CN114605547A - 具有类tcr抗体结合域的亲和性实体及其用途 - Google Patents
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Abstract
本发明提供多种具有类T细胞受体(TCRL)结合域的亲和性结合实体及其使用方法。更具体地，所述多个组合物结合HLA‑A2/WT1+、HLA‑A2/MAGE‑A4、HLA‑A2/MAGE‑A9、HLA‑A2/PAP或HLA‑A2/TyrD+的细胞，因此可用于诊断和治疗。
Description
本申请为申请号CN201680040163.X(PCT申请号为PCT/IL2016/050600)、申请日2016年6月8日、发明名称“具有高亲和性和优良特异性的类TCR抗体结合域的亲和性实体及其用途”的分案申请。
技术领域及背景技术
本发明在其一些实施例中有关于多个亲和性结合实体，所述亲和性结合实体包括具有高亲和性和优良特异性的一类TCR抗体结合域及其用途。
肿瘤和病毒感染的多个细胞被多个CD8+细胞毒性T细胞识别，作为回应，所述多个CD8+细胞毒性T细胞被活化以消灭这些细胞。为了能被活化，所述克隆型T细胞受体(TCR)需要遇到由所述细胞膜表面的主要组织兼容性复合体(MHC)分子所表现的一特定的胜肽抗原。多个细胞经过恶性转化或病毒感染后表现衍生自多个肿瘤相关抗原或多个病毒蛋白在所述细胞的多个第一类MHC分子上。因此，多个疾病特异性MHC-肽复合物对于多个免疫治疗方法是多个理想的目标。一种这样的方法将多个TCR对于MHC肽复合物的所述独特的优异特异性但低固有亲和性变换成具有对多个肿瘤或病毒表位赋有一类TCR特异性的多个高亲和性可溶性抗体分子。所述多个抗体，称为多个TCR抗体，被开发为一新类别的免疫治疗药物，所述免疫治疗药物能够靶向多个肿瘤和病毒感染的细胞，并且介导它们的特异性杀伤。除了它们的多个治疗能力外，类TCR抗体被开发为针对癌症和多个传染病的多个诊断试剂，以及作为研究第一类MHC抗原的表现的多个有价值的研究工具。
发明内容
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一人类主要组织兼容性复合体(MHC)限定的方式结合HLA-A2/TyrD369-377。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/TyrD369-377。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/WT1126-134。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，其特征在于，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/MAGE-A4328-343。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/MAGE-A9344-359。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/PAP360-375。
根据本发明的一些实施例，所述亲和性结合实体选自于由一抗体、一嵌合抗原受体(CAR)和一T细胞受体(TCR)组成的群组。
根据本发明的一些实施例，所述亲和性结合实体是一抗体。
根据本发明的一些实施例，所述亲和性结合实体是一TCR。
根据本发明的一些实施例，所述亲和性结合实体是一CAR。
根据本发明的一些实施例，所述亲和性结合实体是一可溶性实体。
根据本发明的一些实施例，所述亲和性结合实体是一人源化抗体。
根据本发明的一些实施例，所述亲和性结合实体包含一治疗部分。
根据本发明的一些实施例，所述亲和性结合实体包括一可检测部分。
根据本发明的一些实施例，所述抗体为一单链抗体，一双特异性抗体或一全长度的抗体。
根据本发明的一些实施例的一个方面，提供了一种分离的多核苷酸，所述多核苷酸包括一核酸序列，用以编码所述亲和性结合实体。
根据本发明的一些实施例的一个方面，提供了一种表达载体，所述多核苷酸可操作地连接至一顺式作用的调控组件。
根据本发明的一些实施例的一个方面，提供了一种细胞，所述细胞包括所述多核苷酸，或所述表达载体。
根据本发明的一些实施例的一个方面，提供了一种药物组合物，所述药物组合物包含所述亲和性结合实体、所述载体，或所述细胞。
根据本发明的一些实施例的一个方面，提供了一种检测一癌细胞的方法，所述方法包括：在允许免疫复合物形成的条件下，使所述抗体与所述细胞接触，其中所述免疫复合物的存在或所述免疫复合物的一水平用以指示出所述癌细胞。
根据本发明的一些实施例的一个方面，提供了一种在需要检测和治疗癌症的一主体中检测和治疗癌症的方法，其特征在于，所述方法包括：
(a)根据所述方法侦测所述主体中多个癌细胞的存在；
(b)当侦测到多个癌细胞时，判断所述主体具有癌症；及
(c)给予所述主体一抗癌疗法。
根据本发明的一些实施例的一个方面，提供了一种在需要检测和治疗癌症的一主体中检测和治疗癌症的方法，所述方法包括：在允许免疫复合物形成的条件下，使所述主体的一细胞与所述抗体接触，其中所述免疫复合物的存在或所述免疫复合物的一水平用以指示出所述癌症。
根据本发明的一些实施例，所述细胞是一皮肤细胞。
根据本发明的一些实施例的一个方面，提供了一种治疗癌症的方法，所述方法包括：给予有需要的一主体一治疗有效数量的所述亲和性结合实体、所述载体或所述细胞，从而治疗癌症。
根据本发明的一些实施例的一个方面，提供了一种用以制备治疗癌症的药物的应用，所述应用使用所述亲和性结合实体、所述载体或所述细胞。
根据本发明的一些实施例，所述亲和性结合实体用于TyrD时，所述癌症选自于由黑色素瘤和胶质母细胞瘤所组成的群组。
根据本发明的一些实施例，所述亲和性结合实体用于威尔姆氏肿瘤蛋白1(WT1)时，所述癌症选自于由慢性髓细胞性白血病、多发性骨髓瘤(MM)、急性淋巴细胞性白血病(ALL)、急性骨髓/骨髓性白血病(AML)、骨髓发育异常综合症(MDS)、间皮瘤、卵巢癌、胃肠癌，例如结肠直肠癌腺癌、甲状腺癌、乳腺癌、肺癌(例如非小细胞肺癌)、黑色素瘤、骨肉瘤、子宫内膜癌、前列腺癌和胶质瘤。
根据本发明的一些实施例，所述亲和性结合实体用于黑色素瘤相关抗原4(MAGE-A4)时，所述癌症选自黑色素瘤、卵巢癌、T细胞白血病/淋巴瘤(例如ATLL)、睾丸癌、头颈癌、膀胱癌及食道癌。
根据本发明的一些实施例，所述亲和性结合实体用于黑色素瘤相关抗原9(MAGE-A9)时，所述癌症选自于由肾细胞癌、膀胱癌、乳腺癌及肝细胞癌所组成的群组。
根据本发明的一些实施例，所述亲和性结合实体用于前列腺性酸性磷酸酶(PAP)时，所述癌症选自于由前列腺癌所组成的群组。
除非另加说明，否则本文所使用的所有技术术语和/科学术语都具有与本发明所属领域的普通技术人员通常所理解的相同的含意。虽然本发明的实施例可以通过类似或等同于本发明的实施例所述的任何方法和物质实施或测试，本发明的实施例、列举的方法和/或物质已在下面描述。在冲突的情况下，将以本专利说明书包括定义以控制。此外，物质、方法和实施例仅是举例性质，并且不必然用以限制。
附图说明
在此描述的本发明的一些实施例仅通过举例的方式并参考附图描述，通过详细说明附图具体的参考资料，应当强调所示的细节仅为举例，用以说明本发明实施例的目的。基于这点，结合所述附图及描述使对本领域技术人员能清楚的实施本发明的实施例。
在附图中:
图1：靶向多个HLA-A2/酪氨酸酶复合物的类TCR抗体的表面结合亲和性测定。所述多个纯化的IgG通过抗小鼠或人类的IgG间接地固定在所述表面等离子共振(SPR)的传感芯片上。分析物是由大肠杆菌表达的多个scHLA-A2复合物的体外重新折叠所产生的多个纯化的重组单链HLA-A2/酪氨酸酶复合物。
图2：通过丙氨酸扫描对于多个类TCR抗体的表位特异性测定。所述酪氨酸酶胜肽序列的多个位置1、2、3、4、5、6、7和8被取代为丙氨酸，所述多个丙氨酸(Ala)突变胜肽被合成，并且以一浓度的10-4至10-5摩尔浓度加至多个T2细胞抗原呈现细胞(APC)中在37℃中12小时。通过流式细胞技术取得在一浓度的10微克/毫升的类TCR抗体下的结合，以及测量通过平均荧光强度所测量的结合强度，并且与野生型(WT)的天然酪氨酸酶胜肽的所述结合强度进行比较。每个Ala取代的位置的所述相对影响被评估为WT胜肽的所述结合的百分比。
图3：多个类TCR抗体D11和D7与加有酪氨酸酶胜肽的多个T2 APC以及多个对照组HLA-A2限定胜肽的结合。多个T2细胞被加入一浓度的10-4至10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用巯基化藻红蛋白(PE)标记的二级抗小鼠IgG所监测。单克隆抗体(MAb)BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图4：多个类TCR抗体D11和D7与加有酪氨酸酶胜肽以及多个对照组HLA-A2限定胜肽的多个T2 APC的结合。多个T2细胞被加入一浓度的10-4至10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图5：类TCR抗体D11与加有酪氨酸酶胜肽以及多个对照组HLA-A2限定胜肽的多个T2 APC的结合。多个T2细胞被加入一浓度的10-4至10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图6：类TCR抗体D7与加有酪氨酸酶胜肽以及多个对照组HLA-A2限定胜肽的多个T2APC的结合。多个T2细胞被加入一浓度的10-4至10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图7：类TCR抗体MC1与加有酪氨酸酶胜肽以及多个对照组HLA-A2限定胜肽的多个T2 APC的结合。多个T2细胞被加入一浓度的10-4至10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图8：类TCR抗体MC1与表达HLA-A2和酪氨酸酶的黑色素瘤细胞的结合。通过流式细胞技术利用二级PE标记的抗人类IgG监测多个黑色素瘤细胞与类TCR抗体MC1的结合。MAbBB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图9：类TCR抗体MC1与HLA-A2+以及酪氨酸酶呈阳性或阴性的多个细胞的结合。通过流式细胞技术利用二级PE标记的抗人类IgG监测表达HLA-A2以及酪氨酸酶呈阳性或阴性的多个肿瘤细胞与类TCR抗体MC1的结合。MAb BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图10：多个类TCR抗体D11和D7与HLA-A2+以及酪氨酸酶呈阳性或阴性的多个细胞的结合。通过流式细胞技术利用二级PE标记的抗小鼠IgG监测表达HLA-A2以及酪氨酸酶呈阳性或阴性的多个肿瘤细胞与类TCR抗体MC1的结合。MAb BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图11：多个类TCR抗体D11和D7与HLA-A2+以及酪氨酸酶呈阴性的多个细胞的结合。通过流式细胞技术利用二级PE标记的抗小鼠IgG监测表达HLA-A2以及酪氨酸酶呈阴性的多个肿瘤细胞与类TCR抗体MC1的结合。MAb BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图12：多个类TCR抗体D11和D7和MC1与HLA-A2+以及酪氨酸酶呈阳性或阴性的多个细胞的多个对比性结合。通过流式细胞技术利用二级PE标记的抗小鼠IgG监测表达HLA-A2以及酪氨酸酶呈阳性或阴性的多个肿瘤细胞与类TCR抗体D11、D7以及MC1的结合。
图13：类TCR抗体D11与HLA-A2+/酪氨酸酶呈阴性的多个正常原代细胞的结合。多个正常原代细胞的组织学来源如标示，通过流式细胞技术利用二级PE标记的抗小鼠IgG监测表达HLA-A2以及酪氨酸酶呈阴性的多个肿瘤细胞与类TCR抗体D11的结合。MAb BB7.2被用来监测HLA-A2的表达。
图14：类TCR抗体D11与HLA-A26/酪氨酸酶呈阴性的多个正常原代细胞的结合。多个正常原代细胞的组织学来源如标示，通过流式细胞技术利用二级PE标记的抗小鼠IgG监测表达HLA-A2以及酪氨酸酶呈阴性的多个肿瘤细胞与类TCR抗体D11的结合。
图15：类TCR抗体D7与HLA-A2+/酪氨酸酶呈阴性的多个正常原代细胞的结合。多个正常原代细胞的组织学来源如标示，通过流式细胞技术利用二级PE标记的抗小鼠IgG监测表达HLA-A2以及酪氨酸酶呈阴性的多个肿瘤细胞与类TCR抗体D7的结合。
图16：BB7.2与多个正常原代细胞的结合。多个正常原代细胞的组织学来源如标示，通过流式细胞技术利用MAb BB7.2及二级PE标记的抗小鼠IgG监测多个正常原代细胞的组织学来源的HLA-A2的表达。
图17：多个类TCR抗体MC1，D11及D7与多个正常外周血单个核细胞(PBMCs)的结合。通过PCR鉴定PBMCs的HLA-A2同源或杂合性的特性。利用二级PE标记的抗小鼠IgG监测多个类TCR抗体的结合。
图18：类TCR抗体D11的选择性的总结。通过利用PE标记的抗小鼠IgG监测HLA-A2+抗原呈阳性以及阴性的多个细胞与类TCR抗体D11的结合。+/-表示通过PCR所测量的酪氨酸酶的信使核糖核酸(mRNA)的基因表达。MAb BB7.2被用来监测HLA-A2的表达。
图19：类TCR抗体D7选择性的总结。通过利用PE标记的抗小鼠IgG监测HLA-A2+抗原呈阳性以及阴性的多个细胞与类TCR抗体D7的结合。+/-表示通过PCR测得的酪氨酸酶mRNA的基因表达。MAb BB7.2被用来监测HLA-A2的表达。
图20：多个类TCR抗体MC1，D11及D7与加有酪氨酸酶胜肽以及相似于酪氨酸酶的多个HLA-A2限定胜肽的多个T2 APC结合。多个T2细胞被加入一浓度的10-4摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。
图21：类TCR抗体D11与加有多个相似于酪氨酸酶胜肽的多个HLA-A2限定胜肽的多个T2 APC结合。多个T2细胞被加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图22：类TCR抗体D11与多个加有相似于酪氨酸酶胜肽的多个HLA-A2限定胜肽的多个T2 APC结合。多个T2细胞被加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图23：类TCR抗体D11与加有多个相似于酪氨酸酶胜肽的多个HLA-A2限定胜肽的多个T2 APC结合。多个T2细胞被加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图24：类TCR抗体D11与加有相似于酪氨酸酶的多个HLA-A2限定胜肽的多个T2 APC结合。多个T2细胞被加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图25：类TCR抗体D7与加有相似于酪氨酸酶的多个HLA-A2限定胜肽的多个T2 APC结合。多个T2细胞被加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图26：类TCR抗体D7与加有相似于酪氨酸酶的多个HLA-A2限定胜肽的多个T2 APC结合。多个T2细胞被加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图27：类TCR抗体D7与加有相似于酪氨酸酶的多个HLA-A2限定胜肽的多个T2 APC结合。多个T2细胞被加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图28：类TCR抗体D7与丙氨酸扫描后所辨识的加有相似于酪氨酸酶的多个HLA-A2限定胜肽的多个T2 APC结合。多个T2细胞加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时，所述酪氨酸酶胜肽以及多个所标示的胜肽是根据D7的表位识别特异性从多个Ala突变胜肽中所筛选的。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图29：靶向多个HLA-A2/WT1复合物的类TCR抗体B47B6的表面结合亲和性测定。多个纯化的IgG通过抗小鼠或人类的IgG间接地固定在所述表面等离子共振(SPR)的传感芯片上。分析物是由大肠杆菌表达的多个scHLA-A2复合物的体外重新折叠所产生的多个纯化的重组单链HLA-A2/WT1复合物。
图30：多个类TCR抗体B47和ESK1与加有WT1 HLA-A2限定胜肽的多个T2 APC的结合。多个T2细胞被加入一浓度的10-4至10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用PE标记的抗小鼠IgG(用于B47)或人类IgG(用于ESK1)所监测。MAb BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图31：多个类TCR抗体B47和ESK1与加有WT1胜肽以及多个对照组HLA-A2限定胜肽的多个T2 APC的结合。多个T2细胞被加入一浓度的10-4摩尔浓度的WT1胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG(用于B47)或人类IgG(用于ESK1)所监测。MAb BB7.2被用来监测HLA-A2的表达，以平均荧光强度(MFI)表示。
图32：多个类TCR抗体B47和ESK1与加有多个相似于WT1胜肽的HLA-A2限定胜肽的多个T2 APC的结合。多个T2细胞被加入一浓度的10-4至10-5摩尔浓度的WT1胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG(用于B47)或人类IgG(用于ESK1)所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图33：类TCR抗体B47与加有WT1胜肽或多个对照组HLA-A2限定胜肽的T2 APCs的结合。多个T2细胞被加入一浓度的10-4摩尔浓度的WT1胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图34：类TCR抗体B47与加有相似于WT1胜肽的HLA-A2限定胜肽的多个T2 APC的结合。多个T2细胞被加入一浓度的10-4至10-5摩尔浓度的WT1胜肽以及多个所标示的胜肽在37℃中12小时。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG(用于B47)或人类IgG(用于ESK1)所监测。MAb BB7.2的结合确保胜肽的加入效率的测量。
图35：多个类TCR抗体B47和ESK1与表达或不表达WT1的HLA-A2呈阳性的多个细胞的结合。结合是通过流式细胞技术利用二级PE标记的抗小鼠IgG(用于B47)或人类IgG(用于ESK1)所监测。MAb BB7.2被用来监测HLA-A2的表达。
图36：类TCR抗体B47的选择性的总结。通过利用PE标记的抗小鼠IgG监测HLA-A2+抗原呈阳性以及阴性的多个细胞与类TCR抗体B47的结合。+/-表示通过PCR测得的WT1 mRNA的基因表达。MAb BB7.2被用来监测HLA-A2的表达。
图37：通过丙氨酸扫描对于多个类TCR抗体的表位特异性测定。所述WT1胜肽序列的多个位置1、3、4、5、7和8被取代为丙氨酸，所述多个丙氨酸(Ala)突变胜肽被合成，并且加至多个抗原呈现细胞(APC)中。通过流式细胞技术取得类TCR抗体ESK1的结合，以及测量通过平均荧光强度所测量的结合强度，并且与野生型(WT)的天然WT1胜肽的所述结合强度进行比较。每个Ala取代的位置的所述相对影响被评估为WT胜肽的所述结合的百分比。数据来自Dao等人《科学转化医学》5:176ra33(2013)。
图38：多个类TCR抗体D11、D7和生物素化的MC1与加有酪氨酸酶胜肽以及相似于酪氨酸酶的多个HLA-A2限定胜肽的多个T2 APC的结合，S17至S23为丙氨酸为基础的多个相似性胜肽。多个T2细胞被加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。多个细胞被在一浓度的10微克/毫升的多个类T细胞受体(TCRL)抗体染色后接着利用二级PE标记的链霉亲和素/抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图39：多个类TCR抗体D11、D7和MC1与加有酪氨酸酶胜肽以及相似于酪氨酸酶的多个HLA-A2限定胜肽的多个T2 APC的结合，KIAA0355、S7、S17至S23为丙氨酸为基础的多个相似性胜肽。多个T2细胞被加入一浓度的10-5摩尔浓度的酪氨酸酶胜肽以及多个所标示的胜肽在37℃中12小时。多个细胞被一浓度的10微克/毫升的多个TCRL抗体染色后接着利用二级PE标记的链霉亲和素/抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图40A至C：多个类TCR抗体D11(图40A)，D7(图40B)和生物素化的MC1(图40C)与HLA-A2+，酪氨酸酶抗原呈阳性或阴性的细胞的结合。通过qPCR对表达HLA-A2的多个肿瘤和正常原代细胞测试酪氨酸酶mRNA的表达。多个肿瘤细胞被一浓度的10微克/毫升的多个TCRL抗体染色后接着利用二级PE标记的链霉亲和素/抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图41：由具有一个抗CD-3臂及一个D11臂的双特异性(BS)TCRL对于HLA-A2+/酪氨酸酶+(阳性)以及HLA-A2+/酪氨酸酶-(阴性)的多个细胞株的杀灭，所述TCRL称为Tyr D11BS TCRL。将Tyr D11 BS TCRL与黑色素瘤HLA-A2+/酪氨酸酶+的多个细胞以及HLA-A2+/酪氨酸酶-的对照组肿瘤细胞培养在一起，多个细胞与所述Tyr D11 BS TCRL以及从多个健康个体中分离的多个未活化
PBMC以10：1E：T的比率(10：1效应物：标靶的比率)培养24小时，通过乳酸脱氢酶(LDH)释放测试测定细胞毒性。
图42：由Tyr D11对于HLA-A2+/酪氨酸酶-的多个正常原代细胞的杀灭，将BS D11与作为对照组的黑色素瘤HLA-A2+/酪氨酸酶+的多个细胞以及HLA-A2+/酪氨酸酶-的多个正常原代细胞细胞培养在一起，多个细胞与所述Tyr D11 BS TCRL以及从多个健康个体中分离的多个未活化PBMC以10：1E：T的比率(10：1效应物：标靶的比率)培养24小时。
图43：由Tyr D7 BS TCRL对于HLA-A2+/酪氨酸酶+以及HLA-A2+/酪氨酸酶-的多个细胞株的杀灭，将D7 BS与黑色素瘤HLA-A2+/酪氨酸酶+的多个细胞以及HLA-A2+/酪氨酸酶-的多个对照组肿瘤细胞培养在一起，多个细胞与所述Tyr D7 BS以及从多个健康个体中分离的多个未活化PBMC以10：1E：T的比率(10：1效应物：标靶的比率)培养24小时。
图44：由D7 BS对于HLA-A2+/酪氨酸酶-的多个正常原代细胞的杀灭，将D7 BS与作为对照组的黑色素瘤HLA-A2+/酪氨酸酶+的多个细胞以及HLA-A2+/酪氨酸酶-的多个正常原代细胞细胞培养在一起，多个细胞与所述Tyr D11 BS TCRL以及从健康个体中分离多个的多个未活化PBMC以10：1E：T的比率(10：1效应物：标靶的比率)培养24小时。
图45显示了D7 BS在预防NOD/SCID小鼠中的S.C.501A黑色素瘤的肿瘤形成的体内功效。
图46：多个类TCR抗体生物素化ESK1和B47B6与加有WT1胜肽以及多个其它HLA-A2限定胜肽的多个T2 APC的结合。多个T2细胞被加入一浓度的10-5摩尔浓度的WT1胜肽以及多个所标示的胜肽在37℃中12小时。多个细胞被一浓度的10微克/毫升的多个TCRL抗体染色后接着利用二级PE标记的链霉亲和素/抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图47：多个类TCR抗体生物素化ESK1和B47B6与加有WT1胜肽以及相似于WT1的多个HLA-A2限定胜肽的多个T2 APC的结合。S2、S6及S7为多个丙氨酸为基础的相似性胜肽。S11为一不规则肽(heteroclitic peptide)。多个T2细胞被加入一浓度的10-5摩尔浓度的WT1胜肽以及多个所标示的胜肽在37℃中12小时。多个细胞被一浓度的10微克/毫升的多个TCRL抗体ESK1和B47B6染色后接着利用二级PE标记的链霉亲和素/抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图48：通过SPR的亲和性-靶向多个HLA-A2/WT1复合物的类TCR抗体ESK1和B47B6的表面结合亲和性测定。纯化的重组的生物化的单链HLA-A2/WT1复合物是由大肠杆菌表达的多个scHLA-A2复合物的体外重新折叠所产生，所述HLA-A2/WT1复合物与中性亲和素(NeutrAvidin)间接地固定在SPR的传感芯片上。纯化的ESK1和B47B6 TCRL的多个抗原结合域(Fab)作为多个分析物。
图49：通过丙氨酸扫描突变来测定表位特异性。所述在多个位置1、2、3、4、5、7、8和9具有丙氨酸取代的多个突变的WT1胜肽被合成并以一浓度的10-5摩尔浓度加至多个T2细胞抗原呈现细胞(APC)中于37℃下12小时。多个细胞被一浓度的10微克/毫升的类TCR抗体B47B6染色，并且通过流式细胞技术分析。每个Ala取代的位置的所述相对影响以结合野生型胜肽的百分比表达。
图50：多个类TCR抗体B47和ESK1与HLA-A2+以及WT1 mRNA呈阳性或阴性的多个细胞的结合。通过qPCR对表达HLA-A2的多个肿瘤细胞进行WT1的mRNA表达的测试。多个肿瘤细胞被10微克/毫升的多个TCRL抗体ESK1和B47B6染色后接着利用二级PE标记的链霉亲和素，以平均荧光强度(MFI)表示。亦表示mRNA的表达的数据以及双特异性形式(具有抗CD3)的多个抗体对细胞的杀灭，如本文所述。
图51A：通过比较B47B6 BS与ESK1 BS对HLA-A2+/WT1+和HLA-A2+/WT1-的多个正常原代细胞的杀灭。将B47B6 BS和ESK1 BS与HLA-A2+/WT1+或HLA-A2+/WT1-的正常原代细胞培养在一起，多个细胞与所述B47B6 BS或ESK1 BS以及与从多个健康个体中分离的多个未活化PBMC以10：1E：T的比率培养24小时。通过乳酸脱氢酶(LDH)释放测试测定细胞毒性。
图51B：通过比较B47B6 BS与ESK1 BS对HLA-A2+/WT1+和HLA-A2+/WT1-的多个细胞株的杀灭。将B47B6 BS和ESK1 BS与HLA-A2+/WT1+或HLA-A2+/WT1-的多个肿瘤细胞培养在一起，多个细胞与所述B47B6 BS或ESK1 BS以及从与多个健康个体中分离的未活化PBMC以10：1E：T的比率培养24小时(#F3-格式-其中所述抗分化簇3(CD3)的单链变异区片段(scFv)与所述Fab的所述轻链可变区域轻链恒定区(VLCL)融合)。
图52：类TCR抗体C106B9与加有MAGE-A4230-239(也被称为MAGE-A4胜肽)胜肽以及多个其它HLA-A2限定胜肽的结合。多个T2细胞被加入一浓度的10-5摩尔浓度的MAGE-A4以及多个所标示的胜肽在37℃中12小时。多个细胞被10微克/毫升的多个TCRL抗体C106B9染色后接着利用二级PE标记的抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图53：类TCR抗体C106B9与加有MAGE-A4胜肽以及多个相似于MAGE-A4的HLA-A2限定胜肽的结合。多个T2细胞被加入10-5摩尔浓度的MAGE-A4以及多个所标示的胜肽在37℃中12小时。多个细胞被一浓度的10微克/毫升的多个TCRL抗体C106B9染色后接着利用二级PE标记的抗小鼠IgG，并且通过流式细胞技术分析。
图54：通过SPR的亲和性-靶向多个HLA-A2/MAGE-A4复合物的类TCR抗体C106B9的表面结合亲和性测定。纯化的重组的生物素化的HLA-A2/MAGE-A4复合物是由大肠杆菌表达的多个scHLA-A2复合物的体外重新折叠所产生，所述HLA-A2/MAGE-A4复合物与中性亲和素间接地固定在SPR的传感芯片上。纯化的C106B9 TCRL Fab作为所述分析物。
图55：通过丙氨酸扫描突变来测定表位特异性。所述在多个位置1、2、3、4、5、7、8和9具有丙氨酸取代的所述多个突变的MAGE-A4胜肽被合成，多个可能的锚定位置由一灰色的星表示。所述多个天然及突变的MAGE-A4胜肽以一浓度的10-5摩尔浓度加至多个T2细胞抗原呈现细胞(APC)中于37℃下12小时。多个细胞被一浓度的10微克/毫升的类TCR抗体C106B9染色，并且通过流式细胞技术分析，多个细胞加入多个突变以及野生型胜肽的MFI值被比较，每个Ala取代的位置的所述相对影响以结合野生型胜肽的百分比表达。
图56：类TCR抗体C106B9与HLA-A2+以及MAGE-A4抗原呈阳性或阴性的多个细胞的结合。通过qPCR确认在多个细胞中MAGE-A4的mRNA的表达。多个肿瘤细胞被10微克/毫升的C106B9染色后接着利用二级PE标记的抗小鼠抗体，以平均荧光强度(MFI)表示。亦表示mRNA的表达的数据以及双特异性形式(具有抗CD3)的多个抗体对细胞的杀灭，如本文所述。
图57：由C106B9 BS对于HLA-A2+/MAGE-A4+以及HLA-A2+/MAGE-A4-的多个细胞株的杀灭，将C106B9 BS与HLA-A2+/MAGE-A4+的多个细胞以及对照组的HLA-A2+/MAGE-A4-的多个细胞培养在一起，多个细胞与所述C106B9 BS以及从多个健康个体中分离的多个未活化PBMC以10：1E：T的比率培养24小时。
图58：由C106B9 BS对于HLA-A2+/MAGE-A4-的多个正常原代细胞株的杀灭，将C106B9 BS与HLA-A2+/MAGE-A4-的多个正常原代细胞培养在一起，多个细胞与所述C106B9BS以及从多个健康个体中分离的多个未活化PBMC以10：1E：T的比率培养24小时。
图59：MAGE-A4 BS C106B9 BS在预防NOD/SCID小鼠中的S.C.黑色素瘤的肿瘤形成的体内功效。
图60：类TCR抗体F184C7与加有MAGE-A9223-231胜肽(也被称为MAGE-A9胜肽)以及多个其它HLA-A2限定胜肽的结合。多个T2细胞被加入10-5摩尔浓度的MAGE-A9以及多个所标示的胜肽在37℃中12小时。多个细胞被一浓度的10微克/毫升的多个TCRL抗体F184C7染色后接着利用二级PE标记的抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图61：类TCR抗体F184C7与加有MAGE-A9胜肽以及多个相似于MAGE-A9的HLA-A2限定胜肽的结合。S8为一以丙氨酸为基础的相似性胜肽。多个T2细胞被加入10-5摩尔浓度的MAGE-A9以及多个所标示的胜肽在37℃中12小时。多个细胞被一浓度的10微克/毫升的多个TCRL抗体F184C7染色后接着利用二级PE标记的抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图62：通过丙氨酸扫描突变来测定表位特异性。所述在多个位置2、3、4、5、6、7、8和9具有丙氨酸取代的所述多个突变MAGE-A9胜肽被合成。所述多个Ala突变以及天然胜肽以一浓度的10-5摩尔浓度被加至多个T2细胞抗原呈现细胞(APC)中于37℃下12小时。多个细胞被一浓度的10微克/毫升的类TCR抗体B47B6染色，并且通过流式细胞技术分析。每个Ala取代的位置的所述相对影响以结合野生型胜肽的百分比表达。
图63：类TCR抗体F184C7与多个HLA-A2+的正常原代细胞的结合。多个正常原代细胞被10微克/毫升的多个TCRL抗体F184C7染色后接着是二级PE标记的抗小鼠抗体，以平均荧光强度(MFI)表示。
图64：类TCR抗体D10A3与加有PAP112-120胜肽(也被称为PAP胜肽)以及多个其它HLA-A2限定胜肽的结合。多个T2细胞被加入一浓度的10-5摩尔浓度的PAP以及多个所标示的胜肽在37℃中12小时。多个细胞被10微克/毫升的多个TCRL抗体C106B9染色后接着利用二级PE标记的抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图65：类TCR抗体D10A3与加有PAP胜肽以及多个相似于PAP的HLA-A2限定胜肽的结合。多个T2细胞被加入一浓度的10-5摩尔浓度的PAP以及多个所标示的胜肽在37℃中12小时。多个细胞被10微克/毫升的多个TCRL抗体D10A3染色后接着利用二级PE标记的抗小鼠IgG，并且通过流式细胞技术分析，以平均荧光强度(MFI)表示。
图66：通过丙氨酸扫描突变来测定表位特异性。所述在多个位置1、3、4、6、7、8和9具有丙氨酸取代的多个突变的PAP胜肽被合成并以一浓度的10-5摩尔浓度加至多个T2细胞抗原呈现细胞(APC)中于37℃下12小时。多个细胞被一浓度的10微克/毫升的类TCR抗体D10A3染色，多个细胞加入多个突变以及野生型胜肽的MFI值被比较，每个Ala取代的位置的所述相对影响以结合野生型胜肽的百分比表达。
图67：类TCR抗体D10A3与多个HLA-A2+的正常原代细胞的结合。多个正常原代细胞被10微克/毫升的多个TCRL抗体D10A3染色后接着利用二级PE标记的抗小鼠抗体，以平均荧光强度(MFI)表示。
图68：D11抗体的多个氨基酸和多个核酸(SEQ ID NO：280-295)。
图69：D7抗体的多个氨基酸和多个核酸(SEQ ID NO：296-311)。
图70：B47B6抗体的多个氨基酸和多个核酸(SEQ ID NO：312-327)。
图71：C106B9抗体的多个氨基酸和多个核酸(SEQ ID NO：328-343)。
图72：F184C7抗体的多个氨基酸和多个核酸(SEQ ID NO：344-359)。
图73：D10A3抗体的多个氨基酸和多个核酸(SEQ ID NO：360-375)。
具体实施例
本发明在其一些实施例中有关于多个亲和性结合实体，所述亲和性结合实体包括具有高亲和性和优良特异性的一类TCR抗体结合域及其用途。
在详细解释本发明的至少一个实施例之前，应当理解本发明不一定限定于本发明在以下描述的细节或所举例的多个实施例。本发明能够以其他实施例或以各种方法来实施或应用。
类T细胞受体(TCR)(TCRL)被赋予针对多个肿瘤表位的一类TCR特异性。不同于对MHC肽抗原复合物表现出低亲和性的多个TCR，多个TCRL的特性是即使所述多个TCRL的可溶性形式也具有亲和性。TCRL被开发为一新颖的治疗类别用于靶向多个肿瘤细胞并介导它们的特异性杀伤。此外，所述多个抗体是多个有价值的研究试剂，允许了人类第一类胜肽-MHC的配体表达以及TCR-胜肽-MHC的多个相互作用的研究。
本发明人现在已经通过一费力的筛选和实验辨识了多个新颖的TCRL，所述多个新颖的TCRL对TyrD-HLA-A2(D7及D11)，WT1-HLA-A2(B47)，MAGE-A4-HLA-A2(C106B9)，MAGE-A9-HLA-A2(F184C7)以及PAP(D10A3)。表现出史无前例的优良特异性，所述多个抗体的所述多个CDR可以被植入在任何亲和性结合实体中，例如具有一效应活性(例如，CAR和TCR)。
因此，根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一人类主要组织兼容性复合体(MHC)限定的方式结合HLA-A2/TyrD369-377。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/TyrD369-377。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/WT1126-134。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，其特征在于，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/MAGE-A4328-343。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/MAGE-A9344-359。
根据本发明的一些实施例的一个方面，提供了一种亲和性结合实体，所述亲和性结合实体包括一抗原结合区域，所述抗原结合区域包括多个N端至C端排列的互补性决定区(CDR)序列：
所述亲和性结合实体能够以一MHC限定的方式结合HLA-A2/PAP360-375。
本文所使用的一“T细胞受体样抗体”或“TCRL”是指与一HLA限定胜肽抗原复合的一MHC结合的一抗体。TCRL与所述TCRL标靶的结合具有一MHC限定的特异性。在缺少所述复合胜肽下，所述TCRL抗体不与所述MHC结合，以及在所述MHC的一缺少下，所述抗体在不与所述胜肽结合。
本文所使用的“结合(binding)”或“结合(binds)”是指抗体-抗原形式的结合，其中通常是，在临床相关的TCRL的情况下，通过表面等离子体共振分析(SPR)测定，在KD低于20纳摩尔浓度的范围内。
所述抗原结合域与所述抗原结合域的抗原的所述亲和性是使用所述抗体的所述可溶性形式来测定，所述抗体的所述抗原结合域的所述多个CDR是从所述抗体的所述可溶性形式所衍生。对于亲和性评估，所述抗原是使用所述抗原的可溶性形式，例如，如下文进一步描述的一单链MHC胜肽复合物。
如本文所使用，术语“KD”是指所述抗原结合域与所述抗原结合域的相对应的抗原之间的所述平衡解离常数。
应当理解，所述亲和性结合实体的所述亲和性是通过多个CDR测定。然而，所述亲和力可以使用本领域已知的多个方法来改善，例如亲和性成熟。
本文所用的“亲和性结合实体”是指一结合部分，所述结合部分以比起对于一非特定抗原更高的一亲和性结合至一特定抗原，，并且赋有一亲和性至少10-6摩尔浓度，如通过本领域已知的多个测试所测定，包含表面等离子体共振技术(SPR)。
根据一具体的实施方案，所述亲和性为500纳摩尔浓度-0.5纳摩尔浓度，100纳摩尔浓度-1纳摩尔浓度，50纳摩尔浓度-1纳摩尔浓度，20纳摩尔浓度-1纳摩尔浓度，10纳摩尔浓度-1纳摩尔浓度。
所述亲和性部分可以选自由TCR，CAR-T以及抗体所组成的所述群组。
根据一具体的实施方案，所述亲和性结合实体是一抗体。尽管与其它亲和性结合实体相比，所述多个抗体的参考文献较详细，本实施方案的所述描述不应被解释为限制性的，本发明平等地与本文所述的多个结合实体相关，特别是在下文进一步描述的所述细胞治疗的意义上。
本发明中使用的术语“抗体”包含多个完整分子及所述完整分子的多个功能片段，例如Fab、F(ab’)2、Fv、scFv、dsFv或多个单域分子，例如VH和VL，所述多个功能片段能够以一MHC限制的形式与一抗原的一表位结合。作为一个更基本的陈述，所述术语“抗体”目的在于包含任何亲和性结合实体，所述亲和性结合实体以一MHC限定的特异性与一表现在一细胞表面上的分子结合。因此，本发明的一些实施例的所述抗体的多个CDR可以被植入在多个人工分子中，例如T细胞受体或多个CAR，如下文进一步描述。
用于实施本发明一些实施例的多个合适的抗体片段包含一免疫球蛋白轻链(本文称为”轻链”)的一互补决定区域(CDR)、一免疫球蛋白重链(本文中称为”重链”)的一互补决定区域、一轻链可变区域、一重链可变区域、一轻链、一重链、一Fd片段，以及所述多个抗体片段基本上包括轻链和重链，例如一Fv区、一单链Fv(scFv)、一双硫键所稳定的Fv(dsFv)、一Fab，一Fab’和一F(ab’)2。
如本文所使用，术语“互补决定区域”或“CDR”可互相转换使用以指出在所述多个重链和轻链多肽的所述可变区域内发现的所述多个抗原结合区。一般地，多个抗体在每个所述VH(CDR HI或HI；CDR H2或H2；以及CDR H3或H3)中包括三个CDR；以及三个在每个所述VL(CDR LI或LI；CDR L2或L2；and CDR L3或L3)中。所述多个CDR序列的多个例子被提供给根据以下实施例I制备的D7和D11-TCRL。另外的实施例包括WT1 B47B6、MAGE-A4 C106B9、MAGE-A9 F184C7、PAP D10A3(如图68-73所示)。
一特定抗体中的所述氨基酸残基的构成一可变区域或一CDR的所述身份可以使用在本领域中已知的方法来测定，并且包括例如由Kabat等人定义的序列变异性的方法(参见例如Kabat等人，1992，《免疫相关的蛋白序列》，第5版，公共健康服务，国家卫生研究院，华盛顿特区)，所述结构环区域的位置如Chothia等人所定义(参见例如Chothia等人，《自然》342：877-883，1989)，使用牛顿的分子的AbM抗体模拟软件(现在是
参见Martin等人，1989，《美国国家科学院院报》86：9268；以及全球的网站万维网站www.bioinf-org.uk/abs)在Kabat和Chothia之间的折衷，如由接触定义所定义的可用的复杂晶体结构(参见MacCallum等人)，《分子生物学杂志》262：732-745，1996)，所述“构型定义”(参见，例如Makabe等人，《生物化学杂志》283：1156-1164，2008)以及IMGT[LeFRanc MP等人(2003)用于免疫球蛋白和T细胞受体的多个可变区域和Ig超家族的个类V区域的IMGT独特编号，《发育和比较免疫学》27：55-77]。
如本文所使用，所述“多个可变区域”和“多个CDR”可以指由本领域已知的任何方法包括方法的组合所定义的多个可变区域和多个CDR。
根据一具体的实施例，所述多个CDR是根据Kabat等人(同上)的来测定。
多个功能性抗体片段包括轻链和重链的整个或基本上整个的可变区域，被定义为如下：
(1)Fv，被定义为由所述轻链(VL)的所述可变区域以及所述重链(VH)的可变区域所组成的一基因工程片段，以双链表达；
(2)单链变异区片段Fv(“scFv”)，一基因工程的单链分子，包含所述轻链的所述可变区域和所述重链的所述可变区域，所述基因工程的单链分子通过一合适的多肽连接子作为一基因融合的单链分子。
(3)双硫键所稳定的Fv(“dsFv”)，一基因工程的抗体，包含所述轻链的所述可变区和所述重链的所述可变区，所述基因工程的抗体通过一基因工程的双硫键连接。
(4)Fab，一抗体分子的一片段包含一抗体分子的一单价抗原结合部分；所述抗体分子的片段可通过以所述木瓜蛋白酶处理整个抗体以产出所述完整的所述轻链和所述重链的所述Fd片段来获得，所述重链的所述Fd片段由所述可变区域及所述重链的所述Fd片段的CH1区域所组成；
(5)Fab’，一抗体分子的一片段包含一抗体分子的单价抗原结合部分，所述抗体分子的片段可通过胃蛋白酶处理整个抗体来获得，然后减小(每抗体分子获得两个Fab’片段)；
(6)F(ab’)2，一抗体分子的一片段包含一抗体分子的一单价抗原结合部分，所述F(ab’)2可通过所述酶胃蛋白酶处理整个抗体来获得(即，由两个双硫键保持在一起的多个Fab’片段的一个二聚体)；以及
(7)多个单域抗体或纳米体由对于抗原具有足够亲和性的单个VH或VL区域所组成。
生产多个多克隆和单克隆抗体的多个方法以及所述多个多克隆和单克隆抗体的多个片段在本领域中是已知的(参见例如参见Harlow和Lane，《抗体：一实验室手册》，冷泉港实验室，纽约，1988，在此引入作为参考资料)。
生产多个多克隆和单克隆抗体的方法以及所述多个多克隆和单克隆抗体的片段在本领域中是已知的(参见例如参见Harlow和Lane，《抗体：一实验室手册》，冷泉港实验室，纽约，1988，在此引入作为参考资料)。
根据本发明一些实施例的多个抗体片段可以通过所述抗体的蛋白水解或者通过在大肠杆菌或多个哺乳动物细胞(例如中国仓鼠卵巢细胞培养或其它蛋白表达系统)里的DNA编码所述片段的表达来制备。多个抗体片段可通过多个常规方法通过胃蛋白酶或木瓜蛋白酶切割多个整个抗体来获得。例如，多个抗体片段可通过胃蛋白酶对多个抗体的酶切来生产，以提供的一5S片段表示为F(ab’)。所述片段可以使用一硫醇还原剂进一步切割所述片段，以及可选地用于由多个双硫键的裂解所产生的多个所述巯基的一阻挡基团来产生多个3.5S的Fab’单价片段。替代地，使用胃蛋白酶的一酶切产生两个单价Fab’片段和Fc片段。所述多个方法描述在例如由Goldenberg，美国专利号4,036,945和4,331,647，以及所述多个专利包含的多个引用，所述多个专利的整体是以引用的方式并入本文中。另参见Porter,R.R.[《生化杂志》73：119-126(1959)]。其它切割抗体的多个方法，例如多个重链的分离以形成多个单价轻-重链片段、多个片段的进一步切割、或其它酶的、也可以使用多个化学技术或遗传技术，只要所述多个片段结合至被所述完整抗体所辨识的所述抗原。
多个Fv片段包括多个VH和VL链的一联结。所述联结可以是非共价的，如Inbar等人所描述[《美国国家科学院院报》69：2659-62(19720)]中所述。替代地，所述多个可变链可通过分子间的一双硫键连接或通过多个化学物质如戊二醛交联。优选地，所述多个Fv片段包括由一胜肽连接子连接的多个VH和VL链。所述多个单链抗原结合蛋白(sFv)是通过构建一结构基因包含多个DNA序列编码由一寡核苷酸连接的所述多个VH和VL区域来制备。所述结构基因被插入在一表达载体中，所述表达载体随后被引入一宿主细胞例如大肠杆菌中，所述多个重组宿主细胞合成一单个多肽链，所述单个多肽链具有一连接符桥接所述两个V域。用于生产sFvs的多个方法描述在例如[Whitlow和Filpula,《方法》2：97-105(1991)；Bird等人，《科学》242：423-426(1988)；Pack等人，《生物/科学》11：1271-77(1993)；以及美国专利号4,746,778，所述专利的全文以引用的方式并入本文中。
一抗体片段的另一种形式是一胜肽，所述胜肽编码一单一互补决定区域(CDR)，多个CDR胜肽(”多个最小识别单元”)可通过构建编码感兴趣的一抗体的所述CDR的多个基因获得。所述多个基因是由，例如通过利用所述聚合酶链式反应从多个抗体产生细胞的RNA合成所述可变区域来制备。参见例如Larrick和FRy[《方法》，2：106-10(1991)]。
多个非人类(例如：鼠类)抗体的多个人源化形式是多个免疫球蛋白、多个免疫球蛋白链或所述多个免疫球蛋白链的多个片段(例如Fv、Fab、Fab’、F(ab’)分支2或其它抗原结合子序列)的多个嵌合分子，所述多个人源化形式含有最小的来源于非人类免疫球蛋白的序列。多个人源化抗体包含多个人类免疫球蛋白(受体抗体)，其中所述多个人类免疫球蛋白内的形成所述受体的一互补决定区域(CDR)的多个残基被替换为从多个非人类物种(供体抗体)例如小鼠、大鼠或兔子的一CDR的多个残基，所述非人类物种的多个残基具有所需特异性、亲和性和容量。在一些例子下，所述人类免疫球蛋白的多个Fv框架残基被替换为相对应的多个非人类残基。多个人源化抗体还可以包括多个在所述受体抗体和所述引入的CDR中都没有发现的残基或多个框架序列，所述受体抗体中也不在导入的CDR或骨架序列中发现的残基。一般而言，所述人源化抗体可能基本上包含全部中的至少一个，并且典型地包括两个，多个可变区域，其中所有或基本上所有的CDR区域对应于一非人类免疫球蛋白的所述多个CDR区域，以及所有或基本上所有的FR区域对应于一非人类免疫球蛋白共有序列的所述多个FR区域。所述人源化抗体理想地还包括一免疫球蛋白恒定区(Fc)的至少一部分，典型地，一人类免疫球蛋白的一免疫球蛋白恒定区(Fc)的至少一部分(Jones等人，《自然》，321：522-525(1986)；Riechmann等人，《自然》，332：323-329(1988)；以及Presta，《结构生物学的目前观点》，2：593-596(1992)]。
用于人源化多个非人类抗体的多个方法在本领域中是已知的。通常，一人源化抗体具有从非人类的一来源中引入的一个或多个氨基酸残基。所述多个非人类氨基酸残基经常被称为多个引入残基，所述多个引入残基通常是从一引入的可变区域中取得。人性化可以基本上按照Winter及多个同事的所述方法[Jones等人，《自然》，321：522-525(1986)；Riechmann等人，《自然》，332：323-329(1988)；Verhoeyen等，《科学》，239：1534-1652(1988)]，通过用啮齿类的多个CDR或多个CDR序列代替一人类抗体的所述相对应的序列。因此，这种人源化抗体是多个嵌合抗体(美国专利号4,816,567)，其中基本上小于一完整的人类可变区域已被来自于一非人类物种的所述相对应的序列取代。实际上，多个人源化抗体通常是多个人类抗体，其中一些CDR残基和可能地一些FR残基是被来自于多个啮齿类抗体中的多个类似位点的多个残基所取代。
多个人类抗体亦可以使用本领域已知的各种技术来生产，包括多个噬菌体展示库[Hoogenboom和Winter，《分子生物杂志》，227：381(1991)；Marks等人，《分子生物杂志》，222：581(1991)]，Cole等人和Boerner等人的所述多个技术也可用于多个人类单克隆抗体的所述制备[Cole等人，《单克隆抗体和癌症治疗》，Alan R.Liss，第77页(1985)和Boerner等人，《免疫杂志》，147(1)：86-95(1991)]。同样地，多个人类抗体可以通过将人类免疫球蛋白基因座引入多个转基因动物来制备，例如，所述多个内源性免疫球蛋白基因已被部分地或完全地去活化的多个小鼠。在挑战上，观察到人类抗体的产生，所述人类抗体在所有方面都非常类似于在人类中所看到的所述抗体，包含基因重排，组合和抗体库。所述方法描述在例如美国专利号5,545,807；5,545,806；5,569,825；5,625,126；5,633,425；5,661,016中，以及在以下的多个科学出版物中：Marks等人，《生物/科技杂志》：779-783(1992)；Lonberg等人，《自然》368：856-859(1994)；Morrison，《自然》368 812-13(1994)；Fishwild等人，《自然生物技术》14，845-51(1996)；Neuberger，《自然生物技术》14：826(1996)；以及:Lonberg和Huszar，《国际免疫评论》13，65-93(1995)。
在一实施例中，所述抗体是一全长抗体，本发明的一抗体的所述多个重链和所述多个轻链可以是全长(例如：一抗体可以包含至少一个，以及优选两个完整的重链和至少一个或两个完整的轻链)或可以包括一抗原结合部分(一Fab，F(ab’)分支2，Fv或一单链变异区片段片段(“scFv”)。在其它实施例中，所述抗体的重链恒定区是选自于例如IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgD和IgE。在一些实施例中，所述免疫球蛋白的同种型选自IgG1、IgG2、IgG3和IgG4，更具体地，IgG1(例如人类的IgG1)或IgG4(例如，人类的IgG4)。所述抗体类型的选择将取决于所述抗体被设计去引发的免疫效应的功能。
本文还涵盖了多个抗体的多个双特异性配置。一种双特异性单克隆抗体(BsMAb，BsAb)是一种人工蛋白，所述人工蛋白由两种不同单克隆抗体的片段所组成，因此与两种不同类型的抗原结合。根据一特定的实施例，所述BsMAb被设计成同时结合到一细胞毒性细胞(例如，使用一类似于CD3的受体)以及一标靶例如将被摧毁的一肿瘤细胞(在下文中进一步描述)。
如本文所使用的短语“嵌合抗原受体(CAR)”是指一重组或合成分子，所述重组或合成分子把对一所需抗原的抗体为基础的特异性结合至一T细胞受体活化的细胞内区域，以生产对所述特异性抗原表现出细胞免疫活性的一嵌合蛋白。
如本文所使用的短语“T细胞受体”或“TCR”是指重组T细胞受体的可溶性以及非可溶性形式。
如本文所使用的短语“MHC(或HLA)限定胜肽”是指潜在地表现在一MHC分子上的一胜肽。所述胜肽可以通过“湿式”实验室程序例如质谱法或通过计算机模拟分析来侦测。一表现有MHC(或HLA)的胜肽是指在体外或体内进行确认的由一MHC分子表现的一胜肽。
根据一具体的实施例，所述MHC限定胜肽是来自于WT1以及所述亲和性结合实体包括B47B6的所述多个CDR。
根据一具体的实施例，所述MHC限定胜肽是来自于TyrD以及所述亲和性结合实体包括D7或D11的所述多个CDR。
根据一具体的实施例，所述MHC限定胜肽是来自于WT1以及所述亲和性结合实体包括C106B9的所述多个CDR。
根据一具体的实施例，所述MHC限定胜肽是来自于MAGE-A9以及所述亲和性结合实体包括F184C7的所述多个CDR。
根据一具体的实施例，所述MHC限定胜肽是来自于PAP以及所述亲和性结合实体包括D10A3的所述多个CDR。
所述上面提到的多个亲和性结合实体的多个CDR描述在图68-73中。
只要保持或甚至改善所述相相应的标靶的所述结合亲和性和可选地特异性，也考虑到多个同源性序列，例如，至少90％的同源性，95％的同源性或甚至至少99％的同源性。
因此，根据本发明的一方面，提供了一分离的多核苷酸，所述多核苷酸包含一核酸序列编码本文所述的所述亲和性结合实体。
本发明还提供了一表达载体，包括可操作地连接至一顺式作用的调控组件的多核苷酸。
本发明的一些实施例的所述核酸构建体(本文也称为一”表达载体”)包含多个附加序列，所述多个附加序列赋予所述载体适合于在多个原核生物、多个真核生物，或优选地两者(例如：多个穿梭载体)中复制和整合。此外，多个典型的克隆载体也可以包含一转录和翻译的起始序列，转录和翻译终止子以及一多腺苷酸化信号。作为示例，所述多个构建体将会典型地包含一5’LTR，一tRNA结合位点，一种包装信号，一种第二链DNA合成的来源，以及一3’LTR或3’LTR的一部分。
本发明一些实施例的所述核酸构建体典型地包含一信号序列用于从一宿主细胞分泌或表现所述亲和性结合实体，其中所述抗体位于所述宿主细胞中。优选地，用于所述目的的所述信号序列是一哺乳动物信号序列。
所述真核启动子典型地包含两种类型的识别序列，所述TATA盒以及多个上游启动子。所述TATA盒，位于所述转录起始位点的上游的25-30个碱基对，被认为参与指引RNA聚合酶开始RNA合成。所述其它上游启动子组件测定转录启动后的所述速率。
优选地，本发明一些实施例的所述核酸构建体所使用的所述启动子在所转化的所述特定细胞群中是活化的。多个细胞类型特异性和/或组织特异性启动子的多个例子包含个启动子组件，例如肝脏特异性的白蛋白[Pinkert等人，(1987)《基因和发展》1：268-277]、多个淋巴特异性启动子[Calame等人，(1988)《免疫学进展》43：235-275]；在多个T细胞受体的多个特定启动子中[Winoto等人，(1989)《欧洲分子生物学组织》8：729-733]和多个免疫球蛋白；[Banerji等人(1983)《细胞》33729-740]，多个神经元特异性启动子，例如所述神经丝启动子[Byrne等人，(1989)《美国国家科学院院刊》86：5473-5477]，多个胰腺特异性启动子[Edlunch等人，(1985)《科学》230：912-916]或多个乳腺特异性启动子，例如所述牛奶乳清蛋白启动子(美国专利号4,973,316以及欧洲申请公开号264,166)。
多个增强子组件可以从多个链接的同源或异源启动子刺激转录至1，000倍。当多个增强子位于转录起始位点的下游或上游时是活化的。来源于多个病毒的许多增强子组件具有一广泛的宿主范围并且在各种组织中是活性的。例如，所述SV40早期基因增强子适用于许多细胞类型。适用于本发明一些实施例的其它增强子/启动子组合物包含衍生自多瘤病毒，人类或鼠类巨细胞病毒(CMV)，衍生自各种逆转录病毒，例如鼠白血病病毒，鼠或金肉瘤病毒和HIV的所述长末端重复。参见，《多个增强子和真核表达》，冷泉港出版社，冷泉港，纽约1983，所述《多个增强子和真核表达》在此引入作为参考文献。
在所述表达载体的所述构建中，所述启动子优选地位于与所述异源转录起始位点大致相同的距离处，如在所述启动子的天然设置中的所述转录起始位点。然而，如本领域已知的，在不丧失启动子功能的情况下，所距离的一些变化是可以容许的。
多聚腺苷酸序列还可以被加入所述表达载体中，以提高TCRL mRNA转录的所述效率。需要两个不同的序列组件用于精确和有效的多聚腺苷酸化：多个富有GU或U的序列位于所述多聚腺苷酸位点的下游以及一高度保守序列的6个核苷酸，AAUAAA，位于上游的11-30个核苷酸。适用于本发明一些实施例的终止和多个多腺苷酸化信号包括来源于SV40的所述多个终止和多个多腺苷酸化信号。
除了已经描述的所述多个组件，本发明一些实施例的所述表达载体通常可以包含其它特化的组件以增加多个克隆核酸的所述表达水平或促进携带所述重组DNA的多个细胞的所述辨识。例如，许多动物病毒含有多个DNA序列促进所述病毒基因体在多个允许的细胞类型中的所述额外的染色体复制。只要通过所述质体上携带的个基因或所述宿主细胞的所述基因体提供多个适当的因子，那么带有所述多个病毒复制子的质体可被游离性的复制。
所述载体可以包括或不包括一真核复制子。如果一真核复制子存在，则使用所述适当的可选择标记在真核细胞中扩增所述载体。如果所述载体不包括一真核复制子，则不可能有游离性的扩增。相反，所述重组DNA整合到所述设计的细胞的所述基因组中，其中所述基因组是所述启动子指导所需核酸的表达的地方。
还提供了多个细胞，所述细胞包括本文所述的多个多核苷酸/多个表达载体。
所述多个细胞通常地被挑选用于多个重组蛋白的高表达(例如，多个细菌，植物或真核细胞，例如，多个CHO，HEK-293细胞)，但当例如将所述TCRL的所述多个CDR被植入在所述多个细胞中一T细胞受体或CAR时，也可以是具有一特异性免疫效应活性的多个宿主细胞(例如，多个T细胞或NK细胞)。如下文进一步的描述。
所述亲和性结合实体的所述高特异性赋于它特别适合于多个诊断和治疗应用。
因此，根据本发明的一个方面，提供了检测表现有一感兴趣的HLA限定胜肽抗原的一细胞的一方法。所述方法包括连接所述细胞与本发明的具有对所述感兴趣的HLA限定胜肽抗原的特异性的所述亲和性结合实体(例如，抗体)接触。所述接触是在允许免疫复合的形成的多个条件下进行，其中所述免疫复合物或所述免疫复合物的水平的一表现指示所述细胞表现有感兴趣的所述HLA限定胜肽抗原。
本文所使用的术语“侦测(detecting)”是指“侦测(detecting)”、“感知(perceiving)＂、“揭露(uncovering)＂、“揭发(exposing)＂、“形象化(visualizing)＂或“辨认(identifying)＂一细胞的动作。所述精确的检测方法依赖于所述可检测部分(在本文中也称为可辨识部分)，所述抗体如本文进一步所述与所述可检测部分结合在一起。
根据本发明的所述多个教示可以把多个单一细胞用作多个细胞。例如，所述多个细胞可以来自任何生物样本，例如细胞株，初代(例如肿瘤培养物)以及多个细胞样本，例如多种外科检体，包括切口或切除检体，细针吸取物等。活组织检查的多个方法在本领域中是已知的。
上述检测方法可用于多个疾病的所述诊断，通过以上所述HLA胜肽复合物的疾病的诊断以的正常表现或不同组织的分布来确定。
本文所使用的术语“诊断(diagnosing)”是指对一疾病进行一分类，测定一疾病的一严重程度(等级或阶段)，监测进展，预测所述疾病的一结果和/或恢复的多个前景。
所述对象可以是正在进行一例行的健康检查的一健康对象(例如，人类)。替代地，所述受试者可能处于所述疾病的风险。另外，替代地，所述方法可用于监测治疗的功效。
所述TCRL可以包括例如，结合至一可识别部分。替代地或另外地，所述TCRL(或一复合物包含相同的TCRL)可以间接地辨识，例如通过使用一种二级抗体。
所述接触可以在体外(即在一细胞株，多个原代细胞中)，体内或体内进行。
如上所述，本发明的方法在多个条件之下足以形成一免疫复合物(例如，本发明的所述多个抗体和与所述MHC复合的所述胜肽之间的一复合物，通常在所述多个细胞未被裂解时)；所述多个条件(例如，多个合适的浓度，多个缓冲液，多个温度，多个反应时间)以及优化所述多个条件的方法是本领域技术人员已知的，并且在此公开了多个例子。
本发明的所述多个亲和性结合实体(例如，抗体)特别适用于所述癌症的治疗。
本文所使用的术语“癌症”定义为由多个异常细胞的所述快速和不受控的生长所表现的疾病。多个癌细胞可以局部地扩散或通过所述血流和淋巴系统到所述身体的其它部位。
所述癌症可以是一血液恶性肿瘤，一实体瘤、原发或转移性肿瘤。各种癌症的多个例子包含但不限于乳腺癌、前列腺癌、卵巢癌、子宫颈癌、皮肤癌、胰腺癌、结肠直肠癌、肾癌、肝癌、脑癌、淋巴瘤、慢性淋巴细胞性白血病(CLL)、白血病、肺癌等。可通过本发明的一些实施例的所述方法治疗的多个额外的非限制性例子提供在以上的表1。
多个可以被治疗的癌症包括没有血管化的肿瘤，或不是基本上血管化的，以及多种血管化的肿瘤。所述癌症可以包括多种非固态肿瘤(例如多个血液肿瘤，例如，白血病和淋巴瘤)或可包括多种实体瘤。本发明的所述多个抗体治疗的癌症类型包含但不限于，癌症、胚瘤及肉瘤，以及一些白血病或淋巴瘤、良性和恶性肿瘤，以及恶性肿瘤，例如肉瘤、癌症和黑色素瘤。还包括多种成人肿瘤/癌症和多种儿科肿瘤/癌症。
多种血液癌症是所述血液或骨髓的多种癌症。血液学(或造血)的癌症的例子包含白血病，包含急性白血病(例如急性淋巴细胞性白血病、急性髓细胞性白血病、急性骨髓性白血病和成髓细胞性白血病、早幼粒细胞性白血病、骨髓单核细胞性白血病、单核细胞性白血病和红白血病)、慢性白血病、(如慢性髓细胞(粒细胞)白血病、慢性粒细胞白血病和慢性淋巴细胞性白血病)、真性红细胞增多症、淋巴瘤、霍奇金病、非霍奇金淋巴瘤(懒惰的、高品位的形式)、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症、重链病、骨髓增生异常综合征、毛细胞白血病和骨髓增生异常综合征。
多个实体瘤是通常是不包含囊肿或多个液体区域的多个异常组织。多种实体瘤可以是良性或恶性。不同类型的实体瘤被命名为形成它们的多个细胞的所述类型(例如多种肉瘤、多种癌症和多种淋巴瘤)。多个实体瘤的多个例子，例如多种多肉瘤和多种癌，包含纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、滑膜肉瘤、间皮瘤和肉瘤，尤因氏瘤，平滑肌肉瘤，横纹肌肉瘤，结肠癌，淋巴恶性肿瘤，胰腺癌，乳腺癌，肺癌，卵巢癌，前列腺癌，肝细胞癌，鳞状细胞癌，基底细胞癌，腺癌，汗腺癌，甲状腺髓样癌、甲状腺乳头状癌、肾上腺皮脂腺癌、乳头状癌、乳头状腺癌、髓样癌、支气管癌，肾细胞癌、肝癌、胆管癌、绒毛膜上皮癌、威尔姆氏瘤、宫颈癌、睾丸肿瘤、睾丸精原细胞瘤、膀胱癌、黑色素瘤、以及中枢神经系统肿瘤(例如胶质瘤(例如脑干胶质瘤和混合性胶质瘤)，胶质母细胞瘤(也被称为多形性胶质母细胞瘤)星形细胞瘤，中枢神经系统(CNS)淋巴瘤、生殖细胞瘤、髓母细胞瘤，神经鞘瘤、颅咽管瘤，室管膜瘤、松果体瘤、血管母细胞瘤，听神经瘤，少突胶质细胞瘤、神经母细胞瘤，脑膜瘤，视网膜母细胞瘤和脑转移瘤)。
根据本发明的一些实施例，所述病理为一实体瘤。
根据本发明的一些实施例，本发明的一些实施例的方法所制备的药物的结果具有一抗肿瘤作用。
本文所使用的术语“抗肿瘤效应”，是指一种生物效应，所述生物效应可通过肿瘤体积的一减少，所述肿瘤细胞数目的一减少，所述转移数目的一减少，寿命的一增加，或与癌性病症相关的各种生理症状的改善来表现。一“抗肿瘤效应”也可以通过本发明的所述药物在第一线预防肿瘤发生的能力来表现。
根据具体的实施方案，当所述亲和性结合实体是用于酪氨酸酶(TyrD)时，所述癌症是选自于由黑色素瘤和胶质母细胞瘤所组成的所述群组。
根据一具体的实施方案，当所述亲和性结合实体是用于WT1时，所述癌症是选自：
表1
| 白血病 |
| 多发性骨髓瘤(MM) |
| 急性淋巴细胞白血病(ALL) |
| 急性髓细胞性白血病(AML) |
| 骨髓增生异常综合征(MDS) |
| 间皮瘤 |
| 卵巢癌 |
| 胃肠道癌症，如大肠癌、腺癌、甲状腺癌 |
| 乳腺癌 |
| 肺癌(如非小细胞肺癌) |
| 黑色素瘤 |
| 骨肉瘤 |
| 子宫内膜癌 |
根据具体的实施方案，当所述亲和性结合实体是用于MAGE时，所述癌症是选自：
表2
表3
| MAGE-A9 |
| 肾细胞癌 |
| 膀胱癌 |
| 乳腺癌 |
| 原发性肝细胞癌。 |
根据一具体的实施方案，当所述亲和性结合实体是用于PAP时，所述癌症是前列腺癌。
所述上面的多个分类皆与诊断及治疗有关。
测定本发明的所述免疫复合物的存在或水平取决于所述抗体所附着的所述可检测部分。
可用于本发明的多个可检测部分的多个例子包含但不限于多个放射性同位素，多个磷光化学品，多个化学发光化学品，多个荧光化学品，多个酶，多个荧光多肽和多个表位标记。所述可检测部分可以是一结合对的一组成，所述组成可通过所述组成与所述结合对以及可直接观察的一标签的一额外的构件的相互作用来辨识。在一例子中，所述结合对的所述组成是通过一相应的标记抗体所辨识的一抗原。在一个例子中，所述标签是一荧光蛋白或一酶产生一比色反应。
多个可检测部分的其它例子包含由正电子发射断层扫描(PET)以及磁共振成像(MRI)可检测的所述多个可检测部分，所有所述可检测部分都是本领域技术人员已知的。
当所述可检测部分是一多肽时，所述免疫标记(即与所述可检测部分偶联的所述抗体)可通过多个重组手段来生产，或化学合成，可通过例如，使用多个固相胜肽合成技术以定义的顺序对一个或多个氨基酸残基的所述逐步加入。使用重组DNA技术(其中编码所述TCRL的所述多核苷酸被转录地融合所述可检测部分)可与本发明抗体结合的多肽可检测部分的例子包含多个荧光多肽，多个磷光多肽，多个酶和多个表位标记。
替代地，本发明的所述多个抗体的一可检测部分的一化学连接可以使用任何合适的化学键，直接或间接的，如通过一肽键(当可检测部分为一多肽时)，或通过一中间连接组件的共价键，例如一连接子胜肽或其它化学部分，例如一有机聚合物来进行。所述多个嵌合胜肽可以通过在所述多个胜肽的所述羧基(C)或氨基(N)末端上的键合来连接，或通过键合至多个内部的化学基团例如直链，支链或环状侧链，内部的碳或氮原子等。本领域普通技术人员可以容易地辨别和制备所述多个修饰的胜肽，使用已知的胜肽合成方法和/或多个胜肽的共价键。美国专利号3,940,475、4,289,747和4,376,110中详细地提供了对多个抗体的荧光标记的描述。
用于偶联两个胜肽部分的示例性方法在下文描述：
SPDP偶联：
可以使用本领域技术人员已知的任何SPDP偶联方法。例如，在一个示例性实施例中，使用如下所述的Cumber等人的方法的一修饰(1985年，《酶学方法》112：207-224)。
一胜肽，例如一可辨识的或治疗部分，(1.7毫克/毫升)与一过量10倍的SPDP(在乙醇中50毫摩尔浓度)混合，所述抗体在20毫摩尔浓度的磷酸钠，0.10摩尔浓度的氢氧化钠(NaCl)pH 7.2中与一过量25倍的SPDP混合，并且每一个反应放置例如，室温下3小时。然后用PBS对所述反应透析。
所述胜肽被还原，例如与50毫摩尔浓度的DTT在室温下1小时。通过G-25管柱(高达5％的样品/管柱体积)在磷酸二氢钾(KH2PO4)pH 6.5下的平衡，将所述被还原的胜肽与所述SPDP-抗体以一摩尔比为1：10抗体：胜肽结合，并在4℃放置过夜以形成一胜肽-抗体偶联物。
戊二醛偶联：
一胜肽(例如，一可辨识或治疗部分)与一抗体的偶联可以通过本领域技术人员已知的使用戊二醛的多个方法来实现。例如，在一个示例性实施例中，使用在下面描述的G.T.Hermanson(1996“抗体修饰和偶联，在生物偶联技术，学术出版社，圣地亚哥)的所述偶联的方法。
所述抗体和所述胜肽(1.1毫克/毫升)与一过量10倍的具0.05％戊二醛的0.1摩尔浓度的磷酸盐及0.15摩尔浓度的氯化钠(pH6.8)溶液相混合，并允许在室温反应2小时。0.01m赖氨酸可以被加入以阻断多个过量的位点。反应后，使用以PBS(10％v样品/管柱体积)平衡的G-25管柱移除所述过量的戊二醛。
碳二亚胺偶联：
一胜肽与一抗体的偶联可通过本领域技术人员已知的多个方法使用一脱水剂例如一种碳二亚胺来实现。最优选地，所述碳二亚胺在4-二甲基氨基吡啶的存在之下使用。正如本领域技术人员所已知的，碳二亚胺的偶联可用于在胜肽的一羧基与一抗体的一羟基之间形成一共价键(导致一酯键的形成)，或一抗体的一氨基基团(导致一酰胺键的形成)或一抗体的一巯基(导致一硫代酯键的形成)。
同样地，碳二亚胺偶联可用于在一抗体的一碳基团与所述胜肽的一羟基、氨基或巯基之间形成多个相似的共价键。参见，通常地，J.March，《高级有机化学：反应的机理和结构》，pp.349-50&372-74(3d ed.)，1985。通过说明，并非限制，所述胜肽使用一种一碳二亚胺，例如如二环己基碳化二亚胺，通过一共价键与一与所述抗体偶联。通常地参见，B.Neises等人的所述多个偶联方法(1978，《应用化学》，国际英文版，17：522；A.Hassner等人(1978，《四面体通讯》4475)；E.P.Boden等人(1986，《有机化学期刊》50：2394)和L.J.Mathias(1979，《合成》561)。所述免疫复合物的水平可以与来自一非患病对象的一对照组样品进行比较，其中免疫复合物形成的上升调节是黑色素瘤的指示。优选地，所述对象是例如与人类相同的物种，优选地与相同的年龄，重量，性别等互相匹配。应当理解，所述对照组样品也可以来自所述相同的对象的一健康组织，在疾病进展之前或疾病缓解之后。
根据一具体实施例，所述侦测是由FACS实现。
如上所述，本发明的所述多个亲和性结合实体，例如，抗体也可用于多个治疗中，其中所述抗体包括一治疗部分。
所述治疗部分可以是所述抗体的一组成部分，例如，在一整个抗体的情况下，所述Fc区活活抗体依赖性细胞介导的细胞毒性作用(ADCC)。ADCC是一种细胞介导的免疫防御机制，其中通过所述免疫系统的一效应细胞主动地裂解一标靶细胞，所述标靶细胞的多个膜-表面抗原已被多个特定的抗体结合。这是多个抗体作为所述体液免疫反应的一部分的多个机制之一，可以起到限制和包含感染的作用。经典的ADCC由多个自然杀伤(NK)细胞所介导，多个巨噬细胞，多个嗜中性粒细胞和多个嗜酸性粒细胞也可以介导ADCC。例如，多个嗜酸性粒细胞可以通过IgE介导的ADCC杀灭已知为蠕虫的一些寄生虫。由于ADCC依赖于一先前的抗体反应，ADCC是所述适应性免疫反应的一部分。
替代地或额外地，所述抗体可以是一双特异性抗体，其中所述治疗部分是一T细胞接合物，例如一个抗CD3抗体或一个抗CD16a，替代地，所述治疗部分可以是一个抗免疫检查点分子(抗PD-1)。
替代地或额外地，所述抗体可以连接到一异源治疗部分(如上述多个偶联的方法)。所述治疗部分可以是，例如一细胞毒性部分、一毒性部分、一细胞因子部分、一药物。
所述抗体可以是一可溶的或非可溶的形式。
多个非可溶的形式可以是那些包含所述抗体的多个CDR的一分子被锚定至或被表现至一细胞或一颗粒上(后者可用于治疗以及多个诊断应用)。
所述多个细胞的例子包括多个免疫细胞，多个T细胞，多个B细胞，多个树突细胞，细胞因子诱导的杀伤细胞(CIK)，自然杀伤T细胞(NKT)，自然杀伤细胞(NK)(自体，同种异体，异种的)。
根据一具体的实施例，所述抗体(或实际上所述抗体的CDR)形成一嵌合抗原受体(CAR)(如上所述)或一人工T细胞受体。因此，编码这样的一分子的一多核苷酸被导入至感兴趣的一细胞中。
根据本发明的一些实施例，所述细胞是一T细胞，一自然杀伤细胞，在一标靶细胞上发挥效应物的杀伤作用的一细胞，在效应T细胞上进行一抑制作用的一细胞，具有一效应物的杀伤功能的一设计的细胞或具有一抑制功能的一设计的细胞。
根据本发明的一些实施例，所述细胞是一T细胞，或αβT细胞或γδT细胞。
根据本发明的一些实施例，所述细胞是一自然杀伤(NK)细胞。
根据本发明的一些实施例，所述自然杀伤细胞用于标靶向癌症。
根据本发明的一些实施例，所述T细胞是一细胞毒性T细胞(效应T细胞)。
根据本发明的一些实施例，细胞毒性T细胞(效应T细胞)用于治疗多个癌症抗原。
根据本发明的一些实施例，所述细胞毒性T细胞用于治疗由一癌症引起或相关的一病理。
根据本发明的一些实施例，所述T细胞包括一Treg细胞)。
根据本发明的一些实施例，所述T细胞包括CD3 T细胞
根据本发明的一些实施例，所述T细胞包括CD4 T细胞。
根据本发明的一些实施例，所述T细胞包括CD8 T细胞。
根据本发明的一些实施例，所述抗原结合域包括一单链变异区片段(scFv)分子。
本发明的所述CAR分子的所述细胞质区域(也称为“细胞内信号区域”)负责所述免疫细胞中的所述多个正常效应功能的至少一者，其中所述CAR已经被置入所述免疫细胞中。
所述术语“效应物功能”是指一细胞的一特定功能。一T细胞的效应功能，例如，可以是细胞溶解的活性或帮助的活性包含所述多个细胞因子的分泌。因此，所述术语“细胞内信号区域”指的是一蛋白的所述部分，其中所述部分将执行器功能信号转换并引导所述细胞进行一专用功能。尽管通常可以使用所述整个细胞内信号区域，但在许多情况下不需要使用所述整个链。在使用所述细胞内信号区域的一截短部分的程度上，只要所述截短部分转导所述效应功能信号，所述截短部分可用于代替所述完整的链。因此所述术语细胞内信号区域表示包含足以转导效应功能信号的胞内信号域的任何的截短部分。
用于本发明的所述CAR分子中的多个细胞内信号区域的多个例子包含所述T细胞受体(TCR)的所述多个细胞质序列以及多个共同受体，在抗原与受体接合后，所述共同受体协同引发的信号转导，以及所述多个序列的任何衍生物或变异体，以及具有相同功能的能力的任何的合成序列。
已知仅通过所述TCR所产生的多个信号不足以完全活化所述T细胞，并且还需要一个二级或共刺激的信号。因此，T细胞的活化可以由两个不同种类的胞质信号序列来介导：那些通过所述TCR引发的抗原依赖性的主要活化方法(多个主要的细胞质信号序列)的方法以及那些以一抗原无关的方式进行提供一个二级或共刺激的信号(多个二级细胞质信号序列)的方法。
多个初级细胞质信号序列以一刺激方式或以一抑制方式调节所述TCR复合物的主要的活化。以一刺激方式起作用的多个主要细胞质信号序列可包含多个信号基序，所述多个信号基序是已知为多个免疫受体酪氨酸为基础的活化基序(ITAMs)。
ITAM的多个例子具备主要用于本发明的多个主要细胞质信号序列包含那些衍生自TCR zeta、FcR gamma、CD3 gamma、CD3 delta、CD3 epsilon、CD5、CD22、CD79a、CD79b及CD66d的ITAM。特别优选的是，本发明的所述CAR中的细胞质信号分子包括衍生自CD3 zeta的一细胞质信号序列。
在一优选实施例中，所述CAR的细胞质区域可以被设计成包括所述CD3-zeta信号区域本身或与结合于在适用于本发明的CAR的背景下任何其它所需的(多个)细胞质区域。例如，所述CAR的所述细胞质区域可以包括一CD3 zeta链部分及一共刺激信号区域。所述共刺激信号区是指所述CAR的一部分包括一共刺激分子的所述细胞内区域。一个共刺激分子是除了一抗原受体或多个淋巴细胞对一抗原的一有效应答所需的所述抗原受体的配体以外的一细胞表面分子。所述多个分子的多个例子包含CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3以及与CD83特异性结合的一配体等。因此，虽然本发明主要以4-1BB作为所述共刺激信号组件，其它共刺激组件均在本发明的范围内。
根据本发明的一些实施例，所述细胞内区域包括一共刺激信号区和一zeta链部分。所述共刺激信号区域是指所述CAR分子的一部分包括一共刺激分子的所述细胞内区域。多个共刺激分子是除多个抗原受体或多个淋巴细胞对抗原的一有效反应所需的多个抗原受体的配体以外的多个细胞表面分子。
本文所使用的“共刺激配体”，包含在一抗原呈现细胞[例如，一aAPC(人工抗原呈现细胞)，树突状细胞，B细胞等]上的一分子，所述分子特异性地结合在T细胞上的一同源的共刺激分子，从而提供一信号，除了由例如，一TCR/CD3复合物与加有胜肽的一MHC分子的结合所提供的所述主信号之外，介导一T细胞反应，包含但不限于，增殖、活化、分化等。一共刺激配体可以包括但不限于，CD7、B7-1(CD80)、B7-2(CD86)，PD-L1、PD-L2、4-1BBL、OX40L、诱导性的共刺激配体(ICOS-L)、细胞间粘附分子(ICAM-1)、CD 30L、CD40、CD70、CD83、HLA-G、MICA、MICB、HVEM、淋巴毒素beta受体、3/TR6、ILT3、ILT4、HVEM、结合Toll配体的受体的一激动剂或抗体以及具体结合B7-H3的一配体。一种共刺激配体也包括，尤其是，与表现在一T细胞上的一共刺激分子特异性结合的一抗体，例如但不限于CD27、CD28、4-1BB、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、光、NKG2C、B7-H3以及与CD83特异性结合的一配体。
一“共刺激分子”是指在T细胞上的所述同源结合配偶体，所述同源结合配偶体与一共刺激配体特异性结合，从而介导所述T细胞的一共刺激应答，例如但不限于，增殖。多个共刺激分子包含但不限于一第一类MHC分子，BTLA及一Toll配体受体。
本文所使用的一“共刺激信号”是指一信号结合于一初级信号，例如TCR/CD3连接，导致T细胞增殖和/或多个关键分子的上升调节或下降调节。
术语“刺激”是指一主要的反应，通过一刺激分子(例如，一TCR/CD3复合物)结合其同源的配体所引发，所述主要的反应是是通过介导一信号转导事件，例如但不限于，通过所述TCRCD3复合物的信号转导。刺激可以介导一些分子的改变的表达，例如TGF-β的下降调节，和/或多个细胞骨架结构的重组等。
一“刺激分子”，如本文所使用的术语，表示在一T细胞上的一分子特异性结合于表现在一抗原呈现细胞上的一同源的刺激配体。
一“刺激分子”，如本文所使用的术语，表示一配体在当表现在一抗原呈现细胞(例如，aAPC，一树突细胞、一B细胞等)上时可特异性地结合于在T细胞上的一同源结合配偶体(本文称为一“刺激分子”)，通过所述T细胞通过介导一初级反应，包含但不限于，激活，引发一免疫反应，增殖等。多个刺激配体在本领域中是已知的，并且尤其是包括，并且加有一胜肽的一第一类MHC分子、一抗CD3抗体、一超激动剂抗cd28抗体和一超激动剂抗cd2抗体。
关于所述细胞质区域，本发明一些实施例的所述CAR分子可以设计成包括所述CD28和/或4-1BB的信号区域本身或与结合于在适用于本发明的CAR的背景下任何其它所需的(多个)细胞质区域。在本发明一些实施例的CAR分子的环境中是有用的。在一个实施例中，所述CAR的所述胞质域可以被设计为进一步包括CD3-zeta的所述信号区域。例如，所述CAR的胞质区域可以包含但不限于CD3-zeta，4-1BB及CD28的多个信号模块及多个组合。
根据本发明的一些实施例，所述细胞内区域包括至少一种，例如，至少两个，至少三个，至少四个，至少五个，例如，至少六个选自于由CD3ζ(CD247、CD3z)、CD28、41BB、ICOS、OX40和CD137所组成的群组中的所述多个多肽。
根据本发明的一些实施例，所述细胞内区域包括所述CD3ζ-链[CD247分子，也称为“CD3-zeta”和”CD3z”；Genbank登录号NP_000725.1和NP_93170.1]，所述CD247分子是来自多个内源性TCR的所述主变送器的信号。
根据本发明的一些实施例，所述细胞内区域包括各种共刺激蛋白受体在所述CAR的所述胞质尾部以提供额外的多个信号至所述T细胞(第二代CAR)例子包含但不限于CD28[例如Genbank登录号NP_001230006.1、NP_001230007.1、NP_006130.1]，4-1BB[肿瘤坏死因子受体超级家族，成员9(TNFRSF 9)，也称为“CD137”，例如Genbank登录号NP_001552.2]，以及ICOS[诱导型T细胞共刺激剂，例如Genbank登录号NP_036224.1]。多个临床前研究表示，所述第二代CAR设计提高了多个T细胞的所述抗肿瘤活性。
根据本发明的一些实施例，所述细胞内区域包括多个信号区域，如CD3z-CD28-41BB或CD3z-CD28-OX40，以进一步增强效力。所述术语”OX40”是指肿瘤坏死因子受体超级家族，成员4(TNFRSF4)，例如Genbank登录号NP_003318.1(多个“第三代”CAR)。
根据本发明的一些实施例，所述细胞内区域包括CD28-CD3z,CD3z,CD28-CD137-CD3z。所述术语”CD137”是指肿瘤坏死因子受体超级家族，成员9(TNFRSF9)，例如Genbank登录号NP_001552.2。
根据本发明的一些实施例，当所述CAR分子被设计用于一自然杀伤细胞时，则所述信号区域可以是CD28和/或CD3ζ。
所述跨膜区域可以是从一天然或从一合成的来源获得。在所述来源是天然的情况下，所述区域可以是来源于任何膜结合或跨膜蛋白。本发明中特定用途的多个跨膜区域可衍生自(即至少包括所述(多个)跨膜区域的)T细胞受体的所述alpha、beta或zeta链、CD28、CD3 epsilon、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154。替代地，所述跨膜区域可以是合成的，在这种情况下所述跨膜区域主要包括疏水残基例如亮氨酸和缬氨酸。优选地，在一合成的跨膜区域的每一端可发现一苯丙氨酸、色氨酸和缬氨酸的三联体。可选地，一种短的寡-或多肽连接物，优选地在2和10个氨基酸长度之间可以在跨膜区域和所述CAR的所述细胞质信号区域之间形成所述连接。一甘氨酸-丝氨酸双联体提供了一特别适合的连接子。
根据本发明的一些实施例，本发明的一些实施例的CAR分子中包括的所述跨膜区域是天然地相关于所述CAR的所述多个区域中的其中一者的一跨膜区域。根据本发明的一些实施例，所述跨膜区域可以通过氨基酸取代来筛选或修饰，以避免所述多个区域结合于所述相同或不同的表面膜蛋白的所述多个跨膜区域，以最小化与所述受体复合物的其它成员的多个相互作用。
根据一些实施例，在CAR分子的所述细胞外区域和所述跨膜区域之间，或在所述细胞质区域与所述CAR分子的所述跨膜区域之间，可包含一间隔区域。如本文所使用，术语“间隔区域”一般表示任何的寡-或多肽，所述寡-或多肽将所述跨膜区域链接到所述多肽链中的所述细胞外区域或所述细胞质区域。一间隔区域可包括多达300个氨基酸，优选地10至100个氨基酸，以及最优选地25至50个氨基酸。
根据本发明一些实施例的一个方面，本发明提供了一种在有需要的一主体中治疗癌症的方法，包括给予所述主体所述亲和性结合实体，从而在所述主体中治疗所述癌症的。
还提供了所述亲和性结合实体的一种用途，如本文所定义的一药物的所述制备，用于治疗一病理例如，癌症。
所述TCRL的所述筛选将会自然依赖于所述TCRL在病理中的表现。多个示例性的TCRL及所述TCRL与多个病理的关联被提供在上表中。
术语“治疗”是指抑制，预防或阻止一病理(疾病，紊乱或病症)的发展和/或导致一病理的所述减少，缓解或回复。本领域技术人员将理解，可以使用各种方法和测试来取得一病理的所述发展，相似地，各种方法和分析可用于取得一病理的减少，缓解或回归。
如本文所使用，术语“受试者”包括多个哺乳动物，优选地在患有所述病理的任何年龄的人类。
本发明一些实施例的所述多个抗体本身可以被给药至一生物体，或在与合适的多种载体或多种赋形剂混合的一药物组合物中。
本文所使用的一“药物组合物”是指在此描述的一种或多种所述活性成分与其它化学成分例如生理学上合适的多种载体和多种赋形剂的制备。一药物组合物的所述目的是促进一化合物至一生物体的给药。
本文中的术语“活性成分”是指用于负责所述生物学效应的所述抗体。
在下文中，短语“生理上可接受的载体”和“药学上可接受的载体”可互换使用，用于指出一载体或一稀释剂不会对一生物体造成显着的刺激，并且不会妨碍所给予的化合物的所述生物学活性和多个性质。一佐剂被包含在所述多个短语之下。
本文的术语“赋形剂”是指一惰性物质被加入至一药物组合物中以进一步促进活性成分的给药。赋形剂的多个例子，不限于，包括碳酸钙，磷酸钙，各种糖类和淀粉的类型，多种纤维素衍生物，明胶，植物油以及多种聚乙二醇。
用于制备和多个药物的给药的技术可在《雷明顿药物科学》麦克出版公司，伊斯顿，宾夕法尼亚州，最新版本中找到，作为参考文献引入在此。
多个合适的给药途径可以，例如包括口腔、直肠、粘膜、尤其是经鼻、肠或胃肠外给药，包含肌内，皮下和髓内注射以及鞘内注射，直接心空内，心内，例如，进入右或左心室腔、进入共同的冠状动脉、静脉内、腹膜内、鼻内或眼内注射。
多种常规方法用于药物递送给中枢神经系统(CNS)包括：多个神经外科策略(例如，脑内注射或脑室内输注)；所述试剂的分子操纵(例如，一嵌合融合蛋白的制备，所述嵌合融合蛋白包括一运输胜肽，所述运输胜肽对一内皮细胞表面分子具有一亲和力，以结合自身不能穿越血脑屏障(BBB)的一试剂)试图利用其中一个BBB的所述内源性运输途径；多个药理学策略被设计为增加一试剂的脂溶性(例如，偶联多个水溶性试剂与多个脂质或胆固醇载体)；以及通过超渗透破坏而暂时破坏bbb的完整性(由将一甘露醇溶液注入所述颈动脉或一生物活性剂如血管紧张胜肽的所述使用)。然而，所述多个策略中的每一者都具有多个限制，例如与一侵入性外科手术相关的所述固有风险，由在所述内源传输系统中固有的限制所施加的一尺寸限制，多个潜在的不期望的生物性副作用与一嵌合分子的全身给药相关联，所述嵌合分子包含一可能在CNS外活化的载体基序，以及在所述脑部的BBB被破坏的多个区域内的脑损伤的所述可能风险，这使得所述方法成为一次等优选的递送方法。
替代地，可以以局部而非全身的方式给予所述药物组合物，例如，通过将所述药物组合物直接注射到一患者的一组织区域中。
所述术语“组织”是指一生物体的一部分被设计成执行一功能或多个功能。多个例子包括，但不限于，脑组织、视网膜、皮肤组织、肝组织、胰腺组织、骨、软骨、结缔组织、血液组织、肌肉组织、心脏组织脑组织、血管组织、肾组织、肺组织、性腺组织、造血组织。
本发明一些实施例的多个药物组合物可以通过本领域已知的方法制备，例如，通过常规的混合、溶解、制粒、糖衣、喷雾、乳化、包封、截留或冻干的多个过程。
因此，根据本发明的一些实施方式所使用的多个药物组合物可以以常规方式使用一种或多种生理上可接受的载体来配制，所述载体包含多个赋形剂和多个助剂，所述多个赋形剂和多个助剂促进所述活性成分在用于药学上的制备上的过程，适当的配方取决于所选择的所述给药途径。
对于注射，所述药物组合物的所述多个活性成分可以配制成多个水溶液，优选地在生理地相容的缓冲液中，如Hank’s溶液，林格氏溶液或生理盐缓冲液。对于粘膜给药，在所述配方中使用适合所述即将被渗透的屏障的多个渗透剂。所述多个渗透剂在本领域中是已知的。
对于口服给药，所述药物组合物可以通过将所述多个活性化合物与本领域已知的多个药学上可接受的载体结合而容易地配制。所述多个载体使得所述药物组合物可以配制成片剂、丸剂、锭剂、胶囊剂、液体、凝胶、糖浆剂、浆料、悬浮液等，用于一患者的口服摄取。用于口服的多个药物制剂可使用一固体赋形剂来制备，可选地研磨所得到的混合物，如果需要，在加入多个合适的辅料后，加工成多个片剂或多个糖衣核心。多个合适的赋形剂，特别是，填料例如多种糖类，包括乳糖、蔗糖、甘露醇或山梨糖醇；纤维素制剂例如，玉米淀粉、大米淀粉、马铃薯淀粉、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、甲基纤维素钠，和/或多种生理上可接受的聚合物，如聚乙烯吡咯烷酮(PVP)。如果需要，可以加入多种崩解剂，例如交联的聚乙烯吡咯烷酮、琼脂或海藻酸或所述海藻酸的盐类例如海藻酸钠。
多个糖衣核心具有多个合适的涂层。为此目的，多种浓缩糖溶液可以被使用，所述多种浓缩糖溶液可任选地含有阿拉伯树胶、滑石(talc)、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇、二氧化钛、漆溶液以及合适的有机溶剂或多个溶剂混合物。多种染料或多种颜料可以被加入至所述多个片剂或糖衣涂层中，用于辨识或表征多个活性化合物剂量的不同组合。
可用于口服的药物组合物，包含由明胶制成的多个推入式胶囊以及由明胶和一增塑剂，例如甘油或山梨糖醇所制成的软的、密封的胶囊。所述多个推入式胶囊可以含有所述活性成分混合于填充剂例如乳糖、粘合剂例如淀粉、润滑剂如滑石粉或硬脂酸镁以及，可选地稳定剂。在多个软胶囊中，所述多个活性成分可以溶解或悬浮在一合适的液体中，如脂肪油、液体石蜡或多种液体聚乙二醇。此外，可以加入稳定剂。用于口服给药的所有配方应具有适合于所选择的给药途径的剂量。
对于口腔给药，所述组合物可以采用常规方式所配制的多个片剂或多个锭剂的形式。
为了通过鼻部吸入，根据本发明一些实施例所使用的所述多个活性成分在使用来自于一加压包装的气溶胶喷雾的形式，或使用合适的推进剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷或二氧化碳的喷雾器下被方便地递送。在加压气雾剂的情况下，所述剂量单位可以通过提供用于输送一计量的数量的一阀门来测定。用于一分配器的胶囊和盒例如，明胶可以被配制成含有所述化合物的一粉末混合物以及一合适的粉末基质例如乳糖或淀粉。
本文所述的药物组合物可配制成用于胃肠外给药，例如，通过静脉注射或连续输注。用于注射的多个配方可以以单位剂量形式呈现，例如在安瓿或多个多剂量容器中，与任选地，一加入的防腐剂。所述多个组合物可以是油性或水性载体中的悬浮液、溶液或乳液，并且可以包含多个配制剂，例如悬浮剂、稳定剂和/或分散剂。
用于肠胃外给药的多个药物组合物包含在水溶性形式的所述活性制剂的多个水溶液。额外地，可将所述多个活性成分的悬浮液制备为合适的油性或以水为基底的注射悬浮液。多种合适的亲脂性溶剂或多种载体包括多种矿物油例如芝麻油，或多个合成脂肪酸酯例如油酸乙酯，多种甘油三酯或多种脂质体。水性注射悬浮液可含有增加所述悬浮液的粘度的多种物质，例如羧甲基纤维素钠，山梨糖醇或葡聚糖。可选地，所述悬浮液也可含有多个合适的稳定剂或增加所述多个活性成分的所述溶解度的试剂以允许所述多个高度浓缩的溶液的制备。
替代地，所述活性成分在使用前可以是粉末形式，用于构成一合适的载体，例如，无菌、无热原的水为基底的溶液。
本发明一些实施例的所述药物组合物也可以被配制成多个直肠组合物例如多种栓剂或多种滞留灌肠剂，例如，多个常规的栓剂基质，例如可可脂或其它甘油酯。
适用于本发明一些实施例的背景中的多个药物组合物包含多个成分，其中所述多个有效成分以一能有效达到预期目的的数量被包含。更具体地，一治疗有效数量是指多个活性成分(TCRL抗体)的数量有效地预防，缓解或改善一病症的症状(例如，癌症)或延长所述被治疗对象的存活。
一治疗有效数量的测定是完全在本领域技术人员的能力内，特别是根据本文所提供的所述详细内容。
对于本发明的方法中使用的任何制剂，所述治疗有效数量或剂量可以最初地从多个体外和细胞培养测试中估计。例如，可以在多个动物模型中配制一剂量以获得一期望的浓度或滴度。所述信息可用于更准确地测定人类中的有用剂量。
本文所述的多个活性成分的毒性和治疗功效可通过在体外、在多种细胞培养或多种实验动物的多个标准药物过程来测定。从所述多个体外和细胞培养测试以及动物研究中所获得的所述数据可用于配制用于人类的剂量的一范围。所述剂量可以根据所采用的所述剂型以及所使用的所述给药途径而变化。所述确切的配方，给药途径和剂量可以通过所述个别的医生根据患者的状况来选择。(参见例如，Fingl等人，1975，在“药物的药理学基础”中，第一章，第一页)。
剂量的数量和间隔可以被单独调节以提供所述活性成分中的TCRL(所述TCRL组织)的水平足以诱导或抑制所述生物效应(最小的有效浓度，MEC)。用于每种制剂中的所述MEC将会不同，但是可以从体外数据中估计。实现MEC所需的剂量将取决于个体的特征和给药途径。多个侦测测试可用于测定多个血浆浓度。
根据待治疗的所述病症的所述严重程度和反应性，给药可以是一单次或一多次的给药，持续从数天至数周的持续时间，或直至达到治愈或治疗疾病状态。
当然，被给予的一组合物的数量将取决于所述被治疗的对象，所述痛苦的所述严重程度，所述给药方式，所述处方医生的所述判断等。
如果需要，本发明的一些实施例的多个组合物也可以被提供在一包装或一分配器装置中，例如一FDA批准的套组(诊断的或治疗的)，所述套组可含有一种或多种含有活性成分的单位剂型。所述包装可以例如包括金属或塑料箔，例如一泡罩包装。所述包装或分配器装置可伴有用于给药的多个指示。所述包装或分配器也可以伴有与所述容器相关的一注意事项，所述容器是在由一政府机构监管规定的药品的制造，使用或出售的形式，所述注意事项反映了所述多个成分或人或兽医管理机构的所述形式的批准。例如，所述注意事项，可以是由美国食品和药物管理局批准的用于多个处方药物或多个处方药物的批准的产品插入物。多个组合物包括还可以制备配制在兼容性药物载体中的本发明的一制剂，被放置在一适当的容器中，并且被标记用于治疗一指示的状况，如上面的进一步的详细描述。
可以预期到在本申请成熟的一专利寿命期间，将开发出许多相关的TCRLs；所述术语TCRLs的范围意在包括所有类似的先前技术。
如本文所使用的术语“约”指±10％。
术语“包括(comprises)”、“包括(comprising)”、“包括(includes)”、“包含(including)”、“具有(having)”及其词形变化是指“包括但不限于”。
术语“由…组成(consisting of)”意思是“包括及不限于”。
术语“基本上由......组成(essentially consisting of)”是指组合物、方法或结构可包括额外的成分、步骤及/或部件，但只有当额外的成分、步骤及/或部件实质上不改变所要求保护的组合物、方法或结构的基本特征及新特征。
本文所使用的单数型式“一”、“一个”及“至少一”包括复数引用，除非上下文另有明确规定。例如，术语“一化合物”或“至少一种化合物”可以包括多个化合物，包括其混合物。
在整个本申请中，本发明的各种实施例可以以一个范围的型式存在。应当理解，以一范围型式的描述仅仅是因为方便及简洁，不应理解为对本发明范围的硬性限制。因此，应当认为所述的范围描述已经具体公开所有可能的子范围以及该范围内的单一数值。例如，应当认为从1到6的范围描述已经具体公开子范围，例如从1到3，从1到4，从1到5，从2到4，从2到6，从3到6等，以及所数范围内的单一数字，例如1、2、3、4、5及6，此不管范围为何皆适用。
每当在本文中指出数值范围，是指包括所指范围内的任何引用的数字(分数或整数)。术语，第一指示数字及第二指示数字"之间的范围”及第一指示数字"到”第二指示数字"的范围"在本文中可互换，并指包括第一及第二指示数字，及其间的所有分数及整数。
如本文所用的术语「方法(method)」指的是用于完成一特定任务的方式(manner)，手段(means)，技术(technique)和程序(procedures)，包括但不限于，那些方式，手段，技术和程序，其是已知的，或是从已知的方式，手段，技术或程序很容易地被化学，药理，生物，生化及医学领域从业者所开发。
如本文所用，术语"治疗"包括终止，基本上抑制，减慢或逆转病症的进程，基本上改善病症的临床或心理症状或基本上预防病症的临床或心理症状的出现。
当参考多个特定的序列列表时，所述参考将被理解为还包括基本上与所述参考的互补序列相对应的多个序列，所述序列包括多个次要的序列变化，由于例如多个定序误差，多个克隆误差或碱基替换，碱基缺失或碱基添加所引起的其他改变所导致，所述多个变化的所述频率在小于五十分之一个核苷酸中，在小于一百分之一个核苷酸中，或者，替代地，在小于二百分之一个核苷酸中，在小于五百分之一个核苷酸中，或在小于一千分之一个核苷酸中，或者，在小于五千分之一个核苷酸中，或者，在小于一万分之一个核苷酸中。
可以理解，本发明的某些特征，为了清楚阐明，描述在独立的实施例的上下文中，也可以是在一单一实施例中以组合提供。相反，本发明的各种特征，为了简明，在一单一实施例的上下文中描述，也可以单独或以任何合适的子组合或以适合于本发明的任何其它描述的实施方式来提供。在各种实施例的上下文中描述的部分特征不应被认为是那些实施例的主要特征，除非该实施例在没有这些组件的情况下不运作。
下面的实施例中描述了本发明的各种实施例和方面，并且如权利要求部分中所要求的，在下面的实施例中发现了实验支持。
多个例子
现在参考以下多个例子，所述多个例子与上述的多个描述以一非限制性的方式一起示出了本发明的一些实施例。
通常地，本文所使用的术语和用于本发明中的所述实验室方法包括分子，生物化学，微生物以及重组DNA技术。所述多个技术在文献中被彻底解释。参见，例如，“分子克隆：实验室手册”Sambrook等人，(1989)；“分子生物学当前议定书”卷一至三，Ausubel，R.M.，ed.(1994)；Ausubel等人，“分子生物学当前议定书”，JohnWileyandSons，Baltimore，Maryland(1989)；Perbal，“分子克隆实用指南”，JohnWiley&Sons，NewYork(1988)；Watson等人，“重组DNA”，美国科学书籍，纽约；Birren等人(eds)“基因组分析：实验室手册系列”，卷一至四，冷泉港实验室出版社，纽约(1998)；在美国专利号4,666,828；4,683,202；4,801,531；5,192,659及5,272,057所阐述的方法；“细胞生物学：实验室手册”，卷一至三，Cellis，J.E.，ed.(1994)；由FReshney，Wiley-Liss的“动物细胞培养-基本技术手册”，纽约(1994)，ThirdEdition；“免疫学中的现行协议”卷一至三，ColiganJ.E.，ed.(1994)；Stites等人(eds)，“基础免疫学和临床免疫学”(第八版)，Appleton&Lange，Norwalk，CT(1994)；Mishell和Shiigi(eds)，“细胞免疫学中的多个选择方法”，W.H.Freeman and Co.,纽约(1980)；现有的免疫分析在专利和科学文献中有广泛的描述。参见,例如,美国专利号3,791,932；3,839,153；3,850,752；3,850,578；3,853,987；3,867,517；3,879,262；3,901,654；3,935,074；3,984,533；3,996,345；4,034,074；4,098,876；4,879,219；5,011,771和5,281,521；"寡核苷酸合成"Gait,M.J.,ed.(1984)；“核酸杂交"Hames,B.D.,和HigginsS.J.,eds.(1985)；"转录和翻译"Hames,B.D.,and Higgins S.J.,eds.(1984)；"动物细胞培养"Freshney,R.I.,ed.(1986)；"固定化细胞和酶"IRL出版社,(1986)；"分子克隆的一实用指南"Perbal,B.,(1984)and"酶学方法"卷1-317,学术出版社；"PCR协议：方法和应用指南",学术出版社,圣地亚哥,加利福尼亚州(1990)；Marshak等人,"蛋白质纯化和鉴定策略-实验室课程手册"CSHL出版社(1996)；所有所述多个文献都以引用的方式并入本文中。在本文献中提供了其它的一般参考文献。在所述多个文献中的所述多个步骤被认为在本领域中是已知的，并为了读者的方便提供。这里所包含的所有信息都以引用的方式并入本文中。
多个常用的材料和方法
生物素化的单链MHC胜肽复合物的制备
多个单链MHC(scMHC)3-胜肽复合物是在异丙基β-D-硫代半乳糖苷(IPTG)的诱导下从大肠杆菌中的多个包涵体里的体外重新折叠产生。简单地说，一scMHC，包含所述β2-微球蛋白的以及所述HLA-A2基因的所述多个细胞外区域通过一柔性连接子连接彼此，所述scMHC被设计以在所述C端包含用于位点特异性生物素化的BirA辨识序列(scMHC-BirA)。在如所述的胜肽的存在下进行体外重新折叠。通过阴离子交换Q-Sepharose色谱(GEHealthcare Life Sciences)分离和纯化正确折叠的多个MHC-胜肽复合物，然后使用所述BirA酶(亲和性)进行位点特异性的生物素化，用于生产多个单链MHC胜肽复合物的一更详细的描述提供在Denkberg等人(2002)PNAS，99：9421-9426中。
流式细胞技术
多个T-B杂化T2细胞被无血清的RPMI 1640培养基清洗，用含有10-4至10-5摩尔浓度的酪氨酸酶369-377YMDGTMSQV(SEQ ID NO：1)/WT1126-134(RMFPNAPYL，SEQ ID NO：141)胜肽/MAGE-A4230-239SEQ ID NO：176/MAGE-A9223-231203/PAP112-120SEQ ID NO：230的胜肽或相关的多个对照组胜肽(列于下表15中)的培养基孵育过夜。使用多个加有胜肽的T2细胞上的HLA-A2-结合抗体BB7.2的MFI与未加载的多个T2细胞(>1)的MFI之间的比率来验证胜肽加载效率，数据不示出。
多个T2或原代细胞或细胞株(106)与10微克/毫升的特定抗体(Ab)(有或无生物素化)在4℃下培养1小时，接着与PE标记的抗小鼠/人/链霉亲和素Ab在4℃下培45分钟，应当理解，抗小鼠二级抗体或链霉亲和素的工作得到与D11和B47B6的相似的结果。最后对细胞进行清洗和分析：
FACS 1:
机器:BD FACS calibur
分析软件:CELLQuest
FACS 2:
机器:Beckman Coulter NAVIOS
分析软件:Kaluza第1.3版
使用所述杂交瘤技术生产HLA-A2/酪氨酸酶369-377/WT1126-134/MAGE-A4230-239/MAGE-A9223-231/PAP112-120的多个类TCR抗体
通过5-6次HLA-A2-胜肽复合物50微克/小鼠的注射使HHD小鼠被免疫化。前2-3次的注射加入QuilA佐剂被皮下给药。通过从对上述复合物免疫的小鼠中分离的多个脾细胞与NSO骨髓瘤细胞的融合产生多个杂交瘤克隆(如前面所述的Weidanz等人2011，《国际免疫学评论》30：328-340)，以及通过如下所述的多个差异性ELISA试验进行筛选和分离。例如，对于多个酪氨酸酶TCRL的筛选，使用所述相关的多个TyrD369-377胜肽HLA-A2复合物并与所述非相关的多个p68-DDX5对照组胜肽(SEQ ID NO：2YLLPAIVHI)HLA-A2配合物相比较。具有多个纯化的HLA-A2-Tyr复合物以及显示其它HLA-A2-限定胜肽(表15)的对照组HLA-A2复合物的ELISA被用于筛选多个特异性克隆，多个分离的杂交瘤克隆被亚克隆以及被定序。两个克隆906-11-D11(称为D11，图68)和905-2-D7(称为D7，图69)被描述。
杂交瘤在HAT DMEM或无血清的DCCM2培养基中生长直到汇合＞80％并且收集上清液。纯化的IgG是通过使用蛋白A管柱作亲和层析从培养上清液分离。所述纯化的蛋白的SDS-PAGE分析显示出均质的，纯的IgG具有预期的分子量为约150千道尔顿。
整个IgG Ab的构建
所述多个H和L Fab基因(仅用于MC1)被克隆以用来表达，如人类IgG1κAb分别进入所述多个真核表达载体pOptiVEC以及pcDNA3.3-TOPO中。每个穿梭表达载体携带了一个不同的基因选择(对于pOptiVEC，所述DHFR/HT-以及对于pcDNA3.3，遗传霉素)。通过使用所述FreeStyle MAX反应剂(Invitrogen)在悬浮培养中将所述两种构建体的共转染至所述二氢叶酸还原酶(DHFR)缺陷型的衍生自多个DG44细胞的中国仓鼠卵巢(CHO)来促进表达。在共转染后，细胞培养在选择性培养基中。与具有酪氨酸酶369-377胜肽的对多个JY T2细胞特异性反应的克隆被调整至在0.5％的血清中生长，并且使用蛋白A亲和层析被进一步地纯化。所述纯化的蛋白的SDS-PAGE分析显示出均质的、纯的IgG具有预期的分子量为～150千道尔顿。
具有上清液或纯化的多个Ab的ELISA
通过使用多个生物素化的scMHC胜肽复合物的ELISA测定各个上清液或多个纯化的TCRL抗体的所述结合特异性。将Maxi sorp 96孔洞的ELISA盘子(Nunc#442404)被涂上牛血清白蛋白-生物素(1微克/孔洞)过夜。在被清洗后，将所述多个盘子用链霉亲和素(1微克/孔洞)放置(1小时，室温)，大量地清洗，并且再用0.25微克的MHC/胜肽配合物放置(1小时，室温)。将所述多个盘子在室温下用PBS/2％脱脂牛奶被封闭30分钟，随后在室温下用1毫克/孔洞的上清液或纯化的多个TCRL抗体放置1小时。在清洗后，所述多个盘子放置有用HRP-偶联/抗人类或小鼠Ab。采用TMB四甲基联苯胺试剂(DAKO，S1599)进行侦测，所述多个HLA-A2-限定胜肽用于所述纯化的上清液或纯化的多个TCRL抗体的多个特异性测试。
Proteon XPR36表面等离子体共振(SPR)的结合分析
IgG类TCR抗体的固定化在25℃呈垂直方向的一通用层介质(GLM)芯片(Bio-Rad实验室，赫拉克勒斯，加利福尼亚州，美国)上进行，所述连续的运行缓冲液为PBST(10毫摩尔浓度的磷酸钠，150毫摩尔浓度的氯化钠，0.005％Tween 20，pH7.4)。用50微升的0.04摩尔浓度的N-乙基-N’-(3-二甲氨基丙基)碳二亚胺(EDC)和0.01摩尔浓度的N-羟基硫代琥珀酰亚胺(磺基-nhs)的一混合物在30微升/分钟的一流速下活化五个通道，将所述抗小鼠或人类IgG/NeutrAvidin稀释在10毫摩尔浓度的乙酸钠缓冲液pH4.5直到一最终浓度25微克/毫升，以及在150微升被注射后紧接着150微升的1摩尔浓度的乙醇胺盐酸盐pH8.5的一注射。所述IgG TCRL抗体/纯化的单链重组HLA-A2/酪氨酸酶/WT1/MAGE-A4/MAGE-A9/PAP复合体配体在PBST中稀释至5-10微克/毫升，以及90微升以30微升/分钟的一流速下以垂直方向注射。所述第六通道维持空着以作为一参考。所述分析物纯化的单链重组HLA-A2/酪氨酸酶/WT1/MAGE-A4/MAGE-A9/PAP复合物/Fab TCRL抗体被(75微升于50微升/分钟)使用五个不同的浓度(1000、500、250、125以及625纳摩尔浓度)于所述ProteOn的所述水平方向注入，在所述第六通道中同时注入运行的缓冲液，用于双重参考以校正所述实验期间所述多个捕获的抗体从所述芯片传感器表面的损失。所有的结合传感图是使用整合的ProteOn管理器(Bio-Rad实验室，赫拉克勒斯，美国)软件中收集，处理及分析。多条结合曲线是使用所述朗缪尔模型描述1∶1结合化学计量来拟合，或使用所述朗缪尔和质量转移限制模型。
多个功能性分析
LDH-释放测试
在一非放射性细胞毒性测试使用
(Promega)测定双特异性TCRL复位向标靶细胞杀伤，所述测试定量地测量乳酸脱氢酶(LDH)，一种在细胞溶解后释放的酶。以一种10分钟偶联酶法测量多个培养上清液中释放的LDH，导致一四唑鎓盐(INT)的所述转化变成一红甲类产物。所述产生的颜色数量与多个裂解的细胞的所述数量成比例。
具体地，多个标靶细胞和多个效应细胞被清洗，计数以及重新悬浮在无酚红的cRPMI培养基(1％FBS)中。将多个标靶细胞被调整至一细胞密度每毫升2.5X105个细胞，并且所述多个反应细胞至一细胞密度每毫升2.5X106个细胞。40微升(1×104细胞)的多个标靶细胞被培养在一96孔V型盘子中。以最高测试浓度制备所述双特异性TCRL测试试剂的一个五倍浓缩液，所述浓缩液在不含酚红的培养基中连续稀释十分之一以得到其它测试的浓度。然后将所述双特异性TCRL以每孔洞20微升加到所述测试盘子中的所述多个标靶细胞中以给予多个最终指示的滴定量。然后将含有所述多个标靶细胞的所述测试的盘子与所述双特异性TCRL混合于37℃/5％CO2下培养20分钟，在培养后，40微升的多个效应细胞(1X105细胞)被加到每个洞孔中，产生一效应物以10：1(E：T)的比率，多个对照组孔洞被单独地设置多个效应细胞以计算标靶自发释放，以及多个标靶细胞与最终的80微克/毫升的洋地黄以计算出最大的释放。每个条件以三重复在一最终体积100微升进行测定。将所述盘子在37℃/5％CO2下培养24小时。在培养期后，所述盘子在700x g下离心5分钟，并且从每一个孔洞中转移50微升至一96孔洞平底Maxisorb盘子(Nunc)中的所述对应的孔洞中，按照制造商的多个说明，使用
测试缓冲液重新构成所述
基质混合物，以及将50微升加入到所述盘子的每个孔洞中。所述盘子被铝箔覆盖，并且在室温放置10分钟。然后在一盘子读取器中记录在490纳米的所述吸亮度。然后使用以下公式计算细胞毒性百分比：特异性裂解＝[(实验-自发效应体-标靶效应物)/(目标最大值-目标自发值)]x 100。用于杀灭试验的多个PBMC是从多个健康志愿者分离，并且具有所有监管的IRB的多个批准及多个书面同意。使用所述Lymphoprep技术分离多个效应PBMC。
多个肿瘤细胞株和多个正常的原代细胞
多个细胞株A375(黑色素瘤)、U2OS(骨肉瘤)、TCCSUP(膀胱癌)和Fib(纤维母细胞)在补充有10％FBS的完整DMEM中培养(全部由GIBCO提供)。501A、SKMel5、Mewo和1938(黑色素瘤)、Saos2(骨肉瘤)、Panc1(胰腺癌)、J82和UMUC3(膀胱)、H1703(非小细胞肺腺癌)、JVM2(覆盖细胞淋巴瘤)、IM9(多发性骨髓瘤)、U266(骨髓瘤)以及SW620(结直肠癌)培养在补充有10％FBS的完整RPMI中(全部由GIBCO提供)。Malme3m(黑色素瘤)、JEKO1(套细胞淋巴瘤)、SET2(必需的血小板抑制剂)以及BV173(B细胞前体白血病)培养在补充有20％FBS的完整RPMI中(全部由GIBCO提供)，thp-1(AML)培养在补充有10％FBS的完整RPMI中(全部由GIBCO提供)和0.05毫摩尔浓度的beta-巯基乙醇(由Thermo-fisher提供)。OVCAR-3(卵巢腺癌)培养在补充有20％FBS的完整RPMI中和0.01毫克/毫升的牛胰岛素(由Sigma提供)。所有细胞株保持在37℃在7.5％CO2的一湿润的空气中以及购自美国模式培养物保藏所。
多个正常的原代肝细胞，多个心脏肌细胞，多个成骨细胞，多个星形细胞，多个支气管上皮细胞，多个结肠平滑肌细胞，多个中皮细胞和多个肾上皮细胞是从Sciencell取得，并且根据所述制造商的多个说明进行培养。所有细胞株保持在37℃在7.5％CO2的一湿润的空气中。
在Expi293系统中的多个可溶性重组Fab Ab的表达和纯化
TyrD11和D7的所述VH-CH1和VL-CL基因、MAGE-A4 C106B9、WT1B47B6和ESK1 IgGs被克隆在所述真核表达载体pcDNA3.4中用于表达为Fab，His-tag被连接到CH1区域的所述C-末端。
通过所述Fectamine转染试剂(Life technologies)将所述两种构建体(重链和轻链)共转染在Expi293表达培养液中的所述多个Expi293F人类细胞(二者都是所述Expi293表达系统的多个组成)中来促进表达。在共转染后，多个细胞被培养6天。在6天后，多个细胞在700x g下离心5分钟。离心后，所述含有D11、D7、C106B9、B47B6或ESK1 Fab的所述上清液从多个细胞中移除并且通过0.22μ过滤器。然后将所述上清液用PBS透析过夜。
通过金属亲和管柱(Talon)纯化所述D11、D7、C106B9、B47B6或ESK1Fab重组蛋白，并且用PBS透析过夜。所述纯化的D11、D7、C106B9、B47B6或ESK1Fab在还原和非还原的SDS-PAGE上分析。
在Expi 293系统中的多个双特异性TCRL的构建，表达和纯化
TyrD11和D7的所述VH-CH1和VL-CL基因，WT1 B47B6和ESK1和MAGE-A4 C106B9，IgGs被克隆所述真核表达载体pcDNA3.4中以用于作为双特异性(BS)于(多个序列如图68-70中所示，ESK1的多个序列可从WO 2015/0761取得)。对于Tyr D11，WT1 B47B6和ESK1和MAGE-A4 C106B9的所述轻链载体，抗CD3(克隆UCHT1)scFv被连接到所述VL区的所述N-末端(BS格式3，#F3)。对于所述重链载体，His-tag被连接到所述CH1区域的所述C末端。对于TyrD7，抗CD3(克隆UCHT1)scFv被连接到重链的所述VH区的所述N-末端(BS格式1，#1)以及His-tag被连接到所述CH1区域的所述C-端。
通过所述Fectamine转染试剂(Life technologies)将所述两种构建体共转染在Expi293表达培养液中的所述多个Expi293F人类细胞(二者都是所述Expi293表达系统的多个组成)中来促进表达。在共转染后，多个细胞被培养6天。在6天后，多个细胞在700x g下离心5分钟。离心后，所述含有所述多个TCRL双特异性抗体的所述上清液从多个细胞中移除并且通过0.22微米的过滤器。然后将所述上清液用PBS透析过夜。
所述多个BS-TCRL的多个重组蛋白是通过金属亲和性(Talon)和尺寸排阻色谱法(Superdex 200 10/300GL GE)的两个步骤纯化。所述多个纯化的BS-TCRL在SDS-PAGE上分析。
多个体内测试
对于501A黑色素瘤细胞株(ATCC，马纳萨斯弗吉尼亚州，美国)
多个细胞被培养在补充有10％胎牛血清(GIBCO，沃尔瑟姆马萨诸塞州，美国)的RPMI 1640生长培养基(GIBCO，沃尔瑟姆马萨诸塞州，美国)中。
人类外周血单个核细胞(PBMC)是使用多个SepMateTM-50管子(Stemcell)从多个健康捐赠者中制备的。
在第0天，多个8-10周岁的雌性NOD/SCID小鼠(Envigo，以色列；n＝6-8)在一单侧被皮下注射(s.c.)5x106个的501A黑色素瘤细胞，+/-25x106个PBMC(效应体：肿瘤细胞的比率5：1)在最终体积0.25毫升的磷酸缓冲溶液(PBS)中；D7双特异性TCRL(0.1毫克/千克)或载体(PBS)以一最终体积为0.2ml在s.c.注射后1小时静脉注射(i.v)给药，包含四个额外的剂量，每24小时给药。
对于A375黑色素瘤细胞株(ATCC，马纳萨斯弗吉尼亚州，美国)
多个细胞被培养在补充有10％胎牛血清(GIBCO，沃尔瑟姆马萨诸塞州，美国)的RPMI 1640生长培养基(GIBCO，沃尔瑟姆马萨诸塞州，美国)中。
使用一快速膨胀指南(REP)从人类外周血单个核细胞(PBMC)制备多个活化的CD8T细胞，使用SepMateTM-50管子(Stemcell)从健康的捐赠者的外周血液中制造多个非活化
的PBMC，接着使用
UntouchedTM人类CD8 T细胞套组(Invitrogen)使CD8T细胞富集，所述多个纯化的CD8 T细胞的活化在预涂有对抗CD3(OKT3)和CD28的多个单克隆抗体的锥形瓶中进行，在补充有10％FBS和100IU/毫升的人类IL-2的培养基中72小时，活化的多个细胞会在补充有10％FBS，3000IU/毫升的IL-2，30毫克/毫升的OKT3以及2x108的受辐射的PBMC。
在第0天，8-10周岁的雌性NOD/SCID小鼠(Envigo，以色列；n＝6-8)在一单侧被皮下注射(s.c.)5x106个的A375黑色素瘤细胞，+/-10x106个REP CD8 T细胞(效应：肿瘤细胞的比率2：1)在最终体积0.25毫升的磷酸缓冲溶液(PBS)；MAGE-A4 C106B9双特异性TCRL(0.1毫克/千克)、WT1 B47B6双特异性TCRL(0.1毫克/千克)或载体(PBS)以一最终体积为0.2ml在s.c.注射后1小时静脉注射(i.v)给药，包含四个额外的剂量，每24小时给药。
在所述两种情况(501A和A375)中以多个游标卡尺在两种垂直尺寸上对多个肿瘤每星期测量两次，以下公式计算出肿瘤体积：
x 3.14
本研究中使用的其它TCRL抗体
在WO 2008/120202中描述了MC1的生成。
ESK1的所述生产(Dao T、Yan S、Veomett N、Pankov D、Zhou L、Korontsvit T、Scott A、Whitten J、Maslak P、Casey E、Tan T、Liu H、Zakhaleva V、Curcio M、Doubrovina E、O'Reilly RJ、Liu C、Scheinberg DA，《用治疗性人抗体靶向细胞内WT1癌基因产物》，《科学转化医学》，2013年3月13日；5(176)：176ra33)。因此ESK1是根据所述公开的序列WO 2015/07761﹐ESK1全长的VH-SEQ ID NO：128和ESK1全长的VL-SEQ ID NO：130在WO2015/070061的序列列表通过合成基因合成产所生的，所述抗体作为IgG使用上面所述Expi293系统在多个HEK293细胞中生产，并且通过使用蛋白A管柱作亲和层析从多个培养上清液纯化。
多个核酸的提取
根据所述制造商的多个说明以RNeasy Plus Mini(Qiagen)从1*106至5*106个细胞培养的细胞中萃取总RNA。
cDNA合成
根据所述制造商的多个说明以
III第一链合成系统(Invitrogen)利用寡dT以及随机六聚体(1∶1)的结合，从1-5微克的RNA合成cDNA。F或定量PCR，以H2O将cDNA稀释成1：5。
常规PCR(PCR)
所述多个PCR循环条件为在95℃中2分钟，接着40个循环的在95℃中20秒、在60℃中1分钟，以及在72℃中1分钟。所述PCR结束在一最终的延长在72℃中10分钟。根据制造商的多个说明，用KAPA HiFi PCR套组(Kapa Biosystems)进行多个反应。
以下多个引子被使用：
TYR_S：TTAGCAAAGCATACCATCA(SEQ ID NO:3)和TYR_AS:CCAGACAAAGAGGTCATAA(SEQ ID NO:4)
对于酪氨酸酶表达(预期产物大小：117个碱基对)和WT1_s：AGGCTGCAATAAGAGATA(SEQ ID NO:5)和WT1_AS：TTCGCTGACAAGTTTTAC(SEQ ID NO:6)用于WT1表达(预期的产物大小：188个碱基对)。
为了可视化所述多个扩增产物，将10微升的样品与2微升的6x加载缓冲液(NewEngland Biolabs)混合，并且在1.5％琼脂糖凝胶中进行电泳，以溴化乙锭对多个DNA标记物(New England Biolabs)染色。在ImageQuant LAS 4000(GE Healthcare LifeSciences)上测定所述多个PCR产物带的存在和强度。
定量PCR(qPCR)
根据所述制造商的多个说明，采用TaqMan基因表达主要混合物在一ABI 7300仪器(Applied Biosystems)上进行定量PCR。即时PCR的所述多个周期条件为在95℃中10分钟，接着40个循环的在95℃中15秒，以及在60℃中1分钟。用于即时PCR的多个探针是从AppliedBiosystems上购买；在5’末端，将它们偶联至所述氟铬FAM。使用以下多个测试(多个引物和多个探针)：对于TYR(cat#Hs00165976)、对于MAGE A4(cat#Hs00751150)，对于WT1(cat#Hs01103751)。Beta-肌动蛋白被作为一看家基因用于标准化(cat#Hs99999903)。
本研究中使用的多个胜肽
*丙氨酸为基础的相似的多个胜肽
*丙氨酸为基础的相似的多个胜肽
*丙氨酸为基础的相似的多个胜肽
实施例1：
对于HLA-A2/酪氨酸酶的多个类TCR抗体
对HLA-A2/酪氨酸369-377具有类TCR特异性的多个Abs＝的分离
MHC-TyrD369-377复合物的生产-本发明人进行的之前的研究显示使用多个大型抗体噬菌体库来产生对肿瘤及多个病毒T细胞表位具有胜肽特异性，HLA-A2限定的特异性的多个重组抗体。所述多个分子被称为多个类TCR抗体。为了生产对所述HLA-A2/TyrD369-377复合物具有一特异性的多个抗体，使用一单链MHC构建体生产表现有所述酪氨酸酶胜肽(Tyrosinase369–377YMDGTMSQV，SEQ ID NO：1)的重组胜肽-HLA-A2复合物。通过5-6次HLA-A2-胜肽复合物50微克/小鼠的注射使多个HHD小鼠被免疫化。前2-3次的注射加入QuilA佐剂被皮下给药。通过从多个被免疫化的小鼠中分离的多个脾细胞与多个NSO骨髓瘤细胞的融合产生多个杂交瘤克隆(如前面所述的Weidanz等人2011，《国际免疫学评论》30：328-340)，以及通过如下所述的多个差异性ELISA试验进行筛选和分离。具有多个纯化的HLA-A2-Tyr复合物以及显示其它HLA-A2-限定胜肽(表15)的对照组HLA-A2复合物的ELISA被用于筛选多个特异性克隆，多个分离的杂交瘤克隆被亚克隆以及被定序。两个克隆906-11-D11(称为D11，图68)和905-2-D7(称为D7，图69)被描述。
对于HLA-A2/酪氨酸酶369-377具有特异性的多个类TCR抗体的特性
为了测定所述多个分离的类TCR抗体的所述表面亲和性，使用了表面等离子体共振(SPR)结合分析，通过抗小鼠或人类的IgG把所述多个分离的纯化的IgG类TCR抗体间接地固定在所述表面等离子共振(SPR)的传感芯片上。所述分析物是在各种浓度下的所述纯化的单链重组HLA-A2/酪氨酸酶复合物。如图1所示，SPR分析的所述多个传感图显示出针对所述HLA-A2/酪氨酸酶特异性的多个类TCR抗体克隆MC1、D11和D7的相似的亲和性，带有对应MC1和D11为4.1纳摩尔浓度，D7为3.8纳摩尔浓度。所述多个结果表明，全部三个类TCR抗体克隆对所述特异性HLA-A2/胜肽复合物都表现出相似的高亲和性的4纳摩尔浓度。
为了研究所述多个分离的类TCR抗体对所述酪氨酸酶369-377胜肽的所述优良胜肽表位特异性，进行了丙氨酸扫瞄，在所述丙氨酸扫瞄中，所述胜肽中的多个特定的残基被突变为丙氨酸，并且通过将所述多个突变的胜肽加在多个T2抗原呈现细胞上以测试所述多个TCR-样抗体与多个Ala突变胜肽的所述结合。通过流式细胞技术监测结合，当通过平均荧光强度(MFI)所测定的，多个TCR-样抗体与所述多个突变胜肽的结合的程度被用来与加有所述未突变酪氨酸酶胜肽的多个T2 APC比较。所述各种Ala突变胜肽(描述在图2)的所述适当的加入是通过流式细胞技术使用BB7.2来监测，所述BB7.2是针对HLA-A2的一单克隆抗体。
与所述天然未突变的酪氨酸酶胜肽相比，所有Ala突变胜肽被有效地加到多个T2细胞上(数据未示出)。通过利用HLA-A2-结合抗体BB7.2的MFI与未加载的多个T2细胞(>1)的MFI之间的比率来验证胜肽加载效率。如图2所示，全部三个类TCR抗体都表现出胜肽依赖性结合，因为多个特定的突变影响了所述结合，并且在多个特定胜肽位置引入Ala时，在所述类TCR抗体的结合强度中引发了一减少。所述多个结果表明，在HLA-A2加入各种Ala突变酪氨酸酶胜肽的情况下，全部三个类TCR抗体都表现出胜肽特异性及限制性的结合，表明所述多个抗体在所述多个抗体的结合性质上是相似于TCR，因此，所述多个抗体以MHC限定以及胜肽特异性的方式来结合所述MHC-胜肽复合物。
然而，所述三个类TCR抗体在所述三个类TCR抗体的优良特异性和胜肽依赖性反应的不同是在于所述胜肽中对Ala突变敏感和受影响的结合灵敏度的位置的数量。当MC1与一单一Ala突变胜肽结合在一个位置#6时显示出90％的一显着下降，D11和D7都表现出对于D11在两个位置#3、6的一大于90％的下降，对于D11在四个位置#3、4、6、7的结合的一大于90％的减少。MC1与多个Ala突变胜肽的结合时进一步观察到在三个位置#1、3、6的一较温和但显着的一大于70％的下降4，6，7，尽管D11和D7在五胜肽残基被突变成Ala(对于D11，位置#1，2，3，4，6，以及对于D7，位置#2，3，4，6，7)时表现出一大于70％的结合的显着减少。
总体而言，通过观察所述各种Ala突变的Tyr胜肽正确地结合Tyr特异性的类TCR抗体的能力，所述丙氨酸扫描分析揭示了D11和D7相较于MC1对多个Ala突变更受影响及敏感。根据图2中所示的所述数据，D11和D7相较于MC1在所述D11和D7的结合性质上具有更高的胜肽限制及敏感度；它们对于九个胜肽残基中的四个的Ala突变敏感(不包含多个锚定位置)，尽管MC1只有对3个位置。D11和D7在它们的结合特性上分别对第五位置七和五敏感。具体地，D11在位置#7减少了68％的所述结合，67％位置#5，59％位置#8；D7在位置#5减少了66％的所述结合，63％位置#1，63％位置#8。
结论，Ala扫描可以被用作测定多个类TCR抗体的所述选择性和优良特异性的一手段，若表现出对Ala突变表现出越高的敏感性，可以观察到越高特异性和胜肽依赖性的结合。所述策略可用于过滤和筛选表现出更高和优化的选择性和特异性性质的所述理想的类TCR抗体如多个MHC-限定胜肽特异性结合物。
对于HLA-A2/酪氨酸酶的多个类TCR抗体的结合选择性和特异性
为了定性出所述多个分离的类TCR抗体的所述结合特异性，通过流式细胞技术取得所述多个纯化的IgG的所述反应性和特异性。将多个特异性或对照组胜肽加入多个T2APC中，并且与所述Ab培养，接着与PE标记的抗人类或小鼠Ab一起培养。如图3-7所示，所述MC1(图7)、D11和D7(图3至6)的多个IgG接合在加有所述酪氨酸酶胜肽的T2细胞上，但不能显着地结合在加有多个对照组胜肽的多个细胞上(表15)。对于MC1，在多个对照组胜肽上观察到非常低的背景的结合具有MCI的比率3-7(图7)，而D11和D7没有表现出任何背景结合(图3至6)。通过MAb BB7.2的结合来监测加载的胜肽呈现的程度，所述MAb BB7.2与所有的HLA-A2胜肽复合物结合。所述多个结果表明，全部三个类TCR抗体都表现出HLA-A2-限定的胜肽特异性的结合，因为它们仅与表现所述酪氨酸酸的多个细胞上，但不与其它HLA-A2限定胜肽结合。
为了探索所述多个HLA-A2/酪氨酸酶类TCR Ab是否能够结合在多个肿瘤细胞的所述表面上的多个内源性衍生的MHC-酪氨酸盐复合物，在来源于多个黑色素瘤患者的多株上进行流式细胞技术分析。将多个细胞与多个抗酪氨酸酶369-377/HLA-A2类TCR抗体一起培养，然后与PE标记的抗人类或抗小鼠Ab一起培养。如图8至12所示，所述多个类TCR抗体辨识出具有一非常高强度的多个酪氨酸酶-阳性和HLA-A2-阳性细胞。如此所示，表示出所述大量的HLA-A2-酪氨酸酶复合物表现在所述多个黑色素瘤细胞的所述表面。所述类TCR抗体的所述染色是非常均匀的；以针对所述酪氨酸蛋白的Ab对所述多个黑色素瘤细胞(例如624.38，及501A)的细胞内染色揭示出，在所测试每一株中的95％的所述多个细胞都表达所述酪氨酸酶蛋白(数据未示出)。在酪氨酸酶-阴性或HLA-A2-阴性细胞中没有被检测到反应性。通过各种组织来源的多种细胞株的广泛的流式细胞分析技术分析，所述多种细胞株为HLA-A2阳性，Ag(酪氨酸酶)阴性的，验证了抗酪氨酸酶/HLA-A2类TCR Abs的特异性。所述分析如图10-12所示，D11和D7的反应性也在一组正常的原代细胞包括多个内皮细胞、纤维细胞、星形细胞、肝细胞、肾细胞、心脏肌细胞、结肠肌肉和PBMC(图13-17)中被测试。没有与所述多个HLA-A2+和Tyr-的正常原代细胞的结合被观察到，而当在PBMC上测试MC1时观察到背景的结合(图17)。D11和D7对HLA-A2+/酪氨酸酶+的多个黑色素瘤细胞以及广泛的组的各种组织来源的HLA-A2+/酪氨酸酶-的细胞包括所述多个正常原代细胞的反应性的所述分析如图18-19所示。D11和D7类TCR抗体的反应性对于表达HLA-A2和所述抗原酪氨酸酶的多个黑色素瘤细胞来说是极为特异性。
所述多个研究的所述总体结论是，所述多个类TCR Ab是特异性的，并且在当HLA等位基因与Ag的所述充分结合存在时，它们仅辨识在细胞表面上表现的所述特定胜肽-MHC复合物。然而，流式细胞技术的数据的仔细评估表示出多个结果展示出与D11和D7相比时的MC1的差异选择性。例如，对MC1与多个HLA-A2+和Tyr-细胞株HepG2，SW620以及Loucy的结合的分析，如图9所示，揭示了由MFI测得的背景的结合，然而，在所述多个细胞上的D11和D7的相似的分析揭示出没有结合(图10和12)。通过并排比较所述三个类TCR抗体在这些和另外的细胞(图12)揭示了MC1表现出与HLA-A2+/tyr+的多个黑色素瘤细胞的显着结合，但在一各式各样的HLA-A2+/Tyr-的多个细胞(SW620、Colo205、HepG2、Panc1、RPMI、DG75、Jeko1和Loucy)上具有背景的结合，而D11和D7对所述多个细胞没有表现出的任何背景的结合。
因此，可以总结出D11和D7相较于MC1更具特异性和选择性，并且综合流式细胞技术研究以及其它分析，例如，利用一大组的不同组织来源的细胞的功能分析是多个有用工具，用于评估多个类TCR抗体的所述选择性，所述细胞表达所述合适的HLA等位基因以及是抗原呈阳性或阴性。
为了进一步评估所述酪氨酸酶特异性的多个类TCR抗体的所述优良特异性，它们对于表现出所述天然酪氨酸酶的序列相似度的多个胜肽的反应性被评估(表5)。
因此，当针对一特定的类TCR抗体的丙氨酸/甘氨酸扫描数据是可使用的如上所述时，进行另一轮的相似的多个胜肽的筛选。基于丙氨酸扫描，测量和评估所述胜肽抗原中的每一个氨基酸残基对于TCRL的结合的所述贡献。通过上述多个工具辨识保持所述多个关键位置的多个相似的胜肽，并且被赋予更高的优先级。所述多个胜肽被合成并且被用于如上所述的优良特异性的评估。
本文所述的策略结合了结合被洗脱的多个HLA胜肽的质谱分析的胜肽序列相似性的计算机模拟分析、多个胜肽数据库以及丙氨酸扫描提供了一工具盒以充分地控制多个胜肽搜索参数，多于其它工具，例如BLAST或ScanProsite所提供的。多个附加参数被采用，包括允许多个胜肽长度的范围、序列的最大允许数量或差异、HLA结合分数的所述要求。所述工具也适用于将某些氨基酸定义为等同的能力。最重要的是突显已经通过质谱分析或从数据库数据或文献发现的多个胜肽的能力。
应用上述工具，合成三种类TCR抗体的优良特异性根据本文所述的标准选择用于评估的相似胜肽的大板(表5)。所述多个相似的胜肽已被加到多个T2 APC上，并且所述多个类TCR抗体的反应性被测试。如图20所示，当在一组的相似的胜肽上测试MC1时，相较于对于天然酪氨酸酶胜肽的结合，观察到所述MC1表示出对酪氨酸酶具有序列相似度的多个胜肽例如KIAA0335和KPNA1的背景结合。然而，如图21至28所示，所述多个类TCR抗体D11和D7不结合任何从一大组的所述被分析的胜肽的相似的胜肽，包含与MC1表示出背景结合的所述KIAA0335和KPNA1胜肽的不辨识。所述多个数据证明了与MC1相比，D11和D7的所述更优异的选择性和优良特异性，并且证明了所述相似胜肽方法的所述用处以及如上所述所开发的多个工具作为多个重要的工具，当为了最佳及最理想的候选物评估一组的类TCR抗体以用于进一步评估时﹐评估出所述选择性和优良特异性分级。
此外，在多个类TCR抗体的丙氨酸扫描后，多个额外的相似的胜肽已经被筛选和测试了。由于所述TyrD胜肽序列中的每一种氨基酸不可能相等地贡献对Tyr TCRL的结合，对于Tyr TCRL结合是关键的所述胜肽残基被辨别出来。一组合的多个合成胜肽被生产，其中所述TyrD九聚体中的每一个氨基酸依次地被丙氨酸取代。通过FACS分析测定Tyr TCRL与带有所述多个丙氨酸取代的多个胜肽中的一者的细胞结合的能力，并将所述多个结合结果与所述非突变胜肽获得的结合结果进行比较。与所述非突变胜肽相比，在丙氨酸取代导致在结合上的一巨大的下降的位置处的所述残基被认为是关键的。然后进行一定向的计算机模拟，以辨识仅包含所述多个关键位置基序的蛋白序列。所述多个胜肽也用于多个Tyr TCRL的特异性评估(表5S17至S23)。所述衍生自多个丙氨酸扫描分析的多个相似的胜肽被合成并加到多个T2 APC细胞上，并且测试D11和D7的所述反应性。如图28所示，没有观察到所述多个胜肽的结合，从而进一步证实和增强所述多个类TCR抗体的所述优良特异性和选择性。
实施例1A
用于HLA-A2/酪氨酸酶的多个类TCR抗体的定性
对HLA-A2/酪氨酸酶369-377具有类TCR特异性的多个Ab的所述优良特异性的比较
为了定性出所述多个分离的类TCR抗体的所述结合特异性，通过流式细胞仪评估所述多个纯化的IgG的反应性和特异性(具有或不含生物素化)。在酪氨酸酶胜肽加入多个T2 APC或多个对照组胜肽(表15)，并且与所述Ab(D7，D11或MC1)一起培养，接着与PE标记的链霉亲和素或PE标记的多个抗小鼠Ab一起培养。如图38所示，多个D11和D7 TCRL结合加有所述酪氨酸酶胜肽的T2细胞，但没有显示与加入对照组胜肽的多个细胞的结合。相反，MC1TCRL显示与加有酪氨酸酶胜肽和作为对照组的所述不相关胜肽的多个T2细胞的结合。
为了进一步评估所述多个D7和D11类TCR抗体的所述特异性，评估它们与对于所述酪氨酸酶胜肽显示序列相似度的多个胜肽的反应性。所述胜肽如表5所示。
如图39中所示，TCRL对于与酪氨酸酶胜肽(例如KIAA0335和KPNA1(表14)以及标记为S2、S4、S5、S9、S11、S13、S18、(S19、S22和S23)具有序列相似性的各种胜肽具有容易检测的结合。多个D11和D7类TCR抗体不结合任何来自于所述相同组的多个相似胜肽的所述多个胜肽。所述多个数据证实了与MC1 TCRL相比，D11和D7 TCRL的所述更优良的选择性和优良特异性，并且证明了所述相似胜肽方法以及如上所述所开发的多个工具的所述用处以评估多个类TCR抗体的所述选择性和优良特异性分级。
本发明人研究了HLA-A2/酪氨酸酶的多个类TCR Ab对于内源性地显示在多个黑色素瘤细胞株的所述表面上的多个MHC-酪氨酸酶胜肽复合物的结合特异性。多个细胞与抗酪氨酸酶369-377/HLA-A2的多个类TCR抗体Ab(具有或不具有生物素化)一起培养，接着与PE标记的链霉亲和素或多个抗小鼠Ab培养。一组的肿瘤细胞及多个正常初级细胞已被定性为HLA-A2(阳性)及酪氨酸酶(阳性或阴性)的表达，被用来比较所述多个类TCR抗体的所述结合。如图40A至C所示，所述多个类TCR抗体辨识多个酪氨酸酶-阳性及HLA-A2-阳性细胞。所述多个类TCR抗体被测试在各种来源的多个HLA-A2-阳性细胞株上，所述细胞株不显示TyrRNA表达(Tyr-阴性)。如图40A至B所示，多个D11和D7 TCRL不结合所述多个细胞中的任何一种，而MC1则容易染上各种HLA-A2+/Tyr-细胞。D7和D11 TCRL不表现任何与正常的原代细胞的结合，而MC1显示出与它们中的一些的可侦测的结合(图40C)。
总体来说，与MC1 TCRL相比，多个D7和D11 TCRL证明了对于辨识由HLA-A2表现的酪氨酸酶胜肽的更优异的特异性及选择性。
多个功能性分析被用来进一步定性所述多个D7和D11类TCR抗体。将多个TCRL的多个可变区融合到一个抗CD3 scFv，所述抗CD3 scFv可以以一双特异性的形式重新靶向多个效应T细胞以杀死肿瘤标靶细胞。如图41至44所示，D7和D11 CD3双特异性类TCR抗体的多个构建体在多个人类PBMC的存在下，在体外显示了对多个黑色素瘤501A细胞的强大的细胞毒性。Panc-1，酪氨酸酶阴性细胞株作为阴性对照组，并且表现出没有细胞毒性。用多个D7和D11 TCRL针对一组的多个HLA-A2+/Tyr-正常人类原代细胞没有细胞毒性被侦测到证实了它们的选择性。
实施例1B
在多个NOD/SCID小鼠中，D7 BS TCRL在s.c.501A黑色素瘤肿瘤形成模型中的体内功效
图45显示了在多个NOD/SCID小鼠中D7 BS TCRL在s.c.501A黑色素瘤肿瘤形成模型中的体内功效。显然，所述双特异性抗体的给药完全抑制了肿瘤形成超过65天的所述实验，如通过肿瘤体积所证实。所述结果支持在本文所述的多个临床设置中TCRL的可变序列的使用。
实施例2
用于HLA-A2/WT1的多个类TCR抗体
对HLA-A2/WT1具有类TCR特异性的多个Ab的分离和定性
为了产生对所述HLA-A2/WT1复合物具有一特异性的所述多个抗体，多个重组胜肽-HLA-A2复合物被生产，所述多个重组胜肽-HLA-A2复合物使用一单链MHC构建体表现所述WT1胜肽(RMFPNAPYL，SEQ ID NO：151)。多个抗体的生产如在所述一般材料和方法以及上述实施例1中所述，一类TCR特异性克隆称为B47(也称为B47B6)被分离以及定性(图70)。
作为类TCR抗体结合选择性的一比较，一类TCR抗体称为ESK1，Dao T、Yan S、Veomett N、Pankov D、Zhou L、Korontsvit T、Scott A、Whitten J、Maslak P、Casey E、TanT、Liu H、Zakhaleva V、Curcio M、Doubrovina E、O'Reilly RJ、Liu C、Scheinberg DA。
通过表面等离子体共振(SPR)结合分析评估B47的所述结合亲和性，通过抗小鼠的IgG把所述分离的纯化的IgG类TCR抗体间接地固定在所述SPR的传感芯片。所述分析物是以各种浓度使用的所述纯化的单链重组HLA-A2/WT1复合物。如图29所示，SPR分析的所述多个传感图显示了对于所述HLA-A2/WT1特异性类TCR抗体克隆B47的一亲和性为4.4纳摩尔浓度。
为了定性所述多个分离的类TCR抗体的所述结合特异性，通过流式细胞技术评估所述多个纯化的IgG的所述反应性和特异性。将多个T2 APC加到特定的或多个对照组胜肽中(表15)并且与Ab一起培养，接着与PE标记的抗人类或小鼠Ab一起培养。如图30和31所示，B47和ESK1结合于加有所述WT1胜肽的多个T2细胞(Figure30)但不与加有多个对照组胜肽的多个细胞结合(图31)。显着性差异是B47和ESK1所观察到的所述结合强度。尽管B47强烈地结合于加有10-4至10-5摩尔浓度的胜肽的多个T2细胞，ESK1较弱地结合于加有10-4摩尔浓度的WT1胜肽的多个T2细胞(对于ESK1的MFI 18与B47的474相比)在胜肽浓度10-5摩尔浓度的B47仍然显着地结合(MFI 88)，而ESK1的结合几乎是无法检测的或非常低的(图30)。所述多个结果表明，B47的所述亲和性和结合灵敏度具有多个显着的差异，与ESK1相比，ESK1结合强度急剧下降相较于B47在胜肽浓度具有10倍下降。B47和ESK1不结合加有多个对照组HLA-A2限定胜肽的多个T2 APC(图31)。所述多个结果表明，两个类TCR抗体都表现出HLA-A2-限定胜肽的特异性结合，因为它们仅与表现所述WT1的多个细胞结合，而非其它HLA-A2限定胜肽。
为了进一步研究所述多个WT1类TCR抗体优良特异性，以上面描述的所述策略对于与计算机模拟的多个相似的胜肽的结合进行了评估。如图32和33所示，B47没有结合在一设计的小组中任何相似的胜肽(表6)。然而，如图32所示，ESK1表现出与两个相似胜肽的低背景结合。在额外的多个对照组胜肽和多个相似胜肽上评估B47(图34)。通过流式细胞技术进行所述多个类TCR抗体的进一步分析，使用是HLA-A2的并且表达或不表达所述WT1抗原的肿瘤细胞。如图35所示，所述ESK1 WT1类TCR样抗体强烈地结合HLA-A2+/WT+BV173和SET2细胞，但是B47没有表现出对于所述多个细胞的任何结合至所述流式细胞技术灵敏度的水平。为了进一步研究特异性，在如通过PCR评估的HLA-A2但不表达所述WT1基因的细胞上评估ESK1和B47的所述反应性。如此所示，B47不与所述多个细胞中的任何细胞结合，而ESK1结合至被发现是WT1阴性的501、A498以及SKMEL细胞。其它WT1阴性细胞没有被ESK1结合。HLA-A2的表达的所述水平被MAb BB7.2所监测，所述MAb BB7.2辨识在所述细胞表面上的所有HLA-A2/胜肽分子。在图36示出了B47 WT-特异性的类TCR抗体的结合数据的一总结。
为了进一步研究ESK1和B47对于HLA-A2+/WT1+BV173和SET2细胞的所述结合的所述矛盾的数据，即可以通过ESK1显着地侦测到结合，而非B47，我们采用直接的生化手段来评估在所述多个细胞上的实际的WT1表现。我们采用来自于各种组织以及BV173和SET2细胞的多个HLA胜肽洗脱策略，接着是多个洗脱的胜肽的MS分析。所述多个实验的所述数据表示，在任何的所述多个MS运行的多个临床组织或多个细胞株中都没有侦测到所述WT1胜肽。在所述BV173或SET-2细胞株的深度分析(mRNA WT1-阳性)未能检测到所述胜肽(Orbitrap或多个Q Exactive MS仪器)。通过Orbitrap MS侦测所述WT1胜肽，接着从多个T2加有胜肽的细胞直接洗脱，所述多个T2细胞被加入各种WT1胜肽浓度的10-5、10-7、10-9摩尔浓度，并且通过所述MS在加有胜肽浓度10-5和10-7摩尔浓度的多个T2 APC的多个洗脱液中侦测到所述胜肽，通过所述MS从加有10-7摩尔浓度的胜肽的多个T2 APC侦测所述胜肽对应于约250个位点/细胞的实际表达(使用所述Orbitrap MS)。
所述多个数据举例说明了所述描述的多个结合工具对于加有胜肽的细胞的所述用处，所述加有胜肽的细胞显示了各种组织学来源的多个相似的胜肽和多个细胞，以评估多个类TCR抗体的所述特异性和选择性。
为了进一步研究表位特异性，在所述WT1胜肽序列上进行丙氨酸扫描诱变。如图37所示，表示了仅有在所述WT1胜肽的位置1中的突变影响ESK1的所述结合强度，表示出与B47相比，ESK1的所述结合选择性和优良特异性是有限的，亦如同所述所观察到的特异性模式，如同所观察到的多个相似的胜肽，以及对于HLA-A2+/WT1-/的多个细胞。所述多个数据表示，与ESK1相比，B47的所述选择性和优良特异性是优异的，并且本文所述的所述工具箱是一有价值的工具以在多个类TCR抗体的筛选、表性以及临床前开发的过程中评估多个类TCR抗体的所述选择性和优良特异性。
实施例2A
用于HLA-A2/WT1的多个类TCR抗体
对HLA-A2/WT1具有TCR样特异性的多个Ab的优良特异性的比较
多个类TCR抗体B47和ESK1的所述选择性被比较。(Dao等人，《科学转化医学》，2013年3月13日；5(176)：176ra33)。
多个T2 APC被加入特定的(WT1，SEQ ID NO：141)或多个对照组胜肽(表15)并且与B47和ESK1抗体一起培养，接着与PE标记的链霉亲和素或多个抗小鼠Ab一起培养。B47和多个ESK1 TCRL两者都结合加有所述WT1胜肽的多个T2细胞，但不结合加有多个对照组胜肽的多个细胞(图46)。一组的多个相似胜肽(表6)被合成以进一步定性出所述WT1 TCRL的特异性。所述B47 TCRL不结合在加有任何的所述多个相似胜肽的T2细胞，而ESK1 TCRL对几种相似胜肽显示出可侦测的结合(图47)。ESK1 TCRL显示了结合至一衍生自HDAC2(组蛋白脱乙酰化酶2，表14)的一相似胜肽，所述相似胜肽是普遍地表现在许多正常细胞中。，WT1-S10(SEQ ID NO：151)被表现在多个正常组织中，如质谱所证实在脑、大脑皮质、心脏、肾脏、肝脏、肺、以及其它正常组织(表14)。
通过SPR对B47和多个ESK1 TCRL的结合的进一步定性显示B47的亲和性(5纳摩尔浓度)比起ESK1(200纳摩尔浓度)更强大，主要由于ESK1与多个MHC-WT1胜肽复合物的分解率较快(图48)。
进行所述WT1胜肽的额外的丙氨酸扫描诱变以改良多个B47类TCR抗体的胜肽表位特异性(图49)。将所述多个突变胜肽加入多个T2细胞上，并且进行如上所述的结合分析。通过流式细胞技术使用针对HLA-A2的BB7.2单克隆抗体监测所述各种Ala突变的加载。
如图49所示，在一些位置处的Ala的多个取代显着地影响B47结合至所述多个突变胜肽。B47 TCRL对多个位置性的取代表现出更大的敏感度(与ESK1相比，图37)。当所述胜肽中的四个残基被突变为丙氨酸(位置1、3、4和7)时，所述B47类TCR抗体失去了＞73％的它对表现的胜肽的结合。一第五个位置位置的敏感度可归因于位置号码5。对于B47和多个ESK1TCRL两者，位置2是关键，因为它被认为是作为所述多个胜肽在所述HLA-A2胜肽结合槽中的一锚定位置。
在B47和ESK1 TCRL之间的进一步定性和比较是在多个肿瘤细胞株和各种来源的原代细胞上进行。如图50所示，B47不结合至一组的细胞，所述一组的细胞都是HLA-A2阳性和WT1 mRNA阳性或阴性的多个细胞。相反，ESK1 TCRL结合至一数量的肿瘤和正常的原代细胞(全部HLA-A2+)。例如，JVM2和IM9(两者皆HLA-A2阳性和WT1阴性)以及多个正常的初级星形细胞显示出结合。细胞毒性试验使用TCRL-aCD3双特异性构建体以及多个人类PBMC显示出B47 TCRL不诱导HLA-A2+/WT1+或HLA-A2+/WT1-的多个细胞的死亡，而ESK1 TCRL-aCD3对一数量的细胞具有细胞毒性，包含WT-1阴性。因此，B47 TCRL在所述双特异性的形式在给合以及功能性活动中皆表现出更优异的特异性，相较于ESK1，所述ESK1结合至以及重新靶向CD3 T细胞至一些细胞，包含多个正常的初代细胞，不管WT-1的表达如何。
实施例3
对HLA-A2/MAGE-A4具有特异性的多个类TCR抗体
实施例3A
对HLA-A2/MAGE-A4具有特异性的TCRL的分离和定性
为了定性所述多个分离的类TCR抗体的所述结合特异性，通过流式细胞技术评估所述多个纯化的IgG的所述反应性和特异性。在多个T2 APC中加入MAGE-A4胜肽或多个对照组胜肽(表15)以及与所述TCRL Ab C106B一起培养，接着与PE标记的链霉亲和素或PE标记的多个抗小鼠Abs一起培养。如图52所示，C106B9结合加有MAGE-A4胜肽的多个T2细胞，但显示不结合加有多个对照组胜肽的多个细胞。
为了进一步评估所述C106B9类TCR抗体的所述特异性，评估它们与对于所述MAGE-A4胜肽显示序列相似度的多个胜肽的反应性。所述胜肽如表8所示。
如图53所示，C106B9 TCRL类TCR抗体不结合任何来自于所述相同组的多个相似胜肽的所述多个胜肽。所述多个数据证明了C106B9的所述高选择性和高特异性，并且证明了所述相似胜肽方法的所述用处以及如上所述所开发的多个工具以评估出多个TCRL的所述选择性和优良特异性。
为了测定所述多个分离的类TCR抗体的所述表面亲和性，使用了表面等离子体共振(SPR)结合分析，通过抗小鼠的IgG把所述分离的纯化的IgG类TCR抗体间接地固定在所述表面等离子共振(SPR)的传感芯片上。所述分析物是在各种浓度下的所述纯化的单链重组HLA-A2/MAGE-A4复合物。如图54所示，SPR分析的所述多个传感图显示出针对所述HLA-A2/MAGE-A4特异性的多个类TCR抗体克隆C106B9的相似的亲和性具有对应的亲和力8.8纳摩尔浓度。
为了研究所述多个分离的类TCR抗体对所述MAGE-A4胜肽的所述优良胜肽表位特异性，进行了丙氨酸扫瞄，在所述丙氨酸扫瞄中，所述胜肽中的多个特定的残基被突变为丙氨酸，并且通过将所述多个突变的胜肽加在多个T2抗原呈现细胞上以测试所述多个类TCR抗体与多个Ala突变胜肽的所述结合(表9)。通过流式细胞技术监测结合，当通过平均荧光强度(MFI)所测定的，多个TCR-样抗体与所述多个突变胜肽的结合的程度被用来与加有所述未突变MAGE-A4胜肽的多个T2 APC比较。所述各种Ala突变胜肽(描述在图2)的所述适当的加入是通过流式细胞技术使用BB7.2来监测，所述BB7.2是针对HLA-A2的一单克隆抗体。
与所述天然未突变的MAGE-A4相比，所有Ala突变胜肽被有效地加到多个T2细胞上(数据未示出)。如图55所示，所述类TCR抗体表现出胜肽依赖性结合，因为多个特定的突变影响了所述结合，并且在多个特定胜肽位置引入Ala时，在所述类TCR抗体的结合强度中引发了一减少。所述多个结果表明，在HLA-A2加入各种Ala突变MAGE-A4胜肽的情况下，MAGE-A4类TCR抗体表现出胜肽特异性及限制性的结合，表明所述抗体在所述抗体的结合性质上是相似于TCR，因此，所述抗体以MHC限定以及胜肽特异性的方式来结合所述MHC-胜肽复合物。
所述C106B9类TCR抗体表现出90％的一显着下降在与Ala突变胜肽结合的四个位置#4、5、6和7。一第五个位置的敏感度可归因于位置号码2(33％的减小)。
总体而言，所述丙氨酸扫描分析揭示了Ala扫描可以被用作测定多个类TCR抗体的所述选择性和优良特异性的一手段，若表现出对Ala突变表现出越高的敏感性，可以观察到越高特异性和胜肽依赖性的结合。所述策略可用于过滤和筛选表现出更高和优化的选择性和特异性性质的所述理想的类TCR抗体如多个MHC-限定胜肽特异性结合物。
本发明人研究了HLA-A2/MAGE-A4的类TCR Ab对于内源性地显示在多个黑色素瘤细胞株的所述表面上的多个MHC-MAGE-A4胜肽复合物的结合特异性。多个细胞与抗MAGE-A4-HLA-A2的多个类TCR抗体Ab一起培养，接着与PE标记的链霉亲和素或多个抗小鼠Ab培养。一组的肿瘤细胞及多个正常初级细胞已被定性出HLA-A2(阳性)及MAGE-A4(阳性或阴性)的表达，被用来比较所述多个类TCR抗体的所述结合。如图56所示，所述类TCR抗体辨识低强度的MAGE-A4-阳性及HLA-A2-阳性的多个细胞。所述类TCR抗体被测试在各种来源的多个HLA-A2-阳性细胞株上，所述细胞株不显示MAGE-A4 RNA表达(MAGE-A4-阴性)，这些具有一MAGE-A4/HLA-A2 TCRL-双特异性的建构体的细胞的杀灭能力也被测试。如图56所示，C106B9不结合所述多个细胞中的任何一种。
多个功能性分析被用来进一步定性所述所述C106B9类TCR抗体。将多个TCRL的多个可变区融合到一个抗CD3 scFv，所述抗CD3 scFv可以以一双特异性的形式重新靶向多个效应T细胞以杀死肿瘤标靶细胞。如图57所示，所述C106B9双特异性类TCR抗体的多个构建体在多个人类PBMC的存在下，在体外显示了对多个MAGE-A4阳性的细胞的强大的细胞毒性。TCCSUP和OVCAR，MAGE-A4阴性细胞株作为阴性对照组，并且表现出没有细胞毒性。如进一步在图58所示，用C106B9 TCRL针对一组的多个HLA-A2+/MAGE-A4-正常人类原代细胞没有细胞毒性被侦测到证实了它们的选择性。
实施例3B
在多个NOD/SCID小鼠中C106B9 BS TCRL在s.c.A375黑色素瘤肿瘤形成模型中的体内功效
图59显示了在多个NOD/SCID小鼠中C106B9 BS TCRL在s.c.A375黑色素瘤肿瘤形成模型中的体内功效。显然，所述双特异性抗体的给药完全抑制了肿瘤形成超过35天的所述实验，如通过肿瘤体积所证实。所述结果支持在本文所述的多个临床设置中TCRL的可变序列的使用。
实施例4
对HLA-A2/MAGE-A9具有特异性的多个类TCR抗体
对HLA-A2/MAGE-A9具有特异性的TCRL的分离和定性
为了定性所述多个分离的类TCR抗体的所述结合特异性，通过流式细胞技术评估所述多个纯化的IgG的所述反应性和特异性。在多个T2 APC中加入MAGE-A9胜肽或多个对照组胜肽以及与所述TCRL Ab F184C7一起培养，接着与PE标记的链霉亲和素或PE标记的多个抗小鼠Abs一起培养。如图60所示，F184C7结合加有MAGE-A9胜肽的多个T2细胞，但显示不结合加有多个对照组胜肽的多个细胞。
为了进一步评估所述F184C7类TCR抗体的所述特异性，它们与对于所述MAGE-A9胜肽显示序列相似度的多个胜肽的反应性被评估。所述胜肽如表10所示。
如图61所示，F184C7 TCRL类TCR抗体不结合任何来自于所述相同组的多个相似胜肽的所述多个胜肽。所述多个数据证明了F184C7的所述高选择性和高特异性，并且证明了所述相似胜肽方法的所述用处以及如上所述所开发的多个工具以评估出多个TCRL的所述选择性和优良特异性。
为了研究所述多个分离的类TCR抗体对所述MAGE-A9胜肽的所述优良胜肽表位特异性，进行了丙氨酸扫瞄，在所述丙氨酸扫瞄中，所述胜肽中的多个特定的残基被突变为丙氨酸，并且通过将所述多个突变的胜肽加在多个T2抗原呈现细胞上以测试所述多个类TCR抗体与多个Ala突变胜肽的所述结合(表11)。通过流式细胞技术监测结合，当通过平均荧光强度(MFI)所测定的，多个TCR-样抗体与所述多个突变胜肽的结合的程度被用来与加有所述未突变MAGE-A4胜肽的多个T2 APC比较。所述各种Ala突变胜肽(描述在图2)的所述适当的加入是通过流式细胞技术使用BB7.2来监测，所述BB7.2是针对HLA-A2的一单克隆抗体。
与所述天然未突变的MAGE-A9相比，所有Ala突变胜肽被有效地加到多个T2细胞上(数据未示出)。如图62所示，所述类TCR抗体表现出胜肽依赖性结合，因为多个特定的突变影响了所述结合，并且在多个特定胜肽位置引入Ala时，在所述类TCR抗体的结合强度中引发了一减少。所述多个结果表明，在HLA-A2加入各种Ala突变MAGE-A9胜肽的情况下，所述类TCR抗体表现出胜肽特异性及限制性的结合，表明所述抗体在所述抗体的结合性质上是相似于TCR，因此，所述抗体以MHC限定以及胜肽特异性的方式来结合所述MHC-胜肽复合物。
所述F184C7类TCR抗体表现出90％的一显着下降在与Ala突变胜肽结合的五个位置#3、5、6、7和8。
总体而言，所述丙氨酸扫描分析揭示了Ala扫描可以被用作测定多个类TCR抗体的所述选择性和优良特异性的一手段，若表现出对Ala突变表现出越高的敏感性，可以观察到越高特异性和胜肽依赖性的结合。所述策略可用于过滤和筛选表现出更高和优化的选择性和特异性性质的所述理想的类TCR抗体如多个MHC-限定胜肽特异性结合物。
本发明人研究了所述HLA-A2/MAGE-A9类TCR Ab对不显示MAGE-A9 RNA表达的各种来源的正常原代细胞的板的结合特异性。如图63所示，F184C7TCRL不与所述多个细胞中的任何一种结合。阳性对照组是加有所述MAGE-A9胜肽的多个T2细胞，所述多个T2细胞被F184C7胜肽强烈地结合。
实施例5
对HLA-A2/PAP具有特异性的多个类TCR抗体
对HLA-A2/PAP具有特异性的TCRL的分离和定性
为了定性所述多个分离的类TCR抗体的所述结合特异性，通过流式细胞技术评估所述多个纯化的IgG的所述反应性和特异性。在多个T2 APC中加入PAP胜肽或多个对照组胜肽以及与所述TCRL Ab D10A3一起培养，接着与PE标记的链霉亲和素或PE标记的多个抗小鼠Abs一起培养。如图64所示，D10A3结合加有PAP胜肽的多个T2细胞，但显示不结合加有多个对照组胜肽的多个细胞。
为了进一步评估所述D10A3类TCR抗体的所述特异性，评估它们与对于所述PAP胜肽显示序列相似度的多个胜肽的反应性。所述胜肽如表12所示。
如图65所示，D10A3 TCRL类TCR抗体不结合任何来自于所述相同组的多个相似胜肽的所述多个胜肽。所述多个数据证明了D10A3的所述高选择性和高特异性，并且证明了所述相似胜肽方法的所述用处以及如上所述所开发的多个工具以评估出多个TCRL的所述选择性和优良特异性。
为了研究所述多个分离的类TCR抗体对所述PAP胜肽的所述优良胜肽表位特异性，进行了丙氨酸扫瞄，在所述丙氨酸扫瞄中，所述胜肽中的多个特定的残基被突变为丙氨酸，并且通过将所述多个突变的胜肽加在多个T2抗原呈现细胞上以测试所述多个类TCR抗体与多个Ala突变胜肽的所述结合(表13)。通过流式细胞技术监测结合，当通过平均荧光强度(MFI)所测定的，多个TCR-样抗体与所述多个突变胜肽的结合的程度被用来与加有所述未突变PAP胜肽的多个T2 APC比较。所述各种Ala突变胜肽(描述在图2)的所述适当的加入是通过流式细胞技术使用BB7.2来监测，所述BB7.2是针对HLA-A2的一单克隆抗体。
与所述天然未突变的PAP相比，所有Ala突变胜肽被有效地加到多个T2细胞上(数据未示出)。如图66所示，所述类TCR抗体表现出胜肽依赖性结合，因为多个特定的突变影响了所述结合，并且在多个特定胜肽位置引入Ala时，在所述类TCR抗体的结合强度中引发了一减少。所述多个结果表明，在HLA-A2加入各种Ala突变PAP胜肽的情况下，所述类TCR抗体表现出胜肽特异性及限制性的结合，表明所述抗体在所述抗体的结合性质上是相似于TCR，因此，所述抗体以MHC限定以及胜肽特异性的方式来结合所述MHC-胜肽复合物。
所述D10A3类TCR抗体表现出90％的一显着下降在与Ala突变胜肽结合的三个位置#3、6和8。，还观察到与在位置#4的一Ala突变胜肽的结合的70％的减少。一第五个位置的敏感度可归因于位置号码7(45％的减少)。
本发明人研究了所述HLA-A2/PAP类TCR Ab对不显示PAP RNA表达的各种来源的正常原代细胞的板的结合特异性。如图67所示，D10A3 TCRL不与所述多个细胞中的任何一种结合。阳性对照组是加有所述PAP胜肽的多个T2细胞，所述多个T2细胞被D10A3胜肽强烈地结合。
虽然本发明已经结合其特定实施例进行了描述，但是显而易见的是，许多备选方案，修饰以及变动对本领域技术人员来说是显而易见的。因此，本发明旨在涵盖所有落入所述权利要求的精神和范围内的所有这样的备选方案，修饰以及变动。
在本说明书中提及的所有出版物，专利和专利申请以其整体作为参考文献并入本说明书中，在同样的程度上，所述独立的出版物、专利或专利申请案被明确地且个别地标示为以引用的方式并入本文中。此外，本申请中任何参考文献的引用或证明不应被解释为承认所述参考文献可用作本发明的现有技术。在同样的程度上，所用的章节标题，不应被认为是必要的限制。
SEQUENCE LISTING
<110> 阿迪塞特生物公司
彼尔高棉, 米拉
丹克贝克, 加利特
瑞特, 约拉姆
贝尔, 伊兰
仙尼克, 卡莲
特布尔, 艾尔巴茨, 耶尔
雪帕贝, 塞里, 耶尔
埃雷尔西格尔, 列乌特
奥伦, 雷蒙特
阿利雪克费斯, 德罗尔希姆尔
<120> 具有类TCR抗体结合域的亲和性实体及其用途
<130> 66429
<150> US 62/172,264
<151> 2015-06-08
<150> NL N2014935
<151> 2015-06-08
<160> 384
<170> SIPOSequenceListing 1.0
<210> 1
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 1
Tyr Met Asp Gly Thr Met Ser Gln Val
1 5
<210> 2
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 2
Tyr Leu Leu Pro Ala Ile Val His Ile
1 5
<210> 3
<211> 19
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(19)
<223> 短胜肽
<400> 3
Thr Thr Ala Gly Cys Ala Ala Ala Gly Cys Ala Thr Ala Cys Cys Ala
1 5 10 15
Thr Cys Ala
<210> 4
<211> 19
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(19)
<223> 短胜肽
<400> 4
Cys Cys Ala Gly Ala Cys Ala Ala Ala Gly Ala Gly Gly Thr Cys Ala
1 5 10 15
Thr Ala Ala
<210> 5
<211> 18
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(18)
<223> 短胜肽
<400> 5
Ala Gly Gly Cys Thr Gly Cys Ala Ala Thr Ala Ala Gly Ala Gly Ala
1 5 10 15
Thr Ala
<210> 6
<211> 18
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(18)
<223> 短胜肽
<400> 6
Thr Thr Cys Gly Cys Thr Gly Ala Cys Ala Ala Gly Thr Thr Thr Thr
1 5 10 15
Ala Cys
<210> 7
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 7
Glu Ala Ala Gly Ile Gly Ile Leu Thr Val
1 5 10
<210> 8
<211> 163
<212> PRT
<213> homo sapiens
<400> 8
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala
35 40 45
Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
50 55 60
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
65 70 75 80
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
85 90 95
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
100 105 110
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
115 120 125
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
130 135 140
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
145 150 155 160
Pro Pro Arg
<210> 9
<211> 164
<212> PRT
<213> homo sapiens
<400> 9
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala
35 40 45
Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
50 55 60
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
65 70 75 80
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
85 90 95
Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
100 105 110
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
115 120 125
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
130 135 140
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
145 150 155 160
Leu Pro Pro Arg
<210> 10
<211> 123
<212> PRT
<213> homo sapiens
<400> 10
Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val
1 5 10 15
Thr Gly Asn Lys Ile Leu Val Lys Gln Ser Pro Met Leu Val Ala Tyr
20 25 30
Asp Asn Ala Val Asn Leu Ser Trp Lys His Leu Cys Pro Ser Pro Leu
35 40 45
Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly
50 55 60
Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe
65 70 75 80
Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn
85 90 95
Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr
100 105 110
Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
115 120
<210> 11
<211> 101
<212> PRT
<213> homo sapiens
<400> 11
Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val
1 5 10 15
Thr Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys
20 25 30
Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
35 40 45
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg
50 55 60
Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
65 70 75 80
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
85 90 95
Ala Ala Tyr Arg Ser
100
<210> 12
<211> 220
<212> PRT
<213> homo sapiens
<400> 12
Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val
1 5 10 15
Thr Gly Asn Lys Ile Leu Val Lys Gln Ser Pro Met Leu Val Ala Tyr
20 25 30
Asp Asn Ala Val Asn Leu Ser Cys Lys Tyr Ser Tyr Asn Leu Phe Ser
35 40 45
Arg Glu Phe Arg Ala Ser Leu His Lys Gly Leu Asp Ser Ala Val Glu
50 55 60
Val Cys Val Val Tyr Gly Asn Tyr Ser Gln Gln Leu Gln Val Tyr Ser
65 70 75 80
Lys Thr Gly Phe Asn Cys Asp Gly Lys Leu Gly Asn Glu Ser Val Thr
85 90 95
Phe Tyr Leu Gln Asn Leu Tyr Val Asn Gln Thr Asp Ile Tyr Phe Cys
100 105 110
Lys Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser
115 120 125
Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro
130 135 140
Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly
145 150 155 160
Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile
165 170 175
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
180 185 190
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
195 200 205
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
210 215 220
<210> 13
<211> 255
<212> PRT
<213> homo sapiens
<400> 13
Met Gly Asn Ser Cys Tyr Asn Ile Val Ala Thr Leu Leu Leu Val Leu
1 5 10 15
Asn Phe Glu Arg Thr Arg Ser Leu Gln Asp Pro Cys Ser Asn Cys Pro
20 25 30
Ala Gly Thr Phe Cys Asp Asn Asn Arg Asn Gln Ile Cys Ser Pro Cys
35 40 45
Pro Pro Asn Ser Phe Ser Ser Ala Gly Gly Gln Arg Thr Cys Asp Ile
50 55 60
Cys Arg Gln Cys Lys Gly Val Phe Arg Thr Arg Lys Glu Cys Ser Ser
65 70 75 80
Thr Ser Asn Ala Glu Cys Asp Cys Thr Pro Gly Phe His Cys Leu Gly
85 90 95
Ala Gly Cys Ser Met Cys Glu Gln Asp Cys Lys Gln Gly Gln Glu Leu
100 105 110
Thr Lys Lys Gly Cys Lys Asp Cys Cys Phe Gly Thr Phe Asn Asp Gln
115 120 125
Lys Arg Gly Ile Cys Arg Pro Trp Thr Asn Cys Ser Leu Asp Gly Lys
130 135 140
Ser Val Leu Val Asn Gly Thr Lys Glu Arg Asp Val Val Cys Gly Pro
145 150 155 160
Ser Pro Ala Asp Leu Ser Pro Gly Ala Ser Ser Val Thr Pro Pro Ala
165 170 175
Pro Ala Arg Glu Pro Gly His Ser Pro Gln Ile Ile Ser Phe Phe Leu
180 185 190
Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu Leu Phe Phe Leu Thr Leu
195 200 205
Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
210 215 220
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
225 230 235 240
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
245 250 255
<210> 14
<211> 199
<212> PRT
<213> homo sapiens
<400> 14
Met Lys Ser Gly Leu Trp Tyr Phe Phe Leu Phe Cys Leu Arg Ile Lys
1 5 10 15
Val Leu Thr Gly Glu Ile Asn Gly Ser Ala Asn Tyr Glu Met Phe Ile
20 25 30
Phe His Asn Gly Gly Val Gln Ile Leu Cys Lys Tyr Pro Asp Ile Val
35 40 45
Gln Gln Phe Lys Met Gln Leu Leu Lys Gly Gly Gln Ile Leu Cys Asp
50 55 60
Leu Thr Lys Thr Lys Gly Ser Gly Asn Thr Val Ser Ile Lys Ser Leu
65 70 75 80
Lys Phe Cys His Ser Gln Leu Ser Asn Asn Ser Val Ser Phe Phe Leu
85 90 95
Tyr Asn Leu Asp His Ser His Ala Asn Tyr Tyr Phe Cys Asn Leu Ser
100 105 110
Ile Phe Asp Pro Pro Pro Phe Lys Val Thr Leu Thr Gly Gly Tyr Leu
115 120 125
His Ile Tyr Glu Ser Gln Leu Cys Cys Gln Leu Lys Phe Trp Leu Pro
130 135 140
Ile Gly Cys Ala Ala Phe Val Val Val Cys Ile Leu Gly Cys Ile Leu
145 150 155 160
Ile Cys Trp Leu Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro
165 170 175
Asn Gly Glu Tyr Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser
180 185 190
Arg Leu Thr Asp Val Thr Leu
195
<210> 15
<211> 277
<212> PRT
<213> homo sapiens
<400> 15
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
210 215 220
Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
225 230 235 240
Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 16
<211> 184
<212> PRT
<213> homo sapiens
<400> 16
Met Ala Pro Leu Leu Pro Ile Arg Thr Leu Pro Leu Ile Leu Ile Leu
1 5 10 15
Leu Ala Leu Leu Ser Pro Gly Ala Ala Asp Phe Asn Ile Ser Ser Leu
20 25 30
Ser Gly Leu Leu Ser Pro Ala Leu Thr Glu Ser Leu Leu Val Ala Leu
35 40 45
Pro Pro Cys His Leu Thr Gly Gly Asn Ala Thr Leu Met Val Arg Arg
50 55 60
Ala Asn Asp Ser Lys Val Val Thr Ser Ser Phe Val Val Pro Pro Cys
65 70 75 80
Arg Gly Arg Arg Glu Leu Val Ser Val Val Asp Ser Gly Ala Gly Phe
85 90 95
Thr Val Thr Arg Leu Ser Ala Tyr Gln Val Thr Asn Leu Val Pro Gly
100 105 110
Thr Lys Phe Tyr Ile Ser Tyr Leu Val Lys Lys Gly Thr Ala Thr Glu
115 120 125
Ser Ser Arg Glu Ile Pro Met Ser Thr Leu Pro Arg Arg Asn Met Glu
130 135 140
Ser Ile Gly Leu Gly Met Ala Arg Thr Gly Gly Met Val Val Ile Thr
145 150 155 160
Val Leu Leu Ser Val Ala Met Phe Leu Leu Val Leu Gly Phe Ile Ile
165 170 175
Ala Leu Ala Leu Gly Ser Arg Lys
180
<210> 17
<211> 273
<212> PRT
<213> homo sapiens
<400> 17
Met Ala Ser Ala Ala Ala Ala Glu Ala Glu Lys Gly Ser Pro Val Val
1 5 10 15
Val Gly Leu Leu Val Val Gly Asn Ile Ile Ile Leu Leu Ser Gly Leu
20 25 30
Ser Leu Phe Ala Glu Thr Ile Trp Val Thr Ala Asp Gln Tyr Arg Val
35 40 45
Tyr Pro Leu Met Gly Val Ser Gly Lys Asp Asp Val Phe Ala Gly Ala
50 55 60
Trp Ile Ala Ile Phe Cys Gly Phe Ser Phe Phe Met Val Ala Ser Phe
65 70 75 80
Gly Val Gly Ala Ala Leu Cys Arg Arg Arg Ser Met Val Leu Thr Tyr
85 90 95
Leu Val Leu Met Leu Ile Val Tyr Ile Phe Glu Cys Ala Ser Cys Ile
100 105 110
Thr Ser Tyr Thr His Arg Asp Tyr Met Val Ser Asn Pro Ser Leu Ile
115 120 125
Thr Lys Gln Met Leu Thr Phe Tyr Ser Ala Asp Thr Asp Gln Gly Gln
130 135 140
Glu Leu Thr Arg Leu Trp Asp Arg Val Met Ile Glu Gln Glu Cys Cys
145 150 155 160
Gly Thr Ser Gly Pro Met Asp Trp Val Asn Phe Thr Ser Ala Phe Arg
165 170 175
Ala Ala Thr Pro Glu Val Val Phe Pro Trp Pro Pro Leu Cys Cys Arg
180 185 190
Arg Thr Gly Asn Phe Ile Pro Leu Asn Glu Glu Gly Cys Arg Leu Gly
195 200 205
His Met Asp Tyr Leu Phe Thr Lys Ala Gly Val Gln Trp His Asn Leu
210 215 220
Ser Ser Leu Gln Arg Leu Pro Pro Gly Phe Lys Gly Phe Ser His Leu
225 230 235 240
Ser Phe Gln Ser Ser Trp Asp Tyr Arg Ala Ala Ser Asn Thr Ser Ala
245 250 255
Thr Pro Ser Thr Ala Thr Arg Gly Val Ser Arg Gly Leu Gly Leu Pro
260 265 270
Ser
<210> 18
<211> 258
<212> PRT
<213> homo sapiens
<400> 18
Met Ala Ser Ala Ala Ala Ala Glu Ala Glu Lys Gly Ser Pro Val Val
1 5 10 15
Val Gly Leu Leu Val Val Gly Asn Ile Ile Ile Leu Leu Ser Gly Leu
20 25 30
Ser Leu Phe Ala Glu Thr Ile Trp Val Thr Ala Asp Gln Tyr Arg Val
35 40 45
Tyr Pro Leu Met Gly Val Ser Gly Lys Asp Asp Val Phe Ala Gly Ala
50 55 60
Trp Ile Ala Ile Phe Cys Gly Phe Ser Phe Phe Met Val Ala Ser Phe
65 70 75 80
Gly Val Gly Ala Ala Leu Cys Arg Arg Arg Ser Met Val Leu Thr Tyr
85 90 95
Leu Val Leu Met Leu Ile Val Tyr Ile Phe Glu Cys Ala Ser Cys Ile
100 105 110
Thr Ser Tyr Thr His Arg Asp Tyr Met Val Ser Asn Pro Ser Leu Ile
115 120 125
Thr Lys Gln Met Leu Thr Phe Tyr Ser Ala Asp Thr Asp Gln Gly Gln
130 135 140
Glu Leu Thr Arg Leu Trp Asp Arg Val Met Ile Glu Gln Glu Cys Cys
145 150 155 160
Gly Thr Ser Gly Pro Met Asp Trp Val Asn Phe Thr Ser Ala Phe Arg
165 170 175
Ala Ala Thr Pro Glu Val Val Phe Pro Trp Pro Pro Leu Cys Cys Arg
180 185 190
Arg Thr Gly Asn Phe Ile Pro Leu Asn Glu Glu Gly Cys Arg Leu Gly
195 200 205
His Met Asp Tyr Leu Phe Thr Lys Gly Cys Phe Glu His Ile Gly His
210 215 220
Ala Ile Asp Ser Tyr Thr Trp Gly Ile Ser Trp Phe Gly Phe Ala Ile
225 230 235 240
Leu Met Trp Thr Leu Pro Val Met Leu Ile Ala Met Tyr Phe Tyr Thr
245 250 255
Met Leu
<210> 19
<211> 245
<212> PRT
<213> homo sapiens
<400> 19
Met Lys Gln Ser Phe Pro Leu Phe Leu Thr Pro Ser Pro Trp Lys Thr
1 5 10 15
Thr Val Leu Leu Leu Tyr Met Arg Ile Cys Tyr Val Pro Ser Tyr Lys
20 25 30
Trp Asn Tyr Ser Ile Gly Leu Ile Tyr Leu Gly Ile Val Ser Glu Leu
35 40 45
Pro His Met Val Gly Ile Gly Gln Asn Ser Ser Phe Asn Ser Trp Met
50 55 60
Glu Ser Gln Phe Leu His Pro Ser Met Glu Pro Gly Gln Trp Leu Pro
65 70 75 80
Tyr Ile Thr Ile Phe Arg Phe Thr His Ile Ile Arg Cys Val Arg Ile
85 90 95
Ser Phe Leu Phe Asn Ile Pro Trp Tyr Gly Tyr Pro His Phe Val Cys
100 105 110
His Ser Ser Val Ser Gly His Leu Gly Tyr Phe Tyr Leu Leu Leu Leu
115 120 125
Trp Leu Val Cys Cys Glu His Arg Cys Thr Asn Ile Cys Ser Arg Gln
130 135 140
Thr Ser Phe Lys Arg Leu Phe Leu Lys Lys Tyr Val Ser Tyr Asn Ile
145 150 155 160
Phe Leu Leu Cys Val Glu Ser Asp Ile Ser Ile Asp Leu Glu Gly Tyr
165 170 175
Gly Met Gly Cys Thr Asn Ile Cys Ser Arg Gln Thr Ser Phe Lys Arg
180 185 190
Leu Phe Lys Arg Lys Tyr Arg Cys Leu Leu Asn Met Phe Leu Val Met
195 200 205
Asn Val Glu Ser Gly Thr Asn Arg Tyr Met Glu Val Arg Arg Ala Trp
210 215 220
Arg Gly Ser Lys Trp Glu Asp Glu Glu Asn Trp Leu Gly Ile Asp Val
225 230 235 240
Tyr Phe Glu Asp Arg
245
<210> 20
<211> 114
<212> PRT
<213> homo sapiens
<400> 20
Met Ala Gly Leu Ala Leu Gln Pro Gly Thr Ala Leu Leu Cys Tyr Ser
1 5 10 15
Cys Lys Ala Gln Val Ser Asn Glu Asp Cys Leu Gln Val Glu Asn Cys
20 25 30
Thr Gln Leu Gly Glu Gln Cys Trp Thr Ala Arg Ile Arg Ala Val Gly
35 40 45
Leu Leu Thr Val Ile Ser Lys Gly Cys Ser Leu Asn Cys Val Asp Asp
50 55 60
Ser Gln Asp Tyr Tyr Val Gly Lys Lys Asn Ile Thr Cys Cys Asp Thr
65 70 75 80
Asp Leu Cys Asn Ala Ser Gly Ala His Ala Leu Gln Pro Ala Ala Ala
85 90 95
Ile Leu Ala Leu Leu Pro Ala Leu Gly Leu Leu Leu Trp Gly Pro Gly
100 105 110
Gln Leu
<210> 21
<211> 386
<212> PRT
<213> homo sapiens
<400> 21
Met Arg Ala Ala Pro Leu Leu Leu Ala Arg Ala Ala Ser Leu Ser Leu
1 5 10 15
Gly Phe Leu Phe Leu Leu Phe Phe Trp Leu Asp Arg Ser Val Leu Ala
20 25 30
Lys Glu Leu Lys Phe Val Thr Leu Val Phe Arg His Gly Asp Arg Ser
35 40 45
Pro Ile Asp Thr Phe Pro Thr Asp Pro Ile Lys Glu Ser Ser Trp Pro
50 55 60
Gln Gly Phe Gly Gln Leu Thr Gln Leu Gly Met Glu Gln His Tyr Glu
65 70 75 80
Leu Gly Glu Tyr Ile Arg Lys Arg Tyr Arg Lys Phe Leu Asn Glu Ser
85 90 95
Tyr Lys His Glu Gln Val Tyr Ile Arg Ser Thr Asp Val Asp Arg Thr
100 105 110
Leu Met Ser Ala Met Thr Asn Leu Ala Ala Leu Phe Pro Pro Glu Gly
115 120 125
Val Ser Ile Trp Asn Pro Ile Leu Leu Trp Gln Pro Ile Pro Val His
130 135 140
Thr Val Pro Leu Ser Glu Asp Gln Leu Leu Tyr Leu Pro Phe Arg Asn
145 150 155 160
Cys Pro Arg Phe Gln Glu Leu Glu Ser Glu Thr Leu Lys Ser Glu Glu
165 170 175
Phe Gln Lys Arg Leu His Pro Tyr Lys Asp Phe Ile Ala Thr Leu Gly
180 185 190
Lys Leu Ser Gly Leu His Gly Gln Asp Leu Phe Gly Ile Trp Ser Lys
195 200 205
Val Tyr Asp Pro Leu Tyr Cys Glu Ser Val His Asn Phe Thr Leu Pro
210 215 220
Ser Trp Ala Thr Glu Asp Thr Met Thr Lys Leu Arg Glu Leu Ser Glu
225 230 235 240
Leu Ser Leu Leu Ser Leu Tyr Gly Ile His Lys Gln Lys Glu Lys Ser
245 250 255
Arg Leu Gln Gly Gly Val Leu Val Asn Glu Ile Leu Asn His Met Lys
260 265 270
Arg Ala Thr Gln Ile Pro Ser Tyr Lys Lys Leu Ile Met Tyr Ser Ala
275 280 285
His Asp Thr Thr Val Ser Gly Leu Gln Met Ala Leu Asp Val Tyr Asn
290 295 300
Gly Leu Leu Pro Pro Tyr Ala Ser Cys His Leu Thr Glu Leu Tyr Phe
305 310 315 320
Glu Lys Gly Glu Tyr Phe Val Glu Met Tyr Tyr Arg Asn Glu Thr Gln
325 330 335
His Glu Pro Tyr Pro Leu Met Leu Pro Gly Cys Ser Pro Ser Cys Pro
340 345 350
Leu Glu Arg Phe Ala Glu Leu Val Gly Pro Val Ile Pro Gln Asp Trp
355 360 365
Ser Thr Glu Cys Met Thr Thr Asn Ser His Gln Gly Thr Glu Asp Ser
370 375 380
Thr Asp
385
<210> 22
<211> 418
<212> PRT
<213> homo sapiens
<400> 22
Met Arg Ala Ala Pro Leu Leu Leu Ala Arg Ala Ala Ser Leu Ser Leu
1 5 10 15
Gly Phe Leu Phe Leu Leu Phe Phe Trp Leu Asp Arg Ser Val Leu Ala
20 25 30
Lys Glu Leu Lys Phe Val Thr Leu Val Phe Arg His Gly Asp Arg Ser
35 40 45
Pro Ile Asp Thr Phe Pro Thr Asp Pro Ile Lys Glu Ser Ser Trp Pro
50 55 60
Gln Gly Phe Gly Gln Leu Thr Gln Leu Gly Met Glu Gln His Tyr Glu
65 70 75 80
Leu Gly Glu Tyr Ile Arg Lys Arg Tyr Arg Lys Phe Leu Asn Glu Ser
85 90 95
Tyr Lys His Glu Gln Val Tyr Ile Arg Ser Thr Asp Val Asp Arg Thr
100 105 110
Leu Met Ser Ala Met Thr Asn Leu Ala Ala Leu Phe Pro Pro Glu Gly
115 120 125
Val Ser Ile Trp Asn Pro Ile Leu Leu Trp Gln Pro Ile Pro Val His
130 135 140
Thr Val Pro Leu Ser Glu Asp Gln Leu Leu Tyr Leu Pro Phe Arg Asn
145 150 155 160
Cys Pro Arg Phe Gln Glu Leu Glu Ser Glu Thr Leu Lys Ser Glu Glu
165 170 175
Phe Gln Lys Arg Leu His Pro Tyr Lys Asp Phe Ile Ala Thr Leu Gly
180 185 190
Lys Leu Ser Gly Leu His Gly Gln Asp Leu Phe Gly Ile Trp Ser Lys
195 200 205
Val Tyr Asp Pro Leu Tyr Cys Glu Ser Val His Asn Phe Thr Leu Pro
210 215 220
Ser Trp Ala Thr Glu Asp Thr Met Thr Lys Leu Arg Glu Leu Ser Glu
225 230 235 240
Leu Ser Leu Leu Ser Leu Tyr Gly Ile His Lys Gln Lys Glu Lys Ser
245 250 255
Arg Leu Gln Gly Gly Val Leu Val Asn Glu Ile Leu Asn His Met Lys
260 265 270
Arg Ala Thr Gln Ile Pro Ser Tyr Lys Lys Leu Ile Met Tyr Ser Ala
275 280 285
His Asp Thr Thr Val Ser Gly Leu Gln Met Ala Leu Asp Val Tyr Asn
290 295 300
Gly Leu Leu Pro Pro Tyr Ala Ser Cys His Leu Thr Glu Leu Tyr Phe
305 310 315 320
Glu Lys Gly Glu Tyr Phe Val Glu Met Tyr Tyr Arg Asn Glu Thr Gln
325 330 335
His Glu Pro Tyr Pro Leu Met Leu Pro Gly Cys Ser Pro Ser Cys Pro
340 345 350
Leu Glu Arg Phe Ala Glu Leu Val Gly Pro Val Ile Pro Gln Asp Trp
355 360 365
Ser Thr Glu Cys Met Thr Thr Asn Ser His Gln Val Leu Lys Val Ile
370 375 380
Phe Ala Val Ala Phe Cys Leu Ile Ser Ala Val Leu Met Val Leu Leu
385 390 395 400
Phe Ile His Ile Arg Arg Gly Leu Cys Trp Gln Arg Glu Ser Tyr Gly
405 410 415
Asn Ile
<210> 23
<211> 353
<212> PRT
<213> homo sapiens
<400> 23
Met Arg Ala Ala Pro Leu Leu Leu Ala Arg Ala Ala Ser Leu Ser Leu
1 5 10 15
Gly Phe Leu Phe Leu Leu Phe Phe Trp Leu Asp Arg Ser Val Leu Ala
20 25 30
Lys Glu Leu Lys Phe Val Thr Leu Val Phe Arg His Gly Asp Arg Ser
35 40 45
Pro Ile Asp Thr Phe Pro Thr Asp Pro Ile Lys Glu Ser Ser Trp Pro
50 55 60
Gln Gly Phe Gly Gln Leu Thr Gln Leu Gly Met Glu Gln His Tyr Glu
65 70 75 80
Leu Gly Glu Tyr Ile Arg Lys Arg Tyr Arg Lys Phe Leu Asn Glu Ser
85 90 95
Tyr Lys His Glu Gln Val Tyr Ile Arg Ser Thr Asp Val Asp Arg Thr
100 105 110
Leu Met Ser Ala Met Thr Asn Leu Ala Ala Leu Phe Pro Pro Glu Gly
115 120 125
Val Ser Ile Trp Asn Pro Ile Leu Leu Trp Gln Pro Ile Pro Val His
130 135 140
Thr Val Pro Leu Ser Glu Asp Gln Asp Phe Ile Ala Thr Leu Gly Lys
145 150 155 160
Leu Ser Gly Leu His Gly Gln Asp Leu Phe Gly Ile Trp Ser Lys Val
165 170 175
Tyr Asp Pro Leu Tyr Cys Glu Ser Val His Asn Phe Thr Leu Pro Ser
180 185 190
Trp Ala Thr Glu Asp Thr Met Thr Lys Leu Arg Glu Leu Ser Glu Leu
195 200 205
Ser Leu Leu Ser Leu Tyr Gly Ile His Lys Gln Lys Glu Lys Ser Arg
210 215 220
Leu Gln Gly Gly Val Leu Val Asn Glu Ile Leu Asn His Met Lys Arg
225 230 235 240
Ala Thr Gln Ile Pro Ser Tyr Lys Lys Leu Ile Met Tyr Ser Ala His
245 250 255
Asp Thr Thr Val Ser Gly Leu Gln Met Ala Leu Asp Val Tyr Asn Gly
260 265 270
Leu Leu Pro Pro Tyr Ala Ser Cys His Leu Thr Glu Leu Tyr Phe Glu
275 280 285
Lys Gly Glu Tyr Phe Val Glu Met Tyr Tyr Arg Asn Glu Thr Gln His
290 295 300
Glu Pro Tyr Pro Leu Met Leu Pro Gly Cys Ser Pro Ser Cys Pro Leu
305 310 315 320
Glu Arg Phe Ala Glu Leu Val Gly Pro Val Ile Pro Gln Asp Trp Ser
325 330 335
Thr Glu Cys Met Thr Thr Asn Ser His Gln Gly Thr Glu Asp Ser Thr
340 345 350
Asp
<210> 24
<211> 335
<212> PRT
<213> homo sapiens
<400> 24
Met Pro Arg Pro Arg Leu Leu Ala Ala Leu Cys Gly Ala Leu Leu Cys
1 5 10 15
Ala Pro Ser Leu Leu Val Ala Leu Asp Ile Cys Ser Lys Asn Pro Cys
20 25 30
His Asn Gly Gly Leu Cys Glu Glu Ile Ser Gln Glu Val Arg Gly Asp
35 40 45
Val Phe Pro Ser Tyr Thr Cys Thr Cys Leu Lys Gly Tyr Ala Gly Asn
50 55 60
His Cys Glu Thr Lys Cys Val Glu Pro Leu Gly Leu Glu Asn Gly Asn
65 70 75 80
Ile Ala Asn Ser Gln Ile Ala Ala Ser Ser Val Arg Val Thr Phe Leu
85 90 95
Gly Leu Gln His Trp Val Pro Glu Leu Ala Arg Leu Asn Arg Ala Gly
100 105 110
Met Val Asn Ala Trp Thr Pro Ser Ser Asn Asp Asp Asn Pro Trp Ile
115 120 125
Gln Val Asn Leu Leu Arg Arg Met Trp Val Thr Gly Val Val Thr Gln
130 135 140
Gly Ala Ser Arg Leu Ala Ser His Glu Tyr Leu Lys Ala Phe Lys Val
145 150 155 160
Ala Tyr Ser Leu Asn Gly His Glu Phe Asp Phe Ile His Asp Val Asn
165 170 175
Lys Lys His Lys Glu Phe Val Gly Asn Trp Asn Lys Asn Ala Val His
180 185 190
Val Asn Leu Phe Glu Thr Pro Val Glu Ala Gln Tyr Val Arg Leu Tyr
195 200 205
Pro Thr Ser Cys His Thr Ala Cys Thr Leu Arg Phe Glu Leu Leu Gly
210 215 220
Cys Glu Leu Asn Gly Cys Ala Asn Pro Leu Gly Leu Lys Asn Asn Ser
225 230 235 240
Ile Pro Asp Lys Gln Ile Thr Ala Ser Ser Ser Tyr Lys Thr Trp Gly
245 250 255
Leu His Leu Phe Ser Trp Asn Pro Ser Tyr Ala Arg Leu Asp Lys Gln
260 265 270
Gly Asn Phe Asn Ala Trp Val Ala Gly Ser Tyr Gly Asn Asp Gln Trp
275 280 285
Leu Gln Ile Phe Pro Gly Asn Trp Asp Asn His Ser His Lys Lys Asn
290 295 300
Leu Phe Glu Thr Pro Ile Leu Ala Arg Tyr Val Arg Ile Leu Pro Val
305 310 315 320
Ala Trp His Asn Arg Ile Ala Leu Arg Leu Glu Leu Leu Gly Cys
325 330 335
<210> 25
<211> 264
<212> PRT
<213> homo sapiens
<400> 25
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Phe Asn
50 55 60
Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg
65 70 75 80
Asp Ile Ser Glu Met Phe Leu Gln Ile Tyr Lys Gln Gly Gly Phe Leu
85 90 95
Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val Val Gln Leu
100 105 110
Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val Glu Thr
115 120 125
Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu Thr
130 135 140
Ile Ser Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe Ser Ala Gln
145 150 155 160
Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu Val Leu Val
165 170 175
Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala Leu Ala Val
180 185 190
Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro Ala
195 200 205
Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr His Thr His
210 215 220
Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu Lys
225 230 235 240
Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro Ala
245 250 255
Val Ala Ala Thr Ser Ala Asn Leu
260
<210> 26
<211> 203
<212> PRT
<213> homo sapiens
<400> 26
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
20 25 30
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
35 40 45
Thr Glu Lys Asn Ala Ile Pro Ala Pro Thr Thr Thr Lys Ser Cys Arg
50 55 60
Glu Thr Phe Leu Lys Cys Phe Cys Arg Phe Ile Asn Lys Gly Val Phe
65 70 75 80
Trp Ala Ser Pro Ile Leu Ser Ser Val Ser Asp Val Pro Phe Pro Phe
85 90 95
Ser Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu
100 105 110
Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala
115 120 125
Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile
130 135 140
Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr
145 150 155 160
His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro
165 170 175
Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr
180 185 190
Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
195 200
<210> 27
<211> 159
<212> PRT
<213> homo sapiens
<400> 27
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Phe Asn
50 55 60
Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg
65 70 75 80
Asp Ile Ser Glu Met Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly
85 90 95
Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu
100 105 110
Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr
115 120 125
Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser
130 135 140
Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
145 150 155
<210> 28
<211> 475
<212> PRT
<213> homo sapiens
<400> 28
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
20 25 30
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
35 40 45
Thr Glu Lys Asn Ala Val Ser Met Thr Ser Ser Val Leu Ser Ser His
50 55 60
Ser Pro Gly Ser Gly Ser Ser Thr Thr Gln Gly Gln Asp Val Thr Leu
65 70 75 80
Ala Pro Ala Thr Glu Pro Ala Ser Gly Ser Ala Ala Thr Trp Gly Gln
85 90 95
Asp Val Thr Ser Val Pro Val Thr Arg Pro Ala Leu Gly Ser Thr Thr
100 105 110
Pro Pro Ala His Asp Val Thr Ser Ala Pro Asp Asn Lys Pro Ala Pro
115 120 125
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
130 135 140
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
145 150 155 160
Ala Pro Asp Asn Arg Pro Ala Leu Gly Ser Thr Ala Pro Pro Val His
165 170 175
Asn Val Thr Ser Ala Ser Gly Ser Ala Ser Gly Ser Ala Ser Thr Leu
180 185 190
Val His Asn Gly Thr Ser Ala Arg Ala Thr Thr Thr Pro Ala Ser Lys
195 200 205
Ser Thr Pro Phe Ser Ile Pro Ser His His Ser Asp Thr Pro Thr Thr
210 215 220
Leu Ala Ser His Ser Thr Lys Thr Asp Ala Ser Ser Thr His His Ser
225 230 235 240
Thr Val Pro Pro Leu Thr Ser Ser Asn His Ser Thr Ser Pro Gln Leu
245 250 255
Ser Thr Gly Val Ser Phe Phe Phe Leu Ser Phe His Ile Ser Asn Leu
260 265 270
Gln Phe Asn Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu
275 280 285
Leu Gln Arg Asp Ile Ser Glu Met Phe Leu Gln Ile Tyr Lys Gln Gly
290 295 300
Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val
305 310 315 320
Val Gln Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp
325 330 335
Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr
340 345 350
Asn Leu Thr Ile Ser Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe
355 360 365
Ser Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu
370 375 380
Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala
385 390 395 400
Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile
405 410 415
Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr
420 425 430
His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro
435 440 445
Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr
450 455 460
Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
465 470 475
<210> 29
<211> 282
<212> PRT
<213> homo sapiens
<400> 29
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Leu Ser
50 55 60
Thr Gly Val Ser Phe Phe Phe Leu Ser Phe His Ile Ser Asn Leu Gln
65 70 75 80
Phe Asn Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu
85 90 95
Gln Arg Asp Ile Ser Glu Met Phe Leu Gln Ile Tyr Lys Gln Gly Gly
100 105 110
Phe Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val Val
115 120 125
Gln Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val
130 135 140
Glu Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn
145 150 155 160
Leu Thr Ile Ser Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe Ser
165 170 175
Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu Val
180 185 190
Leu Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala Leu
195 200 205
Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe
210 215 220
Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr His
225 230 235 240
Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr
245 250 255
Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn
260 265 270
Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
275 280
<210> 30
<211> 238
<212> PRT
<213> homo sapiens
<400> 30
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Ile Tyr
50 55 60
Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly
65 70 75 80
Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn
85 90 95
Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala
100 105 110
Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Val Ser Asp Val Pro
115 120 125
Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile
130 135 140
Ala Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr
145 150 155 160
Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln
165 170 175
Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr
180 185 190
Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp
195 200 205
Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu
210 215 220
Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
225 230 235
<210> 31
<211> 241
<212> PRT
<213> homo sapiens
<400> 31
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Phe Leu
50 55 60
Gln Ile Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe
65 70 75 80
Arg Pro Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly
85 90 95
Thr Ile Asn Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr
100 105 110
Glu Ala Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Val Ser
115 120 125
Asp Val Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val Pro Gly
130 135 140
Trp Gly Ile Ala Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala
145 150 155 160
Ile Val Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn
165 170 175
Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met
180 185 190
Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser
195 200 205
Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly
210 215 220
Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn
225 230 235 240
Leu
<210> 32
<211> 198
<212> PRT
<213> homo sapiens
<400> 32
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
20 25 30
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
35 40 45
Thr Glu Lys Asn Ala Leu Ser Thr Gly Val Ser Phe Phe Phe Leu Ser
50 55 60
Phe His Ile Ser Asn Leu Gln Phe Asn Ser Ser Leu Glu Asp Pro Ser
65 70 75 80
Thr Asp Tyr Tyr Gln Glu Leu Gln Arg Asp Ile Ser Glu Met Phe Leu
85 90 95
Gln Ile Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe
100 105 110
Arg Pro Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly
115 120 125
Thr Ile Asn Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr
130 135 140
Glu Ala Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Gly Cys
145 150 155 160
Leu Ser Val Pro Pro Lys Glu Leu Arg Ala Ala Gly His Leu Ser Ser
165 170 175
Pro Gly Tyr Leu Pro Ser Tyr Glu Arg Val Pro His Leu Pro His Pro
180 185 190
Trp Ala Leu Cys Ala Pro
195
<210> 33
<211> 189
<212> PRT
<213> homo sapiens
<400> 33
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Phe Asn
50 55 60
Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg
65 70 75 80
Asp Ile Ser Glu Met Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala
85 90 95
Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu
100 105 110
Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu
115 120 125
Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro
130 135 140
Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg
145 150 155 160
Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser
165 170 175
Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
180 185
<210> 34
<211> 177
<212> PRT
<213> homo sapiens
<400> 34
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Leu Ser
50 55 60
Thr Gly Val Ser Phe Phe Phe Leu Ser Phe His Ile Ser Asn Leu Gln
65 70 75 80
Phe Asn Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu
85 90 95
Gln Arg Asp Ile Ser Glu Met Ala Val Cys Gln Cys Arg Arg Lys Asn
100 105 110
Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met
115 120 125
Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser
130 135 140
Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly
145 150 155 160
Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn
165 170 175
Leu
<210> 35
<211> 255
<212> PRT
<213> homo sapiens
<400> 35
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
20 25 30
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
35 40 45
Thr Glu Lys Asn Ala Phe Asn Ser Ser Leu Glu Asp Pro Ser Thr Asp
50 55 60
Tyr Tyr Gln Glu Leu Gln Arg Asp Ile Ser Glu Met Phe Leu Gln Ile
65 70 75 80
Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro
85 90 95
Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile
100 105 110
Asn Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala
115 120 125
Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Val Ser Asp Val
130 135 140
Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly
145 150 155 160
Ile Ala Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val
165 170 175
Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly
180 185 190
Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu
195 200 205
Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr
210 215 220
Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser
225 230 235 240
Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
245 250 255
<210> 36
<211> 150
<212> PRT
<213> homo sapiens
<400> 36
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
20 25 30
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
35 40 45
Thr Glu Lys Asn Ala Phe Asn Ser Ser Leu Glu Asp Pro Ser Thr Asp
50 55 60
Tyr Tyr Gln Glu Leu Gln Arg Asp Ile Ser Glu Met Ala Val Cys Gln
65 70 75 80
Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp
85 90 95
Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg
100 105 110
Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser
115 120 125
Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala
130 135 140
Ala Thr Ser Ala Asn Leu
145 150
<210> 37
<211> 158
<212> PRT
<213> homo sapiens
<400> 37
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
20 25 30
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
35 40 45
Thr Glu Lys Asn Ala Ile Pro Ala Pro Thr Thr Thr Lys Ser Cys Arg
50 55 60
Glu Thr Phe Leu Lys Cys Phe Cys Arg Phe Ile Asn Lys Gly Val Phe
65 70 75 80
Trp Ala Ser Pro Ile Leu Ser Ser Val Trp Gly Trp Gly Ala Arg Leu
85 90 95
Gly His Arg Ala Ala Gly Ala Gly Leu Cys Ser Gly Cys Ala Gly His
100 105 110
Cys Leu Ser His Cys Leu Gly Cys Leu Ser Val Pro Pro Lys Glu Leu
115 120 125
Arg Ala Ala Gly His Leu Ser Ser Pro Gly Tyr Leu Pro Ser Tyr Glu
130 135 140
Arg Val Pro His Leu Pro His Pro Trp Ala Leu Cys Ala Pro
145 150 155
<210> 38
<211> 484
<212> PRT
<213> homo sapiens
<400> 38
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Val Ser
50 55 60
Met Thr Ser Ser Val Leu Ser Ser His Ser Pro Gly Ser Gly Ser Ser
65 70 75 80
Thr Thr Gln Gly Gln Asp Val Thr Leu Ala Pro Ala Thr Glu Pro Ala
85 90 95
Ser Gly Ser Ala Ala Thr Trp Gly Gln Asp Val Thr Ser Val Pro Val
100 105 110
Thr Arg Pro Ala Leu Gly Ser Thr Thr Pro Pro Ala His Asp Val Thr
115 120 125
Ser Ala Pro Asp Asn Lys Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala
130 135 140
His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr
145 150 155 160
Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Asn Arg Pro Ala
165 170 175
Leu Gly Ser Thr Ala Pro Pro Val His Asn Val Thr Ser Ala Ser Gly
180 185 190
Ser Ala Ser Gly Ser Ala Ser Thr Leu Val His Asn Gly Thr Ser Ala
195 200 205
Arg Ala Thr Thr Thr Pro Ala Ser Lys Ser Thr Pro Phe Ser Ile Pro
210 215 220
Ser His His Ser Asp Thr Pro Thr Thr Leu Ala Ser His Ser Thr Lys
225 230 235 240
Thr Asp Ala Ser Ser Thr His His Ser Thr Val Pro Pro Leu Thr Ser
245 250 255
Ser Asn His Ser Thr Ser Pro Gln Leu Ser Thr Gly Val Ser Phe Phe
260 265 270
Phe Leu Ser Phe His Ile Ser Asn Leu Gln Phe Asn Ser Ser Leu Glu
275 280 285
Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg Asp Ile Ser Glu
290 295 300
Met Phe Leu Gln Ile Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn
305 310 315 320
Ile Lys Phe Arg Pro Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe
325 330 335
Arg Glu Gly Thr Ile Asn Val His Asp Val Glu Thr Gln Phe Asn Gln
340 345 350
Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val
355 360 365
Ser Val Ser Asp Val Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly
370 375 380
Val Pro Gly Trp Gly Ile Ala Leu Leu Val Leu Val Cys Val Leu Val
385 390 395 400
Ala Leu Ala Ile Val Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg
405 410 415
Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr
420 425 430
His Pro Met Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val
435 440 445
Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly
450 455 460
Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr
465 470 475 480
Ser Ala Asn Leu
<210> 39
<211> 219
<212> PRT
<213> homo sapiens
<400> 39
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Phe Asn
50 55 60
Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg
65 70 75 80
Asp Ile Ser Glu Met Phe Leu Gln Ile Tyr Lys Gln Gly Gly Phe Leu
85 90 95
Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val Val Gln Leu
100 105 110
Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val Glu Thr
115 120 125
Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu Thr
130 135 140
Ile Ser Asp Val Ser Val Trp Gly Trp Gly Ala Arg Leu Gly His Arg
145 150 155 160
Ala Ala Gly Ala Gly Leu Cys Ser Gly Cys Ala Gly His Cys Leu Ser
165 170 175
His Cys Leu Gly Cys Leu Ser Val Pro Pro Lys Glu Leu Arg Ala Ala
180 185 190
Gly His Leu Ser Ser Pro Gly Tyr Leu Pro Ser Tyr Glu Arg Val Pro
195 200 205
His Leu Pro His Pro Trp Ala Leu Cys Ala Pro
210 215
<210> 40
<211> 217
<212> PRT
<213> homo sapiens
<400> 40
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Gly Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser
20 25 30
Val Pro Ser Ser Thr Glu Lys Asn Ala Ile Tyr Lys Gln Gly Gly Phe
35 40 45
Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val Val Gln
50 55 60
Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val Glu
65 70 75 80
Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu
85 90 95
Thr Ile Ser Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe Ser Ala
100 105 110
Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu Val Leu
115 120 125
Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala Leu Ala
130 135 140
Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro
145 150 155 160
Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr His Thr
165 170 175
His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu
180 185 190
Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro
195 200 205
Ala Val Ala Ala Thr Ser Ala Asn Leu
210 215
<210> 41
<211> 239
<212> PRT
<213> homo sapiens
<400> 41
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Ile Pro
50 55 60
Ala Pro Thr Thr Thr Lys Ser Cys Arg Glu Thr Phe Leu Lys Trp Pro
65 70 75 80
Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile
85 90 95
Asn Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala
100 105 110
Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Val Ser Asp Val
115 120 125
Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly
130 135 140
Ile Ala Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val
145 150 155 160
Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly
165 170 175
Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu
180 185 190
Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr
195 200 205
Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser
210 215 220
Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
225 230 235
<210> 42
<211> 230
<212> PRT
<213> homo sapiens
<400> 42
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
20 25 30
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
35 40 45
Thr Glu Lys Asn Ala Ile Pro Ala Pro Thr Thr Thr Lys Ser Cys Arg
50 55 60
Glu Thr Phe Leu Lys Trp Pro Gly Ser Val Val Val Gln Leu Thr Leu
65 70 75 80
Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val Glu Thr Gln Phe
85 90 95
Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu Thr Ile Ser
100 105 110
Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe Ser Ala Gln Ser Gly
115 120 125
Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu Val Leu Val Cys Val
130 135 140
Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala Leu Ala Val Cys Gln
145 150 155 160
Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp
165 170 175
Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg
180 185 190
Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser
195 200 205
Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala
210 215 220
Ala Thr Ser Ala Asn Leu
225 230
<210> 43
<211> 212
<212> PRT
<213> homo sapiens
<400> 43
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
20 25 30
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
35 40 45
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Ile Pro
50 55 60
Ala Pro Thr Thr Thr Lys Ser Cys Arg Glu Thr Phe Leu Lys Cys Phe
65 70 75 80
Cys Arg Phe Ile Asn Lys Gly Val Phe Trp Ala Ser Pro Ile Leu Ser
85 90 95
Ser Val Ser Asp Val Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly
100 105 110
Val Pro Gly Trp Gly Ile Ala Leu Leu Val Leu Val Cys Val Leu Val
115 120 125
Ala Leu Ala Ile Val Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg
130 135 140
Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr
145 150 155 160
His Pro Met Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val
165 170 175
Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly
180 185 190
Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr
195 200 205
Ser Ala Asn Leu
210
<210> 44
<211> 273
<212> PRT
<213> homo sapiens
<400> 44
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 10 15
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
20 25 30
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
35 40 45
Thr Glu Lys Asn Ala Leu Ser Thr Gly Val Ser Phe Phe Phe Leu Ser
50 55 60
Phe His Ile Ser Asn Leu Gln Phe Asn Ser Ser Leu Glu Asp Pro Ser
65 70 75 80
Thr Asp Tyr Tyr Gln Glu Leu Gln Arg Asp Ile Ser Glu Met Phe Leu
85 90 95
Gln Ile Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe
100 105 110
Arg Pro Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly
115 120 125
Thr Ile Asn Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr
130 135 140
Glu Ala Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Val Ser
145 150 155 160
Asp Val Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val Pro Gly
165 170 175
Trp Gly Ile Ala Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala
180 185 190
Ile Val Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn
195 200 205
Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met
210 215 220
Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser
225 230 235 240
Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly
245 250 255
Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn
260 265 270
Leu
<210> 45
<211> 575
<212> PRT
<213> homo sapiens
<400> 45
Met Asp Leu Val Leu Lys Arg Cys Leu Leu His Leu Ala Val Ile Gly
1 5 10 15
Ala Leu Leu Ala Val Gly Ala Thr Lys Gly Ser Gln Val Trp Gly Gly
20 25 30
Gln Pro Val Tyr Pro Gln Glu Thr Asp Asp Ala Cys Ile Phe Pro Asp
35 40 45
Gly Gly Pro Cys Pro Ser Gly Ser Trp Ser Gln Lys Arg Ser Phe Val
50 55 60
Tyr Val Trp Lys Thr Trp Gly Gln Tyr Trp Gln Val Leu Gly Gly Pro
65 70 75 80
Val Ser Gly Leu Ser Ile Gly Thr Gly Arg Ala Met Leu Gly Thr His
85 90 95
Thr Met Glu Val Thr Val Tyr His Arg Arg Gly Ser Arg Ser Tyr Val
100 105 110
Pro Leu Ala His Ser Ser Ser Ala Phe Thr Ile Thr Asp Gln Val Pro
115 120 125
Phe Ser Val Ser Val Ser Gln Leu Arg Ala Leu Asp Gly Gly Asn Lys
130 135 140
His Phe Leu Arg Asn Gln Pro Leu Thr Phe Ala Leu Gln Leu His Asp
145 150 155 160
Pro Ser Gly Tyr Leu Ala Glu Ala Asp Leu Ser Tyr Thr Trp Asp Phe
165 170 175
Gly Asp Ser Ser Gly Thr Leu Ile Ser Arg Ala Leu Val Val Thr His
180 185 190
Thr Tyr Leu Glu Pro Gly Pro Val Thr Ala Gln Val Val Leu Gln Ala
195 200 205
Ala Ile Pro Leu Thr Ser Cys Gly Ser Ser Pro Val Pro Gly Thr Thr
210 215 220
Asp Gly His Arg Pro Thr Ala Glu Ala Pro Asn Thr Thr Ala Gly Gln
225 230 235 240
Val Pro Thr Thr Glu Val Val Gly Thr Thr Pro Gly Gln Ala Pro Thr
245 250 255
Ala Glu Pro Ser Gly Thr Thr Ser Val Gln Val Pro Thr Thr Glu Val
260 265 270
Ile Ser Thr Ala Pro Val Gln Met Pro Thr Ala Glu Ser Thr Gly Met
275 280 285
Thr Pro Glu Lys Val Pro Val Ser Glu Val Met Gly Thr Thr Leu Ala
290 295 300
Glu Met Ser Thr Pro Glu Ala Thr Gly Met Thr Pro Ala Glu Val Ser
305 310 315 320
Ile Val Val Leu Ser Gly Thr Thr Ala Ala Gln Val Thr Thr Thr Glu
325 330 335
Trp Val Glu Thr Thr Ala Arg Glu Leu Pro Ile Pro Glu Pro Glu Gly
340 345 350
Pro Asp Ala Ser Ser Ile Met Ser Thr Glu Ser Ile Thr Gly Ser Leu
355 360 365
Gly Pro Leu Leu Asp Gly Thr Ala Thr Leu Arg Leu Val Lys Arg Gln
370 375 380
Val Pro Leu Asp Cys Val Leu Tyr Arg Tyr Gly Ser Phe Ser Val Thr
385 390 395 400
Leu Asp Ile Val Gln Gly Ile Glu Ser Ala Glu Ile Leu Gln Ala Val
405 410 415
Pro Ser Gly Glu Gly Asp Ala Phe Glu Leu Thr Val Ser Cys Gln Gly
420 425 430
Gly Leu Pro Lys Glu Ala Cys Met Glu Ile Ser Ser Pro Gly Cys Gln
435 440 445
Pro Pro Ala Gln Arg Leu Cys Gln Pro Val Leu Pro Ser Pro Ala Cys
450 455 460
Gln Leu Val Leu His Gln Ile Leu Lys Gly Gly Ser Gly Thr Tyr Cys
465 470 475 480
Leu Asn Val Ser Leu Ala Asp Thr Asn Ser Leu Ala Val Val Ser Thr
485 490 495
Gln Leu Ile Met Pro Gly Gln Glu Ala Gly Leu Gly Gln Val Pro Leu
500 505 510
Ile Val Gly Ile Leu Leu Val Leu Met Ala Val Val Leu Ala Ser Leu
515 520 525
Ile Tyr Arg Arg Arg Leu Met Lys Gln Asp Phe Ser Val Pro Gln Leu
530 535 540
Pro His Ser Ser Ser His Trp Leu Arg Leu Pro Arg Ile Phe Cys Ser
545 550 555 560
Cys Pro Ile Gly Glu Asn Ser Pro Leu Leu Ser Gly Gln Gln Val
565 570 575
<210> 46
<211> 661
<212> PRT
<213> homo sapiens
<400> 46
Met Asp Leu Val Leu Lys Arg Cys Leu Leu His Leu Ala Val Ile Gly
1 5 10 15
Ala Leu Leu Ala Val Gly Ala Thr Lys Val Pro Arg Asn Gln Asp Trp
20 25 30
Leu Gly Val Ser Arg Gln Leu Arg Thr Lys Ala Trp Asn Arg Gln Leu
35 40 45
Tyr Pro Glu Trp Thr Glu Ala Gln Arg Leu Asp Cys Trp Arg Gly Gly
50 55 60
Gln Val Ser Leu Lys Val Ser Asn Asp Gly Pro Thr Leu Ile Gly Ala
65 70 75 80
Asn Ala Ser Phe Ser Ile Ala Leu Asn Phe Pro Gly Ser Gln Lys Val
85 90 95
Leu Pro Asp Gly Gln Val Ile Trp Val Asn Asn Thr Ile Ile Asn Gly
100 105 110
Ser Gln Val Trp Gly Gly Gln Pro Val Tyr Pro Gln Glu Thr Asp Asp
115 120 125
Ala Cys Ile Phe Pro Asp Gly Gly Pro Cys Pro Ser Gly Ser Trp Ser
130 135 140
Gln Lys Arg Ser Phe Val Tyr Val Trp Lys Thr Trp Gly Gln Tyr Trp
145 150 155 160
Gln Val Leu Gly Gly Pro Val Ser Gly Leu Ser Ile Gly Thr Gly Arg
165 170 175
Ala Met Leu Gly Thr His Thr Met Glu Val Thr Val Tyr His Arg Arg
180 185 190
Gly Ser Arg Ser Tyr Val Pro Leu Ala His Ser Ser Ser Ala Phe Thr
195 200 205
Ile Thr Asp Gln Val Pro Phe Ser Val Ser Val Ser Gln Leu Arg Ala
210 215 220
Leu Asp Gly Gly Asn Lys His Phe Leu Arg Asn Gln Pro Leu Thr Phe
225 230 235 240
Ala Leu Gln Leu His Asp Pro Ser Gly Tyr Leu Ala Glu Ala Asp Leu
245 250 255
Ser Tyr Thr Trp Asp Phe Gly Asp Ser Ser Gly Thr Leu Ile Ser Arg
260 265 270
Ala Leu Val Val Thr His Thr Tyr Leu Glu Pro Gly Pro Val Thr Ala
275 280 285
Gln Val Val Leu Gln Ala Ala Ile Pro Leu Thr Ser Cys Gly Ser Ser
290 295 300
Pro Val Pro Gly Thr Thr Asp Gly His Arg Pro Thr Ala Glu Ala Pro
305 310 315 320
Asn Thr Thr Ala Gly Gln Val Pro Thr Thr Glu Val Val Gly Thr Thr
325 330 335
Pro Gly Gln Ala Pro Thr Ala Glu Pro Ser Gly Thr Thr Ser Val Gln
340 345 350
Val Pro Thr Thr Glu Val Ile Ser Thr Ala Pro Val Gln Met Pro Thr
355 360 365
Ala Glu Ser Thr Gly Met Thr Pro Glu Lys Val Pro Val Ser Glu Val
370 375 380
Met Gly Thr Thr Leu Ala Glu Met Ser Thr Pro Glu Ala Thr Gly Met
385 390 395 400
Thr Pro Ala Glu Val Ser Ile Val Val Leu Ser Gly Thr Thr Ala Ala
405 410 415
Gln Val Thr Thr Thr Glu Trp Val Glu Thr Thr Ala Arg Glu Leu Pro
420 425 430
Ile Pro Glu Pro Glu Gly Pro Asp Ala Ser Ser Ile Met Ser Thr Glu
435 440 445
Ser Ile Thr Gly Ser Leu Gly Pro Leu Leu Asp Gly Thr Ala Thr Leu
450 455 460
Arg Leu Val Lys Arg Gln Val Pro Leu Asp Cys Val Leu Tyr Arg Tyr
465 470 475 480
Gly Ser Phe Ser Val Thr Leu Asp Ile Val Gln Gly Ile Glu Ser Ala
485 490 495
Glu Ile Leu Gln Ala Val Pro Ser Gly Glu Gly Asp Ala Phe Glu Leu
500 505 510
Thr Val Ser Cys Gln Gly Gly Leu Pro Lys Glu Ala Cys Met Glu Ile
515 520 525
Ser Ser Pro Gly Cys Gln Pro Pro Ala Gln Arg Leu Cys Gln Pro Val
530 535 540
Leu Pro Ser Pro Ala Cys Gln Leu Val Leu His Gln Ile Leu Lys Gly
545 550 555 560
Gly Ser Gly Thr Tyr Cys Leu Asn Val Ser Leu Ala Asp Thr Asn Ser
565 570 575
Leu Ala Val Val Ser Thr Gln Leu Ile Met Pro Gly Gln Glu Ala Gly
580 585 590
Leu Gly Gln Val Pro Leu Ile Val Gly Ile Leu Leu Val Leu Met Ala
595 600 605
Val Val Leu Ala Ser Leu Ile Tyr Arg Arg Arg Leu Met Lys Gln Asp
610 615 620
Phe Ser Val Pro Gln Leu Pro His Ser Ser Ser His Trp Leu Arg Leu
625 630 635 640
Pro Arg Ile Phe Cys Ser Cys Pro Ile Gly Glu Asn Ser Pro Leu Leu
645 650 655
Ser Gly Gln Gln Val
660
<210> 47
<211> 668
<212> PRT
<213> homo sapiens
<400> 47
Met Asp Leu Val Leu Lys Arg Cys Leu Leu His Leu Ala Val Ile Gly
1 5 10 15
Ala Leu Leu Ala Val Gly Ala Thr Lys Val Pro Arg Asn Gln Asp Trp
20 25 30
Leu Gly Val Ser Arg Gln Leu Arg Thr Lys Ala Trp Asn Arg Gln Leu
35 40 45
Tyr Pro Glu Trp Thr Glu Ala Gln Arg Leu Asp Cys Trp Arg Gly Gly
50 55 60
Gln Val Ser Leu Lys Val Ser Asn Asp Gly Pro Thr Leu Ile Gly Ala
65 70 75 80
Asn Ala Ser Phe Ser Ile Ala Leu Asn Phe Pro Gly Ser Gln Lys Val
85 90 95
Leu Pro Asp Gly Gln Val Ile Trp Val Asn Asn Thr Ile Ile Asn Gly
100 105 110
Ser Gln Val Trp Gly Gly Gln Pro Val Tyr Pro Gln Glu Thr Asp Asp
115 120 125
Ala Cys Ile Phe Pro Asp Gly Gly Pro Cys Pro Ser Gly Ser Trp Ser
130 135 140
Gln Lys Arg Ser Phe Val Tyr Val Trp Lys Thr Trp Gly Gln Tyr Trp
145 150 155 160
Gln Val Leu Gly Gly Pro Val Ser Gly Leu Ser Ile Gly Thr Gly Arg
165 170 175
Ala Met Leu Gly Thr His Thr Met Glu Val Thr Val Tyr His Arg Arg
180 185 190
Gly Ser Arg Ser Tyr Val Pro Leu Ala His Ser Ser Ser Ala Phe Thr
195 200 205
Ile Thr Asp Gln Val Pro Phe Ser Val Ser Val Ser Gln Leu Arg Ala
210 215 220
Leu Asp Gly Gly Asn Lys His Phe Leu Arg Asn Gln Pro Leu Thr Phe
225 230 235 240
Ala Leu Gln Leu His Asp Pro Ser Gly Tyr Leu Ala Glu Ala Asp Leu
245 250 255
Ser Tyr Thr Trp Asp Phe Gly Asp Ser Ser Gly Thr Leu Ile Ser Arg
260 265 270
Ala Leu Val Val Thr His Thr Tyr Leu Glu Pro Gly Pro Val Thr Ala
275 280 285
Gln Val Val Leu Gln Ala Ala Ile Pro Leu Thr Ser Cys Gly Ser Ser
290 295 300
Pro Val Pro Gly Thr Thr Asp Gly His Arg Pro Thr Ala Glu Ala Pro
305 310 315 320
Asn Thr Thr Ala Gly Gln Val Pro Thr Thr Glu Val Val Gly Thr Thr
325 330 335
Pro Gly Gln Ala Pro Thr Ala Glu Pro Ser Gly Thr Thr Ser Val Gln
340 345 350
Val Pro Thr Thr Glu Val Ile Ser Thr Ala Pro Val Gln Met Pro Thr
355 360 365
Ala Glu Ser Thr Gly Met Thr Pro Glu Lys Val Pro Val Ser Glu Val
370 375 380
Met Gly Thr Thr Leu Ala Glu Met Ser Thr Pro Glu Ala Thr Gly Met
385 390 395 400
Thr Pro Ala Glu Val Ser Ile Val Val Leu Ser Gly Thr Thr Ala Ala
405 410 415
Gln Val Thr Thr Thr Glu Trp Val Glu Thr Thr Ala Arg Glu Leu Pro
420 425 430
Ile Pro Glu Pro Glu Gly Pro Asp Ala Ser Ser Ile Met Ser Thr Glu
435 440 445
Ser Ile Thr Gly Ser Leu Gly Pro Leu Leu Asp Gly Thr Ala Thr Leu
450 455 460
Arg Leu Val Lys Arg Gln Val Pro Leu Asp Cys Val Leu Tyr Arg Tyr
465 470 475 480
Gly Ser Phe Ser Val Thr Leu Asp Ile Val Gln Gly Ile Glu Ser Ala
485 490 495
Glu Ile Leu Gln Ala Val Pro Ser Gly Glu Gly Asp Ala Phe Glu Leu
500 505 510
Thr Val Ser Cys Gln Gly Gly Leu Pro Lys Glu Ala Cys Met Glu Ile
515 520 525
Ser Ser Pro Gly Cys Gln Pro Pro Ala Gln Arg Leu Cys Gln Pro Val
530 535 540
Leu Pro Ser Pro Ala Cys Gln Leu Val Leu His Gln Ile Leu Lys Gly
545 550 555 560
Gly Ser Gly Thr Tyr Cys Leu Asn Val Ser Leu Ala Asp Thr Asn Ser
565 570 575
Leu Ala Val Val Ser Thr Gln Leu Ile Met Pro Val Pro Gly Ile Leu
580 585 590
Leu Thr Gly Gln Glu Ala Gly Leu Gly Gln Val Pro Leu Ile Val Gly
595 600 605
Ile Leu Leu Val Leu Met Ala Val Val Leu Ala Ser Leu Ile Tyr Arg
610 615 620
Arg Arg Leu Met Lys Gln Asp Phe Ser Val Pro Gln Leu Pro His Ser
625 630 635 640
Ser Ser His Trp Leu Arg Leu Pro Arg Ile Phe Cys Ser Cys Pro Ile
645 650 655
Gly Glu Asn Ser Pro Leu Leu Ser Gly Gln Gln Val
660 665
<210> 48
<211> 118
<212> PRT
<213> homo sapiens
<400> 48
Met Pro Arg Glu Asp Ala His Phe Ile Tyr Gly Tyr Pro Lys Lys Gly
1 5 10 15
His Gly His Ser Tyr Thr Thr Ala Glu Glu Ala Ala Gly Ile Gly Ile
20 25 30
Leu Thr Val Ile Leu Gly Val Leu Leu Leu Ile Gly Cys Trp Tyr Cys
35 40 45
Arg Arg Arg Asn Gly Tyr Arg Ala Leu Met Asp Lys Ser Leu His Val
50 55 60
Gly Thr Gln Cys Ala Leu Thr Arg Arg Cys Pro Gln Glu Gly Phe Asp
65 70 75 80
His Arg Asp Ser Lys Val Ser Leu Gln Glu Lys Asn Cys Glu Pro Val
85 90 95
Val Pro Asn Ala Pro Pro Ala Tyr Glu Lys Leu Ser Ala Glu Gln Ser
100 105 110
Pro Pro Pro Tyr Ser Pro
115
<210> 49
<211> 1069
<212> PRT
<213> homo sapiens
<400> 49
Met Pro Arg Ala Pro Arg Cys Arg Ala Val Arg Ser Leu Leu Arg Ser
1 5 10 15
His Tyr Arg Glu Val Leu Pro Leu Ala Thr Phe Val Arg Arg Leu Gly
20 25 30
Pro Gln Gly Trp Arg Leu Val Gln Arg Gly Asp Pro Ala Ala Phe Arg
35 40 45
Ala Leu Val Ala Gln Cys Leu Val Cys Val Pro Trp Asp Ala Arg Pro
50 55 60
Pro Pro Ala Ala Pro Ser Phe Arg Gln Val Ser Cys Leu Lys Glu Leu
65 70 75 80
Val Ala Arg Val Leu Gln Arg Leu Cys Glu Arg Gly Ala Lys Asn Val
85 90 95
Leu Ala Phe Gly Phe Ala Leu Leu Asp Gly Ala Arg Gly Gly Pro Pro
100 105 110
Glu Ala Phe Thr Thr Ser Val Arg Ser Tyr Leu Pro Asn Thr Val Thr
115 120 125
Asp Ala Leu Arg Gly Ser Gly Ala Trp Gly Leu Leu Leu Arg Arg Val
130 135 140
Gly Asp Asp Val Leu Val His Leu Leu Ala Arg Cys Ala Leu Phe Val
145 150 155 160
Leu Val Ala Pro Ser Cys Ala Tyr Gln Val Cys Gly Pro Pro Leu Tyr
165 170 175
Gln Leu Gly Ala Ala Thr Gln Ala Arg Pro Pro Pro His Ala Ser Gly
180 185 190
Pro Arg Arg Arg Leu Gly Cys Glu Arg Ala Trp Asn His Ser Val Arg
195 200 205
Glu Ala Gly Val Pro Leu Gly Leu Pro Ala Pro Gly Ala Arg Arg Arg
210 215 220
Gly Gly Ser Ala Ser Arg Ser Leu Pro Leu Pro Lys Arg Pro Arg Arg
225 230 235 240
Gly Ala Ala Pro Glu Pro Glu Arg Thr Pro Val Gly Gln Gly Ser Trp
245 250 255
Ala His Pro Gly Arg Thr Arg Gly Pro Ser Asp Arg Gly Phe Cys Val
260 265 270
Val Ser Pro Ala Arg Pro Ala Glu Glu Ala Thr Ser Leu Glu Gly Ala
275 280 285
Leu Ser Gly Thr Arg His Ser His Pro Ser Val Gly Arg Gln His His
290 295 300
Ala Gly Pro Pro Ser Thr Ser Arg Pro Pro Arg Pro Trp Asp Thr Pro
305 310 315 320
Cys Pro Pro Val Tyr Ala Glu Thr Lys His Phe Leu Tyr Ser Ser Gly
325 330 335
Asp Lys Glu Gln Leu Arg Pro Ser Phe Leu Leu Ser Ser Leu Arg Pro
340 345 350
Ser Leu Thr Gly Ala Arg Arg Leu Val Glu Thr Ile Phe Leu Gly Ser
355 360 365
Arg Pro Trp Met Pro Gly Thr Pro Arg Arg Leu Pro Arg Leu Pro Gln
370 375 380
Arg Tyr Trp Gln Met Arg Pro Leu Phe Leu Glu Leu Leu Gly Asn His
385 390 395 400
Ala Gln Cys Pro Tyr Gly Val Leu Leu Lys Thr His Cys Pro Leu Arg
405 410 415
Ala Ala Val Thr Pro Ala Ala Gly Val Cys Ala Arg Glu Lys Pro Gln
420 425 430
Gly Ser Val Ala Ala Pro Glu Glu Glu Asp Thr Asp Pro Arg Arg Leu
435 440 445
Val Gln Leu Leu Arg Gln His Ser Ser Pro Trp Gln Val Tyr Gly Phe
450 455 460
Val Arg Ala Cys Leu Arg Arg Leu Val Pro Pro Gly Leu Trp Gly Ser
465 470 475 480
Arg His Asn Glu Arg Arg Phe Leu Arg Asn Thr Lys Lys Phe Ile Ser
485 490 495
Leu Gly Lys His Ala Lys Leu Ser Leu Gln Glu Leu Thr Trp Lys Met
500 505 510
Ser Val Arg Asp Cys Ala Trp Leu Arg Arg Ser Pro Gly Val Gly Cys
515 520 525
Val Pro Ala Ala Glu His Arg Leu Arg Glu Glu Ile Leu Ala Lys Phe
530 535 540
Leu His Trp Leu Met Ser Val Tyr Val Val Glu Leu Leu Arg Ser Phe
545 550 555 560
Phe Tyr Val Thr Glu Thr Thr Phe Gln Lys Asn Arg Leu Phe Phe Tyr
565 570 575
Arg Lys Ser Val Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln His
580 585 590
Leu Lys Arg Val Gln Leu Arg Glu Leu Ser Glu Ala Glu Val Arg Gln
595 600 605
His Arg Glu Ala Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile
610 615 620
Pro Lys Pro Asp Gly Leu Arg Pro Ile Val Asn Met Asp Tyr Val Val
625 630 635 640
Gly Ala Arg Thr Phe Arg Arg Glu Lys Arg Ala Glu Arg Leu Thr Ser
645 650 655
Arg Val Lys Ala Leu Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg
660 665 670
Pro Gly Leu Leu Gly Ala Ser Val Leu Gly Leu Asp Asp Ile His Arg
675 680 685
Ala Trp Arg Thr Phe Val Leu Arg Val Arg Ala Gln Asp Pro Pro Pro
690 695 700
Glu Leu Tyr Phe Val Lys Val Asp Val Thr Gly Ala Tyr Asp Thr Ile
705 710 715 720
Pro Gln Asp Arg Leu Thr Glu Val Ile Ala Ser Ile Ile Lys Pro Gln
725 730 735
Asn Thr Tyr Cys Val Arg Arg Tyr Ala Val Val Gln Lys Ala Ala His
740 745 750
Gly His Val Arg Lys Ala Phe Lys Ser His Val Ser Thr Leu Thr Asp
755 760 765
Leu Gln Pro Tyr Met Arg Gln Phe Val Ala His Leu Gln Glu Thr Ser
770 775 780
Pro Leu Arg Asp Ala Val Val Ile Glu Gln Ser Ser Ser Leu Asn Glu
785 790 795 800
Ala Ser Ser Gly Leu Phe Asp Val Phe Leu Arg Phe Met Cys His His
805 810 815
Ala Val Arg Ile Arg Gly Lys Ser Tyr Val Gln Cys Gln Gly Ile Pro
820 825 830
Gln Gly Ser Ile Leu Ser Thr Leu Leu Cys Ser Leu Cys Tyr Gly Asp
835 840 845
Met Glu Asn Lys Leu Phe Ala Gly Ile Arg Arg Asp Gly Leu Leu Leu
850 855 860
Arg Leu Val Asp Asp Phe Leu Leu Val Thr Pro His Leu Thr His Ala
865 870 875 880
Lys Thr Phe Leu Ser Tyr Ala Arg Thr Ser Ile Arg Ala Ser Leu Thr
885 890 895
Phe Asn Arg Gly Phe Lys Ala Gly Arg Asn Met Arg Arg Lys Leu Phe
900 905 910
Gly Val Leu Arg Leu Lys Cys His Ser Leu Phe Leu Asp Leu Gln Val
915 920 925
Asn Ser Leu Gln Thr Val Cys Thr Asn Ile Tyr Lys Ile Leu Leu Leu
930 935 940
Gln Ala Tyr Arg Phe His Ala Cys Val Leu Gln Leu Pro Phe His Gln
945 950 955 960
Gln Val Trp Lys Asn Pro Thr Phe Phe Leu Arg Val Ile Ser Asp Thr
965 970 975
Ala Ser Leu Cys Tyr Ser Ile Leu Lys Ala Lys Asn Ala Gly Met Ser
980 985 990
Leu Gly Ala Lys Gly Ala Ala Gly Pro Leu Pro Ser Glu Ala Val Gln
995 1000 1005
Trp Leu Cys His Gln Ala Phe Leu Leu Lys Leu Thr Arg His Arg
1010 1015 1020
Val Thr Tyr Val Pro Leu Leu Gly Ser Leu Arg Thr Ala Gln Thr
1025 1030 1035
Gln Leu Ser Arg Lys Leu Pro Gly Thr Thr Leu Thr Ala Leu Glu
1040 1045 1050
Ala Ala Ala Asn Pro Ala Leu Pro Ser Asp Phe Lys Thr Ile Leu
1055 1060 1065
Asp
<210> 50
<211> 1132
<212> PRT
<213> homo sapiens
<400> 50
Met Pro Arg Ala Pro Arg Cys Arg Ala Val Arg Ser Leu Leu Arg Ser
1 5 10 15
His Tyr Arg Glu Val Leu Pro Leu Ala Thr Phe Val Arg Arg Leu Gly
20 25 30
Pro Gln Gly Trp Arg Leu Val Gln Arg Gly Asp Pro Ala Ala Phe Arg
35 40 45
Ala Leu Val Ala Gln Cys Leu Val Cys Val Pro Trp Asp Ala Arg Pro
50 55 60
Pro Pro Ala Ala Pro Ser Phe Arg Gln Val Ser Cys Leu Lys Glu Leu
65 70 75 80
Val Ala Arg Val Leu Gln Arg Leu Cys Glu Arg Gly Ala Lys Asn Val
85 90 95
Leu Ala Phe Gly Phe Ala Leu Leu Asp Gly Ala Arg Gly Gly Pro Pro
100 105 110
Glu Ala Phe Thr Thr Ser Val Arg Ser Tyr Leu Pro Asn Thr Val Thr
115 120 125
Asp Ala Leu Arg Gly Ser Gly Ala Trp Gly Leu Leu Leu Arg Arg Val
130 135 140
Gly Asp Asp Val Leu Val His Leu Leu Ala Arg Cys Ala Leu Phe Val
145 150 155 160
Leu Val Ala Pro Ser Cys Ala Tyr Gln Val Cys Gly Pro Pro Leu Tyr
165 170 175
Gln Leu Gly Ala Ala Thr Gln Ala Arg Pro Pro Pro His Ala Ser Gly
180 185 190
Pro Arg Arg Arg Leu Gly Cys Glu Arg Ala Trp Asn His Ser Val Arg
195 200 205
Glu Ala Gly Val Pro Leu Gly Leu Pro Ala Pro Gly Ala Arg Arg Arg
210 215 220
Gly Gly Ser Ala Ser Arg Ser Leu Pro Leu Pro Lys Arg Pro Arg Arg
225 230 235 240
Gly Ala Ala Pro Glu Pro Glu Arg Thr Pro Val Gly Gln Gly Ser Trp
245 250 255
Ala His Pro Gly Arg Thr Arg Gly Pro Ser Asp Arg Gly Phe Cys Val
260 265 270
Val Ser Pro Ala Arg Pro Ala Glu Glu Ala Thr Ser Leu Glu Gly Ala
275 280 285
Leu Ser Gly Thr Arg His Ser His Pro Ser Val Gly Arg Gln His His
290 295 300
Ala Gly Pro Pro Ser Thr Ser Arg Pro Pro Arg Pro Trp Asp Thr Pro
305 310 315 320
Cys Pro Pro Val Tyr Ala Glu Thr Lys His Phe Leu Tyr Ser Ser Gly
325 330 335
Asp Lys Glu Gln Leu Arg Pro Ser Phe Leu Leu Ser Ser Leu Arg Pro
340 345 350
Ser Leu Thr Gly Ala Arg Arg Leu Val Glu Thr Ile Phe Leu Gly Ser
355 360 365
Arg Pro Trp Met Pro Gly Thr Pro Arg Arg Leu Pro Arg Leu Pro Gln
370 375 380
Arg Tyr Trp Gln Met Arg Pro Leu Phe Leu Glu Leu Leu Gly Asn His
385 390 395 400
Ala Gln Cys Pro Tyr Gly Val Leu Leu Lys Thr His Cys Pro Leu Arg
405 410 415
Ala Ala Val Thr Pro Ala Ala Gly Val Cys Ala Arg Glu Lys Pro Gln
420 425 430
Gly Ser Val Ala Ala Pro Glu Glu Glu Asp Thr Asp Pro Arg Arg Leu
435 440 445
Val Gln Leu Leu Arg Gln His Ser Ser Pro Trp Gln Val Tyr Gly Phe
450 455 460
Val Arg Ala Cys Leu Arg Arg Leu Val Pro Pro Gly Leu Trp Gly Ser
465 470 475 480
Arg His Asn Glu Arg Arg Phe Leu Arg Asn Thr Lys Lys Phe Ile Ser
485 490 495
Leu Gly Lys His Ala Lys Leu Ser Leu Gln Glu Leu Thr Trp Lys Met
500 505 510
Ser Val Arg Asp Cys Ala Trp Leu Arg Arg Ser Pro Gly Val Gly Cys
515 520 525
Val Pro Ala Ala Glu His Arg Leu Arg Glu Glu Ile Leu Ala Lys Phe
530 535 540
Leu His Trp Leu Met Ser Val Tyr Val Val Glu Leu Leu Arg Ser Phe
545 550 555 560
Phe Tyr Val Thr Glu Thr Thr Phe Gln Lys Asn Arg Leu Phe Phe Tyr
565 570 575
Arg Lys Ser Val Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln His
580 585 590
Leu Lys Arg Val Gln Leu Arg Glu Leu Ser Glu Ala Glu Val Arg Gln
595 600 605
His Arg Glu Ala Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile
610 615 620
Pro Lys Pro Asp Gly Leu Arg Pro Ile Val Asn Met Asp Tyr Val Val
625 630 635 640
Gly Ala Arg Thr Phe Arg Arg Glu Lys Arg Ala Glu Arg Leu Thr Ser
645 650 655
Arg Val Lys Ala Leu Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg
660 665 670
Pro Gly Leu Leu Gly Ala Ser Val Leu Gly Leu Asp Asp Ile His Arg
675 680 685
Ala Trp Arg Thr Phe Val Leu Arg Val Arg Ala Gln Asp Pro Pro Pro
690 695 700
Glu Leu Tyr Phe Val Lys Val Asp Val Thr Gly Ala Tyr Asp Thr Ile
705 710 715 720
Pro Gln Asp Arg Leu Thr Glu Val Ile Ala Ser Ile Ile Lys Pro Gln
725 730 735
Asn Thr Tyr Cys Val Arg Arg Tyr Ala Val Val Gln Lys Ala Ala His
740 745 750
Gly His Val Arg Lys Ala Phe Lys Ser His Val Ser Thr Leu Thr Asp
755 760 765
Leu Gln Pro Tyr Met Arg Gln Phe Val Ala His Leu Gln Glu Thr Ser
770 775 780
Pro Leu Arg Asp Ala Val Val Ile Glu Gln Ser Ser Ser Leu Asn Glu
785 790 795 800
Ala Ser Ser Gly Leu Phe Asp Val Phe Leu Arg Phe Met Cys His His
805 810 815
Ala Val Arg Ile Arg Gly Lys Ser Tyr Val Gln Cys Gln Gly Ile Pro
820 825 830
Gln Gly Ser Ile Leu Ser Thr Leu Leu Cys Ser Leu Cys Tyr Gly Asp
835 840 845
Met Glu Asn Lys Leu Phe Ala Gly Ile Arg Arg Asp Gly Leu Leu Leu
850 855 860
Arg Leu Val Asp Asp Phe Leu Leu Val Thr Pro His Leu Thr His Ala
865 870 875 880
Lys Thr Phe Leu Arg Thr Leu Val Arg Gly Val Pro Glu Tyr Gly Cys
885 890 895
Val Val Asn Leu Arg Lys Thr Val Val Asn Phe Pro Val Glu Asp Glu
900 905 910
Ala Leu Gly Gly Thr Ala Phe Val Gln Met Pro Ala His Gly Leu Phe
915 920 925
Pro Trp Cys Gly Leu Leu Leu Asp Thr Arg Thr Leu Glu Val Gln Ser
930 935 940
Asp Tyr Ser Ser Tyr Ala Arg Thr Ser Ile Arg Ala Ser Leu Thr Phe
945 950 955 960
Asn Arg Gly Phe Lys Ala Gly Arg Asn Met Arg Arg Lys Leu Phe Gly
965 970 975
Val Leu Arg Leu Lys Cys His Ser Leu Phe Leu Asp Leu Gln Val Asn
980 985 990
Ser Leu Gln Thr Val Cys Thr Asn Ile Tyr Lys Ile Leu Leu Leu Gln
995 1000 1005
Ala Tyr Arg Phe His Ala Cys Val Leu Gln Leu Pro Phe His Gln
1010 1015 1020
Gln Val Trp Lys Asn Pro Thr Phe Phe Leu Arg Val Ile Ser Asp
1025 1030 1035
Thr Ala Ser Leu Cys Tyr Ser Ile Leu Lys Ala Lys Asn Ala Gly
1040 1045 1050
Met Ser Leu Gly Ala Lys Gly Ala Ala Gly Pro Leu Pro Ser Glu
1055 1060 1065
Ala Val Gln Trp Leu Cys His Gln Ala Phe Leu Leu Lys Leu Thr
1070 1075 1080
Arg His Arg Val Thr Tyr Val Pro Leu Leu Gly Ser Leu Arg Thr
1085 1090 1095
Ala Gln Thr Gln Leu Ser Arg Lys Leu Pro Gly Thr Thr Leu Thr
1100 1105 1110
Ala Leu Glu Ala Ala Ala Asn Pro Ala Leu Pro Ser Asp Phe Lys
1115 1120 1125
Thr Ile Leu Asp
1130
<210> 51
<211> 353
<212> PRT
<213> homo sapiens
<400> 51
Met Ala His Phe Pro Gly Phe Gly Gln Ser Leu Leu Phe Gly Tyr Pro
1 5 10 15
Val Tyr Val Phe Gly Asp Cys Val Gln Gly Asp Trp Cys Pro Ile Ser
20 25 30
Gly Gly Leu Cys Ser Ala Arg Leu His Arg His Ala Leu Leu Ala Thr
35 40 45
Cys Pro Glu His Gln Ile Thr Trp Asp Pro Ile Asp Gly Arg Val Ile
50 55 60
Gly Ser Ala Leu Gln Phe Leu Ile Pro Arg Leu Pro Ser Phe Pro Thr
65 70 75 80
Gln Arg Thr Ser Lys Thr Leu Lys Val Leu Thr Pro Pro Ile Thr His
85 90 95
Thr Thr Pro Asn Ile Pro Pro Ser Phe Leu Gln Ala Met Arg Lys Tyr
100 105 110
Ser Pro Phe Arg Asn Gly Tyr Met Glu Pro Thr Leu Gly Gln His Leu
115 120 125
Pro Thr Leu Ser Phe Pro Asp Pro Gly Leu Arg Pro Gln Asn Leu Tyr
130 135 140
Thr Leu Trp Gly Gly Ser Val Val Cys Met Tyr Leu Tyr Gln Leu Ser
145 150 155 160
Pro Pro Ile Thr Trp Pro Leu Leu Pro His Val Ile Phe Cys His Pro
165 170 175
Gly Gln Leu Gly Ala Phe Leu Thr Asn Val Pro Tyr Lys Arg Ile Glu
180 185 190
Lys Leu Leu Tyr Lys Ile Ser Leu Thr Thr Gly Ala Leu Ile Ile Leu
195 200 205
Pro Glu Asp Cys Leu Pro Thr Thr Leu Phe Gln Pro Ala Arg Ala Pro
210 215 220
Val Thr Leu Thr Ala Trp Gln Asn Gly Leu Leu Pro Phe His Ser Thr
225 230 235 240
Leu Thr Thr Pro Gly Leu Ile Trp Thr Phe Thr Asp Gly Thr Pro Met
245 250 255
Ile Ser Gly Pro Cys Pro Lys Asp Gly Gln Pro Ser Leu Val Leu Gln
260 265 270
Ser Ser Ser Phe Ile Phe His Lys Phe Gln Thr Lys Ala Tyr His Pro
275 280 285
Ser Phe Leu Leu Ser His Gly Leu Ile Gln Tyr Ser Ser Phe His Asn
290 295 300
Leu His Leu Leu Phe Glu Glu Tyr Thr Asn Ile Pro Ile Ser Leu Leu
305 310 315 320
Phe Asn Glu Lys Glu Ala Asp Asp Asn Asp His Glu Pro Gln Ile Ser
325 330 335
Pro Gly Gly Leu Glu Pro Leu Ser Glu Lys His Phe Arg Glu Thr Glu
340 345 350
Val
<210> 52
<211> 345
<212> PRT
<213> homo sapiens
<400> 52
Met Ala His Phe Pro Gly Phe Gly Gln Ser Leu Leu Tyr Gly Tyr Pro
1 5 10 15
Val Tyr Val Phe Gly Asp Cys Val Gln Ala Asp Trp Cys Pro Ile Ser
20 25 30
Gly Gly Leu Cys Ser Pro Arg Leu His Arg His Ala Leu Leu Ala Thr
35 40 45
Cys Pro Glu His Gln Ile Thr Trp Asp Pro Ile Asp Gly Arg Val Val
50 55 60
Gly Ser Pro Leu Gln Tyr Leu Ile Pro Arg Leu Pro Ser Phe Pro Thr
65 70 75 80
Gln Arg Thr Ser Lys Thr Leu Lys Val Leu Thr Pro Pro Thr Thr Pro
85 90 95
Val Thr Pro Lys Val Pro Pro Ser Phe Phe Gln Ser Val Arg Arg His
100 105 110
Ser Pro Tyr Arg Asn Gly Cys Leu Glu Thr Thr Leu Gly Glu Gln Leu
115 120 125
Pro Ser Leu Ala Phe Pro Glu Pro Gly Leu Arg Pro Gln Asn Val Tyr
130 135 140
Thr Ile Trp Gly Lys Thr Ile Val Cys Leu Tyr Ile Tyr Gln Leu Ser
145 150 155 160
Pro Pro Met Thr Trp Pro Leu Ile Pro His Val Ile Phe Cys Asn Pro
165 170 175
Arg Gln Leu Gly Ala Phe Leu Ser Asn Val Pro Pro Lys Arg Leu Glu
180 185 190
Glu Leu Leu Tyr Lys Leu Tyr Leu His Thr Gly Ala Ile Ile Ile Leu
195 200 205
Pro Glu Asp Ala Leu Pro Thr Thr Leu Phe Gln Pro Val Arg Ala Pro
210 215 220
Cys Val Gln Thr Thr Trp Asn Thr Gly Leu Leu Pro Tyr Gln Pro Asn
225 230 235 240
Leu Thr Thr Pro Gly Leu Ile Trp Thr Phe Asn Asp Gly Ser Pro Met
245 250 255
Ile Ser Gly Pro Cys Pro Lys Ala Gly Gln Pro Ser Leu Val Val Gln
260 265 270
Ser Ser Leu Leu Ile Phe Glu Arg Phe Gln Thr Lys Ala Tyr His Pro
275 280 285
Ser Tyr Leu Leu Ser His Gln Leu Ile Gln Tyr Ser Ser Phe His His
290 295 300
Leu Tyr Leu Leu Phe Asp Glu Tyr Thr Thr Ile Pro Phe Ser Leu Leu
305 310 315 320
Phe Lys Glu Lys Glu Gly Asp Asp Arg Asp Asn Asp Pro Leu Pro Gly
325 330 335
Ala Thr Ala Ser Pro Gln Gly Gln Asn
340 345
<210> 53
<211> 180
<212> PRT
<213> homo sapiens
<400> 53
Met Gln Ala Glu Gly Arg Gly Thr Gly Gly Ser Thr Gly Asp Ala Asp
1 5 10 15
Gly Pro Gly Gly Pro Gly Ile Pro Asp Gly Pro Gly Gly Asn Ala Gly
20 25 30
Gly Pro Gly Glu Ala Gly Ala Thr Gly Gly Arg Gly Pro Arg Gly Ala
35 40 45
Gly Ala Ala Arg Ala Ser Gly Pro Gly Gly Gly Ala Pro Arg Gly Pro
50 55 60
His Gly Gly Ala Ala Ser Gly Leu Asn Gly Cys Cys Arg Cys Gly Ala
65 70 75 80
Arg Gly Pro Glu Ser Arg Leu Leu Glu Phe Tyr Leu Ala Met Pro Phe
85 90 95
Ala Thr Pro Met Glu Ala Glu Leu Ala Arg Arg Ser Leu Ala Gln Asp
100 105 110
Ala Pro Pro Leu Pro Val Pro Gly Val Leu Leu Lys Glu Phe Thr Val
115 120 125
Ser Gly Asn Ile Leu Thr Ile Arg Leu Thr Ala Ala Asp His Arg Gln
130 135 140
Leu Gln Leu Ser Ile Ser Ser Cys Leu Gln Gln Leu Ser Leu Leu Met
145 150 155 160
Trp Ile Thr Gln Cys Phe Leu Pro Val Phe Leu Ala Gln Pro Pro Ser
165 170 175
Gly Gln Arg Arg
180
<210> 54
<211> 309
<212> PRT
<213> homo sapiens
<400> 54
Met Ser Leu Glu Gln Arg Ser Leu His Cys Lys Pro Glu Glu Ala Leu
1 5 10 15
Glu Ala Gln Gln Glu Ala Leu Gly Leu Val Cys Val Gln Ala Ala Thr
20 25 30
Ser Ser Ser Ser Pro Leu Val Leu Gly Thr Leu Glu Glu Val Pro Thr
35 40 45
Ala Gly Ser Thr Asp Pro Pro Gln Ser Pro Gln Gly Ala Ser Ala Phe
50 55 60
Pro Thr Thr Ile Asn Phe Thr Arg Gln Arg Gln Pro Ser Glu Gly Ser
65 70 75 80
Ser Ser Arg Glu Glu Glu Gly Pro Ser Thr Ser Cys Ile Leu Glu Ser
85 90 95
Leu Phe Arg Ala Val Ile Thr Lys Lys Val Ala Asp Leu Val Gly Phe
100 105 110
Leu Leu Leu Lys Tyr Arg Ala Arg Glu Pro Val Thr Lys Ala Glu Met
115 120 125
Leu Glu Ser Val Ile Lys Asn Tyr Lys His Cys Phe Pro Glu Ile Phe
130 135 140
Gly Lys Ala Ser Glu Ser Leu Gln Leu Val Phe Gly Ile Asp Val Lys
145 150 155 160
Glu Ala Asp Pro Thr Gly His Ser Tyr Val Leu Val Thr Cys Leu Gly
165 170 175
Leu Ser Tyr Asp Gly Leu Leu Gly Asp Asn Gln Ile Met Pro Lys Thr
180 185 190
Gly Phe Leu Ile Ile Val Leu Val Met Ile Ala Met Glu Gly Gly His
195 200 205
Ala Pro Glu Glu Glu Ile Trp Glu Glu Leu Ser Val Met Glu Val Tyr
210 215 220
Asp Gly Arg Glu His Ser Ala Tyr Gly Glu Pro Arg Lys Leu Leu Thr
225 230 235 240
Gln Asp Leu Val Gln Glu Lys Tyr Leu Glu Tyr Arg Gln Val Pro Asp
245 250 255
Ser Asp Pro Ala Arg Tyr Glu Phe Leu Trp Gly Pro Arg Ala Leu Ala
260 265 270
Glu Thr Ser Tyr Val Lys Val Leu Glu Tyr Val Ile Lys Val Ser Ala
275 280 285
Arg Val Arg Phe Phe Phe Pro Ser Leu Arg Glu Ala Ala Leu Arg Glu
290 295 300
Glu Glu Glu Gly Val
305
<210> 55
<211> 314
<212> PRT
<213> homo sapiens
<400> 55
Met Pro Leu Glu Gln Arg Ser Gln His Cys Lys Pro Glu Glu Gly Leu
1 5 10 15
Glu Ala Arg Gly Glu Ala Leu Gly Leu Val Gly Ala Gln Ala Pro Ala
20 25 30
Thr Glu Glu Gln Glu Ala Ala Ser Ser Ser Ser Thr Leu Val Glu Val
35 40 45
Thr Leu Gly Glu Val Pro Ala Ala Glu Ser Pro Asp Pro Pro Gln Ser
50 55 60
Pro Gln Gly Ala Ser Ser Leu Pro Thr Thr Met Asn Tyr Pro Leu Trp
65 70 75 80
Ser Gln Ser Tyr Glu Asp Ser Ser Asn Gln Glu Glu Glu Gly Pro Ser
85 90 95
Thr Phe Pro Asp Leu Glu Ser Glu Phe Gln Ala Ala Leu Ser Arg Lys
100 105 110
Val Ala Glu Leu Val His Phe Leu Leu Leu Lys Tyr Arg Ala Arg Glu
115 120 125
Pro Val Thr Lys Ala Glu Met Leu Gly Ser Val Val Gly Asn Trp Gln
130 135 140
Tyr Phe Phe Pro Val Ile Phe Ser Lys Ala Ser Ser Ser Leu Gln Leu
145 150 155 160
Val Phe Gly Ile Glu Leu Met Glu Val Asp Pro Ile Gly His Leu Tyr
165 170 175
Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr Asp Gly Leu Leu Gly Asp
180 185 190
Asn Gln Ile Met Pro Lys Ala Gly Leu Leu Ile Ile Val Leu Ala Ile
195 200 205
Ile Ala Arg Glu Gly Asp Cys Ala Pro Glu Glu Lys Ile Trp Glu Glu
210 215 220
Leu Ser Val Leu Glu Val Phe Glu Gly Arg Glu Asp Ser Ile Leu Gly
225 230 235 240
Asp Pro Lys Lys Leu Leu Thr Gln His Phe Val Gln Glu Asn Tyr Leu
245 250 255
Glu Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala Cys Tyr Glu Phe Leu
260 265 270
Trp Gly Pro Arg Ala Leu Val Glu Thr Ser Tyr Val Lys Val Leu His
275 280 285
His Met Val Lys Ile Ser Gly Gly Pro His Ile Ser Tyr Pro Pro Leu
290 295 300
His Glu Trp Val Leu Arg Glu Gly Glu Glu
305 310
<210> 56
<211> 1225
<212> PRT
<213> homo sapiens
<400> 56
Met Lys Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu
1 5 10 15
Arg His Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu
20 25 30
Thr Tyr Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln
35 40 45
Glu Val Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val
50 55 60
Pro Leu Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp
65 70 75 80
Asn Tyr Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr
85 90 95
Thr Pro Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu
100 105 110
Arg Ser Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn
115 120 125
Pro Gln Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His
130 135 140
Lys Asn Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg
145 150 155 160
Ala Cys His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly
165 170 175
Glu Ser Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly
180 185 190
Gly Cys Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu
195 200 205
Gln Cys Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala
210 215 220
Cys Leu His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala
225 230 235 240
Leu Val Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu
245 250 255
Gly Arg Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn
260 265 270
Tyr Leu Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His
275 280 285
Asn Gln Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys
290 295 300
Ser Lys Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu
305 310 315 320
Arg Glu Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly
325 330 335
Cys Lys Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp
340 345 350
Gly Asp Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln
355 360 365
Val Phe Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala
370 375 380
Trp Pro Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val
385 390 395 400
Ile Arg Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln
405 410 415
Gly Leu Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly
420 425 430
Ser Gly Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His
435 440 445
Thr Val Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu
450 455 460
His Thr Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala
465 470 475 480
Cys His Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr
485 490 495
Gln Cys Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu
500 505 510
Glu Cys Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg
515 520 525
His Cys Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val
530 535 540
Thr Cys Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr
545 550 555 560
Lys Asp Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro
565 570 575
Asp Leu Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala
580 585 590
Cys Gln Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp
595 600 605
Asp Lys Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile
610 615 620
Ile Ser Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val
625 630 635 640
Phe Gly Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr
645 650 655
Met Arg Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro
660 665 670
Ser Gly Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr
675 680 685
Glu Leu Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val
690 695 700
Tyr Lys Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val
705 710 715 720
Ala Ile Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu
725 730 735
Ile Leu Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val
740 745 750
Ser Arg Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr
755 760 765
Gln Leu Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg
770 775 780
Gly Arg Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala
785 790 795 800
Lys Gly Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu
805 810 815
Ala Ala Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr
820 825 830
Asp Phe Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His
835 840 845
Ala Asp Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile
850 855 860
Leu Arg Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val
865 870 875 880
Thr Val Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile
885 890 895
Pro Ala Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro
900 905 910
Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys
915 920 925
Trp Met Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser
930 935 940
Glu Phe Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln
945 950 955 960
Asn Glu Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg
965 970 975
Ser Leu Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu
980 985 990
Tyr Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly
995 1000 1005
Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg
1010 1015 1020
Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu
1025 1030 1035
Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser
1040 1045 1050
Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu
1055 1060 1065
Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser
1070 1075 1080
Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val
1085 1090 1095
Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro
1100 1105 1110
Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro
1115 1120 1125
Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu
1130 1135 1140
Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly
1145 1150 1155
Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala
1160 1165 1170
Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp
1175 1180 1185
Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro
1190 1195 1200
Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
1205 1210 1215
Leu Gly Leu Asp Val Pro Val
1220 1225
<210> 57
<211> 1240
<212> PRT
<213> homo sapiens
<400> 57
Met Pro Arg Gly Ser Trp Lys Pro Gln Val Cys Thr Gly Thr Asp Met
1 5 10 15
Lys Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg
20 25 30
His Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr
35 40 45
Tyr Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu
50 55 60
Val Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro
65 70 75 80
Leu Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn
85 90 95
Tyr Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr
100 105 110
Pro Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg
115 120 125
Ser Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro
130 135 140
Gln Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys
145 150 155 160
Asn Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala
165 170 175
Cys His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu
180 185 190
Ser Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly
195 200 205
Cys Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln
210 215 220
Cys Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys
225 230 235 240
Leu His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu
245 250 255
Val Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly
260 265 270
Arg Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr
275 280 285
Leu Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn
290 295 300
Gln Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser
305 310 315 320
Lys Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg
325 330 335
Glu Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys
340 345 350
Lys Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly
355 360 365
Asp Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val
370 375 380
Phe Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp
385 390 395 400
Pro Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile
405 410 415
Arg Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly
420 425 430
Leu Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser
435 440 445
Gly Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr
450 455 460
Val Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His
465 470 475 480
Thr Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys
485 490 495
His Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln
500 505 510
Cys Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu
515 520 525
Cys Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His
530 535 540
Cys Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr
545 550 555 560
Cys Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys
565 570 575
Asp Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp
580 585 590
Leu Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys
595 600 605
Gln Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp
610 615 620
Lys Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile
625 630 635 640
Ser Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe
645 650 655
Gly Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met
660 665 670
Arg Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser
675 680 685
Gly Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu
690 695 700
Leu Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr
705 710 715 720
Lys Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala
725 730 735
Ile Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile
740 745 750
Leu Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser
755 760 765
Arg Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln
770 775 780
Leu Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly
785 790 795 800
Arg Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys
805 810 815
Gly Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala
820 825 830
Ala Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp
835 840 845
Phe Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala
850 855 860
Asp Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu
865 870 875 880
Arg Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr
885 890 895
Val Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro
900 905 910
Ala Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln
915 920 925
Pro Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp
930 935 940
Met Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu
945 950 955 960
Phe Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn
965 970 975
Glu Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser
980 985 990
Leu Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr
995 1000 1005
Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly
1010 1015 1020
Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg
1025 1030 1035
Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu
1040 1045 1050
Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser
1055 1060 1065
Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu
1070 1075 1080
Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser
1085 1090 1095
Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val
1100 1105 1110
Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro
1115 1120 1125
Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro
1130 1135 1140
Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu
1145 1150 1155
Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly
1160 1165 1170
Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala
1175 1180 1185
Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp
1190 1195 1200
Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro
1205 1210 1215
Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
1220 1225 1230
Leu Gly Leu Asp Val Pro Val
1235 1240
<210> 58
<211> 1055
<212> PRT
<213> homo sapiens
<400> 58
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys
625 630 635 640
Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser
645 650 655
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
660 665 670
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
675 680 685
Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
690 695 700
Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
705 710 715 720
Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
725 730 735
Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
740 745 750
Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
755 760 765
Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
770 775 780
Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
785 790 795 800
Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
805 810 815
Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
820 825 830
Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
835 840 845
Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
850 855 860
Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
865 870 875 880
Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
885 890 895
Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
900 905 910
Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
915 920 925
Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
930 935 940
Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
945 950 955 960
Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
965 970 975
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
980 985 990
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
995 1000 1005
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr
1010 1015 1020
Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly
1025 1030 1035
Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg
1040 1045 1050
Asn Met
1055
<210> 59
<211> 603
<212> PRT
<213> homo sapiens
<400> 59
Met Lys Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu
1 5 10 15
Arg His Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu
20 25 30
Thr Tyr Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln
35 40 45
Glu Val Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val
50 55 60
Pro Leu Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp
65 70 75 80
Asn Tyr Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr
85 90 95
Thr Pro Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu
100 105 110
Arg Ser Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn
115 120 125
Pro Gln Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His
130 135 140
Lys Asn Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg
145 150 155 160
Ala Cys His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly
165 170 175
Glu Ser Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly
180 185 190
Gly Cys Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu
195 200 205
Gln Cys Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala
210 215 220
Cys Leu His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala
225 230 235 240
Leu Val Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu
245 250 255
Gly Arg Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn
260 265 270
Tyr Leu Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His
275 280 285
Asn Gln Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys
290 295 300
Ser Lys Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu
305 310 315 320
Arg Glu Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly
325 330 335
Cys Lys Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp
340 345 350
Gly Asp Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln
355 360 365
Val Phe Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala
370 375 380
Trp Pro Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val
385 390 395 400
Ile Arg Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln
405 410 415
Gly Leu Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly
420 425 430
Ser Gly Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His
435 440 445
Thr Val Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu
450 455 460
His Thr Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala
465 470 475 480
Cys His Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr
485 490 495
Gln Cys Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu
500 505 510
Glu Cys Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg
515 520 525
His Cys Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val
530 535 540
Thr Cys Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr
545 550 555 560
Lys Asp Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro
565 570 575
Asp Leu Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala
580 585 590
Cys Gln Pro Cys Pro Ile Asn Cys Thr His Ser
595 600
<210> 60
<211> 1255
<212> PRT
<213> homo sapiens
<400> 60
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys
625 630 635 640
Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser
645 650 655
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
660 665 670
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
675 680 685
Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
690 695 700
Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
705 710 715 720
Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
725 730 735
Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
740 745 750
Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
755 760 765
Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
770 775 780
Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
785 790 795 800
Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
805 810 815
Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
820 825 830
Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
835 840 845
Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
850 855 860
Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
865 870 875 880
Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
885 890 895
Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
900 905 910
Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
915 920 925
Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
930 935 940
Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
945 950 955 960
Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
965 970 975
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
980 985 990
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
995 1000 1005
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr
1010 1015 1020
Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly
1025 1030 1035
Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg
1040 1045 1050
Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu
1055 1060 1065
Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser
1070 1075 1080
Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu
1085 1090 1095
Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser
1100 1105 1110
Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val
1115 1120 1125
Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro
1130 1135 1140
Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro
1145 1150 1155
Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu
1160 1165 1170
Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly
1175 1180 1185
Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala
1190 1195 1200
Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp
1205 1210 1215
Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro
1220 1225 1230
Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
1235 1240 1245
Leu Gly Leu Asp Val Pro Val
1250 1255
<210> 61
<211> 781
<212> PRT
<213> homo sapiens
<400> 61
Met Ala Thr Gln Ala Asp Leu Met Glu Leu Asp Met Ala Met Glu Pro
1 5 10 15
Asp Arg Lys Ala Ala Val Ser His Trp Gln Gln Gln Ser Tyr Leu Asp
20 25 30
Ser Gly Ile His Ser Gly Ala Thr Thr Thr Ala Pro Ser Leu Ser Gly
35 40 45
Lys Gly Asn Pro Glu Glu Glu Asp Val Asp Thr Ser Gln Val Leu Tyr
50 55 60
Glu Trp Glu Gln Gly Phe Ser Gln Ser Phe Thr Gln Glu Gln Val Ala
65 70 75 80
Asp Ile Asp Gly Gln Tyr Ala Met Thr Arg Ala Gln Arg Val Arg Ala
85 90 95
Ala Met Phe Pro Glu Thr Leu Asp Glu Gly Met Gln Ile Pro Ser Thr
100 105 110
Gln Phe Asp Ala Ala His Pro Thr Asn Val Gln Arg Leu Ala Glu Pro
115 120 125
Ser Gln Met Leu Lys His Ala Val Val Asn Leu Ile Asn Tyr Gln Asp
130 135 140
Asp Ala Glu Leu Ala Thr Arg Ala Ile Pro Glu Leu Thr Lys Leu Leu
145 150 155 160
Asn Asp Glu Asp Gln Val Val Val Asn Lys Ala Ala Val Met Val His
165 170 175
Gln Leu Ser Lys Lys Glu Ala Ser Arg His Ala Ile Met Arg Ser Pro
180 185 190
Gln Met Val Ser Ala Ile Val Arg Thr Met Gln Asn Thr Asn Asp Val
195 200 205
Glu Thr Ala Arg Cys Thr Ala Gly Thr Leu His Asn Leu Ser His His
210 215 220
Arg Glu Gly Leu Leu Ala Ile Phe Lys Ser Gly Gly Ile Pro Ala Leu
225 230 235 240
Val Lys Met Leu Gly Ser Pro Val Asp Ser Val Leu Phe Tyr Ala Ile
245 250 255
Thr Thr Leu His Asn Leu Leu Leu His Gln Glu Gly Ala Lys Met Ala
260 265 270
Val Arg Leu Ala Gly Gly Leu Gln Lys Met Val Ala Leu Leu Asn Lys
275 280 285
Thr Asn Val Lys Phe Leu Ala Ile Thr Thr Asp Cys Leu Gln Ile Leu
290 295 300
Ala Tyr Gly Asn Gln Glu Ser Lys Leu Ile Ile Leu Ala Ser Gly Gly
305 310 315 320
Pro Gln Ala Leu Val Asn Ile Met Arg Thr Tyr Thr Tyr Glu Lys Leu
325 330 335
Leu Trp Thr Thr Ser Arg Val Leu Lys Val Leu Ser Val Cys Ser Ser
340 345 350
Asn Lys Pro Ala Ile Val Glu Ala Gly Gly Met Gln Ala Leu Gly Leu
355 360 365
His Leu Thr Asp Pro Ser Gln Arg Leu Val Gln Asn Cys Leu Trp Thr
370 375 380
Leu Arg Asn Leu Ser Asp Ala Ala Thr Lys Gln Glu Gly Met Glu Gly
385 390 395 400
Leu Leu Gly Thr Leu Val Gln Leu Leu Gly Ser Asp Asp Ile Asn Val
405 410 415
Val Thr Cys Ala Ala Gly Ile Leu Ser Asn Leu Thr Cys Asn Asn Tyr
420 425 430
Lys Asn Lys Met Met Val Cys Gln Val Gly Gly Ile Glu Ala Leu Val
435 440 445
Arg Thr Val Leu Arg Ala Gly Asp Arg Glu Asp Ile Thr Glu Pro Ala
450 455 460
Ile Cys Ala Leu Arg His Leu Thr Ser Arg His Gln Glu Ala Glu Met
465 470 475 480
Ala Gln Asn Ala Val Arg Leu His Tyr Gly Leu Pro Val Val Val Lys
485 490 495
Leu Leu His Pro Pro Ser His Trp Pro Leu Ile Lys Ala Thr Val Gly
500 505 510
Leu Ile Arg Asn Leu Ala Leu Cys Pro Ala Asn His Ala Pro Leu Arg
515 520 525
Glu Gln Gly Ala Ile Pro Arg Leu Val Gln Leu Leu Val Arg Ala His
530 535 540
Gln Asp Thr Gln Arg Arg Thr Ser Met Gly Gly Thr Gln Gln Gln Phe
545 550 555 560
Val Glu Gly Val Arg Met Glu Glu Ile Val Glu Gly Cys Thr Gly Ala
565 570 575
Leu His Ile Leu Ala Arg Asp Val His Asn Arg Ile Val Ile Arg Gly
580 585 590
Leu Asn Thr Ile Pro Leu Phe Val Gln Leu Leu Tyr Ser Pro Ile Glu
595 600 605
Asn Ile Gln Arg Val Ala Ala Gly Val Leu Cys Glu Leu Ala Gln Asp
610 615 620
Lys Glu Ala Ala Glu Ala Ile Glu Ala Glu Gly Ala Thr Ala Pro Leu
625 630 635 640
Thr Glu Leu Leu His Ser Arg Asn Glu Gly Val Ala Thr Tyr Ala Ala
645 650 655
Ala Val Leu Phe Arg Met Ser Glu Asp Lys Pro Gln Asp Tyr Lys Lys
660 665 670
Arg Leu Ser Val Glu Leu Thr Ser Ser Leu Phe Arg Thr Glu Pro Met
675 680 685
Ala Trp Asn Glu Thr Ala Asp Leu Gly Leu Asp Ile Gly Ala Gln Gly
690 695 700
Glu Pro Leu Gly Tyr Arg Gln Asp Asp Pro Ser Tyr Arg Ser Phe His
705 710 715 720
Ser Gly Gly Tyr Gly Gln Asp Ala Leu Gly Met Asp Pro Met Met Glu
725 730 735
His Glu Met Gly Gly His His Pro Gly Ala Asp Tyr Pro Val Asp Gly
740 745 750
Leu Pro Asp Leu Gly His Ala Gln Asp Leu Met Asp Gly Leu Pro Pro
755 760 765
Gly Asp Ser Asn Gln Leu Ala Trp Phe Asp Thr Asp Leu
770 775 780
<210> 62
<211> 781
<212> PRT
<213> homo sapiens
<400> 62
Met Ala Thr Gln Ala Asp Leu Met Glu Leu Asp Met Ala Met Glu Pro
1 5 10 15
Asp Arg Lys Ala Ala Val Ser His Trp Gln Gln Gln Ser Tyr Leu Asp
20 25 30
Ser Gly Ile His Ser Gly Ala Thr Thr Thr Ala Pro Ser Leu Ser Gly
35 40 45
Lys Gly Asn Pro Glu Glu Glu Asp Val Asp Thr Ser Gln Val Leu Tyr
50 55 60
Glu Trp Glu Gln Gly Phe Ser Gln Ser Phe Thr Gln Glu Gln Val Ala
65 70 75 80
Asp Ile Asp Gly Gln Tyr Ala Met Thr Arg Ala Gln Arg Val Arg Ala
85 90 95
Ala Met Phe Pro Glu Thr Leu Asp Glu Gly Met Gln Ile Pro Ser Thr
100 105 110
Gln Phe Asp Ala Ala His Pro Thr Asn Val Gln Arg Leu Ala Glu Pro
115 120 125
Ser Gln Met Leu Lys His Ala Val Val Asn Leu Ile Asn Tyr Gln Asp
130 135 140
Asp Ala Glu Leu Ala Thr Arg Ala Ile Pro Glu Leu Thr Lys Leu Leu
145 150 155 160
Asn Asp Glu Asp Gln Val Val Val Asn Lys Ala Ala Val Met Val His
165 170 175
Gln Leu Ser Lys Lys Glu Ala Ser Arg His Ala Ile Met Arg Ser Pro
180 185 190
Gln Met Val Ser Ala Ile Val Arg Thr Met Gln Asn Thr Asn Asp Val
195 200 205
Glu Thr Ala Arg Cys Thr Ala Gly Thr Leu His Asn Leu Ser His His
210 215 220
Arg Glu Gly Leu Leu Ala Ile Phe Lys Ser Gly Gly Ile Pro Ala Leu
225 230 235 240
Val Lys Met Leu Gly Ser Pro Val Asp Ser Val Leu Phe Tyr Ala Ile
245 250 255
Thr Thr Leu His Asn Leu Leu Leu His Gln Glu Gly Ala Lys Met Ala
260 265 270
Val Arg Leu Ala Gly Gly Leu Gln Lys Met Val Ala Leu Leu Asn Lys
275 280 285
Thr Asn Val Lys Phe Leu Ala Ile Thr Thr Asp Cys Leu Gln Ile Leu
290 295 300
Ala Tyr Gly Asn Gln Glu Ser Lys Leu Ile Ile Leu Ala Ser Gly Gly
305 310 315 320
Pro Gln Ala Leu Val Asn Ile Met Arg Thr Tyr Thr Tyr Glu Lys Leu
325 330 335
Leu Trp Thr Thr Ser Arg Val Leu Lys Val Leu Ser Val Cys Ser Ser
340 345 350
Asn Lys Pro Ala Ile Val Glu Ala Gly Gly Met Gln Ala Leu Gly Leu
355 360 365
His Leu Thr Asp Pro Ser Gln Arg Leu Val Gln Asn Cys Leu Trp Thr
370 375 380
Leu Arg Asn Leu Ser Asp Ala Ala Thr Lys Gln Glu Gly Met Glu Gly
385 390 395 400
Leu Leu Gly Thr Leu Val Gln Leu Leu Gly Ser Asp Asp Ile Asn Val
405 410 415
Val Thr Cys Ala Ala Gly Ile Leu Ser Asn Leu Thr Cys Asn Asn Tyr
420 425 430
Lys Asn Lys Met Met Val Cys Gln Val Gly Gly Ile Glu Ala Leu Val
435 440 445
Arg Thr Val Leu Arg Ala Gly Asp Arg Glu Asp Ile Thr Glu Pro Ala
450 455 460
Ile Cys Ala Leu Arg His Leu Thr Ser Arg His Gln Glu Ala Glu Met
465 470 475 480
Ala Gln Asn Ala Val Arg Leu His Tyr Gly Leu Pro Val Val Val Lys
485 490 495
Leu Leu His Pro Pro Ser His Trp Pro Leu Ile Lys Ala Thr Val Gly
500 505 510
Leu Ile Arg Asn Leu Ala Leu Cys Pro Ala Asn His Ala Pro Leu Arg
515 520 525
Glu Gln Gly Ala Ile Pro Arg Leu Val Gln Leu Leu Val Arg Ala His
530 535 540
Gln Asp Thr Gln Arg Arg Thr Ser Met Gly Gly Thr Gln Gln Gln Phe
545 550 555 560
Val Glu Gly Val Arg Met Glu Glu Ile Val Glu Gly Cys Thr Gly Ala
565 570 575
Leu His Ile Leu Ala Arg Asp Val His Asn Arg Ile Val Ile Arg Gly
580 585 590
Leu Asn Thr Ile Pro Leu Phe Val Gln Leu Leu Tyr Ser Pro Ile Glu
595 600 605
Asn Ile Gln Arg Val Ala Ala Gly Val Leu Cys Glu Leu Ala Gln Asp
610 615 620
Lys Glu Ala Ala Glu Ala Ile Glu Ala Glu Gly Ala Thr Ala Pro Leu
625 630 635 640
Thr Glu Leu Leu His Ser Arg Asn Glu Gly Val Ala Thr Tyr Ala Ala
645 650 655
Ala Val Leu Phe Arg Met Ser Glu Asp Lys Pro Gln Asp Tyr Lys Lys
660 665 670
Arg Leu Ser Val Glu Leu Thr Ser Ser Leu Phe Arg Thr Glu Pro Met
675 680 685
Ala Trp Asn Glu Thr Ala Asp Leu Gly Leu Asp Ile Gly Ala Gln Gly
690 695 700
Glu Pro Leu Gly Tyr Arg Gln Asp Asp Pro Ser Tyr Arg Ser Phe His
705 710 715 720
Ser Gly Gly Tyr Gly Gln Asp Ala Leu Gly Met Asp Pro Met Met Glu
725 730 735
His Glu Met Gly Gly His His Pro Gly Ala Asp Tyr Pro Val Asp Gly
740 745 750
Leu Pro Asp Leu Gly His Ala Gln Asp Leu Met Asp Gly Leu Pro Pro
755 760 765
Gly Asp Ser Asn Gln Leu Ala Trp Phe Asp Thr Asp Leu
770 775 780
<210> 63
<211> 781
<212> PRT
<213> homo sapiens
<400> 63
Met Ala Thr Gln Ala Asp Leu Met Glu Leu Asp Met Ala Met Glu Pro
1 5 10 15
Asp Arg Lys Ala Ala Val Ser His Trp Gln Gln Gln Ser Tyr Leu Asp
20 25 30
Ser Gly Ile His Ser Gly Ala Thr Thr Thr Ala Pro Ser Leu Ser Gly
35 40 45
Lys Gly Asn Pro Glu Glu Glu Asp Val Asp Thr Ser Gln Val Leu Tyr
50 55 60
Glu Trp Glu Gln Gly Phe Ser Gln Ser Phe Thr Gln Glu Gln Val Ala
65 70 75 80
Asp Ile Asp Gly Gln Tyr Ala Met Thr Arg Ala Gln Arg Val Arg Ala
85 90 95
Ala Met Phe Pro Glu Thr Leu Asp Glu Gly Met Gln Ile Pro Ser Thr
100 105 110
Gln Phe Asp Ala Ala His Pro Thr Asn Val Gln Arg Leu Ala Glu Pro
115 120 125
Ser Gln Met Leu Lys His Ala Val Val Asn Leu Ile Asn Tyr Gln Asp
130 135 140
Asp Ala Glu Leu Ala Thr Arg Ala Ile Pro Glu Leu Thr Lys Leu Leu
145 150 155 160
Asn Asp Glu Asp Gln Val Val Val Asn Lys Ala Ala Val Met Val His
165 170 175
Gln Leu Ser Lys Lys Glu Ala Ser Arg His Ala Ile Met Arg Ser Pro
180 185 190
Gln Met Val Ser Ala Ile Val Arg Thr Met Gln Asn Thr Asn Asp Val
195 200 205
Glu Thr Ala Arg Cys Thr Ala Gly Thr Leu His Asn Leu Ser His His
210 215 220
Arg Glu Gly Leu Leu Ala Ile Phe Lys Ser Gly Gly Ile Pro Ala Leu
225 230 235 240
Val Lys Met Leu Gly Ser Pro Val Asp Ser Val Leu Phe Tyr Ala Ile
245 250 255
Thr Thr Leu His Asn Leu Leu Leu His Gln Glu Gly Ala Lys Met Ala
260 265 270
Val Arg Leu Ala Gly Gly Leu Gln Lys Met Val Ala Leu Leu Asn Lys
275 280 285
Thr Asn Val Lys Phe Leu Ala Ile Thr Thr Asp Cys Leu Gln Ile Leu
290 295 300
Ala Tyr Gly Asn Gln Glu Ser Lys Leu Ile Ile Leu Ala Ser Gly Gly
305 310 315 320
Pro Gln Ala Leu Val Asn Ile Met Arg Thr Tyr Thr Tyr Glu Lys Leu
325 330 335
Leu Trp Thr Thr Ser Arg Val Leu Lys Val Leu Ser Val Cys Ser Ser
340 345 350
Asn Lys Pro Ala Ile Val Glu Ala Gly Gly Met Gln Ala Leu Gly Leu
355 360 365
His Leu Thr Asp Pro Ser Gln Arg Leu Val Gln Asn Cys Leu Trp Thr
370 375 380
Leu Arg Asn Leu Ser Asp Ala Ala Thr Lys Gln Glu Gly Met Glu Gly
385 390 395 400
Leu Leu Gly Thr Leu Val Gln Leu Leu Gly Ser Asp Asp Ile Asn Val
405 410 415
Val Thr Cys Ala Ala Gly Ile Leu Ser Asn Leu Thr Cys Asn Asn Tyr
420 425 430
Lys Asn Lys Met Met Val Cys Gln Val Gly Gly Ile Glu Ala Leu Val
435 440 445
Arg Thr Val Leu Arg Ala Gly Asp Arg Glu Asp Ile Thr Glu Pro Ala
450 455 460
Ile Cys Ala Leu Arg His Leu Thr Ser Arg His Gln Glu Ala Glu Met
465 470 475 480
Ala Gln Asn Ala Val Arg Leu His Tyr Gly Leu Pro Val Val Val Lys
485 490 495
Leu Leu His Pro Pro Ser His Trp Pro Leu Ile Lys Ala Thr Val Gly
500 505 510
Leu Ile Arg Asn Leu Ala Leu Cys Pro Ala Asn His Ala Pro Leu Arg
515 520 525
Glu Gln Gly Ala Ile Pro Arg Leu Val Gln Leu Leu Val Arg Ala His
530 535 540
Gln Asp Thr Gln Arg Arg Thr Ser Met Gly Gly Thr Gln Gln Gln Phe
545 550 555 560
Val Glu Gly Val Arg Met Glu Glu Ile Val Glu Gly Cys Thr Gly Ala
565 570 575
Leu His Ile Leu Ala Arg Asp Val His Asn Arg Ile Val Ile Arg Gly
580 585 590
Leu Asn Thr Ile Pro Leu Phe Val Gln Leu Leu Tyr Ser Pro Ile Glu
595 600 605
Asn Ile Gln Arg Val Ala Ala Gly Val Leu Cys Glu Leu Ala Gln Asp
610 615 620
Lys Glu Ala Ala Glu Ala Ile Glu Ala Glu Gly Ala Thr Ala Pro Leu
625 630 635 640
Thr Glu Leu Leu His Ser Arg Asn Glu Gly Val Ala Thr Tyr Ala Ala
645 650 655
Ala Val Leu Phe Arg Met Ser Glu Asp Lys Pro Gln Asp Tyr Lys Lys
660 665 670
Arg Leu Ser Val Glu Leu Thr Ser Ser Leu Phe Arg Thr Glu Pro Met
675 680 685
Ala Trp Asn Glu Thr Ala Asp Leu Gly Leu Asp Ile Gly Ala Gln Gly
690 695 700
Glu Pro Leu Gly Tyr Arg Gln Asp Asp Pro Ser Tyr Arg Ser Phe His
705 710 715 720
Ser Gly Gly Tyr Gly Gln Asp Ala Leu Gly Met Asp Pro Met Met Glu
725 730 735
His Glu Met Gly Gly His His Pro Gly Ala Asp Tyr Pro Val Asp Gly
740 745 750
Leu Pro Asp Leu Gly His Ala Gln Asp Leu Met Asp Gly Leu Pro Pro
755 760 765
Gly Asp Ser Asn Gln Leu Ala Trp Phe Asp Thr Asp Leu
770 775 780
<210> 64
<211> 529
<212> PRT
<213> homo sapiens
<400> 64
Met Leu Leu Ala Val Leu Tyr Cys Leu Leu Trp Ser Phe Gln Thr Ser
1 5 10 15
Ala Gly His Phe Pro Arg Ala Cys Val Ser Ser Lys Asn Leu Met Glu
20 25 30
Lys Glu Cys Cys Pro Pro Trp Ser Gly Asp Arg Ser Pro Cys Gly Gln
35 40 45
Leu Ser Gly Arg Gly Ser Cys Gln Asn Ile Leu Leu Ser Asn Ala Pro
50 55 60
Leu Gly Pro Gln Phe Pro Phe Thr Gly Val Asp Asp Arg Glu Ser Trp
65 70 75 80
Pro Ser Val Phe Tyr Asn Arg Thr Cys Gln Cys Ser Gly Asn Phe Met
85 90 95
Gly Phe Asn Cys Gly Asn Cys Lys Phe Gly Phe Trp Gly Pro Asn Cys
100 105 110
Thr Glu Arg Arg Leu Leu Val Arg Arg Asn Ile Phe Asp Leu Ser Ala
115 120 125
Pro Glu Lys Asp Lys Phe Phe Ala Tyr Leu Thr Leu Ala Lys His Thr
130 135 140
Ile Ser Ser Asp Tyr Val Ile Pro Ile Gly Thr Tyr Gly Gln Met Lys
145 150 155 160
Asn Gly Ser Thr Pro Met Phe Asn Asp Ile Asn Ile Tyr Asp Leu Phe
165 170 175
Val Trp Met His Tyr Tyr Val Ser Met Asp Ala Leu Leu Gly Gly Ser
180 185 190
Glu Ile Trp Arg Asp Ile Asp Phe Ala His Glu Ala Pro Ala Phe Leu
195 200 205
Pro Trp His Arg Leu Phe Leu Leu Arg Trp Glu Gln Glu Ile Gln Lys
210 215 220
Leu Thr Gly Asp Glu Asn Phe Thr Ile Pro Tyr Trp Asp Trp Arg Asp
225 230 235 240
Ala Glu Lys Cys Asp Ile Cys Thr Asp Glu Tyr Met Gly Gly Gln His
245 250 255
Pro Thr Asn Pro Asn Leu Leu Ser Pro Ala Ser Phe Phe Ser Ser Trp
260 265 270
Gln Ile Val Cys Ser Arg Leu Glu Glu Tyr Asn Ser His Gln Ser Leu
275 280 285
Cys Asn Gly Thr Pro Glu Gly Pro Leu Arg Arg Asn Pro Gly Asn His
290 295 300
Asp Lys Ser Arg Thr Pro Arg Leu Pro Ser Ser Ala Asp Val Glu Phe
305 310 315 320
Cys Leu Ser Leu Thr Gln Tyr Glu Ser Gly Ser Met Asp Lys Ala Ala
325 330 335
Asn Phe Ser Phe Arg Asn Thr Leu Glu Gly Phe Ala Ser Pro Leu Thr
340 345 350
Gly Ile Ala Asp Ala Ser Gln Ser Ser Met His Asn Ala Leu His Ile
355 360 365
Tyr Met Asn Gly Thr Met Ser Gln Val Gln Gly Ser Ala Asn Asp Pro
370 375 380
Ile Phe Leu Leu His His Ala Phe Val Asp Ser Ile Phe Glu Gln Trp
385 390 395 400
Leu Arg Arg His Arg Pro Leu Gln Glu Val Tyr Pro Glu Ala Asn Ala
405 410 415
Pro Ile Gly His Asn Arg Glu Ser Tyr Met Val Pro Phe Ile Pro Leu
420 425 430
Tyr Arg Asn Gly Asp Phe Phe Ile Ser Ser Lys Asp Leu Gly Tyr Asp
435 440 445
Tyr Ser Tyr Leu Gln Asp Ser Asp Pro Asp Ser Phe Gln Asp Tyr Ile
450 455 460
Lys Ser Tyr Leu Glu Gln Ala Ser Arg Ile Trp Ser Trp Leu Leu Gly
465 470 475 480
Ala Ala Met Val Gly Ala Val Leu Thr Ala Leu Leu Ala Gly Leu Val
485 490 495
Ser Leu Leu Cys Arg His Lys Arg Lys Gln Leu Pro Glu Glu Lys Gln
500 505 510
Pro Leu Leu Met Glu Lys Glu Asp Tyr His Ser Leu Tyr Gln Ser His
515 520 525
Leu
<210> 65
<211> 693
<212> PRT
<213> homo sapiens
<400> 65
Met Val Asp Pro Val Gly Phe Ala Glu Ala Trp Lys Ala Gln Phe Pro
1 5 10 15
Asp Ser Glu Pro Pro Arg Met Glu Leu Arg Ser Val Gly Asp Ile Glu
20 25 30
Gln Glu Leu Glu Arg Cys Lys Ala Ser Ile Arg Arg Leu Glu Gln Glu
35 40 45
Val Asn Gln Glu Arg Phe Arg Met Ile Tyr Leu Gln Thr Leu Leu Ala
50 55 60
Lys Glu Lys Lys Ser Tyr Asp Arg Gln Arg Trp Gly Phe Arg Arg Ala
65 70 75 80
Ala Gln Ala Pro Asp Gly Ala Ser Glu Pro Arg Ala Ser Ala Ser Arg
85 90 95
Pro Gln Pro Ala Pro Ala Asp Gly Ala Asp Pro Pro Pro Ala Glu Glu
100 105 110
Pro Glu Ala Arg Pro Asp Gly Glu Gly Ser Pro Gly Lys Ala Arg Pro
115 120 125
Gly Thr Ala Arg Arg Pro Gly Ala Ala Ala Ser Gly Glu Arg Asp Asp
130 135 140
Arg Gly Pro Pro Ala Ser Val Ala Ala Leu Arg Ser Asn Phe Glu Arg
145 150 155 160
Ile Arg Lys Gly His Gly Gln Pro Gly Ala Asp Ala Glu Lys Pro Phe
165 170 175
Tyr Val Asn Val Glu Phe His His Glu Arg Gly Leu Val Lys Val Asn
180 185 190
Asp Lys Glu Val Ser Asp Arg Ile Ser Ser Leu Gly Ser Gln Ala Met
195 200 205
Gln Met Glu Arg Lys Lys Ser Gln His Gly Ala Gly Ser Ser Val Gly
210 215 220
Asp Ala Ser Arg Pro Pro Tyr Arg Gly Arg Ser Ser Glu Ser Ser Cys
225 230 235 240
Gly Val Asp Gly Asp Tyr Glu Asp Ala Glu Leu Asn Pro Arg Phe Leu
245 250 255
Lys Asp Asn Leu Ile Asp Ala Asn Gly Gly Ser Arg Pro Pro Trp Pro
260 265 270
Pro Leu Glu Tyr Gln Pro Tyr Gln Ser Ile Tyr Val Gly Gly Met Met
275 280 285
Glu Gly Glu Gly Lys Gly Pro Leu Leu Arg Ser Gln Ser Thr Ser Glu
290 295 300
Gln Glu Lys Arg Leu Thr Trp Pro Arg Arg Ser Tyr Ser Pro Arg Ser
305 310 315 320
Phe Glu Asp Cys Gly Gly Gly Tyr Thr Pro Asp Cys Ser Ser Asn Glu
325 330 335
Asn Leu Thr Ser Ser Glu Glu Asp Phe Ser Ser Gly Gln Ser Ser Arg
340 345 350
Val Ser Pro Ser Pro Thr Thr Tyr Arg Met Phe Arg Asp Lys Ser Arg
355 360 365
Ser Pro Ser Gln Asn Ser Gln Gln Ser Phe Asp Ser Ser Ser Pro Pro
370 375 380
Thr Pro Gln Cys His Lys Arg His Arg His Cys Pro Val Val Val Ser
385 390 395 400
Glu Ala Thr Ile Val Gly Val Arg Lys Thr Gly Gln Ile Trp Pro Asn
405 410 415
Asp Gly Glu Gly Ala Phe His Gly Asp Ala Asp Gly Ser Phe Gly Thr
420 425 430
Pro Pro Gly Tyr Gly Cys Ala Ala Asp Arg Ala Glu Glu Gln Arg Arg
435 440 445
His Gln Asp Gly Leu Pro Tyr Ile Asp Asp Ser Pro Ser Ser Ser Pro
450 455 460
His Leu Ser Ser Lys Gly Arg Gly Ser Arg Asp Ala Leu Val Ser Gly
465 470 475 480
Ala Leu Glu Ser Thr Lys Ala Ser Glu Leu Asp Leu Glu Lys Gly Leu
485 490 495
Glu Met Arg Lys Trp Val Leu Ser Gly Ile Leu Ala Ser Glu Glu Thr
500 505 510
Tyr Leu Ser His Leu Glu Ala Leu Leu Leu Pro Met Lys Pro Leu Lys
515 520 525
Ala Ala Ala Thr Thr Ser Gln Pro Val Leu Thr Ser Gln Gln Ile Glu
530 535 540
Thr Ile Phe Phe Lys Val Pro Glu Leu Tyr Glu Ile His Lys Glu Phe
545 550 555 560
Tyr Asp Gly Leu Phe Pro Arg Val Gln Gln Trp Ser His Gln Gln Arg
565 570 575
Val Gly Asp Leu Phe Gln Lys Leu Ala Ser Gln Leu Gly Val Tyr Arg
580 585 590
Ala Phe Val Asp Asn Tyr Gly Val Ala Met Glu Met Ala Glu Lys Cys
595 600 605
Cys Gln Ala Asn Ala Gln Phe Ala Glu Ile Ser Glu Asn Leu Arg Ala
610 615 620
Arg Ser Asn Lys Asp Ala Lys Asp Pro Thr Thr Lys Asn Ser Leu Glu
625 630 635 640
Thr Leu Leu Tyr Lys Pro Val Asp Arg Val Thr Arg Ser Thr Leu Val
645 650 655
Leu His Asp Leu Leu Lys His Thr Pro Ala Ser His Pro Asp His Pro
660 665 670
Leu Leu Gln Asp Ala Leu Arg Ile Ser Gln Asn Phe Leu Ser Ser Ile
675 680 685
Asn Glu Glu Ile Thr
690
<210> 66
<211> 464
<212> PRT
<213> homo sapiens
<400> 66
Met Asp Phe Ser Arg Asn Leu Tyr Asp Ile Gly Glu Gln Leu Asp Ser
1 5 10 15
Glu Asp Leu Ala Ser Leu Lys Phe Leu Ser Leu Asp Tyr Ile Pro Gln
20 25 30
Arg Lys Gln Glu Pro Ile Lys Asp Ala Leu Met Leu Phe Gln Arg Leu
35 40 45
Gln Glu Lys Arg Met Leu Glu Glu Ser Asn Leu Ser Phe Leu Lys Glu
50 55 60
Leu Leu Phe Arg Ile Asn Arg Leu Asp Leu Leu Ile Thr Tyr Leu Asn
65 70 75 80
Thr Arg Lys Glu Glu Met Glu Arg Glu Leu Gln Thr Pro Gly Arg Ala
85 90 95
Gln Ile Ser Ala Tyr Arg Val Met Leu Tyr Gln Ile Ser Glu Glu Val
100 105 110
Ser Arg Ser Glu Leu Arg Ser Phe Lys Phe Leu Leu Gln Glu Glu Ile
115 120 125
Ser Lys Cys Lys Leu Asp Asp Asp Met Asn Leu Leu Asp Ile Phe Ile
130 135 140
Glu Met Glu Lys Arg Val Ile Leu Gly Glu Gly Lys Leu Asp Ile Leu
145 150 155 160
Lys Arg Val Cys Ala Gln Ile Asn Lys Ser Leu Leu Lys Ile Ile Asn
165 170 175
Asp Tyr Glu Glu Phe Ser Lys Gly Glu Glu Leu Cys Gly Val Met Thr
180 185 190
Ile Ser Asp Ser Pro Arg Glu Gln Asp Ser Glu Ser Gln Thr Leu Asp
195 200 205
Lys Val Tyr Gln Met Lys Ser Lys Pro Arg Gly Tyr Cys Leu Ile Ile
210 215 220
Asn Asn His Asn Phe Ala Lys Ala Arg Glu Lys Val Pro Lys Leu His
225 230 235 240
Ser Ile Arg Asp Arg Asn Gly Thr His Leu Asp Ala Gly Ala Leu Thr
245 250 255
Thr Thr Phe Glu Glu Leu His Phe Glu Ile Lys Pro His Asp Asp Cys
260 265 270
Thr Val Glu Gln Ile Tyr Glu Ile Leu Lys Ile Tyr Gln Leu Met Asp
275 280 285
His Ser Asn Met Asp Cys Phe Ile Cys Cys Ile Leu Ser His Gly Asp
290 295 300
Lys Gly Ile Ile Tyr Gly Thr Asp Gly Gln Glu Ala Pro Ile Tyr Glu
305 310 315 320
Leu Thr Ser Gln Phe Thr Gly Leu Lys Cys Pro Ser Leu Ala Gly Lys
325 330 335
Pro Lys Val Phe Phe Ile Gln Ala Cys Gln Gly Asp Asn Tyr Gln Lys
340 345 350
Gly Ile Pro Val Glu Thr Asp Ser Glu Glu Gln Pro Tyr Leu Glu Met
355 360 365
Asp Leu Ser Ser Pro Gln Thr Arg Tyr Ile Pro Asp Glu Ala Asp Phe
370 375 380
Leu Leu Gly Met Ala Thr Val Asn Asn Cys Val Ser Tyr Arg Asn Pro
385 390 395 400
Ala Glu Gly Thr Trp Tyr Ile Gln Ser Leu Cys Gln Ser Leu Arg Glu
405 410 415
Arg Cys Pro Arg Gly Asp Asp Ile Leu Thr Ile Leu Thr Glu Val Asn
420 425 430
Tyr Glu Val Ser Asn Lys Asp Asp Lys Lys Asn Met Gly Lys Gln Met
435 440 445
Pro Gln Pro Thr Phe Thr Leu Arg Lys Lys Leu Val Phe Pro Ser Asp
450 455 460
<210> 67
<211> 538
<212> PRT
<213> homo sapiens
<400> 67
Met Glu Gly Gly Arg Arg Ala Arg Val Val Ile Glu Ser Lys Arg Asn
1 5 10 15
Phe Phe Leu Gly Ala Phe Pro Thr Pro Phe Pro Ala Glu His Val Glu
20 25 30
Leu Gly Arg Leu Gly Asp Ser Glu Thr Ala Met Val Pro Gly Lys Gly
35 40 45
Gly Ala Asp Tyr Ile Leu Leu Pro Phe Lys Lys Met Asp Phe Ser Arg
50 55 60
Asn Leu Tyr Asp Ile Gly Glu Gln Leu Asp Ser Glu Asp Leu Ala Ser
65 70 75 80
Leu Lys Phe Leu Ser Leu Asp Tyr Ile Pro Gln Arg Lys Gln Glu Pro
85 90 95
Ile Lys Asp Ala Leu Met Leu Phe Gln Arg Leu Gln Glu Lys Arg Met
100 105 110
Leu Glu Glu Ser Asn Leu Ser Phe Leu Lys Glu Leu Leu Phe Arg Ile
115 120 125
Asn Arg Leu Asp Leu Leu Ile Thr Tyr Leu Asn Thr Arg Lys Glu Glu
130 135 140
Met Glu Arg Glu Leu Gln Thr Pro Gly Arg Ala Gln Ile Ser Ala Tyr
145 150 155 160
Arg Val Met Leu Tyr Gln Ile Ser Glu Glu Val Ser Arg Ser Glu Leu
165 170 175
Arg Ser Phe Lys Phe Leu Leu Gln Glu Glu Ile Ser Lys Cys Lys Leu
180 185 190
Asp Asp Asp Met Asn Leu Leu Asp Ile Phe Ile Glu Met Glu Lys Arg
195 200 205
Val Ile Leu Gly Glu Gly Lys Leu Asp Ile Leu Lys Arg Val Cys Ala
210 215 220
Gln Ile Asn Lys Ser Leu Leu Lys Ile Ile Asn Asp Tyr Glu Glu Phe
225 230 235 240
Ser Lys Glu Arg Ser Ser Ser Leu Glu Gly Ser Pro Asp Glu Phe Ser
245 250 255
Asn Gly Glu Glu Leu Cys Gly Val Met Thr Ile Ser Asp Ser Pro Arg
260 265 270
Glu Gln Asp Ser Glu Ser Gln Thr Leu Asp Lys Val Tyr Gln Met Lys
275 280 285
Ser Lys Pro Arg Gly Tyr Cys Leu Ile Ile Asn Asn His Asn Phe Ala
290 295 300
Lys Ala Arg Glu Lys Val Pro Lys Leu His Ser Ile Arg Asp Arg Asn
305 310 315 320
Gly Thr His Leu Asp Ala Gly Ala Leu Thr Thr Thr Phe Glu Glu Leu
325 330 335
His Phe Glu Ile Lys Pro His Asp Asp Cys Thr Val Glu Gln Ile Tyr
340 345 350
Glu Ile Leu Lys Ile Tyr Gln Leu Met Asp His Ser Asn Met Asp Cys
355 360 365
Phe Ile Cys Cys Ile Leu Ser His Gly Asp Lys Gly Ile Ile Tyr Gly
370 375 380
Thr Asp Gly Gln Glu Ala Pro Ile Tyr Glu Leu Thr Ser Gln Phe Thr
385 390 395 400
Gly Leu Lys Cys Pro Ser Leu Ala Gly Lys Pro Lys Val Phe Phe Ile
405 410 415
Gln Ala Cys Gln Gly Asp Asn Tyr Gln Lys Gly Ile Pro Val Glu Thr
420 425 430
Asp Ser Glu Glu Gln Pro Tyr Leu Glu Met Asp Leu Ser Ser Pro Gln
435 440 445
Thr Arg Tyr Ile Pro Asp Glu Ala Asp Phe Leu Leu Gly Met Ala Thr
450 455 460
Val Asn Asn Cys Val Ser Tyr Arg Asn Pro Ala Glu Gly Thr Trp Tyr
465 470 475 480
Ile Gln Ser Leu Cys Gln Ser Leu Arg Glu Arg Cys Pro Arg Gly Asp
485 490 495
Asp Ile Leu Thr Ile Leu Thr Glu Val Asn Tyr Glu Val Ser Asn Lys
500 505 510
Asp Asp Lys Lys Asn Met Gly Lys Gln Met Pro Gln Pro Thr Phe Thr
515 520 525
Leu Arg Lys Lys Leu Val Phe Pro Ser Asp
530 535
<210> 68
<211> 496
<212> PRT
<213> homo sapiens
<400> 68
Met Asp Phe Ser Arg Asn Leu Tyr Asp Ile Gly Glu Gln Leu Asp Ser
1 5 10 15
Glu Asp Leu Ala Ser Leu Lys Phe Leu Ser Leu Asp Tyr Ile Pro Gln
20 25 30
Arg Lys Gln Glu Pro Ile Lys Asp Ala Leu Met Leu Phe Gln Arg Leu
35 40 45
Gln Glu Lys Arg Met Leu Glu Glu Ser Asn Leu Ser Phe Leu Lys Glu
50 55 60
Leu Leu Phe Arg Ile Asn Arg Leu Asp Leu Leu Ile Thr Tyr Leu Asn
65 70 75 80
Thr Arg Lys Glu Glu Met Glu Arg Glu Leu Gln Thr Pro Gly Arg Ala
85 90 95
Gln Ile Ser Ala Tyr Arg Phe His Phe Cys Arg Met Ser Trp Ala Glu
100 105 110
Ala Asn Ser Gln Cys Gln Thr Gln Ser Val Pro Phe Trp Arg Arg Val
115 120 125
Asp His Leu Leu Ile Arg Val Met Leu Tyr Gln Ile Ser Glu Glu Val
130 135 140
Ser Arg Ser Glu Leu Arg Ser Phe Lys Phe Leu Leu Gln Glu Glu Ile
145 150 155 160
Ser Lys Cys Lys Leu Asp Asp Asp Met Asn Leu Leu Asp Ile Phe Ile
165 170 175
Glu Met Glu Lys Arg Val Ile Leu Gly Glu Gly Lys Leu Asp Ile Leu
180 185 190
Lys Arg Val Cys Ala Gln Ile Asn Lys Ser Leu Leu Lys Ile Ile Asn
195 200 205
Asp Tyr Glu Glu Phe Ser Lys Gly Glu Glu Leu Cys Gly Val Met Thr
210 215 220
Ile Ser Asp Ser Pro Arg Glu Gln Asp Ser Glu Ser Gln Thr Leu Asp
225 230 235 240
Lys Val Tyr Gln Met Lys Ser Lys Pro Arg Gly Tyr Cys Leu Ile Ile
245 250 255
Asn Asn His Asn Phe Ala Lys Ala Arg Glu Lys Val Pro Lys Leu His
260 265 270
Ser Ile Arg Asp Arg Asn Gly Thr His Leu Asp Ala Gly Ala Leu Thr
275 280 285
Thr Thr Phe Glu Glu Leu His Phe Glu Ile Lys Pro His Asp Asp Cys
290 295 300
Thr Val Glu Gln Ile Tyr Glu Ile Leu Lys Ile Tyr Gln Leu Met Asp
305 310 315 320
His Ser Asn Met Asp Cys Phe Ile Cys Cys Ile Leu Ser His Gly Asp
325 330 335
Lys Gly Ile Ile Tyr Gly Thr Asp Gly Gln Glu Ala Pro Ile Tyr Glu
340 345 350
Leu Thr Ser Gln Phe Thr Gly Leu Lys Cys Pro Ser Leu Ala Gly Lys
355 360 365
Pro Lys Val Phe Phe Ile Gln Ala Cys Gln Gly Asp Asn Tyr Gln Lys
370 375 380
Gly Ile Pro Val Glu Thr Asp Ser Glu Glu Gln Pro Tyr Leu Glu Met
385 390 395 400
Asp Leu Ser Ser Pro Gln Thr Arg Tyr Ile Pro Asp Glu Ala Asp Phe
405 410 415
Leu Leu Gly Met Ala Thr Val Asn Asn Cys Val Ser Tyr Arg Asn Pro
420 425 430
Ala Glu Gly Thr Trp Tyr Ile Gln Ser Leu Cys Gln Ser Leu Arg Glu
435 440 445
Arg Cys Pro Arg Gly Asp Asp Ile Leu Thr Ile Leu Thr Glu Val Asn
450 455 460
Tyr Glu Val Ser Asn Lys Asp Asp Lys Lys Asn Met Gly Lys Gln Met
465 470 475 480
Pro Gln Pro Thr Phe Thr Leu Arg Lys Lys Leu Val Phe Pro Ser Asp
485 490 495
<210> 69
<211> 479
<212> PRT
<213> homo sapiens
<400> 69
Met Asp Phe Ser Arg Asn Leu Tyr Asp Ile Gly Glu Gln Leu Asp Ser
1 5 10 15
Glu Asp Leu Ala Ser Leu Lys Phe Leu Ser Leu Asp Tyr Ile Pro Gln
20 25 30
Arg Lys Gln Glu Pro Ile Lys Asp Ala Leu Met Leu Phe Gln Arg Leu
35 40 45
Gln Glu Lys Arg Met Leu Glu Glu Ser Asn Leu Ser Phe Leu Lys Glu
50 55 60
Leu Leu Phe Arg Ile Asn Arg Leu Asp Leu Leu Ile Thr Tyr Leu Asn
65 70 75 80
Thr Arg Lys Glu Glu Met Glu Arg Glu Leu Gln Thr Pro Gly Arg Ala
85 90 95
Gln Ile Ser Ala Tyr Arg Val Met Leu Tyr Gln Ile Ser Glu Glu Val
100 105 110
Ser Arg Ser Glu Leu Arg Ser Phe Lys Phe Leu Leu Gln Glu Glu Ile
115 120 125
Ser Lys Cys Lys Leu Asp Asp Asp Met Asn Leu Leu Asp Ile Phe Ile
130 135 140
Glu Met Glu Lys Arg Val Ile Leu Gly Glu Gly Lys Leu Asp Ile Leu
145 150 155 160
Lys Arg Val Cys Ala Gln Ile Asn Lys Ser Leu Leu Lys Ile Ile Asn
165 170 175
Asp Tyr Glu Glu Phe Ser Lys Glu Arg Ser Ser Ser Leu Glu Gly Ser
180 185 190
Pro Asp Glu Phe Ser Asn Gly Glu Glu Leu Cys Gly Val Met Thr Ile
195 200 205
Ser Asp Ser Pro Arg Glu Gln Asp Ser Glu Ser Gln Thr Leu Asp Lys
210 215 220
Val Tyr Gln Met Lys Ser Lys Pro Arg Gly Tyr Cys Leu Ile Ile Asn
225 230 235 240
Asn His Asn Phe Ala Lys Ala Arg Glu Lys Val Pro Lys Leu His Ser
245 250 255
Ile Arg Asp Arg Asn Gly Thr His Leu Asp Ala Gly Ala Leu Thr Thr
260 265 270
Thr Phe Glu Glu Leu His Phe Glu Ile Lys Pro His Asp Asp Cys Thr
275 280 285
Val Glu Gln Ile Tyr Glu Ile Leu Lys Ile Tyr Gln Leu Met Asp His
290 295 300
Ser Asn Met Asp Cys Phe Ile Cys Cys Ile Leu Ser His Gly Asp Lys
305 310 315 320
Gly Ile Ile Tyr Gly Thr Asp Gly Gln Glu Ala Pro Ile Tyr Glu Leu
325 330 335
Thr Ser Gln Phe Thr Gly Leu Lys Cys Pro Ser Leu Ala Gly Lys Pro
340 345 350
Lys Val Phe Phe Ile Gln Ala Cys Gln Gly Asp Asn Tyr Gln Lys Gly
355 360 365
Ile Pro Val Glu Thr Asp Ser Glu Glu Gln Pro Tyr Leu Glu Met Asp
370 375 380
Leu Ser Ser Pro Gln Thr Arg Tyr Ile Pro Asp Glu Ala Asp Phe Leu
385 390 395 400
Leu Gly Met Ala Thr Val Asn Asn Cys Val Ser Tyr Arg Asn Pro Ala
405 410 415
Glu Gly Thr Trp Tyr Ile Gln Ser Leu Cys Gln Ser Leu Arg Glu Arg
420 425 430
Cys Pro Arg Gly Asp Asp Ile Leu Thr Ile Leu Thr Glu Val Asn Tyr
435 440 445
Glu Val Ser Asn Lys Asp Asp Lys Lys Asn Met Gly Lys Gln Met Pro
450 455 460
Gln Pro Thr Phe Thr Leu Arg Lys Lys Leu Val Phe Pro Ser Asp
465 470 475
<210> 70
<211> 464
<212> PRT
<213> homo sapiens
<400> 70
Met Asp Phe Ser Arg Asn Leu Tyr Asp Ile Gly Glu Gln Leu Asp Ser
1 5 10 15
Glu Asp Leu Ala Ser Leu Lys Phe Leu Ser Leu Asp Tyr Ile Pro Gln
20 25 30
Arg Lys Gln Glu Pro Ile Lys Asp Ala Leu Met Leu Phe Gln Arg Leu
35 40 45
Gln Glu Lys Arg Met Leu Glu Glu Ser Asn Leu Ser Phe Leu Lys Glu
50 55 60
Leu Leu Phe Arg Ile Asn Arg Leu Asp Leu Leu Ile Thr Tyr Leu Asn
65 70 75 80
Thr Arg Lys Glu Glu Met Glu Arg Glu Leu Gln Thr Pro Gly Arg Ala
85 90 95
Gln Ile Ser Ala Tyr Arg Val Met Leu Tyr Gln Ile Ser Glu Glu Val
100 105 110
Ser Arg Ser Glu Leu Arg Ser Phe Lys Phe Leu Leu Gln Glu Glu Ile
115 120 125
Ser Lys Cys Lys Leu Asp Asp Asp Met Asn Leu Leu Asp Ile Phe Ile
130 135 140
Glu Met Glu Lys Arg Val Ile Leu Gly Glu Gly Lys Leu Asp Ile Leu
145 150 155 160
Lys Arg Val Cys Ala Gln Ile Asn Lys Ser Leu Leu Lys Ile Ile Asn
165 170 175
Asp Tyr Glu Glu Phe Ser Lys Gly Glu Glu Leu Cys Gly Val Met Thr
180 185 190
Ile Ser Asp Ser Pro Arg Glu Gln Asp Ser Glu Ser Gln Thr Leu Asp
195 200 205
Lys Val Tyr Gln Met Lys Ser Lys Pro Arg Gly Tyr Cys Leu Ile Ile
210 215 220
Asn Asn His Asn Phe Ala Lys Ala Arg Glu Lys Val Pro Lys Leu His
225 230 235 240
Ser Ile Arg Asp Arg Asn Gly Thr His Leu Asp Ala Gly Ala Leu Thr
245 250 255
Thr Thr Phe Glu Glu Leu His Phe Glu Ile Lys Pro His Asp Asp Cys
260 265 270
Thr Val Glu Gln Ile Tyr Glu Ile Leu Lys Ile Tyr Gln Leu Met Asp
275 280 285
His Ser Asn Met Asp Cys Phe Ile Cys Cys Ile Leu Ser His Gly Asp
290 295 300
Lys Gly Ile Ile Tyr Gly Thr Asp Gly Gln Glu Ala Pro Ile Tyr Glu
305 310 315 320
Leu Thr Ser Gln Phe Thr Gly Leu Lys Cys Pro Ser Leu Ala Gly Lys
325 330 335
Pro Lys Val Phe Phe Ile Gln Ala Cys Gln Gly Asp Asn Tyr Gln Lys
340 345 350
Gly Ile Pro Val Glu Thr Asp Ser Glu Glu Gln Pro Tyr Leu Glu Met
355 360 365
Asp Leu Ser Ser Pro Gln Thr Arg Tyr Ile Pro Asp Glu Ala Asp Phe
370 375 380
Leu Leu Gly Met Ala Thr Val Asn Asn Cys Val Ser Tyr Arg Asn Pro
385 390 395 400
Ala Glu Gly Thr Trp Tyr Ile Gln Ser Leu Cys Gln Ser Leu Arg Glu
405 410 415
Arg Cys Pro Arg Gly Asp Asp Ile Leu Thr Ile Leu Thr Glu Val Asn
420 425 430
Tyr Glu Val Ser Asn Lys Asp Asp Lys Lys Asn Met Gly Lys Gln Met
435 440 445
Pro Gln Pro Thr Phe Thr Leu Arg Lys Lys Leu Val Phe Pro Ser Asp
450 455 460
<210> 71
<211> 235
<212> PRT
<213> homo sapiens
<400> 71
Met Asp Phe Ser Arg Asn Leu Tyr Asp Ile Gly Glu Gln Leu Asp Ser
1 5 10 15
Glu Asp Leu Ala Ser Leu Lys Phe Leu Ser Leu Asp Tyr Ile Pro Gln
20 25 30
Arg Lys Gln Glu Pro Ile Lys Asp Ala Leu Met Leu Phe Gln Arg Leu
35 40 45
Gln Glu Lys Arg Met Leu Glu Glu Ser Asn Leu Ser Phe Leu Lys Glu
50 55 60
Leu Leu Phe Arg Ile Asn Arg Leu Asp Leu Leu Ile Thr Tyr Leu Asn
65 70 75 80
Thr Arg Lys Glu Glu Met Glu Arg Glu Leu Gln Thr Pro Gly Arg Ala
85 90 95
Gln Ile Ser Ala Tyr Arg Val Met Leu Tyr Gln Ile Ser Glu Glu Val
100 105 110
Ser Arg Ser Glu Leu Arg Ser Phe Lys Phe Leu Leu Gln Glu Glu Ile
115 120 125
Ser Lys Cys Lys Leu Asp Asp Asp Met Asn Leu Leu Asp Ile Phe Ile
130 135 140
Glu Met Glu Lys Arg Val Ile Leu Gly Glu Gly Lys Leu Asp Ile Leu
145 150 155 160
Lys Arg Val Cys Ala Gln Ile Asn Lys Ser Leu Leu Lys Ile Ile Asn
165 170 175
Asp Tyr Glu Glu Phe Ser Lys Glu Arg Ser Ser Ser Leu Glu Gly Ser
180 185 190
Pro Asp Glu Phe Ser Asn Asp Phe Gly Gln Ser Leu Pro Asn Glu Lys
195 200 205
Gln Thr Ser Gly Ile Leu Ser Asp His Gln Gln Ser Gln Phe Cys Lys
210 215 220
Ser Thr Gly Glu Ser Ala Gln Thr Ser Gln His
225 230 235
<210> 72
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 72
Ile Leu Lys Glu Pro Val His Gly Val
1 5
<210> 73
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 73
Ser Leu Tyr Asn Thr Val Ala Thr Leu
1 5
<210> 74
<211> 8
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(8)
<223> 短胜肽
<400> 74
Ile Leu Glu Pro Val His Gly Val
1 5
<210> 75
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 75
Gly Ile Leu Gly Phe Val Phe Thr Leu
1 5
<210> 76
<211> 252
<212> PRT
<213> Influenza A virus
<400> 76
Met Ser Leu Leu Thr Glu Val Glu Thr Tyr Val Leu Ser Ile Val Pro
1 5 10 15
Ser Gly Pro Leu Lys Ala Glu Ile Ala Gln Arg Leu Glu Asp Val Phe
20 25 30
Ala Gly Lys Asn Thr Asp Leu Glu Ala Leu Met Glu Trp Leu Lys Thr
35 40 45
Arg Pro Ile Leu Ser Pro Leu Thr Lys Gly Ile Leu Gly Phe Val Phe
50 55 60
Thr Leu Thr Val Pro Ser Glu Arg Gly Leu Gln Arg Arg Arg Phe Val
65 70 75 80
Gln Asn Ala Leu Asn Gly Asn Gly Asp Pro Asn Asn Met Asp Arg Ala
85 90 95
Val Lys Leu Tyr Arg Lys Leu Lys Arg Glu Ile Thr Phe His Gly Ala
100 105 110
Lys Glu Val Ala Leu Ser Tyr Ser Ala Gly Ala Leu Ala Ser Cys Met
115 120 125
Gly Leu Ile Tyr Asn Arg Met Gly Ala Val Thr Thr Glu Val Ala Phe
130 135 140
Ala Val Val Cys Ala Thr Cys Glu Gln Ile Ala Asp Ser Gln His Arg
145 150 155 160
Ser His Arg Gln Met Val Thr Thr Thr Asn Pro Leu Ile Arg His Glu
165 170 175
Asn Arg Met Val Leu Ala Ser Thr Thr Ala Lys Ala Met Glu Gln Met
180 185 190
Ala Gly Ser Ser Glu Gln Ala Ala Glu Ala Met Glu Val Ala Ser Gln
195 200 205
Ala Arg Gln Met Val Gln Ala Met Arg Ala Ile Gly Thr Pro Pro Ser
210 215 220
Ser Ser Ala Gly Leu Lys Asp Asp Leu Leu Glu Asn Leu Gln Ala Tyr
225 230 235 240
Gln Lys Arg Met Gly Val Gln Met Gln Arg Phe Lys
245 250
<210> 77
<211> 584
<212> PRT
<213> Influenza A virus
<400> 77
Met Lys Ala Ile Ile Val Leu Leu Met Val Val Thr Ser Asn Ala Asp
1 5 10 15
Arg Ile Cys Thr Gly Ile Thr Ser Ser Asn Ser Pro His Val Val Lys
20 25 30
Thr Ala Thr Gln Gly Glu Val Asn Val Thr Gly Val Ile Pro Leu Thr
35 40 45
Thr Thr Pro Thr Lys Ser His Phe Ala Asn Leu Lys Gly Thr Gln Thr
50 55 60
Arg Gly Lys Leu Cys Pro Asn Cys Phe Asn Cys Thr Asp Leu Asp Val
65 70 75 80
Ala Leu Gly Arg Pro Lys Cys Met Gly Asn Thr Pro Ser Ala Lys Val
85 90 95
Ser Ile Leu His Glu Val Lys Pro Ala Thr Ser Gly Cys Phe Pro Ile
100 105 110
Met His Asp Arg Thr Lys Ile Arg Gln Leu Pro Asn Leu Leu Arg Gly
115 120 125
Tyr Glu Asn Ile Arg Leu Ser Thr Ser Asn Val Ile Asn Thr Glu Thr
130 135 140
Ala Pro Gly Gly Pro Tyr Lys Val Gly Thr Ser Gly Ser Cys Pro Asn
145 150 155 160
Val Ala Asn Gly Asn Gly Phe Phe Asn Thr Met Ala Trp Val Ile Pro
165 170 175
Lys Asp Asn Asn Lys Thr Ala Ile Asn Pro Val Thr Val Glu Val Pro
180 185 190
Tyr Ile Cys Ser Glu Gly Glu Asp Gln Ile Thr Val Trp Gly Phe His
195 200 205
Ser Asp Asp Lys Thr Gln Met Glu Arg Leu Tyr Gly Asp Ser Asn Pro
210 215 220
Gln Lys Phe Thr Ser Ser Ala Asn Gly Val Thr Thr His Tyr Val Ser
225 230 235 240
Gln Ile Gly Gly Phe Pro Asn Gln Thr Glu Asp Glu Gly Leu Lys Gln
245 250 255
Ser Gly Arg Ile Val Val Asp Tyr Met Val Gln Lys Pro Gly Lys Thr
260 265 270
Gly Thr Ile Val Tyr Gln Arg Gly Ile Leu Leu Pro Gln Lys Val Trp
275 280 285
Cys Ala Ser Gly Arg Ser Lys Val Ile Lys Gly Ser Leu Pro Leu Ile
290 295 300
Gly Glu Ala Asp Cys Leu His Glu Lys Tyr Gly Gly Leu Asn Lys Ser
305 310 315 320
Lys Pro Tyr Tyr Thr Gly Glu His Ala Lys Ala Ile Gly Asn Cys Pro
325 330 335
Ile Trp Val Lys Thr Pro Leu Lys Leu Ala Asn Gly Thr Lys Tyr Arg
340 345 350
Pro Pro Ala Lys Leu Leu Lys Glu Arg Gly Phe Phe Gly Ala Ile Ala
355 360 365
Gly Phe Leu Glu Gly Gly Trp Glu Gly Met Ile Ala Gly Trp His Gly
370 375 380
Tyr Thr Ser His Gly Ala His Gly Val Ala Val Ala Ala Asp Leu Lys
385 390 395 400
Ser Thr Gln Glu Ala Ile Asn Lys Ile Thr Lys Asn Leu Asn Tyr Leu
405 410 415
Ser Glu Leu Glu Val Lys Asn Leu Gln Arg Leu Ser Gly Ala Met Asn
420 425 430
Glu Leu His Asp Glu Ile Leu Glu Leu Asp Glu Lys Val Asp Asp Leu
435 440 445
Arg Ala Asp Thr Ile Ser Ser Gln Ile Glu Leu Ala Val Leu Leu Ser
450 455 460
Asn Glu Gly Ile Ile Asn Ser Glu Asp Glu His Leu Leu Ala Leu Glu
465 470 475 480
Arg Lys Leu Lys Lys Met Leu Gly Pro Ser Ala Val Glu Ile Gly Asn
485 490 495
Gly Cys Phe Glu Thr Lys His Lys Cys Asn Gln Thr Cys Leu Asp Arg
500 505 510
Ile Ala Ala Gly Thr Phe Asn Ala Gly Asp Phe Ser Leu Pro Thr Phe
515 520 525
Asp Ser Leu Asn Ile Thr Ala Ala Ser Leu Asn Asp Asp Gly Leu Asp
530 535 540
Asn His Thr Ile Leu Leu Tyr Tyr Ser Thr Ala Ala Ser Ser Leu Ala
545 550 555 560
Val Thr Leu Met Ile Ala Ile Phe Ile Val Tyr Met Val Ser Arg Asp
565 570 575
Asn Val Ser Cys Ser Ile Cys Leu
580
<210> 78
<211> 566
<212> PRT
<213> Influenza A virus
<400> 78
Met Lys Thr Ile Ile Ala Leu Ser Tyr Ile Leu Cys Leu Val Phe Ala
1 5 10 15
Gln Lys Leu Pro Gly Asn Asp Asn Ser Thr Ala Thr Leu Cys Leu Gly
20 25 30
His His Ala Val Pro Asn Gly Thr Ile Val Lys Thr Ile Thr Asn Asp
35 40 45
Gln Ile Glu Val Thr Asn Ala Thr Glu Leu Val Gln Ser Ser Ser Thr
50 55 60
Gly Gly Ile Cys Asp Ser Pro His Gln Ile Leu Asp Gly Glu Asn Cys
65 70 75 80
Thr Leu Ile Asp Ala Leu Leu Gly Asp Pro Gln Cys Asp Gly Phe Gln
85 90 95
Asn Lys Lys Trp Asp Leu Phe Val Glu Arg Ser Lys Ala Tyr Ser Asn
100 105 110
Cys Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser Leu Arg Ser Leu Val
115 120 125
Ala Ser Ser Gly Thr Leu Glu Phe Asn Asn Glu Ser Phe Asn Trp Thr
130 135 140
Gly Val Thr Gln Asn Gly Thr Ser Ser Ala Cys Lys Arg Arg Ser Asn
145 150 155 160
Asn Ser Phe Phe Ser Arg Leu Asn Trp Leu Thr His Leu Lys Phe Lys
165 170 175
Tyr Pro Ala Leu Asn Val Thr Met Pro Asn Asn Glu Lys Phe Asp Lys
180 185 190
Leu Tyr Ile Trp Gly Val His His Pro Gly Thr Asp Asn Asp Gln Ile
195 200 205
Ser Leu Tyr Ala Gln Ala Ser Gly Arg Ile Thr Val Ser Thr Lys Arg
210 215 220
Ser Gln Gln Thr Val Ile Pro Ser Ile Gly Ser Arg Pro Arg Ile Arg
225 230 235 240
Asp Val Pro Ser Arg Ile Ser Ile Tyr Trp Thr Ile Val Lys Pro Gly
245 250 255
Asp Ile Leu Leu Ile Asn Ser Thr Gly Asn Leu Ile Ala Pro Arg Gly
260 265 270
Tyr Phe Lys Ile Arg Ser Gly Lys Ser Ser Ile Met Arg Ser Asp Ala
275 280 285
Pro Ile Gly Lys Cys Asn Ser Glu Cys Ile Thr Pro Asn Gly Ser Ile
290 295 300
Pro Asn Asp Lys Pro Phe Gln Asn Val Asn Arg Ile Thr Tyr Gly Ala
305 310 315 320
Cys Pro Arg Tyr Val Lys Gln Asn Thr Leu Lys Leu Ala Thr Gly Met
325 330 335
Arg Asn Val Pro Glu Lys Gln Thr Arg Gly Ile Phe Gly Ala Ile Ala
340 345 350
Gly Phe Ile Glu Asn Gly Trp Glu Gly Met Val Asp Gly Trp Tyr Gly
355 360 365
Phe Arg His Gln Asn Ser Glu Gly Thr Gly Gln Ala Ala Asp Leu Lys
370 375 380
Ser Thr Gln Ala Ala Ile Asn Gln Ile Asn Gly Lys Leu Asn Arg Leu
385 390 395 400
Ile Gly Lys Thr Asn Glu Lys Phe His Gln Ile Glu Lys Glu Phe Ser
405 410 415
Glu Val Glu Gly Arg Ile Gln Asp Leu Glu Lys Tyr Val Glu Asp Thr
420 425 430
Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu Val Ala Leu Glu
435 440 445
Asn Gln His Thr Ile Asp Leu Thr Asp Ser Glu Met Asn Lys Leu Phe
450 455 460
Glu Arg Thr Lys Lys Gln Leu Arg Glu Asn Ala Glu Asp Met Gly Asn
465 470 475 480
Gly Cys Phe Lys Ile Tyr His Lys Cys Asp Asn Ala Cys Ile Gly Ser
485 490 495
Ile Arg Asn Gly Thr Tyr Asp His Asp Val Tyr Arg Asp Glu Ala Leu
500 505 510
Asn Asn Arg Phe Gln Ile Lys Gly Val Glu Leu Lys Ser Gly Tyr Lys
515 520 525
Asp Trp Ile Leu Trp Ile Ser Phe Ala Ile Ser Cys Phe Leu Leu Cys
530 535 540
Val Ala Leu Leu Gly Phe Ile Met Trp Ala Cys Gln Lys Gly Asn Ile
545 550 555 560
Arg Cys Asn Ile Cys Ile
565
<210> 79
<211> 466
<212> PRT
<213> Influenza B virus
<400> 79
Met Leu Pro Ser Thr Val Gln Thr Leu Thr Leu Leu Leu Thr Ser Gly
1 5 10 15
Gly Val Leu Leu Ser Leu Tyr Val Ser Ala Ser Leu Ser Tyr Leu Leu
20 25 30
Tyr Ser Asp Val Leu Leu Lys Phe Ser Ser Thr Lys Thr Thr Ala Pro
35 40 45
Thr Met Ser Leu Glu Cys Thr Asn Ala Ser Asn Ala Gln Thr Val Asn
50 55 60
His Ser Ala Thr Lys Glu Met Thr Phe Pro Pro Pro Glu Pro Glu Trp
65 70 75 80
Thr Tyr Pro Arg Leu Ser Cys Gln Gly Ser Thr Phe Gln Lys Ala Leu
85 90 95
Leu Ile Ser Pro His Arg Phe Gly Glu Ile Lys Gly Asn Ser Ala Pro
100 105 110
Leu Ile Ile Arg Glu Pro Phe Val Ala Cys Gly Pro Lys Glu Cys Arg
115 120 125
His Phe Ala Leu Thr His Tyr Ala Ala Gln Pro Gly Gly Tyr Tyr Asn
130 135 140
Gly Thr Arg Lys Asp Arg Asn Lys Leu Arg His Leu Val Ser Val Lys
145 150 155 160
Leu Gly Lys Ile Pro Thr Val Glu Asn Ser Ile Phe His Met Ala Ala
165 170 175
Trp Ser Gly Ser Ala Cys His Asp Gly Arg Glu Trp Thr Tyr Ile Gly
180 185 190
Val Asp Gly Pro Asp Asn Asp Ala Leu Val Lys Ile Lys Tyr Gly Glu
195 200 205
Ala Tyr Thr Asp Thr Tyr His Ser Tyr Ala His Asn Ile Leu Arg Thr
210 215 220
Gln Glu Ser Ala Cys Asn Cys Ile Gly Gly Asp Cys Tyr Leu Met Ile
225 230 235 240
Thr Asp Gly Ser Ala Ser Gly Ile Ser Lys Cys Arg Phe Leu Lys Ile
245 250 255
Arg Glu Gly Arg Ile Ile Lys Glu Ile Leu Pro Thr Gly Arg Val Glu
260 265 270
His Thr Glu Glu Cys Thr Cys Gly Phe Ala Ser Asn Lys Thr Ile Glu
275 280 285
Cys Ala Cys Arg Asp Asn Ser Tyr Thr Ala Lys Arg Pro Phe Val Lys
290 295 300
Leu Asn Val Glu Thr Asp Thr Ala Glu Ile Arg Leu Met Cys Thr Lys
305 310 315 320
Thr Tyr Leu Asp Thr Pro Arg Pro Asp Asp Gly Ser Ile Ala Gly Pro
325 330 335
Cys Glu Ser Asn Gly Asp Lys Trp Leu Gly Gly Ile Lys Gly Gly Phe
340 345 350
Val His Gln Arg Met Ala Ser Lys Ile Gly Arg Trp Tyr Ser Arg Thr
355 360 365
Met Ser Lys Thr Asn Arg Met Gly Met Glu Leu Tyr Val Lys Tyr Asp
370 375 380
Gly Asp Pro Trp Thr Asp Ser Asp Ala Leu Thr Leu Ser Gly Val Met
385 390 395 400
Val Ser Ile Glu Glu Pro Gly Trp Tyr Ser Phe Gly Phe Glu Ile Lys
405 410 415
Asp Lys Lys Cys Asp Val Pro Cys Ile Gly Ile Glu Met Val His Asp
420 425 430
Gly Gly Lys Asp Thr Trp His Ser Ala Ala Thr Ala Ile Tyr Cys Leu
435 440 445
Met Gly Ser Gly Gln Leu Leu Trp Asp Thr Val Thr Gly Val Asp Met
450 455 460
Ala Leu
465
<210> 80
<211> 565
<212> PRT
<213> Influenza C virus
<400> 80
Met Ser Asp Arg Arg Gln Asn Arg Lys Thr Pro Asp Glu Gln Arg Lys
1 5 10 15
Ala Asn Ala Leu Ile Ile Asn Glu Asn Ile Glu Ala Tyr Ile Ala Ile
20 25 30
Cys Lys Glu Val Gly Leu Asn Gly Asp Glu Met Leu Ile Leu Glu Asn
35 40 45
Gly Ile Ala Ile Glu Lys Ala Ile Arg Ile Cys Cys Asp Gly Lys Tyr
50 55 60
Gln Glu Lys Arg Glu Lys Lys Ala Arg Glu Ala Gln Arg Ala Asp Ser
65 70 75 80
Asn Phe Asn Ala Asp Ser Ile Gly Ile Arg Leu Val Lys Arg Ala Gly
85 90 95
Ser Gly Thr Asn Ile Thr Tyr His Ala Val Val Glu Leu Thr Ser Arg
100 105 110
Ser Arg Ile Val Gln Ile Leu Lys Ser His Trp Gly Asn Glu Leu Asn
115 120 125
Arg Ala Lys Ile Ala Gly Lys Arg Leu Gly Phe Ser Ala Leu Phe Ala
130 135 140
Ser Asn Leu Glu Ala Ile Ile Tyr Gln Arg Gly Arg Asn Ala Ala Arg
145 150 155 160
Arg Asn Gly Ser Ala Glu Leu Phe Thr Leu Thr Gln Gly Ala Gly Ile
165 170 175
Glu Thr Arg Tyr Lys Trp Ile Met Glu Lys His Ile Gly Ile Gly Val
180 185 190
Leu Ile Ala Asp Ala Lys Gly Leu Ile Asn Gly Lys Arg Glu Gly Lys
195 200 205
Arg Gly Val Asp Ala Asn Val Lys Leu Arg Ala Gly Thr Thr Gly Ser
210 215 220
Pro Leu Glu Arg Ala Met Gln Gly Ile Glu Lys Lys Ala Phe Pro Gly
225 230 235 240
Pro Leu Arg Ala Leu Ala Arg Arg Val Val Lys Ala Asn Tyr Asn Asp
245 250 255
Ala Arg Glu Ala Leu Asn Val Ile Ala Glu Ala Ser Leu Leu Leu Lys
260 265 270
Pro Gln Ile Thr Asn Lys Met Thr Met Pro Trp Cys Met Trp Leu Ala
275 280 285
Ala Arg Leu Thr Leu Lys Asp Glu Phe Ala Asn Phe Cys Ala Tyr Ala
290 295 300
Gly Arg Arg Ala Phe Glu Val Phe Asn Ile Ala Met Glu Lys Ile Gly
305 310 315 320
Ile Cys Ser Phe Gln Gly Thr Ile Met Asn Asp Asp Glu Ile Glu Ser
325 330 335
Ile Glu Asp Lys Ala Gln Val Leu Met Met Ala Cys Phe Gly Leu Ala
340 345 350
Tyr Glu Asp Phe Ser Leu Val Ser Ala Met Val Ser His Pro Leu Lys
355 360 365
Leu Arg Asn Arg Met Lys Ile Gly Asn Phe Arg Val Gly Glu Lys Val
370 375 380
Ser Thr Val Leu Ser Pro Leu Leu Arg Phe Thr Arg Trp Ala Glu Phe
385 390 395 400
Ala Gln Arg Phe Ala Leu Gln Ala Asn Thr Ser Arg Glu Gly Ala Gln
405 410 415
Ile Ser Asn Ser Ala Val Phe Ala Val Glu Arg Lys Ile Thr Thr Asp
420 425 430
Val Gln Arg Val Glu Glu Leu Leu Asn Lys Val Gln Ala His Glu Asp
435 440 445
Glu Pro Leu Gln Thr Leu Tyr Lys Lys Val Arg Glu Gln Ile Ser Ile
450 455 460
Ile Gly Arg Asn Lys Ser Glu Ile Lys Glu Phe Leu Gly Ser Ser Met
465 470 475 480
Tyr Asp Leu Asn Asp Gln Glu Lys Gln Asn Pro Ile Asn Phe Arg Ser
485 490 495
Gly Ala His Pro Phe Phe Phe Glu Phe Asp Pro Asp Tyr Asn Pro Ile
500 505 510
Arg Val Lys Arg Pro Lys Lys Pro Ile Ala Lys Arg Asn Ser Asn Ile
515 520 525
Ser Arg Leu Glu Glu Glu Gly Met Asp Glu Asn Ser Glu Ile Gly Gln
530 535 540
Ala Lys Lys Met Lys Pro Leu Asp Gln Leu Thr Ser Thr Ser Ser Asn
545 550 555 560
Ile Pro Gly Lys Asn
565
<210> 81
<211> 498
<212> PRT
<213> Influenza A virus
<400> 81
Met Ala Ser Gln Gly Thr Lys Arg Ser Tyr Glu Gln Met Glu Thr Asp
1 5 10 15
Gly Glu Arg Gln Asn Ala Thr Glu Ile Arg Ala Ser Val Gly Lys Met
20 25 30
Ile Asp Gly Ile Gly Arg Phe Tyr Ile Gln Met Cys Thr Glu Leu Lys
35 40 45
Leu Ser Asp Tyr Glu Gly Arg Leu Ile Gln Asn Ser Leu Thr Ile Glu
50 55 60
Arg Met Val Leu Ser Ala Phe Asp Glu Arg Arg Asn Lys Tyr Leu Glu
65 70 75 80
Glu His Pro Ser Ala Gly Lys Asp Pro Lys Lys Thr Gly Gly Pro Ile
85 90 95
Tyr Lys Arg Val Asp Gly Lys Trp Met Arg Glu Leu Val Leu Tyr Asp
100 105 110
Lys Glu Glu Ile Arg Arg Ile Trp Arg Gln Ala Asn Asn Gly Asp Asp
115 120 125
Ala Thr Ala Gly Leu Thr His Met Met Ile Trp His Ser Asn Leu Asn
130 135 140
Asp Thr Thr Tyr Gln Arg Thr Arg Ala Leu Val Arg Thr Gly Met Asp
145 150 155 160
Pro Arg Met Cys Ser Leu Met Gln Gly Ser Thr Leu Pro Arg Arg Ser
165 170 175
Gly Ala Ala Gly Ala Ala Val Lys Gly Val Gly Thr Met Val Met Glu
180 185 190
Leu Ile Arg Met Ile Lys Arg Gly Ile Asn Asp Arg Asn Phe Trp Arg
195 200 205
Gly Glu Asn Gly Arg Lys Thr Arg Ser Ala Tyr Glu Arg Met Cys Asn
210 215 220
Ile Leu Lys Gly Lys Phe Gln Thr Ala Ala Gln Arg Ala Met Met Asp
225 230 235 240
Gln Val Arg Glu Ser Arg Asn Pro Gly Asn Ala Glu Ile Glu Asp Leu
245 250 255
Ile Phe Leu Ala Arg Ser Ala Leu Ile Leu Arg Gly Ser Val Ala His
260 265 270
Lys Ser Cys Leu Pro Ala Cys Val Tyr Gly Pro Ala Ile Ala Ser Gly
275 280 285
Tyr Asn Phe Glu Lys Glu Gly Tyr Ser Leu Val Gly Ile Asp Pro Phe
290 295 300
Lys Leu Leu Gln Asn Ser Gln Val Tyr Ser Leu Ile Arg Pro Asn Glu
305 310 315 320
Asn Pro Ala His Lys Ser Gln Leu Val Trp Met Ala Cys Asn Ser Ala
325 330 335
Ala Phe Glu Asp Leu Arg Val Leu Ser Phe Ile Arg Gly Thr Lys Val
340 345 350
Ser Pro Arg Gly Lys Leu Ser Thr Arg Gly Val Gln Ile Ala Ser Asn
355 360 365
Glu Asn Met Asp Thr Met Glu Ser Ser Thr Leu Glu Leu Arg Ser Arg
370 375 380
Tyr Trp Ala Ile Arg Thr Arg Ser Gly Gly Asn Thr Asn Gln Gln Arg
385 390 395 400
Ala Ser Ala Gly Gln Ile Ser Val Gln Pro Ala Phe Ser Val Gln Arg
405 410 415
Asn Leu Pro Phe Asp Lys Pro Thr Ile Met Ala Ala Phe Thr Gly Asn
420 425 430
Thr Glu Gly Arg Thr Ser Asp Met Arg Ala Glu Ile Ile Arg Met Met
435 440 445
Glu Gly Ala Lys Pro Glu Glu Met Ser Phe Gln Gly Arg Gly Val Phe
450 455 460
Glu Leu Ser Asp Glu Lys Ala Thr Asn Pro Ile Val Pro Ser Phe Asp
465 470 475 480
Met Ser Asn Glu Gly Ser Tyr Phe Phe Gly Asp Asn Ala Glu Glu Tyr
485 490 495
Asp Asn
<210> 82
<211> 498
<212> PRT
<213> Influenza A virus
<400> 82
Met Ala Ser Gln Gly Thr Lys Arg Ser Tyr Glu Gln Met Glu Thr Gly
1 5 10 15
Gly Glu Arg Gln Asn Ala Thr Glu Ile Arg Ala Ser Val Gly Arg Met
20 25 30
Val Gly Gly Ile Gly Arg Phe Tyr Val Gln Met Cys Thr Glu Leu Lys
35 40 45
Leu Ser Asp Gln Glu Gly Arg Leu Ile Gln Asn Ser Ile Thr Ile Glu
50 55 60
Arg Met Val Leu Ser Ala Phe Asp Glu Arg Arg Asn Arg Tyr Leu Glu
65 70 75 80
Glu His Pro Ser Ala Gly Lys Asp Pro Lys Lys Thr Gly Gly Pro Ile
85 90 95
Tyr Arg Arg Arg Asp Gly Lys Trp Val Arg Glu Leu Ile Leu Tyr Asp
100 105 110
Lys Glu Glu Ile Arg Arg Ile Trp Arg Gln Ala Asn Asn Gly Glu Asp
115 120 125
Ala Thr Ala Gly Leu Thr His Met Met Ile Trp His Ser Asn Leu Asn
130 135 140
Asp Ala Thr Tyr Gln Arg Thr Arg Ala Leu Val Arg Thr Gly Met Asp
145 150 155 160
Pro Arg Met Cys Ser Leu Met Gln Gly Ser Thr Leu Pro Arg Arg Ser
165 170 175
Gly Ala Ala Gly Ala Ala Ile Lys Gly Val Gly Thr Met Val Met Glu
180 185 190
Leu Ile Arg Met Ile Lys Arg Gly Ile Asn Asp Arg Asn Phe Trp Arg
195 200 205
Gly Asp Asn Gly Arg Arg Thr Arg Ile Ala Tyr Glu Arg Met Cys Asn
210 215 220
Ile Leu Lys Gly Lys Phe Gln Thr Ala Ala Gln Arg Ala Met Met Asp
225 230 235 240
Gln Val Arg Glu Ser Arg Asn Pro Gly Asn Ala Glu Ile Glu Asp Leu
245 250 255
Ile Phe Leu Ala Arg Ser Ala Leu Ile Leu Arg Gly Ser Val Ala His
260 265 270
Lys Ser Cys Leu Pro Ala Cys Val Tyr Gly Leu Ala Val Ala Ser Gly
275 280 285
Tyr Asp Phe Glu Arg Glu Gly Tyr Ser Leu Val Gly Ile Asp Pro Phe
290 295 300
Arg Leu Leu Gln Asn Ser Gln Val Phe Ser Leu Ile Arg Pro Asn Glu
305 310 315 320
Asn Pro Ala His Lys Ser Gln Leu Val Trp Met Ala Cys His Ser Ala
325 330 335
Ala Phe Glu Asp Leu Arg Val Ser Ser Phe Ile Arg Gly Thr Arg Val
340 345 350
Ile Pro Arg Gly Gln Leu Ser Thr Arg Gly Val Gln Ile Ala Ser Asn
355 360 365
Glu Asn Val Glu Ala Met Asp Ser Ser Thr Leu Glu Leu Arg Ser Arg
370 375 380
Tyr Trp Ala Ile Arg Thr Arg Ser Gly Gly Asn Thr Asn Gln Gln Arg
385 390 395 400
Ala Ser Ala Gly Gln Ile Ser Val Gln Pro Thr Phe Ser Val Gln Arg
405 410 415
Asn Leu Pro Phe Glu Arg Pro Thr Ile Met Ala Ala Phe Lys Gly Asn
420 425 430
Thr Glu Gly Arg Thr Ser Asp Met Arg Thr Glu Ile Ile Arg Met Met
435 440 445
Glu Ser Ala Arg Pro Glu Asp Val Ser Phe Gln Gly Arg Gly Val Phe
450 455 460
Glu Leu Ser Asp Glu Lys Ala Thr Asn Pro Ile Val Pro Ser Phe Asp
465 470 475 480
Met Ser Asn Glu Gly Ser Tyr Phe Phe Gly Asp Asn Ala Glu Glu Tyr
485 490 495
Asp Asn
<210> 83
<211> 560
<212> PRT
<213> Influenza B virus
<400> 83
Met Ser Asn Met Asp Ile Asp Ser Ile Asn Thr Gly Thr Ile Asp Lys
1 5 10 15
Thr Pro Glu Glu Leu Thr Pro Gly Thr Ser Gly Ala Thr Arg Pro Ile
20 25 30
Ile Lys Pro Ala Thr Leu Ala Pro Pro Ser Asn Lys Arg Thr Arg Asn
35 40 45
Pro Ser Pro Glu Arg Thr Thr Thr Ser Ser Glu Thr Asp Ile Gly Arg
50 55 60
Lys Ile Gln Lys Lys Gln Thr Pro Thr Glu Ile Lys Lys Ser Val Tyr
65 70 75 80
Lys Met Val Val Lys Leu Gly Glu Phe Tyr Asn Gln Met Met Val Lys
85 90 95
Ala Gly Leu Asn Asp Asp Met Glu Arg Asn Leu Ile Gln Asn Ala Gln
100 105 110
Ala Val Glu Arg Ile Leu Leu Ala Ala Thr Asp Asp Lys Lys Thr Glu
115 120 125
Tyr Gln Lys Lys Arg Asn Ala Arg Asp Val Lys Glu Gly Lys Glu Glu
130 135 140
Ile Asp His Asn Lys Thr Gly Gly Thr Phe Tyr Lys Met Val Arg Asp
145 150 155 160
Asp Lys Thr Ile Tyr Phe Ser Pro Ile Lys Ile Thr Phe Leu Lys Glu
165 170 175
Glu Val Lys Thr Met Tyr Lys Thr Thr Met Gly Ser Asp Gly Phe Ser
180 185 190
Gly Leu Asn His Ile Met Ile Gly His Ser Gln Met Asn Asp Val Cys
195 200 205
Phe Gln Arg Ser Lys Gly Leu Lys Arg Val Gly Leu Asp Pro Ser Leu
210 215 220
Ile Ser Thr Phe Ala Gly Ser Thr Leu Pro Arg Arg Ser Gly Thr Thr
225 230 235 240
Gly Val Ala Ile Lys Gly Gly Gly Thr Leu Val Asp Glu Ala Ile Arg
245 250 255
Phe Ile Gly Arg Ala Met Ala Asp Arg Gly Leu Leu Arg Asp Ile Lys
260 265 270
Ala Lys Thr Ala Tyr Glu Lys Ile Leu Leu Asn Leu Lys Asn Lys Cys
275 280 285
Ser Ala Pro Gln Gln Lys Ala Leu Val Asp Gln Val Ile Gly Ser Arg
290 295 300
Asn Pro Gly Ile Ala Asp Ile Glu Asp Leu Thr Leu Leu Ala Arg Ser
305 310 315 320
Met Val Val Val Arg Pro Ser Val Ala Ser Lys Val Val Leu Pro Ile
325 330 335
Ser Ile Tyr Ala Lys Ile Pro Gln Leu Gly Phe Asn Thr Glu Glu Tyr
340 345 350
Ser Met Val Gly Tyr Glu Ala Met Ala Leu Tyr Asn Met Ala Thr Pro
355 360 365
Val Ser Ile Leu Arg Met Gly Asp Asp Ala Lys Asp Lys Ser Gln Leu
370 375 380
Phe Phe Met Ser Cys Phe Gly Ala Ala Tyr Glu Asp Leu Arg Val Leu
385 390 395 400
Ser Ala Leu Thr Gly Thr Glu Phe Lys Pro Arg Ser Ala Leu Lys Cys
405 410 415
Lys Gly Phe His Val Pro Ala Lys Glu Gln Val Glu Gly Met Gly Ala
420 425 430
Ala Leu Met Ser Ile Lys Leu Gln Phe Trp Ala Pro Met Thr Arg Ser
435 440 445
Gly Gly Asn Glu Val Ser Gly Glu Gly Gly Ser Gly Gln Ile Ser Cys
450 455 460
Ser Pro Val Phe Ala Val Glu Arg Pro Ile Ala Leu Ser Lys Gln Ala
465 470 475 480
Val Arg Arg Met Leu Ser Met Asn Val Glu Gly Arg Asp Ala Asp Val
485 490 495
Lys Gly Asn Leu Leu Lys Met Met Asn Asp Ser Met Ala Lys Lys Thr
500 505 510
Ser Gly Asn Ala Phe Ile Gly Lys Lys Met Phe Gln Ile Ser Asp Lys
515 520 525
Asn Lys Val Asn Pro Ile Glu Ile Pro Ile Lys Gln Thr Ile Pro Asn
530 535 540
Phe Phe Phe Gly Arg Asp Thr Ala Glu Asp Tyr Asp Asp Leu Asp Tyr
545 550 555 560
<210> 84
<211> 248
<212> PRT
<213> Influenza B virus
<400> 84
Met Ser Leu Phe Gly Asp Thr Ile Ala Tyr Leu Leu Ser Leu Ile Glu
1 5 10 15
Asp Gly Glu Gly Lys Ala Glu Leu Ala Glu Lys Leu His Cys Trp Phe
20 25 30
Gly Gly Lys Glu Phe Asp Leu Asp Ser Ala Leu Glu Trp Ile Lys Asn
35 40 45
Lys Arg Cys Leu Thr Asp Ile Gln Lys Ala Leu Ile Gly Ala Ser Ile
50 55 60
Cys Phe Leu Lys Pro Lys Asp Gln Glu Arg Lys Arg Arg Phe Ile Thr
65 70 75 80
Glu Pro Leu Ser Gly Met Gly Thr Thr Ala Thr Lys Lys Lys Gly Leu
85 90 95
Ile Leu Ala Glu Arg Lys Met Arg Arg Cys Val Ser Phe His Glu Ala
100 105 110
Phe Glu Ile Ala Glu Gly His Glu Ser Ser Ala Leu Leu Tyr Cys Leu
115 120 125
Met Val Met Tyr Leu Asn Pro Glu Asn Tyr Ser Met Gln Val Lys Leu
130 135 140
Gly Thr Leu Cys Ala Leu Cys Glu Lys Gln Ala Ser His Ser His Arg
145 150 155 160
Ala His Ser Arg Ala Ala Arg Ser Ser Val Pro Gly Val Arg Arg Glu
165 170 175
Met Gln Met Val Ser Ala Met Asn Thr Ala Lys Thr Met Asn Gly Met
180 185 190
Gly Lys Gly Glu Asp Val Gln Lys Leu Ala Glu Glu Leu Gln Asn Asn
195 200 205
Ile Gly Val Leu Arg Ser Leu Gly Ala Ser Gln Lys Asn Gly Glu Gly
210 215 220
Ile Ala Lys Asp Val Met Glu Val Leu Lys Gln Ser Ser Met Gly Asn
225 230 235 240
Ser Ala Leu Val Arg Lys Tyr Leu
245
<210> 85
<211> 97
<212> PRT
<213> Influenza A virus
<400> 85
Met Ser Leu Leu Thr Glu Val Glu Thr Pro Ile Arg Asn Glu Trp Gly
1 5 10 15
Cys Arg Cys Asn Gly Ser Ser Asp Pro Leu Ala Ile Ala Ala Asn Ile
20 25 30
Ile Gly Ile Leu His Leu Ile Leu Trp Ile Leu Asp Arg Leu Phe Phe
35 40 45
Lys Cys Ile Tyr Arg Arg Phe Lys Tyr Gly Leu Lys Gly Gly Pro Ser
50 55 60
Thr Glu Gly Val Pro Lys Ser Met Arg Glu Glu Tyr Arg Lys Glu Gln
65 70 75 80
Gln Ser Ala Val Asp Ala Asp Asp Gly His Phe Val Ser Ile Glu Leu
85 90 95
Glu
<210> 86
<211> 281
<212> PRT
<213> Influenza B virus
<400> 86
Met Ala Asp Asn Met Thr Thr Thr Gln Ile Glu Val Gly Pro Gly Ala
1 5 10 15
Thr Asn Ala Thr Ile Asn Phe Glu Ala Gly Ile Leu Glu Cys Tyr Glu
20 25 30
Arg Phe Ser Trp Gln Arg Ala Leu Asp Tyr Pro Gly Gln Asp Arg Leu
35 40 45
His Arg Leu Lys Arg Lys Leu Glu Ser Arg Ile Lys Thr His Asn Lys
50 55 60
Ser Glu Pro Glu Asn Lys Arg Met Ser Leu Glu Glu Arg Lys Ala Ile
65 70 75 80
Gly Val Lys Met Met Lys Val Leu Leu Phe Met Asp Pro Ser Ala Gly
85 90 95
Ile Glu Gly Phe Glu Pro Tyr Cys Val Lys Asn Pro Ser Thr Ser Lys
100 105 110
Cys Pro Asn Tyr Asp Trp Thr Asp Tyr Pro Pro Thr Pro Gly Lys Tyr
115 120 125
Leu Asp Asp Ile Glu Glu Glu Pro Glu Asn Val Asp His Pro Ile Glu
130 135 140
Val Val Leu Arg Asp Met Asn Asn Lys Asp Ala Arg Gln Lys Ile Lys
145 150 155 160
Asp Glu Val Asn Thr Gln Lys Glu Gly Lys Phe Arg Leu Thr Ile Lys
165 170 175
Arg Asp Ile Arg Asn Val Leu Ser Leu Arg Val Leu Val Asn Gly Thr
180 185 190
Phe Leu Lys His Pro Asn Gly Asp Lys Ser Leu Ser Thr Leu His Arg
195 200 205
Leu Asn Ala Tyr Asp Gln Asn Gly Gly Leu Val Ala Lys Leu Val Ala
210 215 220
Thr Asp Asp Arg Thr Val Glu Asp Glu Lys Asp Gly His Arg Ile Leu
225 230 235 240
Asn Ser Leu Phe Glu Arg Phe Asp Glu Gly His Ser Lys Pro Ile Arg
245 250 255
Ala Ala Glu Thr Ala Val Gly Val Leu Ser Gln Phe Gly Gln Glu His
260 265 270
Arg Leu Ser Pro Glu Glu Gly Asp Asn
275 280
<210> 87
<211> 122
<212> PRT
<213> Influenza B virus
<400> 87
Met Ala Asp Asn Met Thr Thr Thr Gln Ile Glu Trp Arg Met Lys Lys
1 5 10 15
Met Ala Ile Gly Ser Ser Thr His Ser Ser Ser Val Leu Met Lys Asp
20 25 30
Ile Gln Ser Gln Phe Glu Gln Leu Lys Leu Arg Trp Glu Ser Tyr Pro
35 40 45
Asn Leu Val Lys Ser Thr Asp Tyr His Gln Lys Arg Glu Thr Ile Arg
50 55 60
Leu Ala Thr Glu Glu Leu Tyr Leu Leu Ser Lys Arg Ile Asp Asp Ser
65 70 75 80
Ile Leu Phe His Lys Thr Val Ile Ala Asn Ser Ser Ile Ile Ala Asp
85 90 95
Met Ile Val Ser Leu Ser Leu Leu Glu Thr Leu Tyr Glu Met Lys Asp
100 105 110
Val Val Glu Val Tyr Ser Arg Gln Cys Leu
115 120
<210> 88
<211> 716
<212> PRT
<213> Influenza A virus
<400> 88
Met Glu Asp Phe Val Arg Gln Cys Phe Asn Pro Met Ile Val Glu Leu
1 5 10 15
Ala Glu Lys Ala Met Lys Glu Tyr Gly Glu Asp Leu Lys Ile Glu Thr
20 25 30
Asn Lys Phe Ala Ala Ile Cys Thr His Leu Glu Val Cys Phe Met Tyr
35 40 45
Ser Asp Phe His Phe Ile Asn Glu Gln Gly Glu Ser Ile Ile Val Glu
50 55 60
Pro Glu Asp Pro Asn Ala Leu Leu Lys His Arg Phe Glu Ile Ile Glu
65 70 75 80
Gly Arg Asp Arg Thr Met Ala Trp Thr Val Val Asn Ser Ile Cys Asn
85 90 95
Thr Thr Gly Ala Glu Lys Pro Lys Phe Leu Pro Asp Leu Tyr Asp Tyr
100 105 110
Lys Glu Asn Arg Phe Ile Glu Ile Gly Val Thr Arg Arg Glu Val His
115 120 125
Ile Tyr Tyr Leu Glu Lys Ala Asn Lys Ile Lys Ser Glu Lys Thr His
130 135 140
Ile His Ile Phe Ser Phe Thr Gly Glu Glu Met Ala Thr Lys Ala Asp
145 150 155 160
Tyr Thr Leu Asp Glu Glu Ser Arg Ala Arg Ile Lys Thr Arg Leu Phe
165 170 175
Thr Ile Arg Gln Glu Met Ala Ser Arg Gly Leu Trp Asp Ser Phe Arg
180 185 190
Gln Ser Glu Arg Gly Glu Glu Thr Ile Glu Glu Arg Phe Glu Ile Thr
195 200 205
Gly Thr Met Arg Arg Leu Ala Asp Gln Ser Leu Pro Pro Asn Phe Ser
210 215 220
Cys Leu Glu Asn Phe Arg Ala Tyr Val Asp Gly Phe Glu Pro Asn Gly
225 230 235 240
Tyr Ile Glu Gly Lys Leu Ser Gln Met Ser Lys Glu Val Asn Ala Arg
245 250 255
Ile Glu Pro Phe Leu Arg Thr Thr Pro Arg Pro Ile Arg Leu Pro Asp
260 265 270
Gly Pro Pro Cys Phe Gln Arg Ser Lys Phe Leu Leu Met Asp Ser Leu
275 280 285
Lys Leu Ser Ile Glu Asp Pro Ser His Glu Gly Glu Gly Ile Pro Leu
290 295 300
Tyr Asp Ala Ile Lys Cys Met Arg Thr Phe Phe Gly Trp Lys Glu Pro
305 310 315 320
Ser Val Val Lys Pro His Gly Lys Gly Ile Asn Pro Asn Tyr Leu Leu
325 330 335
Ser Trp Lys Gln Val Leu Ala Glu Leu Gln Asp Ile Glu Ser Glu Glu
340 345 350
Lys Ile Pro Arg Thr Lys Asn Met Lys Lys Thr Ser Gln Leu Lys Trp
355 360 365
Ala Leu Gly Glu Asn Met Ala Pro Glu Lys Val Asp Phe Asp Asp Cys
370 375 380
Lys Asp Ile Ser Asp Leu Lys Gln Tyr Asp Ser Asp Glu Pro Glu Leu
385 390 395 400
Arg Ser Leu Ser Ser Trp Ile Gln Asn Glu Phe Asn Lys Ala Cys Glu
405 410 415
Leu Thr Asp Ser Ile Trp Ile Glu Leu Asp Glu Ile Gly Glu Asp Val
420 425 430
Ala Pro Ile Glu His Ile Ala Ser Met Arg Arg Asn Tyr Phe Thr Ala
435 440 445
Glu Val Ser His Cys Arg Ala Thr Glu Tyr Ile Met Lys Gly Val Tyr
450 455 460
Ile Asn Thr Ala Leu Leu Asn Ala Ser Cys Ala Ala Met Asp Asp Phe
465 470 475 480
Gln Leu Ile Pro Met Ile Ser Lys Cys Arg Thr Lys Glu Gly Arg Arg
485 490 495
Lys Thr Asn Leu Tyr Gly Phe Ile Ile Lys Gly Arg Ser His Leu Arg
500 505 510
Asn Asp Thr Asp Val Val Asn Phe Val Ser Met Glu Phe Ser Leu Thr
515 520 525
Asp Pro Arg Leu Glu Pro His Lys Trp Glu Lys Tyr Cys Val Leu Glu
530 535 540
Ile Gly Asp Met Leu Leu Arg Ser Ala Ile Gly Gln Val Ser Arg Pro
545 550 555 560
Met Phe Leu Tyr Val Arg Thr Asn Gly Thr Ser Lys Ile Lys Met Lys
565 570 575
Trp Gly Met Glu Met Arg Arg Cys Leu Leu Gln Ser Leu Gln Gln Ile
580 585 590
Glu Ser Met Ile Glu Ala Glu Ser Ser Val Lys Glu Lys Asp Met Thr
595 600 605
Lys Glu Phe Phe Glu Asn Arg Ser Glu Thr Trp Pro Ile Gly Glu Ser
610 615 620
Pro Lys Gly Val Glu Glu Gly Ser Ile Gly Lys Val Cys Arg Thr Leu
625 630 635 640
Leu Ala Lys Ser Val Phe Asn Ser Leu Tyr Ala Ser Pro Gln Leu Glu
645 650 655
Gly Phe Ser Ala Glu Ser Arg Lys Leu Leu Leu Ile Val Gln Ala Leu
660 665 670
Arg Asp Asn Leu Glu Pro Gly Thr Phe Asp Leu Gly Gly Leu Tyr Glu
675 680 685
Ala Ile Glu Glu Cys Leu Ile Asn Asp Pro Trp Val Leu Leu Asn Ala
690 695 700
Ser Trp Phe Asn Ser Phe Leu Thr His Ala Leu Arg
705 710 715
<210> 89
<211> 752
<212> PRT
<213> Influenza B virus
<400> 89
Met Asn Ile Asn Pro Tyr Phe Leu Phe Ile Asp Val Pro Ile Gln Ala
1 5 10 15
Ala Ile Ser Thr Thr Phe Pro Tyr Thr Gly Val Pro Pro Tyr Ser His
20 25 30
Gly Thr Gly Thr Gly Tyr Thr Ile Asp Thr Val Ile Arg Thr His Glu
35 40 45
Tyr Ser Asn Lys Gly Lys Gln Tyr Ile Ser Asp Val Thr Gly Cys Val
50 55 60
Met Val Asp Pro Thr Asn Gly Pro Leu Pro Glu Asp Asn Glu Pro Ser
65 70 75 80
Ala Tyr Ala Gln Leu Asp Cys Val Leu Glu Ala Leu Asp Arg Met Asp
85 90 95
Glu Glu His Pro Gly Leu Phe Gln Ala Gly Ser Gln Asn Ala Met Glu
100 105 110
Ala Leu Met Val Thr Thr Val Asp Lys Leu Thr Gln Gly Arg Gln Thr
115 120 125
Phe Asp Trp Thr Val Cys Arg Asn Gln Pro Ala Ala Thr Ala Leu Asn
130 135 140
Thr Thr Ile Thr Ser Phe Arg Leu Asn Asp Leu Asn Gly Ala Asp Lys
145 150 155 160
Gly Gly Leu Val Pro Phe Cys Gln Asp Ile Ile Asp Ser Leu Asp Lys
165 170 175
Pro Glu Met Ile Phe Phe Thr Val Lys Asn Ile Lys Lys Lys Leu Pro
180 185 190
Ala Lys Asn Arg Lys Gly Phe Leu Ile Lys Arg Ile Pro Met Lys Val
195 200 205
Lys Asp Arg Ile Thr Arg Val Glu Tyr Ile Lys Arg Ala Leu Ser Leu
210 215 220
Asn Thr Met Thr Lys Asp Ala Glu Arg Gly Lys Leu Lys Arg Arg Ala
225 230 235 240
Ile Ala Thr Ala Gly Ile Gln Ile Arg Gly Phe Val Leu Val Val Glu
245 250 255
Asn Leu Ala Lys Asn Ile Cys Glu Asn Leu Glu Gln Ser Gly Leu Pro
260 265 270
Val Gly Gly Asn Glu Lys Lys Ala Lys Leu Ser Asn Ala Val Ala Lys
275 280 285
Met Leu Ser Asn Cys Pro Pro Gly Gly Ile Ser Met Thr Val Thr Gly
290 295 300
Asp Asn Thr Lys Trp Asn Glu Cys Leu Asn Pro Arg Ile Phe Leu Ala
305 310 315 320
Met Thr Glu Arg Ile Thr Arg Asp Ser Pro Ile Trp Phe Arg Asp Phe
325 330 335
Cys Ser Ile Ala Pro Val Leu Phe Ser Asn Lys Ile Ala Arg Leu Gly
340 345 350
Lys Gly Phe Met Ile Thr Ser Lys Thr Lys Arg Leu Lys Ala Gln Ile
355 360 365
Pro Cys Pro Asp Leu Phe Asn Ile Pro Leu Glu Arg Tyr Asn Glu Glu
370 375 380
Thr Arg Ala Lys Leu Lys Lys Leu Lys Pro Phe Phe Asn Glu Glu Gly
385 390 395 400
Thr Ala Ser Leu Ser Pro Gly Met Met Met Gly Met Phe Asn Met Leu
405 410 415
Ser Thr Val Leu Gly Val Ala Ala Leu Gly Ile Lys Asn Ile Gly Asn
420 425 430
Lys Glu Tyr Leu Trp Asp Gly Leu Gln Ser Ser Asp Asp Phe Ala Leu
435 440 445
Phe Val Asn Ala Lys Asp Glu Glu Thr Cys Met Glu Gly Ile Asn Asp
450 455 460
Phe Tyr Arg Thr Cys Lys Leu Leu Gly Ile Asn Met Ser Lys Lys Lys
465 470 475 480
Ser Tyr Cys Asn Glu Thr Gly Met Phe Glu Phe Thr Ser Met Phe Tyr
485 490 495
Arg Asp Gly Phe Val Ser Asn Phe Ala Met Glu Leu Pro Ser Phe Gly
500 505 510
Val Ala Gly Val Asn Glu Ser Ala Asp Met Ala Ile Gly Met Thr Ile
515 520 525
Ile Lys Asn Asn Met Ile Asn Asn Gly Met Gly Pro Ala Thr Ala Gln
530 535 540
Thr Ala Ile Gln Leu Phe Ile Ala Asp Tyr Arg Tyr Thr Tyr Lys Cys
545 550 555 560
His Arg Gly Asp Ser Lys Val Glu Gly Lys Arg Met Lys Ile Ile Lys
565 570 575
Glu Leu Trp Glu Asn Thr Lys Gly Arg Asp Gly Leu Leu Val Ala Asp
580 585 590
Gly Gly Pro Asn Leu Tyr Asn Leu Arg Asn Leu His Ile Pro Glu Ile
595 600 605
Ile Leu Lys Tyr Asn Ile Met Asp Pro Glu Tyr Lys Gly Arg Leu Leu
610 615 620
His Pro Gln Asn Pro Phe Val Gly His Leu Ser Ile Glu Gly Ile Lys
625 630 635 640
Glu Ala Asp Ile Thr Pro Ala His Gly Pro Ile Lys Lys Met Asp Tyr
645 650 655
Asp Ala Val Ser Gly Thr His Ser Trp Arg Thr Lys Arg Asn Arg Ser
660 665 670
Ile Leu Asn Thr Asp Gln Arg Asn Met Ile Leu Glu Glu Gln Cys Tyr
675 680 685
Ala Lys Cys Cys Asn Leu Phe Glu Ala Cys Phe Asn Ser Ala Ser Tyr
690 695 700
Arg Lys Pro Val Gly Gln His Ser Met Leu Glu Ala Met Ala His Arg
705 710 715 720
Leu Arg Met Asp Ala Arg Leu Asp Tyr Glu Ser Gly Arg Met Ser Lys
725 730 735
Glu Asp Phe Glu Lys Ala Met Ala His Leu Gly Glu Ile Gly Tyr Met
740 745 750
<210> 90
<211> 759
<212> PRT
<213> Influenza A virus
<400> 90
Met Glu Arg Ile Lys Glu Leu Arg Asn Leu Met Ser Gln Ser Arg Thr
1 5 10 15
Arg Glu Ile Leu Thr Lys Thr Thr Val Asp His Met Ala Ile Ile Lys
20 25 30
Lys Tyr Thr Ser Gly Arg Gln Glu Lys Asn Pro Ala Leu Arg Met Lys
35 40 45
Trp Met Met Ala Met Lys Tyr Pro Ile Thr Ala Asp Lys Arg Ile Thr
50 55 60
Glu Met Ile Pro Glu Arg Asn Glu Gln Gly Gln Thr Leu Trp Ser Lys
65 70 75 80
Met Asn Asp Ala Gly Ser Asp Arg Val Met Val Ser Pro Leu Ala Val
85 90 95
Thr Trp Trp Asn Arg Asn Gly Pro Met Thr Asn Thr Val His Tyr Pro
100 105 110
Lys Ile Tyr Lys Thr Tyr Phe Glu Arg Val Glu Arg Leu Lys His Gly
115 120 125
Thr Phe Gly Pro Val His Phe Arg Asn Gln Val Lys Ile Arg Arg Arg
130 135 140
Val Asp Ile Asn Pro Gly His Ala Asp Leu Ser Ala Lys Glu Ala Gln
145 150 155 160
Asp Val Ile Met Glu Val Val Phe Pro Asn Glu Val Gly Ala Arg Ile
165 170 175
Leu Thr Ser Glu Ser Gln Leu Thr Ile Thr Lys Glu Lys Lys Glu Glu
180 185 190
Leu Gln Asp Cys Lys Ile Ser Pro Leu Met Val Ala Tyr Met Leu Glu
195 200 205
Arg Glu Leu Val Arg Lys Thr Arg Phe Leu Pro Val Ala Gly Gly Thr
210 215 220
Ser Ser Val Tyr Ile Glu Val Leu His Leu Thr Gln Gly Thr Cys Trp
225 230 235 240
Glu Gln Met Tyr Thr Pro Gly Gly Glu Val Lys Asn Asp Asp Val Asp
245 250 255
Gln Ser Leu Ile Ile Ala Ala Arg Asn Ile Val Arg Arg Ala Ala Val
260 265 270
Ser Ala Asp Pro Leu Ala Ser Leu Leu Glu Met Cys His Ser Thr Gln
275 280 285
Ile Gly Gly Ile Arg Met Val Asp Ile Leu Lys Gln Asn Pro Thr Glu
290 295 300
Glu Gln Ala Val Gly Ile Cys Lys Ala Ala Met Gly Leu Arg Ile Ser
305 310 315 320
Ser Ser Phe Ser Phe Gly Gly Phe Thr Phe Lys Arg Thr Ser Gly Ser
325 330 335
Ser Val Lys Arg Glu Glu Glu Val Leu Thr Gly Asn Leu Gln Thr Leu
340 345 350
Lys Ile Arg Val His Glu Gly Tyr Glu Glu Phe Thr Met Val Gly Arg
355 360 365
Arg Ala Thr Ala Ile Leu Arg Lys Ala Thr Arg Arg Leu Ile Gln Leu
370 375 380
Ile Val Ser Gly Arg Asp Glu Gln Ser Ile Ala Glu Ala Ile Ile Val
385 390 395 400
Ala Met Val Phe Ser Gln Glu Asp Cys Met Ile Lys Ala Val Arg Gly
405 410 415
Asp Leu Asn Phe Val Asn Arg Ala Asn Gln Arg Leu Asn Pro Met His
420 425 430
Gln Leu Leu Arg His Phe Gln Lys Asp Ala Lys Val Leu Phe Gln Asn
435 440 445
Trp Gly Val Glu Pro Ile Asp Asn Val Met Gly Met Ile Gly Ile Leu
450 455 460
Pro Asp Met Thr Pro Ser Ile Glu Met Ser Met Arg Gly Val Arg Ile
465 470 475 480
Ser Lys Met Gly Val Asp Glu Tyr Ser Ser Thr Glu Arg Val Val Val
485 490 495
Ser Ile Asp Arg Phe Leu Arg Val Arg Asp Gln Arg Gly Asn Val Leu
500 505 510
Leu Ser Pro Glu Glu Val Ser Glu Thr Gln Gly Thr Glu Lys Leu Thr
515 520 525
Ile Thr Tyr Ser Ser Ser Met Met Trp Glu Ile Asn Gly Pro Glu Ser
530 535 540
Val Leu Val Asn Thr Tyr Gln Trp Ile Ile Arg Asn Trp Glu Thr Val
545 550 555 560
Lys Ile Gln Trp Ser Gln Asn Pro Thr Met Leu Tyr Asn Lys Met Glu
565 570 575
Phe Glu Pro Phe Gln Ser Leu Val Pro Lys Ala Ile Arg Gly Gln Tyr
580 585 590
Ser Gly Phe Val Arg Thr Leu Phe Gln Gln Met Arg Asp Val Leu Gly
595 600 605
Thr Phe Asp Thr Ala Gln Ile Ile Lys Leu Leu Pro Phe Ala Ala Ala
610 615 620
Pro Pro Lys Gln Ser Arg Met Gln Phe Ser Ser Phe Thr Val Asn Val
625 630 635 640
Arg Gly Ser Gly Met Arg Ile Leu Val Arg Gly Asn Ser Pro Val Phe
645 650 655
Asn Tyr Asn Lys Ala Thr Lys Arg Leu Thr Val Leu Gly Lys Asp Ala
660 665 670
Gly Thr Leu Thr Glu Asp Pro Asp Glu Gly Thr Ala Gly Val Glu Ser
675 680 685
Ala Val Leu Arg Gly Phe Leu Ile Leu Gly Lys Glu Asp Arg Arg Tyr
690 695 700
Gly Pro Ala Leu Ser Ile Asn Glu Leu Ser Asn Leu Ala Lys Gly Glu
705 710 715 720
Lys Ala Asn Val Leu Ile Gly Gln Gly Asp Val Val Leu Val Met Lys
725 730 735
Arg Lys Arg Asp Ser Ser Ile Leu Thr Asp Ser Gln Thr Ala Thr Lys
740 745 750
Arg Ile Arg Met Ala Ile Asn
755
<210> 91
<211> 109
<212> PRT
<213> Influenza B virus
<400> 91
Met Leu Glu Pro Leu Gln Ile Leu Ser Ile Cys Ser Phe Ile Leu Ser
1 5 10 15
Ala Leu His Phe Met Ala Trp Thr Ile Gly His Leu Asn Gln Ile Lys
20 25 30
Arg Gly Val Asn Leu Lys Ile Gln Ile Arg Asn Pro Asn Lys Glu Ala
35 40 45
Ile Asn Arg Glu Val Ser Ile Leu Arg His Asn Tyr Gln Lys Glu Ile
50 55 60
Gln Ala Lys Glu Thr Met Lys Lys Ile Leu Ser Asp Asn Met Glu Val
65 70 75 80
Leu Gly Asp His Ile Val Val Glu Gly Leu Ser Thr Asp Glu Ile Ile
85 90 95
Lys Met Gly Glu Thr Val Leu Glu Val Glu Glu Leu Gln
100 105
<210> 92
<211> 100
<212> PRT
<213> Influenza B virus
<400> 92
Met Asn Asn Ala Thr Phe Asn Cys Thr Asn Ile Asn Pro Ile Thr His
1 5 10 15
Ile Arg Gly Ser Ile Ile Ile Thr Ile Cys Val Ser Leu Ile Val Ile
20 25 30
Leu Ile Val Phe Gly Cys Ile Ala Lys Ile Phe Ile Asn Lys Asn Asn
35 40 45
Cys Thr Asn Asn Val Ile Arg Val His Lys Arg Ile Lys Cys Pro Asp
50 55 60
Cys Glu Pro Phe Cys Asn Lys Arg Asp Asp Ile Ser Thr Pro Arg Ala
65 70 75 80
Gly Val Asp Ile Pro Ser Phe Ile Leu Pro Gly Leu Asn Leu Ser Glu
85 90 95
Gly Thr Pro Asn
100
<210> 93
<211> 498
<212> PRT
<213> Influenza A virus
<400> 93
Met Ala Ser Gln Gly Thr Lys Arg Ser Tyr Glu Gln Met Glu Thr Asp
1 5 10 15
Gly Glu Arg Gln Asn Ala Thr Glu Ile Arg Ala Ser Val Gly Lys Met
20 25 30
Ile Gly Gly Ile Gly Arg Phe Tyr Ile Gln Met Cys Thr Glu Leu Lys
35 40 45
Leu Ser Asp Tyr Glu Gly Arg Leu Ile Gln Asn Ser Leu Thr Ile Glu
50 55 60
Arg Met Val Leu Ser Ala Phe Asp Glu Arg Arg Asn Lys Tyr Leu Glu
65 70 75 80
Glu His Pro Ser Ala Gly Lys Asp Pro Lys Lys Thr Gly Gly Pro Ile
85 90 95
Tyr Arg Arg Val Asn Gly Lys Trp Met Arg Glu Leu Ile Leu Tyr Asp
100 105 110
Lys Glu Glu Ile Arg Arg Ile Trp Arg Gln Ala Asn Asn Gly Asp Asp
115 120 125
Ala Thr Ala Gly Leu Thr His Met Met Ile Trp His Ser Asn Leu Asn
130 135 140
Asp Ala Thr Tyr Gln Arg Thr Arg Ala Leu Val Arg Thr Gly Met Asp
145 150 155 160
Pro Arg Met Cys Ser Leu Met Gln Gly Ser Thr Leu Pro Arg Arg Ser
165 170 175
Gly Ala Ala Gly Ala Ala Val Lys Gly Val Gly Thr Met Val Met Glu
180 185 190
Leu Val Arg Met Ile Lys Arg Gly Ile Asn Asp Arg Asn Phe Trp Arg
195 200 205
Gly Glu Asn Gly Arg Lys Thr Arg Ile Ala Tyr Glu Arg Met Cys Asn
210 215 220
Ile Leu Lys Gly Lys Phe Gln Thr Ala Ala Gln Lys Ala Met Met Asp
225 230 235 240
Gln Val Arg Glu Ser Arg Asp Pro Gly Asn Ala Glu Phe Glu Asp Leu
245 250 255
Thr Phe Leu Ala Arg Ser Ala Leu Ile Leu Arg Gly Ser Val Ala His
260 265 270
Lys Ser Cys Leu Pro Ala Cys Val Tyr Gly Pro Ala Val Ala Ser Gly
275 280 285
Tyr Asp Phe Glu Arg Glu Gly Tyr Ser Leu Val Gly Ile Asp Pro Phe
290 295 300
Arg Leu Leu Gln Asn Ser Gln Val Tyr Ser Leu Ile Arg Pro Asn Glu
305 310 315 320
Asn Pro Ala His Lys Ser Gln Leu Val Trp Met Ala Cys His Ser Ala
325 330 335
Ala Phe Glu Asp Leu Arg Val Leu Ser Phe Ile Lys Gly Thr Lys Val
340 345 350
Val Pro Arg Gly Lys Leu Ser Thr Arg Gly Val Gln Ile Ala Ser Asn
355 360 365
Glu Asn Met Glu Thr Met Glu Ser Ser Thr Leu Glu Leu Arg Ser Arg
370 375 380
Tyr Trp Ala Ile Arg Thr Arg Ser Gly Gly Asn Thr Asn Gln Gln Arg
385 390 395 400
Ala Ser Ala Gly Gln Ile Ser Ile Gln Pro Thr Phe Ser Val Gln Arg
405 410 415
Asn Leu Pro Phe Asp Arg Thr Thr Val Met Ala Ala Phe Thr Gly Asn
420 425 430
Thr Glu Gly Arg Thr Ser Asp Met Arg Thr Glu Ile Ile Arg Met Met
435 440 445
Glu Ser Ala Arg Pro Glu Asp Val Ser Phe Gln Gly Arg Gly Val Phe
450 455 460
Glu Leu Ser Asp Glu Lys Ala Ala Ser Pro Ile Val Pro Ser Phe Asp
465 470 475 480
Met Ser Asn Glu Gly Ser Tyr Phe Phe Gly Asp Asn Ala Glu Glu Tyr
485 490 495
Asp Asn
<210> 94
<211> 548
<212> PRT
<213> Human herpesvirus 5
<400> 94
Met Glu Ser Arg Gly Arg Arg Cys Pro Glu Met Ile Ser Val Leu Gly
1 5 10 15
Pro Ile Ser Gly His Val Leu Lys Ala Val Phe Ser Arg Gly Asp Thr
20 25 30
Pro Val Leu Pro His Glu Thr Arg Leu Leu Gln Thr Gly Ile His Val
35 40 45
Arg Val Ser Gln Pro Ser Leu Ile Leu Val Ser Gln Tyr Thr Pro Asp
50 55 60
Ser Thr Pro Cys His Arg Gly Asp Asn Gln Leu Gln Val Gln His Thr
65 70 75 80
Tyr Phe Thr Gly Ser Glu Val Glu Asn Val Ser Val Asn Glu Pro Met
85 90 95
Ser Ile Tyr Val Tyr Ala Leu Pro Leu Lys Met Leu Asn Ile Pro Ser
100 105 110
Ile Asn Val His His Tyr Pro Ser Ala Ala Glu Arg Lys His Arg His
115 120 125
Leu Pro Val Ala Asp Ala Val Ile His Ala Ser Gly Lys Gln Met Trp
130 135 140
Gln Ala Arg Leu Thr Val Ser Gly Leu Ala Trp Thr Arg Gln Gln Asn
145 150 155 160
Gln Trp Lys Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe Val Phe Pro
165 170 175
Thr Lys Asp Val Ala Leu Arg His Val Val Cys Ala His Glu Leu Val
180 185 190
Cys Ser Met Glu Asn Thr Arg Ala Thr Lys Met Gln Val Ile Gly Asp
195 200 205
Gln Tyr Val Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp Val Pro Ser
210 215 220
Gly Lys Leu Phe Met His Val Thr Leu Gly Ser Asp Val Glu Glu Asp
225 230 235 240
Leu Thr Met Thr Arg Asn Pro Gln Pro Phe Met Arg Pro His Glu Arg
245 250 255
Asn Gly Phe Thr Val Leu Cys Pro Lys Asn Met Ile Ile Lys Pro Gly
260 265 270
Lys Ile Ser His Ile Met Leu Asp Val Ala Phe Thr Ser His Glu His
275 280 285
Phe Gly Leu Leu Cys Pro Lys Ser Ile Pro Gly Leu Ser Ile Ser Gly
290 295 300
Asn Leu Leu Met Asn Gly Gln Gln Ile Phe Leu Glu Val Gln Ala Ile
305 310 315 320
Arg Glu Thr Val Glu Leu Arg Gln Tyr Asp Pro Val Ala Ala Leu Phe
325 330 335
Phe Phe Asp Ile Asp Leu Leu Leu Gln Arg Gly Pro Gln Tyr Ser Glu
340 345 350
His Pro Thr Phe Thr Ser Gln Tyr Arg Ile Gln Gly Lys Leu Glu Tyr
355 360 365
Arg His Thr Trp Asp Arg His Asp Glu Gly Ala Ala Gln Gly Asp Asp
370 375 380
Asp Val Trp Thr Ser Gly Ser Asp Ser Asp Glu Glu Leu Val Thr Thr
385 390 395 400
Glu Arg Lys Thr Pro Arg Val Thr Gly Gly Gly Ala Met Ala Gly Ala
405 410 415
Ser Thr Ser Ala Gly Arg Lys Arg Lys Ser Ala Ser Ser Ala Thr Ala
420 425 430
Cys Thr Ser Gly Val Met Thr Arg Gly Arg Leu Lys Ala Glu Ser Thr
435 440 445
Val Ala Pro Glu Glu Asp Thr Asp Glu Asp Ser Asp Asn Glu Ile His
450 455 460
Asn Pro Ala Val Phe Thr Trp Pro Pro Trp Gln Ala Gly Ile Leu Ala
465 470 475 480
Arg Asn Leu Val Pro Met Val Ala Thr Val Gln Gly Gln Asn Leu Lys
485 490 495
Tyr Gln Glu Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg Ile Phe Ala
500 505 510
Glu Leu Glu Gly Val Trp Gln Pro Ala Ala Gln Pro Lys Arg Arg Arg
515 520 525
His Arg Gln Asp Ala Leu Pro Gly Pro Cys Ile Ala Ser Thr Pro Lys
530 535 540
Lys His Arg Gly
545
<210> 95
<211> 561
<212> PRT
<213> Human herpesvirus 5
<400> 95
Met Glu Ser Arg Gly Arg Arg Cys Pro Glu Met Ile Ser Val Leu Gly
1 5 10 15
Pro Ile Ser Gly His Val Leu Lys Ala Val Phe Ser Arg Gly Asp Thr
20 25 30
Pro Val Leu Pro His Glu Thr Arg Leu Leu Gln Thr Gly Ile His Val
35 40 45
Arg Val Ser Gln Pro Ser Leu Ile Leu Val Ser Gln Tyr Thr Pro Asp
50 55 60
Ser Thr Pro Cys His Arg Gly Asp Asn Gln Leu Gln Val Gln His Thr
65 70 75 80
Tyr Phe Thr Gly Ser Glu Val Glu Asn Val Ser Val Asn Val His Asn
85 90 95
Pro Thr Gly Arg Ser Ile Cys Pro Ser Gln Glu Pro Met Ser Ile Tyr
100 105 110
Val Tyr Ala Leu Pro Leu Lys Met Leu Asn Ile Pro Ser Ile Asn Val
115 120 125
His His Tyr Pro Ser Ala Ala Glu Arg Lys His Arg His Leu Pro Val
130 135 140
Ala Asp Ala Val Ile His Ala Ser Gly Lys Gln Met Trp Gln Ala Arg
145 150 155 160
Leu Thr Val Ser Gly Leu Ala Trp Thr Arg Gln Gln Asn Gln Trp Lys
165 170 175
Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe Val Phe Pro Thr Lys Asp
180 185 190
Val Ala Leu Arg His Val Val Cys Ala His Glu Leu Val Cys Ser Met
195 200 205
Glu Asn Thr Arg Ala Thr Lys Met Gln Val Ile Gly Asp Gln Tyr Val
210 215 220
Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp Val Pro Ser Gly Lys Leu
225 230 235 240
Phe Met His Val Thr Leu Gly Ser Asp Val Glu Glu Asp Leu Thr Met
245 250 255
Thr Arg Asn Pro Gln Pro Phe Met Arg Pro His Glu Arg Asn Gly Phe
260 265 270
Thr Val Leu Cys Pro Lys Asn Met Ile Ile Lys Pro Gly Lys Ile Ser
275 280 285
His Ile Met Leu Asp Val Ala Phe Thr Ser His Glu His Phe Gly Leu
290 295 300
Leu Cys Pro Lys Ser Ile Pro Gly Leu Ser Ile Ser Gly Asn Leu Leu
305 310 315 320
Met Asn Gly Gln Gln Ile Phe Leu Glu Val Gln Ala Ile Arg Glu Thr
325 330 335
Val Glu Leu Arg Gln Tyr Asp Pro Val Ala Ala Leu Phe Phe Phe Asp
340 345 350
Ile Asp Leu Leu Leu Gln Arg Gly Pro Gln Tyr Ser Glu His Pro Thr
355 360 365
Phe Thr Ser Gln Tyr Arg Ile Gln Gly Lys Leu Glu Tyr Arg His Thr
370 375 380
Trp Asp Arg His Asp Glu Gly Ala Ala Gln Gly Asp Asp Asp Val Trp
385 390 395 400
Thr Ser Gly Ser Asp Ser Asp Glu Glu Leu Val Thr Thr Glu Arg Lys
405 410 415
Thr Pro Arg Val Thr Gly Gly Gly Ala Met Ala Gly Ala Ser Thr Ser
420 425 430
Ala Gly Arg Lys Arg Lys Ser Ala Ser Ser Ala Thr Ala Cys Thr Ser
435 440 445
Gly Val Met Thr Arg Gly Arg Leu Lys Ala Glu Ser Thr Val Ala Pro
450 455 460
Glu Glu Asp Thr Asp Glu Asp Ser Asp Asn Glu Ile His Asn Pro Ala
465 470 475 480
Val Phe Thr Trp Pro Pro Trp Gln Ala Gly Ile Leu Ala Arg Asn Leu
485 490 495
Val Pro Met Val Ala Thr Val Gln Gly Gln Asn Leu Lys Tyr Gln Glu
500 505 510
Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg Ile Phe Ala Glu Leu Glu
515 520 525
Gly Val Trp Gln Pro Ala Ala Gln Pro Lys Arg Arg Arg His Arg Gln
530 535 540
Asp Ala Leu Pro Gly Pro Cys Ile Ala Ser Thr Pro Lys Lys His Arg
545 550 555 560
Gly
<210> 96
<211> 551
<212> PRT
<213> Human herpesvirus 5
<400> 96
Met Ala Ser Val Leu Gly Pro Ile Ser Gly His Val Leu Lys Ala Val
1 5 10 15
Phe Ser Arg Gly Asp Thr Pro Val Leu Pro His Glu Thr Arg Leu Leu
20 25 30
Gln Thr Gly Ile His Val Arg Val Ser Gln Pro Ser Leu Ile Leu Val
35 40 45
Ser Gln Tyr Thr Pro Asp Ser Thr Pro Cys His Arg Gly Asp Asn Gln
50 55 60
Leu Gln Val Gln His Thr Tyr Phe Thr Gly Ser Glu Val Glu Asn Val
65 70 75 80
Ser Val Asn Val His Asn Pro Thr Gly Arg Ser Ile Cys Pro Ser Gln
85 90 95
Glu Pro Met Ser Ile Tyr Val Tyr Ala Leu Pro Leu Lys Met Leu Asn
100 105 110
Ile Pro Ser Ile Asn Val His His Tyr Pro Ser Ala Ala Glu Arg Lys
115 120 125
His Arg His Leu Pro Val Ala Asp Ala Val Ile His Ala Ser Gly Lys
130 135 140
Gln Met Trp Gln Ala Arg Leu Thr Val Ser Gly Leu Ala Trp Thr Arg
145 150 155 160
Gln Gln Asn Gln Trp Lys Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe
165 170 175
Val Phe Pro Thr Lys Asp Val Ala Leu Arg His Val Val Cys Ala His
180 185 190
Glu Leu Val Cys Ser Met Glu Asn Thr Arg Ala Thr Lys Met Gln Val
195 200 205
Ile Gly Asp Gln Tyr Val Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp
210 215 220
Val Pro Ser Gly Lys Leu Phe Met His Val Thr Leu Gly Ser Asp Val
225 230 235 240
Glu Glu Asp Leu Thr Met Thr Arg Asn Pro Gln Pro Phe Met Arg Pro
245 250 255
His Glu Arg Asn Gly Phe Thr Val Leu Cys Pro Lys Asn Met Ile Ile
260 265 270
Lys Pro Gly Lys Ile Ser His Ile Met Leu Asp Val Ala Phe Thr Ser
275 280 285
His Glu His Phe Gly Leu Leu Cys Pro Lys Ser Ile Pro Gly Leu Ser
290 295 300
Ile Ser Gly Asn Leu Leu Met Asn Gly Gln Gln Ile Phe Leu Glu Val
305 310 315 320
Gln Ala Ile Arg Glu Thr Val Glu Leu Arg Gln Tyr Asp Pro Val Ala
325 330 335
Ala Leu Phe Phe Phe Asp Ile Asp Leu Leu Leu Gln Arg Gly Pro Gln
340 345 350
Tyr Ser Glu His Pro Thr Phe Thr Ser Gln Tyr Arg Ile Gln Gly Lys
355 360 365
Leu Glu Tyr Arg His Thr Trp Asp Arg His Asp Glu Gly Ala Ala Gln
370 375 380
Gly Asp Asp Asp Val Trp Thr Ser Gly Ser Asp Ser Asp Glu Glu Leu
385 390 395 400
Val Thr Thr Glu Arg Lys Thr Pro Arg Val Thr Gly Gly Gly Ala Met
405 410 415
Ala Gly Ala Ser Thr Ser Ala Gly Arg Lys Arg Lys Ser Ala Ser Ser
420 425 430
Ala Thr Ala Cys Thr Ala Gly Val Met Thr Arg Gly Arg Leu Lys Ala
435 440 445
Glu Ser Thr Val Ala Pro Glu Glu Asp Thr Asp Glu Asp Ser Asp Asn
450 455 460
Glu Ile His Asn Pro Ala Val Phe Thr Trp Pro Pro Trp Gln Ala Gly
465 470 475 480
Ile Leu Ala Arg Asn Leu Val Pro Met Val Ala Thr Val Gln Gly Gln
485 490 495
Asn Leu Lys Tyr Gln Glu Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg
500 505 510
Ile Phe Ala Glu Leu Glu Gly Val Trp Gln Pro Ala Ala Gln Pro Lys
515 520 525
Arg Arg Arg His Arg Gln Asp Ala Leu Pro Gly Pro Cys Ile Ala Ser
530 535 540
Thr Pro Lys Lys His Arg Gly
545 550
<210> 97
<211> 551
<212> PRT
<213> Human herpesvirus 5
<400> 97
Met Ala Ser Val Leu Gly Pro Ile Ser Gly His Val Leu Lys Ala Val
1 5 10 15
Phe Ser Arg Gly Asp Thr Pro Val Leu Pro His Glu Thr Arg Leu Leu
20 25 30
Gln Thr Gly Ile His Val Arg Val Ser Gln Pro Ser Leu Ile Leu Val
35 40 45
Ser Gln Tyr Thr Pro Asp Ser Thr Pro Cys His Arg Gly Asp Asn Gln
50 55 60
Leu Gln Val Gln His Thr Tyr Phe Thr Gly Ser Glu Val Glu Asn Val
65 70 75 80
Ser Val Asn Val His Asn Pro Thr Gly Arg Ser Ile Cys Pro Ser Gln
85 90 95
Glu Pro Met Ser Ile Tyr Val Tyr Ala Leu Pro Leu Lys Met Leu Asn
100 105 110
Ile Pro Ser Ile Asn Val His His Tyr Pro Ser Ala Ala Glu Arg Lys
115 120 125
His Arg His Leu Pro Val Ala Asp Ala Val Ile His Ala Ser Gly Lys
130 135 140
Gln Met Trp Gln Ala Arg Leu Thr Val Ser Gly Leu Ala Trp Thr Arg
145 150 155 160
Gln Gln Asn Gln Trp Lys Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe
165 170 175
Val Phe Pro Thr Lys Asp Val Ala Leu Arg His Val Val Cys Ala His
180 185 190
Glu Leu Val Cys Ser Met Glu Asn Thr Arg Ala Thr Lys Met Gln Val
195 200 205
Ile Gly Asp Gln Tyr Val Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp
210 215 220
Val Pro Ser Gly Lys Leu Phe Met His Val Thr Leu Gly Ser Asp Val
225 230 235 240
Glu Glu Asp Leu Thr Met Thr Arg Asn Pro Gln Pro Phe Met Arg Pro
245 250 255
His Glu Arg Asn Gly Phe Thr Val Leu Cys Pro Lys Asn Met Ile Ile
260 265 270
Lys Pro Gly Lys Ile Ser His Ile Met Leu Asp Val Ala Phe Thr Ser
275 280 285
His Glu His Phe Gly Leu Leu Cys Pro Lys Ser Ile Pro Gly Leu Ser
290 295 300
Ile Ser Gly Asn Leu Leu Met Asn Gly Gln Gln Ile Phe Leu Glu Val
305 310 315 320
Gln Ala Ile Arg Glu Thr Val Glu Leu Arg Gln Tyr Asp Pro Val Ala
325 330 335
Ala Leu Phe Phe Phe Asp Ile Asp Leu Leu Leu Gln Arg Gly Pro Gln
340 345 350
Tyr Ser Glu His Pro Thr Phe Thr Ser Gln Tyr Arg Ile Gln Gly Lys
355 360 365
Leu Glu Tyr Arg His Thr Trp Asp Arg His Asp Glu Gly Ala Ala Gln
370 375 380
Gly Asp Asp Asp Val Trp Thr Ser Gly Ser Asp Ser Asp Glu Glu Leu
385 390 395 400
Val Thr Thr Glu Arg Lys Thr Pro Arg Val Thr Gly Gly Gly Ala Met
405 410 415
Ala Gly Ala Ser Thr Ser Ala Gly Arg Lys Arg Lys Ser Ala Ser Ser
420 425 430
Ala Thr Ala Cys Thr Ala Gly Val Met Thr Arg Gly Arg Leu Lys Ala
435 440 445
Glu Ser Thr Val Ala Pro Glu Glu Asp Thr Asp Glu Asp Ser Asp Asn
450 455 460
Glu Ile His Asn Pro Ala Val Phe Thr Trp Pro Pro Trp Gln Ala Gly
465 470 475 480
Ile Leu Ala Arg Asn Leu Val Pro Met Val Ala Thr Val Gln Gly Gln
485 490 495
Asn Leu Lys Tyr Gln Glu Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg
500 505 510
Ile Phe Ala Glu Leu Glu Gly Val Trp Gln Pro Ala Ala Gln Pro Lys
515 520 525
Arg Arg Arg His Arg Gln Asp Ala Leu Pro Gly Pro Cys Ile Ala Ser
530 535 540
Thr Pro Lys Lys His Arg Gly
545 550
<210> 98
<211> 353
<212> PRT
<213> Human T-lymphotropic virus 1]
<400> 98
Met Ala His Phe Pro Gly Phe Gly Gln Ser Leu Leu Phe Gly Tyr Pro
1 5 10 15
Val Tyr Val Phe Gly Asp Cys Val Gln Gly Asp Trp Cys Pro Ile Ser
20 25 30
Gly Gly Leu Cys Ser Ala Arg Leu His Arg His Ala Leu Leu Ala Thr
35 40 45
Cys Pro Glu His Gln Ile Thr Trp Asp Pro Ile Asp Gly Arg Val Ile
50 55 60
Gly Ser Ala Leu Gln Phe Leu Ile Pro Arg Leu Pro Ser Phe Pro Thr
65 70 75 80
Gln Arg Thr Ser Lys Thr Leu Lys Val Leu Thr Pro Pro Ile Thr His
85 90 95
Thr Thr Pro Asn Ile Pro Pro Ser Phe Leu Gln Ala Met Arg Lys Tyr
100 105 110
Ser Pro Phe Arg Asn Gly Tyr Met Glu Pro Thr Leu Gly Gln His Leu
115 120 125
Pro Thr Leu Ser Phe Pro Asp Pro Gly Leu Arg Pro Gln Asn Leu Tyr
130 135 140
Thr Leu Trp Gly Gly Ser Val Val Cys Met Tyr Leu Tyr Gln Leu Ser
145 150 155 160
Pro Pro Ile Thr Trp Pro Leu Leu Pro His Val Ile Phe Cys His Pro
165 170 175
Gly Gln Leu Gly Ala Phe Leu Thr Asn Val Pro Tyr Lys Arg Ile Glu
180 185 190
Lys Leu Leu Tyr Lys Ile Ser Leu Thr Thr Gly Ala Leu Ile Ile Leu
195 200 205
Pro Glu Asp Cys Leu Pro Thr Thr Leu Phe Gln Pro Ala Arg Ala Pro
210 215 220
Val Thr Leu Thr Ala Trp Gln Asn Gly Leu Leu Pro Phe His Ser Thr
225 230 235 240
Leu Thr Thr Pro Gly Leu Ile Trp Thr Phe Thr Asp Gly Thr Pro Met
245 250 255
Ile Ser Gly Pro Cys Pro Lys Asp Gly Gln Pro Ser Leu Val Leu Gln
260 265 270
Ser Ser Ser Phe Ile Phe His Lys Phe Gln Thr Lys Ala Tyr His Pro
275 280 285
Ser Phe Leu Leu Ser His Gly Leu Ile Gln Tyr Ser Ser Phe His Asn
290 295 300
Leu His Leu Leu Phe Glu Glu Tyr Thr Asn Ile Pro Ile Ser Leu Leu
305 310 315 320
Phe Asn Glu Lys Glu Ala Asp Asp Asn Asp His Glu Pro Gln Ile Ser
325 330 335
Pro Gly Gly Leu Glu Pro Leu Ser Glu Lys His Phe Arg Glu Thr Glu
340 345 350
Val
<210> 99
<211> 345
<212> PRT
<213> Human T-lymphotropic virus 1]
<400> 99
Met Ala His Phe Pro Gly Phe Gly Gln Ser Leu Leu Tyr Gly Tyr Pro
1 5 10 15
Val Tyr Val Phe Gly Asp Cys Val Gln Ala Asp Trp Cys Pro Ile Ser
20 25 30
Gly Gly Leu Cys Ser Pro Arg Leu His Arg His Ala Leu Leu Ala Thr
35 40 45
Cys Pro Glu His Gln Ile Thr Trp Asp Pro Ile Asp Gly Arg Val Val
50 55 60
Gly Ser Pro Leu Gln Tyr Leu Ile Pro Arg Leu Pro Ser Phe Pro Thr
65 70 75 80
Gln Arg Thr Ser Lys Thr Leu Lys Val Leu Thr Pro Pro Thr Thr Pro
85 90 95
Val Thr Pro Lys Val Pro Pro Ser Phe Phe Gln Ser Val Arg Arg His
100 105 110
Ser Pro Tyr Arg Asn Gly Cys Leu Glu Thr Thr Leu Gly Glu Gln Leu
115 120 125
Pro Ser Leu Ala Phe Pro Glu Pro Gly Leu Arg Pro Gln Asn Val Tyr
130 135 140
Thr Ile Trp Gly Lys Thr Ile Val Cys Leu Tyr Ile Tyr Gln Leu Ser
145 150 155 160
Pro Pro Met Thr Trp Pro Leu Ile Pro His Val Ile Phe Cys Asn Pro
165 170 175
Arg Gln Leu Gly Ala Phe Leu Ser Asn Val Pro Pro Lys Arg Leu Glu
180 185 190
Glu Leu Leu Tyr Lys Leu Tyr Leu His Thr Gly Ala Ile Ile Ile Leu
195 200 205
Pro Glu Asp Ala Leu Pro Thr Thr Leu Phe Gln Pro Val Arg Ala Pro
210 215 220
Cys Val Gln Thr Thr Trp Asn Thr Gly Leu Leu Pro Tyr Gln Pro Asn
225 230 235 240
Leu Thr Thr Pro Gly Leu Ile Trp Thr Phe Asn Asp Gly Ser Pro Met
245 250 255
Ile Ser Gly Pro Cys Pro Lys Ala Gly Gln Pro Ser Leu Val Val Gln
260 265 270
Ser Ser Leu Leu Ile Phe Glu Arg Phe Gln Thr Lys Ala Tyr His Pro
275 280 285
Ser Tyr Leu Leu Ser His Gln Leu Ile Gln Tyr Ser Ser Phe His His
290 295 300
Leu Tyr Leu Leu Phe Asp Glu Tyr Thr Thr Ile Pro Phe Ser Leu Leu
305 310 315 320
Phe Lys Glu Lys Glu Gly Asp Asp Arg Asp Asn Asp Pro Leu Pro Gly
325 330 335
Ala Thr Ala Ser Pro Gln Gly Gln Asn
340 345
<210> 100
<400> 100
000
<210> 101
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 101
Ser Thr Asn Arg Gln Ser Gly Arg Gln
1 5
<210> 102
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 102
Leu Leu Phe Gly Tyr Pro Val Tyr Val
1 5
<210> 103
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 103
Gly Leu Ser Pro Thr Val Trp Leu Ser Val
1 5 10
<210> 104
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 104
Ala Met Asp Gly Thr Met Ser Gln Val
1 5
<210> 105
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 105
Tyr Ala Asp Gly Thr Met Ser Gln Val
1 5
<210> 106
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 106
Tyr Met Ala Gly Thr Met Ser Gln Val
1 5
<210> 107
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 107
Tyr Met Asp Ala Thr Met Ser Gln Val
1 5
<210> 108
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 108
Tyr Met Asp Gly Ala Met Ser Gln Val
1 5
<210> 109
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 109
Tyr Met Asp Gly Thr Ala Ser Gln Val
1 5
<210> 110
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 110
Tyr Met Asp Gly Thr Met Ala Gln Val
1 5
<210> 111
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 111
Tyr Met Asp Gly Thr Met Ser Ala Val
1 5
<210> 112
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 112
Tyr Met Asp Gly Thr Met Ser Gln Ala
1 5
<210> 113
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 113
Tyr Met Asp Gly Thr Met Ser Gln Val
1 5
<210> 114
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 114
Tyr Met Asn Gly Thr Met Ser Gln Val
1 5
<210> 115
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 115
Tyr Met Asp Asn Val Met Ser Glu Val
1 5
<210> 116
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 116
Val Met Asp Ser Lys Ile Val Gln Val
1 5
<210> 117
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 117
Leu Met Asn Gly Thr Leu Lys Gln Val
1 5
<210> 118
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 118
Ser Gln Asp Gly Thr Arg Ser Gln Val
1 5
<210> 119
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 119
Val Met Asp Thr Thr Lys Ser Gln Val
1 5
<210> 120
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 120
Gly Met Asp Gly Thr Gln Gln Gln Ile
1 5
<210> 121
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 121
Gly Met Val Gly Thr Met Thr Glu Val
1 5
<210> 122
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<223> short peptide
<400> 122
Met Met Asp Ala Thr Phe Ser Ala Val
1 5
<210> 123
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 123
Gln Met Asp Pro Thr Gly Ser Gln Leu
1 5
<210> 124
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 124
Ser Met Asp Gly Ser Met Arg Thr Val
1 5
<210> 125
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 125
Trp Met Asp Gly Ile Ala Ser Gln Ile
1 5
<210> 126
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 126
Tyr Leu Glu Gly Ile Leu Ser Gln Val
1 5
<210> 127
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 127
Tyr Met Ala Ile Lys Met Ser Gln Leu
1 5
<210> 128
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 128
Tyr Met Asp Ala Val Val Ser Leu Val
1 5
<210> 129
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 129
Tyr Met Asp Gly Thr Asn Arg Arg Ile
1 5
<210> 130
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 130
Tyr Met Asp Pro Ser Thr Tyr Gln Val
1 5
<210> 131
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 131
Tyr Met Leu Gly Thr Asn His Gln Leu
1 5
<210> 132
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 132
Tyr Met Pro Gly Thr Ala Ser Leu Ile
1 5
<210> 133
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 133
Tyr Met Arg Glu Thr Arg Ser Gln Leu
1 5
<210> 134
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 134
Met Met Asp Gly Ala Met Gly Tyr Val
1 5
<210> 135
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 135
Asn Met Asp Ser Phe Met Ala Gln Val
1 5
<210> 136
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 136
Gln Met Asp Phe Ile Met Ser Cys Val
1 5
<210> 137
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 137
Tyr Glu Asp Leu Lys Met Tyr Gln Val
1 5
<210> 138
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 138
Tyr Met Asp Thr Ile Met Glu Leu Val
1 5
<210> 139
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 139
Tyr Thr Asp Leu Ala Met Ser Thr Val
1 5
<210> 140
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 140
Tyr Val Asp Phe Val Met Ser Ser Val
1 5
<210> 141
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 141
Arg Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210> 142
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 142
Leu Asp Phe Pro Asn Leu Pro Tyr Leu
1 5
<210> 143
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 143
Arg Cys Phe Pro Asn Cys Pro Phe Leu
1 5
<210> 144
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 144
Leu Met Phe Glu Asn Ala Ala Tyr Leu
1 5
<210> 145
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 145
Arg Met Phe Pro Asn Lys Tyr Ser Leu
1 5
<210> 146
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 146
Arg Leu Phe Pro Asn Ala Lys Phe Leu
1 5
<210> 147
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 147
Arg Leu Phe Pro Asn Leu Pro Glu Leu
1 5
<210> 148
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 148
Arg Met Phe Pro Thr Pro Pro Ser Leu
1 5
<210> 149
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 149
Arg Met Val Pro Arg Ala Val Tyr Leu
1 5
<210> 150
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 150
Arg Met Phe Phe Asn Gly Arg Tyr Ile
1 5
<210> 151
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 151
Arg Met Leu Pro His Ala Pro Gly Val
1 5
<210> 152
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 152
Tyr Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210> 153
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 153
Ala Met Asp Pro Asn Ala Ala Tyr Val
1 5
<210> 154
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 154
Ile Cys Phe Pro Asn Ala Pro Lys Val
1 5
<210> 155
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 155
Asn Met Phe Glu Asn Gly Cys Tyr Leu
1 5
<210> 156
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 156
Asn Met Pro Pro Asn Phe Pro Tyr Ile
1 5
<210> 157
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 157
Arg Glu Met Thr Gln Ala Pro Tyr Leu
1 5
<210> 158
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 158
Arg Met Ala Pro Arg Ala Pro Trp Ile
1 5
<210> 159
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 159
Arg Met Glu Pro Arg Ala Pro Trp Ile
1 5
<210> 160
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 160
Arg Met Glu Pro Arg Ala Pro Trp Val
1 5
<210> 161
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 161
Arg Met Phe Leu Asn Asn Pro Ser Ile
1 5
<210> 162
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 162
Arg Met Phe Gln Gln Thr Phe Tyr Leu
1 5
<210> 163
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 163
Arg Met Asn Pro Asn Ser Pro Ser Ile
1 5
<210> 164
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 164
Arg Gln Phe Pro Asn Ala Ser Leu Ile
1 5
<210> 165
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 165
Arg Gln Phe Pro Asn Lys Asp Ala Leu
1 5
<210> 166
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 166
Arg Val Phe Pro Trp Ala Ser Ser Leu
1 5
<210> 167
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 167
Arg Leu Phe Pro Trp Gly Asn Lys Leu
1 5
<210> 168
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 168
Ala Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210> 169
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 169
Arg Ala Phe Pro Asn Ala Pro Tyr Leu
1 5
<210> 170
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 170
Arg Met Ala Pro Asn Ala Pro Tyr Leu
1 5
<210> 171
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 171
Arg Met Phe Ala Asn Ala Pro Tyr Leu
1 5
<210> 172
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 172
Arg Met Phe Pro Ala Ala Pro Tyr Leu
1 5
<210> 173
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 173
Arg Met Phe Pro Asn Ala Ala Tyr Leu
1 5
<210> 174
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 174
Arg Met Phe Pro Asn Ala Pro Ala Leu
1 5
<210> 175
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 175
Arg Met Phe Pro Asn Ala Pro Tyr Ala
1 5
<210> 176
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 176
Gly Val Tyr Asp Gly Arg Glu His Thr Val
1 5 10
<210> 177
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 177
Gly Leu Ala Asp Gly Arg Thr His Thr Val
1 5 10
<210> 178
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 178
Gly Val Ser Asp Gly Arg Trp His Ser Val
1 5 10
<210> 179
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 179
Gly Val Tyr Asp Gly Glu Glu His Ser Val
1 5 10
<210> 180
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 180
Gly Leu Tyr Asp Gly Met Glu His Leu
1 5
<210> 181
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 181
Gly Val Ser Asp Gly Gln Trp His Thr Val
1 5 10
<210> 182
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 182
Gly Val Tyr Ala Gly Arg Glu His Phe Leu
1 5 10
<210> 183
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 183
Gly Leu Tyr Asp Gly Met Glu His Leu Ile
1 5 10
<210> 184
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 184
Ala Ser Tyr Asp Gly Thr Glu Val Thr Val
1 5 10
<210> 185
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 185
Ala Val Leu Asp Gly Arg Glu Leu Arg Val
1 5 10
<210> 186
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 186
Gly Leu Tyr Asp Gly Ile Glu His Phe Met
1 5 10
<210> 187
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 187
Gly Leu Tyr Asp Gly Pro Val His Glu Val
1 5 10
<210> 188
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 188
Gly Val Cys Ala Gly Arg Glu His Phe Ile
1 5 10
<210> 189
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 189
Gly Val Tyr Ala Gly Arg Pro Leu Ser Val
1 5 10
<210> 190
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 190
Thr Val Tyr Asp Leu Arg Glu Gln Ser Val
1 5 10
<210> 191
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 191
Val Val Asp Asp Gly Val Glu His Thr Ile
1 5 10
<210> 192
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 192
Gly Val Phe Asp Gly Leu His Thr Val
1 5
<210> 193
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 193
Ala Val Tyr Asp Gly Arg Glu His Thr Val
1 5 10
<210> 194
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 194
Gly Ala Tyr Asp Gly Arg Glu His Thr Val
1 5 10
<210> 195
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 195
Gly Val Ala Asp Gly Arg Glu His Thr Val
1 5 10
<210> 196
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 196
Gly Val Tyr Ala Gly Arg Glu His Thr Val
1 5 10
<210> 197
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 197
Gly Val Tyr Asp Ala Arg Glu His Thr Val
1 5 10
<210> 198
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 198
Gly Val Tyr Asp Gly Ala Glu His Thr Val
1 5 10
<210> 199
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 199
Gly Val Tyr Asp Gly Arg Ala His Thr Val
1 5 10
<210> 200
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 200
Gly Val Tyr Asp Gly Arg Glu Ala Thr Val
1 5 10
<210> 201
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 201
Gly Val Tyr Asp Gly Arg Glu His Ala Val
1 5 10
<210> 202
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 202
Gly Val Tyr Asp Gly Arg Glu His Thr Ala
1 5 10
<210> 203
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 203
Ala Leu Ser Val Met Gly Val Tyr Val
1 5
<210> 204
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 204
Ala Leu Ser Val Leu Gly Val Met Val
1 5
<210> 205
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 205
Ala Leu Ser Arg Lys Gly Ile Tyr Val
1 5
<210> 206
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 206
Ala Leu Ser Val Met Tyr Ser Tyr Leu
1 5
<210> 207
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 207
Ala Val Ser His Met Gly Val Leu Val
1 5
<210> 208
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 208
Leu Leu Ser Leu Met Gly Val Leu Val
1 5
<210> 209
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 209
Val Leu Ser Ile Met Gly Val Tyr Ala
1 5
<210> 210
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 210
Ala Leu Gln Val Arg Lys Val Tyr Val
1 5
<210> 211
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 211
Ala Leu Gln Val Tyr Gly Val Glu Val
1 5
<210> 212
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 212
Ala Leu Ser Val Ala Gly Gly Phe Val
1 5
<210> 213
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 213
Ala Leu Ser Val Leu Gly Lys Val Val
1 5
<210> 214
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 214
Ala Leu Ser Val Met Ile Pro Ala Val
1 5
<210> 215
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 215
Asp Leu Ser Val Cys Ser Val Tyr Val
1 5
<210> 216
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 216
Ile Leu Gly Val Met Gly Val Asp Val
1 5
<210> 217
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 217
Leu Leu Ser Val Asn Gly Val Ser Val
1 5
<210> 218
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 218
Ser Leu Ser Pro Met Gly Arg Tyr Val
1 5
<210> 219
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 219
Ala Leu Ser Ala Val Met Gly Val Thr Leu
1 5 10
<210> 220
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 220
Ala Ile Leu Leu Val Met Gly Val Asp Val
1 5 10
<210> 221
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 221
Ala Leu Ser Asp His His Val Tyr Leu
1 5
<210> 222
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 222
Ala Ala Ser Val Met Gly Val Tyr Val
1 5
<210> 223
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 223
Ala Leu Ala Val Met Gly Val Tyr Val
1 5
<210> 224
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 224
Ala Leu Ser Ala Met Gly Val Tyr Val
1 5
<210> 225
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 225
Ala Leu Ser Val Ala Gly Val Tyr Val
1 5
<210> 226
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 226
Ala Leu Ser Val Met Ala Val Tyr Val
1 5
<210> 227
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 227
Ala Leu Ser Val Met Gly Ala Tyr Val
1 5
<210> 228
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 228
Ala Leu Ser Val Met Gly Val Ala Val
1 5
<210> 229
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 229
Ala Leu Ser Val Met Gly Val Tyr Ala
1 5
<210> 230
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 230
Thr Leu Met Ser Ala Met Thr Asn Leu
1 5
<210> 231
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 231
Thr Leu Met Ser Ala Glu Ala Asn Leu
1 5
<210> 232
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 232
Gln Leu Cys Ser Ala Met Thr Gln Leu
1 5
<210> 233
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 233
Arg Leu Met Ser Ala Leu Thr Gln Leu
1 5
<210> 234
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 234
Gly Leu Met Ser Leu Thr Thr Asn Leu
1 5
<210> 235
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 235
Gly Leu Met Ser Met Ala Thr Asn Leu
1 5
<210> 236
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 236
Gly Leu Met Ser Met Thr Thr Asn Leu
1 5
<210> 237
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 237
Leu Leu Met Ser Ile Ser Thr Asn Leu
1 5
<210> 238
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 238
Gln Leu Pro Ser Thr Met Thr Asn Leu
1 5
<210> 239
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 239
Thr Leu Ala Ser Ser Met Gly Asn Leu
1 5
<210> 240
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 240
Thr Leu Phe Ser Ala Leu Thr Gly Leu
1 5
<210> 241
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 241
Thr Leu Gly Ser Ala Thr Thr Glu Leu
1 5
<210> 242
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 242
Thr Leu Met Arg Ala Met Thr Asp Cys
1 5
<210> 243
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 243
Thr Leu Met Ser Met Val Ala Asn Leu
1 5
<210> 244
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 244
Thr Leu Pro Ser Ala Glu Thr Ala Leu
1 5
<210> 245
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 245
Thr Leu Pro Ser Arg Met Thr Val Leu
1 5
<210> 246
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 246
Arg Leu Met Ser Ala Leu Thr Gln Val
1 5
<210> 247
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 247
Ser Ile His Ser Gln Met Thr Asn Leu
1 5
<210> 248
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 248
Ser Ile Met Phe Ala Met Thr Pro Leu
1 5
<210> 249
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 249
Thr Ile Val Ala Ala Met Ser Asn Leu
1 5
<210> 250
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 250
Thr Leu Ile Thr Ala Met Glu Gln Leu
1 5
<210> 251
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 251
Thr Leu Thr Ser Asn Met Ser Gln Leu
1 5
<210> 252
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 252
Ala Leu Met Ser Ala Met Thr Asn Leu
1 5
<210> 253
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 253
Thr Leu Ala Ser Ala Met Thr Asn Leu
1 5
<210> 254
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 254
Thr Leu Met Ala Ala Met Thr Asn Leu
1 5
<210> 255
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 255
Thr Leu Met Ser Ala Ala Thr Asn Leu
1 5
<210> 256
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 256
Thr Leu Met Ser Ala Met Ala Asn Leu
1 5
<210> 257
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 257
Thr Leu Met Ser Ala Met Thr Ala Leu
1 5
<210> 258
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 258
Thr Leu Met Ser Ala Met Thr Asn Ala
1 5
<210> 259
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 259
Val Met Asp Ser Lys Ile Val Gln Val
1 5
<210> 260
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 260
Arg Met Leu Pro His Ala Pro Gly Val
1 5
<210> 261
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 261
Ala Met Asp Pro Asn Ala Ala Tyr Val
1 5
<210> 262
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 262
Arg Met Asn Pro Asn Ser Pro Ser Ile
1 5
<210> 263
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 263
Gly Leu Ala Asp Gly Arg Thr His Thr Val
1 5 10
<210> 264
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 264
Gly Leu Tyr Asp Gly Pro Val His Glu Val
1 5 10
<210> 265
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 265
Gly Val Phe Asp Gly Leu His Thr Val
1 5
<210> 266
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 266
Ala Leu Ser Asp His His Val Tyr Leu
1 5
<210> 267
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 267
Arg Leu Met Ser Ala Leu Thr Gln Leu
1 5
<210> 268
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 268
Arg Leu Met Ser Ala Leu Thr Gln Val
1 5
<210> 269
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 269
Glu Leu Ala Gly Ile Gly Ile Leu Thr Val
1 5 10
<210> 270
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 270
Asn Leu Val Pro Met Val Ala Thr Val
1 5
<210> 271
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 271
Ser Leu Tyr Asn Thr Val Ala Thr Leu
1 5
<210> 272
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 272
Tyr Met Asp Gly Thr Met Ser Gln Val
1 5
<210> 273
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 273
Arg Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210> 274
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 短胜肽
<400> 274
Gly Val Tyr Asp Gly Arg Glu His Thr Val
1 5 10
<210> 275
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 275
Thr Leu Met Ser Ala Met Thr Asn Leu
1 5
<210> 276
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 276
Ala Leu Ser Val Met Gly Val Tyr Val
1 5
<210> 277
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 277
Lys Ala Ser Glu Lys Ile Phe Tyr Val
1 5
<210> 278
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 278
Ser Leu Leu Met Trp Ile Thr Gln Cys
1 5
<210> 279
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 279
Thr Leu Phe Asp Tyr Glu Val Arg Leu
1 5
<210> 280
<211> 702
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(702)
<223> D11轻链的核酸序列
<400> 280
atgagaccgt ctattcagtt cctggggctc ttgttgttct ggcttcatgg tgctcagtgt 60
gacatccaga tgacacagtc tccatcctca ctgtctgcat ctctgggagg caaagtcacc 120
atcacatgca aggcaagcca agacattcac aactatatag cttggtacca acacaagcct 180
gtaaaaggtc ctaggctgct catacattac acatctacat tacagccagg caccccatca 240
aggttcagtg gaagtgggtc tgggagagat tattccttca gcatcagcaa cctggagcct 300
gaagatattg caacttatta ttgtctacag tatgataatc tgtggacgtt cggtggaggc 360
accaagctgg aaatcaaacg ggctgatgct gcaccaactg tatccatctt cccaccatcc 420
agtgagcagt taacatctgg aggtgcctca gtcgtgtgct tcttgaacaa cttctacccc 480
aaagacatca atgtcaagtg gaagattgat ggcagtgaac gacaaaatgg cgtcctgaac 540
agttggactg atcaggacag caaagacagc acctacagca tgagcagcac cctcacgttg 600
accaaggacg agtatgaacg acataacagc tatacctgtg aggccactca caagacatca 660
acttcaccca ttgtcaagag cttcaacagg aatgagtgtt ag 702
<210> 281
<211> 233
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(233)
<223> D11轻链的氨基酸序列
<400> 281
Met Arg Pro Ser Ile Gln Phe Leu Gly Leu Leu Leu Phe Trp Leu His
1 5 10 15
Gly Ala Gln Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Gly Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Asp
35 40 45
Ile His Asn Tyr Ile Ala Trp Tyr Gln His Lys Pro Val Lys Gly Pro
50 55 60
Arg Leu Leu Ile His Tyr Thr Ser Thr Leu Gln Pro Gly Thr Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser
85 90 95
Asn Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp
100 105 110
Asn Leu Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
115 120 125
Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu
130 135 140
Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro
145 150 155 160
Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn
165 170 175
Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr
180 185 190
Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His
195 200 205
Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile
210 215 220
Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 282
<211> 1398
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(1398)
<223> D11重链的核酸序列
<400> 282
atggacaggc ttacttcctc attcctgctg ctgattgtcc ctgcatatgt cctttcccag 60
gtaactctga aagagtctgg ccctgggata ttgcagccct cccagaccct cagtctgact 120
tgttctttct ctgggttttc actgaccact tctggtatgg gtgtgagctg gattcgtcag 180
ccttcaggaa agggtctgga gtggctggca cacatttact gggatgatga caagcgctat 240
aacccatccc tgaagagccg actcacaatc tccaaggata cctccagaaa ccaggtattc 300
ctcaagatca ccagtgtgga cgctgcagat actgccacat actactgtgc tcgaaaggac 360
tacggtagta gcttctatgc tatgcactac tggggtcaag gaacctcagt caccgtctcc 420
tcagccaaaa cgacaccccc atctgtctat ccactggccc ctggatctgc tgcccaaact 480
aactccatgg tgaccctggg atgcctggtc aagggctatt tccctgagcc agtgacagtg 540
acctggaact ctggatccct gtccagcggt gtgcacacct tcccagctgt cctgcagtct 600
gacctctaca ctctgagcag ctcagtgact gtcccctcca gcacctggcc cagcgagacc 660
gtcacctgca acgttgccca cccggccagc agcaccaagg tggacaagaa aattgtgccc 720
agggattgtg gttgtaagcc ttgcatatgt acagtcccag aagtatcatc tgtcttcatc 780
ttccccccaa agcccaagga tgtgctcacc attactctga ctcctaaggt cacgtgtgtt 840
gtggtagaca tcagcaagga tgatcccgag gtccagttca gctggtttgt agatgatgtg 900
gaggtgcaca cagctcagac gcaaccccgg gaggagcagt tcaacagcac tttccgctca 960
gtcagtgaac ttcccatcat gcaccaggac tggctcaatg gcaaggagtt caaatgcagg 1020
gtcaacagtg cagctttccc tgcccccatc gagaaaacca tctccaaaac caaaggcaga 1080
ccgaaggctc cacaggtgta caccattcca cctcccaagg agcagatggc caaggataaa 1140
gtcagtctga cctgcatgat aacagacttc ttccctgaag acattactgt ggagtggcag 1200
tggaatgggc agccagcgga gaactacaag aacactcagc ccatcatgga cacagatggc 1260
tcttacttcg tctacagcaa gctcaatgtg cagaagagca actgggaggc aggaaatact 1320
ttcacctgct ctgtgttaca tgagggcctg cacaaccacc atactgagaa gagcctctcc 1380
cactctcctg gtaaatga 1398
<210> 283
<211> 465
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(465)
<223> D11重链的氨基酸序列
<400> 283
Met Asp Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Tyr
1 5 10 15
Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln
20 25 30
Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu
35 40 45
Thr Thr Ser Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys
50 55 60
Gly Leu Glu Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr
65 70 75 80
Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Arg
85 90 95
Asn Gln Val Phe Leu Lys Ile Thr Ser Val Asp Ala Ala Asp Thr Ala
100 105 110
Thr Tyr Tyr Cys Ala Arg Lys Asp Tyr Gly Ser Ser Phe Tyr Ala Met
115 120 125
His Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr
130 135 140
Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr
145 150 155 160
Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser
195 200 205
Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn
210 215 220
Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro
225 230 235 240
Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser
245 250 255
Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr
260 265 270
Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp
275 280 285
Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr
290 295 300
Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser
305 310 315 320
Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr
355 360 365
Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr
370 375 380
Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln
385 390 395 400
Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met
405 410 415
Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys
420 425 430
Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu
435 440 445
Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly
450 455 460
Lys
465
<210> 284
<211> 33
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(33)
<223> D11轻链CDR的核酸序列
<400> 284
aaggcaagcc aagacattca caactatata gct 33
<210> 285
<211> 21
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(21)
<223> D11轻链CDR的核酸序列
<400> 285
tacacatcta cattacagcc a 21
<210> 286
<211> 24
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(24)
<223> D11轻链CDR的核酸序列
<400> 286
ctacagtatg ataatctgtg gacg 24
<210> 287
<211> 11
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(11)
<223> D11轻链CDR的氨基酸序列
<400> 287
Lys Ala Ser Gln Asp Ile His Asn Tyr Ile Ala
1 5 10
<210> 288
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(7)
<223> D11轻链CDR的氨基酸序列
<400> 288
Tyr Thr Ser Thr Leu Gln Pro
1 5
<210> 289
<211> 8
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(8)
<223> D11轻链CDR的氨基酸序列
<400> 289
Leu Gln Tyr Asp Asn Leu Trp Thr
1 5
<210> 290
<211> 21
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(21)
<223> D11重链CDR的核酸序列
<400> 290
acttctggta tgggtgtgag c 21
<210> 291
<211> 48
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(48)
<223> D11重链CDR的核酸序列
<400> 291
cacatttact gggatgatga caagcgctat aacccatccc tgaagagc 48
<210> 292
<211> 36
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(36)
<223> D11重链CDR的核酸序列
<400> 292
aaggactacg gtagtagctt ctatgctatg cactac 36
<210> 293
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(7)
<223> D11重链CDR的氨基酸序列
<400> 293
Thr Ser Gly Met Gly Val Ser
1 5
<210> 294
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(16)
<223> D11重链CDR的氨基酸序列
<400> 294
His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 295
<211> 12
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(12)
<223> D11重链CDR的氨基酸序列
<400> 295
Lys Asp Tyr Gly Ser Ser Phe Tyr Ala Met His Tyr
1 5 10
<210> 296
<211> 705
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(705)
<223> D7轻链的核酸序列
<400> 296
atgagtgtgc ccactcaggt cctggggttg ctgctgctgt ggcttacaga tgccagatgt 60
gacatccaga tgactcagtc tccagcctcc ctatctgtat ctgtgggaga aactgtcacc 120
atcacatgtc gagcaagtga tattatttac agtaatttag catggtatca gcagaaacag 180
ggaaaatctc ctcagctcct ggtctatgct gcaacaaact tagcagctgg tgtgccatca 240
aggttcagtg gcagtggatc aggcacacag tattccctca agatcaatag cctgcagtct 300
gaagattttg ggacttatta ctgtcaacat ttttggggta gttcaatctc gttcggctcg 360
gggacaaagt tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 705
<210> 297
<211> 234
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(234)
<223> D7轻链的氨基酸序列
<400> 297
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser
20 25 30
Val Ser Val Gly Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Asp Ile
35 40 45
Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro
50 55 60
Gln Leu Leu Val Tyr Ala Ala Thr Asn Leu Ala Ala Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn
85 90 95
Ser Leu Gln Ser Glu Asp Phe Gly Thr Tyr Tyr Cys Gln His Phe Trp
100 105 110
Gly Ser Ser Ile Ser Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 298
<211> 1380
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(1380)
<223> D7重链的核酸序列
<400> 298
atggctgtcc tggtgctgtt cctctgcctg gttgcatttc caagctgtgt cctgtcccag 60
gtgcaactga aggaatcagg acctggtctg gtggcgccct cacagagcct gtccatcact 120
tgcactgtct ctgggttttc attaaccagc tatggtgtac actgggttcg ccagcctcca 180
ggaaagggtc tggagtggct gggagtaata tgggctggtg gaaccacaaa ttataattcg 240
gctctcatgt ccagactgag catcagcaga gacaactcca agagccaagt tttcttagaa 300
atgaacagtc tgcaaactga tgacacagcc atttactact gtgccagaga tggtcacttc 360
cactttgact tctggggcca aggcaccact ctcacagtct cctcagccaa aacgacaccc 420
ccatctgtct atccactggc ccctggatct gctgcccaaa ctaactccat ggtgaccctg 480
ggatgcctgg tcaagggcta tttccctgag ccagtgacag tgacctggaa ctctggatcc 540
ctgtccagcg gtgtgcacac cttcccagct gtcctgcagt ctgacctcta cactctgagc 600
agctcagtga ctgtcccctc cagcacctgg cccagcgaga ccgtcacctg caacgttgcc 660
cacccggcca gcagcaccaa ggtggacaag aaaattgtgc ccagggattg tggttgtaag 720
ccttgcatat gtacagtccc agaagtatca tctgtcttca tcttcccccc aaagcccaag 780
gatgtgctca ccattactct gactcctaag gtcacgtgtg ttgtggtaga catcagcaag 840
gatgatcccg aggtccagtt cagctggttt gtagatgatg tggaggtgca cacagctcag 900
acgcaacccc gggaggagca gttcaacagc actttccgct cagtcagtga acttcccatc 960
atgcaccagg actggctcaa tggcaaggag ttcaaatgca gggtcaacag tgcagctttc 1020
cctgccccca tcgagaaaac catctccaaa accaaaggca gaccgaaggc tccacaggtg 1080
tacaccattc cacctcccaa ggagcagatg gccaaggata aagtcagtct gacctgcatg 1140
ataacagact tcttccctga agacattact gtggagtggc agtggaatgg gcagccagcg 1200
gagaactaca agaacactca gcccatcatg gacacagatg gctcttactt cgtctacagc 1260
aagctcaatg tgcagaagag caactgggag gcaggaaata ctttcacctg ctctgtgtta 1320
catgagggcc tgcacaacca ccatactgag aagagcctct cccactctcc tggtaaatga 1380
<210> 299
<211> 459
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(459)
<223> D7重链的氨基酸序列
<400> 299
Met Ala Val Leu Val Leu Phe Leu Cys Leu Val Ala Phe Pro Ser Cys
1 5 10 15
Val Leu Ser Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala
20 25 30
Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Thr Ser Tyr Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Ala Gly Gly Thr Thr Asn Tyr Asn Ser
65 70 75 80
Ala Leu Met Ser Arg Leu Ser Ile Ser Arg Asp Asn Ser Lys Ser Gln
85 90 95
Val Phe Leu Glu Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr
100 105 110
Tyr Cys Ala Arg Asp Gly His Phe His Phe Asp Phe Trp Gly Gln Gly
115 120 125
Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr
130 135 140
Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu
145 150 155 160
Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp
165 170 175
Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu
180 185 190
Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser
195 200 205
Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser
210 215 220
Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys
225 230 235 240
Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro
245 250 255
Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr
260 265 270
Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser
275 280 285
Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg
290 295 300
Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile
305 310 315 320
Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn
325 330 335
Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
340 345 350
Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu
355 360 365
Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe
370 375 380
Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala
385 390 395 400
Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr
405 410 415
Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly
420 425 430
Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His
435 440 445
Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455
<210> 300
<211> 33
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(33)
<223> D7重链CDR的核酸序列
<400> 300
cgagcaagtg atattattta cagtaattta gca 33
<210> 301
<211> 21
<212> DNA
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(21)
<223> D7重链CDR的氨基酸序列
<400> 301
gctgcaacaa acttagcagc t 21
<210> 302
<211> 27
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(27)
<223> D7轻链CDR的核酸序列
<400> 302
caacattttt ggggtagttc aatctcg 27
<210> 303
<211> 11
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(11)
<223> D7轻链CDR的氨基酸序列
<400> 303
Arg Ala Ser Asp Ile Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 304
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(7)
<223> D7轻链CDR的氨基酸序列
<400> 304
Ala Ala Thr Asn Leu Ala Ala
1 5
<210> 305
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> D7轻链CDR的氨基酸序列
<400> 305
Gln His Phe Trp Gly Ser Ser Ile Ser
1 5
<210> 306
<211> 15
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(15)
<223> D7重链CDR的核酸序列
<400> 306
agctatggtg tacac 15
<210> 307
<211> 48
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(48)
<223> D7重链CDR的核酸序列
<400> 307
gtaatatggg ctggtggaac cacaaattat aattcggctc tcatgtcc 48
<210> 308
<211> 24
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(24)
<223> D7重链CDR的核酸序列
<400> 308
gatggtcact tccactttga cttc 24
<210> 309
<211> 5
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(5)
<223> D7重链CDR的氨基酸序列
<400> 309
Ser Tyr Gly Val His
1 5
<210> 310
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(16)
<223> D7重链CDR的氨基酸序列
<400> 310
Val Ile Trp Ala Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 311
<211> 8
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(8)
<223> D7重链CDR的氨基酸序列
<400> 311
Asp Gly His Phe His Phe Asp Phe
1 5
<210> 312
<211> 642
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(642)
<223> B47B6轻链的核酸序列
<400> 312
gatattgtgc tcactcagtc tccagccacc ctgtctgtga gtccaggaga tagcgtcagt 60
ctttcctgca gggccagcca aagtattagc aacagcctac actggtatca acaaaaatca 120
catgagtctc caaggcttct catcaagtat gcttcccagt ccatctctgg aatcccctct 180
aggttcagtg gcagtggatc agggacagat ttcactctca gtatcaacag tgtggagact 240
gaagattttg gaatgtattt ctgtcaacag agttacagct ggcctctcac gttcggtgct 300
gggtccaagc tggagctgaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gt 642
<210> 313
<211> 214
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(214)
<223> B47B6轻链的氨基酸序列
<400> 313
Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Asp Ser Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Ser
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Thr
65 70 75 80
Glu Asp Phe Gly Met Tyr Phe Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Ala Gly Ser Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 314
<211> 1323
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(1323)
<223> B47B6重链的核酸序列
<400> 314
gaagtgcagt tggtggagtc ggggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cgttttcagt agctatgaca tgtcttgggt tcgccaggct 120
caggagaaga ggctggagtg ggtcgcatac atgagtagtg gtggcggcac ctactatcca 180
gacactgtga agggccgatt caccatctcc agagacaatg ccaagaacac cctgcacctg 240
caaatgagca gcctgaagtc tgaggacaca gccatgtatt actgtgcaag acatgatgag 300
attactaact ttgactactg gggccaaggc accactctca cagtctcctc agccaaaacg 360
acacccccat ctgtctatcc actggcccct ggatctgctg cccaaactaa ctccatggtg 420
accctgggat gcctggtcaa gggctatttc cctgagccag tgacagtgac ctggaactct 480
ggatccctgt ccagcggtgt gcacaccttc ccagctgtcc tgcagtctga cctctacact 540
ctgagcagct cagtgactgt cccctccagc acctggccca gcgagaccgt cacctgcaac 600
gttgcccacc cggccagcag caccaaggtg gacaagaaaa ttgtgcccag ggattgtggt 660
tgtaagcctt gcatatgtac agtcccagaa gtatcatctg tcttcatctt ccccccaaag 720
cccaaggatg tgctcaccat tactctgact cctaaggtca cgtgtgttgt ggtagacatc 780
agcaaggatg atcccgaggt ccagttcagc tggtttgtag atgatgtgga ggtgcacaca 840
gctcagacgc aaccccggga ggagcagttc aacagcactt tccgctcagt cagtgaactt 900
cccatcatgc accaggactg gctcaatggc aaggagttca aatgcagggt caacagtgca 960
gctttccctg cccccatcga gaaaaccatc tccaaaacca aaggcagacc gaaggctcca 1020
caggtgtaca ccattccacc tcccaaggag cagatggcca aggataaagt cagtctgacc 1080
tgcatgataa cagacttctt ccctgaagac attactgtgg agtggcagtg gaatgggcag 1140
ccagcggaga actacaagaa cactcagccc atcatggaca cagatggctc ttacttcgtc 1200
tacagcaagc tcaatgtgca gaagagcaac tgggaggcag gaaatacttt cacctgctct 1260
gtgttacatg agggcctgca caaccaccat actgagaaga gcctctccca ctctcctggt 1320
aaa 1323
<210> 315
<211> 441
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(441)
<223> B47B6重链的氨基酸序列
<400> 315
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Gln Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Met Ser Ser Gly Gly Gly Thr Tyr Tyr Pro Asp Thr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu His Leu
65 70 75 80
Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg His Asp Glu Ile Thr Asn Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp
180 185 190
Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys
210 215 220
Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val
245 250 255
Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe
260 265 270
Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu
275 280 285
Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala
305 310 315 320
Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg
325 330 335
Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met
340 345 350
Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro
355 360 365
Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn
370 375 380
Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val
385 390 395 400
Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr
405 410 415
Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu
420 425 430
Lys Ser Leu Ser His Ser Pro Gly Lys
435 440
<210> 316
<211> 33
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(33)
<223> B47B6轻链CDR的核酸序列
<400> 316
agggccagcc aaagtattag caacagccta cac 33
<210> 317
<211> 21
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(21)
<223> B47B6轻链CDR的核酸序列
<400> 317
tatgcttccc agtccatctc t 21
<210> 318
<211> 27
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(27)
<223> B47B6轻链CDR的核酸序列
<400> 318
caacagagtt acagctggcc tctcacg 27
<210> 319
<211> 11
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(11)
<223> B47B6轻链CDR的氨基酸序列
<400> 319
Arg Ala Ser Gln Ser Ile Ser Asn Ser Leu His
1 5 10
<210> 320
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(7)
<223> B47B6轻链CDR的氨基酸序列
<400> 320
Tyr Ala Ser Gln Ser Ile Ser
1 5
<210> 321
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> B47B6轻链CDR的氨基酸序列
<400> 321
Gln Gln Ser Tyr Ser Trp Pro Leu Thr
1 5
<210> 322
<211> 15
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(15)
<223> B47B6重链CDR的核酸序列
<400> 322
agctatgaca tgtct 15
<210> 323
<211> 48
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(48)
<223> B47B6重链CDR的核酸序列
<400> 323
tacatgagta gtggtggcgg cacctactat ccagacactg tgaagggc 48
<210> 324
<211> 27
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(27)
<223> B47B6重链CDR的核酸序列
<400> 324
catgatgaga ttactaactt tgactac 27
<210> 325
<211> 5
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(5)
<223> B47B6重链CDR的氨基酸序列
<400> 325
Ser Tyr Asp Met Ser
1 5
<210> 326
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(16)
<223> B47B6重链CDR的氨基酸序列
<400> 326
Tyr Met Ser Ser Gly Gly Gly Thr Tyr Tyr Pro Asp Thr Val Lys Gly
1 5 10 15
<210> 327
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> B47B6重链CDR的氨基酸序列
<400> 327
His Asp Glu Ile Thr Asn Phe Asp Tyr
1 5
<210> 328
<211> 639
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(639)
<223> C106B9轻链的核酸序列
<400> 328
caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60
ataacctgca gtgtcagctc aagtgtagat tacattcact ggttccagca gaagccaggc 120
acttctccca aattctggat ttatagcaca tccatcctgg cttctggagt ccctgctcgc 180
ttcagtggca gtggatctgg gacctcttac tctctcacaa tcagccgaat ggaggctgaa 240
gatgctgcca cttattactg ccagcaaagg agtagttacc cacccacgtt cggctcgggg 300
acaaagttgg aaataaaacg ggctgatgct gcaccaactg tatccatctt cccaccatcc 360
agtgagcagt taacatctgg aggtgcctca gtcgtgtgct tcttgaacaa cttctacccc 420
aaagacatca atgtcaagtg gaagattgat ggcagtgaac gacaaaatgg cgtcctgaac 480
agttggactg atcaggacag caaagacagc acctacagca tgagcagcac cctcacgttg 540
accaaggacg agtatgaacg acataacagc tatacctgtg aggccactca caagacatca 600
acttcaccca ttgtcaagag cttcaacagg aatgagtgt 639
<210> 329
<211> 213
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(213)
<223> C106B9轻链的氨基酸序列
<400> 329
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Ser Val Ser Ser Ser Val Asp Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Phe Trp Ile Tyr
35 40 45
Ser Thr Ser Ile Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Tyr Pro Pro Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 330
<211> 1320
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(1320)
<223> C106B9重链的核酸序列
<400> 330
caggttcaac tgcagcagtc tggaggtgag gtgatgaagc ctggggcctc agtgaagctt 60
tcctgcaagg ctactggcta cacattcact ggctactgga tagagtggat aaaacagagg 120
cctggacatg gccttgagtg gattggagag attttacctg gaagtggtgg tactaactac 180
aatgagaaat tcaagggcaa ggccacattc actgcacata catcctccaa cacagcctac 240
atgcaactca gcagcctgac aactgaggac tctgccatct attactgtgc aagggatagt 300
aactccttta cttactgggg ccaagggact ctggtcactg tctcttcagc caaaacgaca 360
cccccatctg tctatccact ggcccctgga tctgctgccc aaactaactc catggtgacc 420
ctgggatgcc tggtcaaggg ctatttccct gagccagtga cagtgacctg gaactctgga 480
tccctgtcca gcggtgtgca caccttccca gctgtcctgc agtctgacct ctacactctg 540
agcagctcag tgactgtccc ctccagcacc tggcccagcg agaccgtcac ctgcaacgtt 600
gcccacccgg ccagcagcac caaggtggac aagaaaattg tgcccaggga ttgtggttgt 660
aagccttgca tatgtacagt cccagaagta tcatctgtct tcatcttccc cccaaagccc 720
aaggatgtgc tcaccattac tctgactcct aaggtcacgt gtgttgtggt agacatcagc 780
aaggatgatc ccgaggtcca gttcagctgg tttgtagatg atgtggaggt gcacacagct 840
cagacgcaac cccgggagga gcagttcaac agcactttcc gctcagtcag tgaacttccc 900
atcatgcacc aggactggct caatggcaag gagttcaaat gcagggtcaa cagtgcagct 960
ttccctgccc ccatcgagaa aaccatctcc aaaaccaaag gcagaccgaa ggctccacag 1020
gtgtacacca ttccacctcc caaggagcag atggccaagg ataaagtcag tctgacctgc 1080
atgataacag acttcttccc tgaagacatt actgtggagt ggcagtggaa tgggcagcca 1140
gcggagaact acaagaacac tcagcccatc atggacacag atggctctta cttcgtctac 1200
agcaagctca atgtgcagaa gagcaactgg gaggcaggaa atactttcac ctgctctgtg 1260
ttacatgagg gcctgcacaa ccaccatact gagaagagcc tctcccactc tcctggtaaa 1320
<210> 331
<211> 440
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(440)
<223> C106B9重链的氨基酸序列
<400> 331
Gln Val Gln Leu Gln Gln Ser Gly Gly Glu Val Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Thr Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Trp Ile Glu Trp Ile Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Phe Thr Ala His Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Thr Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Asp Ser Asn Ser Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala
115 120 125
Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu
130 135 140
Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly
145 150 155 160
Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp
165 170 175
Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro
180 185 190
Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys
195 200 205
Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile
210 215 220
Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val
245 250 255
Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val
260 265 270
Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala
305 310 315 320
Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro
325 330 335
Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala
340 345 350
Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu
355 360 365
Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr
370 375 380
Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr
385 390 395 400
Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe
405 410 415
Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys
420 425 430
Ser Leu Ser His Ser Pro Gly Lys
435 440
<210> 332
<211> 30
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(30)
<223> C106B9轻链CDR的核酸序列
<400> 332
agtgtcagct caagtgtaga ttacattcac 30
<210> 333
<211> 21
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(21)
<223> C106B9轻链CDR的核酸序列
<400> 333
agcacatcca tcctggcttc t 21
<210> 334
<211> 27
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(27)
<223> C106B9轻链CDR的核酸序列
<400> 334
cagcaaagga gtagttaccc acccacg 27
<210> 335
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> C106B9轻链CDR的氨基酸序列
<400> 335
Ser Val Ser Ser Ser Val Asp Tyr Ile His
1 5 10
<210> 336
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(7)
<223> C106B9轻链CDR的氨基酸序列
<400> 336
Ser Thr Ser Ile Leu Ala Ser
1 5
<210> 337
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> C106B9轻链CDR的氨基酸序列
<400> 337
Gln Gln Arg Ser Ser Tyr Pro Pro Thr
1 5
<210> 338
<211> 15
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(15)
<223> C106B9重链CDR的核酸序列
<400> 338
ggctactgga tagag 15
<210> 339
<211> 51
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(51)
<223> C106B9重链CDR的核酸序列
<400> 339
gagattttac ctggaagtgg tggtactaac tacaatgaga aattcaaggg c 51
<210> 340
<211> 21
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(21)
<223> C106B9重链CDR的核酸序列
<400> 340
gatagtaact cctttactta c 21
<210> 341
<211> 5
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(5)
<223> C106B9重链CDR的氨基酸序列
<400> 341
Gly Tyr Trp Ile Glu
1 5
<210> 342
<211> 17
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(17)
<223> C106B9重链CDR的氨基酸序列
<400> 342
Glu Ile Leu Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 343
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(7)
<223> C106B9重链CDR的氨基酸序列
<400> 343
Asp Ser Asn Ser Phe Thr Tyr
1 5
<210> 344
<211> 642
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(642)
<223> F184C7轻链的核酸序列
<400> 344
gacatccaga tgactcagtc tccagcctcc ctatctgtat ctgtgggaga aactgtcacc 60
atcacatgtc gagcaagtga gaatatttac agaaatttag catggtatca gcagaaacag 120
ggaaaatctc ctcaactcct ggtccatgct gcaacaaact tagcagatgg tgtgccatca 180
aggttcagtg gcagtggatc agacacacag tattccctca agatcaacag cctgcagtct 240
gaagattttg ggaattatta ctgtcaacat ttttggggga ctccgctcac gttcggtgct 300
gggaccaagc tggagctgaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gt 642
<210> 345
<211> 214
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(214)
<223> F184C7轻链的氨基酸序列
<400> 345
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Arg Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
His Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Asp Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Gly Asn Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 346
<211> 1338
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(1338)
<223> F184C7重链的核酸序列
<400> 346
caggttcagc tgcagcagtc tggacctgag atggtgaagc ctggggcctc agtgaagatt 60
ccctgcaagg cttctggcta cgcattcagt agctcctgga tgaactgggt gaagcagagg 120
cctggaaagg gtcttgagtg gattggacgg atttatcctg gagatggaga tactaactac 180
aatgagaagt tcaagggcaa ggccacactg actgtagaca aatcctccag cacagtctac 240
atgcaactca gcagcctgac atctgaggac tctgcggtct acttctgtgc aagagaggct 300
actacggtag tggccccgta ctactttgac tactggggcc aaggcaccac tctcacagtc 360
tcctcagcca aaacgacacc cccatctgtc tatccactgg cccctggatc tgctgcccaa 420
actaactcca tggtgaccct gggatgcctg gtcaagggct atttccctga gccagtgaca 480
gtgacctgga actctggatc cctgtccagc ggtgtgcaca ccttcccagc tgtcctgcag 540
tctgacctct acactctgag cagctcagtg actgtcccct ccagcacctg gcccagcgag 600
accgtcacct gcaacgttgc ccacccggcc agcagcacca aggtggacaa gaaaattgtg 660
cccagggatt gtggttgtaa gccttgcata tgtacagtcc cagaagtatc atctgtcttc 720
atcttccccc caaagcccaa ggatgtgctc accattactc tgactcctaa ggtcacgtgt 780
gttgtggtag acatcagcaa ggatgatccc gaggtccagt tcagctggtt tgtagatgat 840
gtggaggtgc acacagctca gacgcaaccc cgggaggagc agttcaacag cactttccgc 900
tcagtcagtg aacttcccat catgcaccag gactggctca atggcaagga gttcaaatgc 960
agggtcaaca gtgcagcttt ccctgccccc atcgagaaaa ccatctccaa aaccaaaggc 1020
agaccgaagg ctccacaggt gtacaccatt ccacctccca aggagcagat ggccaaggat 1080
aaagtcagtc tgacctgcat gataacagac ttcttccctg aagacattac tgtggagtgg 1140
cagtggaatg ggcagccagc ggagaactac aagaacactc agcccatcat ggacacagat 1200
ggctcttact tcgtctacag caagctcaat gtgcagaaga gcaactggga ggcaggaaat 1260
actttcacct gctctgtgtt acatgagggc ctgcacaacc accatactga gaagagcctc 1320
tcccactctc ctggtaaa 1338
<210> 347
<211> 446
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(446)
<223> F184C7重链的氨基酸序列
<400> 347
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Met Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Pro Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Val Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Glu Ala Thr Thr Val Val Ala Pro Tyr Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro
115 120 125
Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met
130 135 140
Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val
180 185 190
Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His
195 200 205
Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys
210 215 220
Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe
225 230 235 240
Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro
245 250 255
Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val
260 265 270
Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr
275 280 285
Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu
290 295 300
Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys
305 310 315 320
Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro
340 345 350
Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile
355 360 365
Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly
370 375 380
Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp
385 390 395 400
Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp
405 410 415
Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His
420 425 430
Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 348
<211> 33
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(33)
<223> F184C7轻链CDR的核酸序列
<400> 348
cgagcaagtg agaatattta cagaaattta gca 33
<210> 349
<211> 21
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(21)
<223> F184C7轻链CDR的核酸序列
<400> 349
gctgcaacaa acttagcaga t 21
<210> 350
<211> 27
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(27)
<223> F184C7轻链CDR的核酸序列
<400> 350
caacattttt gggggactcc gctcacg 27
<210> 351
<211> 11
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(11)
<223> F184C7轻链CDR的氨基酸序列
<400> 351
Arg Ala Ser Glu Asn Ile Tyr Arg Asn Leu Ala
1 5 10
<210> 352
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(7)
<223> F184C7轻链CDR的氨基酸序列
<400> 352
Ala Ala Thr Asn Leu Ala Asp
1 5
<210> 353
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> F184C7轻链CDR的氨基酸序列
<400> 353
Gln His Phe Trp Gly Thr Pro Leu Thr
1 5
<210> 354
<211> 22
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(22)
<223> F184C7重链CDR的核酸序列
<400> 354
attcagtagc tcctggatga ac 22
<210> 355
<211> 51
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(51)
<223> F184C7重链CDR的核酸序列
<400> 355
cggatttatc ctggagatgg agatactaac tacaatgaga agttcaaggg c 51
<210> 356
<211> 39
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(39)
<223> F184C7重链CDR的核酸序列
<400> 356
gaggctacta cggtagtggc cccgtactac tttgactac 39
<210> 357
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(7)
<223> F184C7重链CDR的氨基酸序列
<400> 357
Phe Ser Ser Ser Trp Met Asn
1 5
<210> 358
<211> 17
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(17)
<223> F184C7重链CDR的氨基酸序列
<400> 358
Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 359
<211> 13
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(13)
<223> F184C7重链CDR的氨基酸序列
<400> 359
Glu Ala Thr Thr Val Val Ala Pro Tyr Tyr Phe Asp Tyr
1 5 10
<210> 360
<211> 642
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(642)
<223> D10A3轻链的核酸序列
<400> 360
aatattgtgc tgacccagac tcccaaattc ctgcttgtat cagcaggaga cagggtttcc 60
ataacctgca aggccagtca gcgtgtgaat aatgatgtag cttggtacca acagaagcca 120
gggcagtctc ctaaactgct gatatactat gcatccaatc gctacactgg agtccctgat 180
cgcttcactg gcagtggata tgggacggat ttcactttca ccatcagcac tgtgcaggct 240
gaagacctgg cagtttattt ctgtcagcag gattatagct ctccattcac gttcggctcg 300
gggacaaagt tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gt 642
<210> 361
<211> 214
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(214)
<223> D10A3轻链的氨基酸序列
<400> 361
Asn Ile Val Leu Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Arg Val Asn Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 362
<211> 1332
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(1332)
<223> D10A3重链的核酸序列
<400> 362
gaggtccagc tgcaacagtt tggaactgag ctggtgaagc ctggggcttc agtgaagata 60
tcctgcaagg cttctggcta cacattcact gactacaaca tggactgggt gaagcagagc 120
catggaaaga gccttgagtg gattggagat attaatccta actatgatac tactacctac 180
aaccagaagt tcaagggaaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac ttctgaggac actgcagtct tttactgtgc aagaaggaac 300
tatggtaact acgtggggtt tgacttctgg ggccaaggca ccactctcac agtctcctca 360
gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 420
tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 480
tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 540
ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 600
acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 660
gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 720
cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 780
gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 840
gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 900
agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 960
aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 1020
aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 1080
agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 1140
aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 1200
tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 1260
acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 1320
tctcctggta aa 1332
<210> 363
<211> 444
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(444)
<223> D10A3重链的氨基酸序列
<400> 363
Glu Val Gln Leu Gln Gln Phe Gly Thr Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asn Pro Asn Tyr Asp Thr Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Phe Tyr Cys
85 90 95
Ala Arg Arg Asn Tyr Gly Asn Tyr Val Gly Phe Asp Phe Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val
115 120 125
Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr
130 135 140
Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr
145 150 155 160
Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser
180 185 190
Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala
195 200 205
Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys
210 215 220
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val
245 250 255
Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe
260 265 270
Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro
290 295 300
Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val
305 310 315 320
Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
325 330 335
Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys
340 345 350
Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp
355 360 365
Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro
370 375 380
Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser
385 390 395 400
Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala
405 410 415
Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
420 425 430
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440
<210> 364
<211> 33
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(33)
<223> D10A3轻链CDR的核酸序列
<400> 364
aaggccagtc agcgtgtgaa taatgatgta gct 33
<210> 365
<211> 21
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(21)
<223> D10A3轻链CDR的核酸序列
<400> 365
tatgcatcca atcgctacac t 21
<210> 366
<211> 27
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(27)
<223> D10A3轻链CDR的核酸序列
<400> 366
cagcaggatt atagctctcc attcacg 27
<210> 367
<211> 11
<212> PRT
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(11)
<223> D10A3轻链CDR的核酸序列
<400> 367
Lys Ala Ser Gln Arg Val Asn Asn Asp Val Ala
1 5 10
<210> 368
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(7)
<223> D10A3轻链CDR的氨基酸序列
<400> 368
Tyr Ala Ser Asn Arg Tyr Thr
1 5
<210> 369
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> D10A3轻链CDR的氨基酸序列
<400> 369
Gln Gln Asp Tyr Ser Ser Pro Phe Thr
1 5
<210> 370
<211> 15
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(15)
<223> D10A3重链CDR的核酸序列
<400> 370
gactacaaca tggac 15
<210> 371
<211> 51
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(51)
<223> D10A3重链CDR的核酸序列
<400> 371
gatattaatc ctaactatga tactactacc tacaaccaga agttcaaggg a 51
<210> 372
<211> 33
<212> DNA
<213> Artificial sequence
<220>
<221> gene
<222> (1)..(33)
<223> D10A3重链CDR的核酸序列
<400> 372
aggaactatg gtaactacgt ggggtttgac ttc 33
<210> 373
<211> 5
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(5)
<223> D10A3重链CDR的氨基酸序列
<400> 373
Asp Tyr Asn Met Asp
1 5
<210> 374
<211> 17
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(17)
<223> D10A3重链CDR的氨基酸序列
<400> 374
Asp Ile Asn Pro Asn Tyr Asp Thr Thr Thr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 375
<211> 11
<212> PRT
<213> Artificial sequence
<220>
<221> PEPTIDE
<222> (1)..(11)
<223> D10A3重链CDR的氨基酸序列
<400> 375
Arg Asn Tyr Gly Asn Tyr Val Gly Phe Asp Phe
1 5 10
<210> 376
<211> 163
<212> PRT
<213> homo sapiens
<400> 376
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala
35 40 45
Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
50 55 60
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
65 70 75 80
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
85 90 95
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
100 105 110
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
115 120 125
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
130 135 140
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
145 150 155 160
Pro Pro Arg
<210> 377
<211> 164
<212> PRT
<213> homo sapiens
<400> 377
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala
35 40 45
Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
50 55 60
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
65 70 75 80
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
85 90 95
Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
100 105 110
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
115 120 125
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
130 135 140
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
145 150 155 160
Leu Pro Pro Arg
<210> 378
<211> 123
<212> PRT
<213> homo sapiens
<400> 378
Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val
1 5 10 15
Thr Gly Asn Lys Ile Leu Val Lys Gln Ser Pro Met Leu Val Ala Tyr
20 25 30
Asp Asn Ala Val Asn Leu Ser Trp Lys His Leu Cys Pro Ser Pro Leu
35 40 45
Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly
50 55 60
Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe
65 70 75 80
Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn
85 90 95
Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr
100 105 110
Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
115 120
<210> 379
<211> 101
<212> PRT
<213> homo sapiens
<400> 379
Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val
1 5 10 15
Thr Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys
20 25 30
Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
35 40 45
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg
50 55 60
Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
65 70 75 80
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
85 90 95
Ala Ala Tyr Arg Ser
100
<210> 380
<211> 220
<212> PRT
<213> homo sapiens
<400> 380
Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val
1 5 10 15
Thr Gly Asn Lys Ile Leu Val Lys Gln Ser Pro Met Leu Val Ala Tyr
20 25 30
Asp Asn Ala Val Asn Leu Ser Cys Lys Tyr Ser Tyr Asn Leu Phe Ser
35 40 45
Arg Glu Phe Arg Ala Ser Leu His Lys Gly Leu Asp Ser Ala Val Glu
50 55 60
Val Cys Val Val Tyr Gly Asn Tyr Ser Gln Gln Leu Gln Val Tyr Ser
65 70 75 80
Lys Thr Gly Phe Asn Cys Asp Gly Lys Leu Gly Asn Glu Ser Val Thr
85 90 95
Phe Tyr Leu Gln Asn Leu Tyr Val Asn Gln Thr Asp Ile Tyr Phe Cys
100 105 110
Lys Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser
115 120 125
Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro
130 135 140
Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly
145 150 155 160
Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile
165 170 175
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
180 185 190
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
195 200 205
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
210 215 220
<210> 381
<211> 255
<212> PRT
<213> homo sapiens
<400> 381
Met Gly Asn Ser Cys Tyr Asn Ile Val Ala Thr Leu Leu Leu Val Leu
1 5 10 15
Asn Phe Glu Arg Thr Arg Ser Leu Gln Asp Pro Cys Ser Asn Cys Pro
20 25 30
Ala Gly Thr Phe Cys Asp Asn Asn Arg Asn Gln Ile Cys Ser Pro Cys
35 40 45
Pro Pro Asn Ser Phe Ser Ser Ala Gly Gly Gln Arg Thr Cys Asp Ile
50 55 60
Cys Arg Gln Cys Lys Gly Val Phe Arg Thr Arg Lys Glu Cys Ser Ser
65 70 75 80
Thr Ser Asn Ala Glu Cys Asp Cys Thr Pro Gly Phe His Cys Leu Gly
85 90 95
Ala Gly Cys Ser Met Cys Glu Gln Asp Cys Lys Gln Gly Gln Glu Leu
100 105 110
Thr Lys Lys Gly Cys Lys Asp Cys Cys Phe Gly Thr Phe Asn Asp Gln
115 120 125
Lys Arg Gly Ile Cys Arg Pro Trp Thr Asn Cys Ser Leu Asp Gly Lys
130 135 140
Ser Val Leu Val Asn Gly Thr Lys Glu Arg Asp Val Val Cys Gly Pro
145 150 155 160
Ser Pro Ala Asp Leu Ser Pro Gly Ala Ser Ser Val Thr Pro Pro Ala
165 170 175
Pro Ala Arg Glu Pro Gly His Ser Pro Gln Ile Ile Ser Phe Phe Leu
180 185 190
Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu Leu Phe Phe Leu Thr Leu
195 200 205
Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
210 215 220
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
225 230 235 240
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
245 250 255
<210> 382
<211> 199
<212> PRT
<213> homo sapiens
<400> 382
Met Lys Ser Gly Leu Trp Tyr Phe Phe Leu Phe Cys Leu Arg Ile Lys
1 5 10 15
Val Leu Thr Gly Glu Ile Asn Gly Ser Ala Asn Tyr Glu Met Phe Ile
20 25 30
Phe His Asn Gly Gly Val Gln Ile Leu Cys Lys Tyr Pro Asp Ile Val
35 40 45
Gln Gln Phe Lys Met Gln Leu Leu Lys Gly Gly Gln Ile Leu Cys Asp
50 55 60
Leu Thr Lys Thr Lys Gly Ser Gly Asn Thr Val Ser Ile Lys Ser Leu
65 70 75 80
Lys Phe Cys His Ser Gln Leu Ser Asn Asn Ser Val Ser Phe Phe Leu
85 90 95
Tyr Asn Leu Asp His Ser His Ala Asn Tyr Tyr Phe Cys Asn Leu Ser
100 105 110
Ile Phe Asp Pro Pro Pro Phe Lys Val Thr Leu Thr Gly Gly Tyr Leu
115 120 125
His Ile Tyr Glu Ser Gln Leu Cys Cys Gln Leu Lys Phe Trp Leu Pro
130 135 140
Ile Gly Cys Ala Ala Phe Val Val Val Cys Ile Leu Gly Cys Ile Leu
145 150 155 160
Ile Cys Trp Leu Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro
165 170 175
Asn Gly Glu Tyr Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser
180 185 190
Arg Leu Thr Asp Val Thr Leu
195
<210> 383
<211> 277
<212> PRT
<213> homo sapiens
<400> 383
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
210 215 220
Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
225 230 235 240
Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 384
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<221> PEPTIDE
<222> (1)..(9)
<223> 短胜肽
<400> 384
Asp Leu Met Gly Tyr Ile Pro Leu Val
1 5
Claims (20)
1.一种亲和性结合实体，其特征在于，所述亲和性结合实体包括抗原结合区域，所述抗原结合区域包括：
(i)免疫球蛋白重链的多个N端至C端排列的互补性决定区(CDR)序列：
CDR1 重链(HC) SEQ ID NO:357 FSSSWMN
CDR2 HC SEQ ID NO:358 RIYPGDGDTNYNEKFKG
CDR3 HC SEQ ID NO:359 EATTVVAPYYFDY及
(i)免疫球蛋白轻链的多个N端至C端排列的互补性决定区(CDR)序列：
CDR1 轻链(LC) SEQ ID NO:351 RASENIYRNLA
CDR2 LC SEQ ID NO:352 AATNLAD
CDR3 LC SEQ ID NO:353 QHFWGTPLT
所述亲和性结合实体能够以人类主要组织兼容性复合体(MHC)限定的方式结合HLA-A2/MAGE-A9344-359。
2.一种亲和性结合实体，其特征在于，所述亲和性结合实体包括抗原结合区域，所述抗原结合区域包括：
(i)免疫球蛋白重链的多个N端至C端排列的互补性决定区(CDR)序列：
CDR1 重链(HC) SEQ ID NO:325 SYDMS
CDR2 HC SEQ ID NO:326 YMSSGGGTYYPDTVKG
CDR3 HC SEQ ID NO:327 HDEITNFDY及
(i)免疫球蛋白轻链的多个N端至C端排列的互补性决定区(CDR)序列：
CDR1 轻链(LC) SEQ ID NO:319 RASQSISNSLH
CDR2 LC SEQ ID NO:320 YASQSIS
CDR3 LC SEQ ID NO:321 QQSYSWPLT
所述亲和性结合实体能够以人类主要组织兼容性复合体限定的方式结合HLA-A2/WT1126-134。
3.一种亲和性结合实体，其特征在于，所述亲和性结合实体包括抗原结合区域，所述抗原结合区域包括：
(i)N端至C端排列的免疫球蛋白重链的多个互补性决定区(CDR)序列：
CDR1 重链(HC) SEQ ID NO:373 DYNMD
CDR2 HC SEQ ID NO:374 DINPNYDTTTYNQKFKG
CDR3 HC SEQ ID NO:375 RNYGNYVGFDF及
(i)N端至C端排列的免疫球蛋白轻链的多个互补性决定区(CDR)序列：
CDR1 轻链(LC) SEQ ID NO:367 KASQRVNNDVA
CDR2 LC SEQ ID NO:368 YASNRYT
CDR3 LC SEQ ID NO:369 QQDYSSPFT
所述亲和性结合实体能够以人类主要组织兼容性复合体限定的方式结合HLA-A2/PAP360-375。
4.如权利要求1至3任一项所述的亲和性结合实体，其特征在于，所述亲和性结合实体选自于由抗体、嵌合抗原受体(CAR)和T细胞受体(TCR)组成的群组。
5.如权利要求1至3任一项所述的亲和性结合实体，其特征在于，所述亲和性结合实体是抗体。
6.如权利要求1至3任一项所述的亲和性结合实体，其特征在于，所述亲和性结合实体是TCR。
7.如权利要求1至3任一项所述的亲和性结合实体，其特征在于，所述亲和性结合实体是CAR。
8.如权利要求1至5任一项所述的亲和性结合实体，其特征在于，所述亲和性结合实体是可溶性实体。
9.如权利要求4或5所述的亲和性结合实体，其特征在于，所述亲和性结合实体是人源化抗体。
10.如权利要求1至5、8至9任一项所述的亲和性结合实体，其特征在于，所述亲和性结合实体包含治疗部分。
11.如权利要求1至5、8至9任一项所述的亲和性结合实体，其特征在于，所述亲和性结合实体包括可检测部分。
12.如权利要求4至5、8至11任一项所述的亲和性结合实体，其特征在于，所述抗体为单链抗体、双特异性抗体或全长度的抗体。
13.一种分离的多核苷酸，其特征在于，所述多核苷酸包括核酸序列，用以编码如权利要求1至12任一项所述的亲和性结合实体。
14.一种表达载体，其特征在于，所述表达载体包括如权利要求13所述的多核苷酸，所述多核苷酸可操作地连接至顺式作用的调控组件。
15.一种细胞，其特征在于，所述细胞包括如权利要求13所述的多核苷酸或如权利要求14所述的表达载体。
16.一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1至12任一项所述的亲和性结合实体、如权利要求14所述的表达载体或如权利要求15所述的细胞。
17.一种利用权利要求1至12任一项所述的亲和性结合实体、权利要求14所述的表达载体、权利要求15所述的细胞或权利要求16所述的药物组合物制备用于在治疗癌症的方法中使用的药物的应用。
18.如权利要求17所述的应用，其特征在于，所述亲和性结合实体用于威尔姆氏肿瘤蛋白1(WT1)时，所述癌症选自于由慢性髓细胞性白血病、多发性骨髓瘤(MM)、急性淋巴细胞性白血病(ALL)、急性骨髓/骨髓性白血病(AML)、骨髓发育异常综合症(MDS)、间皮瘤、卵巢癌、胃肠癌、甲状腺癌、乳腺癌、肺癌、黑色素瘤、骨肉瘤、子宫内膜癌、前列腺癌和胶质瘤所组成的群组。
19.如权利要求17所述的应用，其特征在于，所述亲和性结合实体用于黑色素瘤相关抗原9(MAGE-A9)时，所述癌症选自于由肾细胞癌、膀胱癌、乳腺癌及肝细胞癌所组成的群组。
20.如权利要求17所述的应用，其特征在于，所述亲和性结合实体用于前列腺性酸性磷酸酶(PAP)时，所述癌症为前列腺癌。
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