CN117425670A - 双特异性嵌合抗原受体和表达此类双特异性嵌合抗原受体的基因工程化免疫细胞 - Google Patents
双特异性嵌合抗原受体和表达此类双特异性嵌合抗原受体的基因工程化免疫细胞 Download PDFInfo
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Abstract
一种双特异性嵌合抗原受体(双特异性CAR),其在细胞外抗原结合结构域中包括单链可变片段(scFv)和单个可变结构域(VHH),其中所述scFv和所述VHH与肿瘤相关抗原结合。本文还提供了表达此类双特异性CAR的基因工程化免疫细胞和所述基因工程化免疫细胞的治疗用途。
Description
相关申请的交叉参考
本申请要求于2021年5月19日提交的美国临时专利申请第63/190,480号的优先权权益,所述美国临时专利申请特此通过引用整体并入本文。
背景技术
过继性细胞转移疗法是一种涉及自体或同种异体免疫细胞的离体扩增以及随后输注到患者中的免疫疗法的类型。可以离体对免疫细胞进行修饰以特异性靶向恶性细胞。修饰包含对T细胞进行工程化以表达嵌合抗原受体(CAR)。如CAR T细胞(CAR-T)疗法等过继性细胞转移疗法的前景通常受到毒性(例如,细胞因子相关的毒性)的限制。例如,过继性细胞转移免疫疗法可能触发细胞因子水平的非生理升高(细胞因子释放综合征),这可能导致接受者死亡(参见例如Morgan等人,《分子疗法(Molecular Therapy)》18(4):843-851,2010)。另外,经修饰的免疫细胞无法在患者体内很好地扩增,可能在体内无法存活很长时间,并且可能对其自身在体内活动引发的细胞毒性环境敏感。
因此,开发改善这些经修饰的免疫细胞的增殖并降低与CAR-T疗法相关的毒性,同时维持或增强治疗疗效的方法具有重大意义。
发明内容
本公开至少部分地基于双特异性嵌合抗原受体(CAR)的开发,所述双特异性CAR包括双特异性细胞外抗原结合结构域,所述双特异性细胞外抗原结合结构域与两个单独抗原或抗原表位结合,由此改善在体内表达此类双特异性嵌合抗原受体的免疫细胞的治疗疗效。
在一些方面,本公开提供了一种双特异性嵌合抗原受体(CAR)多肽,所述双特异性CAR多肽包括:(a)第一抗原结合部分;(b)第二抗原结合部分;(c)共刺激信号传导结构域;以及(d)细胞质信号传导结构域。所述第一抗原结合部分可以为单结构域抗体可变片段,如VHH片段,并且所述第二抗原结合部分可以为单链可变片段(scFv)。
所述第一抗原结合部分与第一肿瘤相关抗原结合,并且所述第二抗原结合部分与第二肿瘤相关抗原结合,所述第二肿瘤相关抗原不同于所述第一肿瘤相关抗原。在一些情况下,所述第一肿瘤抗原和所述第二肿瘤抗原选自5T4、CD2、CD3、CD5、CD7、CD19、CD20、CD22、CD30、CD33、CD38、CD70、CD123、CD133、CD171、CEA、CS1、BCMA、BAFF-R、PSMA、PSCA、桥粒芯蛋白(Dsg3)、HER-2、FAP、FSHR、NKG2D、GD2、EGFRVIII、间皮素、ROR1、MAGE、MUC1、MUC16、GPC3、Lewis Y、Claudin18.2和VEGFRII。在具体实例中,所述第一肿瘤抗原为CD19,并且所述第二肿瘤抗原为BCMA。可替代地,所述第一肿瘤抗原为BCMA,并且所述第二肿瘤抗原为CD19。
在一些实施例中,本文所公开的双特异性CAR多肽中的所述第一抗原结合部分为与CD19结合的VHH片段(抗CD19 VHH),并且所述第二抗原结合部分为与BCMA结合的scFv(抗BCMA scFv)。可替代地,所述第一抗原结合部分为与BCMA结合的VHH(抗BCMA VHH),并且所述第二抗原结合部分为与CD19结合的scFv片段(抗CD19 scFv)。
在一些实例中,所述双特异性CAR包括抗CD19 scFv,所述抗CD19 scFv可以包括SEQ ID NO:7、8或9的氨基酸序列。可替代地或另外地,所述双特异性CAR进一步包括抗BCMAVHH,所述抗BCMA VHH可以包括SEQ ID NO:4、5或6的氨基酸序列。在具体实例中,所述双特异性CAR包括SEQ ID NO:11的氨基酸序列(例如,作为细胞外双特异性抗原结合结构域)。
在其它实例中,所述双特异性CAR包括抗CD19 VHH,所述抗CD19 VHH可以包括SEQID NO:1、2或3的氨基酸序列。可替代地或另外地,所述双特异性CAR进一步包括抗BCMAscFv,所述抗BCMA scFv可以包括SEQ ID NO:10的氨基酸序列。此类双特异性CAR可以包括SEQ ID NO:11、12、71或72的氨基酸序列。在一个具体实例中,所述双特异性CAR包括SEQ IDNO:11的氨基酸序列(例如,作为细胞外双特异性抗原结合结构域)。在另一个具体实例中,所述双特异性CAR包括SEQ ID NO:12的氨基酸序列(例如,作为细胞外双特异性抗原结合结构域)。
在其它方面,本公开提供了一种双特异性嵌合抗原受体(CAR)多肽,所述双特异性CAR多肽包括:(a)第一抗原结合部分,所述第一抗原结合部分为与BCMA结合的APRIL截短片段;(b)第二抗原结合部分,所述第二抗原结合部分为单结构域抗体可变片段(VHH)或与肿瘤相关抗原(例如,CD19)结合的单链可变片段(scFv);(c)共刺激信号传导结构域;以及(d)细胞质信号传导结构域。
在一些情况下,所述与BCMA结合的APRIL截短片段包括与SEQ ID NO:58至少90%相同的氨基酸序列。在一些实例中,所述APRIL截短片段包括SEQ ID NO:58的氨基酸序列。可替代地或另外地,所述第二抗原结合部分为抗CD19 scFv或抗CD19 VHH。在一些实例中,所述第二抗原结合部分为抗CD19 scFv,所述抗CD19 scFv可以包括SEQ ID NO:7、8或9的氨基酸序列。在其它实例中,所述第二抗原结合部分为抗CD19 VHH,所述抗CD19 VHH可以包括SEQ ID NO:1、2或3的氨基酸序列。在具体实例中,所述双特异性CAR多肽可以包括SEQ IDNO:59、60、61或62的氨基酸序列(例如,作为细胞外双特异性抗原结合结构域)。
本文所公开的任何双特异性CAR多肽可以进一步包括位于所述第一抗原结合部分与所述第二抗原结合部分之间的肽接头。此类肽接头的长度可以为约4-40个氨基酸。在一些实例中,本文所公开的双特异性CAR多肽可以包括来自4-1BB或CD28的共刺激信号传导结构域。可替代地或另外地,所述双特异性CAR多肽中的所述细胞质信号传导结构域可以包括CD3z细胞质信号传导结构域、IL-2Rβ细胞质信号传导结构域或其组合。在具体实例中,所述双特异性CAR多肽中的所述细胞质信号传导结构域包括CD3□细胞质信号传导结构域和所述IL-2Rβ细胞质信号传导结构域两者。在一些情况下,所述细胞质信号传导结构域包括CD3z细胞质信号传导结构域,所述CD3z细胞质信号传导结构域任选地包括STAT结合基序,例如,位于C末端处的STAT结合基序。
本文所公开的任何双特异性CAR多肽可以进一步为跨膜结构域、铰链结构域或其组合。在一些情况下,所述跨膜结构域和/或所述铰链结构域可以位于所述第一抗原结合部分或所述第二抗原结合部分与所述共刺激结构域之间。在一些实例中,所述跨膜结构域和/或所述铰链结构域来自CD8。
本文所提供的示例性双特异性CAR多肽可以包括SEQ ID NO:63-70的任何氨基酸序列。
在其它方面,本公开还提供了一种基因工程化免疫细胞群体,所述基因工程化免疫细胞表达如本文所公开的双特异性CAR多肽。所述基因工程化免疫细胞(如T细胞)群体可以进一步包括以下特征中的一个或多个特征:(a)具有一个或多个被破坏的编码一种或多种促炎细胞因子的内源性基因;和(b)表达一种或多种靶向所述促炎细胞因子的拮抗剂。在一些实施例中,所述促炎细胞因子包含干扰素γ(IFNγ)、白介素6(IL-6)、GM-CSF、白介素1(IL-1)或其组合。
在一些实施例中,所述基因工程化免疫细胞群体可以包括被破坏的内源性干扰素γ基因、被破坏的内源性GM-CSF基因或其组合。在一些情况下,所述内源性干扰素γ基因、所述内源性GM-CSF基因或两者被CRISPR/Cas基因编辑系统破坏。
可替代地或另外地,所述基因工程化免疫细胞表达IL-6拮抗剂、IFNγ拮抗剂、IL-1拮抗剂或其组合。在一些实例中,所述IL-6拮抗剂为对人IL6具有特异性的抗体(抗IL6抗体)或对人IL6R具有特异性的抗体(抗IL6R抗体)。在一些实例中,所述IFNγ拮抗剂为对人IFNγ具有特异性的抗体(抗IFNγ抗体)。在一些情况下,所述抗IL6抗体、所述抗IFNγ抗体或两者可以为scFv抗体。
在一些实例中,所述基因工程化免疫细胞表达抗IFNγscFv,所述抗IFNγscFv包括重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:13的氨基酸序列,所述轻链可变区包括SEQ ID NO:14的氨基酸序列。此类抗IFNγscFv可以包括SEQ ID NO:15的氨基酸序列。在其它实例中,所述基因工程化免疫细胞表达抗IFNγscFv,所述抗IFNγscFv包括重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:16的氨基酸序列,所述轻链可变区包括SEQ ID NO:17的氨基酸序列。此类抗IFNγscFv可以包括SEQ ID NO:18的氨基酸序列。在又其它实例中,所述基因工程化免疫细胞表达抗IFNγscFv,所述抗IFNγscFv包括重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:19的氨基酸序列,所述轻链可变区包括SEQ ID NO:20的氨基酸序列。此类抗IFNγscFv可以包括SEQ ID NO:21的氨基酸序列。
在一些具体实例中,表达本文所公开的任何抗IFNγscFv抗体的基因工程化免疫细胞可以进一步表达双特异性CAR,所述双特异性CAR包括SEQ ID NO:63、64、65或66的氨基酸序列。
在一些实例中,所述基因工程化免疫细胞表达抗IL6 scFv,所述抗IL6 scFv可以包括重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:24的氨基酸序列,所述轻链可变区包括SEQ ID NO:25的氨基酸序列。在其它实例中,所述基因工程化免疫细胞表达抗IL6 scFv,所述抗IL6 scFv可以包括重链可变区和轻链可变区,所述重链可变区包括SEQID NO:26的氨基酸序列,所述轻链可变区包括SEQ ID NO:27的氨基酸序列。在又其它实例中,所述基因工程化免疫细胞表达抗IL6 scFv,所述抗IL6 scFv可以包括重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:30的氨基酸序列,所述轻链可变区包括SEQ IDNO:31的氨基酸序列。
可替代地,所述基因工程化免疫细胞表达抗IL6 scFv,所述抗IL6 scFv可以包括重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:22的氨基酸序列,所述轻链可变区包括SEQ ID NO:23的氨基酸序列。在其它实例中,所述基因工程化免疫细胞表达抗IL6scFv,所述抗IL6 scFv可以包括重链可变区和轻链可变区,所述重链可变区包括SEQ IDNO:28的氨基酸序列,所述轻链可变区包括SEQ ID NO:29的氨基酸序列。在又其它实例中,所述基因工程化免疫细胞表达抗IL6R scFv,所述抗IL6R scFv可以包括重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:32的氨基酸序列,所述轻链可变区包括SEQ IDNO:33的氨基酸序列。
在具体实例中,所述基因工程化免疫细胞可以表达抗IL6 scFv或抗IL6R scFv,所述抗IL6 scFv或所述抗IL6R scFv包括SEQ ID NO:34、35、36或37的氨基酸序列。
在一些实例中,所述基因工程化免疫细胞表达IL-1拮抗剂,为IL-1RA,所述IL-1RA可以包括SEQ ID NO:36的氨基酸序列。
本文所公开的基因工程化免疫细胞群体可以包括T细胞、肿瘤浸润性淋巴细胞、自然杀伤(NK)细胞、树突状细胞、巨噬细胞、B细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、肥大细胞、髓源性抑制细胞、间充质干细胞、其前体或其组合。在一些情况下,所述免疫细胞为人免疫细胞。在具体实例中,所述人免疫细胞包括人T细胞。
此外,本公开提供了一种药物组合物,所述药物组合物包括本文所公开的免疫细胞群体以及药学上可接受的载剂。
在又其它方面,本公开的特征在于一种用于减少或消除受试者体内不期望的细胞的方法,所述方法包括向有需要的受试者施用治疗有效量的本文所公开的免疫细胞群体或包括此类免疫细胞群体的药物组合物。在一些情况下,所述受试者为患有癌症的人类患者,所述癌症包括表达所述第一肿瘤相关抗原、所述第二肿瘤相关抗原或两者的癌细胞。
在一些实例中,所述受试者为患有实体瘤或血液学癌症的人类患者。例如,所述人类患者可能患有实体瘤,所述实体瘤可能为乳腺癌、肺癌、胰腺癌、肝癌、胶质母细胞瘤(GBM)、前列腺癌、卵巢癌、间皮瘤、结肠癌或胃癌。在其它实例中,所述人类患者可能患有血液学癌症,所述血液学癌症可能为白血病、淋巴瘤或多发性骨髓瘤。
此外,在本公开的范围内的是本文所述的用于治疗本文所述的靶疾病(例如,癌症)的免疫细胞群体和药物组合物,以及此类免疫细胞群体和药物组合物在制备用于治疗靶疾病(如癌症)的药物中的用途。
在以下描述中阐述了本发明的一个或多个实施例的细节。根据以下附图和若干实施例的详细说明并且根据所附权利要求,本发明的其它特征或优点将变得显而易见。
附图说明
图1是示出在双特异性嵌合抗原受体(CAR)的细胞外抗原结合结构域中具有抗原结合部分(例如,scFv和VHH)的串联布置的双特异性CAR多肽的示例性设计的示意图。
图2A-2C包含示出接受分泌示例性抗IFNγscFv以及任选地示例性抗IL6 scFv的双特异性抗BCMAVHH/抗CD19 scFv CAR T细胞的ALL患者的外周血中CAR-T细胞扩增和IFNγ水平的图。图2A:来自接受分泌示例性抗IFNγscFv的双特异性抗BCMA VHH/抗CD19 scFvCAR T细胞的ALL患者的CAR+T细胞表达。图2B:ALL患者的外周IFNγ水平。图2C:接受分泌示例性抗IFNγscFv和示例性抗IL6 scFv两者的双特异性抗BCMA VHH/抗CD19 scFv CAR T细胞的ALL患者的外周血中IFNγ的水平。
图3A-3E包含示出被诊断为患有难治性和复发性多发性骨髓瘤(MM)并用表达单独的双特异性抗CD19 VHH scFv/抗BCMA scFv CAR或其与抗IFNγscFv的组合的基因工程化T细胞治疗的患者的外周血中CAR-T细胞扩增和IFNγ水平的图。图3A和3C-3D:用共表达双特异性CAR和抗IFNγscFv的基因工程化T细胞治疗的患者的CAR-T细胞扩增。图3B:用共表达双特异性CAR和抗IFNγscFv的基因工程化T细胞治疗的示例性患者的血液IFNγ水平。图3E:用表达双特异性CAR但不表达抗IFNγscFv的基因工程化T细胞治疗的患者的CAR-T细胞扩增。
图4A-4C包含示出表达单独的双特异性抗CD19 VHH scFv/抗BCMA scFv-CAR或其与抗IFNγscFv的组合的基因工程化T细胞的体外细胞毒性的图。图4A:靶向Nalm6细胞。图4B:靶向MM1S细胞。图4C:靶向RPMI 8226细胞。
具体实施方式
过继性细胞转移免疫疗法依赖于免疫细胞激活和细胞因子分泌以消除疾病细胞,如癌细胞。然而,CAR-T细胞在患者体内并不总是扩增或激活良好。
本公开旨在通过例如开发靶向多种肿瘤相关抗原或肿瘤相关抗原的多个部分的双特异性嵌合抗原受体(CAR)来克服与当前过继性CAR-T疗法相关的限制,由此改善体内治疗疗效。在一些情况下,本文所公开的双特异性CAR中的多个抗原结合部分可以呈单结构域抗体形式(例如,VHH)和单链可变片段(scFv)形式的组合。
据观察,包含scFv-scFv串联形式的双特异性CAR在一些情况下表现出CAR表达问题,所述问题可能是由两个scFv结合部分之间的干扰引起的。在不受理论约束的情况下,VHH/scFv双特异性CAR形式被设计用于解决此潜在的CAR表达问题。迄今为止测试的呈VHH/scFv形式的示例性双特异性CAR在免疫细胞中全部表现出令人满意的表达。表达本文所公开的双特异性CAR的基因工程化免疫细胞(例如,T细胞)可以包括另外的基因修饰,所述基因修饰例如被工程化以表达促炎细胞因子的拮抗剂,被工程化以破坏促炎细胞因子的内源性基因或其组合。
I.双特异性嵌合抗原受体
在一些方面,本公开提供了一种双特异性嵌合抗原受体(CAR),其能够与两种不同肿瘤相关抗原或肿瘤相关抗原的两个不同抗原表位(其可以在同一抗原中)结合。
CAR是一种人工(非天然存在的)受体,所述人工受体对所关注靶抗原(例如,肿瘤细胞抗原)具有结合特异性,并且能够在与靶抗原结合时在免疫细胞表达中触发免疫应答。CAR通常包括与至少一个细胞内信号传导结构域融合的细胞外抗原结合结构域。Cartellieri等人,《生物医学与生物技术杂志(J Biomed Biotechnol)》2010:956304,2010。本文所公开的双特异性CAR包括对不同靶抗原或不同抗原表位具有特异性的两个抗原结合部分(即,第一抗原结合部分和第二抗原结合部分)。在一些情况下,本文所公开的双特异性CAR可以为包括作为细胞外结构域和细胞内结构域的两个抗原结合部分的单个多肽,所述多肽可以包括一个或多个信号传导结构域,例如共刺激信号传导结构域、细胞质信号传导结构域或其组合。细胞外结构域和细胞内结构域可以通过铰链结构域、跨膜结构域或其组合连接。
在一些实例中,柔性肽接头(例如,富含G/S的接头)可以用于连接两个相邻的功能结构域,例如两个抗原结合部分。例如,富含G/S的接头可以包括(G4S)n的基序,其中n为1、2、3、4、5或6。示例性富含G/S的接头包含G4S(SEQ ID NO:75)、(G4S)3(SEQ ID NO:76)或和(G4S)4(SEQ ID NO:77)。在另一个实例中,柔性肽接头可以包括EAAAK(SEQ ID NO:74)的基序。此类肽接头可以包含基序的一个或多个拷贝,例如基序的1、2、3、4、5或6个拷贝。
可以在图1中找到本文所公开的双特异性CAR的示例性设计。
(a)双特异性细胞外抗原结合结构域
本文所公开的双特异性CAR多肽的细胞外抗原结合结构域对两种所关注抗原(例如,病理抗原,如肿瘤相关抗原,也称为癌症抗原)或两个抗原表位具有特异性。如本文所使用的,肿瘤相关抗原(TAA)是相对于非肿瘤细胞或其它类型的肿瘤细胞在肿瘤细胞或特定类型的肿瘤细胞上表现出升高水平的抗原。
细胞外抗原结合结构域包括能够与两种所关注抗原(例如,两种肿瘤相关抗原)或所关注抗原的两个抗原表位结合的第一抗原结合结构域和第二抗原结合结构域。所关注抗原也可以为在细胞上表达的任何天然分子,所述天然分子已被鉴定为用于各种类型的癌症的有前景的免疫疗法靶抗原。
在一些实施例中,本文所述的双特异性CAR多肽的第一抗原结合结构域可以呈单结构域抗体形式,例如仅重链抗体片段(VHH),并且第二抗原结合结构域可以呈单链可变片段(scFv)形式。
单结构域抗体(如VHH)为一种包含单个单体可变抗体结构域的抗体。此类抗体可以源自羊驼重链IgG抗体。可替代地,能够与特异性靶抗原结合的VHH抗体可以通过常规方法(例如,抗体文库筛选)分离。
scFv片段包含通过柔性肽接头连接的重链可变区(VH)和轻链可变区(VL)。在一些实例中,scFv可以处于VH至VL朝向(N末端至C末端)。可替代地,scFv可以处于VL至VL朝向(N末端至C末端)。用于连接scFv片段的VH和VL结构域(或本文所公开的双特异性CAR多肽中的任何两个相邻功能结构域)的柔性肽接头可以为富含G/S的肽接头,所述富含G/S的肽接头在本领域中通常用于融合多肽。下文序列表2中提供了示例性肽接头。
VHH和scFv可以通过柔性肽接头(如G/S肽接头)连接,所述柔性肽接头在本领域中通常用于连接两个功能结构域。在一些情况下,细胞外结构域可以处于VHH至scFv朝向(N末端至C末端)。可替代地,细胞外结构域可以处于scFv至VHH朝向(N末端至C末端)。参见图1所示的示例性布置。
在一些实施例中,第一抗原结合结构域和第二抗原结合结构域可以与两种肿瘤相关抗原结合。肿瘤相关抗原的非限制性实例包含5T4、CD2、CD3、CD5、CD7、CD19、CD20、CD22、CD30、CD33、CD38、CD70、CD123、CD133、CD171、CEA、CS1、BCMA、BAFF-R、seprase(也称为FAP)、PSMA、PSCA、桥粒芯蛋白(Dsg3)、HER-2、FAP、FSHR、NKG2D、GD2、EGFRVIII、间皮素、ROR1、MAGE、MUC1、MUC16、GPC3、Lewis Y、Claudin 18.2和VEGFRII。
在其它实例中,靶肿瘤抗原之一为FAP,所述FAP是一种在癌症相关成纤维细胞(CAF)上表达的表面表达的蛋白水解酶。FAP被视为如前列腺癌、肺癌和胰腺癌以及间皮瘤等癌的基质微环境的主要组成部分。此外,与正常组织相比,FAP在很大一部分患者肿瘤和患者源性胶质母细胞瘤培养物中始终过表达。
在一些实施例中,双特异性CAR的细胞外抗原结合结构域靶向CD19和B细胞成熟抗原(BCMA)。在一些实例中,细胞外抗原结合结构域包括呈VHH形式的抗CD19抗原结合结构域(抗CD19 VHH)。序列表1中提供了抗CD19 VHH片段的实例(SEQ ID NO:1-3)。参见例如S.R.Banihashemi等人,《伊朗基础医学杂志(Iran J Basic Med Sci),21(5):455-464,2018和CN 1053848258,所述文献的相关公开内容出于本文所引用的主题和目的通过引用并入。可替代地,细胞外抗原结合结构域包括呈scFv形式的抗CD19抗原结合结构域(抗CD19scFv)。序列表1中还提供了抗CD19 scFv的实例(SEQ ID NO:7-9、71)。还参见WO 2020/135335,其内容通过引用整体并入本文。在一些情况下,抗CD19 VHH或抗CD19 scFv可以源自序列表1中提供的示例性抗CD19 VHH或示例性抗CD19 scFv,所述示例性抗CD19 VHH或示例性抗CD19 scFv例如具有相同的重链和轻链互补决定区(CDR)。序列表1中列出的示例性抗体的基于Kabat定义确定的重链和轻链CDR呈粗体形式并加下划线。
靶向CD19和BCMA的双特异性CAR的细胞外结合结构域可以包括呈VHH形式的抗BCMA抗原结合结构域(抗BCMA VHH)。序列表1中提供了抗BCMA VHH片段的实例(SEQ ID NO:4-6)。还参见WO2018/237037,其相关公开内容出于本文所引用的主题和目的通过引用并入。可替代地,细胞外抗原结合结构域包括呈scFv形式的抗BCMA抗原结合结构域(抗BCMAscFv)。序列表1中还提供了抗BCMA scFv的实例(SEQ ID NO:10-12、72)。在一些情况下,抗BCMA VHH或抗BCMA scFv可以源自序列表1中提供的任何示例性抗BCMA VHH或示例性抗BCMA scFv,所述示例性抗BCMA VHH或示例性抗BCMA scFv例如具有相同的重链和轻链互补决定区(CDR)。序列表1中列出的示例性抗体的基于Kabat定义确定的重链和轻链CDR呈粗体形式并加下划线。
本文所述的抗CD19/抗BCMA双特异性CAR多肽可以包括抗CD19 VHH结合部分和抗BCMA scFv结合部分,所述抗CD19 VHH结合部分和抗BCMA scFv结合部分可以处于任何合适的朝向,例如,抗CD19 VHH/抗BCMA scFv(N末端至C末端)或抗BCMA scFv/抗CD19 VHH(N末端至C末端)。抗CD19 VHH和抗BCMA scFv片段可以通过柔性肽接头连接,例如序列表1和序列表2中提供的柔性肽接头。可替代地,本文所述的抗CD19/抗BCMA双特异性CAR多肽可以包括抗BCMA VHH结合部分和抗CD19scFv结合部分,所述抗BCMA VHH结合部分和抗CD19 scFv结合部分可以处于任何合适的朝向,例如,抗BCMA VHH/抗CD19 scFv(N末端至C末端)或抗CD19 scFv/抗BCMA VHH(N末端至C末端)。抗BCMA VHH和抗CD19 scFv片段可以通过柔性肽接头连接,例如序列表1和序列表2中提供的柔性肽接头。
在一些实例中,本文所述的抗CD19/抗BCMA双特异性CAR多肽包括:(a)抗CD19scFv,所述抗CD19 scFv包括SEQ ID NO:7、8或9的氨基酸序列;以及(b)抗BCMA VHH,所述抗BCMA VHH包括SEQ ID NO:4、5或6的氨基酸序列。
在一些实例中,本文所述的抗CD19/抗BCMA双特异性CAR多肽包括:(a)抗CD19VHH,所述抗CD19 VHH包括SEQ ID NO:1、2或3的氨基酸序列;以及(b)抗BCMA scFv,所述抗BCMAscFv包括SEQ ID NO:10的氨基酸序列。
本文所公开的靶向CD19和BCMA两者的双特异性CAR的示例性细胞外结构域包括序列表1中提供的SEQ ID NO:11、12、71和72中的任一者的氨基酸序列。
在一些实施例中,抗CD19/抗BCMA双特异性CAR多肽可以包括:(a)与BCMA结合的截短的APRIL片段(例如,APRIL的典型序列的残基116至250(Uniprot 075888),Lee,L.等人,2018,《血液(Blood)》,131(7):746–758);以及(b)与CD19结合的抗原结合部分,例如呈VHH或scFv形式,如本文所公开的任何抗CD19 VHH或抗CD19 scFv(参见序列表1)。APRIL(增殖诱导配体)是用于BCMA和跨膜激活剂的天然高亲和力配体以及钙调节剂和亲环素配体(TACI)。APRIL也称为TNFSF13。APRIL的氨基末端与蛋白多糖结合,但不参与和BCMA或TACI的相互作用。在一些情况下,截短的APRIL片段(trAPRIL)可以包括用于与BCMA结合但不具有蛋白多糖结合活性的天然存在的人APRIL的残基116至250(例如,由其组成)。在一种情况下,trAPRIL缺乏来自野生型APRIL分子的N末端115个氨基酸。参见美国专利第10,160,794号,所述美国专利的相关公开内容出于本文所引用的目的和主题通过引用并入。作为一个实例,用于制备双特异性CAR的trAPRIL可以被示出为SEQ ID NO:58。可替代地,trAPRIL片段可以与SEQ ID NO:58具有至少85%、88%、90%、92%、95%、97%、99%的同一性并与BCMA结合。BCMA结合可以通过本领域已知的任何方法来确定,例如,如美国专利第10,160,794号中描述的方法。
在一些实例中,抗CD19部分可以为抗CD19 scFv,所述抗CD19 scFv例如包括SEQID NO:7、8或9的氨基酸序列。可替代地,抗CD19部分可以为抗CD19 VHH,所述抗CD19 VHH例如包括SEQ ID NO:1、2或3的氨基酸序列。
抗CD19部分可以通过柔性肽接头连接到trAPRIL,例如本文所公开的柔性肽接头(例如,SEQ ID NO:57或73)。在一些情况下,抗CD19部分可以位于相对于trAPRIL的N末端部分处。可替代地,trAPRIL可以位于相对于抗CD19部分的N末端部分处。含trAPRIL的双特异性细胞外结构域的实例包含SEQ ID NO:59、60、61和62。
(b)细胞内信号传导结构域
本文所公开的任何双特异性CAR多肽可以进一步包括共刺激结构域。共刺激结构域的非限制性来源包含OX40、CD70、CD27、CD28、CD5、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、DAP10和DAP12。因此,CAR可以具有源自4-1BB、OX40、CD70、CD27、CD28、CD5、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、DAP10和DAP12或其任何组合的共刺激结构域。在一些实例中,双特异性CAR可以包括来自共刺激受体4-1BB(又名CD137),例如来自人4-1BB的共刺激结构域。4-1BB共刺激信号传导结构域的一个实例包括氨基酸序列SEQ ID NO:39(例如,由其组成)。
可替代地或另外地,双特异性CAR多肽可以进一步包括细胞质信号传导结构域,所述细胞质信号传导结构域包括ITAM,如CD3ζ信号传导结构域。示例性CD3ζ信号传导结构域包含但不限于包括SEQ ID NO:43(例如,由其组成)的片段。在一些情况下,CD3ζ信号传导结构域可以被修饰以插入STAT结合基序,例如,连接到其C末端部分。STAT3结合基序可以具有氨基酸序列YX1X2Q,其中X1和X2各自独立地为氨基酸。具体地,YX1X2Q基序可以是YRHQ(SEQID NO:41)。在一些实例中,含CD3ζ信号传导结构域和STAT3结合基序的CAR构建体中的片段可以包括SEQ ID NO:42的氨基酸序列(例如,由其组成)。
在一些情况下,本文所公开的双特异性CAR多肽可以进一步包括IL-2Rβ信号传导结构域,所述IL-2Rβ信号传导结构域可以任选地与含ITAM的细胞质信号传导结构域(如CD3ζ信号传导结构域)、另外的共刺激结构域(如来自4-1BB的共刺激结构域)或两者组合。在不受理论约束的情况下,IL2Rβ信号传导结构域的存在可以显著改善CAR-T细胞在体内的持久性,所述CAR-T细胞表达包括此类CAR-T细胞的双特异性CAR多肽。IL2Rβ是白介素-2受体(IL-2R)的β链。IL-2Rβ信号传导结构域是指能够触发由IL-2/IL-2R相互作用介导的信号传导通路的(例如,合适物种,如人的)IL2Rβ多肽中的片段。IL-2Rβ多肽和其中的信号传导结构域是本领域已知的。例如,GENBANK登录号NP_000869.1(其内容通过引用并入本文)中提供了人IL-2Rβ多肽。来自其它物种的IL-2Rβ多肽可以从如GENBANK等可公开获得的基因数据库获得。
在一些实例中,本文所公开的双特异性CAR多肽中使用的IL2Rβ信号传导结构域包括与SEQ ID NO:40的氨基酸序列至少80%(例如,至少85%、90%、95%、98%或以上)相同的氨基酸序列。在一个实例中,IL2Rβ信号传导结构域包括SEQ ID NO:40(例如,由其组成)。
使用Karlin和Altschul《美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)》87:2264-68,1990的算法来确定两个氨基酸序列的“同一性百分比”,所述算法如Karlin和Altschul《美国国家科学院院刊》90:5873-77,1993中那样进行修改。此类算法并入Altschul等人,《分子生物学杂志(J.Mol.Biol.)》215:403-10,1990的NBLAST和XBLAST程序(2.0版)中。可以用XBLAST程序(分值=50,字长=3)来执行BLAST蛋白质检索以获得与所关注蛋白质分子同源的氨基酸序列。当两个序列之间存在空位时,可以利用如Altschul等人,《核酸研究(Nucleic Acids Res.)》25(17):3389-3402,1997中描述的带空位的BLAST(Gapped BLAST)。当利用BLAST程序和带空位的BLAST程序时,可以使用相应程序(例如,XBLAST和NBLAST)的默认参数。
(c)其它CAR组分
本文所公开的任何双特异性CAR多肽可以进一步包括跨膜结构域(TMD)、铰链结构域或两者。在一些实例中,TMD可以位于细胞外抗原结合结构域与细胞内信号传导结构域之间。参见图1。可替代地或另外地,当细胞内信号传导结构域包括一个或多个共刺激信号传导结构域和/或细胞质信号传导结构域的组合时,铰链结构域可以位于细胞外抗原结合结构域与TMD之间、位于TMD与细胞内信号传导结构域之间或位于细胞内信号传导结构域内。在此可以使用通常用于双特异性CAR多肽构建的任何TMD和/或铰链结构域。参见美国专利第10,160,794号。
在一些实例中,TMD可以从合适的细胞表面受体获得,如T细胞受体的α、β或ζ链的细胞表面受体、CD28、CD3ε、CD3δ、CD3γ、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、CD271、TNFRSF19和杀伤细胞免疫球蛋白样受体(KIR)。在一些实例中,铰链结构域可以属于CD28、CD8、IgD或IgG,如IgG1或IgG4。参见美国专利第10,160,794号。在一个实例中,TMD可以属于人CD8a,例如包括SEQ ID NO:38的氨基酸序列或由其组成。
在一些实例中,双特异性CAR也可以包括铰链结构域,所述铰链结构域可以连接到双特异性细胞外抗原结合结构域的C末端和跨膜结构域的N末端。合适的铰链结构域可以源自CD28、CD8、IgD或IgG,如IgG1和IgG4。在一个实例中,铰链结构域可以属于人CD8,例如包括SEQ ID NO:53的氨基酸序列或由其组成。在一些情况下,TMD和铰链结构域可以通过柔性肽接头连接,如本文所公开的柔性肽接头。
用于构建双特异性CAR多肽的任何组分可以为天然存在的蛋白质的片段(例如,细胞受体,如免疫细胞受体,如本文所公开的免疫细胞受体)。可替代地,CAR组分可以为野生型对应物的变体,所述变体可以与野生型对应物共享至少90%的序列同一性并基本上维持相同的生物活性。在一些情况下,变体相对于野生型对应物可以包含至多15个(例如,至多12、10、8、6、5、4、3、2或1个)氨基酸残基取代。在一些实例中,一个或多个氨基酸残基取代是保守氨基酸残基取代。
如本文所使用的,“保守氨基酸取代”是指不改变进行氨基酸取代的蛋白质的相对电荷或大小特性的氨基酸取代。可以根据用于改变本领域的普通技术人员已知的多肽序列的方法来制备变体,所述方法如编制这种方法的参考文献中发现的,所述参考文献例如《分子克隆:实验室手册(Molecular Cloning:A Laboratory Manual)》,J.Sambrook等人编辑,第二版,纽约冷泉港的冷泉港实验室出版社(Cold Spring Harbor Laboratory Press,Cold Spring Harbor,New York),1989或《当代分子生物学实验指南(Current Protocolsin Molecular Biology)》,F.M.Ausubel等人编辑,纽约约翰威利父子出版公司(JohnWiley&Sons,Inc.,New York)。氨基酸的保守取代包含在以下组中的氨基酸之间进行的取代:(a)A→G,S;(b)R→K,H;(c)N→Q,H;(d)D→E,N;(e)C→S,A;(f)Q→N;(g)E→D,Q;(h)G→A;(i)H→N,Q;(j)I→L,V;(k)L→I,V;(l)K→R,H;(m)M→L,I,Y;(n)F→Y,M,L;(o)P→A;(p)S→T;(q)T→S;(r)W→Y,F;(s)Y→W,F以及(t)V→I,L。
(d)示例性双特异性CAR多肽
本文所公开的示例性双特异性CAR多肽从N末端到C末端可以包括第一抗原结合部分、柔性肽接头(例如,SEQ ID NO:57)、第二抗原结合部分、铰链结构域(例如,CD8铰链,如SEQ ID NO:53)、跨膜结构域(例如,CD8跨膜结构域,如SEQ ID NO:38)、共刺激结构域(例如,4-1BB共刺激结构域,如SEQ ID NO:39)、IL2Rb信号传导结构域(例如,SEQ ID NO:40)和细胞质信号传导结构域(例如,CD3z信号传导结构域,如SEQ ID NO:42或43)。在一些情况下,双特异性CAR多肽可以进一步包括在N末端处的信号肽,例如序列表1中提供的示例性信号肽(SEQ ID NO:45-52)。
在一些实例中,双特异性CAR多肽对CD19和BCMA具有特异性,并且包括上述组分。实例包含SEQ ID NO:64、66、68或70(成熟多肽)和SEQ ID NO:63、65、67或69(包含N末端信号肽)。
II.表达双特异性CAR的基因工程化免疫细胞
一方面,本公开提供了一种免疫细胞(例如,T细胞)群体,所述免疫细胞包括表达本文所述的任何双特异性CAR多肽的基因工程化免疫细胞(例如,T细胞)。免疫细胞群体可以进一步包括一个或多个被破坏的内源性促炎细胞因子基因。如本文所使用的,术语“内源性”是指天然来源于生物体内。可替代地或另外地,表达任何双特异性CAR多肽的基因工程化免疫细胞可以进一步表达一种或多种靶向促炎细胞因子的拮抗剂(例如,外源性)。此类基因工程化免疫细胞在体内将抑制由促炎细胞因子介导的信号传导。在一些情况下,本文所公开的基因工程化免疫细胞可以在体内表现出对多于一种细胞因子信号传导的抑制。
出于本公开的目的,将明确理解的是术语“拮抗剂”涵盖所有鉴定的术语、标题和功能状态和特点,由此靶蛋白本身、靶蛋白的生物活性或生物活性的结果在任何有意义的程度上(例如至少20%、50%、70%、85%、90%或以上)被基本上无效、降低或中和。
促炎细胞因子的非限制性实例包含IL2、IL1α、IL1β、IL-5、IL-6、IL-7、IL-8、IL-9、IL-12、IL-15、IL-17、IL-18、IL-21、IL-23、sIL-1RI、sIL-2Rα、sIL6R、IFNα、IFNβ、IFNγ、MIPα、MIPβ、CSF1、LIF、G-CSF、GM-CSF、CXCL10、CCL5、嗜酸性粒细胞趋化因子、TNF、MCP1、MIG、RAGE、CRP、血管生成素-2、VWF、TGFα、VEGF、EGF、HGF、FGF、穿孔蛋白、颗粒酶和铁蛋白。在一些情况下,促炎细胞因子包含干扰素γ(IFNγ)、白介素6(IL-6)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、白介素1(IL-1)或其组合。
A.免疫细胞
任何免疫细胞都可以用于使本文所述的细胞工程化。在一些实施例中,免疫细胞可以源自例如但不限于干细胞。干细胞可以是成体干细胞、非人胚胎干细胞,更具体地非人干细胞、脐带血干细胞、祖细胞、骨髓干细胞、诱导多能干细胞、全能干细胞或造血干细胞。在其它实施例中,免疫细胞由诱导多能细胞(iPSC)群体的分化产生。
用于制备本文所公开的工程化细胞的有用免疫细胞可以为T细胞、NK细胞、肿瘤浸润性淋巴细胞、树突状细胞、巨噬细胞、B细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、肥大细胞、髓源性抑制细胞、间充质干细胞、其前体或其组合。T细胞选自由以下组成的组:炎性T淋巴细胞、细胞毒性T淋巴细胞、调节性T淋巴细胞或辅助性T淋巴细胞。在一些实施例中,T细胞可以源自由CD4+T淋巴细胞和CD8+T淋巴细胞组成的组。在一个实例中,免疫细胞为人免疫细胞。代表性人免疫细胞为CD34+细胞。
在一些实施例中,免疫细胞可以直接从受试者(例如,人类受试者)采集。如本文所述对细胞进行基因修饰,并将基因工程化免疫细胞输注回同一受试者,例如在CAR-T细胞疗法中。在这种情况下,基因工程化免疫细胞对接受CAR-T细胞治疗的受试者是自体的。在另一个实施例中,免疫细胞可以直接从供体受试者采集、修饰,并且将基因工程化免疫细胞输注到需要疗法(例如,CAR-T细胞疗法)的接受者受试者中。供体免疫细胞是与接受者受试者HLA匹配的,即,细胞对接受者受试者是同种异体的。在一些实施例中,免疫细胞从受试者的外周血中采集,在本文所公开的基因修饰之前在体外扩增。
B.促炎细胞因子的拮抗剂
在一些情况下,本文所公开的基因工程化免疫细胞可以被工程化以表达一种或多种针对促炎细胞因子的拮抗剂,例如本文所公开的拮抗剂。在一些实例中,拮抗剂为IL-6拮抗性抗体,例如,抗IL6抗体、抗IL6R抗体或抗gp130抗体。可替代地或另外地,基因工程化免疫细胞可以被工程化以表达一种或多种IL-1拮抗剂,例如,IL-1RA或本领域已知的或本文所公开的其它拮抗剂。可替代地或另外地,基因工程化免疫细胞可以被工程化以表达一种或多种IFNγ拮抗剂,例如,拮抗性IFNγ抗体或本领域已知的或本文所公开的其它抗体。
本文所公开的典型抗体分子包括重链可变区(VH)和轻链可变区(VL),所述VH和VL通常参与抗原结合。VH和VL区可以进一步细分为高变区,也称为“互补决定区”(“CDR”),其散布有更保守的被称为“框架区”(“FR”)的区。每个VH和VL通常由按以下顺序从氨基末端到羧基末端布置的三个CDR和四个FR构成:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。框架区和CDR的范围可以使用本领域已知的方法,例如通过Kabat定义、Chothia定义、AbM定义和/或接触定义来精确地鉴定,所有所述定义均是本领域熟知的。参见例如,Kabat,E.A.等人,(1991)《具有免疫学意义的蛋白质序列(Sequences of Proteins of Immunological Interest)》,第五版,美国卫生与公众服务部(U.S.Department of Health and Human Services),NIH公开号91-3242;Chothia等人,(1989)《自然(Nature)》342:877;Chothia,C.等人(1987)《分子生物学杂志》196:901-917;Al-lazikani等人(1997)《分子生物学杂志》273:927-948;和Almagro,《分子识别杂志(J.Mol.Recognit.)》17:132-143(2004)。也可以参见英国医学研究委员会(Medical Research Council)的人类基因组作图项目资源(Human GenomeMapping Project Resources)和伦敦大学学院生物信息学和计算生物学组网站上描述的抗体规则。
如本文所使用的抗体(以复数形式可互换地使用)是能够通过位于免疫球蛋白分子的可变区的至少一个抗原识别位点来与靶蛋白(例如,IL-6或IL-6R)特异性结合的免疫球蛋白分子。如本文所使用的,术语“抗体”不但涵盖完整(例如,全长)抗体和重链抗体(例如,羊驼重链IgG抗体),而且涵盖其抗原结合片段(如Fab、Fab'、F(ab')2、Fv)、单链(scFv)、单结构域抗体(sdAb;VHH)(也称为纳米抗体)、其突变体、包括抗体部分的融合蛋白、人源化抗体、嵌合抗体、双功能抗体、线性抗体、单链抗体、多特异性抗体(例如,双特异性抗体)以及包括所需特异性的抗原识别位点的免疫球蛋白分子的任何其它经修饰的构型,所述经修饰的构型包含抗体的糖基化变体、抗体的氨基酸序列变体和经共价修饰的抗体。抗体包含任何类的抗体,如IgD、IgE、IgG、IgA或IgM(或其亚类),并且抗体不需要属于任何特定类。根据其重链恒定结构域的抗体氨基酸序列,可以将免疫球蛋白分派为不同类。存在五大类免疫球蛋白:IgA、IgD、IgE、IgG和IgM,并且这些类中的几类可以进一步分为亚类(同种型),例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类免疫球蛋白的重链恒定结构域分别称为α、δ、ε、γ和μ。不同类免疫球蛋白的亚基结构和三维构型是众所周知的。
在一些实施例中,本文所述的“结合”靶蛋白或其受体的抗体可以与靶蛋白或受体特异性结合。与靶标或表位“特异性结合”(在本文中可互换地使用)的抗体是本领域中所熟知的术语,并且用于确定这种特异性结合的方法也是本领域中所熟知的。如果分子与特定靶抗原比所述分子与替代性靶标更频繁地、更快速地、持续时间更长地和/或亲和力更大地反应或缔合,则所述分子被称为展现出“特异性结合”。如果抗体与靶细胞因子比所述抗体与其它物质亲和力更大地、亲合性更高地、更容易地和/或持续时间更长地结合,则所述抗体与靶细胞因子“特异性地结合”。例如,与IL-6或IL-6R表位特异性地(或优先地)结合的抗体是比其与其它IL-6表位、非IL-6表位、其它IL-6R表位或非IL-6R表位亲和力更大地、亲合性更高地、更容易地和/或持续时间更长地结合这个IL-6表位或IL-6R表位的抗体。通过阅读此定义还应理解,例如,与第一靶抗原特异性地结合的抗体可以或可以不与第二靶抗原特异性地结合或优先地结合。如此,“特异性结合”或“优先结合”不一定需要(尽管其可以包含)排他结合。通常,但不是必然地,提及结合意指优先结合。
本文所述的抗体可以是鼠、大鼠、人类或任何其它来源(包含嵌合抗体或人源化抗体)。此类抗体是非天然存在的,例如在没有人类行为(例如,用所期望的抗原或其片段免疫此类动物)的情况下将不会在动物中产生。
本文所述的抗体中的任何抗体可以是单克隆的或多克隆的。“单克隆抗体”是指同质抗体群体,并且“多克隆抗体”是指异质抗体群体。这两个术语并不限制抗体的来源或制备抗体的方式。
在一个实例中,本文所述的方法中使用的抗体是人源化抗体。人源化抗体是指为特异性嵌合免疫球蛋白、免疫球蛋白链或其含有衍生自非人免疫球蛋白的最小序列的抗原结合片段的非人(例如,鼠)抗体的形式。在大多数情况下,人源化抗体为人免疫球蛋白(接受者抗体),其中来自接受者的互补决定区(CDR)的残基被来自如小鼠、大鼠或兔等具有期望的特异性、亲和力和能力的非人物种(供体抗体)的CDR的残基替换。在一些情况下,人免疫球蛋白的Fv框架区(FR)残基被对应的非人残基替代。此外,人源化抗体可以包括既未在接受者抗体中发现也未在导入的CDR或框架序列中发现但被包含在内以进一步精化和优化抗体性能的残基。通常,人源化抗体将包括至少一个并且典型地两个可变结构域中的基本上所有可变结构域,其中所有或基本上所有CDR区对应于非人免疫球蛋白的那些区,并且所有或基本上所有FR区是人免疫球蛋白共有序列的那些区。人源化抗体最佳地还将包括免疫球蛋白恒定区或结构域(Fc)的至少一部分,典型地是人免疫球蛋白恒定区的至少一部分。抗体可以具有如WO 99/58572所描述的修饰的Fc区。其它形式的人源化抗体具有关于原始抗体改变的一个或多个CDR(一个、两个、三个、四个、五个和/或六个),也称为“源自”来自原始抗体的一个或多个CDR的一个或多个CDR。人源化抗体还可以涉及亲和力成熟。
在一些实施例中,本文所述的靶蛋白的拮抗性抗体对靶蛋白(例如,人IL-6、人IL-6R或人IFNγ)或其抗原表位具有合适的结合亲和力。如本文所使用的,“结合亲和力”是指表观缔合常数或KA。KA是解离常数(KD)的倒数。本文所述的拮抗性抗体对于靶抗原或抗原表位的结合亲和力(KD)可以为至少10-5M、10-6M、10-7M、10-8M、10-9M、10-10M或更低。增大的结合亲和力对应于减小的KD。抗体相对于第二抗原对第一抗原的更高亲和力结合可以通过比用于结合第二抗原的KA(或数值KD)更高的用于结合第一抗原的KA(或更小的数值KD)来指示。在这种情况下,所述抗体相对于第二抗原(例如,第二构象或其模拟物中的相同的第一蛋白质;或第二蛋白质)对第一抗原(例如,第一构象或其模拟物中的第一蛋白质)具有特异性。在一些实施例中,与对前体形式的靶蛋白或另一种蛋白(例如,与靶蛋白处于同一家族的炎性蛋白)的结合亲和力相比,本文所述的拮抗性抗体对成熟形式的靶蛋白具有更高的结合亲和力(更高的KA或更小的KD)。结合亲和力的差异(例如,对于特异性或其它比较)可以为至少1.5倍、2倍、3倍、4倍、5倍、10倍、15倍、20倍、37.5倍、50倍、70倍、80倍、91倍、100倍、500倍、1000倍、10,000倍或105倍。
可以通过各种方法来确定结合亲和力(或结合特异性),包含平衡透析、平衡结合、凝胶过滤、ELISA、表面等离子共振或光谱学(例如,使用荧光测定)。用于评估结合亲和力的示例性条件为处于HBS-P缓冲液(10mM HEPES pH7.4,150mM NaCl,0.005%(v/v)表面活性剂P20)中。这些技术可以用于根据靶蛋白浓度测量结合的结合蛋白的浓度。结合的结合蛋白的浓度([结合(Bound)])通常通过以下等式与游离靶蛋白([游离(Free)])的浓度相关:
[结合]=[游离]/(Kd+[游离])
然而,并不总是需要对KA进行精确测定,因为有时例如通过功能性测定,例如体外或体内测定中的活性足以获得对亲和力的定量测量、获得对亲和力的定性测量或者获得对亲和力的推断,所述亲和力例如是使用如ELISA或FACS分析等方法确定的、与KA成比例并且因此可以用于比较,如确定更高的亲和力是否例如是其2倍。
下文提供了一些实例。
(a)靶向IL6信号传导的拮抗性抗体
在一些实施例中,表达本文所述的双特异性CAR多肽的基因工程化免疫细胞也可以表达IL-6拮抗剂。
IL-6通过包括膜糖蛋白gp130和IL-6受体(IL-6R)的复合物进行信号传导(参见例如,Hibi等人,《细胞(Cell)》,63(6):1149-57,1990)。IL-6与靶细胞上的IL-6R结合促进gp130同源二聚化和随后的信号转导。如本文所使用的,IL-6R包含膜结合和可溶性形式的IL-6R(sIL-6R)两者。当与IL-6结合时,可溶性IL-6R(sIL-6R)充当激动剂并且还可以促进gp130二聚化和信号传导。可能发生反式信号传导(Trans-signaling),由此特定细胞类型的sIL-6R分泌诱导仅表达gp130的细胞以对IL-6作出应答(参见例如,Taga等人,《免疫学年度评论(Annu Rev Immunol.)》,15:797-819,1997;以及Rose-John等人,《生物化学杂志(Biochem J.)》,300(Pt 2):281-90,1994)。在一个实例中,sIL-6R包括人IL-6R的细胞外结构域(参见例如,Peters等人,《实验医学杂志(J Exp Med.)》,183(4):1399-406,1996)。
在一些实施例中,本文所公开的经修饰的免疫细胞表达IL-6拮抗剂,所述IL-6拮抗剂可以为与IL-6或IL-6受体(IL-6R,包含gp130)结合的抗体。此类抗体(拮抗性抗体)可以干扰免疫细胞上IL-6/IL-6R的结合,从而抑制IL-6介导的细胞信号传导。
在一些实施例中,本文所述的IL-6拮抗性抗体可以结合并抑制IL-6信号传导至少50%(例如,60%、70%、80%、90%、95%或更高)。本文所述的IL-6拮抗性抗体的抑制活性可以通过本领域已知的常规方法确定。
示例性抗IL-6抗体和抗IL-6R抗体的重链可变结构域(VH)和轻链可变结构域(VL)在下面提供(参考抗体1-6),CDR以粗体示出(根据伦敦大学学院生物信息学和计算生物学组网站描述的抗体规则确定)。
序列表1中提供了抑制IL-6信号传导通路的示例性抗体,包含抗IL-6抗体、抗IL-6R抗体和抗gp130抗体(AB1-AB6和IL6拮抗剂scFv1-scFv4),所有抗体均在本公开的范围内。
在一些实施例中,本文所述的IL-6拮抗性抗体与IL-6抗原(例如,人IL-6)或IL-6R(例如,人IL-6R)中与本文所提供的参考抗体之一(例如,AB1-AB6中的任何一种,如AB1或AB2)相同的表位结合,或者与参考抗体竞争与IL-6或IL-6R抗原结合。本文提供的参考抗体包含抗体1-6,本文提供每种抗体的结构特征和结合活性。与本文所述的参考抗体结合同一表位的抗体可以与参考抗体结合完全一样的表位或基本上重叠的表位(例如,含有少于3个非重叠氨基酸残基、少于2个非重叠氨基酸残基或仅1个非重叠氨基酸残基)。可以通过本领域熟知的竞争测定来确定两种抗体是否彼此竞争与同源抗原结合。此类抗体可以被鉴定为本领域技术人员已知的抗体,例如,具有基本上相似的结构特征(例如,互补决定区)的抗体,和/或通过本领域已知的测定鉴定的抗体。例如,可以使用参考抗体之一进行竞争测定,以确定候选抗体是否与参考抗体结合相同的表位或与其竞争与IL-6或IL-6R抗原的结合。
在一些情况下,本文所公开的IL-6拮抗性抗体可以包括与本文所公开的参考抗体相同的重链CDR和/或相同的轻链CDR(例如例如,AB1-AB6中的任何一种,如AB1或AB2)。重链和/或轻链CDR是负责抗原结合的区/残基;此类区/残基可以通过本领域已知的方法从参考抗体(如上所示)的重链/轻链序列的氨基酸序列中鉴定。参见例如伦敦大学学院生物信息学和计算生物学组网站描述的抗体规则;Almagro,《分子识别杂志(J.Mol.Recognit.)》17:132-143(2004);Chothia等人,《分子生物学杂志》227:799-817(1987),以及本领域已知的或本文所公开的其它方法。抗体中CDR区的确定完全在本领域的技术范围内,例如,本文所公开的方法,例如Kabat方法(Kabat等人,《具有免疫学意义的蛋白质序列》(第5版,1991,马里兰州贝塞斯达的国立卫生研究院(National Institutes of Health,Bethesda,Md.))或Chothia方法(Chothia等人,1989,《自然》,342:877;Al-lazikani等人,(1997)《分子生物学杂志》273:927-948)。如本文所使用的,CDR可以指通过本领域已知的任何方法定义的CDR。两种抗体具有相同的CDR意味着两种抗体具有通过相同方法测定的所述CDR的相同氨基酸序列。
此外,在本公开的范围内的是本文所公开的任何示例性抗IL-6或抗IL-6R抗体的功能变体(例如,AB1-AB6中的任何一种,如AB1或AB2)。相对于参考抗体,功能变体可以包含VH和/或VL中或一个或多个HC CDR和/或一个或多个LC CDR中的一个或多个氨基酸残基变异,同时保留与参考抗体基本上相似的结合和生物活性(例如,基本上相似的结合亲和力、结合特异性、抑制活性或其组合)。
在一些实例中,本文所公开的IL-6拮抗性抗体包括HC CDR1、HC CDR2和HC CDR3,与参考抗体(如AB1-AB6中的任何一种,例如AB1或AB2)的HC CDR1、HC CDR2和HC CDR3相比,它们总共包含不超过10个氨基酸变异(例如,不超过9、8、7、6、5、4、3、2或1个氨基酸变异)。“总共”是指所有三个HC CDR中氨基酸变异的总数在限定的范围内。可替代地或另外地,抗IL-6或抗IL-6R抗体可以包括LC CDR1、LC CDR2和LC CDR3,与参考抗体的LC CDR1、LC CDR2和LC CDR3相比,它们总共含有不超过10个氨基酸变异(例如,不超过9个、8个、7个、6个、5个、4个、3个、2个或1个氨基酸变异)。
在一些实例中,本文所公开的IL-6拮抗性抗体可以包括HC CDR1、HC CDR2和HCCDR3,其中至少一者包含不超过5个氨基酸变异(例如,不超过4、3、2或1个氨基酸变异)作为参考抗体(例如,AB1-AB6中的任何一种,如AB1或AB2)的对应HC CDR。在具体实例中,所述抗体包括HC CDR3,其包含不超过5个氨基酸变异(例如,不超过4、3、2或1个氨基酸变异)作为参考抗体(例如,AB1-AB6中的任何一种,如AB1或AB2)的HC CDR3。可替代地或另外地,IL-6拮抗性抗体可以包括LC CDR1、LC CDR2和LC CDR3,与参考抗体的对应LC CDR相比,它们中的至少一个含有不超过5个氨基酸变异(例如,不超过4个、3个、2个或1个氨基酸变异)。在具体实例中,所述抗体包括LC CDR3,与参考抗体的LC CDR3相比,其含有不超过5个氨基酸变异(例如,不超过4个、3个、2个或1个氨基酸变异)。
在某些情况下,氨基酸残基变异可以是保守氨基酸残基取代。参见本文的公开内容。
在一些实施例中,本文所公开的IL-6拮抗性抗体可以包括与参考抗体(如AB1-AB6中的任何一种,例如AB1或AB2)的重链CDR总共至少80%(例如,85%、90%、95%或98%)相同的重链CDR。可替代地或另外地,所述抗体可以包括与参考抗体的轻链CDR总共至少80%(例如,85%、90%、95%或98%)相同的轻链CDR。在一些实施例中,IL-6拮抗性抗体可以包括与参考抗体(如AB1-AB6中的任何一种,例如AB1或AB2)的重链可变区至少80%(例如,85%、90%、95%或98%)相同的重链可变区和/或与参考抗体的轻链可变区至少80%(例如,85%、90%、95%或98%)相同的轻链可变区。
本公开也提供了本文所公开的任何参考IL-6拮抗性抗体的种系变体。相对于其亲本抗体,种系变体的框架区含有一个或多个朝向对应种系序列的突变。为了制备种系变体,亲本抗体的重链或轻链可变区序列或其部分(例如,框架序列)可以用作对抗体种系序列数据库的查询(例如,伦敦大学学院生物信息学和计算生物学组网站描述的抗体规则;thevbase2网站或国际免疫遗传学(ImMunoGeneTics)/>网站)以鉴定亲本抗体所使用的对应种系序列以及种系序列与亲本抗体之间的一个或多个框架区中的氨基酸残基变异。然后可以基于种系序列将一个或多个氨基酸取代引入亲本抗体中,以产生种系变体。
在一些实例中,本文所述的拮抗性抗体为人抗体或人源化抗体。可替代地或另外地,拮抗性抗体为scFv。下文序列表2中提供了示例性scFv抗体。
(b)IL-1拮抗剂
在一些实施例中,表达本文所述的双特异性CAR的基因工程化免疫细胞也可以表达IL-1拮抗剂。
白介素-1是本领域已知的细胞因子,并且包含两种同种型,IL-1α和IL-1β。IL-1在急性炎症的上调和下调以及其它生物学途径中发挥重要作用。
在一些实例中,在本文所公开的基因工程化免疫细胞中表达的IL-1拮抗剂可以为白介素-1受体拮抗剂(IL-1RA)。IL-1RA是天然存在的多肽,可以由如免疫细胞、上皮细胞和脂肪细胞等各种类型的细胞分泌。它与细胞表面IL-1R受体结合,从而阻止由IL-1/IL-1R相互作用触发的细胞信号传导。人IL-1RA由IL1RN基因编码。在一个实例中,人IL-1RA包括SEQID NO:54的氨基酸序列(成熟蛋白)。在一些情况下,人IL-1RA可以在N末端处包括信号肽,例如包括SEQ ID NO:55或SEQ ID NO:56的氨基酸序列。
其它IL-1拮抗剂包含但不限于抗IL-1α或抗IL-1β抗体(参见Fredericks ZL等人,2004,《蛋白质工程、设计和选择(Protein Eng Des Sel.)》17(1):95-106);美国专利第7,531,166号和第8,383,778号,所述专利内容通过引用以其整体并入本文。
(c)IFNγ拮抗剂
在一些实施例中,本文所述的基因工程化免疫细胞可以表达IFNγ拮抗剂与本文所公开的双特异性CAR的组合,还任选地与本文也公开的一种或多种另外的基因修饰的组合。
IFNγ拮抗剂可以阻断三元IFNγ/IFNγR1/IFNγR2的形成。IFNγR1是配体结合和信号传导所必需的。IFNγ拮抗剂可以是拮抗性抗IFNγ抗体或其抗原结合片段;分泌型IFNγ受体或该受体的配体结合片段;和拮抗性抗IFNγR抗体或其抗原结合片段,IFNγ拮抗剂由此阻断IFNγ/IFNγR相互作用和下游信号传导。在一个实施例中,IFNγ拮抗剂是分泌型的。拮抗性抗IFNγ抗体或其抗原结合片段结合体内释放的IFNγ配体,因此IFNγ配体不能与细胞表面表达的天然受体IFNγR1相互作用。分泌型IFNγ受体或配体结合片段充当诱饵受体,并捕获体内释放的IFNγ配体,因此IFNγ配体也不能与其天然受体(细胞表面表达的IFNγR1)相互作用。在一个实施例中,分泌型IFNγR或配体结合片段是天然的人IFNγ受体的细胞外部分。拮抗性抗IFNγR抗体或其抗原结合片段与细胞上表达的IFNγ受体结合,并阻止IFNγ配体与受体的相互作用以及随后配体诱导的含有两个IFNγR1和两个IFNγR2亚基的完整受体复合物的组装。完整的受体复合物是IFNγ信号传导路径所必需的。
在一些实施例中,本文所公开的经修饰的免疫细胞表达IFNγ拮抗性抗体。在一些实例中,本文所述的IFNγ拮抗性抗体可以抑制IFNγ信号传导至少50%(例如,60%、70%、80%、90%、95%或更高)。本文所述的IFNγ拮抗性抗体的抑制活性可以通过本领域已知的常规方法确定。
下文序列表1中提供了示例性抗IFNγ抗体和抗IL-6R抗体的重链可变结构域(VH)和轻链可变结构域(VL)(参考抗IFNγ1-3),其中CDR呈加粗形式并加下划线(基于Kabat定义)。
在一些实施例中,本文所述的IFNγ拮抗性抗体与IFNγ抗原(例如,人IFNγ)中与本文所提供的参考抗体之一(例如,抗IFNγ1-3中的任何一种)相同的表位结合,或与参考抗体竞争与IFNγ抗原结合。本文所提供的参考抗体包含抗IFNγ1-3,本文中提供了每种参考抗体的结构特征和结合活性。参见序列表2。在一个实例中,抗人IFN-γ抗体可以源自AMG811,描述于美国专利7,335,743中,所述美国专利的相关部分出于本文所引用的主题和目的通过引用并入本文。可替代地,抗人IFN-γ抗体可以源自芳妥珠单抗(fontolizumab)或依马利尤单抗(emapalumab)。可以在美国专利第9,682,142号中找到其它拮抗性抗IFNγ抗体或其抗原结合片段,所述美国专利的内容出于本文所引用的主题和目的通过引用并入。
在一些情况下,本文所公开的IFNγ拮抗性抗体可以包括与本文所公开的参考抗体(例如例如,抗IFNγ1-3中的任何一种)相同的重链CDR和/或相同的轻链CDR。
也在本公开的范围内的是本文所公开的任何示例性抗IFNγ抗体(例如,抗IFNγ1-3中的任何一种)的功能变体。相对于参考抗体,功能变体可以包含VH和/或VL中或一个或多个HC CDR和/或一个或多个LC CDR中的一个或多个氨基酸残基变异,同时保留与参考抗体基本上相似的结合和生物活性(例如,基本上相似的结合亲和力、结合特异性、抑制活性或其组合)。
在一些实例中,本文所公开的IFNγ拮抗性抗体包括HC CDR1、HC CDR2和HC CDR3,与参考抗体(如抗IFNγ1-3中的任何一种)的HC CDR1、HC CDR2和HC CDR3相比,它们共同包含不超过10个氨基酸变异(例如,不超过9、8、7、6、5、4、3、2或1个氨基酸变异)。可替代地或另外地,抗IFNγ抗体可以包括LC CDR1、LC CDR2和LC CDR3,与参考抗体的LC CDR1、LCCDR2和LC CDR3相比,它们总共包含不超过10个氨基酸变异(例如,不超过9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实例中,本文所公开的IFNγ拮抗性抗体可以包括HC CDR1、HC CDR2和HCCDR3,与参考抗体(例如,抗IFNγ1-3中的任何一种)的对应HC CDR相比,它们中的至少一个包含不超过5个氨基酸变体(例如,不超过4、3、2或1个氨基酸变体)。在具体实例中,所述抗体包括HC CDR3,与参考抗体(例如,抗IFNγ1-3中的任何一种)的HC CDR3相比,它们包含不超过5个氨基酸变异(例如,不超过4、3、2或1个氨基酸变异)。可替代地或另外地,IFNγ拮抗性抗体可以包括LC CDR1、LC CDR2和LC CDR3,与参考抗体的对应LC CDR相比,它们中的至少一个包含不超过5个氨基酸变异(例如,不超过4、3、2或1个氨基酸变异)。在具体实例中,所述抗体包括LC CDR3,与参考抗体的LC CDR3相比,其含有不超过5个氨基酸变异(例如,不超过4个、3个、2个或1个氨基酸变异)。
在某些情况下,氨基酸残基变异可以是保守氨基酸残基取代。参见本文的公开内容。
在一些实施例中,本文所公开的IFNγ拮抗性抗体可以包括与参考抗体(如抗IFNγ1-3中的任何一种)的重链CDR总共至少80%(例如,85%、90%、95%或98%)相同的重链CDR。可替代地或另外地,所述抗体可以包括与参考抗体的轻链CDR总共至少80%(例如,85%、90%、95%或98%)相同的轻链CDR。在一些实施例中,IFNγ拮抗性抗体可以包括与参考抗体(如抗IFNγ1-3中的任何一种)的重链可变区至少80%(例如,85%、90%、95%或98%)相同的重链可变区和/或与参考抗体的轻链可变区至少80%(例如,85%、90%、95%或98%)相同的轻链可变区。
本公开也提供了本文所公开的任何参考IFNγ拮抗性抗体的种系变体。在一些实例中,本文所述的拮抗性抗体为人抗体或人源化抗体。可替代地或另外地,拮抗性抗体为scFv。下文序列表2中提供了示例性scFv抗体。
在其它实施例中,本文所公开的INFγ拮抗剂可以为可溶性IFNγR片段,例如天然人IFNγ受体的细胞外部分。示例性IFNγR片段在本领域中是已知的,例如在美国专利第5,578,707号和第7,449,176号中所述,所述美国专利的相关公开内容出于本文所引用的主题和目的通过引用并入本文。高亲和力IFNγ受体复合物由两种I型膜蛋白构成,即IFNγR1(IFNγRα)和IFNγR2(IFNγRβ)。这两种蛋白质都是II型细胞因子受体家族的成员,两者的序列同一性大约为52%。IFNγR1是配体结合亚基,对IFNγ结合和受体内化来说是必要和充分的。IFNγR2是IFNγ信号传导所必需的,但自身不结合IFNγ。人IFNγR1 cDNA编码499氨基酸(aa)残基蛋白,所述残基蛋白具有17aa信号肽、228aa细胞外结构域、23aa跨膜结构域和221aa细胞内结构域。拮抗IFNγ信号传导的可溶性IFNγR片段可以包括228aa细胞外结构域。
在又其它实施例中,本文所公开的IFNγ拮抗剂可以为拮抗性抗IFNγR抗体或其抗原结合片段,例如,在美国专利第4,897,264号和第7,449,176号中所述的拮抗性抗IFNγR抗体或其抗原结合片段,所述美国专利的相关公开内容出于本文所引用的主题和目的通过引用并入。
本文所述的任何IFNγ拮抗剂可以包括位于IFNγ阻断剂的N末端处的信号肽,使得所述IFNγ拮抗剂可以由表达此类信号肽的基因工程化免疫细胞分泌。序列表2中提供了示例性信号肽,所述信号肽中的任何一种都可以用于IFNγ拮抗剂。
C.内源性促炎细胞因子基因的破坏
在一些实施例中,表达本文所公开的任何双特异性CAR,任选地还表达本文也公开的一种或多种拮抗剂的基因工程化免疫细胞可以具有一个或多个被破坏的内源性促炎细胞因子基因(例如,GM-CSF基因和/或IFNγ基因)。下文提供了一些实例。
(a)内源性干扰素γ基因的破坏
在一些情况下,本文所公开的基因工程化免疫细胞被基因工程化以提供与不具备此类基因修饰的对应免疫细胞相比降低的IFNγ水平,例如,与对应免疫细胞相比降低至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或至少95%。由此类基因工程化免疫细胞产生的IFNγ的量可以通过本领域已知的任何方法来确定,例如,通过用此类经修饰的细胞治疗的患者的细胞培养基或血液IFNγ水平的ELISA测定来确定。
在其它情况下,与不具有此类基因修饰的对应免疫细胞相比,基因工程化免疫细胞可以降低降低的IFNγR(例如,IFNγR1)水平,例如,与对应免疫细胞相比降低至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或至少95%。
在一些实例中,IFNγ的减少可以通过破坏内源性IFNγ基因和/或内源性IFNγR基因来实现,例如通过基因编辑实现。预期表达本文所公开的任何双特异性CAR的此类基因工程化免疫细胞将在体内具有由IFNγ信号传导介导的有限细胞因子释放综合征。
可以使用本领域已知的用于下调宿主细胞中的内源性基因表达的任何方法(包含基因编辑)来降低本文所述的IFNγ或IFNγR的表达水平。分别在GENBANK基因ID:3458和基因ID:3459中找到人IFNγ和IFNγR1的基因组信息。
在一些实例中,基因编辑方法可以用于破坏内源性IFNγ或IFNγR基因。基因编辑系统可能涉及能够切割内源性等位基因中的靶区的核酸内切酶。在不存在模板核酸的情况下,非同源性末端连接可以修复基因组中的双链断裂,并且将突变(例如,插入、缺失和/或移码)引入到靶位点中。
在一些实例中,敲除事件可以与敲入事件结合——编码期望分子(例如,本文所述的IL6拮抗剂、IFNγ拮抗剂或IL1拮抗剂)的外源性核酸可以通过基因编辑与同源重组的组合插入到IFNγ或IFNγR基因的基因组基因座中,以在靶基因组位点处插入外源性核酸,由此破坏内源性靶基因。
在一个实例中,可以通过CRISPR/Cas介导的基因编辑方法例如使用CRISPR/Cas9介导的基因编辑系统来实现对内源性IFNγ或IFNγR基因的破坏。为了破坏IFNγ基因,可以使用对辅助原间隔子相邻基序(PAM)的靶位点具有特异性的向导RNA(gRNA)。sgRNA分子含有融合到支架tracrRNA序列的定制设计的短crRNA序列。序列表3中提供了人IFNγ基因中的示例性基因靶位点(例如,在外显子1中)、gRNA的对应间隔子序列和示例性单向导RNA(sgRNA)。这些gRNA中的任何一种都可以用于破坏人IFNγ基因。
为了破坏IFNγR基因,可以使用可从傲锐东源公司(OriGene Technologies)商购获得的IFNγR1人基因敲除试剂盒(CRISPR),目录号KN202761。使用此类试剂盒的方法是本领域已知的。
在其它情况下,IFNγ或IFNγR水平的降低可以通过反义寡核苷酸使用反义技术或通过RNA干扰技术干扰RNA(例如,shRNA或siRNA)来实现。可替代地,可以使用核酶来实现这一目标。反义寡核苷酸或干扰RNA是包括与内源性靶基因的靶区互补的片段或其转录物的寡核苷酸。此类反义寡核苷酸可以通过常规方法递送到靶细胞中。可替代地,表达载体(如慢病毒载体或其等效物)可以用于表达此类反义寡核苷酸或干扰RNA。
D.基因工程化免疫细胞群体
在一些方面,本文提供了一种基因工程化免疫细胞群体,所述基因工程化免疫细胞表达本文所述的任何双特异性CAR(例如,抗CD19/抗BCMA双特异性CAR)并且包括一种或多种另外的基因修饰,所述基因修饰例如被工程化以表达一种或多种靶向促炎细胞因子的拮抗剂,被工程化以减少内源性促炎细胞因子的表达(例如,通过例如基因编辑破坏内源性基因)或其组合。
在一些实例中,表达如本文所公开的双特异性CAR(例如,抗CD19/抗BCMA双特异性CAR)的基因工程化免疫细胞可以进一步表达抑制IL6信号传导的拮抗性抗体(例如,scFv抗体)、抑制IFNγ信号传导的拮抗性抗体(例如,scFv抗体)、IL1拮抗剂或其组合。本文公开了此类拮抗剂的实例。
可替代地或另外地,本文所公开的基因工程化免疫细胞可以包含一个或多个被破坏的编码一种或多种促炎细胞因子(例如,IFNγ或GM-CSF)的内源性基因。基因工程化免疫细胞可以包括所关注基因(例如,编码TCR组分的基因或编码MHC I类或MHC II类组分的基因)的另外的基因编辑。在一些情况下,编码本文所公开的任何拮抗剂的核酸可以插入在被破坏的基因座处。
基因工程化免疫细胞群体可以是异质的,包括具有不同基因修饰或不同基因修饰组合的细胞。例如,群体中的一个细胞亚群可以共表达双特异性CAR和促炎细胞因子的拮抗剂,而群体中的另一个细胞亚群可以表达双特异性CAR并具有被破坏的内源性靶基因。群体中的细胞共同具有本文所公开的所有期望的基因修饰。在一些情况下,免疫细胞群体的一部分可以在每个细胞中表现出所有期望的基因修饰,例如(a)表达双特异性CAR与表达IL6拮抗剂和/或IFNγ拮抗剂的组合;(b)表达双特异性CAR与敲低内源性IFNγ基因和/或GM-CSF基因的组合;或(c)表达双特异性CAR与表达IL6拮抗剂和/或IFNγ拮抗剂和敲低内源性IFNγ基因和/或GM-CSF基因的组合。在一些实例中,此类部分可以构成本文所公开的基因工程化免疫细胞总群体的至少20%(例如,至少30%、至少40%或至少50%)。
可以在WO2019/178259和WO2020/146239中找到CAR-T细胞的特异性敲入和敲除基因修饰,包含IFNγ拮抗剂、IL-6拮抗剂和IL-1拮抗剂,所述文献中的每一个的相关公开内容出于本文所公开的目的和主题通过引用并入。
III.制备基因工程化免疫细胞的方法
可以将任何敲入修饰和敲除修饰通过本文所述的常规方法(method)和/或方法(approach)引入合适的免疫细胞中。通常,此类方法将涉及将基因物质递送到合适的免疫细胞中,以下调靶内源性炎性蛋白的表达、表达所关注细胞因子拮抗剂或表达所关注免疫抑制性细胞因子。
(A)敲入修饰
为了产生本文所述的一种或多种双特异性CAR、IFNγ拮抗剂、IL-6拮抗剂和IL-1拮抗剂的敲入,可以将一种或多种双特异性CAR、IFNγ拮抗剂、IL-6拮抗剂和IL-1拮抗剂的编码序列克隆到合适的表达载体(例如,包含但不限于慢病毒载体、逆转录病毒载体、腺病毒载体、腺相关载体、PiggyBac转座子载体和Sleeping Beauty转座子载体)中,并且使用常规重组技术将其引入到宿主免疫细胞中。Sambrook等人,《分子克隆:实验室手册》,第3版,冷泉港实验室出版社。结果,本公开的经修饰的免疫细胞可以包括一种或多种编码至少一种双特异性CAR、IFNγ拮抗剂、IL-6拮抗剂或IL-1拮抗剂的外源性核酸。在一些情况下,此类分子的编码序列被整合到细胞的基因组中。在一些情况下,此类分子的编码序列未整合到细胞的基因组中。
敲入是指将外源性核酸引入到宿主细胞中。在一些情况下,外源性核酸可以插入到宿主细胞的基因组位点中(例如,用于稳定表达经编码的基因产物)。可替代地,外源性核酸可以存在于染色体外(例如,用于瞬时表达经编码的基因产物)。
包括所关注编码序列的外源性核酸可以进一步包括合适的启动子,所述启动子可以与编码序列可操作地连接。如本文所使用的,启动子是指核酸上的核苷酸序列(位点),RNA聚合酶可以与所述核苷酸序列结合,以启动编码DNA(例如,对于细胞因子拮抗剂)转录成mRNA,然后将其翻译成对应的蛋白质(即,基因的表达)。当启动子相对于编码序列处于正确的功能位置和朝向以控制(“驱动”)所述编码序列的转录起始和表达(以产生对应的蛋白质分子)时,所述启动子被认为与编码序列“可操作地连接”。在一些情况下,本文所述的启动子可以是组成型的,其启动独立于其它调节因子的转录。在一些情况下,本文所述的启动子可以是诱导型的,其依赖于用于转录的调节因子。示例性启动子包含但不限于泛素、RSV、CMV、EF1α和PGK1。在一个实例中,可以通过常规方法将与一个或多个合适的启动子可操作地连接的对如本文所述的一种或多种炎性细胞因子的一种或多种拮抗剂进行编码的一个或多个核酸引入免疫细胞中,以驱动一种或多种拮抗剂的表达。
另外,本文所述的外源性核酸可以进一步含有例如,以下中的一些或全部:可选择标志物基因,如用于在哺乳动物细胞中选择稳定或瞬时转染子的新霉素基因;用于高水平转录的来自人CMV的立即早期基因的增强子/启动子序列;用于mRNA稳定性的来自SV40的转录终止和RNA加工信号;用于适当的附加型复制的SV40多瘤复制起点和ColE1;通用多克隆位点;以及用于正义和反义RNA的体外转录的T7和SP6 RNA启动子。用于产生含有转基因的载体的合适方法是本领域熟知的且可获得的。Sambrook等人,《分子克隆:实验室手册》,第3版,冷泉港实验室出版社。
在一些情况下,可以以多顺反子方式在一个表达盒中构建一种或多种双特异性CAR、IFNγ拮抗剂、IL-6拮抗剂或IL-1拮抗剂,使得各个分子作为单独的多肽表达。在一些实例中,可以在两个编码序列之间插入内部核糖体进入位点来实现这一目标。可替代地,可以将编码自切割肽(例如T2A或P2A)的核苷酸序列插入两个编码序列之间。以下实例中提供了此类多顺反子表达盒的示例性设计。
(B)敲除修饰
可以使用本领域已知的用于下调宿主细胞中的内源性基因表达的任何方法来降低本文所述的靶内源性细胞因子/蛋白质的产量水平。基因编辑方法可能涉及使用能够切割内源性等位基因中的靶区的核酸内切酶。在不存在模板核酸的情况下,非同源性末端连接可以修复基因组中的双链断裂,并且将突变(例如,插入、缺失和/或移码)引入到靶位点中。基因编辑方法通常基于参与靶核酸中产生双链断裂的核酸内切酶的类型来分类。实例包含但不限于,成簇的规律间隔的短回文重复序列(CRISPR)/核酸内切酶系统、基于转录激活因子样效应子的核酸酶(TALEN)、锌指核酸酶(ZFN)、核酸内切酶(例如,ARC归巢核酸内切酶)、大范围核酸酶(例如,mega-TAL)或其组合。
在本领域中已经描述了使用大范围核酸酶(包含经修饰大范围核酸酶)的各种基因编辑系统;参见例如,Steentoft等人,《糖生物学(Glycobiology)》24(8):663-80,2014;Belfort和Bonocora,《分子生物学方法》1123:1-26,2014;Hafez和Hausner,《基因组(Genome)》55(8):553-69,(2012);以及本文中引用的参考文献的综述。在一些实例中,敲除事件可以与敲入事件相结合——编码所需分子的外源核酸,如本文所述的那些,可以通过基因编辑插入到靶内源性基因的基因座中。
可替代地,可以通过本领域已知的方法使用反义寡核苷酸(例如,如shRNA或siRNA等干扰RNA)或核酶来实现任何敲除修饰。对靶细胞因子/蛋白质具有特异性的反义寡核苷酸是指与细胞因子的内源性基因或对此类内源性基因进行编码的mRNA的靶区互补或部分地互补的寡核苷酸。此类反义寡核苷酸可以通过常规方法递送到靶细胞中。可替代地,表达载体如慢病毒载体或其等价物可用于表达此类反义寡核苷酸。
(C)包括经修饰免疫细胞的免疫细胞群体的制备
可以通过将所述敲除修饰中的一种或多种敲入修饰、一种或多种敲除修饰或其组合引入宿主免疫细胞群体中来制备包括本文所述的任何经修饰免疫细胞或其组合的免疫细胞群体。可以以任何顺序将敲入修饰和敲除修饰引入宿主细胞中。
在一些情况下,在先前的修饰事件之后和在下一个修饰事件之前,以顺序的方式将一种或多种修饰引入宿主细胞中而无需分离和/或富集经修饰细胞。在那种情况下,所得免疫细胞群体可以是异质的,所述免疫细胞群体包括具有不同的修饰或不同的修饰组合的细胞。这种免疫细胞群体还可以包括未经修饰免疫细胞。相对于宿主免疫细胞的总数,可以通过诱导这种修饰的遗传物质的量来控制免疫细胞群体中发生的每个修饰事件的水平。还参见以上讨论。
在其它情况下,在第一修饰事件之后在进行第二修饰事件之前,可以分离并富集经修饰免疫细胞。此方法将导致产生基本上同质的免疫细胞群体,所述基本上同质的免疫细胞群体具有引入细胞中的所有敲入修饰和/或敲除修饰。
在一些实例中,将一种或多种敲入修饰和一种或多种敲除修饰分别引入宿主免疫细胞中。例如,通过基因编辑进行敲除修饰以敲除靶细胞因子的内源性基因,并且通过将用于产生一种或多种细胞因子拮抗剂的单独的外源性表达盒递送到宿主免疫细胞中来进行敲入修饰。在一些情况下,敲入和敲除事件可以同时发生,例如,敲入盒可以插入到待敲除的靶基因的基因座中。
IV.治疗应用
在一些方面,本公开提供了一种治疗疾病或病症的基于细胞疗法的方法,所述方法包括向有需要的受试者施用本文所述的免疫细胞群体或本文所述的药物组合物。包括如本文所述的经修饰的免疫细胞的任何免疫细胞群体可以用于治疗如白血病或淋巴瘤等靶疾病的过继性免疫细胞疗法(即,CAR-T)。由于引入到免疫细胞中的敲入和敲除修饰,特别是CAR的敲入、IL-6拮抗性抗体的敲入、IL-1拮抗剂或其组合,此类敲入和敲除修饰的治疗用途将有望改善治疗细胞的增殖,同时实现相同或更好的治疗效果。
为了实践本文所述的治疗方法,可以将有效量的免疫细胞群体(包括如本文所述的任何经修饰免疫细胞)通过合适的途径(例如,静脉内输注)施用于需要治疗的受试者。免疫细胞群体的一种或多种可以在施用之前与药学上可接受的载剂混合以形成药物组合物,这也在本公开的范围内。免疫细胞对于受试者而言可以是自体的,即,免疫细胞是从需要治疗的受试者获得的,被修饰以减少例如本文所述的一种或多种靶细胞因子/蛋白质的表达,以表达本文所述的一种或多种细胞因子拮抗剂,以表达CAR构建体和/或外源性TCR或其组合。然后可以将所得经修饰免疫细胞施用于同一受试者。与施用非自体细胞相比,将自体细胞施用于受试者可以导致免疫细胞的排斥减少。可替代地,免疫细胞可以为同种异体细胞,即,所述细胞是从第一受试者获得的,如本文所述进行修饰并且将其施用于不同于第一受试者但属于同一物种的第二受试者。例如,同种异体免疫细胞可以源自人类供体,并且施用于不同于所述供体的人类接受者。
在一个实施例中,在细胞疗法之前,所述受试者接受淋巴细胞清除治疗以调整所述受试者以进行细胞疗法。淋巴细胞清除治疗的实例包括向受试者施用氟达拉滨和环磷酰胺中的一种或多种。
待治疗的受试者可以是哺乳动物(例如,人、小鼠、猪、牛、大鼠、狗、豚鼠、兔子、仓鼠、猫、山羊、绵羊或猴子)。所述受试者可能患有癌症、患有感染性疾病或免疫病症。示例性癌症包含但不限于血液系统恶性肿瘤(例如,B细胞急性成淋巴细胞性白血病、慢性淋巴细胞性白血病和多发性骨髓瘤)。示例性感染性疾病包含但不限于人免疫缺陷病毒(HIV)感染、爱泼斯坦-巴尔病毒(Epstein-Barr virus)(EBV)感染、人乳头瘤病毒(HPV)感染、登革病毒感染、疟疾、败血症和大肠杆菌(Escherichia coli)感染。示例性免疫病症包含但不限于自身免疫疾病,如类风湿性关节炎、I型糖尿病、系统性红斑狼疮、炎性肠病、多发性硬化症、格林-巴利综合征(Guillain-Barre syndrome)、慢性炎性脱髓鞘性多发性神经病、银屑病、格雷夫斯病(Graves'disease)、桥本氏甲状腺炎(Hashimoto's thyroiditis)、重症肌无力和血管炎。
在一些情况下,本文所公开的基因工程化免疫细胞(如T细胞)表达靶向CD19和BCMA两者的双特异性CAR(例如,本文所公开的双特异性CAR)。此类双特异性CAR-T细胞可以用于治疗患有CD19+和/或BCMA+癌症(例如,血液学癌症或实体瘤)的人类患者。在一些实例中,所述癌症可以是淋巴细胞性白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、套细胞淋巴瘤、大B细胞淋巴瘤或非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)。在其它实例中,所述癌症可以是多发性骨髓瘤、复发性多发性骨髓瘤或难治性多发性骨髓瘤。可替代地,人类患者可能患有乳腺癌、胃癌、成神经细胞瘤或骨肉瘤。
在一些实施例中,本文所述的CAR-T细胞可用于治疗B细胞相关癌症。非限制性B细胞相关癌症包含:多发性骨髓瘤、恶性浆细胞肿瘤、霍奇金氏淋巴瘤(Hodgkin'slymphoma)、结节性淋巴细胞主要霍奇金氏淋巴瘤、卡勒氏病(Kahler's disease)和骨髓瘤、浆细胞白血病、浆细胞瘤、B细胞幼淋巴细胞性白血病、毛细胞白血病、B细胞非霍奇金氏淋巴瘤(NHL)、急性骨髓性白血病(AML)、慢性淋巴细胞性白血病(CLL)、急性淋巴细胞性白血病(ALL)、慢性骨髓性白血病(CML)、滤泡性淋巴瘤、伯基特淋巴瘤(Burkitt'slymphoma)、边缘区淋巴瘤、套细胞淋巴瘤、大细胞淋巴瘤、前体B淋巴母细胞淋巴瘤、骨髓性白血病、瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom's macroglobulienemia)、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、边缘区淋巴瘤、粘膜相关淋巴组织淋巴瘤、小细胞淋巴细胞淋巴瘤、套细胞淋巴瘤、伯基特淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、淋巴浆细胞性淋巴瘤、瓦尔登斯特伦巨球蛋白血症、淋巴结边缘区B细胞淋巴瘤、脾边缘区淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、淋巴瘤样肉芽肿病、富含T细胞/组织细胞的大B细胞淋巴瘤、原发性中枢神经系统淋巴瘤、原发性皮肤弥漫性大B细胞淋巴瘤(腿型)、老年人EBV阳性弥漫性大B细胞淋巴瘤、与炎症相关的弥漫性大B细胞淋巴瘤、血管内大B细胞淋巴瘤、ALK阳性大B细胞淋巴瘤、浆母细胞性淋巴瘤(PBL)、HHV8相关多中心卡斯特莱曼病引发的大B细胞淋巴瘤、特征介于弥漫性大B细胞淋巴瘤和伯基特淋巴瘤之间的未分类的B细胞淋巴瘤、特征介于弥漫性大B细胞淋巴瘤和经典型霍奇金氏淋巴瘤之间的未分类的B细胞淋巴瘤,以及其它B细胞相关淋巴瘤。
如本文所使用的术语“有效量”是指单独地或与一种或多种活性剂组合地赋予受试者治疗效果所需的每种活性剂的量。如本领域技术人员所认识到的,有效量根据所治疗的特定病状、病状的严重程度、包含年龄、身体状况、大小、性别和体重的个体患者参数、治疗持续时间、施用途径、赋形剂使用、与其它活性剂的共同使用(如果有的话)以及在健康从业者的知识和专业知识内的相似因素而变化。待施用的量取决于待治疗的受试者,包含例如个体免疫系统产生细胞介导的免疫应答的能力。需要施用的活性成分的精确量取决于从业者的判断。然而,本领域技术人员可以容易地确定合适的剂量范围。
如本文所使用的术语“治疗”是指将包含一种或多种活性剂的组合物应用于或施用于受试者,所述受试者患有靶疾病、靶疾病的症状或对靶疾病的易感性,其目的是治愈、痊愈、减轻、缓解、改变、补救、改善、改进或影响疾病、疾病的症状或对疾病的易感性。
可以通过合适的途径,例如静脉输注,向需要治疗的人类患者施用有效量的免疫细胞。在一些情况下,可将约1×106至约1×108个CAR+T细胞给予人类患者(例如,白血病患者、淋巴瘤患者或多发性骨髓瘤患者)。在一些实例中,人类患者可以接受多剂量的免疫细胞。例如,患者可以连续两天接受两剂免疫细胞。在一些情况下,第一剂量与第二剂量相同。在其它情况下,第一剂量少于第二剂量,或第二剂量少于第一剂量。
在本文所公开的任何涉及使用免疫细胞的治疗方法中,受试者可以在进行细胞疗法的同时施用IL-2。更具体地,可以在细胞疗法之前、期间或之后,通过合适的途径给予受试者有效量的IL-2。在一些实施例中,在施用免疫细胞后给予受试者IL-2。
可替代地或另外地,在免疫细胞输注后,通过本文所公开的细胞疗法治疗的受试者可以不用涉及IL-6拮抗剂(细胞疗法中使用的免疫细胞产生的IL-6拮抗剂除外)治疗。
包括如本文所述的经修饰免疫细胞的免疫细胞群体可以与用于癌症的其它类型的疗法(如化学疗法、外科手术、放射、基因疗法等)结合使用。此类疗法可以与本文所述的免疫疗法同时地或顺序地(以任何顺序)施用。当与另外的治疗剂共同施用时,由于相加作用或协同作用,可以降低每种药剂的合适的治疗有效剂量。
在一些实施例中,所述治疗癌症的方法在输注基因工程化细胞的14天内不会在被治疗的受试者中引发严重的CRS。在治疗方法的一个实施例中,被治疗的受试者可能不需要接受另外的抗IL-6疗法,如托珠单抗(tocilizumab)。在一些实施例中,被治疗的受试者可能不需要接受类固醇疗法来抑制免疫系统。在其它实施例中,被治疗的受试者可以接受如甲基强的松龙(methylprednisolone)和地塞米松(dexamethasone)等免疫抑制类固醇,同时输注本文所公开的免疫细胞。经验丰富的临床医生将能够确定受试者的生命体征和症状,以在治疗期间监测和评估CRS的级别/严重程度,并及时施用适当的药物以抑制发展中的CRS。
在一些实施例中,在本文所公开的CAR-T疗法之前,受试者经受合适的抗癌疗法(例如,本文所公开的疗法)以降低肿瘤负荷。例如,受试者(例如,人类癌症患者)可以经受化学疗法(例如,包括单一化学治疗剂或两种或多种化学治疗剂的组合),所用剂量可显著降低肿瘤负荷。在一些情况下,化学疗法可将受试者的总白细胞计数降低至108/L以下,例如107/L以下。可以通过常规方法监测初始抗癌疗法后和/或本文所公开的CAR-T细胞疗法后患者的肿瘤负荷。如果在初始抗癌疗法后和/或CAR-T疗法后患者癌细胞表现出高生长速率,则所述患者可能经受新一轮化学疗法以减轻肿瘤负荷,随后接受本文所公开的任何CAR-T疗法。
可用于与本文所述的经修饰免疫细胞组合的其它抗癌治疗剂的非限制性实例包含但不限于免疫检查点抑制剂(例如,PDL1、PD1和CTLA4抑制剂)、抗血管生成剂(例如,TNP-470、血小板因子4、血小板反应蛋白-1、金属蛋白酶的组织抑制剂、催乳素、血管抑素、内皮抑素、bFGF可溶性受体、转化生长因子β、干扰素α、干扰素γ、可溶性KDR和FLT-1受体以及胎盘增殖素相关蛋白);VEGF拮抗剂(例如,抗VEGF抗体、VEGF变体、可溶性VEGF受体片段);化学治疗化合物。示例性化学治疗化合物包含嘧啶类似物(例如,5-氟尿嘧啶、氟尿苷(floxuridine)、卡培他滨(capecitabine)、吉西他滨(gemcitabine)和阿糖胞苷(cytarabine));嘌呤类似物(例如,氟达拉滨);叶酸拮抗剂(例如,巯基嘌呤(mercaptopurine)和硫鸟嘌呤(thioguanine));抗增殖剂或抗有丝分裂剂,例如长春花生物碱(vinca alkaloids);微管干扰剂,如紫杉烷(taxane)(例如,紫杉醇(paclitaxel)、多西他赛(docetaxel))、长春新碱(vincristin)、长春碱(vinblastin)、诺考达唑(nocodazole)、埃坡霉素(epothilones)和长春瑞滨(navelbine),以及表鬼臼毒素(epidipodophyllotoxin);DNA损伤剂(例如,放线菌素(actinomycin)、安吖啶(amsacrine)、蒽环霉素(anthracycline)、博来霉素(bleomycin)、白消安(busulfan)、喜树碱(camptothecin)、卡铂(carboplatin)、苯丁酸氮芥(chlorambucil)、顺铂(cisplatin)、环磷酰胺、癌得星(cytoxan)、更生霉素(dactinomycin)、道诺霉素(daunorubicin)、阿霉素(doxorubicin)、表柔比星(epirubicin)、己二胺(hexamethyhnelamine)、奥沙利铂(oxaliplatin)、异环磷酰胺(iphosphamide)、美法仑(melphalan)、二氯甲基二乙胺(merchlorehtamine)、丝裂霉素(mitomycin)、米托蒽醌(mitoxantrone)、亚硝基脲(nitrosourea)、普卡霉素(plicamycin)、甲基苄肼(procarbazine)、紫杉酚(taxol)、泰索帝(taxotere)、替尼泊苷(teniposide)、三乙烯硫代磷酰胺(triethylenethiophosphoramide)和依托泊苷(etoposide))。
在一些实施例中,放射或放射和化学疗法与包括本文所述的经修饰的免疫细胞的细胞群体组合使用。另外的有用的药剂和疗法可以在《医师案头参考(Physician's DeskReference)》,增刊第59版,(2005),Thomson P D R,Montvale N.J.;Gennaro等人,编辑《雷明顿药学科学与实践(Remington's The Science and Practice of Pharmacy)》,增刊第20版,(2000),马里兰州巴尔的摩的利平科特·威廉姆斯和威尔金斯公司(LippincottWilliams and Wilkins,Baltimore Md.);Braunwald等人,编辑《哈里森内科医学原理(Harrison's Principles of Internal Medicine)》,增刊第15版,(2001),纽约麦格劳·希尔公司(McGraw Hill,NY);Berkow等人,编辑《默克诊断与疗法手册(The Merck Manualof Diagnosis and Therapy)》,(1992),新泽西州拉威的默克研究实验室(Merck ResearchLaboratories,Rahway N.J.)中找到。
V.用于治疗用途或制备基因工程化免疫细胞的试剂盒
本公开还提供了用于涉及一种或多种本文所述的免疫细胞群体的本文所述的任何靶疾病的试剂盒,以及用于制备如本文所述的经修饰的免疫细胞的试剂盒。
如本文所述的用于治疗用途的试剂盒可以包含包括免疫细胞群体的一个或多个容器,所述免疫细胞群体可以被调配成药物组合物。免疫细胞群体包括本文所述的任何经修饰的免疫细胞或其组合。免疫细胞(如本文所述的T淋巴细胞、NK细胞和其它细胞)群体可以进一步表达本文所述的双特异性CAR构建体。
在一些实施例中,试剂盒可以另外包括在本文所述的任何方法中使用免疫细胞群体的说明书。所包含的说明书可以包括将免疫细胞群体或包括所述免疫细胞群体的药物组合物施用于受试者以在受试者中实现预期活性的描述。试剂盒可以进一步包括基于鉴定受试者是否需要治疗来选择适合于治疗的受试者的描述。在一些实施例中,说明书包括将免疫细胞群体或包括所述免疫细胞群体的药物组合物施用于需要治疗的受试者的描述。
与免疫细胞群体或包括如本文所述的免疫细胞群体的药物组合物的使用相关的说明书通常包含关于用于预期治疗的剂量、给药方案和施用途径的信息。容器可以是单位剂量、散装包装(例如,多剂量包装)或亚单位剂量。在本公开的试剂盒中提供的说明书通常是在标签或包装插页上的书面说明。标签或包装插页指示药物组合物用于治疗受试者的疾病或病症、延迟受试者的疾病或病症的发作和/或减轻受试者的疾病或病症。
本文中提供的试剂盒采用合适的包装。合适的包装包含但不限于小瓶、瓶、广口瓶、软包装等。还设想了与具体装置(如吸入器、鼻腔施用装置或输注装置)组合使用的包装。试剂盒可以具有无菌进口端(例如,容器可以是具有可被皮下注射针刺穿的塞子的静脉内溶液袋或小瓶)。容器还可以具有无菌进口端。药物组合物中的至少一种活性剂是包括任何经修饰的免疫细胞或其组合的免疫细胞群体(例如,T淋巴细胞或NK细胞)。
试剂盒任选地可以提供如缓冲剂等另外的组分以及解释性信息。通常,试剂盒包括容器和在容器上或与容器相关的标签或一个或多个包装插页。在一些实施例中,本公开提供了包括以上所描述的试剂盒的内容物的制品。
这里还提供了用于制备本文所述的经修饰的免疫细胞的试剂盒。这种试剂盒可以包含一个或多个容器,每个容器含有用于将敲入修饰和/或敲除修饰引入免疫细胞中的试剂。例如,试剂盒可以含有用于进行如本文所述的一种或多种敲除修饰的基因编辑系统的一种或多种组分。可替代地或另外地,试剂盒可以包括用于表达也如本文所述的细胞因子拮抗剂的一种或多种外源性核酸,以及用于将外源性核酸递送到宿主免疫细胞中的试剂。这种试剂盒可以进一步包含用于对宿主免疫细胞进行所期望的修饰的说明书。
一般技术
除非另有说明,否则本公开的实践将采用本领域技术范围内的分子生物学(包含重组技术)、微生物学、细胞生物学、生物化学、免疫学和嵌合抗原受体(CAR)免疫疗法的常规技术。此类技术在如以下等文献中进行了充分解释:《分子克隆:实验室手册》,第二版(Sambrook等人,1989)冷泉港出版社;《寡核苷酸合成(Oligonucleotide Synthesis)》(M.J.Gait,编辑1984);《分子生物学方法(Methods in Molecular Biology)》,胡马纳出版社(Humana Press);《细胞生物学:实验室手册(Cell Biology:A Laboratory Notebook)》(J.E.Cellis,编辑,1989)学术出版社(Academic Press);《动物细胞培养(Animal CellCulture)》(R.I.Freshney,编辑,1987);《细胞和组织培养导论(Introduction to Celland Tissue Culture)》(J.P.Mather和P.E.Roberts,1998),普莱南出版社(PlenumPress);《细胞和组织培养:实验室程序(Cell and Tissue Culture:LaboratoryProcedures》(A.Doyle、J.B.Griffiths和D.G.Newell,编辑,1993-8)约翰·威利父子出版公司(J.Wiley and Sons);《酶学方法(Methods in Enzymology)》(学术出版社公司(Academic Press,Inc.);《实验免疫学手册(Handbook of Experimental Immunology)》(D.M.Weir和C.C.Blackwell,编辑):《哺乳动物细胞基因转移载体(Gene TransferVectors for Mammalian Cells)》(J.M.Miller和M.P.Calos,编辑,1987);《当代分子生物学实验指南》(F.M.Ausubel等人,编辑1987);《PCR:聚合酶链反应(PCR:The PolymeraseChain Reaction)》(Mullis等人,编辑1994);《当代免疫学指南(Current Protocols inImmunology)》(J.E.Coligan等人,编辑,1991);《精编分子生物学实验指南(ShortProtocols in Molecular Biology)》(约翰威利父子出版公司,1999);《免疫生物学(Immunobiology)》(C.A.Janeway和P.Travers,1997);《抗体(Antibodies)》(P.Finch,1997);《抗体:实用方法(Antibodies:a practical approach)》(D.Catty.,编辑,IRL出版社(IRL Press),1988-1989);《单克隆抗体:实用方法(Monoclonal antibodies:apractical approach)》(P.Shepherd和C.Dean,编辑,牛津大学出版社(Oxford UniversityPress),2000);《使用抗体:实验室手册(Using antibodies:a laboratory manual)》(E.Harlow和D.Lane,冷泉港实验室出版社,1999);《抗体》(M.Zanetti和J.D.Capra,编辑,哈伍德学术出版社,1995);《DNA克隆:A practical Approach)》,第I卷和第II卷(D.N.Glover,编辑,1985);《核酸杂交(Nucleic Acid Hybridization)》(B.D.Hames和S.J.Higgins,编辑,1985);《转录和翻译(Transcription and Translation)》(B.D.Hames和S.J.Higgins,编辑,1984);《动物细胞培养》(R.I.Freshney编辑,1986);《固定化细胞和酶(Immobilized Cells Enzymes)》(B.Perbal,IRL出版社,1986);《分子克隆实用指南(Apractical Guide To Molecular Cloning)》(F.M.Ausubel等人,编辑1984);《嵌合抗原受体(CAR)免疫疗法(Chimeric Antigen Receptor(CAR)Immunotherapy)》(D.W.Lee和N.N.Shah,编辑,爱思唯尔(Elservier),2019,ISBN:9780323661812);《嵌合抗原受体(CAR)免疫疗法基础(Basics of Chimeric Antigen Receptor(CAR)Immunotherapy)》(M.Y.Balkhi,学术出版公司(Academic Press),爱思唯尔科学(Elsevier Science),2019,ISBN:9780128197479);《嵌合抗原受体T细胞的发育和生产(Chimeric Antigen ReceptorT Cells Development and Production)》(V.K.C.R.Malmegrim和K.Swiech,编辑,美国施普林格出版社(Springer US),2020,ISBN:9781071601488);《细胞和基因治疗(Cell and Gene Therapies)》(C.Bollard,S.A.Abutalib和M.-A.Perales,编辑,施普林格国际出版社(Springer International),2018,ISBN:9783319543680)和《开发用于疾病免疫疗法的共刺激分子(Developing Costimulatory Molecules forImmunotherapy of Diseases)》(M.A.Mir,爱思唯尔科学,2015,ISBN:9780128026755)。
本公开的应用不限于在本文的说明书中阐述的或在附图中展示的构造细节和组件布置。本公开能够具有其它实施例并且能够以不同的方式实践或进行。而且,本文所使用的措辞和术语是出于说明的目的并且不应该被认为具有限制性。本文中对“包含”、“包括”或“具有”、“含有”、“涉及”及其变化的使用意在涵盖其后列出的项及其等效物以及另外的项。还如在本说明书和所附权利要求中所使用的,除非上下文另有明确指示,否则单数形式“一个(a)”、“一种(an)”以及“所述(the)”包含复数指代物。
无需进一步详细阐述,相信本领域技术人员能够基于以上描述,最大限度地利用本发明。因此,以下具体实施例应被解释为仅是说明性的,并且不以任何方式限制本公开的其余部分。出于本文所提及的目的或主题,本文所引用的所有出版物均通过引用并入。
序列表1.抗体序列:
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序列表2:嵌合抗原受体序列和其组成部分
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序列表3.靶向IFNγ的向导RNA序列
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实例
实例1:表达双特异性嵌合抗原受体(CAR)的基因工程化T细胞的制备
从人类患者供体采集血液样品,并通过常规实践从血液样品中分离外周血单核细胞(PBMC)。将编码抗CD19/抗BCMA双特异性CAR以及任选地抗IFNγscFv(SEQ ID NO:21或SEQ ID NO:18)和/或抗IL6 scFv(SEQ ID NO:35)的慢病毒表达载体引入到PBMC中,以允许表达双特异性CAR以及任选地抗IFNγscFv和抗IL6 scFv。
对抗CD19/抗BCMA双特异性CAR的两种设计进行探索:(a)抗CD19 VHH/抗BCMAscFv;以及(b)抗BCMA VHH/抗CD19 scFv。所有双特异性CAR构建体包含CD8前导序列(SEQID NO:45)、GS接头(SEQ ID NO:57)、CD8铰链结构域(SEQ ID NO:53)、CD8跨膜结构域(SEQID NO:38)、4-1BB共刺激结构域(SEQ ID NO:39)、IL-2Rb信号传导结构域(SEQ ID NO:40)和CD3z信号传导结构域(SEQ ID NO:42)。参见序列表2。(a)的构建体包括SEQ ID NO:65的氨基酸序列;(b)的构建体包括SEQ ID NO:67的氨基酸序列。
在一些情况下,使用包括构建体(a)或(b)的编码序列和通过T2A编码序列接头连接的抗IFNγscFv(SEQ ID NO:21或SEQ ID NO:18)的编码序列的双顺反子表达载体来产生表达双特异性CAR和抗IFNγscFv(分泌型)两者的基因工程化T细胞。在其它情况下,三顺反子表达载体包括构建体(a)或(b)的编码序列、通过T2A编码序列与(a)和(b)的编码序列连接的抗IFNγscFv(SEQ ID NO:21或SEQ ID NO:18)的编码序列以及通过P2A编码序列与抗IFNγscFv的编码序列连接的抗IL6 scFv(SEQ ID NO:35)的编码序列。
通过抗CD3/CD28珠(赛默科技公司(Thermo scientific))激活从健康供体收集的原代T细胞。一天后,用慢病毒载体转导T细胞,所述慢病毒载体编码上述双特异性CAR以及任选地上文所公开的抗IFNγscFv和抗IL6 scFv中的一种。将经转导的细胞扩增并通过FACS分析测试CD3表达,并且对CD3+群体进行门控以进行进一步分析。
使用识别CAR中的抗体片段的生物素化的初级抗体和与链霉亲和素缀合的荧光标记的次级抗体,通过流式细胞术分析CAR表达。
通过将CAR-T细胞与靶抗原呈递细胞(APC)或靶肿瘤细胞共培养来分析双特异性Car-T细胞的功能,以评估CAR-T细胞增殖、细胞毒性或其组合。
实例2:用抗CD19/抗BCMA双特异性CAR-T细胞治疗急性淋巴细胞性白血病(ALL)患者
用下文详述的双特异性CAR-T细胞治疗患有急性淋巴细胞性白血病(ALL)的人类患者。
(A)用分泌抗IFNγscFv的双特异性CAR T细胞进行治疗
在标准淋巴细胞清除治疗后,通过静脉内输注向被诊断为患有难治性和复发性急性淋巴细胞性白血病(ALL)的患者(ALL患者1)施用仅分泌示例性抗IFNγscFv(参见上述实例1,包括SEQ ID NO:21的氨基酸序列)的双特异性CAR T细胞(抗BCMA VHH/抗CD19 scFv,参见实例1中的设计(b)),剂量为0.4×108个CAR+T细胞。
治疗后,从所述患者中采集血液样品。随着时间的推移检测到CAR-T细胞的显著扩增(图2A),并且在血液样品中检测到低水平的IFNγ(图2B)。此结果表明,共表达抗IFNγscFv的双特异性抗CD19/BCMACAR-T细胞足以诱导持久CAR+T细胞扩增。此患者在临床疗效上示出完全应答。在此治疗期间,仅观察到2级CRS。
(B)用分泌抗IL6 scFv和抗IFNγscFv的双特异性CAR-T细胞进行治疗
通过静脉内输注向被诊断为患有ALL的患者(ALL患者2)施用表达包括上述实例1中公开的氨基酸序列的抗IL6 scFv和抗IFNγscFv两者的双特异性CAR-T细胞(抗BCMAVHH/抗CD19 scFv,参见实例1中的设计(b))。此患者在临床疗效上示出完全应答。在此治疗期间,仅观察到1级CRS。与患者1类似,在治疗后,患者2的血液样本中也示出低水平的IFNγ(图2C)。
实例3:用双特异性抗CD19/抗BCMACAR-T细胞治疗多发性骨髓瘤(MM)患者
通过静脉内输注向至多3名被诊断为患有难治性和复发性MM的患者(MM患者1、MM患者2和MM患者3)施用共表达双特异性CAR构建体(a)和上述实例1中公开的包括SEQ IDNO:21的氨基酸序列的抗IFNγscFv的CAR-T细胞(患者1,0.4×108;患者2,0.8×108;患者3,0.8×108个CAR+T细胞)。向一名被诊断为患有难治性和复发性MM的患者(MM患者4)施用表达双特异性CAR构建体(a)但不表达抗IFNγscFv的CAR-T细胞。
治疗后,确定每名MM患者的CAR+T细胞扩增和IFNγ水平。在此实例中治疗的所有MM患者中均检测到CAR+T细胞的显著扩增。图3A和3C-3D。在用表达双特异性CAR和抗IFNγscFv两者的CAR-T细胞治疗的患者的外周血中也检测到低水平的IFNγ。参见图3B,了解一名代表性患者的数据。这表明,共表达抗IFNγscFv的双特异性抗CD19/BCMA CAR-T细胞能够诱导稳健的CAR+T细胞扩增。通过共表达双特异性CAR和抗IFNγscFv治疗的MM患者在治疗后实现完全应答(CR)。尽管骨髓检查在治疗前在患者1中检测到79.5%异常浆细胞,但在治疗期间通过10mg去甲肾上腺素在1天内成功缓解仅短暂出现的轻度低血压,并且因此观察到3级CRS。在此治疗期间,在患者2和患者3中仅观察到1级CRS。
在用表达双特异性CAR但不表达抗IFNγscFv的T细胞治疗的MM患者中也观察到CAR-T细胞扩增。图3E。此患者的临床应答正在评估中。在此治疗期间,仅观察到1级CRS。
实例4:双特异性CAR-T细胞的体外细胞毒性测定
在此实例中评估共表达双特异性CAR构建体(a)和上述实例1中公开的抗IFNγscFv(SEQ ID NO:21)的CAR-T细胞以及仅表达双特异性CAR构建体(a)的CAR-T细胞的体外细胞毒性。
将人T细胞激活并转导以产生表达双特异性CAR和抗IFNγscFv两者或仅表达双特异性CAR的基因工程化T细胞。将所产生的工程化T细胞与表达绿色荧光蛋白(GFP,作为报告基因)的靶肿瘤细胞以各种效应物与靶标(E:T)比率一起温育。通过对活的GFP+靶细胞的数量进行计数,通过流式细胞术来评估杀伤疗效,所述数量与细胞毒性水平反相关。如图4A-4C所示,两种类型的CAR-T细胞对Nalm6细胞(B细胞前体白血病细胞)、MM1S细胞(多发性骨髓瘤细胞)和RPMI 8226细胞(浆细胞瘤细胞)示出一定水平的细胞毒性。抗IFNγscFv的共表达对针对MM1S细胞和RPMI 8226细胞的CAR-T细胞毒性没有示出显著影响;然而,发现其降低了针对Nalm6细胞的细胞毒性。参见相对于图4B和4C的图4A。
其它实施例
本说明书中公开的所有特征可以以任何组合来组合。本说明书中公开的每个特征可以被用于相同、等效或类似目的的替代性特征替换。因此,除非另有明确说明,否则所公开的每个特征仅仅是等效或类似特征的通用系列的实例。
通过以上描述,本领域的技术人员可以很容易地确定本发明的实质特性,并且在不偏离本发明的精神和范围的情况下,可以对本发明进行各种改变和修改以使其适于各种用途和条件。因此,其它实施例也在权利要求范围内。
等效形式
尽管本文已经描述和展示了若干个发明实施例,但本领域的普通技术人员将容易想到用于执行本文所述的功能和/或获得结果和/或优点中的一个或多个优点的各种其它装置和/或结构,并且此类变化和/或修改中的每个变化和/或修改被认为是在本文所述的发明实施例的范围内。更一般地,本领域的技术人员将容易地理解,本文所述的所有参数、尺寸、材料和构型意味着示例性的,并且实际参数、尺寸、材料和/或构型将取决于使用本发明教导的一种或多种具体应用。仅使用常规实验,本领域的技术人员将认识到或能够确定本文所述的具体本发明实施例的许多等效物。因此,应理解,前述实施例仅以实例的方式呈现,并且在所附权利要求及其等效物的范围内,可以以不同于具体描述的和要求保护的方式来实践本发明实施例。本公开的本发明实施例涉及本文所述的每个单独的特征、系统、物品、材料、试剂盒和/或方法。此外,两个或更多个这样的特征、系统、物品、材料、试剂盒和/或方法的任何组合,如果这样的特征、系统、物品、材料、试剂盒和/或方法并不相互矛盾,被包含在本公开的发明范围内。
如本文定义和使用的所有定义应理解为先于字典定义,通过引用并入的文献中的定义,和/或所定义的术语的普通含义。
本文所公开的所有参考文献、专利和专利申请均通过引用关于各自所引用的主题而并入本文,在某些情况下可以涵盖整个文件。
除非明确相反指出,否则本说明书和权利要求中使用的不定冠词“一个(a)”和“一种(an)”应理解为表示“至少一个”。
如本文在说明书和权利要求中使用的,短语“和/或”应理解为意指如此结合的要素的“任一或两者”,即,在一些情况下结合存在和在其它情况下分离存在的要素。用“和/或”列出的多个要素应以相同的方式解释,即,如此结合的要素中的“一个或多个要素”。除了通过“和/或”从句具体标识的要素之外,还可以任选地存在其它要素,而无论是与具体标识的那些要素相关还是不相关。因此,作为非限制性实例,在一个实施例中,当与如“包括”等开放式语言结合使用时,对“A和/或B”的引用可以仅指A(任选地包含除B以外的要素);在另一个实施例中,仅指B(任选地包含除A以外的要素);在又另一个实施例中,指A和B两者(任选地包含其它要素);等。
如本文中在本说明书和权利要求中所使用的,“或”应被理解为具有与如上所定义的“和/或”相同的含义。例如,在将列表中的项分开时,“或”或“和/或”应被解释为包含性的,即,包含许多要素或要素列表中的至少一个要素,但还包含多于一个要素以及任选地另外的未列出的项。仅仅明确地指示相反的术语,如“……中的仅一个”或“……中的恰好一个”或者在权利要求中使用时,“由……组成”将指代包含多个要素或要素列表中的恰好一个要素。一般而言,当之前有排他性术语,如“任一个”、“……之一”、“……中的仅一个”、或“……中的恰好一个”时,如本文所使用的,术语“或”应当仅被解释为指示排他性替代方案(即,“一个或另一个而不是两个”)。当在权利要求中使用时,“基本上由……组成”应当具有如在专利法领域中所使用的普通含义。
如在本说明书和权利要求中所使用的,关于一个或多个要素的清单的短语“至少一个”应被理解为是指选自要素清单中的任一个或多个要素的至少一个要素、但不一定包含要素清单内具体列出的每一个要素的至少一个、并且不排除要素清单中要素的任何组合。这个定义还允许可以可选地存在除了在短语“至少一个”所指的要素清单内具体标识的要素之外的要素,而无论是否与具体标识的那些元素相关还是不相关。因此,作为非限制性实例,在一个实施例中,“A和B中的至少一个”(或等效地,“A或B中的至少一个”,或等效地“A和/或B中的至少一个”)可以指任选地包含多于一个A,不存在B(并且任选地包含除B以外的元素)的至少一个;在另一个实施例中,可以指任选地包含多于一个B,不存在A(并且任选地包含除A以外的元素)的至少一个;在又另一个实施例中,可以指任选地包含多于一个A的至少一个,以及任选地包含多于一个B(以及任选地包含其它元素)的至少一个;等。
还应该理解,除非明确相反地指出,否则在本文要求保护的包含多于一个步骤或动作的任何方法中,方法的步骤或动作的顺序不一定限于叙述方法的步骤或动作的顺序。
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<110> 细胞编辑有限责任公司(Celledit LLC)
<120> 双特异性嵌合抗原受体和表达此类双特异性嵌合抗原受体的
基因工程化免疫细胞
<130> 112126-0034-70005WO00
<140> 尚未分配
<141> 与此同时
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<151> 2021-05-19
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Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly Lys Arg Ala
130 135 140
Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu Gly Ser His
145 150 155 160
Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Thr Leu Leu
165 170 175
Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala Arg Phe Ser
180 185 190
Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp Pro Val Glu
195 200 205
Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg Thr Ile Pro
210 215 220
Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Ser Thr Ser
225 230 235 240
Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Gln Ile
245 250 255
Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val
260 265 270
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Ser Ile
275 280 285
Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met Gly Trp
290 295 300
Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe Arg Gly
305 310 315 320
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
325 330 335
Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Leu
340 345 350
Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr
355 360 365
Val Ser Ser
370
<210> 13
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Ser
20 25 30
Trp Ile Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ser Asp Gly Glu Val His Tyr Asn Gln Asp Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Leu Pro Trp Phe Ala Asp Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 14
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 14
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Asp Thr Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gly Gln Ser Tyr Asn Tyr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys Arg
100 105
<210> 15
<211> 240
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 15
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Asp Thr Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gly Gln Ser Tyr Asn Tyr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ser Ser Val Lys Val Ser
130 135 140
Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Ser Trp Ile Asn Trp Val
145 150 155 160
Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro
165 170 175
Ser Asp Gly Glu Val His Tyr Asn Gln Asp Phe Lys Asp Lys Ala Thr
180 185 190
Leu Thr Val Asp Lys Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser
195 200 205
Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Phe Leu
210 215 220
Pro Trp Phe Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
225 230 235 240
<210> 16
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 16
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Ser Ser Gly Trp Tyr Val Pro His Trp Phe Asp Pro
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 17
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 17
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Gly
85 90 95
Ser Asn Arg Trp Met Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 18
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 18
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Gly
85 90 95
Ser Asn Arg Trp Met Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
115 120 125
Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met
145 150 155 160
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala
165 170 175
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
210 215 220
Asp Gly Ser Ser Gly Trp Tyr Val Pro His Trp Phe Asp Pro Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser
245
<210> 19
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 19
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Leu Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Gly Ser Gly Ser Tyr Phe Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 20
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 20
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser Gly Gly Ser Ser
85 90 95
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 21
<211> 240
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 21
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser Gly Gly Ser Ser
85 90 95
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser
130 135 140
Cys Lys Gly Ser Gly Tyr Asn Phe Thr Ser Tyr Trp Ile Gly Trp Val
145 150 155 160
Arg Gln Met Pro Gly Lys Gly Leu Glu Leu Met Gly Ile Ile Tyr Pro
165 170 175
Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr
180 185 190
Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser
195 200 205
Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Gly Ser Gly Ser Tyr
210 215 220
Phe Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
225 230 235 240
<210> 22
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 22
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Arg Asp Ser Phe Asp Ile Trp Gly Gln Gly Thr Met Val
100 105 110
Thr Val Ser Ser
115
<210> 23
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 23
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 24
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 24
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Lys Ile Ser Pro Gly Gly Ser Trp Thr Tyr Tyr Ser Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Leu Trp Gly Tyr Tyr Ala Leu Asp Ile Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 25
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 25
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ile Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Met Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Met Gln Trp Ser Gly Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 26
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 26
Glu Val Gln Leu Val Glu Ser Gly Gly Lys Leu Leu Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Ala Met Ser Trp Phe Arg Gln Ser Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Glu Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Trp Gly Tyr Tyr Ala Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 27
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 27
Gln Ile Val Leu Ile Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 28
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 28
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser
115
<210> 29
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 29
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 30
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Asn Tyr
20 25 30
Tyr Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Ile Ile Tyr Gly Ser Asp Glu Thr Ala Tyr Ala Thr Ser Ala Ile
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Asp Ser Ser Asp Trp Asp Ala Lys Phe Asn Leu Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 31
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 31
Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Asn Asn Glu
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Leu Arg Asn
85 90 95
Ile Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 32
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Phe Asn Asp Tyr
20 25 30
Phe Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Met Arg Asn Lys Asn Tyr Gln Tyr Gly Thr Tyr Tyr Ala Glu
50 55 60
Ser Leu Glu Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Glu Ser Tyr Tyr Gly Phe Thr Ser Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val
115
<210> 33
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 33
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asn Ala Asn Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Ala Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 34
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 34
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu
115 120 125
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys
130 135 140
Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Ser Trp Asn
165 170 175
Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe Leu Gln Met Asn Gly Leu
195 200 205
Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Gly Arg Asp Ser
210 215 220
Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
225 230 235
<210> 35
<211> 240
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 35
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ile Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Met Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Met Gln Trp Ser Gly Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
115 120 125
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
130 135 140
Ala Ser Gly Phe Thr Phe Ser Pro Phe Ala Met Ser Trp Val Arg Gln
145 150 155 160
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Lys Ile Ser Pro Gly Gly
165 170 175
Ser Trp Thr Tyr Tyr Ser Asp Thr Val Thr Gly Arg Phe Thr Ile Ser
180 185 190
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
195 200 205
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Leu Trp Gly Tyr
210 215 220
Tyr Ala Leu Asp Ile Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
225 230 235 240
<210> 36
<211> 240
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 36
Gln Ile Val Leu Ile Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
115 120 125
Gly Gly Lys Leu Leu Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
130 135 140
Ala Ser Gly Phe Thr Phe Ser Ser Phe Ala Met Ser Trp Phe Arg Gln
145 150 155 160
Ser Pro Glu Lys Arg Leu Glu Trp Val Ala Glu Ile Ser Ser Gly Gly
165 170 175
Ser Tyr Thr Tyr Tyr Pro Asp Thr Val Thr Gly Arg Phe Thr Ile Ser
180 185 190
Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Glu Met Ser Ser Leu Arg
195 200 205
Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly Leu Trp Gly Tyr
210 215 220
Tyr Ala Leu Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
225 230 235 240
<210> 37
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 37
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Arg Ala
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg
180 185 190
Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr
210 215 220
Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly
225 230 235 240
Thr Lys Val Glu Ile Lys
245
<210> 38
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 38
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 39
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 39
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 40
<211> 94
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 40
Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys Asn
1 5 10 15
Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser Ser Glu His Gly
20 25 30
Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe
35 40 45
Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu Glu Val Leu Glu
50 55 60
Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn Thr Asp Ala Tyr Leu
65 70 75 80
Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr His Leu Val
85 90
<210> 41
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 41
Tyr Arg His Gln
1
<210> 42
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 42
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu Pro Pro Arg
100 105 110
<210> 43
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 43
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 44
<211> 691
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 44
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys
115 120 125
Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser
130 135 140
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
145 150 155 160
Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile
165 170 175
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu
180 185 190
Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn
195 200 205
Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr
210 215 220
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
225 230 235 240
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Glu Val Gln
245 250 255
Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly Ser Leu Arg
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His Ala Met Thr
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile
290 295 300
Ser Gly Ser Gly Asp Tyr Thr His Tyr Ala Asp Ser Val Lys Gly Arg
305 310 315 320
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met
325 330 335
Asn Ser Leu Arg Ala Glu Asp Ser Ala Val Tyr Tyr Cys Ala Lys Asp
340 345 350
Glu Asp Gly Gly Ser Leu Leu Gly His Arg Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
370 375 380
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
385 390 395 400
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
405 410 415
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
420 425 430
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
435 440 445
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
450 455 460
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
465 470 475 480
Gly Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys
485 490 495
Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu
500 505 510
Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe
515 520 525
Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro
530 535 540
Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn
545 550 555 560
Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr
565 570 575
His Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
580 585 590
Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
595 600 605
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
610 615 620
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
625 630 635 640
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
645 650 655
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
660 665 670
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu
675 680 685
Pro Pro Arg
690
<210> 45
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 45
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 46
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 46
Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala
1 5 10 15
Ala Gln Pro Ala Met Ala
20
<210> 47
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 47
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala
<210> 48
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 48
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser
<210> 49
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 49
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ser
1 5 10 15
Ser Arg Ala
<210> 50
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 50
Met Arg Arg Met Gln Leu Leu Leu Leu Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser
20
<210> 51
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 51
Met Ala Thr Gly Ser Arg Thr Ser Leu Leu Leu Ala Phe Gly Leu Leu
1 5 10 15
Cys Leu Pro Trp Leu Gln Glu Gly Ser Ala
20 25
<210> 52
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 52
Met Ala Leu Glu Thr Ile Cys
1 5
<210> 53
<211> 45
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 53
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 54
<211> 152
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 54
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 55
<211> 178
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 55
Met Ala Thr Gly Ser Arg Thr Ser Leu Leu Leu Ala Phe Gly Leu Leu
1 5 10 15
Cys Leu Pro Trp Leu Gln Glu Gly Ser Ala Arg Pro Ser Gly Arg Lys
20 25 30
Ser Ser Lys Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr
35 40 45
Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro
50 55 60
Asn Val Asn Leu Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His
65 70 75 80
Ala Leu Phe Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val
85 90 95
Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr
100 105 110
Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg
115 120 125
Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly
130 135 140
Trp Phe Leu Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr
145 150 155 160
Asn Met Pro Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu
165 170 175
Asp Glu
<210> 56
<211> 159
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 56
Met Ala Leu Glu Thr Ile Cys Arg Pro Ser Gly Arg Lys Ser Ser Lys
1 5 10 15
Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu
20 25 30
Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn
35 40 45
Leu Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe
50 55 60
Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly
65 70 75 80
Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser
85 90 95
Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser
100 105 110
Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu
115 120 125
Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro
130 135 140
Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
145 150 155
<210> 57
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 57
Gly Gly Gly Gly Ser Pro Ala Gly
1 5
<210> 58
<211> 136
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 58
His Ser Val Leu His Leu Val Pro Ile Asn Ala Thr Ser Lys Asp Asp
1 5 10 15
Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala Leu Arg Arg Gly Arg
20 25 30
Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile Gln Asp Ala Gly Val
35 40 45
Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp Val Thr Phe Thr Met
50 55 60
Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg Gln Glu Thr Leu Phe
65 70 75 80
Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp Arg Ala Tyr Asn Ser
85 90 95
Cys Tyr Ser Ala Gly Val Phe His Leu His Gln Gly Asp Ile Leu Ser
100 105 110
Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn Leu Ser Pro His Gly
115 120 125
Thr Phe Leu Gly Phe Val Lys Leu
130 135
<210> 59
<211> 411
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 59
His Ser Val Leu His Leu Val Pro Ile Asn Ala Thr Ser Lys Asp Asp
1 5 10 15
Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala Leu Arg Arg Gly Arg
20 25 30
Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile Gln Asp Ala Gly Val
35 40 45
Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp Val Thr Phe Thr Met
50 55 60
Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg Gln Glu Thr Leu Phe
65 70 75 80
Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp Arg Ala Tyr Asn Ser
85 90 95
Cys Tyr Ser Ala Gly Val Phe His Leu His Gln Gly Asp Ile Leu Ser
100 105 110
Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn Leu Ser Pro His Gly
115 120 125
Thr Phe Leu Gly Phe Val Lys Leu Ser Gly Gly Gly Ser Asp Pro Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Pro Ala Gly Asp Ile Gln Met Thr Gln Thr Thr Ser Ser
165 170 175
Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser
180 185 190
Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly
195 200 205
Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val
210 215 220
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr
225 230 235 240
Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln
245 250 255
Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
260 265 270
Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser
275 280 285
Thr Lys Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala
290 295 300
Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu
305 310 315 320
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu
325 330 335
Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
340 345 350
Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln
355 360 365
Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr
370 375 380
Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
385 390 395 400
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
405 410
<210> 60
<211> 389
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 60
His Ser Val Leu His Leu Val Pro Ile Asn Ala Thr Ser Lys Asp Asp
1 5 10 15
Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala Leu Arg Arg Gly Arg
20 25 30
Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile Gln Asp Ala Gly Val
35 40 45
Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp Val Thr Phe Thr Met
50 55 60
Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg Gln Glu Thr Leu Phe
65 70 75 80
Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp Arg Ala Tyr Asn Ser
85 90 95
Cys Tyr Ser Ala Gly Val Phe His Leu His Gln Gly Asp Ile Leu Ser
100 105 110
Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn Leu Ser Pro His Gly
115 120 125
Thr Phe Leu Gly Phe Val Lys Leu Gly Gly Gly Gly Ser Pro Ala Gly
130 135 140
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
145 150 155 160
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
165 170 175
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
180 185 190
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
210 215 220
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
225 230 235 240
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly
245 250 255
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys
260 265 270
Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser
275 280 285
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
290 295 300
Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile
305 310 315 320
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu
325 330 335
Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn
340 345 350
Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr
355 360 365
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
370 375 380
Val Thr Val Ser Ser
385
<210> 61
<211> 280
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 61
His Ser Val Leu His Leu Val Pro Ile Asn Ala Thr Ser Lys Asp Asp
1 5 10 15
Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala Leu Arg Arg Gly Arg
20 25 30
Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile Gln Asp Ala Gly Val
35 40 45
Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp Val Thr Phe Thr Met
50 55 60
Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg Gln Glu Thr Leu Phe
65 70 75 80
Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp Arg Ala Tyr Asn Ser
85 90 95
Cys Tyr Ser Ala Gly Val Phe His Leu His Gln Gly Asp Ile Leu Ser
100 105 110
Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn Leu Ser Pro His Gly
115 120 125
Thr Phe Leu Gly Phe Val Lys Leu Ser Gly Gly Gly Ser Asp Pro Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Gln Val Lys Leu Glu Glu Ser Gly Gly Glu Leu Val Gln
165 170 175
Pro Gly Gly Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe
180 185 190
Ser Ile Asn Arg Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg
195 200 205
Ala Phe Val Ala Ser Ile Thr Val Arg Gly Ile Thr Asn Tyr Ala Asp
210 215 220
Ser Val Lys Gly Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr
225 230 235 240
Ile Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr
245 250 255
Tyr Cys Asn Ala Val Ser Ser Asn Arg Asp Pro Asp Tyr Trp Gly Gln
260 265 270
Gly Thr Gln Val Thr Val Ser Ser
275 280
<210> 62
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 62
His Ser Val Leu His Leu Val Pro Ile Asn Ala Thr Ser Lys Asp Asp
1 5 10 15
Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala Leu Arg Arg Gly Arg
20 25 30
Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile Gln Asp Ala Gly Val
35 40 45
Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp Val Thr Phe Thr Met
50 55 60
Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg Gln Glu Thr Leu Phe
65 70 75 80
Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp Arg Ala Tyr Asn Ser
85 90 95
Cys Tyr Ser Ala Gly Val Phe His Leu His Gln Gly Asp Ile Leu Ser
100 105 110
Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn Leu Ser Pro His Gly
115 120 125
Thr Phe Leu Gly Phe Val Lys Leu Gly Gly Gly Gly Ser Pro Ala Gly
130 135 140
Gln Val Lys Leu Glu Glu Ser Gly Gly Glu Leu Val Gln Pro Gly Gly
145 150 155 160
Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Ser Ile Asn
165 170 175
Arg Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Ala Phe Val
180 185 190
Ala Ser Ile Thr Val Arg Gly Ile Thr Asn Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ile Tyr Leu
210 215 220
Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
225 230 235 240
Ala Val Ser Ser Asn Arg Asp Pro Asp Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser
260
<210> 63
<211> 714
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 63
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
130 135 140
Lys Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro
145 150 155 160
Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro
165 170 175
Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu
180 185 190
Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala
195 200 205
Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val
210 215 220
Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr
225 230 235 240
Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp
245 250 255
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro
260 265 270
Ala Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro
275 280 285
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
290 295 300
Ser His Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
305 310 315 320
Trp Val Ser Ala Ile Ser Gly Ser Gly Asp Tyr Thr His Tyr Ala Asp
325 330 335
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
340 345 350
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Val Tyr
355 360 365
Tyr Cys Ala Lys Asp Glu Asp Gly Gly Ser Leu Leu Gly His Arg Gly
370 375 380
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr Thr Thr Pro Ala
385 390 395 400
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
405 410 415
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
420 425 430
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
435 440 445
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
450 455 460
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
465 470 475 480
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
485 490 495
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly
500 505 510
Pro Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys
515 520 525
Phe Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp
530 535 540
Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala
545 550 555 560
Pro Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln
565 570 575
Leu Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln
580 585 590
Gly Gln Asp Pro Thr His Leu Val Arg Val Lys Phe Ser Arg Ser Ala
595 600 605
Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
610 615 620
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
625 630 635 640
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
645 650 655
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
660 665 670
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
675 680 685
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr
690 695 700
Arg His Gln Ala Leu Pro Pro Arg Ser Gly
705 710
<210> 64
<211> 693
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 64
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys
115 120 125
Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser
130 135 140
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
145 150 155 160
Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile
165 170 175
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu
180 185 190
Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn
195 200 205
Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr
210 215 220
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
225 230 235 240
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Glu Val Gln
245 250 255
Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly Ser Leu Arg
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His Ala Met Thr
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile
290 295 300
Ser Gly Ser Gly Asp Tyr Thr His Tyr Ala Asp Ser Val Lys Gly Arg
305 310 315 320
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met
325 330 335
Asn Ser Leu Arg Ala Glu Asp Ser Ala Val Tyr Tyr Cys Ala Lys Asp
340 345 350
Glu Asp Gly Gly Ser Leu Leu Gly His Arg Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
370 375 380
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
385 390 395 400
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
405 410 415
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
420 425 430
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
435 440 445
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
450 455 460
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
465 470 475 480
Gly Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys
485 490 495
Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu
500 505 510
Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe
515 520 525
Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro
530 535 540
Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn
545 550 555 560
Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr
565 570 575
His Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
580 585 590
Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
595 600 605
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
610 615 620
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
625 630 635 640
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
645 650 655
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
660 665 670
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu
675 680 685
Pro Pro Arg Ser Gly
690
<210> 65
<211> 713
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 65
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Lys Leu Glu Glu Ser Gly Gly Glu Leu
20 25 30
Val Gln Pro Gly Gly Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn
35 40 45
Ile Phe Ser Ile Asn Arg Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys
50 55 60
Gln Arg Ala Phe Val Ala Ser Ile Thr Val Arg Gly Ile Thr Asn Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Val Asp Lys Ser Lys
85 90 95
Asn Thr Ile Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Asn Ala Val Ser Ser Asn Arg Asp Pro Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro
130 135 140
Ala Gly Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser
145 150 155 160
Leu Gly Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr
165 170 175
Ile Leu Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln
180 185 190
Pro Pro Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val
195 200 205
Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr
210 215 220
Ile Asp Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln
225 230 235 240
Ser Arg Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
245 250 255
Lys Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser
260 265 270
Thr Lys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys
275 280 285
Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
290 295 300
Thr Asp Tyr Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu
305 310 315 320
Lys Trp Met Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala
325 330 335
Tyr Asp Phe Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser
340 345 350
Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr
355 360 365
Tyr Phe Cys Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln
370 375 380
Gly Thr Ser Val Thr Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro
385 390 395 400
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
405 410 415
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
420 425 430
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
435 440 445
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
450 455 460
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
465 470 475 480
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
485 490 495
Glu Glu Glu Glu Gly Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro
500 505 510
Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe
515 520 525
Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu
530 535 540
Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro
545 550 555 560
Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu
565 570 575
Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly
580 585 590
Gln Asp Pro Thr His Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp
595 600 605
Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
610 615 620
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
625 630 635 640
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
645 650 655
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
660 665 670
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
675 680 685
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg
690 695 700
His Gln Ala Leu Pro Pro Arg Ser Gly
705 710
<210> 66
<211> 692
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 66
Gln Val Lys Leu Glu Glu Ser Gly Gly Glu Leu Val Gln Pro Gly Gly
1 5 10 15
Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Ser Ile Asn
20 25 30
Arg Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Ala Phe Val
35 40 45
Ala Ser Ile Thr Val Arg Gly Ile Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ile Tyr Leu
65 70 75 80
Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Val Ser Ser Asn Arg Asp Pro Asp Tyr Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Asp Ile Val
115 120 125
Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly Lys Arg Ala
130 135 140
Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu Gly Ser His
145 150 155 160
Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Thr Leu Leu
165 170 175
Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala Arg Phe Ser
180 185 190
Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp Pro Val Glu
195 200 205
Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg Thr Ile Pro
210 215 220
Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Ser Thr Ser
225 230 235 240
Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Gln Ile
245 250 255
Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val
260 265 270
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Ser Ile
275 280 285
Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met Gly Trp
290 295 300
Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe Arg Gly
305 310 315 320
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
325 330 335
Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Leu
340 345 350
Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr
355 360 365
Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
370 375 380
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
385 390 395 400
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
405 410 415
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
420 425 430
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys
435 440 445
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
450 455 460
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
465 470 475 480
Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val
485 490 495
Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser
500 505 510
Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro
515 520 525
Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu
530 535 540
Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn Thr
545 550 555 560
Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr His
565 570 575
Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
580 585 590
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
595 600 605
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
610 615 620
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
625 630 635 640
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
645 650 655
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
660 665 670
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu Pro
675 680 685
Pro Arg Ser Gly
690
<210> 67
<211> 714
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 67
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
20 25 30
Ile Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Ser Ser His Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Asp Tyr Thr His
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser
100 105 110
Ala Val Tyr Tyr Cys Ala Lys Asp Glu Asp Gly Gly Ser Leu Leu Gly
115 120 125
His Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Pro Ala Gly Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
145 150 155 160
Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp
165 170 175
Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val
180 185 190
Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser
195 200 205
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser
210 215 220
Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn
225 230 235 240
Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly
245 250 255
Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys
260 265 270
Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser
275 280 285
Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp
290 295 300
Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp
305 310 315 320
Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu
325 330 335
Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe
340 345 350
Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys
355 360 365
Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly
370 375 380
Gln Gly Thr Ser Val Thr Val Ser Ser Gly Ser Thr Thr Thr Pro Ala
385 390 395 400
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
405 410 415
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
420 425 430
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
435 440 445
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
450 455 460
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
465 470 475 480
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
485 490 495
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly
500 505 510
Pro Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys
515 520 525
Phe Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp
530 535 540
Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala
545 550 555 560
Pro Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln
565 570 575
Leu Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln
580 585 590
Gly Gln Asp Pro Thr His Leu Val Arg Val Lys Phe Ser Arg Ser Ala
595 600 605
Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
610 615 620
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
625 630 635 640
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
645 650 655
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
660 665 670
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
675 680 685
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr
690 695 700
Arg His Gln Ala Leu Pro Pro Arg Ser Gly
705 710
<210> 68
<211> 693
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 68
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Asp Tyr Thr His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Glu Asp Gly Gly Ser Leu Leu Gly His Arg Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Asp
115 120 125
Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp
130 135 140
Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu
145 150 155 160
Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr
165 170 175
His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
180 185 190
Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu
195 200 205
Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr
210 215 220
Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly Ser
225 230 235 240
Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys Leu
245 250 255
Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val
260 265 270
Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp
275 280 285
Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp
290 295 300
Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr
305 310 315 320
Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser
325 330 335
Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr
340 345 350
Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
355 360 365
Thr Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
370 375 380
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
385 390 395 400
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
405 410 415
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
420 425 430
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
435 440 445
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
450 455 460
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
465 470 475 480
Gly Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys
485 490 495
Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu
500 505 510
Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe
515 520 525
Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro
530 535 540
Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn
545 550 555 560
Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr
565 570 575
His Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
580 585 590
Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
595 600 605
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
610 615 620
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
625 630 635 640
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
645 650 655
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
660 665 670
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu
675 680 685
Pro Pro Arg Ser Gly
690
<210> 69
<211> 713
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 69
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu
20 25 30
Ala Met Ser Leu Gly Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu
35 40 45
Ser Val Thr Ile Leu Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys
50 55 60
Pro Gly Gln Pro Pro Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln
65 70 75 80
Thr Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe
85 90 95
Thr Leu Thr Ile Asp Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr
100 105 110
Cys Leu Gln Ser Arg Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys
115 120 125
Leu Glu Ile Lys Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly
130 135 140
Glu Gly Ser Thr Lys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu
145 150 155 160
Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly
165 170 175
Tyr Thr Phe Thr Asp Tyr Ser Ile Asn Trp Val Lys Arg Ala Pro Gly
180 185 190
Lys Gly Leu Lys Trp Met Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro
195 200 205
Ala Tyr Ala Tyr Asp Phe Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr
210 215 220
Ser Ala Ser Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp
225 230 235 240
Thr Ala Thr Tyr Phe Cys Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr
245 250 255
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser
260 265 270
Pro Ala Gly Gln Val Lys Leu Glu Glu Ser Gly Gly Glu Leu Val Gln
275 280 285
Pro Gly Gly Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe
290 295 300
Ser Ile Asn Arg Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg
305 310 315 320
Ala Phe Val Ala Ser Ile Thr Val Arg Gly Ile Thr Asn Tyr Ala Asp
325 330 335
Ser Val Lys Gly Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr
340 345 350
Ile Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr
355 360 365
Tyr Cys Asn Ala Val Ser Ser Asn Arg Asp Pro Asp Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro
385 390 395 400
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
405 410 415
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
420 425 430
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
435 440 445
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
450 455 460
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
465 470 475 480
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
485 490 495
Glu Glu Glu Glu Gly Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro
500 505 510
Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe
515 520 525
Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu
530 535 540
Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro
545 550 555 560
Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu
565 570 575
Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly
580 585 590
Gln Asp Pro Thr His Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp
595 600 605
Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
610 615 620
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
625 630 635 640
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
645 650 655
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
660 665 670
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
675 680 685
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg
690 695 700
His Gln Ala Leu Pro Pro Arg Ser Gly
705 710
<210> 70
<211> 692
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 70
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
100 105 110
Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys
115 120 125
Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly
130 135 140
Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp
145 150 155 160
Tyr Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp
165 170 175
Met Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp
180 185 190
Phe Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala
195 200 205
Tyr Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe
210 215 220
Cys Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
225 230 235 240
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Gln Val
245 250 255
Lys Leu Glu Glu Ser Gly Gly Glu Leu Val Gln Pro Gly Gly Pro Leu
260 265 270
Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Ser Ile Asn Arg Met
275 280 285
Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Ala Phe Val Ala Ser
290 295 300
Ile Thr Val Arg Gly Ile Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg
305 310 315 320
Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ile Tyr Leu Gln Met
325 330 335
Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala Val
340 345 350
Ser Ser Asn Arg Asp Pro Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr
355 360 365
Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
370 375 380
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
385 390 395 400
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
405 410 415
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
420 425 430
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys
435 440 445
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
450 455 460
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
465 470 475 480
Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val
485 490 495
Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser
500 505 510
Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro
515 520 525
Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu
530 535 540
Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn Thr
545 550 555 560
Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr His
565 570 575
Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
580 585 590
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
595 600 605
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
610 615 620
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
625 630 635 640
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
645 650 655
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
660 665 670
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu Pro
675 680 685
Pro Arg Ser Gly
690
<210> 71
<211> 372
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 71
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys
115 120 125
Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser
130 135 140
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
145 150 155 160
Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile
165 170 175
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu
180 185 190
Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn
195 200 205
Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr
210 215 220
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
225 230 235 240
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Glu Val Gln
245 250 255
Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly Ser Leu Arg
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His Ala Met Thr
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile
290 295 300
Ser Gly Ser Gly Asp Tyr Thr His Tyr Ala Asp Ser Val Lys Gly Arg
305 310 315 320
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met
325 330 335
Asn Ser Leu Arg Ala Glu Asp Ser Ala Val Tyr Tyr Cys Ala Lys Asp
340 345 350
Glu Asp Gly Gly Ser Leu Leu Gly His Arg Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser
370
<210> 72
<211> 371
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 72
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
100 105 110
Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys
115 120 125
Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly
130 135 140
Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp
145 150 155 160
Tyr Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp
165 170 175
Met Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp
180 185 190
Phe Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala
195 200 205
Tyr Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe
210 215 220
Cys Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
225 230 235 240
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Gln Val
245 250 255
Lys Leu Glu Glu Ser Gly Gly Glu Leu Val Gln Pro Gly Gly Pro Leu
260 265 270
Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Ser Ile Asn Arg Met
275 280 285
Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Ala Phe Val Ala Ser
290 295 300
Ile Thr Val Arg Gly Ile Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg
305 310 315 320
Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ile Tyr Leu Gln Met
325 330 335
Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala Val
340 345 350
Ser Ser Asn Arg Asp Pro Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr
355 360 365
Val Ser Ser
370
<210> 73
<211> 27
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 73
Ser Gly Gly Gly Ser Asp Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
<210> 74
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 74
Glu Ala Ala Ala Lys
1 5
<210> 75
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 75
Gly Gly Gly Gly Ser
1 5
<210> 76
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 76
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 77
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 77
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 78
<211> 690
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 78
Gln Val Lys Leu Glu Glu Ser Gly Gly Glu Leu Val Gln Pro Gly Gly
1 5 10 15
Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Ser Ile Asn
20 25 30
Arg Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Ala Phe Val
35 40 45
Ala Ser Ile Thr Val Arg Gly Ile Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ile Tyr Leu
65 70 75 80
Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Val Ser Ser Asn Arg Asp Pro Asp Tyr Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Asp Ile Val
115 120 125
Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly Lys Arg Ala
130 135 140
Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu Gly Ser His
145 150 155 160
Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Thr Leu Leu
165 170 175
Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala Arg Phe Ser
180 185 190
Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp Pro Val Glu
195 200 205
Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg Thr Ile Pro
210 215 220
Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Ser Thr Ser
225 230 235 240
Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Gln Ile
245 250 255
Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val
260 265 270
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Ser Ile
275 280 285
Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met Gly Trp
290 295 300
Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe Arg Gly
305 310 315 320
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
325 330 335
Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Leu
340 345 350
Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr
355 360 365
Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
370 375 380
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
385 390 395 400
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
405 410 415
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
420 425 430
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys
435 440 445
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
450 455 460
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
465 470 475 480
Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val
485 490 495
Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser
500 505 510
Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro
515 520 525
Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu
530 535 540
Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn Thr
545 550 555 560
Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr His
565 570 575
Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
580 585 590
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
595 600 605
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
610 615 620
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
625 630 635 640
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
645 650 655
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
660 665 670
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu Pro
675 680 685
Pro Arg
690
<210> 79
<211> 691
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 79
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Asp Tyr Thr His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Glu Asp Gly Gly Ser Leu Leu Gly His Arg Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Asp
115 120 125
Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp
130 135 140
Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu
145 150 155 160
Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr
165 170 175
His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
180 185 190
Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu
195 200 205
Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr
210 215 220
Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly Ser
225 230 235 240
Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys Leu
245 250 255
Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val
260 265 270
Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp
275 280 285
Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp
290 295 300
Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr
305 310 315 320
Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser
325 330 335
Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr
340 345 350
Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
355 360 365
Thr Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
370 375 380
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
385 390 395 400
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
405 410 415
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
420 425 430
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
435 440 445
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
450 455 460
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
465 470 475 480
Gly Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys
485 490 495
Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu
500 505 510
Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe
515 520 525
Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro
530 535 540
Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn
545 550 555 560
Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr
565 570 575
His Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
580 585 590
Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
595 600 605
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
610 615 620
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
625 630 635 640
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
645 650 655
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
660 665 670
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu
675 680 685
Pro Pro Arg
690
<210> 80
<211> 690
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 80
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
100 105 110
Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys
115 120 125
Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly
130 135 140
Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp
145 150 155 160
Tyr Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp
165 170 175
Met Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp
180 185 190
Phe Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala
195 200 205
Tyr Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe
210 215 220
Cys Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
225 230 235 240
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Ala Gly Gln Val
245 250 255
Lys Leu Glu Glu Ser Gly Gly Glu Leu Val Gln Pro Gly Gly Pro Leu
260 265 270
Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Ser Ile Asn Arg Met
275 280 285
Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Ala Phe Val Ala Ser
290 295 300
Ile Thr Val Arg Gly Ile Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg
305 310 315 320
Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ile Tyr Leu Gln Met
325 330 335
Asn Ala Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala Val
340 345 350
Ser Ser Asn Arg Asp Pro Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr
355 360 365
Val Ser Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
370 375 380
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
385 390 395 400
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
405 410 415
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
420 425 430
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys
435 440 445
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
450 455 460
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
465 470 475 480
Gly Cys Glu Leu Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val
485 490 495
Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser
500 505 510
Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro
515 520 525
Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu
530 535 540
Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn Thr
545 550 555 560
Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr His
565 570 575
Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
580 585 590
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
595 600 605
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
610 615 620
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
625 630 635 640
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
645 650 655
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
660 665 670
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu Pro
675 680 685
Pro Arg
690
<210> 81
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 81
gaaatataca agttatatct tgg 23
<210> 82
<211> 20
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 82
gaaauauaca aguuauaucu 20
<210> 83
<211> 100
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 83
gaaauauaca aguuauaucu guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 84
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 84
tttcagctct gcatcgtttt gg 22
<210> 85
<211> 19
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 85
uuucagcucu gcaucguuu 19
<210> 86
<211> 100
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 86
guuucagcuc ugcaucguuu guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 87
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 87
ttcagctctg catcgttttg gg 22
<210> 88
<211> 19
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 88
uucagcucug caucguuuu 19
<210> 89
<211> 100
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 89
guucagcucu gcaucguuuu guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 90
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 90
gcatcgtttt gggttctctt gg 22
<210> 91
<211> 19
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 91
gcaucguuuu ggguucucu 19
<210> 92
<211> 99
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 92
gcaucguuuu ggguucucug uuuuagagcu agaaauagca aguuaaaaua aggcuagucc 60
guuaucaacu ugaaaaagug gcaccgaguc ggugcuuuu 99
<210> 93
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 93
tctcttggct gttactgcca gg 22
<210> 94
<211> 19
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 94
ucucuuggcu guuacugcc 19
<210> 95
<211> 100
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 95
gucucuuggc uguuacugcc guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 96
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 96
ttcttttaca tatgggtcct gg 22
<210> 97
<211> 19
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 97
uucuuuuaca uaugggucc 19
<210> 98
<211> 100
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 98
guucuuuuac auaugggucc guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 99
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 99
ttctgcttct tttacatatg gg 22
<210> 100
<211> 19
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 100
uucugcuucu uuuacauau 19
<210> 101
<211> 100
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 101
guucugcuuc uuuuacauau guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 102
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 102
tttctgcttc ttttacatat gg 22
<210> 103
<211> 19
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 103
uuucugcuuc uuuuacaua 19
<210> 104
<211> 100
<212> RNA
<213> 人工序列
<220>
<223> 合成的
<400> 104
guuucugcuu cuuuuacaua guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
Claims (44)
1.一种双特异性嵌合抗原受体(CAR)多肽,其包括:
a)第一抗原结合部分;
b)第二抗原结合部分;
c)共刺激信号传导结构域;以及
d)细胞质信号传导结构域,
其中所述第一抗原结合部分为单结构域抗体可变片段(VHH),并且所述第二抗原结合部分为单链可变片段(scFv),并且
其中所述第一抗原结合部分与第一肿瘤相关抗原结合,并且所述第二抗原结合部分与第二肿瘤相关抗原结合,所述第二肿瘤相关抗原任选地不同于所述第一肿瘤相关抗原。
2.根据权利要求1所述的双特异性CAR多肽,其中所述第一肿瘤抗原和所述第二肿瘤抗原选自由以下组成的组:5T4、CD2、CD3、CD5、CD7、CD19、CD20、CD22、CD30、CD33、CD38、CD70、CD123、CD133、CD171、CEA、CS1、BCMA、BAFF-R、PSMA、PSCA、桥粒芯蛋白(Dsg3)、HER-2、FAP、FSHR、NKG2D、GD2、EGFRVIII、间皮素、ROR1、MAGE、MUC1、MUC16、GPC3、Lewis Y、Claudin 18.2和VEGFRII。
3.根据权利要求1所述的双特异性CAR多肽,其中所述第一肿瘤抗原为CD19,并且所述第二肿瘤抗原为BCMA,或所述第一肿瘤抗原为BCMA,并且所述第二肿瘤抗原为CD19。
4.根据权利要求3所述的双特异性CAR多肽,其中所述第一抗原结合部分为与CD19结合的VHH片段(抗CD19 VHH),并且所述第二抗原结合部分为与BCMA结合的scFv(抗BCMAscFv);或者其中所述第一抗原结合部分为与BCMA结合的VHH(抗BCMA VHH),并且所述第二抗原结合部分为与CD19结合的scFv片段(抗CD19 scFv)。
5.根据权利要求4所述的双特异性CAR多肽,其中所述抗CD19 scFv包括SEQ ID NO:7、8或9的氨基酸序列;和/或其中所述抗BCMA VHH包括SEQ ID NO:4、5或6的氨基酸序列。
6.根据权利要求5所述的双特异性CAR多肽,其中a)和b)包括SEQ ID NO:11、44、63、64、67、68、71或79的氨基酸序列,任选地SEQ ID NO:11的氨基酸序列。
7.根据权利要求4所述的双特异性CAR多肽,其中所述抗CD19 VHH包括SEQ ID NO:1、2或3的氨基酸序列;和/或其中所述抗BCMA scFv包括SEQ ID NO:10的氨基酸序列。
8.根据权利要求7所述的双特异性CAR多肽,其中a)和b)包括SEQ ID NO:12、65、66、69、70、72、78或80的氨基酸序列,任选地SEQ ID NO:12的氨基酸序列。
9.一种双特异性嵌合抗原受体(CAR)多肽,其包括:
a)第一抗原结合部分,所述第一抗原结合部分为与BCMA结合的APRIL截短片段;
b)第二抗原结合部分,所述第二抗原结合部分为与肿瘤相关抗原结合的单结构域抗体可变片段(VHH)或单链可变片段(scFv);
c)共刺激信号传导结构域;以及
d)细胞质信号传导结构域,
10.根据权利要求9所述的双特异性CAR多肽,其中所述与BCMA结合的APRIL截短片段包括与SEQ ID NO:58至少90%相同的氨基酸序列;任选地其中所述APRIL截短片段包括SEQID NO:58的氨基酸序列。
11.根据权利要求9或权利要求10所述的双特异性CAR多肽,其中所述第二抗原结合部分为抗CD19 scFv或抗CD19 VHH。
12.根据权利要求11所述的双特异性CAR多肽,其中所述抗CD19 scFv包括SEQ ID NO:7、8或9的氨基酸序列;或者其中所述抗CD19 VHH包括SEQ ID NO:1、2或3的氨基酸序列。
13.根据权利要求12所述的双特异性CAR多肽,其中a)和b)包括SEQ ID NO:59、60、61或62的氨基酸序列。
14.根据权利要求1至13中任一项所述的双特异性CAR多肽,其进一步包括位于所述第一抗原结合部分与所述第二抗原结合部分之间的肽接头,任选地其中所述肽接头的长度为约4-40个氨基酸。
15.根据权利要求1至14中任一项所述的双特异性CAR多肽,其中所述共刺激信号传导结构域来自4-1BB或CD28。
16.根据权利要求1至15中任一项所述的双特异性CAR多肽,其中所述细胞质信号传导结构域包括CD3z细胞质信号传导结构域、IL-2Rβ细胞质信号传导结构域或其组合。
17.根据权利要求16所述的双特异性CAR多肽,其中所述细胞质信号传导结构域包括CD3z细胞质信号传导结构域,所述CD3z细胞质信号传导结构域任选地包括STAT结合基序。
18.根据权利要求1至17中任一项所述的双特异性CAR多肽,其进一步包括跨膜结构域、铰链结构域或其组合,所述跨膜结构域、铰链结构域或其组合任选地位于所述第一抗原结合部分或所述第二抗原结合部分与所述共刺激结构域之间。
19.根据权利要求18所述的双特异性CAR多肽,其中所述跨膜结构域和/或所述铰链结构域来自CD8。
20.根据权利要求1所述的双特异性CAR多肽,其包括SEQ ID NO:63-70中的任一者的氨基酸序列。
21.一种基因工程化免疫细胞群体,所述基因工程化免疫细胞表达根据权利要求1至20中任一项所述的双特异性CAR多肽。
22.根据权利要求21所述的基因工程化免疫细胞群体,其进一步包括以下特征中的一个或多个特征:
e)具有一个或多个被破坏的编码一种或多种促炎细胞因子的内源性基因;和
f)表达一种或多种靶向所述促炎细胞因子的拮抗剂。
23.根据权利要求22所述的基因工程化免疫细胞群体,其中所述促炎细胞因子选自由以下组成的组:干扰素γ(IFNγ)、白介素6(IL-6)、GM-CSF和白介素1(IL-1)。
24.根据权利要求22或权利要求23所述的基因工程化免疫细胞群体,其中所述基因工程化免疫细胞包括被破坏的内源性干扰素γ基因、被破坏的内源性GM-CSF基因或其组合。
25.根据权利要求24所述的基因工程化免疫细胞群体,其中所述内源性干扰素γ基因、所述内源性GM-CSF基因或两者被CRISPR/Cas基因编辑系统破坏。
26.根据权利要求22至25中任一项所述的基因工程化免疫细胞群体,其中所述基因工程化免疫细胞表达IL-6拮抗剂、IFNγ拮抗剂、IL-1拮抗剂或其组合。
27.根据权利要求26所述的基因工程化免疫细胞群体,其中所述IL-6拮抗剂为对人IL6具有特异性的抗体(抗IL6抗体)或对人IL6R具有特异性的抗体(抗IL6R抗体),和/或其中所述IFNγ拮抗剂为对人IFNγ具有特异性的抗体(抗IFNγ抗体)。
28.根据权利要求27所述的基因工程化免疫细胞群体,其中所述抗IL6抗体、所述抗IFNγ抗体或两者均为scFv抗体。
29.根据权利要求28所述的基因工程化免疫细胞群体,其中所述基因工程化免疫细胞表达抗IFNγscFv,所述抗IFNγscFv包括:
(i)重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:13的氨基酸序列,所述轻链可变区包括SEQ ID NO:14的氨基酸序列;
(ii)重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:16的氨基酸序列,所述轻链可变区包括SEQ ID NO:17的氨基酸序列;或
(iii)重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:19的氨基酸序列,所述轻链可变区包括SEQ ID NO:20的氨基酸序列。
30.根据权利要求29所述的基因工程化免疫细胞群体,其中所述抗IFNγscFv包括SEQID NO:15、18或21的氨基酸序列。
31.根据权利要求30所述的基因工程化免疫细胞群体,其中所述基因工程化免疫细胞表达双特异性CAR,所述双特异性CAR包括SEQ ID NO:44、63-70或78-80中的任一者的氨基酸序列。
32.根据权利要求28所述的基因工程化免疫细胞群体,其中所述基因工程化免疫细胞表达抗IL6 scFv,所述抗IL6 scFv包括:
(a)重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:24的氨基酸序列,所述轻链可变区包括SEQ ID NO:25的氨基酸序列;
(b)重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:26的氨基酸序列,所述轻链可变区包括SEQ ID NO:27的氨基酸序列;或
(c)重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:30的氨基酸序列,所述轻链可变区包括SEQ ID NO:31的氨基酸序列。
33.根据权利要求28所述的基因工程化免疫细胞群体,其中所述基因工程化免疫细胞表达抗IL6R scFv,所述IL6R scFv包括:
(a)重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:22的氨基酸序列,所述轻链可变区包括SEQ ID NO:23的氨基酸序列;
(b)重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:28的氨基酸序列,所述轻链可变区包括SEQ ID NO:29的氨基酸序列;或
(c)重链可变区和轻链可变区,所述重链可变区包括SEQ ID NO:32的氨基酸序列,所述轻链可变区包括SEQ ID NO:33的氨基酸序列。
34.根据权利要求32或权利要求33所述的基因工程化免疫细胞群体,其中所述抗IL6scFv或所述抗IL6R scFv包括SEQ ID NO:34、35、36或37的氨基酸序列。
35.根据权利要求22至26中任一项所述的基因工程化免疫细胞群体,其中所述基因工程化免疫细胞表达IL-1拮抗剂,并且其中所述IL-1拮抗剂为IL-1RA,所述IL-1RA包括SEQID NO:54的氨基酸序列。
36.根据权利要求22至35中任一项所述的基因工程化免疫细胞群体,其中所述基因工程化免疫细胞包括T细胞、肿瘤浸润性淋巴细胞、自然杀伤(NK)细胞、树突状细胞、巨噬细胞、B细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、肥大细胞、髓源性抑制细胞、间充质干细胞、其前体或其组合。
37.根据权利要求22至36中任一项所述的基因工程化免疫细胞群体,其中所述免疫细胞为人免疫细胞。
38.根据权利要求37所述的基因工程化免疫细胞群体,其包括人T细胞。
39.一种药物组合物,其包括根据权利要求22至38中任一项所述的免疫细胞群体以及药学上可接受的载剂。
40.一种用于减少或消除受试者体内不期望的细胞的方法,所述方法包括向有需要的受试者施用治疗有效量的根据权利要求22至38中任一项所述的免疫细胞群体或根据权利要求39所述的药物组合物。
41.根据权利要求40所述的方法,其中所述受试者是患有癌症的人类患者,所述癌症包括表达所述第一肿瘤相关抗原、所述第二肿瘤相关抗原或两者的癌细胞。
42.根据权利要求40或权利要求41所述的方法,其中所述受试者是患有实体瘤或血液学癌症的人类患者。
43.根据权利要求42所述的方法,其中所述人类患者患有实体瘤,所述实体瘤选自由以下组成的组:乳腺癌、肺癌、胰腺癌、肝癌、胶质母细胞瘤(GBM)、前列腺癌、卵巢癌、间皮瘤、结肠癌和胃癌。
44.根据权利要求42所述的方法,其中所述人类患者患有血液学癌症,所述血液学癌症为白血病、淋巴瘤或多发性骨髓瘤。
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