CN110198737A - 靶向psma的三特异性蛋白质及使用方法 - Google Patents
靶向psma的三特异性蛋白质及使用方法 Download PDFInfo
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Abstract
本文提供了包含与CD3结合的结构域、半衰期延长结构域和与PSMA结合的结构域的靶向前列腺特异性膜抗原(PSMA)的三特异性蛋白质。还提供了其药物组合物,以及用于制备这类靶向PSMA的三特异性蛋白质的核酸、重组表达载体和宿主细胞。还公开了使用所公开的靶向PSMA的三特异性蛋白质预防和/或治疗疾病、病况和病症的方法。
Description
交叉引用
本申请要求于2016年11月23日提交的第62/426,069号美国临时申请和2016年11月23日提交的第62/426,077号美国临时申请的权益,这些临时申请通过引用以其全文并入本文。
序列表
本申请包含序列表,该序列表已经以ASCII格式通过电子方式提交,并且通过引用整体并入本文。所述ASCII副本创建于2017年11月22日,被命名为47517-708_601_SL.txt,大小为150,911字节。
背景技术
在多种临床环境中常常需要选择性破坏单个细胞或特定的细胞类型。例如,癌症疗法的首要目标是特定地破坏肿瘤细胞,同时使健康细胞和组织保持完整且不受损伤。一种这样的方法是诱导针对肿瘤的免疫应答,使得免疫效应细胞如自然杀伤(NK)细胞或细胞毒性T淋巴细胞(CTL)攻击并破坏肿瘤细胞。
发明内容
本文提供了三特异性抗原结合蛋白质,其药物组合物,用于制备这类三特异性抗原结合蛋白质的核酸、重组表达载体和宿主细胞,以及用于治疗疾病、病症或病况的方法。在一个方面,本文描述了靶向前列腺特异性膜抗原(PSMA)的三特异性蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与PSMA特异性结合的第三结构域(C),其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接。在一些实施方案中,第一结构域包含各自能够与人CD3特异性结合的可变轻链和可变重链。在一些实施方案中,第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。在一些实施方案中,第一结构域是人源化的或人的。在一些实施方案中,第一结构域与表达CD3的细胞上的CD3结合的KD为150nM或更低。在一些实施方案中,第二结构域结合人血清白蛋白。在一些实施方案中,第二结构域包含scFv、可变重链(VH)结构域、可变轻链(VL)结构域、肽、配体或小分子。在一些实施方案中,第二结构域包含一种或多种选自SEQ ID NO:89-112的序列。在一些实施方案中,第三结构域包含与PSMA特异性结合的scFv、VH结构域、VL结构域、非Ig结构域、配体、knottin或小分子实体。在一些实施方案中,第三结构域包含一种或多种选自SEQ ID NO:113-140的序列。
在一些实施方案中,连接体L1和L2各自独立地选自(GS)n(SEQ ID NO:153)、(GGS)n(SEQ ID NO:154)、(GGGS)n(SEQ ID NO:155)、(GGSG)n(SEQ ID NO:156)、(GGSGG)n(SEQID NO:157)或(GGGGS)n(SEQ ID NO:158),其中n为1、2、3、4、5、6、7、8、9或10。在一些实施方案中,连接体L1和L2各自独立地为(GGGGS)4(SEQ ID NO:159)或(GGGGS)3(SEQ ID NO:160)。在一些实施方案中,所述结构域以H2N-(A)-(C)-(B)-COOH的顺序连接。在一些实施方案中,所述结构域以H2N-(B)-(C)-(A)-COOH的顺序连接。
在一些实施方案中,所述蛋白质小于约80kDa。在一些实施方案中,所述蛋白质为约50kDa至约75kDa。在一些实施方案中,所述蛋白质小于约60kDa。在一些实施方案中,所述蛋白质具有至少约50小时的消除半衰期。在一些实施方案中,所述蛋白质具有至少约100小时的消除半衰期。在一些实施方案中,与针对相同PSMA的IgG相比,所述蛋白质具有增加的组织穿透。
在一些实施方案中,所述蛋白质包含选自SEQ ID NO:140-152的序列。
在另一个方面,本文提供了药物组合物,其包含(i)根据以上实施方案中任一项所述的靶向PSMA的三特异性蛋白质,和(ii)药学上可接受的载剂(carrier)。
本文还提供了治疗需要癌症治疗的个体的方法,该方法包括施用有效量的根据以上实施方案中任一项所述的药物组合物或靶向PSMA的三特异性蛋白质。在一些实施方案中,所述癌症是前列腺癌或肾癌。
一个实施方案提供了靶向PSMA的三特异性蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与PSMA特异性结合的第三结构域(C),其中第二结构域包含一种或多种选自SEQ ID NO:113-140的序列。在一些实施方案中,结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接。在一些实施方案中,第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。在一些实施方案中,第二结构域包含一种或多种选自SEQ ID NO:89-112的序列。
一个实施方案提供了靶向PSMA的三特异性蛋白质,其中所述蛋白质包含选自SEQID NO:140-152的序列。在一些实施方案中,所述蛋白质包含选自SEQ ID NO:150-152的序列。
一个实施方案提供了靶向前列腺特异性膜抗原(PSMA)的三特异性蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与PSMA特异性结合的第三结构域(C),其中所述结构域以H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接,并且其中第三结构域包含一种或多种选自SEQ ID NO:113-140的序列。
一个实施方案提供了靶向PSMA的三特异性蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与PSMA特异性结合的第三结构域(C),其中所述结构域以H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接,并且其中第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。
一个实施方案提供了治疗前列腺癌的方法,该方法包括施用有效量的靶向PSMA的三特异性蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与PSMA特异性结合的第三结构域(C),其中所述结构域以H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接,并且其中第三结构域包含一种或多种选自SEQ ID NO:113-140的序列。
一个实施方案提供了治疗前列腺癌的方法,该方法包括施用有效量的靶向PSMA的三特异性蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与PSMA特异性结合的第三结构域(C),其中所述结构域以H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接,并且其中第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。
援引并入
本说明书中提及的所有出版物、专利和专利申请均通过引用并入本文,其程度如同特别地且单独地指出每个单独的出版物、专利或专利申请通过引用而并入。
附图说明
本发明的新特征在随附的权利要求书中具体阐述。通过参考以下对利用到本发明原理的说明性实施方案加以阐述的详细描述及其附图,将会对本发明的特征和优点获得更好的理解,在这些附图中:
图1是示例性靶向PMSA的三特异性抗原结合蛋白质的示意图,其中该蛋白质具有包含抗CD3ε单链可变片段(scFv)和抗HSA可变重链区的恒定核心元件;以及PMSA结合域,该PMSA结合域可以是VH、scFv、非Ig结合物或配体。
图2A-图2B比较了对CD3具有不同亲和力的示例性靶向PSMA的三特异性蛋白质(靶向PSMA的TriTAC分子)诱导T细胞杀伤人前列腺癌细胞的能力。图2A示出了不同的靶向PSMA的TriTAC分子在前列腺癌模型LNCaP中的杀伤。图2B示出了不同的靶向PSMA的TriTAC分子在前列腺癌模型22Rv1中的杀伤。图2C示出了靶向PSMA的TriTAC在LNCaP和22Rv1前列腺癌模型中的EC50值。
图3示出了在静脉内(i.v.)施用(100μg/kg)后的三周内,靶向PSMA的TriTAC C236在食蟹猴中的血清浓度。
图4示出了在静脉内(i.v.)施用(100μg/kg)后的三周内,具有不同CD3亲和力的靶向PSMA的TriTAC分子在食蟹猴中的血清浓度。
图5A-图5C示出了对PSMA具有不同亲和力的靶向PSMA的TriTAC分子诱导T细胞杀伤人前列腺癌细胞系LNCaP的能力。图5A示出了在不存在人血清白蛋白的情况下进行的实验,以靶向PSMA的BiTE作为阳性对照。图5B示出了在人血清白蛋白的存在下进行的实验,以靶向PSMA的BiTE作为阳性对照。图5C示出了在LNCaP前列腺癌模型中,在存在或不存在HSA的情况下,靶向PSMA的TriTAC的EC50值,以靶向PSMA的BiTE作为阳性对照。
图6显示了在小鼠异种移植实验中,靶向PSMA的TriTAC分子抑制人前列腺癌细胞的肿瘤生长的能力。
图7A-图7D示出了在使用表达或不表达靶蛋白质的靶细胞系的细胞杀伤试验中,TriTAC分子的特异性。图7A示出了在LNCaP、KMS12BM和OVCAR8细胞系中的EGFR和PSMA表达。图7B示出了PSMA、EGFR和阴性对照TriTAC对LNCaP肿瘤细胞的杀伤。图7C示出了PSMA、EGFR和阴性对照TriTAC对KMS12BM肿瘤细胞的杀伤。图7D示出了PSMA、EGFR和阴性对照TriTAC对OVCAR8细胞的杀伤。
图8A-图8D描绘了在37℃下预温育和冷冻/解冻循环对TriTAC活性的影响。图8A示出了在37℃下预温育或冷冻/解冻循环后的PSMA TriTAC C235活性。图8B示出了在37℃下预温育或冷冻/解冻循环后的PSMA TriTAC C359活性。图8C示出了在37℃下预温育或冷冻/解冻循环后的PSMA TriTAC C360活性。图8D示出了在37℃下预温育或冷冻/解冻循环后的PSMA TriTAC C361活性。
图9A-图9B描绘了本发明的靶向PSMA的TriTAC分子在T细胞依赖性细胞毒性试验(TDCC)中在重导向T细胞杀伤方面的活性。图9A示出了靶向PSMA的TriTAC分子在重新引导来自食蟹猴供体G322的食蟹猴外周血单个核细胞(PBMC)杀伤LNCaP细胞的影响。图9B示出了靶向PSMA的TriTAC分子在重新引导来自食蟹猴供体D173的食蟹猴PBMC杀伤MDAPCa2b细胞的影响。
图10描绘了本发明的靶向PSMA的TriTAC分子对T细胞活化标志物CD25和CD69的表达的影响。
图11描绘了本发明的靶向PSMA的TriTAC分子在表达PSMA的靶细胞的存在下刺激T细胞增殖的能力。
图12A-图12B描绘了由靶向PSMA的TriTAC分子重导向的对LnCaP细胞的T细胞杀伤。图12A示出了由PSMA PH1T TriTAC(SEQ ID No:150)和PSMA PH1 TriTAC(SEQ ID NO:151)分子重导向的对LnCaP细胞的T细胞杀伤。图12B示出了由PSMA Z2 TriTAC(SEQ ID NO:152)重导向的对LnCaP细胞的T细胞杀伤。
具体实施方式
本文描述了靶向前列腺特异性膜抗原(PSMA)的三特异性蛋白质,其药物组合物,以及用于制备这类蛋白质的核酸、重组表达载体和宿主细胞。还提供了使用所公开的靶向PSMA的三特异性蛋白质预防和/或治疗疾病、病况和病症的方法。所述靶向PSMA的三特异性蛋白质能够特异性结合PSMA以及CD3,并且具有半衰期延长结构域,如与人血清白蛋白(HSA)结合的结构域。图1描绘了三特异性抗原结合蛋白质的一种非限制性实例。
在一个方面,所述靶向PSMA的三特异性蛋白质包含与CD3特异性结合的结构域(A)、与人血清白蛋白(HSA)特异性结合的结构域(B)以及与PSMA特异性结合的结构域(C)。靶向PSMA的三特异性蛋白质中的这三个结构域以任意顺序排列。因此,预计所述靶向PSMA的三特异性蛋白质的结构域顺序为:
H2N-(A)-(B)-(C)-COOH、
H2N-(A)-(C)-(B)-COOH、
H2N-(B)-(A)-(C)-COOH、
H2N-(B)-(C)-(A)-COOH、
H2N-(C)-(B)-(A)-COOH或
H2N-(C)-(A)-(B)-COOH。
在一些实施方案中,所述靶向PSMA的三特异性蛋白质具有H2N-(A)-(B)-(C)-COOH的结构域顺序。在一些实施方案中,所述靶向PSMA的三特异性蛋白质具有H2N-(A)-(C)-(B)-COOH的结构域顺序。在一些实施方案中,所述靶向PSMA的三特异性蛋白质具有H2N-(B)-(A)-(C)-COOH的结构域顺序。在一些实施方案中,所述靶向PSMA的三特异性蛋白质具有H2N-(B)-(C)-(A)-COOH的结构域顺序。在一些实施方案中,所述靶向PSMA的三特异性蛋白质具有H2N-(C)-(B)-(A)-COOH的结构域顺序。在一些实施方案中,所述靶向PSMA的三特异性蛋白质具有H2N-(C)-(A)-(B)-COOH的结构域顺序。
在一些实施方案中,所述靶向PSMA的三特异性蛋白质具有HSA结合域作为中间结构域,使得结构域顺序为H2N-(A)-(B)-(C)-COOH或H2N-(C)-(B)-(A)-COOH。预计在HSA结合域作为中间结构域的这类实施方案中,赋予CD3和PSMA结合域额外的柔性以结合其各自的靶标。
在一些实施方案中,本文所述的靶向PSMA的三特异性蛋白质包含具有表10中所述序列(SEQ ID NO:140-152)及其子序列的多肽。在一些实施方案中,该三特异性抗原结合蛋白质包含与表10中所述序列(SEQ ID NO:140-152)具有至少70%-95%或更高同源性的多肽。在一些实施方案中,该三特异性抗原结合蛋白质包含与表10中所述序列(SEQ ID NO:140-152)具有至少70%、75%、80%、85%、90%、95%或更高同源性的多肽。在一些实施方案中,该三特异性抗原结合蛋白质具有包含表10中所述序列(SEQ ID NO:140-152)的至少一部分的序列。在一些实施方案中,该PSMA三特异性抗原结合蛋白质包含含有表10中所述序列(SEQ ID NO:140-152)中的一种或多种序列的多肽。在进一步的实施方案中,该PSMA三特异性抗原结合蛋白质包含如表10中的序列(SEQ ID NO:140-152)所述的一种或多种CDR。
本文所述的靶向PSMA的三特异性蛋白质被设计为允许通过募集细胞毒性T细胞来特异性靶向表达PSMA的细胞。这与ADCC(抗体依赖性细胞介导的细胞毒性)相比提高了功效,ADCC是利用针对唯一抗原的全长抗体并且不能直接募集细胞毒性T细胞。相反,通过接合在这些细胞上特异性表达的CD3分子,所述靶向PSMA的三特异性蛋白质可使细胞毒性T细胞与表达PSMA的细胞以高度特异性的方式交联,从而将T细胞的细胞毒性潜能引导至靶细胞。本文所述的靶向PSMA的三特异性蛋白质经由与表面表达的CD3蛋白质结合而接合细胞毒性T细胞,这形成TCR的一部分。数个PSMA三特异性抗原结合蛋白质与CD3和特定细胞表面上表达的PSMA的同时结合引起T细胞活化,并介导特定PSMA表达细胞的后续裂解。因此,预期靶向PSMA的三特异性蛋白质显示出强烈的、特异的和有效的靶细胞杀伤。在一些实施方案中,本文所述的靶向PSMA的三特异性蛋白质刺激细胞毒性T细胞杀死靶细胞以消除致病细胞(例如,表达PSMA的肿瘤细胞)。在一些这样的实施方案中,细胞被选择性地消除,从而减小毒副作用的可能性。
与传统单克隆抗体和其他较小的双特异性分子相比,本文所述的靶向PSMA的三特异性蛋白质提供进一步的治疗优点。通常,重组蛋白质药物的有效性在很大程度上取决于蛋白质本身的内在药代动力学。一种这样的益处在于,本文所述的靶向PSMA的三特异性蛋白质由于具有半衰期延长结构域,如对HSA具有特异性的结构域,而具有延长的药代动力学消除半衰期。就此而言,在一些实施方案中,本文所述的靶向PSMA的三特异性蛋白质具有约两天、三天、约五天、约七天、约10天、约12天或约14天的延长的血清消除半衰期。这与具有相对短得多的消除半衰期的其他结合蛋白质如BiTE或DART分子形成对照。例如,BiTE CD19×CD3双特异性scFv-scFv融合分子由于其消除半衰期短而需要连续的静脉内输注(i.v.)药物递送。所述靶向PSMA的三特异性蛋白质的较长的内在半衰期解决了这个问题,从而允许增加的治疗潜力,如低剂量药物制剂、减少的定期给药和/或新的药物组合物。
本文所述的靶向PSMA的三特异性蛋白质还具有对于增强的组织穿透和组织分布而言最优的大小。较大的大小限制或阻止蛋白质在靶组织中的穿透或分布。本文所述的靶向PSMA的三特异性蛋白质通过具有允许增强的组织穿透和分布的小尺寸而避免了这一问题。因此,在一些实施方案中,本文所述的靶向PSMA的三特异性蛋白质具有约50kD至约80kD、约50kD至约75kD、约50kD至约70kD或约50kD至约65kD的大小。因此,所述靶向PSMA的三特异性蛋白质的大小优于约150kD的IgG抗体以及约55kD但半衰期没有延长并因此快速通过肾脏清除的BiTE和DART双抗体分子。
在进一步的实施方案中,本文所述的靶向PSMA的三特异性蛋白质具有针对增强的组织穿透和分布而言最优的大小。在这些实施方案中,靶向PSMA的三特异性蛋白质被构建为尽可能小,同时保留对其靶标的特异性。因此,在这些实施方案中,本文所述的靶向PSMA的三特异性蛋白质具有约20kD至约40kD,或约25kD至约35kD至约40kD、至约45kD、至约50kD、至约55kD、至约60kD、至约65kD的大小。在一些实施方案中,本文所述的靶向PSMA的三特异性蛋白质具有约50kD、49kD、48kD、47kD、46kD、45kD、44kD、43kD、42kD、41kD、40kD、约39kD、约38kD、约37kD、约36kD、约35kD、约34kD、约33kD、约32kD、约31kD、约30kD、约29kD、约28kD、约27kD、约26kD、约25kD、约24kD、约23kD、约22kD、约21kD或约20kD的大小。获得小尺寸的示例性方法是对每个结构域都采用单结构域抗体(sdAb)片段。例如,特定的PSMA三特异性抗原结合蛋白质具有抗CD3 sdAb、抗HSA sdAb和针对PSMA的sdAb。这使得示例性PSMA三特异性抗原结合蛋白质的大小减小至40kD以下。因此,在一些实施方案中,所述靶向PSMA的三特异性蛋白质的结构域都是单结构域抗体(sdAb)片段。在其他实施方案中,本文所述的靶向PSMA的三特异性蛋白质包含针对HSA和/或PSMA的小分子实体(SME)结合物。SME结合物是大小平均为约500Da至2000Da的小分子,并且通过已知方法如分选酶连接或缀合而附接至靶向PSMA的三特异性蛋白质。在这些情况下,PSMA三特异性抗原结合蛋白质的结构域之一为分选酶识别序列,例如,LPETG(SEQ ID NO:57)。为了将SME结合物附接至具有分选酶识别序列的PSMA三特异性抗原结合蛋白质,将该蛋白质与分选酶和SME结合物一起温育,从而分选酶将SME结合物附接至该识别序列。已知的SME结合物包括与前列腺特异性膜抗原(PSMA)结合的MIP-1072和MIP-1095。在另外的实施方案中,本文所述的靶向PSMA的三特异性蛋白质中与PSMA结合的结构域包含用于结合PSMA的knottin肽。Knottin是具有半胱氨酸结支架(knot scaffold)的二硫键稳定的肽,并且具有约3.5kD的平均大小。预期Knottin与某些肿瘤分子如PSMA结合。在进一步的实施方案中,本文所述的靶向PSMA的三特异性蛋白质中与PSMA结合的结构域包含天然PSMA配体。
本文所述的靶向PSMA的三特异性蛋白质的另一个特征是,它们是具有其结构域的柔性连接的单多肽设计。这允许容易地产生并制备靶向PSMA的三特异性蛋白质,因为它们可以由易于引入载体中的单个cDNA分子编码。另外,由于本文所述的靶向PSMA的三特异性蛋白质为单体单多肽链,因此不存在链配对问题或不需要二聚化。预计本文所述的靶向PSMA的三特异性蛋白质的聚集趋势减小,不同于其他报道的分子,如具有Fc-γ免疫球蛋白结构域的双特异性蛋白质。
在本文所述的靶向PSMA的三特异性蛋白质中,结构域通过内部连接体L1和L2连接,其中L1连接靶向PSMA的三特异性蛋白质的第一和第二结构域,而L2连接靶向PSMA的三特异性蛋白质的第二和第三结构域。连接体L1和L2具有优化的长度和/或氨基酸组成。在一些实施方案中,连接体L1和L2具有相同的长度和氨基酸组成。在其他实施方案中,L1和L2不同。在某些实施方案中,内部连接体L1和/或L2是“短的”,即,由0、1、2、3、4、5、6、7、8、9、10、11或12个氨基残基组成。因此,在某些情况下,内部连接体由约12个或更少的氨基酸残基组成。在0个氨基酸残基的情况下,内部连接体为肽键。在某些实施方案中,内部连接体L1和/或L2是“长的”,即,由15、20或25个氨基残基组成。在一些实施方案中,这些内部连接体由约3个至约15个,例如8、9或10个连续氨基酸残基组成。关于内部连接体L1和L2的氨基酸组成,选择具有以下性质的肽,即,能赋予靶向PSMA的三特异性蛋白质柔性,不干扰结合域,以及抵抗蛋白酶切割。例如,甘氨酸和丝氨酸残基通常提供蛋白酶抗性。适合于连接靶向PSMA的三特异性蛋白质中的结构域的内部连接体的实例包括但不限于(GS)n(SEQ ID NO:153)、(GGS)n(SEQ ID NO:154)、(GGGS)n(SEQ ID NO:155)、(GGSG)n(SEQ ID NO:156)、(GGSGG)n(SEQ ID NO:157)或(GGGGS)n(SEQ ID NO:158),其中n为1、2、3、4、5、6、7、8、9或10。在一个实施方案中,内部连接体L1和/或L2为(GGGGS)4(SEQ ID NO:159)或(GGGGS)3(SEQ ID NO:160)。
CD3结合域
T细胞应答的特异性由TCR对抗原(在主要组织相容性复合物MHC的环境中展示)的识别来介导。作为TCR的一部分,CD3是包含CD3γ(gamma)链、CD3δ(delta)链和存在于细胞表面上的两条CD3ε(epsilon)链的蛋白质复合物。CD3与TCR的α(alpha)和β(beta)链缔合并与CD3ζ(zeta)一起构成完整的TCR。CD3在T细胞上诸如通过固定化抗CD3抗体的簇集导致T细胞活化,这类似于T细胞受体的接合,但不依赖于其克隆特有的特异性。
在一个方面,本文所述的靶向PSMA的三特异性蛋白质包含与CD3特异性结合的结构域。在一个方面,本文所述的靶向PSMA的三特异性蛋白质包含与人CD3特异性结合的结构域。在一些实施方案中,本文所述的靶向PSMA的三特异性蛋白质包含与CD3γ特异性结合的结构域。在一些实施方案中,本文所述的靶向PSMA的三特异性蛋白质包含与CD3δ特异性结合的结构域。在一些实施方案中,本文所述的靶向PSMA的三特异性蛋白质包含与CD3ε特异性结合的结构域。
在进一步的实施方案中,本文所述的靶向PSMA的三特异性蛋白质包含与TCR特异性结合的结构域。在某些情况下,本文所述的靶向PSMA的三特异性蛋白质包含特异性结合TCR的α链的结构域。在某些情况下,本文所述的靶向PSMA的三特异性蛋白质包含特异性结合TCR的β链的结构域。
在某些实施方案中,本文所述的靶向PSMA的三特异性蛋白质的CD3结合域不仅表现出有效的对人CD3的CD3结合亲和力,而且还显示出与相应的食蟹猴CD3蛋白质的优异的交叉反应性。在一些情况下,靶向PSMA的三特异性蛋白质的CD3结合域与来自食蟹猴的CD3具有交叉反应性。在某些情况下,针对CD3的人:食蟹猴KD比例为5至0.2。
在一些实施方案中,PSMA三特异性抗原结合蛋白质的CD3结合域可以是与CD3结合的任何结构域,包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些情况下,CD3结合域来源于该PSMA三特异性抗原结合蛋白质最终将在其中使用的相同物种是有益的。例如,对于人用而言,PSMA三特异性抗原结合蛋白质的CD3结合域包含来自抗体或抗体片段的抗原结合域的人或人源化残基可能是有益的。
因此,在一个方面,所述抗原结合域包含人源化或人抗体或抗体片段,或者鼠抗体或抗体片段。在一个实施方案中,人源化或人抗CD3结合域包含本文所述的人源化或人抗CD3结合域的轻链互补决定区1(LC CDR1)、轻链互补决定区2(LC CDR2)和轻链互补决定区3(LC CDR3)中的一个或多个(例如,全部三个),以及/或者本文所述的人源化或人抗CD3结合域的重链互补决定区1(HC CDR1)、重链互补决定区2(HC CDR2)和重链互补决定区3(HCCDR3)中的一个或多个(例如,全部三个),例如,人源化或人抗CD3结合域包含一个或多个,例如全部三个LC CDR,以及一个或多个,例如全部三个HC CDR。
在一些实施方案中,人源化或人抗CD3结合域包含对CD3具有特异性的人源化或人轻链可变区,其中对CD3具有特异性的轻链可变区在人轻链框架区中包含人或非人轻链CDR。在某些情况下,该轻链框架区为λ(lamda)轻链框架。在其他情况下,该轻链框架区为κ(kappa)轻链框架。
在一些实施方案中,人源化或人抗CD3结合域包含对CD3具有特异性的人源化或人重链可变区,其中对CD3具有特异性的重链可变区在人重链框架区中包含人或非人重链CDR。
在某些情况下,重链和/或轻链的互补决定区衍生自已知的抗CD3抗体,例如,莫罗单抗-CD3(OKT3)、奥昔珠单抗(TRX4)、替利珠单抗(MGA031)、维西珠单抗(Nuvion)、SP34、TR-66或X35-3、VIT3、BMA030(BW264/56)、CLB-T3/3、CRIS7、YTH12.5、F111-409、CLB-T3.4.2、TR-66、WT32、SPv-T3b、11D8、XIII-141、XIII-46、XIII-87、12F6、T3/RW2-8C8、T3/RW2-4B6、OKT3D、M-T301、SMC2、F101.01、UCHT-1和WT-31。
在一个实施方案中,抗CD3结合域为包含本文提供的氨基酸序列的轻链和重链的单链可变片段(scFv)。如本文所用的,“单链可变片段”或“scFv”是指包含轻链可变区的抗体片段和至少一个包含重链可变区的抗体片段,其中该轻链和重链可变区经由短的柔性多肽连接体连续连接,并且能够表达为单多肽链,并且其中该scFv保留其所衍生自的完整抗体的特异性。在一个实施方案中,抗CD3结合域包含:轻链可变区,其包含具有本文提供的轻链可变区的氨基酸序列的至少一个、两个或三个修饰(例如,置换)但不超过30、20或10个修饰(例如,置换)的氨基酸序列,或与本文提供的氨基酸序列具有95%-99%同一性的序列;和/或重链可变区,其包含具有本文提供的重链可变区的氨基酸序列的至少一个、两个或三个修饰(例如,置换)但不超过30、20或10个修饰(例如,置换)的氨基酸序列,或与本文提供的氨基酸序列具有95%-99%同一性的序列。在一个实施方案中,人源化或人抗CD3结合域为scFv,并且包含本文所述氨基酸序列的轻链可变区经由scFv连接体附接至包含本文所述氨基酸序列的重链可变区。scFv的轻链可变区和重链可变区可以是例如以下方向中的任何一种:轻链可变区-scFv连接体-重链可变区或重链可变区-scFv连接体-轻链可变区。
在一些情况下,根据已知方法制备与CD3结合的scFv。例如,可通过利用柔性多肽连接体将VH和VL区连接在一起来产生scFv分子。该scFv分子包含具有优化的长度和/或氨基酸组成的scFv连接体(例如,Ser-Gly连接体)。因此,在一些实施方案中,该scFv连接体的长度使得VH或VL结构域可以与其他可变域进行分子间缔合,从而形成CD3结合位点。在某些实施方案中,这样的scFv连接体是“短的”,即,由0、1、2、3、4、5、6、7、8、9、10、11或12个氨基酸残基组成。因此,在某些情况下,该scFv连接体由约12个或更少的氨基酸残基组成。在0个氨基酸残基的情况下,该scFv连接体为肽键。在一些实施方案中,这些scFv连接体由约3个至约15个,例如8、9或10个连续氨基酸残基组成。关于scFv连接体的氨基酸组成,选择能赋予柔性、不干扰可变域以及允许链间折叠以使两个可变域一起形成功能性CD3结合位点的肽。例如,包含甘氨酸和丝氨酸残基的scFv连接体通常提供蛋白酶抗性。在一些实施方案中,scFv中的连接体包含甘氨酸和丝氨酸残基。该scFv连接体的氨基酸序列可通过例如噬菌体展示法进行优化,以提高scFv的CD3结合和产率。适合于连接scFv中可变轻链结构域和可变重链结构域的肽scFv连接体的实例包括但不限于(GS)n(SEQ ID NO:153)、(GGS)n(SEQID NO:154)、(GGGS)n(SEQ ID NO:155)、(GGSG)n(SEQ ID NO:156)、(GGSGG)n(SEQ ID NO:157)或(GGGGS)n(SEQ ID NO:158),其中n为1、2、3、4、5、6、7、8、9或10。在一个实施方案中,该scFv连接体可以是(GGGGS)4(SEQ ID NO:159)或(GGGGS)3(SEQ ID NO:160)。连接体长度的变化可以保持或增强活性,从而在活性研究中产生优异的功效。
在一些实施方案中,PSMA三特异性抗原结合蛋白质的CD3结合域对表达CD3的细胞上的CD3具有亲和力,其KD为1000nM或更低、500nM或更低、200nM或更低、100nM或更低、80nM或更低、50nM或更低、20nM或更低、10nM或更低、5nM或更低、1nM或更低或者0.5nM或更低。在一些实施方案中,PSMA三特异性抗原结合蛋白质的CD3结合域对CD3ε、CD3γ或CD3δ具有亲和力,其KD为1000nM或更低、500nM或更低、200nM或更低、100nM或更低、80nM或更低、50nM或更低、20nM或更低、10nM或更低、5nM或更低、1nM或更低或者0.5nM或更低。在进一步的实施方案中,PSMA三特异性抗原结合蛋白质的CD3结合域对CD3具有低亲和力,即,约100nM或更高。
与CD3结合的亲和力可通过例如PSMA三特异性抗原结合蛋白质本身或其CD3结合域与测定板上包被的CD3、微生物细胞表面上展示的CD3、溶液中的CD3等结合的能力来确定。本发明的PSMA三特异性抗原结合蛋白质本身或其CD3结合域与CD3的结合活性可以如下测定:将配体(例如,CD3)或PSMA三特异性抗原结合蛋白质本身或其CD3结合域固定至珠子、基底、细胞等。可将试剂添加至合适的缓冲液中并将结合配偶体在给定的温度下温育一段时间。洗涤以去除未结合的物质后,可采用例如SDS、高pH缓冲液等释放结合的蛋白质,并通过例如表面等离子体共振(SPR)进行分析。
在一些实施方案中,本文所述的CD3结合域包含具有表7中所述序列(SEQ ID NO:1-88)及其子序列的多肽。在一些实施方案中,该CD3结合域包含与表7中所述序列(SEQ IDNO:1-88)具有至少70%-95%或更高同源性的多肽。在一些实施方案中,该CD3结合域包含与表7中所述序列(SEQ ID NO:1-88)具有至少70%、75%、80%、85%、90%、95%或更高同源性的多肽。在一些实施方案中,该CD3结合域具有包含表7中所述序列(SEQ ID NO:1-88)的至少一部分的序列。在一些实施方案中,该CD3结合域包含含有表7中所述序列(SEQ IDNO:1-88)中的一种或多种序列的多肽。
在某些实施方案中,CD3结合域包含具有重链CDR1的scFv,该重链CDR1包含SEQ IDNO:16和22-33。在某些实施方案中,CD3结合域包含具有重链CDR2的scFv,该重链CDR2包含SEQ ID NO:17和34-43。在某些实施方案中,CD3结合域包含具有重链CDR3的scFv,该重链CDR3包含SEQ ID NO:18和44-53。在某些实施方案中,CD3结合域包含具有轻链CDR1的scFv,该轻链CDR1包含SEQ ID NO:19和54-66。在某些实施方案中,CD3结合域包含具有轻链CDR2的scFv,该轻链CDR2包含SEQ ID NO:20和67-79。在某些实施方案中,CD3结合域包含具有轻链CDR3的scFv,该轻链CDR3包含SEQ ID NO:21和80-86。
半衰期延长结构域
本文涉及延长抗原结合域的半衰期的结构域。预期这样的结构域包括但不限于HSA结合域、Fc结构域、小分子和本领域已知的其他半衰期延长结构域。
人血清白蛋白(HSA)(分子量约为67kDa)是血浆中最丰富的蛋白质,以约50mg/ml(600μM)存在,并且在人体中具有大约20天的半衰期。HSA用来维持血浆pH,对胶体血压有贡献,起到许多代谢物和脂肪酸的载剂的作用,并且充当血浆中主要的药物转运蛋白。
与白蛋白的非共价缔合延长了短寿命蛋白质的消除半衰期。例如,与仅施用Fab片段相比,当分别静脉内施用于小鼠和兔时,白蛋白结合域与Fab片段的重组融合体导致25倍和58倍的体内清除率,以及26倍和37倍的半衰期延长。在另一个实例中,当用脂肪酸对胰岛素进行酰化以促进与白蛋白的缔合时,在兔或猪中皮下注射时观察到持久的效果。总之,这些研究证明了白蛋白结合与延长的作用之间存在联系。
在一个方面,本文所述的靶向PSMA的三特异性蛋白质包含半衰期延长结构域,例如与HSA特异性结合的结构域。在一些实施方案中,PSMA三特异性抗原结合蛋白质的HSA结合域可以是与HSA结合的任何结构域,包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些实施方案中,该HSA结合域是对HSA具有特异性的单链可变片段(scFv)、单结构域抗体如重链可变域(VH)、轻链可变域(VL)和骆驼科来源的单结构域抗体的可变域(VHH)、肽、配体或小分子实体。在某些实施方案中,该HSA结合域是单结构域抗体。在其他实施方案中,该HSA结合域是肽。在进一步的实施方案中,该HSA结合域是小分子。在一些实施方案中,考虑到PSMA三特异性抗原结合蛋白质的HSA结合域相当小并且不超过25kD、不超过20kD、不超过15kD或不超过10kD。在某些情况下,该HSA结合蛋白质如果是肽或小分子实体,则为5kD或更小。
PSMA三特异性抗原结合蛋白质的半衰期延长结构域导致PSMA三特异性抗原结合蛋白质本身的药效学和药代动力学改变。如上所述,半衰期延长结构域延长了消除半衰期。半衰期延长结构域还改变药效学性质,包括三特异性抗原结合蛋白质的组织分布、穿透和扩散的改变。在一些实施方案中,与没有半衰期延长结构域的蛋白质相比,半衰期延长结构域提供改善的组织(包括肿瘤)靶向、组织分布、组织穿透、组织内的扩散和增强的功效。在一个实施方案中,治疗方法有效且高效地利用减少量的三特异性抗原结合蛋白质,从而导致副作用减小,如非肿瘤细胞的细胞毒性降低。
此外,可以选择半衰期延长结构域的结合亲和力,以便针对特定三特异性抗原结合蛋白质中的特定消除半衰期。因此,在一些实施方案中,该半衰期延长结构域具有高结合亲和力。在其他实施方案中,该半衰期延长结构域具有中等结合亲和力。在另外其他的实施方案中,该半衰期延长结构域具有低或微小的结合亲和力。示例性的结合亲和力包括10nM或更低(高)、10nM至100nM(中等)和大于100nM(低)的KD浓度。如上所述,通过已知方法如表面等离子体共振(SPR)测定与HSA的结合亲和力。
在一些实施方案中,本文所述的HSA结合域包含具有表8中所述序列(SEQ ID NO:89-112)及其子序列的多肽。在一些实施方案中,该HSA结合域包含与表8中所述序列(SEQID NO:89-112)具有至少70%-95%或更高同源性的多肽。在一些实施方案中,该HSA结合域包含与表8中所述序列(SEQ ID NO:89-112)具有至少70%、75%、80%、85%、90%、95%或更高同源性的多肽。在一些实施方案中,该HSA结合域具有包含表8中所述序列(SEQ ID NO:89-112)的至少一部分的序列。在一些实施方案中,该HSA结合域包含含有表8中所述序列(SEQ ID NO:89-112)中的一种或多种序列的多肽。
在一些实施方案中,本文所述的HSA结合域包含具有CDR1的单结构域抗体,该CDR1包含SE ID NO:96和99-101。在一些实施方案中,本文所述的HSA结合域包含具有CDR1的单结构域抗体,该CDR1包含SE ID NO:97和102-107。在一些实施方案中,本文所述的HSA结合域包含具有CDR1的单结构域抗体,该CDR1包含SE ID NO:98、108和109。
前列腺特异性膜抗原(PSMA)结合域
前列腺特异性膜抗原(PSMA)是在前列腺组织中表达的100kD的II型膜糖蛋白,它与转铁蛋白受体具有序列同一性,具有NAALADase活性。PSMA在前列腺癌中表达量增加,并且在这些患者的血清中也可检测到升高的PSMA水平。PSMA表达随着疾病进展而增加,在目前没有针对性疗法的转移性、激素难治性疾病中最高。
除了所描述的CD3和半衰期延长结构域之外,本文所述的靶向PSMA的三特异性蛋白质还包含与PSMA结合的结构域。本文所述的靶向PSMA的三特异性蛋白质的设计允许PSMA结合域为柔性的,因为该PSMA结合域可以是任何类型的结合域,包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些实施方案中,该PSMA结合域为单链可变片段(scFv)、单结构域抗体如重链可变域(VH)、轻链可变域(VL)和骆驼科来源的单结构域抗体的可变域(VHH)。在其他实施方案中,该PSMA结合域为非Ig结合域,即,抗体模拟物,如anticalin、affilin、affibody分子、affimer、affitin、alphabody、avimer、DARPin、fynomer、kunitz结构域肽和单抗体(monobody)。在进一步的实施方案中,该PSMA结合域为与PSMA结合或缔合的配体或肽。在更进一步的实施方案中,该PSMA结合域为knottin。在更进一步的实施方案中,该PSMA结合域为小分子实体。
在一些实施方案中,所述PSMA结合域包含以下通式:f1-r1-f2-r2-f3-r3-f4,其中r1、r2和r3分别是互补决定区CDR1、CDR2和CDR3,而f1、f2、f3和f4是框架残基,并且其中r1包含SEQ ID No.114、SEQ ID No.115、SEQ ID No.116或SEQ ID No.125,r2包含SEQ IDNo.117、SEQ ID NO.118、SEQ ID No.119、SEQ ID No.120、SEQ ID No.121、SEQ ID No.122、SEQ ID No.123或SEQ ID NO:126,而r3包含SEQ ID No.124或SEQ ID NO:127。
在一些实施方案中,所述PSMA结合域包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQ ID No.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ ID No.164(DX7YGY)所示。在一些实施方案中,氨基酸残基X1、X2、X3、X4、X5、X6和X7独立地选自谷氨酸、脯氨酸、丝氨酸、组氨酸、苏氨酸、天冬氨酸、甘氨酸、赖氨酸、苏氨酸、谷氨酰胺和酪氨酸。在一些实施方案中,X1是脯氨酸。在一些实施方案中,X2是组氨酸。在一些实施方案中,X3是天冬氨酸。在一些实施方案中,X4是赖氨酸。在一些实施方案中,X5是谷氨酰胺。在一些实施方案中,X6是酪氨酸。在一些实施方案中,X7是丝氨酸。在一些实施方案中,本发明的PSMA结合蛋白质可以包含CDR1、CDR2和CDR3序列,其中X1是谷氨酸,X2是组氨酸,X3是天冬氨酸,X4是甘氨酸,X5是苏氨酸,X6是丝氨酸,且X7是丝氨酸。
在一些实施方案中,所述PSMA结合蛋白质包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQ ID No.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ ID No.164(DX7YGY)所示,其中X1是脯氨酸。在一些实施方案中,该PSMA结合蛋白质包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQ IDNo.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ ID No.164(DX7YGY)所示,其中X5是谷氨酰胺。在一些实施方案中,该PSMA结合蛋白质包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQID No.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ ID No.164(DX7YGY)所示,其中X6是酪氨酸。在一些实施方案中,该PSMA结合蛋白质包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQ ID No.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ IDNo.164(DX7YGY)所示,其中X4是赖氨酸且X7是丝氨酸。在一些实施方案中,该PSMA结合蛋白质包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQ ID No.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ ID No.164(DX7YGY)所示,其中X2是组氨酸,X3是天冬氨酸,X4是赖氨酸,且X7是丝氨酸。在一些实施方案中,该PSMA结合蛋白质包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQ ID No.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ ID No.164(DX7YGY)所示,其中X1是脯氨酸,X2是组氨酸,X3是天冬氨酸,且X7是丝氨酸。在一些实施方案中,该PSMA结合蛋白质包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQ ID No.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ ID No.164(DX7YGY)所示,其中X2是组氨酸,X3是天冬氨酸,X5是谷氨酰胺,且X7是丝氨酸。在一些实施方案中,该PSMA结合蛋白质包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQ IDNo.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ ID No.164(DX7YGY)所示,其中X2是组氨酸,X3是天冬氨酸,X6是酪氨酸,且X7是丝氨酸。在一些实施方案中,该PSMA结合蛋白质包含CDR1、CDR2和CDR3,其中(a)CDR1的氨基酸序列如SEQ ID No.162(RFMISX1YX2MH)所示,(b)CDR2的氨基酸序列如SEQ ID No.163(X3INPAX4X5TDYAEX6VKG)所示,且(c)CDR3的氨基酸序列如SEQ ID No.164(DX7YGY)所示,其中X2是组氨酸,X3是天冬氨酸,且X7是丝氨酸。
在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是谷氨酸,X2是组氨酸,X3是苏氨酸,X4是甘氨酸,X5是苏氨酸,X6是丝氨酸,且X7是丝氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是谷氨酸,X2是组氨酸,X3是苏氨酸,X4是甘氨酸,X5是苏氨酸,X6是丝氨酸,且X7是丝氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是谷氨酸,X2是丝氨酸,X3是苏氨酸,X4是赖氨酸,X5是苏氨酸,X6是丝氨酸,且X7是丝氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是脯氨酸,X2是丝氨酸,X3是苏氨酸,X4是甘氨酸,X5是苏氨酸,X6是丝氨酸,且X7是甘氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是谷氨酸,X2是丝氨酸,X3是苏氨酸,X4是甘氨酸,X5是谷氨酰胺,X6是丝氨酸,且X7是甘氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是谷氨酸,X2是丝氨酸,X3是苏氨酸,X4是甘氨酸,X5是苏氨酸,X6是酪氨酸,且X7是甘氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是谷氨酸,X2是组氨酸,X3是天冬氨酸,X4是赖氨酸,X5是苏氨酸,X6是丝氨酸,且X7是丝氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是脯氨酸,X2是组氨酸,X3是天冬氨酸,X4是甘氨酸,X5是苏氨酸,X6是丝氨酸,且X7是丝氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是谷氨酸,X2是组氨酸,X3是天冬氨酸,X4是谷氨酰胺,X5是苏氨酸,X6是丝氨酸,且X7是丝氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X1是谷氨酸,X2是组氨酸,X3是天冬氨酸,X4是甘氨酸,X5是苏氨酸,X6是酪氨酸,且X7是丝氨酸。在一些实施方案中,本发明的PSMA结合域可以包含CDR1、CDR2和CDR3序列,其中X2是组氨酸,且X7是丝氨酸。示例性的框架序列被公开为SEQ ID NO:165-168。
在一些实施方案中,本文所述的PSMA结合域包含具有表9中所述序列(SEQ ID NO:113-140)及其子序列的多肽。在一些实施方案中,该HSA结合域包含与表9中所述序列(SEQID NO:113-140)具有至少70%-95%或更高同源性的多肽。在一些实施方案中,该HSA结合域包含与表9中所述序列(SEQ ID NO:113-140)具有至少70%、75%、80%、85%、90%、95%或更高同源性的多肽。在一些实施方案中,该HSA结合域具有包含表9中所述序列(SEQ IDNO:113-140)的至少一部分的序列。在一些实施方案中,该HSA结合域包含含有表9中所述序列(SEQ ID NO:113-140)中的一种或多种序列的多肽。
在一些实施方案中,本文所述的PSMA结合域包含具有CDR1的单结构域抗体,该CDR1包含SE ID NO:114-116和125。在一些实施方案中,本文所述的PSMA结合域包含具有CDR1的单结构域抗体,该CDR1包含SEQ ID NO:117-123和126。在一些实施方案中,本文所述的PSMA结合域包含具有CDR1的单结构域抗体,该CDR1包含SE ID NO:124和127。
PSMA三特异性蛋白质修饰
本文所述的靶向PSMA的三特异性蛋白质包括衍生物或类似物,其中(i)氨基酸被不是由遗传密码编码的氨基酸残基置换,(ii)成熟多肽与另一化合物如聚乙二醇融合,或(iii)额外的氨基酸与该蛋白质融合,如前导序列或分泌序列或用于纯化该蛋白质的序列。
典型的修饰包括但不限于乙酰化、酰化、ADP-核糖基化、酰胺化、黄素的共价附接、血红素部分的共价附接、核苷酸或核苷酸衍生物的共价附接、脂质或脂质衍生物的共价附接、磷脂酰肌醇的共价附接、交联、环化、二硫键形成、脱甲基化、共价交联的形成、胱氨酸的形成、焦谷氨酸的形成、甲酰化、γ羧化、糖基化、GPI锚形成、羟基化、碘化、甲基化、肉豆蔻酰化、氧化、蛋白水解加工、磷酸化、异戊二烯化、外消旋化、硒化、硫酸化、转移RNA介导的向蛋白质添加氨基酸,如精氨酰化和泛素化。
在本文所述的靶向PSMA的三特异性蛋白质中的任何位置进行修饰,所述位置包括肽骨架、氨基酸侧链和氨基或羧基末端。可用于修饰靶向PSMA的三特异性蛋白质的某些常见肽修饰包括糖基化、脂质附接、硫酸化、谷氨酸残基的γ-羧化、羟基化、多肽中的氨基或羧基或两者被共价修饰的封闭,以及ADP-核糖基化。
编码靶向PSMA的三特异性蛋白质的多核苷酸
在一些实施方案中,还提供了编码本文所述的PSMA三特异性抗原结合蛋白质的多核苷酸分子。在一些实施方案中,该多核苷酸分子以DNA构建体的形式提供。在其他实施方案中,该多核苷酸分子以信使RNA转录物的形式提供。
所述多核苷酸分子通过已知方法构建,例如通过将编码由肽连接体隔开,或在其他实施方案中通过肽键直接连接的三个结合域的基因组合成单个基因构建体,该单个基因构建体与合适的启动子以及可选的合适的转录终止子可操作地连接,并且将其在细菌或其他合适的表达系统例如CHO细胞中表达。在PSMA结合域为小分子的实施方案中,该多核苷酸含有编码CD3结合域和半衰期延长结构域的基因。在半衰期延长结构域为小分子的实施方案中,该多核苷酸含有编码与CD3和PSMA结合的结构域的基因。根据所采用的载体系统和宿主,可使用任何数目的合适的转录和翻译元件,包括组成型和诱导型启动子。选择启动子使得其驱动该多核苷酸在相应宿主细胞中的表达。
在一些实施方案中,将所述多核苷酸插入载体中,优选表达载体中,这代表进一步的实施方案。该重组载体可根据已知方法来构建。特别感兴趣的载体包括质粒、噬菌粒、噬菌体衍生物、病毒(virii)(例如,逆转录病毒、腺病毒、腺伴随病毒、疱疹病毒、慢病毒等)和粘粒。
可利用多种表达载体/宿主系统,以包含并表达编码所述三特异性抗原结合蛋白质的多肽的多核苷酸。表达载体的实例是用于在大肠杆菌中表达的pSKK(Le Gall等人,JImmunol Methods.(2004)285(1):111-27)或用于在哺乳动物细胞中表达的pcDNA5(Invitrogen)。
因此,在一些实施方案中,如本文所述的靶向PSMA的三特异性蛋白质通过以下步骤产生:将编码如上所述蛋白质的载体引入宿主细胞中,并在允许蛋白质结构域表达的条件下培养所述宿主细胞,可将其分离并任选地进一步纯化。
药物组合物
在一些实施方案中,还提供了药物组合物,其包含本文所述的PSMA三特异性抗原结合蛋白质、包含编码靶向PSMA的三特异性蛋白质的多肽的多核苷酸的载体或被该载体转化的宿主细胞,以及至少一种药学上可接受的载剂。术语“药学上可接受的载剂”包括但不限于不干扰成分的生物活性的有效性且对所施用的患者无毒的任何载剂。合适的药物载剂的实例是本领域公知的,并且包括磷酸盐缓冲盐水溶液、水、乳液如水包油乳液、各种类型的润湿剂、无菌溶液等。这样的载剂可通过常规方法配制,并且可以以合适的剂量施用于受试者。优选地,该组合物是无菌的。这些组合物还可含有辅料如防腐剂、乳化剂和分散剂。可通过包含各种抗细菌剂和抗真菌剂来确保阻止微生物的作用。
在药物组合物的一些实施方案中,本文所述的靶向PSMA的三特异性蛋白质被包封在纳米颗粒中。在一些实施方案中,该纳米颗粒是富勒烯、液晶、脂质体、量子点、超顺磁纳米颗粒、树状聚体或纳米棒。在药物组合物的其他实施方案中,将PSMA三特异性抗原结合蛋白质附接至脂质体。在一些情况下,PSMA三特异性抗原结合蛋白质与脂质体表面缀合。在一些情况下,PSMA三特异性抗原结合蛋白质被包封在脂质体的壳内。在一些情况下,该脂质体为阳离子脂质体。
本文所述的靶向PSMA的三特异性蛋白质被考虑用作药物。给药通过不同方式实现,例如,通过静脉内、腹膜内、皮下、肌肉内、局部或真皮内给药。在一些实施方案中,给药途径取决于疗法的种类和药物组合物中包含的化合物的种类。给药方案将由主治医师根据其他临床因素来确定。对于任何一名患者的剂量依赖于许多因素,包括患者体型、体表面积、年龄、性别、待施用的具体化合物、给药时间和途径、疗法的种类、总体健康和其他同时施用的药物。“有效剂量”是指活性成分的量,该量足以影响疾病的病程和严重程度,从而导致这种病理学的减轻或缓解,并且可使用已知方法来确定。
治疗方法
在一些实施方案中,本文还提供了用于刺激有需要的个体的免疫系统的方法和用途,其包括施用本文所述的靶向PSMA的三特异性蛋白质。在一些情况下,本文所述的靶向PSMA的三特异性蛋白质的施用诱导和/或保持对表达PSMA的细胞的细胞毒性。在一些情况下,该表达PSMA的细胞是癌细胞。
本文还提供了用于治疗与PSMA相关的疾病、病症或病况的方法和用途,其包括向有需要的个体施用本文所述的靶向PSMA的三特异性蛋白质。与PSMA相关的疾病、病症或病况包括但不限于增生性疾病或肿瘤性疾病。在一个实施方案中,与PSMA相关的疾病、病症或病况是前列腺癌。在另一个实施方案中,与PSMA相关的疾病、病症或病况是肾癌。
在一些实施方案中,该前列腺癌是晚期前列腺癌。在一些实施方案中,该前列腺癌是抗药性的。在一些实施方案中,该前列腺癌是抗雄激素药物抗性的。在一些实施方案中,该前列腺癌是转移性的。在一些实施方案中,该前列腺癌是转移性且抗药性的(例如,抗雄激素药物抗性的)。在一些实施方案中,该前列腺癌是去势抗性的。在一些实施方案中,该前列腺癌是转移性且去势抗性的。在一些实施方案中,该前列腺癌是恩杂鲁胺抗性的。在一些实施方案中,该前列腺癌是恩杂鲁胺和阿比特龙(arbiraterone)抗性的。在一些实施方案中,该前列腺癌是恩杂鲁胺、阿比特龙和比卡鲁胺抗性的。在一些实施方案中,该前列腺癌是多西他赛抗性的。在一些实施方案中,该前列腺癌是恩杂鲁胺、阿比特龙、比卡鲁胺和多西他赛抗性的。
在一些实施方案中,施用本文所述的靶向PSMA的三特异性蛋白质抑制前列腺癌细胞生长;抑制前列腺癌细胞迁移;抑制前列腺癌细胞侵袭;改善前列腺癌的症状;减小前列腺癌肿瘤的大小;减少前列腺癌肿瘤的数目;减少前列腺癌细胞的数目;诱导前列腺癌细胞坏死、焦亡(pyroptosis)、胀亡(oncosis)、凋亡、自噬或其他细胞死亡;或增强选自恩杂鲁胺、阿比特龙、多西他赛、比卡鲁胺及其任意组合的化合物的治疗效果。
在一些实施方案中,所述方法包括通过施用本文所述的靶向PSMA的三特异性蛋白质抑制前列腺癌细胞生长。在一些实施方案中,所述方法包括通过施用本文所述的靶向PSMA的三特异性蛋白质抑制前列腺癌细胞迁移。在一些实施方案中,所述方法包括通过施用本文所述的靶向PSMA的三特异性蛋白质抑制前列腺癌细胞侵袭。在一些实施方案中,所述方法包括通过施用本文所述的靶向PSMA的三特异性蛋白质改善前列腺癌的症状。在一些实施方案中,所述方法包括通过施用本文所述的靶向PSMA的三特异性蛋白质减小前列腺癌肿瘤的大小。在一些实施方案中,所述方法包括通过施用本文所述的靶向PSMA的三特异性蛋白质减少前列腺癌肿瘤的数目。在一些实施方案中,所述方法包括通过施用本文所述的靶向PSMA的三特异性蛋白质减少前列腺癌细胞的数目。在一些实施方案中,所述方法包括通过施用本文所述的靶向PSMA的三特异性蛋白质诱导前列腺癌细胞坏死、焦亡、胀亡、凋亡、自噬或其他细胞死亡。
在一些实施方案中,如本文所用的,“治疗”或“处理”是指治疗性处理,其中目的是减缓(减轻)不期望的生理病况、病症或疾病,或是获得有益或期望的临床结果。对于本文所述的目的,有益或期望的临床结果包括但不限于症状的减轻;病况、病症或疾病程度的减小;病况、病症或疾病状态的稳定(即不恶化);病况、病症或疾病的延迟发作或进展减缓;病况、病症或疾病状态的改善;以及病况、病症或疾病的可检测到的或不可检测的缓解(部分或全部的)或者增强或改善。治疗包括引发临床上显著的反应,而没有过高水平的副作用。治疗还包括与不接受治疗的情况下预期的生存期相比延长生存期。在其他实施方案中,“治疗”或“处理”是指预防性措施,其中目的是例如在易患疾病的人(例如,携带诸如前列腺癌等疾病的遗传标志物的个体)中,延迟不希望的生理病况、病症或疾病的发作或者降低其严重程度。
在本文所述方法的一些实施方案中,靶向PSMA的三特异性蛋白质与用于治疗特定疾病、病症或病况的物质联合施用。物质包括但不限于涉及抗体、小分子(例如,化疗药物)、激素(甾体、肽等)的疗法,放疗(γ射线,X射线,和/或放射性同位素、微波、UV辐射等的定向递送),基因疗法(例如,反义疗法(antisense)、逆转录病毒疗法等),和其他免疫疗法。在一些实施方案中,靶向PSMA的三特异性蛋白质与止泻剂、止吐剂、镇痛药、阿片类药物和/或非甾体抗炎药联合施用。在一些实施方案中,靶向PSMA的三特异性蛋白质在手术之前、期间或之后施用。
某些定义
如本文所用的,“消除半衰期”以其普通含义使用,如在Goodman和Gillman的ThePharmaceutical Basis of Therapeutics 21-25(Alfred Goodman Gilman、LouisS.Goodman和Alfred Gilman编著,第六版1980)中所述。简言之,该术语意在包括药物消除的时间过程的定量量度。大多数药物的消除是指数式的(即,遵循一级动力学),因为药物浓度通常并未接近消除过程的饱和所需的浓度。指数过程的速率可由其速率常数k或由其半衰期t1/2表示,速率常数k表示每单位时间的分数变化,半衰期t1/2表示该过程完成50%所需的时间。这两个常数的单位分别是时间-1和时间。该反应的一级速率常数和半衰期简单相关(k×t1/2=0.693)并且可以相应地互换。由于一级消除动力学指示每单位时间损失恒定分数的药物,因此药物浓度的对数相对于时间的图形在初始分布阶段之后(即在药物吸收和分布完成之后)一直是线性的。可从这样的图形准确地确定药物消除的半衰期。
如本文所用的,短语“前列腺癌”或“晚期前列腺癌”包括已经进展到超过疾病早期阶段的一类前列腺癌。一般而言,晚期前列腺癌与预后不良相关。晚期前列腺癌的类型包括但不限于转移性前列腺癌、抗药性前列腺癌如抗雄激素抗性前列腺癌(例如,恩杂鲁胺抗性前列腺癌、阿比特龙抗性前列腺癌、比卡鲁胺抗性前列腺癌等)、激素难治性前列腺癌、去势抗性前列腺癌、转移性去势抗性前列腺癌、多西他赛抗性前列腺癌、雄激素受体剪接变体-7(AR-V7)诱导的抗药性前列腺癌如AR-V7诱导的抗雄激素抗性前列腺癌(例如,AR-V7诱导的恩杂鲁胺抗性前列腺癌)、醛-酮还原酶家族1成员C3(AKR1C3)诱导的抗药性前列腺癌如AKR1C3诱导的抗雄激素抗性前列腺癌(例如,AKR1C3诱导的恩杂鲁胺抗性前列腺癌)及其组合。在一些情况下,晚期前列腺癌通常不会对采用一种或多种以下常规前列腺癌疗法的治疗有反应,或对其有抗性:恩杂鲁胺、阿比特龙、比卡鲁胺和多西他赛。本发明的化合物、组合物和方法用于治疗前列腺癌,如晚期前列腺癌,包括本文公开的任何一种或多种(例如,两种、三种、四种、五种、六种、七种、八种、九种、十种或更多种)类型的晚期前列腺癌。
实施例
实施例1:评估三特异性抗原结合分子的结合和细胞毒活性的方法
蛋白质产生
将三特异性分子的序列克隆到哺乳动物表达载体pcDNA 3.4(Invitrogen)中,其之前是前导序列,之后是6x组氨酸标签(SEQ ID NO:161)。将Expi293F细胞(LifeTechnologies A14527)以0.2-8×1e6个细胞/ml悬浮保持在Optimum Growth Flasks(Thomson)中的Expi293培养基中。根据Expi293Expression System Kit(LifeTechnologies,A14635)方案,将纯化的质粒DNA转染到Expi293细胞中,并在转染后保持4-6天。通过亲和色谱法和脱盐色谱法对条件培养基进行部分纯化。三特异性蛋白质随后通过离子交换进行精制,或者用Amicon Ultra离心过滤单元(EMD Millipore)浓缩,施加到Superdex 200大小排阻介质(GE Healthcare),并在含有赋形剂的中性缓冲液中解析。通过SDS-PAGE和分析SEC评估级分合并和最终纯度。
亲和力测量
使用Octet仪器通过生物层干涉法测量所有结合域分子的亲和力。
PSMA亲和力如下测量:将人PSMA-Fc蛋白质(100nM)加载到抗人IgG Fc生物传感器上120秒,随后是60秒基线,之后通过将该传感器端头在三特异性分子的稀释系列中温育180秒来测量缔合,然后解离50秒。EGFR和CD3亲和力如下测量:分别将人EGFR-Fc蛋白质或人CD3-Flag-Fc蛋白质(100nM)加载到抗人IgG Fc生物传感器上120秒,随后是60秒基线,之后通过将该传感器端头在三特异性分子稀释系列中温育180秒来测量缔合,然后解离300秒。通过将生物素化的白蛋白加载到链霉亲和素生物传感器上,然后按照与CD3亲和力测量相同的动力学参数,测量对人血清白蛋白(HSA)的亲和力。所有步骤均在30℃下在含0.25%酪蛋白的磷酸盐缓冲盐水中进行。
细胞毒性试验
使用人T细胞依赖性细胞毒性(TDCC)试验来测量T细胞接合物(包括三特异性分子)引导T细胞杀伤肿瘤细胞的能力(Nazarian等人,2015.J Biomol Screen.20:519-27)。在该试验中,将T细胞和靶癌细胞系细胞在384孔板中以10:1的比例混合在一起,并添加不同量的T细胞接合物。48小时后,洗去T细胞,留下未被T细胞杀死的靶细胞附着在板上。为了对剩余的活细胞进行定量,使用Luminescent Cell Viability Assay(Promega)。在一些情况下,将靶细胞工程化为表达萤光素酶。在这些情况下,通过用试剂(Promega)进行发光萤光素酶试验来评估靶细胞的活力,其中活力与萤光素酶活性的量成正比。
稳定性试验
在非人灵长类动物血清的存在下,以低浓度评估三特异性结合蛋白质的稳定性。将TriTAC在食蟹猴血清(BioReclamationIVT)中稀释至33μg/ml,并在37℃下温育2天或进行5次冷冻/解冻循环。处理后,在细胞毒性(TDCC)试验中评估样品,并将其剩余活性与未处理的储备溶液进行比较。
异种移植试验
在异种移植实验(Crown Bioscience,Taicang)中评估了三特异性结合蛋白质的体内功效。在第0天用5e6个22Rv1人前列腺癌细胞与5e6个静息的、从健康人供体中分离的人T细胞的混合物接种缺乏共同γ链的NOD/SCID小鼠(NCG,南京大学模型动物研究中心(Model Animal Research Center ofNanjing University))。将小鼠随机分成三组,并用媒介物、0.5mg/kg PSMA TriTAC C324或0.5mg/kg PSMA BiTE处理。每天经由静脉内团注进行处理,持续10天。每天检查动物的发病率和死亡率。每周两次用卡尺测量肿瘤体积。该研究在30天后终止。
PK分析
本研究的目的是评价三特异性结合蛋白质在静脉内注射后的单剂量药代动力学。经由在约1分钟内进行的缓慢静脉内(IV)团注向每组2只首次进行实验的食蟹猴(1只雄性和1只雌性)给予化合物。剂量施用后,每天进行一次笼侧观察,并且每周记录体重。到施用剂量后21天,收集血液样品并处理成血清以供药代动力学分析。
用电致发光读出器(Meso Scale Diagnostics,Rockville)从猴血清测定测试品的浓度。使用具有固定的重组CD3的96孔板捕获分析物。根据制造商的说明书,在MSD读取器上用磺基标记的重组PSMA进行检测。
实施例2:评估CD3亲和力对三特异性分子的性质的影响
研究了具有不同CD3结合域的靶向PSMA的三特异性分子,以证明改变CD3亲和力的作用。示例性靶向PSMA的三特异性分子在图1中示出。表1列出了每种分子对三种结合配偶体(PSMA、CD3、HSA)的亲和力。使用Octet仪器(Pall Forté Bio)通过生物层干涉法测量亲和力。降低的CD3亲和力导致在T细胞介导的细胞毒性方面的效力损失(图2A-图2C)。在食蟹猴中评估这些三特异性分子的药代动力学性质。对CD3具有高亲和力的分子,如TriTACC236,具有大约90h的终末半衰期(图3)。尽管与T细胞上的CD3结合的能力改变,但图4中显示的具有不同CD3亲和力的两种分子的终末半衰期非常相似。然而,降低的CD3亲和力似乎导致更大的分布体积,这与T细胞对三特异性分子的隔离的减少相一致。在研究期间没有注意到不良的临床观察结果或体重变化。
表1:对人和食蟹猴抗原的结合亲和力
实施例3:评估PSMA亲和力对三特异性分子的性质的影响
研究了具有不同PSMA结合域的靶向PSMA的三特异性分子,以证明改变PSMA亲和力的作用。表2列出了每种分子对三种结合配偶体(PSMA、CD3、HSA)的亲和力。降低的PSMA亲和力导致在T细胞介导的细胞毒性方面的效力损失(图5A-图5C)。
表2:对人和食蟹猴抗原的结合亲和力
实施例4:靶向PSMA的三特异性分子的体内功效
评估了靶向PSMA的三特异性分子C324抑制小鼠中的肿瘤生长的能力。对于该实验,用表达PSMA的人前列腺肿瘤细胞(22Rv1)皮下接种用人T细胞重建的免疫受损小鼠,并且每天用0.5mg/kg的靶向PSMA的BiTE或TriTAC分子静脉内(i.v.)处理,持续10天。测量肿瘤生长30天。在实验过程中,三特异性分子能够以与BiTE分子相当的功效抑制肿瘤生长(图6)。
实施例5:三特异性分子的特异性
为了评估靶向PSMA的TriTAC分子的特异性,用对PSMA呈阴性的肿瘤细胞测试其诱导T细胞杀伤肿瘤细胞的能力(图7A)。靶向EGFR的TriTAC分子充当阳性对照,靶向GFP的TriTAC分子充当阴性对照。具有不同PSMA结合域的所有三种TriTAC都显示出预期的针对PSMA阳性细胞系LNCaP的活性(图7B),但在PSMA阴性肿瘤细胞系KMS12BM和OVCAR8中未达到EC50(图7C和图7D)。EC50总结于表3中。在非常高的TriTAC浓度(>1nM)下,对于TriTAC C362和C363可以观察到一些有限的脱靶细胞杀伤,而C364在任何测试条件下都没有显示出显著的细胞杀伤。
表3:TriTAC分子在抗原阳性和阴性肿瘤细胞系中的细胞杀伤活性(EC50[pM])
TriTAC | LNCaP | KMS12BM | OVCAR8 |
PSMA p8TriTAC C362 | 13.0 | >10,000 | >10,000 |
PSMA HDS TriTAC C363 | 6.2 | >10,000 | >10,000 |
PSMA HTS TriTAC C364 | 0.8 | >10,000 | >10,000 |
EGFR TriTAC C131 | 9.4 | >10,000 | 6 |
GFP TriTAC C | >10,000 | >10,000 | >10,000 |
实施例6:应激测试和蛋白质稳定性
将四种靶向PSMA的三特异性分子在食蟹猴血清中以低浓度(33.3μg/ml)温育48小时,或在食蟹猴血清中进行五次冷冻解冻循环。处理后,在细胞杀伤试验中评估TriTAC分子的生物活性,并与无应激的样品(“阳性对照”)进行比较(图8A-图8D)。所有分子都保持大部分其细胞杀伤活性。TriTAC C362是最具应激抗性的,并且在此处测试的条件下似乎未失去任何活性。
实施例7:异种移植肿瘤模型
在异种移植模型中评价前述实施例的靶向PSMA的三特异性蛋白质。
向雄性免疫缺陷NCG小鼠的右背侧皮下接种5×106个22Rv1细胞。当肿瘤达到100至200mm3时,将动物分成3个处理组。第2组和第3组(各8只动物)腹膜内注射1.5×107个活化的人T细胞。三天后,随后用50μg实施例1的PSMA三特异性抗原结合蛋白质的总共9个静脉内剂量(qdx9d)处理第3组的动物。第1组和第2组仅用媒介物处理。测量体重和肿瘤体积30天。
预计与相应媒介物处理的对照组中的肿瘤生长相比,用PSMA三特异性抗原结合蛋白质处理的小鼠中的肿瘤生长具有显著降低的生长。
实施例8:关于向前列腺癌患者施用实施例1的PSMA三特异性抗原结合蛋白质的概念验
证临床试验方案
这是用于研究实施例1的PSMA三特异性抗原结合蛋白质作为前列腺治疗方法的I/II期临床试验。
研究结果:
主要:前述实施例的靶向PSMA的三特异性蛋白质的最大耐受剂量
次要:确定前述实施例的靶向PSMA的三特异性蛋白质的体外反应是否与临床反应相关
I期
最大耐受剂量(MTD)在该试验的I期部分确定。
1.1最大耐受剂量(MTD)在该试验的I期部分确定。
1.2满足合格性标准的患者加入针对前述实施例的靶向PSMA的三特异性蛋白质的试验。
1.3目标是确定前述实施例的靶向PSMA的三特异性蛋白质可以在参与者中安全施用而没有严重的或难以处理的副作用的最高剂量。给定的剂量取决于之前已经入选该研究的参与者的数目以及剂量耐受程度。并非所有参与者都接受相同的剂量。
II期
2.1随后的II期部分以MTD进行治疗,目的是确定采用前述实施例的靶向PSMA的三特异性蛋白质的疗法是否会导致至少20%的反应率。II期的主要结果---确定采用前述实施例的靶向PSMA的三特异性蛋白质的疗法是否会致使至少20%的患者实现临床反应(强烈反应(blast response)、轻微反应、部分反应或完全反应)。
合格性
从2001年至2007年,根据当前的世界卫生组织分类,经组织学证实的新诊断的侵袭性前列腺癌
疾病的任何阶段
用多西他赛和泼尼松(+/-手术)治疗
年龄≥18岁
Karnofsky体能状态≥50%或ECOG体能状态为0-2
预期寿命≥6周
实施例9:在使用一组表达PSMA的细胞系和来自不同供体的T细胞的重导向T细胞杀伤
试验中,示例性PSMA抗原结合蛋白质(靶向PSMA的TriTAC分子)的活性
进行该研究以证明示例性PSMA三特异性抗原结合蛋白质的活性不限于LNCaP细胞或单一细胞供体。
使用来自四个不同供体的T细胞和表达PSMA的人前列腺癌细胞系VCaP、LNCaP、MDAPCa2b和22Rv1进行重导向T细胞杀伤试验。除一个例外之外,PSMA三特异性抗原结合蛋白质能够使用来自所有供体的T细胞引导对这些癌细胞系的杀伤,EC50值为0.2至1.5pM,如表4所示。对于前列腺癌细胞系22Rv1和供体24,没有或几乎没有观察到杀伤(数据未示出)。供体24也仅导致MDAPCa2b细胞系的约50%的杀伤,而来自其他3个供体的T细胞导致对该细胞系的几乎完全的杀伤(数据未示出)。对照试验证明,PSMA三特异性抗原结合蛋白质的杀伤是PSMA特异性的。当用靶向绿色荧光蛋白(GFP)而不是PSMA的对照三特异性蛋白质处理表达PSMA的细胞时,未观察到杀伤(数据未示出)。类似地,PSMA三特异性抗原结合蛋白质对缺乏PSMA表达的细胞系NCI-1563和HCT116无活性,也显示在表4中。
表4:来自使用六种人癌症细胞系和四个不同T细胞供体的TDCC试验的EC50值
实施例10:在重导向T细胞杀伤试验中,示例性PSMA三特异性抗原结合蛋白质(靶向
PSMA的TriTAC分子)对细胞因子表达的刺激
进行该研究以通过测量活化的T细胞分泌到测定培养基中的细胞因子来证明重导向T细胞杀伤试验期间示例性PSMA三特异性抗原结合蛋白质对T细胞的活化。
分析从以上实施例9中所述的重导向T细胞杀伤试验收集的条件培养基的细胞因子TNFα和IFNγ的表达。使用AlphaLISA测定(Perkin-Elmer)测量细胞因子。将滴定量的PSMA抗原结合蛋白质添加到来自四个不同供体的T细胞和四种表达PSMA的细胞系LNCaP、VCaP、MDAPCa2b和22Rv1导致TNFα的水平增加。条件培养基中TNFα表达和IFNγ表达水平的结果分别显示在表5和表6中。PSMA抗原结合蛋白质诱导这些细胞因子表达的EC50值的范围为3至15pM。对于靶向GFP的对照三特异性蛋白质,未观察到细胞因子水平增加。类似地,当用缺乏PSMA表达的两种细胞系HCT116和NCI-H1563进行测定时,PSMA HTS TriTAC也不增加TNFα或IFNγ表达。
表5:采用六种人癌症细胞系和来自四个不同供体的T细胞的PSMA三特异性抗原结合蛋
白质TDCC试验中,培养基中的TNFα表达的EC50值
细胞系 | 供体24 | 供体8144 | 供体41 | 供体72 |
LNCaP | 4.9E-12 | 2.8E-12 | 4.0E-12 | 3.2E-12 |
VCaP | 3.2E-12 | 2.9E-12 | 2.9E-12 | 2.9E-12 |
MDAPCa2b | 2.1E-11 | 4.0E-12 | 5.5E-12 | 3.6E-12 |
22Rv1 | 8.9E-12 | 2.5E-12 | 4.0E-12 | 3.3E-12 |
HCT116 | >1E-8 | >1E-8 | >1E-8 | >1E-8 |
NCI-H1563 | >1E-8 | >1E-8 | >1E-8 | >1E-8 |
表6:采用六种人癌症细胞系和来自四个不同供体的T细胞的PSMA三特异性抗原结合蛋
白质TDCC试验中,培养基中的IFNγ表达的EC50值
细胞系 | 供体24 | 供体8144 | 供体41 | 供体72 |
LNCaP | 4.2E-12 | 4.2E-12 | 4.2E-12 | 2.8E-12 |
VCaP | 5.1E-12 | 1.5E-11 | 3.4E-12 | 4.9E-12 |
MDAPCa2b | 1.5E-11 | 5.8E-12 | 9.7E-12 | 3.5E-12 |
22Rv1 | 7.8E-12 | 3.0E-12 | 9.1E-12 | 3.0E-12 |
HCT116 | >1E-8 | >1E-8 | >1E-8 | >1E-8 |
NCI-H1563 | >1E-8 | >1E-8 | >1E-8 | >1E-8 |
实施例11:在使用来自食蟹猴的T细胞的重导向T细胞杀伤试验(TDCC)中,示例性PSMA
三特异性抗原结合蛋白质(靶向PSMA的TriTAC)的活性
进行该研究以测试示例性PSMA三特异性抗原结合蛋白质引导来自食蟹猴的T细胞杀伤表达PSMA的细胞系的能力。
使用来自食蟹猴的外周血单个核细胞(PBMC)建立TDCC试验。将食蟹猴PBMC以10:1的比例添加至LNCaP细胞。观察到PSMA三特异性抗原结合蛋白质重新引导食蟹猴PBMC对LNCaP的杀伤,EC50值为11pM。结果在图9A中示出。为了证实这些结果,使用第二种细胞系MDAPCa2b,并测试来自第二个食蟹猴供体的PBMC。观察到重导向的靶细胞杀伤,EC50值为2.2pM。结果在图9B中示出。杀伤是PSMA三特异性抗原结合蛋白的抗PMSA臂所特有的,因为对于靶向GFP的阴性对照三特异性蛋白质未观察到杀伤。这些数据证明,PSMA抗原结合性三特异性蛋白质可以引导食蟹猴T细胞杀伤表达人PSMA的靶细胞。
实施例12:在使用示例性PSMA三特异性抗原结合蛋白质(靶向PSMA的TriTAC分子)的重
导向T细胞杀伤试验中,T细胞活化标志物的表达
进行该研究以评估当示例性PSMA三特异性抗原结合蛋白质引导T细胞杀伤靶细胞时,T细胞是否被活化。
使用以上实施例中描述的重导向T细胞杀伤试验的条件建立试验。通过使用流式细胞术测量T细胞表面上CD25和CD69的表达来评估T细胞活化。将PSMA三特异性抗原结合蛋白质添加至纯化的人T细胞与前列腺癌细胞系VCaP的10:1混合物。在添加渐增量的PSMA三特异性抗原结合蛋白质后,观察到增加的CD69表达和CD25表达,如图10所示。对于CD69的EC50值为0.3pM,而对于CD25的EC50值为0.2pM。在这些试验中包含靶向GFP的三特异性蛋白质作为阴性对照,并且对于靶向GFP的三特异性蛋白质观察到CD69或CD25表达没有或几乎没有增加,同样在图10中示出。
实施例13:在表达PSMA的靶细胞的存在下,示例性PSMA三特异性抗原结合蛋白质(靶向
PSMA的TriTAC分子)对T细胞增殖的刺激
该研究作为另一方法,用来证明示例性PSMA三特异性抗原结合蛋白质在重新引导T细胞杀伤靶细胞时能够激活T细胞。
如上所述,使用LNCaP靶细胞,用T细胞重导向杀伤试验的条件建立T细胞增殖试验,并测量72小时时存在的T细胞数目。示例性PSMA三特异性抗原结合蛋白质刺激增殖,EC50值为0.5pM。作为阴性对照,在该试验中包含靶向GFP的三特异性蛋白质,并且对于该蛋白质未观察到增殖增加。T细胞增殖试验的结果在图11中示出。
实施例14:三种示例性PSMA三特异性抗原结合蛋白质(靶向PSMA的TriTAC分子PH1T、PH
和Z2)对LNCaP细胞的重导向T细胞杀伤
进行该研究以测试具有如SEQ ID No:150、151和152所示序列的三种示例性PSMA三特异性抗原结合蛋白质重新引导T细胞杀伤LNCaP细胞系的能力。
在如以上实施例中所述设置的TDCC试验中,PSMA PH1T TriTAC(SEQ ID No:150)和PSMA PH1 TriTAC(SEQ ID NO:151)蛋白质引导杀伤,EC50值分别为25pM和20pM,如图12A所示;PSMA Z2 TriTAC(SEQ ID NO:152)蛋白质引导杀伤,EC50值为0.8pM,如图12B所示。
表7:CD3结合域序列
表8:HSA结合域序列
表9:PSMA结合域序列
表10:靶向PSMA的三特异性蛋白质的序列
表11:PSMA结合域CDR序列
<u>SEQ ID Nos.</u> | <u>序列</u> |
SEQ ID No.162 | RFMISX<sub>1</sub>YX<sub>2</sub>MH |
SEQ ID No.163 | X<sub>3</sub>INPAX<sub>4</sub>X<sub>5</sub>TDYAEX<sub>6</sub>VKG |
SEQ ID No.164 | DX<sub>7</sub>YGY |
表12:示例性框架序列
SEQ ID NO: | 描述 | 序列 |
165 | 框架(f1) | EVQLVESGGGLVQPGGSLTLSCAAS |
166 | 框架(f2) | WVRQAPGKGLEWVS |
167 | 框架(f3) | RFTISRDNAKNTLYLQMNSLRAEDTAVYYC |
168 | 框架(f4) | DGYGYRGQGTLVTVSS |
虽然本文已经显示并描述了本发明的优选实施方案,但是对于本领域技术人员显而易见的是,这些实施方案仅以示例的方式提供。在不脱离本发明的情况下,本领域技术人员现将想到许多变化、改变和替换。应当理解,本文所述的本发明实施方案的各种替代方案均可用于实施本发明。以下权利要求旨在限定本发明的范围,并且由此涵盖这些权利要求范围内的方法和结构及其等同物。
序列表
<110> 哈普恩治疗公司
<120> 靶向PSMA的三特异性蛋白质及使用方法
<130> 47517-708.601
<140>
<141>
<150> 62/426,069
<151> 2016-11-23
<150> 62/426,077
<151> 2016-11-23
<160> 168
<170> PatentIn version 3.5
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Ala Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Gln Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Asp Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Ile Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 9
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Val Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Glu Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Ile Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 10
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Pro Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Asn Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Asn Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Lys Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Met Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 11
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Gly Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Glu Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Pro Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Val Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Glu Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 12
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Asn Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asp Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr His Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Val Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 13
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Gly Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Tyr Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Phe Asn Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ala Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 14
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Glu Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Glu Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Leu Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Ser Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Phe Gly Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 15
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 16
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 16
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
1 5 10
<210> 17
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 17
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys
<210> 18
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 18
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 19
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 19
Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 20
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 20
Gly Thr Lys Phe Leu Ala Pro
1 5
<210> 21
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 21
Val Leu Trp Tyr Ser Asn Arg Trp Val
1 5
<210> 22
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 22
Gly Asn Thr Phe Asn Lys Tyr Ala Met Asn
1 5 10
<210> 23
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 23
Gly Phe Glu Phe Asn Lys Tyr Ala Met Asn
1 5 10
<210> 24
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 24
Gly Phe Met Phe Asn Lys Tyr Ala Met Asn
1 5 10
<210> 25
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 25
Gly Phe Thr Tyr Asn Lys Tyr Ala Met Asn
1 5 10
<210> 26
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 26
Gly Phe Thr Phe Asn Asn Tyr Ala Met Asn
1 5 10
<210> 27
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 27
Gly Phe Thr Phe Asn Gly Tyr Ala Met Asn
1 5 10
<210> 28
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 28
Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn
1 5 10
<210> 29
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 29
Gly Phe Thr Phe Asn Glu Tyr Ala Met Asn
1 5 10
<210> 30
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 30
Gly Phe Thr Phe Asn Lys Tyr Pro Met Asn
1 5 10
<210> 31
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 31
Gly Phe Thr Phe Asn Lys Tyr Ala Val Asn
1 5 10
<210> 32
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 32
Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn
1 5 10
<210> 33
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 33
Gly Phe Thr Phe Asn Lys Tyr Ala Leu Asn
1 5 10
<210> 34
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 34
Arg Ile Arg Ser Gly Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys
<210> 35
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 35
Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys
<210> 36
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 36
Arg Ile Arg Ser Lys Tyr Asn Lys Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys
<210> 37
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 37
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Glu Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys
<210> 38
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 38
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Glu Tyr Ala Asp Ser
1 5 10 15
Val Lys
<210> 39
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 39
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Lys Asp Ser
1 5 10 15
Val Lys
<210> 40
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 40
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Glu
1 5 10 15
Val Lys
<210> 41
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 41
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ala
1 5 10 15
Val Lys
<210> 42
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 42
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln
1 5 10 15
Val Lys
<210> 43
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 43
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Asp
1 5 10 15
Val Lys
<210> 44
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 44
His Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 45
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 45
His Thr Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 46
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 46
His Gly Asn Phe Asn Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 47
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 47
His Gly Asn Phe Gly Asp Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 48
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 48
His Gly Asn Phe Gly Asn Ser His Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 49
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 49
His Gly Asn Phe Gly Asn Ser Pro Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 50
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 50
His Gly Asn Phe Gly Asn Ser Gln Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 51
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 51
His Gly Asn Phe Gly Asn Ser Leu Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 52
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 52
His Gly Asn Phe Gly Asn Ser Gly Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 53
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 53
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Thr
1 5 10
<210> 54
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 54
Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 55
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 55
Gly Glu Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 56
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 56
Gly Ser Tyr Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 57
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 57
Gly Ser Ser Phe Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 58
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 58
Gly Ser Ser Lys Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 59
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 59
Gly Ser Ser Ser Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 60
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 60
Gly Ser Ser Thr Gly Tyr Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 61
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 61
Gly Ser Ser Thr Gly Ala Val Val Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 62
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 62
Gly Ser Ser Thr Gly Ala Val Thr Asp Gly Asn Tyr Pro Asn
1 5 10
<210> 63
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 63
Gly Ser Ser Thr Gly Ala Val Thr Lys Gly Asn Tyr Pro Asn
1 5 10
<210> 64
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 64
Gly Ser Ser Thr Gly Ala Val Thr His Gly Asn Tyr Pro Asn
1 5 10
<210> 65
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 65
Gly Ser Ser Thr Gly Ala Val Thr Val Gly Asn Tyr Pro Asn
1 5 10
<210> 66
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 66
Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn
1 5 10
<210> 67
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 67
Gly Ile Lys Phe Leu Ala Pro
1 5
<210> 68
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 68
Gly Thr Glu Phe Leu Ala Pro
1 5
<210> 69
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 69
Gly Thr Tyr Phe Leu Ala Pro
1 5
<210> 70
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 70
Gly Thr Ser Phe Leu Ala Pro
1 5
<210> 71
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 71
Gly Thr Asn Phe Leu Ala Pro
1 5
<210> 72
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 72
Gly Thr Lys Leu Leu Ala Pro
1 5
<210> 73
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 73
Gly Thr Lys Glu Leu Ala Pro
1 5
<210> 74
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 74
Gly Thr Lys Ile Leu Ala Pro
1 5
<210> 75
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 75
Gly Thr Lys Met Leu Ala Pro
1 5
<210> 76
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 76
Gly Thr Lys Val Leu Ala Pro
1 5
<210> 77
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 77
Gly Thr Lys Phe Asn Ala Pro
1 5
<210> 78
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 78
Gly Thr Lys Phe Gly Ala Pro
1 5
<210> 79
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 79
Gly Thr Lys Phe Leu Val Pro
1 5
<210> 80
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 80
Thr Leu Trp Tyr Ser Asn Arg Trp Val
1 5
<210> 81
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 81
Ala Leu Trp Tyr Ser Asn Arg Trp Val
1 5
<210> 82
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 82
Val Leu Trp Tyr Asp Asn Arg Trp Val
1 5
<210> 83
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 83
Val Leu Trp Tyr Ala Asn Arg Trp Val
1 5
<210> 84
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 84
Val Leu Trp Tyr Ser Asn Ser Trp Val
1 5
<210> 85
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 85
Val Leu Trp Tyr Ser Asn Arg Trp Ile
1 5
<210> 86
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 86
Val Leu Trp Tyr Ser Asn Arg Trp Ala
1 5
<210> 87
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 87
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Leu Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Glu Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Pro Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Asn Phe Leu Ala Pro Gly Thr Pro Glu Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Ala Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 88
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 88
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Glu Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Asp Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Gly Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Val Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Glu Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 89
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 89
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 90
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 90
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ala Asp Thr Leu Tyr Ala Asp Ser Leu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Lys Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 91
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 91
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Lys Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 92
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 92
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Thr Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 93
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 93
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Lys Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 94
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 94
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 95
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 95
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 96
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 96
Gly Phe Thr Phe Ser Ser Phe Gly Met Ser
1 5 10
<210> 97
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 97
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 98
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 98
Gly Gly Ser Leu Ser Arg
1 5
<210> 99
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 99
Gly Phe Thr Phe Ser Arg Phe Gly Met Ser
1 5 10
<210> 100
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 100
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
1 5 10
<210> 101
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 101
Gly Phe Thr Tyr Ser Ser Phe Gly Met Ser
1 5 10
<210> 102
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 102
Ser Ile Ser Gly Ser Gly Ala Asp Thr Leu Tyr Ala Asp Ser Leu Lys
1 5 10 15
<210> 103
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 103
Ser Ile Ser Gly Ser Gly Thr Asp Thr Leu Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 104
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 104
Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 105
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 105
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Glu Ser Val Lys
1 5 10 15
<210> 106
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 106
Ser Ile Ser Gly Ser Gly Thr Asp Thr Leu Tyr Ala Glu Ser Val Lys
1 5 10 15
<210> 107
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 107
Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys
1 5 10 15
<210> 108
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 108
Gly Gly Ser Leu Ser Lys
1 5
<210> 109
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 109
Gly Gly Ser Leu Ser Val
1 5
<210> 110
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 110
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 111
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 111
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Thr Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 112
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 112
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 113
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 113
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 114
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 114
Arg Phe Met Ile Ser Glu Tyr His Met His
1 5 10
<210> 115
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 115
Arg Phe Met Ile Ser Pro Tyr Ser Met His
1 5 10
<210> 116
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 116
Arg Phe Met Ile Ser Pro Tyr His Met His
1 5 10
<210> 117
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 117
Asp Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys Gly
1 5 10 15
<210> 118
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 118
Thr Ile Asn Pro Ala Lys Thr Thr Asp Tyr Ala Glu Ser Val Lys Gly
1 5 10 15
<210> 119
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 119
Thr Ile Asn Pro Ala Gly Gln Thr Asp Tyr Ala Glu Ser Val Lys Gly
1 5 10 15
<210> 120
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 120
Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Tyr Val Lys Gly
1 5 10 15
<210> 121
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 121
Asp Ile Asn Pro Ala Lys Thr Thr Asp Tyr Ala Glu Ser Val Lys Gly
1 5 10 15
<210> 122
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 122
Asp Ile Asn Pro Ala Gly Gln Thr Asp Tyr Ala Glu Ser Val Lys Gly
1 5 10 15
<210> 123
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 123
Asp Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Tyr Val Lys Gly
1 5 10 15
<210> 124
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 124
Asp Ser Tyr Gly Tyr
1 5
<210> 125
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 125
Arg Phe Met Ile Ser Glu Tyr Ser Met His
1 5 10
<210> 126
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 126
Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys Gly
1 5 10 15
<210> 127
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 127
Asp Gly Tyr Gly Tyr
1 5
<210> 128
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 128
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 129
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 129
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 130
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 130
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 131
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 131
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Lys Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 132
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 132
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 Arg Phe Met Ile Ser Pro Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 133
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 133
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Gln Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 134
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 134
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Tyr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 135
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 135
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Pro Ala Lys Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 136
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 136
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 Arg Phe Met Ile Ser Pro Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 137
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 137
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Pro Ala Gly Gln Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 138
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 138
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Tyr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 139
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 139
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 140
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 141
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 141
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
260 265 270
Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
290 295 300
Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 142
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 142
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
260 265 270
Phe Asn Asn Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Gly Tyr Asn Asn Tyr Ala Thr
290 295 300
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Gly Ser Tyr Thr Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Asn Ala Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ala Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 143
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 143
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Glu
260 265 270
Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Glu Thr
290 295 300
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Leu
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Gly Ser Ser Ser Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Gly Ala Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 144
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 144
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
260 265 270
Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
290 295 300
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 145
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 145
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 Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
260 265 270
Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
290 295 300
Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 146
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 146
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
260 265 270
Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
290 295 300
Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 147
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 147
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
260 265 270
Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
290 295 300
Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 148
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 148
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 149
<211> 512
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 149
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Thr Cys Ala Ala Ser Gly Arg Thr Ser Arg Ser Tyr
20 25 30
Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Gly Ile Ser Trp Arg Gly Asp Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Asp
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Ala Ala Ala Gly Ser Ala Trp Tyr Gly Thr Leu Tyr Glu Tyr Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
130 135 140
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
145 150 155 160
Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
165 170 175
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu
180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
195 200 205
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
275 280 285
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
305 310 315 320
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
325 330 335
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
355 360 365
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
385 390 395 400
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
405 410 415
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
420 425 430
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
435 440 445
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
450 455 460
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
465 470 475 480
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
485 490 495
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
500 505 510
<210> 150
<211> 508
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 150
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Arg
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Tyr Ser Gly Val Thr Val Asn Val Tyr
20 25 30
Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Asn Ile Asn Trp Ser Gly Asn Asn Arg Asp Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 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 Ser Glu Lys Pro Gly Arg Leu Gly Glu Tyr Asp Tyr Gly Ser Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys
145 150 155 160
Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
195 200 205
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Val Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu His His His His His His
500 505
<210> 151
<211> 508
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 151
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Tyr Ser Gly Val Thr Val Asn Val Tyr
20 25 30
Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Asn Ile Asn Trp Ser Gly Asn Asn Arg Asp Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 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 Ser Glu Lys Pro Gly Arg Leu Gly Glu Tyr Asp Tyr Gly Ser Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys
145 150 155 160
Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
195 200 205
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Val Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu His His His His His His
500 505
<210> 152
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 152
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
260 265 270
Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
290 295 300
Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 153
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<220>
<221> MISC_FEATURE
<222> (1)..(20)
<223> 该序列可包含1-10个"Gly Ser"
重复单元
<400> 153
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10 15
Gly Ser Gly Ser
20
<210> 154
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(30)
<223> 该序列可包含1-10个"Gly Gly Ser"
重复单元
<400> 154
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly
1 5 10 15
Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
20 25 30
<210> 155
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(40)
<223> 该序列可包含1-10个"Gly Gly Gly Ser"
重复单元
<400> 155
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
20 25 30
Gly Gly Gly Ser Gly Gly Gly Ser
35 40
<210> 156
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(40)
<223> 该序列可包含1-10个"Gly Gly Ser Gly"
重复单元
<400> 156
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly
20 25 30
Gly Gly Ser Gly Gly Gly Ser Gly
35 40
<210> 157
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(50)
<223> 该序列可包含1-10个"Gly Gly Ser Gly Gly"
重复单元
<400> 157
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
1 5 10 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
20 25 30
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Gly Gly
50
<210> 158
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(50)
<223> 该序列可包含1-10个"Gly Gly Gly Gly Ser"
重复单元
<400> 158
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
35 40 45
Gly Ser
50
<210> 159
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 159
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 160
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 160
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 161
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
6xHis标签
<400> 161
His His His His His His
1 5
<210> 162
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<220>
<221> MOD_RES
<222> (6)..(6)
<223> Glu、Pro、Ser、His、Thr、Asp、Gly、Lys、Gln或Tyr
<220>
<221> MOD_RES
<222> (8)..(8)
<223> Glu、Pro、Ser、His、Thr、Asp、Gly、Lys、Gln或Tyr
<400> 162
Arg Phe Met Ile Ser Xaa Tyr Xaa Met His
1 5 10
<210> 163
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Glu、Pro、Ser、His、Thr、Asp、Gly、Lys、Gln或Tyr
<220>
<221> MOD_RES
<222> (6)..(7)
<223> Glu、Pro、Ser、His、Thr、Asp、Gly、Lys、Gln或Tyr
<220>
<221> MOD_RES
<222> (13)..(13)
<223> Glu、Pro、Ser、His、Thr、Asp、Gly、Lys、Gln或Tyr
<400> 163
Xaa Ile Asn Pro Ala Xaa Xaa Thr Asp Tyr Ala Glu Xaa Val Lys Gly
1 5 10 15
<210> 164
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<220>
<221> MOD_RES
<222> (2)..(2)
<223> Glu、Pro、Ser、His、Thr、Asp、Gly、Lys、Gln或Tyr
<400> 164
Asp Xaa Tyr Gly Tyr
1 5
<210> 165
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 165
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser
20 25
<210> 166
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 166
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10
<210> 167
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 167
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
20 25 30
<210> 168
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 168
Asp Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10 15
Claims (74)
1.一种靶向前列腺特异性膜抗原(PSMA)的三特异性蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与PSMA特异性结合的第三结构域(C),
其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接。
2.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域包含各自能够与人CD3特异性结合的可变轻链和可变重链。
3.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。
4.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域是人源化的或人的。
5.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域与表达CD3的细胞上的CD3结合的KD为150nM或更低。
6.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域结合人血清白蛋白。
7.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域包含scFv、可变重链(VH)结构域、可变轻链(VL)结构域、肽、配体或小分子。
8.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域包含一种或多种选自SEQ ID NO:89-112的序列。
9.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述第三结构域包含与PSMA特异性结合的scFv、VH结构域、VL结构域、非Ig结构域、配体、knottin或小分子实体。
10.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述第三结构域包含一种或多种选自SEQ ID NO:113-140的序列。
11.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中连接体L1和L2各自独立地选自(GS)n(SEQ ID NO:153)、(GGS)n(SEQ ID NO:154)、(GGGS)n(SEQ ID NO:155)、(GGSG)n(SEQ ID NO:156)、(GGSGG)n(SEQ ID NO:157)或(GGGGS)n(SEQ ID NO:158),其中n为1、2、3、4、5、6、7、8、9或10。
12.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中连接体L1和L2各自独立地为(GGGGS)4(SEQ ID NO:159)或(GGGGS)3(SEQ ID NO:160)。
13.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述结构域以H2N-(A)-(C)-(B)-COOH的顺序连接。
14.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述结构域以H2N-(B)-(C)-(A)-COOH的顺序连接。
15.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质小于约80kDa。
16.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质为约50kDa至约75kDa。
17.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质小于约60kDa。
18.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质具有至少约50小时的消除半衰期。
19.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质具有至少约100小时的消除半衰期。
20.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中与针对相同PSMA的IgG相比,所述蛋白质具有增加的组织穿透。
21.如权利要求1所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质包含选自SEQ IDNO:140-152的序列。
22.一种药物组合物,其包含(i)如权利要求1-21中任一项所述的靶向PSMA的三特异性蛋白质,和(ii)药学上可接受的载剂。
23.一种治疗需要癌症治疗的个体的方法,该方法包括施用有效量的如权利要求22所述的药物组合物。
24.如权利要求23所述的方法,其中所述癌症是前列腺癌或肾癌。
25.一种靶向PSMA的三特异性蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与PSMA特异性结合的第三结构域(C),
其中所述第二结构域包含一种或多种选自SEQ ID NO:113-140的序列。
26.如权利要求25所述的靶向PSMA的三特异性蛋白质,其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接。
27.如权利要求25或26所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。
28.如权利要求25、26或27所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域包含一种或多种选自SEQ ID NO:89-112的序列。
29.一种靶向PSMA的三特异性蛋白质,其中所述蛋白质包含选自SEQ ID NO:140-152的序列。
30.如权利要求29所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质包含选自SEQID NO:150-152的序列。
31.一种靶向前列腺特异性膜抗原(PSMA)的三特异性蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与PSMA特异性结合的第三结构域(C),
其中所述结构域以H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接,并且其中所述第三结构域包含一种或多种选自SEQ ID NO:113-140的序列。
32.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域包含各自能够与人CD3特异性结合的可变轻链和可变重链。
33.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。
34.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域是人源化的或人的。
35.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域与表达CD3的细胞上的CD3结合的KD为150nM或更低。
36.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域结合人血清白蛋白。
37.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域包含scFv、可变重链(VH)结构域、可变轻链(VL)结构域、肽、配体或小分子。
38.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域包含一种或多种选自SEQ ID NO:89-112的序列。
39.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述第三结构域包含与PSMA特异性结合的scFv、VH结构域、VL结构域、非Ig结构域、配体、knottin或小分子实体。
40.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中连接体L1和L2各自独立地选自(GS)n(SEQ ID NO:153)、(GGS)n(SEQ ID NO:154)、(GGGS)n(SEQ ID NO:155)、(GGSG)n(SEQ ID NO:156)、(GGSGG)n(SEQ ID NO:157)或(GGGGS)n(SEQ ID NO:158),其中n为1、2、3、4、5、6、7、8、9或10。
41.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中连接体L1和L2各自独立地为(GGGGS)4(SEQ ID NO:159)或(GGGGS)3(SEQ ID NO:160)。
42.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述结构域以H2N-(C)-L1-(B)-L2-(A)-COOH的顺序连接。
43.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质小于约80kDa。
44.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质为约50kDa至约75kDa。
45.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质小于约60kDa。
46.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质具有至少约50小时的消除半衰期。
47.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质具有至少约100小时的消除半衰期。
48.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中与针对相同PSMA的IgG相比,所述蛋白质具有增加的组织穿透。
49.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质包含选自SEQID NO:140-152的序列。
50.靶向PSMA的三特异性蛋白质,其中所述蛋白质包含选自SEQ ID NO:150-152的序列。
51.一种药物组合物,其包含(i)根据权利要求31所述的靶向PSMA的三特异性蛋白质,和(ii)药学上可接受的载剂。
52.一种靶向PSMA的三特异性蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与PSMA特异性结合的第三结构域(C),
其中所述结构域以H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接,并且其中所述第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。
53.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域包含各自能够与人CD3特异性结合的可变轻链和可变重链。
54.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。
55.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域是人源化的或人的。
56.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述第一结构域与表达CD3的细胞上的CD3结合的KD为150nM或更低。
57.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域结合人血清白蛋白。
58.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域包含scFv、可变重链(VH)结构域、可变轻链(VL)结构域、肽、配体或小分子。
59.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述第二结构域包含一种或多种选自SEQ ID NO:89-112的序列。
60.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述第三结构域包含与PSMA特异性结合的scFv、VH结构域、VL结构域、非Ig结构域、配体、knottin或小分子实体。
61.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中连接体L1和L2各自独立地选自(GS)n(SEQ ID NO:153)、(GGS)n(SEQ ID NO:154)、(GGGS)n(SEQ ID NO:155)、(GGSG)n(SEQ ID NO:156)、(GGSGG)n(SEQ ID NO:157)或(GGGGS)n(SEQ ID NO:158),其中n为1、2、3、4、5、6、7、8、9或10。
62.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中连接体L1和L2各自独立地为(GGGGS)4(SEQ ID NO:159)或(GGGGS)3(SEQ ID NO:160)。
63.如权利要求31所述的靶向PSMA的三特异性蛋白质,其中所述结构域以H2N-(C)-L1-(B)-L2-(A)-COOH的顺序连接。
64.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质小于约80kDa。
65.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质为约50kDa至约75kDa。
66.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质小于约60kDa。
67.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质具有至少约50小时的消除半衰期。
68.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质具有至少约100小时的消除半衰期。
69.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中与针对相同PSMA的IgG相比,所述蛋白质具有增加的组织穿透。
70.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质包含选自SEQID NO:140-152的序列。
71.如权利要求52所述的靶向PSMA的三特异性蛋白质,其中所述蛋白质包含选自SEQID NO:150-152的序列。
72.一种药物组合物,其包含(i)根据权利要求52所述的靶向PSMA的三特异性蛋白质,和(ii)药学上可接受的载剂。
73.一种治疗前列腺癌的方法,该方法包括施用有效量的靶向PSMA的三特异性蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与PSMA特异性结合的第三结构域(C),
其中所述结构域以H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接,并且其中所述第三结构域包含一种或多种选自SEQ ID NO:113-140的序列。
74.一种治疗前列腺癌的方法,该方法包括施用有效量的靶向PSMA的三特异性蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与PSMA特异性结合的第三结构域(C),
其中所述结构域以H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接,并且其中所述第一结构域包含一种或多种选自SEQ ID NO:1-88的序列。
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EP3544629A1 (en) | 2019-10-02 |
KR20190087539A (ko) | 2019-07-24 |
US10844134B2 (en) | 2020-11-24 |
BR112019010602A2 (pt) | 2019-12-17 |
WO2018098356A1 (en) | 2018-05-31 |
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MX2019006045A (es) | 2019-11-11 |
IL266801A (en) | 2019-07-31 |
CA3044729A1 (en) | 2018-05-31 |
AU2017363302A1 (en) | 2019-06-27 |
JP7215997B2 (ja) | 2023-01-31 |
US20210095047A1 (en) | 2021-04-01 |
JP2019535763A (ja) | 2019-12-12 |
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