和IgG4,并且其中所述嵌合结构域为人免疫球蛋白重链CH2结构域,其根据EU编号系统,在所述位置有下列氨基酸块:233P、234V、235A和在236位置无残基或G以及327G、330S和331S,并且与来自具有所述修饰氨基酸的人IgG1、IgG2或IgG4的CH2序列(残基231-340)至少98%相同。
要使用的优选CH2部分序列的实例可(完全或部分)如下:
231-
APPVA GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEK-334(SEQ ID No.5);
和
231-
APPVA GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEK-334(SEQ ID No.6),具有下划线变化,在297位置携带N(糖基化变体)或选自A、G和Q组(去糖基化变体)的残基。
在本发明的双特异性多肽分子中,所述Fc结构域可包含CH3结构域,其含有至少一个促进异二聚体形成的突变。为了使所需的异二聚体双特异性-Fc蛋白的产量最大化并简化纯化程序,可以将“杵臼结构”突变工程化入Fc结构域中。采用这种设计,透过向一条链添加突出的大疏水残基(“杵”)并在另一条链上产生互补疏水袋(“臼”),驱动Fc结构域形成异二聚体而不非它们的正常同二聚体。“杵”变体可以透过用较大的氨基酸替换小氨基酸来插入到对侧结构域中的“臼”中,所述对侧结构域透过用较小的残基替换大的残基而产生(Ridgway,JBB;Presta,LG;Carter,P.“Knobs-into-holes”engineering of antibody CH3domains for heavy chain heterodimerization.Protein Eng.1996,9,617–621;WO2002/002781)。
优选的是根据本发明所述的双特异性多肽分子,其中所述杵臼结构突变选自T366W作为杵以及T366'S、L368'A和Y407'V作为CH3结构域中的臼(参见,例如WO 98/50431)。透过包含突变K409A和F405'K可以进一步扩展该组突变,如Wei et al.(Structural basis of a novel heterodimeric Fc for bispecific antibodyproduction,Oncotarget.2017)一文所述。另一个杵可以是T366Y,臼为Y407'T。
本发明的双特异性多肽分子还可以包含在第一多肽链上的至少一个半胱氨酸残基和第二多肽链上的至少一个半胱氨酸残基之间的人工引入的半胱氨酸桥,以便改善分子的稳定性,最佳情况是不干扰具有二价分子的结合特征,和/或用于改善异二聚化。为了增加稳定性,可透过在杵和臼链的CH3结构域中添加单个半胱氨酸来引入二硫键。优选的是根据本发明所述的双特异性多肽分子,其中Fc结构域包含含有至少一个另外的半胱氨酸残基的CH3结构域,例如:S354C和/或Y349C。
优选的是根据本发明所述的双特异性多肽分子,其中所述CD分子选自免疫应答相关的CD分子组、CD3(例如:CD3γ、CD3δ和CD3ε链)、CD4、CD7、CD8、CD10、CD11b、CD11c、CD14、CD16、CD18、CD22、CD25、CD28、CD32a、CD32b、CD33、CD41、CD41b、CD42a、CD42b、CD44、CD45RA、CD49、CD55、CD56、CD61、CD64、CD68、CD94、CD90、CD117、CD123、CD125、CD134、CD137、CD152、CD163、CD193、CD203c、CD235a、CD278、CD279、CD287、Nkp46、NKG2D、GITR、FcεRI、TCRα/β、TCRγ/δ和HLA-DR。取决于根据本发明所述的双特异性多肽分子的两种抗原结合实体的组合,可以实现关于分子功能的特定优势,特别是增强活性。
优选的是根据本发明所述的示例性双特异性多肽分子,其中第一多肽链中的区域包含VD1的SEQ ID No.28、VR1的SEQ ID No.29、LINK1的SEQ ID No.3;第二多肽链中的区域包含VD2的SEQ ID No.31、VR2的SEQ ID No.32和LINK2的SEQ ID No.30。
进一步优选的是根据本发明所述的示例性双特异性多肽分子,其中第一多肽链中的Fc区包含SEQ ID No.26(Fc1),第二多肽链中的FC区包含SEQ ID No.27(Fc2)。
进一步优选的是根据本发明所述的示例性双特异性多肽分子,其包含含有SEQ IDNo.16的第一多肽链(1.全分子链)和含有SEQ ID No.17的第二多肽链(2.全分子链)。
更进一步优选的是根据本发明所述的示例性双特异性多肽分子,其中结合人免疫细胞(例如CD3)表面抗原的表位的所述第一结合位点(VD1)(VD2)人源化;和/或结合所述MHC相关肽表位的所述第二结合位点(VR1)(VR2)亲和力成熟。
人源化抗体是来自非人物种的抗体(或其部分),其蛋白质序列已经被修饰以增加它们与人体天然产生的抗体变体的相似性。“人源化”工艺通常应用于为人体施用而开发的单克隆抗体(例如,作为抗癌药物开发的抗体)。用于人源化的合适方法可从文献中获知,例如在Olimpieri,Pier Paolo,Paolo Marcatili和Anna Tramontano中综述。“Tabhu:Toolsfor Antibody Humanization.”Bioinformatics 31.3(2015):434–435.PMC;Safdari Y,Farajnia S,Asgharzadeh M,Khalili M.Antibody humanization methods-a review andupdate.Biotechnol Genet Eng Rev.2013;29:175-86;or Ahmadzadeh V,Farajnia S,Feizi MA,Nejad RA.Antibody humanization methods for development oftherapeutic applications.MonoclonAntibImmunodiagnImmunother.2014Apr;33(2):67-73.
通常,TCR和抗体的体外亲和力成熟可以根据文献中描述的方法获得,特别是使用酵母或噬菌体表面展示技术(基于,例如:Holler PD,et al.In vitro evolution of a Tcell receptor with high affinity for peptide/MHC.Proc Natl Acad Sci USA.2000May 9;97(10):5387-92;Boder ET et al.,Directed evolution of antibody fragmentswith monovalent femtomolar antigen-binding affinity.Proc Natl Acad SciUSA.2000Sep 26;97(20):10701-5;以及作为最近的一个实例,Zhao Q,et al.Affinitymaturation of T-cell receptor-like antibodies for Wilms tumor 1peptidegreatly enhances therapeutic potential.Leukemia.2015;29(11):2238-2247)。
本说明书中的结合位点(VD1)(VD2)和(VR1)(VR2)优选分别特异性结合至人免疫细胞的表面抗原和肽-HLA分子复合体。与本说明书结合位点相关,本文所使用的“特异性结合”及其语法变体用于表示对肽-HLA分子复合体和/或100μM或更小的抗体表位具有结合亲和力(KD)的位点。本说明书的结合位点(VD1)(VD2)和(VR1)(VR2)分别与CD抗体表位或肽-HLA分子复合体结合,结合亲和力(KD)为约100μM或更低、约50μM或更低、约25μM或更低,或约10μM或更低。更优选的是具有约1μM或更低、约100nM或更低、约50nM或更低、约25nM或更低、约10nM或更低、约5nM或更低、约2nM或更低、约1nM或更低、约500pM或更低、约200pM或更低、约100pM或更低的结合亲和力的高亲和力结合位点。本发明结合位点的优选结合亲和力范围的非限制性实例包括约10pM至约100pM、100pM至约1nM、1nM至约10nM、约10nM至约20nM、约20nM至约30nM、约30nM至约40nM、约40nM至约50nM、约50nM至约60nM、约60nM至约70nM、约70nM至约80nM、约80nM至约90nM、约90nM至约100nM,例如,如实施例6中所述,透过生物层干涉测量法测量。
一方面,本公开内容提出了与本文所述的氨基酸序列具有至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性的多肽,例如:氨基酸序列1至58。另一方面,本公开内容提出了与本文所述的氨基酸序列具有至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性的第一或第二多肽。再一方面,本公开内容提出了与本文所述的一个或多个氨基酸序列具有至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性的双特异性多肽分子。本公开内容进一步提出了一些方面,其中至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%的百分比同一性适用于图1中描述的任何结构区序列,例如:VD1、VR1、Link1、VR2、VD2、Link2或铰链区,并且如本文所述或是本文所公开的序列的一部分。
一方面,本文所述的多肽或双特异性多肽分子可以以各种方式改变,包括氨基酸取代、缺失、截短以及插入一个或多个氨基酸。另一方面,本文所述的多肽或双特异性多肽分子可能包括1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45或50或更多个氨基酸取代、缺失或插入。再一方面,本文所述的多肽或双特异性多肽分子可能包括1至5、1至10、1至20、2至5、2至10、5至20、5至50或10至100个氨基酸取代、缺失或插入。一方面,1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45或50或更多个氨基酸取代、缺失或插入适用于图1中描述的任何结构区,例如:VD1、VR1、Link1、VR2、VD2、Link2或铰链区。本公开内容进一步提出了一些方面,其中1至5、1至10、1至20、2至5、2至10、5至20、5至50或10至100个氨基酸取代、缺失或插入适用于图1中描述的任何结构区的序列,例如:VD1、VR1、Link1、VR2、VD2、Link2或铰链区,并且如本文所述或是本文所公开序列的一部分。
一方面,可以将1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45或50或更多个氨基酸添加到本文所述的多肽或双特异性多肽分子的N末端或C末端,例如:氨基酸序列1至58。
一方面,VD1可能与SEQ ID NO:28的氨基酸序列具有至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%同一性。
一方面,VR1可能与SEQ ID NO:29的氨基酸序列具有至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%同一性。
一方面,LINK1或LINK2可能与SEQ ID NO:30的氨基酸序列具有至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%同一性。
一方面,VD2可能与SEQ ID NO:31的氨基酸序列具有至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%同一性。
一方面,VR2可能与SEQ ID NO:32的氨基酸序列具有至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%同一性。
一方面,铰链可能与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4的氨基酸序列具有至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%同一性。一方面,CH2结构域可能与SEQ ID NO:5或SEQ ID NO:6的氨基酸序列具有至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%同一性。
一方面,Fc区可能与SEQ ID NO:26或SEQ ID NO:27的氨基酸序列具有至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%同一性。
一方面,本公开内容提出了与SEQ ID NO:43、44、45或46的氨基酸序列具有至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性的多肽。
一方面,本文公开的多肽或双特异性多肽分子可以透过在多肽链内的不同(可能为选择性)位点上取代一个或多个残基而被修饰。此取代可能是保守性的,例如,其中一个氨基酸被具有类似结构和特点的另一个氨基酸所取代,比如其中一个疏水性氨基酸被另一个疏水性氨基酸取代。更保守的取代是具有相同或类似的大小和化学性质的氨基酸间的取代,例如,亮氨酸被异亮氨酸取代。在天然同源蛋白质家族序列变异的研究中,某些氨基酸的取代往往比其他氨基酸更具有耐受性,这些氨基酸往往表现出与原氨基酸的大小、电荷、极性和疏水性之间的相似性相关,这是确定“保守取代”的基础。
在根据本发明所述的双特异性多肽分子的另一优选实施方案中,所述分子携带与其偶联或共轭的活性剂或其部分。所述活性剂可选自由可检测标记、免疫刺激分子和治疗剂组成的组。
可检测标记可选自由生物素、链霉抗生物素蛋白、酶或其催化活性片段、放射性核素、纳米颗粒、顺磁性金属离子,或萤光、磷光或化学发光分子组成的组。用于诊断目的的可检测标记包括例如:萤光标记、放射性标记、酶、核酸探针和造影剂。
可能与本发明分子相关的治疗剂包括免疫调节剂、放射性化合物、酶(例如:穿孔素)、化学治疗剂(例如:顺铂)或毒素。其他合适的治疗剂包括小分子细胞毒性剂,即具有杀死分子量小于700道尔顿的哺乳动物细胞能力的化合物。此类化合物还可含有能够具有细胞毒性作用的有毒金属。此外,应理解这些小分子细胞毒性剂还包括前体药物,即在生理条件下衰变或被转化以释放细胞毒性剂的化合物。此类药剂的实例包括顺铂、美登素衍生物、雷查霉素、卡奇霉素、多西他赛、依托泊苷、吉西他滨、异环磷醯胺、伊立替康、美法仑、米托蒽醌、吓吩姆钠光敏素II、替莫唑胺、拓扑替康、葡糖醛酸三甲曲沙、耳他汀E、长春新碱和多柔比星;肽细胞毒素,即,具有杀伤哺乳动物细胞能力的蛋白质或其片段。例如,蓖麻毒素、白喉毒素、假单胞菌细菌外毒素A、Dnase和RNase;放射性核素,即元素的不稳定同位素,其在衰减的同时发出一种或多种的α或β粒子或γ射线。例如,碘-131、铼-186、铟-111、钇-90、铋-210和-213、锕-225和砹-213;螯合剂可用于促进这些放射性核素与分子或其多聚体的结合;免疫刺激剂,即,刺激免疫应答的免疫效应分子。例如,细胞因子(如IL-2和IFN-γ)、趋化因子(如:IL-8)、血小板因子4、黑色素瘤生长刺激蛋白、补体启动剂;或异种蛋白结构域、同种异体蛋白结构域、病毒/细菌蛋白结构域、病毒/细菌肽。
然后,本发明的另一方面涉及编码本文公开的第一多肽链和/或第二多肽链的核酸分子,或包含这种核酸的表达载体。核酸分子可以DNA、cDNA、PNA、RNA及其组合。编码特定肽、寡肽或多肽的核苷酸序列可为天然核苷酸序列,也可为合成核苷酸序列。一般来说,编码肽、多肽以及本发明蛋白的DNA片段由cDNA片段和短寡核苷酸衔接物,或一系列寡核苷酸组成,以提供一种合成基因,该基因能够在包含源自微生物或病毒操纵子的调节元素的重组转录单元中被表达。术语“表达产物”系指多肽或蛋白,它是基因序列和任何核酸序列的翻译产物,这些序列编码遗传密码退化所造成的同等物,从而编码同样的氨基酸。“片断”这一术语,当指的是一种编码序列时,表示包含非完整编码区的DNA的一部分,其表达产物与完整编码区表达产物基本上具有相同的生物学功能或活性。根据预期用途,可以对核酸进行密码子优化以在合适的(例如:微生物)宿主细胞中表达。遗传密码冗余让一些氨基酸被一个以上的密码子编码,但某些密码子没有其他密码子“理想”,因为匹配tRNA以及其他因子的相对可用性(Gustafsson et al.,2004)。
该核酸可能为,例如,DNA、cDNA、PNA、RNA或其组合物,它们可为单链和/或双链、或多聚核苷酸的原生或稳定形式(如:具有硫代磷酸骨架的多聚核苷酸),并且只要它编码多肽链,就可能包含也可能不包含内含子。
然后可以在合适的宿主中包含和/或表达核酸(例如:DNA)以产生包含本发明多肽链的多肽。因此,可根据已知技术使用编码本发明多肽链的核酸(例如DNA),用本文所述方法适当修饰后,构建表达载体,然后表达载体用于转化合适宿主细胞,从而表达和产生本发明中的多肽,如本领域所知。编码构成本发明化合物多肽链的核酸(例如:DNA,或在逆转录病毒载体的情况下,RNA)可能被加入到其他多种核酸(例如:DNA)序列,从而引入到合适的宿主中。同伴核酸将取决于宿主的性质、DNA引入宿主的方式、以及是否需要保持为游离体还是要相互结合。一般来说,核酸可以适当的方向和正确的表达阅读框架附着到一种表达载体(如质粒)中。如有必要,该核酸可能与所需宿主所识别的相应转录和翻译调节控制核苷酸序列连接,尽管表达载体中一般存在此类控制功能。然后,该载体使用标准方法被引入宿主。一般来说,并不是所有的宿主都会被载体转化。因此,有必要选择转化过的宿主细胞。选择方法包括用任何必要的控制元素向表达载体插入一个核酸序列,该序列对转化细胞中的可选择性属性(如抗生素耐药性)进行编码。另外,有这种选择属性的基因可在另外一个载体上,该载体用来协同转化所需的宿主细胞。然后,本发明中的重组核酸所转化的宿主细胞在本文中所述本领域技术人员熟悉的合适条件下培养足够长的时间,从而表达之后可回收的肽。
有许多已知的表达系统,包括细菌(如大肠杆菌和枯草芽孢杆菌)、酵母(如酵母菌)、丝状真菌(如曲霉菌)、植物细胞、动物细胞及昆虫细胞。该系统可优选为哺乳动物细胞,如来自ATCC细胞生物学库(Cell Biology Collection)中的CHO细胞。
在一项实施方案中,该说明书提出了如本文中所描述的产生分子的方法,该方法包括在适于促进所述链表达的条件下培养能够表达多肽链的宿主细胞。
一方面,为了获得表达本说明书分子的细胞,将编码包含TCR-α和/或TCR-β结合结构域的多肽链的核酸克隆到表达载体中,例如γ逆转录病毒或慢病毒。另一方面,为了获得表达本说明书分子的细胞,RNA透过本领域中已知的技术(例如,体外转录系统)合成。然后透过电穿孔将体外合成的RNA引入合适的细胞中以表达多肽链。
为了增加表达,编码本说明书链的核酸在操作上可连接到强启动子,例如逆转录病毒长末端重复序列(LTR)、巨细胞病毒(CMV)、鼠干细胞病毒(MSCV)U3、磷酸甘油酸激酶(PGK)、β-肌动蛋白、泛素蛋白和猿猴病毒40(SV40)/CD43复合启动子、延伸因子(EF)-1a和脾脏病灶形成病毒(SFFV)启动子。在一优选实施方案中,启动子与被表达的核酸异源。除了强启动子外,本说明书的表达盒可能含有附加的元素,可提高转基因表达,包括中枢多聚嘌呤区(cPPT),其促进了慢病毒构建体的核易位(Follenzi et al.,2000),和土拨鼠肝炎病毒转录后调控元素(wPRE),其透过提高RNA稳定性增加转基因表达水平(Zufferey et al.,1999)。
本发明分子的α和β结合结构域链可由位于分开的载体核酸进行编码,或者可透过位于同一载体的多核苷酸编码。
在一实施方案中,宿主细胞被改变结构以表达本说明书的分子。本说明书的宿主细胞相对于待治疗的患者可以为同种异体或自体的。
本发明的再一方面涉及一种药物组合物,其包含根据本发明所述的双特异性多肽分子、根据本发明所述的核酸或表达载体或根据本发明所述的细胞以及一种或多种药用载体或赋形剂。本发明的组合物包括可用于制造药物组合物的原料药组合物(例如,杂质或非无菌组合物)和可用于制备单位剂型的药物组合物(即,适合给予受试者或患者的组合物)。此类组合物包含预防或治疗有效量的本文公开的预防和/或治疗性双特异性多肽分子(药剂)或药剂和药用载体的组合。优选地,本发明的组合物包含预防或治疗有效量的一种或多种本发明分子和药用载体。
药物组合物优选包含游离形式或盐形式的分子。优选的情况是,盐为分子的药用盐,例如:氯化物或乙酸(三氟乙酸)盐。必须注意的是,本发明分子的盐与其体内状态的分子基本上不同,因为该分子不是体内的盐。
因此,本发明的一项实施方案涉及根据本发明所述的非天然分子,其已经合成产生(例如:合成)为药用盐。合成产生肽和/或多肽的方法是本领域公知的。根据本发明所述分子的盐与其体内状态的分子显著不同,因为这些体内产生的分子不是盐。优选地,盐为分子的药用盐。本发明的这些盐包括碱和碱土盐类,诸如Hofmeister系列的盐,包含阴离子PO4 3-、SO4 2-、CH3COO-、Cl-、Br-、NO3 -、ClO4 -、I-、SCN-和阳离子NH4 +、Rb+、K+、Na+、Cs+、Li+、Zn2+、Mg2 +、Ca2+、Mn2+、Cu2+和Ba2+。特别地,盐选自(NH4)3PO4、(NH4)2HPO4、(NH4)H2PO4、(NH4)2SO4、NH4CH3COO、NH4Cl、NH4Br、NH4NO3、NH4CIO4、NH4I、NH4SCN、Rb3PO4、Rb2HPO4、RbH2PO4、Rb2SO4、Rb4CH3COO、Rb4Cl、Rb4Br、Rb4NO3、Rb4CIO4、Rb4I、Rb4SCN、K3PO4、K2HPO4、KH2PO4、K2SO4、KCH3COO、KCl、KBr、KNO3、KClO4、KI、KSCN、Na3PO4、Na2HPO4、NaH2PO4、Na2SO4、NaCH3COO、NaCl、NaBr、NaNO3、NaCIO4、NaI、NaSCN、ZnCI2 Cs3PO4、Cs2HPO4、CsH2PO4、Cs2SO4、CsCH3COO、CsCl、CsBr、CsNO3、CsCIO4、CsI、CsSCN、Li3PO4、Li2HPO4、LiH2PO4、Li2SO4、LiCH3COO、LiCl、LiBr、LiNO3、LiClO4、LiI、LiSCN、Cu2SO4、Mg3(PO4)2、Mg2HPO4、Mg(H2PO4)2、Mg2SO4、Mg(CH3COO)2、MgCl2、MgBr2、Mg(NO3)2、Mg(ClO4)2、MgI2、Mg(SCN)2、MnCl2、Ca3(PO4),、Ca2HPO4、Ca(H2PO4)2、CaSO4、Ca(CH3COO)2、CaCl2、CaBr2、Ca(NO3)2、Ca(ClO4)2、CaI2、Ca(SCN)2、Ba3(PO4)2、Ba2HPO4、Ba(H2PO4)2、BaSO4、Ba(CH3COO)2、BaCl2、BaBr2、Ba(NO3)2、Ba(ClO4)2、BaI2和Ba(SCN)2。特别优选为NH乙酸、MgCl2、KH2PO4、Na2SO4、KCl、NaCl和CaCl2,例如:氯化物或乙酸盐(三氟乙酸)盐。
一方面,本文所述的多肽为药用盐的形式。另一方面,药用盐形式的多肽为结晶形式。
一方面,本文所述的药用盐是指具有在药物应用可接受范围内毒性特征的盐。
此处使用的“药用盐”系指所公开的肽的一种衍生物,其中该肽由制酸或药剂的碱盐进行改性。例如,用与适合的酸反应的游离碱(通常其中的中性药物有一个中性–NH2基团)制备酸式盐。适合制备酸盐的酸包括有机酸,如:乙酸、丙酸、羟基酸、丙酮酸、草酸、苹果酸、丙二酸、丁二酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸酸、肉桂酸、扁桃酸、甲磺酸、甲磺酸、苯磺酸、水杨酸等等、以及无机酸,如:盐酸、氢溴酸、硫酸、硝酸和磷酸等。相反,可在一种肽上提呈的酸性基团的碱盐制剂使用药用碱基进行制备,如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙、三甲胺等等。
一方面,药用盐可提高本文所述肽的溶解度和/或稳定性。另一方面,本文所述的药用盐可透过常规方法由相应的载体肽或复合体制备,方法例如用本文所述的肽或复合体使适当的酸或碱发生反应。另一方面,药用盐为结晶形式或半结晶形式。再一方面,药用盐可能包括例如:PH Stahl和CG Wermuth所著的《Handbook of Pharmaceutical Salts:Properties,Selection,and Use》(药用盐手册:特征、选择和使用)(Wiley-VCH 2002),LDBighley,SM Berge,DC Monkhouse,《Encyclopedia of Pharmaceutical Technology》(制剂技术百科全书)Eds.J.Swarbrick and JC Boylan,Vol.13,Marcel Dekker,Inc.,NewYork,Basel,Hong Kong 1995,pp.453-499中所述的药用盐,各参考文献透过引用整体并入本文。
本发明还包括药物组合物,其包含本发明的双特异性多肽分子和对特定癌抗原具有特异性的治疗性抗体(例如:肿瘤特异性单克隆抗体)和药用载体。
在一具体实施方案中,术语“药用”意指由联邦或州政府监管机构批准或在《美国药典》或其他公认的药典中列出用于动物,更特别是人类。术语“载体”是指与治疗剂一起施用的稀释剂、辅助赋形剂或载体。此类药物载体可以是无菌液体,例如:水和油,包括石油、动物油、植物油或合成油,诸如:花生油、大豆油、矿物油、芝麻油等。当静脉内施用药物组合物时,水为优选载体。盐水溶液和葡萄糖水溶液和甘油溶液也可用作液体载体,特别是用于可注射溶液。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、矽胶、硬脂酸钠、甘油单硬脂酸酯、滑石、氯化钠、磷酸钠、乙酸钠、L-组氨酸、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。如果需要,该组合物还可含有少量的润湿剂或乳化剂或pH缓冲剂。这些组合物可以采用溶液、悬浮液、乳剂、片剂、丸剂、胶囊、粉剂、缓释制剂等形式。通常,本发明组合物的成分以单位剂量形式单独或混合供应,例如,作为干燥冻干粉或无水浓缩物供应,包装在密封容器内,如:示有活性剂数量的安瓿或小袋内。当组合物透过输注施用时,可以用含有无菌药用级水或盐水的输液瓶配药。当透过注射施用组合物时,可提供一安瓿无菌注射用水或盐水,以便可以在施用前混合成分。
那么,本发明的另一方面涉及根据本发明所述的双特异性多肽分子、根据本发明所述的核酸或表达载体、根据本发明所述的细胞或根据本发明所述的药物组合物用于药物中。通常,双特异性多肽分子的使用取决于所述分子识别的肽-抗原的医疗背景,进一步描述如下文。
优选的是根据本发明所述的双特异性多肽分子、根据本发明所述的核酸或表达载体、或根据本发明所述的细胞、或根据本发明所述的药物组合物用于治疗或预防选自免疫疾病、传染病、中毒和癌症的疾病或病症,包括治疗或预防各种癌症或其他异常增殖性疾病,包括(但不限于)如下:癌,包括膀胱、乳腺、结肠、肾、肝、肺、卵巢、胰腺、胃、前列腺、宫颈、甲状腺和皮肤癌;包括鳞状细胞癌;淋巴谱系造血系统肿瘤,包括白血病、急性淋巴细胞白血病、急性淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、伯基特淋巴瘤;骨髓谱系造血系统肿瘤,包括急性和慢性髓性白血病和早幼粒细胞白血病;间充质来源肿瘤,包括纤维肉瘤和横纹肌肉瘤;其他肿瘤,包括黑色素瘤、精原细胞瘤、畸胎癌、神经母细胞瘤和胶质瘤;中枢和外周神经系统肿瘤,包括星形细胞瘤、神经母细胞瘤、神经胶质瘤、神经鞘瘤和骨肉瘤;和其他肿瘤,包括黑色素瘤、着色性干皮病、角化棘皮瘤、精原细胞瘤、甲状腺滤泡癌和畸胎癌。其他癌症可能包括但不限于滤泡性淋巴瘤、具有p53突变的癌、乳腺、前列腺和卵巢激素依赖性肿瘤、以及癌前病变,例如:家族性腺瘤性息肉病和骨髓增生异常征候群。在具体的实施方案中,透过本发明的方法和组合物治疗或预防卵巢、膀胱、乳腺、结肠、肺、皮肤、胰腺或子宫的恶性肿瘤或增生不良变化(例如:化生和异常增生)或过度增殖性疾病。在其他具体实施方案中,透过本发明的方法和组合物治疗或预防肉瘤、黑色素瘤或白血病。
本发明进一步涉及在患者或受试者中引发免疫应答的方法,包括给予治疗有效量的根据本发明所述的双特异性多肽分子或根据本发明所述的药物组合物。一方面,将根据本发明所述的双特异性多肽分子群或根据本发明所述的药物组合物施用于有需要的患者或受试者。
本发明进一步涉及杀灭患者或受试者靶细胞的方法,包括向患者施用有效量的根据本发明所述的双特异性多肽分子。
本发明还提出了预防、治疗或管理受试者中与炎性病症相关的一种或多种症状的方法,其进一步包括给予所述受试者治疗或预防有效量的一种或多种本发明的抗炎剂。本发明还提出了预防、治疗或管理与自身免疫疾病相关的一种或多种症状的方法,其进一步包括给予所述受试者治疗或预防有效量的一种或多种本发明的免疫调节剂。可以透过本发明的分子治疗或预防的传染病由感染因子引起,包括但不限于病毒、细菌、真菌、原生动物和病毒。使用本发明的分子结合本发明的方法可以治疗或预防的病毒性疾病包括但不限于由A型肝炎、B型肝炎、C型肝炎、流感、水痘、腺病毒、I型单纯疱疹(HSV-I)、II型单纯疱疹(HSV-II)、牛瘟、鼻病毒、埃可病毒、轮状病毒、呼吸道合胞病毒、乳头瘤病毒、乳多空病毒、巨细胞病毒、棘皮病毒、虫媒病毒、汉坦病毒、柯萨奇病毒、腮腺炎病毒、麻疹病毒、风疹病毒、脊髓灰质炎病毒、小痘、爱泼斯坦巴尔病毒、I型人类免疫缺陷病毒(HIV-I)、II型人类免疫缺陷病毒(HIV-II)、以及病毒性疾病因子(如:病毒脑膜炎、脑炎、登革热或小痘)引起的疾病。
使用本发明的分子结合本发明的方法可以治疗或预防的细菌性疾病包括但不限于由分枝杆菌立克次氏体、支原体、奈瑟球菌、肺炎链球菌、伯氏疏螺旋体(莱姆病)、抗坏血酸杆菌(炭疽)、破伤风、链球菌、葡萄球菌、分枝杆菌、破伤风、百日咳、霍乱、鼠疫、白喉、衣原体、金黄色葡萄球菌和军团菌引起的疾病。
使用本发明的分子结合本发明的方法可以治疗或预防由原生动物引起的原生动物疾病包括但不限于利什曼原虫、可哥地亚虫、锥虫或疟疾。使用本发明的分子结合本发明的方法可以治疗或预防由寄生虫引起的寄生虫病包括但不限于衣原体和立克次氏体。
感染因子和疾病的实例包括但不限于细菌(例如,大肠杆菌、肺炎克雷伯菌、金黄色葡萄球菌、粪肠球菌、白色念珠菌、普通变形杆菌、草绿色葡萄球菌和铜绿假单胞菌)、病原体(例如,B-淋巴细胞乳多空病毒(LPV);百日咳博多特氏菌;博尔纳病病毒(BDV);牛冠状病毒;脉络丛脑膜炎病毒;登革热病毒;病毒,大肠杆菌;埃博拉病毒;艾柯病毒1;艾柯病毒-11(EV);内毒素(LPS);肠道细菌肠道孤儿病毒;肠道病毒;猫白血病病毒;口蹄疫病毒;长臂猿白血病病毒(GALV);革兰氏阴性菌;幽门螺杆菌;乙型肝炎病毒(HBV);单纯疱疹病毒;HIV-I;人巨细胞病毒;人类冠状病毒;甲、乙和丙型流感;军团菌;墨西哥利什曼原虫;单核细胞增生李斯特氏菌;麻疹病毒;脑膜炎球菌;麻疹病毒;小鼠肝炎病毒;小鼠白血病病毒;小鼠γ疱疹病毒;小鼠逆转录病毒S;小鼠冠状病毒小鼠肝炎病毒;鸟分枝杆菌-M;淋球菌;新城疫病毒;细小病毒B19;恶性疟原虫;痘病毒;假单胞菌;轮状病毒;伤寒沙门氏菌;志贺氏菌;链球菌;T细胞嗜淋巴细胞病毒1;痘苗病毒)。
于是,本发明的再一方面涉及治疗疾病或病症的方法,包括给予治疗有效量的根据本发明所述的双特异性多肽分子、根据本发明所述的核酸或表达载体、根据本发明所述的细胞或根据本发明所述的药物组合物。
本发明的双特异性多肽分子可用于透过施用双特异性多肽分子而改善的疾病或病症的预防或治疗方法中。此类治疗可以与一种或多种药用载体或赋形剂一起提供在药物组合物中。治疗性双特异性多肽分子通常作为无菌药物组合物的一部分提供,其通常包括药用载体。该药物组合物可以是任何合适的形式(取决于将其给予患者的所需方法)。它可以以单位剂型提供,通常以密封容器中提供,并且可以作为套药的一部分提供。此类套药通常(但不一定)包括使用说明书。它可包括多个所述单位剂型。药物组合物可以适于透过任何合适的途径给药,例如:肠外(包括皮下、肌肉内或静脉内)途径。此类组合物可透过药学领域已知的任何方法制备,例如:透过在无菌条件下将活性成分与载体或赋形剂混合。
一方面,本文所述的肽或其他分子可与水性载体组合。一方面,水性载体选自离子交换剂、氧化铝、硬脂酸铝、硬脂酸镁、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油混合物、盐或电解质,如酯硫酸鱼精蛋白、磷酸氢二钠、磷酸二钙、磷酸氢钾、氯化钠、锌盐、胶体二氧化矽、三矽酸镁、聚乙烯基吡咯烷酮、聚乙烯吡咯烷酮-醋酸乙烯酯、纤维素类物质(例如:微晶纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素乙酸琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯)、淀粉、乳糖一水合物、甘露糖醇、海藻糖十二烷基硫酸钠和交联羧甲基纤维素钠、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、聚甲基丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物和羊毛脂。
一方面,水性载体含有多种组分,例如水和非水性载体组分,例如如本文所述的那些组分。另一方面,当与本文所述的肽或其他分子组合时,水性载体能够改善性质,例如改善溶解度、有效性和/或改进免疫治疗。此外,组合物可包含辅料,如:缓冲剂、结合剂、冲击剂、稀释剂、香料、润滑剂等。“药用稀释剂”例如可能包括溶剂、填充剂、稳定剂、分散介质、涂层、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等,它们在生理学上是相容的。药用稀释剂的实例包括盐水、磷酸盐缓冲盐水、右旋糖、甘油、乙醇等中的一种或多种以及它们的组合物。在许多情况下,优选在组合物中包含一种或多种等渗剂(例如:海藻糖和蔗糖等糖类)、多元醇(例如:甘露醇、山梨糖醇)或氯化钠。药用物质(如:润湿剂)或少量辅助物质(如:润湿剂或乳化剂、防腐剂或缓冲剂)也在本发明范围内。此外,组合物可能含有赋形剂,如缓冲液、黏合剂、爆破剂、稀释剂、香精和润滑剂。
本发明的双特异性多肽分子的剂量可在较大范围内变化,这取决于待治疗的疾病或病症、待治疗个体的年龄和状况等;例如,双特异性多肽分子的合适剂量范围可以为25ng/kg至50μg/kg。医生将最终确定要使用的适当剂量。
本发明的药物组合物、载体、核酸和细胞可以以基本上纯的形式提供,例如:至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的纯度。
本发明的每个方面的优选特征是作必要修改后的每个其他方面。本文提到的现有技术档在法律允许的最大范围内并入。尽管已经详细描述了本发明及其优点,但是应该理解,在不脱离所附权利要求限定的本发明精神和范围的情况下,可以进行各种改变、替换和变更。在以下实施例中将进一步说明本发明,这些实施例仅用于说明目的,并不意图以任何方式限制本发明。
图1显示了本发明优选实施方案含有人IgG1 Fc的双特异性多肽分子的示意图。VD1、VD2=源自抗体的可变结构域;VR1、VR2=源自TCR的可变结构域;Link1、Link2=连接接头;Cys-Cys=半胱氨酸桥。
图2显示了在本发明的背景下测试的4种不同的含有IgG Fc的双特异性多肽分子构建体的示意图。黑色=TCR衍生的可变结构域;浅灰色=抗体衍生的可变结构域;白色=源自人IgG的恒定结构域。杵-臼突变用圆柱表示。双抗体分子IA-ID根据本发明所述。
图3显示了根据图2中描绘构建体的具有分子设计的不同双特异性TCR/mAb分子的HPLC-SEC分析,其透过2-柱纯化方法纯化。不同分子的单体含量测定如下。II:93.84%;III:96.54%;IV:98.49%;IA_1:95.48%;IA_3:98.45%;ID_1:95.75%;IC_4:95.22%;IC_5:92.76%;ID_4:99.31%;ID_5:99.44%.
图4显示了设计为基于IgG4的分子的不同双特异性TCR/mAb构建体(如图2所示)的效力测定结果。在增加浓度的双特异性TCR(bssTCR)分子的存在下,将Jurkat_NFATRE_luc2细胞与载有T2细胞的HIV-肽SLYNTVATL(SEQ ID No.7)共温育。双特异性TCR/mAb双抗体分子IA-IgG4表现出比两种备选双特异性TCR/mAb分子更高的效力。
图5显示了设计为基于IgG1的分子的不同双特异性TCR/mAb构建体(如图2所示)的效力测定结果。在增加浓度的双特异性TCR(bssTCR)分子的存在下,将Jurkat_NFATRE_luc2细胞与载有T2细胞的HIV-肽SLYNTVATL(SEQ ID No.7)共温育。双特异性TCR/mAb双抗体分子ID_1、IA_3和IA1表现出比三种备选双特异性TCR/mAb分子显著更高的效力。
图6显示了利用靶向作用于TCR-CD3复合体的不同可变抗体结构域用不同的基于IgG1的双特异性TCR/mAb构建体(如图2所示)进行的效力测定的结果。构建体ID_1包含靶向作用于CD3的UCHT1(V9)抗体的可变结构域,而构建体ID_4和ID_5包含α/βTCR特异性抗体BMA031的可变结构域。在增加浓度的双特异性TCR(bssTCR)分子的存在下,将Jurkat_NFATRE_luc2细胞与载有T2细胞的HIV-肽SLYNTVATL(SEQ ID No.7)共温育。
图7显示了本发明分子中VD和VR结构域可能方向的示意图。VH:抗体衍生的VH结构域,VL:抗体衍生的VL结构域,Vα:TCR衍生的Vα;Vβ:TCR衍生的Vβ。
图8显示了基于IgG1的不同双特异性TCR/mAb分子内聚集体(HMWS-高分子量物质)的HPLC-SEC分析结果。分别在纯化后和分子在40℃下储存1周和2周后分析聚集体。
图9显示了用基于IgG1的不同双特异性TCR/mAb分子进行的效力测定的结果。分别在纯化后和分子在40℃下储存1周和2周后分析效力。在40℃下压力保存不会导致分子效力的显著丧失,但是对于分子III和IV,检测到了Jurkat T细胞的非特异性(即,靶标非依赖性)活化的急剧增加。
图10显示了设计为基于IgG1的分子的不同双特异性TCR/mAb构建体(如图2所示)的LDH释放测定结果。在增加浓度的双特异性TCR(bssTCR)分子的存在下,将从健康供体分离的PBMC与载有T2细胞的HIV-肽SLYNTVATL(SEQ ID No.7)共温育。双特异性TCR/mAb双抗体分子IA_3和ID_1诱导比三种备选双特异性TCR/mAb分子显著更高的靶细胞裂解。如右图所示,测试的双特异性TCR/mAb构建体均未诱导载有无关肽(SEQ ID No.49)的T2细胞的可检测裂解。
图11显示了HLA-A*02上呈递的靶向作用于肿瘤相关肽PRAME-004(SEQ ID No.49)的双特异性TCR/mAb双抗体构建体IA_5的LDH释放测定的结果。在增加浓度的TCR/mAb双抗体分子存在下,以效应子:靶标比率为5:1时,将从健康供体分离的CD8阳性T细胞与癌细胞系UACC-257、SW982和U2OS共培育,这些细胞系细胞表面上呈递不同量的PRAME-004:HLA-A*02-1复合体(每个细胞分别约1100、约770和约240个拷贝,透过M/S分析测定)。共培养48小时后,根据制造商的说明书(Promega),利用LDH释放测定法定量靶细胞裂解。
图12显示了双特异性TCR/mAb双抗体构建体IA_5和IA_6的LDH释放测定的结果,其利用稳定性/亲和力成熟的TCR及其增强形式,分别针对HLA-A*02上呈递的肿瘤相关肽PRAME-004(SEQ ID No.49)。在增加浓度的TCR/mAb双抗体分子存在下,将从健康供体分离的CD8阳性T细胞与U2OS共培育,该细胞系每个细胞呈递约240个拷贝的PRAME-004:HLA-A*02-1复合体或非负载T2细胞(效应子:靶标比率为5:1)。共培养48小时后,根据制造商的说明书(Promega),利用LDH释放测定法定量靶细胞裂解。
图13显示了TCR/mAb双抗体构建体IA_5和IA_6的热应激稳定性研究的结果,其利用稳定性/亲和力成熟的TCR及其增强形式,分别针对HLA-A*02上呈递的肿瘤相关肽PRAME-004(SEQ ID No.49)。为此,将蛋白质以1mg/mL的浓度在PBS中配制,随后在40℃下储存两周。使用HPLC-SEC评估了蛋白质完整性和回收。因而,根据在主峰之前洗脱的峰面积百分比确定高分子量物质的量。透过比较未受应力和应力样本的主峰面积来计算单体蛋白的回收率。
实施例
实施例1
含Fc的双特异性TCR/mAb双抗体和对照分子的设计。
设计含Fc的双特异性TCR/mAb双抗体和对照分子(如图2所示)以特异性结合至人TCR-CD3复合体和肽:MHC复合体,其包含与HLA-A2*01结合的HIV衍生肽SLYNTVATL(SQ IDNo.7)。为了靶向作用于TCR-CD3复合体,使用了衍生自CD3特异性人源化抗体hUCHT1(V9)的VH和VL结构域,如Zhu et al.(Identification of heavy chain residues in ahumanized anti-CD3 antibody important for efficient antigen binding and Tcell activation.J Immunol,1995,155,1903–1910)所述,或衍生自α/βTCR特异性抗体BMA031的VH和VL结构域,如Shearman et al.(Construction,expression andcharacterization of humanized antibodies directed against the human alpha/beta T cell receptor.J Immunol,1991,147,4366-73)所述并用于人源化版本变体10(内部产生的资料)。为了靶向作用于肽:MHC复合体,利用了前述稳定性和亲和力成熟的人单链T细胞受体868Z11的Vα和Vβ结构域,如Aggen et al.(Identification and engineeringof human variable regions that allow expression of stable single-chain T cellreceptors.PEDS,2011,24,361–372)一文所公开。
在含Fc的双特异性TCR/mAb双抗体的情况下,透过基因合成获得编码VH和VL(分别对应于VD1和VD2)、Va和Vb(分别对应于VR1和VR2)的各种组合以及编码接头Link1和Link2的DNA序列。将得到的DNA序列框内克隆至编码衍生自人IgG4[登录号:K01316]和IgG1[登录号:P01857]的铰链区、CH2和CH3结构域的表达载体中,并进一步进行工程化处理。进行工程设计以将杵臼结构突变并入到CH3结构域中,其具有和不具有额外的链间二硫键稳定性;去除CH2中的N-糖基化位点(例如:N297Q突变);引入Fc沉寂突变;根据Reiter et al.(Stabilization of the Fv Fragments in Recombinant Immunotoxins by DisulfideBonds Engineered into Conserved Framework Regions.Biochemistry,1994,33,5451–5459)所述的方法,分别将额外的二硫键稳定化引入VL和VH中。产生的双特异性TCR/mAb双抗体、变体以及相应序列的概述列于表1中。
表1:所有产生和评估的含Fc的双特异性TCR/mAb双抗体的概述:
KiH:杵臼结构;K/O:Fc沉寂;KiH-ds:用人工二硫键稳定的杵臼结构,连接CH3:CH3';ds-hUCHT1(V9):二硫键稳定的hUCHT1(V9)可变结构域;Link1:连接VR1和VD1的接头。
表2构建了表现出相同特异性的各种对照分子,其利用所述VH、VL、Vα和Vβ结构域与包含如上所述的工程化特征的IgG1-或IgG4-衍生恒定结构域组合。
表2:所有产生和评估的含Fc的双特异性对照分子的概述:
KiH:杵臼结构;K/O:Fc沉寂。
实施例2
含Fc的双特异性TCR/mAb双抗体的产生和纯化
用于表达重组蛋白的载体设计为单顺反子,由HCMV衍生的启动子元件pUC19衍生物控制。根据标准培养方法在大肠杆菌中扩增质粒DNA,随后使用市售套药(Macherey&Nagel)纯化。根据制造商的说明书(ExpiCHOTMsystem;Thermo Fisher Scientific),将纯化的质粒DNA用于CHO-S细胞的暂态转染。将转染的CHO细胞在32℃至37℃下培养6-14天,并接受一至两次ExpiCHOTMFeed溶液进料。
透过离心(4000×g;30分钟)收集条件细胞上清液,并透过过滤(0.22μm)澄清。使用配备的Pure 25L FPLC系统(GE Lifesciences)纯化双特异性分子,以线上进行亲和力和尺寸排阻色谱。按照标准亲和层析方案,在蛋白A柱(GE Lifesciences)上进行亲和层析。在从亲和柱洗脱(pH 2.8)后直接进行尺寸排阻色谱,以使用Superdex 200pg 16/600柱(GE Lifesciences)按照标准方案获得高纯度单体蛋白。使用根据预测的蛋白质序列计算的消光系数,在NanoDrop系统(Thermo Scientific)上测定蛋白质浓度。使用Vivaspin装置(Sartorius)进行浓缩(如果需要)和缓冲液交换。最后,将纯化的分子在2-8℃温度下以约1mg/mL的浓度保存在磷酸盐缓冲盐水中。
由于治疗性蛋白质在酸性暴露下应表现出合理的稳定性以促进稳健的工业纯化工艺,因此评估从蛋白质A捕获柱洗脱的单体蛋白质的百分比(表3)。显然,将稳定突变引入分子以及选择结合结构域的不同方向显著影响酸性暴露时的稳定性。
表3:捕获柱酸性洗脱后单体蛋白的分数:
在尺寸排阻色谱后,纯化的双特异性分子显示高纯度(>93%的单体蛋白质),透过HPLC-SEC在MabPac SEC-1柱(5μm,7.8×300mm)上测定,其在Agilent 1100系统内包含300mM NaCl的50mM磷酸钠pH 6.8中运行(参见图3)。非还原和还原SDS-PAGE证实了不同双特异性TCR/mAb分子的纯度和预期大小(资料未显示)。
实施例3
由含Fc的TCR/mAb双抗体诱导的特异性和靶细胞依赖性T细胞活化
使用T细胞活化生物测定法(Promega)评估含Fc的TCR/mAb双抗体对T细胞活化的效力。该测定由基因工程化的Jurkat细胞系组成,该细胞系表达由NFAT反应元件(NFAT-RE)驱动的萤光素酶报告基因。根据制造商的说明进行测定。简而言之,在增加浓度的双特异性TCR/mAb分子存在下,随后将负载HIV特异性肽SLYNTVATL(SEQ ID No.7)或不载入肽(未载入对照)的T2细胞与Promega修饰的Jurkat细胞进行共培养。透过测量发光强度在16-20小时后分析Jurkat报告基因T细胞活化。
分别描述了基于IgG4(图4)和基于IgG1的双特异性TCR/mAb分子(图5)的代表性效力测定结果。资料表明,无论使用的恒定结构域的IgG同种型如何,与备选双特异性TCR/mAb构建体II、III和IV相比,含Fc的TCR/mAb双抗体构建体IA和ID均显示出优异的T细胞活化,按活化幅度和/或相应的EC50值进行测量。此外,针对未负载的T2细胞诱导的含Fc的TCR/mAb双抗体的非特异性T细胞活化低于或至少等于备选双特异性TCR/mAb构建体观察到的非特异性活化水平。根据上述结果,双特异性TCR/mAb双抗体分子是用于治疗干预的优选分子,因为它们以高度靶向依赖性方式诱导强的效应T细胞活化。
此外,LDH释放测定(Promega)用于定量由不同双特异性TCR/mAb分子诱导的SLYNTVATL(SEQ ID No.7)肽负载T2细胞的PBMC介导裂解(图10)。与T细胞活化生物测定的上述结果一致,含Fc的TCR/mAb双抗体构建体IA和ID再次优于备选双特异性TCR/mAb构建体II、III和IV,如靶细胞裂解绝对水平增加和实现靶细胞半数最大(EC50)杀伤所需的TCR双特异性浓度降低所示。对于TCR/mAb构建体II、III和IV,TCR/mAb双抗体构建体1A和ID不诱导载有无关肽(SEQ ID No.49)的T2细胞裂解,证明对T2细胞的靶标特异性裂解。
实施例4
开发含Fc的双特异性TCR/mAb双抗体作为分子平台
设计含Fc的双特异性TCR/mAb双抗体构建体以用作分子平台,分别为靶向作用于不同肽:MHC复合体和效应细胞表面抗原的不同TCR衍生的和mAb衍生的可变结构域提供支架。为了验证作为平台的适合性,在第一组分子中交换mAb衍生的可变结构域。使用相同的结构域方向(构建体ID_4和ID_5)或不同方向(IC_4、IC_5)将hUCHT1(V9)抗CD3抗体(构建体ID_1)的可变结构域替换为hBMA031(var10)抗TCR抗体的结构域(详见表1和图7)。如上所述进行这些分子的表达、纯化和表征。根据HPLC-SEC分析,最终制剂的纯度和完整性超过92%。
效力测定结果显示了靶向依赖性Jurkat报告基因T细胞活化和针对抗体可变结构域hUCHT1(构建体ID_1)和hBMA031(构建体ID_4和ID_5)未负载T2细胞的最小非特异性活性,从而支援双特异性TCR/mAb双抗体构建体的平台适合性(图6)。值得注意的是,当构建体ID_4和ID_5的可变TCR和mAb结构域在每条多肽链上切换形成构建体IC_4和IC_5时,未观察到T细胞活化(资料未显示)。后一发现表明,尽管双特异性TCR/mAb双抗体可用作掺入不同TCR和mAb可变结构域的平台构建体,但需要彻底优化结构域方向以实现分子的最佳活性。
实施例5
含Fc的双特异性TCR/mAb双抗体的稳定性
最初利用蛋白质热转换测定法(Thermo Fisher Scientific)根据制造商的说明使用7500即时PCR系统(Applied Biosciences)评估双特异性TCR/mAb分子的稳定性。简而言之,将纯化的分子与PTS缓冲液和PTS染料混合,并经受升高的温度梯度,持续监测样本的萤光。使用PTS软体(Thermo Fisher Scientific)分析记录的萤光信号,并透过衍生方法计算熔解温度(TM)。
透过将溶解在PBS中的纯化分子在40℃下储存长达两周来进行压力稳定性研究。使用HPLC-SEC分析样本的蛋白质完整性,并使用如上所述的T细胞活化测定法(Promega)分析效力。
如预期的那样,透过HPLC-SEC分析测定,在40℃下储存诱导聚集体/高分子量物质的形成(参见图8)。在40℃下纯化和温育后基于IgG1的分子的效力测定结果显示于图9中。尽管在40℃下储存后两种受测试分子均未显示效力显著降低,但观察到压力分子III和IV诱导了显著量的非特异性(即,靶标非依赖性)Jurkat T细胞活化。相反,尽管存在如HPLC-SEC中所见的一些聚集体,但双特异性TCR/mAb双抗体仍保留其靶标依赖性效力。
实施例6:
癌症靶向性双特异性TCR/mAb双抗体分子的产生
为了进一步验证双特异性TCR/mAb双抗体构建体的平台能力,将TCR衍生的可变结构域与TCR的可变结构域交换,其透过酵母展示技术根据先前描述的方法进行稳定性/亲和力成熟(Smith et al,2015,T Cell Receptor Engineering and Analysis Using theYeast Display Platform.Methods Mol Biol.1319:95-141)。在HLA-A*02背景下特异性结合于HIV衍生肽SLYNTVATL(SEQ ID No.7)的TCR可变结构域与特异性结合于肿瘤相关肽PRAME-004(SEQ ID No.49)(与HLA-A*02结合)的TCR可变结构域交换。此外,人源化T细胞募集抗体hUCHT1(V9)的可变结构域与新的人源化形式UCHT1抗体hUCHT1(Var17)的可变结构域交换,产生PRAME-004靶向TCR/mAb双抗体分子IA_5(包含SEQ ID No.43和SEQ IDNo.44)。如实施例2中所述进行该分子的表达、纯化和表征。根据HPLC-SEC分析,最终制剂的纯度和完整性超过96%。
透过生物层干涉测定法测定双特异性TCR/mAb双抗体构建体对PRAME-004:HLA-A*02的结合亲和力。使用制造商推荐的设置在Octet RED384系统上进行测量。简而言之,在分析HLA-A*02/PRAME-004连续稀释之前,将纯化的双特异性TCR/mAb双抗体分子载入到生物感测器(AHC)上。
该PRAME-004靶向TCR/mAb双抗体构建体对肿瘤细胞裂解诱导的活性透过评估人癌细胞系UACC-257、SW982和U2OS的人CD8阳性T细胞介导的裂解来评价,这些人癌细胞系的肿瘤细胞表面上在HLA-A*02背景下呈递不同复制量的PRAME-004肽(透过定量M/S分析,每个细胞中,UACC-257-约1100、SW982-约770、U2OS-约240个PRAME-004拷贝),测定透过LDH释放测定法确定。
如图11所示,PRAME-004靶向TCR/mAb双抗体构建体IA_5诱导PRAME-004阳性肿瘤细胞系的浓度依赖性裂解。即使是每个肿瘤细胞表达少至240个PRAME-004拷贝数的肿瘤细胞U2OS也可透过该TCR/mAb双抗体分子有效地进行裂解。这些结果进一步证明TCR/mAb双抗体形式可用作分子平台,允许引入不同TCR的可变结构域以及不同T细胞募集抗体的可变结构域。
实施例7:
TCR/mAb双抗体构建体的工程改造性
构建体IA_5中使用的可变TCR结构域对PRAME-004的亲和力和TCR稳定性进一步增强,并用于工程改造成TCR/mAb双抗体支架,产生构建体IA_6(包含SEQ ID No.45和SEQ IDNo.46)。如实施例2中所述进行TCR/mAb双抗体分子IA_5和IA_6的表达、纯化和表征。根据HPLC-SEC分析,最终制剂的纯度和完整性超过97%。
在肿瘤细胞系U2OS呈递少量PRAME-004:HLA-A*02或未负载T2细胞作为靶细胞的细胞毒性实验中评估了针对PRAME-004的稳定性和亲和力增强的TCR/mAb双抗体变体IA_6的效力。
如图12中所示,当与前体构建体IA_5相比时,发明人观察并增加了包含稳定性/亲和力增强的TCR变体的可变结构域的TCR/Ab双抗体分子IA_6的细胞毒性效力。对于两种构建体IA_5和IA_6,可以确认PRAME-004依赖性裂解,因为未检测到靶标阴性T2细胞的细胞溶解。
将蛋白质构建体进一步在40℃下进行热应激长达两周,以分析PRAME-004特异性TCR/mAb双抗体变体IA_5和IA_6的稳定性。热应激后的HPLC-SEC分析显示,与前体构建体IA_5相比,变体IA_6的稳定性显著提高(参见图13)。对于IA_6而言,构建体的高分子物质(即,在主峰之前洗脱)的温度诱导增加不如IA_5明显。与此结果一致,热应激后IA_5和IA_6的完整单体蛋白回收率分别为87%和92%。
这些示例性工程资料证明,透过掺入稳定性/亲和力增强的TCR可变结构域,可以进一步改善高效和稳定的TCR/mAb双抗体构建体,从而产生具有优异特征的治疗性蛋白质。
实施例8:
优选构建体的实例
除了如本文所述的HIV特异性TCR双特异性构建体(Seq ID No.16和Seq IDNo.17,在方向D中),本发明还提出了接受测试的几种其他示例性HIV特异性构建体。这些构建体基于针对CD3(UCHT1)的潜在抗体的改进人源化变体,其在所有四种可能的方向(SeqID No.51至Seq ID No.58,方向AD)上与本文公开的HIV特异性TCR868融合。
使用VH-1-46和VK1-018分别作为重链和轻链CDR的受体框架进行UCHT1人源化。选定的J区段为JK1和JH4,分别用于轻链和重链。
所获得的结果示于下表4。
V9(Zhu et al,1995) | 本发明 | |
DRB1分数 | 1232 | ~1190 |
滴度[mg/L] | 0.75 | 3 |
F(ab)的Tm[℃] | 83.0 | 86.4 |
效应细胞活化的EC50[pM] | 63 | 8 |
表4中的资料表明,本发明的人源化可能具有较低的免疫原性(较低的DRB1评分);分子更稳定(熔化温度升高约3℃);与标准品(V9)相比,更有效(EC50降低~8x)(关于测定,参见实施例3)。
序列名单
<110> Immatics biotechnologies
<120> 改进的双特异性多肽分子
<130> I33034WO01
<150> US 62/532,713
<151> 2017-07-14
<150> DE 10 2017 115 966.5
<151> 2017-07-14
<150> DE 10 2017 119 866.0
<151> 2017-08-30
<150> DE 10 2018 108 995.3
<151> 2018-04-16
<150> US 62/658,318
<151> 2018-04-16
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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 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
420 425 430
Glu 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 Leu Gly Lys
450 455 460
<210> 10
<211> 478
<212> PRT
<213> Homo sapiens
<400> 10
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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr
130 135 140
Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp
145 150 155 160
Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile
165 170 175
Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp
180 185 190
Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile
195 200 205
Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser
210 215 220
Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr
225 230 235 240
Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys Thr His
245 250 255
Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
370 375 380
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
420 425 430
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 11
<211> 459
<212> PRT
<213> Homo sapiens
<400> 11
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
65 70 75 80
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
85 90 95
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
100 105 110
Ile Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser
115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
130 135 140
Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys
145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu
165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr
180 185 190
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
195 200 205
Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys
210 215 220
Val Glu Ile Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
225 230 235 240
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
245 250 255
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
260 265 270
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
275 280 285
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
290 295 300
Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
305 310 315 320
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
325 330 335
Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
340 345 350
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
355 360 365
Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe
370 375 380
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
385 390 395 400
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
405 410 415
Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
420 425 430
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
435 440 445
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 12
<211> 478
<212> PRT
<213> Homo sapiens
<400> 12
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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr
130 135 140
Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp
145 150 155 160
Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile
165 170 175
Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp
180 185 190
Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile
195 200 205
Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser
210 215 220
Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr
225 230 235 240
Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys Thr His
245 250 255
Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
370 375 380
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
420 425 430
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 13
<211> 459
<212> PRT
<213> Homo sapiens
<400> 13
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
65 70 75 80
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
85 90 95
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
100 105 110
Ile Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser
115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
130 135 140
Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys
145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu
165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr
180 185 190
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
195 200 205
Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys
210 215 220
Val Glu Ile Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
225 230 235 240
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
245 250 255
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
260 265 270
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
275 280 285
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
290 295 300
Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
305 310 315 320
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
325 330 335
Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
340 345 350
Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp
355 360 365
Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe
370 375 380
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
385 390 395 400
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
405 410 415
Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
420 425 430
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
435 440 445
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 14
<211> 478
<212> PRT
<213> Homo sapiens
<400> 14
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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr
130 135 140
Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp
145 150 155 160
Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile
165 170 175
Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp
180 185 190
Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile
195 200 205
Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser
210 215 220
Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr
225 230 235 240
Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys Thr His
245 250 255
Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
370 375 380
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
420 425 430
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 15
<211> 459
<212> PRT
<213> Homo sapiens
<400> 15
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
65 70 75 80
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
85 90 95
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
100 105 110
Ile Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser
115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
130 135 140
Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys
145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu
165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr
180 185 190
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
195 200 205
Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys
210 215 220
Val Glu Ile Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
225 230 235 240
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
245 250 255
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
260 265 270
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
275 280 285
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
290 295 300
Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
305 310 315 320
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
325 330 335
Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
340 345 350
Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp
355 360 365
Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe
370 375 380
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
385 390 395 400
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
405 410 415
Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
420 425 430
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
435 440 445
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 16
<211> 474
<212> PRT
<213> Homo sapiens
<400> 16
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
65 70 75 80
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
85 90 95
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
100 105 110
Ile Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser
115 120 125
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
130 135 140
Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Arg Gln
145 150 155 160
Ala Pro Gly Lys Cys Leu Glu Trp Val Ala Leu Ile Asn Pro Tyr Lys
165 170 175
Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser
180 185 190
Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg
195 200 205
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly
210 215 220
Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro
260 265 270
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
275 280 285
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
290 295 300
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
305 310 315 320
Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
325 330 335
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
340 345 350
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
355 360 365
Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu
370 375 380
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
385 390 395 400
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
405 410 415
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
420 425 430
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
435 440 445
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
450 455 460
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 17
<211> 463
<212> PRT
<213> Homo sapiens
<400> 17
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 Ile Arg 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 Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
115 120 125
Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His
130 135 140
Asp Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe
145 150 155 160
Ile Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro
165 170 175
Asp Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn
180 185 190
Ile Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
195 200 205
Ser Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu
210 215 220
Thr Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys Thr
225 230 235 240
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile
340 345 350
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 18
<211> 462
<212> PRT
<213> Homo sapiens
<400> 18
Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly
1 5 10 15
Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr Val
20 25 30
Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln
35 40 45
Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg Phe
50 55 60
Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn Ala
65 70 75 80
Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp Thr
85 90 95
Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val Thr
100 105 110
Glu Asp Leu Lys Asn Gly Gly Gly Ser Gly Gly Gly Gly Gln Ile Gln
115 120 125
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
130 135 140
Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met His Trp Tyr
145 150 155 160
Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser
165 170 175
Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
180 185 190
Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ala Ala
195 200 205
Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Gly
210 215 220
Gly Thr Lys Val Glu Ile Lys Glu Pro Lys Ser Ser Asp Lys Thr His
225 230 235 240
Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 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 Gln 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 Ser Ile Glu Lys Thr Ile Ser
340 345 350
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
355 360 365
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 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 Tyr 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 Lys
450 455 460
<210> 19
<211> 472
<212> PRT
<213> Homo sapiens
<400> 19
Glu 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 Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys
85 90 95
Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
130 135 140
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
145 150 155 160
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
165 170 175
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
180 185 190
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
195 200 205
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
210 215 220
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
225 230 235 240
Ile Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
245 250 255
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
305 310 315 320
Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
340 345 350
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
370 375 380
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 20
<211> 467
<212> PRT
<213> Homo sapiens
<400> 20
Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly
1 5 10 15
Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr Val
20 25 30
Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln
35 40 45
Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg Phe
50 55 60
Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn Ala
65 70 75 80
Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp Thr
85 90 95
Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val Thr
100 105 110
Glu Asp Leu Lys Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
130 135 140
Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser
145 150 155 160
Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp
165 170 175
Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
180 185 190
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
195 200 205
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro
210 215 220
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Glu Pro Lys Ser
225 230 235 240
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 21
<211> 472
<212> PRT
<213> Homo sapiens
<400> 21
Glu 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 Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys
85 90 95
Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
130 135 140
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
145 150 155 160
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
165 170 175
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
180 185 190
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
195 200 205
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
210 215 220
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
225 230 235 240
Ile Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
245 250 255
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
305 310 315 320
Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
340 345 350
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
370 375 380
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 22
<211> 462
<212> PRT
<213> Homo sapiens
<400> 22
Gln 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 Ser Ala Thr Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr
115 120 125
Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp
130 135 140
Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile
145 150 155 160
Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp
165 170 175
Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile
180 185 190
Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser
195 200 205
Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr
210 215 220
Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys Thr His
225 230 235 240
Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 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 Gln 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 Ser Ile Glu Lys Thr Ile Ser
340 345 350
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
355 360 365
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 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 Tyr 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 Lys
450 455 460
<210> 23
<211> 472
<212> PRT
<213> Homo sapiens
<400> 23
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
65 70 75 80
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
85 90 95
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
100 105 110
Ile Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser
115 120 125
Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys
130 135 140
Ala Ser Gly Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln
145 150 155 160
Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn
165 170 175
Asp Val Thr Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr
180 185 190
Ser Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg
195 200 205
Ser Glu Asp Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp
210 215 220
Tyr Asp Gly Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
245 250 255
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
305 310 315 320
Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
340 345 350
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
370 375 380
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 24
<211> 468
<212> PRT
<213> Homo sapiens
<400> 24
Gln 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 Ser Ala Thr Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Glu Ala Gly Val Thr Gln Ser Pro
115 120 125
Thr His Leu Ile Lys Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser
130 135 140
Pro Lys Ser Gly His Asp Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly
145 150 155 160
Gln Gly Pro Gln Phe Ile Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln
165 170 175
Arg Gly Asn Phe Pro Asp Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr
180 185 190
Ser Ser Glu Leu Asn Ile Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu
195 200 205
Tyr Leu Cys Ala Ser Ser Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly
210 215 220
Pro Gly Ile Arg Leu Thr Val Thr Glu Asp Leu Lys Asn Glu Pro Lys
225 230 235 240
Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val
245 250 255
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr
305 310 315 320
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser
340 345 350
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val
370 375 380
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Lys
465
<210> 25
<211> 472
<212> PRT
<213> Homo sapiens
<400> 25
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
65 70 75 80
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
85 90 95
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
100 105 110
Ile Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser
115 120 125
Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys
130 135 140
Ala Ser Gly Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln
145 150 155 160
Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn
165 170 175
Asp Val Thr Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr
180 185 190
Ser Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg
195 200 205
Ser Glu Asp Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp
210 215 220
Tyr Asp Gly Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
245 250 255
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
305 310 315 320
Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
340 345 350
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
370 375 380
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 26
<211> 231
<212> PRT
<213> Homo sapiens
<400> 26
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25 30
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
35 40 45
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
50 55 60
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
65 70 75 80
Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
85 90 95
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
100 105 110
Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
115 120 125
Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
130 135 140
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
145 150 155 160
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
165 170 175
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
180 185 190
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
195 200 205
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
210 215 220
Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 27
<211> 231
<212> PRT
<213> Homo sapiens
<400> 27
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25 30
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
35 40 45
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
50 55 60
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
65 70 75 80
Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
85 90 95
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
100 105 110
Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
115 120 125
Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys
130 135 140
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
145 150 155 160
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
165 170 175
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
180 185 190
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
195 200 205
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
210 215 220
Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 28
<211> 113
<212> PRT
<213> Homo sapiens
<400> 28
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
65 70 75 80
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
85 90 95
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
100 105 110
Ile
<210> 29
<211> 122
<212> PRT
<213> Homo sapiens
<400> 29
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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 30
<211> 8
<212> PRT
<213> Homo sapiens
<400> 30
Gly Gly Gly Ser Gly Gly Gly Gly
1 5
<210> 31
<211> 117
<212> PRT
<213> Homo sapiens
<400> 31
Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly
1 5 10 15
Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr Val
20 25 30
Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln
35 40 45
Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg Phe
50 55 60
Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn Ala
65 70 75 80
Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp Thr
85 90 95
Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val Thr
100 105 110
Glu Asp Leu Lys Asn
115
<210> 32
<211> 107
<212> PRT
<213> Homo sapiens
<400> 32
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 Ile Arg 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 Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105
<210> 33
<211> 478
<212> PRT
<213> Homo sapiens
<400> 33
Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly
1 5 10 15
Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr Val
20 25 30
Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln
35 40 45
Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg Phe
50 55 60
Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn Ala
65 70 75 80
Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp Thr
85 90 95
Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val Thr
100 105 110
Glu Asp Leu Lys Asn Gly Ser Ala Asp Asp Ala Lys Lys Asp Ala Ala
115 120 125
Lys Lys Asp Gly Lys Ser Gln Lys Glu Val Glu Gln Asn Ser Gly Pro
130 135 140
Leu Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser
145 150 155 160
Asp Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys
165 170 175
Ser Pro Glu Leu Ile Met Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp
180 185 190
Gly Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu
195 200 205
Leu Ile Arg Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala
210 215 220
Val Arg Gly Ala His Asp Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser
225 230 235 240
Leu Leu Val Thr Pro His Ile Glu Pro Lys Ser Ser Asp Lys Thr His
245 250 255
Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
370 375 380
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
420 425 430
Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 34
<211> 451
<212> PRT
<213> Homo sapiens
<400> 34
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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
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 Gln 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 Ser 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 Trp 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> 35
<211> 698
<212> PRT
<213> Homo sapiens
<400> 35
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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
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 Gln 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 Ser 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 Ser Cys Ala 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 Val 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 Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
450 455 460
Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His
465 470 475 480
Asp Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe
485 490 495
Ile Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro
500 505 510
Asp Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn
515 520 525
Ile Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
530 535 540
Ser Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu
545 550 555 560
Thr Val Thr Glu Asp Leu Lys Asn Gly Ser Ala Asp Asp Ala Lys Lys
565 570 575
Asp Ala Ala Lys Lys Asp Gly Lys Ser Gln Lys Glu Val Glu Gln Asn
580 585 590
Ser Gly Pro Leu Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys
595 600 605
Thr Tyr Ser Asp Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr
610 615 620
Ser Gly Lys Ser Pro Glu Leu Ile Met Ser Ile Tyr Ser Asn Gly Asp
625 630 635 640
Lys Glu Asp Gly Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr
645 650 655
Ile Ser Leu Leu Ile Arg Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr
660 665 670
Leu Cys Ala Val Arg Gly Ala His Asp Tyr Ala Leu Asn Phe Gly Lys
675 680 685
Gly Thr Ser Leu Leu Val Thr Pro His Ile
690 695
<210> 36
<211> 692
<212> PRT
<213> Homo sapiens
<400> 36
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 Ile Arg 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 Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
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 Glu Pro Lys Ser Ser Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 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 Gln 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 Ser 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 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp 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 Glu Ala Gly
435 440 445
Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly Gln Gln Val
450 455 460
Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr Val Ser Trp Tyr
465 470 475 480
Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln Tyr Val Arg
485 490 495
Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg Phe Ser Gly His
500 505 510
Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn Ala Leu Leu Leu
515 520 525
Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp Thr Val Ser Tyr
530 535 540
Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val Thr Glu Asp Leu
545 550 555 560
Lys Asn Gly Ser Ala Asp Asp Ala Lys Lys Asp Ala Ala Lys Lys Asp
565 570 575
Gly Lys Ser Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val
580 585 590
Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly
595 600 605
Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu
610 615 620
Leu Ile Met Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe
625 630 635 640
Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg
645 650 655
Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly
660 665 670
Ala His Asp Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val
675 680 685
Thr Pro His Ile
690
<210> 37
<211> 698
<212> PRT
<213> Homo sapiens
<400> 37
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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
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 Gln 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 Ser 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 Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
450 455 460
Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His
465 470 475 480
Asp Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe
485 490 495
Ile Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro
500 505 510
Asp Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn
515 520 525
Ile Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
530 535 540
Ser Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu
545 550 555 560
Thr Val Thr Glu Asp Leu Lys Asn Gly Ser Ala Asp Asp Ala Lys Lys
565 570 575
Asp Ala Ala Lys Lys Asp Gly Lys Ser Gln Lys Glu Val Glu Gln Asn
580 585 590
Ser Gly Pro Leu Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys
595 600 605
Thr Tyr Ser Asp Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr
610 615 620
Ser Gly Lys Ser Pro Glu Leu Ile Met Ser Ile Tyr Ser Asn Gly Asp
625 630 635 640
Lys Glu Asp Gly Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr
645 650 655
Ile Ser Leu Leu Ile Arg Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr
660 665 670
Leu Cys Ala Val Arg Gly Ala His Asp Tyr Ala Leu Asn Phe Gly Lys
675 680 685
Gly Thr Ser Leu Leu Val Thr Pro His Ile
690 695
<210> 38
<211> 696
<212> PRT
<213> Homo sapiens
<400> 38
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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln 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 Gly Leu Pro Ser Ser 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 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala 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 Val Ser Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu 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 Leu Gly
435 440 445
Lys Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg
450 455 460
Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr
465 470 475 480
Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe
485 490 495
Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg
500 505 510
Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn
515 520 525
Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp
530 535 540
Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val
545 550 555 560
Thr Glu Asp Leu Lys Asn Gly Ser Ala Asp Asp Ala Lys Lys Asp Ala
565 570 575
Ala Lys Lys Asp Gly Lys Ser Gln Lys Glu Val Glu Gln Asn Ser Gly
580 585 590
Pro Leu Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr
595 600 605
Ser Asp Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly
610 615 620
Lys Ser Pro Glu Leu Ile Met Ser Ile Tyr Ser Asn Gly Asp Lys Glu
625 630 635 640
Asp Gly Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Ile Ser
645 650 655
Leu Leu Ile Arg Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys
660 665 670
Ala Val Arg Gly Ala His Asp Tyr Ala Leu Asn Phe Gly Lys Gly Thr
675 680 685
Ser Leu Leu Val Thr Pro His Ile
690 695
<210> 39
<211> 690
<212> PRT
<213> Homo sapiens
<400> 39
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 Ile Arg 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 Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
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
Asn 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 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Glu Ala Gly Val Thr
435 440 445
Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly Gln Gln Val Thr Leu
450 455 460
Arg Cys Ser Pro Lys Ser Gly His Asp Thr Val Ser Trp Tyr Gln Gln
465 470 475 480
Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln Tyr Val Arg Gly Glu
485 490 495
Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg Phe Ser Gly His Gln Tyr
500 505 510
Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn Ala Leu Leu Leu Gly Asp
515 520 525
Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp Thr Val Ser Tyr Glu Gln
530 535 540
Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val Thr Glu Asp Leu Lys Asn
545 550 555 560
Gly Ser Ala Asp Asp Ala Lys Lys Asp Ala Ala Lys Lys Asp Gly Lys
565 570 575
Ser Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu
580 585 590
Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln
595 600 605
Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile
610 615 620
Met Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala
625 630 635 640
Gln Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser
645 650 655
Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His
660 665 670
Asp Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro
675 680 685
His Ile
690
<210> 40
<211> 428
<212> PRT
<213> Homo sapiens
<400> 40
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 Ile Arg 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 Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
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
Asn 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 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
210 215 220
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
225 230 235 240
Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
245 250 255
Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val
260 265 270
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr
275 280 285
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
290 295 300
Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
305 310 315 320
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
325 330 335
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
340 345 350
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
355 360 365
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
370 375 380
Ser Thr Tyr Ser Leu Ser Asn Thr Leu Thr Leu Ser Lys Ala Asp Tyr
385 390 395 400
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
405 410 415
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
420 425
<210> 41
<211> 1392
<212> PRT
<213> Homo sapiens
<400> 41
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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln 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 Gly Leu Pro Ser Ser 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 Gln Glu Glu Met 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 Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu 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 Leu Gly
435 440 445
Lys Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg
450 455 460
Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr
465 470 475 480
Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe
485 490 495
Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg
500 505 510
Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn
515 520 525
Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp
530 535 540
Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val
545 550 555 560
Thr Glu Asp Leu Lys Asn Gly Ser Ala Asp Asp Ala Lys Lys Asp Ala
565 570 575
Ala Lys Lys Asp Gly Lys Ser Gln Lys Glu Val Glu Gln Asn Ser Gly
580 585 590
Pro Leu Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr
595 600 605
Ser Asp Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly
610 615 620
Lys Ser Pro Glu Leu Ile Met Ser Ile Tyr Ser Asn Gly Asp Lys Glu
625 630 635 640
Asp Gly Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Ile Ser
645 650 655
Leu Leu Ile Arg Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys
660 665 670
Ala Val Arg Gly Ala His Asp Tyr Ala Leu Asn Phe Gly Lys Gly Thr
675 680 685
Ser Leu Leu Val Thr Pro His Ile Glu Val Gln Leu Val Glu Ser Gly
690 695 700
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
705 710 715 720
Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Arg Gln Ala
725 730 735
Pro Gly Lys Gly Leu Glu Trp Val Ala Leu Ile Asn Pro Tyr Lys Gly
740 745 750
Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Val
755 760 765
Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala
770 775 780
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp
785 790 795 800
Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val
805 810 815
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys
820 825 830
Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys
835 840 845
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
850 855 860
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
865 870 875 880
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
885 890 895
Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val
900 905 910
Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
915 920 925
Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
930 935 940
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
945 950 955 960
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
965 970 975
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
980 985 990
Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
995 1000 1005
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
1010 1015 1020
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
1025 1030 1035
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
1040 1045 1050
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
1055 1060 1065
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
1070 1075 1080
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
1085 1090 1095
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
1100 1105 1110
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
1115 1120 1125
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
1130 1135 1140
Gly Lys Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
1145 1150 1155
Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly
1160 1165 1170
His Asp Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro
1175 1180 1185
Gln Phe Ile Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly
1190 1195 1200
Asn Phe Pro Asp Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser
1205 1210 1215
Ser Glu Leu Asn Ile Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu
1220 1225 1230
Tyr Leu Cys Ala Ser Ser Asp Thr Val Ser Tyr Glu Gln Tyr Phe
1235 1240 1245
Gly Pro Gly Ile Arg Leu Thr Val Thr Glu Asp Leu Lys Asn Gly
1250 1255 1260
Ser Ala Asp Asp Ala Lys Lys Asp Ala Ala Lys Lys Asp Gly Lys
1265 1270 1275
Ser Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro
1280 1285 1290
Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly
1295 1300 1305
Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro
1310 1315 1320
Glu Leu Ile Met Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
1325 1330 1335
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu
1340 1345 1350
Leu Ile Arg Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys
1355 1360 1365
Ala Val Arg Gly Ala His Asp Tyr Ala Leu Asn Phe Gly Lys Gly
1370 1375 1380
Thr Ser Leu Leu Val Thr Pro His Ile
1385 1390
<210> 42
<211> 214
<212> PRT
<213> Homo sapiens
<400> 42
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 Ile Arg 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 Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
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> 43
<211> 461
<212> PRT
<213> Homo sapiens
<400> 43
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Phe Ser Leu Leu Ile Arg Asp Ser Gln
65 70 75 80
Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Ala Val Ile Asp Asn Ser
85 90 95
Asn Gly Gly Ile Leu Thr Phe Gly Thr Gly Thr Arg Leu Thr Ile Ile
100 105 110
Pro Asn Ile Gln Asn Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln
115 120 125
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
130 135 140
Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp
145 150 155 160
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr
165 170 175
Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
180 185 190
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile
195 200 205
Ala Thr Tyr Phe Cys Gln Gln Gly Gln Thr Leu Pro Trp Thr Phe Gly
210 215 220
Gln Gly Thr Lys Val Glu Ile Lys Glu Pro Lys Ser Ser Asp Lys Thr
225 230 235 240
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile
340 345 350
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
<210> 44
<211> 477
<212> PRT
<213> Homo sapiens
<400> 44
Glu 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
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Lys Ala Gly Val Thr Gln Thr Pro Arg Tyr Leu Ile Lys Thr
130 135 140
Arg Gly Gln Gln Val Thr Leu Ser Cys Ser Pro Ile Pro Gly His Arg
145 150 155 160
Ser Val Ser Trp Tyr Gln Gln Thr Pro Gly Gln Gly Leu Gln Phe Leu
165 170 175
Phe Glu Tyr Val His Gly Ala Glu Arg Asn Lys Gly Asn Phe Pro Gly
180 185 190
Arg Phe Ser Gly Arg Gln Phe Ser Asn Ser Ser Ser Glu Met Asn Ile
195 200 205
Ser Asn Leu Glu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser
210 215 220
Pro Trp Asp Ser Pro Asn Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
225 230 235 240
Thr Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys Thr
245 250 255
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
260 265 270
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
275 280 285
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
290 295 300
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
305 310 315 320
Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser
325 330 335
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
340 345 350
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile
355 360 365
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
370 375 380
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
385 390 395 400
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
405 410 415
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
420 425 430
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
435 440 445
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
450 455 460
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475
<210> 45
<211> 463
<212> PRT
<213> Homo sapiens
<400> 45
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp Ser Gln
65 70 75 80
Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Ala Val Ile Asp Asn Asp
85 90 95
Gln Gly Gly Ile Leu Thr Phe Gly Thr Gly Thr Arg Leu Thr Ile Ile
100 105 110
Pro Asn Ile Gln Asn Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln
115 120 125
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
130 135 140
Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp
145 150 155 160
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr
165 170 175
Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
180 185 190
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile
195 200 205
Ala Thr Tyr Phe Cys Gln Gln Gly Gln Thr Leu Pro Trp Thr Phe Gly
210 215 220
Gln Gly Thr Lys Val Glu Ile Lys Glu Pro Lys Ser Ser Asp Lys Thr
225 230 235 240
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile
340 345 350
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 46
<211> 479
<212> PRT
<213> Homo sapiens
<400> 46
Glu 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
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Lys Ala Gly Val Thr Gln Thr Pro Arg Tyr Leu Ile Lys Thr
130 135 140
Arg Gly Gln Gln Val Thr Leu Ser Cys Ser Pro Ile Pro Gly His Arg
145 150 155 160
Ala Val Ser Trp Tyr Gln Gln Thr Pro Gly Gln Gly Leu Gln Phe Leu
165 170 175
Phe Glu Tyr Val His Gly Glu Glu Arg Asn Lys Gly Asn Phe Pro Gly
180 185 190
Arg Phe Ser Gly Arg Gln Phe Ser Asn Ser Ser Ser Glu Met Asn Ile
195 200 205
Ser Asn Leu Glu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser
210 215 220
Pro Trp Asp Ser Pro Asn Val Gln Tyr Phe Gly Pro Gly Thr Arg Leu
225 230 235 240
Thr Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys Thr
245 250 255
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
260 265 270
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
275 280 285
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
290 295 300
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
305 310 315 320
Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser
325 330 335
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
340 345 350
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile
355 360 365
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
370 375 380
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
385 390 395 400
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
405 410 415
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
420 425 430
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
435 440 445
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
450 455 460
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 47
<211> 229
<212> PRT
<213> Homo sapiens
<400> 47
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25 30
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
35 40 45
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
50 55 60
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
65 70 75 80
Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
85 90 95
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
100 105 110
Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
115 120 125
Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
130 135 140
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
145 150 155 160
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
165 170 175
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
180 185 190
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
195 200 205
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
210 215 220
Leu Ser Leu Ser Pro
225
<210> 48
<211> 229
<212> PRT
<213> Homo sapiens
<400> 48
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25 30
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
35 40 45
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
50 55 60
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
65 70 75 80
Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
85 90 95
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
100 105 110
Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
115 120 125
Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys
130 135 140
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
145 150 155 160
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
165 170 175
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
180 185 190
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
195 200 205
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
210 215 220
Leu Ser Leu Ser Pro
225
<210> 49
<211> 9
<212> PRT
<213> Homo sapiens
<400> 49
Ser Leu Leu Gln His Leu Ile Gly Leu
1 5
<210> 50
<211> 6
<212> PRT
<213> Homo sapiens
<400> 50
Glu Leu Leu Gly Gly Pro
1 5
<210> 51
<211> 457
<212> PRT
<213> Homo sapiens
<400> 51
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
65 70 75 80
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
85 90 95
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
100 105 110
Ile Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser
115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
130 135 140
Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys
145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His
165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr
180 185 190
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe
195 200 205
Cys Gln Gln Gly Gln Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys
210 215 220
Val Glu Ile Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
225 230 235 240
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
245 250 255
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
260 265 270
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
275 280 285
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
290 295 300
Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
305 310 315 320
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
325 330 335
Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
340 345 350
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp
355 360 365
Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe
370 375 380
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
385 390 395 400
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
405 410 415
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
420 425 430
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
435 440 445
Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455
<210> 52
<211> 476
<212> PRT
<213> Homo sapiens
<400> 52
Glu 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
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr
130 135 140
Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp
145 150 155 160
Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile
165 170 175
Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp
180 185 190
Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile
195 200 205
Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser
210 215 220
Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr
225 230 235 240
Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys Thr His
245 250 255
Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro
370 375 380
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
420 425 430
Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475
<210> 53
<211> 457
<212> PRT
<213> Homo sapiens
<400> 53
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 Ile Arg 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 Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Gln Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val
115 120 125
Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly
130 135 140
Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu
145 150 155 160
Leu Ile Met Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe
165 170 175
Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg
180 185 190
Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly
195 200 205
Ala His Asp Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val
210 215 220
Thr Pro His Ile Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
225 230 235 240
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
245 250 255
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
260 265 270
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
275 280 285
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
290 295 300
Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
305 310 315 320
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
325 330 335
Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
340 345 350
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp
355 360 365
Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe
370 375 380
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
385 390 395 400
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
405 410 415
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
420 425 430
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
435 440 445
Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455
<210> 54
<211> 476
<212> PRT
<213> Homo sapiens
<400> 54
Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly
1 5 10 15
Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr Val
20 25 30
Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln
35 40 45
Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg Phe
50 55 60
Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn Ala
65 70 75 80
Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp Thr
85 90 95
Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val Thr
100 105 110
Glu Asp Leu Lys Asn Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln
115 120 125
Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys
130 135 140
Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Leu Ile
165 170 175
Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe Gln Asp Arg
180 185 190
Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu
195 200 205
Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser
210 215 220
Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His
245 250 255
Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro
370 375 380
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
420 425 430
Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475
<210> 55
<211> 461
<212> PRT
<213> Homo sapiens
<400> 55
Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly
1 5 10 15
Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr Val
20 25 30
Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln
35 40 45
Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg Phe
50 55 60
Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu Asn Ile Asn Ala
65 70 75 80
Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Asp Thr
85 90 95
Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg Leu Thr Val Thr
100 105 110
Glu Asp Leu Lys Asn Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln
115 120 125
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
130 135 140
Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp
145 150 155 160
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr
165 170 175
Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
180 185 190
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile
195 200 205
Ala Thr Tyr Phe Cys Gln Gln Gly Gln Thr Leu Pro Trp Thr Phe Gly
210 215 220
Gln Gly Thr Lys Val Glu Ile Lys Glu Pro Lys Ser Ser Asp Lys Thr
225 230 235 240
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile
340 345 350
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
<210> 56
<211> 472
<212> PRT
<213> Homo sapiens
<400> 56
Glu 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
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro
130 135 140
Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser
145 150 155 160
Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu
165 170 175
Ile Met Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr
180 185 190
Ala Gln Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp
195 200 205
Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala
210 215 220
His Asp Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr
225 230 235 240
Pro His Ile Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro
260 265 270
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
275 280 285
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
290 295 300
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
305 310 315 320
Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
325 330 335
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
340 345 350
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
355 360 365
Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu
370 375 380
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
385 390 395 400
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
405 410 415
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
420 425 430
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
435 440 445
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
450 455 460
Gln Lys Ser Leu Ser Leu Ser Pro
465 470
<210> 57
<211> 462
<212> PRT
<213> Homo sapiens
<400> 57
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 Ile Arg 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 Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Gln Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gly Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile
115 120 125
Lys Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly
130 135 140
His Asp Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln
145 150 155 160
Phe Ile Phe Gln Tyr Val Arg Gly Glu Glu Arg Gln Arg Gly Asn Phe
165 170 175
Pro Asp Arg Phe Ser Gly His Gln Tyr Pro Asn Tyr Ser Ser Glu Leu
180 185 190
Asn Ile Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala
195 200 205
Ser Ser Asp Thr Val Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Ile Arg
210 215 220
Leu Thr Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys
225 230 235 240
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser
245 250 255
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
260 265 270
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
275 280 285
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
290 295 300
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val
305 310 315 320
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
325 330 335
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr
340 345 350
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
355 360 365
Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys
370 375 380
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
385 390 395 400
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
405 410 415
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
420 425 430
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
435 440 445
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
<210> 58
<211> 472
<212> PRT
<213> Homo sapiens
<400> 58
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp Ser Lys
65 70 75 80
Leu Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Gly Ala His Asp
85 90 95
Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
100 105 110
Ile Gly Gly Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser
115 120 125
Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys
130 135 140
Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Arg Gln
145 150 155 160
Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys
165 170 175
Gly Val Ser Thr Tyr Ala Gln Lys Phe Gln Asp Arg Val Thr Leu Thr
180 185 190
Val Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg
195 200 205
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly
210 215 220
Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro
260 265 270
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
275 280 285
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
290 295 300
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
305 310 315 320
Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
325 330 335
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
340 345 350
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
355 360 365
Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu
370 375 380
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
385 390 395 400
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
405 410 415
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
420 425 430
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
435 440 445
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
450 455 460
Gln Lys Ser Leu Ser Leu Ser Pro
465 470
Claims (21)
1.一种双特异性多肽分子,其选自包含第一多肽链和第二多肽链的分子组,其中:
第一多肽链包含与人免疫效应细胞的细胞表面抗原特异性结合的抗体的可变结构域(VD1)的第一结合区,和
与MHC相关肽表位特异性结合的TCR的可变结构域(VR1)的第一结合区,和连接所述结构域的第一接头(LINK1);
第二多肽链包含与MHC相关肽表位特异性结合的TCR的可变结构域(VR2)的第二结合区,和
与人免疫效应细胞的细胞表面抗原特异性结合的抗体的可变结构域(VD2)的第二结合区,和
连接所述结构域的第二接头(LINK2);
其中所述第一结合区(VD1)和所述第二结合区(VD2)结合形成结合免疫效应细胞的细胞表面抗原的的第一结合位点(VD1)(VD2);
所述第一结合区(VR1)和所述第二结合区(VR2)结合形成结合所述MHC相关肽表位的第二结合位点(VR1)(VR2);
其中所述两条多肽链与人IgG铰链结构域和/或人IgG Fc结构域或其二聚化部分融合;和
其中所述两条多肽链透过所述铰链结构域和/或Fc结构域之间的共价键和/或非共价键连接;和
其中所述双特异性多肽分子能够同时结合细胞表面分子和MHC相关肽表位,和双特异性多肽分子,其中两个多肽链中结合区的顺序选自VD1-VR1和VR2-VD2或VD1-VR2和VR1-VD2或VD2-VR1和VR2-VD1或VD2-VR2和VR1-VD1,并且其中结构域透过LINK1或LINK2连接。
2.根据权利要求1所述的双特异性多肽分子,其中所述多肽链中结合区的顺序选自VD1-VR1和VD2-VR2;并且其中结构域分别透过LINK1或LINK2连接。
3.根据权利要求1所述的双特异性多肽分子,其中所述接头序列LINK1和/或LINK2含有至少一个选自GGGS、GGGGS、TVLRT、TVSSAS和TVLSSAS的序列基序。
4.根据权利要求1至3中任一项所述的双特异性多肽分子,其中所述第一和第二多肽链还包含至少一个铰链结构域和衍生自人IgG1、IgG2或IgG4的Fc结构域或其部分。
5.根据权利要求4所述的双特异性多肽分子,其中所述Fc结构域在选自233、234、235、236、297和331位置的残基处包含至少一个效应子功能沉寂突变,优选其中所述效应子功能沉寂突变透过用衍生自IgG2或IgG4相应残基取代233、234、235、236和331位置的至少一个残基而产生。
6.根据权利要求3至5中任一项所述的双特异性多肽分子,其中所述Fc结构域包含CH3结构域,其含有至少一个促进异二聚体形成的突变。
7.根据权利要求6所述的双特异性多肽分子,其中所述突变位于选自366、368、405和407的任何位置,优选地,其中所述突变包含T366W和T366'S、L368A'和Y407'V作为杵臼结构突变。
8.根据权利要求3至7中任一项所述的双特异性多肽分子,其中所述Fc结构域包含CH2和CH3结构域,所述CH2和CH3结构域包含至少两个另外的半胱氨酸残基,例如:S354C和Y349C或L242C和K334C。
9.根据权利要求1-8中任一项所述的双特异性多肽分子,其中所述抗体衍生的结构域VD1和VD2显示工程化的二硫键桥,其在VD1和VD2之间引入共价键,并且其中所述半胱氨酸在VL情况下被引入框架区(FR)4,在VH情况下被引入框架区2。
10.根据权利要求1-9中任一项所述的双特异性多肽分子,其中已知所述细胞表面分子诱导免疫细胞的活化,或者是选自免疫应答相关分子、CD3(例如:CD3γ、CD3δ和CD3ε链)、CD4、CD7、CD8、CD10、CD11b、CD11c、CD14、CD16、CD18、CD22、CD25、CD28、CD32a、CD32b、CD33、CD41、CD41b、CD42a、CD42b、CD44、CD45RA、CD49、CD55、CD56、CD61、CD64、CD68、CD94、CD90、CD117、CD123、CD125、CD134、CD137、CD152、CD163、CD193、CD203c、CD235a、CD278、CD279、CD287、Nkp46、NKG2D、GITR、FcεRI、TCRα/β、TCRγ/δ、HLA-DR所组成的群中的至少一种。
11.根据权利要求1至10中任一项所述的双特异性多肽分子,其中第一多肽链中的区域包含VD1的SEQ ID No.28、VR1的SEQ ID No.29、LINK1的SEQ ID No.3;第二多肽链中的区域包含VD2的SEQ ID No.31、VR2的SEQ ID No.32和LINK2的SEQ ID No.30。
12.根据权利要求3至11中任一项所述的双特异性多肽分子,其中第一多肽链中的FC区包含SEQ ID No.26至SEQ ID No.47(Fc1),第二多肽链中的FC区包含SEQ ID No.27或SEQID No.48(Fc2)。
13.双特异性多肽分子,其包含含有SEQ ID No.16或SEQ ID No.43或SEQ ID No.45或SEQ ID No.51、53、55或57的第一多肽链,和含有SEQ ID No.17或SEQ ID 44或SEQ IDNo.46或SEQ ID No.52、54、56或58的第二多肽链。
14.根据权利要求1至13中任一项所述的双特异性多肽分子,其中所述分子携带可检测标记。
15.根据权利要求1至14中任一项所述的双特异性多肽分子,其中结合所述免疫细胞的细胞表面抗原的所述第一结合位点(VD1)(VD2)被人源化;和/或结合所述MHC相关肽表位的所述第二结合位点(VR1)(VR2)成熟以获得更高的亲和力和/或稳定性。
16.编码根据权利要求1至15任一项所述的第一多肽链和/或第二多肽链的核酸,或包含至少一种所述核酸的表达载体。
17.一种宿主细胞,其包含并任选表达权利要求16所定义的载体。
18.一种药物组合物,其包含根据权利要求1至15中任一项所述的双特异性多肽分子、根据权利要求16所述的核酸或载体、或根据权利要求17所述的细胞,以及一种或多种药用载体或赋形剂。
19.根据权利要求1至15中任一项所述的双特异性多肽分子、根据权利要求16所述的核酸或载体、根据权利要求17所述的细胞、或根据权利要求18所述的药物组合物用于药物中。
20.根据权利要求1至15中任一项所述的双特异性多肽分子、根据权利要求16所述的核酸或载体、根据权利要求17所述的细胞、或根据权利要求18所述的药物组合物用于治疗或预防选癌症、传染病和自免疫疾病的疾病或病症。
21.一种治疗疾病或病症的方法,包括给予治疗有效量的根据权利要求1至15中任一项所述的双特异性多肽分子、根据权利要求16所述的核酸或载体、根据权利要求17所述的细胞、或根据权利要求18所述的药物组合物。
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