使用嵌合抗原受体（CARS）的胎盘样硫酸软骨素的免疫治疗靶向和使用具有分割蛋白结合系统的CARS的癌症的免疫治疗靶向的制作方法

发明领域本发明提供了组合物和方法，其用于使用与var2csa融合的嵌合抗原受体(car)即var2-car或与分割蛋白结合系统融合的嵌合抗原受体(car)即spy-car的癌症免疫疗法治疗，编码这些构建体的载体和包含car的重组t-细胞。发明背景在基于细胞的过继免疫治疗中，可以修饰从患者分离的免疫细胞以表达合成的蛋白质，其使得细胞在其随后转移回患者体内后能够执行新的治疗功能。这样的合成蛋白质的实例是嵌合抗原受体(car)。目前使用的car的实例是细胞外靶标识别结构域(例如，抗原结合scfv链)、跨膜结构域(例如来自cd8或cd28)和一个或多个细胞内信号传导结构域(包括cd28，ox40/4-1bb和cd3ζ)的融合物。抗原接合后，car的细胞内信号传导部分可以在免疫细胞中引发活化相关的反应；如溶细胞分子的释放以诱导肿瘤细胞死亡等。嵌合抗原受体(car)描述于porter等人,2011,n.engl.j.med.365:725-733；和kalos等人,2011,sci.transl.med.3:95ra73中。分割蛋白结合系统(spbs)的特征在于蛋白质的两个分割片段重构成稳定的共价锁定结构的能力。这种spbs的一个例子是spy-tag-spy-catcher系统，其包含来自化脓性链球菌(pmid：20235501)的纤连蛋白结合蛋白(fbab)的第二免疫球蛋白样胶原粘附素结构域(cnab2)的反应性亚单位蛋白质伴侣(spy-tag和spy-catcher)。spytag和spycatcher通过自发的多肽键形成相互作用，并且是分割蛋白结合系统的一个实例(zakeri,b.等人pnas.2012)。如果一个蛋白质含有spytag，另一个蛋白质含有spycather，这两个蛋白质将通过spytag和spycather之间的共价相互作用自发连接，这确保了spytag和spycatcher连接蛋白之间的高结合强度和一对一的相互作用。spytag-spycatcher系统与其它分割蛋白结合系统一起在veggiani等人,2014,trendsbiotechnol.oct；32(10):506-12中描述。spycatcher蛋白质序列(116aa)在体内显示出一定程度的免疫原性，其可以通过截短蛋白质的n-末端部分(aa1-24)(pmid：25434527)来减小。虽然是非免疫原性的，但是δn-spycatcher序列保留了对13aaspytag序列(pmid：25434527)的完全结合能力，因此可用于免疫敏感应用，如疫苗生产或嵌合免疫受体。硫酸软骨素a(csa)属于糖胺聚糖(gag)家族，其是交替的氨基糖和己糖醛酸残基的连接于蛋白聚糖的线性聚合物。存在几种类型的gag，包括：硫酸软骨素(cs)，硫酸皮肤素(ds或csb)，硫酸乙酰肝素(hs)和肝素。虽然这些gag的多糖主链是简单的，但在诸如硫酸化和糖醛酸差向异构化的修饰中出现相当大的多样性。这是不同gag的域结构和生物活性的广泛多样性的基础。在包括癌症在内的各种人类疾病中已经报道了csa的异常或不适当的表达。csa链被定义为主要是硫酸软骨素a，但csa链也可以沿着csa链具有少数ds或csc。疟原虫恶性疟原虫(plasmodiumfalciparum)在其复杂生命周期的几乎所有阶段都使用宿主细胞蛋白聚糖。子孢子通过与高度硫酸化的硫酸乙酰肝素蛋白聚糖(hspg)相互作用的表面表达的环子孢子蛋白感染肝脏中的肝细胞。红细胞的裂殖子感染是通过与血型糖蛋白a上的唾液酸结合的eba-175介导的。此外，许多介导宿主内皮粘附的恶性疟原虫红细胞膜蛋白1(pfemp1)蛋白已被描述为聚糖结合性的。其中之一是var2csa，它是pfemp1蛋白家族的独特成员。var2csa以高亲和力结合胎盘的绒毛间隙中的附接至蛋白聚糖(所谓的硫酸软骨素蛋白聚糖(cspg))的特定类型的硫酸软骨素a(csa)。var2csa是在恶性疟原虫感染的红细胞(ie)表面上表达的大的多结构域蛋白(350kda)，并且var2csa-csa相互作用负责胎盘疟疾(pm)中的胎盘特异性隔离(placentaspecificsequestration)。重要的是，来自fcr3和3d7型寄生虫的重组全长var2csa胞外结构域在低纳摩尔范围内显示出对csa的亲和力。发明目的本发明的实施方案的目的是提供使用与var2csa融合的嵌合抗原受体(car)即var2-car或与分割蛋白结合系统融合的嵌合抗原受体(car)即spy-car的组合物和方法，编码其的载体，以及包含car的重组t细胞。在一些实施方案中，car的scfv部分被分割蛋白结合系统的一部分，例如spytag(seqidno：130)，spycatcher(seqidno：129)或spycatcher-δn(seqidno：136)取代。在这些实施方案中，疾病抗原识别分子例如抗体，scfv单链，纳米抗体或重组蛋白(包括单特异性或双特异性的var2csa肽或其片段)通过分割蛋白结合系统连接到car。本发明还涉及使用var2csa的硫酸软骨素a(csa)修饰特异性的car。在一些实施方案中，car的scfv部分被至少包含最小csa结合结构域id1-id2a的var2csa变体所取代。本发明的实施方案的其它目的是提供用于使用用于治疗与抗原例如疾病相关抗原例如疾病相关csa的不适当表达相关的病况的能够结合分割蛋白的car的方法。本发明实施方案的其它目的是提供其中var2csa嵌合构建体、其多肽或片段用于靶向具有csa的表达例如不适当表达的组织或细胞的方法。本发明还包括能够植入针对细胞和组织的免疫应答的基于var2csa的双特异性融合蛋白(双特异性性var2)，例如var2csa和免疫细胞结合结构域之间的融合蛋白，例如scfv抗cd3结构域。发明概述本发明人已经发现重组var2csa以高亲和力和特异性结合在疾病相关蛋白聚糖的有限库上的胎盘样csa链。更重要的是，本发明人已经发现，胎盘样csa链在几乎所有类型的人类肿瘤中独特地重新表达，并且重组var2csa蛋白以高和特异性的亲和力结合癌细胞上和原发癌组织中的胎盘样csa。var2sca的此功能可用于提供适合于免疫治疗的构建体，该构建体包含car的元件或结构域，例如至少包含cd28和cd3ζ结构域。因此，本发明人提示使用var2csa和csa之间的该特异性和高亲和力结合来植入针对具有胎盘样csa修饰的蛋白聚糖的高表达或其它方式的不适当表达的人类肿瘤和转移的免疫应答。这可以通过car和var2csa之间的直接遗传融合(var2-car)获得。也可以通过在分割蛋白结合系统的片段(例如spytag或spycatcher)上融合到car(spy-car)获得，并随后体外或体内附接融合到相应的spytag或spycatcher的重组var2csa蛋白。spy-car可用于附接靶向分子不同于var2csa(例如抗体或抗体片段)的其它情况。通过使用对胎盘样csa和免疫细胞如cd3阳性细胞具有双特异性的双特异性var2csa蛋白，也可以获得免疫细胞至具有胎盘样csa的高表达或不适当表达的肿瘤组织或其它组织的植入。这通过将var2csa与特异于某一免疫细胞群体(如cd3阳性细胞)的单链抗体(如scfv抗cd3)融合获得。通过将car技术与分割蛋白质系统相结合，可以制备通用car，其可以通过用与分割蛋白的其它部分融合的癌靶向蛋白进一步治疗患者来进行个性化治疗。可以控制剂量，治疗可以停止，并且在治疗方案的过程中可以改变治疗。特别是通过制作分割系统car和相应的var2csa分割蛋白，可以在治疗患者之前完美控制var2csa蛋白质折叠、结合亲和力、结合特异性以及良好生产规范的二次修饰的监测。因此，在第一方面，本发明涉及一种多肽，其包含i)第一多肽结构域，其是嵌合抗原受体(car)的跨膜结构域和胞内结构域，以及ii)选自var2csa多肽或分割蛋白结合系统的肽部分的第二胞外多肽结构域。在第二方面，本发明涉及多肽，其包含i)第一多肽结构域，其是var2csa多肽或其它肿瘤靶向剂，例如单链scfv，和ii)选自分割蛋白结合系统的肽部分、单结构域抗体例如scfv或纳米抗体中的一个或多个的第二多肽结构域。应当理解，本文所述的包含car和分割蛋白结合系统的肽部分的任何构建体可以以任何方向在嵌合构建体中正向或反向翻译形成。因此，作为实例，spytaq氨基酸序列可以是ahivmvdaykptk(seqidno：130)或反向的ktpkyadvmviha(seqidno：137)。在一些实施方案中，根据本发明的var2csa的分离的蛋白质片段包含id2a。在第三方面，本发明涉及包含编码本发明多肽的核苷酸序列的分离的核酸分子。在另一方面，本发明涉及包含分离的核酸分子的表达载体，其包含编码本发明多肽的核苷酸序列。在另一方面，本发明涉及包含本发明载体的细胞。在一些实施方案中，细胞选自αβτ细胞，γδt细胞，自然杀伤(nk)细胞，细胞毒性t淋巴细胞(ctl)，调节性t细胞或其任何组合。在另一方面，本发明涉及双组分治疗剂，其包含a)第一组分，其是多肽，所述多肽包含i)第一多肽结构域，其是嵌合抗原受体(car)的跨膜结构域和胞内结构域，以及ii)第二多肽结构域，其是连接至所述car的胞外部分的分割蛋白结合系统的肽部分；和b)第二组分，其是多肽，所述多肽包含i)第一多肽结构域，其是var2csa多肽或任何其它肿瘤靶向剂，例如抗体或scfv，以及ii)第二多肽结构域，其是分割蛋白结合系统的肽部分；任选地还包含iii)单结构域抗体，例如scfv或纳米抗体，其中由组分a)和b)定义的分割蛋白结合系统的所述肽部分自发形成不可逆的异肽键。在另一方面，本发明涉及治疗或预防受试者中的与例如癌症中csa的表达例如不适当表达相关的任何适应症或病况的发生的方法，所述方法包括：(a)在促进活化的条件下培养细胞毒性淋巴细胞群；(b)用编码多肽的载体转染(a)的淋巴细胞群，所述多肽包含i)第一多肽结构域，其是嵌合抗原受体(car)的跨膜结构域和胞内结构域，以及ii)第二多肽结构域，其选自var2csa多肽或任何其它靶向剂，例如抗体；(c)将治疗或预防有效量的(b)的经转染的淋巴细胞施用于具有所述适应症或处于具有所述适应症的风险中的受试者；其中包含car的结构域的多肽具有针对靶向部分的结合特异性，或可被靶向部分结合；从而治疗或预防所述受试者的所述适应症。在另一方面，本发明涉及治疗或预防受试者中的与例如癌症中csa的表达例如不适当表达相关的任何适应症或病况的发生的方法，所述方法包括：(a)在促进活化的条件下培养细胞毒性淋巴细胞群；(b)用编码多肽的载体转染(a)的淋巴细胞群，所述多肽包含i)第一多肽结构域，其是嵌合抗原受体(car)的跨膜结构域和胞内结构域，以及ii)第二多肽结构域，其是连接至所述car的胞外部分的分割蛋白结合系统的肽部分；(c)将治疗或预防有效量的(b)的经转染的淋巴细胞施用于具有所述适应症或处于具有所述适应症的风险中的受试者；和(d)施用多肽，所述多肽包含i)第一多肽结构域，其为var2csa多肽或其它靶向剂，例如抗体，和ii)第二多肽结构域，其是分割蛋白结合系统的肽部分，其中在两种不同的多肽中定义的分割蛋白结合系统的所述肽部分自发形成不可逆的异肽键；从而治疗或预防所述受试者的所述适应症。在另一方面，本发明涉及用作药物的根据本发明的多肽或根据本发明的双组分治疗剂。在另一方面，本发明涉及包含根据本发明的多肽或根据本发明的双组分治疗剂的药物组合物。在另一方面，本发明涉及根据本发明的多肽或根据本发明的双组分治疗剂用于制备药物的用途。在另一方面，本发明涉及根据本发明的多肽或根据本发明的双组分治疗剂或根据本发明的药物组合物，用于治疗例如癌症，关节炎，关节病，多发性硬化和神经损伤后愈合，软骨修复，伤口愈合和牛皮癣中与涉及csa的表达例如不适当表达的病况相关的任何适应症。在另一方面，本发明涉及与任何其它合适的抗癌剂的组合的根据本发明的多肽，或根据本发明的双组分治疗剂或根据本发明的药物组合物。在一些实施方案中，癌症选自所有表达csa的恶性肿瘤，包括癌(包括但不限于乳腺癌，胰腺癌，卵巢癌，子宫内膜癌，肝细胞癌，肺癌，结肠癌，前列腺癌，宫颈癌，睾丸癌，基底细胞皮肤癌，透明细胞肾细胞癌，头颈鳞状细胞癌，皮肤鳞状细胞癌，外阴角质化鳞状细胞癌和外阴基底细胞癌)，肉瘤(包括但不限于纤维肉瘤，去分化的软骨和脂肪肉瘤，平滑肌肉瘤，脂肪肉瘤，粘液样脂肪肉瘤，子宫体平滑肌肉瘤，骨肉瘤，尤文肉瘤和横纹肌肉瘤，滑膜肉瘤，孤立性纤维瘤)，造血系统癌(包括但不限于慢性淋巴细胞白血病(cll)，急性淋巴细胞白血病(all)，急性骨髓性白血病(aml)，b细胞、t细胞和大颗粒淋巴瘤)，神经上皮组织的肿瘤，例如但不限于星形细胞瘤(多形性黄色星形细胞瘤，纤维性星形细胞瘤，间变性星形细胞瘤，多形性成胶质细胞瘤)，少突神经胶质瘤，室管膜瘤，脉络丛肿瘤，少突星形细胞瘤，神经胶质肉瘤，神经节胶质细胞瘤，视网膜母细胞瘤，神经细胞瘤，神经母细胞瘤(成感觉神经细胞瘤和神经节成神经细胞瘤)，髓母细胞瘤，非典型畸胎样横纹肌样瘤和所有类型的神经内分泌癌以及任何其它表达csa的癌症。应当理解，对于包含var2csa多肽的融合或嵌合蛋白，可以使用本文定义的任何var2csa序列和多肽。因此，该方面不限于使用最小结合片段。这在使用术语var2csa序列或多肽时均适用，并且在用于医学治疗或靶向时相应地是等同相关的。发明详述在一些实施方案中，本发明的多肽包含car的scfv部分和var2csa肽。在其它实施方案中，重组var2csa肽使用分割-蛋白结合系统连接至car。在其它实施方案中，使用分割蛋白结合系统将疾病靶向单位(例如抗体，单链结合物(scfv)或重组肽)连接至car。本发明还包括基于var2csa的融合蛋白，其能够通过双重结合至胎盘样csa和免疫细胞特异性受体来募集针对表达胎盘样csa的细胞和组织的免疫应答(双特异性var2)。单或双特异性var2-car：根据本发明的多肽构建体可以包含与car的跨膜结构域和胞内结构域组合的var2csa。在本发明的一些方面，修饰宿主的免疫细胞以表达本发明的包含car的所述多肽构建体。人类t淋巴细胞表达肿瘤定向嵌合抗原受体(car)的遗传工程改造可以产生抗肿瘤的效应细胞，其能够绕过肿瘤免疫逃逸机制，这是由于蛋白质-抗原加工和呈递中的异常。此外，这些转基因受体可以针对不是蛋白质来源的肿瘤相关抗原。在本公开内容的某些实施方案中，存在被修饰以包含至少一种car的ctl。在特定情况下，细胞毒性t淋巴细胞(ctls)包含嵌合、非天然和至少部分地手工改造的受体。在特定情况下，除了car之外，根据本发明的多肽构建体还包含一种，两种，三种，四种或更多种组分，并且在一些实施方案中，一种或多种组分促进t淋巴细胞靶向或结合到包含肿瘤抗原(例如var2csa多肽)的癌细胞。在具体实施方案中，根据本发明的多肽构建体包含作为胞质信号传导结构域的部分或全部的和/或一种或多种共刺激分子的一部分或全部(例如共刺激分子的胞内结构域)的car，和单独的(单特异性)var2csa多肽或与特异于肿瘤抗原的抗体、单链scfv或重组肽融合的var2csa多肽(双特异性var2-car)。在某些方面，抗体针对可由例如替莫唑胺(tmz)治疗的癌细胞的细胞表面上的靶抗原。在某些实施方案中，使用胞质信号传导结构域，例如衍生自t细胞受体ζ-链的那些，作为嵌合受体至少一部分，以便在嵌合受体与目标抗原接合之后产生t淋巴细胞增殖的刺激信号和效应子功能。实例将包括但不限于来自共刺激分子如cd27，cd28，4-ibb和ox40的胞内结构域或细胞因子受体如il7和il15的信号传导成分。在特定实施方案中，共刺激分子用于增强抗原接合后由car产生的t细胞的活化、增殖和细胞毒性。在具体实施方案中，共刺激分子是cd28，ox40和4-1bb，细胞因子和细胞因子受体是il7和il15。car可以是第一代，第二代或第三代(其中信号传导由cd3ζ以及由cd28和肿瘤坏死因子受体(tnfr)结构域，例如4-1bb或ox40提供的共刺激提供的car)或任何其它car，其包含至少一个这些结构域。根据本发明的var2-car的多肽构建体还可以含有信号肽(sp)，使得构建体的car部分可以被糖基化并锚定在免疫效应细胞的细胞膜中。跨膜结构域(td)将胞外结构域连接到胞内结构域并当由细胞表达时驻留在细胞膜内，并且可以衍生自天然或合成来源。如果来源是天然的，则该结构域可以衍生自任何膜结合或跨膜蛋白。例如，跨膜区域可以衍生自t细胞受体，cd28，cd3ε，cd45，cd4，cd5，cd8，cd9，cd16，cd22，cd33，cd37，cd64，cd80，cd86，cd134，cd137或cd154的α、β或ζ链(即，至少包含其跨膜区域)。或者，td可以是合成的，在这种情况下，它将主要包含疏水残基，如亮氨酸和缬氨酸。在一些情况下，在合成的td的每个末端将发现苯丙氨酸、色氨酸和缬氨酸的三元组。car还可以包括铰链序列。铰链序列是促进蛋白质柔性的氨基酸的短序列(参见，例如，woof等人,nat.rev.immunol,4(2):89-99(2004))。铰链序列可以位于抗原识别部分和td之间。铰链序列可以是从任何合适的分子衍生或获得的任何合适的序列。在一些实施方案中，例如，铰链序列衍生自cd8a分子或cd28分子，或衍生自igg，例如igg1铰链区根据本发明的包含var2-car的多肽构建体可以针对其它疾病相关表位具有双重特异性，包括但不限于cd19，cd20，cd22，κ或轻链，cd30，cd33，cd123，cd38，ror1，her2/erbb2，erbb3/4，egfr，egfrviii，epha2，fap，癌胚抗原，egp2，egp40，间皮素，tag72，psma，nkg2d配体，b7-h6，il-13受体cc2，il-11受体a，muc1，muc16，ca9，gd2，gd3，hmw-maa，cd171，lewisy，g250/caix，hla-aimageal，hla-a2ny-eso-1，psc1，叶酸受体α，cd44v7/8，8h9，ncam，vegf受体，5t4，胎儿achr，nkg2d配体，cd44v6，tem1，tem8，由肿瘤表达的病毒相关抗原或通过基因组分析和肿瘤差异表达研究鉴定的其它肿瘤相关抗原。根据本发明的包含嵌合抗原受体(car)的跨膜结构域和胞内结构域的多肽构建体可以进一步包含其它调节元件或自杀基因系统，例如诱导型半胱天冬酶-9(icasp9)(clacksont.等人(1998).proc.natl.acad.sci.u.s.a.9510437–10442；straathofk.c.等人(2005).blood1054247–4254),或睡美人(sb)转座子系统(maitisn等人,jimmunother.2013feb；36(2):112-23)。分割蛋白结合系统(spbs)：在本发明中，spytag-spycatcherspbs可以与car技术组合。用spbs的片段(例如spycatcher序列)替代car构建体的scfv结构域将允许与spbs的另一部分融合的靶向单元(例如scfv和抗体或重组蛋白)的翻译后连接到car。spytag和spycatcher之间的相互作用在lys31的未质子化的胺亲核攻击asp117的羰基碳时发生，由邻近的glu77催化。介导这种结合的最小肽是ahivmvda(seqidno：131)，而产生序列ahivmvdaykptk(seqidno：130)的c-末端延伸提供了称为“spytag”的最佳区域(zakeri等人pnas2012)。spycatcher是来自化脓性链球菌的fbab蛋白的cnab2结构域的一部分，并且与由cnab2结构域的另一部分组成的spytag结合。当cnab2结构域的这两个多肽混合时，它们会自发形成不可逆的异肽键，从而完成cnab2结构域的形成。在本发明中也可以使用k-tag/spytag/spyligase系统。来自化脓链球菌的cnab2结构域可用于产生共价肽-肽连接系统(fiererjo等人，2014)。这通过将cnab2分割为三个部分来完成：a)13个氨基酸的spytag(seqidno：130)，b)称为k-tag的cnab2的β-链(seqidno132)，和c)由其余的spycatcher多肽构建的spyligase(seqidno：133)。通过表达具有在c-或n-末端融合的小k-tag的靶向蛋白质，并将该融合蛋白与呈现spytag的t细胞以及spyligase一起混合，k-tag融合抗原将通过spyligase促进的spytag与k-tag的共价连接附接至spytag-vlp。相反，k-tag也可以遗传地插入到car中，由此靶向抗原随后应在c-或n-末端被融合到spytag。作为在t细胞表面上靶向抗原的共价偶联的相似策略的一部分，另外一对分割蛋白结合配偶体可用于本发明。来自化脓性链球菌的主要菌毛蛋白spy0128可以被分割成两个片段split-spy0128(spy0128的残基18-299)(seqidno：135)和异肽(spy0128的残基293-308(tdkdmtitftnkkdae))(seqidno134)，它们共同形成分子间共价络合物(zakeri，b.等人，2010)。与描述的spytag-spycatcher策略一致，可以将spy0128异肽插入到tcr或靶向抗原中，并且对于split-spy0128结合配偶体也是相同的。再次简单混合或预注射标记的靶向蛋白将导致t细胞上标记的car与靶向抗原之间的共价相互作用。spy-car也可用于通过将k-标记的抗体，k-tag连接的抗体，k-tag连接的scfv链，k-标记的重组蛋白或其组合连接到spy-car来构建双特异性或多特异性car，获得双特异性或多特异性car构建体。应该理解，spytag可能被spy0128异肽取代，spycatcher由split-spy0128取代。目前使用的car不易于药理学控制。分割蛋白结合系统的使用可以促进car能够在体内针对特定抗原激活和失活。本发明的一个重要方面是i)收集，ii)修饰和iii)输注来自具有高表达或不适当表达的胎盘样csa的受试者(例如癌症患者)的t细胞群。在收集步骤中，从患者血液样品中纯化t细胞。在修饰步骤中，用编码由至少胞外分割蛋白结合结构域(如spytag或spycatcher)、跨膜结构域(如cd8或cd28)和激活结构域(如cd3ζ)组成的car的载体转染t细胞群。然后静脉内施用与分割蛋白结合系统的其它部分标记、缀合或融合的抗原结合分子，例如抗体，单链scfv或重组var2csa多肽。该分子将结合由car提供的分割蛋白的相应部分，这将使得car能够结合感兴趣的靶标并激活。在输注步骤中，将表达car的重组t细胞注射到患者体内，建立能够对靶标反应的t细胞群。该原理可以应用于任何肿瘤结合分子(包括但不限于抗体，scfv单链和重组蛋白)，并且具有如下优点：a)可以用相同的car输注靶向许多不同的肿瘤抗原或靶标。b)可以通过暂停输注spytag(或类似的肽)肿瘤靶标分子来恢复治疗。c)可以使用复合靶向剂，例如重组var2sca，其不容易制成嵌合体作为car构建体的一部分。双特异性var2蛋白：由于varcsa可以作为单链重组蛋白产生，因此可以与能够识别特定疾病靶标的其它单链蛋白融合。例如，将var2csa融合到靶向cd3的scfv链将能够将表达cd3的免疫细胞募集到表达胎盘样csa的细胞和组织。因此，这种双重特异性的基于var2csa的分子可用于植入针对具有胎盘样csa表达的细胞和组织的t细胞应答。在一些实施方案中，var2csa可以遗传融合到单链抗体，例如scfv链或纳米抗体，产生双特异性var2csa蛋白。在一些实施方案中，这种双特异性var2csa蛋白可以含有分割蛋白结合标签，例如spytag或k-tag。在一些实施方案中，双特异性var2csa蛋白可以通过分裂结合蛋白系统连接到car。var2csa多肽本发明基于以下事实：疟疾蛋白的一部分(所谓的var2csa)可以以非常高的特异性和非常高的结合强度结合癌症特异性csa和细胞外csa缀合的cspg。该部分技术描述于wo2013117705a1中。csa与许多重要因素如生长激素，细胞因子，趋化因子和粘附分子相互作用，并被认为参与结构稳定，胞质分裂，细胞增殖，分化，细胞迁移，组织形态发生，器官发生，感染和伤口修复。cs链由n-乙酰基-d-半乳糖胺(galnac)和葡萄糖醛酸残基的交替单元组成。葡萄糖醛酸可以在其c2位硫酸化，galnac可以在c4和/或c6硫酸化，产生各种二糖单元。糖骨架的不同修饰允许cs链的结构和功能异质性。胎盘粘附恶性疟原虫寄生虫与主要为c4硫酸化的cs链特异性结合。已经显示重组var2csa蛋白以前所未有的高亲和力和特异性结合csa。这可能是由于与csa的相互作用，其不仅取决于带电的硫酸盐，而且还取决于cs主链。本发明的发明人已经证明，存在于胎盘中的csa非常类似于在各种癌细胞包括癌症干细胞上呈现的csa。这通过表达var2csa的疟疾寄生虫特异性地粘附至c32黑素瘤细胞上的csa和人类脑癌细胞的事实得到证明。因此，本发明依赖于var2csa重组蛋白和胎盘样csa之间的高亲和性和特异性。通过标记该蛋白质，本发明可用于广泛的应用，包括在体内追踪转移瘤和诊断转移性疾病。通过将var2csa偶联到凋亡或细胞毒性试剂上，本发明可用于特异性靶向和消除癌细胞和癌症干细胞。通过使用var2csa重组蛋白的简单治疗，可以中和csa的活性，从而抑制表达csa的癌细胞的肿瘤发生和/或转移。csa可以存在于许多蛋白质主链上，例如cspg4，cd44，双糖聚糖，核心蛋白聚糖，多能聚糖，聚集蛋白聚糖(软骨中的主要cspg)，基底膜聚糖，多配体聚糖。本发明被设想为与恶性黑素瘤癌(包括在黑素瘤细胞表面具有csa链的具有cspg4的皮肤、眼和结膜黑素瘤)特别相关。该gag链被认为参与有丝分裂和转移。然而，cspg4不仅是特异于黑素瘤。本发明人对来自人体组织和细胞系的大实验组的数据进行的微阵列和组织阵列分析表明cspg4和其它类型的含csa的蛋白聚糖可能存在于源自所有三种细胞胚层的广泛范围的癌症类型。这些癌症类型包括癌(乳腺癌，胰腺癌，卵巢癌，子宫内膜癌，肝细胞癌，肺癌，结肠癌，前列腺癌，宫颈癌，睾丸癌，基底细胞皮肤癌，透明细胞肾细胞癌，头颈鳞状细胞癌，皮肤鳞状细胞癌，外阴角质化鳞状细胞癌和外阴基底细胞癌)，肉瘤(乳腺脂肪肉瘤，纤维肉瘤，去分化的软骨和脂肪肉瘤，平滑肌肉瘤，脂肪肉瘤，粘液样脂肪肉瘤，子宫体平滑肌肉瘤，骨肉瘤，尤文肉瘤和横纹肌肉瘤)，造血系统癌(慢性淋巴细胞白血病(cll)，急性淋巴细胞白血病(all)，急性骨髓性白血病(aml)，b细胞、t细胞和大颗粒淋巴瘤)，神经上皮组织的肿瘤，例如星形细胞瘤(多形性黄色星形细胞瘤，纤维性星形细胞瘤，间变性星形细胞瘤，多形性成胶质细胞瘤)，少突神经胶质瘤，室管膜瘤，脉络丛肿瘤，少突星形细胞瘤，神经胶质肉瘤，神经节胶质细胞瘤，视网膜母细胞瘤，神经细胞瘤，神经母细胞瘤(成感觉神经细胞瘤和神经节成神经细胞瘤)，髓母细胞瘤，非典型畸胎样横纹肌样瘤和所有类型的神经内分泌癌。本发明的发明人已经鉴定了一种疟疾蛋白var2csa，其以小于10nm的亲和力结合胎盘的间隙空间中的csa。已经以高产率生产了var2csa的较小的重组部分，其结合具有与全长和天然var2csa蛋白质相似的特征的csa。重组var2csa蛋白不与其它类型的cs(例如硫酸软骨素c(c6s)或高度硫酸化的gag如硫酸乙酰肝素(hs))结合。可以产生重组蛋白质以在各种表达系统(包括s2细胞，t.ni细胞，cho细胞和大肠杆菌菌株包括bl21和shuffle细胞(tmnewenglandbiolabs))中以高亲和力结合csa。本发明的发明人还鉴定了以非常高的亲和力(nm)和高特异性结合csa的单个小(75kda)抗原。表3(参见实施例2)列出了使用生物传感器技术的分析的所有var2csa蛋白的csa亲和力。本发明的发明人已经表明，该var2csa重组蛋白以低浓度强烈地结合到广泛的癌细胞系，包括皮肤黑素瘤(c32，mewo)，肺癌(a549)，乳腺癌(hcc1395)，骨肉瘤(u2os，mnng/hos)，横纹肌肉瘤(rh30)和皮肤t细胞淋巴瘤(表4和5)。作为对照分子，使用另外一种var2csa蛋白，其与最小结合性var2csa构建体相同，除了在分子的c-末端部分中151个氨基酸的截短。此截短移除csa结合。重组var2csa结合所有表达cspg4的细胞系和表达具有csa链的其它cspg分子的癌细胞系(例如t细胞淋巴瘤)。重组var2csa蛋白不能与人红细胞和外周血单核细胞(pbmc)相互作用(表4)。本发明的发明人已经通过var2csa与附接于给定的蛋白聚糖的胎盘样csa链之间的特异性相互作用，显示疟疾寄生虫粘附于癌细胞和原发性人类肿瘤。因此，可以设想重组var2csa及其缀合物可用于引导针对肿瘤环境的免疫应答。使用var2csa靶向肿瘤上的csa相对于其它现有的治疗方法的优势有很多：1)var2csa和csa之间的相互作用具有前所未有的高亲和力和高度特异性。2)var2csa是进化型精制疟疾蛋白，因此治疗不太可能会破坏患者的耐受性并引起自身免疫反应。3)var2csa是稳定的蛋白质，具有很好的表征，可以在与大规模蛋白质生产相容的生物体中高度表达。4)var2csa是具有多种血清变体的多态性蛋白质。反复治疗可通过不同的血清变体提供，以避免中和抗体的问题。5)var2csa天然暴露在恶性疟原虫感染的红细胞上，因此本质上是人血清中稳定的蛋白质，并且已被证明是高度抗蛋白酶的。使用双特异性的基于var2csa的分子(如var2csa-scfv-cd3融合蛋白)的优点众多：1)var2csa结合由多种恶性疾病适应症表达的常见的与癌症相关的csa修饰，因此双特异性var2sca融合蛋白可以将t细胞应答直接植入csa阳性肿瘤环境。2)由于在给定的恶性疾病中表达的几种蛋白聚糖上存在恶性相关的csa修饰，所以给定的癌症不太可能通过下调特定的蛋白聚糖来产生对双特异性var2csa融合蛋白的抗性。3)由于var2csa序列在疟原虫恶性疟原虫的进化过程中被天然优化，以逃避人类免疫防御机制和血清蛋白酶，因此患者不太可能发展针对双特异性var2csa-融合蛋白的免疫(或其它)抗性。4)表达var2csa的疟原虫只能隔离到胎盘(并且不能在人体/脉管系统中其它地方发现)的事实证明，双特异性var2csa融合蛋白将被预测在治疗环境中具有最小的不利影响。使用var2csa-car相对于基于scfv的car的优点有很多：1)var2csa结合由多种恶性疾病适应症表达的常见癌症相关csa修饰，因此var2-car具有广泛但癌症特异性的靶向范围，并且可用于多种癌症适应症。2)由于在给定的恶性疾病中表达的几种蛋白聚糖中存在恶性相关的csa修饰，所以给定的癌症不可能通过下调特异性的蛋白聚糖来产生对var2csa-car的抗性。3)由于var2csa序列在恶性疟原虫疟原虫的进化过程中被自然优化，以逃避人类免疫防御机制和血清蛋白酶，因此患者不太可能针对基于var2csa的car发展免疫(或其它)抗性。4)表达var2csa的疟原虫只能隔离到胎盘(并且不能在人体/脉管系统中其它地方发现)的事实证明，var2csa-car将被预测在治疗环境中具有最小的不利影响。使用分割蛋白结合系统(spy-car)的car相对于传统的第一代，第二代和第三代car的优点有很多：1)spy-car本身不构成靶向序列，本身不会对人抗原产生反应。2)spy-car可以使用var2csa-spy蛋白“武装”，这将使var2csa-spy-spy-car能够针对所选择的疾病靶标产生反应。3)spy-car可以用任何给定的靶向分子进行“武装”，所述靶向分子与分割蛋白结合系统的相应片段融合或缀合，这将使靶向序列-spy-spy-car能够针对所选择的疾病靶标产生反应。4)spy-car转导的t细胞可以在体外用var2csa-spy蛋白进行“武装”，这将使得var2csa-spy-spy-car能够针对所选择的疾病靶标产生反应。5)spy-car转导的t细胞可以用任何给定的靶向分子进行“武装”，所述靶向分子在体外与融合蛋白结合系统的相应片段融合或缀合，这将使靶向序列-spy-spy-car能够针对所选择的疾病靶标产生反应。6)spy-car转导的t细胞可以用在体外通过k-tag彼此连接的靶向分子的任何给定的聚合物复合物进行“武装”，这将使得靶向序列-spy-spy-car能够针对所选择的疾病靶标产生反应。7)spy-car转导的t细胞可以通过用与分割蛋白结合系统的相应片段融合或缀合的靶向序列追踪spy-car转导的t细胞而在体内用var2csa-spy蛋白进行“武装”，这将使得var2csa-spy-spy-car能够能够针对所选择的疾病靶标产生反应。8)spy-car转导的t细胞可以通过用与分割蛋白结合系统的相应片段融合或缀合的靶向序列追踪spy-car转导的t细胞而在体内用与分割蛋白结合系统的相应片段融合或缀合的任何给定的靶向分子进行“武装”，这将使得靶向序列-spy-spy-car能够能够针对所选择的疾病靶标产生反应。9)spy-car转导的t细胞可以通过用与分割蛋白结合系统的相应片段融合或缀合的靶向序列追踪spy-car转导的t细胞而在体外或体内用通过k-tag彼此连接的靶向分子的任何给定聚合复合物进行“武装”，这将使得靶向序列-spy-spy-car能够能够针对所选择的疾病靶标产生反应。10)由于活化的细胞毒性t细胞的寿命有限，var2csa-spy-spy-car转导的t细胞或用与分割蛋白结合系统的相应片段融合或缀合的任何给定的靶向分子武装的t细胞将随着时间的推移从生物体中清除，同时保持“非武装”的表达spy-car的记忆t细胞。因此，var2csa-spy-spy-car“武装”的t细胞群体将随着时间的推移通过在脾脏中自然清除而消除。在发生疾病复发的情况下，仅表达spy-car的持续记忆性t细胞随后可以通过用与分割蛋白结合系统的相应片段融合的相同或新的疾病靶向序列追踪该细胞进行体内“重新武装”。11)spy-car可以用不能在重组t细胞中作为嵌合蛋白产生任何的癌靶向部分进行武装。12)在car治疗期间，spy-car可以首先用一个spy-标记的蛋白质进行“武装”，并且在发生抗药性时，或者如果癌症改变表型，或者诱导对spy-标记蛋白的免疫应答，则spy-car可以用另一个二线spy-标记的癌症靶向分子武装。定义术语“spytag”是指来自化脓链球菌的fbab蛋白质的cnab2结构域的一部分，其被优化以结合由cnab2结构域的另一部分(seqidno：130和131)组成的spycatcher。当lys31的未质子化的胺亲核攻击asp117的羰基碳时发生相互作用，由相邻的glu77催化。介导该结合的最小肽是ahivmvda，而产生序列ahivmvdaykptk的c末端延伸提供了称为“spytag”的最佳区域(zakeri,b.等人pnas.2012)。术语“spycatcher”是指来自化脓链球菌的fbab蛋白质的cnab2结构域的一部分，其被优化为结合由cnab2结构域的另一部分(seqidno：129)组成的spytag。spycatcher可以是cnab2的残基1-113，并且结合可以通过以下两个突变进行优化：i34e和m69y(zakeri,b.等人pnas,2012)。本文中可互换使用的术语“多核苷酸”和“核酸”是指任何长度的核苷酸(核糖核苷酸或脱氧核糖核苷酸)的聚合形式。因此，该术语包括但不限于单链，双链或多链dna或rna，基因组dna，cdna，dna-rna杂交体，或包含嘌呤和嘧啶碱基或其它天然、化学或生物化学修饰的、非天然的或衍生的核苷酸碱基的聚合物。术语“抗体”和“免疫球蛋白”包括任何同种型的抗体或免疫球蛋白，保留与抗原特异性结合的抗体片段，包括但不限于fab，fv，scfv和fd片段，嵌合抗体，人源化抗体，单链抗体和包含抗体的抗原结合部分和非抗体蛋白质的融合蛋白。“抗体片段”包含完整抗体的一部分，例如完整抗体的抗原结合或可变区。抗体片段的实例包括fab，fab'，f(ab')2和fv片段；双体；线性抗体(zapata等人,proteineng.8(10):1057-1062(1995))；单链抗体分子；和由抗体片段形成的多特异性抗体。抗体的木瓜蛋白酶消化产生两个相同的抗原结合片段，称为“fab”片段，各自具有单个抗原结合位点，以及残留的“fc”片段，此名称反映了容易结晶的能力。本文所用的术语“var2csa多肽”是指由恶性疟原虫表达的特异性红细胞膜蛋白1(pfemp1)蛋白的胞外部分，其与硫酸软骨素蛋白聚糖(cspg)相互作用并且特征在于具有seqidno：55或seqidno：56或其片段或变体的序列，其具有结合可以呈现在蛋白聚糖(cspg)上的硫酸软骨素a(csa)的能力。在一些实施方案中，根据本发明的var2csa多肽至少包含var2csa的蛋白质片段，该片段由a)id1和b)dbl2xb的连续氨基酸序列组成。在一些实施方案中，根据本发明的var2csa多肽至少包含var2csa的蛋白质片段，该片段由a)id1和b)dbl2xb和c)id2a的连续氨基酸序列组成。在var2csa多肽的定义中包括在salantia.等人mol.micro2003jul；49(1):179-91,khunraep.等人,jmolbiol.2010apr2；397(3):826-34,srivastavaa.等人,procnatlacadsciusa.2010mar16；107(11):4884-9,m.等人,jbiolchem.2011may6；286(18):15908-17,或srivastavaa.等人,plosone.2011；6(5):e20270中描述的多肽。本文所用的术语“id1”是指var2csa的结构域，其特征在于具有与seqidno：1的1-152所鉴定的氨基酸序列具有至少70％序列同一性的氨基酸序列。本文所用的术语“dbl2xb”是指var2csa的结构域，其特征在于具有与seqidno：1的153-577所鉴定的氨基酸序列具有至少70％序列同一性的氨基酸序列。本文所用的术语“id2a”是指var2csa的结构域，其特征在于其氨基酸序列包含来自seqidno：1的氨基酸578-640的n-末端的至少20，至少21，至少22，至少23，至少24，至少25，至少26，至少27，至少28，至少29，至少30，至少31，至少32，至少33，至少34，至少35，至少36，至少37，至少38，至少39，至少40，至少41，至少42，至少43，至少44，至少45，至少46，至少47，至少48，至少49，至少50，至少51，至少52，至少53，至少54，至少55，至少56，至少57，至少58，至少59，至少60，至少61，或至少62，例如63个连续氨基酸，并且与这样的连续氨基酸序列具有至少70％的序列同一性。在一些实施方案中，本文所指的由seqidno：1-75或其片段鉴定的任何一个序列的至少70％的氨基酸序列同一性是指与该序列具有至少71,72,73,74,75,76,77,78,79,80,81,8,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98或99％序列同一性的序列。如本文所用的术语“变体”或“多个变体”是指具有seqidno：55或seqidno：56的氨基酸序列的var2csa多肽或包含seqidno：1-54的氨基酸序列的片段var2csa多肽，其片段或变体保留结合蛋白聚糖(cspg)上的硫酸软骨素a(csa)的能力，其中一个或多个氨基酸已经被另一个氨基酸取代和/或其中一个或多个氨基酸已缺失和/或其中一个或多个氨基酸已被插入到多肽中和/或其中一个或多个氨基酸已加入到该多肽中。这种添加可以在n-末端或c-末端或两者上发生。该定义中的“变体”或“多个变体”在能够结合硫酸软骨素a(csa)方面仍具有功能活性。在一些实施方案中，变体与seqidno：1-75和128的序列，例如seqidno：1,3-5,10,11,29,34,36-38,41,43-45,48,53-56,60-70,72-75和128的序列具有至少70％，例如至少71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98或99％的序列同一性。本文所用的术语“功能性变体”，“功能片段”和“功能性衍生物”是指seqidno：55或seqidno：56的变体，片段，截短形式以及衍生物，例如seqidno：1,3-5,10,11,29,34,36-38,41,43-45,48,53-56,60-70,72-75和128的任一个，所述多肽包括seqidno：55或seqidno：56的必需的结合序列部分，并且至少具有结合硫酸软骨素a(csa)的能力。应当理解，var2csa功能变体或功能片段可以具有选自作为变体和/或片段和/或衍生物的两个或三个特征。var2csa多肽的功能性变体或片段包括当在本文所述的测定中测试时显示在相同细胞类型中产生的野生型var2csa多肽的结合亲和力的至少约25％，例如至少约50％，例如至少约75％，例如至少约90％的那些。本文所用的术语“免疫学片段”是指具有基本上相同的功能活性和以相同空间取向被抗体识别的氨基酸序列的片段。因此，特异性抗体将结合多肽和其免疫学片段。本文所用的术语“另一个氨基酸”是指与该位置天然存在的氨基酸不同的一个氨基酸。这包括但不限于可由多核苷酸编码的氨基酸。在一些实施方案中，不同的氨基酸是天然的l-型并且可以由多核苷酸编码。本文所用的术语“衍生物”旨在表示相对于通过seqidno：55或seqidno：56鉴定的野生型var2csa或其片段，显示基本上相同或改善的生物活性的var2csa多肽，其中母体肽的一个或多个氨基酸已被化学修饰，例如通过烷基化，peg化，酰化，酯形成或酰胺形成等。术语“构建体”旨在表示可以基于编码目标多肽的完整或部分天然存在的核苷酸序列的多核苷酸片段。构建体可任选地含有其它多核苷酸片段。以类似的方式，术语“可由多核苷酸构建体编码的氨基酸”涵盖可以由上述定义的多核苷酸构建体编码的氨基酸，即氨基酸如ala，val，leu，ile，met，phe，trp，pro，gly，ser，thr，cys，tyr，asn，glu，lys，arg，his，asp和gln。本文所用的术语“载体”是指能够在宿主细胞中扩增的任何核酸实体。因此，载体可以是自主复制载体，即一种载体，其作为染色体外实体存在，其复制独立于染色体复制，例如质粒。或者，载体可以是当被引入宿主细胞时被整合到宿主细胞基因组中并与其已被整合到其中的染色体一起复制的载体。载体的选择通常取决于其被引入的宿主细胞。载体包括但不限于质粒载体，噬菌体载体，病毒或粘粒载体。载体通常含有复制起点和至少一个可选择的基因，即编码易于检测的产物或其存在对细胞生长至关重要的基因。如本文所用，术语“合适的生长培养基”是指含有培养细胞和编码本发明的var2csa多肽的核酸序列的表达所需的营养物和其它成分的培养基。在本文中，术语“治疗”意在包括预防，治愈和缓解例如癌症中的涉及csa的表达例如不适当表达的疾病、病症或病况的症状。因此，根据本发明的var2csa多肽、缀合物或衍生物的预防和治疗性施用包括在术语“治疗”中。本文所用的术语“受试者”是指任何动物，特别是哺乳动物，例如人，并且可以在适当的情况下与术语“患者”互换使用。本领域已知的术语“序列同一性”是指通过比较序列确定的两个或更多个多肽分子或两个或更多个核酸分子的序列之间的关系。在本领域中，“同一性”还指根据情况如通过两个或更多个核苷酸残基或两个或更多个氨基酸残基的串之间的匹配数确定的核酸分子之间或多肽之间的序列相关性程度。“同一性”测量具有由特定数学模型或计算机程序(即“算法”)寻址的间隙对齐(如果有的话)的两个或更多个序列中的较小者之间的相同匹配的百分比。术语“相似度”是相关概念，但与“同一性”不同，是指包括相同匹配和保守替代匹配的序列关系。如果两个多肽序列具有例如(分数(10/20))相同的氨基酸，并且其余部分都是非保守取代，则同一性和相似度百分比均为50％。如果在同一个例子中还有5个保守取代的位置，那么同一性百分比仍然是50％，但相似度百分比为75％((分数(15/20)))。因此，在存在保守取代的情况下，两个多肽之间的相似度将高于这两个多肽之间的同一性百分比。对seqidno：1-56、60-70和72-75、128的氨基酸序列的保守修饰(以及对编码核苷酸的相应修饰)将产生具有与天然存在的var2csa多肽相似的功能和化学特征的var2csa多肽。相比之下，var2csa多肽的功能和/或化学特征的实质性修饰可以通过选择seqidno：1-56、60-70、72-75和128的氨基酸序列中的取代来完成，这样的取代在其维持(a)取代区域中分子骨架的结构，例如作为片状或螺旋构象，(b)在靶位点处分子的电荷或疏水性，或(c)大部分侧链的作用上显著不同。例如，“保守氨基酸取代”可以包括用非天然残基取代天然氨基酸残基，使得对该位置上的氨基酸残基的极性或电荷几乎没有影响或没有影响。此外，多肽中的任何天然残基也可以被丙氨酸取代，如先前对于“丙氨酸扫描诱变”所描述的(参见例如maclennan等人,1998,actaphysiol.scand.suppl.643:55-67；sasaki等人,1998,adv.biophys.35:1-24，其讨论了丙氨酸扫描诱变)。期望的氨基酸取代(无论是保守的还是非保守的)可以由本领域技术人员在需要这样的取代时确定。例如，氨基酸取代可用于鉴定优选含有var2csa的本发明多肽的重要残基，或增加或降低本文所述的多肽的亲和力。天然存在的残基可以根据共同的侧链性质分为几类：1)疏水性：正亮氨酸，met，ala，val，leu，ile；2)中性亲水性：cys，ser，thr，asn，gln；3)酸性：asp，glu；4)碱性：his，lys，arg；5)影响链取向的残基：gly，pro；和6)芳香族：trp，tyr，phe。例如，非保守替代可能涉及到这些类之一的成员与来自另一类的成员的交换。这种取代的残基可以被引入与非恶性疟原虫var2csa多肽同源的恶性疟原虫var2csa多肽的区域，或者被引入分子的非同源区域。在进行这种改变时，可以考虑氨基酸的亲水指数。基于它们的疏水性和电荷特性，每个氨基酸被指定亲水指数，它们是：异亮氨酸(+4.5)；缬氨酸(+4.2)；亮氨酸(+3.8)；苯丙氨酸(+2.8)；半胱氨酸/胱氨酸(+2.5)；甲硫氨酸(+1.9)；丙氨酸(+1.8)；甘氨酸(-0.4)；苏氨酸(-0.7)；丝氨酸(-0.8)；色氨酸(-0.9)；酪氨酸(-1.3)；脯氨酸(-1.6)；组氨酸(-3.2)；谷氨酸(-3.5)；谷氨酰胺(-3.5)；天冬氨酸(-3.5)；天冬酰胺(-3.5)；赖氨酸(-3.9)；和精氨酸(-4.5)。亲水性氨基酸指数在赋予蛋白质交互式生物学功能中的重要性在本领域中是得到认可的。kyte等人,j.mol.biol.,157:105-131(1982)。已知某些氨基酸可以替代具有相似亲水指数或分数的其它氨基酸，并且仍然保留类似的生物学活性。在根据亲水指数进行变化时，优选亲水指数在±2以内的氨基酸取代，特别优选在±1以内的氨基酸取代，并且更优选在±0.5以内。还应理解在本领域中，可以基于亲水性有效地制备类似氨基酸的取代，特别是当由此产生的生物功能等同的蛋白质或肽旨在用于免疫学实施方案中时，如在本文的实例中。由其相邻氨基酸的亲水性决定的蛋白质的最大局部平均亲水性与其免疫原性和抗原性(即与蛋白质的生物学性质)相关。以下亲水性值被分配给氨基酸残基：精氨酸(+3.0)；赖氨酸('3.0)；天冬氨酸(+3.0±1)；谷氨酸(+3.0±1)；丝氨酸(+0.3)；天冬酰胺(+0.2)；谷氨酰胺(+0.2)；甘氨酸(0)；苏氨酸(-0.4)；脯氨酸(-0.5±1)；丙氨酸(-0.5)；组氨酸(-0.5)；半胱氨酸(-1.0)；甲硫氨酸(-1.3)；缬氨酸(-1.5)；亮氨酸(-1.8)；异亮氨酸(-1.8)；酪氨酸(-2.3)；苯丙氨酸(-2.5)；色氨酸(-3.4)。在基于相似的亲水性值进行改变时，优选亲水性值在±2以内的氨基酸取代，特别优选在±1以内的氨基酸取代，并且更特别优选在±0.5以内。还可以基于亲水性从主要氨基酸序列鉴定表位。这些区域也称为“表位核心区域”。技术人员将能够使用公知的技术来确定如seqidno：1-75和128所示的多肽的合适变体。为了鉴定可以在不破坏活性的情况下改变的分子的合适区域，本领域技术人员可以针对不被认为对活性重要的区域。例如，当来自相同物种或来自其它物种的具有相似活性的相似多肽是已知的时，本领域技术人员可将var2csa多肽的氨基酸序列与此类相似多肽进行比较。通过这样的比较，可以鉴定在相似多肽中保守的分子的残基和部分。应当理解，相对于这种类似多肽不保守的var2csa多肽区域中的变化将不太可能不利地影响var2csa多肽的生物学活性和/或结构。本领域技术人员还将知道，即使在相对保守的区域中，也可以在保留活性的情况下用化学上相似的氨基酸替代天然存在的残基(保守氨基酸残基取代)。因此，即使对生物活性或结构可能重要的区域也可以进行保守的氨基酸取代而不破坏生物活性或不影响多肽结构。此外，本领域技术人员可以审查鉴定相似多肽中对于活性或结构重要的残基的结构功能研究。鉴于这样的比较，可以预测var2csa多肽中对应于对相似多肽的活性或结构重要的氨基酸残基的氨基酸残基的重要性。本领域技术人员可以选择本发明的var2csa多肽和其它多肽的这样预测的重要氨基酸残基的化学上相似的氨基酸取代。本领域技术人员还可以分析与相似多肽中的该结构相关的三维结构和氨基酸序列。鉴于该信息，本领域技术人员可以相对于其三维结构预测多肽的氨基酸残基的比对。本领域技术人员可以选择不对预测在蛋白质表面上的氨基酸残基进行彻底改变，因为这样的残基可能参与与其它分子的重要相互作用。此外，本领域技术人员可以产生在每个所需氨基酸残基处含有单个氨基酸取代的测试变体。然后可以使用如本文所述的活性测定法筛选变体。这样的变体可用于收集关于合适变体的信息。例如，如果发现特定氨基酸残基的改变导致破坏的，不希望地降低的或不合适的活性，则将避免具有这种变化的变体。换句话说，基于从这种常规实验收集的信息，本领域技术人员可以容易地确定氨基酸，其中应该单独地或与其它突变组合避免进一步的取代。一些科学出版物专门用于预测二级结构。参见moultj.,curr.op.inbiotech.,7(4):422-427(1996),chou等人,biochemistry,13(2):222-245(1974)；chou等人,biochemistry,113(2):211-222(1974)；chou等人,adv.enzymol.relat.areasmol.biol,47:45-148(1978)；chou等人,ann.rev.biochem.,47:251-276和chou等人,biophys.j.,26:367-384(1979)。此外，计算机程序目前可用于辅助预测二级结构。预测二级结构的一种方法是基于同源建模。例如，具有大于30％的序列同一性或大于40％的相似性的两个多肽或蛋白质通常具有相似的结构拓扑结构。蛋白质结构数据库(pdb)的最近扩展提供了二级结构的增强的可预测性，包括多肽或蛋白质结构内潜在的折叠数量。参见holm等人,nucl.acid.res.,27(1):244-247(1999)。已经提出(brenner等人,curr.op.struct.biol.,7(3):369-376(1997))，在给定的多肽或蛋白质中存在有限数量的折叠，并且一旦已解析关键的结构数量，结构预测将在准确性上获得巨大的增长。预测二级结构的其它方法包括“线面法”(jones,d.,curr.opin.struct.biol.,7(3):377-87(1997)；sippl等人,structure,4(1):15-9(1996))，“侧貌分析法”(bowie等人,science,253:164-170(1991)；gribskov等人,meth.enzymol.,183:146-159(1990)；gribskov等人,proc.nat.acad.sci.,84(13):4355-4358(1987))和“进化连接法”(参见home，同上，和brenner，同上)。相关多肽的鉴定和相似性可以通过已知方法容易地计算。这些方法包括但不限于computationalmolecularbiology,lesk,a.m.,ed.,oxforduniversitypress,newyork,1988；biocomputing:informaticsandgenomeprojects,smith,d.w.,ed.,academicpress,newyork,1993；computeranalysisofsequencedata,part1,griffin,a.m.,andgriffin,h.g.,eds.,humanapress,newjersey,1994；sequenceanalysisinmolecularbiology,vonheinje,g.,academicpress,1987；sequenceanalysisprimer,gribskov,m.anddevereux,j.,eds.,m.stocktonpress,newyork,1991；和carillo等人,siamj.appliedmath.,48:1073(1988)中描述的那些。确定同一性和/或相似性的优选方法被设计为在测试的序列之间给出最大的匹配。在可公开获得的计算机程序中描述了确定同一性和相似性的方法。用于确定两个序列之间的同一性和相似性的优选计算机程序方法包括但不限于gcg程序包，包括gap(devereux等人,nucl.acid.res.,12:387(1984)；geneticscomputergroup,universityofwisconsin,madison,wis.),blastp,blastn,和fasta(altschul等人,j.mol.biol.,215:403-410(1990))。blastx程序可从国家生物技术信息中心(ncbi)和其它来源(blastmanual，altschul等人ncb/nlm/nihbethesda,md.20894；altschul等人，同上)公开获得。公知的smithwaterman算法也可以用来确定同一性。用于比对两个氨基酸序列的某些比对方案可以导致两个序列的仅短区域的匹配，并且即使两个全长序列之间没有显著关系，该小的比对区域也可能具有非常高的序列同一性。因此，在优选的实施方案中，所选择的比对方法(gap程序)将导致跨越靶多肽的至少50个连续氨基酸的比对。例如，通过使用计算机算法gap(geneticscomputergroup,universityofwisconsin,madison,wis.)，待确定百分比序列同一性的两个多肽被比对以最佳匹配它们各自的氨基酸(“匹配跨度”，由算法确定)。间隙开口罚分(计算为平均对角线的3倍；“平均对角线”是所使用的比较矩阵的对角线的平均值；“对角线”是通过特定比较矩阵分配给每个完美氨基酸匹配的得分或数字)和间隙延伸罚分(通常是间隙开口罚分的{分数(1/10)}倍)以及诸如pam250或blosum62的比较矩阵与算法结合使用。标准比较矩阵(对于pam250比较矩阵参见dayhoff等人,atlasofproteinsequenceandstructure,vol.5,supp.3(1978)；对于blosum62比较矩阵henikoff等人,proc.natl.acad.sciusa,89:10915-10919(1992))也通过算法使用。多肽序列比较的优选参数包括：算法：needleman等人,j.mol.biol,48:443-453(1970)；比较矩阵：来自henikoff等人,proc.natl.acad.sci.usa,89:10915-10919(1992)的blosum62；间隙罚分：12，间隙长度罚分：4，相似度阈值：0。gap程序对上述参数是可用的。上述参数是使用gap算法的多肽比较的默认参数(以及对于末端间隙无罚分)。核酸分子序列比较的优选参数包括：算法：needleman等人,j.molbiol.,48:443-453(1970)；比较矩阵：匹配＝+10，错配＝0，间隙罚分：50，间隙长度罚分：3。gap程序对上述参数也是可用的。上述参数是核酸分子比较的默认参数。可以使用其它示例性算法，间隙开口罚分，间隙延伸罚分，比较矩阵，相似性阈值等，包括在programmanual,wisconsinpackage,version9,september,1997中列出的那些。要做出的具体选择对于本领域技术人员将是显而易见的，并且将取决于进行的具体比较，例如dna与dna，蛋白质与蛋白质，蛋白质与dna的对比；此外，比较是否在给定的序列对之间(在这种情况下通常优选为gap或bestfit)或在序列的一个序列和大型数据库之间(在这种情况下优选为fasta或blasta)。本发明的发明人已经解决并找到了与pm中胎盘粘附的分子机理相关的以下关键问题的答案：1)描述了与var2csa序列相关的差异csa粘附，2)什么是var2csa与csa结合的精确的最小结构要求，3)var2csa与csa之间存在什么类型的化学相互作用，和最后4)该信息是否可用于设计最佳疫苗抗原？通过表达相同的fcr3和3d7var2csa截短提，本发明人显示var2csa以相似的亲和力和特异性结合csa，而不管寄生虫株系来源。这两个序列具有79.6％的序列同一性。本发明人进一步证明，高csa结合亲和力保留在几个较短的片段中，并且包含来自侧翼域间的小区域的dbl2x形成包含高亲和性csa结合位点的紧密核心。本发明人在计算机中定义了var2csa中的推定的gag结合位点，并且通过缺失和取代，本发明人发现这些位点的突变对cspg结合没有影响。通过使用聚电解质-蛋白质相互作用的理论，本发明人已经表明，var2csa-csa相互作用可能不仅仅取决于离子相互作用。最后，本发明人已经显示出几种短var2csa片段能够诱导粘附-阻断抗体的产生，并且抗粘附抗体靶向所提出的csa结合区域。这些数据提供了对pfemp1分子与其配体之间的相互作用的生物化学性质的第一次详细了解。制备本发明的多肽本文描述的本发明的var2csa多肽和其它多肽可以通过重组核酸技术并如wo2013/117705中所述来产生。通常，修饰克隆的野生型var2csa核酸序列以编码所需的蛋白质。然后将该修饰的序列插入到表达载体中，其进而被转化或转染到宿主细胞中。高等真核细胞，特别是培养的哺乳动物细胞可用作宿主细胞。也可以使用原核细胞例如乳酸乳球菌或大肠杆菌来表达多肽，只要这些原核生物能够产生二硫键或蛋白质被正确地重新折叠。此外，酵母菌株也可以用于表达蛋白质，包括酿酒酵母和毕赤酵母。氨基酸序列改变可以通过多种技术来完成。核酸序列的修饰可以是通过位点特异性诱变。用于位点特异性诱变的技术是本领域熟知的，并且描述于例如zollerandsmith(dna3:479-488,1984)或"splicingbyextensionoverlap",horton等人,gene77,1989,pp.61-68中。因此，通过使用var2csa的核苷酸和氨基酸序列，可以引入选择的改变。同样，利用特异性引物使用聚合酶链反应制备dna构建体的方法是本领域技术人员熟知的(参见pcrprotocols,1990,academicpress,sandiego,california,usa。本发明的多肽还可以包含非天然存在的氨基酸残基。非天然存在的氨基酸包括但不限于β-丙氨酸，去氨基组氨酸，反式-3-甲基脯氨酸，2,4-甲脯氨酸，顺式-4-羟脯氨酸，反式-4-羟脯氨酸，n-甲基甘氨酸，别苏氨酸，甲基苏氨酸，羟乙基半胱氨酸，羟乙基高半胱氨酸，硝基谷氨酰胺，高谷氨酰胺，哌啶酸，噻唑烷羧酸，脱氢脯氨酸，3-和4-甲基脯氨酸，3,3-二甲基脯氨酸，叔亮氨酸，正缬氨酸，2-氮杂苯丙氨酸，3-氮杂苯丙氨酸，4-氮杂苯丙氨酸和4-氟苯丙氨酸。本领域已知几种方法将非天然存在的氨基酸残基并入多肽中。例如，可以使用体外系统，其中使用化学氨酰化的抑制性trna抑制无义突变。合成氨基酸和氨基酰化trna的方法是本领域已知的。含有无义突变的质粒的转录和翻译在包含大肠杆菌s30提取物和市售的酶和其它试剂的无细胞系统中进行。多肽通过色谱纯化。参见，例如，robertson等人,j.am.chem.soc.113:2722,1991；ellman等人,methodsenzymol.202:301,1991；chung等人,science259:806-9,1993；chung等人,proc.natl.acad.sci.usa90:10145-9,1993。在第二种方法中，通过显微注射突变的mrna和化学氨基酰化的抑制性trna在非洲爪蟾中进行翻译(turcatti等人,j.biol.chem.271:19991-8,1996)。在第三种方法中，大肠杆菌细胞在不存在需要被置换的天然氨基酸(例如苯丙氨酸)的情况下，并且在存在所需的非天然存在的氨基酸(例如2-氮杂苯丙氨酸，3-氮杂苯丙氨酸，4-氮杂苯丙氨酸或4-氟苯丙氨酸)的情况下培养。将非天然存在的氨基酸并入多肽中代替其天然对应物。参见koide等人,biochem.33:7470-6,1994。天然存在的氨基酸残基可以通过体外化学修饰转化为非天然存在的物质。化学修饰可以与定点诱变组合以进一步扩大取代范围(wynnandrichards,proteinsci.2:395-403,1993)。编码本发明的本发明的var2csa多肽和其它多肽的核酸构建体可以适当地为基因组或cdna来源，例如通过制备基因组或cdna文库并通过使用合成寡核苷酸探针根据标准技术杂交来筛选编码全部或部分多肽的dna序列(参见sambrook等人,molecularcloning:alaboratorymanual,2nd.ed.coldspringharborlabora-tory,coldspringharbor,newyork,1989)。编码var2csa多肽的核酸构建体也可以通过建立的标准方法合成制备，例如由beaucageandcaruthers,tetrahedronletters22(1981),1859-1869描述的亚磷酰胺方法，由matthes等人,embojournal3(1984),801-805描述的方法。根据亚磷酰胺方法，寡核苷酸例如在自动dna合成仪中合成，纯化，退火，连接并克隆在合适的载体中。编码恶性疟原虫var2csa多肽和本发明的其它多肽的dna序列也可以通过使用特异性引物的聚合酶链反应来制备，例如us4,683,202，saiki等人，science239(1988)，487-491，或sambrook等人，同上。此外，核酸构建体可以是混合的合成和基因组、混合的合成和cdna或混合的基因组和cdna来源，其按照标准技术通过连接合成、基因组或cdna来源的片段(视情况而定)、对应于整个核酸构建体各个部分的片段来制备。核酸构建体优选为dna构建体。用于生产根据本发明的var2csa多肽和其它多肽的dna序列通常将在var2csa的氨基末端编码前原多肽，以获得适当的翻译后加工和从宿主细胞分泌。根据本发明的编码恶性疟原虫var2csa多肽和其它多肽的dna序列通常插入可以是任何载体的重组载体，其可以方便地经历重组dna程序，并且载体的选择通常将取决于要引入的宿主细胞。因此，载体可以是自主复制载体，即一种载体，其作为染色体外实体存在，其复制独立于染色体复制，例如质粒。或者，载体可以是当被引入宿主细胞时被整合到宿主细胞基因组中并与其已被整合到其中的染色体一起复制的载体。载体优选是表达载体，其中编码恶性疟原虫var2csa多肽和根据本发明的其它多肽的dna序列可操作地连接到dna转录所需的其它片段。通常，表达载体衍生自质粒或病毒dna，或可以含有这两者的元件。术语“可操作地连接”表示这些片段被布置成使得它们配合作用于其预期目的，例如，转录起始于启动子，并通过编码多肽的dna序列向前进行。用于表达根据本发明的var2csa多肽和其它多肽的表达载体将包含能够引导克隆的基因或cdna的转录的启动子。启动子可以是任何dna序列，其显示在所选宿主细胞中的转录活性，并且可以衍生自编码与宿主细胞同源或异源的蛋白质的基因。在哺乳动物细胞中用于引导编码恶性疟原虫var2csa多肽的dna的转录的合适的启动子的实例是sv40启动子(subramani等人,mol.cellbiol.1(1981),854-864)，mt-1(金属硫蛋白基因)启动子(palmiter等人,science222(1983),809-814)，cmv启动子(boshart等人,cell41:521-530,1985)或腺病毒2主要晚期启动子(kaufmanandsharp,mol.cell.biol,2:1304-1319,1982)。用于昆虫细胞的合适启动子的实例是多角体蛋白启动子(us4,745,051；vasuvedan等人,febslett.311,(1992)7-11)，p10启动子(j.m.vlak等人,j.gen.virology69,1988,pp.765-776)，苜蓿银纹夜蛾核型多角体病毒碱性蛋白启动子(ep397485)，杆状病毒立即早期基因1启动子(us5,155,037；us5,162,222)或杆状病毒39k延迟早期基因启动子(us5,155,037；us5,162,222)。适用于酵母宿主细胞的启动子的实例包括来自酵母糖酵解基因的启动子(hitzeman等人,j.biol.chem.255(1980),12073-12080；alberandkawasaki,j.mol.appl.gen.1(1982),419-434)或醇脱氢酶基因(young等人,ingeneticengineeringofmicroorganismsforchemicals(hollaender等人,eds.),plenumpress,newyork,1982)或tpi1(us4,599,311)或adh2-4c(russell等人,nature304(1983),652-654)启动子。用于丝状真菌宿主细胞的合适的启动子的实例是例如adh3启动子(mcknight等人,theemboj.4(1985),2093-2099)或tpia启动子。其它有用的启动子的实例是衍生自编码米曲霉(a.oryzae)taka淀粉酶，米赫根毛霉(rhizomucormiehei)天冬氨酸蛋白酶，黑曲霉(a.niger)中性α-淀粉酶，黑曲霉酸稳定性α-淀粉酶，黑曲霉或泡盛曲霉(a.awamori)葡糖淀粉酶(glua)，米赫根毛霉脂肪酶，米曲霉碱性蛋白酶，米曲霉丙糖磷酸异构酶或构巢曲霉乙酰胺酶的基因的那些。优选的是taka-淀粉酶和glua启动子。合适的启动子在例如ep238023和ep383779中被提及。根据需要，编码恶性疟原虫var2csa多肽和其它多肽的dna序列也可以可操作地连接到合适的终止子，例如人生长激素终止子(palmiter等人,science222,1983,pp.809-814)或tpi1(alberandkawasaki,j.mol.appl.gen.1,1982,pp.419-434)或adh3(mcknight等人,theemboj.4,1985,pp.2093-2099)终止子。表达载体还可以含有位于启动子下游和var2csa序列本身的插入位点的上游的一组rna剪接位点。可以从腺病毒和/或免疫球蛋白基因获得优选的rna剪接位点。表达载体中还包含位于插入位点下游的聚腺苷酸化信号。特别优选的聚腺苷酸化信号包括来自sv40(kaufman和sharp，同上)的早期或晚期多腺苷酸化信号，来自腺病毒5eb区域的多腺苷酸化信号，人生长激素基因终止子(denoto等人nucl.acidsres.9:3719-3730,1981)或来自恶性疟原虫、人或牛基因的多腺苷酸化信号。表达载体还可以包括位于启动子和rna剪接位点之间的非编码病毒前导序列，例如腺病毒2三联前导序列；和增强子序列，例如sv40增强子。为了将本发明的恶性疟原虫var2csa多肽和其它多肽引导到宿主细胞的分泌途径中，可以在重组载体中提供分泌信号序列(也称为前导序列，前原序列或前序列)。分泌信号序列在正确的阅读框架中连接至编码根据本发明的恶性疟原虫var2csa多肽和其它多肽的dna序列。分泌信号序列通常位于编码肽的dna序列5'。分泌信号序列可以通常与蛋白质相关联或可以来自编码另一种分泌蛋白质的基因。为了从酵母细胞分泌，分泌信号序列可以编码任何信号肽，其确保表达的根据本发明的恶性疟原虫var2csa多肽和其它多肽的有效导向进入细胞的分泌途径。信号肽可以是天然存在的信号肽或其功能部分，或其也可以是合成肽。已经发现合适的信号肽是α因子信号肽(参见us4,870,008)，小鼠唾液淀粉酶的信号肽(参见o.hagenbuchle等人,nature289,1981,pp.643-646)，修饰的羧肽酶信号肽(参见l.a.valls等人,cell48,1987,pp.887-897)，酵母bar1信号肽(参见wo87/02670)或酵母天冬氨酸蛋白酶3(yap3)信号肽(参见m.egel-mitani等人,yeast6,1990,pp.127-137)。为了在酵母中有效分泌，编码前导肽的序列也可以插入信号序列的下游和编码本发明的恶性疟原虫var2csa多肽和其它多肽的dna序列的上游。前导肽的功能是允许表达的肽从内质网引导到高尔基体，并进一步分泌到分泌囊泡中，以分泌到培养基中(即根据本发明的恶性疟原虫var2csa多肽和其它多肽跨细胞壁或至少通过细胞膜进入酵母细胞的周质空间)。前导肽可以是酵母α-因子前导序列(其用途描述于例如us4,546,082，us4,870,008，ep16201，ep123294，ep123544和ep163529中)。或者，前导肽可以是合成的前导肽，其是在自然界中未发现的前导肽。合成前导肽可以例如如wo89/02463或wo92/11378中所述构建。为了在丝状真菌中使用，信号肽可以方便地来自编码曲霉属淀粉酶或葡糖淀粉酶的基因，编码米赫根毛霉脂肪酶或蛋白酶或柔毛腐质霉(humicolalanuginosa)脂肪酶的基因。信号肽优选衍生自编码米曲霉taka淀粉酶、黑曲霉中性α-淀粉酶、黑曲霉酸稳定淀粉酶或黑曲霉葡糖淀粉酶的基因。合适的信号肽公开于，例如，ep238023和ep215594。为了在昆虫细胞中使用，信号肽可以方便地衍生自昆虫基因(参见wo90/05783)，例如鳞翅目烟草天蛾脂肪动力激素前体信号肽(参见us5,023,328)。用于分别连接编码根据本发明的恶性疟原虫var2csa多肽和其它多肽的dna序列、启动子和任选地终止子和/或分泌信号序列并将其插入含有复制所需信息的合适载体中的程序是本领域技术人员公知的(参见例如sambrook等人,molecularcloning:alaboratorymanual,coldspringharbor,newyork,1989)。转染哺乳动物细胞和表达引入细胞的dna序列的方法描述于例如kaufmanandsharp,j.mol.biol.159(1982),601-621；southernandberg,j.mol.appl.genet.1(1982),327-341；loyter等人,proc.natl.acad.sci.usa79(1982),422-426；wigler等人,cell14(1978),725；corsaroandpearson,somaticcellgenetics7(1981),603,grahamandvandereb,virology52(1973),456；和neumann等人,emboj.1(1982),841–845中。将克隆的dna序列通过例如磷酸钙介导的转染(wigler等人,cell14:725-732,1978；corsaroandpearson,somaticcellgenetics7:603-616,1981；grahamandvandereb,virology52d:456-467,1973)或电穿孔(neumann等人,emboj.1:841-845,1982)引入培养的哺乳动物细胞中。为了鉴定和选择表达外源dna的细胞，赋予选择性表型(选择性标记)的基因通常与感兴趣的基因或cdna一起引入细胞。优选的选择性标记包括赋予对药物例如新霉素、潮霉素和甲氨蝶呤的抗性的基因。可选择标记可以是可扩增的选择性标记。优选的可扩增的选择性标记是二氢叶酸还原酶(dhfr)序列。thilly(mammaliancelltechnology,butterworthpublishers,stoneham,ma,incorporatedhereinbyreference，其通过引用并入本文)综述了选择性标记。本领域技术人员将容易地选择合适的选择性标记。选择性标记可以与感兴趣的基因在分开的质粒上同时引入细胞，或者它们可以被引入到相同的质粒上。如果在相同的质粒上，选择性标记和感兴趣的基因可能在不同的启动子或相同的启动子的控制下，后一种布置产生双顺反子信息。这种类型的构建体在本领域中是已知的(例如，levinson和simonsen，u.s.4,713,339)。将额外的dna(称为“载体dna”)添加到引入细胞的混合物中也可能是有利的。细胞吸收dna后，将它们生长在合适的生长培养基中，通常1-2天，以开始表达感兴趣的基因。如本文所用，术语“合适的生长培养基”是指含有细胞生长和感兴趣的恶性疟原虫var2csa多肽的表达所需的营养物质和其它成分的培养基。培养基通常包括碳源，氮源，必需氨基酸，必需的糖，维生素，盐，磷脂，蛋白质和生长因子。然后应用药物选择以针对稳定地表达选择性标记的细胞的生长进行选择。对于已经用可扩增的选择性标记转染的细胞，可以增加药物浓度以针对增加的克隆序列拷贝数进行选择，从而增加表达水平。然后对稳定转染的细胞的克隆针对表达感兴趣的恶性疟原虫var2csa多肽进行筛选。其中引入编码根据本发明的恶性疟原虫var2csa多肽和其它多肽的dna序列的宿主细胞可以是能够产生翻译后修饰的多肽的任何细胞并且包括酵母，真菌和更高等的真核细胞。用于本发明的哺乳动物细胞系的实例是cos-1(atcccrl1650)，幼仓鼠肾(bhk)和293(atcccrl1573；graham等人,j.gen.virol.36:59-72,1977)细胞系。优选的bhk细胞系是tk-ts13bhk细胞系(waechterandbaserga,proc.natl.acad.sci.usa79:1106-1110,1982，通过引用并入本文)，以下称为bhk570细胞。bhk570细胞系已经保藏在美国典型培养物保藏中心，12301parklawndr.,rockville,md.20852，atcc保藏号为crl10314。tk-ts13bhk细胞系也可从atcc以保藏号crl1632获得。此外，本发明中可以使用许多其它细胞系，包括rathepi(大鼠肝癌；atcccrl1600)，大鼠hepii(大鼠肝癌；atcccrl1548)，tcmk(atccccl139)，人肺(atcchb8065)，nctc1469(atccccl9.1)，cho(atccccl61)和dukx细胞(urlaubandchasin,proc.natl.acad.sci.usa77:4216-4220,1980)。合适的酵母细胞的实例包括酵母属(saccharomycesspp.)和裂殖酵母属(schizosac-charomycesspp.)的细胞，特别是酿酒酵母(saccharomycescerevisiae)或克氏酵母(saccharomyceskluyveri)的菌株。用异源dna转化酵母细胞并从中产生异源多肽的方法描述于例如，us4,599,311，us4,931,373，us4,870,008，5,037,743和us4,845,075中，所有这些都通过引用并入本文。通过由选择性标记确定的表型选择转化的细胞，通常是耐药性或在不存在特定营养物例如亮氨酸的情况下生长的能力。用于酵母的优选载体是us4,931,373中公开的pot1载体。根据本发明的编码恶性疟原虫var2csa多肽和其它多肽的dna序列之前可以有信号序列和任选地前导序列，例如如上文所述的。合适的酵母细胞的其它实例是克鲁维酵母属例如乳酸克鲁维酵母(k.lactis)、汉逊酵母属(hansenula)例如多形汉逊酵母(h.polymorpha)或毕赤酵母属例如巴斯德毕赤酵母(p.pastoris)的菌株(参见gleeson等人,j.gen.microbiol.132,1986,pp.3459-3465；us4,882,279)。其它真菌细胞的实例是丝状真菌的细胞，例如。曲霉属(aspergillusspp.)，脉孢菌属(neurosporaspp.)，镰刀菌属(fusariumspp.)或木霉属(trichodermaspp.)，特别是米曲霉、构巢曲霉或黑曲霉的菌株。使用曲霉菌属用于蛋白质的表达描述于例如，ep272277，ep238023，ep184438中。例如，可以如malardier等人,1989,gene78:147-156所述进行尖孢镰孢(f.oxysporum)的转化。木霉属的转化可以例如如ep244234中所述执行。当丝状真菌用作宿主细胞时，可以用本发明的dna构建体进行转化，方便地通过将dna构建体整合到宿主染色体中以获得重组宿主细胞。通常认为这种整合是有利的，因为dna序列更可能在细胞中得到稳定的维持。可以根据常规方法例如，通过同源或异源重组将dna构建体整合到宿主染色体中。昆虫细胞的转化和其中的异源多肽的产生可以如us4,745,051；us4,879,236；us5,155,037；5,162,222；ep397,485中所述，其全部内容通过引用并入本文。用作宿主的昆虫细胞系可以适当地是鳞翅目细胞系，例如草地夜蛾(spodopterafrugiperda)细胞或粉纹夜蛾(trichoplusiani)细胞(参见us5,077,214)。培养条件可以适当地如wo89/01029或wo89/01028或任何上述参考文献所述。然后在允许恶性疟原虫var2csa多肽表达的条件下，在合适的营养培养基中培养上述转化或转染的宿主细胞，之后从培养物中回收所有或部分所得肽。用于培养细胞的培养基可以是适于生长宿主细胞的任何常规培养基，例如含有适当补充物的最小或复杂培养基。合适的培养基可从商业供应商获得，或者可以根据公开的配方制备(例如在美国典型培养物保藏中心的目录中)。然后可以通过常规方法从培养基中回收由细胞产生的恶性疟原虫var2csa多肽，包括通过离心或过滤从培养基中分离宿主细胞，通过盐例如硫酸铵沉淀上清液或滤液的蛋白水性组分，通过各种色谱法纯化，例如离子交换层析，凝胶层析，亲和层析等，这取决于所涉及的多肽的类型。转基因动物技术可用于产生本发明的var2csa多肽和其它多肽。优选在宿主雌性哺乳动物的乳腺内产生蛋白质。乳腺中的表达以及随后将感兴趣的蛋白分泌到乳中克服了从其它来源分离蛋白质所遇到的许多困难。乳容易收集，可获得的量大，并且生物化学表征良好。此外，主要的乳蛋白以高浓度(通常为约1至15g/l)存在于乳中。从商业角度来看，显然优选使用具有大产乳量的物种作为宿主。虽然可以使用较小的动物如小鼠和大鼠(并且在原理证明阶段是优选的)，但是优选使用家畜哺乳动物，包括但不限于猪，山羊，绵羊和牛。绵羊是特别优选的，这是因为以下因素：在这种物种中转基因的先前历史，乳产率，成本和用于收集绵羊乳的设备的可用性(对于影响宿主物种的选择的因素的比较参见例如wo88/00239)。通常期望选择一些已经饲养用于产乳的宿主动物，例如eastfriesland羊，或者在后期通过育种转基因品系来引入奶畜。无论如何，应该使用已知健康状况良好的动物。为了在乳腺中获得表达，使用来自乳蛋白基因的转录启动子。乳蛋白基因包括编码酪蛋白(参见美国专利5,304,489)，β乳球蛋白，乳清蛋白和乳清酸性蛋白的那些基因。β乳球蛋白(blg)启动子是优选的。在羊β乳球蛋白基因的情况下，通常使用基因的5'侧翼序列的至少近端406bp的区域，尽管5'侧翼序列的大部分最高约5kbp是优选的，例如包含5'侧翼启动子和β乳球蛋白基因的非编码部分的dna片段(参见whitelaw等，biochem.j.286：3139(1992))。来自其它物种的启动子dna的类似片段也是合适的。β乳球蛋白基因的其它区域也可以掺入构建体中，如待表达基因的基因组区域。在本领域中普遍接受的是，缺乏内含子的构建体例如与含有这些dna序列的构建体相比表达差(参见brinster等人,proc.natl.acad.sci.usa85:836840(1988)；palmiter等人,proc.natl.acad.sci.usa88:478482(1991)；whitelaw等人,transgenicres.1:313(1991)；wo89/01343；和wo91/02318，各自其通过引用并入本文)。在这方面，在可能的情况下通常优选使用含有编码感兴趣的蛋白质或多肽的基因的全部或部分天然内含子的基因组序列，因此进一步包含来自例如β乳球蛋白基因的至少一些内含子是优选的。一个这样的区域是提供来自羊β乳球蛋白基因的3'非编码区的内含子剪接和rna多腺苷酸化的dna区段。当代替基因的天然3'非编码序列时，该羊β乳球蛋白片段可以增强和稳定感兴趣的蛋白质或多肽的表达水平。在其它实施方案中，围绕var2csa序列的起始atg的区域被来自乳特异性蛋白质基因的相应序列替换。这种替代提供了推定的组织特异性起始环境以增强表达。替代整个var2csa前原和5'非编码序列为例如blg基因的那些序列是方便的，尽管较小的区域可以被替换。为了在转基因动物中表达本发明的var2csa多肽和其它多肽，编码var2csa的dna片段与其表达所需的其它dna区段可操作地连接以产生表达单元。这样的其它区段包括上文所述的启动子，以及提供转录终止和mrna的多聚腺苷酸化的序列。表达单元还将包括与编码修饰的var2csa的区段可操作地连接的编码分泌信号序列的dna区段。分泌信号序列可以是天然分泌信号序列，或者可以是另一种蛋白质，例如乳蛋白质的分泌信号序列(参见例如vonheijne,nucl.acidsres.14:46834690(1986)；和meade等人,u.s.4,873,316，其通过引用并入本文)。用于转基因动物的表达单元的构建通过将var2csa序列插入含有其它dna区段的质粒或噬菌体载体中进行，尽管表达单元可以通过基本上任何连接序列构建。提供含有编码乳蛋白质的dna片段的载体并且替换乳蛋白的编码序列为var2csa变体的编码序列是特别方便的；从而产生包含乳蛋白基因的表达调控序列的基因融合体。无论如何，在质粒或其它载体中克隆表达单元有助于var2csa序列的扩增。扩增方便地在细菌(例如大肠杆菌)宿主细胞中进行，因此载体通常包括复制起点和在细菌宿主细胞中有功能的选择标记。然后将表达单元引入所选宿主物种的受精卵(包括早期胚胎)中。引入异源dna可以通过几种途径之一完成，包括显微注射(例如美国专利号4,873,191)，逆转录病毒感染(jaenisch,science240:14681474(1988))或使用胚胎干(es)细胞的位点定向整合(由bradley等人,bio/technology10:534539(1992)综述)。然后将卵子植入假妊娠雌性的输卵管或子宫，并允许发育成型。在其生殖系中携带引入的dna的后代可以以正常的孟德尔方式将dna转移到其后代，从而允许转基因群的发育。生产转基因动物的一般方法是本领域已知的(参见例如hogan等人,manipulatingthemouseembryo:alaboratorymanual,coldspringharborlaboratory,1986；simons等人,bio/technology6:179183(1988)；wall等人,biol.reprod.32:645651(1985)；buhler等人,bio/technology8:140143(1990)；ebert等人,bio/technology9:835838(1991)；krimpenfort等人,bio/technology9:844847(1991)；wall等人,j.cell.biochem.49:113120(1992)；u.s.4,873,191；u.s.4,873,316；wo88/00239,wo90/05188,wo92/11757；和gb87/00458)。将外源dna序列引入哺乳动物及其生殖细胞的技术最初在小鼠中开发(参见例如，gordon等人,proc.natl.acad.sci.usa77:73807384(1980)；gordonandruddle,science214:12441246(1981)；palmiterandbrinster,cell41:343345(1985)；brinster等人,proc.natl.acad.sci.usa82:44384442(1985)；和hogan等(同上))。这些技术随后适用于大型动物，包括家畜物种(参见例如wo88/00239，wo90/05188和wo92/11757；和simons等人,bio/technology6:179183(1988))。总而言之，在目前用于生产转基因小鼠或家畜的最有效的途径中，根据已建立的技术将感兴趣的dna的数百个线性分子注射入受精卵的原核之一。也可以使用将dna注射到受精卵的细胞质中。也可以使用转基因植物的生产。表达可以被泛化或定向到特定的器官，例如块茎(参见，hiatt,nature344:469479(1990)；edelbaum等人,j.interferonres.12:449453(1992)；sijmons等人,bio/technology8:217221(1990)；和ep0255378)。施用和药物组合物组合治疗本说明书中定义的优选包含var2csa的多肽、衍生物或缀合物可以与一种或多种其它癌症试剂同时或相继施用，和/或与其它已知疗法组合使用。这些因素可以以单剂型提供，其中单剂型包含两种化合物，或以包含var2csa多肽的制剂作为第一单位剂型以及一种或更多其它化合物的制剂作为第二单位剂型的组分试剂盒的形式提供。当在本说明书中提及第一或第二或第三等单位剂型时，这并不表示优选的施用顺序，而是为了方便起见而进行。可以与var2csa多肽组合使用的合适的其它癌症药物或疗法包括已经在市场上或在开发中的抗体，包括维莫拉本(hoffmann-laroche)，针对mcsp的人单克隆抗体，therapeutical(micrometinc)抗mcsp，其使用bite抗体平台技术，以及对mcsp具有特异性的细胞毒性t细胞的继代转移。“同时”给药var2csa多肽的制剂和一种或多种其它化合物的制剂是指以单剂型施用化合物，或施用第一药剂，然后施用第二药剂，其时间间隔不超过15分钟，优选10分钟，更优选5分钟，更优选2分钟。任何一个因素都可以先施用。“相继”给药是指施用第一药剂，然后施用第二药剂，其时间间隔超过15分钟。可以首先施用两个单位剂型中的任一种。优选地，通过相同的静脉内通路注射两种产品。本发明的另一个目的是提供包含根据本发明的多肽的药物制剂，优选含有以0mg/ml至1mg/ml的血清/血浆浓度存在的var2csa，并且其中制剂具有2.0到10.0的ph。制剂还可以包含缓冲体系，防腐剂，张度剂，螯合剂，稳定剂和表面活性剂。在本发明的一些实施方案中，药物制剂是水性制剂，即包含水的制剂。这种制剂通常是溶液或悬浮液。在本发明的另一个实施方案中，药物制剂是水溶液。术语“水性制剂”定义为包含至少50％w/w水的制剂。同样，术语“水溶液”定义为包含至少50％w/w水的溶液，术语“水性悬浮液”定义为包含至少50％w/w水的悬浮液。在其它实施方案中，药物制剂是冷冻干燥的制剂，医师或患者在使用前向其加入溶剂和/或稀释剂。在其它实施方案中，药物制剂是可在没有任何先前溶解的情况下使用的即用干燥制剂(例如冷冻干燥或喷雾干燥的)。在另一方面，本发明涉及包含含有var2csa的多肽的水溶液和缓冲液的药物制剂，其中含有var2csa的多肽以0-1mg/ml或更高的血清/血浆浓度存在，其中制剂具有约2.0至约10.0的ph。在本发明的其它实施方案中，制剂的ph选自2.0,2.1,2.2,2.3,2.4,2.5,2.6,2.7,2.8,2.9,3.0,3.1,3.2,3.3,3.4,3.5,3.6,3.7,3.8,3.9,4.0,4.1,4.2,4.3,4.4,4.5,4.6,4.7,4.8,4.9,5.0,5.1,5.2,5.3,5.4,5.5,5.6,5.7,5.8,5.9,6.0,6.1,6.2,6.3,6.4,6.5,6.6,6.7,6.8,6.9,7.0,7.1,7.2,7.3,7.4,7.5,7.6,7.7,7.8,7.9,8.0,8.1,8.2,8.3,8.4,8.5,8.6,8.7,8.8,8.9,9.0,9.1,9.2,9.3,9.4,9.5,9.6,9.7,9.8,9.9和10.0。在本发明的另一个实施方案中，缓冲液选自乙酸钠，碳酸钠，柠檬酸盐，甘氨酰甘氨酸，组氨酸，甘氨酸，赖氨酸，精氨酸，磷酸二氢钠，磷酸氢二钠，磷酸钠和三(羟甲基)氨基甲烷，二甘氨酸，三甲基甘氨酸，苹果酸，琥珀酸，马来酸，富马酸，酒石酸，天冬氨酸或其混合物。这些特定缓冲液中的每一个构成本发明的替代实施方案。在本发明的另一个实施方案中，制剂还包含药学上可接受的防腐剂。在本发明的另一个实施方案中，防腐剂选自苯酚，邻甲酚，间甲酚，对甲酚，对羟基苯甲酸甲酯，对羟基苯甲酸丙酯，2-苯氧基乙醇，对羟基苯甲酸丁酯，2-苯乙醇，苯甲醇，氯丁醇和硫代吗啉，布洛芬醇，苯甲酸，亚胺脲，氯己定，脱氢乙酸钠，氯甲酚，对羟基苯甲酸乙酯，苄索氯铵，氯苯啶(3p-氯苯氧基丙烷-1,2-二醇)或其混合物。在本发明的另一个实施方案中，防腐剂以0.1mg/ml至20mg/ml的浓度存在。在本发明的另一个实施方案中，防腐剂以0.1mg/ml至5mg/ml的浓度存在。在本发明的另一个实施方案中，防腐剂以5mg/ml至10mg/ml的浓度存在。在本发明的另一个实施方案中，防腐剂以10mg/ml至20mg/ml的浓度存在。这些特定防腐剂中的每一种构成本发明的替代实施方案。在药物组合物中使用防腐剂是本领域技术人员所熟知的。为方便起见，参考remington:thescienceandpracticeofpharmacy,19thedition,1995。在本发明的另一个实施方案中，制剂还包含等渗剂。在本发明的另一个实施方案中，等渗剂选自盐(例如氯化钠)，糖或糖醇，氨基酸(例如l-甘氨酸，l-组氨酸，精氨酸，赖氨酸，异亮氨酸，天冬氨酸，色氨酸，苏氨酸)，糖醇(例如甘油(丙三醇)，1,2-丙二醇(丙二醇)，1,3-丙二醇，1,3-丁二醇)聚乙二醇(例如peg400)或其混合物。可以使用任何糖如单糖，二糖或多糖或水溶性葡聚糖，包括例如果糖，葡萄糖，甘露糖，山梨糖，木糖，麦芽糖，乳糖，蔗糖，海藻糖，葡聚糖，支链淀粉，糊精，环糊精，可溶性淀粉，羟乙基淀粉和羧甲基纤维素钠。在一些实施方案中，糖添加剂是蔗糖。糖醇被定义为具有至少一个-oh基团的c4-c8烃，并且包括例如甘露糖醇，山梨糖醇，肌醇，半乳糖醇，二糖醇，木糖醇和阿拉伯糖醇。在一些实施方案中，糖醇添加剂是甘露糖醇。上述糖或糖醇可以单独使用或组合使用。只要糖或糖醇在液体制剂中溶解，并且不会对使用本发明的方法达到的稳定效果产生不利影响，则所用量没有固定的限制。在一些实施方案中，糖或糖醇浓度为约1mg/ml至约150mg/ml。在本发明的另一个实施方案中，等渗剂以1mg/ml至50mg/ml的浓度存在。在本发明的另一个实施方案中，等渗剂以1mg/ml至7mg/ml的浓度存在。在本发明的另一个实施方案中，等渗剂以8mg/ml至24mg/ml的浓度存在。在本发明的另一个实施方案中，等渗剂以25mg/ml至50mg/ml的浓度存在。这些特定等渗剂中的每一种构成本发明的替代实施方案。在药物组合物中使用等渗剂是本领域技术人员所熟知的。为方便起见，参考remington:thescienceandpracticeofpharmacy,19thedition,1995。在本发明的另一个实施方案中，制剂还包含螯合剂。在本发明的另一个实施方案中，螯合剂选自乙二胺四乙酸(edta)，柠檬酸和天冬氨酸的盐，以及它们的混合物。在本发明的另一个实施方案中，螯合剂以0.1mg/ml至5mg/ml的浓度存在。在本发明的另一个实施方案中，螯合剂的浓度为0.1mg/ml至2mg/ml。在本发明的另一个实施方案中，螯合剂以2mg/ml至5mg/ml的浓度存在。这些特定螯合剂中的每一种构成本发明的替代实施方案。在药物组合物中使用螯合剂是本领域技术人员所熟知的。为方便起见，参考remington:thescienceandpracticeofpharmacy,19thedition,1995。在本发明的另一个实施方案中，制剂还包含稳定剂。在药物组合物中使用稳定剂是本领域技术人员所熟知的。为方便起见，参考remington:thescienceandpracticeofpharmacy,19thedition,1995。更具体地，本发明的组合物是稳定的液体药物组合物，其治疗活性成分包括在液体药物制剂储存期间可能显示聚集体形成的多肽。“聚集体形成”是指多肽分子之间的物理相互作用，其导致形成可能保持可溶性的寡聚体或从溶液沉淀的大的可见聚集体。“储存期间”是指液体药物组合物或制剂制备后，不立即施用于受试者。相反，在制备之后，将其包装用于以液体形式、冷冻状态或干燥形式储存，以便稍后重建成适合施用于受试者的液体形式或其它形式。“干燥形式”是指液体药物组合物或制剂通过冷冻干燥(即，冻干；例如参见williamsandpolli(1984)j.parenteralsci.technol.38:48-59)，喷雾干燥(参见masters(1991)inspray-dryinghandbook(5thed；longmanscientificandtechnical,essez,u.k.),pp.491-676；broadhead等人(1992)drugdevel.ind.pharm.18:1169-1206；和mumenthaler等人(1994)pharm.res.11:12-20)或空气干燥(carpenterandcrowe(1988)cryobiology25:459-470；androser(1991)biopharm.4:47-53)进行干燥。在储存液体药物组合物期间多肽的聚集体形成可能不利地影响该多肽的生物活性，导致药物组合物的治疗功效丧失。此外，当使用输注系统施用含多肽的药物组合物时，聚集体形成可能引起其它问题，例如管道、膜或泵的堵塞。本发明的药物组合物可以进一步包含一定量的氨基酸碱，其足以在储存组合物期间降低多肽的聚集体形成。“氨基酸碱”是指氨基酸或氨基酸的组合，其中任何给定的氨基酸以其游离碱形式或其盐形式存在。当使用氨基酸的组合时，所有氨基酸可以以其游离碱形式存在，所有氨基酸可以以其盐形式存在，或一些氨基酸可以以其游离碱形式存在，而其它氨基酸以其盐形式存在。在一些实施方案中，用于制备本发明组合物的氨基酸是携带带电荷侧链的那些，例如精氨酸，赖氨酸，天冬氨酸和谷氨酸。特定氨基酸(例如甘氨酸，甲硫氨酸，组氨酸，咪唑，精氨酸，赖氨酸，异亮氨酸，天冬氨酸，色氨酸，苏氨酸及其混合物)的任何立体异构体(即l，d或dl异构体)或这些立体异构体的组合可以存在于本发明的药物组合物中，只要特定氨基酸以其游离碱形式或其盐形式存在即可。在一些实施方案中，使用l-立体异构体。本发明的组合物也可以用这些氨基酸的类似物配制。“氨基酸类似物”是指天然存在的氨基酸的衍生物，其在存储本发明的液体药物组合物期间产生减少聚集体形成的期望效果。合适的精氨酸类似物包括例如氨基胍，鸟氨酸和n-单乙基l-精氨酸，合适的甲硫氨酸类似物包括乙硫氨酸和丁硫氨酸，合适的半胱氨酸类似物包括s-甲基-l半胱氨酸。与其它氨基酸一样，氨基酸类似物以其游离碱形式或其盐形式并入组合物中。在本发明的另一个实施方案中，氨基酸或氨基酸类似物以足以防止或延迟蛋白质聚集的浓度使用。在本发明的另一个实施方案中，可以加入甲硫氨酸(或其它含硫氨基酸或氨基酸类似物)以抑制甲硫氨酸残基氧化成甲硫氨酸亚砜，当作为治疗剂的多肽是包含至少一个易受这样的氧化的甲硫氨酸残基的多肽时。“抑制”是指甲硫氨酸氧化物质随时间的最小积累。抑制甲硫氨酸氧化导致多肽保留在其适当的分子形式。可以使用任何甲硫氨酸的立体异构体(l，d或dl异构体)或其组合。添加量应该足以抑制甲硫氨酸残基的氧化，使得甲硫氨酸亚砜的量可以被管理机构接受。通常，这意味着该组合物含有不超过约10％至约30％的甲硫氨酸亚砜。通常，这可以通过加入甲硫氨酸来实现，使得加入的甲硫氨酸与甲硫氨酸残基的比例范围为约1:1至约1000:1，例如10:1至约100:1。在本发明的另一个实施方案中，制剂还包含选自高分子量聚合物或低分子化合物的稳定剂。在本发明的另一个实施方案中，稳定剂选自聚乙二醇(例如peg3350)，聚乙烯醇(pva)，聚乙烯吡咯烷酮，羧基-/羟基纤维素或其衍生物(例如hpc，hpc-sl，hpc-l和hpmc)，环糊精，含硫物质如一硫代甘油，巯基乙酸和2-甲硫基乙醇，以及不同的盐(如氯化钠)。这些特定稳定剂中的每一种构成本发明的替代实施方案。药物组合物还可以包含另外的稳定剂，其进一步增强其中的治疗活性多肽的稳定性。本发明特别感兴趣的稳定剂包括但不限于保护多肽免受甲硫氨酸氧化的甲硫氨酸和edta，以及保护多肽免受与冻融或机械剪切有关的聚集的非离子表面活性剂。在本发明的另一个实施方案中，制剂还包含表面活性剂。在本发明的另一个实施方案中，表面活性剂选自去垢剂，乙氧基化蓖麻油，聚乙二醇化甘油酯，乙酰化单甘油酯，脱水山梨糖醇脂肪酸酯，聚氧丙烯-聚氧乙烯嵌段聚合物(例如泊洛沙姆，如f68，泊洛沙姆188和407，tritonx-100)，聚氧乙烯脱水山梨糖醇脂肪酸酯，聚氧乙烯和聚乙烯衍生物如烷基化和烷氧基化衍生物(twenens，例如tween-20，tween-40，tween-80和brij-35)，单酸甘油酯或其乙氧基化衍生物，甘油二酸酯或其聚氧乙烯衍生物，醇，甘油，凝集素和磷脂(例如磷脂酰丝氨酸，磷脂酰胆碱，磷脂酰乙醇胺，磷脂酰肌醇，二磷脂酰甘油和鞘磷脂)，磷脂衍生物(例如二棕榈酰磷脂酸)和溶血磷脂(例如棕榈酰溶血磷脂酰l-丝氨酸和乙酰胺，胆碱，丝氨酸或苏氨酸的1-酰基-sn-甘油基-3-磷酸酯)和溶血磷脂酰基和磷脂酰胆碱的烷基，烷氧基(烷基酯)，烷氧基(烷基醚)-衍生物，例如溶血磷脂酰胆碱的月桂酰和肉豆蔻酰衍生物，二棕榈酰磷脂酰胆碱和极性头基的修饰，即胆碱，乙醇胺，磷脂酸，丝氨酸，苏氨酸，甘油，肌醇和带正电荷的dodac，dotma，dcp，bishop，溶血磷脂酰丝氨酸和溶血磷脂酰苏氨酸，和甘油磷脂(例如头孢氨酸)，甘油糖脂(例如半乳糖吡喃糖苷)，鞘糖脂(例如神经酰胺，神经节苷脂)，十二烷基磷酸胆碱，鸡蛋溶血卵磷脂，夫西地酸衍生物(例如牛磺-二氢福西丁钠等)，长链脂肪酸和其盐c6-c12(例如油酸和辛酸)，酰基肉碱和衍生物，赖氨酸、精氨酸或组氨酸的nα-酰化衍生物或赖氨酸或精氨酸的侧链酰化衍生物，二肽的nα-酰化衍生物，其包含赖氨酸，精氨酸或组氨酸和中性或酸性氨基酸的任何组合，三肽的nα酰化衍生物，其包含中性氨基酸和两个带电荷的氨基酸的组合，dss(多库酯钠，cas登记号[577-11-7])，多库酯钙，cas登记号[128-49-4])，多库酯钾，cas登记号[7491-09-0])，sds(十二烷基硫酸钠或十二烷基硫酸钠)，辛酸钠，胆酸或其衍生物，胆汁酸及其盐和甘氨酸或牛磺酸缀合物，熊去氧胆酸，胆酸钠，脱氧胆酸钠，牛磺胆酸钠，甘胆酸钠，n-十六烷基-n,n-二甲基-3-氨基-1-丙磺酸盐，阴离子(烷基-芳基磺酸盐)单价表面活性剂，两性离子表面活性剂(例如n-烷基-n,n-二甲基氨基-1-丙磺酸盐，3-胆酰胺-1-丙基二甲基铵-1-丙磺酸盐，阳离子表面活性剂(季铵碱)(例如十六烷基三甲基溴化铵，氯化十六烷基吡啶)，非离子表面活性剂(例如十二烷基β-d-吡喃葡萄糖苷)，泊洛沙胺(例如tetronic's)，它们是依次添加环氧丙烷和环氧乙烷至乙二胺衍生的四官能嵌段共聚物，或表面活性剂可以选自咪唑啉衍生物或其混合物。这些特定表面活性剂中的每一种都构成本发明的替代实施方案。在药物组合物中使用表面活性剂是本领域技术人员所熟知的。为方便起见，参考remington:thescienceandpracticeofpharmacy,19thedition,1995。其它成分可能存在于本发明的肽药物制剂中。这些其它成分可以包括润湿剂，乳化剂，抗氧化剂，填充剂，张力调节剂，螯合剂，金属离子，油性载体，蛋白质(例如，人血清白蛋白，明胶或蛋白质)和两性离子(例如氨基酸如甜菜碱，牛磺酸，精氨酸，甘氨酸，赖氨酸和组氨酸)。这些其它成分当然不应该不利地影响本发明的药物制剂的整体稳定性。含有根据本发明的多肽的药物组合物可以在需要这样治疗的患者的几个部位施用，例如在局部部位，例如皮肤和粘膜部位，旁路吸收部位，例如在动脉、静脉、心脏中的施用，以及涉及吸收的部位，例如在皮肤、皮肤下、肌肉或腹部中的施用。局部施用可能在治疗与局部炎症有关的病况上具有特别的优点，例如治疗与烧伤有关的炎症或与皮肤相关的其它病况。因此，在一些实施方案中，通过局部给药施用。在一些具体实施方案中，眼滴剂可用于与眼睛相关的病症，例如角膜炎，例如弥漫性层状角膜炎(dlk)。根据本发明的药物组合物的施用可以通过几种施用途径，例如舌，舌下，颊，口腔，口服，胃和肠中，鼻，肺，例如通过细支气管和肺泡或其组合，表皮，皮肤，透皮，阴道，直肠，眼睛，例如通过结膜，尿道和肠胃外施用给需要这种治疗的患者。本发明的组合物可以以几种剂型施用，例如作为溶液，悬浮液，乳剂，微乳液，多重乳液，泡沫，药膏，糊剂，膏药，软膏剂，片剂，包衣片剂，漂洗剂，胶囊剂，例如硬明胶胶囊和软明胶胶囊，栓剂，直肠胶囊，滴剂，凝胶，喷雾剂，粉剂，气溶胶，吸入剂，滴眼剂，眼用软膏，眼用漂洗剂，阴道栓，阴道环，阴道软膏，注射溶液，原位转化溶液，例如原位胶凝，原位固化，原位沉淀，原位结晶，输液和植入物。本发明的组合物可以例如通过共价、疏水和静电相互作用进一步配合或附接至药物载体、药物递送系统和先进药物递送系统，以进一步增强多肽的稳定性，增加生物利用度，增加溶解度，减少不良反应，实现本领域技术人员熟知的慢性治疗，并增加患者依从性或其任何组合。载体、药物递送系统和先进药物递送系统的实例包括但不限于聚合物，例如纤维素和衍生物，多糖，例如葡聚糖和衍生物，淀粉和衍生物，聚(乙烯醇)，丙烯酸酯和甲基丙烯酸酯聚合物，聚乳酸和聚乙醇酸及其嵌段共聚物，聚乙二醇，载体蛋白，例如白蛋白，凝胶，例如热凝胶体系，例如本领域技术人员熟知的嵌段共聚体系，胶束，脂质体，微球，纳米颗粒，病毒样颗粒，细菌样颗粒，液晶及其分散体，l2相及其分散体，它们是本领域技术人员所熟知的脂质-水体系中的相行为，聚合胶束，多重乳液，自乳化，自微乳化，环糊精及其衍生物，以及树枝状大分子。本发明的组合物可用于使用例如计量吸入器，干粉吸入器和雾化器来制备含有var2csa的多肽的固体，半固体，粉末和溶液用于肺部施用，所有这些都是本领域技术人员所熟知的装置。本发明的组合物特别可用于配制受控的，持续的，延长的，迟缓的和缓释的药物递送系统。更具体地，但不限于，组合物可用于制备肠胃外受控释放和持续释放系统(两种系统导致施用次数减少多次)，其是本领域技术人员众所周知的。甚至更优选的是皮下施用的受控释放和持续释放系统。不限制本发明的范围，有用的受控释放系统和组合物的实例是水凝胶，油性凝胶，液晶，聚合胶束，微球，纳米颗粒。用于制备可用于本发明组合物的受控释放系统的方法包括但不限于结晶，缩合，共结晶，沉淀，共沉淀，乳化，分散，高压均化，包封，喷雾干燥，微囊化，凝聚，相分离，溶剂蒸发以产生微球，挤出和超临界流体过程。一般参考handbookofpharmaceuticalcontrolledrelease(wise,d.l.,ed.marceldekker,newyork,2000)anddrugandthepharmaceuticalsciencesvol.99:proteinformulationanddelivery(macnally,e.j.,ed.marceldekker,newyork,2000)。肠胃外施用可以通过注射器，任选的笔状注射器通过皮下，肌内，腹膜内或静脉内注射进行。或者，肠胃外施用可以通过输液泵进行。另外的选择是组合物，其可以是用于以鼻或肺部喷雾形式施用根据本发明的优选含有var2csa的多肽的溶液或悬浮液。作为另外的选择，含有本发明多肽的药物组合物也可适用于透皮给药，例如，通过无针注射或来自贴剂，任选地离子电渗贴剂或经粘膜(例如，颊)施用。术语“稳定的制剂”是指具有增加的物理稳定性，增加的化学稳定性或增加的物理和化学稳定性的制剂。本文使用的蛋白质制剂的术语“物理稳定性”是指蛋白质形成蛋白质的生物学无活性和/或不溶性聚集体的倾向，这是由于将蛋白质暴露于热机械应力和/或与不稳定的界面和表面例如疏水性表面和界面的相互作用导致的。通过目视检查和/或浊度测量，将填充在合适的容器(例如药筒或小瓶)中的制剂在不同温度下暴露于机械/物理应力(例如搅拌)持续不同时间段来评价含水蛋白质制剂的物理稳定性。制剂的目视检查在具有深色背景的尖锐聚焦光下进行。制剂的浊度的特征在于将浊度的程度排列在例如0至3的刻度上的视觉评分(没有浊度的制剂对应于视觉评分0，并且在日光下显示视觉浊度的制剂对应于视觉评分3)。当在日光下显示视觉浊度时，制剂被分类为关于蛋白质聚集的物理不稳定性。或者，可以通过本领域技术人员熟知的简单浊度测量来评估制剂的浊度。水性蛋白质制剂的物理稳定性也可以通过使用蛋白质的构象状态的光谱试剂或探针来评价。探针优选是优先结合蛋白质的非天然构象异构体的小分子。蛋白质结构的小分子光谱探针的一个实例是硫磺素t。硫磺素t是荧光染料，已广泛用于检测淀粉样蛋白原纤维。在原纤维的存在下，也许还存在其它蛋白质构型，当与原纤维蛋白形式结合时，硫磺素t在约450nm下产生新的激发最大值，并且在约482nm处产生增强的发射。未结合的硫磺素t在这些波长上基本上是非荧光的。其它小分子可用作蛋白质结构从天然状态到非天然状态的变化的探针。例如优先结合蛋白质的暴露的疏水斑块的“疏水patch”探针。疏水斑块在天然状态下通常被埋蛋白质的三级结构内，但随着蛋白质开始展开或变性而被暴露出来。这些小分子光谱探针的实例是芳香族，疏水性染料，如安瑟沙，吖啶，菲咯啉等。其它光谱探针是金属-氨基酸络合物，例如疏水氨基酸例如苯丙氨酸，亮氨酸，异亮氨酸，甲硫氨酸和缬氨酸等的钴金属络合物。本文所用的蛋白质制剂的术语“化学稳定性”是指蛋白质结构中的化学共价变化，导致与天然蛋白质结构相比具有潜在的较低生物效力和/或潜在增加的免疫原性的化学降解产物的形成。根据天然蛋白质的类型和性质以及蛋白质暴露的环境可以形成各种化学降解产物。如本领域技术人员所熟知的，在蛋白质制剂的储存和使用过程中，通常可能不能完全避免消除化学降解，并且常常会观察到越来越多的化学降解产物。大多数蛋白质易于脱酰胺，这是其中谷氨酰胺酰基或天冬酰胺酰基残基中的侧链酰胺基团被水解形成游离羧酸的过程。其它降解途径涉及形成高分子量转化产物，其中两个或更多个蛋白质分子通过酰胺化和/或二硫相互作用共价结合，导致形成共价结合的二聚体，低聚物和聚合物降解产物(stabilityofproteinpharmaceuticals,ahern.t.j.&manningm.c.,plenumpress,newyork1992)。可以提及氧化(例如甲硫氨酸残基)作为化学降解的另一个变型。蛋白质制剂的化学稳定性可以通过在暴露于不同环境条件之后的各个时间点测量化学降解产物的量来评估(降解产物的形成通常可以通过例如升高的温度来加速)。每个单独降解产物的量通常通过使用各种色谱技术(例如sec-hplc和/或rp-hplc)根据分子大小和/或电荷分离降解产物来确定。因此，如上所述，“稳定的制剂”是指具有增加的物理稳定性，增加的化学稳定性或增加的物理和化学稳定性的制剂。一般来说，制剂在使用和储存期间必须是稳定的(符合推荐的使用和储存条件)，直到失效期为止。在本发明的一些实施方案中，包含var2csa多肽的药物制剂在使用超过6周以及储存超过3年时是稳定的。在本发明的其它实施方案中，包含var2csa多肽的药物制剂在使用超过4周以及储存超过3年时是稳定的。在本发明的另一个实施方案中，包含var2csa多肽的药物制剂在使用超过4周和储存超过两年时是稳定的。在本发明的另一个实施方案中，包含var2csa多肽的药物制剂在使用超过2周和超过两年时是稳定的。使用根据本发明的多肽的适应症根据本发明的优选含有var2csa的多肽可以用于与csa的表达例如不适当表达相关的广泛适应症，例如在各种癌症中，例如转移性癌症包括黑素瘤，如c32黑素瘤，肉瘤，肺癌，少突胶质细胞瘤，人脑肿瘤，包括神经胶质瘤，白血病，例如淋巴细胞白血病和急性骨髓性白血病，和癌，例如鳞状细胞癌和乳腺癌，肾细胞癌，软骨肉瘤和胰腺细胞癌。多肽也可以用于癌症干细胞，因此在发展成癌症前靶向细胞。与csa的表达例如不适当表达相关的其它病况是软骨的病况和/或瘢痕组织的发展。本发明的具体实施方案如本文所述，本发明涉及多肽，其包含i)第一多肽结构域，其是嵌合抗原受体(car)的跨膜结构域和胞内结构域，以及ii)选自var2csa多肽或分割蛋白结合系统的肽部分的第二胞外多肽结构域，以及多肽其包含i)第一多肽结构域，其是var2csa多肽或其它肿瘤靶向剂，例如单链scfv，和ii)选自分割蛋白结合系统的肽部分、单结构域抗体例如scfv或纳米抗体中的一个或多个的第二多肽结构域。在一些实施方案中，包含所述car和分割蛋白结合系统的肽部分的多肽可以在体外或体内与分割蛋白标记的肿瘤靶向剂例如抗体组合。在一些实施方案中，分割蛋白结合系统的一个肽部分选自k-tag(seqidno：132)，spycatcher(seqidno：129)，spycatcher-δn(seqidno：136)，spytag(seqidno：130)，最小spytag序列(seqidno：131)，split-spy0128(seqidno：135)，异肽spy0128(seqidno：134)或其任何反向序列或其具有至少约80％，例如至少约82,84,86,88,90,92,94,96,98或99％的序列同一性的变体。在一些实施方案中，多肽还包含一个或多个接头或铰链序列，例如gc接头。在一些实施方案中，var2csa多肽由seqidno：55或seqidno：56或其具有结合硫酸软骨素a(csa)的能力的片段或变体组成，所述硫酸软骨素a(csa)可以是被呈现在蛋白聚糖(cspg)上的。在一些实施方案中，var2csa多肽是var2csa的片段，其由以下的连续氨基酸序列组成：a)id1，和b)dbl2xb，以及任选地c)id2a。在一些实施方案中，var2csa多肽以通过小于100nm，例如小于80nm，例如小于70nm，例如小于60nm，例如小于50nm，例如小于40nm，例如小于30nm，例如小于26nm，例如小于24nm，小于22nm，例如小于20nm，例如小于18nm，例如小于16nm，例如小于14nm，例如小于12nm，例如小于10nm，例如小于9nm，例如小于8nm，例如小于7nm，例如小于6nm，或小于4nm的kd测量的亲和力结合蛋白聚糖(cspg)上的硫酸软骨素a(csa)。在一些实施方案中，var2csa多肽包含与seqidno：1的1-577，seqidno：3的1-592，seqidno：4的1-579，seqidno：5的1-576，seqidno：10的1-586，seqidno：11的1-579，seqidno：29的1-565，seqidno：34的1-584，seqidno：36的1-569，seqidno：37的1-575，seqidno：38的1-592，seqidno：41的1-603，seqidno：43的1-588，seqidno：44的1-565，seqidno：45的1-589，seqidno：48的1-573，seqidno：53的1-583，seqidno：54的1-569或seqidno：128的1-640的任何一个氨基酸序列具有至少70％序列同一性的氨基酸序列。在一些实施方案中，var2csa多肽包含与seqidno：1的578-640，seqidno：3的593-656，seqidno：4的580-643，seqidno：5的577-640，seqidno：10的587-650，seqidno：11的580-643，seqidno：29的566-628，seqidno：34的585-647，seqidno：36的570-632，seqidno：37的576-639，seqidno：38的593-655，seqidno：41的604-667，seqidno：43的589-652，seqidno：44的566-628，seqidno：45的590-653，seqidno：48的574-637，seqidno：53的584-646或seqidno：54的570-632的氨基酸序列具有至少70％序列同一性的氨基酸序列。在一些实施方案中，var2csa多肽包含与seqidno：2,6,8,9,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,30,31,32,33,35,39,40,42,46,47,49,50,51,52,或128的氨基酸序列具有至少70％序列同一性的氨基酸序列。在一些实施方案中，var2csa多肽由与seqidno：1的1-577，seqidno：3的1-592，seqidno：4的1-579，seqidno：5的1-576，seqidno：10的1-586，seqidno：11的1-579，seqidno：29的1-565，seqidno：34的1-584，seqidno：36的1-569，seqidno：37的1-575，seqidno：38的1-592，seqidno：41的1-603，seqidno：43的1-588，seqidno：44的1-565，seqidno：45的1-589，seqidno：48的1-573，seqidno：53的1-583，seqidno：54的1-569或seqidno：128的1-640的任何一个氨基酸序列具有至少70％序列同一性的氨基酸序列组成。在一些实施方案中，var2csa多肽由选自seqidno：1,3-5,10,11,29,34,36-38,41,43-45,48,53,54和128的氨基酸序列组成。在一些实施方案中，var2csa多肽由长度小于700个氨基酸，例如小于690个氨基酸，例如小于680个氨基酸，例如小于670个氨基酸，例如小于660个氨基酸，例如小于650个氨基酸，例如小于640个氨基酸，例如小于630个氨基酸，例如小于620个氨基酸，例如小于610个氨基酸，例如小于600个氨基酸，例如小于590个氨基酸，例如小于580个氨基酸，例如小于570个氨基酸的氨基酸序列组成。在一些实施方案中，var2csa多肽具有在非还原条件下在sds-page上的小于约100kda的分子量。在一些实施方案中，var2csa多肽是非糖基化的。在一些实施方案中，嵌合抗原受体(car)的所述跨膜结构域和/或胞内结构域来源于第1代、第2代或第3代car。在一些实施方案中，包含嵌合抗原受体(car)的跨膜结构域和胞内结构域作为第一多肽结构域的所述多肽还包含其它调节元件或自杀基因系统，例如诱导型半胱天冬酶-9(icasp9)或睡美人(sb)转座子系统。在一些实施方案中，嵌合抗原受体(car)的所述跨膜结构域和/或胞内结构域包含cd28和/或cd3ζ信号转导结构域。在一些实施方案中，嵌合抗原受体(car)的所述跨膜结构域和/或胞内结构域是如wo2014127261，wo13126729，wo13126733，wo14055442，wo14055771，wo2014039523，wo14179759和wo14138704中任一个所描述的。序列，包括var2csa多肽的序列：>fcr3745个氨基酸|640aa；下划线序列对应于fcr3的id1结构域，粗体字序列对应于fcr3的dbl2xb结构域。剩余序列是id2a(seqidno：1)nyikgdpyfaeyatklsfilnpsdannpsgetanhndeacncnesgissvgqaqtsgpssnktcithssiktnkkkeckdvklgvrendkdlkicviedtslsgvdncccqdllgilqencsdnkrgsssndscdnknqdecqkklekvfasltngykcdkcksgtsrskkkwiwkkssgneeglqeeyantiglpprtqslylgnlpklenvcedvkdinfdtkekflagclivsfhegknlkkrypqnknsgnkenlckaleysfadygdlikgtsiwdneytkdlelnlqnnfgklfgkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgaemnittcnadgsvtgsgsscddiptidlipqylrflqewvenfceqrqakvkdvitncksckesgnkcktecktkckdecekykkfieacgtagggigtagspwskrwdqiykryskhiedakrnrkagtkncgtssttnaaastdenkcvqsdidsffkhlidiglttpssylsnvlddnicgadkapwttyttytttekcnkerdksksqssdtlvvvnvpsplgntpyrykyacqckiptneetcddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrsnsskld>gi|254952610|gb|act97135.1|var2csa[恶性疟原虫]|341aa(seqidno:2)kcdkcksgtsrsrkiwtwrkssgnkeglqeeyantiglsprtqllylgnlrklenvcedvtdinfdtkekflagcliaafhegknlkkrylekkkgdnnsklckdlkysfadygdlikgtsiwdndftkdlelnlqqifgklfrkyikkknisteqdtsyssldelreswwntnkkyiwlamkhgagmnsttcscsgdsssgenqtnscddiptidlipqylrflqewvehfceqrqakvkdvitncnsckesggtcnsdcekkcknkcdayktfiedckgvggtgtagsswvkrwyqiymryskyiedakrnrkagtkscgtssttnvsvstdenkcvqs->m24745个氨基酸|656aa(seqidno:3)dyikgdpyfaeyatklsfilnssdannpsgetanhndevcnpneseissvgqaqtsdpssnktcnthssikankkkvckhvklginnndkvlrvcviedtslsgvenccfkdllgilqencsdnksgsssngscnnknqeaceknlekvlasltncykcdkcksgtstvnknwiwkkssgnkeglqkeyantiglpprthslylgnlpklenvcedvkdinfdtkekflagcliaafhegknlkkrypqnknddnnsklckaleysfadygdlikgtsiwdneytkdlelnlqqifgklfrkyikknisteqdtlyssldelreswwntnkkyiwlamkhgagmnittccgdgsvtgsgsscddiptidlipqylrflqewvehfckqrqekvkdvinscnsckntssktklgdtcnsdcekkckiecekykkfieecrtavggtagsswskrwdqiykmyskhiedakrnrkagtkncgittgtisgessgansgvtttenkcvqsdidsffkhlidiglttpssylsivlddnicgddkapwttyttyttytttekcnkerdksksqqsntsvvvnvpsplgntphgykyacqckiptneetcddrkeymnqwisdtsknpkgsgstnndyelytyngvketklpkklnspkld>kmwii745个氨基酸|643aa(seqidno:4)dyikddpyskeyttklsfilnssdantssgetanhndeacncneseissvgqaqtsgpssnktcithsfikankkkvckdvklgvrendkvlrvcviedtslsgvdncccqdllgilqencsdnkrgsssngscnnknqdecqkklekvfvsltngykcdkcksgtstvnkkwiwkkssgnekglqkeyantiglpprtqslylgnlpklgnvcedvtdinfdtkekflagcliaafhegknlkishekkkgdngkklckaleysfadygdlikgtsiwdneytkdlelnlqkafgklfgkyikkniasdentsyssldelreswwntnkkyiwtamkhgaemnstmcnadgsvtgsgsscddipttdfipqylrflqewvehfckqrqekvnaviencnsckntsgerkiggtcngdcktecknkceayknfiedckggdgtagsswvkrwdqiykryskhiedakrnrkagtkscgpssitnasvstdenkcvqsdidsffkhlidiglttpssylsivldenncgednapwttyttytttekcnkdkkksksqscntavvvnvpsplgntpheykyacqckiptteetcddrkeymnqwisdtskkqkgsgstnndyelytytgvketklpkklnspkld>1248745个氨基酸|640aa(seqidno:5)syvkndpyskeyvtklsfilnpsdannpsgetanhndeacnpneseiasvgqaqtsdrlsqkacithsfigankkivckdvklgvrekdkdlkicvieddslrgvenccfkdllgilqencsdnksgsssngscnnknqdecqkkldealaslhngykcdkcksgtsrskkiwtwrkfpgngeglqkeyantiglpprtqslylgnlrklenvckgvtdinfdtkekflagcliaafhegknlkisnkkknddngkklckdlkysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikkniasdentlyssldelreswwntnkkyiwlamkhgttcssgsgdngdgsvtgsgsscddmstidlipqylrflqewvehfckqrqekvkdviencksckntsgeriiggtcgsdcktkckgecdayknfieeckrgdgtagspwskrwdqiymryskyiedakrnrkagtkncgtssttnaaenkcvqsdidsffkhlidiglttpssylsivldenicgddkapwttyttytttekcnketdksksqscntavvvnvpsplgntphgykyaceckiptteetcddrkeymnqwisdtskkpkggrstnndyelytyngvketklpkksssskld>gi|254952618|gb|act97139.1|var2csa[恶性疟原虫]|358aa(seqidno:6)kcekckseqskknnniwiwrkfpgngeglqkeyantiglpprthslylgnlpklenvckdvkdinfdtkekflagcliaafhegknlkttypqnknadnnsklckdlkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikkniasdentlyssldelreswwntnkkyiwlamkhgaemnstmcngdgsvtgssdsgsttcsgdngsiscddiptidlipqylrflqewvehfckqrqekvkpviencksckntsgeriiggtcgsdcekkckgecdaykkfieeckgggggtgtagspwskrwdqiykryskyiedakrnrkagtkscgpssttnaaastteskcvqs>gi|254952592|gb|act97126.1|var2csa[恶性疟原虫]|333aa(seqidno:7)kcdkckseqskknnknwiwkqfpgngeglqkeyantiglpprthslylgnlpklenvckgvtdinfdtkekflagcliaafhegknlktshekkkgdngkklckdlkysfadygdlikgtsiwdndftkdlelnlqqifgklfrkyikknisaeqdtsyssldelreswwntnkkyiwlamkhgttcssgsgdngdgsvtgsgsscddmpttdfipqylrflqewvehfckqrqekvnavitncksckesggtcnsdcekkckdecekykkfieecrtaadgtagsswskrwdqiykmyskhiedakrnrkagtkncgtssttnaaenkcvqs>gi|90193467|gb|abd92329.1|红细胞膜蛋白1[恶性疟原虫]|269aa(seqidno:8)dyikddpyskeyttklsfilnssdantssgetanhndeacncneseiasveqasisdrssqkayithssiktnkkkvckyvklginnndkvlrvcviedtslsgvenccfkdllgilqencsdnkrgssfndscnnnneeacqkklekvlasltngykcekcksgtsrskkkwiwkkssgkegglqkeyantiglpprtqslylgnlpklenvckgvtdinfdtkekflagcliaafhegknlkpshqnknddnnsklckdlkysfady>gi|254952616|gb|act97138.1|var2csa[恶性疟原虫]|333aa(seqidno:9)kcdkcksgtsrskkkwtwrkssgnkeglqkeyantiglpprthslylgnlrklenvcedvtdinfdtkekflagcliaafhegknlkttypqnknddnnsklckalkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikknisteqhtsyssldelreswwntnkkyiwlamkhgaemngttcscsgdssddiptidlipqylrflqewvehfckqrqakvnavinscnsckntsgerklggtcgsecktecknkcdaykefidgtgsgggtgtagsswvkrwdqiykryskyiedakrnrkagskncgtssttnaaeskcvqs>hb31745个氨基酸|650aa(seqidno:10)syvknnpysaeyvtklsfilnssdantssetpskyydevcncneseissvgqaqtsgpssnktcithssiktnkkkvckdvklginnndkvlrvcviedtslsgvdncccqdllgilqencsdknqsgsssngscnnknqdecqkklekvfasltngykcdkcksgtsrskkkwiwrkssgneeglqkeyantiglpprtqslylgnlrklenvckgvtdinfdtkekflagcliaafhegknlkttypqnkkklckdlkysfadygdlikgtsiwdneytkdlelnlqkafgklfrkyikknisteqhtlyssldelreswwntnkkyiwlamkhgagmnsttccgdgsvtgsgsscddiptidlipqylrflqewvehfckqrqekvnaviencnsckecgdtcngecktecekkckiecekyktfieecvtavggtsgspwskrwdqiykryskyiedakrnrkagtkncgittgtisgessgansgvtttenkcvqsdidsffkhlidiglttpssylsivlddnicgadnapwttyttyttytttkncdikkktpksqpintsvvvnvpsplgntphgykyacqckiptteescddrkeymnqwiidtskkqkgsgstnndyelytyngvketklpkksssskld>hb32745个氨基酸|643aa(seqidno:11)syvkddpysaeyvtklsfilnssdantssetpskyydevcncneseissvgqaqtsgpssnktcithssiktnkkkvckdvklginnndkvlrvcviedtslsgvdncccqdllgilqencsdknqsgsssngscnnknqdecqkklekvfasltngykcdkcksgtsrskkkwiwrkssgneeglqkeyantiglpprtqslylgnlpklenvckgvtdiiydtkekflsgcliaafhegknlktshekknddngkklckaleysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgagmnsttcsgdgsvtgsgsscddmptidlipqylrflqewvehfckqrqekvkdvitncnsckecgdtcngecktecktkckgecekyknfieecngtadggtsgsswskrwdqiykryskyiedakrnrkagtkncgtssttnaaasttenkcvqsdidsffkhlidiglttpssylsnvlddnicgedkapwttyttyttkncdiqkktpkpqscdtlvvvnvpsplgntphgykyvceckiptteetcddrkeymnqwiidtskkqkgsgstnndyelytyngvqikqaagtlknskld>gi|90193475|gb|abd92333.1|红细胞膜蛋白1[恶性疟原虫]|269aa(seqidno:12)nyikgdpysaeyatklsfilnssdtenasekiqknndevcncneseiasveqapisdrssqkacithssikankkkvckhvklgvrendkdlkicviedtslsgvdncccqdllgilqencsdnksgsssngscnnnneeicqkklekvlasltngykcdkcksgtstvnknwiwkkysgkegglqeeyantiglpprtqslylgnlpklenvcedvkdinfdtkekflagcliaafhegknlktsnkkknddnnsklckalkysfady>gi|254952600|gb|act97130.1|var2csa[恶性疟原虫]|344aa(seqidno:13)kcdkcksgtstvnkkwiwkkysgtegglqeeyantialpprtqslylgnlpklenvckdvtdinfdtkekflagcliaafhegknlkttylekkkgdngkknddnnsklckalkysfadygdlikgtsiwdndftkdlelnlqqifgklfrkyikkniasdentlyssldelreswwntnkkyiwlamkhgagmnstmcnadgsvtgsgsscddiptidlipqylrflqewvehfckqrqakvkdvitncnsckecggtcngecktecekkckgecdaykkfieeckgkadegtsgsswskrwdqiykryskyiedakrnrkagtkncgpssttstaeskcvqs>gi|254952598|gb|act97129.1|var2csa[恶性疟原虫]|334aa(seqidno:14)kcdkckseqskknnniwiwkkssgtegglqkeyantialpprtqslylgnlrklenvcedvkdinfdtkekflagcliaafhegknlkkrylekkngdnnsklckalkysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikknntaeqhtsyssldelreswwntnkkyiwlamkhgttcssgsgdngsiscddiptidlipqylrflqewvehfceqrqgkvnaviencnsckntssktklggtcngeckteckgecdaykefiekckgtaaegtsgsswvkrwyqiymryskyiedakrnrkagtkncgtssttstaeskcvqs>gi|254952596|gb|act97128.1|var2csa[恶性疟原虫]|332aa(seqidno:15)kcdkckseqskknnniwiwkkssgtegglqkeyantialpprtqslylgnlrklenvcedvkdinfdtkekflagcliaafhegknlkkrylekkngdnnsklckalkysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgttcssgsgdngsiscddiptidlipqylrflqewvehfceqrqekvkdvikncnsckecggtcngecktecknkckdecdaykkfieecegkaaegtsgsswskrwdqiykryskyiedakrnrkagtkncgtssttstaenkcvqs>gi|90193465|gb|abd92328.1|红细胞膜蛋白1[恶性疟原虫]|267aa(seqidno:16)nyikddpysaeyttklsfilnssdtenasekiqknndevcnpnesgiacvelaqtsgsssnktcnthsfikankkkvckdvklginkkdkdlkicvieddslrgvdncccqdllgilqencsdknqsgsssngscnnknqeacqkklenvfasltngykcekckseqskknnknwiwkkysvkeeglqkeyantialpprtqslylgnlpklgnvckgvtdinfdtkekflagcliaafhegknlkttylqnkkklckalkysfady>gi|90193477|gb|abd92334.1|红细胞膜蛋白1[恶性疟原虫]|263aa(seqidno:17)dyikgdpyfaeyatklsfilnssdantssgetanhndeacnpneseiasveqasisdrssqkacnthssikankkkeckhvklgvrendkdlkicviedtslsgvdncccqdllgilqencsdnkrgsssngscdknseeicqkkldealaslhngyknqkckseqskknknkwiwkkssgnekglqkeyantiglpprtqslylgnlpklenvcedvtdinfdtkekflagcliaafhegknlkttypqnknddngkklckd>gi|254952594|gb|act97127.1|var2csa[恶性疟原虫]|338aa(seqidno:18)kcdkckseqskknnniwiwkkssgnkkglqkeyantiglpprtqslylgnlpklenvckdvtdinfdtkekflagcliaafhegknlkisnekknddngkklckdlkysfadygdlikgtsiwdneytkdlelnlqnnfgklfrkyikknntaeqhtlyssldelreswwntnkkyiwlamkhgttcssgsgdngdgsvtgsgsscddmstidlipqylrflqewvehfckqrqekvnaviencnsckntssktklggtcngecktecekkckdecekykefieeckrgdgtagspwvkrwdqiymryskyiedakrnrkagtkscgtsaaenkcvqs>gi|254952602|gb|act97131.1|var2csa[恶性疟原虫]|341aa(seqidno:19)kcdkckseqskknnniwiwkkssgdekglqkeyantialpprtqslylgnlpklenvckdvtdinfdtkekflagcliaafhegknlktshqnknadngkknddngkklckalkysfadygdlikgtsiwdneytkdlelnlqqifgklfrkyikrnntaeqhtlyssldelreswwntnkkyiwlamkhgttcssgsgdngdgsvtgsgsscddmstidlipqylrflqewvehfckqrqekvkdvitncnsckecggtcgsdcktkceaykkfieecngtadggtsgsswskrwdqiykryskyiedakrnrkagtkncgpssgansgvtttenkcvqs>gi|254952660|gb|act97160.1|var2csa[恶性疟原虫]|352aa(seqidno:20)kcekceseqskknnkywiwkkssgngeglqeeyantialpprthslclvclhekegkktqelknirtnsellkeriiaafhegknlktspqnkndngkklckdlkysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikknntaeqhtlyssldelreswwntnkkyiwlamkhgagmnstmcnadgsvtgssdsgsttccgdngsiscddmptidlipqylrflqewvehfceqrqekvnavitncksckecggtcnsdcekkckaykefiekckgggtegtsgsswskrwdqiykrhskhiedakrnrkagtkncgittgtisgessgansgvtttenkcvqs>gi|254952652|gb|act97156.1|var2csa[恶性疟原虫]|344aa(seqidno:21)kcdkcksgtsrsrkiwtwrkfrgngeglqkeyantiglsprtqllylvclhekgkktqelknistnsellkewiiaafhegknlkttypqkknddngkklckalkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikkniasdentsyssldelreswwntnkkyiwtamkhgagmngttccgdgsvtgssdsgsttccgdgsvtgsgsscddiptidlipqylrflqewvehfceqrqekvkdvitncksckesekkcknkcdaykefidgtgsgggtgtagsswskrwdqiymryskyiedakrnrkagtkncgtssgansgvtttenkcvqs>gi|254952622|gb|act97141.1|var2csa[恶性疟原虫]|350aa(seqidno:22)kcekckseqskknnkiwtwrkfpgngeglqkeyantiglsprtqllylvclhekgkktqhktistnsellkewiiaafhegknlkkrylekkkgdnnsklckdlkysfadygdlikgtsiwdndftkdlelnlqqifgklfrkyikkniasdentsyssldelreswwntnkkyiwtamkhgagmnstmcngdgsvtgssdsgsttcsgdngsiscddiptidlipqylrflqewvehfceqrqekvkdvikncnsckecggtcngecktecknkckdecekyknfievctggdgtagspwskrwyqiymryskyiedakrnrkagtkscgtssgansgvttteskcvqs>gi|254952626|gb|act97143.1|var2csa[恶性疟原虫]|359aa(seqidno:23)kcekckseqskknnknwiwrkfpgngeglqkeyantiglpprthslylvclhekgkktqelknirtnsellkewiiaafhegknlkkryhqnnnsgnkkklckaleysfadygdlikgtsiwdneytkdlelnlqqifgklfrkyikknisteqdtlyssldelreswwntnkkyiwlamkhgagmnsttccgdgsvtgssdsgsttcsgdngsiscddmptidlipqylrflqewvehfceqrqekvkdviencksckntsgeriiggtcngecktecekkckaaceayktfieecegkaaegtsgsswskrwyqiymryskyiedakrnrkagtkncgkssgansgvtttenkcvqs>gi|90193469|gb|abd92330.1|红细胞膜蛋白1[恶性疟原虫]|270aa(seqidno:24)nyikddpyskeyvtklsfipnssdannpsgetanhndevcnpneseissvehaqtsvllsqkayithssikankkkvckyvklgvrendkdlkicvieddslrgvenccfkdflrilqencsdnkresssngscnnnneeaceknldealasltncyknqkcksgtstvnnnkwiwkkssgkegglqkeyantiglpprtqslclvvcldekegktqelknirtnsellkewiiaafhegknlkkryhqnknddnnsklckalkysfady>gi|254952644|gb|act97152.1|var2csa[恶性疟原虫]|334aa(seqidno:25)kcdkckseqskknnkywiwkkysvkegglqkeyantialpprtqslclvvcldekegktqelknirtnsellkeriiaafhegknlktyhekkkgddgkklckdlkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikknntaeqhtsyssldelreswwntnkkyiwtamkhgaemngttcscsgdssndiptidlipqylrflqewvehfceqrqakvnavikncksckecggtcngecktecktkckgecekykefiekcegqaaegtsgsswskrwyqiymryskyiedakrnrkagtkncgtssgansgvtttenkcvqs>gi|254952642|gb|act97151.1|var2csa[恶性疟原虫]|351aa(seqidno:26)kcdkckseqskknnknwiwkkysgtegglqkeyantialpprtqslylvclhekeektqelknistnsellkewiiaafhegknlkispqnkndngknlckdlkysfadygdlikgtsiwdndftkdlelnlqqifgklfrkyikknntaeqdtlyssldelreswwntnkkyiwtamkhgagmngttccgdgsvtgssdsgsttccgdgsvtgsgsscddiptidlipqylrflqewvehfceqrqakvkdvikncnsckecggtcngecktecekkckgeceaykkfiekcnggggegtsgsswskrwdqiymryskyiedakrnrkagtkncgtssttnaaenkcvqs>gi|254952658|gb|act97159.1|var2csa[恶性疟原虫]|353aa(seqidno:27)kcdkcksgtstvnkkwiwkkfpgkegglqeeyantialpprtqslclvvcldekegktqhktistnsellkewiiaafhegknlkisnkkkndennsklckdlkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikknntaeqdtsyssldelreswwntnkkyiwlamkhgttcssgsgdngdgsvtgssdsgsttccgdgsvtgsgsscddiptidlipqylrflqewvehfckqrqakvkdviencksckntssktklgdtcnsdcktkckvacekykefiekcvsaaggtsgsswvkrwdqiymryskyiedakrnrkagtkncgpssttstaeskcvqs>gi|254952640|gb|act97150.1|var2csa[恶性疟原虫]|327aa(seqidno:28)kcdkcksgtstvnkkwiwkkysgkegglqkeyantiglpprtqslclvclhekegktqelknistnsellkewiiaafhegknlkisnkkknddngkklckdlkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikknntaeqdtlyssldelreswwntnkkyiwtamkhgagmnsttcscsgdssndiptidlipqylrflqewvehfckqrqekvnavitncksckesggtcnsdcekkckiecekyknfiekcvtaaggtsgsswskrwdqiykmyskyiedakrnrkagtkncgpssttnaaastdenkcvqs>dd2full745个氨基酸|628aa(seqidno:29)nyikgdpyfaeyatklsfilnssdtenasetpskyydeacncneseiasvgqaqtsgpssnktcithssiktnkkkeckdvklginnndkvlrvcviedtslsgvdncccqdllgilqencsdnkrgsssngscdknseeicqkklekvfasltngykcdkcksgtsrskkkwiwkkssgneeglqkeyantiglpprtqslclvclhekegktqhktistnsellkewiiaafhegknlktshekknddngkklckaleysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikknntaeqhtsyssldelreswwntnkkyiwtamkhgagmngttcscsgdssndmptidlipqylrflqewvehfckqrqekvnaviencnsckesggtcnsdcktecknkceaykefiedckgggtgtagspwskrwdqiykryskhiedakrnrkagtkncgtssttnaaastdenkcvqsdvdsffkhlidiglttpssylsnvlddnicgadkapwttyttytttkncdiqkktpksqscdtlvvvnvpsplgntpheykyaceckiptteetcddrkeymnqwscgsaqtvrgrsgkddyelytyngvketkplgtlknskld>gi|254952636|gb|act97148.1|var2csa[恶性疟原虫]|350aa(seqidno:30)kcekckseqskknnknwiwrkfrgtegglqeeyantiglpprtqslclvvcldekgkktqelknirtnsellkewiiaafhegknlkpshqnknsgnkenlckalkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikknntaeqhtsyssldelreswwntnkkyiwtamkhgaemngttcnadgsvtgssdsgsttcsgdngsiscddiptidlipqylrflqewvehfckqrqekvnavinscnsckntssktklgdtcnsdcktkckiecekyktfiekcvtaaggtsgspwskrwdqiykryskyiedakrnrkagtkncgpssttstaeskcvqs>gi|254952638|gb|act97149.1|var2csa[恶性疟原虫]|330aa(seqidno:31)kcdkckseqskknnknwiwrkysgngeglqkeyantiglpprthslylvclhekegktqelknirtnsellkewiiaafhegknlkttylenkndenkkklckalkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikkniasdentlyssldelreswwntnkkyiwtamkhgaemngttcssgsgdngsiscddiptidlipqylrflqewvghfckqrqekvnavitncnsckesggtcnsdcekkckiecekykkfieecrtaaggtsgspwskrwdqiykmyskyiedakrnrkagtkncgpssttstaeskcvqs>gi|254952628|gb|act97144.1|var2csa[恶性疟原虫]|334aa(seqidno:32)kcdkckseqskknnknwiwrkysgngeglqkeyantiglpprthslylvclhekegktqhktistnsellkewiiaafhegknlkkrypqnnnsgnkkklckdlkysfadygdlikgtsiwdneytkdlelnlqkafgklfrkyikkniasdentlyssldelreswwntnkkyiwlamkhgaemngtmcnadgsvtgsgsscddmstidlipqylrflqewvehfceqrqakvkdvinscksckesgdtcnsdcekkcknkcdayktfieefctadggtagspwskrwdqiykryskyiedakrnrkagtkncgtssgansgvtttenkcvqs>gi|254952630|gb|act97145.1|var2csa[恶性疟原虫]|350aa(seqidno:33)kcdkcksgtstvnknwiwkkysgkeeglqkeyantialpprthslylvclhekgkktqelknirtnsellkewiiaafhegknlktspqnnnsgnkkklckalkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikknntaeqhtsyssldelreswwntnkkyiwlamkhgaemngttccgdgsvtgssdsgsttcsgdngsiscddmpttdfipqylrflqewvehfckqrqekvkhvmescksckecgdtcngecktecekkcknkceayktfiekcvsadggtsgsswskrwdqiymryskyiedakrnrkagtkncgtssttnaaastaenkcvqs>p13745个氨基酸|647aa(seqidno:34)dyikddpysaeyatklsfilnpsdantssgetanhndevcncneseiasvelapisdsssnktcithsfigankkkeckdvklgvrekdkdlkicvieddslrgvencccqdllgilqencsdnksgsssngscdknsedecqkklenvfaslkngykcdkcksgtstvnkkwiwrkysgngeglqkeyantiglpprthslylvclhekegktqhktistnsellkewiiaafhegknlktshqnnnsgnkkklckalkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikkniasdentsyssldelreswwntnkkyiwlamkhgaemnstmcngdgsvtgssdsgsttcsgdngsiscddiptidlipqylrflqewvehfckqrqekvkdvitncksckesgdtcnsdcekkcknkceaykkfieerrtaaqgtaesswvkrwdqiymryskyiedakrnrkagtkscgpssttnaaastaenkcvqsdidsffkhlidiglttpssylsivlddnicgadnapwttyttytttkncdikkktpkpqscdtlvvvnvpsplgntpheykyacqcrtpnkqescddrkeymnqwssgsaqtvrgrstnndyelytyngvketkplgtlknskld>gi|254952608|gb|act97134.1|var2csa[恶性疟原虫]|341aa(seqidno:35)kcdkcksgtstvnkkwiwrkssgnkeglqkeyantiglpprtqslylgnlpklenvcedvkdinfdtkekflagclivsfhegknlktshekknddngkklckaleysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgagmnittccgdgssgenqtnscddiptidlipqylrflqewvehfckqrqekvnavvtncksckesggtcngecktkcknkcevyktfidnvgdgtagspwvkrwdqiykryskhiedakrnrkagtkncgittgtisgessgatsgvtttenkcvqs>7g8745个氨基酸|632aa(seqidno:36)nyikddpyskeyvtklsfipnssdantssekiqknndevcnpnesgissveqaqtsgpssnktcithssikankkkeckdvklgvrendkdlkicviedtslsgvdncccqdllgilqencsdnkrgsssndscdnknqdecqkkldealeslhngyknqkcksgtstvnkkwiwkkssgnkeglqkeyantiglpprtqslylgnlpklenvskgvtdiiydtkekflagclivsfhegknlktshekknddngkklckaleysfadygdlikgtsiwdneytkdlelnlqkafgklfrkyikknisaeqdtsyssldelreswwntnkkyiwiamkhgagmngttccgdgssgenqtnscddiptidlipqylrflqewvehfceqrqakvkdvitncksckntsgerkiggtcngecktkcknkceayktfiehckggdgtagsswvkrwdqiykryskhiedakrnrkagtkscgtstaenkcvqsdidsffkhlidiglttpssylsivldenncgedkapwttytttkncdiqkdksksqssdtlvvvnvpsplgntphgykyacqckiptteetcddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrssstkld>indo745个氨基酸|639aa(seqidno:37)dyikgdpysaeyvtklsfipnssdannpsekiqknndevcncneseissvgqasisdpssnktcnthssikankkkvckdvklgvrendkvlkicviehtslrgvdnccfkdllgilqepridknqsgsssngscdknseeaceknlekvlasltngykcdkcksgtsrskkkwiwkkysgkegglqeeyantiglpprtqslclvvcldekegktqelknistnsellkewiiaafpegknlkpspekkkgdngkklckdlkysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikkniasdentlyssldelreswwntnkkyiwlamkhgagmnstmcnadgsvtgsgsscddmptidlipqylrflqewvehfckqrqekvkpviencnsckntsserkiggtcnsdcktecknkcevykkfiedckggdgtagsswskrwdqiykryskyiedakrnrkagtkncgpssttnaaenkcvqsdidsffkhlidiglttpssylstvlddnicgednapwttyttytttkncdkdkkksksqscdtlvvvnvpsplgntpheykyacecrtpnkqescddrkeymnqwisdntknpkgsgsgkdyyelytyngvdvkpttvrssstkld>mc745个氨基酸|655aa(seqidno:38)dyikgdpyfaeyatklsfilnssdantssgetanhndeacncneseissvehasisdpssnktcnthssikankkkvckhvklgvrendkdlrvcviehtslsgvenccfkdflrilqencsdnksgsssngscdknneeaceknlekvfasltncykcekckseqskknnkkwtwrkssgnkgglqeeyantiglpprtqslclvvcldekegkktqelknirtnsellkewiiaafhegknlkpshekknddngkknddnnsklckdlkysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikkniasdentlyssldelreswwntnkkyiwlamkhgaemngttcnadgsvtgsgsscddiptidlipqylrflqewvehfckqrqakvkdviencksckesgnkcktecknkceaykkfienckggdgtagsswvkrwdqiymryskyiedakrnrkagtkncgpssitnvsastdenkcvqsdidsffkhlidiglttpssylsivlddnicgddkapwttyttyttyttyttyttyttytttkncdkerdksksqscntavvvnvpsplgntpheykyacecrtpsnkelcddrkeymnqwssgsaqtvrdrsgkdyyelytyngvketklpkklnsskld>gi|254952650|gb|act97155.1|var2csa[恶性疟原虫]|347aa(seqidno:39)kcdkckseqskknnkywiwkkssvkeeglqkeyantialpprthslclvvcldekgkktqelknistnsellkeriiaafhegknlkttylekknadnnsklckalkysfadygdlikgtsiwdneytkdlelnlqqifgklfrkyikknntaeqhtlyssldelreswwntnkkyiwlamkhgagmngttccgdgsvtgssdsgsttcsgdngsiscddmpttdfipqylrflqewvehfckqrqekvkdviencnscknnlgkteinekcktecknkceayknfiekfctadggtsgspwskrwdqiykryskyiedakrnrkagtkncgtssttstaenkcvqs>gi|254952648|gb|act97154.1|var2csa[恶性疟原虫]|335aa(seqidno:40)kcekcksgtstvnkywiwrkssgnkeglqkeyantialpprthslclvvcldekegktqelknistnsellkeriiaafhegenlktshekkkgddgkknadnnsklckalkysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikkniasdentsyssldelreswwntnkkyiwlamkhgagmngttcscsgdssddmpttdfipqylrflqewvehfckqrqenvnaviencnsckecggtcnsdcekkcktecknkceayknfiekfctadggtsgyswskrwdqiykryskyiedakrnrkagtkscgtssttstaeskcvqs>ghana2745个氨基酸|667aa(seqidno:41)syvknnpyskeyvtklsfilnpsdannpsetpskyydevcncnesgiacvgqaqtsgpssnktcithsfigankkkvckdvklgvrekdkdlkicviedtylsgvdnccfkdflgmlqencsdnksgsssngscnnknqdeceknldealasltngykcekcksgtstvnkywiwrkssgnkeglqkeyantialpprthslclvvcldekegktqhktistnsellkewiiaafhegknlktshekkkgddgkknadnnsklckalkysfadygdlikgtsiwdndftkdlelnlqkifgklfrkyikkniasdentsyssldelreswwntnkkyiwlamkhgagmnsttccgdgsvtgssdsgsttccgdgsvtgsgsscddmpttdfipqylrflqewvehfckqrqenvnaviencnsckecggtcnsdcekkckteckgecdaykefiekcnggaaegtsgsswskrwdqiykryskyiedakrnrkagtkncgtssttstaeskcvqsdidsffkhlidiglttpssylsivldenicgadnapwttyttyttyttytttekcnketdksklqqcntsvvvnvpsplgntphgykyvcecrtpnkqetcddrkeymnqwisdntknpkgsrstnndyelytyngvqikpttvrsnstkld>gi|254952634|gb|act97147.1|var2csa[恶性疟原虫]|348aa(seqidno:42)kcdkckseqskknnknwiwkkssgnekglqkeyantiglpprtqslclvvcldekegktqelknirtnsellkewiiaafhegknlktshekkkgdnnsklckdlkysfadygdlikgtsiwdneytkdlelnlqnnfgklfrkyikkniasdentsyssldelreswwntnkkyiwlamkhgagmnsttcssgsgsttcssgsgsttcssgsgdscddmptidlipqylrflqewvehfckqrqekvnavikncnsckesggtcngecktecknkceayktfieefctadggtsgspwskrwdqiykmyskhiedakrnrkagtkncgpssttnvsvstdenkcvqs>ghana1745个氨基酸|652aa(seqidno:43)dyikddpyfaeyvtklsfilnssdannpsgetanhndevcnpnesgiasveqaqtsdpssnktcnthssikankkkvckhvklgvrendkdlkicviehtslsgvencccqdflrilqencsdnksgsssngscnnknqeaceknlekvlasltncykcdkckseqskknnknwiwkkssgnekglqkeyantiglpprtqslclvvcldekegktqelknirtnsellkewiiaafhegknlkkrypqnknddnnsklckdlkysfadygdlikgtsiwdneytkdlelnlqnnfgklfrkyikknisteqdtlyssldelreswwntnkkyiwlamkhgagmnsttcssgsgsttcssgsgsttcssgsgdscddmpttdfipqylrflqewvehfckqrqekvnavikncnsckesggtcngecktecknkceayktfieefctadggtsgspwskrwdqiykmyskhiedakrnrkagtkncgpssttnvsvstdenkcvqsdidsffkhlidiglttpssylsivlddnicgedkapwttyttytttkkcnketdksksqscntavvvnvpsplgntphgykyaceckiptteetcddrkeymnqwiidtskkqkgsgsgkddyelytyngvdvkpttvrsnstkld>v1s1745个氨基酸|628aa(seqidno:44)dyikddpysaqyttklsfilnpsdantssekiqknndeacncnesgissvgqaqtsgpssnktcithssikankkkvckdvklginnndkvlrvcviedtslsgvdncccqdllgilqencsdnkrgsssngscnnnneeaceknldeapaslhngyknqkcksgtsrskkkwiwkkssgnekglqeeyantiglpprtqslclvclhekegktqhktistnsellkewiiaafhegknlktshekknddngkklckaleysfadygdlikgtsiwdneytkdlelnlqkafgklfrkyikknntaeqdtsyssldelreswwntnkkyiwiamkhgagmngttcscsgdssndmptidlipqylrflqewvehfceqrqakvkdvitncksckesgnkcktecktkckdecekyktfiedcngggtgtagsswvkrwdqiykryskhiedakrnrkagtkncgpssitnaaastdenkcvqsdidsffkhlidiglttpssylsnvldenscgddkapwttyttytttkncdiqkdksksqpintsvvvnvpsplgntpyrykyaceckiptteescddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrsnsskld>raj116_var25745个氨基酸|653aa(seqidno:45)dyikgdpyfaeyatklsfilnpsdtenasetpskyydeacnpneseiasveqaqtsgpssnktcithssiktnkkkeckdvklgvrendkdlkicviedtslsgvdnccfkdllgilqencsdnkrgsssndscnnnneeaceknldealasltngykcdkcksgtstvnkkwtwrkssgneeglqkeyantiglpprtqslclvclhekegktkhktistnsellkewiiaafhegknlktshekknddngkklckaleysfadygdlikgtsiwdneytkdlelnlqkafgklfrkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgaemngttcssgsgdngdssitgssdsgsttcsgdngsiscddipttdfipqylrflqewvehfceqrqakvkdvinscnscnesggtcngecktkckdecekykkfiedcnggdgtagsswvkrwdqiykryskhiedakrnrkagtkncgpssitnaaastdenkcvqsdvdsffkhlidiglttpssylsivldenscgddkapwttyttytttekcnkerdksksqssdtlvvvnvpsplgntpheykyaceckiptneetcddrkdymnqwisdtskkqkgsgsgkdyyelytyngvqikqaagrssstkld>gi|31323048|gb|aap37940.1|var2csa[恶性疟原虫]|490aa(seqidno:46)kcdkckseqskknnnkwiwkkysgngeglqkeyantiglpprtqslclvclhekegktqhktistnsellkewiiaafhegknlkkrypqnknddnnsklckaleysfadygdlikgtsiwdneytkdlelnlqkafgklfrkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgaemngttcssgsgdngdsscddiptidlipqylrflqewvehfckqrqakvkdvinscnsckntsgerkiggtcnsdcekkckvacdayktfieecrtavggtagsswvkrwdqiykryskhiedakrnrkagtkncgpssttnaaenkcvqsdidsffkhlidiglttpssylsnvldenscgadkapwttyttyttyttyttytttekcnkerdksksqqsntsvvvnvpsplgntpheykyaceckiptteetcddrkeymnqwiidntknpkgsgstdndyelytyngvqikqaagrssstkld>gi|254952620|gb|act97140.1|var2csa[恶性疟原虫]|335aa(seqidno:47)kcekcksgtstvnnkwiwrkssgkegglqkeyantiglpprtqslylgnlpklenvckgvtdiiydtkekflsgcliaafhegknlkttylekknddngkklckaleysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikknntaeqdtsyssldelreswwntnkkyiwiamkhgagmngttcssgsgdssndipttdfipqylrflqewvenfceqrqakvkpviencnsckesggtcngecktkckvacdaykkfidgtgsgggsrptgiagsswskrwdqiykryskhiedakrnrkagtkncgpssitnvsvstdenkcvqs>t2c6745个氨基酸|637aa(seqidno:48)nyikddpyskeyvtklsfipnssdantssekiqknndevcnpnesgissveqaqtsdpssnktcithssikankkkeckdvklgvrendkdlkicviehtslsgvdnccfkdflrmlqepridknqrgsssngscdknseeaceknldealasltngykcdkckseqskknnnkwiwkkfpgkegglqeeyantiglpprtqylclvvcldekegktqelknirtnsellkewiiaafhegknlkttypqkknddngkklckdlkysfadygdlikgtsiwdneytknvelnlqnnfgklfrkyikknntaeqdtsyssldelreswwntnkkyiwlamkhgaemnsttccgdgsvtgsgsscddiptidlipqylrflqewvehfckqrqakvkdvitncnsckesgnkcktecknkckdecekykkfieacgtavggtgtagspwskrwdqiykryskhiedakrnrkagtkncgpssttnaaenkcvqsdidsffkhlidiglttpssylsivlddnicgadkapwttyttyttencdiqkktpksqscdtlvvvnvpsplgntphgykyacqcrtpnkqescddrkeymnqwiidntknpkgsgsgkdyyelckyngvketkplgtlknskld>gi|254952632|gb|act97146.1|var2csa[恶性疟原虫]|330aa(seqidno:49)kcdkckseqskknnnkwiwrkfpgkegglqkeyantiglpprtqslclvclhekegktqhktistnsellkewiiaafhegknlkttylekknaenkkklckalkysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgagmngtmcnadgsvtgsgsscddmpttdfipqylrflqewvehfckqrqakvkdviencksckesgnkcktecknkcdayktfieecgtavggtagsswvkrwdqiykryskhiedakrnrkagtkncgtssttnaaastaenkcvqs>gi|90193487|gb|abd92339.1|红细胞膜蛋白1[恶性疟原虫]|269aa(seqidno:50)nyikddpyskeyvtklsfilnssdaenasetpskyydeacncnesgissveqasisdrssqkacnthsfigankkkvckhvklgvrendkdlkicvieddslrgvenccfkdflrmlqepridknqrgsssndscnnnneeaceknldealaslhngyknqkckseqskknnnkwiwkkssgkegglqkeyantiglpprtqslclvclhekegktqhktistnsellkewiidafhegknlkttylekkkgdngkklckalkysfady>gi|254952646|gb|act97153.1|var2csa[恶性疟原虫]|347aa(seqidno:51)kcdkckseqskknnknwiwkkssgkegglqkeyantialpprtqslclvvclhekegktqhktistnsellkewiidafhegknlkttylekqnadngkknadnnsklckdlkysfadygdlikgtsiwdneytkdlelnlqqifgklfrkyikkniasdentlyssldelreswwntnkkyiwtamkhgaemngttcssgsgdsssgenqtnscddiptidlipqylrflqewvehfceqrqakvkdvitncksckesggtcnsdcktkckgecekykkfiekckgggtegtsgsswvkrwyqiymryskyiedakrnrkagtkscgtssgansgvttteskcvqs>gi|90193485|gb|abd92338.1|红细胞膜蛋白1[恶性疟原虫]|269aa(seqidno:52)dyikddpyskeyttklsfilnssdantssekiqknndevcnpneseissveqaqtsrpssnktcithssikankkkvckdvklgvrendkvlrvcviehtslsgvencccqdllgilqencsdnkrgsssngscdknseeaceknldealasltncyknqkckseqskknnnkwiwkkssgnekglqkeyantiglpprtqslclvclhekegktqelknistnsellkewiiaafhegknlkttypqnknddngkklfkdlkysfady>mts1745个氨基酸|646aa(seqidno:53)dyikddpyskeyttklsfilnssdantssekiqknndevcnpneseissveqaqtsrpssnktcithssikankkkvckdvklgvrendkvlrvcviehtslsgvencccqdllgilqencsdnkrgsssngscdknseeaceknldealasltncyknqkckseqskknnnkwiwkkssgkegglqkeyantiglpprtqslylgnlpklenvckgvtdinfdtkekflagcliaafhegknlkttylekknddngkklckaleysfadygdlikgtsiwdneytkdlelnlqkafgklfrkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgagmngttcssgsgdssndipttdfipqylrflqewvenfceqrqakvkdviencnsckntsgerkigdtcnsdcekkckdecekykkfiedckggdgtagsswvkrwdqiykryskhiedakrnrkagtkncgittgtisgessgatsgvtttenkcvqsdidsffkhlidiglttpssylsnvlddnicgednapwttyttyttekcnketdksksqqsntavvvnvpsplgntphgykyaceckiptteetcddrkeymnqwscgsaqtvrdrsgkddyelckyngvqikqaagtlknskld>q8i639(q8i639_plaf7)恶性疟原虫(分离株3d7),632aa胞外部分(seqidno:54)nyikgdpyfaeyatklsfilnssdannpsekiqknndevcncnesgiasveqeqisdpssnktcithssikankkkvckhvklgvrendkdlrvcviehtslsgvencccqdflrilqencsdnksgsssngscnnknqeaceknlekvlasltncykcdkckseqskknnknwiwkkssgkegglqkeyantiglpprtqslclvvcldekgkktqelknirtnsellkewiiaafhegknlkpshekknddngkklckaleysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikknntaeqdtsyssldelreswwntnkkyiwlamkhgagmnsttccgdgsvtgsgsscddiptidlipqylrflqewvehfckqrqekvkpviencksckesggtcngecktecknkcevykkfiedckggdgtagsswvkrwdqiykryskyiedakrnrkagtkncgpssttnaaenkcvqsdidsffkhlidiglttpssylsivlddnicgadkapwttyttytttekcnketdksklqqcntavvvnvpsplgntphgykyacqckiptneetcddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrsnsskld>q8i639(q8i639_plaf7)恶性疟原虫(分离株3d7),完整的2730aa胞外部分(seqidno:55)mdkssiankieaylgaksddskidqslkadpsevqyygsggdgyylrknickitvnhsdsgtndpcdripppygdndqwkcaiilskvsekpenvfvpprrqrmcinnleklnvdkirdkhafladvlltarnegerivqnhpdtnssnvcnalersfadiadiirgtdlwkgtnsnleqnlkqmfakirendkvlqdkypkdqnyrklredwwnanrqkvwevitcgarsndllikrgwrtsgksngdnklelcrkcghyeekvptkldyvpqflrwltewiedfyrekqnliddmerhreectsedhkskegtsycstckdkckkycecvkkwksewenqknkytelyqqnknetsqkntsryddyvkdffkkleanysslenyikgdpyfaeyatklsfilnssdannpsekiqknndevcncnesgiasveqeqisdpssnktcithssikankkkvckhvklgvrendkdlrvcviehtslsgvencccqdflrilqencsdnksgsssngscnnknqeaceknlekvlasltncykcdkckseqskknnknwiwkkssgkegglqkeyantiglpprtqslclvvcldekgkktqelknirtnsellkewiiaafhegknlkpshekknddngkklckaleysfadygdlikgtsiwdneytkdlelnlqkifgklfrkyikknntaeqdtsyssldelreswwntnkkyiwlamkhgagmnsttccgdgsvtgsgsscddiptidlipqylrflqewvehfckqrqekvkpviencksckesggtcngecktecknkcevykkfiedckggdgtagsswvkrwdqiykryskyiedakrnrkagtkncgpssttnaaenkcvqsdidsffkhlidiglttpssylsivlddnicgadkapwttyttytttekcnketdksklqqcntavvvnvpsplgntphgykyacqckiptneetcddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrsnssklddkdvtffnlfeqwnkeiqyqieqymtntkiscnneknvlsrvsdeaaqpkfsdnerdrnsithedknckekckcyslwiekindqwdkqkdnynkfqrkqiydankgsqnkkvvslsnflffscweeyiqkyfngdwskiknigsdtfeflikkcgndsgdgetifseklnnaekkckenestnnkmkssetscdcsepiyirgcqpkiydgkifpgkggekqwickdtiihgdtngacipprtqnlcvgelwdkryggrsnikndtkeslkqkiknaiqketellyeyhdkgtaiisrnpmkgqkekeeknndsnglpkgfchavqrsfidyknmilgtsvniyeyigklqedikkiiekgttkqngktvgsgaenvnawwkgiegemwdavrcaitkinkkqkkngtfsidecgifpptgndedqsvswfkewseqfcierlqyeknirdactnngqgdkiqgdckrkceeykkyisekkqewdkqktkyenkyvgksasdllkenypecisanfdfifndnieyktyypygdyssicsceqvkyyeynnaekknnkslchekgndrtwskkyikklengrtlegvyvpprrqqlclyelfpiiiknknditnakkelletlqivaereayylwkqyhahndttylahkkaccairgsfydlediikgndlvhdeytkyidsklneifdssnkndietkrartdwweneaiavpnitganksdpktirqlvwdamqsgvrkaideekekkkpnenfppcmgvqhigiakpqfirwleewtnefcekytkyfedmksncnlrkgaddcddnsnieckkacanytnwlnpkriewngmsnyynkiyrksnkesedgkdysmimeptvidylnkrcngeingnyiccscknigenstsgtvnkklqkketqcednkgpldlmnkvlnkmdpkysehkmkctevylehveeqlkeidnaikdyklypldrcfddkskmkvcdligdaigckhktkldeldewndvdmrdpynkykgvlipprrrqlcfsrivrgpanlrnlkefkeeilkgaqsegkflgnyynedkdkekaleamknsfydyeyiikgsdmltniqfkdikrkldrlleketnntekvddwwetnkksiwnamlcgykksgnkiidpswctipttetppqflrwikewgtnvciqkeehkeyvkskcsnvtnlgaqesesknctseikkyqewsrkrsiqweaisegykkykgmdefkntfknikepdanepnaneylkkhcskcpcgfndmqeitkytnigneafkqikeqvdipaeledviyrlkhheydkgndyicnkykninvnmkknnddtwtdlvknssdinkgvllpprrknlflkidesdickykrdpklfkdfiyssaiseverlkkvygeaktkvvhamkysfadigsiikgddmmennssdkigkilgdgvgqnekrkkwwdmnkyhiwesmlcgykhaygnisendrkmldipnnddehqflrwfqewtenfctkrnelyenmvtacnsakcntsngsvdkkecteacknysnfilikkkeyqslnsqydmnyketkaekkespeyfkdkcngecsclseyfkdetrwknpyetlddtevknncmckppppasnntsdilqktipfgialalgsiaflfmkkkpktpvdllrvldipkgdygiptpkssnryipyasdrykgktyiymegdtsgdddkyiwdl>fcr3(seqidno:56)完整的2734aa胞外部分(577aa高亮的对应id1-dbl2b)mdststiankieeylgaksddskidellkadpseveyyrsggdgdylknnickitvnhsdsgkydpcekklppyddndqwkcqqnssdgsgkpenicvpprrerlctynlenlkfdkirdnnafladvlltarnegekivqnhpdtnssnvcnalersfadladiirgtdqwkgtnsnleknlkqmfakirendkvlqdkypkdqkytklreawwnanrqkvwevitcgarsndllikrgwrtsgksdrkknfelcrkcghyekevptkldyvpqflrwltewiedfyrekqnliddmerhreectredhkskegtsycstckdkckkycecvkkwktewenqenkykdlyeqnknktsqkntsryddyvkdffekleanysslenyikgdpyfaeyatklsfilnpsdannpsgetanhndeacncnesgissvgqaqtsgpssnktcithssiktnkkkeckdvklgvrendkdlkicviedtslsgvdncccqdllgilqencsdnkrgsssndscdnknqdecqkklekvfasltngykcdkcksgtsrskkkwiwkkssgneeglqeeyantiglpprtqslylgnlpklenvcedvkdinfdtkekflagclivsfhegknlkkrypqnknsgnkenlckaleysfadygdlikgtsiwdneytkdlelnlqnnfgklfgkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgaemnittcnadgsvtgsgsscddiptidlipqylrflqewvenfceqrqakvkdvitncksckesgnkcktecktkckdecekykkfieacgtagggigtagspwskrwdqiykryskhiedakrnrkagtkncgtssttnaaastdenkcvqsdidsffkhlidiglttpssylsnvlddnicgadkapwttyttytttekcnkerdksksqssdtlvvvnvpsplgntpyrykyacqckiptneetcddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrsnsskldgndvtffnlfeqwnkeiqyqieqymtnaniscidekevldsvsdegtpkvrggyedgrnnntdqgtnckekckcyklwiekindqwgkqkdnynkfrskqiydankgsqnkkvvslsnflffscweeyiqkyfngdwskiknigsdtfeflikkcgnnsahgeeifneklknaekkckenestdtninksetscdlnatnyirgcqsktydgkifpgkggekqwickdtiihgdtngacipprtqnlcvgelwdksyggrsnikndtkellkekiknaihketellyeyhdtgtaiiskndkkgqkgkndpnglpkgfchavqrsfidyknmilgtsvniyehigklqedikkiiekgtpqqkdkiggvgsstenvnawwkgieremwdavrcaitkinkknnnsifngdecgvspptgndedqsvswfkewgeqfcierlryeqnireactingknekkcinsksgqgdkiqgackrkcekykkyisekkqewdkqktkyenkyvgksasdllkenypecisanfdfifndnieyktyypygdyssicsceqvkyykynnaekknnkslcyekdndmtwskkyikklengrslegvyvpprrqqlclyelfpiiikneegmekakeelletlqivaereayylwkqynptgkgiddankkaccairgsfydlediikgndlvhdeytkyidsklneifgssdtndidtkrartdwwenetitngtdrktirqlvwdamqsgvryaveeknenfplcmgvehigiakpqfirwleewtnefcekytkyfedmkskcdppkradtcgdnsnieckkacanytnwlnpkriewngmsnyynkiyrksnkeseggkdysmimaptvidylnkrchgeingnyiccscknigaynttsgtvnkklqkketeceeekgpldlmnevlnkmdkkysahkmkctevylehveeqlneidnaikdyklypldrcfddqtkmkvcdliadaigckdktkldeldewndmdlrgtynkhkgvlipprrrqlcfsrivrgpanlrslnefkeeilkgaqsegkflgnyykehkdkekaleamknsfydyediikgtdmltniefkdikikldrlleketnntkkaedwwktnkksiwnamlcgykksgnkiidpswctipttetppqflrwikewgtnvciqkqehkeyvkskcsnvtnlgaqasesnnctseikkyqewsrkrsirwetiskrykkykrmdilkdvkepdantylrehcskcpcgfndmeemnnnednekeafkqikeqvkipaeledviyrikhheydkgndyicnkyknihdrmkknngnfvtdnfvkksweisngvlipprrknlflyidpskiceykkdpklfkdfiywsafteverlkkayggarakvvhamkysftdigsiikgddmmeknssdkigkilgdtdgqnekrkkwwdmnkyhiwesmlcgyreaegdtetnencrfpdiesvpqflrwfqewsenfcdrrqklydklnsecisaectngsvdnskcthacvnyknyiltkkteyeiqtnkydnefknknsndkdapdylkekcndnkceclnkhiddknktwknpyetledtfkskcdcpkplpspikpddlppqadepfdptilqttipfgialalgsiaflfmkviyiyiyvccicmyvcmyvcmyvcmyvcmyvcmhvcmlcvyviyvfkiciyiekekrkk>bpti,蛋白酶抑制剂(seqidno:57)rpdfcleppytgpckariiryfynakaglcqtfvyggcrakrnnfksaedcmrtcgga>pe38,假单胞菌外毒素a(seqidno：58)(下划线的kdel表示对根据本发明的构建体可任选的信号序列)rhrqprgweqleqcgypvqrlvalylaarlswnqvdqvirnalaspgsggdlgeaireqpeqarlaltlaaaeserfvrqgtgndeagaangpadsgdallernyptgaeflgdggdisfstrgtqnwtverllqahrqleergyvfvgyhgtfleaaqsivfggvrarsqdldaiwrgfyiagdpalaygyaqdqepdargrirngallrvyvprsslpgfyrtsltlaapeaageverlighplplrldaitgpeeeggrletilgwplaertvvipsaiptdprnvggdldpssipdkeqaisalpdyasqpgkpprkdel>pe38lr,pe38的变体(seqidno:59)(下划线的kdel表示对根据本发明的构建体可任选的信号序列)rhrqprgweqlyptgaeflgdggdisfstrgtqnwtverllqahrqleergyvfvgyhgtfleaaqsivfggvrarsqdldaiwrgfyiagdpalaygyaqdqepdargrirngallrvyvprsslpgfyrtsltlaapeaageverlighplplrldaitgpeeeggrletilgwplaertvvipsaiptdprnvggdldpssipdkeqaisalpdyasqpgkpprkdel与假单胞菌外毒素a(pe38)的截短片段融合的var2csa多肽的序列融合的var2csa-pe38蛋白可以具有修饰，例如n末端的蛋白酶抑制剂(bpti)和/或免疫原性较低的优化的pe38序列(pe38lr)>bpti-id1-id2afcr3-pe38lr(seqidno：60)，下划线的序列对应于fcr3的id1结构域，粗体字序列对应于fcr3的dbl2xb结构域，下划线和粗体序列为id2arpdfcleppytgpckariiryfynakaglcqtfvyggcrakrnnfksaedcmrtcgganyikgdpyfaeyatklsfilnpsdannpsgetanhndeacncnesgissvgqaqtsgpssnktcithssiktnkkkeckdvklgvrendkdlkicviedtslsgvdncccqdllgilqencsdnkrgsssndscdnknqdecqkklekvfasltngykcdkcksgtsrskkkwiwkkssgneeglqeeyantiglpprtqslylgnlpklenvcedvkdinfdtkekflagclivsfhegknlkkrypqnknsgnkenlckaleysfadygdlikgtsiwdneytkdlelnlqnnfgklfgkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgaemnittcnadgsvtgsgsscddiptidlipqylrflqewvenfceqrqakvkdvitncksckesgnkcktecktkckdecekykkfieacgtagggigtagspwskrwdqiykryskhiedakrnrkagtkncgtssttnaaastdenkcvqsdidsffkhlidiglttpssylsnvlddnicgadkapwttyttytttekcnkerdksksqssdtlvvvnvpsplgntpyrykyacqckiptneetcddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrsnsskldrhrqprgweqlyptgaeflgdggdisfstrgtqnwtverllqahrqleergyvfvgyhgtfleaaqsivfggvrarsqdldaiwrgfyiagdpalaygyaqdqepdargrirngallrvyvprsslpgfyrtsltlaapeaageverlighplplrldaitgpeeeggrletilgwplaertvvipsaiptdprnvggdldpssipdkeqaisalpdyasqpgkpprkdel>bpti-id1-id2afcr3-pe38(seqidno:61)rpdfcleppytgpckariiryfynakaglcqtfvyggcrakrnnfksaedcmrtcgganyikgdpyfaeyatklsfilnpsdannpsgetanhndeacncnesgissvgqaqtsgpssnktcithssiktnkkkeckdvklgvrendkdlkicviedtslsgvdncccqdllgilqencsdnkrgsssndscdnknqdecqkklekvfasltngykcdkcksgtsrskkkwiwkkssgneeglqeeyantiglpprtqslylgnlpklenvcedvkdinfdtkekflagclivsfhegknlkkrypqnknsgnkenlckaleysfadygdlikgtsiwdneytkdlelnlqnnfgklfgkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgaemnittcnadgsvtgsgsscddiptidlipqylrflqewvenfceqrqakvkdvitncksckesgnkcktecktkckdecekykkfieacgtagggigtagspwskrwdqiykryskhiedakrnrkagtkncgtssttnaaastdenkcvqsdidsffkhlidiglttpssylsnvlddnicgadkapwttyttytttekcnkerdksksqssdtlvvvnvpsplgntpyrykyacqckiptneetcddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrsnsskldpeggslaaltahqachlpletftrhrqprgweqleqcgypvqrlvalylaarlswnqvdqvirnalaspgsggdlgeaireqpeqarlaltlaaaeserfvrqgtgndeagaangpadsgdallernyptgaeflgdggdisfstrgtqnwtverllqahrqleergyvfvgyhgtfleaaqsivfggvrarsqdldaiwrgfyiagdpalaygyaqdqepdargrirngallrvyvprsslpgfyrtsltlaapeaageverlighplplrldaitgpeeeggrletilgwplaertvvipsaiptdprnvggdldpssipdkeqaisalpdyasqpgkpprkdel>id1-id2afcr3-pe38(seqidno:62)nyikgdpyfaeyatklsfilnpsdannpsgetanhndeacncnesgissvgqaqtsgpssnktcithssiktnkkkeckdvklgvrendkdlkicviedtslsgvdncccqdllgilqencsdnkrgsssndscdnknqdecqkklekvfasltngykcdkcksgtsrskkkwiwkkssgneeglqeeyantiglpprtqslylgnlpklenvcedvkdinfdtkekflagclivsfhegknlkkrypqnknsgnkenlckaleysfadygdlikgtsiwdneytkdlelnlqnnfgklfgkyikknntaeqdtsyssldelreswwntnkkyiwtamkhgaemnittcnadgsvtgsgsscddiptidlipqylrflqewvenfceqrqakvkdvitncksckesgnkcktecktkckdecekykkfieacgtagggigtagspwskrwdqiykryskhiedakrnrkagtkncgtssttnaaastdenkcvqsdidsffkhlidiglttpssylsnvlddnicgadkapwttyttytttekcnkerdksksqssdtlvvvnvpsplgntpyrykyacqckiptneetcddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrsnss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diptidlipqylrflqewvenfceqrqakvkdvitncksckesgnkcktecktkckdecekykkfieacgtagggigtagspwskrwdqiykryskhiedakrnrkagtkncgtssttnaaastdenkcvqsdidsffkhlidiglttpssylsnvlddnicgadkapwttyttytttekcnkerdksksqssdtlvvvnvpsplgntpyrykyacqckiptneetcddrkeymnqwscgsartmkrgykndnyelckyngvdvkpttvrsnsskld>spycatcher(seqidno:129)gamvdtlsglsseqgqsgdmtieedsathikfskrdedgkelagatmelrdssgktistwisdgqvkdfylypgkytfvetaapdgyevataitftvneqgqvtvngkatkgdahi>spytag(seqidno:130)ahivmvdaykptk>最小spytag序列(seqidno:131)ahivmvda>cnab2的β-链(k-tag)(seqidno:132)athikfskrdspyligase(seqidno:133)hhhhhhdydgqsgdgkelagatmelrdssgktistwisdgqvkdfylypgkytfvetaapdgyevataitftvneqgqvtvngkatkggsggsggsgedsathi>异肽spy0128(seqidno:134)tdkdmtitftnkkdae>split-spy0128(seqidno:135)attvhgetvvngakltvtknldlvnsnalipntdftfkiepdttvnedgnkfkgvalntpmtkvtytnsdkggsntktaefdfsevtfekpgvyyykvteekidkvpgvsydttsytvqvhvlwneeqqkpvatyivgykegskvpiqfknsldsttltvkkkvsgtggdrskdfnfgltlkanqyykasekvmiekttkggqapvqteasidqlyhftlkdgesikvtnlpvgvdyvvteddyksekyttnvevspqdgavkniagnsteqetstdkdmti>spycatcher-δn(seqidno:136)edsathikfskrdedgkelagatmelrdssgktistwisdgqvkdfylypgkytfvetaapdgyevataitftvneqgqvtvngkatkgdahi>反向的spytag序列(seqidno:137)ktpkyadvmviha实施例方法方法1-克隆和蛋白质表达使用特异性引物(表2)，从密码子优化的fcr3(genbank登录号gu249598)或3d7(genbank登录号jq247428)var2csa基因扩增var2csa序列片段。在一步pcr中扩增简单片段。在两步pcr中制备氨基酸取代构建体。第一个pcr扩增了来自密码子优化的fcr3模板的两个片段，其含有重叠的互补末端。第二个pcr扩增了总构建体，使用两个重叠片段作为模板，使用特异于外部边界的引物。对所有片段进行测序以进行验证。将片段克隆到杆状病毒载体pacgp67-a(bdbiosciences)(被修饰成在c-末端含有v5和his标签)或pet大肠杆菌表达载体中。蛋白质在杆状病毒感染的昆虫细胞中表达作为分泌到细胞培养上清液的可溶性蛋白质或在大肠杆菌shuffle细胞中表达。使用用于基因设计的标准算法设计合成基因，考虑了二级dna和rna结构、重复区域和给定表达细胞系统的密码子选择。合成基因被制备用于spy-tag和spy-catcher融合以及car设计。方法2-蛋白纯化和sds-page使用交叉流(gehealthcare)透析含有分泌的重组蛋白的经过滤的上清液。透析在10mmnah2po4(ph7.4，sigma-aldrich)和500mmnacl中进行。将所得溶液过滤(0.2μm)，加入咪唑至终浓度为15mm。然后将蛋白质在1mlhisselect柱(h8286，sigma-aldrich)上纯化。结合的蛋白质用10mmnah2po4(ph7.4)，500mmnacl和500mm咪唑洗脱。通过使用20mmtris(ph8)和200mmnacl中的hiload16/60superdex200柱(gehealthcare)的尺寸排阻色谱法进一步纯化石英晶体微量天平测量和saxs所需的蛋白质以获得单体。通过sds-page验证蛋白质的纯度和结构完整性。方法3-elisa将falcon微量滴定板(351172，bdbiosciences)以3μg/ml的cspg(牛)(d8428，sigma)或hspg(h4777，sigma)和100μg/ml的csa(c9819，sigma)，csc(400675，seikagaku)和csb(c3788，sigma)在4℃孵育过夜。然后用振荡器在37℃下用tsm结合缓冲液(20mmtris,150mmnacl,2mmcacl2,0.05％tween-20,1％bsa,ph7.4，25℃)封闭板2小时。在tsm结合缓冲液中制备蛋白质的2倍稀释系列(1.56mm-100mm)，并加入至板中，将其在37℃下在振荡器上孵育1小时。所有测量一式三份进行。将板在tsm洗涤缓冲液(20mmtris,150mmnacl,2mmcacl2,0.05％tween-20,ph7.4，25℃)中洗涤三次。然后将板与1:3000的抗v5-hrp抗体(r96125，invitrogen)一起在tsm结合缓冲液中于37℃在振荡器上孵育1小时。将板在tsm洗涤缓冲液中洗涤三次。最后用邻苯二胺底物(dako)显影板15分钟。将反应用2.5mh2so4淬灭。在490nm处测量吸光度。方法4-石英晶体微量天平(attanaa100)在attanaa100(attanaab)上进行实验，使用镀金10mhz、at-切割石英晶体，聚苯乙烯芯片(3611-3103attanaab)。将所有缓冲液和试剂过滤至0.2μm。配体是以100μg/ml的浓度包被的cspg(牛)(d8428，sigma)或hspg(h4777，sigma)。通过加入配体溶液并在室温下静置孵育30分钟进行包被。随后用含有0.1％无ig的bsa(bsa-50，rockland)的pbs封闭平板，在室温下进行30分钟。在每次实验之前，使用制造商预先定义的日常洗涤程序，将attanaa100用1％sds洗涤。洗涤后，将运行缓冲液以25微升/分钟的流速在25℃下交换为pbs，并使机器稳定在0.5hz/min的最大频率变化。经稳定后，pbs被注射多次以显示注射过程对基线影响最小。在注射样品前，将pbs作为空白注射。从最低浓度开始，以1:3稀释系列(0.25μg/ml-60μg/ml)注射分析物。缔合时间设置为84秒，解离为5分钟。由于结合的高亲和力，注射后不可能再生结合表面。收集的数据在attester评估软件(attanaab)中进行处理。曲线在简单的1：1模型中拟合。通过曲线拟合确定kon和koff，并且基于kd＝koff/kon计算kd。方法5-癌细胞结合测定流式细胞术(fcm)用于检测var2csa最小结合多肽对各种细胞系表面表达的cspg的反应性。细胞在补充有10％胎牛血清(cho细胞，c32)，hamsf12(bewo)的rpmi中培养，在37℃下保持在5％二氧化碳中，或从cpd缓冲液中的人血液样品(红细胞)中纯化。将细胞的等分试样(1×105)在+4℃在黑暗中平稳搅拌的情况下依次暴露于在facs2(pbs+2％fcs)中稀释的var2csa最小结合多肽(150,75或37nm)和α-v5-fitc(1:800)(invitrogen)持续30分钟。作为阴性对照，使用截短形式的最小结合多肽和facs2缓冲液。基于正向和侧向散射信号门控完整细胞。使用fc500流式细胞仪(beckmancoulter)从至少5000个细胞获得数据。在单个测定中处理和分析与特定细胞系相关的所有样品。方法6-癌细胞结合测定作为上述流式细胞术测定的替代方案，将细胞与在hbss中稀释的var2csa最小结合多肽和α-v5-fitc(1：500)(invitrogen)一起孵育。以与上述相同的浓度使用var2csa多肽。在α-v5-fitc染色后，将细胞在hbss中洗涤3次，收集在无酶细胞分离缓冲液(invitrogen)中，并在facscalibur(bdbiosciences)上进行fl-1信号强度的分析。缩写：cidr，半胱氨酸丰富的域间区域；csa，硫酸软骨素a；cspg，硫酸软骨素蛋白聚糖；dbl，duffy结合样结构域；fcm，流式细胞术；fv2，无n末端片段的var2csa蛋白的全长胞外结构域；hspg，硫酸乙酰肝素蛋白聚糖；id，域间；ie，恶性疟原虫感染的红细胞；nts，n末端区段；pm，胎盘疟疾；pfemp1，恶性疟原虫红细胞膜蛋白1；pm，胎盘疟疾。方法7-石蜡包埋的人体组织样品的染色使用免疫组织化学(ihc)研究重组var2csa与从人类患者获得的原发性癌症组织的结合。将在未进行抗原恢复的载玻片上点样的石蜡包埋组织在室温下与0.1-500nmv5-var2csa变体或v5-对照蛋白(dbl4)孵育1小时，洗涤8分钟，用1:700小鼠抗-v5抗体孵育30分钟，洗涤8分钟。随后使用ventanadiscoveryxt平台利用ultramap抗小鼠hrp检测结合的抗v5。实施例1截短的重组var2csa蛋白质的产生根据先前定义的结构域边界产生所有蛋白质截短体(m,jorgensenlm,nielsenma,clausentm,ditlevsb,等人jbiolchem286:15908-15917)。为了简化起见，我们将cidrpam结构域划分为两个结构域id2a和id2b，其中id2a是不包含类似cidr的序列的cidrpam的n端部分，id2b对应于类似cidr的序列。我们还使用了一个新的dbl2x边界，其结合了id2a的93个氨基酸。为了简化起见，我们将这个边界称为dbl2xb，而旧的边界称为dbl2xa。用于克隆的引物列于表2中。如方法1中所述，片段在杆状病毒感染的昆虫细胞中表达为可溶性蛋白质。大多数蛋白质是基于fcr3基因型产生的。一些fcr3片段没有表达，而是基于3d7基因型进行制备的。蛋白质在分析中可互换使用，因为我们表明来自两种基因型的重组var2csa均等地与csa结合。当通过sds-page比较还原和非还原样品时，所有蛋白质都显示出凝胶迁移率的变化(方法2)。这与分子内二硫键的形成是一致的。一些蛋白质通过非还原型sds-page检测到形成高分子量复合物。这可能是由于在不成对的半胱氨酸之间形成分子间二硫键。这通过使用dtt将复合物还原成单体蛋白来证实。实施例2来自fcr3和3d7的var2csa以类似的亲和性和特异性结合csa与3d7或nf54(ie)相比，fcr3感染的红细胞(ie)在体外更强地粘附至csa。如果差异与表达的var2csa的序列差异相关，则该信息可用于定义粘附过程中涉及的残基。为了测试这一点，我们制作了一系列重叠的3d7var2csa片段，与我们以前针对fcr3测试的相同。首先在固相结合测定(elisa)(方法3中描述)中针对特异性cspg结合筛选蛋白质。然后通过尺寸排阻层析进一步纯化与cspg特异性结合的蛋白质，以获得纯单体蛋白质，并在石英晶体微量天平(attanaa100)上进行动力学分析(分别为方法2和4)。在固相结合测定中，3d7var2csa片段显示出与其fcr3对应物非常相似的结合特征。在动力学分析中也是如此(表3)。传感图显示了在不同蛋白质浓度下收集的缔合和解离数据。这允许确定缔合速率常数(kon)，解离速率常数(koff)和平衡常数(kd)。与峰值响应水平一起，这些参数给出了cspg结合亲和力的估计。3d7和fcr3片段之间没有明显差异。一些片段显示出较低的亲和力，但是这个特征在片段对应物中得到保持。这表明3d7和fcr3var2csa蛋白以相同的方式折叠并起作用。表3：产生的var2csa蛋白的csa结合亲和力。亲和性作为使用石英晶体微量天平生物传感器(attanaa100)的动力学实验中确定的kd(nm)值给出。n/a：由于缺乏对csa的结合，不能确定kd值的蛋白质。*etal,jbc,2011中公开的蛋白实施例3核心-csa结合位点位于dbl2x结构域内已经表明，var2csa中的最小csa结合区位于dbl2x-id2b内，需要侧翼结构域用于完全亲和结合(m,jorgensenlm,nielsenma,clausentm,ditlevsb,等人jbiolchem286:15908-15917)。在这里我们分析了var2csa的较短片段，以进一步绘制csa结合所需的区域。首先针对在elisa中与csa蛋白聚糖(cspg)的结合筛选截短的蛋白质，然后进一步纯化以获得用于在石英晶体微量天平上检测的单体(分别为方法3、2和4)。最小结合区域为id1-dbl2xb(表3)。该区域显示21.8nm的结合亲和力，其与全长var2csa的结合亲和力相当。胎盘ie对低硫酸化胎盘cspg具有高选择性。它们不粘附到任何其它糖胺聚糖(gag)，例如硫酸乙酰肝素(hs)。对于全长重组var2csa蛋白也是如此。固相结合测定显示含有最小csa结合区的var2csa片段特异性结合csa。为了证实这一点，进一步测试了最小结合片段与石英晶体微量天平上的硫酸乙酰肝素蛋白聚糖(hspg)的结合(方法4)。没有片段结合hspg。实施例4var2csa最小csa结合区域特异性结合到一大组癌细胞许多不同的癌细胞与蛋白聚糖cspg4的高表达有关。该分子最初被描述为黑色素瘤的标志物，但最近已经发现许多癌症形式，包括癌症干细胞。与cspg4附接的cs链已知主要是csa。通过流式细胞仪分析最小的var2csa片段之一(id1-id2a)与一大组各种各样的癌细胞系的结合(方法5和6)。非csa结合蛋白id1-dbl2xa用作阴性对照。var2csa重组蛋白(id1-id2a)以75nm强烈结合转录cspg4的所有癌细胞系(微阵列数据)，包括皮肤黑素瘤(c32，mewo)，肺癌(a549)，乳腺癌(hcc1395)，骨肉瘤(u2os，mnng/hos)，横纹肌肉瘤(rh30)(表4和表5)。该蛋白质也与不表达cspg4的皮肤t细胞淋巴瘤强烈结合(表4)。阴性对照蛋白id1-dbl2xa不结合任何测试的细胞系(表4)。此外，id1-id2a与作为对照细胞的人红细胞没有相互作用。还分析了野生型和gag缺陷型中国仓鼠卵巢(cho)细胞的id1-id2a相互作用。当分析cho-745细胞系(其中gag合成被破坏)时，id1-id2a与野生型cho细胞的强烈相互作用被完全消除。通过将var2csa与csa，csc或hs预混合抑制var2csa与细胞结合来证实相互作用的csa特异性。csc和hs对结合没有任何影响，而csa有效地消除了var2csa与癌细胞的结合。根据这些结果，使用var2csa的dbl1-id2a或id1-id2a片段，通过流式细胞术筛选出较大组的癌细胞(表6和7)。该筛选的主要目的是鉴定适合体内异种移植建模的细胞系。表4.使用var2csa的最小结合结构域(id1-id2a)染色癌细胞系和阴性对照细胞。细胞与单独的培养基(空白)或75nm的重组蛋白(id1-dbl2或id1-id2a)一起孵育30分钟，然后与1:800的抗v5-fitc(invitrogen)孵育，细胞在每次孵育之间洗涤三次。显示了使用fc500流式细胞仪(bectondickinson)从最少5000个细胞记录的平均fitc荧光值。表5.使用重组var2csa的癌细胞系染色将细胞与单独的培养基(空白)或75nm的重组蛋白(dbl1-id2a或id1-id2a)一起孵育30分钟，然后与1:800的抗v5-fitc(invitrogen)孵育，细胞在每次孵育之间洗涤三次。显示了使用hal100zeiss显微镜从最少4个高功率场图像记录的fitc荧光强度的中值评分。ns：无染色；+：弱；++：中等；+++：强；++++：非常强。表6筛选用于结合重组var2csa的多种人类癌细胞系(使用dbl1-id2a或id1-id2a)。如方法5和6所述，通过流式细胞术测量结合。ns：无染色；+：弱；++：中等；+++：强；++++：非常强。表7用于结合重组var2csa的更多人细胞癌细胞系的筛选(使用dbl1-id2a或id1-id2a)如方法5和6所述，通过流式细胞术测量结合。显示的值是使用200nm的蛋白质浓度的平均荧光强度。实施例5重组var2csa以高亲和力结合癌细胞使用石英晶体微量天平生物传感器(attanacell200)分析重组var2csa片段dbl1-id2a对癌细胞系、c32黑素瘤和两个cho细胞系(实施例8中所述)的结合亲和力。针对与细胞表面的结合分析蛋白质的2倍稀释系列(25-400nm)，其中在每个新蛋白质注射之间再生结合表面。估计结合亲和力在纳摩尔范围内(表8)，其与对纯受体的结合亲和力相似(表3)。表8.重组dbl1-id2a(大肠杆菌)对表达csa(c32和chowt)和缺乏与csa阴性细胞系(cho745)的结合的癌细胞的估计结合亲和力(kd)n/a：由于缺乏对细胞的结合，kd无法确定实施例6重组var2csa蛋白以高特异性结合癌组织使用免疫组织化学(ihc)研究重组var2csa与从人类患者获得的原发性癌症组织的结合。该方法采用人胎盘组织为阳性对照，扁桃体和肝组织为阴性对照。在ventanadiscoveryxt平台上优化了染色方案，没有进行表位修复。将贴在玻片上的石蜡包埋组织在室温下与0.1-500nmv5-var2csa(id1-id2a)或v5-对照蛋白(dbl4)孵育1小时，洗涤8分钟，与1：700小鼠抗-v5抗体孵育30分钟，洗涤8分钟。随后使用ultramap抗小鼠hrp检测结合的抗v5。v5-var2csa以0.5nm浓度染色人胎盘，在扁桃体或正常肝脏中无染色。通过向反应缓冲液中加入200μg/μlcsa可以完全阻断染色。v5-对照蛋白质不会在任何测试浓度下染色人胎盘组织。当用1nmv5-var2csa染色时，代表24个正常器官的多器官组织微阵列(tma)显示低或无染色，而乳腺，结肠，直肠，前列腺，肾，肝，膀胱，胰腺，鳞状细胞，肺，胆囊，胃，睾丸，卵巢，子宫，肾上腺，甲状腺和胸腺，造血系统和结缔组织(肉瘤)的癌样品阳性染色，强度等于或高于人胎盘阳性对照组织(表9)。表9.使用重组var2csa检测原代人肿瘤样品上的csa。表格显示了实施例10中所述的主要癌症组所染色的阳性数/病例总数。阳性染色定义为等于或高于胎盘组织中观察到的强度。实施例7鉴定由var2csa靶向的潜在cspg分子筛选具有v5-标签的重组var2csa蛋白(dbl1-id2a)与一组转染的表达>3000个人膜受体的hek293细胞的结合。已经鉴定了一组25个受体作为var2csa的潜在靶标(表10)。var2csa与这些受体之间的相互作用将通过在hek293系统和elisa中通过csa和hs的抑制进行结合特异性的分析来进一步验证。表10.实验鉴定为var2csa潜在靶标的受体。实施例8双特异性var2csa-scfv-抗cd3蛋白已经将dbl1-id2a和id1-id2avar2csa基因片段与编码针对cd3的单链抗体的scfv序列融合。这些var2csa-scfv蛋白在大肠杆菌或昆虫细胞中表达。这些var2csa-scfv蛋白针对表达csa的癌细胞和表达cd3的t细胞是双特异性的。因此，这些蛋白质能够通过var2csa结构域结合肿瘤环境中的csa，同时通过scfv-抗cd3结构域募集cd3阳性t细胞。实施例9var2csa-spy融合蛋白已经将dbl1-id2a和id1-id2avar2csa基因片段融合到spytag、k-tag、spycatcher和spycather-δn(seqidno：130,129,136)的各种变体。这些var2csa-spy蛋白在大肠杆菌或昆虫细胞中表达。重组var2csa-spy蛋白可以与相应的分割蛋白结合配偶体形成异肽键。例如，var2csa-spytag可以结合任何具有spycatcher或δn-spycather序列的分子；var2csa-spycatcher或var2csa-δn-spycather可以与任何具有spytag序列的分子结合；var2csa-spytag可以在spyligase存在下与任何具有k-tag序列的分子结合；或var2csa-k-tag可以在spyligase存在下与任何具有k-tag序列的分子结合。此外，var2csa-k-tag可以在spyligase存在下通过k-tag聚合(彼此连接)，并随后与任何蛋白质表达spycatcher(如spy-car)组合。因此，这些蛋白质能够结合具有分割蛋白结合系统的相应序列的任何蛋白质序列。通过将spy标记的var2csa蛋白与spy-catcher或spy-catcher标记的var2csa与spy-tag简单混合，我们观察到蛋白质之间的快速和有效的偶联，如通过尺寸排阻色谱法或sdspage所测量的。将spy标记的var2csa注射到具有建立的肿瘤的小鼠中，随后iv注射荧光标记的spy-catcher，通过ivis体内成像和死后分析证明，spy-tag和spy-catcher的异肽键和配对确实在体内发生。实施例10双特异性var2csa-spy-scfv-抗cd3融合蛋白已经将dbl1-id2a和id1-id2avar2csa基因片段与spytag、k-tag、spycatcher和spycather-δn(seqidno：130,129,136)和编码针对cd3的单链抗体的scfv序列的各种变体融合。这些var2csa-spy蛋白在大肠杆菌或昆虫细胞中表达。重组var2csa-spy-scfv-抗-cd3融合蛋白可以与相应的分割蛋白结合配偶体形成异肽键。例如，var2csa-spy-scfv-抗-cd3可以结合任何具有spycatcher或δn-spycather序列的分子；var2csa-spycatcher-scfv-抗-cd3或var2csa-δn-spycather-scfv-抗-cd3可以结合任何具有spytag序列的分子；var2csa-spy-scfv-抗-cd3可以在spyligase存在下与任何具有k-tag序列的分子结合；或var2csa-k-tag-scfv抗cd3可以在spyligase存在下与任何具有k-标记序列的分子结合。此外，var2csa-k-tag-scfv-抗-cd3可以在spyligase存在下通过k-tag聚合(彼此连接)，并随后与任何蛋白质表达spycatcher(例如spy-car)组合。如实施例9所述合成和验证var2csa-spy-scfv-抗-cd3蛋白。实施例11表达var2csa(var2-car)的嵌合抗原受体使用密码子优化算法(optimizer，pmid：17439967)合成car编码序列，并亚克隆到编码第二代(cd28跨膜和细胞内t细胞信号传导结构域和cd3-ζ链胞内t细胞信号传导结构域)；或第三代(与cd8，4-1bb和cd3-ζ细胞内t细胞信号传导结构域连接的cd28跨膜结构域)的“目的”载体中。通过用编码car逆转录病毒载体的质粒和rd114包膜糖蛋白转染293gp包装细胞(clonetech)，48-72小时后收集培养上清液(s/n)产生逆转录病毒载体上清液。将培养上清液冷冻或立即用于将okt3和il-2活化的人pbmc转导连续2天(在用预先暴露于含有s/n的载体的稀释液的rectronectin(clonetech)包被的平板上培养淋巴细胞)。通过流式细胞术测定转导的t细胞上的car表达。(表11)。表11.通过流式细胞术检测转导的t细胞的质膜上的var2-car的表达。阳性细胞百分比阴性细胞百分比var2-car61.40％38.60％实施例12表达spy-car的嵌合抗原受体使用密码子优化算法(optimizer，pmid：17439967)合成car编码序列spytag，spycatcher，δn-spycatcher或k-tag(seqidno：130，129，136或132)，并亚克隆到编码第二代(cd28跨膜和细胞内t细胞信号传导结构域和cd3-ζ链胞内t细胞信号转导结构域)；或第三代(与cd28，4-1bb和cd3-ζ细胞内t细胞信号传导结构域连接的cd8跨膜结构域)的“目的”载体。通过用编码car逆转录病毒载体和rd114包膜糖蛋白的质粒转染293gp包装细胞(clonetech)，48-72小时后收集培养上清液(s/n)产生逆转录病毒载体上清液。将培养上清液冷冻或立即用于将okt3和il-2活化的人pbmc转导连续2天(在用预先暴露于含有s/n的载体的稀释液的rectronectin(clonetech)包被的平板上培养淋巴细胞)。通过流式细胞术测定转导的t细胞上的car表达(表12)。表12.通过流式细胞术检测的转导的t细胞的质膜上的spy-car的表达。阳性细胞百分比阴性细胞百分比spy-car64.82％35.18％实施例13表达spy-car并随后与var2-spy融合蛋白连接的嵌合抗原受体：var2-spy-spy-car使用密码子优化算法(optimizer，pmid：17439967)合成car编码序列spytag，spycatcher，δn-spycatcher或k-标签(seqidno：130，129，136或132)，并亚克隆到编码第二代(cd28跨膜和细胞内t细胞信号传导结构域和cd3-ζ链细胞内t细胞信号转导结构域)；或第三代(与cd28，4-1bb和cd3-ζ细胞内t细胞信号结构域连接的cd8跨膜结构域)的“目的”载体。通过用编码car逆转录病毒载体和rd114包膜糖蛋白的质粒转染293gp包装细胞(clonetech)，48-72小时后收集培养上清液(s/n)产生逆转录病毒载体上清液。将培养物上清液冷冻或立即用于转导okt3和il-2活化的人pbmc连续2天(在用预先暴露于含有s/n的载体的稀释液的rectronectin(clonetech)包被的平板上培养淋巴细胞)。spy-car转基因t细胞随后与相应的var2csa-spy融合蛋白(对应于spy-car的分割蛋白结合系统的另一半)孵育以产生完全功能的var2csa-spy-spy-car受体。通过流式细胞术和/或共同免疫荧光测定转导的t细胞上的car表达(表13)。表13.随后将spy-car转基因t细胞与相应的var2csa-spy融合蛋白(对应于spy-car的分割蛋白结合系统的另一半)孵育以产生武装的var2csa-spy-spy-car受体，如通过流式细胞术和免疫荧光(if)共定位测量的。实施例14比较和选择var2-car为了针对var2-car和var2-spy-spy-car的转导效率进行归一化，分析效应t细胞的百分比car表达(转导百分比)。基于此，计算效应细胞与靶细胞的比率(e:t比率)。这与％裂解进行比较。一个裂解单位被定义为以10:1的e:t比率的靶细胞的30％裂解(如专利申请wo2013059593a1中所定义)。这个功能“单位”定义量化了所比较的每个转导的效应细胞群体中裂解活性的量。裂解单位表示构建体之间转导效率差异的归一化e：t比值。实施例15不同var2-car的裂解活性为了比较不同var2-car构建体的裂解潜力，使用五种不同的表达csa的肿瘤细胞系(例如colo205结肠直肠癌，reh白血病，um-uc13膀胱癌，pc-3前列腺癌和rh30儿科横纹肌肉瘤)在5lcr释放ctl测定或比色细胞毒性测定中比较编码正向和反向翻译的var2csa的car。作为对照，还在非表达csa的非致瘤性hek293细胞上测试var2-car。根据实施例14所述的各个car构建体的转导百分比，将e：t比率归一化，因此裂解值是直接可比的。var2-car的裂解活性的一个实例示于表14中。实施例16不同var2-spy-spy-car的裂解活性为了比较不同var2-spy-spy-car构建体的裂解潜力，使用五种不同的表达csa的肿瘤细胞系(例如colo205结肠直肠癌，reh白血病，um-uc13膀胱癌，pc-3前列腺癌和rh30儿科横纹肌肉瘤)在5lcr释放ctl测定或比色细胞毒性测定中比较编码正向和反向翻译的var2-spy-spy-car构建体的car。作为对照，还在非表达csa的非致瘤性hek293细胞上测试var2-spy-spy-car。根据实施例14所述的各个car构建体的转导百分比，将e：t比率归一化，因此裂解值是直接可比的。var2-spy武装的spy-car的裂解活性的一个实例示于表14中。表14.用var2-car或spy-car纯化和转导随后用var2-spy武装t细胞，如实施例13所示。将car以指定的e：t比率加入到uc13细胞中，t细胞介导的细胞毒性为如实施例15和16所述测量。实施例17不同var2-car和var2-spy-spy-car在体内的裂解活性在第0天，用被改造以表达荧光素酶的csa阳性的人癌细胞系(例如colo205结肠直肠癌，reh白血病，um-uc13膀胱癌，pc-3前列腺癌和rh30小儿横纹肌肉瘤)注射nsg(nodscidγ)免疫缺陷小鼠。在第3天，用1x107个对照t细胞(“模拟组”，未转导)或用var2-car和var2-spy-spy-car转导的1x107个t细胞处理小鼠。使用ivis的生物发光成像在30天的时间段内测量肿瘤负荷。用3mgd-荧光素(caliperlifesciences，inc。)腹膜内(i.p.)注射小鼠，注射后4分钟，麻醉的小鼠以10-60秒的暴露时间成像。livingimage软件用于将每只小鼠的生物发光信号分析为光子/s/cm/sr。附加说明本文引用的所有参考文献，包括出版物，专利申请和专利通过引用并入本文，其程度如同每个参考文献被单独地和具体地指示通过引用并入和在本文以其整体示出。在描述本发明的上下文中(特别是在所附权利要求的上下文中)中使用术语“一个”和“一种”和“所述”以及类似的指示物应被解释为包括单数和复数，除非本文另有说明或明显与上下文相矛盾。术语“包含”，“具有”，“含有”和“包括”将被解释为开放式术语(即意义“包括但不限于”)，除非另有说明。除非本文另有说明，本文中值的范围的描述仅旨在用作单独提及落在该范围内的每个单独值的速记方法，并且将每个单独的值并入本说明书中，如同在本文中单独列举一样。本文所述的所有方法可以以任何合适的顺序进行，除非本文另有说明或以其它方式明确地与上下文相矛盾。本文提供的任何和所有示例或示例性语言(例如“例如”)的使用仅旨在更好地举例说明本发明，并且不对本发明的范围构成限制，除非另有说明。说明书中的任何语言不应被解释为指示任何未被要求保护的元素对于本发明的实践是必需的。本文描述了本发明的优选实施方案，包括本发明人已知的用于实施本发明的最佳模式。在阅读前面的描述之后，这些优选实施方案的变化对于本领域普通技术人员来说可能变得明显。本发明人期望本领域技术人员适当地使用这种变化，并且发明人旨在以与本文具体描述的不同的方式实施本发明。因此，本发明包括根据适用法律允许的所附权利要求中列举的主题的所有修改和等同物。此外，除非本文另有说明或明确地与上下文相矛盾，本发明涵盖了所有可能变化的上述元件的任何组合。序列表<110>var2pharmaceuticalsaps<120>使用嵌合抗原受体（cars）的胎盘样硫酸软骨素的免疫治疗靶向和使用具有分割蛋白结合系统的cars的癌症的免疫治疗靶向<130>20308pct00<160>137<170>patentinversion3.5<210>1<211>640<212>prt<213>人工<220><223>人工构建体<400>1asntyrilelysglyaspprotyrphealaglutyralathrlysleu151015serpheileleuasnproseraspalaasnasnproserglygluthr202530alaasnhisasnaspglualacysasncysasngluserglyileser354045servalglyglnalaglnthrserglyproserserasnlysthrcys505560ilethrhisserserilelysthrasnlyslyslysglucyslysasp65707580vallysleuglyvalarggluasnasplysaspleulysilecysval859095ilegluaspthrserleuserglyvalaspasncyscyscysglnasp100105110leuleuglyileleuglngluasncysseraspasnlysargglyser115120125serserasnaspsercysaspasnlysasnglnaspglucysglnlys130135140lysleuglulysvalphealaserleuthrasnglytyrlyscysasp145150155160lyscyslysserglythrserargserlyslyslystrpiletrplys165170175lysserserglyasnglugluglyleuglngluglutyralaasnthr180185190ileglyleuproproargthrglnserleutyrleuglyasnleupro195200205lysleugluasnvalcysgluaspvallysaspileasnpheaspthr210215220lysglulyspheleualaglycysleuilevalserphehisglugly225230235240lysasnleulyslysargtyrproglnasnlysasnserglyasnlys245250255gluasnleucyslysalaleuglutyrserphealaasptyrglyasp260265270leuilelysglythrseriletrpaspasnglutyrthrlysaspleu275280285gluleuasnleuglnasnasnpheglylysleupheglylystyrile290295300lyslysasnasnthralagluglnaspthrsertyrserserleuasp305310315320gluleuargglusertrptrpasnthrasnlyslystyriletrpthr325330335alametlyshisglyalaglumetasnilethrthrcysasnalaasp340345350glyservalthrglyserglysersercysaspaspileprothrile355360365aspleuileproglntyrleuargpheleuglnglutrpvalgluasn370375380phecysgluglnargglnalalysvallysaspvalilethrasncys385390395400lyssercyslysgluserglyasnlyscyslysthrglucyslysthr405410415lyscys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