CN112294760A - 一种液体制剂及其应用 - Google Patents

一种液体制剂及其应用 Download PDF

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CN112294760A
CN112294760A CN201910685007.4A CN201910685007A CN112294760A CN 112294760 A CN112294760 A CN 112294760A CN 201910685007 A CN201910685007 A CN 201910685007A CN 112294760 A CN112294760 A CN 112294760A
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张晋宇
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Abstract

本申请涉及一种液体制剂，其包括油相溶剂系统和蛋白质，其中所述油相溶剂系统包括油相溶剂，所述油相溶剂的质量分数为约50％以上。

Description

一种液体制剂及其应用
技术领域
本申请涉及生物医药领域，具体的涉及一种液体制剂及其应用。
背景技术
肿瘤是一种严重威胁人类健康的疾病，近年来，免疫治疗作为一种新疗法，在肿瘤治疗中显示出了巨大的潜力。细胞因子(Cytokine)是体内非常重要的免疫信号，细胞因子融合蛋白技术是当今肿瘤免疫疗法的另一个热点方向。该方法是基于这些细胞因子具有相同或相关的功能活性而各自作用靶点不同，利用基因工程技术将两种或多种细胞因子融合在一起。但是目前利用细胞因子融合蛋白技术进行肿瘤治疗的效果仍不尽人意，有较多需要改进之处。
发明内容
本申请提供了一种液体制剂，其包括油相溶剂系统和蛋白质，其中所述油相溶剂系统包括油相溶剂，所述油相溶剂的质量分数为约50％以上。
在某些实施方式中，所述油相溶剂选自以下组：甘油、丙二醇、聚乙二醇、聚乙烯吡咯烷酮、甘露醇、山梨醇、聚氧丙烯和氨基丁三醇。
在某些实施方式中，所述油相溶剂的质量分数为约60％以上。
在某些实施方式中，所述油相溶剂的质量分数为约70％以上。
在某些实施方式中，所述蛋白质的质量分数为约1％-约50％。
在某些实施方式中，所述蛋白质包括细胞因子和/或抗体。
在某些实施方式中，所述细胞因子包括选自下组的两种或更多种：IL12、IL2、GMCSF、IL7、IL15、IL21和FLT3L。
在某些实施方式中，所述细胞因子源自哺乳动物。
在某些实施方式中，所述蛋白质包括融合蛋白，且所述融合蛋白中包含选自下组的至少两种细胞因子：IL12、IL2、GMCSF、IL7、IL15、IL21和FLT3L。
在某些实施方式中，所述蛋白质包括融合蛋白，且所述融合蛋白中包含选自以下的任一组细胞因子：
a)IL12、IL2和GMSCF；
b)IL12、IL7和GMSCF；
c)IL12、IL15和GMSCF；
d)IL12、IL21和GMSCF；
e)IL12、IL2和FLT3L；
f)IL12、IL7和FLT3L；
g)IL12、IL15和FLT3L；以及，
h)IL12、IL21和FLT3L。
在某些实施方式中，所述蛋白质还包括靶向部分。
在某些实施方式中，所述靶向部分能够特异性识别和/或结合肿瘤相关抗原。
在某些实施方式中，所述肿瘤相关抗原选自下组：纤连蛋白的EDB结构域、纤连蛋白的EDA结构域和细胞坏死区域(necrotic regions)。
在某些实施方式中，所述靶向部分包括抗体或其抗原结合片段。
在某些实施方式中，所述靶向部分包含下组中任一项所示的氨基酸序列：SEQ IDNO:1-15。
在某些实施方式中，所述蛋白质包含下组中任一项所示的氨基酸序列：SEQ IDNO:32-67。
在某些实施方式中，所述蛋白质为单链蛋白质。
在某些实施方式中，所述单链蛋白质包含下组中任一项所示的氨基酸序列：SEQID NO:32-51。
在某些实施方式中，所述蛋白质为由第一多肽链及第二多肽链组成的二聚体，所述第一多肽链不同于所述第二多肽链。
在某些实施方式中，所述第一多肽链包含IL12a，所述第二多肽链包含IL12b。
在某些实施方式中，IL2或其功能性片段位于所述第一多肽链中或所述第二多肽链中，GMCSF或其功能性片段位于所述第一多肽链中或所述第二多肽链中，且所述一个或多个靶向部分各自独立地位于所述第一多肽链中或所述第二多肽链中。
在某些实施方式中，在所述第一多肽链中，从N端到C端依次包含所述IL2或其功能性片段、所述IL12a或其功能性片段和所述GMCSF或其功能性片段。
在某些实施方式中，在所述第一多肽链中，从N端到C端依次包含所述靶向部分、所述IL12a或其功能性片段、所述IL2或其功能性片段以及所述GMCSF或其功能性片段。
在某些实施方式中，在所述第二多肽链中，从N端到C端依次包含所述IL12b或其功能性片段和所述靶向部分。
在某些实施方式中，其中，
a)所述第一多肽链包含SEQ ID NO:53所示的氨基酸序列且所述第二多肽链包含SEQ ID NO:52所示的氨基酸序列；
b)所述第一多肽链包含SEQ ID NO:55所示的氨基酸序列且所述第二多肽链包含SEQ ID NO:54所示的氨基酸序列；
c)所述第一多肽链包含SEQ ID NO:56所示的氨基酸序列且所述第二多肽链包含SEQ ID NO:57所示的氨基酸序列；
d)所述第一多肽链包含SEQ ID NO:58所示的氨基酸序列且所述第二多肽链包含SEQ ID NO:59所示的氨基酸序列；
e)所述第一多肽链包含SEQ ID NO:60所示的氨基酸序列且所述第二多肽链包含SEQ ID NO:61所示的氨基酸序列；
f)所述第一多肽链包含SEQ ID NO:62所示的氨基酸序列且所述第二多肽链包含SEQ ID NO:63所示的氨基酸序列；
g)所述第一多肽链包含SEQ ID NO:64所示的氨基酸序列且所述第二多肽链包含SEQ ID NO:65所示的氨基酸序列；
h)所述第一多肽链包含SEQ ID NO:66所示的氨基酸序列且所述第二多肽链包含SEQ ID NO:67所示的氨基酸序列。
另一方面，本申请还提供了一种药物，其包含本申请所述的液体制剂。
在某些实施方式中，其中所述液体制剂被配制为注射剂。
在某些实施方式中，本申请所述的药物还包含稀释剂，其中所述稀释剂与所述液体制剂彼此不混合。
另一方面，本申请还提供了本申请所述的液体制剂在制备治疗肿瘤的药物中的用途。
在某些实施方式中，其中所述肿瘤包括肺癌。
在某些实施方式中，本申请所述的液体制剂，其用于治疗肿瘤。
另一方面，本申请还提供了一种治疗肿瘤的方法，其包括向有需要的受试者施用本申请所述的液体制剂。
在某些实施方式中，其中所述施用方法为瘤内注射。
另一方面，本申请还提供了一种用于制备本申请所述的液体制剂的辅料，其包含油相溶剂，所述油相溶剂的质量分数为约50％以上。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书如下：
图1显示甘油对小鼠体内肿瘤生长的影响；
图2显示本申请所述的液体制剂对小鼠体内肿瘤生长的影响；
图3显示本申请所述的液体制剂对小鼠体内肿瘤生长的影响；
图4显示本申请所述的液体制剂对小鼠体内肿瘤生长的影响；
图5显示本申请所述的液体制剂对小鼠体内肿瘤生长的影响；
图6显示本申请所述的液体制剂对小鼠体内肿瘤生长的影响。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
以下对本申请做进一步描述：在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
在本申请中，术语“液体制剂”通常指一种呈液体状的药物组合物，其通常包含活性成分和可药用的载体或赋形剂。例如，在本申请中，所述液体制剂可以包括油相溶剂系统和蛋白质，其中所述油相溶剂系统包括油相溶剂，所述油相溶剂的质量分数为约50％以上。所述油相溶剂可以包括甘油、丙二醇和/或聚乙二醇。在本申请中，可以将蛋白质分散或者溶解在油相溶剂中，以制备本申请所述的液体制剂。
在本申请中，术语“蛋白质”可以被认为属于“细胞因子融合蛋白”，其通常是指能够通过基因重组技术将两种或多种细胞因子融合在一起获得的融合蛋白。其既具有其组成因子独特的生物学活性或使其某些活性显著提高，还可能会通过生物学活性的互补及协同效应发挥出较单一细胞因子简单配伍所不具备的复合生物学功能，甚至还可能会产生一些新的结构及生物学功能。
在本申请中，术语“IL12”、“IL12a”、“IL12b”、“IL2”、“GMCSF”、“IL7”、“IL15”、“IL21”、“FLT3L”可以被认为属于“细胞因子”。所述“细胞因子”通常是指由免疫细胞(如单核、巨噬细胞、T细胞、B细胞、NK细胞等)和某些非免疫细胞(例如，内皮细胞、表皮细胞、纤维母细胞等)经刺激而合成、分泌的一类具有广泛生物学活性的小分子蛋白质。所述细胞因子对于细胞间相互作用、细胞的生长和分化有重要调节作用。在本申请中，所述细胞因子可以选自下组中的一种或多种：白细胞介素(Interleukin，IL)、FMS相关酪氨酸激酶3配体(FLT3L)和集落刺激因子(Colony Stimulating Factor，CSF)。所述白细胞介素通常是指由淋巴细胞、单核细胞或其它非单个核细胞产生的细胞因子。在本申请中，所述白细胞介素可以选自下组中的一种或多种：IL12、IL2、IL7、IL15、IL21。在本申请中，所述集落刺激因子通常是指可刺激不同的造血干细胞在半固体培养基中形成细胞集落的细胞因子。在本申请中，所述集落刺激因子可以是粒细胞巨噬细胞集落刺激因子(Granulocyte MacrophageColony Stimulating Factor，GMCSF)。
在本申请中，术语“IL12”通常是指白细胞介素-12，IL12可以在细胞间相互作用、免疫调节、造血以及炎症过程中起重要调节作用。IL12的分子通常是一种异源二聚体，其通常包括两个亚基，两个亚基分别是p40亚基(40kd)和p35亚基(35kd)，这两个亚基通过二硫键连接在一起。在本申请中，含有p35亚基(35kd)的IL12可以以IL12a表示，含有p40亚基(40kd)的IL12可以以IL12b表示。例如，来源于小鼠的IL12(mIL12)中的p35亚基可包含如SEQ ID NO:16所示的氨基酸序列，p40亚基可包含如SEQ ID NO:17所示的氨基酸序列。又例如，来源于人的IL12(hIL12)中的p35亚基可包含如SEQ ID NO:18所示的氨基酸序列，p40亚基可包含如SEQ ID NO:19所示的氨基酸序列。
在本申请中，术语“IL2”通常是指白细胞介素-2，IL2在细胞间相互作用、免疫调节、造血以及炎症过程中起重要调节作用。例如，来源于小鼠的IL2(mIL2)可包含如SEQ IDNO:20所示的氨基酸序列。又例如，来源于人的IL2(hIL2)可包含如SEQ ID NO:21所示的氨基酸序列。
在本申请中，术语“IL15”通常是指白细胞介素-15，IL15在细胞间相互作用、免疫调节、造血以及炎症过程中起重要调节作用。例如，来源于小鼠的IL15(mIL15)可包含如SEQID NO:22所示的氨基酸序列。又例如，来源于人的IL15(hIL15)可包含如SEQ ID NO:23所示的氨基酸序列。
在本申请中，术语“IL7”通常是指白细胞介素-7，IL7在细胞间相互作用、免疫调节、造血以及炎症过程中起重要调节作用。例如，来源于小鼠的IL7(mIL7)可包含如SEQ IDNO:24所示的氨基酸序列。又例如，来源于人的IL7(hIL7)可包含如SEQ ID NO:25所示的氨基酸序列。
在本申请中，术语“IL21”通常是指白细胞介素-21，IL21在细胞间相互作用、免疫调节、造血以及炎症过程中起重要调节作用。例如，来源于小鼠的IL21(mIL21)可包含如SEQID NO:26所示的氨基酸序列。又例如，来源于人的IL21(hIL21)可包含如SEQ ID NO:27所示的氨基酸序列。
在本申请中，术语“FLT3L”通常是指FMS相关酪氨酸激酶3配体，其可调节非红系造血干细胞的增殖和分化，促进前B淋巴细胞、树突状细胞、NK细胞、细胞毒T淋巴细胞的增殖、分化和成熟，具有重要的抗肿瘤作用。例如，来源于小鼠的FLT3L(mFLT3L)可包含如SEQ IDNO:28所示的氨基酸序列。又例如，来源于人的FLT3L(hFLT3L)可包含如SEQ ID NO:29所示的氨基酸序列。
在本申请中，术语“GMCSF”通常是指粒细胞巨噬细胞集落刺激因子。所述GMCSF可带有4个α螺旋束结构。例如，来源于小鼠的GMCSF(mGMCSF)可包含如SEQ ID NO:30所示的氨基酸序列。又例如，来源于人的GMCSF(hGMCSF)可包含如SEQ ID NO:31所示的氨基酸序列。
在本申请中，术语“抗体”通常指免疫球蛋白或其片段或其衍生物，涵盖包括抗原结合位点的任何多肽，无论其是在体外还是体内产生的。该术语包括但不限于多克隆的、单克隆的、单特异性的、多特异性的、非特异性的、人源化的、单链的、嵌合的、合成的、重组的、杂化的、突变的和移植的抗体。除非另外被术语“完整的”修饰，如在“完整的抗体”中，为了本发明的目的，术语“抗体”也包括抗体片段，比如Fab、F(ab')2、Fv、scFv、Fd、dAb和保持抗原结合功能(即，特异性结合例如OX40或PD-Ll)的其它抗体片段。通常，这样的片段应当包括抗原结合结构域。
基本的4链抗体单元是由两个相同的轻(L)链和两个相同的重(H)链组成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元与另外一个称为J链的多肽组成，且含有10个抗原结合位点，而IgA抗体包括2-5个可以与J链相结合聚合形成多价组合的基本4链单元。就IgG而言，4链单元一般为约150,000道尔顿。每个L链通过一个共价二硫键与H链连接，而两个H链通过一个或多个取决于H链同种型的二硫键相互连接。每个H和L链还具有规则间隔的链内二硫化桥键。每个H链在N末端具有可变结构域(VH)，对于α和γ链各自继之以三个恒定结构域(CH)、对于μ和ε同种型继之以四个CH结构域。每个L链在N末端具有可变结构域(VL)，在其另一端具有恒定结构域。VL与VH对应，且CL与重链的第一恒定结构域(CH1)相对应。特定的氨基酸残基被认为在轻链和重链可变结构域之间形成界面。VH和VL配对一起形成单个抗原结合位点。对于不同类别抗体的结构和性质，参见例如Basic and ClinicalImmunology,8th Edition,Daniel P.Sties,Abba I.Terr and Tristram G.Parsolw(eds),Appleton&Lange,Norwalk,Conn.,1994，第71页和第6章。来自任何脊椎动物物种的L链可以基于其恒定结构域的氨基酸序列被分为两种明显不同的类型中的一种，称为κ和λ。取决于其重链(CH)恒定结构域的氨基酸序列，可以将免疫球蛋白分为不同的类别或同种型。存在五类免疫球蛋白：IgA、IgD、IgE、IgG和IgM，具有分别被命名为α、δ、ε、γ和μ的重链。基于CH序列和功能方面的相对小的差异，将γ和α类进一步分成亚类，例如，人表达下述亚类：IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgK1。
在本申请中，术语“靶向部分”通常是指一类针对某一些特殊组织、细胞起作用的部分。例如，靶向部分能够特异性靶向肿瘤相关抗原。在本申请中，所述靶向部分包括抗体或其抗原结合片段。
本文使用的术语“特异性识别和/或结合”通常指可测量的和可再现的相互作用，比如靶标和抗体之间的结合，可在分子(包括生物分子)的异质群体存在的情况可决定靶标的存在。例如，特异性结合靶标(其可以为表位)的抗体是以比它结合其它靶标更大的亲和性、亲合力、更容易、和/或以更大的持续时间结合该靶标的抗体。在一个实施方案中，抗体结合无关靶标的程度小于抗体对靶标的结合的约10％，如例如通过放射免疫分析(RIA)测量的。在某些实施方案中，特异性结合靶标的抗体具有<1x10-6M、<1x10-7M、<1x10-8M、<1x10- 9M或<1x10-10M的解离常数(KD)。在某些实施方案中，抗体特异性结合蛋白质上的表位，所述表位在不同种属的蛋白质中是保守的。在另一个实施方案中，特异性结合可以包括但不要求排他性地结合。
在本申请中，术语“肿瘤相关抗原”(tumor-associated antigen，TAA)，通常是指在肿瘤细胞或正常细胞上存在的抗原分子。所述肿瘤相关抗原可以包括：胚胎性蛋白、糖蛋白抗原和鳞状细胞抗原。所述肿瘤相关抗原可以选自下组：纤连蛋白的EDB结构域、纤连蛋白的EDA结构域和细胞坏死区域(necrotic regions)。
在本申请中，术语“抗原结合片段”通常是指具有抗原结合活性的片段。在本申请中，所述抗原结合片段可以选自下组：Fab，Fab’，F(ab’)2，F(ab)2，dAb，分离的互补决定区CDR，Fv和scFv。
在本申请中，术语“单链蛋白质”通常是指由一个连续氨基酸残基的不间断序列组成的一级结构的多肽。例如，在本申请中，所述单链蛋白质可以包含下组中任一项所示的氨基酸序列：SEQ ID NO:32-51。
在本申请中，术语“二聚体”通常指由两个通常是非共价键合的单体单位形成的高分子复合物。每个单体单位可以是大分子，比如多肽链或多核苷酸。例如，在本申请中，所述蛋白质可以为由第一多肽链及第二多肽链组成的二聚体。
在本申请中，术语“多肽链”通常指包括两个或多个共价连接的肽的大分子。多肽链之内的肽可以通过一个肽键彼此连接。每条多肽链可以包括一个N-末端或氨基末端和一个C-末端或羧基末端。
在本申请中，术语“功能性片段”通常是指保留某种特定功能的片段，例如，IL12a功能性片段是指保留IL12a的功能的片段。例如，IL12a功能性片段可以为IL12a，片段(GenBank:AIC49052.1)。又例如，IL12b功能性片段可以为IL12b，片段(GenBank:AIC54621.1)。
在本申请中，术语“注射剂”通常是指药物制成的供注入体内的无菌溶液(包括乳浊液和混悬液)以及供临用前配成溶液或混悬液的无菌粉末或浓溶液。例如，注射剂可以通过静脉注射或者皮下注射的方式使药物进入体内。在本申请中，所述液体制剂可以被配制为注射剂。
在本申请中，术语“稀释剂”通常指用于稀释物质的溶剂，例如使物质浓度降低的溶剂。在本申请中，所述药物还可以包含稀释剂，所述稀释剂与所述液体制剂彼此不混合。
在本申请中，术语“肿瘤”通常指由异常细胞生长形成的赘生物或实体病变。在本申请中，肿瘤可以是实体瘤或血液瘤。例如，肿瘤可包括肺癌。
在本申请中，术语“受试者”通常指人类或非人类动物，包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴。
在本申请中，术语“施用”通常是指向受试者(例如，患者)给予一定剂量的液体制剂或药物的方法。施用可通过任何合适的方式进行，包括肠胃外、肺内和鼻内，以及(如果局部治疗需要)损伤内施用。肠胃外输注包括例如肌肉内、静脉内、动脉内、腹膜内或皮下施用。可以通过任何合适的途径，例如通过注射(诸如静脉内或皮下注射)来给药，这部分地取决于施用是短暂的或长期的。本文涵盖各种给药排程，包括但不限于单次施用或各种时间点内的多次施用、推注施用和脉冲输注。例如，在本申请中，所述施用可以为瘤内注射。所述“瘤内注射”通常是指向肿瘤内部注射一定剂量的液体制剂或者药物。
在本申请中，术语“辅料”通常是指辅助性材料，例如辅助制备某种物质的材料。例如在本申请中，用于制备所述的液体制剂的辅料可以包含油相溶剂，所述油相溶剂的质量分数可以为约50％以上。
在本申请中，术语“包含”通常是指包括明确指定的特征，但不排除其他要素。
在本申请中，术语“约”通常是指在指定数值以上或以下0.5％-10％的范围内变动，例如在指定数值以上或以下0.5％、1％、1.5％、2％、2.5％、3％、3.5％、4％、4.5％、5％、5.5％、6％、6.5％、7％、7.5％、8％、8.5％、9％、9.5％、或10％的范围内变动。
液体制剂
一方面，本申请提供一种液体制剂，其可以包括油相溶剂系统和蛋白质，其中所述油相溶剂系统可以包括油相溶剂，所述油相溶剂的质量分数可以为约50％以上。
此外，在某些实施方式中，所述油相溶剂的质量分数可以为约60％以上。例如，在另一些实施方式中，所述油相溶剂的质量分数可以为约70％以上。例如，所述油相溶剂的质量分数可以为约50％-约60％、约60％-约70％、约70％-约80％、约80％-约90％、约90％-约95％、约50％-约70％、约50％-约80％、约50％-约90％、约50％-约95％、约60％-约80％、约60％-约90％、约60％-约95％、约70％-约90％、约70％-约95％、或约80％-约95％。
在本申请中，所述油相溶剂可以选自以下组：甘油、丙二醇、聚乙二醇、聚乙烯吡咯烷酮、甘露醇、山梨醇、聚氧丙烯和氨基丁三醇。
在本申请中，所述油相溶剂可以为甘油，所述甘油的质量分数可以为约50％以上。在某些实施方式中，所述甘油的质量分数可以为约60％以上。例如，在另一些实施方式中，所述甘油的质量分数可以为约70％以上。例如，所述甘油的质量分数可以为约50％-约60％、约60％-约70％、约70％-约80％、约80％-约90％、约90％-约95％、约50％-约70％、约50％-约80％、约50％-约90％、约50％-约95％、约60％-约80％、约60％-约90％、约60％-约95％、约70％-约90％、约70％-约95％、或约80％-约95％。
在本申请中，所述蛋白质的质量分数可以为约1％-约50％，例如所述蛋白质的质量分数可以为约约1％-约10％、约1％-约20％、约1％-约30％、约1％-约40％、约1％-约50％、5％-约10％、约5％-约20％、约5％-约30％、约5％-约40％、约5％-约50％、约10％-约20％、约10％-约30％、约10％-约40％、约10％-约50％、约20％-约30％、约20％-约40％、约20％-约50％、约30％-约40％、约30％-约50％、约40％-约50％、或约45％-约50％。
在某些实施方式中，可以通过将所述蛋白质溶解或者分散在所述油相溶剂系统中(例如油相溶剂中)以制备本申请所述的液体制剂。
在本申请中，所述油相溶剂和所述蛋白质可以是彼此互溶的，也可以是彼此不互溶的。
在本申请中，所述油相溶剂和所述蛋白质之间具有协同效应，从而增强本申请所述的液体制剂在治疗肿瘤方面的效果。
在本申请中，本申请所述的液体制剂可以用于治疗肿瘤，其中的油相溶剂与蛋白质可以相互协同作用，从而增强肿瘤的治疗效果，例如，相比于单纯的油相溶剂或者单纯的蛋白质，本申请所述的液体制剂在肿瘤治疗方面的效果呈现显著和增强。又例如，单纯的蛋白溶液通常无法诱导肿瘤消退，而使用本申请所述的液体制剂则可以诱导肿瘤的消退。
在本申请中，所述液体制剂可以用于抑制肿瘤生长。例如，本申请的液体制剂可以抑制或延缓疾病的发展或进展，可以通过促进细胞因子的表达减小肿瘤的大小(甚至基本消除肿瘤)，和/或可以减轻和/或稳定疾病状态。
此外，还需要说明的是，本申请所述的液体制剂，除了可以包括油相溶剂系统和蛋白质之外，还可以包括氨基酸，所述氨基酸可以为甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸中的任意一种或多种。本申请所述的液体制剂还可以包括抗菌剂或者抗氧化剂。所述抗氧化剂可以为抗坏血酸、亚硫酸钠或亚硫酸氢钠中的任意一种或多种。本申请所述的液体制剂还可以包括缓冲剂，所述缓冲剂可以为硼酸盐、碳酸氢盐、Tris-HCl、柠檬酸盐、磷酸盐或其它有机酸中的任一种或多种。本申请所述的液体制剂还可以包括膨胀剂，例如甘露醇或甘氨酸。本申请所述的液体制剂还可以包括螯合剂，例如乙二胺四乙酸(EDTA。本申请所述的液体制剂还可以包括络合剂，例如咖啡因、聚乙烯吡咯烷酮、β-环糊精或羟基丙基-β-环糊精中的任一种或多种。本申请所述的液体制剂还可以包括糖类，例如葡萄糖、甘露糖或糊精。本申请所述的液体制剂还可以包括防腐剂，例如苯扎氯铵、苯甲酸、水杨酸、硫柳汞、苯乙醇、羟苯甲酸甲酯、羟苯甲酸丙酯、双氯苯双胍己烷、山梨酸或过氧化氢中的任一种或多种。
蛋白质
在本申请中，所述蛋白质可以包括细胞因子和/或抗体。
在本申请中，所述抗体可以选自下组的一种或多种：单克隆抗体、多克隆抗体、抗体片段、嵌合抗体、双特异性抗体、杂缀合物抗体、单链(ScFv)、包含抗体部分的融合蛋白(例如结构域抗体)、人源化抗体和免疫球蛋白分子的包含所需特异性的抗原识别位点的任何其它经修饰的构型。其中，抗体片段可以选自Fab、Fab′、F(ab′)2、Fv和Fc中的一种或多种。包含抗体部分的融合蛋白可以为结构域抗体。
在本申请中，所述抗体还可以包括抗体的糖基化变体、抗体的氨基酸序列变体和共价修饰的抗体。所述抗体可以是犬的、大鼠的、人的，或任何其它来源的，例如嵌合的或人源化的抗体。
在本申请中，所述细胞因子可以为以下的任意一种：IL12、IL2、GMCSF、IL7、IL15、IL21和FLT3L。
在本申请中，所述细胞因子也可以包括选自下组的两种或更多种：IL12、IL2、GMCSF、IL7、IL15、IL21和FLT3L。其中所述细胞因子可以源自哺乳动物。所述哺乳动物可以为人或小鼠。例如，源自小鼠的IL12a(用mIL12a表示)的氨基酸序列可以如SEQ ID NO.16所示，源自小鼠的IL12b(用mIL12b表示)的氨基酸序列可以如SEQ ID NO.17所示，源自小鼠的IL2(用mIL2表示)的氨基酸序列可以如SEQ ID NO.20所示，源自小鼠的GMCSF(用mGMCSF表示)的氨基酸序列可以如SEQ ID NO.30所示，源自小鼠的IL7(用mIL7表示)的氨基酸序列可以如SEQ ID NO.24所示，源自小鼠的IL15(用mIL15表示)的氨基酸序列可以如SEQ IDNO.22所示，源自小鼠的IL21(用mIL21表示)的氨基酸序列可以如SEQ ID NO.26所示，源自小鼠的FLT3L(用mFLT3L表示)的氨基酸序列可以如SEQ ID NO.28所示。又例如，源自人的IL12a(用hIL12a表示)的氨基酸序列可以如SEQ ID NO.18所示，源自人的IL12b(用hIL12b表示)的氨基酸序列可以如SEQ ID NO.19所示，源自人的IL2(用hIL2表示)的氨基酸序列可以如SEQ ID NO.21所示，源自人的GMCSF(用hGMCSF表示)的氨基酸序列可以如SEQ IDNO.31所示，源自人的IL7(用hIL7表示)的氨基酸序列可以如SEQ ID NO.25所示，源自人的IL15(用hIL15表示)的氨基酸序列可以如SEQ ID NO.23所示，源自人的IL21(用hIL21表示)的氨基酸序列可以如SEQ ID NO.27所示，源自人的FLT3L(用hFLT3L表示)的氨基酸序列可以如SEQ ID NO.29所示。
在本申请中，所述蛋白质可以包括融合蛋白，该融合蛋白将所述细胞因子，即IL12、IL2、IL7、IL15、IL21、FLT3L和GMCSF中的两种或多种，通过基因重组技术融合在一起。所述蛋白质可以既具有组成其因子独特的生物学活性，又可以通过生物学活性的互补及协同效应发挥出较单一细胞因子所不具备的生物学功能，甚至还可以产生一些新的结构及生物学功能。例如，在本申请中，所述蛋白质可以包括融合蛋白，且所述融合蛋白中包含选自以下的任一组细胞因子：a)IL12、IL2和GMSCF；b)IL12、IL7和GMSCF；c)IL12、IL15和GMSCF；d)IL12、IL21和GMSCF；e)IL12、IL2和FLT3L；f)IL12、IL7和FLT3L；g)IL12、IL15和FLT3L；以及，h)IL12、IL21和FLT3L。
在本申请中，所述蛋白质还可以包括靶向部分，所述靶向部分的数量可以为1个或多个。所述靶向部分可以是相同的，也可以是不同的。所述靶向部分能够特异性识别和/或结合肿瘤相关抗原。其中所述肿瘤相关抗原可以选自下组：纤连蛋白的EDB结构域、纤连蛋白的EDA结构域和细胞坏死区域(necrotic regions)。所述靶向部分可以包括抗体或其抗原结合片段。
在本申请中，所述抗原结合片段可以选自下组：Fab，Fab’，F(ab’)2，F(ab)2，dAb，分离的互补决定区CDR，Fv和scFv。在某些实施方式中，所述抗原结合片段可以为scFv。
在本申请中，所述靶向部分可以包含下组中任一项所示的氨基酸序列：SEQ IDNO:1-15。
例如，所述蛋白质的靶向部分可以选自下组：L19VL(其氨基酸序列可以如SEQ IDNO.10所示)、L19VH(其氨基酸序列可以如SEQ ID NO.11所示)、F8VL(其氨基酸序列可以如SEQ ID NO.12所示)、F8VH(其氨基酸序列可以如SEQ ID NO.13所示)、NHS76VL(其氨基酸序列可以如SEQ ID NO.14所示)和NHS76VH(其氨基酸序列可以如SEQ ID NO.15所示)。
需要说明的是，在本申请中，所述细胞因子之间或者所述细胞因子与所述靶向部分之间均可以通过连接子连接。所述连接子可以为连接肽。在本申请中，所述连接子可以包含下组中任一项所示的氨基酸序列：SEQ ID NO:73-76。
例如，所述细胞因子之间可以通过所述连接子连接。在本申请中，所述IL12a、IL12b、IL2、IL7、IL15、IL21、FLT3L和GMCSF之间可通过所述连接肽进行连接。例如，所述连接肽可包含如SEQ ID NO.73或SEQ ID NO.75所示的氨基酸序列。
例如，所述细胞因子和所述靶向部分可以通过所述连接子连接。在本申请中，所述靶向部分与IL12a、IL12b、IL2、IL7、IL15、IL21、FLT3L和GMCSF之间可通过所述连接肽进行连接。例如，所述连接肽可以包含SEQ ID NO:73-76中的任一项所示的氨基酸序列。
在本申请中，所述蛋白质可以包含下组中任一项所示的氨基酸序列：SEQ ID NO:32-67。
例如，在本申请中，所述蛋白质可以为单链蛋白质，其中所述单链蛋白质可以包含下组中任一项所示的氨基酸序列：SEQ ID NO:32-51。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL2的N端融合，mIL2的C端和mGMCSF的N端融合，从而形成mIL12b-mIL12a-mIL2-mGMCSF单链蛋白质，用mIL12bIL12aIL2GMCSF表示(其氨基酸序列可以如SEQ ID NO.32所示)。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL7的N端融合，mIL7的C端和mGMCSF的N端融合，从而形成mIL12b-mIL12a-mIL7-mGMCSF单链蛋白质，用mIL12bIL12aIL7GMCSF表示(其氨基酸序列可以如SEQ ID NO.33所示)。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL15的N端融合，mIL15的C端和mGMCSF的N端融合，从而形成mIL12b-mIL12a-mIL15-mGMCSF单链蛋白质，用mIL12bIL12aIL15GMCSF表示(其氨基酸序列可以如SEQ ID NO.34所示)。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL21的N端融合，mIL21的C端和mGMCSF的N端融合，从而形成mIL12b-mIL12a-mIL21-mGMCSF单链蛋白质，用mIL12bIL12aIL21GMCSF表示(其氨基酸序列可以如SEQ ID NO.35所示)。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL2的N端融合，mIL2的C端和mFLT3L的N端融合，从而形成mIL12b-mIL12a-mIL2-mFLT3L单链蛋白质，用mIL12bIL12aIL2FLT3L表示(其氨基酸序列可以如SEQ ID NO.36所示)。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL7的N端融合，mIL7的C端和mFLT3L的N端融合，从而形成mIL12b-mIL12a-mIL7-mFLT3L单链蛋白质，用mIL12bIL12aIL7FLT3L表示(其氨基酸序列可以如SEQ ID NO.37所示)。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL15的N端融合，mIL15的C端和mFLT3L的N端融合，从而形成mIL12b-mIL12a-mIL15-mFLT3L单链蛋白质，用mIL12bIL12aIL15FLT3L表示(其氨基酸序列可以如SEQ ID NO.38所示)。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL21的N端融合，mIL21的C端和mFLT3L的N端融合，从而形成mIL12b-mIL12a-mIL21-mFLT3L单链蛋白质，用mIL12bIL12aIL21FLT3L表示(其氨基酸序列可以如SEQ ID NO.39所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL2的N端融合，hIL2的C端和hGMCSF的N端融合，从而形成hIL12b-hIL12a-hIL2-hGMCSF单链蛋白质，用hIL12bIL12aIL2GMCSF表示(其氨基酸序列可以如SEQ ID NO.40所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL7的N端融合，hIL7的C端和hGMCSF的N端融合，从而形成hIL12b-hIL12a-hIL7-hGMCSF单链蛋白质，用hIL12bIL12aIL7GMCSF表示(其氨基酸序列可以如SEQ ID NO.41所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL15的N端融合，hIL15的C端和hGMCSF的N端融合，从而形成hIL12b-hIL12a-hIL15-hGMCSF单链蛋白质，用hIL12bIL12aIL15GMCSF表示(其氨基酸序列可以如SEQ ID NO.42所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL21的N端融合，hIL21的C端和hGMCSF的N端融合，从而形成hIL12b-hIL12a-hIL21-hGMCSF单链蛋白质，用hIL12bIL12aIL21GMCSF表示(其氨基酸序列可以如SEQ ID NO.43所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL2的N端融合，hIL2的C端和hFLT3L的N端融合，从而形成hIL12b-hIL12a-hIL2-hFLT3L单链蛋白质，用hIL12bIL12aIL2FLT3L表示(其氨基酸序列可以如SEQ ID NO.44所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL7的N端融合，hIL7的C端和hFLT3L的N端融合，从而形成hIL12b-hIL12a-hIL7-hFLT3L单链蛋白质，用hIL12bIL12aIL7FLT3L表示(其氨基酸序列可以如SEQ ID NO.45所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL15的N端融合，hIL15的C端和hFLT3L的N端融合，从而形成hIL12b-hIL12a-hIL15-hFLT3L单链蛋白质，用hIL12bIL12aIL15FLT3L表示(其氨基酸序列可以如SEQ ID NO.46所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL21的N端融合，hIL21的C端和hFLT3L的N端融合，从而形成hIL12b-hIL12a-hIL21-hFLT3L单链蛋白质，用hIL12bIL12aIL21FLT3L表示(其氨基酸序列可以如SEQ ID NO.47所示)。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL2的N端融合，mIL2的C端和NHS76VH的N端融合，NHS76VH的C端和F8VL的N端融合，F8VL的C端和F8VH的N端融合，F8VH的C端和NHS76VL的N端融合，NHS76VL的C端和mGMCSF的N端融合，从而形成mIL12b-mIL12a-mIL2-NHS76VH-F8VL-F8VH-NHS76VL-mGMCSF单链蛋白质。需要说明的是，该单链蛋白质的连接子中含有凝血酶切割位点，该单链蛋白质的名称用mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr表示(其氨基酸序列可以如SEQ ID NO.48所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL2的N端融合，hIL2的C端和NHS76VH的N端融合，NHS76VH的C端和F8VL的N端融合，F8VL的C端和F8VH的N端融合，F8VH的C端和NHS76VL的N端融合，NHS76VL的C端和hGMCSF的N端融合，从而形成hIL12b-hIL12a-hIL2-NHS76VH-F8VL-F8VH-NHS76VL-hGMCSF单链蛋白质。需要说明的是，该单链蛋白质的连接子中含有凝血酶切割位点，该单链蛋白质的名称用hIL12bIL12aIL2DiaNHS76F8GMCSF-Thr表示(其氨基酸序列可以如SEQ ID NO.49所示)。
例如，所述单链蛋白质的结构可以为，mIL12b的C端和mIL12a的N端融合，mIL12a的C端和mIL2的N端融合，mIL2的C端和F8VH的N端融合，F8VH的C端和F8VL的N端融合，F8VL的C端和F8VH的N端融合，F8VH的C端和F8VL的N端融合，F8VL的C端和mGMCSF的N端融合，从而形成mIL12b-mIL12a-mIL2-F8VH-F8VL-F8VH-F8VL-mGMCSF单链蛋白质，用mIL12bIL12aIL2DiaF8GMCSF表示(其氨基酸序列可以如SEQ ID NO.50所示)。
例如，所述单链蛋白质的结构可以为，hIL12b的C端和hIL12a的N端融合，hIL12a的C端和hIL2的N端融合，hIL2的C端和F8VH的N端融合，F8VH的C端和F8VL的N端融合，F8VL的C端和F8VH的N端融合，F8VH的C端和F8VL的N端融合，F8VL的C端和hGMCSF的N端融合，从而形成hIL12b-hIL12a-hIL2-F8VH-F8VL-F8VH-F8VL-hGMCSF单链蛋白质，用hIL12bIL12aIL2DiaF8GMCSF表示(其氨基酸序列可以如SEQ ID NO.51所示)。
又例如，在本申请中，所述蛋白质还可以为由第一多肽链及第二多肽链组成的二聚体，所述第一多肽链不同于所述第二多肽链。其中所述第一多肽链可以包含IL12a，所述第二多肽链可以包含IL12b。
在本申请中，其中IL2或其功能性片段可以位于所述第一多肽链中或所述第二多肽链中，GMCSF或其功能性片段可以位于所述第一多肽链中或所述第二多肽链中，且所述一个或多个靶向部分可以各自独立地位于所述第一多肽链中或所述第二多肽链中。
在本申请中，在所述第一多肽链中，从N端到C端可以依次包含所述IL2或其功能性片段、所述IL12a或其功能性片段和所述GMCSF或其功能性片段。
在本申请中，在所述第一多肽链中，从N端到C端可以依次包含所述靶向部分、所述IL12a或其功能性片段、所述IL2或其功能性片段以及所述GMCSF或其功能性片段。
在本申请中，在所述第二多肽链中，从N端到C端可以依次包含所述IL12b或其功能性片段和所述靶向部分。
在某些实施方式中，在本申请所述的二聚体中，所述第一多肽链可以包含SEQ IDNO:53所示的氨基酸序列且所述第二多肽链可以包含SEQ ID NO:52所示的氨基酸序列。
在某些实施方式中，在本申请所述的二聚体中，所述第一多肽链可以包含SEQ IDNO:55所示的氨基酸序列且所述第二多肽链可以包含SEQ ID NO:54所示的氨基酸序列；
在某些实施方式中，在本申请所述的二聚体中，所述第一多肽链可以包含SEQ IDNO:56所示的氨基酸序列且所述第二多肽链可以包含SEQ ID NO:57所示的氨基酸序列；
在某些实施方式中，在本申请所述的二聚体中，所述第一多肽链可以包含SEQ IDNO:58所示的氨基酸序列且所述第二多肽链可以包含SEQ ID NO:59所示的氨基酸序列；
在某些实施方式中，在本申请所述的二聚体中，所述第一多肽链可以包含SEQ IDNO:60所示的氨基酸序列且所述第二多肽链可以包含SEQ ID NO:61所示的氨基酸序列；
在某些实施方式中，在本申请所述的二聚体中，所述第一多肽链可以包含SEQ IDNO:62所示的氨基酸序列且所述第二多肽链可以包含SEQ ID NO:63所示的氨基酸序列；
在某些实施方式中，在本申请所述的二聚体中，所述第一多肽链可以包含SEQ IDNO:64所示的氨基酸序列且所述第二多肽链可以包含SEQ ID NO:65所示的氨基酸序列；
在某些实施方式中，在本申请所述的二聚体中，所述第一多肽链可以包含SEQ IDNO:66所示的氨基酸序列且所述第二多肽链可以包含SEQ ID NO:67所示的氨基酸序列。
例如，在所述二聚体中，mIL12b的C端可以和F8VH的N端融合，F8VH的C端可以和F8VL的N端融合形成第二多肽链(其氨基酸序列可以如SEQ ID NO.52所示)，且F8VH的C端可以和F8VL的N端融合，F8VL的C端可以和mIL12a的N端融合，mIL12a的C端可以和mIL2的N端融合，mIL2的C端可以和mGMCSF的N端融合形成第一多肽链(其氨基酸序列可以如SEQ ID NO.53所示)，从而形成mIL12b-F8VH-F8VL-F8VH-F8VL-mIL12a-mIL2-mGMCSF二聚体，用mIL12bscF8-scF8IL12aIL2GMCSF表示。
例如，在所述二聚体中，hIL12b的C端可以和NHS76VH的N端融合，NHS76VH的C端可以和NHS76VL的N端融合形成第二多肽链(其氨基酸序列可以如SEQ ID NO.54所示)，且NHS76VH的C端可以和NHS76VL的N端融合，NHS76VL的C端可以和hIL12a的N端融合，hIL12a的C端可以和hIL2的N端融合，hIL2的C端可以和hGMCSF的N端融合形成第一多肽链(其氨基酸序列可以如SEQ ID NO.55所示)，从而形成hIL12b-NHS76VH-NHS76VL-NHS76VH-NHS76VL-hIL12a-hIL2-hGMCSF二聚体，用hIL12bscNHS76-scNHS76IL12aIL2GMCSF表示。
例如，在所述二聚体中，mIL12a的C端和mIL2的N端可以融合形成mIL12a-mIL2第一多肽链(序列如SEQ ID NO.56所示)，且mIL12b的C端和mGMCSF的N端可以融合形成mIL12b-mGMCSF第二多肽链(序列如SEQ ID NO.57所示)，从而形成mIL12a-mIL2-mIL12b-mGMCSF二聚体，用mIL12aIL2IL12bGMCSF表示。
例如，在所述二聚体中，mIL12a的C端和mIL7的N端可以融合形成mIL12a-mIL7第一多肽链(序列如SEQ ID NO.58所示)，且mIL12b的C端和mGMCSF的N端可以融合形成mIL12b-mGMCSF第二多肽链(序列如SEQ ID NO.59所示)，从而形成mIL12a-mIL7-mIL12b-mGMCSF二聚体，用mIL12aIL7IL12bGMCSF表示。
例如，在所述二聚体中，mIL12a的C端和mIL21的N端可以融合形成mIL12a-mIL21第一多肽链(序列如SEQ ID NO.60所示)，且mIL12b的C端和mGMCSF的N端可以融合形成mIL12b-mGMCSF第二多肽链(序列如SEQ ID NO.61所示)，从而形成mIL12a-mIL21-mIL12b-mGMCSF二聚体，用mIL12aIL21IL12bGMCSF表示。
例如，在所述二聚体中，hIL12a的C端和hIL2的N端可以融合形成hIL12a-hIL2第一多肽链(序列如SEQ ID NO.62所示)，且hIL12b的C端和hGMCSF的N端可以融合形成hIL12b-hGMCSF第二多肽链(序列如SEQ ID NO.63所示)，从而形成hIL12a-hIL2-hIL12b-hGMCSF二聚体，用hIL12aIL2IL12bGMCSF表示。
例如，在所述二聚体中，hIL12a的C端和hIL7的N端可以融合形成hIL12a-hIL7第一多肽链(序列如SEQ ID NO.64所示)，且hIL12b的C端和hGMCSF的N端可以融合形成hIL12b-hGMCSF第二多肽链(序列如SEQ ID NO.65所示)，从而形成hIL12a-hIL7-hIL12b-hGMCSF二聚体，用hIL12aIL7IL12bGMCSF表示。
例如，在所述二聚体中，hIL12a的C端和hIL21的N端可以融合形成hIL12a-hIL21第一多肽链(序列如SEQ ID NO.66所示)，且hIL12b的C端和hGMCSF的N端可以融合形成hIL12b-hGMCSF第二多肽链(序列如SEQ ID NO.67所示)，从而形成hIL12a-hIL21-hIL12b-hGMCSF二聚体，用hIL12aIL21IL12bGMCSF表示。
在本申请中涉及的蛋白质、多肽和/或氨基酸序列，还应理解为至少包含以下的范围：与该所述蛋白质或多肽具备相同或类似功能的变体或同源物。
在本申请中，所述变体可以为，在所述蛋白质和/或所述多肽(例如，所述蛋白质分子)的氨基酸序列中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽。例如，所述功能性变体可包含已经通过至少1个，例如1-30个、1-20个或1-10个，又例如1个、2个、3个、4个或5个氨基酸取代、缺失和/或插入而具有氨基酸改变的蛋白质或多肽。所述功能性变体可基本上保持改变(例如取代、缺失或添加)之前的所述蛋白质或所述多肽的生物学特性。例如，所述功能性变体可保持改变之前的所述蛋白质或所述多肽的至少60％，70％，80％，90％，或100％的生物学活性。
在本申请中，所述同源物可以为，与所述蛋白质和/或所述多肽(例如，所述蛋白质分子)的氨基酸序列具有至少约80％(例如，具有至少约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或更高的)序列同源性的蛋白质或多肽。
在本申请中，所述同源性通常是指两个或多个序列之间的相似性、类似或关联。可以通过以下方式计算“序列同源性百分比”：将两条待比对的序列在比较窗中进行比较，确定两条序列中存在相同核酸碱基(例如，A、T、C、G、I)或相同氨基酸残基(例如，Ala、Pro、Ser、Thr、Gly、Val、Leu、Ile、Phe、Tyr、Trp、Lys、Arg、His、Asp、Glu、Asn、Gln、Cys和Met)的位置的数目以得到匹配位置的数目，将匹配位置的数目除以比较窗中的总位置数(即，窗大小)，并且将结果乘以100，以产生序列同源性百分比。为了确定序列同源性百分数而进行的比对，可以按本领域已知的多种方式实现，例如，使用可公开获得的计算机软件如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以确定用于比对序列的适宜参数，包括为实现正在比较的全长序列范围内或目标序列区域内最大比对所需要的任何算法。所述同源性也可以通过以下的方法测定：FASTA和BLAST。对FASTA算法的描述可以参见W.R.Pearson和D.J.Lipman的“用于生物学序列比较的改进的工具”，美国国家科学院院刊(Proc.Natl.Acad.Sci.)，85：2444-2448，1988；和D.J.Lipman和W.R.Pearson的“快速灵敏的蛋白质相似性搜索”，Science，227：1435-1441，1989。对BLAST算法的描述可参见S.Altschul、W.Gish、W.Miller、E.W.Myers和D.Lipman的“一种基本的局部对比(alignment)搜索工具”，分子生物学杂志，215：403-410，1990。
药物、用途、治疗肿瘤的方法
另一方面，本申请还提供了一种药物，其包含本申请所述的液体制剂。其中所述液体制剂可以被配制为注射剂，以使本申请所述的液体制剂可以用于静脉注射或者皮下注射。
在某些实施方式中，本申请所述药物可以被配制用于口服给药，静脉内给药，肌肉内给药，在肿瘤部位的原位给药，吸入，直肠给药，阴道给药，经皮给药或通过皮下储存库给药。
在本申请中，本申请所述的药物还可以包含稀释剂，其中所述稀释剂与所述液体制剂彼此不混合，以便在需要不同浓度的本申请所述的液体制剂的时候，可以用所述稀释剂对本申请所述液体制剂进行稀释。
在某些实施方式中，本申请所述的药物还可以包含药学上可接受的载体。例如，所述药学上可接受的载体可以包括缓冲剂、抗氧化剂、防腐剂、低分子量多肽、蛋白质、亲水聚合物、氨基酸、糖、螯合剂、反离子、金属复合物和/或非离子表面活性剂等。例如，所述药学上可接受的载体可以包括赋形剂，例如，所述赋形剂可以选自下组：淀粉、糊精、蔗糖、乳糖、硬脂酸镁、硫酸钙、羧甲基素、滑石粉、海藻酸钙凝胶、壳聚糖和纳米微球等。例如，所述药学上可接受的载体还可以选自下组：pH调节剂、渗透压调节剂、增溶剂和抑菌剂。
另一方面，本申请还提供了本申请所述的液体制剂在制备治疗肿瘤的药物中的用途。其中所述肿瘤可以包括肺癌。
另一方面，本申请还提供了一种治疗肿瘤的方法，其包括向有需要的受试者施用本申请所述的液体制剂。
其中所述施用方法可以为瘤内注射，例如向肿瘤内部注射本申请所述的液体制剂。在某些实施方式中，所述施用方法也可以为口服给药，静脉内给药，肌肉内给药，在肿瘤部位的原位给药，吸入，直肠给药，阴道给药，经皮给药或通过皮下储存库给药。
此外，在某些实施方式中，所施用的本申请所述液体制剂的剂量水平可以视以下情况而变化：被递送的分子、给药途径和患者的大小(体重、体表面或器官大小)和/或身体状况(年龄及一般健康状况)。
另一方面，本申请提供了一种液体制剂或药物，其用于治疗肿瘤。其中所述肿瘤可以包括肺癌。
另一方面，本申请还提供了一种用于制备本申请所述的液体制剂的辅料，其包含油相溶剂，所述油相溶剂的质量分数为约50％以上，例如，所述辅料中的油相溶剂的质量分数可以为约50％-约60％、约60％-约70％、约70％-约80％、约80％-约90％、约90％-约95％、约50％-约70％、约50％-约80％、约50％-约90％、约50％-约95％、约60％-约80％、约60％-约90％、约60％-约95％、约70％-约90％、约70％-约95％、或约80％-约95％，以便本申请所述的液体制剂能够易于制备。
实施例
给出下述实施例仅仅是为了阐释本申请的液体制剂、药物和用途等，而不用于限制本申请发明的范围，也不意欲表示下述试验是进行的全部和唯一的试验。已经进行了努力以确保所用数值(例如数量、温度等)的准确性，但是应当考虑到某些实验误差和偏差。除非另有说明，否则份数为重量份，分子量为重均分子量，温度为摄氏温度，压力为常压或接近常压。可以使用标准缩写词，例如bp，碱基对；kb，千碱基对；pl，微微升；s或sec，秒；min，分钟；h或hr，小时；aa，氨基酸；nt，核苷酸；iv，静脉注射；i.m.，肌内；i.p.，腹膜内；s.c.，皮下等。
试剂：DMEM培养基、1640培养基、胎牛血清购自lifetechnologies公司；细胞培养瓶、培养板购自Corning公司；强力霉素(DOX)购自上海生工生物工程有限公司；嘌呤霉素(Puromycin)、Blasticidin购自Chemicon公司；限制性内切酶购自Takara和NEB公司；连接酶购自NEB公司；DNA聚合酶购自Takara公司；质粒提取试剂盒、胶回收试剂盒购自OmegaBiotech公司；引物合成由上海生工生物工程有限公司完成；基因合成由南京金斯瑞公司完成；ELISA试剂盒购于博士德公司。
实施例1 mIL12bIL12aIL2GMCSF蛋白质的表达
1.1构建表达载体
mIL12bIL12aIL2GMCSF蛋白质，其前端带有分泌信号肽，后端加入6*His以便纯化，合成mIL12bIL12aIL2GMCSF蛋白质基因对应的DNA序列，序列中在BamHI或XhoI位点处用简并密码子突变掉，合成序列的前后端分别带有BamHI和XhoI酶切位点，酶切合成的带有目的基因的质粒，体系如下：5μg质粒、4μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积40μl，37℃静置12小时。取出EP管，加入4.4μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收mIL12bIL12aIL2GMCSF蛋白质基因片段，待用。
mIL12bIL12aIL2GMCSF蛋白质的氨基酸序列如SEQ ID NO.32所示，编码所述mIL12bIL12aIL2GMCSF的核苷酸序列如SEQ ID NO.68所示。
在EP管内酶切载体pLentis-CMV-MCS-IRES-PURO，体系如下：2μg pLentis-CMV-MCS-IRES-PURO载体质粒、3μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积30μl，37℃静置12小时。取出EP管，加入3.3μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收pLentis-CMV-MCS-IRES-PURO载体片段，待用。
连接mIL12bIL12aIL2GMCSF和pLentis-CMV-MCS-IRES-PURO，体系如下，2μlpLentis-CMV-MCS-IRES-PURO载体片段、2μl基因片段、1μl连接酶缓冲液、0.5μl T4DNA连接酶和水4.5μl。置于室温连接4小时。然后将连接体系进行大肠杆菌感受态的转化。第二天从转化的平板上挑取菌落，置于LB培养基中37度摇床内过夜培养，使用质粒提取试剂盒从培养的细菌中提取质粒，通过酶切鉴定基因片段是否成功连入载体中，然后将正确的载体测序，确定构建成功。获得表达载体pLentis-CMV-mIL12bIL12aIL2GMCSF-IRES-PURO。
1.2制备表达病毒
1)消化培养的293FT细胞，计数后将3×106个细胞/孔铺入10cm培养皿中，培养液体积为10ml。
2)第二天晚上，观察细胞状态，如果细胞状态好，进行转染。在培养板中加入氯喹至终浓度25μM，取一只试管，加入灭菌水及以下质粒(pMD2.G 6μg+pSPAX2 15μg+上述1.1实施例获得的表达载体20μg)，总体积为1045μl，然后加入2M CaCl2 155μl，混匀，最后再加入1200μl 2×HBS，边滴加边振荡，滴加完毕后，迅速将混合物加入到细胞培养孔中，轻轻摇晃混匀。
3)第三天早上，观察细胞状态，将培养基换为10ml新鲜DMEM培养基。
4)第五天早上，观察细胞状态，并收集培养皿中的上清，用0.45μm滤器过滤，然后置于高速离心管中，50000g离心2小时，小心弃去上清，尽量用吸水纸吸干液体，然后用200μl HBSS重悬沉淀，溶解2小时后分装成小管，-70℃保存。
1.3制备表达细胞
消化培养的293A细胞，按105个细胞/孔接种到6孔板中，培养体积为1ml。24小时后，加入10μl表达上述目的基因的病毒(即实施例1.2获得的病毒)，在培养箱内继续培养24小时后，弃去上清，换为新鲜的培养基继续培养。待细胞长满后，将其传出到培养瓶中，加入终浓度3μg/ml嘌呤霉素，继续培养，每两天更换一次培养基，并保持嘌呤霉素的浓度，筛选一周后，存活的细胞即为稳定表达所述蛋白的细胞，命名为293A-mIL12bIL12aIL2GMCSF。
1.4蛋白表达纯化
将构建的表达mIL12bIL12aIL2GMCSF的细胞293A-mIL12bIL12aIL2GMCSF，传代到15cm培养皿中，待细胞长满后，将培养基换为30ml CDM4HEK293，继续培养5天，然后收集上清，0.45μm滤器过滤，再用50kd的AMICON ULTRA-15超滤浓缩，获得的浓缩蛋白液用镍螯合磁珠(购于海狸生物科技有限公司)进行纯化，操作流程按说明书进行，获得的纯化蛋白液再用AMICON ULTRA-0.5超滤管进行超滤，将缓冲液置换为PBS，最后获得的蛋白液用IL12p70ELISA试剂盒检测蛋白浓度，将蛋白浓度用PBS调整到2μg/μl后，分装后于-20℃保存。
实施例2 蛋白质分子mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr的表达
2.1构建表达载体
mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr蛋白质，其前端带有分泌信号肽，后端加入6*His以便纯化，合成基因对应的DNA序列，序列中有BamHI或XhoI位点处用简并密码子突变掉，合成序列前后端分别带有BamHI和XhoI酶切位点，酶切合成的带有目的基因的质粒，体系如下：5μg质粒、4μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积40μl，37℃静置12小时。取出EP管，加入4.4μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr蛋白质基因片段，待用。需要说明的是，mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr蛋白质的连接子中含有凝血酶切割位点。
mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr蛋白质的氨基酸序列如SEQ ID NO.48所示，编码所述mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr的核苷酸序列如SEQ ID NO.69所示
在EP管内酶切载体pLentis-CMV-MCS-IRES-PURO，体系如下：2μg pLentis-CMV-MCS-IRES-PURO载体质粒、3μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积30μl，37℃静置12小时。取出EP管，加入3.3μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收pLentis-CMV-MCS-IRES-PURO载体片段，待用。
连接mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr和pLentis-CMV-MCS-IRES-PURO，体系如下，2μl pLentis-CMV-MCS-IRES-PURO载体片段、2μl基因片段、1μl连接酶缓冲液、0.5μlT4DNA连接酶和水4.5μl。置于室温连接4小时。然后将连接体系进行大肠杆菌感受态的转化。第二天从转化的平板上挑取菌落，置于LB培养基中37度摇床内过夜培养，使用质粒提取试剂盒从培养的细菌中提取质粒，通过酶切鉴定片段是否成功连入载体中，然后将正确的载体测序，确定构建成功。获得表达载体pLentis-CMV-mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr-IRES-PURO。
2.2制备表达病毒
1)消化培养的293FT细胞，计数后将3×106个细胞/孔铺入10cm培养皿中，培养液体积为10ml。
2)第二天晚上，观察细胞状态，如果细胞状态好，进行转染。在培养板中加入氯喹至终浓度25μM，取一只试管，加入灭菌水及以下质粒(pMD2.G 6μg+pSPAX2 15μg+实施例2.1获得的表达载体20μg)，总体积为1045μl，然后加入2M CaCl2 155μl，混匀，最后再加入1200μl 2×HBS，边滴加边振荡，滴加完毕后，迅速将混合物加入到细胞培养孔中，轻轻摇晃混匀。
3)第三天早上，观察细胞状态，将培养基换为10ml新鲜DMEM培养基。
4)第五天早上，观察细胞状态，并收集培养皿中的上清，用0.45μm滤器过滤，然后置于高速离心管中，50000g离心2小时，小心弃去上清，尽量用吸水纸吸干液体，然后用200μl HBSS重悬沉淀，溶解2小时后分装成小管，-70℃保存。
2.3制备表达细胞
消化培养的293A细胞，按105个细胞/孔接种到6孔板中，培养体积为1ml。24小时后，加入10μl表达上述目的基因的病毒(即实施例2.2获得的病毒)，在培养箱内继续培养24小时后，弃去上清，换为新鲜的培养基继续培养。待细胞长满后，将其传出到培养瓶中，加入终浓度3μg/ml嘌呤霉素，继续培养，每两天更换一次培养基，并保持嘌呤霉素的浓度，筛选一周后，存活的细胞即为稳定表达所述蛋白的细胞，命名为293A-mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr。
2.4蛋白表达纯化
将构建的表达mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr的细胞293A-mIL12bIL12aIL2Di aNHS76F8GMCSF-Thr，传代到15cm培养皿中，待细胞长满后，将培养基换为30ml CDM4HEK293，继续培养5天，然后收集上清，0.45μm滤器过滤，再用50kd的AMICONULTRA-15超滤浓缩，获得的浓缩蛋白液用镍螯合磁珠(购于海狸生物科技有限公司)进行纯化，操作流程按说明书进行，获得的纯化蛋白液再用AMICON ULTRA-0.5超滤管进行超滤，将缓冲液置换为PBS，最后获得的蛋白液用IL12p70ELISA试剂盒检测蛋白浓度，将蛋白浓度用PBS调整到2μg/μl后，分装后于-20℃保存。
实施例3 mIL12bIL12aIL7GMCSF蛋白质的表达
3.1构建表达载体
mIL12bIL12aIL7GMCSF蛋白质，其前端带有分泌信号肽，后端加入6*His以便纯化，合成mIL12bIL12aIL7GMCSF蛋白质基因对应的DNA序列，序列中在BamHI或XhoI位点处用简并密码子突变掉，合成序列的前后端分别带有BamHI和XhoI酶切位点，酶切合成的带有目的基因的质粒，体系如下：5μg质粒、4μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积40μl，37℃静置12小时。取出EP管，加入4.4μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收mIL12bIL12aIL7GMCSF蛋白质基因片段，待用。
mIL12bIL12aIL7GMCSF蛋白质的氨基酸序列如SEQ ID NO.33所示，编码所述mIL12bIL12aIL7GMCSF的核苷酸序列如SEQ ID NO.70所示。
在EP管内酶切载体pLentis-CMV-MCS-IRES-PURO，体系如下：2μg pLentis-CMV-MCS-IRES-PURO载体质粒、3μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积30μl，37℃静置12小时。取出EP管，加入3.3μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收pLentis-CMV-MCS-IRES-PURO载体片段，待用。
连接mIL12bIL12aIL7GMCSF和pLentis-CMV-MCS-IRES-PURO，体系如下，2μlpLentis-CMV-MCS-IRES-PURO载体片段、2μl基因片段、1μl连接酶缓冲液、0.5μl T4DNA连接酶和水4.5μl。置于室温连接4小时。然后将连接体系进行大肠杆菌感受态的转化。第二天从转化的平板上挑取菌落，置于LB培养基中37度摇床内过夜培养，使用质粒提取试剂盒从培养的细菌中提取质粒，通过酶切鉴定基因片段是否成功连入载体中，然后将正确的载体测序，确定构建成功。获得表达载体pLentis-CMV-mIL12bIL12aIL7GMCSF-IRES-PURO。
3.2制备表达病毒
1)消化培养的293FT细胞，计数后将3×106个细胞/孔铺入10cm培养皿中，培养液体积为10ml。
2)第二天晚上，观察细胞状态，如果细胞状态好，进行转染。在培养板中加入氯喹至终浓度25μM，取一只试管，加入灭菌水及以下质粒(pMD2.G 6μg+pSPAX2 15μg+上述3.1实施例获得的表达载体20μg)，总体积为1045μl，然后加入2M CaCl2 155μl，混匀，最后再加入1200μl 2×HBS，边滴加边振荡，滴加完毕后，迅速将混合物加入到细胞培养孔中，轻轻摇晃混匀。
3)第三天早上，观察细胞状态，将培养基换为10ml新鲜DMEM培养基。
4)第五天早上，观察细胞状态，并收集培养皿中的上清，用0.45μm滤器过滤，然后置于高速离心管中，50000g离心2小时，小心弃去上清，尽量用吸水纸吸干液体，然后用200μl HBSS重悬沉淀，溶解2小时后分装成小管，-70℃保存。
3.3制备表达细胞
消化培养的293A细胞，按105个细胞/孔接种到6孔板中，培养体积为1ml。24小时后，加入10μl表达上述目的基因的病毒(即实施例3.2获得的病毒)，在培养箱内继续培养24小时后，弃去上清，换为新鲜的培养基继续培养。待细胞长满后，将其传出到培养瓶中，加入终浓度3μg/ml嘌呤霉素，继续培养，每两天更换一次培养基，并保持嘌呤霉素的浓度，筛选一周后，存活的细胞即为稳定表达所述蛋白的细胞，命名为293A-mIL12bIL12aIL7GMCSF。
3.4蛋白表达纯化
将构建的表达mIL12bIL12aIL7GMCSF的细胞293A-mIL12bIL12aIL7GMCSF，传代到15cm培养皿中，待细胞长满后，将培养基换为30ml CDM4HEK293，继续培养5天，然后收集上清，0.45μm滤器过滤，再用50kd的AMICON ULTRA-15超滤浓缩，获得的浓缩蛋白液用镍螯合磁珠(购于海狸生物科技有限公司)进行纯化，操作流程按说明书进行，获得的纯化蛋白液再用AMICON ULTRA-0.5超滤管进行超滤，将缓冲液置换为PBS，最后获得的蛋白液用IL12p70ELISA试剂盒检测蛋白浓度，将蛋白浓度用PBS调整到2μg/μl后，分装后于-20℃保存。
实施例4 mIL12bIL12aIL21GMCSF蛋白质的表达
4.1构建表达载体
mIL12bIL12aIL21GMCSF蛋白质，其前端带有分泌信号肽，后端加入6*His以便纯化，合成mIL12bIL12aIL21GMCSF蛋白质基因对应的DNA序列，序列中在BamHI或XhoI位点处用简并密码子突变掉，合成序列的前后端分别带有BamHI和XhoI酶切位点，酶切合成的带有目的基因的质粒，体系如下：5μg质粒、4μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积40μl，37℃静置12小时。取出EP管，加入4.4μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收mIL12bIL12aIL21GMCSF蛋白质基因片段，待用。
mIL12bIL12aIL21GMCSF蛋白质的氨基酸序列如SEQ ID NO.35所示，编码所述mIL12bIL12aIL21GMCSF的核苷酸序列如SEQ ID NO.71所示。
在EP管内酶切载体pLentis-CMV-MCS-IRES-PURO，体系如下：2μg pLentis-CMV-MCS-IRES-PURO载体质粒、3μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积30μl，37℃静置12小时。取出EP管，加入3.3μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收pLentis-CMV-MCS-IRES-PURO载体片段，待用。
连接mIL12bIL12aIL21GMCSF和pLentis-CMV-MCS-IRES-PURO，体系如下，2μlpLentis-CMV-MCS-IRES-PURO载体片段、2μl基因片段、1μl连接酶缓冲液、0.5μl T4DNA连接酶和水4.5μl。置于室温连接4小时。然后将连接体系进行大肠杆菌感受态的转化。第二天从转化的平板上挑取菌落，置于LB培养基中37度摇床内过夜培养，使用质粒提取试剂盒从培养的细菌中提取质粒，通过酶切鉴定基因片段是否成功连入载体中，然后将正确的载体测序，确定构建成功。获得表达载体pLentis-CMV-mIL12bIL12aIL21GMCSF-IRES-PURO。
4.2制备表达病毒
1)消化培养的293FT细胞，计数后将3×106个细胞/孔铺入10cm培养皿中，培养液体积为10ml。
2)第二天晚上，观察细胞状态，如果细胞状态好，进行转染。在培养板中加入氯喹至终浓度25μM，取一只试管，加入灭菌水及以下质粒(pMD2.G 6μg+pSPAX2 15μg+上述4.1实施例获得的表达载体20μg)，总体积为1045μl，然后加入2M CaCl2 155μl，混匀，最后再加入1200μl 2×HBS，边滴加边振荡，滴加完毕后，迅速将混合物加入到细胞培养孔中，轻轻摇晃混匀。
3)第三天早上，观察细胞状态，将培养基换为10ml新鲜DMEM培养基。
4)第五天早上，观察细胞状态，并收集培养皿中的上清，用0.45μm滤器过滤，然后置于高速离心管中，50000g离心2小时，小心弃去上清，尽量用吸水纸吸干液体，然后用200μl HBSS重悬沉淀，溶解2小时后分装成小管，-70℃保存。
4.3制备表达细胞
消化培养的293A细胞，按105个细胞/孔接种到6孔板中，培养体积为1ml。24小时后，加入10μl表达上述目的基因的病毒(即实施例4.2获得的病毒)，在培养箱内继续培养24小时后，弃去上清，换为新鲜的培养基继续培养。待细胞长满后，将其传出到培养瓶中，加入终浓度3μg/ml嘌呤霉素，继续培养，每两天更换一次培养基，并保持嘌呤霉素的浓度，筛选一周后，存活的细胞即为稳定表达所述蛋白的细胞，命名为293A-mIL12bIL12aIL21GMCSF。
4.4蛋白表达纯化
将构建的表达mIL12bIL12aIL21GMCSF的细胞293A-mIL12bIL12aIL21GMCSF，传代到15cm培养皿中，待细胞长满后，将培养基换为30ml CDM4HEK293，继续培养5天，然后收集上清，0.45μm滤器过滤，再用50kd的AMICON ULTRA-15超滤浓缩，获得的浓缩蛋白液用镍螯合磁珠(购于海狸生物科技有限公司)进行纯化，操作流程按说明书进行，获得的纯化蛋白液再用AMICON ULTRA-0.5超滤管进行超滤，将缓冲液置换为PBS，最后获得的蛋白液用IL12p70ELISA试剂盒检测蛋白浓度，将蛋白浓度用PBS调整到2μg/μl后，分装后于-20℃保存。
实施例5 mIL12aIL2IL12bGMCSF蛋白质的表达
5.1构建表达载体
mIL12aIL2IL12bGMCSF蛋白是由mIL12aIL2和mIL12bGMCSF组成的异二聚体，其中mIL12aIL2后端加入6*His以便纯化，合成mIL12aIL2IL12bGMCSF蛋白质基因对应的DNA序列，两段肽链中间加入T2A切割肽使其翻译后形成异二聚体，序列中在BamHI或XhoI位点处用简并密码子突变掉，合成序列的前后端分别带有BamHI和XhoI酶切位点，酶切合成的带有目的基因的质粒，体系如下：5μg质粒、4μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积40μl，37℃静置12小时。取出EP管，加入4.4μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收mIL12aIL2IL12bGMCSF蛋白质基因片段，待用。
mIL12aIL2IL12bGMCSF蛋白质的第二多肽链氨基酸序列如SEQ ID NO.57所示，第一多肽链氨基酸序列如SEQ ID NO.56所示，编码所述mIL12aIL2IL12bGMCSF的核苷酸序列如SEQ ID NO.72所示。
在EP管内酶切载体pLentis-CMV-MCS-IRES-PURO，体系如下：2μg pLentis-CMV-MCS-IRES-PURO载体质粒、3μl酶切缓冲液、1μl BamHI和1μl XhoI，加水至总体积30μl，37℃静置12小时。取出EP管，加入3.3μl 10×上样缓冲液，用1％琼脂糖凝胶进行电泳，电泳后回收pLentis-CMV-MCS-IRES-PURO载体片段，待用。
连接mIL12aIL2IL12bGMCSF和pLentis-CMV-MCS-IRES-PURO，体系如下，2μlpLentis-CMV-MCS-IRES-PURO载体片段、2μl基因片段、1μl连接酶缓冲液、0.5μl T4DNA连接酶和水4.5μl。置于室温连接4小时。然后将连接体系进行大肠杆菌感受态的转化。第二天从转化的平板上挑取菌落，置于LB培养基中37度摇床内过夜培养，使用质粒提取试剂盒从培养的细菌中提取质粒，通过酶切鉴定基因片段是否成功连入载体中，然后将正确的载体测序，确定构建成功。获得表达载体pLentis-CMV-mIL12aIL2IL12bGMCSF-IRES-PURO。
5.2制备表达病毒
1)消化培养的293FT细胞，计数后将3×106个细胞/孔铺入10cm培养皿中，培养液体积为10ml。
2)第二天晚上，观察细胞状态，如果细胞状态好，进行转染。在培养板中加入氯喹至终浓度25μM，取一只试管，加入灭菌水及以下质粒(pMD2.G 6μg+pSPAX2 15μg+上述5.1实施例获得的表达载体20μg)，总体积为1045μl，然后加入2M CaCl2 155μl，混匀，最后再加入1200μl 2×HBS，边滴加边振荡，滴加完毕后，迅速将混合物加入到细胞培养孔中，轻轻摇晃混匀。
3)第三天早上，观察细胞状态，将培养基换为10ml新鲜DMEM培养基。
4)第五天早上，观察细胞状态，并收集培养皿中的上清，用0.45μm滤器过滤，然后置于高速离心管中，50000g离心2小时，小心弃去上清，尽量用吸水纸吸干液体，然后用200μl HBSS重悬沉淀，溶解2小时后分装成小管，-70℃保存。
5.3制备表达细胞
消化培养的293A细胞，按105个细胞/孔接种到6孔板中，培养体积为1ml。24小时后，加入10μl表达上述目的基因的病毒(即实施例5.2获得的病毒)，在培养箱内继续培养24小时后，弃去上清，换为新鲜的培养基继续培养。待细胞长满后，将其传出到培养瓶中，加入终浓度3μg/ml嘌呤霉素，继续培养，每两天更换一次培养基，并保持嘌呤霉素的浓度，筛选一周后，存活的细胞即为稳定表达所述蛋白的细胞，命名为293A-mIL12aIL2IL12bGMCSF。
5.4蛋白表达纯化
将构建的表达mIL12aIL2IL12bGMCSF的细胞293A-mIL12aIL2IL12bGMCSF，传代到15cm培养皿中，待细胞长满后，将培养基换为30ml CDM4HEK293，继续培养5天，然后收集上清，0.45μm滤器过滤，再用50kd的AMICON ULTRA-15超滤浓缩，获得的浓缩蛋白液用镍螯合磁珠(购于海狸生物科技有限公司)进行纯化，操作流程按说明书进行，获得的纯化蛋白液再用AMICON ULTRA-0.5超滤管进行超滤，将缓冲液置换为PBS，最后获得的蛋白液用IL12p70ELISA试剂盒检测蛋白浓度，将蛋白浓度用PBS调整到0.2μg/μl后，分装后于-20℃保存。
实施例6 甘油注射液对小鼠肿瘤生长的影响
将5×105个消化培养的小鼠肺癌细胞(LLC)注射到C57BL/6小鼠身体右侧皮下，待肿瘤的长径达到7-10mm时开始进行治疗。用PBS分别配制50％，60％和70％浓度的甘油溶液，使用29G的胰岛素注射器吸取配制的甘油溶液，缓慢注射到肿瘤内，注射体积为150μl，注射完后将针头滞留少许时间以减少溶液的溢出。注射后的小鼠放回笼内，记录小鼠的存活情况，只注射PBS的小鼠作为对照。结果如图1所示，50％浓度的甘油溶液注射后，小鼠存活率为12.5％，60％和70％浓度的甘油溶液注射后，小鼠存活率为25％，说明甘油溶液有一定的抗肿瘤效果。
实施例7 mIL12bIL12aIL2GMCSF注射液对小鼠肿瘤生长的影响
将5×105个消化培养的小鼠肺癌细胞(LLC)注射到C57BL/6小鼠身体右侧皮下，待肿瘤的长径达到7-10mm时开始进行治疗。
用实施例1制备的蛋白溶液配制一系列不同甘油质量百分数的本申请液体制剂(即mIL12bIL12aIL2GMCSF甘油注射液)。具体方法为：取实施例1制备的蛋白溶液50μl，然后加入到50μl甘油中，迅速用枪头吹打混匀，避免产生气泡，得到50％甘油浓度的液体制剂，蛋白溶液50ul加入到75ul甘油中，得到60％甘油浓度的液体制剂，蛋白溶液50ul加入到117ul甘油中，得到70％甘油浓度的液体制剂。对照组的对比例制剂的制备方法为：取实施例1制备的蛋白溶液50μl，然后加入到117μl PBS中，迅速用枪头吹打混匀，避免产生气泡，得到制备的对比例制剂1。使用29G的胰岛素注射器吸取配制的本申请的液体制剂或对比例制剂1，缓慢注射到肿瘤内，注射完后将针头滞留少许时间以减少溶液的溢出。注射后的小鼠放回笼内，记录小鼠的存活情况。结果如图2所示，图中PBS表示对照组，可以看出，本申请的液体制剂(即mIL12bIL12aIL2GMCSF甘油注射液)注射后，小鼠全部存活，表明甘油溶液和蛋白质分子产生了协同作用，从而共同抑制肿瘤的生长。
实施例8 mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr注射液对小鼠肿瘤生长的影响
将5×105个消化培养的小鼠肺癌细胞(LLC)注射到C57BL/6小鼠身体右侧皮下，待肿瘤的长径达到7-10mm时开始进行治疗。
用实施例2制备的蛋白溶液配制一系列不同甘油质量百分数的本申请液体制剂(即mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr甘油注射液)。具体方法为：取实施例2制备的蛋白溶液50μl，然后加入到50μl甘油中，迅速用枪头吹打混匀，避免产生气泡，得到50％甘油浓度的液体制剂，蛋白溶液50ul加入到75ul甘油中，得到60％甘油浓度的液体制剂，蛋白溶液50ul加入到117ul甘油中，得到70％甘油浓度的液体制剂。对照组的对比例制剂的制备方法为：取实施例2制备的蛋白溶液50μl，然后加入到117μl PBS中，迅速用枪头吹打混匀，避免产生气泡，得到制备的对比例制剂2。使用29G的胰岛素注射器吸取配制的本申请的液体制剂(即mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr甘油注射液)或对比例制剂2，缓慢注射到肿瘤内，注射完后将针头滞留少许时间以减少溶液的溢出。注射后的小鼠放回笼内，记录小鼠的存活情况。结果如图3所示，图中PBS表示对照组，可以看出，本申请的液体制剂mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr甘油注射液注射后，小鼠全部存活，表明甘油溶液和蛋白质分子产生了协同作用，从而共同抑制肿瘤的生长。
实施例9 mIL12bIL12aIL7GMCSF注射液对小鼠肿瘤生长的影响
将5×105个消化培养的小鼠肺癌细胞(LLC)注射到C57BL/6小鼠身体右侧皮下，待肿瘤的长径达到7-10mm时开始进行治疗。
取实施例3制备的蛋白溶液50μl，然后加入到80μl甘油中，迅速用枪头吹打混匀，避免产生气泡，得到制备的本申请的液体制剂。对照组的对比例制剂的制备方法为：取实施例3制备的蛋白溶液50μl，然后加入到80μl PBS中，迅速用枪头吹打混匀，避免产生气泡，得到制备的对比例制剂3。使用29G的胰岛素注射器吸取配制的本申请的液体制剂或对比例制剂3，缓慢注射到肿瘤内，注射完后将针头滞留少许时间以减少溶液的溢出。注射后的小鼠放回笼内，记录小鼠的存活情况。结果如图4所示，图中PBS表示对照组，可以看出，本申请的液体制剂(即mIL12bIL12aIL7GMCSF甘油注射液)注射后，小鼠全部存活，表明甘油溶液和蛋白质分子产生了协同作用，从而共同抑制肿瘤的生长。
实施例10 mIL12bIL12aIL21GMCSF注射液对小鼠肿瘤生长的影响
将5×105个消化培养的小鼠肺癌细胞(LLC)注射到C57BL/6小鼠身体右侧皮下，待肿瘤的长径达到7-10mm时开始进行治疗。
取实施例4制备的蛋白溶液50μl，然后加入到80μl甘油中，迅速用枪头吹打混匀，避免产生气泡，得到制备的本申请的液体制剂。对照组的对比例制剂的制备方法为：取实施例4制备的蛋白溶液50μl，然后加入到80μl PBS中，迅速用枪头吹打混匀，避免产生气泡，得到制备的对比例制剂4。使用29G的胰岛素注射器吸取配制的本申请的液体制剂或对比例制剂4，缓慢注射到肿瘤内，注射完后将针头滞留少许时间以减少溶液的溢出。注射后的小鼠放回笼内，记录小鼠的存活情况。结果如图5所示，图中PBS表示对照组，可以看出，本申请的液体制剂(即mIL12bIL12aIL21GMCSF甘油注射液)注射后，小鼠全部存活，表明甘油溶液和蛋白质分子产生了协同作用，从而共同抑制肿瘤的生长。
实施例11 mIL12aIL2IL12bGMCSF注射液对小鼠肿瘤生长的影响
将5×105个消化培养的小鼠肺癌细胞(LLC)注射到C57BL/6小鼠身体右侧皮下，待肿瘤的长径达到7-10mm时开始进行治疗。
取实施例5制备的蛋白溶液50μl，然后加入到80μl甘油中，迅速用枪头吹打混匀，避免产生气泡，得到制备的本申请的液体制剂。对照组的对比例制剂的制备方法为：取实施例5制备的蛋白溶液50μl，然后加入到80μl PBS中，迅速用枪头吹打混匀，避免产生气泡，得到制备的对比例制剂5。使用29G的胰岛素注射器吸取配制的本申请的液体制剂或对比例制剂5，缓慢注射到肿瘤内，注射完后将针头滞留少许时间以减少溶液的溢出。注射后的小鼠放回笼内，记录小鼠的存活情况。结果如图6所示，图中PBS表示对照组，可以看出，本申请的液体制剂(即mIL12aIL2IL12bGMCSF甘油注射液)注射后，小鼠全部存活，表明甘油溶液和蛋白质分子产生了协同作用，从而共同抑制肿瘤的生长。
前述详细说明是以解释和举例的方式提供的，并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的，且保留在所附的权利要求和其等同方案的范围内。
序列表
<110> 张晋宇
<120> 一种液体制剂及其应用
<130> 0069-PA-007
<160> 76
<170> PatentIn version 3.5
<210> 1
<211> 469
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> DiaL19
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Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
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Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
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Thr Val Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly
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Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
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Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro
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Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser Ser Arg Ala Thr
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Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
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Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
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Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe Gly Gln Gly Thr Lys Val
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Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser
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Ser Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
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Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
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Ser Phe Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
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Trp Val Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp
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Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
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Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
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Tyr Cys Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
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Leu Val Thr Val Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser
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Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
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Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp Tyr Gln Gln
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Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser Ser Arg
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Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
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Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe Gly Gln Gly Thr
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Lys Val Glu Ile Lys
465
<210> 2
<211> 477
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> DiaF8
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Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Phe
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Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
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Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly Glu Ile Val Leu Thr
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Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
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Ser Cys Arg Ala Ser Gln Ser Val Ser Met Pro Phe Leu Ala Trp Tyr
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Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser
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Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
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Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
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Val Tyr Tyr Cys Gln Gln Met Arg Gly Arg Pro Pro Thr Phe Gly Gln
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Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser
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Gly Ser Ser Ser Ser Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
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Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
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Phe Thr Phe Ser Leu Phe Thr Met Ser Trp Val Arg Gln Ala Pro Gly
275 280 285
Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr
290 295 300
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
305 310 315 320
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Ala Lys Ser Thr His Leu Tyr Leu Phe Asp
340 345 350
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly
355 360 365
Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro
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Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Met
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Pro Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
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Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe
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Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu
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Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
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<210> 3
<211> 475
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> DiaNHS76
<400> 3
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly
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Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
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Ile Gly Ser Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
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Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Lys Trp Ser Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Ser Gly Gly Ser Ser Glu Leu Thr Gln
115 120 125
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
130 135 140
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
145 150 155 160
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
165 170 175
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Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
195 200 205
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
210 215 220
Thr Lys Leu Thr Val Leu Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly
225 230 235 240
Ser Ser Ser Ser Gly Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
245 250 255
Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr
260 265 270
Ser Ile Ser Ser Gly Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly
275 280 285
Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr His Ser Gly Ser Thr Tyr
290 295 300
Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser
305 310 315 320
Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr
325 330 335
Ala Val Tyr Tyr Cys Ala Arg Gly Lys Trp Ser Lys Phe Asp Tyr Trp
340 345 350
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly Ser
355 360 365
Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr
370 375 380
Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser
385 390 395 400
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly
405 410 415
Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser
420 425 430
Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp
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Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val
450 455 460
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
465 470 475
<210> 4
<211> 476
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> DiaNHS76F8
<400> 4
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly
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Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Ser Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Lys Trp Ser Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln
115 120 125
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser
130 135 140
Cys Arg Ala Ser Gln Ser Val Ser Met Pro Phe Leu Ala Trp Tyr Gln
145 150 155 160
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser
165 170 175
Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
180 185 190
Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val
195 200 205
Tyr Tyr Cys Gln Gln Met Arg Gly Arg Pro Pro Thr Phe Gly Gln Gly
210 215 220
Thr Lys Val Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly
225 230 235 240
Ser Ser Ser Ser Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Ser Leu Phe Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr
290 295 300
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
305 310 315 320
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
325 330 335
Ala Val Tyr Tyr Cys Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr
340 345 350
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly
355 360 365
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
370 375 380
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
385 390 395 400
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
405 410 415
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
420 425 430
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
435 440 445
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
450 455 460
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
465 470 475
<210> 5
<211> 472
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> DiaNHS76L19
<400> 5
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Ser Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Lys Trp Ser Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln
115 120 125
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser
130 135 140
Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp Tyr Gln
145 150 155 160
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser Ser
165 170 175
Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
180 185 190
Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val
195 200 205
Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe Gly Gln Gly
210 215 220
Thr Lys Val Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly
225 230 235 240
Ser Ser Ser Ser Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Ser Ser Phe Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr
290 295 300
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
305 310 315 320
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
325 330 335
Ala Val Tyr Tyr Cys Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly
340 345 350
Gln Gly Thr Leu Val Thr Val Gly Gly Ser Gly Gly Ser Ser Glu Leu
355 360 365
Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile
370 375 380
Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln
385 390 395 400
Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn
405 410 415
Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn
420 425 430
Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp
435 440 445
Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly
450 455 460
Gly Gly Thr Lys Leu Thr Val Leu
465 470
<210> 6
<211> 476
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> DiaF8NHS76
<400> 6
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Phe
20 25 30
Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly Ser Ser Glu Leu Thr
115 120 125
Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr
130 135 140
Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln
145 150 155 160
Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg
165 170 175
Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr
180 185 190
Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr
195 200 205
Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly
210 215 220
Gly Thr Lys Leu Thr Val Leu Ser Ser Ser Ser Gly Ser Ser Ser Ser
225 230 235 240
Gly Ser Ser Ser Ser Gly Gln Val Gln Leu Gln Glu Ser Gly Pro Gly
245 250 255
Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly
260 265 270
Tyr Ser Ile Ser Ser Gly Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro
275 280 285
Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr His Ser Gly Ser Thr
290 295 300
Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr
305 310 315 320
Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Ala Arg Gly Lys Trp Ser Lys Phe Asp Tyr
340 345 350
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly
355 360 365
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
370 375 380
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Met Pro
385 390 395 400
Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
405 410 415
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
420 425 430
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
435 440 445
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Met Arg Gly Arg Pro
450 455 460
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
465 470 475
<210> 7
<211> 473
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> DiaF8L19
<400> 7
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Phe
20 25 30
Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly Glu Ile Val Leu Thr
115 120 125
Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
130 135 140
Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp Tyr
145 150 155 160
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser
165 170 175
Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
180 185 190
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
195 200 205
Val Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe Gly Gln
210 215 220
Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser
225 230 235 240
Gly Ser Ser Ser Ser Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Phe Thr Phe Ser Ser Phe Ser Met Ser Trp Val Arg Gln Ala Pro Gly
275 280 285
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr
290 295 300
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
305 310 315 320
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp
340 345 350
Gly Gln Gly Thr Leu Val Thr Val Gly Gly Ser Gly Gly Glu Ile Val
355 360 365
Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
370 375 380
Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Met Pro Phe Leu Ala
385 390 395 400
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly
405 410 415
Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly
420 425 430
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp
435 440 445
Phe Ala Val Tyr Tyr Cys Gln Gln Met Arg Gly Arg Pro Pro Thr Phe
450 455 460
Gly Gln Gly Thr Lys Val Glu Ile Lys
465 470
<210> 8
<211> 472
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> DiaL19NHS76
<400> 8
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Gly Gly Ser Gly Gly Ser Ser Glu Leu Thr Gln Asp Pro Ala
115 120 125
Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp
130 135 140
Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln
145 150 155 160
Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile
165 170 175
Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr
180 185 190
Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser
195 200 205
Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly Thr Lys Leu
210 215 220
Thr Val Leu Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser
225 230 235 240
Ser Gly Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro
245 250 255
Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser
260 265 270
Ser Gly Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu
275 280 285
Glu Trp Ile Gly Ser Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro
290 295 300
Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln
305 310 315 320
Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
325 330 335
Tyr Cys Ala Arg Gly Lys Trp Ser Lys Phe Asp Tyr Trp Gly Gln Gly
340 345 350
Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly Glu Ile Val Leu
355 360 365
Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
370 375 380
Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp
385 390 395 400
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr Ala
405 410 415
Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser
420 425 430
Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe
435 440 445
Ala Val Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe Gly
450 455 460
Gln Gly Thr Lys Val Glu Ile Lys
465 470
<210> 9
<211> 473
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> DiaL19F8
<400> 9
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly
115 120 125
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
130 135 140
Ser Gln Ser Val Ser Met Pro Phe Leu Ala Trp Tyr Gln Gln Lys Pro
145 150 155 160
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr
165 170 175
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
180 185 190
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
195 200 205
Gln Gln Met Arg Gly Arg Pro Pro Thr Phe Gly Gln Gly Thr Lys Val
210 215 220
Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser
225 230 235 240
Ser Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
245 250 255
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
260 265 270
Leu Phe Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
275 280 285
Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp
290 295 300
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
305 310 315 320
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
325 330 335
Tyr Cys Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr Trp Gly Gln
340 345 350
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly Glu Ile Val
355 360 365
Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
370 375 380
Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala
385 390 395 400
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr
405 410 415
Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly
420 425 430
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp
435 440 445
Phe Ala Val Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe
450 455 460
Gly Gln Gly Thr Lys Val Glu Ile Lys
465 470
<210> 10
<211> 108
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> L19VL
<400> 10
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Tyr Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 11
<211> 114
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> L19VH
<400> 11
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val
<210> 12
<211> 108
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> F8VL
<400> 12
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Met Pro
20 25 30
Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Met Arg Gly Arg Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 118
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> F8VH
<400> 13
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Phe
20 25 30
Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 14
<211> 108
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> NHS76VL
<400> 14
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 15
<211> 117
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> NHS76VH?
<400> 15
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Ser Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Lys Trp Ser Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 16
<211> 193
<212> PRT
<213> Mus musculus
<400> 16
Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg
1 5 10 15
Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys
20 25 30
Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile
35 40 45
Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu
50 55 60
His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr
65 70 75 80
Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu
85 90 95
Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe
100 105 110
Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile
115 120 125
Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu
130 135 140
Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala
145 150 155 160
Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe
165 170 175
Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser
180 185 190
Ala
<210> 17
<211> 313
<212> PRT
<213> Mus musculus
<400> 17
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser
305 310
<210> 18
<211> 197
<212> PRT
<213> Homo sapiens
<400> 18
Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu
1 5 10 15
His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys
20 25 30
Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp
35 40 45
His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu
50 55 60
Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr
65 70 75 80
Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe
85 90 95
Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr
100 105 110
Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys
115 120 125
Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu
130 135 140
Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser
145 150 155 160
Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu
165 170 175
Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser
180 185 190
Tyr Leu Asn Ala Ser
195
<210> 19
<211> 306
<212> PRT
<213> Homo sapiens
<400> 19
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser
305
<210> 20
<211> 149
<212> PRT
<213> Mus musculus
<400> 20
Ala Pro Thr Ser Ser Ser Thr Ser Ser Ser Thr Ala Glu Ala Gln Gln
1 5 10 15
Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln His Leu Glu Gln Leu Leu
20 25 30
Met Asp Leu Gln Glu Leu Leu Ser Arg Met Glu Asn Tyr Arg Asn Leu
35 40 45
Lys Leu Pro Arg Met Leu Thr Phe Lys Phe Tyr Leu Pro Lys Gln Ala
50 55 60
Thr Glu Leu Lys Asp Leu Gln Cys Leu Glu Asp Glu Leu Gly Pro Leu
65 70 75 80
Arg His Val Leu Asp Leu Thr Gln Ser Lys Ser Phe Gln Leu Glu Asp
85 90 95
Ala Glu Asn Phe Ile Ser Asn Ile Arg Val Thr Val Val Lys Leu Lys
100 105 110
Gly Ser Asp Asn Thr Phe Glu Cys Gln Phe Asp Asp Glu Ser Ala Thr
115 120 125
Val Val Asp Phe Leu Arg Arg Trp Ile Ala Phe Cys Gln Ser Ile Ile
130 135 140
Ser Thr Ser Pro Gln
145
<210> 21
<211> 133
<212> PRT
<213> Homo sapiens
<400> 21
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 22
<211> 133
<212> PRT
<213> Mus musculus
<400> 22
Gly Ile His Val Phe Ile Leu Gly Cys Val Ser Val Gly Leu Pro Lys
1 5 10 15
Thr Glu Ala Asn Trp Ile Asp Val Arg Tyr Asp Leu Glu Lys Ile Glu
20 25 30
Ser Leu Ile Gln Ser Ile His Ile Asp Thr Thr Leu Tyr Thr Asp Ser
35 40 45
Asp Phe His Pro Ser Cys Lys Val Thr Ala Met Asn Cys Phe Leu Leu
50 55 60
Glu Leu Gln Val Ile Leu His Glu Tyr Ser Asn Met Thr Leu Asn Glu
65 70 75 80
Thr Val Arg Asn Val Leu Tyr Leu Ala Asn Ser Thr Leu Ser Ser Asn
85 90 95
Lys Asn Val Ala Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu
100 105 110
Lys Thr Phe Thr Glu Phe Leu Gln Ser Phe Ile Arg Ile Val Gln Met
115 120 125
Phe Ile Asn Thr Ser
130
<210> 23
<211> 133
<212> PRT
<213> Homo sapiens
<400> 23
Gly Ile His Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro Lys
1 5 10 15
Thr Glu Ala Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu
20 25 30
Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser
35 40 45
Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu
50 55 60
Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp
65 70 75 80
Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn
85 90 95
Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu
100 105 110
Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met
115 120 125
Phe Ile Asn Thr Ser
130
<210> 24
<211> 129
<212> PRT
<213> Mus musculus
<400> 24
Glu Cys His Ile Lys Asp Lys Glu Gly Lys Ala Tyr Glu Ser Val Leu
1 5 10 15
Met Ile Ser Ile Asp Glu Leu Asp Lys Met Thr Gly Thr Asp Ser Asn
20 25 30
Cys Pro Asn Asn Glu Pro Asn Phe Phe Arg Lys His Val Cys Asp Asp
35 40 45
Thr Lys Glu Ala Ala Phe Leu Asn Arg Ala Ala Arg Lys Leu Lys Gln
50 55 60
Phe Leu Lys Met Asn Ile Ser Glu Glu Phe Asn Val His Leu Leu Thr
65 70 75 80
Val Ser Gln Gly Thr Gln Thr Leu Val Asn Cys Thr Ser Lys Glu Glu
85 90 95
Lys Asn Val Lys Glu Gln Lys Lys Asn Asp Ala Cys Phe Leu Lys Arg
100 105 110
Leu Leu Arg Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Lys Gly Ser
115 120 125
Ile
<210> 25
<211> 152
<212> PRT
<213> Homo sapiens
<400> 25
Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu Ser Val Leu
1 5 10 15
Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu Ile Gly Ser
20 25 30
Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His Ile Cys Asp
35 40 45
Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg Lys Leu Arg
50 55 60
Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu His Leu Leu
65 70 75 80
Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr Gly Gln Val
85 90 95
Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro Thr Lys Ser
100 105 110
Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp Leu
115 120 125
Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn Lys
130 135 140
Ile Leu Met Gly Thr Lys Glu His
145 150
<210> 26
<211> 129
<212> PRT
<213> Mus musculus
<400> 26
His Lys Ser Ser Pro Gln Gly Pro Asp Arg Leu Leu Ile Arg Leu Arg
1 5 10 15
His Leu Ile Asp Ile Val Glu Gln Leu Lys Ile Tyr Glu Asn Asp Leu
20 25 30
Asp Pro Glu Leu Leu Ser Ala Pro Gln Asp Val Lys Gly His Cys Glu
35 40 45
His Ala Ala Phe Ala Cys Phe Gln Lys Ala Lys Leu Lys Pro Ser Asn
50 55 60
Pro Gly Asn Asn Lys Thr Phe Ile Ile Asp Leu Val Ala Gln Leu Arg
65 70 75 80
Arg Arg Leu Pro Ala Arg Arg Gly Gly Lys Lys Gln Lys His Ile Ala
85 90 95
Lys Cys Pro Ser Cys Asp Ser Tyr Glu Lys Arg Thr Pro Lys Glu Phe
100 105 110
Leu Glu Arg Leu Lys Trp Leu Leu Gln Lys Met Ile His Gln His Leu
115 120 125
Ser
<210> 27
<211> 133
<212> PRT
<213> Homo sapiens
<400> 27
Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser
130
<210> 28
<211> 206
<212> PRT
<213> Mus musculus
<400> 28
Gly Thr Pro Asp Cys Tyr Phe Ser His Ser Pro Ile Ser Ser Asn Phe
1 5 10 15
Lys Val Lys Phe Arg Glu Leu Thr Asp His Leu Leu Lys Asp Tyr Pro
20 25 30
Val Thr Val Ala Val Asn Leu Gln Asp Glu Lys His Cys Lys Ala Leu
35 40 45
Trp Ser Leu Phe Leu Ala Gln Arg Trp Ile Glu Gln Leu Lys Thr Val
50 55 60
Ala Gly Ser Lys Met Gln Thr Leu Leu Glu Asp Val Asn Thr Glu Ile
65 70 75 80
His Phe Val Thr Ser Cys Thr Phe Gln Pro Leu Pro Glu Cys Leu Arg
85 90 95
Phe Val Gln Thr Asn Ile Ser His Leu Leu Lys Asp Thr Cys Thr Gln
100 105 110
Leu Leu Ala Leu Lys Pro Cys Ile Gly Lys Ala Cys Gln Asn Phe Ser
115 120 125
Arg Cys Leu Glu Val Gln Cys Gln Pro Asp Ser Ser Thr Leu Leu Pro
130 135 140
Pro Arg Ser Pro Ile Ala Leu Glu Ala Thr Glu Leu Pro Glu Pro Arg
145 150 155 160
Pro Arg Gln Leu Leu Leu Leu Leu Leu Leu Leu Leu Pro Leu Thr Leu
165 170 175
Val Leu Leu Ala Ala Ala Trp Gly Leu Arg Trp Gln Arg Ala Arg Arg
180 185 190
Arg Gly Glu Leu His Pro Gly Val Pro Leu Pro Ser His Pro
195 200 205
<210> 29
<211> 209
<212> PRT
<213> Homo sapiens
<400> 29
Thr Gln Asp Cys Ser Phe Gln His Ser Pro Ile Ser Ser Asp Phe Ala
1 5 10 15
Val Lys Ile Arg Glu Leu Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val
20 25 30
Thr Val Ala Ser Asn Leu Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp
35 40 45
Arg Leu Val Leu Ala Gln Arg Trp Met Glu Arg Leu Lys Thr Val Ala
50 55 60
Gly Ser Lys Met Gln Gly Leu Leu Glu Arg Val Asn Thr Glu Ile His
65 70 75 80
Phe Val Thr Lys Cys Ala Phe Gln Pro Pro Pro Ser Cys Leu Arg Phe
85 90 95
Val Gln Thr Asn Ile Ser Arg Leu Leu Gln Glu Thr Ser Glu Gln Leu
100 105 110
Val Ala Leu Lys Pro Trp Ile Thr Arg Gln Asn Phe Ser Arg Cys Leu
115 120 125
Glu Leu Gln Cys Gln Pro Asp Ser Ser Thr Leu Pro Pro Pro Trp Ser
130 135 140
Pro Arg Pro Leu Glu Ala Thr Ala Pro Thr Ala Pro Gln Pro Pro Leu
145 150 155 160
Leu Leu Leu Leu Leu Leu Pro Val Gly Leu Leu Leu Leu Ala Ala Ala
165 170 175
Trp Cys Leu His Trp Gln Arg Thr Arg Arg Arg Thr Pro Arg Pro Gly
180 185 190
Glu Gln Val Pro Pro Val Pro Ser Pro Gln Asp Leu Leu Leu Val Glu
195 200 205
His
<210> 30
<211> 124
<212> PRT
<213> Mus musculus
<400> 30
Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val
1 5 10 15
Glu Ala Ile Lys Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
20 25 30
Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys
35 40 45
Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg
50 55 60
Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
65 70 75 80
Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
85 90 95
Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr
100 105 110
Asp Ile Pro Phe Glu Cys Lys Lys Pro Gly Gln Lys
115 120
<210> 31
<211> 127
<212> PRT
<213> Homo sapiens
<400> 31
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
1 5 10 15
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
20 25 30
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
35 40 45
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
50 55 60
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
65 70 75 80
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
85 90 95
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
100 105 110
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
115 120 125
<210> 32
<211> 824
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL2GMCSF
<400> 32
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Ser
530 535 540
Ser Ser Thr Ala Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
545 550 555 560
Gln Gln His Leu Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser
565 570 575
Arg Met Glu Asn Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Phe
580 585 590
Lys Phe Tyr Leu Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys
595 600 605
Leu Glu Asp Glu Leu Gly Pro Leu Arg His Val Leu Asp Leu Thr Gln
610 615 620
Ser Lys Ser Phe Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile
625 630 635 640
Arg Val Thr Val Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys
645 650 655
Gln Phe Asp Asp Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp
660 665 670
Ile Ala Phe Cys Gln Ser Ile Ile Ser Thr Ser Pro Gln Gly Gly Gly
675 680 685
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Arg
690 695 700
Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys
705 710 715 720
Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu
725 730 735
Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val
740 745 750
Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr
755 760 765
Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr
770 775 780
Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr
785 790 795 800
Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe
805 810 815
Glu Cys Lys Lys Pro Gly Gln Lys
820
<210> 33
<211> 804
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL7GMCSF
<400> 33
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser Glu Cys His Ile Lys Asp Lys Glu
530 535 540
Gly Lys Ala Tyr Glu Ser Val Leu Met Ile Ser Ile Asp Glu Leu Asp
545 550 555 560
Lys Met Thr Gly Thr Asp Ser Asn Cys Pro Asn Asn Glu Pro Asn Phe
565 570 575
Phe Arg Lys His Val Cys Asp Asp Thr Lys Glu Ala Ala Phe Leu Asn
580 585 590
Arg Ala Ala Arg Lys Leu Lys Gln Phe Leu Lys Met Asn Ile Ser Glu
595 600 605
Glu Phe Asn Val His Leu Leu Thr Val Ser Gln Gly Thr Gln Thr Leu
610 615 620
Val Asn Cys Thr Ser Lys Glu Glu Lys Asn Val Lys Glu Gln Lys Lys
625 630 635 640
Asn Asp Ala Cys Phe Leu Lys Arg Leu Leu Arg Glu Ile Lys Thr Cys
645 650 655
Trp Asn Lys Ile Leu Lys Gly Ser Ile Gly Gly Gly Gly Ser Gly Gly
660 665 670
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Arg Ser Pro Ile Thr
675 680 685
Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys Glu Ala Leu Asn
690 695 700
Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu Val Glu Val Val
705 710 715 720
Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val Gln Thr Arg Leu
725 730 735
Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr Lys Leu Lys Gly
740 745 750
Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr Cys Pro Pro Thr
755 760 765
Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr Ala Asp Phe Ile
770 775 780
Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe Glu Cys Lys Lys
785 790 795 800
Pro Gly Gln Lys
<210> 34
<211> 808
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL15GMCSF
<400> 34
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser Gly Ile His Val Phe Ile Leu Gly
530 535 540
Cys Val Ser Val Gly Leu Pro Lys Thr Glu Ala Asn Trp Ile Asp Val
545 550 555 560
Arg Tyr Asp Leu Glu Lys Ile Glu Ser Leu Ile Gln Ser Ile His Ile
565 570 575
Asp Thr Thr Leu Tyr Thr Asp Ser Asp Phe His Pro Ser Cys Lys Val
580 585 590
Thr Ala Met Asn Cys Phe Leu Leu Glu Leu Gln Val Ile Leu His Glu
595 600 605
Tyr Ser Asn Met Thr Leu Asn Glu Thr Val Arg Asn Val Leu Tyr Leu
610 615 620
Ala Asn Ser Thr Leu Ser Ser Asn Lys Asn Val Ala Glu Ser Gly Cys
625 630 635 640
Lys Glu Cys Glu Glu Leu Glu Glu Lys Thr Phe Thr Glu Phe Leu Gln
645 650 655
Ser Phe Ile Arg Ile Val Gln Met Phe Ile Asn Thr Ser Gly Gly Gly
660 665 670
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Arg
675 680 685
Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys
690 695 700
Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu
705 710 715 720
Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val
725 730 735
Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr
740 745 750
Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr
755 760 765
Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr
770 775 780
Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe
785 790 795 800
Glu Cys Lys Lys Pro Gly Gln Lys
805
<210> 35
<211> 804
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL21GMCSF
<400> 35
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser His Lys Ser Ser Pro Gln Gly Pro
530 535 540
Asp Arg Leu Leu Ile Arg Leu Arg His Leu Ile Asp Ile Val Glu Gln
545 550 555 560
Leu Lys Ile Tyr Glu Asn Asp Leu Asp Pro Glu Leu Leu Ser Ala Pro
565 570 575
Gln Asp Val Lys Gly His Cys Glu His Ala Ala Phe Ala Cys Phe Gln
580 585 590
Lys Ala Lys Leu Lys Pro Ser Asn Pro Gly Asn Asn Lys Thr Phe Ile
595 600 605
Ile Asp Leu Val Ala Gln Leu Arg Arg Arg Leu Pro Ala Arg Arg Gly
610 615 620
Gly Lys Lys Gln Lys His Ile Ala Lys Cys Pro Ser Cys Asp Ser Tyr
625 630 635 640
Glu Lys Arg Thr Pro Lys Glu Phe Leu Glu Arg Leu Lys Trp Leu Leu
645 650 655
Gln Lys Met Ile His Gln His Leu Ser Gly Gly Gly Gly Ser Gly Gly
660 665 670
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Arg Ser Pro Ile Thr
675 680 685
Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys Glu Ala Leu Asn
690 695 700
Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu Val Glu Val Val
705 710 715 720
Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val Gln Thr Arg Leu
725 730 735
Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr Lys Leu Lys Gly
740 745 750
Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr Cys Pro Pro Thr
755 760 765
Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr Ala Asp Phe Ile
770 775 780
Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe Glu Cys Lys Lys
785 790 795 800
Pro Gly Gln Lys
<210> 36
<211> 906
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL2FLT3L
<400> 36
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Ser
530 535 540
Ser Ser Thr Ala Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
545 550 555 560
Gln Gln His Leu Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser
565 570 575
Arg Met Glu Asn Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Phe
580 585 590
Lys Phe Tyr Leu Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys
595 600 605
Leu Glu Asp Glu Leu Gly Pro Leu Arg His Val Leu Asp Leu Thr Gln
610 615 620
Ser Lys Ser Phe Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile
625 630 635 640
Arg Val Thr Val Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys
645 650 655
Gln Phe Asp Asp Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp
660 665 670
Ile Ala Phe Cys Gln Ser Ile Ile Ser Thr Ser Pro Gln Gly Gly Gly
675 680 685
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Thr Pro Asp
690 695 700
Cys Tyr Phe Ser His Ser Pro Ile Ser Ser Asn Phe Lys Val Lys Phe
705 710 715 720
Arg Glu Leu Thr Asp His Leu Leu Lys Asp Tyr Pro Val Thr Val Ala
725 730 735
Val Asn Leu Gln Asp Glu Lys His Cys Lys Ala Leu Trp Ser Leu Phe
740 745 750
Leu Ala Gln Arg Trp Ile Glu Gln Leu Lys Thr Val Ala Gly Ser Lys
755 760 765
Met Gln Thr Leu Leu Glu Asp Val Asn Thr Glu Ile His Phe Val Thr
770 775 780
Ser Cys Thr Phe Gln Pro Leu Pro Glu Cys Leu Arg Phe Val Gln Thr
785 790 795 800
Asn Ile Ser His Leu Leu Lys Asp Thr Cys Thr Gln Leu Leu Ala Leu
805 810 815
Lys Pro Cys Ile Gly Lys Ala Cys Gln Asn Phe Ser Arg Cys Leu Glu
820 825 830
Val Gln Cys Gln Pro Asp Ser Ser Thr Leu Leu Pro Pro Arg Ser Pro
835 840 845
Ile Ala Leu Glu Ala Thr Glu Leu Pro Glu Pro Arg Pro Arg Gln Leu
850 855 860
Leu Leu Leu Leu Leu Leu Leu Leu Pro Leu Thr Leu Val Leu Leu Ala
865 870 875 880
Ala Ala Trp Gly Leu Arg Trp Gln Arg Ala Arg Arg Arg Gly Glu Leu
885 890 895
His Pro Gly Val Pro Leu Pro Ser His Pro
900 905
<210> 37
<211> 886
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL7FLT3L
<400> 37
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser Glu Cys His Ile Lys Asp Lys Glu
530 535 540
Gly Lys Ala Tyr Glu Ser Val Leu Met Ile Ser Ile Asp Glu Leu Asp
545 550 555 560
Lys Met Thr Gly Thr Asp Ser Asn Cys Pro Asn Asn Glu Pro Asn Phe
565 570 575
Phe Arg Lys His Val Cys Asp Asp Thr Lys Glu Ala Ala Phe Leu Asn
580 585 590
Arg Ala Ala Arg Lys Leu Lys Gln Phe Leu Lys Met Asn Ile Ser Glu
595 600 605
Glu Phe Asn Val His Leu Leu Thr Val Ser Gln Gly Thr Gln Thr Leu
610 615 620
Val Asn Cys Thr Ser Lys Glu Glu Lys Asn Val Lys Glu Gln Lys Lys
625 630 635 640
Asn Asp Ala Cys Phe Leu Lys Arg Leu Leu Arg Glu Ile Lys Thr Cys
645 650 655
Trp Asn Lys Ile Leu Lys Gly Ser Ile Gly Gly Gly Gly Ser Gly Gly
660 665 670
Gly Gly Ser Gly Gly Gly Gly Ser Gly Thr Pro Asp Cys Tyr Phe Ser
675 680 685
His Ser Pro Ile Ser Ser Asn Phe Lys Val Lys Phe Arg Glu Leu Thr
690 695 700
Asp His Leu Leu Lys Asp Tyr Pro Val Thr Val Ala Val Asn Leu Gln
705 710 715 720
Asp Glu Lys His Cys Lys Ala Leu Trp Ser Leu Phe Leu Ala Gln Arg
725 730 735
Trp Ile Glu Gln Leu Lys Thr Val Ala Gly Ser Lys Met Gln Thr Leu
740 745 750
Leu Glu Asp Val Asn Thr Glu Ile His Phe Val Thr Ser Cys Thr Phe
755 760 765
Gln Pro Leu Pro Glu Cys Leu Arg Phe Val Gln Thr Asn Ile Ser His
770 775 780
Leu Leu Lys Asp Thr Cys Thr Gln Leu Leu Ala Leu Lys Pro Cys Ile
785 790 795 800
Gly Lys Ala Cys Gln Asn Phe Ser Arg Cys Leu Glu Val Gln Cys Gln
805 810 815
Pro Asp Ser Ser Thr Leu Leu Pro Pro Arg Ser Pro Ile Ala Leu Glu
820 825 830
Ala Thr Glu Leu Pro Glu Pro Arg Pro Arg Gln Leu Leu Leu Leu Leu
835 840 845
Leu Leu Leu Leu Pro Leu Thr Leu Val Leu Leu Ala Ala Ala Trp Gly
850 855 860
Leu Arg Trp Gln Arg Ala Arg Arg Arg Gly Glu Leu His Pro Gly Val
865 870 875 880
Pro Leu Pro Ser His Pro
885
<210> 38
<211> 890
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL15FLT3L
<400> 38
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser Gly Ile His Val Phe Ile Leu Gly
530 535 540
Cys Val Ser Val Gly Leu Pro Lys Thr Glu Ala Asn Trp Ile Asp Val
545 550 555 560
Arg Tyr Asp Leu Glu Lys Ile Glu Ser Leu Ile Gln Ser Ile His Ile
565 570 575
Asp Thr Thr Leu Tyr Thr Asp Ser Asp Phe His Pro Ser Cys Lys Val
580 585 590
Thr Ala Met Asn Cys Phe Leu Leu Glu Leu Gln Val Ile Leu His Glu
595 600 605
Tyr Ser Asn Met Thr Leu Asn Glu Thr Val Arg Asn Val Leu Tyr Leu
610 615 620
Ala Asn Ser Thr Leu Ser Ser Asn Lys Asn Val Ala Glu Ser Gly Cys
625 630 635 640
Lys Glu Cys Glu Glu Leu Glu Glu Lys Thr Phe Thr Glu Phe Leu Gln
645 650 655
Ser Phe Ile Arg Ile Val Gln Met Phe Ile Asn Thr Ser Gly Gly Gly
660 665 670
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Thr Pro Asp
675 680 685
Cys Tyr Phe Ser His Ser Pro Ile Ser Ser Asn Phe Lys Val Lys Phe
690 695 700
Arg Glu Leu Thr Asp His Leu Leu Lys Asp Tyr Pro Val Thr Val Ala
705 710 715 720
Val Asn Leu Gln Asp Glu Lys His Cys Lys Ala Leu Trp Ser Leu Phe
725 730 735
Leu Ala Gln Arg Trp Ile Glu Gln Leu Lys Thr Val Ala Gly Ser Lys
740 745 750
Met Gln Thr Leu Leu Glu Asp Val Asn Thr Glu Ile His Phe Val Thr
755 760 765
Ser Cys Thr Phe Gln Pro Leu Pro Glu Cys Leu Arg Phe Val Gln Thr
770 775 780
Asn Ile Ser His Leu Leu Lys Asp Thr Cys Thr Gln Leu Leu Ala Leu
785 790 795 800
Lys Pro Cys Ile Gly Lys Ala Cys Gln Asn Phe Ser Arg Cys Leu Glu
805 810 815
Val Gln Cys Gln Pro Asp Ser Ser Thr Leu Leu Pro Pro Arg Ser Pro
820 825 830
Ile Ala Leu Glu Ala Thr Glu Leu Pro Glu Pro Arg Pro Arg Gln Leu
835 840 845
Leu Leu Leu Leu Leu Leu Leu Leu Pro Leu Thr Leu Val Leu Leu Ala
850 855 860
Ala Ala Trp Gly Leu Arg Trp Gln Arg Ala Arg Arg Arg Gly Glu Leu
865 870 875 880
His Pro Gly Val Pro Leu Pro Ser His Pro
885 890
<210> 39
<211> 886
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL21FLT3L
<400> 39
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser His Lys Ser Ser Pro Gln Gly Pro
530 535 540
Asp Arg Leu Leu Ile Arg Leu Arg His Leu Ile Asp Ile Val Glu Gln
545 550 555 560
Leu Lys Ile Tyr Glu Asn Asp Leu Asp Pro Glu Leu Leu Ser Ala Pro
565 570 575
Gln Asp Val Lys Gly His Cys Glu His Ala Ala Phe Ala Cys Phe Gln
580 585 590
Lys Ala Lys Leu Lys Pro Ser Asn Pro Gly Asn Asn Lys Thr Phe Ile
595 600 605
Ile Asp Leu Val Ala Gln Leu Arg Arg Arg Leu Pro Ala Arg Arg Gly
610 615 620
Gly Lys Lys Gln Lys His Ile Ala Lys Cys Pro Ser Cys Asp Ser Tyr
625 630 635 640
Glu Lys Arg Thr Pro Lys Glu Phe Leu Glu Arg Leu Lys Trp Leu Leu
645 650 655
Gln Lys Met Ile His Gln His Leu Ser Gly Gly Gly Gly Ser Gly Gly
660 665 670
Gly Gly Ser Gly Gly Gly Gly Ser Gly Thr Pro Asp Cys Tyr Phe Ser
675 680 685
His Ser Pro Ile Ser Ser Asn Phe Lys Val Lys Phe Arg Glu Leu Thr
690 695 700
Asp His Leu Leu Lys Asp Tyr Pro Val Thr Val Ala Val Asn Leu Gln
705 710 715 720
Asp Glu Lys His Cys Lys Ala Leu Trp Ser Leu Phe Leu Ala Gln Arg
725 730 735
Trp Ile Glu Gln Leu Lys Thr Val Ala Gly Ser Lys Met Gln Thr Leu
740 745 750
Leu Glu Asp Val Asn Thr Glu Ile His Phe Val Thr Ser Cys Thr Phe
755 760 765
Gln Pro Leu Pro Glu Cys Leu Arg Phe Val Gln Thr Asn Ile Ser His
770 775 780
Leu Leu Lys Asp Thr Cys Thr Gln Leu Leu Ala Leu Lys Pro Cys Ile
785 790 795 800
Gly Lys Ala Cys Gln Asn Phe Ser Arg Cys Leu Glu Val Gln Cys Gln
805 810 815
Pro Asp Ser Ser Thr Leu Leu Pro Pro Arg Ser Pro Ile Ala Leu Glu
820 825 830
Ala Thr Glu Leu Pro Glu Pro Arg Pro Arg Gln Leu Leu Leu Leu Leu
835 840 845
Leu Leu Leu Leu Pro Leu Thr Leu Val Leu Leu Ala Ala Ala Trp Gly
850 855 860
Leu Arg Trp Gln Arg Ala Arg Arg Arg Gly Glu Leu His Pro Gly Val
865 870 875 880
Pro Leu Pro Ser His Pro
885
<210> 40
<211> 808
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL2GMCSF
<400> 40
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln
530 535 540
Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
545 550 555 560
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys
565 570 575
Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
580 585 590
Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
595 600 605
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val
610 615 620
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
625 630 635 640
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
645 650 655
Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly
660 665 670
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Arg Ser Pro Ser
675 680 685
Pro Ser Thr Gln Pro Trp Glu His Val Asn Ala Ile Gln Glu Ala Arg
690 695 700
Arg Leu Leu Asn Leu Ser Arg Asp Thr Ala Ala Glu Met Asn Glu Thr
705 710 715 720
Val Glu Val Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu
725 730 735
Gln Thr Arg Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr
740 745 750
Lys Leu Lys Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His
755 760 765
Cys Pro Pro Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe
770 775 780
Glu Ser Phe Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe
785 790 795 800
Asp Cys Trp Glu Pro Val Gln Glu
805
<210> 41
<211> 827
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL7GMCSF
<400> 41
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln
530 535 540
Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met
545 550 555 560
Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys
565 570 575
Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala
580 585 590
Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe
595 600 605
Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn
610 615 620
Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala
625 630 635 640
Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys
645 650 655
Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys
660 665 670
Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu His Gly Gly Gly
675 680 685
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Arg
690 695 700
Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val Asn Ala Ile Gln
705 710 715 720
Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr Ala Ala Glu Met
725 730 735
Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp Leu Gln Glu Pro
740 745 750
Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly
755 760 765
Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met Ala Ser His Tyr
770 775 780
Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile
785 790 795 800
Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp Phe Leu Leu Val
805 810 815
Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
820 825
<210> 42
<211> 808
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL15GMCSF
<400> 42
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Gly Ile His Val Phe Ile Leu Gly Cys Phe Ser
530 535 540
Ala Gly Leu Pro Lys Thr Glu Ala Asn Trp Val Asn Val Ile Ser Asp
545 550 555 560
Leu Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr
565 570 575
Leu Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met
580 585 590
Lys Cys Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp
595 600 605
Ala Ser Ile His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn
610 615 620
Ser Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys
625 630 635 640
Glu Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val
645 650 655
His Ile Val Gln Met Phe Ile Asn Thr Ser Gly Gly Gly Gly Ser Gly
660 665 670
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Arg Ser Pro Ser
675 680 685
Pro Ser Thr Gln Pro Trp Glu His Val Asn Ala Ile Gln Glu Ala Arg
690 695 700
Arg Leu Leu Asn Leu Ser Arg Asp Thr Ala Ala Glu Met Asn Glu Thr
705 710 715 720
Val Glu Val Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu
725 730 735
Gln Thr Arg Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr
740 745 750
Lys Leu Lys Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His
755 760 765
Cys Pro Pro Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe
770 775 780
Glu Ser Phe Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe
785 790 795 800
Asp Cys Trp Glu Pro Val Gln Glu
805
<210> 43
<211> 808
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL21GMCSF
<400> 43
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg
530 535 540
Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu
545 550 555 560
Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu
565 570 575
Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn
580 585 590
Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys
595 600 605
Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu
610 615 620
Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe
625 630 635 640
Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu
645 650 655
Ser Ser Arg Thr His Gly Ser Glu Asp Ser Gly Gly Gly Gly Ser Gly
660 665 670
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Arg Ser Pro Ser
675 680 685
Pro Ser Thr Gln Pro Trp Glu His Val Asn Ala Ile Gln Glu Ala Arg
690 695 700
Arg Leu Leu Asn Leu Ser Arg Asp Thr Ala Ala Glu Met Asn Glu Thr
705 710 715 720
Val Glu Val Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu
725 730 735
Gln Thr Arg Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr
740 745 750
Lys Leu Lys Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His
755 760 765
Cys Pro Pro Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe
770 775 780
Glu Ser Phe Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe
785 790 795 800
Asp Cys Trp Glu Pro Val Gln Glu
805
<210> 44
<211> 890
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL2FLT3L
<400> 44
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln
530 535 540
Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
545 550 555 560
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys
565 570 575
Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
580 585 590
Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
595 600 605
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val
610 615 620
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
625 630 635 640
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
645 650 655
Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly
660 665 670
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gln Asp Cys Ser Phe Gln
675 680 685
His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser
690 695 700
Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln
705 710 715 720
Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg
725 730 735
Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu
740 745 750
Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe
755 760 765
Gln Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg
770 775 780
Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile
785 790 795 800
Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp
805 810 815
Ser Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr
820 825 830
Ala Pro Thr Ala Pro Gln Pro Pro Leu Leu Leu Leu Leu Leu Leu Pro
835 840 845
Val Gly Leu Leu Leu Leu Ala Ala Ala Trp Cys Leu His Trp Gln Arg
850 855 860
Thr Arg Arg Arg Thr Pro Arg Pro Gly Glu Gln Val Pro Pro Val Pro
865 870 875 880
Ser Pro Gln Asp Leu Leu Leu Val Glu His
885 890
<210> 45
<211> 909
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL7FLT3L
<400> 45
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln
530 535 540
Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met
545 550 555 560
Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys
565 570 575
Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala
580 585 590
Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe
595 600 605
Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn
610 615 620
Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala
625 630 635 640
Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys
645 650 655
Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys
660 665 670
Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu His Gly Gly Gly
675 680 685
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gln Asp Cys
690 695 700
Ser Phe Gln His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg
705 710 715 720
Glu Leu Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser
725 730 735
Asn Leu Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu
740 745 750
Ala Gln Arg Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met
755 760 765
Gln Gly Leu Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys
770 775 780
Cys Ala Phe Gln Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn
785 790 795 800
Ile Ser Arg Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys
805 810 815
Pro Trp Ile Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys
820 825 830
Gln Pro Asp Ser Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu
835 840 845
Glu Ala Thr Ala Pro Thr Ala Pro Gln Pro Pro Leu Leu Leu Leu Leu
850 855 860
Leu Leu Pro Val Gly Leu Leu Leu Leu Ala Ala Ala Trp Cys Leu His
865 870 875 880
Trp Gln Arg Thr Arg Arg Arg Thr Pro Arg Pro Gly Glu Gln Val Pro
885 890 895
Pro Val Pro Ser Pro Gln Asp Leu Leu Leu Val Glu His
900 905
<210> 46
<211> 890
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL15FLT3L
<400> 46
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Gly Ile His Val Phe Ile Leu Gly Cys Phe Ser
530 535 540
Ala Gly Leu Pro Lys Thr Glu Ala Asn Trp Val Asn Val Ile Ser Asp
545 550 555 560
Leu Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr
565 570 575
Leu Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met
580 585 590
Lys Cys Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp
595 600 605
Ala Ser Ile His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn
610 615 620
Ser Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys
625 630 635 640
Glu Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val
645 650 655
His Ile Val Gln Met Phe Ile Asn Thr Ser Gly Gly Gly Gly Ser Gly
660 665 670
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gln Asp Cys Ser Phe Gln
675 680 685
His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser
690 695 700
Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln
705 710 715 720
Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg
725 730 735
Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu
740 745 750
Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe
755 760 765
Gln Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg
770 775 780
Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile
785 790 795 800
Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp
805 810 815
Ser Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr
820 825 830
Ala Pro Thr Ala Pro Gln Pro Pro Leu Leu Leu Leu Leu Leu Leu Pro
835 840 845
Val Gly Leu Leu Leu Leu Ala Ala Ala Trp Cys Leu His Trp Gln Arg
850 855 860
Thr Arg Arg Arg Thr Pro Arg Pro Gly Glu Gln Val Pro Pro Val Pro
865 870 875 880
Ser Pro Gln Asp Leu Leu Leu Val Glu His
885 890
<210> 47
<211> 890
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL21FLT3L
<400> 47
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg
530 535 540
Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu
545 550 555 560
Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu
565 570 575
Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn
580 585 590
Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys
595 600 605
Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu
610 615 620
Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe
625 630 635 640
Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu
645 650 655
Ser Ser Arg Thr His Gly Ser Glu Asp Ser Gly Gly Gly Gly Ser Gly
660 665 670
Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gln Asp Cys Ser Phe Gln
675 680 685
His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser
690 695 700
Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln
705 710 715 720
Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg
725 730 735
Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu
740 745 750
Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe
755 760 765
Gln Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg
770 775 780
Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile
785 790 795 800
Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp
805 810 815
Ser Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr
820 825 830
Ala Pro Thr Ala Pro Gln Pro Pro Leu Leu Leu Leu Leu Leu Leu Pro
835 840 845
Val Gly Leu Leu Leu Leu Ala Ala Ala Trp Cys Leu His Trp Gln Arg
850 855 860
Thr Arg Arg Arg Thr Pro Arg Pro Gly Glu Gln Val Pro Pro Val Pro
865 870 875 880
Ser Pro Gln Asp Leu Leu Leu Val Glu His
885 890
<210> 48
<211> 1316
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr
<400> 48
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Ser
530 535 540
Ser Ser Thr Ala Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
545 550 555 560
Gln Gln His Leu Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser
565 570 575
Arg Met Glu Asn Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Phe
580 585 590
Lys Phe Tyr Leu Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys
595 600 605
Leu Glu Asp Glu Leu Gly Pro Leu Arg His Val Leu Asp Leu Thr Gln
610 615 620
Ser Lys Ser Phe Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile
625 630 635 640
Arg Val Thr Val Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys
645 650 655
Gln Phe Asp Asp Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp
660 665 670
Ile Ala Phe Cys Gln Ser Ile Ile Ser Thr Ser Pro Gln Gly Gly Gly
675 680 685
Gly Ser Leu Val Pro Arg Gly Ser Gly Gly Gly Gly Ser Gln Val Gln
690 695 700
Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser
705 710 715 720
Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly Tyr Tyr Trp
725 730 735
Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Ser
740 745 750
Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg
755 760 765
Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu
770 775 780
Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly
785 790 795 800
Lys Trp Ser Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
805 810 815
Ser Ser Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly
820 825 830
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
835 840 845
Ser Gln Ser Val Ser Met Pro Phe Leu Ala Trp Tyr Gln Gln Lys Pro
850 855 860
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr
865 870 875 880
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
885 890 895
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
900 905 910
Gln Gln Met Arg Gly Arg Pro Pro Thr Phe Gly Gln Gly Thr Lys Val
915 920 925
Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser
930 935 940
Ser Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
945 950 955 960
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
965 970 975
Leu Phe Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
980 985 990
Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp
995 1000 1005
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
1010 1015 1020
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
1025 1030 1035
Val Tyr Tyr Cys Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr
1040 1045 1050
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly
1055 1060 1065
Gly Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu
1070 1075 1080
Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser
1085 1090 1095
Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val
1100 1105 1110
Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp
1115 1120 1125
Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile
1130 1135 1140
Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser
1145 1150 1155
Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly Thr Lys
1160 1165 1170
Leu Thr Val Leu Ser Ser Ser Ser Gly Leu Val Pro Arg Gly Ser
1175 1180 1185
Ser Ser Ser Gly Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg
1190 1195 1200
Pro Trp Lys His Val Glu Ala Ile Lys Glu Ala Leu Asn Leu Leu
1205 1210 1215
Asp Asp Met Pro Val Thr Leu Asn Glu Glu Val Glu Val Val Ser
1220 1225 1230
Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val Gln Thr Arg Leu
1235 1240 1245
Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr Lys Leu Lys
1250 1255 1260
Gly Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr Cys Pro
1265 1270 1275
Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr Ala
1280 1285 1290
Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe
1295 1300 1305
Glu Cys Lys Lys Pro Gly Gln Lys
1310 1315
<210> 49
<211> 1300
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL2DiaNHS76F8GMCSF-Thr
<400> 49
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln
530 535 540
Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
545 550 555 560
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys
565 570 575
Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
580 585 590
Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
595 600 605
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val
610 615 620
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
625 630 635 640
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
645 650 655
Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Leu
660 665 670
Val Pro Arg Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
675 680 685
Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys
690 695 700
Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly Tyr Tyr Trp Gly Trp Ile
705 710 715 720
Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr His
725 730 735
Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile
740 745 750
Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val
755 760 765
Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Lys Trp Ser
770 775 780
Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
785 790 795 800
Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
805 810 815
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
820 825 830
Val Ser Met Pro Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
835 840 845
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
850 855 860
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
865 870 875 880
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Met
885 890 895
Arg Gly Arg Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
900 905 910
Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Glu
915 920 925
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
930 935 940
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Phe Thr
945 950 955 960
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
965 970 975
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
980 985 990
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
995 1000 1005
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
1010 1015 1020
Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr Trp Gly Gln Gly
1025 1030 1035
Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly Ser Ser Glu
1040 1045 1050
Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val
1055 1060 1065
Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser
1070 1075 1080
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
1085 1090 1095
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly
1100 1105 1110
Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln
1115 1120 1125
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser
1130 1135 1140
Gly Asn His Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
1145 1150 1155
Ser Ser Ser Ser Gly Leu Val Pro Arg Gly Ser Ser Ser Ser Gly
1160 1165 1170
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His
1175 1180 1185
Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg
1190 1195 1200
Asp Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu
1205 1210 1215
Met Phe Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu
1220 1225 1230
Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly
1235 1240 1245
Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His Cys Pro Pro
1250 1255 1260
Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser
1265 1270 1275
Phe Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe Asp
1280 1285 1290
Cys Trp Glu Pro Val Gln Glu
1295 1300
<210> 50
<211> 1316
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bIL12aIL2DiaF8GMCSF
<400> 50
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Ser
530 535 540
Ser Ser Thr Ala Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
545 550 555 560
Gln Gln His Leu Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser
565 570 575
Arg Met Glu Asn Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Phe
580 585 590
Lys Phe Tyr Leu Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys
595 600 605
Leu Glu Asp Glu Leu Gly Pro Leu Arg His Val Leu Asp Leu Thr Gln
610 615 620
Ser Lys Ser Phe Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile
625 630 635 640
Arg Val Thr Val Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys
645 650 655
Gln Phe Asp Asp Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp
660 665 670
Ile Ala Phe Cys Gln Ser Ile Ile Ser Thr Ser Pro Gln Gly Gly Gly
675 680 685
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
690 695 700
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
705 710 715 720
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Phe Thr Met Ser Trp
725 730 735
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Ser
740 745 750
Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
755 760 765
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
770 775 780
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ser Thr
785 790 795 800
His Leu Tyr Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
805 810 815
Ser Ser Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly
820 825 830
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
835 840 845
Ser Gln Ser Val Ser Met Pro Phe Leu Ala Trp Tyr Gln Gln Lys Pro
850 855 860
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr
865 870 875 880
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
885 890 895
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
900 905 910
Gln Gln Met Arg Gly Arg Pro Pro Thr Phe Gly Gln Gly Thr Lys Val
915 920 925
Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser
930 935 940
Ser Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
945 950 955 960
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
965 970 975
Leu Phe Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
980 985 990
Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp
995 1000 1005
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
1010 1015 1020
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
1025 1030 1035
Val Tyr Tyr Cys Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr
1040 1045 1050
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly
1055 1060 1065
Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
1070 1075 1080
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val
1085 1090 1095
Ser Met Pro Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
1100 1105 1110
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
1115 1120 1125
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
1130 1135 1140
Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
1145 1150 1155
Gln Gln Met Arg Gly Arg Pro Pro Thr Phe Gly Gln Gly Thr Lys
1160 1165 1170
Val Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser
1175 1180 1185
Ser Ser Ser Gly Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg
1190 1195 1200
Pro Trp Lys His Val Glu Ala Ile Lys Glu Ala Leu Asn Leu Leu
1205 1210 1215
Asp Asp Met Pro Val Thr Leu Asn Glu Glu Val Glu Val Val Ser
1220 1225 1230
Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val Gln Thr Arg Leu
1235 1240 1245
Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr Lys Leu Lys
1250 1255 1260
Gly Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr Cys Pro
1265 1270 1275
Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr Ala
1280 1285 1290
Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe
1295 1300 1305
Glu Cys Lys Lys Pro Gly Gln Lys
1310 1315
<210> 51
<211> 1300
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bIL12aIL2DiaF8GMCSF
<400> 51
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln
530 535 540
Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
545 550 555 560
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys
565 570 575
Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
580 585 590
Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
595 600 605
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val
610 615 620
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
625 630 635 640
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
645 650 655
Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly
660 665 670
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
675 680 685
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
690 695 700
Ala Ser Gly Phe Thr Phe Ser Leu Phe Thr Met Ser Trp Val Arg Gln
705 710 715 720
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly
725 730 735
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
740 745 750
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
755 760 765
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ser Thr His Leu Tyr
770 775 780
Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
785 790 795 800
Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
805 810 815
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
820 825 830
Val Ser Met Pro Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
835 840 845
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
850 855 860
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
865 870 875 880
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Met
885 890 895
Arg Gly Arg Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
900 905 910
Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Glu
915 920 925
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
930 935 940
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Phe Thr
945 950 955 960
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
965 970 975
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
980 985 990
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
995 1000 1005
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
1010 1015 1020
Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr Trp Gly Gln Gly
1025 1030 1035
Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly Glu Ile Val
1040 1045 1050
Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg
1055 1060 1065
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Met Pro Phe
1070 1075 1080
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
1085 1090 1095
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe
1100 1105 1110
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
1115 1120 1125
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Met Arg
1130 1135 1140
Gly Arg Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1145 1150 1155
Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly
1160 1165 1170
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His
1175 1180 1185
Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg
1190 1195 1200
Asp Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu
1205 1210 1215
Met Phe Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu
1220 1225 1230
Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly
1235 1240 1245
Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His Cys Pro Pro
1250 1255 1260
Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser
1265 1270 1275
Phe Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe Asp
1280 1285 1290
Cys Trp Glu Pro Val Gln Glu
1295 1300
<210> 52
<211> 559
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bscF8-scF8IL12aIL2GMCSF的第二多肽链（鼠mIL12bscF8链）
<400> 52
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Ser Ala Asp Gly Gly Glu
305 310 315 320
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
325 330 335
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Phe Thr
340 345 350
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
355 360 365
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
370 375 380
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
385 390 395 400
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
405 410 415
Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu
420 425 430
Val Thr Val Ser Ser Ser Ser Gly Asp Gly Ser Ser Gly Gly Ser Gly
435 440 445
Gly Ala Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
450 455 460
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val
465 470 475 480
Ser Met Pro Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
485 490 495
Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp
500 505 510
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
515 520 525
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Met Arg
530 535 540
Gly Arg Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
545 550 555
<210> 53
<211> 742
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12bscF8-scF8IL12aIL2GMCSF的第一多肽链（鼠mscF8IL12aIL2GMCSF链）
<400> 53
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Phe
20 25 30
Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ser Thr His Leu Tyr Leu Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ser Ser Gly Asp Gly Ser Ser Gly Gly Ser
115 120 125
Gly Gly Ala Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
130 135 140
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
145 150 155 160
Val Ser Met Pro Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
165 170 175
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
180 185 190
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
195 200 205
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Met
210 215 220
Arg Gly Arg Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
225 230 235 240
Gly Ser Ala Asp Gly Gly Arg Val Ile Pro Val Ser Gly Pro Ala Arg
245 250 255
Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val
260 265 270
Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp
275 280 285
Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr
290 295 300
Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg
305 310 315 320
Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr
325 330 335
Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys
340 345 350
Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His
355 360 365
Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp
370 375 380
Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys
385 390 395 400
Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys
405 410 415
Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val
420 425 430
Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Ser Ser Ser
450 455 460
Thr Ala Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
465 470 475 480
His Leu Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser Arg Met
485 490 495
Glu Asn Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Phe Lys Phe
500 505 510
Tyr Leu Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys Leu Glu
515 520 525
Asp Glu Leu Gly Pro Leu Arg His Val Leu Asp Leu Thr Gln Ser Lys
530 535 540
Ser Phe Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile Arg Val
545 550 555 560
Thr Val Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys Gln Phe
565 570 575
Asp Asp Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp Ile Ala
580 585 590
Phe Cys Gln Ser Ile Ile Ser Thr Ser Pro Gln Gly Gly Gly Gly Ser
595 600 605
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Arg Ser Pro
610 615 620
Ile Thr Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys Glu Ala
625 630 635 640
Leu Asn Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu Val Glu
645 650 655
Val Val Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val Gln Thr
660 665 670
Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr Lys Leu
675 680 685
Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr Cys Pro
690 695 700
Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr Ala Asp
705 710 715 720
Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe Glu Cys
725 730 735
Lys Lys Pro Gly Gln Lys
740
<210> 54
<211> 551
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bscNHS76-scNHS76IL12aIL2GMCSF的第二多肽链（人hIL12bscNHS76链）
<400> 54
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Ser Ala Asp Gly Gly Gln Val Gln Leu Gln Glu Ser Gly
305 310 315 320
Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val
325 330 335
Ser Gly Tyr Ser Ile Ser Ser Gly Tyr Tyr Trp Gly Trp Ile Arg Gln
340 345 350
Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr His Ser Gly
355 360 365
Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val
370 375 380
Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala
385 390 395 400
Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Lys Trp Ser Lys Phe
405 410 415
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Ser Gly
420 425 430
Asp Gly Ser Ser Gly Gly Ser Gly Gly Ala Ser Ser Ser Glu Leu Thr
435 440 445
Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr
450 455 460
Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln
465 470 475 480
Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg
485 490 495
Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr
500 505 510
Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr
515 520 525
Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly
530 535 540
Gly Thr Lys Leu Thr Val Leu
545 550
<210> 55
<211> 732
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12bscNHS76-scNHS76IL12aIL2GMCSF的第一多肽链（人hscNHS76IL12aIL
2GMCSF链）
<400> 55
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Ser Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Lys Trp Ser Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ser Ser Gly Asp Gly Ser Ser Gly Gly Ser Gly
115 120 125
Gly Ala Ser Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala
130 135 140
Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser
145 150 155 160
Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu
165 170 175
Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe
180 185 190
Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala
195 200 205
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser
210 215 220
Gly Asn His Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
225 230 235 240
Ser Ala Asp Gly Gly Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly
245 250 255
Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser
260 265 270
Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr
275 280 285
Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr
290 295 300
Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu
305 310 315 320
Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser
325 330 335
Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu
340 345 350
Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu
355 360 365
Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala
370 375 380
Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val
385 390 395 400
Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile
405 410 415
Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile
420 425 430
Asp Arg Val Met Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr
450 455 460
Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met
465 470 475 480
Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met
485 490 495
Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His
500 505 510
Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn
515 520 525
Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser
530 535 540
Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe
545 550 555 560
Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn
565 570 575
Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly
580 585 590
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala
595 600 605
Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val Asn Ala Ile
610 615 620
Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr Ala Ala Glu
625 630 635 640
Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp Leu Gln Glu
645 650 655
Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln Gly Leu Arg
660 665 670
Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met Ala Ser His
675 680 685
Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys Ala Thr Gln
690 695 700
Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp Phe Leu Leu
705 710 715 720
Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
725 730
<210> 56
<211> 357
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12aIL2IL12bGMCSF的第一多肽链
<400> 56
Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg
1 5 10 15
Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys
20 25 30
Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile
35 40 45
Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu
50 55 60
His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr
65 70 75 80
Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu
85 90 95
Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe
100 105 110
Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile
115 120 125
Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu
130 135 140
Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala
145 150 155 160
Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe
165 170 175
Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser
180 185 190
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
195 200 205
Ala Pro Thr Ser Ser Ser Thr Ser Ser Ser Thr Ala Glu Ala Gln Gln
210 215 220
Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln His Leu Glu Gln Leu Leu
225 230 235 240
Met Asp Leu Gln Glu Leu Leu Ser Arg Met Glu Asn Tyr Arg Asn Leu
245 250 255
Lys Leu Pro Arg Met Leu Thr Phe Lys Phe Tyr Leu Pro Lys Gln Ala
260 265 270
Thr Glu Leu Lys Asp Leu Gln Cys Leu Glu Asp Glu Leu Gly Pro Leu
275 280 285
Arg His Val Leu Asp Leu Thr Gln Ser Lys Ser Phe Gln Leu Glu Asp
290 295 300
Ala Glu Asn Phe Ile Ser Asn Ile Arg Val Thr Val Val Lys Leu Lys
305 310 315 320
Gly Ser Asp Asn Thr Phe Glu Cys Gln Phe Asp Asp Glu Ser Ala Thr
325 330 335
Val Val Asp Phe Leu Arg Arg Trp Ile Ala Phe Cys Gln Ser Ile Ile
340 345 350
Ser Thr Ser Pro Gln
355
<210> 57
<211> 452
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12aIL2IL12bGMCSF的第二多肽链
<400> 57
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Arg Ser Pro Ile Thr
325 330 335
Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys Glu Ala Leu Asn
340 345 350
Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu Val Glu Val Val
355 360 365
Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val Gln Thr Arg Leu
370 375 380
Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr Lys Leu Lys Gly
385 390 395 400
Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr Cys Pro Pro Thr
405 410 415
Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr Ala Asp Phe Ile
420 425 430
Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe Glu Cys Lys Lys
435 440 445
Pro Gly Gln Lys
450
<210> 58
<211> 337
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12aIL7IL12bGMCSF的第一多肽链
<400> 58
Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg
1 5 10 15
Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys
20 25 30
Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile
35 40 45
Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu
50 55 60
His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr
65 70 75 80
Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu
85 90 95
Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe
100 105 110
Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile
115 120 125
Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu
130 135 140
Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala
145 150 155 160
Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe
165 170 175
Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser
180 185 190
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
195 200 205
Glu Cys His Ile Lys Asp Lys Glu Gly Lys Ala Tyr Glu Ser Val Leu
210 215 220
Met Ile Ser Ile Asp Glu Leu Asp Lys Met Thr Gly Thr Asp Ser Asn
225 230 235 240
Cys Pro Asn Asn Glu Pro Asn Phe Phe Arg Lys His Val Cys Asp Asp
245 250 255
Thr Lys Glu Ala Ala Phe Leu Asn Arg Ala Ala Arg Lys Leu Lys Gln
260 265 270
Phe Leu Lys Met Asn Ile Ser Glu Glu Phe Asn Val His Leu Leu Thr
275 280 285
Val Ser Gln Gly Thr Gln Thr Leu Val Asn Cys Thr Ser Lys Glu Glu
290 295 300
Lys Asn Val Lys Glu Gln Lys Lys Asn Asp Ala Cys Phe Leu Lys Arg
305 310 315 320
Leu Leu Arg Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Lys Gly Ser
325 330 335
Ile
<210> 59
<211> 452
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12aIL7IL12bGMCSF的第二多肽链
<400> 59
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Arg Ser Pro Ile Thr
325 330 335
Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys Glu Ala Leu Asn
340 345 350
Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu Val Glu Val Val
355 360 365
Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val Gln Thr Arg Leu
370 375 380
Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr Lys Leu Lys Gly
385 390 395 400
Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr Cys Pro Pro Thr
405 410 415
Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr Ala Asp Phe Ile
420 425 430
Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe Glu Cys Lys Lys
435 440 445
Pro Gly Gln Lys
450
<210> 60
<211> 337
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12aIL21IL12bGMCSF的第一多肽链
<400> 60
Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg
1 5 10 15
Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys
20 25 30
Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile
35 40 45
Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu
50 55 60
His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr
65 70 75 80
Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu
85 90 95
Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe
100 105 110
Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile
115 120 125
Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu
130 135 140
Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala
145 150 155 160
Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe
165 170 175
Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser
180 185 190
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
195 200 205
His Lys Ser Ser Pro Gln Gly Pro Asp Arg Leu Leu Ile Arg Leu Arg
210 215 220
His Leu Ile Asp Ile Val Glu Gln Leu Lys Ile Tyr Glu Asn Asp Leu
225 230 235 240
Asp Pro Glu Leu Leu Ser Ala Pro Gln Asp Val Lys Gly His Cys Glu
245 250 255
His Ala Ala Phe Ala Cys Phe Gln Lys Ala Lys Leu Lys Pro Ser Asn
260 265 270
Pro Gly Asn Asn Lys Thr Phe Ile Ile Asp Leu Val Ala Gln Leu Arg
275 280 285
Arg Arg Leu Pro Ala Arg Arg Gly Gly Lys Lys Gln Lys His Ile Ala
290 295 300
Lys Cys Pro Ser Cys Asp Ser Tyr Glu Lys Arg Thr Pro Lys Glu Phe
305 310 315 320
Leu Glu Arg Leu Lys Trp Leu Leu Gln Lys Met Ile His Gln His Leu
325 330 335
Ser
<210> 61
<211> 452
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> mIL12aIL21IL12bGMCSF的第二多肽链
<400> 61
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Arg Ser Pro Ile Thr
325 330 335
Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys Glu Ala Leu Asn
340 345 350
Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu Val Glu Val Val
355 360 365
Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val Gln Thr Arg Leu
370 375 380
Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr Lys Leu Lys Gly
385 390 395 400
Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr Cys Pro Pro Thr
405 410 415
Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr Ala Asp Phe Ile
420 425 430
Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe Glu Cys Lys Lys
435 440 445
Pro Gly Gln Lys
450
<210> 62
<211> 345
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12aIL2IL12bGMCSF的第一多肽链
<400> 62
Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu
1 5 10 15
His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys
20 25 30
Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp
35 40 45
His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu
50 55 60
Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr
65 70 75 80
Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe
85 90 95
Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr
100 105 110
Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys
115 120 125
Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu
130 135 140
Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser
145 150 155 160
Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu
165 170 175
Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser
180 185 190
Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
195 200 205
Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu
210 215 220
Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile
225 230 235 240
Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe
245 250 255
Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu
260 265 270
Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys
275 280 285
Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile
290 295 300
Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala
305 310 315 320
Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe
325 330 335
Cys Gln Ser Ile Ile Ser Thr Leu Thr
340 345
<210> 63
<211> 448
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12aIL2IL12bGMCSF的第二多肽链
<400> 63
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His
325 330 335
Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp
340 345 350
Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe
355 360 365
Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys
370 375 380
Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met
385 390 395 400
Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser
405 410 415
Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys
420 425 430
Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
435 440 445
<210> 64
<211> 364
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12aIL7IL12bGMCSF的第一多肽链
<400> 64
Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu
1 5 10 15
His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys
20 25 30
Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp
35 40 45
His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu
50 55 60
Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr
65 70 75 80
Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe
85 90 95
Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr
100 105 110
Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys
115 120 125
Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu
130 135 140
Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser
145 150 155 160
Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu
165 170 175
Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser
180 185 190
Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
195 200 205
Gly Gly Gly Ser Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr
210 215 220
Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys
225 230 235 240
Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg
245 250 255
His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala
260 265 270
Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp
275 280 285
Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys
290 295 300
Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln
305 310 315 320
Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys
325 330 335
Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr
340 345 350
Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu His
355 360
<210> 65
<211> 448
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12aIL7IL12bGMCSF的第二多肽链
<400> 65
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His
325 330 335
Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp
340 345 350
Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe
355 360 365
Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys
370 375 380
Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met
385 390 395 400
Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser
405 410 415
Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys
420 425 430
Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
435 440 445
<210> 66
<211> 345
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12aIL21IL12bGMCSF的第一多肽链
<400> 66
Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu
1 5 10 15
His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys
20 25 30
Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp
35 40 45
His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu
50 55 60
Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr
65 70 75 80
Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe
85 90 95
Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr
100 105 110
Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys
115 120 125
Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu
130 135 140
Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser
145 150 155 160
Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu
165 170 175
Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser
180 185 190
Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
195 200 205
Gly Gly Gly Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln
210 215 220
Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val
225 230 235 240
Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp
245 250 255
Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr
260 265 270
Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg
275 280 285
Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr
290 295 300
Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu
305 310 315 320
Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser
325 330 335
Ser Arg Thr His Gly Ser Glu Asp Ser
340 345
<210> 67
<211> 448
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> hIL12aIL21IL12bGMCSF的第二多肽链
<400> 67
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His
325 330 335
Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp
340 345 350
Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe
355 360 365
Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys
370 375 380
Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met
385 390 395 400
Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser
405 410 415
Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys
420 425 430
Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
435 440 445
<210> 68
<211> 2472
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 编码mIL12bIL12aIL2GMCSF的核酸
<400> 68
atgtgggagc tggagaaaga cgtttatgtt gtagaggtgg actggactcc cgatgcccct 60
ggagaaacag tgaacctcac ctgtgacacg cctgaagaag atgacatcac ctggacctca 120
gaccagagac atggagtcat aggctctgga aagaccctga ccatcactgt caaagagttt 180
ctagatgctg gccagtacac ctgccacaaa ggaggcgaga ctctgagcca ctcacatctg 240
ctgctccaca agaaggaaaa tggaatttgg tccactgaaa ttttaaaaaa tttcaaaaac 300
aagactttcc tgaagtgtga agcaccaaat tactccggac ggttcacgtg ctcatggctg 360
gtgcaaagaa acatggactt gaagttcaac atcaagagca gtagcagttc ccctgactct 420
cgggcagtga catgtggaat ggcgtctctg tctgcagaga aggtcacact ggaccaaagg 480
gactatgaga agtattcagt gtcctgccag gaggatgtca cctgcccaac tgccgaggag 540
accctgccca ttgaactggc gttggaagca cggcagcaga ataaatatga gaactacagc 600
accagcttct tcatcaggga catcatcaaa ccagacccgc ccaagaactt gcagatgaag 660
cctttgaaga actcacaggt ggaggtcagc tgggagtacc ctgactcctg gagcactccc 720
cattcctact tctccctcaa gttctttgtt cgaatccagc gcaagaaaga aaagatgaag 780
gagacagagg aggggtgtaa ccagaaaggt gcgttcctcg tagagaagac atctaccgaa 840
gtccaatgca aaggcgggaa tgtctgcgtg caagctcagg atcgctatta caattcctcg 900
tgcagcaagt gggcatgtgt tccctgcagg gtccgatccg gaggcggtgg aagtggcggt 960
ggaggctctg gaggtggcgg aagcagggtc attccagtct ctggacctgc caggtgtctt 1020
agccagtccc gaaacctgct gaagaccaca gatgacatgg tgaagacggc cagagaaaaa 1080
ctgaaacatt attcctgcac tgctgaagac atcgatcatg aagacatcac acgggaccaa 1140
accagcacat tgaagacctg tttaccactg gaactacaca agaacgagag ttgcctggct 1200
actagagaga cttcttccac aacaagaggg agctgcctgc ccccacagaa gacgtctttg 1260
atgatgaccc tgtgccttgg tagcatctat gaggacttga agatgtacca gacagagttc 1320
caggccatca acgcagcact tcagaatcac aaccatcagc agatcattct agacaagggc 1380
atgctggtgg ccatcgatga gctgatgcag tctctgaatc ataatggcga gactctgcgc 1440
cagaaacctc ctgtgggaga agcagaccct tacagagtga aaatgaagct ctgcatcctg 1500
cttcacgcct tcagcacccg cgtcgtgacc atcaacaggg tgatgggcta tctgagctcc 1560
gccggtggag gaggttctgg aggcggtgga agtggtggcg gaggtagcgc acccacttca 1620
agctccactt caagctctac agcggaagca cagcagcagc agcagcagca gcagcagcag 1680
cagcagcacc tggagcagct gttgatggac ctacaggagc tcctgagcag gatggagaat 1740
tacaggaacc tgaaactccc caggatgctc accttcaaat tttacttgcc caagcaggcc 1800
acagaattga aagatcttca gtgcctagaa gatgaacttg gacctctgcg gcatgttctg 1860
gatttgactc aaagcaaaag ctttcaattg gaagatgctg agaatttcat cagcaatatc 1920
agagtaactg ttgtaaaact aaagggctct gacaacacat ttgagtgcca attcgatgat 1980
gagtcagcaa ctgtggtgga ctttctgagg agatggatag ccttctgtca aagcatcatc 2040
tcaacaagcc ctcaaggcgg agggggttca ggtgggggcg ggagcggagg tggcggatcg 2100
gcacccaccc gctcacccat cactgtcacc cggccttgga agcatgtaga ggccatcaaa 2160
gaagccctga acctcctgga tgacatgcct gtcacgttga atgaagaggt agaagtcgtc 2220
tctaacgagt tctccttcaa gaagctaaca tgtgtgcaga cccgcctgaa gatattcgag 2280
cagggtctac ggggcaattt caccaaactc aagggcgcct tgaacatgac agccagctac 2340
taccagacat actgcccccc aactccggaa acggactgtg aaacacaagt taccacctat 2400
gcggatttca tagacagcct taaaaccttt ctgactgata tcccctttga atgcaaaaaa 2460
ccaggccaaa aa 2472
<210> 69
<211> 3948
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 编码mIL12bIL12aIL2DiaNHS76F8GMCSF-Thr的核酸
<400> 69
atgtgggagc tggagaaaga cgtttatgtt gtagaggtgg actggactcc cgatgcccct 60
ggagaaacag tgaacctcac ctgtgacacg cctgaagaag atgacatcac ctggacctca 120
gaccagagac atggagtcat aggctctgga aagaccctga ccatcactgt caaagagttt 180
ctagatgctg gccagtacac ctgccacaaa ggaggcgaga ctctgagcca ctcacatctg 240
ctgctccaca agaaggaaaa tggaatttgg tccactgaaa ttttaaaaaa tttcaaaaac 300
aagactttcc tgaagtgtga agcaccaaat tactccggac ggttcacgtg ctcatggctg 360
gtgcaaagaa acatggactt gaagttcaac atcaagagca gtagcagttc ccctgactct 420
cgggcagtga catgtggaat ggcgtctctg tctgcagaga aggtcacact ggaccaaagg 480
gactatgaga agtattcagt gtcctgccag gaggatgtca cctgcccaac tgccgaggag 540
accctgccca ttgaactggc gttggaagca cggcagcaga ataaatatga gaactacagc 600
accagcttct tcatcaggga catcatcaaa ccagacccgc ccaagaactt gcagatgaag 660
cctttgaaga actcacaggt ggaggtcagc tgggagtacc ctgactcctg gagcactccc 720
cattcctact tctccctcaa gttctttgtt cgaatccagc gcaagaaaga aaagatgaag 780
gagacagagg aggggtgtaa ccagaaaggt gcgttcctcg tagagaagac atctaccgaa 840
gtccaatgca aaggcgggaa tgtctgcgtg caagctcagg atcgctatta caattcctcg 900
tgcagcaagt gggcatgtgt tccctgcagg gtccgatccg gaggcggtgg aagtggcggt 960
ggaggctctg gaggtggcgg aagcagggtc attccagtct ctggacctgc caggtgtctt 1020
agccagtccc gaaacctgct gaagaccaca gatgacatgg tgaagacggc cagagaaaaa 1080
ctgaaacatt attcctgcac tgctgaagac atcgatcatg aagacatcac acgggaccaa 1140
accagcacat tgaagacctg tttaccactg gaactacaca agaacgagag ttgcctggct 1200
actagagaga cttcttccac aacaagaggg agctgcctgc ccccacagaa gacgtctttg 1260
atgatgaccc tgtgccttgg tagcatctat gaggacttga agatgtacca gacagagttc 1320
caggccatca acgcagcact tcagaatcac aaccatcagc agatcattct agacaagggc 1380
atgctggtgg ccatcgatga gctgatgcag tctctgaatc ataatggcga gactctgcgc 1440
cagaaacctc ctgtgggaga agcagaccct tacagagtga aaatgaagct ctgcatcctg 1500
cttcacgcct tcagcacccg cgtcgtgacc atcaacaggg tgatgggcta tctgagctcc 1560
gccggtggag gaggttctgg aggcggtgga agtggtggcg gaggtagcgc acccacttca 1620
agctccactt caagctctac agcggaagca cagcagcagc agcagcagca gcagcagcag 1680
cagcagcacc tggagcagct gttgatggac ctacaggagc tcctgagcag gatggagaat 1740
tacaggaacc tgaaactccc caggatgctc accttcaaat tttacttgcc caagcaggcc 1800
acagaattga aagatcttca gtgcctagaa gatgaacttg gacctctgcg gcatgttctg 1860
gatttgactc aaagcaaaag ctttcaattg gaagatgctg agaatttcat cagcaatatc 1920
agagtaactg ttgtaaaact aaagggctct gacaacacat ttgagtgcca attcgatgat 1980
gagtcagcaa ctgtggtgga ctttctgagg agatggatag ccttctgtca aagcatcatc 2040
tcaacaagcc ctcaaggcgg agggggttca ctcgtcccaa gaggaagtgg aggtggcgga 2100
tcgcaggtgc agctgcagga gagcggcccc ggcctggtga agcccagcga gaccctgagc 2160
ctgacctgcg ccgtgagcgg ctacagcatc agcagcggct actactgggg ctggatcagg 2220
cagccccccg gcaagggcct ggagtggatc ggcagcatct accacagcgg cagcacctac 2280
tacaacccca gcctgaagag cagggtgacc atcagcgtgg acaccagcaa gaaccagttc 2340
agcctgaagc tgagcagcgt gaccgccgcc gacaccgccg tgtactactg cgccaggggc 2400
aagtggagca agttcgacta ctggggccag ggcaccctgg tgaccgtgag cagcggcggt 2460
agcggagggg aaattgtgtt gacgcagtct ccaggcaccc tgtctttgtc tccaggggaa 2520
agagccaccc tctcctgcag ggccagtcag agtgttagca tgccgttttt agcctggtac 2580
cagcagaaac ctggccaggc tcccaggctc ctcatctatg gtgcatccag cagggccact 2640
ggcatcccag acaggttcag tggcagtggg tctgggacag acttcactct caccatcagc 2700
agactggagc ctgaagattt tgcagtgtat tactgtcagc agatgcgtgg tcggccgccg 2760
acgttcggcc aagggaccaa ggtggaaatc aaatcttcaa gtagcggttc aagttcctct 2820
ggatcgtcaa gctctggtga ggtgcagctg ttggagtctg ggggaggctt ggtacagcct 2880
ggggggtccc tgagactctc ctgtgcagcc tctggattca cctttagcct gtttacgatg 2940
agctgggtcc gccaggctcc agggaagggg ctggagtggg tctcagctat tagtggtagt 3000
ggtggtagca catactacgc agactccgtg aagggccggt tcaccatctc cagagacaat 3060
tccaagaaca cgctgtatct gcaaatgaac agcctgagag ccgaggacac ggccgtatat 3120
tactgtgcga aaagtactca tttgtatctt tttgactact ggggccaggg aaccctggtc 3180
accgtctcca gtggcggtag cggagggagc agcgagctga cccaggaccc cgccgtgagc 3240
gtggccctgg gccagaccgt gaggatcacc tgccagggcg acagcctgag gagctactac 3300
gccagctggt accagcagaa gcccggccag gcccccgtgc tggtgatcta cggcaagaac 3360
aacaggccca gcggcatccc cgacaggttc agcggcagca gcagcggcaa caccgccagc 3420
ctgaccatca ccggcgccca ggccgaggac gaggccgact actactgcaa cagcagggac 3480
agcagcggca accacgtggt gttcggcggc ggcaccaagc tgaccgtgct gtcttcaagt 3540
agcggtctcg tcccaagagg aagttcaagc tctggtgcac ccacccgctc acccatcact 3600
gtcacccggc cttggaagca tgtagaggcc atcaaagaag ccctgaacct cctggatgac 3660
atgcctgtca cgttgaatga agaggtagaa gtcgtctcta acgagttctc cttcaagaag 3720
ctaacatgtg tgcagacccg cctgaagata ttcgagcagg gtctacgggg caatttcacc 3780
aaactcaagg gcgccttgaa catgacagcc agctactacc agacatactg ccccccaact 3840
ccggaaacgg actgtgaaac acaagttacc acctatgcgg atttcataga cagccttaaa 3900
acctttctga ctgatatccc ctttgaatgc aaaaaaccag gccaaaaa 3948
<210> 70
<211> 2412
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 编码mIL12bIL12aIL7GMCSF的核酸
<400> 70
atgtgggagc tggagaaaga cgtttatgtt gtagaggtgg actggactcc cgatgcccct 60
ggagaaacag tgaacctcac ctgtgacacg cctgaagaag atgacatcac ctggacctca 120
gaccagagac atggagtcat aggctctgga aagaccctga ccatcactgt caaagagttt 180
ctagatgctg gccagtacac ctgccacaaa ggaggcgaga ctctgagcca ctcacatctg 240
ctgctccaca agaaggaaaa tggaatttgg tccactgaaa ttttaaaaaa tttcaaaaac 300
aagactttcc tgaagtgtga agcaccaaat tactccggac ggttcacgtg ctcatggctg 360
gtgcaaagaa acatggactt gaagttcaac atcaagagca gtagcagttc ccctgactct 420
cgggcagtga catgtggaat ggcgtctctg tctgcagaga aggtcacact ggaccaaagg 480
gactatgaga agtattcagt gtcctgccag gaggatgtca cctgcccaac tgccgaggag 540
accctgccca ttgaactggc gttggaagca cggcagcaga ataaatatga gaactacagc 600
accagcttct tcatcaggga catcatcaaa ccagacccgc ccaagaactt gcagatgaag 660
cctttgaaga actcacaggt ggaggtcagc tgggagtacc ctgactcctg gagcactccc 720
cattcctact tctccctcaa gttctttgtt cgaatccagc gcaagaaaga aaagatgaag 780
gagacagagg aggggtgtaa ccagaaaggt gcgttcctcg tagagaagac atctaccgaa 840
gtccaatgca aaggcgggaa tgtctgcgtg caagctcagg atcgctatta caattcctcg 900
tgcagcaagt gggcatgtgt tccctgcagg gtccgatccg gaggcggtgg aagtggcggt 960
ggaggctctg gaggtggcgg aagcagggtc attccagtct ctggacctgc caggtgtctt 1020
agccagtccc gaaacctgct gaagaccaca gatgacatgg tgaagacggc cagagaaaaa 1080
ctgaaacatt attcctgcac tgctgaagac atcgatcatg aagacatcac acgggaccaa 1140
accagcacat tgaagacctg tttaccactg gaactacaca agaacgagag ttgcctggct 1200
actagagaga cttcttccac aacaagaggg agctgcctgc ccccacagaa gacgtctttg 1260
atgatgaccc tgtgccttgg tagcatctat gaggacttga agatgtacca gacagagttc 1320
caggccatca acgcagcact tcagaatcac aaccatcagc agatcattct agacaagggc 1380
atgctggtgg ccatcgatga gctgatgcag tctctgaatc ataatggcga gactctgcgc 1440
cagaaacctc ctgtgggaga agcagaccct tacagagtga aaatgaagct ctgcatcctg 1500
cttcacgcct tcagcacccg cgtcgtgacc atcaacaggg tgatgggcta tctgagctcc 1560
gccggtggag gaggttctgg aggcggtgga agtggtggcg gaggtagcga gtgccacatt 1620
aaagacaaag aaggtaaagc atatgagagt gtactgatga tcagcatcga tgaattggac 1680
aaaatgacag gaactgatag taattgcccg aataatgaac caaacttttt tagaaaacat 1740
gtatgtgatg atacaaagga agctgctttt ctaaatcgtg ctgctcgcaa gttgaagcaa 1800
tttcttaaaa tgaatatcag tgaagaattc aatgtccact tactaacagt atcacaaggc 1860
acacaaacac tggtgaactg cacaagtaag gaagaaaaaa acgtaaagga acagaaaaag 1920
aatgatgcat gtttcctaaa gagactactg agagaaataa aaacttgttg gaataaaatt 1980
ttgaagggca gtataggcgg agggggttca ggtgggggcg ggagcggagg tggcggatcg 2040
gcacccaccc gctcacccat cactgtcacc cggccttgga agcatgtaga ggccatcaaa 2100
gaagccctga acctcctgga tgacatgcct gtcacgttga atgaagaggt agaagtcgtc 2160
tctaacgagt tctccttcaa gaagctaaca tgtgtgcaga cccgcctgaa gatattcgag 2220
cagggtctac ggggcaattt caccaaactc aagggcgcct tgaacatgac agccagctac 2280
taccagacat actgcccccc aactccggaa acggactgtg aaacacaagt taccacctat 2340
gcggatttca tagacagcct taaaaccttt ctgactgata tcccctttga atgcaaaaaa 2400
ccaggccaaa aa 2412
<210> 71
<211> 2412
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 编码mIL12bIL12aIL21GMCSF的核酸
<400> 71
atgtgggagc tggagaaaga cgtttatgtt gtagaggtgg actggactcc cgatgcccct 60
ggagaaacag tgaacctcac ctgtgacacg cctgaagaag atgacatcac ctggacctca 120
gaccagagac atggagtcat aggctctgga aagaccctga ccatcactgt caaagagttt 180
ctagatgctg gccagtacac ctgccacaaa ggaggcgaga ctctgagcca ctcacatctg 240
ctgctccaca agaaggaaaa tggaatttgg tccactgaaa ttttaaaaaa tttcaaaaac 300
aagactttcc tgaagtgtga agcaccaaat tactccggac ggttcacgtg ctcatggctg 360
gtgcaaagaa acatggactt gaagttcaac atcaagagca gtagcagttc ccctgactct 420
cgggcagtga catgtggaat ggcgtctctg tctgcagaga aggtcacact ggaccaaagg 480
gactatgaga agtattcagt gtcctgccag gaggatgtca cctgcccaac tgccgaggag 540
accctgccca ttgaactggc gttggaagca cggcagcaga ataaatatga gaactacagc 600
accagcttct tcatcaggga catcatcaaa ccagacccgc ccaagaactt gcagatgaag 660
cctttgaaga actcacaggt ggaggtcagc tgggagtacc ctgactcctg gagcactccc 720
cattcctact tctccctcaa gttctttgtt cgaatccagc gcaagaaaga aaagatgaag 780
gagacagagg aggggtgtaa ccagaaaggt gcgttcctcg tagagaagac atctaccgaa 840
gtccaatgca aaggcgggaa tgtctgcgtg caagctcagg atcgctatta caattcctcg 900
tgcagcaagt gggcatgtgt tccctgcagg gtccgatccg gaggcggtgg aagtggcggt 960
ggaggctctg gaggtggcgg aagcagggtc attccagtct ctggacctgc caggtgtctt 1020
agccagtccc gaaacctgct gaagaccaca gatgacatgg tgaagacggc cagagaaaaa 1080
ctgaaacatt attcctgcac tgctgaagac atcgatcatg aagacatcac acgggaccaa 1140
accagcacat tgaagacctg tttaccactg gaactacaca agaacgagag ttgcctggct 1200
actagagaga cttcttccac aacaagaggg agctgcctgc ccccacagaa gacgtctttg 1260
atgatgaccc tgtgccttgg tagcatctat gaggacttga agatgtacca gacagagttc 1320
caggccatca acgcagcact tcagaatcac aaccatcagc agatcattct agacaagggc 1380
atgctggtgg ccatcgatga gctgatgcag tctctgaatc ataatggcga gactctgcgc 1440
cagaaacctc ctgtgggaga agcagaccct tacagagtga aaatgaagct ctgcatcctg 1500
cttcacgcct tcagcacccg cgtcgtgacc atcaacaggg tgatgggcta tctgagctcc 1560
gccggtggag gaggttctgg aggcggtgga agtggtggcg gaggtagcca taaatcaagc 1620
ccccaagggc cagatcgcct cctgattaga cttcgtcacc ttattgacat tgttgaacag 1680
ctgaaaatct atgaaaatga cttggatcct gaacttctat cagctccaca agatgtaaag 1740
gggcactgtg agcatgcagc ttttgcctgt tttcagaagg ccaaactcaa gccatcaaac 1800
cctggaaaca ataagacatt catcattgac ctcgtggccc agctcaggag gaggctgcct 1860
gccaggaggg gaggaaagaa acagaagcac atagctaaat gcccttcctg tgattcgtat 1920
gagaaaagga cacccaaaga attcctagaa agactaaaat ggctccttca aaagatgatt 1980
catcagcatc tctccggcgg agggggttca ggtgggggcg ggagcggagg tggcggatcg 2040
gcacccaccc gctcacccat cactgtcacc cggccttgga agcatgtaga ggccatcaaa 2100
gaagccctga acctcctgga tgacatgcct gtcacgttga atgaagaggt agaagtcgtc 2160
tctaacgagt tctccttcaa gaagctaaca tgtgtgcaga cccgcctgaa gatattcgag 2220
cagggtctac ggggcaattt caccaaactc aagggcgcct tgaacatgac agccagctac 2280
taccagacat actgcccccc aactccggaa acggactgtg aaacacaagt taccacctat 2340
gcggatttca tagacagcct taaaaccttt ctgactgata tcccctttga atgcaaaaaa 2400
ccaggccaaa aa 2412
<210> 72
<211> 2613
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 编码mIL12aIL2IL12bGMCSF的核酸
<400> 72
atgtgtcaat cacgctacct cctctttttg gccacccttg ccctcctaaa ccacctcagt 60
ttggccaggg tcattccagt ctctggacct gccaggtgtc ttagccagtc ccgaaacctg 120
ctgaagacca cagatgacat ggtgaagacg gccagagaaa aactgaaaca ttattcctgc 180
actgctgaag acatcgatca tgaagacatc acacgggacc aaaccagcac attgaagacc 240
tgtttaccac tggaactaca caagaacgag agttgcctgg ctactagaga gacttcttcc 300
acaacaagag ggagctgcct gcccccacag aagacgtctt tgatgatgac cctgtgcctt 360
ggtagcatct atgaggactt gaagatgtac cagacagagt tccaggccat caacgcagca 420
cttcagaatc acaaccatca gcagatcatt ctagacaagg gcatgctggt ggccatcgat 480
gagctgatgc agtctctgaa tcataatggc gagactctgc gccagaaacc tcctgtggga 540
gaagcagacc cttacagagt gaaaatgaag ctctgcatcc tgcttcacgc cttcagcacc 600
cgcgtcgtga ccatcaacag ggtgatgggc tatctgagct ccgccggtgg aggaggttct 660
ggaggcggtg gaagtggtgg cggaggtagc gcacccactt caagctccac ttcaagctct 720
acagcggaag cacagcagca gcagcagcag cagcagcagc agcagcagca cctggagcag 780
ctgttgatgg acctacagga gctcctgagc aggatggaga attacaggaa cctgaaactc 840
cccaggatgc tcaccttcaa attttacttg cccaagcagg ccacagaatt gaaagatctt 900
cagtgcctag aagatgaact tggacctctg cggcatgttc tggatttgac tcaaagcaaa 960
agctttcaat tggaagatgc tgagaatttc atcagcaata tcagagtaac tgttgtaaaa 1020
ctaaagggct ctgacaacac atttgagtgc caattcgatg atgagtcagc aactgtggtg 1080
gactttctga ggagatggat agccttctgt caaagcatca tctcaacaag ccctcaagag 1140
ggcagaggaa gtcttctaac atgcggtgac gtggaggaga atcccggccc tatgtgtcct 1200
cagaagctaa ccatctcctg gtttgccatc gttttgctgg tgtctccact catggccatg 1260
tgggagctgg agaaagacgt ttatgttgta gaggtggact ggactcccga tgcccctgga 1320
gaaacagtga acctcacctg tgacacgcct gaagaagatg acatcacctg gacctcagac 1380
cagagacatg gagtcatagg ctctggaaag accctgacca tcactgtcaa agagtttcta 1440
gatgctggcc agtacacctg ccacaaagga ggcgagactc tgagccactc acatctgctg 1500
ctccacaaga aggaaaatgg aatttggtcc actgaaattt taaaaaattt caaaaacaag 1560
actttcctga agtgtgaagc accaaattac tccggacggt tcacgtgctc atggctggtg 1620
caaagaaaca tggacttgaa gttcaacatc aagagcagta gcagttcccc tgactctcgg 1680
gcagtgacat gtggaatggc gtctctgtct gcagagaagg tcacactgga ccaaagggac 1740
tatgagaagt attcagtgtc ctgccaggag gatgtcacct gcccaactgc cgaggagacc 1800
ctgcccattg aactggcgtt ggaagcacgg cagcagaata aatatgagaa ctacagcacc 1860
agcttcttca tcagggacat catcaaacca gacccgccca agaacttgca gatgaagcct 1920
ttgaagaact cacaggtgga ggtcagctgg gagtaccctg actcctggag cactccccat 1980
tcctacttct ccctcaagtt ctttgttcga atccagcgca agaaagaaaa gatgaaggag 2040
acagaggagg ggtgtaacca gaaaggtgcg ttcctcgtag agaagacatc taccgaagtc 2100
caatgcaaag gcgggaatgt ctgcgtgcaa gctcaggatc gctattacaa ttcctcgtgc 2160
agcaagtggg catgtgttcc ctgcagggtc cgatccggag gcggtggaag tggcggtgga 2220
ggctctggag gtggcggaag cgcacccacc cgctcaccca tcactgtcac ccggccttgg 2280
aagcatgtag aggccatcaa agaagccctg aacctcctgg atgacatgcc tgtcacgttg 2340
aatgaagagg tagaagtcgt ctctaacgag ttctccttca agaagctaac atgtgtgcag 2400
acccgcctga agatattcga gcagggtcta cggggcaatt tcaccaaact caagggcgcc 2460
ttgaacatga cagccagcta ctaccagaca tactgccccc caactccgga aacggactgt 2520
gaaacacaag ttaccaccta tgcggatttc atagacagcc ttaaaacctt tctgactgat 2580
atcccctttg aatgcaaaaa accaggccaa aaa 2613
<210> 73
<211> 15
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 连接子1--用于细胞因子之间、细胞因子和靶向之间的连接
<400> 73
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 74
<211> 16
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 连接子2--细胞因子和靶向之间的连接
<400> 74
Gly Gly Gly Gly Ser Leu Val Pro Arg Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 75
<211> 15
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 连接子3--用于细胞因子之间、细胞因子和靶向之间的连接
<400> 75
Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly
1 5 10 15
<210> 76
<211> 15
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 连接子4--细胞因子和靶向之间的连接
<400> 76
Ser Ser Ser Ser Gly Leu Val Pro Arg Gly Ser Ser Ser Ser Gly
1 5 10 15

Claims (34)

1.液体制剂，其包括油相溶剂系统和蛋白质，其中所述油相溶剂系统包括油相溶剂，所述油相溶剂的质量分数为约50％以上。
2.根据权利要求1所述的液体制剂，其中所述油相溶剂选自以下组：甘油、丙二醇、聚乙二醇、聚乙烯吡咯烷酮、甘露醇、山梨醇、聚氧丙烯和氨基丁三醇。
3.根据权利要求1-2中任一项所述的液体制剂，其中所述油相溶剂的质量分数为约60％以上。
4.根据权利要求1-3中任一项所述的液体制剂，其中所述油相溶剂的质量分数为约70％以上。
5.根据权利要求1-4中任一项所述的液体制剂，其中所述蛋白质的质量分数为约1％-约50％。
6.根据权利要求1-5中任一项所述的液体制剂，其中所述蛋白质包括细胞因子和/或抗体。
7.根据权利要求6所述的液体制剂，其中所述细胞因子包括选自下组的两种或更多种：IL12、IL2、GMCSF、IL7、IL15、IL21和FLT3L。
8.根据权利要求6-7中任一项所述的液体制剂，其中所述细胞因子源自哺乳动物。
9.根据权利要求1-8中任一项所述的液体制剂，其中所述蛋白质包括融合蛋白，且所述融合蛋白中包含选自下组的至少两种细胞因子：IL12、IL2、GMCSF、IL7、IL15、IL21和FLT3L。
10.根据权利要求1-9中任一项所述的液体制剂，其中所述蛋白质包括融合蛋白，且所述融合蛋白中包含选自以下的任一组细胞因子：
a)IL12、IL2和GMSCF；
b)IL12、IL7和GMSCF；
c)IL12、IL15和GMSCF；
d)IL12、IL21和GMSCF；
e)IL12、IL2和FLT3L；
f)IL12、IL7和FLT3L；
g)IL12、IL15和FLT3L；以及，
h)IL12、IL21和FLT3L。
11.根据权利要求1-10中任一项所述的液体制剂，其中所述蛋白质还包括靶向部分。
12.根据权利要求11所述的液体制剂，其中所述靶向部分能够特异性识别和/或结合肿瘤相关抗原。
13.根据权利要求12所述的液体制剂，其中所述肿瘤相关抗原选自下组：纤连蛋白的EDB结构域、纤连蛋白的EDA结构域和细胞坏死区域(necrotic regions)。
14.根据权利要求11-13中任一项所述的液体制剂，其中所述靶向部分包括抗体或其抗原结合片段。
15.根据权利要求11-14中任一项所述的液体制剂，其中所述靶向部分包含下组中任一项所示的氨基酸序列：SEQ ID NO:1-15。
16.根据权利要求1-15中任一项所述的液体制剂，其中所述蛋白质包含下组中任一项所示的氨基酸序列：SEQ ID NO:32-67。
17.根据权利要求1-16中任一项所述的液体制剂，其中所述蛋白质为单链蛋白质。
18.根据权利要求17所述的液体制剂，其中所述单链蛋白质包含下组中任一项所示的氨基酸序列：SEQ ID NO:32-51。
19.根据权利要求1-18中任一项所述的液体制剂，其中所述蛋白质为由第一多肽链及第二多肽链组成的二聚体，所述第一多肽链不同于所述第二多肽链。
20.根据权利要求19所述的液体制剂，其中所述第一多肽链包含IL12a，所述第二多肽链包含IL12b。
21.根据权利要求19-20中任一项所述的液体制剂，其中IL2或其功能性片段位于所述第一多肽链中或所述第二多肽链中，GMCSF或其功能性片段位于所述第一多肽链中或所述第二多肽链中，且所述一个或多个靶向部分各自独立地位于所述第一多肽链中或所述第二多肽链中。
22.根据权利要求19-21中任一项所述的液体制剂，其中在所述第一多肽链中，从N端到C端依次包含所述IL2或其功能性片段、所述IL12a或其功能性片段和所述GMCSF或其功能性片段。
23.根据权利要求19-22中任一项所述的液体制剂，其中在所述第一多肽链中，从N端到C端依次包含所述靶向部分、所述IL12a或其功能性片段、所述IL2或其功能性片段以及所述GMCSF或其功能性片段。
24.根据权利要求19-23中任一项所述的液体制剂，其中在所述第二多肽链中，从N端到C端依次包含所述IL12b或其功能性片段和所述靶向部分。
25.根据权利要求19-24中任一项所述的液体制剂，其中，
a)所述第一多肽链包含SEQ ID NO:53所示的氨基酸序列且所述第二多肽链包含SEQID NO:52所示的氨基酸序列；
b)所述第一多肽链包含SEQ ID NO:55所示的氨基酸序列且所述第二多肽链包含SEQID NO:54所示的氨基酸序列；
c)所述第一多肽链包含SEQ ID NO:56所示的氨基酸序列且所述第二多肽链包含SEQID NO:57所示的氨基酸序列；
d)所述第一多肽链包含SEQ ID NO:58所示的氨基酸序列且所述第二多肽链包含SEQID NO:59所示的氨基酸序列；
e)所述第一多肽链包含SEQ ID NO:60所示的氨基酸序列且所述第二多肽链包含SEQID NO:61所示的氨基酸序列；
f)所述第一多肽链包含SEQ ID NO:62所示的氨基酸序列且所述第二多肽链包含SEQID NO:63所示的氨基酸序列；
g)所述第一多肽链包含SEQ ID NO:64所示的氨基酸序列且所述第二多肽链包含SEQID NO:65所示的氨基酸序列；
h)所述第一多肽链包含SEQ ID NO:66所示的氨基酸序列且所述第二多肽链包含SEQID NO:67所示的氨基酸序列。
26.药物，其包含权利要求1-25中任一项所述的液体制剂。
27.根据权利要求26所述的药物，其中所述液体制剂被配制为注射剂。
28.根据权利要求26-27中任一项所述的药物，其还包含稀释剂，其中所述稀释剂与所述液体制剂彼此不混合。
29.权利要求1-25中任一项所述的液体制剂在制备治疗肿瘤的药物中的用途。
30.根据权利要求29所述的用途，其中所述肿瘤包括肺癌。
31.权利要求1-25中任一项所述的液体制剂，其用于治疗肿瘤。
32.治疗肿瘤的方法，其包括向有需要的受试者施用权利要求1-25中任一项所述的液体制剂。
33.根据权利要求32所述的方法，其中所述施用方法为瘤内注射。
34.一种用于制备权利要求1-25中任一项所述的液体制剂的辅料，其包含油相溶剂，所述油相溶剂的质量分数为约50％以上。
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甘素玲等: "超声引导下瘤内注射甘油治疗子宫肌瘤的临床研究", 《CNKI中国知网科技成果》 *

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