CN108699131A - 具有双重抗病毒和免疫调节活性的hiv抗体衍生物 - Google Patents
具有双重抗病毒和免疫调节活性的hiv抗体衍生物 Download PDFInfo
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Abstract
本发明涉及基于突变型CD4‑IgG骨架的针对HIV的抗体衍生物,其具有增强的抗病毒和免疫调节活性。这些抗体衍生物包括gp41衍生的多肽和任选的人类CCR5受体序列。这些抗体衍生物的特征为具有提高的(i)阻碍人类免疫缺陷病毒(HIV)进入宿主细胞和(ii)经由自然杀手(NK)细胞的活化引发效应功能的能力。本发明进一步涉及表达所述抗体衍生物的核酸、载体和宿主细胞,以及其在人体健康中的治疗性及诊断性应用。
Description
技术领域
本发明涉及具有增强的抗病毒和免疫调节活性的针对HIV的抗体衍生物。本发明的抗体衍生物的特征为具有提高的(i)阻碍人类免疫缺陷病毒(human immunodeficiencyvirus;HIV)进入宿主细胞和(ii)经由自然杀手(natural killer;NK)细胞和其它免疫***细胞的活化引发效应功能的能力。公开和示例这些多肽的各种形式。表达这些多肽的分离核酸、载体和宿主细胞,以及其在人体健康中的治疗性和诊断性应用也在本发明的范围内。
背景技术
HIV感染是全球人体健康的主要威胁之一。据估算自1981年世界范围内已超过7.8千万感染人类免疫缺陷病毒。在同一时间范围内,这些感染个体接近一般已死于所得后天免疫缺乏症候群(Acquired Immunodeficiency Syndrome;AIDS)。参见UNAIDS,http://www.unaids.org/,2015年10月。
保护性抗体的生成是研发针对人类病原体的疫苗的主要机制。然而,对能够引发针对HIV的这类抗体的免疫原的研发至今尚未成功。这些免疫原的设计首先需要鉴别保守表位以确保连续和稳定反应,并且其次设计适当呈递那些表位的新的和更有效的免疫原。参见Haynes B,《免疫学新观点(Curr Opin Immunol.)》2015;35:39-47。相比于这些免疫原设计的不足进展,最近已鉴别从HIV感染个体中分离的针对HIV包膜糖蛋白的大量新型有效的广谱抗体(即广泛中和抗体,bNAb)。参见Mascola J等人,《免疫学综述(Immunol Rev.)》2013;254:225-244。另外,还已经提出基于抗体结构的合成分子作为新的治疗剂。参见Gardner M等人,《自然(Nature)》2015;519:87-91。实际上,高度有效的抗体可保护未感染个体免于获得HIV或可用于HIV感染患者的根除策略。参见Mascola,2013,见上文。还已经提议使用对包膜糖蛋白的中和抗体和其子单元防止体内HIV复制。参见Yang X等人,《病毒学杂志(J.Virol.)》2005;79:3500-3508。
在治疗领域,抗体尤其相关,这归因于其以下双重功能:作为抗病毒剂能够经由结合于HIV包膜糖蛋白阻碍HIV复制;和经由抗体链的恒定区(Fc)与在NK和其它细胞的表面上表达的Fc受体CD16的相互作用作为NK细胞活化剂。此相互作用能够使CD16+免疫细胞经由称为抗体依赖性细胞的细胞毒性(antibody-dependent cellular cytotoxicity;ADCC)的机制杀灭感染细胞。参见Milligan C等人,《细胞宿主与微生物(Cell Host Microbe.)》2015;17:500-506。看来保护未感染受试者需要两种活性。因此,所属领域需要具有增加的抗病毒和ADCC活性的中和抗体。
发明内容
在第一方面中,本发明涉及从N端到C端包含以下的抗体衍生物:
(a)人类CD4受体的D1和D2胞外结构域;
(b)人类IgG的Fc部分;
(c)选自由以下组成的组的部分:
(i)序列(GGGGS)n的连接子多肽,其中1≤n≤10,
(ii)人类CCR5受体序列和
(iii)其组合,以及
(d)gp41衍生的多肽。
本发明的抗体衍生物具有高于所属领域中已知的任何其它可比抗体衍生物的抗病毒和ADCC活性。参见Gardner,2015,见上文。
在另一方面中,本发明涉及编码本发明的抗体衍生物的核酸;包含所述核酸的载体以及包含前文表明的核酸和载体的宿主细胞。
在另一方面中,本发明涉及医药组合物,其包含本发明的抗体衍生物、核酸、载体和宿主细胞,或其混合物。
在另一方面中,本发明是针对一种组合,其包含本发明的抗体衍生物、核酸、载体、宿主细胞和医药组合物以及至少一种治疗剂。
在仍另一方面中,本发明涉及将本发明的抗体衍生物、核酸、载体、宿主细胞、医药组合物和组合或其混合物用作药剂。在这一方面的另一版本中,本发明涉及将本发明的抗体衍生物、核酸、载体、宿主细胞、医药组合物和组合或其混合物用于治疗或预防HIV感染或AIDS。在这一方面的替代形式中,本发明涉及治疗或预防受试者中的HIV感染或AIDS的方法,其包含向受试者给药治疗有效量的本发明的抗体衍生物、核酸、载体、宿主细胞、医药组合物和组合,或其混合物。在这一方面的另一替代形式中,本发明涉及将本发明的抗体衍生物、核酸、载体、宿主细胞、医药组合物和组合或其混合物用于制造供治疗或预防HIV感染或AIDS用的药剂。
另外,本发明涉及制备本发明的抗体衍生物的方法,其包含以下步骤:(a)培养包含根据本发明的核酸的宿主细胞;(b)表达核酸序列;和(c)从宿主细胞培养物回收抗体衍生物。
在另一方面中,本发明涉及使HIV失活的方法,其包含以下步骤:使病毒与本发明的抗体衍生物接触。
在另一方面中,本发明是针对诱导gp120在HIV感染细胞中表达的方法,其包含以下步骤:使感染细胞与本发明的抗体衍生物、核酸、载体、宿主细胞、医药组合物和组合或其混合物接触。
在另一方面中,本发明涉及检测样品中的HIV的方法,其包含以下步骤:(a)使样品与本发明的抗体衍生物接触和(b)判定抗体衍生物是否特异性结合到样品的分子。
在仍另一方面中,本发明涉及一种试剂盒,其包含本发明的抗体衍生物、核酸、载体、宿主细胞和医药组合物,或其混合物。
附图说明
图1.引入人类IgG1分子中以获得本发明的第一代抗体衍生物的不同变化的示意图。
图2.第一代抗体衍生物分子-1-5的示意图。
图3.测定分子-5中的连接子多肽长度的基本原理的示意图。假设(i)gp120和T-20标靶区的辅助受体结合位点(三聚体中心中的gp41)之间的距离为和(ii)连接子将采纳肽键距离为的α螺旋结构,认为具有至少20个残基的连接子是允许CCR5和T-20序列与其各别标靶同时相互作用所必需的。考虑以上考虑,其中n=4的柔性连接子(GGGGS)n(SEQ ID NO:5)包括在CCR5与T-20序列之间。
图4.第一代抗体衍生物分子-0-6的中和能力,(a)HIV NL4-3分离株的中和;(b)HIV BaL分离株的中和和(c)HIV AC10分离株的中和。
图5.所选择的第一代抗体衍生物分子-1、分子-5和分子-6的ADCC活性。抗体IgGb12包括于分析中作为对照。
图6.第二代抗体衍生物分子-7-11的示意图。
图7.第二代抗体衍生物分子-7-8和分子-10-11对一组NL4-3、BAL和AC10HIV分离株的中和能力。分子-0、分子-1和分子-5包括于分析中作为参考,(a)HIV NL4-3分离株的中和;(b)HIV BaL分离株的中和;和(c)HIV AC10分离株的中和。
图8.所选择第二代抗体衍生物分子-5、分子-7和分子-8的ADCC活性。抗体IgGb12和分子-1包括于分析中作为对照。
图9.第二代抗体衍生物分子-5、分子-7和分子-8对一组HIV SVBP亚型分离株的中和能力。分子-0和分子-1包括于分析中作为参考。
图10.所选择分子对一组HIV分离株的IC50值的概述。
图11.在指示浓度的抗逆转录病毒药物存在下分子-5的抗病毒效能,(a)3TC;(b)依法韦仑(efavirenz)和(c)雷特格韦(raltegravir)。
图12.分子-5和分子-7的C34衍生物针对HIV感染性(BaL分离株)的不可逆失活。
图13.在蛋白质的C端中显示不同gp41多肽的分子-5和分子-7衍生物对一组HIV亚型B病毒的IC50值的概述。分子-1、分子-6用作参考。
图14.显示不同IgG子类的分子-7衍生物对一组HIV亚型B病毒的IC50值的概述。
图15.用AAV治疗的小鼠中的抗体衍生物的血浆水平,(a)AAV注射两周之后;和(b)AAV注射三周之后。
图16.用分子5(0.5毫克/动物)或用PBS(对照感染)治疗的人类化小鼠的HIV感染一周之后确定的HIV血浆病毒血症。
图17.提高浓度的分子-5对在其表面上表达NL4-3(左)或BaL(右)HIV Env醣蛋白的慢性感染MOLT细胞的结合。
图18.表达质粒pABT-5的图式。展示质粒的主要特征,如可选标记和开放阅读框架。
图19.表达质粒pABT-7的图式。展示质粒的主要特征,如可选标记和开放阅读框架。
图20.表达质粒pABT-8的图式。展示质粒的主要特征,如可选标记和开放阅读框架。
微生物的寄存
质粒pABT-5、pABT-7和pABT-8分别以寄存编号DSM 32188、DSM 32189和DSM32190在2015年10月27日寄存在德意志联邦共和国D-38124不伦瑞克,DSMZ-Deutsche Sammlungvon Mikroorganismen und Zellkulturen,Inhoffenstraβe 7B。
序列表
随附序列表中所描绘的核酸和氨基酸序列使用所属领域常规应用的标准字母缩写和编码展示。仅显示了每条核酸序列的一条链,但互补链被理解为包括在对所呈现的链的任何引用中。在随附序列表中:
SEQ ID NO:1是人类CD4受体的D1结构域的氨基酸序列。
SEQ ID NO:2是人类CD4受体的D2结构域的氨基酸序列。
SEQ ID NO:3是人类IgG1的Fc部分的氨基酸序列。
SEQ ID NO:4是具有G236A、S239D、A330L和I332E点突变的人类IgG1的Fc部分的氨基酸序列。
SEQ ID NO:5是连接子多肽的氨基酸序列。
SEQ ID NO:6是人类CCR5受体的N端区的氨基酸序列。
SEQ ID NO:7是T-20多肽的氨基酸序列。
SEQ ID NO:8是T-1249多肽的氨基酸序列。
SEQ ID NO:9是C34多肽的氨基酸序列。
SEQ ID NO:10是T-2635多肽的氨基酸序列。
SEQ ID NO:11是分子-0的氨基酸序列。
SEQ ID NO:12是分子-1的氨基酸序列。
SEQ ID NO:13是分子-2的氨基酸序列。
SEQ ID NO:14是分子-3的氨基酸序列。
SEQ ID NO:15是分子-4的氨基酸序列。
SEQ ID NO:16是分子-5的氨基酸序列。
SEQ ID NO:17是分子-6的氨基酸序列。
SEQ ID NO:18是分子-7的氨基酸序列。
SEQ ID NO:19是分子-8的氨基酸序列。
SEQ ID NO:20是分子-10的氨基酸序列。
SEQ ID NO:21是分子-11的氨基酸序列。
SEQ ID NO:22是人类CD4受体的D1结构域的核苷酸序列。
SEQ ID NO:23是人类CD4受体的D2结构域的核苷酸序列。
SEQ ID NO:24是人类IgG1的Fc部分的核苷酸序列。
SEQ ID NO:25是具有G236A、S239D、A330L和I332E点突变的人类IgG1的Fc部分的核苷酸序列。
SEQ ID NO:26是连接子多肽的核苷酸序列。
SEQ ID NO:27是人类CCR5受体的5'末端区的核苷酸序列。
SEQ ID NO:28是T-20多肽的核苷酸序列。
SEQ ID NO:29是T-1249多肽的核苷酸序列。
SEQ ID NO:30是C34多肽的核苷酸序列。
SEQ ID NO:31是T-2635多肽的核苷酸序列。
SEQ ID NO:32是分子-0的核苷酸序列。
SEQ ID NO:33是分子-1的核苷酸序列。
SEQ ID NO:34是分子-2的核苷酸序列。
SEQ ID NO:35是分子-3的核苷酸序列。
SEQ ID NO:36是分子-4的核苷酸序列。
SEQ ID NO:37是分子-5的核苷酸序列。
SEQ ID NO:38是分子-6的核苷酸序列。
SEQ ID NO:39是分子-7的核苷酸序列。
SEQ ID NO:40是分子-8的核苷酸序列。
SEQ ID NO:41是分子-10的核苷酸序列。
SEQ ID NO:42是分子-11的核苷酸序列。
具体实施方式
本发明涉及具有增强的双重抗病毒和免疫调节活性的HIV抗体衍生物。本发明的抗体衍生物的特征为具有提高的(i)阻碍人类免疫缺陷病毒(HIV)进入宿主细胞和(ii)经由自然杀手(NK)细胞的活化引发效应功能的能力。
1.通用术语和表达的定义
如本文所用的术语“AC10”指代HIV原始分离株,其特征为其对抗CD4结合位点抗体的抗性。AC10分类为2级分离株。参见Seaman M等人,《病毒学杂志》2010;84:1439-1452。
如本文所用的术语“腺相关病毒”或“AAV”指代微小病毒科家族的病毒成员,所述微小病毒科家族包含约5,000种核苷酸的线性单链DNA基因组。所属领域中已知AAV的至少11种识别血清型(AAVl-11)。
如本文所用的术语“AAV载体”指代具有以下的核酸:AAV 5'反向末端重复(inverted terminal repeat;ITR)序列和侧接可操作地连接于转录调节元件(例如启动子、增强子)的编码多肽序列的AAV 3'ITR以及聚腺苷酸化序列。AAV载体可任选地包括一个或多个嵌入在编码多肽序列的外显子之间的内含子。参见Samulski J等人,《病毒学年评(Annu.Rev.Virol.)》2014;1:427-451。
如本文所用的术语“AIDS”指代HIV感染的症状期,并包括后天性免疫缺陷症候群(通常称为AIDS)和“ARC”或AIDS相关综合症。参见Adler M等人,《英国医学期刊(Brit.Med.J.)》1987;294:1145-1147。AIDS的免疫和临床表现为本领域中所熟知并包括例如由免疫不足引起的机会性感染和癌症。
如本文所用的术语“氨基酸”是指天然存在的和合成氨基酸,以及以与天然存在的氨基酸类似的方式起作用的氨基酸类似物和氨基酸模拟物。氨基酸在本文中可以由其通常已知的三字母符号或由IUPAC-IUB生物化学命名法委员会(Biochemical NomenclatureCommission)所推荐的单字母符号来提及。同样地,核苷酸可以由其通常接受的单字母编码来提及。
如本文所用的术语“抗体药物结合物”或“ADC”指代结合到治疗剂的抗体、抗原结合抗体片段、抗体衍生物、抗体复合物或抗体融合蛋白。结合可以是共价或非共价的。优选地,结合是共价的。
如本文所用的术语“抗逆转录病毒疗法”或“AT”指代给药一种或多种抗逆转录病毒药物(即HIV抗逆转录病毒)以抑制HIV的复制。通常,AT涉及给药至少一种抗逆转录病毒剂(或通常抗逆转录病毒的混合物),如核苷逆转录酶抑制剂(例如齐多夫定(zidovudine)(AZT,拉米夫定(lamivudine)(3TC)和阿巴卡韦(阿巴卡韦)))、非核苷逆转录酶抑制剂(例如奈韦拉平(nevirapine)和依法韦仑(efavirenz))以及蛋白酶抑制剂(例如茚地那韦(indinavir)、利托那韦(ritonavir)和咯匹那韦(lopinavir))。术语高度活性抗逆转录病毒疗法(“HAART”)指代被设计成积极抑制HIV复制和疾病进展的治疗方案。HAART通常由三种或更多种不同药物组成,例如两种核苷逆转录酶抑制剂和蛋白酶抑制剂。
如本文所用的术语“结合功效”指代分子对CD4受体以及优选地所述受体的D1和D2结构域的亲和力。在本发明的背景下,“亲和力”意味着抗体衍生物例如对gp120的CD4结合位点的结合强度。如本文所用,术语“结合”或“特异性结合”指代结合对(例如两种蛋白质或化合物)之间,优选地(i)gp120的CD4结合位点与(ii)CD4受体或CD4受体的D1和D2结构域之间的相互作用。在一些实施例中,相互作用具有至多10-6摩尔/升、至多10-7摩尔/升、或至多10-8摩尔/升的亲和力常数。一般来说,短语“结合”或“特异性结合”指代化合物对另一化合物的特异性结合,其中如通过任何标准分析所测量,结合水平统计学上显著高于分析的背景对照。
如本文所用的术语“C34”指代覆盖gp41的HR2区的部分的SEQ ID NO:9的gp41衍生的多肽。参见Eggink D等人,《病毒学杂志》2008;82(13):6678-6688。
如本文所用的术语“CCR5”指代人类C-C趋化因子受体5,又称为CD195,一种偶合到G蛋白的7跨膜结构域受体。CCR5结合于不同趋化因子并在HIV进入靶细胞的过程期间充当HIV Env的辅助受体。HIV辅助受体功能涉及CCR5的不同区;然而,第一相互作用确立在CCR5的N端胞外区与位于gp120子单元的HIV Env的辅助受体结合位点之间。参见Lagenaur L等人,《逆转录病毒学(Retrovirology)》2010;7:11。人类CCR5的完整蛋白质序列具有UniProt寄存编号P51681(2015年8月18日)。
如本文所用的术语“CD4”或“CD4受体”指代分化4的集群,一种在T辅助细胞、单核细胞、巨噬细胞和树突状细胞的表面上表达的醣蛋白。CD4在T细胞受体(T cell receptor;TCR)与抗原呈递细胞连接中辅助T细胞受体。使用其驻留在T细胞内部的部分,CD4通过募集称为酪氨酸激酶lck的酶放大由TCR产生的信号,所述酶对活化涉及活化T细胞的信号级联的许多分子为至关重要的。人类CD4的完整蛋白质序列具有UniProt寄存编号P01730(2012年6月18日)。
如本文所用的术语“密码子优化”指代反映在不改变其氨基酸序列下改善参考多肽的表达的宿主生物体的典型密码子使用的核酸中密码子的变化。存在若干所属领域中已知的用于密码子优化的方法和软件。参见Narum D等人,《感染与免疫(Infect.Immun.)》2001;69(12):7250-7253);Outchkourov N等人,《蛋白质表达与纯化(ProteinExpr.Purif.)》2002;24(1):18-24;Feng L等人,《生物化学(Biochemistry)》2000;39(50):15399-15409和Humphreys D等人,《蛋白质表达与纯化》2000;20(2):252-264。
如本文所用的术语“包含(comprising/包含)”还公开根据公认的专利实践的“由……组成”。
如本文所用的术语“Env”或“gp160”指代具有HIV的外膜蛋白(Env)的抗原特异性或生物功能并包涵两个子单元gp120和gp41糖蛋白的醣蛋白。野生型(wt)gp160多肽的示例性序列为可用的。参见基因银行寄存编号AAB05604和AAD12142。
如本文所用的术语“片段可结晶区”或“Fc区”指代与称为Fc受体的细胞表面受体和互补***的一些蛋白质相互作用的抗体的尾区。
如本文所用的表述“功能等效变异体”指代:(i)由修饰、缺失或***或一种或多种氨基酸产生并基本上保留其参考多肽的活性的多肽;和(ii)由修饰、缺失或***或一种或多种碱基产生并基本上保留由参考核酸表达的多肽的活性的聚核苷酸。在本发明的上下文中涵盖的功能等效变异体包括展示与序列SEQ ID NO:1-10至少60%、70%、80%、85%、90%、92%、94%、96%、98%、99%相似性或一致性的多肽或展示与序列SEQ ID NO:22-31至少60%、70%、80%、85%、90%、92%、94%、96%、98%、99%相似性或一致性的聚核苷酸。两种多肽或两种聚核苷酸之间的一致程度或相似程度通过使用计算机实施的演算法和所属领域中广泛已知的方法测定。氨基酸的两个序列之间的一致性和相似性优选地使用BLASTP演算法测定。参见Altschul S等人,《BLAST手册(BLAST Manual)》(NCBI NLM NIH,Bethesda,MD,USA,2001)。
如本文所用的术语“融合蛋白”是指通过基因技术产生的蛋白质,其由两种或更多种来源于不同蛋白质的功能结构域组成。融合蛋白可以通过常规手段(例如借助于编码适合细胞中的所述融合蛋白的核苷酸序列的基因表达)获得。
如本文所用的术语“gp41”指代人类免疫缺陷病毒-1包膜糖蛋白gp41。Gp41是与gp120一起形成HIV-1的Env醣蛋白的子单元。Env是由三个外部子单元(gp120)和三个跨膜子单元(gp41)构成的三聚体。gp41蛋白的胞外部分含有三个基本功能区:融合肽(FP)、N端七肽重复(HR1)和C端七肽重复(HR2)。HR1和HR2区含有许多具有形成卷曲结构的倾向的白氨酸拉链状基序。参见Peisajovich S,Shai Y,《生物化学与生物物理学报(Biochem.Biophys.Acta)》2003;1614:122-129;Suárez T等人,《欧洲生物化学学会联合会快报(FEBS Lett.)》2000;477:145-149;Chan D等人,《细胞(Cell)》1997;89:263-273。大量HIV gp-41的核酸和氨基酸序列为公众可容易获得的。参见HIV序列数据库,http://www.hiv.lanl.gov/content/sequence/HIV/mainpage.html,2015年11月。
如本文所用的术语“gp41抑制剂”包括一系列覆盖gp41的HR2区的具有不同长度的多肽。这些抑制剂包括但不限于T-20、C34、T-1249和T-2635gp41衍生的多肽。
如本文所用的表述“gp41衍生的多肽”指代来源于gp41的七肽重复1(HR1)或七肽重复2(HR2)基序的多肽。gp41HRl和HR2序列为本领域中所熟知。参见Lupas A,《生物化学趋势(Trends Biochem.Sci.)》1996;21:375-382和Chambers P等人,《普通病毒学杂志(J.Gen.Virol.)》1990;71:3075-3080。优选地,gp41衍生的多肽来源于HR2。gp41衍生的多肽可含有位于其N端或C端的其它外源性氨基酸。优选地,外源性氨基酸少于10个、更优选少于5个、和最优选少于3个。
如本文所用的术语“gp120”指代具有HIV的外膜蛋白(env)的抗原特异性或生物功能的醣蛋白。“gp120蛋白”是来源于Env多肽的gp120区的分子。gp120的氨基酸序列为约511个氨基酸。Gp120是表观分子量为120kD的经大量N-糖基化的蛋白质。Gpl20含有五个与五个可变结构域(Vl-V5)穿插的相对保守结构域(C1-C5)。可变结构域含有扩展的氨基酸取代、***和缺失。“gpl20多肽”包括单子单元和多聚体两者。gp41部分锚定在(并横跨)病毒粒子的膜双层中,而gpl20区段突入周围环境。gp120的受体结合结构域定位到蛋白质的N端一半。这之后为富脯氨酸区(proline rich region;PRR),其表现为通信结合于融合机构的受体的铰链或触发子。gp120的C端是高度保守的并与gp41相互作用。参见基因银行寄存编号AAB05604和AAD12142。
如本文所用的术语“HIV”包括HIV-1和HIV-2、SHIV和SIV。“HIV-1”意味着人类免疫缺陷病毒1型。HIV-1包括但不限于胞外病毒颗粒和与HIV-1感染细胞相关的HIV-1的形式。HIV-1病毒可表示包括实验室菌株和原始分离株的任何已知主要亚型(类别A、B、C、D、E、F、G和H)或***亚型(群组O)。“HIV-2”意味着人类免疫缺陷病毒2型。HIV-2包括但不限于胞外病毒颗粒和与HIV-2感染细胞相关的HIV-2的形式。术语“SIV”指代猿猴免疫缺陷病毒,其为感染猴子、黑猩猩和其它非人类灵长类动物的HIV样病毒。SIV包括但不限于胞外病毒颗粒和与SIV感染细胞相关的SIV的形式。
如本文所用的术语“HIV暴露”指代未感染受试者与患有HIV感染或AIDS的受试者的接触;或与这类HIV感染受试者的体液的接触,其中来自感染受试者的这类体液接触粘膜、组织切口或擦伤(例如针棒、无保护***),或未感染受试者的其它表面,其方式为使得病毒可以从感染受试者或感染受试者的体液传输到未感染受试者。
如本文所用的术语“HIV感染”指代HIV病毒在个体中存在的指示,包括无症状血清阳性、AIDS相关综合症(ARC)和后天免疫缺乏症候群(AIDS)。
如本文所用的术语“IC50”指代抑制50%给定生物过程或生物过程的组分(即酶、细胞、细胞受体或微生物)所需的特定活性剂的量。
在两种或更多种核酸或多肽的情形下术语“一致”或百分比“一致性”指代当针对最大一致性比较和比对(视需要引入空隙)时,两种或更多种序列或子序列相同或具有指定百分比的相同的核苷酸或氨基酸残基,不考虑将任何保守性氨基酸取代作为序列一致性的部分。一致性百分比可以使用序列比较软件或演算法或通过目视检查测量。所属领域中已知可用于获得氨基酸或核苷酸序列的比对的各种演算法和软件。适用于测定序列相似性的演算法的实例包括但不限于BLAST、有空隙BLAST和BLAST 2.0、WU-BLAST-2、ALIGN、和ALIGN-2演算法。参见Altschul S等人,《核酸研究(Nuc.Acids Res.)》1977;25:3389-3402;Altschul S等人,《分子生物学杂志(J.Mol.Biol.)》1990;215:403-410;Altschul S等人,《酶学方法(Meth.Enzymol.)》1996;266:460-480;Karlin S等人,《美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)》1990;87:2264-2268;Karlin S等人,《美国国家科学院院刊》1993;90:5873-5877,基因泰克公司,美国加利福尼亚州南旧金山,http://blast.ncbi.nlm.nih.gov/Blast.cgi,2015年11月。用于比较的序列比对方法在所属领域中是众所周知的。可以例如通过以下进行用于比较的最优序列比对:史密斯-沃特曼(Smith-Waterman)局部同源算法、尼德曼-翁施(Needleman-Wunsch)同源性比对演算法、皮尔逊-利普曼(Pearson-Lipman)相似性检索方法、这些演算法的计算机化实施或手动比对和目视检查。参见Smith T等人,《应用数学进展(Adv.Appl.Math.)》1981;2:482-489;Needleman S等人,《分子生物学杂志(J.Mol.Biol.)》1970;48:443-453;Pearson W等人,Lipman D,《美国国家科学院院刊》1988;85:2444-2448;GAP、BESTFIT、FASTA和TFASTA程式、威斯康星遗传软件包、遗传学计算机组,美国威斯康星州麦迪逊;Ausubel F等人编,《分子生物学的短方案(Short Protocols in Molecular Biology)》,第5版(约翰·威利父子公司(John Wiley and Sons,Inc.),美国纽约州纽约,2002)。
如本文所用的术语“试剂盒”指代含有进行本发明的使用和方法所必需的不同试剂的产品,其经封装以便使其传输和存储。适用于封装试剂盒的组分的材料包括晶体、塑料(例如聚乙烯、聚丙烯、聚碳酸酯)、瓶子、小瓶、纸张或包封。
如本文所用的术语“中和抗体”是结合于胞外分子(例如病原病毒的表面中的蛋白质或蛋白质结构域)并干扰胞外分子感染细胞或调节其活性的能力的任何抗体、抗原结合片段或抗体衍生物。通常,本发明的抗体衍生物可结合于胞外分子的表面并能够在无所述抗体衍生物存在下或在阴性对照存在下相对于胞外分子到细胞的附着,抑制其至少99%、95%、90%、85%、80%、75%、70%、60%、50%、45%、40%、35%、30%、25%、20%或10%到细胞的偶合。用于确认抗体衍生物是否中和的方法已描述于所属领域中。参见Li M等人,《病毒学杂志》2005;79:10108-10125;Wei X等人,《自然》2003;422:307-312和MontefioriD,《现行免疫学方法(Curr.Protoc.Immunol.)》2005;Jan,第12章:第12.11单元。在本发明的背景下,病原体优选地是HIV,并且更具体来说是HIV病毒包膜的gp120蛋白。具体来说,术语“HIV中和抗体”指代具有对gp120的CD4结合位点(如IgGb12)的亲和力的抗体衍生物。术语“中和抗体”包括bnAb的子类别。如本文所用,“广泛中和抗体”或“bnAb”理解为通过任何方法获得的抗体,当以有效剂量递送时,所述抗体可用作对超过7种HIV菌株、优选超过8种、9种、10种、11种、12种、13种、14种、15种、16种、17种、18种、19种、20种或更多种HIV菌株的用于预防或治疗HIV感染或AIDS的治疗剂。
如本文所用的术语“NK细胞”指代“自然杀伤细胞”,一种对先天免疫***至关重要的细胞毒性淋巴细胞。NK细胞提供对病毒感染细胞的快速反应并对肿瘤形成做出响应,在感染大约3天后起作用。通常,免疫细胞检测在感染细胞表面呈现的HLA,触发造成溶解或细胞凋亡的细胞因子释放。NK细胞为独特的,然而因为其具有在无抗体和HLA存在下识别应激细胞的能力,所以允许快得多的免疫反应。NK细胞定义为大颗粒状淋巴细胞并构成从产生B和T淋巴细胞的常见淋巴祖细胞分化的第三种细胞。已知NK细胞在其中其进入循环的骨髓、***、脾、扁桃体和胸腺中分化并成熟。NK细胞通常表达人类中的表面标记物CD16(FcγRIII)和CD56。
如本文所用的术语“NL4-3”和“BaL”指代常用于实验室的两种不同HIV分离株。NL4-3分离株从NY5和LAV前病毒克隆。参见Adachi A等人,病毒学杂志1986;59:284-291。BaL分离株从粘附细胞的原代培养物中获得,所述粘附细胞从肺组织中移植。参见GartnerS等人,《科学(Science)》1986;233:215-219。
如本文中可互换使用的术语“核酸”、“聚核苷酸”和“核苷酸序列”是指具有任何长度并由核糖核苷酸或脱氧核糖核苷酸构成的任何聚合物形式。术语包括单链和双链聚核苷酸两种,以及经修饰的聚核苷酸(例如甲基化、保护性)。通常,核酸是“编码序列”,如本文所用其指代在合适调节序列控制下放置时经转录并翻译为宿主细胞中的多肽的DNA序列。编码序列的界限通过5'(氨基)端处的起始密码子和3'(羧基)端处的翻译终止密码子确定。编码序列可包括但不限于原核序列、来自真核mRNA的cDNA、来自真核(例如哺乳动物)DNA的基因组DNA序列以及甚至合成DNA序列。转录终止序列将通常位于编码序列的3'处。
如本文所用的术语“可操作地连接”意味着所关注的核苷酸序列以允许核苷酸序列表达的方式连接到调节序列(例如在体外转录/翻译***中或在将载体引入宿主细胞中的宿主细胞中)。参见Auer H,《自然生物技术(Nature Biotechnol.)》2006;24:41-43。
如本文所用的表述“HIV分离株组”指代设计成用作Env假病毒以促进中和抗体反应的标准化2/3级评估的一批参考HIV分离株。参见Mascola R等人,病毒学杂志2005;79(16):10103。假病毒展现中和表型,其为大多数原始HIV-1分离株的典型。gp160基因从以性方式获得的急性/早期感染克隆并包含广泛范围内的亚型B内的基因、抗原和地理多样性。这些克隆使用CCR5作为辅助受体。参见Li等人,病毒学杂志2005;79(16):10108-10125。
如本文所用的表述“肠胃外给药(parenteral administration/administeredparenterally)”意味着除经肠和局部给药以外的给药模式,通常通过注射并且包括但不限于静脉内、肌肉内、动脉内、鞘内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊椎内、硬膜外和胸骨内注射和输注。
如本文所用的表述“医药学上可接受的载剂”包括生理学上与本发明的抗体衍生物、核酸、载体和宿主细胞相容的任何和所有溶剂、分散介质、包衣、抗细菌和抗真菌剂、等张和吸收延迟剂。
术语“多肽”、“肽”和“蛋白质”在本文中可互换使用以指代氨基酸残基的聚合物。所述术语适用于氨基酸聚合物,其中一个或多个氨基酸残基是相应天然存在的氨基酸的人造化学模拟剂,以及适用于天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。
如本文所用的术语“预防(prevent/preventing/prevention)”指代抑制受试者中的疾病发生的起始或降低受试者中的疾病发生率。预防可以是完整的(例如受试者中的病理细胞完全不存在)。预防还可以是部分的,例如降低受试者中的病理细胞的发生率。预防还指代降低对临床病状的易感性。在本发明的背景内,术语“预防(prevent/preventing/prevention)”具体指代防止或降低维持HIV暴露的受试者中的HIV感染机率。
如本文所用的术语“样品”指代任何生物流体并且具体来说指代从受试者中获得的血液、血清、血浆、淋巴、唾液、外周血液细胞或组织细胞血清、***、痰液、头脊柱液(CRL)、泪液、粘液、汗水、乳汁或脑提取物。身体组织可包含胸腺、***、脾、骨髓或扁桃体组织。术语“样品”还指代非生物样品(例如从水、饮料中获得)。
如本文所用的术语“受试者”指代个体、植物或动物,如人类、非人类灵长类动物(例如黑猩猩和其它猿以及猴物种);家畜,如鸟、鱼、、牛、绵羊、猪、山羊和马;驯养哺乳动物,如狗和猫;实验动物,包括啮齿动物,如小鼠、大鼠和豚鼠。术语并不指示特定年龄或性别。术语“受试者”涵盖胚胎和胎儿。在一优选实施例中,受试者是人类。
如本文所用的术语“T-1249”指代覆盖gp41的HR2区的部分的SEQ ID NO:8的gp41衍生的多肽。参见Eggink,2008,见上文。
如本文所用的术语“T-20”指代覆盖gp41的HR2区的部分的SEQ ID NO:7的gp41衍生的多肽,又称为恩夫韦地(enfuvirtide)。参见CAS[159519-65-0]和US 5,464,933。这一多肽在纳摩尔范围中具有抗病毒活性并且已经用于针对HIV感染的疗法。参见Zhang D等人,《治疗专利的专家意见(Expert Opin Ther Pat.)》2015;25:159-173和Eggink,2008,见上文。
如本文所用的术语“T-2635”指代覆盖gp41的HR2区的部分的SEQ ID NO:10的gp41衍生的多肽。参见Eggink,2008,见上文。
如本文所用的术语“治疗剂”指代适用于治疗或预防疾病的原子、分子或化合物。治疗剂的实例包括但不限于抗体、抗体片段、HIV抗逆转录病毒、药物、细胞毒性剂、促细胞凋亡剂、毒素、核酸酶(例如DNA酶和RNA酶)、激素、免疫调节剂、螯合剂、硼化合物、光敏剂或染放射性核寡核苷干扰RN siRN RNA抗血管生成化学治疗细胞因趋化因前结合蛋肽或其组合。
如本文所用的术语“治疗有效量”指代在受试者中产生治疗反应或所需效果的本发明的抗体衍生物、核酸、载体、医药组合物或其混合物的剂量或量。
如本文所用的术语“疗法”或“治疗性”指代使用本发明的抗体衍生物、核酸、载体、医药组合物或其混合物用于治疗或预防包括但不限于HIV和AIDS的疾病。
如本文所用的术语“治疗(treat/treatment)”指代给药本发明的抗体衍生物、核酸、载体、宿主细胞或医药组合物以用于在其临床征象已出现之后控制疾病进展。疾病进展的控制应理解成意味着有益或所需的临床结果,其包括但不限于症状减轻、疾病持续时间减少、病理状态稳定(具体地说避免进一步恶化)、疾病进展延迟、病理状态改善和缓解(均为部分和全部)。疾病进展的控制还涉及与不应用治疗的预期存活期相比存活期的延长。在本发明的情形内,术语“治疗(treat/treatment)”具体指代停止或减缓HIV感染受试者中的健康CD4+T细胞的感染和破坏。其还指代停止和减缓所获得免疫缺乏疾病的症状起始,如极低的CD4+T细胞计数和机会病原体造成的重复感染。有益或所需临床结果包括但不限于:绝对未处理CD4+T细胞计数的增加(范围10-3520)、CD4+T细胞相对于全部循环免疫细胞的百分比的增加(范围1-50%)、或呈正常CD4+T细胞计数在未感染受试者中的百分比形式的CD4+T细胞计数的增加(范围1-161%)。“治疗”也可意味着相比于受试者不接受任何HIV靶向治疗时的预期存活期延长感染受试者的存活期。
如本文所用的术语“载体”指代直链或圆形核酸分子,其包含可操作地连接于提供在宿主细胞中的自主复制的其它链段的本发明的核酸,或根据核酸分子的表达盒。
2.抗体衍生物
在第一方面中,本发明涉及从N端到C端包含以下的抗体衍生物:
(a)人类CD4受体的D1和D2胞外结构域;
(b)人类IgG的Fc部分;
(c)选自由以下组成的组的部分:(i)序列(GGGGS)n的连接子多肽,其中1≤n≤10;(ii)人类CCR5受体序列和(iii)其组合以及
(d)gp41衍生的多肽。
本发明的抗体衍生物的特征为具有增加的抗病毒和ADCC活性。
在一个实施例中,本发明的抗体衍生物的D1结构域包含人类CD4受体(即UniProtKB数据库寄存编号P01730)或其功能等效变异体的氨基酸26-125。在另一实施例中,抗体衍生物的D2结构域包含人类CD4受体或其功能等效变异体的氨基酸126-203。优选地,D1和D2结构域分别包含序列SEQ ID NO:1和SEQ ID NO:2或其功能等效变异体。
在另一实施例中,人类IgG的Fc部分包含IgG1、IgG2、IgG3或IgG4同型的Fc部分。优选地,IgG同型是IgG1。更优选地,人类IgG的Fc部分包含G236A、S239D、A330L和I332E点突变或其功能等效变异体。最优选的是包含SEQ ID NO:4或其功能等效变异体的人类IgG1的Fc部分。
在另一实施例中,本发明的抗体衍生物的部分选自由以下组成的组:(i)序列(GGGGS)n(SEQ ID NO:5)的连接子多肽,其中1≤n≤10;(ii)人类CCR5受体序列;(iii)(i)和(ii)的组合以及(i)、(ii)和(iii)的功能等效变异体。在这个实施例的一个形式中,部分仅包含连接子或人类CCR5受体序列或其功能等效变异体。在这个实施例的另一形式中,部分包含连接子和人类CCR5受体序列或其功能等效变异体的组合。优选地,当采用组合时,连接子附着于人类CCR5受体序列的C端。优选地,部分包含仅连接子或连接子和人类CCR5受体序列或其功能等效变异体的组合。优选地,人类CCR5受体序列包含SEQ ID NO:6或其功能等效变异体。
在另一实施例中,gp41衍生的多肽包含T-20、T-4912、C34、T-2635多肽、其组合或其功能等效变异体。优选地,gp41衍生的多肽包含T-20多肽或其功能等效变异体。更优选地,T-20多肽包含SEQ ID NO:7。
在另一实施例中,本发明的抗体衍生物包含分子-5、分子-6、分子-7、分子-8、分子-10、分子-11或其功能等效变异体。优选地,抗体衍生物包含分子-5、分子-7、分子-8或其功能等效变异体。更优选地,抗体衍生物包含分子-7。在这个实施例的一个形式中,分子-5、分子-6、分子-7、分子-8、分子-10和分子-11分别包含序列SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20和SEQ ID NO:21或其功能等效变异体。
优选地,本发明的抗体衍生物包含:
(1)(a)人类CD4受体的D1和D2胞外结构域;(b)人类IgG1的Fc部分;(c)选自由以下组成的组的部分:(i)序列(GGGGS)n的连接子多肽,其中1≤n≤10;(ii)人类CCR5受体序列和(iii)其组合;以及(d)选自由以下组成的组的gp41衍生的多肽:T-20、T-1249、C34和T-2635,其中IgG1是野生型或含有G236A、S239D、A330L和I332E点突变,
(2)(a)人类CD4受体的D1和D2胞外结构域;(b)人类IgG2的Fc部分;(c)选自由以下组成的组的部分:(i)序列(GGGGS)n的连接子多肽,其中1≤n≤10;(ii)人类CCR5受体序列和(iii)其组合;以及(d)选自由以下组成的组的gp41衍生的多肽:T-20、T-1249、C34和T-2635,
(3)(a)人类CD4受体的D1和D2胞外结构域;(b)人类IgG3的Fc部分;(c)选自由以下组成的组的部分:(i)序列(GGGGS)n的连接子多肽,其中1≤n≤10;(ii)人类CCR5受体序列和(iii)其组合;以及(d)选自由以下组成的组的gp41衍生的多肽:T-20、T-1249、C34和T-2635,以及
(4)(a)人类CD4受体的D1和D2胞外结构域;(b)人类IgG4的Fc部分;(c)选自由以下组成的组的部分:(i)序列(GGGGS)n的连接子多肽,其中1≤n≤10;(ii)人类CCR5受体序列和(iii)其组合;以及(d)选自由以下组成的组的gp41衍生的多肽:T-20、T-1249、C34和T-2635。
更优选地,本发明的抗体衍生物包含:(a)人类CD4受体的D1和D2胞外结构域;(b)含有G236A、S239D、A330L和I332E点突变的人类IgG1的Fc部分;(c)选自由以下组成的组的部分:(i)序列(GGGGS)n的连接子多肽,其中1≤n≤10;(ii)人类CCR5受体序列和(iii)其组合;以及(d)选自由以下组成的组的gp41衍生的多肽:T-20、T-1249、C34和T-2635。
本发明的抗体衍生物适用于防止(即中和)分子(例如HIV)附着到在其表面中表达所述集群的细胞(例如T-辅助细胞、单核细胞、巨噬细胞、树突状细胞)中的人类CD4受体。优选地,本发明的抗体衍生物用于防止位于HIV的病毒包膜的gp160蛋白附着到在T-辅助细胞中发现的人类CD4受体。本发明的抗体衍生物的中和能力的特征可在于10ng/mL或更低的IC50,和优选地低于5ng/mL、低于2.5ng/mL、低于1.25ng/mL、低于0.625ng/mL、低于0.312μg/mL、低于0.156ng/mL、低于0.07ng/mL或低于0.035ng/mL的IC50。
在另一实施例中,本发明的抗体衍生物可以通过共价结合到聚合物来化学改性,例如以增加其循环半衰期。将多肽附着到聚合物的方法为所属领域中已知的。参见US4,766,106、US 4,179,337、US 4,495,285和US 4,609,546。优选地,聚合物是聚氧乙基化多元醇和聚乙二醇(PEG)。PEG是具有以下通式的水溶性聚合物:R(O--CH2--CH2)n O--R,其中R可以是氢或保护基,如烷基或烷醇基。优选地,保护基具有在1个与8个之间的碳,更优选地其是甲基。优选地,n是在1与1,000之间,并且更优选地在2与500之间的整数。PEG的优选平均分子量在1,000与40,000之间、更优选地在2,000与20,000之间并且最优选地在3,000与12,000之间。
在另一实施例中,本发明的抗体衍生物附着于治疗剂以形成抗体药物结合物(antibody drug conjugate;ADC)。举例来说,用于治疗由AIDS起始引起或支持的机会性疾病及病状(例如卡波西肉瘤(Kaposi's sarcoma))的治疗剂可以用由本发明的抗体衍生物和干扰素-α、脂质体蒽环霉素(例如多希(Doxil))或太平洋紫杉醇形成的ADC治疗。有效治疗其它机会性疾病,如病毒和细菌感染(例如带状疱疹、肺炎、肺结核)、皮肤病和与AIDS相关联的其它类型的癌症(例如淋巴瘤)的其它ADC还可以通过组合本发明的抗体衍生物和合适治疗剂来设计。
3.核酸、载体和宿主细胞
在另一方面中,本发明涉及编码本发明的抗体衍生物的核酸,和包含所述核酸的表达盒和载体。
优选地,核酸是聚核苷酸,其包括但不限于由核苷酸间磷酸二酯键联连接的脱氧核糖核苷酸(DNA)和核糖核苷酸(RNA)。在一优选实施例中,本发明的核酸包含编码以下的聚核苷酸:人类CD4受体的D1和D2胞外结构域(SEQ ID NO:22、SEQ ID NO:23)、人类IgG1的Fc部分(SEQ ID NO:24)、连接子多肽(SEQ ID NO:26)、人类CCR5受体(SEQ ID NO:27)和T-20多肽(SEQ ID NO:28)或其功能等效变异体。优选地,本发明的核酸编码分子-5(SEQ IDNO:37)、分子-6(SEQ ID NO:38)、分子-7(SEQ ID NO:39)、分子-8(SEQ ID NO:40)、分子-10(SEQ ID NO:41)、分子-11(SEQ ID NO:42)或其功能等效变异体。本发明的核酸的功能等效变异体可以借助于一个或若干个核苷酸相对于其参考序列的***、缺失或取代获得。优选地,编码本发明的核酸的功能等效变异体的聚核苷酸是以下聚核苷酸:其序列使其在高度受限条件中与其参考核酸杂交。高度受限杂交的典型条件包括在42℃下在14个小时期间在6X SSC(1X SSC:0.15M NaCl,0.015M柠檬酸钠)和40%甲酰胺培育,之后为在60℃下使用0.5X SSC,0.1%SDS进行一个或若干个洗涤循环。或者,高度受限条件包括包含以下的那些:在6X SSC中在约50℃-55℃的温度下杂交和在1-3X SSC中在68℃的温度下进行最终洗涤。适度的限制性条件包含在0.2或0.3M NaCl中在约50℃的温度下杂交直到大约65℃,之后为在0.2X SSC,0.1%SDS(十二烷基硫酸钠)中在约50℃下洗涤直到大约55℃。在一个另外的实施例中,本发明的核酸是密码子优化的。
在另一实施例中,实际上使用具有与其参考核酸至少80%、85%、90%、95%或99%相似性的核酸变体,其中所述变体编码本发明的抗体衍生物或其功能等效变异体。
本发明的核酸可需要用限制酶切割以便连接至载体(例如可以去除1、2或3个末端核苷酸)。在另一实施例中,本发明涉及所述核酸,其中其已用限制酶在每一端切割。
在另一实施例中,本发明涉及表达盒,其包含本发明的核酸、启动子序列和3'-UTR以及任选地选择标记。
在又一实施例中,本发明涉及包含本发明的核酸的载体。在这个实施例的另一方面中,本发明的核酸包含于由所述载体包含的表达盒中。根据本发明的合适载体包括但不限于原核载体,如pUC18、pUC19;和Bluescript质粒和其衍生物,如mp18、mp19、pBR322、pMB9、ColE1、pCRl和RP4质粒;噬菌体和穿梭载体,如pSA3和pAT28载体;酵母中的表达载体,如2微米质粒型载体;整合质粒;YEP载体;着丝粒质粒和类似物;昆虫细胞中的表达载体,如pAC系列和pVL系列的载体;植物中的表达载体,如pIBI、pEarleyGate、pAVA、pCAMBIA、pGSA、pGWB、pMDC、pMY、pORE系列和类似物的载体;以及基于病毒载体(例如腺病毒、腺相关病毒、逆转录病毒、慢病毒)或非病毒载体的优异真核细胞中的表达载体,如pSilencer 4.1-CMV(生命技术公司(Life Technologies Corp.),美国加利福尼亚州卡尔斯巴德)、pcDNA3、pcDNA 3.1、pcDNA3.1/hyg pHCMV/Zeo、pCR3.1、pEFl/His、pIND/GS、pRc/HCMV2、pSV40/Zeo2、pTRACER-HCMV、pUB6/V5-His、pVAXl、pZeoSV2、pCI、pSVL和pKSV-10、pBPV-1、pML2d和pTDTl载体。优选地,载体是pcDNA3.1载体。更优选地,载体是pABT-5、pABT-7和pABT-8。
在另一实施例中,病毒载体是AAV载体。编码本发明的抗体衍生物的AAV载体可以根据所属领域中熟知的分子生物学技术构建。参见Brown T,《基因克隆(Gene Cloning)》(Chapman&Hall,英国伦敦,1995);Watson R等人,《重组DNA(Recombinant DNA)》,第2版(Scientific American Books,美国纽约州纽约,1992);Alberts B等人,《细胞的分子生物学(Molecular Biology of the Cell)》(Garland Publishing Inc.,美国纽约州纽约,2008);Innis M等人编,《PCR方案.方法和应用指导(PCR Protocols.A Guide to Methodsand Applications)》(Academic Press Inc.,美国加利福尼亚州圣地亚哥,1990);ErlichH编,《PCR技术.DNA扩增的原理和应用(PCR Technology.Principles and Applicationsfor DNA Amplification)》(Stockton Press,美国纽约州纽约,1989);Sambrook J等人,《分子克隆.实验室手册(Molecular Cloning.A Laboratory Manual)》(Cold SpringHarbor Laboratory Press,美国纽约州冷泉港,1989);Bishop T等人,《核酸和蛋白质序列.实践方法(Nucleic Acid and Protein Sequence.A Practical Approach)》(IRLPress,英国牛津,1987);Reznikoff W编,《最大化基因表达(Maximizing GeneExpression)》(Butterworths Publishers,美国马萨诸塞州斯托纳姆,1987);Davis L等人,《基础分子生物学方法(Basic Methods in Molecular Biology)》(Elsevier SciencePublishing Co.,美国纽约州纽约,1986);Schleef M编,《用于疗法和疫苗接种的质粒(Plasmid for Therapy and Vaccination)》(Wiley-VCH Verlag GmbH,特拉华州魏因海姆,2001)。
举例来说,可以采用HEK-293细胞(表达E1基因)、提供腺病毒功能的辅助质粒、提供来自血清型2的AAV rep基因和来自所需血清型的cap基因(例如AAV8)的辅助质粒、以及最后具有ITR和所关注的构建体的骨架质粒(例如分子-5、分子-7)。为产生表达本发明的抗体衍生物的AAV载体,抗体衍生物的cDNA可以在普遍存在的(例如CAG)或细胞特异性启动子的控制下克隆为AAV骨架质粒。
AAV载体(病毒载体粒子)可以使用具有修饰的三种质粒通过HEK293细胞的不含辅助病毒的转染产生。参见Matsushita T等人,《基因疗法(Gene Ther.)》1998;5:938-945和Wright J等人,《分子疗法(Mol.Ther.)》2005;12:171-178。细胞可以在补充有10%BFS(胎牛血清)的达尔伯克改良伊格尔培养基(Dulbeccos's Modified Eagle Medium;DMEM)中在滚瓶(RB)(Corning Inc.,美国纽约州康宁)中培养到70%汇合度并随后用以下共转染:1)携带由病毒ITR侧接的表达盒的质粒(上文所述);2)携带AAV rep2和对应cap(cap1和cap9基因)的辅助质粒;以及3)携带腺病毒辅助功能的质粒。载体随后可使用标准方案或如先前描述的优化方案通过两种连续氯化铯梯度纯化。参见Ayuso E等人,《基因疗法(GeneTher.)》2010;17:503-510。载体可以经进一步对PBS渗析,过滤,通过定量聚合酶链反应(quantitative polymerase chain reaction;qPCR)滴定并存储在-80℃下直到使用。
在另一实施例中,本发明涉及包含本发明的核酸、表达盒或载体的宿主细胞。根据本发明使用的宿主细胞可以是任何细胞类型,包括真核细胞和原核细胞两种。优选地,细胞包括原核细胞、酵母细胞或哺乳动物细胞。更优选地,宿主细胞是HEK-293和CHO细胞。
4.医药组合物
在另一方面,本发明指代含有以下中的至少一种的医药组合物:本发明的抗体衍生物、核酸、载体或宿主细胞(在下文中单独或共同称为“本发明的活性剂”)或其混合物,其用医药学上可接受的载剂配制。所述医药组合物用于治疗受试者中的HIV或AIDS或预防未感染受试者的HIV感染。在一个实施例中,组合物包括本发明的多种(例如两种或更多种)抗体衍生物、核酸、载体或宿主细胞的混合物。在本发明的一个实施例中,组合物至少包含分子-3、分子-4、分子-5、分子-6、分子-7、分子-8、分子-10、分子-11、或表达所述抗体衍生物的核酸、载体或宿主细胞或其混合物。优选地,组合物至少包含分子-5、分子-7、分子-8、或表达所述抗体衍生物的核酸、载体或宿主细胞或其混合物。更优选地,组合物至少包含分子-7或表达所述抗体衍生物的核酸、载体或宿主细胞或其混合物。包含本发明的抗体衍生物的医药组合物的制备为所属领域中已知。参见McNally E等人编,《蛋白质配制物和递送(Protein Formulation and Delivery)》(Marcel Dekker,Inc.,美国纽约州纽约,2000);Hovgaard L等人编,《肽和蛋白质的医药配制物研发(Pharmaceutical FormulationDevelopment of Peptides and Proteins)》,第2版(CRC Press,美国佛罗里达州波卡拉顿,2012)以及Akers M等人,《医药生物技术(Pharm Biotechnol.)》2002;14:47-127。
优选地,载剂适用于静脉内、肌肉内、皮下、肠胃外、脊髓或表皮给药(例如通过注射或输注)。取决于给药途径,本发明的活性剂可以包覆于材料中以保护试剂免于遭受可使试剂失活的条件作用。
在本发明的另一实施例中,提供专门适用于基因疗法(“被动免疫接种”)的医药组合物。所述医药组合物包含本发明的核酸或载体或其混合物中的至少一种并根据所属领域中已知的方法制备。参见AndréS等人,《病毒学杂志》1998,72:1497-1503;Mulligan M,Webber J,AIDS 1999;13(增刊A):S105-S112;O'Hagan D等人,《病毒学杂志》2001;75:9037-9043和Rainczuk A等人,《感染与免疫(Infect.Immun.)》2004;72:5565-5573。本发明的核酸所嵌入的特定载体骨架并不重要,只要所述核酸在受试者中充分表达即可。合适载体的实例包括但不限于病毒和质粒。优选地,当采用病毒载体时使用AAV载体。优选地,当采用质粒载体时使用pcDNA3.1和pVAX1(英杰公司(Invitrogen),美国加利福尼亚州卡尔斯巴德);在英杰公司网站http://www.thermofisher.com/uk/en/home/brands/invitrogen.html,2015年10月可用的DNA序列;pNGVL(国家基因载体实验室,密歇根大学,美国密歇根州);以及p414cyc(ATCC寄存编号87380)和p414GALS(ATCC寄存编号87344)。更优选地,将pcDNA3.1质粒用作质粒载体。最优选地,质粒载体是pABT-5、pABT-7和pABT-8。
被动免疫接种的设计和应用为所属领域中已知。参见Donnelly J等人,《免疫学年评(Annu.Rev.Immunol.)》1997;15:617-648;Robinson H,Pertmer T,《病毒研究进展(Adv.Virus Res.)》2000;55:1-74;Gurunathan S等人,《免疫学年评》2000;18:927-974(2000)和Ulmer J,《药物发现与研究的当前观点(Curr.Opin.Drug Discov.Devel.)》2001;4:192-197。简单来说,本发明的情形内的被动免疫接种被配置以引导受试者中的抗体衍生物的体内表达。参见Ulmer J等人,《科学》1993;259:1745-1749。通常,核克隆为针对真核生物中的表达优化的细菌质粒并由以下组成:(i)细菌中用于繁殖的复制起点,通常如ColE1的大肠杆菌(E.coli)来源;(ii)用于选择细菌中的质粒的抗生素抗性基因,通常为卡那霉素;(iii)用于哺乳动物细胞中的最优表达的强启动子,如巨细胞病毒(CMV)或猴病毒40(SV40);(iv)用于***所关注基因的在启动子下游的多个克隆位点以及(v)用于稳定mRNA的SV40或牛生长素(bovine growth hormone;BGH)聚腺苷酸化信号。
本发明的仍另一个目的为利用具有能够表达本发明的抗体衍生物的非病原性或减毒细菌菌株递送载体,所述菌株如(但不限于)埃希氏菌属(Escherichia spp.)、沙门氏菌菌属(Salmonella spp.)、志贺氏菌菌属(Shigella spp.)、分枝杆菌(Mycobacteriumspp.)以及李斯特菌菌属(Listeria spp.)。
所采用的特定埃希氏菌菌株对于本发明并非至关重要的。可以用于本发明的埃希氏菌菌株的实例包括大肠杆菌菌株DH5a、HB 101、HS-4、4608-58、1184-68、53638-C-17、13-80和6-81、产肠毒素大肠杆菌、致肠病大肠杆菌和肠出血性大肠杆菌。参见:Sambrook,1989,见上文;Sansonetti P等人,《微生物学年报(Ann.Microbiol.)》1982;132A:351-355);Evans D等人,《感染与免疫》1975;12:656-667;Donnenberg S等人,《传染病杂志(J.Infect.Dis.)》1994;169:831-838;以及McKee M,O'Brien A,《感染与免疫》1995;63:2070-2074。
所采用的特定沙门氏菌菌株对于本发明并非至关重要的。可以用于本发明的沙门氏菌菌株的实例包括伤寒沙门菌(S.typhi)(ATCC寄存编号7251)、鼠伤寒沙门氏菌(S.typhimurium)(ATCC寄存编号13311)、禽伤寒沙门氏菌(S.galinarum)(ATCC寄存编号9184)、肠炎杆菌(S.enteriditis)(ATCC寄存编号4931)、鼠伤寒沙门氏菌(S.typhimurium)(ATCC寄存编号6994)、伤寒沙门菌aroC、aroD双重突变体突变体(Hone D等人,《疫苗(Vaccine)》1991;9:810-816)和鼠伤寒沙门氏菌aroA突变体(Mastroeni D等人,《微型心肌梗塞病理学(Micro.Pathol.)》1992;13:477-491)。
所采用的特定志贺氏菌菌株对于本发明并非至关重要的。可以用于本发明的志贺氏菌菌株的实例包括福氏志贺氏菌(S.flexneri)(ATCC寄存编号29903)、福氏志贺氏菌CVD1203(ATCC寄存编号55556)、福氏志贺氏菌15D(Sizemore D等人,《疫苗》1997;15:804-807;Sizemore D等人,《科学》1995,270:299-302)、宋内志贺菌(S.sonnei)(ATCC寄存编号29930)和痢疾志贺菌(S.dysenteriae)(ATCC寄存编号13313)。
所采用的特定分枝杆菌菌株对于本发明并非至关重要的。可以用于本发明的分枝杆菌菌株的实例包括结核分枝杆菌(M.tuberculosis)CDC1551菌株(Griffith T等人,《美国呼吸与重症护理医学(Am.J.Respir.Crit.Care Med.)》1995;152:808-811);结核分枝杆菌北京菌株(van Soolingen D等人,《临床微生物学杂志(J.Clin.Microbiol.)》1995;33:3234-3238)、结核分枝杆菌H37Rv菌株(ATCC寄存编号25618)、结核分枝杆菌泛酸盐营养缺陷型菌株(Sambandamurthy V,《自然医学(Nat.Med.)》2002;8:1171-1174)、结核分枝杆菌rpoV突变体菌株(Collins D等人,美国国家科学院院刊1995;92:8036)、结核分枝杆菌白氨酸营养缺陷型菌株(Hondalus M等人,《感染与免疫》2000;68(5):2888-2898)、BCG丹麦菌株(ATCC寄存编号35733)、BCG日本菌株(ATCC寄存编号35737)、BCG芝加哥菌株(ATCC寄存编号27289)、BCG哥本哈根菌株(ATCC编号27290)、BCG巴斯德菌株(ATCC寄存编号35734)、BCG葛兰素菌株(ATCC寄存编号35741)、BCG康诺特菌株(ATCC寄存编号35745)和BCG蒙特利尔(ATCC寄存编号35746)。
所采用的特定李斯特菌株对于本发明并非至关重要的。可以用于本发明的单核细胞增多性李斯特菌菌株的实例包括但不限于:单核细胞增多性李斯特菌菌株10403S(Stevens R等人,《病毒学杂志》2004;78:8210-8218)、绵羊李斯特杆菌(L.ivanovii)和斯氏利斯特菌(L.seeligeri)菌株(Haas A等人,《生物化学与生物物理学报(Biochim.Biophys.Acta.)》1992;1130:81-84)或突变体单核细胞增多性李斯特菌菌株,如(i)actA plcB双重突变体(Peters C等人,《欧洲微生物学会联合会免疫学与医学微生物学(FEMS Immunol.Med.Microbiol.)》2003;35:243-253和Angelakopoulos H等人,《感染与免疫》2002;70:3592-3601)或(ii)丙氨酸消旋酶基因和D-氨基酸转氨酶基因的dal dat双重突变体(Thompson R等人,《感染与免疫》1998;66:3552-3561)。
使用细菌媒剂递送载体的方法为本领域中众所周知的。参见US 6,500,419、US5,877,159和US 5,824,538;Shata M等人,《今日分子医学(Mol.Med.Today)》2000;6:66-71;Hone D,Shata M,病毒学杂志2001;75:9665-9670;Shata M等人,《疫苗》2001;20:623-629;Rapp U和Kaufmann S,《国际免疫学(Int.Immunol.)》2004,16:597-605;Dietrich G等人,《分子治疗学新见(Curr.Opin.Mol.Ther.)》2003;5:10-19和Gentschev I等人,《生物技术杂志(J.Biotechnol.)》2000;83:19-26。用于表达本发明的抗体衍生物的由所述细菌媒剂递送的质粒的类型并不是至关重要的。
在另一实施例中,还提供用于递送本发明的核酸的AAV载体的用途。
本发明的医药组合物可以通过所属领域中已知的多种方法给药。如熟练技术人员将了解,给药途径或模式将取决于所需结果而变化。本发明的活性剂可以使用将保护试剂免于快速释放的载剂制备,例如控制释放配制物,包括植入物、经皮贴片和微囊封递送***。可以使用可生物降解的生物相容性聚合物,如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯以及聚乳酸。用于制备这类配制物的许多方法是所属领域一般已知的。参见Robinson J等人编,《持续和控制释放药物递送***(Sustained and Controlled ReleaseDrug Delivery Systems)》(马塞尔·德克尔公司(Marcel Dekker,Inc.),美国纽约州纽约,1978)。
为通过某些给药途径给药本发明的活性剂,可能有必要用材料包覆试剂或共同给药试剂与材料以防止其失活或确保其体内适当分布。举例来说,可以向受试者以合适载剂(例如脂质体)或稀释剂形式给药试剂。医药学上可接受的稀释剂包括但不限于生理食盐水和缓冲水溶液。脂质体包括水包油包水CGF乳液以及常规脂质体。参见Strejan G等人,《神经免疫学杂志(J.Neuroimmunol.)》1984;7:27-41。制造脂质体的许多方法为所属领域中已知的。参见US 4,522,811、US 5,374,548和US 5,399,331。脂质体可包含选择性传输至特定细胞或器官并因此促进靶向药物递送的一种或多种部分。示例性靶向部分包括叶酸或生物素、甘露糖苷和表面活性剂蛋白A受体。在本发明的一个实施例中,本发明的活性剂在脂质体中配制;在一更佳实施例中,脂质体包括靶向部分。在一最优选实施例中,脂质体中的活性剂通过快速注射递送。
医药学上可接受的载剂包括无菌水溶液或分散液以及即用制备无菌可注射溶液或分散液的无菌粉末。就其用途与本发明的活性剂相容来说,本文中涵盖这类媒介在本发明的医药组合物的制备中的用途。补充活性化合物也可并入到医药组合物中。
医药组合物通常为无菌的并且在制造和存储条件下稳定。组合物可配制为溶液、微乳液、脂质体或适合于活性剂浓度的其它有序结构。载剂可以是溶剂或含有例如水、乙醇、多元醇(例如丙三醇、丙二醇、液体聚乙二醇)的分散介质或其合适混合物。可以例如通过使用涂层(如卵磷脂)、在分散液情况下通过维持所需粒度以及通过使用表面活性剂来维持适当流动性。在许多情况下,优选在组合物中包括等渗剂,例如糖、多元醇(例如甘露糖醇、山梨糖醇)或氯化钠。可注射组合物的延长吸收可以通过在组合物中包括延迟吸收的化合物(例如单硬脂酸盐、明胶)来引起。
无菌可注射溶液可以通过将本发明的活性剂以所需量与上文列举的成分中的一个或组合(根据需要)并入适当溶剂中,接着灭菌微过滤来制备。一般来说,通过将活性剂并入含有碱性分散介质和来自上文所列举的那些成分的所需其它成分的无菌媒剂中来制备分散液。在无菌粉末用于制备无菌可注射溶液的情况下,优选的制备方法是真空干燥和冷冻干燥(即冻干),这些方法由其先前无菌过滤的溶液得到活性成分加任何额外所希望的成分的粉末。
可以调整剂量方案以提供最优的所需反应(例如治疗性反应)。举例来说,如由治疗情况的紧急状态所指示的,可以给药单次推注,可以随着时间给药若干分次剂量,或可以按比例地减少或增加剂量。举例来说,本发明的抗体衍生物可以通过皮下注射每周一次或两次或通过皮下注射每月一次或两次给药。
将肠胃外组合物配制成容易给药和剂量均一的单位剂型特别有利。如本文所使用,剂量单位形式是指适合作为单一剂量用于待治疗受试者的物理分散单元;每个单元含有经计算以与所需医药载剂结合产生所需治疗效果的预定量的活性剂。关于本发明的单位剂型的规格由活性剂的独特特征和要获得的具体治疗效果指定并且直接取决于这些。
医药学上可接受的抗氧化剂的实例包括但不限于水溶性抗氧化剂(例如抗坏血酸、半胱氨酸氢氯化物、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠)、油溶性抗氧化剂(例如棕榈酸抗坏血酸酯、丁基化羟基大茴香醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚)和金属螯合剂(例如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸)。本发明的医药组合物的配制物包括适用于口服、经鼻、局部(例如颊内和舌下)、经直肠、经***或肠胃外给药的那些。这些配制物可以合宜地呈现为单位剂型,并且可以通过所属领域中已知的任何方法来制备。可以与载剂材料组合以产生单一剂型的活性剂的量将取决于所治疗受试者和给药的特定模式而变化。可以与载剂材料组合以产生单一剂型的活性剂的量将一般是产生治疗效果的组合物的那种量。一般来说,这一量将在活性剂的约0.001%到约90%、优选地约0.005%到约70%和最优选地约0.01%到约30%范围内。
适用于经***给药的本发明的配制物还包括***栓剂、棉塞、乳膏、凝胶、糊剂、泡沫材料或合适的含有如所属领域中已知的这类载剂的喷雾配制物。用于局部或经皮给药本发明的化合物的剂型包括散剂、喷雾剂、软膏、糊剂、乳膏、乳液、凝胶、溶液、贴片以及吸入剂。可以在无菌条件下混合本发明的活性剂与医药学上可接受的载剂和可能需要的任何防腐剂、缓冲剂或推进剂。
本发明的医药组合物还可以含有佐剂,如防腐剂、湿润剂、乳化剂和分散剂。微生物存在的预防可以通过灭菌程序和包括各种抗细菌和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、酚类山梨酸)来确保。还期望的是在组合物中包括等渗剂(例如糖、氯化钠)。
可以改变本发明的医药组合物中的活性剂的实际剂量水平以便实现受试者中的所需治疗反应。所选剂量水平将取决于多种药物动力学因素,包括所采用的本发明的特定试剂的活性、其量、给药途径、给药时间、所采用的特定活性剂的分泌或表达速率、治疗持续时间、与所采用的特定组合物组合使用的其它药物、化合物或材料、所治疗受试者的年龄、性别、体重、病状、一般健康状况和先前病史以及医疗领域中熟知的类似因素。一般熟***低的水平下开始给药医药组合物中采用的本发明的活性剂并且逐渐提高剂量直到实现所需效果。一般来说,本发明组合物的合适日剂量应是可有效产生治疗效果的最低剂量的活性剂的量。这类有效剂量将一般取决于上文所述的因素。优选的是给药是肠胃外,更优选地,静脉内、肌肉内、腹膜内或皮下。视需要,医药组合物的有效日剂量可以在每天中的合适间隔任选地以单位剂型分别以所施加的二、三、四、五、六或更多次子剂量给药。尽管单独给药本发明的活性剂为可能的,但优选地以医药组合物形式给药所述试剂。
本发明的医药组合物可以用所属领域中已知的医疗装置给药。举例来说,在一优选实施例中,本发明的药物组合物可以用无针皮下注射装置给药。参见US 5,399,163、US5,383,851、US 5,312,335、US 5,064,413、US 4,941,880、US 4,790,824或US 4,596,556。适用于本发明的熟知植入物和模块的实例包括但不限于:用于以不同速率分配药品的输液泵(例如US 4,447,233(非可植入,控制速率)、US 4,447,224(可植入,可变速率)、US 4,487,603(可植入,控制速率))、用于经由皮肤给药药剂的装置(例如US 4,486,194)和渗透压药物递送***(例如US 4,439,196和US 4,475,196)。所属领域的技术人员已知许多其它这类植入物、传递***和模块。
本发明的医药组合物必须是无菌的并且是流体从而组合物可通过注射器递送。除水以外,载剂可以是等渗缓冲盐水溶液、乙醇、多元醇(例如丙三醇、丙二醇、液体聚乙烯二醇)和其合适混合物。举例来说,可以通过使用如卵磷脂的包衣、通过在分散液的情况下维持所需粒度和通过使用表面活性剂来维持适当流动性。在许多情况下,优选在组合物中包括等渗剂,例如糖、多元醇(例如甘露糖醇、山梨糖醇)或氯化钠。通过使组合物中包括延迟吸收的试剂(例如单硬脂酸铝或明胶),可以实现可注射组合物的长期吸收。
5.治疗和预防方法
在另一方面中,本发明是针对用于治疗或预防受试者中的HIV感染或AIDS的方法,其包含向所述受试者给药以下中的至少一种:本发明的抗体衍生物、核酸、载体、宿主细胞或医药组合物或其混合物。与HIV感染或AIDS症状有关的本发明的活性剂和医药组合物的有益治疗或预防效果包括例如:预防或延迟暴露于HIV的受试者的初始感染;减少感染HIV的受试者中的病毒负荷;延长HIV感染的无症状期;维持其病毒含量已经由抗逆转录病毒疗法(AT)降低的HIV感染受试者中的低病毒负荷;在未经药物治疗的受试者中和在用AT治疗的受试者中,增加CD4T细胞的含量或减少CD4T细胞的减少,HIV-1特异性和非特异性两者;提高患有AIDS的受试者的总体健康或生活品质以及延长患有AIDS的受试者的预期寿命。医师或兽医可以比较治疗效果与治疗之前的受试者病状,或未经治疗的受试者的预期病状以判定治疗是否有效抑制AIDS。在一优选实施例中,本发明的活性剂和医药组合物用于预防HIV感染或AIDS。在另一优选实施例中,本发明的活性剂和医药组合物用于治疗HIV感染或AIDS。
本发明的活性剂和医药组合物可以适用于治疗HIV感染或AIDS。尽管可能罹患HIV或其等效物的所有受试者都可以以此方式进行治疗(例如黑猩猩、猕猴、狒狒或人类),但本发明的活性剂和医药组合物尤其针对其在人类中的治疗用途。常常,可能需要超过一种给药来产生所需治疗效果;确切的方案(剂量和频率)可以通过标准临床程序确立。
本发明进一步涉及降低或去除与HIV感染或AIDS相关的症状。这些包括与HIV感染的次要症状期相关的症状,包括例如带状疱疹、皮疹、指甲感染、口疮、复发性鼻喉感染和体重减轻。另外,与HIV感染的主要症状期相关的其它症状包括例如鹅口疮和***鹅口疮(念珠菌(Candida))、持续性腹泻、体重减轻、持续性咳嗽和再活化肺结核或复发性疱疹感染,如唇疱疹(单纯疱疹(herpes simplex))。可以根据本发明治疗的全盛期AIDS的其它症状包括例如腹泻、恶心和呕吐、鹅口疮和口疮、持续性、复发性***感染和***、持续性全身***病(persistent generalized lymphadenopathy;PGL)、严重皮肤感染、疣和癣、呼吸感染、肺炎、尤其肺炎肺囊虫肺炎(Pneumocystis carinii pneumonia;PCP)、带状疱疹(herpes zoster/shingles)、神经***问题,如手和脚的疼痛、麻木或“发麻”、中枢神经***功能异常、卡波西氏肉瘤(Kaposi's sarcoma)、淋巴瘤、肺结核或其它类似机会性感染。
在另一优选实施例中,向HIV感染受试者或暴露于HIV的受试者给药本发明的活性剂或医药组合物与至少一种治疗剂的组合。优选地,指示治疗剂通常用于预防或治疗HIV或AIDS。合适的治疗剂包括但不限于:当前抗逆转录病毒疗法(antiretroviral therapy;AT)和高度活性抗逆转录病毒疗法(highly active antiretroviral therapy;HAART)方案的形成药物部分,如非核苷逆转录酶抑制剂(例如依法韦仑、奈韦拉平、地拉韦啶(delavirdine)、依曲韦林(etravirine)、利匹韦林(rilpivirine))、核苷模拟逆转录酶抑制剂(例如齐多夫定、替诺福韦(tenofovir)、拉米夫定、恩曲他滨(emtricitabine))和蛋白酶抑制剂(例如沙奎那韦(saquinavir)、利托那韦、茚地那韦、奈非那韦(nelfinavir)、安普那韦(amprenavir)),在下文中独立或共同称为“HIV抗逆转录病毒”。在这个实施例的一个形式中,至少一种本发明的活性剂或药物组合物和至少一种HIV抗逆转录病毒同时一起向受试者给药。在另一形式中,在向受试者施用任何HIV抗逆转录病毒之前给药至少一种本发明的活性剂或药物组合物。在又一形式中,在已向受试者施用HIV抗逆转录病毒之后,例如在中断AT或HAART方案之后给药至少一种本发明的活性剂或药物组合物。
另外,本发明的抗体衍生物还可以与可诱导感染细胞的表面上的HIV gp120的表达的治疗剂一起给药,因此允许其通过NK细胞快速移除。参见Siliciano J等人,《过敏与临床免疫学杂志(J Allergy Clin Immunol.)》2014;134(1):12-19。
6.中和和检测方法
在另一方面中,本发明涉及使HIV失活的方法,其包含以下步骤:使病毒与本发明的至少一种抗体衍生物接触。优选地,所述方法针对含有HIV或疑似含有HIV的样品进行。方法可以在促进抗体衍生物偶合到如所属领域所描述的HIV的条件下进行。参见Lu L等人,《逆转录病毒学》2012;9(104),1-14。
在另一方面中,本发明涉及检测附着到样品中的人类CD4受体的D1和D2结构域的分子或其片段(例如HIV、gp120)的方法,其包含以下步骤:(a)使样品与本发明的抗体衍生物接触和(b)判定抗体衍生物是否特异性结合到样品中的分子。所述样品可以是生物样品,包括但不限于血液、血清、尿液、组织或来自非感染、感染或可能感染的受试者(例如维持周期性或间歇性HIV暴露的受试者)的其它生物材料。样品还可以是非生物性的(例如从水、饮料中获得)。优选地,分子是HIV并且更优选地是HIV的gp120病毒包膜蛋白。
在这一方面的一优选实施例中,本发明涉及检测样品中的HIV的方法,其包含以下步骤:(a)使样品与本发明的抗体衍生物接触和(b)判定抗体衍生物是否特异性结合到样品中的HIV分子。优选地,样品是血浆样品或血清样品。
样品可以首先***纵以使其更适用于检测方法。在一优选实施例中,延长样品与抗体衍生物之间的接触(即在适用于样品和抗体衍生物稳定的条件下培育)。接触步骤期间的条件可以由熟练技术人员以常规方式确定。可用于接触步骤的合适缓冲液包括不干扰待进行的分析的生理缓冲液。举例来说,可采用Tris或三乙醇胺(TEA)。缓冲液(和包括缓冲溶液的所得溶解试剂)的pH值可以在约2.0到约10.0、任选地约4.0到约9.0、优选地约7.0到约8.5并且甚至更优选地约7.5到约8.0范围内、或为约7.0、约7.5、约8.0、或约8.5。示例性“接触”条件可包含15分钟到4小时的培育(例如在4℃、37℃下或在室温下培育1hr)。然而,这些可视需要根据例如相互作用的结合配偶体的性质改变。样品可以任选地经历轻微摇荡、混合或旋转。另外,可以添加其它合适试剂,如封闭剂以减少非特异性结合。举例来说,可以使用1-4%BSA或其它合适的封端剂(例如乳)。接触条件可以取决于检测方法的目标改变和调适。举例来说,如果培育温度是例如室温或37℃,那么这可增加鉴别在这些条件下稳定(例如在人体中发现的条件下稳定)的粘合剂的可能性。
优选地,使本发明的抗体衍生物与样品在允许复合物在抗体衍生物与样品中所呈现的分子或其片段之间形成的条件下接触。随后检测到表明例如样品中存在HIV的复合物的形成并通过合适手段测量。这些检测和测量手段取决于结合搭配物的性质并包括但不限于:均相和非均相结合分析,例如放射性免疫分析(RIA)、ELISA、免疫荧光法、免疫组织化学、流式细胞测量术(例如FACS)、BIACORE和西方墨点法分析。尤其用于大规模分析受试者血清和血液和血液来源的产物的优选分析技术是流式细胞测量术、ELISA和西方墨点法技术。
在一优选实施例中,通过流式细胞测量术(例如FACS)进行测量。如本文所用,术语“流式细胞测量术”指代一种分析,其中材料在样品中的比例通过以下测定:标记材料(例如通过将标记抗体结合到材料);使含有材料的流体流穿过光束;通过一系列滤光器和反射镜将从样品发射的光分离为构成波长并检测光。流式细胞测量术允许单细胞的一些特征的敏感性检测和快速定量,如相对尺寸复杂性和内源荧光,以及可以标记有荧光染料的任何细胞化合物的定量分析。参见Melamed M等人,《流式细胞测量和细胞分选(Flow Cytometryand Cell Sorting)》,第2版(Wiley-Liss,美国纽约州纽约,1990)。流式细胞测量术的一个主要优势是基于大量粒子或细胞的分析物的快速定量。一般来说,选用作可检测标记的荧光染料基于其受具有激光器所使用的波长的光的激发时发荧光的能力而选择。当荧光染料受激光束激发时,其发光,所述光随后通过流式细胞仪的光电倍增管评估。这种技术能够在1到2分钟内分析10,000个细胞/粒子。流式细胞仪具有滤光器,所述滤光器检测在不同波长下发荧光的各种荧光染料的放射,并允许四种或更多种用作可检测标记的不同荧光染料,这意味着目前可以同时检测至少4种不同分子。这些用于分析样品的方法和设备可在市面上购得并为本领域中众所周知的(例如FACSCalibur流式细胞仪;BD Biosciences公司,美国新泽西州富兰克林湖)。
在一优选实施例中,所述测量包含优选地通过流式细胞测量术使用能够结合于抗体衍生物、优选地结合于所述抗体衍生物的Fc区的报告子分析样品。优选地,报告子包含可检测部分并且更优选地,其是偶合到可检测部分的Fc特异性二次抗体。
有用的可检测部分包括荧光团。“荧光团”(或“荧光染料”或“发色团”)应理解为在光激发时可再发光的荧光化合物。可使用的荧光团包括生物(例如蛋白质)和化学荧光团。示例性生物荧光团包含T-蓝宝石、蔚蓝、mCFPm、CyPet、EGFP、PA-EGFP、翡翠、EYFP、Venus、mCitrine、mKO、mOrange、DSRed、JRed、mStrawberry、mCherry、PA-mCherry、mRuby、Tomato、mPlum、mKate、mKatushka、Kaede、Halotag和超黄道氟。示例性化学荧光团包含Alexafluor、若丹明(Rhodamine)、氟硼荧、四甲基罗丹明、花青苷染料、荧光素、量子点、IR染料、FM染料、ATTO染料。二次抗体也可标记有适用于检测的酶,例如辣根过氧化酶、β-半乳糖苷酶、荧光素酶、碱性磷酸酶或葡萄糖氧化酶。当抗体标记有可检测酶时,其可以通过添加酶使用的其它试剂催化可以辨别的反应产物来检测到。举例来说,当存在试剂辣根过氧化酶时,添加过氧化氢和二氨基联苯胺可产生彩色的反应产物,其可目视检测。抗体还可以标记有生物素并通过亲和素或链霉亲和素结合的间接测量检测。应注意,亲和素本身可用酶或荧光标记来标记。
优选地,所采用的Fc二次抗体对衍生一次抗体的物种(例如人类)具有特异性。在一个实施例中,所述Fc特异性二次抗体选自由以下组成的组:IgA(例如IgA1、IgA2)、IgD、IgE、IgG(例如IgG1、IgG2、IgG3、IgG4)和IgM。优选地,二次抗体是IgG并且更优选地是IgG1。所述Fc特异性二次抗体可以是任何脊椎动物抗体,优选地任何哺乳动物抗体,并且更优选地任何非人类抗体(例如兔、小鼠、大鼠、山羊、马、绵羊或驴抗体)。
为了用作前述分析中的试剂,本发明的抗体衍生物宜结合到微量滴定孔的内表面。本发明的抗体衍生物可以直接结合到微量滴定孔。然而,抗体衍生物到孔的最大结合可以通过在添加抗体衍生物之前用聚赖氨酸预处理孔来实现。此外,本发明的抗体衍生物可以通过所属领域中已知的手段共价连接到孔。一般来说,使用在0.01到100μg/mL之间的本发明的抗体衍生物以用于涂布,尽管还可使用较高以及较低的量。随后将样品添加到用本发明的抗体衍生物涂布的孔。
7.试剂盒
在另一方面,本发明指代包含以下中的至少一种的试剂盒:本发明的抗体衍生物、核酸、载体、宿主细胞、医药组合物或组合或其混合物。本发明的试剂盒的组分可以任选地封装在合适容器中并标记用于HIV或AIDS的检测、失活、诊断、预防或治疗或其相关病状。试剂盒的组分可以按水性、优选地无菌溶液形式或按用于复水的冻干、优选地无菌配制物形式存储在单位或多剂量容器中。容器可以由多种材料(诸如玻璃或塑料)形成,并且可以具有无菌接入端口(例如容器可以是静脉内溶液袋或具有可由皮下注射针刺穿的塞子的小瓶)。试剂盒可以进一步包含更多个包含医药学上可接受的载剂的容器。其可进一步包括从商业和用户观点期望的其它材料,包括但不限于缓冲液、稀释液、过滤器、针、注射器、用于一种或多种合适宿主细胞或其它活性剂的培养基。试剂盒可含有惯常包括于诊断和治疗产品的商业包装中的说明书,其含有例如关于指示、用法、剂量、制造、给药、禁忌或关于使用这类诊断和治疗产品的警告的信息。
本文中所提及的所有公开都以全文引用的方式并入本文中。现已大体上描述本发明,将通过参考以下实例将更容易理解本发明,除非指定,否则所述实例借助于说明提供并且并不打算限制本发明。
一般程序
1.CD4-huIgG衍生物的构建
人类CD4分子的两种胞外结构域(D1和D2)连接到人类IgG1的Fc部分,所述胞外结构域包括铰链、CH2和CH3结构域,以获得CD4-IgG1分子。基于CD4-IgG1骨架,设计具有以下特征的抗体衍生物:
(a)增加ADCC介导反应的Fc链的位置G236A/S239D/A330L/I332E中的突变。参见Bournazos S等人,《细胞》2014;158:1243-1253。
(b)人类CCR5的N端胞外序列在Fc链(MDYQVSSPIYDINYYTSEPCQKINVKQIA)(SEQ IDNO:6)的C端处的添加
(c)T-20序列在Fc链(YTSLIHSLIEESQNQQEKKNEQELLELDKASLWNWF)(SEQ ID NO:7)的C端处的添加
(d)具有可变数目的灵活链路(GGGGS)(SEQ ID NO:5)的CCR5序列(MDYQVSSPIYDINYYTSEPCQKINVKQIA)(SEQ ID NO:6)和T-20序列(YTSLIHSLIEESQNQQEKKNEQELLELDKASLWNWF)(SEQ ID NO:7)的依序添加。
使用基因技术方法以及pcDNA3.1和pcDNA3.4表达质粒合成表达本发明的抗体衍生物的所有聚核苷酸。
使用0.5μg/μL下的10mM Tris缓冲液pH 8重构质粒。使用1μL质粒和以下制造说明转化One Shot TOP10化学感受态大肠杆菌(生命技术公司(Life Technologies Corp.),美国加利福尼亚州卡尔斯巴德)。简单来说,将1μL质粒添加到细菌小瓶并在冰上培育15分钟。在此之后,将试管在42℃下培育30秒并立即置于冰上持续两分钟。将细菌再悬浮于250μLSOC培养基(生命技术公司,美国加利福尼亚州卡尔斯巴德)中并在Innova 4000恒温振荡培养箱(New Brunswick Scientific有限公司,美国康涅狄格州恩菲尔德)中在37℃和225rpm下培育1小时。之后,将100μL 1/100细胞培养物的稀释液扩散于安比西林(ampicillin)选择(100μg/mL)LB琼脂板上。板在Heraeus培养箱(赛默飞世尔科技(Thermo FisherScientific),美国马萨诸塞州沃尔瑟姆)中在37℃下培育16-24小时。分离一个菌落并接种至5mL安比西林(100μg/mL)选择LB培养基并在37℃和225rpm下在Innova 4000恒温振荡培养箱(New Brunswick Scientific有限公司,美国康涅狄格州恩菲尔德)中培育8小时。在此之后,500mL安比西林(100μg/mL)选择LB培养基接种有500μL前述培养物并如先前所描述在37℃和225rpm下培育16小时。细菌在艾本德离心机5810R(赛默飞世尔科技,美国马萨诸塞州沃尔瑟姆)中在室温下通过3000xg下的离心收集45分钟并且质粒使用凯杰质粒Maxi试剂盒(Qiagen NV,荷兰芬洛)并根据制造商的说明书分离。纯化的质粒通过分光光度法使用nanodrop 1000仪器(赛默飞世尔科技,美国马萨诸塞州沃尔瑟姆)定量。
2.蛋白质生产、定量和纯化
根据制造商的说明书使用Calphos转染试剂盒(宝生物工程株式会社,日本大津市)用编码本发明的不同抗体衍生物的质粒转染HEK-293细胞。48小时之后,收集上清液,经由0.45μm过滤器(EMD Millipore,默克集团,德国达姆施塔特)通过过滤澄清并存储在-20℃下使用。
抗体衍生物通过ELISA定量。简单来说,Maxisorp 96-F板(Nunc,赛默飞世尔科技,美国马萨诸塞州沃尔瑟姆)在4℃下用100微升/孔的F(ab)2山羊抗人类IgG(Fc特异性)抗体(Jackson ImmunoResearch Labs公司,美国宾夕法尼亚州西格罗夫)以PBS中的1μg/mL培育过夜。在用PBS/10%FBS/0.05%吐温20封闭并洗涤之后,将封闭缓冲液中的培养物上清液(含有重组蛋白)的连续稀释液添加到板(100微升/孔)并在4℃培育过夜。作为标准液,使用0.1μg/mL、0.05μg/mL和0.025μg/mL纯化eCD4-Ig蛋白的稀释液。板经再次洗涤并添加封闭缓冲液中的1/10000稀释度下的二次抗体HRP-F(ab)2山羊抗人类IgG(Fc特异性)(JacksonImmunoResearch Labs公司,美国宾夕法尼亚州西格罗夫)(100微升/孔)并在室温下培育一小时。板经洗涤并且结合抗体使用OPD基质检测并且添加4N H2SO4停止反应。在ELISA板读取器中在492nm下测量产物。
使用蛋白A琼脂糖(通用电气医疗集团,美国康涅狄格州斯坦福德)管柱纯化蛋白质。如上文所指出,使用无血清培养基通过瞬时转染制备蛋白质。上清液经收集,在3000xg下离心10分钟并在0.45μm下过滤以去除细胞碎片。将澄清上清液添加到先前洗涤的蛋白A琼脂糖珠粒并在首尾相连旋转下在4℃下培育过夜。蛋白A用Tris缓冲液盐水(TBS)洗涤并且结合蛋白用4M MgCl2溶离。或者,蛋白质使用CaptureSelect FcXL亲和力基质(赛默飞世尔科技,美国马萨诸塞州沃尔瑟姆)管柱纯化并用甘氨酸缓冲液pH=3.5溶离。经纯化的蛋白质对PBS渗析,通过超过滤浓缩,通过ELISA或分光光度法定量并存储在-80℃下直到使用。
3.中和分析
使用Env表达质粒和pSG3载体产生HIV-1分离株NL4-3、BaL、AC10、SVBP6、SVBP8、SVBP11、SVBP12、SVBP14、SVBP15、SVBP17、SVBP18和SVBP19作为假病毒。参见Sánchez-Palomino S等人,《疫苗》2011;29:5250-5259。通过抗体衍生物的无细胞病毒中和通过标准基于TZM-bl的分析测试。参见Li,2005,见上文。简单来说,在96孔培养板中,使用200TCID50(组织培养感染剂量)在37℃下历经一小时用50μL假病毒储备液预培育100μL先前稀释的抗体衍生物。随后,添加100μL含有10,000TZM-bl荧光素酶-报告子靶细胞/孔。板在37℃和5%CO2下培养48小时。测试1000到0.1ng/mL的抗体衍生物的连续稀释液。用右旋糖苷(西格玛-奥德里奇公司,美国密苏里州圣路易)处理TZM-bl报告子细胞以增强感染性。荧光素酶基质Britelite Plus(珀金埃尔默公司,美国马萨诸塞州沃尔瑟姆)用于读数。使用经拟合为一条具有可变希尔斜率(希尔斜率)的位点抑制曲线的标准化值计算中和数据的非线性拟合。所有统计分析和非线性拟合都使用GraphPad Prism v5.0软件进行。
4.ADCC分析
为评价不同抗体衍生物活化由NK细胞造成的HIV感染细胞的NK介导的破坏的能力,根据Alpert M等人,《病毒学杂志》2012,86:12039-12052进行ADCC分析。简单来说,NK细胞株KHYG-1CD16+用作效应细胞的来源并且CEM.NKR.CCR5+Luc细胞株用作靶细胞的来源。在分析5天前,靶细胞用高度感染性BaL分离株储备液感染并在37℃下在R10培养基(补充有10%胎牛血清的RPMI)中培养。为设定分析,在U形底96孔板中总体积为200μL的不同浓度的抗体衍生物或基于抗体的分子存在下,在补充有10U/ml重组IL-2的R10培养基中用105效应细胞培养104个靶细胞(其>40%经高效感染)。在37℃下培育8小时之后,再悬浮细胞并使150μL细胞悬浮液与50μL荧光素酶基质Britelite Plus(珀金埃尔默公司,美国马萨诸塞州沃尔瑟姆)混合。荧光素酶单元用于读数。因为靶细胞在HIV感染时表达荧光素酶,所以荧光素酶活性的降低是抗体和NK介导的细胞杀灭的直接测量。
实例1
经工程改造的CD4IgG融合蛋白的设计
如先前报告制备huCD4-小鼠IgG融合蛋白。在过去已经使用这种融合蛋白鉴别抗CD4结合位点抗体。参见Carrillo J等人,《公共科学图书馆·综合(PLOS One)》2015;10(3):0120648;图1。然而,因为已知CD4-IgG1分子具有有限的治疗潜能,所以将若干变化引入到CD4-IgG1蛋白的序列以提高其抗病毒和ADCC活性。参见Jacobson J等人,《抗微生物剂化学疗法(Antimicrob Agents Chemother.)》2004;48(2):423-429。
首先,使人类IgG1的Fc区在位置G236A、S239D、A330L和I332E中突变,如所属领域所描述,从而增加ADCC介导反应。参见Bournazos,2014,见上文。旨在增加与HIV Env的相互作用的其它修饰包括添加对应于CCR5(SEQ ID NO:6)的N端胞外区的29氨基酸序列或添加在Fc链的C端末端处的T-20(SEQ ID NO:7)序列。参见Gardner,2015,见上文。据推测添加能够结合于gp41并阻碍HIV进入的预融合事件的肽可对抗病毒活性造成协同效应。因此,设计含有CCR5(SEQ ID NO:6)和T-20(SEQ ID NO:7)两者的抗体衍生物。参见图1和2。
进一步推测如果CCR5和T-20序列能够同时与其各别标靶区域相互作用,那么将发生协同作用。因此,提出从共同受体结合位点跨越到gp41的连接子。参见图3。
出于比较目的,还如先前所描述制备eCD4-IgG1融合蛋白(分子-1)。目前,eCD4-IgG1融合蛋白是所属领域中已知的最有效的抗HIV经工程化的抗体。参见Gardner,2015,见上文。为提供较佳的比较基础,分子-1的Fc链在本发明的抗体衍生物中(即在位置G236A、S239D、A330L和I332E中)进一步突变以获得eCD4-mIgG1融合蛋白(分子-2)。
实例2
第一代抗体衍生物的抗病毒活性
使用以下三种不同病毒进行标准中和分析以评估本发明的抗体衍生物的抗病毒活性:(i)X4-单向转变实验室分离株HIV-1菌株NL4-3;(ii)R5-单向转变实验室分离株HIV-1菌株BaL;以及(iii)尤其难以中和的2级型病毒HIV-1菌株AC10分离株。另外,使用熟知组的HIV亚型B病毒进行中和活性的进一步特征化。参见Li,2005,见上文。
简单来说,在96孔培养板中,使用200TCID50在37℃下历经一小时用50μL假病毒储备液预培育100μL先前稀释的血浆样品。随后,添加100μL含有10,000TZM-bl荧光素酶-报告子靶细胞/孔。板在37℃和5%CO2下培养48小时。测试1000到0.1ng/mL的抗体衍生物的连续稀释液。用右旋糖苷(西格玛-奥德里奇公司,美国密苏里州圣路易)处理TZM-bl报告子细胞以增强感染性。荧光素酶基质Britelite Plus(珀金埃尔默公司,美国马萨诸塞州沃尔瑟姆)用于读数。使用经拟合为一条具有可变希尔斜率(希尔斜率)的位点抑制曲线的标准化值计算中和数据的非线性拟合。所有统计分析和非线性拟合都使用GraphPad Prism v5.0软件进行。
所测试的所有分子都有效阻碍NL4-3和BaL分离株的感染性。对于NL4-3中和,含CCR5的分子-4展示7.1ng/mL的IC50值,而含T-20的分子-3更加有效,展示2.2ng/mL的IC50值。参考分子eCD4-IgG(分子-1,IC50值:1.2ng/mL)和其Fc突变的衍生物分子-2(IC50=1.1ng/mL)观察到更低值。最有效的化合物是含有CCR5和T-20序列的抗体衍生物(分子-5),其展示0.06ng/mL的IC50值。这一数据表明CCR5和T-20序列与柔性连接子的组合带来提高的抗病毒效能。参见图4(a);表1。仅含有CD4序列的分子-0和分子-6观察到较低的中和活性。
BaL分离株观察到类似结果。BaL中和分析中的抗病毒活性的排名为分子-4<分子-3<分子-1(eCD4-IgG)<分子-2(eCD4-mIgG1)<分子-5。此外,分子-5展示IC50值为0.01ng/mL的最高效能,比eCD4-IgG1蛋白有效100倍。参见图4(b);表1。此外,仅含有CD4序列的分子-0和分子-6观察到较低的中和活性。
意外地,仅分子-5展示对AC10分离株的任何抗病毒活性;抗体衍生物的其余部分在所测试的浓度范围内低效。参见图4(c);表1。
表1
实例3
第一代抗体衍生物的抗体依赖性细胞的细胞毒性(ADCC)活性
本发明的抗体衍生物的额外特征是其活化NK细胞和介导ADCC的能力。这个机制对于有效和快速去除HIV感染细胞而言为重要的并有助于保护未感染受试者免于HIV暴露和获得。参见Euler Z等人,《AIDS Res人类逆转录病毒(AIDS Res Hum Retroviruses)》2015;31(1):13-24。
使用所属领域中先前报道的测试评估本发明的抗体衍生物的ADCC活性。参见Alpert M等人,《病毒学杂志》2012,86:12039-12052。在此分析中,NK细胞的杀灭能力通过感染HIV的报告子细胞株中的荧光素酶表达的减少测量。含有CCR5和T-20序列的抗体衍生物(分子-5)诱导ADCC的能力与CD4-IgG1融合蛋白(即含有突变Fc片段的分子-6)和eCD4-IgG1融合蛋白(分子-1)比较。剂量反应曲线对感染HIV BaL分离株的细胞的分析展示分子-1和IgGb12的IC50值分别为71.4和66.2ng/mL,而含有突变Fc残基的分子展示较低的IC50值。破坏HIV感染细胞的分子-6和分子-5分别具有15.0和14.9ng/mL的IC50值。参见图5。这些数据表明在抗体的Fc区中添加突变可显著增强其保护能力。
实例4
连接子长度的优化和CCR5序列的作用分析
尽管分子-5展示显著高于参考eCD4-IgG1融合蛋白(分子-1)的抗病毒(+10,000%)和ADCC(500%)活性,但提出对本发明的抗体衍生物的原始设计的进一步修改以便增强其活性。这些修改的目的是:(i)优化连接子的长度和(ii)评价包括CCR5序列是否显著促进抗体衍生物的抗病毒和ADCC活性。根据以上方案制备一批新的抗体衍生物。这些抗体衍生物显示不同的连接子长度并包括或不包括CCR5序列。参见图6。
实例5
第二代抗体衍生物的抗病毒活性
进行标准中和分析以评估如实例2中所描述的经修饰抗体衍生物的抗病毒活性。
所测试的所有分子都有效阻碍NL4-3和BaL分离株的感染性。对于NL4-3中和而言,分子-5、分子-7和分子-8展示最高的效能,分别具有0.06、0.017和0.031ng/mL的IC50值。分子-10展示IC50为1.8ng/mL的最低效能,而分子-11展示IC50为0.35ng/mL的中间活性。参考化合物分子-1(eCD4-IgG1)和分子-0(CD4-IgG1)的IC50值分别为1.2和8.9ng/mL。值得注意的,分子-5、分子-7和分子-8比分子-1更加有效。举例来说,针对NL4-3病毒分子-7比分子-1有效1000%。参见图7(a);表2。
BaL分离株观察到类似结果。抗病毒活性的排名为分子-7≤分子-8≤分子-5<分子-11<分子-1(eCD4-IgG1)<分子-10。此外,分子-7展示IC50值为0.005ng/mL的最高效能,比分子-1(eCD4-IgG1)参考蛋白有效20,000%。参见图7(b);表2。
重要的是,仅根据本发明的经修饰抗体衍生物(即分子-7、分子-5、分子-11和分子-8)展示对AC10分离株的抗病毒活性。分子-7显示IC50值为1.3ng/mL的最高抗病毒活性,而分子-8和分子-5显示低两种/三倍的效能;此效能仍远高于分子-1(eCD4-IgG1,其展示IC50>100ng/mL)。参见图7(c);表2。
以上数据意外地表明CCR5序列对于抗病毒活性而言可能为非必要的,因为分子-5和分子-7两者展示类似的抗病毒活性。CCR5序列可能充当间隔序列而非提供抗病毒活性的益处。相比于CD4对于gp120或T-20多肽对gp41的亲和力,这可能与CCR5N端区与gp120的相互作用的较低亲和力相一致。另外,这些结果还表明(a)连接子长度本身或(b)与引入到Fc区的突变的组合对本发明的抗体衍生物的抗病毒活性造成影响。这一特性将通过比较分子-5和分子-8与分子-1对全部三种分离株的IC50值来表明,所述比较展示具有连接子但无CCR5序列的突变蛋白质(分子-8)具有与具有连接子和CCR5序列(分子-5)可比的效能以及远高于无连接子的非突变蛋白质(分子-1)的效能。参见图7(a)-(c);表2。
表2
实例6
第二代抗体衍生物的抗体依赖性细胞的细胞毒性(ADCC)活性
根据实例3中所描述的方案评估经修饰抗体衍生物的ADCC活性。
使分子-5、分子-7和分子-8诱导ADCC活性的能力与eCD4-IgG1(分子-1)和中和抗体IgGb12相比较。剂量反应曲线对感染HIV BaL分离株的细胞的分析展示分子-5、分子-7和分子-8具有相似效能,IC50值分别为14.9、23.8和14.3ng/mL。另一方面,参考分子分子-1和IgGb12分别展示71.4和66.2ng/mL的IC50值,这表明其有效性低于分子-5、分子-7和分子-8。参见图8。
此外,这些结果表明引入到抗体衍生物的Fc区的突变增强ADCC活性。分子-5和分子-8比分子-1有效500%,而分子-7比分子-1有效300%。
为进一步表征抗体衍生物的提高的抗病毒或中和ADCC活性,对一组熟知的HIV亚型B病毒分析分子-5、分子-7和分子-8。参见Li,2005,见上文。出于比较实例目的另外使用分子-0和分子-1。总之,分子-0展示较低的抗病毒活性并且不能够在100ng/mL下中和原始分离株。分子-1展示略微较高的活性,但仅所述组中的一种病毒在100ng/mL以下经中和。参见图9。相比之下,分子-5、分子-7和分子-8能够阻碍IC50值在1到25ng/mL范围内的所有原始分离株。参见图10。
实例7
抗体衍生物与抗逆转录病毒药物的组合的抗病毒活性
在不同浓度的以下抗逆转录病毒药物存在下进行标准中和分析以评估针对HIV分离株NL4-3的分子-5的抗病毒活性:3TC/拉米夫定、依法韦仑(EFV)和雷特格韦(RAL),如实例2中所描述。在以下浓度的抗逆转录病毒药物存在下确定分子-5的分子IC50值(浓度范围:0.02到0.00001μg/mL):
3TC-40、8、1.6、0.32、0.064、0.013、0.0026和0.0005μM;
EFV-0.1、0.02、0.004、0.0008、0.0002、0.00003、0.000006和0.000001μM;以及
RAL-0.05、0.01、0.002、0.0004、0.00008、0.00002、0.000003和0.0000006μM。
分子-5在所有情况下都有效阻碍HIV感染,其中IC50在高pg/mL范围内(104pg/mL是检测到的最低值,而257pg/mL最高)。参见图11(a)-(c)。
实例8
抗体衍生物的病毒失活活性
为评估由抗体衍生物诱导的HIV的不可逆失活,用分子-5的连续稀释液(浓度范围:0.7μg/mL到0.7pg/mL)或分子-7的C34衍生物(浓度范围:1μg/mL到1pg/mL)在DMEM培养基中培育高度感染性HIV BaL病毒储备液。在37℃下培育1小时之后,样品用DMEM稀释并且病毒和可溶性蛋白质通过添加LentiX Concentrator试剂(Takara/ClontechLaboratories公司,美国加利福尼亚州山景城)分离。混合物在4℃培育30min并随后在4℃下在1,500x g下离心45分钟。去除上清液并使病毒颗粒再悬浮于DMEM中。经处理病毒的感染性通过在TZM-bl细胞中的滴定分析。参见Li M等人,《病毒学杂志》2005;79:10108-10125。针对各制剂计算TCID50值评估经处理病毒的残存感染性。
两种所测试的分子都有效使BaL病毒储备液的感染性不可逆地失活,其中分子-5和分子-7的C34衍生物的IC50值分别为0.055和0.044μg/mL。引人注目地,在两种蛋白质的高于0.1μg/mL的浓度下未检测到病毒感染性;因此,实现病毒感染性效价超过五个对数的降低。参见图12。
实例9
显示不同gp41肽的抗体衍生物的抗病毒活性
将沉默突变引入分子-5和分子-7的全序列中以允许切除T20序列(SEQ ID NO:28)。这个序列被以下序列置换:T1249(SEQ ID NO:29)、C34(SEQ ID NO:30)和T2635(SEQID NO:31)。
分子通过如上文所述的HEK-293T细胞的瞬时转染制备并且进行标准中和分析以评估这些新的分子-5和分子-7衍生物对一组HIV SVBP亚型B分离株的抗病毒活性,所述分离株包括经实验室调适和原始分离株。参见图13。
所有分子-5和分子-7衍生物分子-5-T-1249、分子-5-C34、分子-5-T-2635、分子-7-T-1249、分子-7-C34和分子-7-T-2635在所有情况下都有效阻碍HIV感染性,其中IC50在pg/mL或ng/mL范围中,相比对照分子分子-1或分子-6展示较高的效能和覆盖率。参见图13。
实例10
显示不同人类IgG序列的抗体衍生物的抗病毒活性
将KpnI和NheI限制位点引入分子-5和分子-7的C34衍生物的全序列中以允许切除具有G236A、S239D、A330L和I332E点突变的人类IgG的Fc部分(SEQ ID:25)。这个序列被野生型人类IgG1(SEQ ID NO:24)、人类IgG2、人类IgG3和人类IgG4序列置换。
如上文所述通过HEK-293T细胞的瞬时转染制备分子并进行标准中和分析以评估NL4-3和BaL病毒(新的分子-5衍生物)对一组HIV SVBP亚型B分离株的抗病毒活性,所述分离株包括实验室调适的以及对于新的分子-7衍生物而言原始难以中和的分离株。
所有分子-5衍生物分子-5-IgG1、分子-5-IgG2、分子-5-IgG3和分子-5-IgG4在所有情况下都类似地有效阻碍HIV感染,其中IC50在pg/mL或ng/mL范围中,展示相似的效能。参见表3。所有分子-7衍生物分子-7-IgG1、分子-7-IgG2、分子-7-IgG3和分子-7-IgG4在所有情况下都类似地有效阻碍HIV感染,其中IC50在pg/mL或ng/mL范围中,展示相似的效能和覆盖率。参见图14。
表3
实例11
体内抗体衍生物的AAV介导表达
在特异性不含病原体(specific pathogen-free;SPF)的条件下通过兄妹交配维持NSG小鼠(Jackson Laboratory,美国缅因州巴港)。
为诱导抗体衍生物在这些动物中稳定表达,将编码分子-5(SEQ ID NO:37)、分子-6(SEQ ID NO:38)、分子-7(SEQ ID NO:39)和分子-8(SEQ ID NO:40)的序列克隆为AAV8表达质粒(CBATEG,巴塞罗那自治大学,西班牙巴塞罗那)。将1×1011个病毒粒子稀释至40μL100mM柠檬酸钠,10mM Tris,pH 8缓冲液中并注入八周龄小鼠的腓肠肌肌肉中。同时,通过腹膜内注射一千万从健康个体中分离的PBMC来人类化小鼠。在两周之后,通过腹膜内注射10000TCDI50NL4-3HIV病毒分离株感染小鼠。每周收集血液样品并且CD4+和CD8+T细胞计数通过流式细胞测量术使用Perfect Count珠粒(Cytognos SL,Salamanca ES)与以下抗体的组合分析:抗人类CD45-V450、CD3-APC/Cγ7、CD4-APC、CD8-V500、CD14-PerCP/Cγ5.5、CD56-PE、CD16-Fitc和抗小鼠CD45PE/Cγ7。使用LSR II流式细胞仪(BD Biosciences公司,美国新泽西州富兰克林湖)分析样品。还使用上述ELISA方法分析样品的抗体衍生物含量。在感染3周之后,小鼠经处死并且收集血液和组织样品。通过流式细胞测量术分析样品并通过qPCR确定病毒负荷和总HIV DNA。
相比于未经治疗组,在大多数经AAV治疗2周和3周的动物中发现可检测含量的抗体衍生物。此外,表达水平在所有动物中都稳定。参见图15(a)和15(b)。
实例12
使用质粒载体的被动免疫接种方案
在特异性不含病原体(specific pathogen-free;SPF)的条件下通过兄妹交配维持NSG小鼠(Jackson Laboratory,美国缅因州巴港)。
使用EndoFree质粒试剂盒(Qiagen NV,荷兰芬洛)在不含内毒素的条件中制备质粒pABT-5、pABT-7和pABT-8。为了体内抗体衍生物的瞬时表达,通过肌肉内或静脉内注射向NGS小鼠给药质粒。在质粒给药之后,每周收集血液样品并使用上述ELISA方法分析抗体衍生物含量。在质粒给药4周之后,小鼠经处死并且收集血液和组织样本并分析其抗体衍生物含量和抗个体基因型抗体。
实例13
分子-5的体内活性
通过瞬时转染在HEK-293T细胞的大容量培养物中制备分子-5。在将上清液装载入CaptureSelect FcXL亲和力基质(赛默飞世尔科技,美国马萨诸塞州沃尔瑟姆)管柱中并用甘氨酸缓冲液pH=3.5溶离结合蛋白之后纯化重组蛋白。在pH中和、渗析和浓缩之后,获得5mg/mL的高纯储备液。
通过腹膜内注射一千万从健康个体中分离的PBMC来人类化NSG免疫缺陷小鼠。在两周之后,通过静脉内注射10,000TCID50NL4-3HIV病毒分离株感染小鼠。在通过腹膜内注射用200μL中的0.5mg纯化分子-5或用相同体积的PBS感染24小时之前和24小时之后治疗小鼠。在通过上颌静脉穿刺感染一周之后收集血液样品并处理以获得血浆样品,使用AbbottReal Time HIV-1(Abbott Laboratories,美国伊利诺斯州雅培公园)分析所述血浆样品的病毒血症水平。用分子-5治疗的动物相比感染一周之后未经治疗的动物展示显著较低的病毒血症水平。参见图16。
实例13
HIV Env糖蛋白的检测
为评估本发明的抗体衍生物鉴别样品中的HIV蛋白质的能力,慢性感染HIV分离株NL4-3或BaL的MOLT细胞用增加量的分子-5培育。结合于这些细胞的抗体用与荧光染料藻红蛋白(PE/Jackson ImmunoResearch Laboratories公司,美国宾夕法尼亚州西格罗夫)偶合的小鼠抗人类IgG抗体揭示并在LSRII流式细胞仪(BD Biosciences公司,美国新泽西州富兰克林湖)中通过流式细胞测量术分析。
分子-5展示可饱和结合于两种HIV感染细胞的高亲和力。参见图17。
序列表
<110> 艾滋基金会研究所
J·卡里略莫丽娜
B·克洛特萨拉
J·M·布兰科阿布厄斯
<120> 具有双重抗病毒和免疫调节活性的HIV抗体衍生物
<130> P1514US
<140> US 14/948,274
<141> 2015-11-21
<160> 42
<170> PatentIn version 3.5
<210> 1
<211> 100
<212> PRT
<213> 智人
<220>
<221> PEPTIDE
<222> (1)..(100)
<223> 人类CD4受体的D1结构域(aa)
<400> 1
Lys Lys Val Val Leu Gly Lys Lys Gly Asp Thr Val Glu Leu Thr Cys
1 5 10 15
Thr Ala Ser Gln Lys Lys Ser Ile Gln Phe His Trp Lys Asn Ser Asn
20 25 30
Gln Ile Lys Ile Leu Gly Asn Gln Gly Ser Phe Leu Thr Lys Gly Pro
35 40 45
Ser Lys Leu Asn Asp Arg Ala Asp Ser Arg Arg Ser Leu Trp Asp Gln
50 55 60
Gly Asn Phe Pro Leu Ile Ile Lys Asn Leu Lys Ile Glu Asp Ser Asp
65 70 75 80
Thr Tyr Ile Cys Glu Val Glu Asp Gln Lys Glu Glu Val Gln Leu Leu
85 90 95
Val Phe Gly Leu
100
<210> 2
<211> 78
<212> PRT
<213> 智人
<220>
<221> PEPTIDE
<222> (1)..(78)
<223> 人类CD4受体的D2结构域(aa)
<400> 2
Thr Ala Asn Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu
1 5 10 15
Thr Leu Glu Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser
20 25 30
Pro Arg Gly Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln
35 40 45
Leu Glu Leu Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn
50 55 60
Gln Lys Lys Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala
65 70 75
<210> 3
<211> 232
<212> PRT
<213> 智人
<220>
<221> PEPTIDE
<222> (1)..(232)
<223> 人类IgG1的Fc部分(aa)
<400> 3
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 4
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 具有G236A、S293D、A330L和I332E点突变的人类IgG1的Fc部分(aa)
<220>
<221> PEPTIDE
<222> (1)..(232)
<223> 具有G236A、S239D、A330L和I332E点突变的人类IgG1的Fc部分(aa)
<400> 4
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Ala Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Leu Pro Glu Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 5
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 连接子多肽(aa)
<220>
<221> PEPTIDE
<222> (1)..(5)
<223> 连接子多肽(aa)
<400> 5
Gly Gly Gly Gly Ser
1 5
<210> 6
<211> 29
<212> PRT
<213> 智人
<220>
<221> PEPTIDE
<222> (1)..(29)
<223> 人类CCR5受体的N端区(aa)
<400> 6
Met Asp Tyr Gln Val Ser Ser Pro Ile Tyr Asp Ile Asn Tyr Tyr Thr
1 5 10 15
Ser Glu Pro Cys Gln Lys Ile Asn Val Lys Gln Ile Ala
20 25
<210> 7
<211> 36
<212> PRT
<213> 人类免疫缺陷病毒
<220>
<221> PEPTIDE
<222> (1)..(36)
<223> T-20多肽(aa)
<400> 7
Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln
1 5 10 15
Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210> 8
<211> 39
<212> PRT
<213> 人类免疫缺陷病毒
<220>
<221> PEPTIDE
<222> (1)..(39)
<223> T-1249多肽(aa)
<400> 8
Trp Gln Glu Trp Glu Gln Lys Ile Thr Ala Leu Leu Glu Gln Ala Gln
1 5 10 15
Ile Gln Gln Glu Lys Asn Glu Tyr Glu Leu Gln Lys Leu Asp Lys Trp
20 25 30
Ala Ser Leu Trp Glu Trp Phe
35
<210> 9
<211> 34
<212> PRT
<213> 人类免疫缺陷病毒
<220>
<221> PEPTIDE
<222> (1)..(34)
<223> C34多肽(aa)
<400> 9
Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His
1 5 10 15
Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu
20 25 30
Leu Leu
<210> 10
<211> 38
<212> PRT
<213> 人类免疫缺陷病毒
<220>
<221> PEPTIDE
<222> (1)..(38)
<223> T-2635多肽(aa)
<400> 10
Thr Thr Trp Glu Ala Trp Asp Arg Ala Ile Ala Glu Tyr Ala Ala Arg
1 5 10 15
Ile Glu Ala Leu Ile Arg Ala Ala Gln Glu Gln Gln Glu Lys Asn Glu
20 25 30
Ala Ala Leu Arg Glu Leu
35
<210> 11
<211> 404
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-0(aa)
<220>
<221> PEPTIDE
<222> (1)..(404)
<223> 融合蛋白分子-0(aa)
<400> 11
Lys Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys
1 5 10 15
Ser Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly
20 25 30
Asn Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg
35 40 45
Ala Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile
50 55 60
Ile Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val
65 70 75 80
Glu Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala
85 90 95
Asn Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu
100 105 110
Glu Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg
115 120 125
Gly Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu
130 135 140
Leu Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys
145 150 155 160
Lys Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Glu Pro Lys Ser
165 170 175
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
180 185 190
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
195 200 205
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
210 215 220
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
225 230 235 240
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
245 250 255
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
260 265 270
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
275 280 285
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
290 295 300
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
305 310 315 320
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
325 330 335
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
340 345 350
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
355 360 365
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
385 390 395 400
Ser Pro Gly Lys
<210> 12
<211> 457
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-1(aa)
<220>
<221> PEPTIDE
<222> (1)..(457)
<223> 融合蛋白分子-1(aa)
<400> 12
Met Pro Met Gly Ser Leu Gln Pro Leu Ala Thr Leu Tyr Leu Leu Gly
1 5 10 15
Met Leu Val Ala Ser Val Leu Ala Lys Lys Val Val Leu Gly Lys Lys
20 25 30
Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser Ile
35 40 45
Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn Gln
50 55 60
Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala Asp
65 70 75 80
Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile Lys
85 90 95
Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu Asp
100 105 110
Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn Ser
115 120 125
Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu Ser
130 135 140
Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly Lys
145 150 155 160
Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu Gln
165 170 175
Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys Val
180 185 190
Glu Phe Lys Ile Asp Ile Val Val Leu Ala Ala Ala Asp Pro Glu Pro
195 200 205
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
210 215 220
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
225 230 235 240
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
245 250 255
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
260 265 270
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
275 280 285
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
290 295 300
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
305 310 315 320
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
325 330 335
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
340 345 350
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
355 360 365
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
370 375 380
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
385 390 395 400
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
405 410 415
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
420 425 430
Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Gly Asp Tyr Ala Asp Tyr
435 440 445
Asp Gly Gly Tyr Tyr Tyr Asp Met Asp
450 455
<210> 13
<211> 457
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-2(aa)
<220>
<221> PEPTIDE
<222> (1)..(457)
<223> 融合蛋白分子-2(aa)
<400> 13
Met Pro Met Gly Ser Leu Gln Pro Leu Ala Thr Leu Tyr Leu Leu Gly
1 5 10 15
Met Leu Val Ala Ser Val Leu Ala Lys Lys Val Val Leu Gly Lys Lys
20 25 30
Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser Ile
35 40 45
Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn Gln
50 55 60
Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala Asp
65 70 75 80
Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile Lys
85 90 95
Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu Asp
100 105 110
Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn Ser
115 120 125
Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu Ser
130 135 140
Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly Lys
145 150 155 160
Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu Gln
165 170 175
Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys Val
180 185 190
Glu Phe Lys Ile Asp Ile Val Val Leu Ala Ala Ala Asp Pro Glu Pro
195 200 205
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
210 215 220
Leu Leu Ala Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
225 230 235 240
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
245 250 255
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
260 265 270
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
275 280 285
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
290 295 300
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
305 310 315 320
Leu Pro Glu Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
325 330 335
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
340 345 350
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
355 360 365
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
370 375 380
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
385 390 395 400
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
405 410 415
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
420 425 430
Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Gly Asp Tyr Ala Asp Tyr
435 440 445
Asp Gly Gly Tyr Tyr Tyr Asp Met Asp
450 455
<210> 14
<211> 478
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-3
<220>
<221> PEPTIDE
<222> (1)..(478)
<223> 融合蛋白分子-3(aa)
<400> 14
Met Asn Arg Gly Val Pro Phe Arg His Leu Leu Leu Val Leu Gln Leu
1 5 10 15
Ala Leu Leu Pro Ala Ala Thr Gln Gly Lys Lys Val Val Leu Gly Lys
20 25 30
Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser
35 40 45
Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn
50 55 60
Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala
65 70 75 80
Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile
85 90 95
Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu
100 105 110
Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn
115 120 125
Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu
130 135 140
Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly
145 150 155 160
Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu
165 170 175
Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys
180 185 190
Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Glu Pro Lys Ser Cys
195 200 205
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Ala
210 215 220
Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
225 230 235 240
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
245 250 255
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
260 265 270
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
275 280 285
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
290 295 300
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro Glu
305 310 315 320
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
325 330 335
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
340 345 350
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
355 360 365
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
370 375 380
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
385 390 395 400
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
405 410 415
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
420 425 430
Pro Gly Lys Gly Gly Gly Gly Ala Ala Ala Tyr Thr Ser Leu Ile His
435 440 445
Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu
450 455 460
Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe
465 470 475
<210> 15
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-4(aa)
<220>
<221> PEPTIDE
<222> (1)..(468)
<223> 融合蛋白分子-4(aa)
<400> 15
Met Asn Arg Gly Val Pro Phe Arg His Leu Leu Leu Val Leu Gln Leu
1 5 10 15
Ala Leu Leu Pro Ala Ala Thr Gln Gly Lys Lys Val Val Leu Gly Lys
20 25 30
Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser
35 40 45
Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn
50 55 60
Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala
65 70 75 80
Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile
85 90 95
Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu
100 105 110
Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn
115 120 125
Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu
130 135 140
Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly
145 150 155 160
Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu
165 170 175
Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys
180 185 190
Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Glu Pro Lys Ser Cys
195 200 205
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Ala
210 215 220
Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
225 230 235 240
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
245 250 255
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
260 265 270
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
275 280 285
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
290 295 300
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro Glu
305 310 315 320
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
325 330 335
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
340 345 350
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
355 360 365
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
370 375 380
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
385 390 395 400
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
405 410 415
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
420 425 430
Pro Gly Lys Gly Gly Gly Gly Asp Tyr Gln Val Ser Ser Pro Ile Tyr
435 440 445
Asp Ile Asn Tyr Tyr Thr Ser Glu Pro Cys Gln Lys Ile Asn Val Lys
450 455 460
Gln Ile Ala Ala
465
<210> 16
<211> 529
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-5(aa)
<220>
<221> PEPTIDE
<222> (1)..(529)
<223> 融合蛋白分子-5(aa)
<400> 16
Met Asn Arg Gly Val Pro Phe Arg His Leu Leu Leu Val Leu Gln Leu
1 5 10 15
Ala Leu Leu Pro Ala Ala Thr Gln Gly Lys Lys Val Val Leu Gly Lys
20 25 30
Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser
35 40 45
Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn
50 55 60
Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala
65 70 75 80
Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile
85 90 95
Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu
100 105 110
Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn
115 120 125
Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu
130 135 140
Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly
145 150 155 160
Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu
165 170 175
Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys
180 185 190
Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Glu Pro Lys Ser Cys
195 200 205
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Ala
210 215 220
Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
225 230 235 240
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
245 250 255
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
260 265 270
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
275 280 285
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
290 295 300
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro Glu
305 310 315 320
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
325 330 335
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
340 345 350
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
355 360 365
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
370 375 380
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
385 390 395 400
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
405 410 415
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
420 425 430
Pro Gly Lys Gly Gly Gly Gly Asp Tyr Gln Val Ser Ser Pro Ile Tyr
435 440 445
Asp Ile Asn Tyr Tyr Thr Ser Glu Pro Cys Gln Lys Ile Asn Val Lys
450 455 460
Gln Ile Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
465 470 475 480
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Tyr Thr Ser
485 490 495
Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn
500 505 510
Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp
515 520 525
Phe
<210> 17
<211> 435
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-6(aa)
<220>
<221> PEPTIDE
<222> (1)..(435)
<223> 融合蛋白分子-6(aa)
<400> 17
Met Asn Arg Gly Val Pro Phe Arg His Leu Leu Leu Val Leu Gln Leu
1 5 10 15
Ala Leu Leu Pro Ala Ala Thr Gln Gly Lys Lys Val Val Leu Gly Lys
20 25 30
Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser
35 40 45
Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn
50 55 60
Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala
65 70 75 80
Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile
85 90 95
Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu
100 105 110
Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn
115 120 125
Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu
130 135 140
Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly
145 150 155 160
Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu
165 170 175
Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys
180 185 190
Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Glu Pro Lys Ser Cys
195 200 205
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Ala
210 215 220
Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
225 230 235 240
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
245 250 255
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
260 265 270
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
275 280 285
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
290 295 300
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro Glu
305 310 315 320
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
325 330 335
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
340 345 350
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
355 360 365
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
370 375 380
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
385 390 395 400
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
405 410 415
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
420 425 430
Pro Gly Lys
435
<210> 18
<211> 513
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-7(aa)
<220>
<221> PEPTIDE
<222> (1)..(513)
<223> 融合蛋白分子-7(aa)
<400> 18
Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile
1 5 10 15
Ser Lys Lys Val Val Leu Gly Lys Lys Gly Asp Thr Val Glu Leu Thr
20 25 30
Cys Thr Ala Ser Gln Lys Lys Ser Ile Gln Phe His Trp Lys Asn Ser
35 40 45
Asn Gln Ile Lys Ile Leu Gly Asn Gln Gly Ser Phe Leu Thr Lys Gly
50 55 60
Pro Ser Lys Leu Asn Asp Arg Ala Asp Ser Arg Arg Ser Leu Trp Asp
65 70 75 80
Gln Gly Asn Phe Pro Leu Ile Ile Lys Asn Leu Lys Ile Glu Asp Ser
85 90 95
Asp Thr Tyr Ile Cys Glu Val Glu Asp Gln Lys Glu Glu Val Gln Leu
100 105 110
Leu Val Phe Gly Leu Thr Ala Asn Ser Asp Thr His Leu Leu Gln Gly
115 120 125
Gln Ser Leu Thr Leu Thr Leu Glu Ser Pro Pro Gly Ser Ser Pro Ser
130 135 140
Val Gln Cys Arg Ser Pro Arg Gly Lys Asn Ile Gln Gly Gly Lys Thr
145 150 155 160
Leu Ser Val Ser Gln Leu Glu Leu Gln Asp Ser Gly Thr Trp Thr Cys
165 170 175
Thr Val Leu Gln Asn Gln Lys Lys Val Glu Phe Lys Ile Asp Ile Val
180 185 190
Val Leu Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
195 200 205
Cys Pro Ala Pro Glu Leu Leu Ala Gly Pro Asp Val Phe Leu Phe Pro
210 215 220
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
225 230 235 240
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
245 250 255
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
260 265 270
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
275 280 285
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
290 295 300
Asn Lys Ala Leu Pro Leu Pro Glu Glu Lys Thr Ile Ser Lys Ala Lys
305 310 315 320
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
325 330 335
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
340 345 350
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
355 360 365
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
370 375 380
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
385 390 395 400
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
405 410 415
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser
420 425 430
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
450 455 460
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Tyr Thr Ser
465 470 475 480
Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn
485 490 495
Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp
500 505 510
Phe
<210> 19
<211> 483
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-8(aa)
<220>
<221> PEPTIDE
<222> (1)..(483)
<223> 融合蛋白分子-8(aa)
<400> 19
Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile
1 5 10 15
Ser Lys Lys Val Val Leu Gly Lys Lys Gly Asp Thr Val Glu Leu Thr
20 25 30
Cys Thr Ala Ser Gln Lys Lys Ser Ile Gln Phe His Trp Lys Asn Ser
35 40 45
Asn Gln Ile Lys Ile Leu Gly Asn Gln Gly Ser Phe Leu Thr Lys Gly
50 55 60
Pro Ser Lys Leu Asn Asp Arg Ala Asp Ser Arg Arg Ser Leu Trp Asp
65 70 75 80
Gln Gly Asn Phe Pro Leu Ile Ile Lys Asn Leu Lys Ile Glu Asp Ser
85 90 95
Asp Thr Tyr Ile Cys Glu Val Glu Asp Gln Lys Glu Glu Val Gln Leu
100 105 110
Leu Val Phe Gly Leu Thr Ala Asn Ser Asp Thr His Leu Leu Gln Gly
115 120 125
Gln Ser Leu Thr Leu Thr Leu Glu Ser Pro Pro Gly Ser Ser Pro Ser
130 135 140
Val Gln Cys Arg Ser Pro Arg Gly Lys Asn Ile Gln Gly Gly Lys Thr
145 150 155 160
Leu Ser Val Ser Gln Leu Glu Leu Gln Asp Ser Gly Thr Trp Thr Cys
165 170 175
Thr Val Leu Gln Asn Gln Lys Lys Val Glu Phe Lys Ile Asp Ile Val
180 185 190
Val Leu Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
195 200 205
Cys Pro Ala Pro Glu Leu Leu Ala Gly Pro Asp Val Phe Leu Phe Pro
210 215 220
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
225 230 235 240
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
245 250 255
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
260 265 270
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
275 280 285
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
290 295 300
Asn Lys Ala Leu Pro Leu Pro Glu Glu Lys Thr Ile Ser Lys Ala Lys
305 310 315 320
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
325 330 335
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
340 345 350
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
355 360 365
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
370 375 380
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
385 390 395 400
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
405 410 415
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser
420 425 430
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Tyr
435 440 445
Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu
450 455 460
Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp
465 470 475 480
Asn Trp Phe
<210> 20
<211> 509
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-10(aa)
<220>
<221> PEPTIDE
<222> (1)..(509)
<223> 融合蛋白分子-10(aa)
<400> 20
Met Asn Arg Gly Val Pro Phe Arg His Leu Leu Leu Val Leu Gln Leu
1 5 10 15
Ala Leu Leu Pro Ala Ala Thr Gln Gly Lys Lys Val Val Leu Gly Lys
20 25 30
Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser
35 40 45
Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn
50 55 60
Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala
65 70 75 80
Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile
85 90 95
Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu
100 105 110
Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn
115 120 125
Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu
130 135 140
Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly
145 150 155 160
Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu
165 170 175
Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys
180 185 190
Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Glu Pro Lys Ser Cys
195 200 205
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Ala
210 215 220
Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
225 230 235 240
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
245 250 255
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
260 265 270
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
275 280 285
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
290 295 300
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro Glu
305 310 315 320
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
325 330 335
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
340 345 350
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
355 360 365
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
370 375 380
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
385 390 395 400
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
405 410 415
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
420 425 430
Pro Gly Lys Gly Gly Gly Gly Asp Tyr Gln Val Ser Ser Pro Ile Tyr
435 440 445
Asp Ile Asn Tyr Tyr Thr Ser Glu Pro Cys Gln Lys Ile Asn Val Lys
450 455 460
Gln Ile Ala Ala Gly Gly Gly Gly Ser Tyr Thr Ser Leu Ile His Ser
465 470 475 480
Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu
485 490 495
Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe
500 505
<210> 21
<211> 541
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白分子-11(aa)
<220>
<221> PEPTIDE
<222> (1)..(541)
<223> 融合蛋白分子-11(aa)
<400> 21
Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile
1 5 10 15
Ser Lys Lys Val Val Leu Gly Lys Lys Gly Asp Thr Val Glu Leu Thr
20 25 30
Cys Thr Ala Ser Gln Lys Lys Ser Ile Gln Phe His Trp Lys Asn Ser
35 40 45
Asn Gln Ile Lys Ile Leu Gly Asn Gln Gly Ser Phe Leu Thr Lys Gly
50 55 60
Pro Ser Lys Leu Asn Asp Arg Ala Asp Ser Arg Arg Ser Leu Trp Asp
65 70 75 80
Gln Gly Asn Phe Pro Leu Ile Ile Lys Asn Leu Lys Ile Glu Asp Ser
85 90 95
Asp Thr Tyr Ile Cys Glu Val Glu Asp Gln Lys Glu Glu Val Gln Leu
100 105 110
Leu Val Phe Gly Leu Thr Ala Asn Ser Asp Thr His Leu Leu Gln Gly
115 120 125
Gln Ser Leu Thr Leu Thr Leu Glu Ser Pro Pro Gly Ser Ser Pro Ser
130 135 140
Val Gln Cys Arg Ser Pro Arg Gly Lys Asn Ile Gln Gly Gly Lys Thr
145 150 155 160
Leu Ser Val Ser Gln Leu Glu Leu Gln Asp Ser Gly Thr Trp Thr Cys
165 170 175
Thr Val Leu Gln Asn Gln Lys Lys Val Glu Phe Lys Ile Asp Ile Val
180 185 190
Val Leu Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
195 200 205
Cys Pro Ala Pro Glu Leu Leu Ala Gly Pro Asp Val Phe Leu Phe Pro
210 215 220
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
225 230 235 240
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
245 250 255
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
260 265 270
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
275 280 285
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
290 295 300
Asn Lys Ala Leu Pro Leu Pro Glu Glu Lys Thr Ile Ser Lys Ala Lys
305 310 315 320
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
325 330 335
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
340 345 350
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
355 360 365
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
370 375 380
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
385 390 395 400
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
405 410 415
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Asp
420 425 430
Tyr Gln Val Ser Ser Pro Ile Tyr Asp Ile Asn Tyr Tyr Thr Ser Glu
435 440 445
Pro Cys Gln Lys Ile Asn Val Lys Gln Ile Ala Ala Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
485 490 495
Gly Gly Gly Ser Gly Gly Gly Gly Ser Tyr Thr Ser Leu Ile His Ser
500 505 510
Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu
515 520 525
Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe
530 535 540
<210> 22
<211> 300
<212> DNA
<213> 智人
<220>
<221> gene
<222> (1)..(300)
<223> 人类CD4受体的D1结构域(nt)
<400> 22
aagaaagtgg tgctgggcaa aaagggcgac accgtggaac tgacctgcac cgccagccag 60
aagaagtcca tccagttcca ctggaagaac agcaaccaga tcaagatcct gggcaaccag 120
ggcagcttcc tgaccaaggg ccccagcaag ctgaacgaca gagccgactc tcggcggagc 180
ctgtgggacc agggcaattt cccactgatc atcaagaacc tgaagatcga ggacagcgac 240
acctacatct gcgaggtgga agatcagaaa gaagaggtgc agctgctggt gttcggcctg 300
<210> 23
<211> 234
<212> DNA
<213> 智人
<220>
<221> gene
<222> (1)..(234)
<223> 人类CD4受体的D2结构域(nt)
<400> 23
accgccaact ccgacaccca tctgctgcag ggccagagcc tgaccctgac actggaaagc 60
cctccaggca gctcccccag cgtgcagtgt agaagccctc ggggcaagaa catccagggc 120
ggcaagacac tgagcgtgtc ccagctggaa ctgcaggaca gcggcacatg gacctgtacc 180
gtgctgcaga accagaaaaa ggtggaattc aagatcgaca tcgtggtgct ggcc 234
<210> 24
<211> 696
<212> DNA
<213> 智人
<220>
<221> gene
<222> (1)..(696)
<223> 人类IgG1的Fc部分
<400> 24
gagcccaaga gctgcgacaa gacccacacc tgtccccctt gtcctgcccc tgaactgctg 60
ggcggaccta gcgtgttcct gttcccccca aagcccaagg acaccctgat gatctcccgg 120
acccccgaag tgacctgcgt ggtggtggat gtgtcccacg aggaccctga agtgaagttc 180
aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcccag agaggaacag 240
tacaacagca cctaccgggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac 300
ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgcccccat cgagaaaacc 360
atcagcaagg ccaagggcca gccccgcgaa ccccaggtgt acacactgcc ccctagcagg 420
gacgagctga ccaagaacca ggtgtccctg acctgtctcg tgaagggctt ttacccctcc 480
gatatcgccg tggaatggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 540
cctgtgctgg actccgacgg ctcattcttc ctgtacagca aactgaccgt ggacaagagc 600
cggtggcagc agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac 660
tacacccaga agtccctgtc cctgagccct ggcaaa 696
<210> 25
<211> 696
<212> DNA
<213> 人工序列
<220>
<223> 具有G236A、S293D、A330L和I332E点突变的人类IgG1的Fc部分(nt)
<220>
<221> gene
<222> (1)..(696)
<223> 具有G236A、S239D、A330L和I332E点突变的人类IgG1的Fc部分(nt)
<400> 25
gagcccaaga gctgcgacaa gacccacacc tgtccccctt gtcctgcccc tgaactgctg 60
gccggacccg acgtgttcct gttcccccca aagcccaagg acaccctgat gatctcccgg 120
acccccgaag tgacctgcgt ggtggtggat gtgtcccacg aggaccctga agtgaagttc 180
aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcccag agaggaacag 240
tacaacagca cctaccgggt ggtgtccgtg ctgacagtgc tgcaccagga ctggctgaac 300
ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctctgcccga ggaaaagacc 360
atcagcaagg ccaagggcca gcccagggaa ccccaggtgt acacactgcc ccccagcaga 420
gatgagctga ccaagaacca ggtgtccctg acctgtctcg tgaagggctt ttacccctcc 480
gatatcgccg tggaatggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 540
cctgtgctgg actccgacgg ctcattcttc ctgtactcca agctgaccgt ggacaagagc 600
agatggcagc agggcaacgt gttcagctgc tccgtgatgc acgaggccct gcacaaccac 660
tacacccaga agtccctgag cctgagccca ggcaaa 696
<210> 26
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 连接子多肽(nt)
<220>
<221> gene
<222> (1)..(15)
<223> 连接子多肽(nt)
<400> 26
ggcggagggg gatct 15
<210> 27
<211> 87
<212> DNA
<213> 智人
<220>
<221> gene
<222> (1)..(87)
<223> 人类CCR5受体的5'末端区(nt)
<400> 27
gattatcagg tgtccagccc catctacgac atcaactact acaccagcga gccctgccag 60
aaaatcaacg tgaagcagat cgccgct 87
<210> 28
<211> 108
<212> DNA
<213> 人类免疫缺陷病毒
<220>
<221> gene
<222> (1)..(108)
<223> T-20多肽(nt)
<400> 28
tacacaagcc tgatccacag cctgatcgag gaaagccaga accagcagga aaagaacgag 60
caggaactgc tggaactgga caagtgggcc agcctgtgga attggttc 108
<210> 29
<211> 117
<212> DNA
<213> 人类免疫缺陷病毒
<220>
<221> gene
<222> (1)..(117)
<223> T-1249多肽(nt)
<400> 29
tggcaggaat gggaacagaa aattaccgcg ctgctggaac aggcgcagat tcagcaggaa 60
aaaaacgaat atgaactgca gaaactggat aaatgggcga gcctgtggga atggttt 117
<210> 30
<211> 102
<212> DNA
<213> 人类免疫缺陷病毒
<220>
<221> gene
<222> (1)..(102)
<223> C34多肽(nt)
<400> 30
tggatggaat gggatcgcga aattaacaac tataccagcc tgattcatag cctgattgaa 60
gaaagccaga accagcagga aaaaaacgaa caggaactgc tg 102
<210> 31
<211> 114
<212> DNA
<213> 人类免疫缺陷病毒
<220>
<221> gene
<222> (1)..(114)
<223> T-2635多肽(nt)
<400> 31
accacctggg aagcgtggga tcgcgcgatt gcggaatatg cggcgcgcat tgaagcgctg 60
attcgcgcgg cgcaggaaca gcaggaaaaa aacgaagcgg cgctgcgcga actg 114
<210> 32
<211> 1230
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-0(nt)
<220>
<221> gene
<222> (1)..(1230)
<223> cDNA分子-0(nt)
<400> 32
aagaaagtgg tgctgggcaa aaagggcgac accgtggaac tgacctgcac cgccagccag 60
aagaagtcca tccagttcca ctggaagaac agcaaccaga tcaagatcct gggcaaccag 120
ggcagcttcc tgaccaaggg ccccagcaag ctgaacgaca gagccgactc tcggcggagc 180
ctgtgggacc agggcaattt cccactgatc atcaagaacc tgaagatcga ggacagcgac 240
acctacatct gcgaggtgga agatcagaaa gaagaggtgc agctgctggt gttcggcctg 300
accgccaact ccgacaccca tctgctgcag ggccagagcc tgaccctgac actggaaagc 360
cctccaggca gctcccccag cgtgcagtgt agaagccctc ggggcaagaa catccagggc 420
ggcaagacac tgagcgtgtc ccagctggaa ctgcaggaca gcggcacatg gacctgtacc 480
gtgctgcaga accagaaaaa ggtggaattc aagatcgaca tcgtggtgct ggccgagccc 540
aagagctgcg acaagaccca cacctgtccc ccttgtcctg cccctgaact gctgggcgga 600
cctagcgtgt tcctgttccc cccaaagccc aaggacaccc tgatgatctc ccggaccccc 660
gaagtgacct gcgtggtggt ggatgtgtcc cacgaggacc ctgaagtgaa gttcaattgg 720
tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 780
agcacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaaa 840
gagtacaagt gcaaggtgtc caacaaggcc ctgcctgccc ccatcgagaa aaccatcagc 900
aaggccaagg gccagccccg cgaaccccag gtgtacacac tgccccctag cagggacgag 960
ctgaccaaga accaggtgtc cctgacctgt ctcgtgaagg gcttttaccc ctccgatatc 1020
gccgtggaat gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg 1080
ctggactccg acggctcatt cttcctgtac agcaaactga ccgtggacaa gagccggtgg 1140
cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1200
cagaagtccc tgtccctgag ccctggcaaa 1230
<210> 33
<211> 1374
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-1(nt)
<220>
<221> gene
<222> (1)..(1374)
<223> cDNA分子-1(nt)
<400> 33
atgcctatgg gaagcctgca gcctctggcc accctgtacc tgctgggaat gctggtggcc 60
tccgtgctgg ccaagaaagt ggtgctgggc aaaaagggcg acaccgtgga actgacctgc 120
accgccagcc agaagaagtc catccagttc cactggaaga acagcaacca gatcaagatc 180
ctgggcaacc agggcagctt cctgaccaag ggccccagca agctgaacga cagagccgac 240
tctcggcgga gcctgtggga ccagggcaat ttcccactga tcatcaagaa cctgaagatc 300
gaggacagcg acacctacat ctgcgaggtg gaagatcaga aagaagaggt gcagctgctg 360
gtgttcggcc tgaccgccaa ctccgacacc catctgctgc agggccagag cctgaccctg 420
acactggaaa gccctccagg cagcagcccc agcgtgcagt gtagaagccc cagaggcaag 480
aacatccagg gcggcaagac cctgagcgtg tcccagctgg aactgcagga tagcggcacc 540
tggacctgca cagtgctgca gaaccagaaa aaggtggaat tcaagatcga catcgtggtg 600
ctggccgctg ccgaccctga gcctaagagc tgcgacaaga cccacacctg tcccccttgt 660
cctgcccctg aactgctggg cggacctagc gtgttcctgt tccccccaaa gcccaaggac 720
accctgatga tctcccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccacgag 780
gaccctgaag tgaagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 840
aagcccagag aggaacagta caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 900
caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa ggccctgcct 960
gcccccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgaacc ccaggtgtac 1020
acactgcccc ctagcaggga cgagctgacc aagaaccagg tgtccctgac ctgtctcgtg 1080
aagggctttt acccctccga tatcgccgtg gaatgggaga gcaacggcca gcccgagaac 1140
aactacaaga ccaccccccc tgtgctggac tccgacggct cattcttcct gtacagcaaa 1200
ctgaccgtgg acaagagccg gtggcagcag ggcaacgtgt tcagctgcag cgtgatgcac 1260
gaggccctgc acaaccacta cacccagaag tccctgtccc tgagccctgg caaaggcggc 1320
ggaggcggag attacgccga ttacgatggc ggctactact acgacatgga ctga 1374
<210> 34
<211> 1374
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-2(nt)
<220>
<221> gene
<222> (1)..(1374)
<223> cDNA分子-2(nt)
<400> 34
atgcctatgg gaagcctgca gcctctggcc accctgtacc tgctgggaat gctggtggcc 60
tccgtgctgg ccaagaaagt ggtgctgggc aaaaagggcg acaccgtgga actgacctgc 120
accgccagcc agaagaagtc catccagttc cactggaaga acagcaacca gatcaagatc 180
ctgggcaacc agggcagctt cctgaccaag ggccccagca agctgaacga cagagccgac 240
tctcggcgga gcctgtggga ccagggcaat ttcccactga tcatcaagaa cctgaagatc 300
gaggacagcg acacctacat ctgcgaggtg gaagatcaga aagaagaggt gcagctgctg 360
gtgttcggcc tgaccgccaa ctccgacacc catctgctgc agggccagag cctgaccctg 420
acactggaaa gccctccagg cagcagcccc agcgtgcagt gtagaagccc cagaggcaag 480
aacatccagg gcggcaagac cctgagcgtg tcccagctgg aactgcagga tagcggcacc 540
tggacctgca cagtgctgca gaaccagaaa aaggtggaat tcaagatcga catcgtggtg 600
ctggccgctg ccgaccctga gcctaagagc tgcgacaaga cccacacctg tcccccttgt 660
cctgcccctg aactgctggc cggacccgac gtgttcctgt tccccccaaa gcccaaggac 720
accctgatga tctcccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccacgag 780
gaccctgaag tgaagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 840
aagcccagag aggaacagta caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 900
caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa ggccctgcct 960
ctgcccgagg aaaagaccat cagcaaggcc aagggccagc ccagggaacc ccaggtgtac 1020
acactgcccc ccagcagaga tgagctgacc aagaaccagg tgtccctgac ctgtctcgtg 1080
aagggctttt acccctccga tatcgccgtg gaatgggaga gcaacggcca gcccgagaac 1140
aactacaaga ccaccccccc tgtgctggac tccgacggct cattcttcct gtacagcaaa 1200
ctgaccgtgg acaagagccg gtggcagcag ggcaacgtgt tcagctgcag cgtgatgcac 1260
gaggccctgc acaaccacta cacccagaag tccctgtccc tgagccctgg caaaggcggc 1320
ggaggcggag attacgccga ttacgatggc ggctactact acgacatgga ctga 1374
<210> 35
<211> 1437
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-3(nt)
<220>
<221> gene
<222> (1)..(1437)
<223> cDNA分子-3(nt)
<400> 35
atgaatagag gcgtgccctt ccggcatctg ctgctggtgc tgcagctggc tctgctgcct 60
gctgccaccc agggcaagaa agtggtgctg ggcaaaaagg gcgacaccgt ggaactgacc 120
tgcaccgcca gccagaagaa gtccatccag ttccactgga agaacagcaa ccagatcaag 180
atcctgggca accagggcag cttcctgacc aagggcccca gcaagctgaa cgacagagcc 240
gactctcggc ggagcctgtg ggaccagggc aatttcccac tgatcatcaa gaacctgaag 300
atcgaggaca gcgacaccta catctgcgag gtggaagatc agaaagaaga ggtgcagctg 360
ctggtgttcg gcctgaccgc caactccgac acccatctgc tgcagggcca gagcctgacc 420
ctgacactgg aaagccctcc aggcagctcc cccagcgtgc agtgtagaag ccctcggggc 480
aagaacatcc agggcggcaa gacactgagc gtgtcccagc tggaactgca ggacagcggc 540
acatggacct gtaccgtgct gcagaaccag aaaaaggtgg aattcaagat cgacatcgtg 600
gtgctggccg agcccaagag ctgcgacaag acccacacct gtcccccttg tcctgcccct 660
gaactgctgg ccggacccga cgtgttcctg ttccccccaa agcccaagga caccctgatg 720
atctcccgga cccccgaagt gacctgcgtg gtggtggatg tgtcccacga ggaccctgaa 780
gtgaagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 840
gaggaacagt acaacagcac ctaccgggtg gtgtccgtgc tgacagtgct gcaccaggac 900
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca aggccctgcc tctgcccgag 960
gaaaagacca tcagcaaggc caagggccag cccagggaac cccaggtgta cacactgccc 1020
cccagcagag atgagctgac caagaaccag gtgtccctga cctgtctcgt gaagggcttt 1080
tacccctccg atatcgccgt ggaatgggag agcaacggcc agcccgagaa caactacaag 1140
accacccccc ctgtgctgga ctccgacggc tcattcttcc tgtactccaa gctgaccgtg 1200
gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1260
cacaaccact acacccagaa gtccctgagc ctgagcccag gcaaaggcgg aggcggagcg 1320
gccgcgtaca catctctgat ccacagcctg atcgaggaaa gccagaacca gcaggaaaag 1380
aacgagcagg aactgctgga actggacaag tgggccagcc tgtggaattg gttctga 1437
<210> 36
<211> 1407
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-4(nt)
<220>
<221> gene
<222> (1)..(1407)
<223> cDNA分子-4(nt)
<400> 36
atgaatagag gcgtgccctt ccggcatctg ctgctggtgc tgcagctggc tctgctgcct 60
gctgccaccc agggcaagaa agtggtgctg ggcaaaaagg gcgacaccgt ggaactgacc 120
tgcaccgcca gccagaagaa gtccatccag ttccactgga agaacagcaa ccagatcaag 180
atcctgggca accagggcag cttcctgacc aagggcccca gcaagctgaa cgacagagcc 240
gactctcggc ggagcctgtg ggaccagggc aatttcccac tgatcatcaa gaacctgaag 300
atcgaggaca gcgacaccta catctgcgag gtggaagatc agaaagaaga ggtgcagctg 360
ctggtgttcg gcctgaccgc caactccgac acccatctgc tgcagggcca gagcctgacc 420
ctgacactgg aaagccctcc aggcagctcc cccagcgtgc agtgtagaag ccctcggggc 480
aagaacatcc agggcggcaa gacactgagc gtgtcccagc tggaactgca ggacagcggc 540
acatggacct gtaccgtgct gcagaaccag aaaaaggtgg aattcaagat cgacatcgtg 600
gtgctggccg agcccaagag ctgcgacaag acccacacct gtcccccttg tcctgcccct 660
gaactgctgg ccggacccga cgtgttcctg ttccccccaa agcccaagga caccctgatg 720
atctcccgga cccccgaagt gacctgcgtg gtggtggatg tgtcccacga ggaccctgaa 780
gtgaagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 840
gaggaacagt acaacagcac ctaccgggtg gtgtccgtgc tgacagtgct gcaccaggac 900
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca aggccctgcc tctgcccgag 960
gaaaagacca tcagcaaggc caagggccag cccagggaac cccaggtgta cacactgccc 1020
cccagcagag atgagctgac caagaaccag gtgtccctga cctgtctcgt gaagggcttt 1080
tacccctccg atatcgccgt ggaatgggag agcaacggcc agcccgagaa caactacaag 1140
accacccccc ctgtgctgga ctccgacggc tcattcttcc tgtactccaa gctgaccgtg 1200
gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1260
cacaaccact acacccagaa gtccctgagc ctgagcccag gcaaaggcgg cggaggcgat 1320
tatcaggtgt ccagccccat ctacgacatc aactactaca ccagcgagcc ctgccagaaa 1380
atcaacgtga agcagatcgc cgcctga 1407
<210> 37
<211> 1593
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-5(nt)
<220>
<221> gene
<222> (1)..(1593)
<223> cDNA分子-5(nt)
<400> 37
atgaatagag gcgtgccctt ccggcatctg ctgctggtgc tgcagctggc tctgctgcct 60
gctgccaccc agggcaagaa agtggtgctg ggcaaaaagg gcgacaccgt ggaactgacc 120
tgcaccgcca gccagaagaa gtccatccag ttccactgga agaacagcaa ccagatcaag 180
atcctgggca accagggcag cttcctgacc aagggcccca gcaagctgaa cgacagagcc 240
gactctcggc ggagcctgtg ggaccagggc aatttcccac tgatcatcaa gaacctgaag 300
atcgaggaca gcgacaccta catctgcgag gtggaagatc agaaagaaga ggtgcagctg 360
ctggtgttcg gcctgaccgc caactccgac acccatctgc tgcagggcca gagcctgacc 420
ctgacactgg aaagccctcc aggcagctcc cccagcgtgc agtgtagaag ccctcggggc 480
aagaacatcc agggcggcaa gacactgagc gtgtcccagc tggaactgca ggacagcggc 540
acatggacct gtaccgtgct gcagaaccag aaaaaggtgg aattcaagat cgacatcgtg 600
gtgctggccg agcccaagag ctgcgacaag acccacacct gtcccccttg tcctgcccct 660
gaactgctgg ccggacccga cgtgttcctg ttccccccaa agcccaagga caccctgatg 720
atctcccgga cccccgaagt gacctgcgtg gtggtggatg tgtcccacga ggaccctgaa 780
gtgaagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 840
gaggaacagt acaacagcac ctaccgggtg gtgtccgtgc tgacagtgct gcaccaggac 900
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca aggccctgcc tctgcccgag 960
gaaaagacca tcagcaaggc caagggccag cccagggaac cccaggtgta cacactgccc 1020
cccagcagag atgagctgac caagaaccag gtgtccctga cctgtctcgt gaagggcttt 1080
tacccctccg atatcgccgt ggaatgggag agcaacggcc agcccgagaa caactacaag 1140
accacccccc ctgtgctgga ctccgacggc tcattcttcc tgtactccaa gctgaccgtg 1200
gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1260
cacaaccact acacccagaa gtccctgagc ctgagcccag gcaaaggcgg cggaggcgat 1320
tatcaggtgt ccagccccat ctacgacatc aactactaca ccagcgagcc ctgccagaaa 1380
atcaacgtga agcagatcgc cgctggcgga gggggatctg ggggcggagg aagcggaggc 1440
ggaggatcag gcgggggagg ctctggggga ggcggatctt acacaagcct gatccacagc 1500
ctgatcgagg aaagccagaa ccagcaggaa aagaacgagc aggaactgct ggaactggac 1560
aagtgggcca gcctgtggaa ttggttctga tga 1593
<210> 38
<211> 1311
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-6(nt)
<220>
<221> gene
<222> (1)..(1311)
<223> cDNA分子-6(nt)
<400> 38
atgaatagag gcgtgccctt ccggcatctg ctgctggtgc tgcagctggc tctgctgcct 60
gctgccaccc agggcaagaa agtggtgctg ggcaaaaagg gcgacaccgt ggaactgacc 120
tgcaccgcca gccagaagaa gtccatccag ttccactgga agaacagcaa ccagatcaag 180
atcctgggca accagggcag cttcctgacc aagggcccca gcaagctgaa cgacagagcc 240
gactctcggc ggagcctgtg ggaccagggc aatttcccac tgatcatcaa gaacctgaag 300
atcgaggaca gcgacaccta catctgcgag gtggaagatc agaaagaaga ggtgcagctg 360
ctggtgttcg gcctgaccgc caactccgac acccatctgc tgcagggcca gagcctgacc 420
ctgacactgg aaagccctcc aggcagctcc cccagcgtgc agtgtagaag ccctcggggc 480
aagaacatcc agggcggcaa gacactgagc gtgtcccagc tggaactgca ggacagcggc 540
acatggacct gtaccgtgct gcagaaccag aaaaaggtgg aattcaagat cgacatcgtg 600
gtgctggccg agcccaagag ctgcgacaag acccacacct gtcccccttg tcctgcccct 660
gaactgctgg ccggacccga cgtgttcctg ttccccccaa agcccaagga caccctgatg 720
atctcccgga cccccgaagt gacctgcgtg gtggtggatg tgtcccacga ggaccctgaa 780
gtgaagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 840
gaggaacagt acaacagcac ctaccgggtg gtgtccgtgc tgacagtgct gcaccaggac 900
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca aggccctgcc tctgcccgag 960
gaaaagacca tcagcaaggc caagggccag cccagggaac cccaggtgta cacactgccc 1020
cccagcagag atgagctgac caagaaccag gtgtccctga cctgtctcgt gaagggcttt 1080
tacccctccg atatcgccgt ggaatgggag agcaacggcc agcccgagaa caactacaag 1140
accacccccc ctgtgctgga ctccgacggc tcattcttcc tgtactccaa gctgaccgtg 1200
gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1260
cacaaccact acacccagaa gtccctgagc ctgagccccg gcaagtgatg a 1311
<210> 39
<211> 1542
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-7(nt)
<220>
<221> gene
<222> (1)..(1542)
<223> cDNA分子-7(nt)
<400> 39
atgtggctgc agtctctgct gctgctgggc accgtggcct gcagcatcag caagaaagtg 60
gtgctgggca agaaaggcga caccgtggaa ctgacctgca ccgccagcca gaagaagtcc 120
atccagttcc actggaagaa cagcaaccag atcaagatcc tgggcaacca gggcagcttc 180
ctgaccaagg gccccagcaa gctgaacgac agagccgact ctcggcggag cctgtgggac 240
cagggcaatt tcccactgat catcaagaac ctgaagatcg aggacagcga cacctacatc 300
tgcgaggtgg aagatcagaa agaagaggtg cagctgctgg tgttcggcct gaccgccaac 360
tccgacaccc atctgctgca gggccagagc ctgaccctga cactggaaag ccctccaggc 420
agcagcccca gcgtgcagtg tagaagcccc agaggcaaga acatccaggg cggcaagacc 480
ctgagcgtgt cccagctgga actgcaggat agcggcacct ggacctgtac cgtgctgcag 540
aaccagaaaa aggtggaatt caagatcgac atcgtggtgc tggccgagcc caagagctgc 600
gacaagaccc acacctgtcc cccttgtcct gcccctgaac tgctggccgg acccgacgtg 660
ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 720
tgcgtggtgg tggatgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 780
ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 840
cgggtggtgt ccgtgctgac agtgctgcac caggactggc tgaacggcaa agagtacaag 900
tgcaaggtgt ccaacaaggc cctgcctctg cccgaggaaa agaccatctc caaggccaag 960
ggccagccca gggaacccca ggtgtacaca ctgcccccca gcagagatga gctgaccaag 1020
aaccaggtgt ccctgacctg tctcgtgaag ggcttttacc cctccgatat cgccgtggaa 1080
tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 1140
gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcagcagggc 1200
aacgtgttca gctgcagcgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1260
ctgagcctga gcccaggcaa aggcggcgga ggatctggcg gaggcggatc tgggggcgga 1320
ggaagtgggg gagggggaag cggaggggga ggctcaggcg ggggaggaag cggaggcggg 1380
ggaagtggcg gcggaggcag tggcggggga ggctccgggg gaggcggctc ttatacaagc 1440
ctgatccaca gcctgatcga ggaaagccag aaccagcagg aaaagaacga gcaggaactg 1500
ctggaactgg acaagtgggc cagcctgtgg aattggttct ga 1542
<210> 40
<211> 1452
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-8(nt)
<220>
<221> gene
<222> (1)..(1452)
<223> cDNA分子-8(nt)
<400> 40
atgtggctgc agtctctgct gctgctgggc accgtggcct gcagcatcag caagaaagtg 60
gtgctgggca agaaaggcga caccgtggaa ctgacctgca ccgccagcca gaagaagtcc 120
atccagttcc actggaagaa cagcaaccag atcaagatcc tgggcaacca gggcagcttc 180
ctgaccaagg gccccagcaa gctgaacgac agagccgact ctcggcggag cctgtgggac 240
cagggcaatt tcccactgat catcaagaac ctgaagatcg aggacagcga cacctacatc 300
tgcgaggtgg aagatcagaa agaagaggtg cagctgctgg tgttcggcct gaccgccaac 360
tccgacaccc atctgctgca gggccagagc ctgaccctga cactggaaag ccctccaggc 420
agcagcccca gcgtgcagtg tagaagcccc agaggcaaga acatccaggg cggcaagacc 480
ctgagcgtgt cccagctgga actgcaggat agcggcacct ggacctgtac cgtgctgcag 540
aaccagaaaa aggtggaatt caagatcgac atcgtggtgc tggccgagcc caagagctgc 600
gacaagaccc acacctgtcc cccttgtcct gcccctgaac tgctggccgg acccgacgtg 660
ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 720
tgcgtggtgg tggatgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 780
ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 840
cgggtggtgt ccgtgctgac agtgctgcac caggactggc tgaacggcaa agagtacaag 900
tgcaaggtgt ccaacaaggc cctgcctctg cccgaggaaa agaccatctc caaggccaag 960
ggccagccca gggaacccca ggtgtacaca ctgcccccca gcagagatga gctgaccaag 1020
aaccaggtgt ccctgacctg tctcgtgaag ggcttttacc cctccgatat cgccgtggaa 1080
tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 1140
gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcagcagggc 1200
aacgtgttca gctgcagcgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1260
ctgagcctga gcccaggcaa aggcggcgga ggatctggcg gaggcggatc tgggggcgga 1320
ggaagtgggg ggggaggctc ttacacaagc ctgatccaca gcctgatcga ggaaagccag 1380
aaccagcagg aaaagaacga gcaggaactg ctggaactgg acaagtgggc cagcctgtgg 1440
aattggttct ga 1452
<210> 41
<211> 1503
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-10(nt)
<220>
<221> gene
<222> (1)..(1503)
<223> cDNA分子-10(nt)
<400> 41
atgtggctgc agtctctgct gctgctgggc accgtggcct gcagcatcag caagaaagtg 60
gtgctgggca agaaaggcga caccgtggaa ctgacctgca ccgccagcca gaagaagtcc 120
atccagttcc actggaagaa cagcaaccag atcaagatcc tgggcaacca gggcagcttc 180
ctgaccaagg gccccagcaa gctgaacgac agagccgact ctcggcggag cctgtgggac 240
cagggcaatt tcccactgat catcaagaac ctgaagatcg aggacagcga cacctacatc 300
tgcgaggtgg aagatcagaa agaagaggtg cagctgctgg tgttcggcct gaccgccaac 360
tccgacaccc atctgctgca gggccagagc ctgaccctga cactggaaag ccctccaggc 420
agcagcccca gcgtgcagtg tagaagcccc agaggcaaga acatccaggg cggcaagacc 480
ctgagcgtgt cccagctgga actgcaggat agcggcacct ggacctgtac cgtgctgcag 540
aaccagaaaa aggtggaatt caagatcgac atcgtggtgc tggccgagcc caagagctgc 600
gacaagaccc acacctgtcc cccttgtcct gcccctgaac tgctggccgg acccgacgtg 660
ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 720
tgcgtggtgg tggatgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 780
ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 840
cgggtggtgt ccgtgctgac agtgctgcac caggactggc tgaacggcaa agagtacaag 900
tgcaaggtgt ccaacaaggc cctgcctctg cccgaggaaa agaccatctc caaggccaag 960
ggccagccca gggaacccca ggtgtacaca ctgcccccca gcagagatga gctgaccaag 1020
aaccaggtgt ccctgacctg tctcgtgaag ggcttttacc cctccgatat cgccgtggaa 1080
tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 1140
gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcagcagggc 1200
aacgtgttca gctgcagcgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1260
ctgagcctga gcccaggcaa aggcggcgga ggcgattatc aggtgtccag ccccatctac 1320
gacatcaact actacaccag cgagccctgc cagaaaatca acgtgaagca gatcgccgct 1380
ggcggagggg gctacacatc tctgatccac agcctgatcg aggaaagcca gaaccagcag 1440
gaaaagaacg agcaggaact gctggaactg gacaagtggg ccagcctgtg gaattggttc 1500
tga 1503
<210> 42
<211> 1626
<212> DNA
<213> 人工序列
<220>
<223> cDNA分子-11(nt)
<220>
<221> gene
<222> (1)..(1626)
<223> cDNA分子-11(nt)
<400> 42
atgtggctgc agtctctgct gctgctgggc accgtggcct gcagcatcag caagaaagtg 60
gtgctgggca agaaaggcga caccgtggaa ctgacctgca ccgccagcca gaagaagtcc 120
atccagttcc actggaagaa cagcaaccag atcaagatcc tgggcaacca gggcagcttc 180
ctgaccaagg gccccagcaa gctgaacgac agagccgact ctcggcggag cctgtgggac 240
cagggcaatt tcccactgat catcaagaac ctgaagatcg aggacagcga cacctacatc 300
tgcgaggtgg aagatcagaa agaagaggtg cagctgctgg tgttcggcct gaccgccaac 360
tccgacaccc atctgctgca gggccagagc ctgaccctga cactggaaag ccctccaggc 420
agcagcccca gcgtgcagtg tagaagcccc agaggcaaga acatccaggg cggcaagacc 480
ctgagcgtgt cccagctgga actgcaggat agcggcacct ggacctgtac cgtgctgcag 540
aaccagaaaa aggtggaatt caagatcgac atcgtggtgc tggccgagcc caagagctgc 600
gacaagaccc acacctgtcc cccttgtcct gcccctgaac tgctggccgg acccgacgtg 660
ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 720
tgcgtggtgg tggatgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 780
ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 840
cgggtggtgt ccgtgctgac agtgctgcac caggactggc tgaacggcaa agagtacaag 900
tgcaaggtgt ccaacaaggc cctgcctctg cccgaggaaa agaccatctc caaggccaag 960
ggccagccca gggaacccca ggtgtacaca ctgcccccca gcagagatga gctgaccaag 1020
aaccaggtgt ccctgacctg tctcgtgaag ggcttttacc cctccgatat cgccgtggaa 1080
tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 1140
gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcagcagggc 1200
aacgtgttca gctgcagcgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1260
ctgagcctga gcccaggcaa aggcggcgga ggcgattatc aggtgtccag ccccatctac 1320
gacatcaact actacaccag cgagccctgc cagaaaatca acgtgaagca gatcgccgct 1380
ggcggagggg gatctggggg cggaggaagc ggaggcggag gatcaggcgg gggaggctct 1440
gggggaggcg gcagtggggg gggaggaagt ggcggaggcg gctcaggcgg aggcggaagc 1500
gggggaggcg gatcttacac aagcctgatc cacagcctga tcgaggaaag ccagaaccag 1560
caggaaaaga acgagcagga actgctggaa ctggacaagt gggccagcct gtggaattgg 1620
ttctga 1626
Claims (20)
1.一种抗体衍生物,从N端到C端包含:
(a)人类CD4的D1和D2胞外结构域;
(b)人类IgG的Fc部分;
(c)选自由以下组成的组的部分:(i)序列(GGGGS)n的连接子多肽,其中1≤n≤10;(ii)人类CCR5受体序列和(iii)其组合以及
(d)gp41衍生的多肽。
2.根据权利要求1所述的抗体衍生物,其中所述人类IgG的所述Fc部分包含IgG1。
3.根据权利要求1或2所述的抗体衍生物,其中所述人类IgG或IgG1的所述Fc部分包含G236A、S239D、A330L以及I332E点突变。
4.根据前述权利要求中任一项所述的抗体衍生物,其中所述人类CCR5受体序列包含SEQ ID NO:6。
5.根据前述权利要求中任一项所述的抗体衍生物,其中所述gp41衍生的多肽包含SEQID NO:7。
6.一种分离核酸,编码根据权利要求1所述的抗体衍生物。
7.根据权利要求6所述的核酸,其已是密码子优化的。
8.一种表达载体,包含根据权利要求6到7所述的核酸。
9.一种宿主细胞,包含根据权利要求1到5中任一项所述的抗体衍生物、根据权利要求6到7所述的核酸或根据权利要求8所述的表达载体。
10.一种医药组合物,包含治疗有效量的根据权利要求1到5中任一项所述的抗体衍生物、根据权利要求6到7所述的核酸、根据权利要求8所述的表达载体、根据权利要求9所述的宿主细胞或其混合物。
11.根据权利要求1到5中任一项所述的抗体衍生物、根据权利要求6到7所述的核酸、根据权利要求8所述的表达载体、根据权利要求9所述的宿主细胞或根据权利要求10所述的医药组合物,其用作药剂。
12.根据权利要求1到5中任一项所述的抗体衍生物、根据权利要求6到7所述的核酸、根据权利要求8所述的表达载体、根据权利要求9所述的宿主细胞或根据权利要求10所述的医药组合物,其用于治疗HIV感染或AIDS。
13.根据权利要求1到5中任一项所述的抗体衍生物、根据权利要求6到7所述的核酸、根据权利要求8所述的表达载体、根据权利要求9所述的宿主细胞或根据权利要求10所述的医药组合物,其用于预防HIV感染或AIDS。
14.一种组合,包含根据权利要求1到5中任一项所述的抗体衍生物、根据权利要求6到7所述的核酸、根据权利要求8所述的表达载体、根据权利要求9所述的宿主细胞、根据权利要求10所述的医药组合物以及至少一种治疗剂。
15.根据权利要求14所述的组合,其中所述治疗剂是HIV抗逆转录病毒的。
16.一种用于制备根据权利要求1到5中任一项所述的抗体衍生物的方法,包含以下步骤:(a)培养包含根据权利要求6到7所述的核酸的宿主细胞;(b)表达所述核酸以及(c)从所述宿主细胞培养物回收所述抗体衍生物。
17.一种使HIV失活的方法,包含以下步骤:使所述病毒与根据权利要求1到5中任一项所述的抗体衍生物接触。
18.一种诱导gp120在HIV感染细胞中表达的方法,包含以下步骤:使所述感染细胞与根据权利要求1到5中任一项所述的抗体衍生物、根据权利要求6到7所述的核酸、根据权利要求8所述的表达载体、根据权利要求9所述的宿主细胞、根据权利要求10所述的医药组合物、根据权利要求14到15所述的组合或其混合物接触。
19.一种检测样品中HIV的方法,包含以下步骤:(a)使所述样品与根据权利要求1到5中任一项所述的抗体衍生物接触;和(b)判定所述抗体衍生物是否特异性结合到所述样品的分子。
20.一种试剂盒,包含根据权利要求1到5中任一项所述的抗体衍生物、根据权利要求6到7所述的核酸、根据权利要求8所述的表达载体、根据权利要求9所述的宿主细胞、根据权利要求10所述的医药组合物、根据权利要求14到15所述的组合或其混合物以及供使用的说明材料。
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PCT/IB2016/001868 WO2017085563A1 (en) | 2015-11-21 | 2016-11-19 | Hiv antibody derivatives with dual antiviral and immunomodulatory activity |
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CN113423731A (zh) * | 2018-10-29 | 2021-09-21 | 株式会社免疫生物研究所 | 抗hiv抗体及其制造方法 |
CN116554356A (zh) * | 2023-05-16 | 2023-08-08 | 武汉大学 | 一种hyperIL-15与sCD4及Fc的融合蛋白及其应用 |
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WO2018207023A2 (en) * | 2017-05-10 | 2018-11-15 | Albajuna Therapeutics, S.L. | Fc-fusion protein derivatives with high dual hiv antiviral and immunomodulatory activity |
WO2023205670A2 (en) * | 2022-04-19 | 2023-10-26 | Purdue Research Foundation | Stable fc fragments, conjugates, compositions, and methods of use |
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