CN113518823A - 多功能的融合蛋白及其用途 - Google Patents
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Abstract
本发明涉及一融合蛋白以及多个治疗的方法,所述多个治疗的方法包括向有需要的一患者施予一治疗有效量的所述融合蛋白。
Description
技术领域
本申请根据35 U.S.C.§119(e)请求在2019年1月7日所提交的美国临时专利申请案第62/789,212号的优先权,其内容通过引用整体并入本文中。
背景技术
多种途径调节受感染细胞及癌细胞的存活,以及诸如T细胞及自然杀手(naturalkiller,NK)细胞的免疫系统的细胞的激活或抑制。向T细胞提供共刺激第二信号及抑制性第二信号的一途径是由程序性死亡1(programmed death 1,PD-1,亦称为CD279)受体及其配体、PD-L1(B7-H1,CD274)及PD-L2(B7-DC,CD273)表示。PD-1是CD28/CTL4家族的成员,其在活化的T细胞而非静息态T细胞上表达(Nishimura等人(1996)Int.Immunol.8:773)。PD-1与其配体的结合介导一抑制信号,其导致降低细胞因子的产生,以及降低T细胞的存活率(Nishimura等人(1999)Immunity 11:141;Nishimura等人(2001)Science 291:319;开姆尼茨等人(2004)J.Immunol.173:945)。
病毒的巨噬细胞炎症蛋白-II(vMIP-II)是由人类疱疹病毒8(HHV-8)所编码的一趋化因子,其可与CC及CXC趋化因子受体相互作用,包括CCR5及CXCR4趋化因子受体。vMIP-II对于HIV-1进入的抑制是通过CCR3、CCR5及CXCR4所介导的,CCR3、CCR5及CXCR4是HIV-1进入一靶细胞的HIV-1受体。
正信号及负信号的复杂的相互作用调节T细胞的活化及T细胞效应因子功能的维持。TNF配体/TNF受体超家族的成员、免疫系统的桥接细胞以及其他器官系统的细胞在此信号矩阵中扮演重要角色。在此过程中,TNF超家族成员通过影响细胞存活及死亡、细胞分化及炎症,促进体内平衡及发病机制。
仍然需要用于治疗诸如癌症的疾病的改良疗法。本发明解决此种需要。
发明内容
如本文所述,本发明涉及具有多点分子附着能力的一融合蛋白以及其使用的方法。
本发明的一方面包括一种融合蛋白,所述融合蛋白包括组分A及/或组分B。组分A包括组分Y、组分Z2及组分Z3。组分B包括组分X’、组分Z2’及组分Z3’。
本发明的另一方面包括一种融合蛋白,所述融合蛋白包括组分A、组分B,及组分C。组分A包括组分Y、组分Z2及组分Z3。组分B包括组分X’、组分Z2’及组分Z3’。组分C包括组分X及组分C’L。组分Y包括PD-1的至少一部分,组分Z2及组分Z2’包括人类Fc的CH2结构域,及组分Z3及组分Z3’包括人类Fc的CH3结构域。组分X’及组分X包括vMIP-II的至少一部分,以及组分CL’包括人类IgG1κ的至少一CH1结构域。
本发明的又另一方面包括一种产生一融合蛋白的方法。所述方法包括向所述细胞施予编码人类PD-1-hFcA的一第一核酸、编码vMIPII-CH’-hFcB的一第二核酸,以及编码vMIPII-CL’的一第三核酸。
本发明的又另一方面包括一种融合蛋白,所述融合蛋白包括如SEQ ID NO:14、SEQID NO:49及SEQ ID NO:57所示的氨基酸序列。
在另一方面,本发明包括一种药物组合物,所述药物组合物包括一药学上可接受的载体及如本文所述的多个融合蛋白中的任一者。
在另一方面,本发明包括一种治疗一患者的一增殖性疾病的方法。所述方法包括向有需要此种治疗的一患者施予一治疗有效量的如本文所述的多个融合蛋白中的任一者。
在以上方面或本文所描述的本发明的任何其他方面的各种实施例中,组分B进一步包括组分Z1’。在某些实施例中,组分A进一步包括组分Z1。
在某些实施例中,所述融合蛋白进一步包括组分C,其中组分C包括组分X及组分CL’。
在某些实施例中,所述融合蛋白进一步包括组分D,其中组分D包括组分Q及组分CL。
在某些实施例中,组分Y包括一配体结构域、一受体结构域、一scFv结构域或一脂质运载蛋白结构域(lipocalin domain)。在某些实施例中,组分Y包括PD-1、CD112R、CD113或MHC-I多肽相关的序列A(MICA)的至少一部分。
在某些实施例中,所述融合蛋白与PD-L1或PD-L2结合。
在某些实施例中,组分X’包括一病毒衍生的肽、一配体衍生的肽、一受体衍生的肽,或一HTS选择的肽。
在某些实施例中,组分X’包括vMIP-II的至少一部分。在某些实施例中,
在某些实施例中,组分X’包括V1或V1Δ。
在某些实施例中,组分X包括一病毒衍生的肽、一配体衍生的肽、一受体衍生的肽或一HTS选择的肽。在某些实施例中,组分X包括V1或V1Δ。
在某些实施例中,所述融合蛋白与CXCR4结合。
在某些实施例中,组分Y及组分Z2通过一铰链连接。在某些实施例中,组分Z1’及组分Z2’通过一铰链连接。
在某些实施例中,组分X’及组分Z1’通过一连接子(lilnker)连接。在某些实施例中,组分X及组分CL通过一连接子连接。在某些实施例中,组分Q及组分CL通过一连接子连接。
在某些实施例中,所述融合蛋白与一免疫细胞上的一受体或配体结合。在某些实施例中,所述受体是一Fc受体。
在某些实施例中,X’包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。
在某些实施例中,组分Y包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。
在某些实施例中,组分X包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。
在某些实施例中,组分Q包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。
在某些实施例中,组分A包括如SEQ ID NOs:14至22中任一者所示的氨基酸序列。
在某些实施例中,组分B包括如SEQ ID NOs:32至35中任一者所示的氨基酸序列。在某些实施例中,组分B包括如SEQ ID NOs:49至55中任一者所示的氨基酸序列。
在某些实施例中,组分A包括如SEQ ID NOs:14至22中任一者所示的氨基酸序列,以及组分B包括如SEQ ID NOs:32至35中任一者所示的氨基酸序列。
在某些实施例中,组分C包括如SEQ ID NOs:57至63中任一者所示的氨基酸序列。
在某些实施例中,组分B包括如SEQ ID NOs:49至55中任一者所示的氨基酸序列,以及组分C包括如SEQ ID NOs:57至63中任一者所示的氨基酸序列。
在某些实施例中,所述融合蛋白能够结合(i)PD-L1或PD-L2,(ii)CXCR4,以及(iii)一免疫细胞上的一Fc受体或配体。
在某些实施例中,组分A包括如SEQ ID NO:29所示的氨基酸序列,以及组分B包括如SEQ ID NO:30所示的氨基酸序列。
在某些实施例中,组分Y包括如SEQ ID NO:1或SEQ ID NO:2所示的氨基酸序列。
在某些实施例中,组分Z2包括如SEQ ID NO:12所示的氨基酸序列及/或组分Z3包括如SEQ ID NO:13所示的氨基酸序列。
在某些实施例中,组分A包括如SEQ ID NO:14或SEQ ID NO:15所示的氨基酸序列。
在某些实施例中,组分B包括如SEQ ID NO:49所示的氨基酸序列。
在某些实施例中,组分X’包括如SEQ ID NO:37所示的氨基酸序列。在某些实施例中,组分X包括如SEQ ID NO:37所示的氨基酸序列。
在某些实施例中,组分Z2’包括如SEQ ID NO:12所示的氨基酸序列及/或组分Z3’包括如SEQ ID NO:48所示的氨基酸序列。
在某些实施例中,组分CL’包括如SEQ ID NO:64所示的氨基酸序列。
在某些实施例中,组分B包括如SEQ ID NO:53所示的氨基酸序列。
在某些实施例中,组分C包括如SEQ ID NO:61所示的氨基酸序列。
在某些实施例中,组分A包括如SEQ ID NOs:14所示的氨基酸序列,组分B包括如SEQ ID NOs:53所示的氨基酸序列,以及组分C包括如SEQ ID NOs:61所示的氨基酸序列。
在某些实施例中,所述方法包括其中所述第一核酸编码如SEQ ID NO:14所示的氨基酸序列,及/或所述第二核酸编码如SEQ ID NO:49所示的氨基酸序列,及/或所述第三核酸编码如SEQ ID NO:57所示的氨基酸序列。
在某些实施例中,所述增殖性疾病是癌症。在某些实施例中,所述癌症是一实体肿瘤。在某些实施例中,所述癌症是胰腺癌、乳腺癌、卵巢癌、膀胱癌、黑色素瘤(melanoma)、胶质母细胞瘤(glioblastoma)、急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)、急性髓性白血病(acute myelogenous leukemia,AML)、多发性骨髓瘤(multiplemyeloma)或结肠癌。
附图说明
当结合附图阅读时,将更好地理解本发明的优选的实施例的以下详细描述。为了说明本发明,在附图中示出目前优选的实施例。然而,应当理解,本发明并不限于附图中所示的实施例的精确的设置及手段。
图1A及图1B是一融合蛋白平台的一些实施例的示意图。
图2是一融合蛋白平台的一些实施例的示意图。所述图说明靶向自然杀手(natural killer,NK)细胞:肿瘤细胞界面的一融合蛋白。
图3是与CXCR4、PD-L1及FcγRIIIa结合的一融合蛋白的示意图。
图4是与CXCR4、PD-L1及FcγRIIIa结合的一融合蛋白与一癌细胞及NK细胞相互作用的示意图。
图5是与CXCR4、PD-L1及FcγRIIIa结合的一融合蛋白与各种类型的细胞可能的相互作用的示意图。
图6是与各种融合蛋白的各种类型的细胞的可能的相互作用的示意图。
图7是与各种融合蛋白的各种类型的细胞的可能的相互作用的示意图。
图8是与各种融合蛋白的肿瘤相关巨噬细胞(M1)可能的相互作用的示意图。
图9是hPD-1-FcA/hFcB(SEQ ID NO:14加上SEQ ID NO:36)的考马斯蓝(Coomassieblue)染色的(还原的)SDS-PAGE凝胶。
图10是hFcA/hFcB(SEQ ID NO:23加上SEQ ID NO:36)的考马斯蓝(Coomassieblue)染色的SDS-PAGE凝胶。
图11是hMICA-FcA/hFcB(SEQ ID NO:22加上SEQ ID NO:36)的考马斯蓝(Coomassie blue)染色的SDS-PAGE凝胶。
图12是hFcA/hTIGIT-FcB(SEQ ID NO:14加上SEQ ID NO:36)、hFcA/hCD155-FcB(SEQ ID NO:23加上SEQ ID NO:32)、hFcA/hFcB(SEQ ID NO:23加上SEQ ID NO:36)及hMICA-FcA/hTIGIT-FcB(SEQ ID NO:22加上SEQ ID NO:33)的考马斯蓝(Coomassie blue)染色的(还原的)SDS-PAGE凝胶。
图13是hCD112R-FcA/hFcB(SEQ ID NO:16加上SEQ ID NO:36)的考马斯蓝(Coomassie blue)染色的SDS-PAGE凝胶。
图14是HA-PD-1-FcA/hCD113-FcB(SEQ ID NO:15加上SEQ ID NO:35)的考马斯蓝(Coomassie blue)染色的SDS-PAGE凝胶。
图15是hFcA/hCD113-FcB(SEQ ID NO:23加上SEQ ID NO:33)及PD-1-hFcA/hCD113-FcB(SEQ ID NO:14加上SEQ ID NO:35)的考马斯蓝(Coomassie blue)染色的SDS-PAGE凝胶。
图16是hFcA/hCD155-FcB(SEQ ID NO:23加上SEQ ID NO:32)的考马斯蓝(Coomassie blue)染色的SDS-PAGE凝胶。
图17是hFcA/TIM-3-hFcB(SEQ ID NO:23加上SEQ ID NO:34)及PD-1-hFcA/TIM-3-hFcB(SEQ ID NO:14加上SEQ ID NO:34)的考马斯蓝(Coomassie blue)染色的SDS-PAGE凝胶。
图18显示hFcA/hTIGIT-FcB(SEQ ID NO:23加上SEQ ID NO:33)与表达人类CD155的细胞结合。
图19显示hFcA/hTIGIT-FcB(SEQ ID NO:23加上SEQ ID NO:33)与表达人类CD112的细胞结合。
图20显示hFcA/hTIGIT-FcB(SEQ ID NO:23加上SEQ ID NO:33)与表达人类TIGIT的细胞结合。
图21显示hFcA/hTIGIT-FcB(SEQ ID NO:23加上SEQ ID NO:33)及hFcA/hCD155-FcB(SEQ ID NO:23加上SEQ ID NO:32)与表达CD16(FcγRIIIa)的细胞结合。
图22显示在SDS-PAGE,考马斯(Coomassie)凝胶染色上分离的及还原(reduced,R)的融合蛋白。如所描绘,‘A’是指hFcA/hFcB(SEQ ID NO:23加上SEQ ID NO:36),‘B’是指PD-1-hFcA/FcB(SEQ ID NO:14加上SEQ ID NO:36),‘C’是指hFcA/VpI-CH’-FcB/VpI-CL(SEQID NO:23加上SEQ ID NO:53及SEQ ID NO:61)以及‘D’是指PD-1-hFcA/VpI-CH’-FcB/VpI-CL(SEQ ID NO:14加上SEQ ID NO:53及SEQ ID NO:61)。
图23A至23D是一系列蛋白质印迹。对来自使用表达构建体所转染的Expi-CHO细胞的条件培养基的蛋白-A纯化的融合蛋白进行蛋白质印迹分析,如图22所示。所观察到的条带与PD-1-hFcA(SEQ ID NO:14)及vMIPII-CL’(SEQ ID NO:57)的预期的一致;针对非还原的(non-reduced,NR)样品为125kDa,针对还原的(reduced,R)样品分别为60kDa及20kDa。使用(图23A)抗PD1的抗体、(图23B)抗IgGκ轻链的抗体、(图23C)抗IgG重链的抗体及(图23D)抗vMIP-II的抗体探测蛋白质印迹。
图24显示融合蛋白与B16黑色素瘤细胞株结合,所述B16黑色素瘤细胞株在其细胞表面上表达PD-L1及CXCR4或CXCR7。测试的融合蛋白是(从上至下的顺序):hFcA/hFcB(SEQID NO:23加上SEQ ID NO:36)、PD-1-hFcA/FcB(SEQ ID NO:14加上SEQ ID NO:36)、hFcA/V1Δmut-CH’-FcB/V1Δmut-CL’(SEQ ID NO:23加上SEQ ID NO:52及SEQ ID NO:60)、hFcA/V1Δ-CH’-FcB/V1Δ-CL’(SEQ ID NO:23加上SEQ ID NO:51及SEQ ID NO:59)、PD-1-hFcA/V1Δmut-CH’-FcB/V1Δmut-CL’(SEQ ID NO:14加上SEQ ID NO:52及SEQ ID NO:60)及PD-1-hFcA/V1Δ-CH’-FcB/V1Δ-CL’(SEQ ID NO:14加上SEQ ID NO:51及SEQ ID NO:59)。
图25显示一transwell分析,测量融合蛋白对于黑色素瘤细胞迁移的抑制作用。显示使用100ng/mL的CXCL12及融合蛋白处理的迁移的B16-F10细胞的单一transwell迁移分析的代表性图像。经测试的融合蛋白是(从上至下的顺序):hFcA/hFcB(SEQ ID NO:23加上SEQ ID NO:36)、PD-1-hFcA/FcB(SEQ ID NO:14加上SEQ ID NO:36)、hFcA/V1Δmut-CH’-FcB/V1Δmut-CL’(SEQ ID NO:23加上SEQ ID NO:52及SEQ ID NO:60)、hFcA/V1Δ-CH’-FcB/V1Δ-CL’(SEQ ID NO:23加上SEQ ID NO:51及SEQ ID NO:59)、PD-1-hFcA/V1Δmut-CH’-FcB/V1Δmut-CL’(SEQ ID NO:14加上SEQ ID NO:52及SEQ ID NO:NO:60)以及PD-1-hFcA/V1Δ-CH’-FcB/V1Δ-CL’(SEQ ID NO:14加上SEQ ID NO:51及SEQ ID NO:59)。分析是使用2%结晶紫进行染色。
图26A至图26B显示在B16F10黑色素瘤皮下模型中通过融合蛋白(fusionprotein,FP)PD1-hFcA/v1Δ-CH’-hFcB/v1Δ-CL’(SEQ ID NO:14加上SEQ ID NO:51及SEQID NO:59)所介导的肿瘤生长的抑制。C57BL/6小鼠在皮下注射接种1×105个B16F10肿瘤细胞后,在第13、14、15、16及21天使用含有100μl(10g/mL)FP的PBS(小鼠R、小鼠2L及小鼠2R)或仅PBS(小鼠X或小鼠L)进行治疗。在图26A中检测并绘制各只小鼠的肿瘤尺寸随时间的变化。图26B显示来自仅PBS治疗组(顶部)及PD1-hFcA/v1Δ-CH’-hFcB/v1Δ-CL’(FP)治疗组(底部)的一只小鼠的代表性图像。
图27显示通过添加多功能的融合蛋白增强NK细胞介导的ADCC。将SKOV-3卵巢细胞株[靶细胞(T)]以3000个细胞/孔接种在96孔盘中,使其粘附,并使用细胞质红色荧光探针(CellTracker Red CMTPX)试剂进行标记。之后使用一绿色荧光Caspase-3试剂标记SKOV-3细胞。将CD16.NK-92细胞株[V158变体,即效应因子细胞(E)]以E:T为5:1的比率与各种融合蛋白为25mg/ml或无蛋白加入孔中,并使用Incucyte活细胞分析系统,检测荧光双阳性(红色+绿色)的细胞的数量。所显示的结果描述20小时的时间点。经测试的融合蛋白:高亲和力(HA)-PD-1-hFcA/FcB(SEQ ID NO:15加上SEQ ID NO:36)、hFcA/hCD113-FcB(SEQ ID NO:23加上SEQ ID NO:35)以及高亲和力(HA)-PD-1-hFcA/hCD113-FcB(SEQ ID NO:15加上SEQ IDNO:35)。
具体实施方式
除非另有定义,本文所使用的所有技术及科学术语与本发明所属领域的普通技术人员通常理解的含义相同。尽管与本文所述的彼等相似或等效的任何方法及材料可用于测试本发明的实施中,但本文描述优选的材料及方法。在描述级要求保护本发明时,将使用以下术语。
亦应理解,本文中使用的术语仅用于描述特定实施例的目的,并不旨在进行限制。
冠词“一(a)”及“一(an)”在本文中用于指代冠词的一个或一个以上(即至少一个)语法对象。例如,“一元素”是指一个元素或一个以上的元素。
当提及诸如数量、持续时间等可测量值时,本文所用的“大约”意在涵盖指定值的±20%或±10%、更优选地±5%、甚至更优选地±1%,且更优选地±0.1%的变化,因为此种变化适合于执行所公开的方法。
如本文中所使用,“活化”是指已被充分地刺激,以诱导细胞因子的产生、可检测的效应子功能,以及细胞增殖中的一或多者的T细胞的状态。术语“活化的T细胞”是指显示一或多个此等活化特征的T细胞等。
如本文中所使用,术语“抗体”是指与一抗原特异性地结合的一免疫球蛋白分子。抗体可为衍生自天然来源或重组来源的完整的免疫球蛋白,且可为完整的免疫球蛋白的免疫反应部分。抗体通常是免疫球蛋白分子的四聚体,亦可作为此种四聚体的高级多聚体存在。本发明中的抗体可以多种形式存在,包括例如多克隆抗体、单克隆抗体、Fv、Fab及F(ab)2,以及单链抗体(scFv)及人源化抗体(哈洛等人,1999,在:使用抗体:实验室手册,Cold Spring Harbor Laboratory Press,NY;哈洛等人,1989,在:抗体:实验室手册,ColdSpring Harbor,New York;休斯顿人,1988,Proc.Natl.Acad.Sci.USA 85:5879-5883;伯德等人,1988,Science 242:423-426)。
术语“抗体片段”是指一完整的抗体的一部分,以及是指一完整的抗体的抗原决定可变区。抗体片段的实例包括,但不限于,Fab、Fab’、F(ab’)2及Fv片段、线性抗体、scFv抗体以及由抗体片段所形成的多特异性抗体。
如本文中所使用,一“抗体重链”是指以其自然发生的构象存在于所有抗体分子中的两种类型的多肽链中较大者。伽玛(γ)、姆(μ)、德尔塔(Δ)、阿尔法(α)及伊普西龙(ε)重链是指五种主要的抗体重链同型。
如本文中所使用,一“抗体轻链”是指以其自然发生的构象存在于所有抗体分子中的两种类型的多肽链中较小者。卡帕(κ)及拉姆达(λ)轻链是指两种主要的抗体轻链同型。
如本文中所使用,术语“合成的抗体”是指使用重组DNA技术产生的抗体,例如由本文所述的噬菌体所表达的抗体。所述术语亦应解释为表示通过合成编码抗体的DNA分子所产生的抗体,且所述DNA分子表达编码一抗体蛋白的RNA,或指定抗体的氨基酸序列,其中DNA、RNA或氨基酸序列已使用本领域可取得且众所周知的合成核酸或氨基酸序列的技术获得。
如本文中所使用,术语“抗原”或“Ag”被定义为诱导免疫反应或结合一免疫识别部分,例如一抗体及一T细胞受体的一分子。此免疫反应可涉及抗体的产生,或特定免疫性胜任细胞的激活,或两者。本领域技术人员会理解任何大分子,包括几乎所有的蛋白质或肽,皆可用作一抗原。此外,抗原可衍生自重组DNA或基因组DNA。本领域技术人员将理解,包括编码引发一免疫应答的蛋白质的核苷酸序列或部分核苷酸序列的任何DNA,因此编码本文中所使用的术语“抗原”。再者,本领域技术人员将理解抗原无需仅由一基因的全长核苷酸序列编码。很明显的,本发明包括,但不限于使用一种以上基因的部分核苷酸序列,且此等核苷酸序列以各种组合排列,以引发所需的免疫反应。此外,本领域技术人员将理解抗原根本无需由一“基因”编码。很明显的,抗原可从一生物样品中产生、合成或衍生。此种生物样品可包括,但不限于一组织样品、一肿瘤样品、一细胞或一生物流体。
如本文中所使用,术语“抗肿瘤作用”是指可表明为肿瘤体积减少、肿瘤细胞数量减少、转移数量减少、预期寿命增加,或改善与癌症状况相关的各种生理症状的一生物性效果。“抗肿瘤作用”亦可通过本发明的肽、多核苷酸、细胞及抗体在预防肿瘤出现在首次出现的位置的能力来表明。
根据本发明,术语“自身抗原”是指被免疫系统识别为外来的任何自身抗原。自身抗原包括,但不限于,细胞蛋白、磷蛋白、细胞表面蛋白、细胞脂质、核酸、糖蛋白,包括细胞表面受体。
如本文中所使用,术语“自身免疫病”被定义为由一自身免疫反应引起的一病症。自身免疫性疾病是对一自身抗原的不适当及过度反应的结果。自身免疫性疾病的例子包括但不限于,阿狄森氏病(Addision’s disease)、斑秃、强直性脊柱炎、自身免疫性肝炎、自身免疫性腮腺炎、克罗恩病(Crohn’sdisease)、糖尿病(第I型)、营养不良性大疱性表皮松解症、附睾炎、肾小球肾炎、格雷夫斯病(Graves’disease)、格林-巴尔综合征(Guillain-Barrsyndrome)、桥本氏病(Hashimoto’s disease)、溶血性贫血、系统性红斑狼疮、多发性硬化症、重症肌无力症、寻常型天疱疮、银屑病、风湿病、类风湿性关节炎、类肉瘤病、硬皮病、薛格连氏综合征(Sjogren's syndrome)、脊椎关节病、甲状腺炎、血管炎、白斑症、粘液性水肿、恶性贫血、溃疡性结肠炎等。
如本文中所使用,术语“自身的(autologous)”是指源自同一个体的任何材料,随后将其重新引入所述个体。
“同种异体(allogeneic)”是指源自同一物种的不同动物的一移植物。
“异种异体(xenogeneic)”是指源自不同物种的动物的一移植物。
如本文中所使用,术语“癌症”被定义为特征在于异常细胞的快速且不受控制的增殖及/或积累的疾病。癌细胞可局部扩散或通过血流及淋巴系统扩散至身体的其他部位。各种癌症的例子包括但不限于,乳腺癌、前列腺癌、卵巢癌、宫颈癌、皮肤癌、胰腺癌、结直肠癌、肾癌、肝癌、脑癌、淋巴瘤、白血病、肺癌等。在某些实施例中,癌症是甲状腺髓样癌(medullary thyroid carcinoma)。
术语“裂解(cleavage)”是指共价键的断裂,例如在一核酸分子的主链中。裂解可通过多种方法引发,包括,但不限于,磷酸二酯键的酶促或化学水解。单链裂解及双链裂解皆是可能的。双链裂解可作为两个不同的单链裂解事例的结果而发生。DNA裂解可导致产生钝端(blunt end)或交错末端(staggered end)。在某些实施例中,融合多肽可用于靶向裂解的双链DNA。
如本文中所使用,术语“保守序列修饰(conservative sequence modification)”旨在指不显着地影响或改变含有氨基酸序列的抗体的结合特性的氨基酸修饰。此种保守修饰包括氨基酸置换、添加及缺失。通过本领域已知的标准技术,例如定点诱变及PCR介导的诱变,可将修饰引入本发明的一抗体中。保守氨基酸置换是其中氨基酸残基被具有相似侧链的氨基酸残基取代。具有相似侧链的氨基酸残基的家族已在本领域中定义。此等家族包括具有碱性侧链(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链(例如,天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如,苏氨酸、缬氨酸、异亮氨酸)及芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此,一抗体的CDR区内的一或多个氨基酸残基可被来自相同侧链家族的其他氨基酸残基取代,且可使用本文中所述的功能分析法测试改变的抗体结合抗原的能力。
“疾病(disease)”是一动物的健康状态,其中所述动物无法维持体内平衡,倘若疾病未改善,则动物的健康继续恶化。相较之下,动物的一“病症(disorder)”是一健康状态,在此种状态下,动物能够维持体内平衡,但动物的健康状况不如无疾病时的健康状态。倘若未加以治疗,一病症不一定会导致动物的健康状况进一步下降。
“有效量”或“治疗有效量”在本文中可互换使用,是指如本文所述的有效实现一特定生物学结果或提供一治疗或预防益处的一化合物、制剂、材料或组合物的量。此种结果可包括,但不限于,通过本领域任何合适的方法所确定的抗肿瘤活性。
“编码”是指多核苷酸,例如基因、cDNA或mRNA)中特定核苷酸序列的固有特性,可用作在生物过程中合成其他聚合物及大分子的模板,此等聚合物及大分子具有一确定的核苷酸序列(即,rRNA、tRNA及mRNA)或一确定的氨基酸序列及由此产生的生物学特性。因此,倘若一基因转录为mRNA,且对应于所述基因的mRNA在细胞或其他生物系统中进行转译产生一蛋白质,则所述基因编码所述蛋白质。编码链,其核苷酸序列与mRNA序列相同,且通常在序列表中提供,以及非编码链,用作一基因或cDNA转录的模板,皆可被称为编码蛋白质或所述基因或cDNA的其他产物。
如本文中所使用,“内源性”是指来自一生物体、细胞、组织或系统的任何材料或在一生物体、细胞、组织或系统的内部所产生的任何材料。
如本文中所使用,术语“外源的”是指从生物体、细胞、组织或系统引入或产生于生物体、细胞、组织或系统之外的任何材料。
如本文中所使用,术语“扩增(expand)”是指数量增加,如T细胞数量增加。在一实施例中,离体扩增的T细胞的数量相对于原始存在于培养物中的数量增加。在另一实施例中,离体扩增的T细胞相对于培养物中的其他细胞类型在数量上增加。如本文中所使用,术语“离体(ex vivo)”是指已从一活生物体(例如,人类)中取出,且在所述生物体的外部(例如,在一培养皿、试管或生物反应器中)繁殖的细胞。
如本文中所使用,术语“表达”定义为一特定的核苷酸序列通过其调节元件,例如一启动子所驱动的转录及或转译。
“表达载体”是指包括一重组多核苷酸的一载体,所述重组多核苷酸包括与待表达的一核苷酸序列可操作地连接的表达控制序列。一表达载体包括用于表达的足够的顺式作用元件(cis-acting element);其他表达元件可由宿主细胞或在一体外表达系统中提供。表达载体包括本领域已知的所有彼等,例如结合重组多核苷酸的粘质体、质粒(例如,裸露的或包括在脂质体中)及病毒(例如,仙台病毒(Sendai virus)、慢病毒、逆转录病毒、腺病毒及腺相关病毒)。
如本文中所使用,“同源”是指在两个聚合分子之间,例如两个核酸分子之间,例如两个DNA分子或两个RNA分子之间,或两个多肽分子之间的亚基序列的同一性。当两个分子中的一亚基位置被同一单体亚基占据时;例如,倘若两个DNA分子中的各个中的一位置被腺嘌呤占据,则其在所述位置是同源的。两个序列之间的同源性是相匹配位置或同源位置的数量的一直接函数;例如,倘若两个序列中一半(例如,十个亚基长度的聚合物中的五个位置)的位置是同源的,则两个序列具有50%的同源性;倘若90%的位置(例如,10个中的9个)是相匹配的或同源的,则两个序列具有90%的同源性。
非人类(例如鼠)抗体的“人源化”形式是嵌合免疫球蛋白、免疫球蛋白链或其片段(例如Fv、Fab、Fab’、F(ab’)2或抗体的其他抗原结合亚序列),其包括衍生自非人类免疫球蛋白的最小序列。在大多数情况下,人源化抗体是人类免疫球蛋白(受体抗体),其中来自受体的一互补决定区(complementary-determining region,CDR)的残基被来自一非人类物种(供体抗体),例如小鼠、具有所需特异性、亲和力及能力的大鼠或兔子的残基取代。在一些情况下,人类免疫球蛋白的Fv框架区(framework region,FR)残基被相应的非人类残基取代。此外,人源化抗体可包括既不在受体抗体中,且亦不在导入的CDR或框架序列中所发现的残基。进行此等修饰是为了进一步完善及优化抗体性能。一般而言,人源化抗体将包括基本上所有的至少一个,通常为两个可变域,其中所有或基本上所有的CDR区对应于一非人类免疫球蛋白的彼等CDR区及所有或基本上所有的FR区是人类免疫球蛋白序列的FR区。人源化抗体优选地亦包括一免疫球蛋白恒定区(immunoglobulin constant region,Fc)的至少一部分,通常是一人类免疫球蛋白的恒定区。更多细节参见琼斯等人,Nature,321:522-525,1986;赖希曼等人,Nature,332:323-329,1988,Presta,Curr.Op.Struct.Biol.,2:593-596,1992。
“完全人源”是指一免疫球蛋白,例如一抗体,其中整个分子是人类来源的或由与所述抗体的一人类形式相同的一氨基酸序列组成。
如本文中所使用,“同一性”是指两个聚合分子之间,特别是两个氨基酸分子之间,例如,两个多肽分子之间的亚基序列同一性。当两个氨基酸序列在相同位置具有相同残基时;例如,倘若两个多肽分子中的各个中的一位置被精氨酸占据,则其在所述位置是相同的。两个氨基酸序列在比对中的相同位置具有相同残基的同一性或程度通常是以百分比表示。两个氨基酸序列之间的同一性是相匹配的位置或相同的位置的数量的一直接函数;例如,倘若两个序列中一半(例如,十个氨基酸长度的聚合物中的五个位置)的位置是同一性的,则两个序列具有50%的同一性;倘若90%的位置(例如,10个中的9个)是相匹配的或同源的,则两个序列具有90%的同一性。
如本文中所使用,术语“免疫球蛋白”或“Ig”被定义为蛋白质的一类别,其作为抗体进行作用。通过B细胞表达的抗体有时称为BCR(B细胞受体)或抗原受体。包括在此种别的蛋白质中的五个成员是IgG、IgM、IgD、IgA及IgE。IgG是最常见的循环抗体。IgM是大多数受试者在初级免疫反应中产生的主要免疫球蛋白。其是在凝集、补体固定及其他抗体反应中最有效的免疫球蛋白,且在防御细菌及病毒方面很重要。IgD是一种免疫球蛋白,无已知的抗体功能,但可作为一抗原受体。IgA是存在于身体分泌物中的主要抗体,例如唾液、眼泪、母乳、胃肠道分泌物以及呼吸道及泌尿生殖道的粘液分泌物。IgE是一种免疫球蛋白,通过在暴露于过敏原时导致来自肥大细胞及嗜碱性粒细胞所释放的介质来介导即时超敏反应。
如本文中所使用,术语“免疫反应”被定义为当淋巴细胞将抗原分子识别为外来物,并诱导抗体的形成及/或激活淋巴细胞,以去除抗原时,发生对一抗原的一细胞反应。
如本文中所使用,术语“脂质运载蛋白(lipocalin)”被定义为蛋白质的一类别,其在自然环境中运输疏水性分子,例如类固醇、比林(bilin)、类视网醇及脂质。其共享序列同源性的有限区域及一共同的三级结构架构,所述共同的三级结构架构包括一个八链反平行β桶,其具有包括一内部配体结合位点的重复的+1拓扑结构。脂质运载蛋白存在于革兰氏阴性细菌、脊椎动物细胞、无脊椎动物细胞及植物中,且与许多生物过程有关,其中包括免疫反应、信息素转运、生物前列腺素合成、类视网醇结合及癌细胞相互作用。脂质运载蛋白可以许多与抗体修饰相同的方式进行修饰,以改变或增强其结合特性,例如,结合一细胞表面分子,并以此方式阻断、增强或以其他方式改变其功能特性。
如本文中所使用,“指导材料(industructional material)”包括一出版物、一录音、一图表或可用于传达本发明的组合物及方法的有用性的任何其他的表达媒介。本发明的试剂盒的指导材料可例如附加在含有本发明的核酸、肽及/或组合物的一容器上,或与含有核酸、肽及/或组合物的一容器一起运输。或者,所述指导材料可与容器分开运输,以便接收者可配合地使用指导材料及化合物。
“分离的”是指改变或脱离自然状态。例如,自然存在于一活体动物中的核酸或肽不是“分离的”,但与其自然状态的共存材料部分地或完全地分离的相同核酸或肽是“分离的”。一分离的核酸或蛋白质可以基本上纯化的形式存在,或者可存在于一非天然的环境,例如,一宿主细胞中。
如本文中所使用,“慢病毒”是指逆转录病毒科的一个属。慢病毒在逆转录病毒中是独一无二的,其能够感染非分裂的细胞;其可将大量遗传信息传递至宿主细胞的DNA中,因此其是一基因传递载体的最有效方法之一。HIV、SIV及FIV皆为慢病毒的例子。衍生自慢病毒的载体提供在体内实现显着水平的基因转移的手段。
如本文中所使用,术语“修饰的”是指本发明的分子或细胞的一改变状态或结构。分子可通过多种方式进行修饰,包括化学性、结构性及功能性的修饰。可通过引入核酸来修饰细胞。
如本文中所使用,术语“调节”是指相较于不存在治疗或化合物的情况下的受试者的反应水平,及/或相较于其他相同的但未经治疗的受试者的反应水平,介导一受试者的反应水平的可检测的增加或减少。所述术语包括扰乱及/或影响一天然信号或反应,从而在一受试者,优选地,一人类中介导一有益的治疗反应。
在本发明的内容中,对于常见的核酸碱基使用以下的缩写。“A”指腺苷,“C”指胞嘧啶,“G”指鸟苷,“T”指胸苷,“U”指尿苷。
除非另有说明,“编码一氨基酸序列的一核苷酸序列”包括彼此简并型式且编码相同的氨基酸序列的所有核苷酸序列。短语编码一蛋白质或一RNA的核苷酸序列亦可包括多个内含子,其程度使得编码蛋白质的核苷酸序列在某些型式中可包括一或多个内含子。
术语“可操作的连接”是指在一调节序列及一异源核酸序列之间的功能性连接,导致后者表达。例如,当一第一核酸序列与一第二核酸序列处于一功能关系时,所述第一核酸序列与所述第二核酸序列是可操作地连接。例如,倘若一启动子影响一编码序列的转录或表达,则所述启动子与所述编码序列是可操作地连接。一般而言,可操作地连接的DNA序列是连续的,且在需要连接两个蛋白质编码区时,在相同的读框(reading frame)中。
术语“过度表达”的肿瘤抗原或一肿瘤抗原的“过度表达”旨在表示来自一疾病区域的细胞中的一肿瘤抗原的一异常表达水平,例如患者的特定组织或器官内的一实体瘤相对于来自所述组织或器官的正常细胞中的表达水平。可通过本领域已知的标准分析法确定患有实体瘤或以肿瘤抗原的过度表达所表征的血液肿瘤的患者。
一免疫原性组合物的“肠胃外”给药包括,例如皮下(subcutaneous,s.c.)、静脉内(intravenous,i.v.)、肌肉内(intramuscular,i.m.)或胸骨内注射,或输注技术。
如本文中所使用,术语“多核苷酸”被定义为核苷酸链。此外,核酸是核苷酸的聚合物。因此,本文中所使用的核酸及多核苷酸是可互换的。本领域技术人员公知核酸是多核苷酸,其可被水解成单体“核苷酸”。所述单体核苷酸可被水解成核苷。如本文中所使用,多核苷酸包括,但不限于,通过本领域可取得的任何方式所获得的所有核酸序列,包括,但不限于重组手段,即,使用普通的克隆技术及PCRTM等,以及通过合成手段,从一重组库或一细胞基因组中克隆核酸序列。
如本文中所使用,术语“肽”、“多肽”及“蛋白质”可互换使用,且是指由通过肽键共价地连接的氨基酸残基所组成的一化合物。一蛋白质或肽必须包括至少两个氨基酸,且对于可构成一蛋白质序列或肽序列的氨基酸的最大数量并无限制。多肽包括含有通过肽键彼此连接的两个或更多个氨基酸的任何肽或蛋白质。如本文中所使用,所述术语指的是短链及更长的链二者,所述短链在本领域中通常亦被称为肽、寡肽及寡聚体,例如,所述更长的链在本领域中通常被称为蛋白质,其具有很多类型。“多肽”包括,例如,生物活性片段、基本上同源的多肽、寡肽、同源二聚体、异源二聚体、多肽的变体、修饰的多肽、衍生物、类似物、融合蛋白等。所述多肽包括天然肽、重组肽、合成肽或其组合。
如本文中所使用,术语“融合蛋白”及“嵌合蛋白”可互换使用,且是指由两个或更多个多肽所组成的一化合物。在一些实施例中,所述两个或更多个多肽是共价地连接。在进一步的实施例中,所述两个或更多个多肽通过肽键、连接子或二硫键共价地连接。融合蛋白可通过本领域技术人员熟知的多种方法产生,最常见的是通过将包括编码或指定一融合蛋白氨基酸序列的一核酸序列的一载体引入一细胞。可将额外的氨基酸或多肽掺入一融合蛋白中,以引发额外的功能特性,例如稳定性、半衰期、多聚化、易于纯化。此种元件的一例子是一多肽连接子。
如本文中所使用,术语“启动子”被定义为被细胞的合成工具或引入的合成工具所识别的一DNA序列,其需要启动一多核苷酸序列的特异性转录。
如本文中所使用,术语“启动子/调节序列”是指表达与启动子/调节序列可操作地连接的一基因产物所需的一核酸序列。在某些情况下,此序列可为核心启动子序列,而在其他情况下,所述序列亦可包括一增强子序列及所述基因产物的表达所需的其他调节元件。例如,所述启动子/调节序列可为以一组织特异性方式表达基因产物的序列。
“组成型(constitutive)”启动子是一核苷酸序列,当与编码或指定一基因产物的一多核苷酸可操作地连接时,导致所述基因产物在细胞的大部分或所有生理条件下在一细胞中产生。
“诱导型(inducible)”启动子是一核苷酸序列,当与编码或指定一基因产物的一多核苷酸可操作地连接时,基本上仅当在细胞中存在对应于启动子的一诱导物时,才导致所述基因产物在细胞中产生。
“组织特异性”启动子是一核苷酸序列,当与编码或指定一基因的一多核苷酸可操作地连接时,基本上仅当细胞是与启动子相对应的组织类型的一细胞时,才导致所述基因产物在细胞中产生。
“信号转导路径”是指在多个信号转导分子之间的生化关系,此等信号转导分子在将一信号从一细胞的一部分传递至一细胞的另一部分中扮演一角色。短语“细胞表面受体”包括能够接收一信号,并跨越一细胞的质膜的传输信号的分子及分子的复合物。
术语“特异性结合”,如本文中所使用的关于一抗体,是指识别一特定的抗原,但基本上不识别或结合一样品中的其他分子的一抗体。例如,与来自一物种的一抗原特异性结合的一抗体亦可与来自一或多种物种的抗原结合。但是,此种跨物种反应性本身不会改变抗体的特异性分类。在另一例子中,特异性结合一抗原的一抗体亦可结合抗原的不同等位基因形式。然而,此种交叉反应性本身不会改变一抗体的特异性分类。在一些情况下,术语“特异性结合”或“特异地结合”可用于指一抗体、一蛋白质或一肽与一第二化学物质的相互作用,以表示所述相互作用是取决于存在化学物种上的一特定结构(例如,一抗原决定簇或表位),例如,一抗体识别并结合至一特定的蛋白质结构,而非一般的蛋白质。倘若一抗体对于表位“A”具有特异性,则在含有标记的“A”及所述抗体的一反应中存在含有表位A(或游离的、未标记的A)的一分子,将减少与所述抗体结合的标记的A的数量。
术语“受试者”旨在包括其中可引发一免疫反应的活生物体(例如,哺乳动物)。其中使用的一“受试者”或“患者”可为一人类或非人类哺乳动物。非人类哺乳动物包括,例如,家畜及宠物,诸如绵羊、牛、猪、犬、猫及鼠哺乳动物。优选地,所述受试者是人类。
如本文中所使用,一“基本上纯化的”细胞是基本上不含其他细胞类型的一细胞。一基本上纯化的细胞亦指已经与其他细胞类型分离的一细胞,所述其他细胞类型通常与其自然发生的状态相关联。在一些情况下,基本上纯化的细胞群是指一同质的细胞群。在其他情况下,此术语仅指在自然状态下与其自然关联的细胞分离的细胞。在一些实施例中,所述细胞在体外培养。在其他的实施例中,所述细胞非为体外培养。
“靶位点”或“靶序列”是指一基因组核酸序列,其定义在足以发生结合的条件下,一结合分子可特异性地结合的一核酸的一部分。
如本文中所使用,术语“治疗”是指治疗及/或预防。通过抑制、缓解或根除疾一疾病状态所获得的一治疗效果。
如本文中所使用,术语“转染的”或“转化的”或“转导的”是指将外源的核酸转移或引入宿主细胞的一过程。一“转染的”或“转化的”或“转导的”细胞是使用外源的核酸进行转染、转化或转导的细胞。所述细胞包括初级受试者细胞及其后代。
术语“转基因”是指已经或即将被人工插入一动物的基因组中的遗传物质,特别是一哺乳动物,且更特别是一活体动物的一哺乳动物细胞。
“治疗”一疾病,如本文中所使用的术语,是指降低一受试者经历的一疾病或病症的至少一体征或症状的频率或严重性。
如本文中所使用,短语“在转录的控制下”或“可操作地连接”是指启动子相对于多核苷酸处于正确的位置及方向,以控制RNA聚合酶的转录起始及多核苷酸的表达。
“载体”是包括一分离的核酸且可用于将分离的核酸递送至一细胞的内部的物质的组合物。许多载体是本领域已知的,包括,但不限于,线性多核苷酸、与离子或两亲化合物相关的多核苷酸、质粒及病毒。因此,术语“载体”包括一自主复制的质粒或一病毒。所述术语亦应解释为包括促进核酸转移至细胞中的非质粒及非病毒化合物,例如聚赖氨酸化合物、脂质体等。一质粒载体的一实例是一附着型载体,其中自我复制是通过源自一病毒,例如,爱泼斯坦-巴尔病毒(Epstein-Barr virus)及BK病毒的调节元件驱动或增强。病毒载体的实例包括,但不限于,仙台病毒(Sendai virus)载体、腺病毒载体、腺相关的病毒载体、逆转录病毒载体、慢病毒载体等。
范围:本公开的全文,本发明的各个方面可以范围格式呈现。应当理解,范围格式的描述仅仅是为了方便及简洁,不应理解为对本发明的范围的不灵活的限制。因此,范围的描述应被视为已明确揭露所有可能的子范围以及所述范围内的各个数值。例如,诸如自1至6的范围的描述应被视为具有具体公开的子范围,例如自1至3、自1至4、自1至5、自2至4、自2至6、自3至6等,以及所述范围内的单个数字,例如1、2、2.7、3、4、5、5.3及6。无论范围的广度如何,其皆适用。
如本发明关于所公开的物质的组合物及方法所设想的,一方面,本发明的实施例包括本文所公开的组分及/或步骤。在另一方面,本发明的实施例基本上由本文所公开的组分及/或步骤组成。在又一方面,本发明的实施例由其中所公开的组分及/或步骤组成。
描述:
提供一种融合蛋白。在一些示例性实施例中,融合蛋白的所述第一组分阻断一趋化因子受体,例如,CXCR4及/或CXCR7(通过融合蛋白中的vMIPII或V1肽或其衍生物的结合),且此阻断用于固定肿瘤细胞并干扰其迁移、侵袭、转移,及其他致瘤的特性;融合蛋白的所述第二组分阻断所述肿瘤细胞上的一检查点抑制剂,例如,PD-L1及/或PD-L2(通过融合蛋白中的PD1或其衍生物的结合),且此阻断用于干扰抑制一肿瘤导向的免疫效应细胞,例如NK细胞;融合蛋白的所述第三组分触发同一免疫效应细胞上的一激活受体,例如FcγRIIIa受体(通过Fcγ或其衍生物在融合蛋白中的结合),其驱动NK细胞活化并促进ADCC及ADCP。
在一些示例性实施例中,融合蛋白的一种组分阻断一肿瘤或其他细胞上的一检查点抑制剂,且另外两种组分各自触发一免疫效应细胞上的不同激活受体。在一些实施例中,当检查点抑制剂位于一肿瘤细胞上时,融合蛋白分子桥接一免疫效应细胞及一靶肿瘤细胞。此外,融合蛋白的三种相互作用,检查点抑制途径阻断及激活受体触发的组合,用于在功能上相互增强,所有三者皆协同驱动所述免疫效应细胞,例如,NK细胞的激活。在一优选的实施例中,通过融合蛋白所阻断的检查点抑制剂是由PD-L1、PD-L2、CD113、CD112、CD155或CD111组成,且通过融合蛋白共同触发的两种激活受体是在NK细胞上的FcγRIIIa受体及4-1BB。
融合蛋白:
提供包括组分A及/或组分B的融合蛋白;其中组分A包括组分Y、组分Z2及组分Z3;以及
其中组分B包括组分X’、组分Z2’及组分Z3’。在一些实施例中,组分B进一步包括组分Z1’。因此,在一些实施例中,组分B包括组分X’、组分Z1’、组分Z2’及组分Z3’。
在一些实施例中,组分A进一步包括组分Z1。因此,在一些实施例中,组分A包括组分Y、组分Z1、组分Z2及组分Z3。
在一些实施例中,融合蛋白进一步包括组分C,其中组分C包括组分X及组分CL’。在进一步的实施例中,组分CL’包括一免疫球蛋白轻链的至少一部分。在一些实施例中,融合蛋白进一步包括组分D,其中组分D包括组分Q及组分CL。在进一步的实施例中,组分CL包括一免疫球蛋白轻链的至少一部分。
在一些实施例中,组分A进一步包括一前导序列。在进一步的实施例中,所述前导序列是一人类白蛋白前导序列。
在一些实施例中,组分B进一步包括一前导序列。在进一步的实施例中,所述前导序列是一人类白蛋白前导序列。
在一些实施例中,组分Y包括一配体结构域、一受体结构域、一scFv结构域或一脂质运载蛋白结构域。在进一步的实施例中,组分Y包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。在更进一步的实施例中,所述融合蛋白与PD-L1或PD-L2结合。
在一些实施例中,组分Z1包括一免疫球蛋白的一结构域、一TNF超家族成员、一TNF-L超家族成员、一转铁蛋白、一转铁蛋白受体、一人类血清白蛋白或一脂质运载蛋白。在一些实施例中,一免疫球蛋白的结构域是一CH1结构域。在一些实施例中,所述免疫球蛋白是IgG。在更进一步的实施例中,所述免疫球蛋白是IgE。
在一些实施例中,组分Z2包括一免疫球蛋白的结构域、一TNF超家族成员、一TNF-L超家族成员、一转铁蛋白、一转铁蛋白受体、一人类血清白蛋白或一脂质运载蛋白。在一些实施例中,一免疫球蛋白的结构域是一CH2结构域。在一些实施例中,所述免疫球蛋白是IgG。在更进一步的实施例中,所述免疫球蛋白是IgE。
在一些实施例中,组分Z3包括一免疫球蛋白的结构域、一TNF超家族成员、一TNF-L超家族成员、一转铁蛋白、一转铁蛋白受体、一人类血清白蛋白或一脂质运载蛋白。在一些实施例中,一免疫球蛋白的一结构域是一CH3结构域。在一些实施例中,所述免疫球蛋白是IgG。在更进一步的实施例中,所述免疫球蛋白是IgE。
在一些实施例中,组分Zl’包括一免疫球蛋白的结构域、一TNF超家族成员、一TNF-L超家族成员、一转铁蛋白、一转铁蛋白受体、一人类血清白蛋白或一脂质运载蛋白。在一些实施例中,一免疫球蛋白的一结构域是一CH1结构域。在一些实施例中,所述免疫球蛋白是IgG。在更进一步的实施例中,所述免疫球蛋白是IgE。
在一些实施例中,组分Z2’包括一免疫球蛋白的结构域、一TNF超家族成员、一TNF-L超家族成员、一转铁蛋白、一转铁蛋白受体、一人类血清白蛋白或一脂质运载蛋白。在一些实施例中,一免疫球蛋白的一结构域是一CH2结构域。在一些实施例中,所述免疫球蛋白是IgG。在更进一步的实施例中,所述免疫球蛋白是IgE。
在一些实施例中,组分Z3’包括一免疫球蛋白的结构域、一TNF超家族成员、一TNF-L超家族成员、一转铁蛋白、一转铁蛋白受体、一人类血清白蛋白或一脂质运载蛋白。在一些实施例中,一免疫球蛋白的一结构域是一CH3结构域。在一些实施例中,所述免疫球蛋白是IgG。在更进一步的实施例中,所述免疫球蛋白是IgE。
在一些实施例中,组分X’包括一病毒衍生的肽、一配体衍生的肽、一受体衍生的肽或一高通量筛选(high-throughput screen,HTS)选择的肽。在一些实施例中,组分X’包括一肽序列,所述肽序列与一趋化因子受体、一细胞因子受体、针对一功能性配体的一反受体、一整联蛋白、一配体或一膜信号传导复合物的一部分结合。在一些实施例中,组分X’包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-1多肽相关序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3或CD48的至少一部分。在进一步的实施例中,组分X’包括vMIP-II的至少一部分。在进一步的实施例中,组分X’包括V1或V1Δ多肽。在更进一步的实施例中,所述融合蛋白与CXCR4结合。
在一些实施例中,组分Q包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3或CD48的至少一部分。
在一些实施例中,组分X包括一病毒衍生的肽、一配体衍生的肽、一受体衍生的肽或一HTS选择的肽。在进一步的实施例中,组分X包括V1或V1Δ多肽。在进一步的实施例中,所述融合蛋白与CXCR4结合。
在一些实施例中,组分Z1’及组分Z2’通过一铰链连接,例如一IgG铰链。在一些实施例中,组分Z1'及组分Z2'通过铰链连接,例如一IgG铰链。在一些实施例中,组分X’及组分Z1’通过一连接子连接。在一些实施例中,组分X及组分CL通过一连接子连接。
在一些实施例中,融合蛋白包括组分A及Fc。在进一步的实施例中,融合蛋白包括组分A及人类FcB(hFcB)。
在一些实施例中,融合蛋白包括组分B及Fc。在进一步的实施例中,融合蛋白包括组分B及人类FcA(hFcA)。
在一些实施例中,组分A及组分B是共价地连接。在一些实施例中,共价连接是经由二硫键或经由一连接子。
在一些实施例中,组分A及组分B不是共价地连接。在一些实施例中,组分A及组分B通过旋钮入孔(knobs-into-holes)的相互作用保持在一起。在一些实施例中,组分A及组分B包括旋钮入孔突变及通过二硫键的共价连接。在一些实施例中,组分A包括突变Y349C及T366W,以及组分B包括突变D356C、T366S、L368A及Y407V(“旋钮入孔”突变)。在此等组分链中的突变及改变的位置由卡巴特(Kabat)编号惯例(约翰逊,G及吴,TT,(2001)NucleicAcids Res,28(1),214-18)定义。
在一些实施例中,融合蛋白包括组分A及一免疫球蛋白的一结构域。在一些实施例中,免疫球蛋白结构域是一Fc结构域。
在一些实施例中,融合蛋白包括组分B及一免疫球蛋白的一结构域。在一些实施例中,免疫球蛋白结构域是一Fc结构域。
在一些实施例中,组分B及组分C是共价地连接。在一些实施例中,N所述共价连接是经由二硫键。
在一些实施例中,组分B及组分C非为共价地连接。
在一些实施例中,组分A及组分D是共价地连接。在一些实施例中,所述共价连接是经由二硫键。
在一些实施例中,组分A及组分D非为共价地连接。
在一些实施例中,融合蛋白与一免疫细胞上的一受体或配体结合。
在一些实施例中,所述受体是一Fc受体。
亦提供一种药物组合物,所述药物组合物包括一药学上可接受的载体及前述实施例中任一者的融合蛋白。
亦提供一种治疗一患者的一增殖性疾病的方法,所述方法包括向有需要此种治疗的一患者施予一治疗有效量的前述实施例中任一者的融合蛋白。在一些实施例中,所述增殖性疾病是癌症。在进一步的实施例中,癌症是实体瘤。在更进一步的实施例中,癌症是所述癌症是胰腺癌、乳腺癌、卵巢癌、膀胱癌、黑色素瘤、胶质母细胞瘤、急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)、急性髓性白血病(acute myelogenous leukemia,AML)、多发性骨髓瘤、结肠癌、肺癌、肝癌、或任何实体或液体肿瘤类型。
本发明提供可用于治疗增殖性疾病,例如癌症的新颖融合蛋白。在表达针对组分Y的一受体或配体及针对组分X’的一受体或配体的细胞上,本发明的融合蛋白可阻断一种或两种所述受体或配体。因此,在共表达针对组分Y的一受体或配体及针对组分X’的一受体或配体的细胞上,本发明的融合蛋白可导致肿瘤细胞的死亡、固定及清除。此外,在表达针对组分Z3或组分Z3’的一受体或配体的细胞上,例如在一自然杀手(natural killer,NK)细胞上,本发明的融合蛋白可触发所述受体或配体,且可导致细胞的活化。因此,本发明的融合蛋白可通过跨越两个相邻的细胞来介导其活性。此外,本发明的融合蛋白可结合在所述细胞上的三种或更多种不同的分子。在一些实施例中,所述融合蛋白可通过引起某些细胞的抑制或减少,或某些细胞的激活或增加来治疗一疾病,例如癌症。
组分A:
组分A包括组分Y、组分Z2及组分Z3。
组分Y:
在一些实施例中,组分Y包括一配体结构域、一受体结构域、一scFv结构域或一脂质运载蛋白结构域。在进一步的实施例中,组分Y包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3或CD48的至少一部分。
组分Y的一示例性序列包括或由以下组成:
GWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQ
组分Y的一示例性序列包括或由以下组成:
GWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFHVVWHRESPSGQTDTLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYVCGVISLAPKIQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQ
(SEQ ID NO:2)高亲和力人类PD-1胞外域。
组分Y的一示例性序列包括或由以下组成:
MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIP
组分Y的一示例性序列包括或由以下组成:
VWEKTVNTEENVYATLGSDVNLTCQTQTVGFFVQMQWSKVTNKIDLIAVYHPQYGFYCAYGRPCESLVTFTETPENGSKWTLHLRNMSCSVSGRYECMLVLYPEGIQTKIYNLLIQTHVTADEWNSNHTIEIEINQTLEIPCFQNSSSKISSEFTYAWSVENSSTDSWVLLSKGIKEDNGTQETLISQNHLISNSTLLKDRVKLGTDYRLHLSPVQIFDDGRKFSCHIRVGPNKILRSSTTVKVFAKPEIPVIVENNSTDVLVERRFTCLLKNVFPKANITWFIDGSFLHDEKEGIYITNEERKGKDGFLELKSVLTRVHSNKPAQSDNLTIWCMALSPVPGNKVWNISSEKITFLLGSEISSTDPPLSVTESTLDTQPSPASSVSPARYPATSSVTLVDVSALRPNTTPQPSNSSMTTRGFNYPWTSSGTDTKKSVSRIPSETYSSSPSGAGSTLHDNVFTSTARAFSEVPTTANGSTKTNHVHITGIVVNKPKDGM
组分Y的一示例性序列包括或由以下组成:
MGHRTLVLPWVLLTLCVTAGTPEVWVQVRMEATELSSFTIRCGFLGSGSISLVTVSWGGPNGAGGTTLAVLHPERGIRQWAPARQARWETQSSISLILEGSGASSPCANTTFCCKFASFPEGSWEACGSLPPSSDPGLSAPPTPAPILRAD
组分Y的一示例性序列包括或由以下组成:
EEVLWHTSVPFAENMSLECVYPSMGILTQVEWFKIGTQQDSIAIFSPTHGMVIRKPYAERVYFLNSTMASNNMTLFFRNASEDDVGYYSCSLYTYPQGTWQKVIQVVQSDSFEAAVPSNSHIVSEPGKNVTLTCQPQMTWPVQAVRWEKIQPRQIDLLTYCNLVHGRNFTSKFPRQIVSNCSHGRWSVIVIPDVTVSDSGLYRCYLQASAGENETFVMRLTVAEGKTDNQYTLFVA
组分Y的一示例性序列包括或由以下组成:
QNLFTKDVTVIEGEVATISCQVNKSDDSVIQLLNPNRQTIYFRDFRPLKDSRFQLLNFSSSELKVSLTNVSISDEGRYFCQLYTDPPQESYTTITVLVPPRNLMIDIQKDTAVEGEEIEVNCTAMASKPATTIRWFKGNTELKGKSEVEEWSDMYTVTSQLMLKVHKEDDGVPVICQVEHPAVTGNLQTQRYLEVQYKPQVHIQMTYPLQGLTREGDALELTCEAIGKPQPVMVTWVRVDDEMPQHAVLSGPNLFINNLNKTDNGTYRCEASNIVGKAHSDYMLYVYDPPTTIPPPTTTTTTTTTTTTTILTIITDSRAGEEGSIRAVDH
组分Y的一示例性序列包括或由以下组成:
PIIVEPHVTAVWGKNVSLKCLIEVNETITQISWEKIHGKSSQTVAVHHPQYGFSVQGEYQGRVLFKNYSLNDATITLHNIGFSDSGKYICKAVTFPLGNAQSSTTVTVLVEPTVSLIKGPDSLIDGGNETVAAICIAATGKPVAHIDWEGDLGEMESTTTSFPNETATIISQYKLFPTRFARGRRITCVVKHPALEKDIRYSFILDIQYAPEVSVTGYDGNWFVGRKGVNLKCNADANPPPFKSVWSRLDGQWPDGLLASDNTLHFVHPLTFNYSGVYICKVTNSLGQRSDQKVIYISDPPTTTTLQPTIQWHPSTADIEDLATEPKKLPFPLSTLATIKDD
组分Y的一示例性序列包括或由以下组成:
AEPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWAEDVLGNKTWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGELFLSQNLETKEWTMPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQELRRYLKSGVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWGDVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSHW
前导序列:
前导序列的一示例性序列包括或由以下组成:
MKWVTFISLLFLFSSAYS
(SEQ ID NO:10)人类白蛋白前导序列。
铰链:
铰链的一示例性序列包括或由以下组成:
EPKSSDKTHTCPPCPAPELLGG
(SEQ ID NO:11)人类IgG铰链。
组分Z2:
组分Z2的一示例性序列包括或由以下组成:
PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAK
(SEQ ID NO:12)IgG1。
组分Z3:
组分Z3的一示例性序列包括或由以下组成:
GQPREPQVCTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK
(SEQ ID NO:13)IgG1。
组分A的一示例性序列包括或由以下组成:
人类PD-1-hFcA:
(SEQ ID NO:14)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分A的另一示例性序列包括或由以下组成:
高亲和力人类PD-1-hFcA:
(SEQ ID NO:15)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分A的另一示例性序列包括或由以下组成:
人类CD112R-hFcA:
(SEQ ID NO:16)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分A的另一示例性序列包括或由以下组成:
人类TIGIT-hFcA:
(SEQ ID NO:17)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分A的另一示例性序列包括或由以下组成:
人类CD96-hFcA:
(SEQ ID NO:18)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分A的另一示例性序列包括或由以下组成:
人类CD226-hFcA:
(SEQ ID NO:19)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分A的另一示例性序列包括或由以下组成:
人类NECL2-hFcA:
(SEQ ID NO:20)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分A的另一示例性序列包括或由以下组成:
人类CD113-hFcA:
(SEQ ID NO:21)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分A的另一示例性序列包括或由以下组成:
人类MICA-hFcA(MHC-I多肽相关的序列A):
(SEQ ID NO:22)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
人类FcA:
(SEQ ID NO:23)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B:
组分B包括X’、组分Z2’及组分Z3’。在一些实施例中,组分X’包括一病毒衍生的肽、一配体衍生的肽、一受体衍生的肽,或一HTS选择的肽。在一些实施例中,组分X’包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-1多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3或CD48的至少一部分。
组分X’:
组分X’的一示例性序列包括或由以下组成:
WPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSMAVFHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGSRSVDIWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGGRPPAQITWHSDLGGMPNTSQVPGFLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESFEKPQLLTVNLTVYYPPEVSISGYDNNWYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQLLIRPVDKPINTTLICNVTNALGARQAELTVQVKEGPPSEHSGMSRN
组分X’的一示例性序列包括或由以下组成:
MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIP
组分X’的一示例性序列包括或由以下组成:
LEDGYKVEVGKNAYLPCSYTLPTSGTLVPMCWGKGFCPWSQCTNELLRTDERNVTYQKSSRYQLKGDLNKGDVSLIIKNVTLDDHGTYCCRIQFPGLMNDKKLELKLDIKAAKVTPAQTAHGDSTTASPRTLTTERNGSETQTLVTLHNNNGTKISTWADEIKDSGETIR
组分X’的一示例性序列包括或由以下组成:
PIIVEPHVTAVWGKNVSLKCLIEVNETITQISWEKIHGKSSQTVAVHHPQYGFSVQGEYQGRVLFKNYSLNDATITLHNIGFSDSGKYICKAVTFPLGNAQSSTTVTVLVEPTVSLIKGPDSLIDGGNETVAAICIAATGKPVAHIDWEGDLGEMESTTTSFPNETATIISQYKLFPTRFARGRRITCVVKHPALEKDIRYSFILDIQYAPEVSVTGYDGNWFVGRKGVNLKCNADANPPPFKSVWSRLDGQWPDGLLASDNTLHFVHPLTFNYSGVYICKVTNSLGQRSDQKVIYISDPPTTTTLQPTIQWHPSTADIEDLATEPKKLPFPLSTLATIKDD
前导序列:
前导序列的一示例性序列包括或由以下组成:
MKWVTFISLLFLFSSAYS
(SEQ ID NO:10)人类白蛋白前导序列。
铰链:
铰链的一示例性序列包括或由以下组成:
EPKSSDKTHTCPPCPAPELLGG
(SEQ ID NO:11)人类IgG铰链。
组分Z2:
组分Z2的一示例性序列包括或由以下组成:
PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAK
(SEQ ID NO:12)IgG1。
组分Z3:
组分Z3的一示例性序列包括或由以下组成:
GQPREPQVCTLPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK
(SEQ ID NO:13)IgG1。
组分B的一示例性序列包括或由以下组成:
人类CD155-hFcB:
(SEQ ID NO:32)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B的一示例性序列包括或由以下组成:
人类TIGIT-hFcB:
(SEQ ID NO:33)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B的一示例性序列包括或由以下组成:
小鼠TIM-3-hFcB:
(SEQ ID NO:34)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B的另一示例性序列包括或由以下组成:
人类CD113-hFcB:
(SEQ ID NO:35)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
人类FcB:
(SEQ ID NO:36)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B包括组分Z1’:
在一些实施例中,组分B进一步包括组分Z1’。因此,在一些实施例中,组分B包括组分X’、组分Z1’、组分Z2’及组分Z3’。
在一些实施例中,组分X’包括一病毒衍生的肽、一配体衍生的肽、一受体衍生的肽,或一HTS选择的肽。在一些实施例中,组分X’包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-1多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3或CD48的至少一部分。在进一步的实施例中,组分X’包括CD155、TIGIT、TIM-3或CD113的至少一部分。
组分X’:
组分X’的一示例性序列包括或由以下组成:
LGASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQLCSKPGVIFLTKRGRQVCADKSKDWVKKLMQQLPVTAR
组分X’的一示例性序列包括或由以下组成:
LGASWHRPDKCCLGYQKRPLP
(SEQ ID NO:38)V1
组分X’的一示例性序列包括或由以下组成:
LGASWHRPDKCALGYQKRPLP
(SEQ ID NO:39)V1Δ
组分X’的一示例性序列包括或由以下组成:
LGASWHRPDACALGYQKRPLP
(SEQ ID NO:40)V1Δmut
组分X’的一示例性序列包括或由以下组成:
LGASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQL
(SEQ ID NO:41)Vp1
组分X’的一示例性序列包括或由以下组成:
LGASWHRPDKCALGYQKRPLPQVLLSSWYPTSQL
(SEQ ID NO:42)Vp1Δ
组分X’的一示例性序列包括或由以下组成:
LGASWHRPDACALGYQKRPLPQVLLSSWYPTSQL
(SEQ ID NO:43)Vp1Δmut
前导序列:
前导序列的一示例性序列包括或由以下组成:
MKWVTFISLLFLFSSAYS
(SEQ ID NO:10)人类白蛋白前导序列。
组分Z1’
组分Z1’的一示例性序列包括或由以下组成:
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVX
(SEQ ID NO:45)
铰链:
铰链的一示例性序列包括或由以下组成:
EPKSSDKTHTCPPCPAPELLGG
(SEQ ID NO:11)人类IgG铰链。
组分Z2’
组分Z2’一示例性序列包括或由以下组成:
PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAK
(SEQ ID NO:12)
组分Z3’
组分Z3’的一示例性序列包括或由以下组成:
GQPREPQVYTLPPSRCELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK
(SEQ ID NO:48)
组分B的一示例性序列包括或由以下组成:
vMIPII-CH’-hFcB:
(SEQ ID NO:49)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B的一示例性序列包括或由以下组成:
V1-CH’-hFcB:
(SEQ ID NO:50)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B的一示例性序列包括或由以下组成:
V1Δ-CH’-hFcB:
(SEQ ID NO:51)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B的一示例性序列包括或由以下组成:
V1Δmut-CH’-hFcB
(SEQ ID NO:52)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B的一示例性序列包括或由以下组成:
Vp1-CH’-hFcB:
(SEQ ID NO:53)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分B的一示例性序列包括或由以下组成:
Vp1Δ-CH’-hFcB:
(SEQ ID NO:54)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
Vp1Δmut-CH’-hFcB:
(SEQ ID NO:55)
斜体-人类白蛋白前导序列
粗体-IgG1铰链区
组分C
在一些实施例中,融合蛋白进一步包括组分C,其中组分C包括组分X及组分CL’。
组分X:
组分X的一示例性序列包括或由以下组成:
LGASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQLCSKPGVIFLTKRGRQVCADKSKDWVKKLMQQLPVTAR
组分X的一示例性序列包括或由以下组成:
LGASWHRPDKCCLGYQKRPLP
(SEQ ID NO:38)V1
组分X的一示例性序列包括或由以下组成:
LGASWHRPDKCALGYQKRPLP
(SEQ ID NO:39)V1Δ
组分X的一示例性序列包括或由以下组成:
LGASWHRPDACALGYQKRPLP
(SEQ ID NO:40)V1Δmut
组分X的一示例性序列包括或由以下组成:
LGASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQL
(SEQ ID NO:41)Vp1
组分X的一示例性序列包括或由以下组成:
LGASWHRPDKCALGYQKRPLPQVLLSSWYPTSQL
(SEQ ID NO:42)Vp1Δ
组分X的一示例性序列包括或由以下组成:
LGASWHRPDACALGYQKRPLPQVLLSSWYPTSQL
(SEQ ID NO:43)Vp1Δmut
在一些实施例中,组分X及组分X’是相同的。在进一步的实施例中,组分X及组分X’是不同的。
前导序列:
前导序列的一示例性序列包括或由以下组成:
MKWVTFISLLFLFSSAYS
(SEQ ID NO:10)人类白蛋白前导序列。
组分CL’:
组分CL’的一示例性序列包括或由以下组成:
KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:64)
组分C的一示例性序列包括或由以下组成:
vMIPII-CL’:
(SEQ ID NO:57)
斜体-人类白蛋白前导序列
组分C的一示例性序列包括或由以下组成:
V1-CL’:
(SEQ ID NO:58)
斜体-人类白蛋白前导序列
组分C的一示例性序列包括或由以下组成:
V1Δ-CL’:
(SEQ ID NO:59)
斜体-人类白蛋白前导序列
组分C的一示例性序列包括或由以下组成:
V1Δmut-CL’:
(SEQ ID NO:60)
斜体-人类白蛋白前导序列
组分C的一示例性序列包括或由以下组成:
Vp1-CL’:
(SEQ ID NO:61)
斜体-人类白蛋白前导序列
组分C的一示例性序列包括或由以下组成:
Vp1Δ-CL’:
(SEQ ID NO:62)
斜体-人类白蛋白前导序列
组分C的一示例性序列包括或由以下组成:
Vp1Δmut-CL’:
(SEQ ID NO:63)
斜体-人类白蛋白前导序列
组分D
在一些实施例中,融合蛋白进一步包括组分D,其中组分D包括组分Q及组分CL。在一些实施例中,组分Q包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。
组分Q的一示例性序列包括或由SEQ ID NO:1、2、3、4、5、6、7、8或9组成。在一些实施例中,组分Q及组分Y是相同的。在进一步的实施例中,组分Q及组分Y是不同的。
组分CL:
组分CL的一示例性序列包括或由以下组成:
KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:64)
融合蛋白的配置:
在本发明的融合蛋白的一些实施例中,当通过本文别处所描述的重组方法制备时,组分A的组分的编码序列直接或通过一连接子框架内融合在一起。如本文中所使用,术语“直接地”是指两者之间无一肽连接子的两种组分的融合(即,在一表达构建体中,编码组分Y、组分Z2及组分Z3的密码子是连续的)。如本文中所使用,“框架内融合”是指融合编码序列的表达产生包括所有的多肽组分的融合蛋白,例如,在一些实施例中,组分A包括框架中的组分Y、组分Z2及组分Z3的所有多肽组分。
在本发明的融合蛋白的一些实施例中,当通过本文别处所描述的重组方法制备时,组分B的组分的编码序列直接或通过一连接子框架内融合在一起。在组分B的表达构建体的一些实施例中,编码组分X’、组分Z2及组分Z3’的密码子是连续的。在进一步的实施例中,在组分B的表达构建体中,编码组分X’、组分Z1’、组分Z2及组分Z3’的密码子是连续的。在一些实施例中,组分B在框架内包括组分X’、组分Z2及组分Z3’的所有多肽组分。在进一步的实施例中,组分B在框架内包括组分X’、组分Z1’、组分Z2’及组分Z3’的所有多肽组分。
在本发明的融合蛋白的一些实施例中,当通过本文别处所描述的重组方法制备时,组分C的组分的编码序列直接或通过一连接子在框架内融合在一起。在组分C的表达构建体的一些实施例中,编码组分X及组分CL’的密码子是连续的。在一些实施例中,组分C在框架内包括组分X及组分CL’的所有多肽组分。
在一些实施例中,任何组分A及任何组分B可相互混合及匹配。在本发明的融合蛋白的一些示例性实施例中,组分A及组分B如表1所示。在一些实施例中,来自表1的组分A及组分B可彼此混合及匹配,且与额外的组分A及组分B选择。所述附加选项亦可相互混合及匹配。组分A或组分B的额外选择可包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3或CD48的至少一部分。
在一些实施例中,融合蛋白包括组分A及hFcB。在一些实施例中,融合蛋白包括组分B及hFcA。
在一些示例性实施例中,融合蛋白的一组分阻断一抑制性受体,融合蛋白的另外两种组分各自触发不同的活化受体。在一优选的实施例中,此三种受体共同位于同一免疫效应细胞,例如,NK细胞的表面上,且融合蛋白的三种相互作用,包括抑制性受体阻断及激活性受体触发的一组合,用于相互加强,所有三者协同驱动NK细胞的激活。
在其他的示例性实施例中,融合蛋白的两种组分各自阻断不同的抑制性受体,且融合蛋白的另一种组分触发一活化受体。在一优选的实施例中,此三种受体共同位于同一免疫效应细胞,例如,NK细胞的表面上,且融合蛋白的三种相互作用,包括抑制性受体阻断及激活性受体触发的一组合,用于相互加强,所有三者协同驱动NK细胞的激活。
在其他的示例性实施例中,融合蛋白的三种组分各自触发一激活受体。在一优选的实施例中,此三种受体共同位于同一免疫效应细胞,例如NK细胞的表面上,且融合蛋白的三种相互作用,皆由激活受体触发组成,用于在功能上相互增强,所有三者协同驱动NK细胞的激活。
针对NK细胞,上述实施例中的活化受体可为驱动NK细胞活化并促进抗体依赖性细胞毒性(antibody-dependent cellular cytotoxicity,ADCC)及抗体依赖性细胞吞噬作用(ADCP)的FcγRIIIa受体。
表1-示例性组分A及组分B
在一些示例性实施例中,融合蛋白包括组分B及组分C。在一些实施例中,任何组分B及任何组分C可相互混合及匹配。在一些实施例中,组分B组分C如表2所示。在一些实施例中,表2的各行显示一融合蛋白中的组分B及组分C的配对。
表2
组分B | 组分C |
vMIPII-CH’-hFcB(SEQ ID NO:49) | vMIPII-CL’(SEQ ID NO:57) |
V1-CH’-hFcB(SEQ ID NO:50) | V1-CL’(SEQ ID NO:58) |
V1Δ-CH’-hFcB(SEQ ID NO:51) | V1Δ-CL’(SEQ ID NO:59) |
V1Δmut-CH’-hFcB(SEQ ID NO:52) | V1Δmut-CL’(SEQ ID NO:60) |
Vp1-CH’-hFcB(SEQ ID NO:53) | Vp1-CL’(SEQ ID NO:61) |
Vp1Δ-CH’-hFcB(SEQ ID NO:54) | Vp1Δ-CL’(SEQ ID NO:62) |
Vp1Δmut-CH’-hFcB(SEQ ID NO:55) | Vp1Δmut-CL’(SEQ ID NO:63) |
在一些实施例中,组分A及组分B通过二硫键稳定的旋钮入孔的相互作用(knobs-into-holes interactions,KiHS-S)结合在一起。在一些实施例中,组分A包括突变Y349C及T366W(例如SEQ ID NO:29),且组分B包括突变D356C、T366S、L368A及Y407V(例如SEQ IDNO:30)(“旋钮入孔(knobs-into-holes)”突变),实现组分A及组分B的强制二聚化。Z1、Z2及Z3组分分别基于人类IgG1的CH1、CH2及CH3结构域的多肽氨基酸骨架。此等组分链中的突变及改变的位置由卡巴特(Kabat)编号惯例(约翰逊,G及吴,TT,(2001)Nucleic Acids Res,28(1),214-18)定义,且基于野生型人类IgG1序列。
野生型人类IgG1(CH1、CH2及CH3结构域)(从氨基酸编号118开始):
(SEQ ID NO:28)
粗体-IgG1铰链区
在一些实施例中,组分A包括或由以下序列(Y349C及T366W)组成:
(SEQ ID NO:29)
粗体-IgG1铰链区(SEQ ID NO:68)
S*-相较于野生型,此突变被添加至铰链区,以消除可能与另一半胱氨酸异常结合的未配对半胱氨酸(cysteine,C)
在一些实施例中,组分B包括或由以下序列(D356C、T366S、L368A及Y407V)组成:
(SEQ ID NO:30)
表1及表2中所示的组分旨在示例性而非限制性的。
在一些示例性实施例中,融合蛋白的一组分阻断肿瘤细胞上有助于所述肿瘤细胞的致瘤性及/或转移潜能的一受体;融合蛋白的一第二组分阻断所述肿瘤细胞上的一检查点抑制剂;融合蛋白的一第三组分触发一免疫效应细胞上的一激活受体。不希望受理论束缚,融合蛋白用于在分子上桥接一免疫效应细胞及一靶肿瘤细胞,且融合蛋白的第二组分及第三组分通过在一免疫效应细胞上阻断及触发一检查点抑制剂的组合来相互加强,例如,NK细胞上的激活受体,共同协同驱动所述免疫效应细胞的激活。
在一优选的实施例中,融合蛋白的所述第一组分阻断趋化因子受体,例如,CXCR4及/或CXCR7(通过融合蛋白中的vMIPII肽或V1肽或其衍生物的结合),且此阻断用于固定肿瘤细胞并干扰其迁移、侵袭、转移及其他的致瘤特性;融合蛋白的所述第二组分阻断所述肿瘤细胞上的一检查点抑制剂,例如,PD-L1及/或PD-L2(通过融合蛋白中PD1或其衍生物的结合),且此阻断用于干扰抑制一肿瘤导向的免疫效应细胞,例如,NK细胞;融合蛋白的所述第三组分触发同一免疫效应细胞上的一激活受体,例如FcγRIIIa受体(通过Fcγ或其衍生物在融合蛋白中的结合),其驱动NK细胞活化并促进ADCC及ADCP。所述实施例的一有利特征是相同的融合蛋白,亦协同调节除NK细胞之外的具有一净抗肿瘤作用的其他免疫细胞(参见图5)。
在一些示例性实施例中,融合蛋白的一组分阻断一肿瘤或其他细胞上的一检查点抑制剂,而另外两种组分各自触发一免疫效应细胞上的不同激活受体。当检查点抑制剂位于一肿瘤细胞上时,融合蛋白实际上作为分子桥接一免疫效应细胞及一靶肿瘤细胞的作用。此外,融合蛋白的三种相互作用,即检查点抑制通路阻断及激活受体触发的组合,在功能上相互增强,所有此三种相互作用共同驱动所述免疫效应细胞,例如NK细胞的激活。在一优选的实施例中,融合蛋白所阻断的检查点抑制剂是由PD-L1、PD-L2、CD113、CD112、CD155或CD111组成,融合蛋白共同触发的两种激活受体是在NK细胞上的FcγRIIIa受体及4-1BB(参见图6)。
在一些示例性实施例中,融合蛋白的一组分阻断一肿瘤或其他细胞上的一检查点抑制剂;融合蛋白的一第二组分阻断一免疫效应细胞上的相同或不同的检查点抑制剂的一共抑制受体;融合蛋白的一第三组分触发一免疫效应细胞上的一激活受体。当检查点抑制剂位于一肿瘤细胞上时,融合蛋白实际上作为一分子桥接免疫效应细胞及一靶肿瘤细胞的作用,且融合蛋白的三者相互作用,即检查点抑制通路阻断及激活受体触发的组合,用于在功能上相互增强,所有三者皆协同驱动所述免疫效应细胞,例如,NK细胞的激活。在一优选的实施例中,通过融合蛋白的第一组分所阻断的检查点抑制剂是由PD-L1、PD-L2、CD113、CD112、CD155或CD111组成;通过融合蛋白所阻断的NK细胞上的共抑制受体是由PD-1、TIGIT、CD96或CD112R组成;且通过融合蛋白所触发的激活受体是FcγRIIIa受体,与NK细胞相同(参见图7)。
在一些示例性实施例中,融合蛋白的一组分阻断一肿瘤相关的M1型巨噬细胞上的“别吃我(don't eat me)”抑制性受体,从而释放其抗肿瘤吞噬及其他活性;融合蛋白的另外两种组分各自触发所述肿瘤相关的巨噬细胞上的一不同激活受体。融合蛋白的三种相互作用,即阻断一巨噬细胞抑制途径及触发巨噬细胞上单独的激活受体的组合,用于功能上相互增强,此三种相互作用共同驱动肿瘤相关的巨噬细胞的激活并促进其抗肿瘤功能。在一优选的实施例中,通过融合蛋白的第一组分所阻断的“别吃我”受体是SIRPα;通过融合蛋白所触发的激活受体是在同一巨噬细胞上的CD40及FcγRIIIa受体(参见图8,左图)。
一肿瘤相关的M1型巨噬细胞上的“别吃我(don't eat me)”抑制性受体,从而释放其抗肿瘤吞噬及其他活性;融合蛋白的一第二组分阻断所述巨噬细胞上的一独特抑制受体;融合蛋白的一第三组分触发所述肿瘤相关巨噬细胞上的激活受体。融合蛋白的三种相互作用,结合阻断两种巨噬细胞抑制途径和触发巨噬细胞上的激活受体,用于功能上相互增强,所有此三种相互作用共同驱动肿瘤相关的巨噬细胞的激活及/或抗肿瘤效应子功能。在一优选的实施例中,通过融合蛋白的第一组分所阻断的“别吃我”受体是SIRPα;通过融合蛋白的第二组分所阻断的抑制受体是PD-1;通过融合蛋白所触发的激活受体是FcγRIIIa受体(参见图8,右图)。
本发明的融合蛋白的优选实施例包括一细胞因子或其一部分或其衍生物,其可并入组分A、组分B、组分C及/或组分D中。其包括彼等熟悉本领域的人广泛已知的细胞因子,其分为许多不同的类别,例如,白介素、肿瘤坏死因子、干扰素、集落刺激因子等;已被赋予各种功能,具有一系列激活特性或抑制特性,例如适应性免疫、促炎信号、抗炎信号、干细胞调节及分化、趋化性、吞噬作用、细胞毒性及抗病毒作用;并与一系列免疫及非免疫细胞靶标相关,例如B细胞、T细胞、NK细胞、巨噬细胞/单核细胞、树突细胞、骨髓基质细胞、干细胞、成纤维细胞、内皮细胞及上皮细胞。优选的实施例包括与适应性免疫相关的细胞因子(例如,IL-2、IL-4、IL-7、IL-9、IL-15、IL-21、GM-CSF);促炎信号传导[例如,IL-1家族(IL-1、IL-18、IL-33、IL-36);IL-6家族(IL-6、IL-11、IL-31、CNTF、CT-1、LIF、OPN、OSM);TNFα家族(TNFα、TNFβ、BAFF、APRIL);IL-17家族(IL-17A-F、IL-25);第I型IFN家族(IFNα、IFNβ、IFNκ、limitin);第II型IFN家族(IFNγ);第III型IFN家族(IFNλ1/IL-29)、IFNλ2/IL-28A、IFNλ3/IL-28B)];以及抗炎信号[IL-12家族(IL-12、IL-23、IL-27、IL-35);以及IL-10家族(IL-10、IL-19、IL-20、IL-22、IL-24、IL-26、IL-28、IL-29)]。参见透纳;马克D.等人:“细胞因子及趋化因子:处于细胞信号传导及炎症疾病的十字路口”,Biochimica et Biophysica Acta1843(2014)2563-2582。
vMIP-II:
在一些实施例中,本发明的融合蛋白的组分可包括vMIP-II或其变体。病毒巨噬细胞炎症蛋白-II(vMIP-II)是一趋化因子,其可与CC及CXC趋化因子受体相互作用,包括CCR5及CXCR4趋化因子受体。CCR5及CXCR4是人类免疫缺陷病毒(human immunodeficiencyvirus 1,HIV-1)进入细胞所需的主要辅助受体。CXCR4亦可被发现于癌细胞上,例如,肿瘤细胞。vMIP-II,一种通过人类疱疹病毒8(human herpesvirus 8;HHV-8)所编码的趋化因子(摩尔,PS等人,Science,274:1739-1744,1996)显示与CC及CXC趋化因子受体的多种相互作用,以及抑制HIV-1通过CCR3、CCR5及CXCR4所介导而进入。参见美国专利公开第2003/0220482号,其全部内容通过引用并入本文中。vMIP-II亦与CXCR7结合,CXCR7如同CXCR4,与肿瘤发生有关。V1(vMIP-II的氨基酸(aa)1-21)及其相关的DV1(D氨基酸异构体)对CXCR4及CXCR7展现拮抗活性,但对CCR5则无拮抗活性。
vMIP抑制天然配体CXCL12的结合。在一些实施例中,Δ表示在第12个氨基酸处的突变,所述突变导致B组分及C组分的两个肽之间的二聚化。在一些实施例中,Δmut表示在第10个氨基酸的突变,所述突变阻止肽的结合,作为一阴性对照。
PD-1:
在一些实施例中,本发明的融合蛋白的组分可包括PD-1或其变体。PD-1(程序性细胞死亡蛋白1,programmed cell death protein),亦称为CD279,是位于细胞表面的一蛋白质,其扮演调节免疫系统对细胞的反应的角色。PD-1通过抑制T细胞炎症活动来下调免疫系统,以及促进自身耐受。不希望受理论束缚,PD-1通过至少两种机制扮演一免疫检查点的角色。PD-1促进淋巴结中的抗原特异性T细胞的凋亡。PD-1亦可降低调节性T细胞的凋亡。PD-1结合配体PD-L1及PD-L2,PD-L1及PD-L2是B7家族的成员。PD-L1及PD-L2在一些肿瘤细胞的表面上表达。在肿瘤细胞上所表达的PD-L1与效应子T细胞及NK细胞上的PD-1结合并抑制其功能。因此,在肿瘤细胞上所表达的PD-L1会抑制效应子T细胞的抗肿瘤活性。
在一些实施例中,本发明的融合蛋白的PD-1变体是高亲和力PD-1。天然PD-1对其配体PD-L1及PD-L2的亲和力相对较低。PD-1胞外域的更高亲和力变体将用作其配体的更强竞争性拮抗剂。人类PD-1及PD-L1之间的PD-1接触残基发生突变,之后评估结合。本文所述的高亲和力PD-1具有10个突变氨基酸,导致对PD-L1的亲和力增强超过10,000倍。针对更多的详细信息,请参见毛特等人,PNAS,112(47):6506-6514,2015。
CD112R:
在一些实施例中,本发明的融合蛋白的组分可包括CD112R或其变体。CD112R在T细胞及NK细胞上表达,并抑制激活反应。CD112广泛地表达在抗原呈现细胞及肿瘤细胞上,是CD112R的配体。CD112R与CD226,一共抑制受体竞争结合CD112。不希望受理论束缚,破坏CD112R-CD112相互作用可增加T细胞反应。人类CD112R包含单一细胞外IgV结构域。本文所述的CD112R融合蛋白变体是由连接至人类IgG1的铰链、CH2及CH3结构域的人类CD112R的整个胞外域所组成。CD112R及其变体可与其配体CD112结合,并作为天然CD112R在NK细胞及T细胞上的一竞争性拮抗剂,从而阻止抑制性信号传导。
CD113:
在一些实施例中,本发明的融合蛋白的组分可包括CD113或其变体。CD113,亦称为脊髓灰质炎病毒受体相关3(poliovirus receptor-related 3,PVRL3)或连接蛋白-3(nectin-3),是免疫球蛋白超家族的一成员,构成粘附连接的一部分。CD113已显示与MLLT4、PARD3及PTPRM相互作用,但不限于此。此外,CD113与TIGIT、CD111、CD112、CD155及其自身结合。本文所述的CD113融合蛋白变体是由连接至人IgG1的铰链、CH2及CH3结构域的天然人类CD113的整个胞外结构域所组成。含有CD113的融合蛋白可作为NK细胞及T细胞上的天然TIGIT的竞争性拮抗剂,防止抑制性信号传导。或者,CD113融合蛋白可与CD112、CD155及/或CD111结合,并分别阻止其与抑制性受体CD112R、TIGIT及CD96的结合,从而恢复NK细胞及T细胞的细胞毒性及细胞因子的产生。
MICA:
在一些实施例中,本发明的融合蛋白的组分可包括MHC-I类多肽相关的序列A(MHCclass I polypeptide-related sequence A,MICA)或其变体。MICA是一细胞表面糖蛋白,所述细胞表面糖蛋白是由位于MHC基因座内的MICA基因所编码。MICA不与β2-微球蛋白相关,亦不如同传统的MHC-I类分子与肽结合。不希望受理论束缚,MICA可作为NKG2D受体的一应激诱导配体(stress-induced ligand)。MICA被在其细胞表面上表达NKG2D的NK细胞、γΔT细胞及CD8+αβT细胞广泛地识别。T细胞及NK细胞对表达MICA的肿瘤细胞的效应子细胞溶解反应是由于NKG2D-MICA结合而启动的。在一些实施例中,MICA变体是由连接至人类IgGl的铰链、CH2及CH3结构域的整个MICA胞外域所组成。MICA在NK细胞及细胞毒性T细胞上触发NKG2D信号是抗肿瘤活性的一重要介质。
CD155:
在一些实施例中,本发明的融合蛋白的组分可包括CD155或其变体。CD155是免疫球蛋白超家族中的第I型跨膜糖蛋白。在人类中,CD155是由脊髓灰质炎病毒受体(poliovirus receptor,PVR)基因所编码。CD155参与在上皮细胞之间的细胞间粘附连接的建立。CD155的外部结构域介导细胞与细胞外基质分子玻连蛋白(vitronectin)的结合,而其细胞内结构域与动力蛋白轻链Tctex-1/DYNLT1相互作用。此外,CD155与NK细胞抑制性受体TIGIT及CD96结合,限制NK细胞的细胞毒性,以及激活受体CD226(DNAM-1)。包含CD155胞外域的融合蛋白可与NK及T细胞上的TIGIT或CD96结合,并作为由肿瘤细胞或抗原呈现细胞(antigen presenting cell,APC)所表达的内源性CD155的一竞争性拮抗剂。含有CD155的融合蛋白亦可与共刺激受体CD226结合,并诱导NK细胞介导的肿瘤靶的裂解。
TIGIT:
在一些实施例中,本发明的融合蛋白的组分可包括TIGIT或其变体。在一些实施例中,TIGIT是小鼠TIGIT。在进一步的实施例中,TIGIT是人类TIGIT。在一些实施例中,TIGIT变体包括与人类IgGl的铰链、CH2及CH3结构域连接的完整的TIGIT胞外IgV样结构域。
TIGIT,亦称为具有Ig及ITIM结构域的T细胞免疫受体,是一种存在于某些T细胞及NK细胞上的免疫受体。TIGIT亦称为WUCAM或Vstm3。TIGIT以高亲和力与树突状细胞(dendritic cell,DC)及巨噬细胞等细胞上的CD155(PVR)结合,并以较低的亲和力与CD112(PVRL2)结合。TIGIT是一检查点抑制剂,且在来自患有癌症,例如黑色素瘤的个体的肿瘤抗原特异性(TA特异性(antigen-specific))CD8+T细胞及CD8+肿瘤浸润淋巴细胞(tumorinfiltrating lymphocyte,TIL)上过表达。不希望受理论束缚,TIGIT的阻断可导致肿瘤抗原特异性CD8+T细胞及TIL CD8+T细胞的细胞增殖、细胞因子的产生及脱颗粒的增加。含有TIGIT的融合蛋白可能与其受体CD155(PVR)及CD112(PVRL2)结合,并阻止其与NK细胞上的TIGIT相互作用。破坏TIGIT与其配体在癌细胞上的相互作用将恢复NK细胞的细胞毒活性及细胞因子的产生。
TIM-3:
在一些实施例中,本发明的融合蛋白的组分可包括TIM-3或其变体。T细胞免疫球蛋白及含粘蛋白结构域-3(T-cell immunoglobulin and mucin-domain containing-3,TIM-3),亦称为甲型肝炎病毒细胞受体2(Hepatitis A virus cellular receptor 2,HAVCR2),是一蛋白质,所述蛋白质在人类中是由HAVCR2基因所编码。HAVCR2是在产生IFNγ的CD4+Th1及CD8+Tc1细胞上所表达的一细胞表面分子。在Th17细胞、调节性T细胞及先天免疫细胞(树突细胞、NK细胞、单核细胞)中亦检测到TIM-3表达。TIM-3是一免疫检查点,并介导T细胞耗竭。不希望受理论束缚,TIM-3在数种癌症的肿瘤浸润淋巴细胞(tumorinfiltrating lymphocyte,TIL)中上调,包括但不限于肺癌、胃癌、头颈癌、神经鞘瘤、黑色素瘤及滤泡B细胞非霍奇金淋巴瘤。在一些实施例中,TIM-3变体包括与人类IgGl的铰链、CH2及CH3结构域连接的整个TIM-3胞外域,包括N端的IgV样结构域。含有TIM-3的融合蛋白可与其天然配体半乳糖凝集素-9(Galectin-9)、西康-1(Ceacam-1)及磷脂酰丝氨酸结合,并阻止其与NK细胞、T细胞及APC上上所表达的内源性TIM-3相互作用,逆转T细胞耗竭,并恢复NK细胞毒性及细胞因子的产生。
肿瘤细胞受体靶(tumor cell receptor target):
在一些实施例中,融合蛋白或其一或多种组分与一瘤细胞受体靶(tumor cellreceptor target)结合。在一些实施例中,所述融合蛋白或其一或多种组分阻止一配体与一肿瘤细胞受体靶的结合。在一些实施例中,所述肿瘤细胞受体靶包括,但不限于,趋化因子受体、缺口受体(notch receptors)、免疫检查点抑制剂,及肿瘤脉管系统配体及受体。在一些实施例中,趋化因子受体包括CXCR4、CCR10或CCR7。在一些实施例中,免疫检查点抑制剂包括PD-L1或PD-L2。在一些实施例中,肿瘤脉管系统靶包括ανβ3、ανβ5、CD13(氨肽酶N)、一NGF基序肽的靶或Tie2(血管生成素-2的受体(receptor for angiopoietin-2))。
免疫细胞受体靶点:
在一些实施例中,免疫细胞受体靶是CD40。在一些实施例中,融合蛋白或其一或多种组分包括激动剂CD40 scFv。在进一步的实施例中,免疫细胞受体靶是SIRPα。在一些实施例中,融合蛋白或其一或多种组分包括拮抗剂SIRPα肽。在一些实施例中,免疫细胞受体靶是4-1BB。在一些实施例中,融合蛋白或其一或多种组分包括激动剂4-1BB scFv或激动剂4-1BB肽。
在一些实施例中,免疫细胞受体靶是CD96。在一些实施例中,本发明的融合蛋白的组分可包括CD96或其变体。在一些实施例中,本发明的融合蛋白的组分可包括CD96的拮抗剂或激动剂。
在一些实施例中,本发明的融合蛋白的组分可包括CD226或其变体。在一些实施例中,本发明的融合蛋白的组分可包括CD226的拮抗剂或激动剂。
在一些实施例中,本发明的融合蛋白的组分可包括TIM-3或其变体。在一些实施例中,本发明的融合蛋白的组分可包括TIM-3的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是CD111。在一些实施例中,本发明的融合蛋白的组分可包括CD111或其变体。在一些实施例中,本发明的融合蛋白的组分可包括CD111的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是CD112。在一些实施例中,本发明的融合蛋白的组分可包括CD112或其变体。在一些实施例中,本发明的融合蛋白的组分可包括CD112的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是CD113。在一些实施例中,本发明的融合蛋白的组分可包括CD113或其变体。在一些实施例中,本发明的融合蛋白的组分可包括CD113的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是CD115。在一些实施例中,本发明的融合蛋白的组分可包括CD115或其变体。在一些实施例中,本发明的融合蛋白的组分可包括CD115的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是TIGIT。在一些实施例中,本发明的融合蛋白的组分可包括TIGIT或其变体。在一些实施例中,本发明的融合蛋白的组分可包括TIGIT的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是KIR2DL1/2/或3或其变体。在一些实施例中,本发明的融合蛋白的组分可包括KIR2DL1/2/或3或其变体。在一些实施例中,本发明的融合蛋白的组分可包括KIR2DL1/2/或3的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是HLA-C。在一些实施例中,本发明的融合蛋白的组分可包括HLA-C的拮抗剂或激动剂。在一些实施例中,本发明的融合蛋白的组分可包括HLA-C的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是NKG2A(CD94)或其变体。在一些实施例中,本发明的融合蛋白的组分可包括NKG2A(CD94)或其变体。在一些实施例中,本发明的融合蛋白的组分可包括NKG2A(CD94)或其变体的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是HLA-E。在一些实施例中,本发明的融合蛋白的组分可包括HLA-E的拮抗剂或激动剂。在一些实施例中,本发明的融合蛋白的组分可包括HLA-E的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是2B4或其变体。在一些实施例中,本发明的融合蛋白的组分可包括2B4或其变体。在一些实施例中,本发明的融合蛋白的组分可包括2B4或其变体的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是CD48或其变体。在一些实施例中,本发明的融合蛋白的组分可包括CD48的拮抗剂或激动剂。在一些实施例中,本发明的融合蛋白的组分可包括CD48或其变体的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是NKG2D或其变体。在一些实施例中,本发明的融合蛋白的组分可包括NKG2D或其变体。在一些实施例中,本发明的融合蛋白的组分可包括NKG2D或其变体的拮抗剂或激动剂。
在一些实施例中,免疫细胞受体靶是MICA/B或ULBP1或其变体。在一些实施例中,本发明的融合蛋白的组分可包括MICA/B或ULBP1的拮抗剂或激动剂。在一些实施例中,本发明的融合蛋白的组分可包括MICA/B或ULBP1或其变体的拮抗剂或激动剂。
在前述实施例的任一者中,免疫细胞是NK细胞、T细胞、树突细胞(dendriticcell,DC)、抗原呈现细胞(antigen-presenting cell,APC)、巨噬细胞,或肿瘤相关的巨噬细胞(M1)。
免疫细胞受体或配体:
在一些实施例中,融合蛋白或其一或多种组分结合一免疫细胞受体或配体。在一些实施例中,与免疫细胞受体或配体的结合导致NK细胞活化(细胞因子产生(IFNγ及TNF)、抗体依赖性细胞毒性(antibody-dependent cellular cytotoxicity,ADCC)及抗体依赖性细胞吞噬作用(antibody-dependent cellular phagocytosis,ADCP))。在一些实施例中,受体是一Fc受体。在一些实施例中,与Fc受体的结合导致NK细胞活化(ADCC及ADCP)。在一些实施例中,Fc受体是Fcγ、Fc∈、Fcα、Fcμ或Fcδ受体。在一些实施例中,免疫细胞受体或配体是TNF超家族的一成员或其受体、TNF-L超家族的一成员或其受体、转铁蛋白或其受体、人类血清白蛋白或其受体,或脂质运载蛋白结构家族的一成员或其受体。
连接子(lilnker)
在一些实施例中,本发明的融合蛋白的组分可任选地通过一肽连接子进行连接。连接子的残基可选自天然存在的氨基酸、非天然存在的氨基酸及修饰的氨基酸。连接子通常将第一组分的羧基末端连接至第二组分的氨基末端。连接子可改变在融合蛋白的两个结构组分之间的距离,以及改变此区域的灵活性。连接子可包含任何数量的氨基酸。因此,连接子可包括例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60个或更多个氨基酸。在一些实施例中,连接子可由3至60个氨基酸残基、3至40个氨基酸残基、3至30个氨基酸残基、3至24个氨基酸残基、3至18个氨基酸残基、或3至15个氨基酸残基。连接子可包括例如2、3、4、5个或更多个氨基酸残基的重复子序列(sub-sequence),包括2、3、4、5、6、7、8、9、10、11、12个或更多个子序列的重复。
连接子可为天然存在的序列或设计的序列。可用于本发明的融合蛋白的肽连接子包括,但不限于,甘氨酸连接子、富含甘氨酸的连接子、丝氨酸-甘氨酸连接子等。富含甘氨酸的连接子包括至少约50%的甘氨酸,且优选地至少约60%的甘氨酸。在一实施例中,连接子包括氨基酸序列Gly-Ser,或其重复。见,例如休斯顿等人,Methods in Enzymology,203:46-88(1991)。在另一实施例中,连接子包括氨基酸序列Gly-Lys或其重复。参见,例如,维特勒等人,Protein Eng,6:989(1993)。在另一实施例中,连接子包括氨基酸序列Gly-Gly-Ser或其重复。在另一实施例中,连接子包括氨基酸序列Gly-Gly-Gly-Gly-Ser(SEQ ID NO:29)或其重复。在某些特定的实施例中,连接子包括氨基酸序列Gly-Gly-Gly-Ser-Gly-Gly-Gly-Ser(SEQ ID NO:30)。在某些实施例中,连接子包含2至12个重复的Gly-Gly-Ser或Gly-Gly-Gly-Ser或Gly-Gly-Gly-Gly-Ser(SEQ ID NO:29)。肽连接子的实例参见美国专利第6,541,219号。在一实施例中,连接子可包括序列GDPLVTAASVLEFGGSGGGSEGGGSEGGGSEGGGSDI(SEQ ID NO:31)。
连接子可用于分离融合蛋白的两种组分,以实现组分的正确折叠,以减少潜在的空间问题,及/或有助于最佳的受体结合。本领域技术人员熟悉肽连接子的设计及选择。例如,参见罗宾逊等人,1998,Proc.Natl.Acad.Sci.USA95:5929-5934。自动化程序亦可用于肽连接子设计(例如克拉斯托等人,2000,Protein Engineering 13:309-312)。
可选的其他元素:
除了组分A、组分B、组分C及/或组分D之外,融合蛋白任选地亦可包括额外的元件。此种额外的元件可包括,但不限于:起始甲硫氨酸、信号肽、抗原多肽、三聚化结构域、一更高阶的多聚化结构域,以及一纯化标志(purification tag),例如His-6。一示例性纯化标签是ASHHHHHHM(SEQ ID NO:46)。在一实施例中,本发明的融合蛋白包括一任选的三聚化结构域。
本发明的融合蛋白任选地包括一信号肽。如本领域技术人员所理解的,信号肽可根据用户的需要、表达系统和其他因素而变化。信号肽是本领域众所周知的,且可使用任何所需的信号肽,包括由本领域技术人员已知的公开可取得的信号肽识别软件所识别/预测的彼等。
在一些实施例中,本发明的融合蛋白包括允许组分之间的灵活性的铰链区。参见洛伯纳等人(2016)Immunol.Reviews 270:113-131。在一些实施例中,组分Y及组分Z2通过一铰链连接,所述铰链例如一IgG铰链。在一些实施例中,组分Z1’及组分Z2’通过一铰链连接,所述铰链例如一IgG铰链。
在一些实施例中,N-连接聚糖与组分A及/或组分B上的Asn连接。在一些实施例中,N-连接聚糖与组分A及/或组分B上的Asn297连接。不希望受理论束缚,其可能会促进FcR结合,且可能促进融合蛋白的结构完整性及热稳定性。参见阿诺德等人(2007)Annu RevImmunol 25:21-50。
在一些实施例中,组分A及/或组分B包括K至A的突变。在一些实施例中,组分A及/或组分B包括K322A突变。不希望受理论束缚,其可减少Clq结合及补体介导的裂解。参见伊杜索吉等人(2000)J.Immunol 164:4178-4184。
在一些实施例中,组分A及组分B包括旋钮入孔(knobs-into-holes)突变。在一些实施例中,组分A包括突变Y349C及T366W,且组分B包括突变D356C、T366S、L368A及Y407V(“旋钮入孔”突变)。不希望受理论束缚,其可促进异二聚化而非同二聚化。见摩劝等人(1998)Nature Biotech.16:677-681。
在一些实施例中,组分A及/或组分B包括增加与新生的Fc受体(neonatal Fcreceptor,FcRn)的结合的突变。在一些实施例中,组分A及/或组分B包括突变M428L及N434S。不希望受理论束缚,其可增加与各种细胞上的新生的Fc受体(neonatal Fcreceptor,FcRn)的结合,延长血清的半衰期。参见郭及艾维森(2011)mAbs 3:422-430。
三聚结构域:
三聚结构域是本领域众所周知的。适合作为本发明的融合蛋白中的一异源三聚化结构域的三聚化结构域的非限制性实例包括:GCN4亮氨酸拉链(zipper)(哈伯里等人,1993,“在GCN4亮氨酸拉链突变体中,在两链、三链及四链卷曲螺旋之间的转换,“Science262(5138):1401-7);来自肺表面活性蛋白的35个氨基酸序列(霍普等人,1994,“胶原蛋白的三螺旋形成的成核位点处的平行的三链α螺旋束”FEBS letters 344(2-3):191-5);来自胶原蛋白的简短重复的七肽序列(麦卡林登等人,200,“α-螺旋的卷曲螺旋寡聚化结构域在胶原蛋白超家族中几乎无处不在”,J Biol Chem.278(43):42200-7.Epub 2003八月14);以及噬菌体T4纤维蛋白“折叠子(foldon)”(参见,例如,米罗什尼科夫等人,1998,“基于噬菌体T4粘附素的工程三聚纤维蛋白”,Protein Eng.11(4):329-32)。示例性三聚化结构域亦公开于美国专利第6,911,205号及第8,147,843号以及美国专利公开的公开案第2010/0136032号。一示例性的三聚化序列是具有以下序列的T4“折叠子(foldon)”:GYIPEAPRDGQAYVRKRGEWVLLSTFL(SEQ ID NO:47)。另一示例性三聚化结构域来自血小板反应蛋白-1(thrombospondin-1),且具有序列:VTTLQDSIRKVTEENKELANELRR(SEQ ID NO:56)。
修饰:
本发明包括本文所述的融合蛋白的变体。虽然通常希望变体显示出增强的与一给定的分子结合的能力,但在一些实施例中,相较于本发明的其他融合蛋白,变体可被设计为活性略微降低,例如在此种情况下,人们会有意地欲减弱活动。此外,可生成具有改变的多聚化特性的变体或衍生物。
优选地,本发明的融合蛋白的变体或衍生物维持氨基酸序列的疏水性/亲水性。
在额外的实施例中,本发明的融合蛋白是SEQ ID NO:14、15、16、17、18、19、20、21、22、32、33、34、35、49、50、51、52、53、54、55、65、66、67、68、69、70或71。在一实施例中,如本领域所理解的彼等术语,本发明的融合蛋白的变体将具有与SEQ ID NO:14、15、16、17、18、19、20、21、22、32、33、34、35、49、50、51、52、53、54、55、65、66、67、68、69、70或71至少80%或更高的序列的同一性或同源性,更优选与SEQ ID NO:14、15、16、17、18、19、20、21、22、32、33、34、35、49、50、51、52、53、54、55、65、66、67、68、69、70或71具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或甚至99%的序列同一性。
本发明亦提供本发明的融合蛋白的化学修饰。此种修饰的非限制性实例可包括但不限于羧基末端的脂族酯或酰胺或含有羧基侧链的残基的脂族酯或酰胺、含羟基残基的O-酰基衍生物,以及氨基-末端氨基酸或含有氨基的残基,例如赖氨酸或精氨酸。
本发明的融合蛋白的其他衍生物包括掺入非天然的氨基酸残基,或磷酸化的氨基酸残基,例如磷酸酪氨酸、磷酸丝氨酸或磷酸苏氨酸残基。其他潜在的修饰包括磺化、生物素化,或添加其他的部分,特别是彼等分子形状类似于磷酸基团的部分。
衍生物亦包括通过糖基化修饰的多肽。此等可通过在各种替代的真核宿主表达系统中的合成及加工的过程中,或在进一步加工步骤的过程中修饰糖基化模式来制备。产生糖基化修饰的方法包括将融合蛋白暴露于源自通常进行此种加工的细胞的糖基化酶,例如哺乳动物糖基化酶。或者,去糖基化酶可用于去除在真核表达系统的生产过程中附着的碳水化合物。此外,亦可修饰编码序列,以便添加糖基化位点或删除或禁用糖基化位点。此外,倘若不需要糖基化,则可在原核宿主表达系统中产生蛋白质。
本发明的融合蛋白的变体及/或衍生物可通过化学合成或通过使用定点诱变来制备(吉尔曼等人,Gene 8:81(1979);罗伯茨等人,Nature 328:731(1987))或因尼斯(Ed.),1990,PCR Protocols:A Guide to Methods and Applications,Academic Press,纽约,NY)或聚合酶链反应方法(polymerase chain reaction,PCR;斋木等人,Science 239:487(1988)),如同多尔蒂等人所举例说明,Nucleic Acids Res.19:2471(1991))来修饰编码完整受体的核酸。
在额外的实施例中,本发明的融合蛋白可进一步包括一或多个额外添加的多肽结构域,以促进蛋白质纯化、增加重组蛋白的表达或增加重组蛋白的溶解度。此种纯化/表达/溶解促进结构域包括,但不限于,金属螯合肽,例如允许在固定的金属上纯化的组氨酸-色氨酸模块(波拉斯,1992,Protein Expr Purif 3-0.26328 1)、允许在固定的免疫球蛋白上纯化的蛋白质A结构域,以及在FLAGS延伸/亲及纯化系统(Immunex公司,西雅图,华盛顿)中使用的结构域。在纯化结构域与组分A及组分B的融合之间包括一可裂解的连接子序列,例如因子Xa或肠激酶(Invitrogen,圣地亚哥,CA),有助于促进纯化。
融合表达载体包括分别融合谷胱甘肽S转移酶(glutathione S transferase,GST)、麦芽糖B结合蛋白或蛋白质A的pGEX(Pharmacia,皮斯卡塔韦,NJ)、pMAL(New EnglandBiolabs,比佛利山,MA)及pRITS(Pharmacia,皮斯卡塔韦,NJ),连接至目标重组蛋白。亦可使用EBV、BKV及其他附加型表达载体(episomal expression vector)(Invitrogen)。此外,亦可使用逆转录病毒及慢病毒表达载体。此外,可调用为在生物体内高水平表达重组蛋白而设计的多种体内表达系统中的任何一者来产生本文所指定的融合蛋白。
如上所述,本发明的融合蛋白可在其N-末端含有一异源信号序列。在某些宿主细胞(例如,哺乳动物宿主细胞)中,融合蛋白的表达及/或分泌可通过使用一异源信号序列而增加。信号序列通常以疏水性氨基酸核心为特征,其通常在一或多个裂解(cleavage)事例的分泌过程中,从成熟的蛋白质上裂解。此种信号肽含有加工位点,当成熟的蛋白质通过分泌途径时,此等加工位点允许将信号序列从成熟蛋白质上裂解下来。因此,本发明涉及所描述的具有一信号序列的多肽,以及信号序列已经被蛋白水解裂解的多肽(即裂解的产物)。
为了增强稳定性及/或反应性,亦可修饰本发明的融合蛋白,以在由天然等位基因变异产生的氨基酸序列中掺入一或多种多态性。此外,可替换或添加D-氨基酸、非天然氨基酸或非氨基酸类似物,以产生在本发明的范围内的修饰融合蛋白。
本发明的氨基酸序列可通过在一合适的表达系统中表达编码相同的核苷酸序列来产生。
此外,或替代地,融合蛋白本身可使用化学方法合成,以全部或部分合成所需氨基酸序列。例如,多肽可通过固相技术合成,从树脂上裂解,并通过制备型高效液相色谱而纯化(例如,克赖顿(1983)蛋白质:结构及分子原理,WH弗里曼公司,纽约N.Y.)。合成多肽的组合物可通过氨基酸分析或测序(例如,埃德曼降解程序(edman degradation procedure))来确认。此外,本发明的融合蛋白或其任何部分的氨基酸序列可在直接合成期间改变及/或使用化学方法与来自其他的亚基或其任何部分的序列组合,以产生变体多肽。
用于检测本发明的任何融合蛋白的任何同源物、衍生物或变体的生物活性的分析法是本领域众所周知的。
活性及效用
在一实施例中,本发明的融合蛋白减少或防止肿瘤细胞迁移、浸润邻近组织,及/或转移至远处部位,实际上固定所述细胞。在另一实施例中,本发明的融合蛋白降低或防止肿瘤细胞逃避吞噬细胞,例如巨噬细胞的吞噬作用,同时亦促进肿瘤细胞的凋亡及/或免疫破坏。在其他的实施例中,本发明的融合蛋白降低或防止肿瘤细胞逃避一吞噬细胞的吞噬作用,同时促进邻近肿瘤细胞的凋亡。因此,本发明的融合蛋白通过多种机制中的任一者促进肿瘤细胞破坏。
PD-1配体或受体在广泛的肿瘤细胞上表达,例如一实体瘤细胞。因此,在一实施例中,本发明提供一种通过将一治疗有效量的本发明的融合蛋白施用于被诊断患有一增殖性疾病的受试者来治疗一增殖性疾病的方法。
根据本发明的融合蛋白可施用于患有一细胞增殖性疾病,例如癌症、及恶性及良性肿瘤的个体(例如哺乳动物,包括动物及人类)。在本发明的一具体实施例中,被治疗的个体是人类。
融合蛋白被认为对多种类型的肿瘤有效,包括但不限于:卵巢癌;宫颈癌;乳腺癌;前列腺癌;睾丸癌、肺癌、肾癌;结直肠癌;皮肤癌;脑癌;白血病,包括急性髓性白血病、慢性髓性白血病、急性淋巴性白血病及慢性淋巴性白血病。
更具体地,可通过本发明的化合物、组合物及方法治疗的癌症包括,但不限于,如下:
心脏癌,包括,例如肉瘤,例如,血管肉瘤、纤维肉瘤、横纹肌肉瘤,及脂肪肉瘤;粘液瘤;横纹肌瘤;纤维瘤;脂肪瘤及畸胎瘤;
肺癌,包括,例如,支气管癌,例如,鳞状细胞癌、未分化小细胞癌、未分化大细胞癌,及腺癌;肺泡及细支气管癌;支气管腺瘤;肉瘤;淋巴瘤;软骨瘤错构瘤;及间皮瘤;
胃肠癌,包括,例如,食道癌,例如,鳞状细胞癌、腺癌、平滑肌肉瘤和淋巴瘤;胃癌,例如,恶性肿瘤、淋巴瘤及平滑肌肉瘤;胰腺癌,例如,导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤,及vip瘤(vipoma);小肠癌,例如,腺癌、淋巴瘤、类癌瘤、卡波西肉瘤(Kaposi’s sarcoma)、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤及纤维瘤;大肠癌,例如,腺癌、管状腺瘤、绒毛状腺瘤、错构瘤及平滑肌瘤;
泌尿生殖道癌,包括,例如,肾癌,例如腺癌、威尔姆氏瘤(Wilm’s tumor)(肾母细胞瘤)、淋巴瘤及白血病;膀胱癌及尿道癌,例如,鳞状细胞癌、移行细胞癌及腺癌;前列腺癌,例如,腺癌及肉瘤;睾丸癌,例如,精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤,及脂肪瘤;
肝癌,包括,例如,肝癌,例如,肝细胞癌;胆管癌;肝母细胞瘤;血管肉瘤;肝细胞腺瘤;及血管瘤;
骨癌,包括,例如,成骨肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤(Ewing’s sarcoma)、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(osteochrondroma)(骨软骨性外生骨肉瘤)(osteocartilaginousexostoses)、外软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤及巨细胞瘤;
神经系统癌,包括,例如,颅骨癌,例如,骨瘤、血管瘤、肉芽肿、黄瘤,及变形性骨炎(osteitis deformans);脑膜癌,例如,脑膜瘤、脑膜肉瘤(meningiosarcoma),及神经胶瘤病;脑癌,例如,星形细胞瘤、成神经管细胞瘤(medulloblastoma)、神经胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性胶质母细胞瘤、寡树突神经胶质瘤(oligodendroglioma)、神经鞘瘤、视网膜母细胞瘤,及先天性肿瘤;以及脊髓癌,例如神经纤维瘤、脑膜瘤、神经胶质瘤,及肉瘤;
妇科癌,包括,例如,子宫癌,例如,子宫内膜癌;宫颈癌,例如,宫颈癌,及癌前宫颈发育不良;卵巢癌,例如,卵巢癌,包括浆液性囊腺癌(serous cystadenocarcinoma)、粘液性囊腺癌、未分类的恶性肿瘤、颗粒膜细胞瘤(granulosa thecal cell tumor)、塞-莱细胞瘤(Sertoli Leydig cell tumor)、无性细胞瘤,及恶性畸胎瘤;外阴癌,例如,鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤,及黑色素瘤;阴道癌,例如,透明细胞癌、鳞状细胞癌、葡萄形肉瘤(botryoid sarcoma),及胚胎性横纹肌肉瘤(embryonal rhabdomyosarcoma);及输卵管癌症,例如恶性肿瘤;
血液癌,包括,例如,血液的癌症,例如,急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、骨髓增殖性疾病、多发性骨髓瘤,及骨髓增生不良综合征(myelodysplastic syndrome)、霍奇金淋巴瘤(Hodgkin’s lymphoma)、非霍奇金淋巴瘤(non-Hodgkin’s lymphoma)(恶性淋巴瘤)以及瓦尔登斯特伦巨球蛋白血症(macroglobulinemia)、血管免疫母细胞性T细胞淋巴瘤(angioimmunoblastic T-cell lymphoma,AITL)、慢性淋巴细胞白血病(chroniclymphocytic leukemia,CLL)、急性非淋巴细胞白血病、慢性淋巴细胞白血病、急性粒细胞白血病、慢性粒细胞白血病、单核细胞白血病、骨髓母细胞性白血病(myeloblasticleukemia)、骨髓细胞白血病(myelocytic leukemia)、骨髓粒细胞白血病(myeloidgranulocytic leukemia)、骨髓单核球白血病(myelomonocytic leukemia);奈格利白血病(Naegeli leukemia);浆细胞白血病;浆细胞白血病;前骨髓性白血病(promyelocyticleukemia);里德细胞白血病(Rieder cell leukemia);席林白血病(Schilling'sleukemia);干细胞白血病;白血球缺乏性白血病(subleukemic leukemia);急性早幼粒细胞白血病;成人T细胞白血病;白血球缺乏性白血病(aleukemic leukemia);白细胞白血病(aleukocythemic leukemia);嗜碱性白血病;胚细胞白血病(blast cell leukemia);牛白血病(bovine leukemia);慢性骨髓性白血病(chronic myelocytic leukemia);皮肤白血病;胚细胞性白血病(embryonal leukemia);未分化细胞白血病(undifferentiated cellleukemia);嗜酸性粒细胞白血病;格罗斯白血病(Gross’leukemia);毛细胞白血病(hairy-cell leukemia);血母细胞性白血病(hemoblastic leukemia);血母细胞性白血病(hemocytoblastic leukemia);组织细胞白血病;干细胞白血病;急性单核细胞白血病;白血球减少性白血病(leukopenic leukemia);淋巴白血病(lymphatic leukemia)、淋巴母细胞性白血病(lymphoblastic leukemia)、淋巴细胞性白血病(lymphocytic leukemia)、淋巴源性白血病(lymphogenous leukemia)、淋巴样白血病(lymphoid leukemia)、淋巴肉瘤细胞白血病、肥大细胞白血病、巨核细胞白血病及微粒细胞白血病;
皮肤癌,包括,例如,恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤(Kaposi’s sarcoma)、痣发育不良痣(moles dysplastic nevi)、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩(keloids)、牛皮癣;以及
肾上腺癌,包括,例如,神经母细胞瘤。
此种癌症的更具体实例包括肾脏癌(kidney cancer)或肾癌(renal cancer)、乳腺癌、结肠癌、直肠癌、结肠直肠癌、肺癌,包括小细胞肺癌、非小细胞肺癌、肺腺癌及肺鳞癌、鳞状细胞癌(例如,上皮鳞状细胞癌)、宫颈癌、卵巢癌、前列腺癌、肝癌、膀胱癌、腹膜癌、肝细胞癌、胃癌(gastric cancer)或胃癌(stomach cancer),包括胃肠癌、胃肠道间质瘤(gastrointestinal stromal tumors,GIST),胰腺癌、头颈癌、胶质母细胞瘤、视网膜母细胞瘤、星形细胞瘤、囊状瘤、腺母细胞瘤、肝细胞瘤、血液系统恶性肿瘤,包括非霍奇金淋巴瘤(non-Hodgkins lymphoma,NHL)、多发性骨髓瘤及急性血液系统恶性肿瘤、子宫内膜或子宫癌、子宫内膜异位症、纤维肉瘤、唾液腺癌腺癌,外阴癌(vulval cancer)、甲状腺癌、食道癌、肝癌、肛门癌、阴茎癌(penile carcinoma)、鼻咽癌、喉癌、卡波西肉瘤(Kaposi’ssarcoma)、黑色素瘤、皮肤癌、神经鞘瘤、寡树突神经胶质瘤(oligodendroglioma)、神经母细胞瘤、横纹肌肉瘤、成骨肉瘤、平滑肌肉瘤、泌尿道癌、甲状腺癌、威尔姆氏瘤(Wilm’stumor),以及B细胞淋巴瘤(包括低级/滤泡性非霍奇金淋巴瘤(non-Hodgkin'slymphoma,NHL);小淋巴细胞(mall lymphocytic,SL)NHL;中级/滤泡性NHL(intermediate grade/follicular NHL);中级弥漫性NHL(intermediate grade diffuse NHL);高级免疫母细胞NHL;高级淋巴母细胞NHL(high grade immunoblastic NHL);高级小非裂解细胞NHL(highgrade small non-cleaved cell NHL);大块病NHL(bulky disease NHL);套细胞淋巴瘤(mantle cell lymphoma);AIDS相关的淋巴瘤;以及瓦尔登斯特伦巨球蛋白血症(Waldenstrom Macroglobulinemia);慢性淋巴细胞白血病(chronic lymphocyticleukemia,CLL);急性淋巴细胞白血病(acute lymphoblastic leukemia;ALL);急性髓性白血病(acute myelogenous leukemia;AML);毛细胞毛细胞白血病(hairy-cell leukemia);慢性骨髓母细胞性白血病(chronic myeloblastic leukemia);及移植后淋巴组织增生性疾病(post-transplant lymphoproliferative disorder,PTLD),以及与晶状体病(phakomatoses)、水肿(例如与脑肿瘤相关的水肿)及梅格斯综合征(Meigs’syndrome)相关的异常血管增殖。如本文中所使用,“肿瘤”是指所有的肿瘤细胞生长及增殖,无论是恶性的或良性的,以及所有癌前及癌变细胞及组织。
癌症可能是实体瘤,可为或可非为转移性的。癌症亦可以一弥漫性组织的形式发生,例如在白血病中。因此,如本文所提供的术语“肿瘤细胞”包括受上述任何一种疾病折磨的细胞。
在一优选的实施例中,所述癌症是实体瘤。在优选的实施例中,所述癌症是胰腺癌、乳腺癌、卵巢癌、膀胱癌、黑色素瘤及胶质母细胞瘤中的一者。
在另一实施例中,癌症是血液学癌症。在优选的实施例中,血液癌症是急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)及急性髓性白血病(acute myelogenousleukemia,AML)中的一者。
药物组合物及给药方案:
本发明的组合物的给药通常是肠胃外的、通过皮下、静脉内、肌肉内或腹膜内注射,或通过输注或通过任何其他可接受的全身性方法。在一优选的实施例中,给药是通过皮下注射。在另一优选的实施例中,给药是通过静脉输注,其通常可在约1至5个小时的时间过程中进行。此外,存在多种口服给药方法用于治疗性蛋白质的给药,此等方法可应用于本发明的治疗性融合蛋白质。
通常,治疗剂量从一低水平向上滴定,以优化安全性及有效性。通常,每日剂量将落在每公斤体重约0.01至20毫克蛋白质的范围内。通常,剂量范围为每公斤体重约0.1至5毫克蛋白质。可对融合蛋白进行各种修饰或衍生物,例如,添加聚乙二醇链(PEG化)(PEGylation)以影响其等药物动力学(pharmacokinetic)及/或药物效应动力学(pharmacodynamic)特性。
为了通过肠胃外给药以外的方式给药融合蛋白,其可需要用一材料包覆蛋白质,或与蛋白质共同给药的一材料,防止其失活。例如,蛋白质可在不完全的佐剂中给药,与酶抑制剂共同给药或在脂质体中给药。酶抑制剂包括胰蛋白酶抑制剂、二异丙基氟磷酸酯(diisopropylfluorophosphate,DEP)及三糖醇(trasylol)。脂质体包括水包油包水的CGF乳剂以及常规的脂质体(斯特雷然等人,1984,J.Neuroimmunol.7:27)。
尽管本发明的组合物可以简单的溶液的形式给药,但其更典型地与其他材料,例如载体,优选地药学上可接受的载体组合使用。有用的药学上可接受的载体可为适合于将本发明的组合物递送给患者的任何相容的、无毒的物质。载体中可包括无菌水、酒精、脂肪、蜡及惰性固体。药学上可接受的佐剂(缓冲剂、分散剂)亦可掺入药物组合物中。通常,可用于肠胃外给药的组合物是众所周知的。例如,雷明顿制药科学(Remington'sPharmaceutical Science),第17版。(麦克出版公司,宾夕法尼亚州伊斯顿,1990)。或者,本发明的组合物可通过可植入的药物递送系统引入一患者体内(厄克特等人,1984,Ann.Rev.Pharmacol.Toxicol.24:199)。
治疗制剂可以许多常规的剂型给药。制剂通常包括至少一活性组分,以及一或多种药学上可接受的载体。制剂可包括适合于口服、直肠、鼻腔或肠胃外(包括皮下、肌内、静脉内及皮内)给药的彼等。
制剂可方便地以单位剂型存在,且可通过药学领域中众所周知的任何方法来制备。参见,例如,吉尔曼等人(版本)(1990),治疗的药理基础,第8版,Pergamon Press;以及雷明顿制药科学(Remington's Pharmaceutical Science),同上,宾夕法尼亚州伊斯顿;安飞士等人(版本)(1993)药物剂型:肠外用药;德克尔,N.Y.,利伯曼等人(版本)(1990)药物剂型:片剂,德克尔,N.Y.;以及利伯曼等人(版本)(1990),药物剂型:分散系统,德克尔,N.Y.
在额外的实施例中,本发明考虑通过基因治疗方法施予所述融合蛋白,例如,施予编码感兴趣的一融合蛋白的一分离的核酸。本发明的融合蛋白的蛋白质建构构体(proteinbuilding block)(例如,组分A及组分B)在编码蛋白质的核酸序列及由此产生的蛋白质氨基酸序列方面皆已得到充分表征。通过重组DNA方法对此种分离的核酸进行工程改造是在本领域技术人员的能力范围内。为了在特定的细胞背景中最大化重组蛋白产量的目的,密码子优化(codon optimization)亦在本领域技术人员的能力范围内。编码融合蛋白的一分离的核酸的施予包括在表述“施用一治疗有效量的本发明的融合蛋白”中。基因治疗方法是本领域众所周知的。参见,例如,WO96/07321,其公开使用基因治疗方法来产生细胞内抗体。基因治疗方法亦已在人类患者中成功证明。参见,例如鲍姆加特纳等人,1998,Circulation97:12,1114-1123,以及最近的菲什,2007,“一种治疗自身免疫性疾病的基因治疗方法”,Immun.Res.18:15-26;以及美国专利第7,378,089号,二者皆通过引用并入本文中。另参见班布里奇等人,2008,“基因疗法对勒伯的(Leber’s)先天性黑蒙症的视功能的影响”,NEngl Med 358:2231-2239;以及马奎尔等人,2008,“勒伯的(Leber’s)先天性黑蒙症的基因转移的安全性及有效性”,NEngl J Med 358:2240-8。将编码融合蛋白的核酸(可任选地包含在一载体中)引入一患者细胞的主要方法有两种:体内(in vivo)及离体(ex vivo)。针对体内递送,核酸被直接注射至所述患者的体内,通常在需要融合蛋白的部位。针对离体治疗,移除患者的细胞,将核酸引入此等分离的细胞中,之后将修饰的细胞直接或例如封装在植入患者体内的多孔膜内给予患者(参见,例如,美国专利第4,892,538号及第5,283,187号)。存在多种技术可用于将核酸引入活细胞中。所述技术是根据核酸是否在体外转移至培养的细胞中,或是在目标宿主的细胞中转移至体内而有所不同。适用于在体外将核酸转移至哺乳动物细胞中的技术包括使用脂质体、电穿孔、显微注射、细胞融合、DEAE-葡聚糖、磷酸钙沉淀法等。常用的基因的离体递送载体是逆转录病毒载体及慢病毒载体。
优选的体内核酸转移技术包括使用病毒载体转染,例如腺病毒、单纯疱疹病毒(Herpes simplex I virus)、腺相关的病毒(adeno-associated virus)、基于脂质的系统(l例,用于脂质介导的基因转移的有用的脂质是DOTMA、DOPE及DC-Cho如)、裸露的DNA及基于转座子(transpon)的表达系统。对于目前已知的基因标记及基因治疗方案的回顾,参见安德森等人,Science256:808-813(1992)。亦参见WO 93/25673及其中引用的参考文献。
“基因疗法”包括通过一单次治疗实现持久效果的常规基因疗法,以及基因治疗剂的施予,其涉及一次性或重复施予一治疗有效的DNA或mRNA。可修饰寡核苷酸,以增强其吸收,例如,通过用不带电的基团取代其带负电的磷酸二酯基团。本发明的融合蛋白可使用基因治疗方法递送,例如在肿瘤床(tumor bed)局部地、鞘内地或全身性地(例如,通过选择性靶向特定组织类型的载体,例如,组织特异性腺相关的病毒载体(tissue-specific adeno-associated viral vector))。在一些实施例中,可使用编码本发明的任何融合蛋白的基因在离体转染来自个体的原代细胞(例如淋巴细胞或干细胞),之后将转染的细胞返回个体的身体。
“治疗(Treating)”或“治疗(treatment)”是指治疗性治疗,其中目的是预防或减缓(减轻)目标病理状况或病症。一受试者在以下情况下被成功“治疗”:在根据本发明的方法接受一治疗量的本发明的融合蛋白之后,所述受试者显示可观察到的及/或可检测的特定的疾病一或多种体征及症状的减少或不存在。例如,针对癌症,癌细胞数量减少或癌细胞不存在;减小肿瘤尺寸;抑制(即,在一定程度上减缓并优选地停止)肿瘤转移;在一定程度上抑制肿瘤生长;与特定癌症相关的一或多种症状在一定程度上缓解及/或缓解的时间延长;降低发病率及死亡率,改善生活质量问题。患者亦可感觉到疾病的体征或症状的减轻。治疗可实现一完全响应(complete response),定义为所有癌症迹象消失,或一部分响应(partial response),其中肿瘤的尺寸减小,优选地减少超过50%,更优选地减少75%。倘若患者经历疾病稳定,则患者亦被视为接受治疗。此等用于评估疾病的成功治疗及改善的参数可通过本领域适当技术的医师熟悉的常规程序容易地检测。
在治疗癌症的情况下,本发明的融合蛋白可任选地与其他化疗剂联合施用于患者。合适的化学治疗剂包括例如烷化剂,例如沙奥特帕(thiotepa)及环磷酰胺(CYTOXANTM);烷基磺酸盐,例如二甲磺酸丁酯、异普西凡(improsiilfan)、哌硫丹(piposulfan);氮丙啶,例如苯并多巴(benzodopa)、碳醌(carboquone)、美托多巴(meturedopa)、乌多巴(uredopa)等;乙烯亚胺及甲基三聚氰胺,包括六甲蜜胺(altretamine)、三亚乙基三聚氰胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺及三羟甲基三聚氰胺;氮芥,例如苯丁酸氮芥、氯萘嗪(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、甲氯乙胺(mechlorethamine)、盐酸甲氯乙胺(mechlorethamine oxidehydrochloride)、美法仑(melphalan)、诺比钦(novembichin)、苯乙酮(phenesterine)、泼尼莫司汀(prednimustine)、三环磷酰胺(trofosfamide)、尿嘧啶芥(uracil mustard);亚硝基脲(uracil mustard),例如卡莫司汀(carmustine)、氯脲佐菌素(chlorozotocin)、福替莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷尼莫司汀(ranimustine);抗生素,例如阿克拉霉素(aclacinomysins)、放线菌素(actinomycin)、红霉素(authramycin)、氮杂丝氨酸(azaserine)、博来霉素(bleomycins)、仙人掌霉素(cactinomycin)、加利车霉素(calicheamicin)、卡比辛(carabicin)、香霉素(caminomycin)、亲碳素(carzinophilin)、色霉素(chromomycins)、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、去托霉素(detorubicin)、6-重氮-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine)、多柔比星(doxorubicin)、表柔比星(epirubicin)、依柔比星(esorubicin)、伊达比星(idarubicin)、马塞洛霉素(marcellomycin)、丝裂霉素(mitomycins)、霉酚酸(mycophenolic acid)、诺加拉霉素(nogalamycin)、橄榄霉素(olivomycins)、培普霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、奎拉霉素(quelamycin)、罗柔比星(rodorubicin)、链霉黑素(streptonigrin)、链脲佐菌素(streptozocin)、结核菌素(tubercidin)、乌苯美司(ubenimex)、齐诺他汀(zinostatin)、唑霉素(zorubicin);抗代谢物,例如甲氨蝶呤(methotrexate)及5-氟尿嘧啶(5-fluorouracil5-FU);叶酸类似物,例如地蝶呤(denopterin)、甲氨蝶呤(methotrexate)、蝶呤(pteropterin)、曲美沙酯(trimetrexate);嘌呤类似物,例如氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、硫胺嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,例如阿西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮杂尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、多西氟尿苷(doxifluridine)、依西他滨(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素,例如卡甾酮(calusterone)、丙酸屈莫他酮(dromostanolone propionate)、表甾烷醇(epitiostanol)、美皮司坦(mepitiostane)、睾酮内酯(testolactone);抗肾上腺素,如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,如弗洛林酸(frolinic acid);乙酰丙酮(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸(aminolevulinic acid);安吖啶(amsacrine);贝司他韦(bestrabucil);比生群(bisantrene);依达沙酯(edatraxate);去脂胺(defofamine);地美可辛(demecolcine);二嗪酮(diaziquone);乙二胺(elformithine);醋酸椭圆(elliptinium acetate);乙醇酸(etoglucid);硝酸镓(gallium nitrate);羟基脲;蘑菇多糖(lentinan);氯硝胺(lonidamine);米托瓜松(mitoguazone);米托蒽醌(mitoxantrone);莫匹达莫(mopidamol);硝酸盐(nitracrine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基酰肼(2-ethylhydrazide);丙卡巴肼(procarbazine);PSK.RTM;雷佐生(razoxane);西佐非朗(sizofiran);螺锗(spirogermanium);萘酸(tenuazonic acid);三嗪酮(triaziquone);2,2’,2”-三氯三乙胺;氨基甲酸酯(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露糖碱(mannomustine);米糖醇(mitobronitol);核糖醇(mitolactol);匹布罗曼(pipobroman);加胞嘧啶(gacytosine);阿拉伯糖苷(arabinoside)(“Ara-C”);环磷酰胺(cyclophosphamide);噻替哌(thiotepa);紫杉烷类(taxane),例如紫杉醇(TAXOL.RTM,Bristol-Myers Squibb Oncology,普林斯顿,N.J.)及多西他赛(docetaxel)(TAXOTERE.RTM,Rhone-Poulenc Rorer,安东尼,法国);苯丁酸氮芥(chlorambucil);吉西他滨(gemcitabine);6-硫鸟嘌呤(6-thioguanine);巯嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂类似物,例如顺铂(cisplatin)及卡铂(cisplatin);长春碱(vinblastine);铂;依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);丝裂霉素C(mitomycin C);米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞滨(vinorelbine);温诺平(vinorelbine);温诺平(navelbine);诺凡酮(novantrone);替尼泊苷(teniposide);道诺霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂(topoisomerase inhibitor)RFS 2000;二氟甲基鸟氨酸(difluoromethylomithine,DMFO);视黄酸(retinoic acid);埃斯霉素(esperamicins);卡培他滨(capecitabine);及任何上述物质的药学上可接受的盐、酸或衍生物。
其他化疗剂亦包括用于调节或抑制对肿瘤的激素作用的抗激素剂,例如抗雌激素,包括例如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、芳香化酶抑制4(5)-咪唑(aromatase inhibiting 4(5)-imidazoles)、4-羟基他莫昔芬(4-hydroxytamoxifen)、三昔芬(trioxifene)、酮昔芬(keoxifene)、LY117018、奥那司酮(onapristone),及托瑞米芬(toremifene)(法瑞斯顿)(Fareston);抗雄激素,例如氟他胺(flutamide)、尼鲁他胺(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide),及戈舍瑞林(goserelin)等;以及任何上述物质的药学上可接受的盐、酸或衍生物。
可与本发明的融合蛋白组合使用的其他肿瘤细胞毒性剂本身是融合蛋白。肿瘤细胞毒性融合蛋白的例子是CTLA-4-FasL及Fn14-TRAIL,其作为顺式环回蛋白(cis loop-back protein),可通过在肿瘤细胞表面产生自凋亡信号环来发挥作用。参见美国专利第7,569,663号,第8,329,657号及第8,039,437号,各个皆通过引用整体并入。反过来,彼等包括TRAIL组分的顺式环回蛋白可与能够使肿瘤细胞对TRAIL敏感并克服TRAIL耐药性的化疗药物联合给药,例如蛋白酶体抑制剂及组蛋白脱乙酰酶(histone deacetylase,HDAC)抑制剂、放线菌酮(cycloheximide)、伊马替尼甲磺酸盐(imatinib mesylate)及其他蛋白质酪氨酸激酶抑制剂(protein tyrosine kinase inhibitors)、17-烯丙氨基-17-脱甲氧基格尔德霉素(17-allylamino-17-demethoxygeldanamycin)、三氧化二砷(arsenic trioxide)及凋亡蛋白质的X连锁抑制剂小分子拮抗剂(X-linked Inhibitors of ApoptosisProtein small molecule antagonists),以及任何此等的药学上可接受的盐、酸或衍生物。
关于癌症治疗方法的其他信息在美国专利7,285,522号中提供,其全部内容通过引用方式并入。
通过以下非限制性实施例说明本发明的实施。本发明不应被解释为仅限于本文所述的组合物及方法,而应被解释为亦包括其他的组合物及方法。本领域技术人员将知道其他的组合物及方法可用于执行本文中所述的程序。
除非另有说明,否则本发明的实施采用分子生物学(包括重组技术)、微生物学、细胞生物学、生物化学及免疫学的常规技术,此等皆在技术人员的能力范围内。此种技术在文献中得到充分解释,例如“分子克隆:实验室手册”,第四版(桑布鲁克,2012);“寡核苷酸合成”(给特,1984),“动物细胞培养”(弗里斯尼,2010);“酶学方法”“实验免疫学手册”(威尔,1997),“哺乳动物细胞的基因转移载体”(米勒及卡洛斯,1987);“分子生物学中的简短规约”(奥苏贝尔,2002),“聚合酶链反应:原理、应用及故障排除”,(巴巴尔,2011);“当前的免疫学规约”(科利根,2002)。此等技术适用于生产本发明的多核苷酸及多肽,因此,可在制造及实践本发明时加以考虑。特定实施例的特别有用的技术将在以下部分中讨论。
实验的实例
下面结合实验例对本发明作进一步详细说明。提供此等示例仅用于说明的目的,除非另有说明,否则不旨在进行限制。因此,本发明决不应被解释为限于以下的实例,而是应被解释为包括由于本文提供的教导而变得明显的任何及所有的变化。
无需进一步说明,相信本领域普通技术人员可利用前述说明及以下说明性实例来制备及利用本发明的化合物并实施要求保护的方法。因此,以下工作实施例具体指出本发明的优选实施例,且不应被解释为以任何方式限制本公开的其余部分。
实例1-融合蛋白结合
融合蛋白构建体及表达
此等融合蛋白的表达质粒构建体是使用从头合成(de novo)的基因片段(赛默飞世尔科技)(ThermoFisher Scientific)产生的,用于各个所需的配体/受体组分,连接至A或B链的铰链、CH2及CH3结构域的合成基因片段(即,Z2、Z3、Z2’或Z3’域)。通过聚合酶链反应(polymerase chain reaction,PCR)将各组分拼接在一起,使用末端含有限制性位点的引物克隆至表达质粒pCEP4中,pCEP4是一EBV附加型表达载体(最初在泰科钦斯基(Tykocinski)实验室开发),可在染色体外以在高拷贝数进行复制。在基因合成时,DNA片段经过密码子优化以在中国仓鼠卵巢悬浮(Chinese hamster ovary suspension)(CHO-S)细胞中表达。使用TransIT-Pro试剂(MIRUS),将A链构建体及B链构建体瞬时共转染至ExpiCHO-S摇瓶培养物中,在37℃下培养24小时,之后在32℃下培养8至10天,从而产生融合蛋白总天数。通过与蛋白A琼脂糖树脂在6℃下混合过夜,从条件培养上清液中纯化蛋白质,之后收集并用非变性中性pH洗脱缓冲液(PIERCE)洗脱。通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳(sodium dodecyl sulfate polyacrylamide gel electrophoresis,SDS-PAGE)验证各个融合蛋白的尺寸及完整性。
融合蛋白结合研究
通过PCR生成表达人类CD155、具有免疫球蛋白及ITIM结构域的T细胞免疫受体(Tcell immunoreceptor with immunoglobulin and ITIM domains,TIGIT)、CD112及CD16(FcγRIIIa)的全长cDNA的配体构建体,并将其克隆至表达质粒pcDNA3.1+(赛默飞世尔科技)(ThermoFisher Scientific)中。使用Lipofectamine 3000(赛默飞世尔)(ThermoFisher)及通过添加G418所选择的稳定转染子,将各个表达构建体转染至CHO-S细胞中。在使用合适的荧光染料偶联的抗配体抗体(黑线)或合适的荧光染料偶联的同种型对照抗体(灰线及实心)进行免疫染色之后,通过流式细胞术检测配体表达。使用FCSalyzer软件分析数据。针对融合蛋白结合研究,将融合蛋白添加至未转染的CHO-S细胞作为对照(灰线及实心)或表达相应配体的CHO-S转染子(transfectant)中,并在6℃下培养1小时,之后洗涤,并使用Cy5偶联的抗人类IgG、Fcγ特异性抗体(黑线)并通过流式细胞术分析。参见图18至20。针对CD16结合研究,将含有TIGIT或CD155的融合蛋白与作为对照(灰线及实心)的未转染的CHO-S细胞或表达CD16的CHO-S转染子一起培养,并通过分别识别TIGIT或CD155的APC偶联抗体或PE偶联抗体进行免疫染色以进行检测(黑线)。参见图21。
实例2-融合蛋白结合分析及迁移分析
蛋白质凝胶分析
在12%SDS-PAGE凝胶上分离并还原的(reduced,R)或非还原的(non-reduced,NR)融合蛋白,并在PageBlue蛋白染色溶液(赛默飞世尔科技)(ThermoFisher Scientific)中染色12小时。参见图22。
免疫印迹分析
之后通过Pierce BCA蛋白质分析试剂盒(赛默飞世尔)(Thermo Fisher)对融合蛋白进行定量,并加载至12%SDS-PAGE凝胶上。将蛋白质电转移至Immobilon-P膜(EMDMillipore,Billerica,MA)上,并在奥德赛(Odyssey)阻断缓冲液(Licor,林肯,NE)中与(A)对抗PD1的Ab及(B)对抗IgG轻链一抗的Ab一起培养12小时。相应的二抗以1:10,000稀释度(Santa Cruz)使用。使用奥德赛(Odyssey)红外成像系统(LI-COR Biosciences,型号#9120)扫描免疫印迹。参见图23。
融合蛋白结合研究
CXCR4/7及PD1+黑色素瘤细胞株,(A)YUMMER1.7细胞或(B)B16,与指定的融合蛋白在6℃下培养1小时,之后洗涤,并使用Cy5偶联的抗人类IgG,Fcγ特异性抗体进行免疫染色,并通过流式细胞术分析(黑实线),未与融合蛋白一起培养的对照样品(实心灰线)如图24所示。
Transwell分析
Transwell插件插入24孔配套板(Corning,目录号#353504)。将细胞悬液以25,000个细胞/腔室的速度接种在顶部入侵室(invasion chamber)中。将含有100ng/mL的CXCL12的DME作为化学引诱剂,添加至各个底部孔中。样品在37℃下培养24小时,以允许细胞迁移。使用棉签去除插件顶端表面上的非侵入细胞,并使用2%结晶紫对迁移至支撑件的下表面的细胞进行染色。参见图25。
实例3-三点触控-101(TriTouch-101)诱导黑色素瘤消退
TriTouch-101 PD1hFcA*vMIPIICH-hFcB*CL(FP)在体内诱导抑制肿瘤生长,B16F10黑色素瘤皮下模型用于证明PD1hFcA*vMIPIICH-hFcB*CL(FP)诱导黑色素瘤消退。简而言之,BL16小鼠在皮下1×105B16F10个细胞后第13、14、15、16及21天,使用100μl(10ug/mL)FP(小鼠R、2L及2R)或PBS(小鼠X或L)处理5次。检测肿瘤尺寸(图26A)。图26B中描绘来自各个治疗组的1只小鼠的代表性图像(X顶部及2R底部)。此等显示TriTouch-101诱导黑色素瘤消退的体内数据,与显示此融合蛋白在迁移分析中抑制黑色素瘤细胞的先前数据一致(图25)。
实例4-NK调节TriTouch蛋白质种类
通过添加多功能融合蛋白来增强ADCC(图27)。SKOV-3卵巢细胞株以3000个细胞/孔接种在96孔板中,使其粘附并使用CellTracker Red CMTPX试剂标记。之后使用绿色荧光Caspase-3试剂标记SKOV-3细胞。将CD16.NK-92细胞株(V158变体)以5:1的E:T与各种融合蛋白25mg/ml或不含蛋白质添加至孔中,并使用Incucyte活细胞分析系统进行分析,检测荧光双阳性(红+绿)细胞的数量。所示结果描述20小时时间点(图27)。
其他的实施例
在本文中对变量的任何定义中的元素列表的叙述包括将所述变量定义为任何单一元素或所列元素的组合(或子组合)。本文中对于实施例的叙述包括作为任何单一实施例或与任何其他的实施例或其部分组合的实施例。
在此引用的各项专利、专利申请及出版物的公开内容皆通过引用整体并入本文中。虽然本发明已参考特定实施例公开,但很明显,本领域的其他技术人员可设计出本发明的其他实施例及变型而不脱离本发明的真实精神及范围。所附权利要求旨在解释为包括所有此种实施例及等效变体。
序列表
<110> 托马斯杰斐逊大学
马克·L·泰科辛斯基
马修·C·韦伯
卡梅拉·罗密欧·史密斯
<120> 多功能的融合蛋白及其用途
<130> 205961-7028WO1(00150)
<150> 62/789,212
<151> 2019-01-07
<160> 69
<170> PatentIn version 3.5
<210> 1
<211> 144
<212> PRT
<213> 智人
<400> 1
Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr Phe
1 5 10 15
Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe Thr
20 25 30
Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr Arg
35 40 45
Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu Asp
50 55 60
Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu Pro
65 70 75 80
Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn Asp
85 90 95
Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln
100 105 110
Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg Ala
115 120 125
Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly Gln
130 135 140
<210> 2
<211> 144
<212> PRT
<213> 智人
<400> 2
Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr Phe
1 5 10 15
Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe Thr
20 25 30
Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe His Val Val Trp His Arg
35 40 45
Glu Ser Pro Ser Gly Gln Thr Asp Thr Leu Ala Ala Phe Pro Glu Asp
50 55 60
Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu Pro
65 70 75 80
Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn Asp
85 90 95
Ser Gly Thr Tyr Val Cys Gly Val Ile Ser Leu Ala Pro Lys Ile Gln
100 105 110
Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg Ala
115 120 125
Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly Gln
130 135 140
<210> 3
<211> 120
<212> PRT
<213> 智人
<400> 3
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro
115 120
<210> 4
<211> 498
<212> PRT
<213> 智人
<400> 4
Val Trp Glu Lys Thr Val Asn Thr Glu Glu Asn Val Tyr Ala Thr Leu
1 5 10 15
Gly Ser Asp Val Asn Leu Thr Cys Gln Thr Gln Thr Val Gly Phe Phe
20 25 30
Val Gln Met Gln Trp Ser Lys Val Thr Asn Lys Ile Asp Leu Ile Ala
35 40 45
Val Tyr His Pro Gln Tyr Gly Phe Tyr Cys Ala Tyr Gly Arg Pro Cys
50 55 60
Glu Ser Leu Val Thr Phe Thr Glu Thr Pro Glu Asn Gly Ser Lys Trp
65 70 75 80
Thr Leu His Leu Arg Asn Met Ser Cys Ser Val Ser Gly Arg Tyr Glu
85 90 95
Cys Met Leu Val Leu Tyr Pro Glu Gly Ile Gln Thr Lys Ile Tyr Asn
100 105 110
Leu Leu Ile Gln Thr His Val Thr Ala Asp Glu Trp Asn Ser Asn His
115 120 125
Thr Ile Glu Ile Glu Ile Asn Gln Thr Leu Glu Ile Pro Cys Phe Gln
130 135 140
Asn Ser Ser Ser Lys Ile Ser Ser Glu Phe Thr Tyr Ala Trp Ser Val
145 150 155 160
Glu Asn Ser Ser Thr Asp Ser Trp Val Leu Leu Ser Lys Gly Ile Lys
165 170 175
Glu Asp Asn Gly Thr Gln Glu Thr Leu Ile Ser Gln Asn His Leu Ile
180 185 190
Ser Asn Ser Thr Leu Leu Lys Asp Arg Val Lys Leu Gly Thr Asp Tyr
195 200 205
Arg Leu His Leu Ser Pro Val Gln Ile Phe Asp Asp Gly Arg Lys Phe
210 215 220
Ser Cys His Ile Arg Val Gly Pro Asn Lys Ile Leu Arg Ser Ser Thr
225 230 235 240
Thr Val Lys Val Phe Ala Lys Pro Glu Ile Pro Val Ile Val Glu Asn
245 250 255
Asn Ser Thr Asp Val Leu Val Glu Arg Arg Phe Thr Cys Leu Leu Lys
260 265 270
Asn Val Phe Pro Lys Ala Asn Ile Thr Trp Phe Ile Asp Gly Ser Phe
275 280 285
Leu His Asp Glu Lys Glu Gly Ile Tyr Ile Thr Asn Glu Glu Arg Lys
290 295 300
Gly Lys Asp Gly Phe Leu Glu Leu Lys Ser Val Leu Thr Arg Val His
305 310 315 320
Ser Asn Lys Pro Ala Gln Ser Asp Asn Leu Thr Ile Trp Cys Met Ala
325 330 335
Leu Ser Pro Val Pro Gly Asn Lys Val Trp Asn Ile Ser Ser Glu Lys
340 345 350
Ile Thr Phe Leu Leu Gly Ser Glu Ile Ser Ser Thr Asp Pro Pro Leu
355 360 365
Ser Val Thr Glu Ser Thr Leu Asp Thr Gln Pro Ser Pro Ala Ser Ser
370 375 380
Val Ser Pro Ala Arg Tyr Pro Ala Thr Ser Ser Val Thr Leu Val Asp
385 390 395 400
Val Ser Ala Leu Arg Pro Asn Thr Thr Pro Gln Pro Ser Asn Ser Ser
405 410 415
Met Thr Thr Arg Gly Phe Asn Tyr Pro Trp Thr Ser Ser Gly Thr Asp
420 425 430
Thr Lys Lys Ser Val Ser Arg Ile Pro Ser Glu Thr Tyr Ser Ser Ser
435 440 445
Pro Ser Gly Ala Gly Ser Thr Leu His Asp Asn Val Phe Thr Ser Thr
450 455 460
Ala Arg Ala Phe Ser Glu Val Pro Thr Thr Ala Asn Gly Ser Thr Lys
465 470 475 480
Thr Asn His Val His Ile Thr Gly Ile Val Val Asn Lys Pro Lys Asp
485 490 495
Gly Met
<210> 5
<211> 151
<212> PRT
<213> 智人
<400> 5
Met Gly His Arg Thr Leu Val Leu Pro Trp Val Leu Leu Thr Leu Cys
1 5 10 15
Val Thr Ala Gly Thr Pro Glu Val Trp Val Gln Val Arg Met Glu Ala
20 25 30
Thr Glu Leu Ser Ser Phe Thr Ile Arg Cys Gly Phe Leu Gly Ser Gly
35 40 45
Ser Ile Ser Leu Val Thr Val Ser Trp Gly Gly Pro Asn Gly Ala Gly
50 55 60
Gly Thr Thr Leu Ala Val Leu His Pro Glu Arg Gly Ile Arg Gln Trp
65 70 75 80
Ala Pro Ala Arg Gln Ala Arg Trp Glu Thr Gln Ser Ser Ile Ser Leu
85 90 95
Ile Leu Glu Gly Ser Gly Ala Ser Ser Pro Cys Ala Asn Thr Thr Phe
100 105 110
Cys Cys Lys Phe Ala Ser Phe Pro Glu Gly Ser Trp Glu Ala Cys Gly
115 120 125
Ser Leu Pro Pro Ser Ser Asp Pro Gly Leu Ser Ala Pro Pro Thr Pro
130 135 140
Ala Pro Ile Leu Arg Ala Asp
145 150
<210> 6
<211> 236
<212> PRT
<213> 智人
<400> 6
Glu Glu Val Leu Trp His Thr Ser Val Pro Phe Ala Glu Asn Met Ser
1 5 10 15
Leu Glu Cys Val Tyr Pro Ser Met Gly Ile Leu Thr Gln Val Glu Trp
20 25 30
Phe Lys Ile Gly Thr Gln Gln Asp Ser Ile Ala Ile Phe Ser Pro Thr
35 40 45
His Gly Met Val Ile Arg Lys Pro Tyr Ala Glu Arg Val Tyr Phe Leu
50 55 60
Asn Ser Thr Met Ala Ser Asn Asn Met Thr Leu Phe Phe Arg Asn Ala
65 70 75 80
Ser Glu Asp Asp Val Gly Tyr Tyr Ser Cys Ser Leu Tyr Thr Tyr Pro
85 90 95
Gln Gly Thr Trp Gln Lys Val Ile Gln Val Val Gln Ser Asp Ser Phe
100 105 110
Glu Ala Ala Val Pro Ser Asn Ser His Ile Val Ser Glu Pro Gly Lys
115 120 125
Asn Val Thr Leu Thr Cys Gln Pro Gln Met Thr Trp Pro Val Gln Ala
130 135 140
Val Arg Trp Glu Lys Ile Gln Pro Arg Gln Ile Asp Leu Leu Thr Tyr
145 150 155 160
Cys Asn Leu Val His Gly Arg Asn Phe Thr Ser Lys Phe Pro Arg Gln
165 170 175
Ile Val Ser Asn Cys Ser His Gly Arg Trp Ser Val Ile Val Ile Pro
180 185 190
Asp Val Thr Val Ser Asp Ser Gly Leu Tyr Arg Cys Tyr Leu Gln Ala
195 200 205
Ser Ala Gly Glu Asn Glu Thr Phe Val Met Arg Leu Thr Val Ala Glu
210 215 220
Gly Lys Thr Asp Asn Gln Tyr Thr Leu Phe Val Ala
225 230 235
<210> 7
<211> 330
<212> PRT
<213> 智人
<400> 7
Gln Asn Leu Phe Thr Lys Asp Val Thr Val Ile Glu Gly Glu Val Ala
1 5 10 15
Thr Ile Ser Cys Gln Val Asn Lys Ser Asp Asp Ser Val Ile Gln Leu
20 25 30
Leu Asn Pro Asn Arg Gln Thr Ile Tyr Phe Arg Asp Phe Arg Pro Leu
35 40 45
Lys Asp Ser Arg Phe Gln Leu Leu Asn Phe Ser Ser Ser Glu Leu Lys
50 55 60
Val Ser Leu Thr Asn Val Ser Ile Ser Asp Glu Gly Arg Tyr Phe Cys
65 70 75 80
Gln Leu Tyr Thr Asp Pro Pro Gln Glu Ser Tyr Thr Thr Ile Thr Val
85 90 95
Leu Val Pro Pro Arg Asn Leu Met Ile Asp Ile Gln Lys Asp Thr Ala
100 105 110
Val Glu Gly Glu Glu Ile Glu Val Asn Cys Thr Ala Met Ala Ser Lys
115 120 125
Pro Ala Thr Thr Ile Arg Trp Phe Lys Gly Asn Thr Glu Leu Lys Gly
130 135 140
Lys Ser Glu Val Glu Glu Trp Ser Asp Met Tyr Thr Val Thr Ser Gln
145 150 155 160
Leu Met Leu Lys Val His Lys Glu Asp Asp Gly Val Pro Val Ile Cys
165 170 175
Gln Val Glu His Pro Ala Val Thr Gly Asn Leu Gln Thr Gln Arg Tyr
180 185 190
Leu Glu Val Gln Tyr Lys Pro Gln Val His Ile Gln Met Thr Tyr Pro
195 200 205
Leu Gln Gly Leu Thr Arg Glu Gly Asp Ala Leu Glu Leu Thr Cys Glu
210 215 220
Ala Ile Gly Lys Pro Gln Pro Val Met Val Thr Trp Val Arg Val Asp
225 230 235 240
Asp Glu Met Pro Gln His Ala Val Leu Ser Gly Pro Asn Leu Phe Ile
245 250 255
Asn Asn Leu Asn Lys Thr Asp Asn Gly Thr Tyr Arg Cys Glu Ala Ser
260 265 270
Asn Ile Val Gly Lys Ala His Ser Asp Tyr Met Leu Tyr Val Tyr Asp
275 280 285
Pro Pro Thr Thr Ile Pro Pro Pro Thr Thr Thr Thr Thr Thr Thr Thr
290 295 300
Thr Thr Thr Thr Thr Ile Leu Thr Ile Ile Thr Asp Ser Arg Ala Gly
305 310 315 320
Glu Glu Gly Ser Ile Arg Ala Val Asp His
325 330
<210> 8
<211> 342
<212> PRT
<213> 智人
<400> 8
Pro Ile Ile Val Glu Pro His Val Thr Ala Val Trp Gly Lys Asn Val
1 5 10 15
Ser Leu Lys Cys Leu Ile Glu Val Asn Glu Thr Ile Thr Gln Ile Ser
20 25 30
Trp Glu Lys Ile His Gly Lys Ser Ser Gln Thr Val Ala Val His His
35 40 45
Pro Gln Tyr Gly Phe Ser Val Gln Gly Glu Tyr Gln Gly Arg Val Leu
50 55 60
Phe Lys Asn Tyr Ser Leu Asn Asp Ala Thr Ile Thr Leu His Asn Ile
65 70 75 80
Gly Phe Ser Asp Ser Gly Lys Tyr Ile Cys Lys Ala Val Thr Phe Pro
85 90 95
Leu Gly Asn Ala Gln Ser Ser Thr Thr Val Thr Val Leu Val Glu Pro
100 105 110
Thr Val Ser Leu Ile Lys Gly Pro Asp Ser Leu Ile Asp Gly Gly Asn
115 120 125
Glu Thr Val Ala Ala Ile Cys Ile Ala Ala Thr Gly Lys Pro Val Ala
130 135 140
His Ile Asp Trp Glu Gly Asp Leu Gly Glu Met Glu Ser Thr Thr Thr
145 150 155 160
Ser Phe Pro Asn Glu Thr Ala Thr Ile Ile Ser Gln Tyr Lys Leu Phe
165 170 175
Pro Thr Arg Phe Ala Arg Gly Arg Arg Ile Thr Cys Val Val Lys His
180 185 190
Pro Ala Leu Glu Lys Asp Ile Arg Tyr Ser Phe Ile Leu Asp Ile Gln
195 200 205
Tyr Ala Pro Glu Val Ser Val Thr Gly Tyr Asp Gly Asn Trp Phe Val
210 215 220
Gly Arg Lys Gly Val Asn Leu Lys Cys Asn Ala Asp Ala Asn Pro Pro
225 230 235 240
Pro Phe Lys Ser Val Trp Ser Arg Leu Asp Gly Gln Trp Pro Asp Gly
245 250 255
Leu Leu Ala Ser Asp Asn Thr Leu His Phe Val His Pro Leu Thr Phe
260 265 270
Asn Tyr Ser Gly Val Tyr Ile Cys Lys Val Thr Asn Ser Leu Gly Gln
275 280 285
Arg Ser Asp Gln Lys Val Ile Tyr Ile Ser Asp Pro Pro Thr Thr Thr
290 295 300
Thr Leu Gln Pro Thr Ile Gln Trp His Pro Ser Thr Ala Asp Ile Glu
305 310 315 320
Asp Leu Ala Thr Glu Pro Lys Lys Leu Pro Phe Pro Leu Ser Thr Leu
325 330 335
Ala Thr Ile Lys Asp Asp
340
<210> 9
<211> 285
<212> PRT
<213> 智人
<400> 9
Ala Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp
1 5 10 15
Gly Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln
20 25 30
Pro Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly
35 40 45
Gln Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr
50 55 60
Arg Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His
65 70 75 80
Ile Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val
85 90 95
Cys Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr
100 105 110
Tyr Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp
115 120 125
Thr Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg
130 135 140
Asn Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala
145 150 155 160
Met His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly
165 170 175
Val Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser
180 185 190
Glu Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe
195 200 205
Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu
210 215 220
Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly
225 230 235 240
Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln
245 250 255
Arg Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro
260 265 270
Val Pro Ser Gly Lys Val Leu Val Leu Gln Ser His Trp
275 280 285
<210> 10
<211> 18
<212> PRT
<213> 智人
<400> 10
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser
<210> 11
<211> 22
<212> PRT
<213> 智人
<400> 11
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly
20
<210> 12
<211> 103
<212> PRT
<213> 智人
<400> 12
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
1 5 10 15
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
20 25 30
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
35 40 45
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
50 55 60
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
65 70 75 80
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
85 90 95
Lys Thr Ile Ser Lys Ala Lys
100
<210> 13
<211> 107
<212> PRT
<213> 智人
<400> 13
Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp
1 5 10 15
Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 14
<211> 396
<212> PRT
<213> 人工序列
<220>
<223> 人类PD-1-hFcA
<400> 14
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn
20 25 30
Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn
35 40 45
Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu
50 55 60
Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala
65 70 75 80
Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val
85 90 95
Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala
100 105 110
Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala
115 120 125
Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr
130 135 140
Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg
145 150 155 160
Pro Ala Gly Gln Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
165 170 175
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
180 185 190
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
195 200 205
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
210 215 220
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
225 230 235 240
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
245 250 255
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val
260 265 270
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
275 280 285
Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg
290 295 300
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly
305 310 315 320
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
325 330 335
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
340 345 350
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
355 360 365
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His
370 375 380
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
385 390 395
<210> 15
<211> 396
<212> PRT
<213> 人工序列
<220>
<223> 高亲和力人类PD-1-hFcA
<400> 15
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn
20 25 30
Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn
35 40 45
Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe His Val
50 55 60
Val Trp His Arg Glu Ser Pro Ser Gly Gln Thr Asp Thr Leu Ala Ala
65 70 75 80
Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val
85 90 95
Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala
100 105 110
Arg Arg Asn Asp Ser Gly Thr Tyr Val Cys Gly Val Ile Ser Leu Ala
115 120 125
Pro Lys Ile Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr
130 135 140
Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg
145 150 155 160
Pro Ala Gly Gln Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
165 170 175
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
180 185 190
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
195 200 205
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
210 215 220
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
225 230 235 240
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
245 250 255
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val
260 265 270
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
275 280 285
Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg
290 295 300
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly
305 310 315 320
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
325 330 335
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
340 345 350
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
355 360 365
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His
370 375 380
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
385 390 395
<210> 16
<211> 403
<212> PRT
<213> 人工序列
<220>
<223> 人类CD112R-hFcA
<400> 16
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Met Gly His Arg Thr Leu Val Leu Pro Trp Val Leu
20 25 30
Leu Thr Leu Cys Val Thr Ala Gly Thr Pro Glu Val Trp Val Gln Val
35 40 45
Arg Met Glu Ala Thr Glu Leu Ser Ser Phe Thr Ile Arg Cys Gly Phe
50 55 60
Leu Gly Ser Gly Ser Ile Ser Leu Val Thr Val Ser Trp Gly Gly Pro
65 70 75 80
Asn Gly Ala Gly Gly Thr Thr Leu Ala Val Leu His Pro Glu Arg Gly
85 90 95
Ile Arg Gln Trp Ala Pro Ala Arg Gln Ala Arg Trp Glu Thr Gln Ser
100 105 110
Ser Ile Ser Leu Ile Leu Glu Gly Ser Gly Ala Ser Ser Pro Cys Ala
115 120 125
Asn Thr Thr Phe Cys Cys Lys Phe Ala Ser Phe Pro Glu Gly Ser Trp
130 135 140
Glu Ala Cys Gly Ser Leu Pro Pro Ser Ser Asp Pro Gly Leu Ser Ala
145 150 155 160
Pro Pro Thr Pro Ala Pro Ile Leu Arg Ala Asp Glu Pro Lys Ser Ser
165 170 175
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
180 185 190
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
195 200 205
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
210 215 220
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
225 230 235 240
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
245 250 255
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
260 265 270
Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
275 280 285
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
290 295 300
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
305 310 315 320
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
325 330 335
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
340 345 350
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
355 360 365
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu
370 375 380
His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
385 390 395 400
Pro Gly Lys
<210> 17
<211> 370
<212> PRT
<213> 人工序列
<220>
<223> 人类TIGIT-hFcA
<400> 17
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala
20 25 30
Glu Lys Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr
35 40 45
Ala Gln Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala
50 55 60
Ile Cys Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp
65 70 75 80
Arg Val Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr
85 90 95
Val Asn Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp
100 105 110
Gly Thr Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val
115 120 125
Ala Glu His Gly Ala Arg Phe Gln Ile Pro Glu Pro Lys Ser Ser Asp
130 135 140
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
145 150 155 160
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
165 170 175
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
180 185 190
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
195 200 205
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
210 215 220
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
225 230 235 240
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
245 250 255
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
260 265 270
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
275 280 285
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
290 295 300
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
305 310 315 320
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
325 330 335
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His
340 345 350
Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
355 360 365
Gly Lys
370
<210> 18
<211> 748
<212> PRT
<213> 人工序列
<220>
<223> 人类CD96-hFcA
<400> 18
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Val Trp Glu Lys Thr Val Asn Thr Glu Glu Asn Val Tyr Ala
20 25 30
Thr Leu Gly Ser Asp Val Asn Leu Thr Cys Gln Thr Gln Thr Val Gly
35 40 45
Phe Phe Val Gln Met Gln Trp Ser Lys Val Thr Asn Lys Ile Asp Leu
50 55 60
Ile Ala Val Tyr His Pro Gln Tyr Gly Phe Tyr Cys Ala Tyr Gly Arg
65 70 75 80
Pro Cys Glu Ser Leu Val Thr Phe Thr Glu Thr Pro Glu Asn Gly Ser
85 90 95
Lys Trp Thr Leu His Leu Arg Asn Met Ser Cys Ser Val Ser Gly Arg
100 105 110
Tyr Glu Cys Met Leu Val Leu Tyr Pro Glu Gly Ile Gln Thr Lys Ile
115 120 125
Tyr Asn Leu Leu Ile Gln Thr His Val Thr Ala Asp Glu Trp Asn Ser
130 135 140
Asn His Thr Ile Glu Ile Glu Ile Asn Gln Thr Leu Glu Ile Pro Cys
145 150 155 160
Phe Gln Asn Ser Ser Ser Lys Ile Ser Ser Glu Phe Thr Tyr Ala Trp
165 170 175
Ser Val Glu Asn Ser Ser Thr Asp Ser Trp Val Leu Leu Ser Lys Gly
180 185 190
Ile Lys Glu Asp Asn Gly Thr Gln Glu Thr Leu Ile Ser Gln Asn His
195 200 205
Leu Ile Ser Asn Ser Thr Leu Leu Lys Asp Arg Val Lys Leu Gly Thr
210 215 220
Asp Tyr Arg Leu His Leu Ser Pro Val Gln Ile Phe Asp Asp Gly Arg
225 230 235 240
Lys Phe Ser Cys His Ile Arg Val Gly Pro Asn Lys Ile Leu Arg Ser
245 250 255
Ser Thr Thr Val Lys Val Phe Ala Lys Pro Glu Ile Pro Val Ile Val
260 265 270
Glu Asn Asn Ser Thr Asp Val Leu Val Glu Arg Arg Phe Thr Cys Leu
275 280 285
Leu Lys Asn Val Phe Pro Lys Ala Asn Ile Thr Trp Phe Ile Asp Gly
290 295 300
Ser Phe Leu His Asp Glu Lys Glu Gly Ile Tyr Ile Thr Asn Glu Glu
305 310 315 320
Arg Lys Gly Lys Asp Gly Phe Leu Glu Leu Lys Ser Val Leu Thr Arg
325 330 335
Val His Ser Asn Lys Pro Ala Gln Ser Asp Asn Leu Thr Ile Trp Cys
340 345 350
Met Ala Leu Ser Pro Val Pro Gly Asn Lys Val Trp Asn Ile Ser Ser
355 360 365
Glu Lys Ile Thr Phe Leu Leu Gly Ser Glu Ile Ser Ser Thr Asp Pro
370 375 380
Pro Leu Ser Val Thr Glu Ser Thr Leu Asp Thr Gln Pro Ser Pro Ala
385 390 395 400
Ser Ser Val Ser Pro Ala Arg Tyr Pro Ala Thr Ser Ser Val Thr Leu
405 410 415
Val Asp Val Ser Ala Leu Arg Pro Asn Thr Thr Pro Gln Pro Ser Asn
420 425 430
Ser Ser Met Thr Thr Arg Gly Phe Asn Tyr Pro Trp Thr Ser Ser Gly
435 440 445
Thr Asp Thr Lys Lys Ser Val Ser Arg Ile Pro Ser Glu Thr Tyr Ser
450 455 460
Ser Ser Pro Ser Gly Ala Gly Ser Thr Leu His Asp Asn Val Phe Thr
465 470 475 480
Ser Thr Ala Arg Ala Phe Ser Glu Val Pro Thr Thr Ala Asn Gly Ser
485 490 495
Thr Lys Thr Asn His Val His Ile Thr Gly Ile Val Val Asn Lys Pro
500 505 510
Lys Asp Gly Met Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
515 520 525
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
530 535 540
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
545 550 555 560
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
565 570 575
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
580 585 590
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
595 600 605
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val
610 615 620
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
625 630 635 640
Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg
645 650 655
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly
660 665 670
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
675 680 685
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
690 695 700
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
705 710 715 720
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His
725 730 735
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
740 745
<210> 19
<211> 486
<212> PRT
<213> 人工序列
<220>
<223> 人类CD226-hFcA
<400> 19
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Glu Glu Val Leu Trp His Thr Ser Val Pro Phe Ala Glu Asn
20 25 30
Met Ser Leu Glu Cys Val Tyr Pro Ser Met Gly Ile Leu Thr Gln Val
35 40 45
Glu Trp Phe Lys Ile Gly Thr Gln Gln Asp Ser Ile Ala Ile Phe Ser
50 55 60
Pro Thr His Gly Met Val Ile Arg Lys Pro Tyr Ala Glu Arg Val Tyr
65 70 75 80
Phe Leu Asn Ser Thr Met Ala Ser Asn Asn Met Thr Leu Phe Phe Arg
85 90 95
Asn Ala Ser Glu Asp Asp Val Gly Tyr Tyr Ser Cys Ser Leu Tyr Thr
100 105 110
Tyr Pro Gln Gly Thr Trp Gln Lys Val Ile Gln Val Val Gln Ser Asp
115 120 125
Ser Phe Glu Ala Ala Val Pro Ser Asn Ser His Ile Val Ser Glu Pro
130 135 140
Gly Lys Asn Val Thr Leu Thr Cys Gln Pro Gln Met Thr Trp Pro Val
145 150 155 160
Gln Ala Val Arg Trp Glu Lys Ile Gln Pro Arg Gln Ile Asp Leu Leu
165 170 175
Thr Tyr Cys Asn Leu Val His Gly Arg Asn Phe Thr Ser Lys Phe Pro
180 185 190
Arg Gln Ile Val Ser Asn Cys Ser His Gly Arg Trp Ser Val Ile Val
195 200 205
Ile Pro Asp Val Thr Val Ser Asp Ser Gly Leu Tyr Arg Cys Tyr Leu
210 215 220
Gln Ala Ser Ala Gly Glu Asn Glu Thr Phe Val Met Arg Leu Thr Val
225 230 235 240
Ala Glu Gly Lys Thr Asp Asn Gln Tyr Thr Leu Phe Val Ala Glu Pro
245 250 255
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
260 265 270
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
275 280 285
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
290 295 300
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
305 310 315 320
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
325 330 335
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
340 345 350
Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro
355 360 365
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
370 375 380
Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
385 390 395 400
Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
405 410 415
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
420 425 430
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
435 440 445
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
450 455 460
Ser Val Leu His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu
465 470 475 480
Ser Leu Ser Pro Gly Lys
485
<210> 20
<211> 580
<212> PRT
<213> 人工序列
<220>
<223> 人类NECL2-hFcA
<400> 20
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Gln Asn Leu Phe Thr Lys Asp Val Thr Val Ile Glu Gly Glu
20 25 30
Val Ala Thr Ile Ser Cys Gln Val Asn Lys Ser Asp Asp Ser Val Ile
35 40 45
Gln Leu Leu Asn Pro Asn Arg Gln Thr Ile Tyr Phe Arg Asp Phe Arg
50 55 60
Pro Leu Lys Asp Ser Arg Phe Gln Leu Leu Asn Phe Ser Ser Ser Glu
65 70 75 80
Leu Lys Val Ser Leu Thr Asn Val Ser Ile Ser Asp Glu Gly Arg Tyr
85 90 95
Phe Cys Gln Leu Tyr Thr Asp Pro Pro Gln Glu Ser Tyr Thr Thr Ile
100 105 110
Thr Val Leu Val Pro Pro Arg Asn Leu Met Ile Asp Ile Gln Lys Asp
115 120 125
Thr Ala Val Glu Gly Glu Glu Ile Glu Val Asn Cys Thr Ala Met Ala
130 135 140
Ser Lys Pro Ala Thr Thr Ile Arg Trp Phe Lys Gly Asn Thr Glu Leu
145 150 155 160
Lys Gly Lys Ser Glu Val Glu Glu Trp Ser Asp Met Tyr Thr Val Thr
165 170 175
Ser Gln Leu Met Leu Lys Val His Lys Glu Asp Asp Gly Val Pro Val
180 185 190
Ile Cys Gln Val Glu His Pro Ala Val Thr Gly Asn Leu Gln Thr Gln
195 200 205
Arg Tyr Leu Glu Val Gln Tyr Lys Pro Gln Val His Ile Gln Met Thr
210 215 220
Tyr Pro Leu Gln Gly Leu Thr Arg Glu Gly Asp Ala Leu Glu Leu Thr
225 230 235 240
Cys Glu Ala Ile Gly Lys Pro Gln Pro Val Met Val Thr Trp Val Arg
245 250 255
Val Asp Asp Glu Met Pro Gln His Ala Val Leu Ser Gly Pro Asn Leu
260 265 270
Phe Ile Asn Asn Leu Asn Lys Thr Asp Asn Gly Thr Tyr Arg Cys Glu
275 280 285
Ala Ser Asn Ile Val Gly Lys Ala His Ser Asp Tyr Met Leu Tyr Val
290 295 300
Tyr Asp Pro Pro Thr Thr Ile Pro Pro Pro Thr Thr Thr Thr Thr Thr
305 310 315 320
Thr Thr Thr Thr Thr Thr Thr Ile Leu Thr Ile Ile Thr Asp Ser Arg
325 330 335
Ala Gly Glu Glu Gly Ser Ile Arg Ala Val Asp His Glu Pro Lys Ser
340 345 350
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
355 360 365
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
370 375 380
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
385 390 395 400
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
405 410 415
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
420 425 430
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
435 440 445
Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro
450 455 460
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
465 470 475 480
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
485 490 495
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
500 505 510
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
515 520 525
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
530 535 540
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
545 550 555 560
Leu His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu
565 570 575
Ser Pro Gly Lys
580
<210> 21
<211> 594
<212> PRT
<213> 人工序列
<220>
<223> 人类CD113-hFcA
<400> 21
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Pro Ile Ile Val Glu Pro His Val Thr Ala Val Trp
20 25 30
Gly Lys Asn Val Ser Leu Lys Cys Leu Ile Glu Val Asn Glu Thr Ile
35 40 45
Thr Gln Ile Ser Trp Glu Lys Ile His Gly Lys Ser Ser Gln Thr Val
50 55 60
Ala Val His His Pro Gln Tyr Gly Phe Ser Val Gln Gly Glu Tyr Gln
65 70 75 80
Gly Arg Val Leu Phe Lys Asn Tyr Ser Leu Asn Asp Ala Thr Ile Thr
85 90 95
Leu His Asn Ile Gly Phe Ser Asp Ser Gly Lys Tyr Ile Cys Lys Ala
100 105 110
Val Thr Phe Pro Leu Gly Asn Ala Gln Ser Ser Thr Thr Val Thr Val
115 120 125
Leu Val Glu Pro Thr Val Ser Leu Ile Lys Gly Pro Asp Ser Leu Ile
130 135 140
Asp Gly Gly Asn Glu Thr Val Ala Ala Ile Cys Ile Ala Ala Thr Gly
145 150 155 160
Lys Pro Val Ala His Ile Asp Trp Glu Gly Asp Leu Gly Glu Met Glu
165 170 175
Ser Thr Thr Thr Ser Phe Pro Asn Glu Thr Ala Thr Ile Ile Ser Gln
180 185 190
Tyr Lys Leu Phe Pro Thr Arg Phe Ala Arg Gly Arg Arg Ile Thr Cys
195 200 205
Val Val Lys His Pro Ala Leu Glu Lys Asp Ile Arg Tyr Ser Phe Ile
210 215 220
Leu Asp Ile Gln Tyr Ala Pro Glu Val Ser Val Thr Gly Tyr Asp Gly
225 230 235 240
Asn Trp Phe Val Gly Arg Lys Gly Val Asn Leu Lys Cys Asn Ala Asp
245 250 255
Ala Asn Pro Pro Pro Phe Lys Ser Val Trp Ser Arg Leu Asp Gly Gln
260 265 270
Trp Pro Asp Gly Leu Leu Ala Ser Asp Asn Thr Leu His Phe Val His
275 280 285
Pro Leu Thr Phe Asn Tyr Ser Gly Val Tyr Ile Cys Lys Val Thr Asn
290 295 300
Ser Leu Gly Gln Arg Ser Asp Gln Lys Val Ile Tyr Ile Ser Asp Pro
305 310 315 320
Pro Thr Thr Thr Thr Leu Gln Pro Thr Ile Gln Trp His Pro Ser Thr
325 330 335
Ala Asp Ile Glu Asp Leu Ala Thr Glu Pro Lys Lys Leu Pro Phe Pro
340 345 350
Leu Ser Thr Leu Ala Thr Ile Lys Asp Asp Glu Pro Lys Ser Ser Asp
355 360 365
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
370 375 380
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
385 390 395 400
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
405 410 415
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
420 425 430
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
435 440 445
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
450 455 460
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
465 470 475 480
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
485 490 495
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
500 505 510
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
515 520 525
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
530 535 540
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
545 550 555 560
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His
565 570 575
Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
580 585 590
Gly Lys
<210> 22
<211> 537
<212> PRT
<213> 人工序列
<220>
<223> 人类MICA-hFcA
<400> 22
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Ala Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val
20 25 30
Leu Ser Trp Asp Gly Ser Val Gln Ser Gly Phe Leu Thr Glu Val His
35 40 45
Leu Asp Gly Gln Pro Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala
50 55 60
Lys Pro Gln Gly Gln Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp
65 70 75 80
Asp Arg Glu Thr Arg Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met
85 90 95
Thr Leu Ala His Ile Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln
100 105 110
Glu Ile Arg Val Cys Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser
115 120 125
Gln His Phe Tyr Tyr Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu
130 135 140
Thr Lys Glu Trp Thr Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala
145 150 155 160
Met Asn Val Arg Asn Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr
165 170 175
His Tyr His Ala Met His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr
180 185 190
Leu Lys Ser Gly Val Val Leu Arg Arg Thr Val Pro Pro Met Val Asn
195 200 205
Val Thr Arg Ser Glu Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg
210 215 220
Ala Ser Gly Phe Tyr Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp
225 230 235 240
Gly Val Ser Leu Ser His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro
245 250 255
Asp Gly Asn Gly Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln
260 265 270
Gly Glu Glu Gln Arg Phe Thr Cys Tyr Met Glu His Ser Gly Asn His
275 280 285
Ser Thr His Pro Val Pro Ser Gly Lys Val Leu Val Leu Gln Ser His
290 295 300
Trp Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
305 310 315 320
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
325 330 335
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
340 345 350
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
355 360 365
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
370 375 380
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
385 390 395 400
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys
405 410 415
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
420 425 430
Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu
435 440 445
Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro
450 455 460
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
465 470 475 480
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
485 490 495
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
500 505 510
Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His Tyr Thr Gln
515 520 525
Lys Ser Leu Ser Leu Ser Pro Gly Lys
530 535
<210> 23
<211> 252
<212> PRT
<213> 人工序列
<220>
<223> 人类FcA
<400> 23
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
20 25 30
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
35 40 45
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
50 55 60
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
65 70 75 80
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
85 90 95
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
100 105 110
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val
115 120 125
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
130 135 140
Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg
145 150 155 160
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly
165 170 175
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
180 185 190
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
195 200 205
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
210 215 220
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His
225 230 235 240
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 24
<211> 323
<212> PRT
<213> 智人
<400> 24
Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln Ala Pro Thr Gln
1 5 10 15
Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro Cys Tyr Leu Gln
20 25 30
Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu Thr Trp Ala Arg
35 40 45
His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln Thr Gln Gly Pro
50 55 60
Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala Ala Arg Leu Gly
65 70 75 80
Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly Leu Arg Val Glu
85 90 95
Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe Pro Gln Gly Ser
100 105 110
Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys Pro Gln Asn Thr
115 120 125
Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro Val Pro Met Ala
130 135 140
Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln Ile Thr Trp His
145 150 155 160
Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val Pro Gly Phe Leu
165 170 175
Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu Val Pro Ser Ser
180 185 190
Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu His Glu Ser Phe
195 200 205
Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val Tyr Tyr Pro Pro
210 215 220
Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr Leu Gly Gln Asn
225 230 235 240
Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro Glu Pro Thr Gly
245 250 255
Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro Phe Ala Val Ala
260 265 270
Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys Pro Ile Asn Thr
275 280 285
Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala Arg Gln Ala Glu
290 295 300
Leu Thr Val Gln Val Lys Glu Gly Pro Pro Ser Glu His Ser Gly Met
305 310 315 320
Ser Arg Asn
<210> 25
<211> 120
<212> PRT
<213> 智人
<400> 25
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro
115 120
<210> 26
<211> 170
<212> PRT
<213> 小鼠
<400> 26
Leu Glu Asp Gly Tyr Lys Val Glu Val Gly Lys Asn Ala Tyr Leu Pro
1 5 10 15
Cys Ser Tyr Thr Leu Pro Thr Ser Gly Thr Leu Val Pro Met Cys Trp
20 25 30
Gly Lys Gly Phe Cys Pro Trp Ser Gln Cys Thr Asn Glu Leu Leu Arg
35 40 45
Thr Asp Glu Arg Asn Val Thr Tyr Gln Lys Ser Ser Arg Tyr Gln Leu
50 55 60
Lys Gly Asp Leu Asn Lys Gly Asp Val Ser Leu Ile Ile Lys Asn Val
65 70 75 80
Thr Leu Asp Asp His Gly Thr Tyr Cys Cys Arg Ile Gln Phe Pro Gly
85 90 95
Leu Met Asn Asp Lys Lys Leu Glu Leu Lys Leu Asp Ile Lys Ala Ala
100 105 110
Lys Val Thr Pro Ala Gln Thr Ala His Gly Asp Ser Thr Thr Ala Ser
115 120 125
Pro Arg Thr Leu Thr Thr Glu Arg Asn Gly Ser Glu Thr Gln Thr Leu
130 135 140
Val Thr Leu His Asn Asn Asn Gly Thr Lys Ile Ser Thr Trp Ala Asp
145 150 155 160
Glu Ile Lys Asp Ser Gly Glu Thr Ile Arg
165 170
<210> 27
<211> 342
<212> PRT
<213> 智人
<400> 27
Pro Ile Ile Val Glu Pro His Val Thr Ala Val Trp Gly Lys Asn Val
1 5 10 15
Ser Leu Lys Cys Leu Ile Glu Val Asn Glu Thr Ile Thr Gln Ile Ser
20 25 30
Trp Glu Lys Ile His Gly Lys Ser Ser Gln Thr Val Ala Val His His
35 40 45
Pro Gln Tyr Gly Phe Ser Val Gln Gly Glu Tyr Gln Gly Arg Val Leu
50 55 60
Phe Lys Asn Tyr Ser Leu Asn Asp Ala Thr Ile Thr Leu His Asn Ile
65 70 75 80
Gly Phe Ser Asp Ser Gly Lys Tyr Ile Cys Lys Ala Val Thr Phe Pro
85 90 95
Leu Gly Asn Ala Gln Ser Ser Thr Thr Val Thr Val Leu Val Glu Pro
100 105 110
Thr Val Ser Leu Ile Lys Gly Pro Asp Ser Leu Ile Asp Gly Gly Asn
115 120 125
Glu Thr Val Ala Ala Ile Cys Ile Ala Ala Thr Gly Lys Pro Val Ala
130 135 140
His Ile Asp Trp Glu Gly Asp Leu Gly Glu Met Glu Ser Thr Thr Thr
145 150 155 160
Ser Phe Pro Asn Glu Thr Ala Thr Ile Ile Ser Gln Tyr Lys Leu Phe
165 170 175
Pro Thr Arg Phe Ala Arg Gly Arg Arg Ile Thr Cys Val Val Lys His
180 185 190
Pro Ala Leu Glu Lys Asp Ile Arg Tyr Ser Phe Ile Leu Asp Ile Gln
195 200 205
Tyr Ala Pro Glu Val Ser Val Thr Gly Tyr Asp Gly Asn Trp Phe Val
210 215 220
Gly Arg Lys Gly Val Asn Leu Lys Cys Asn Ala Asp Ala Asn Pro Pro
225 230 235 240
Pro Phe Lys Ser Val Trp Ser Arg Leu Asp Gly Gln Trp Pro Asp Gly
245 250 255
Leu Leu Ala Ser Asp Asn Thr Leu His Phe Val His Pro Leu Thr Phe
260 265 270
Asn Tyr Ser Gly Val Tyr Ile Cys Lys Val Thr Asn Ser Leu Gly Gln
275 280 285
Arg Ser Asp Gln Lys Val Ile Tyr Ile Ser Asp Pro Pro Thr Thr Thr
290 295 300
Thr Leu Gln Pro Thr Ile Gln Trp His Pro Ser Thr Ala Asp Ile Glu
305 310 315 320
Asp Leu Ala Thr Glu Pro Lys Lys Leu Pro Phe Pro Leu Ser Thr Leu
325 330 335
Ala Thr Ile Lys Asp Asp
340
<210> 28
<211> 330
<212> PRT
<213> 智人
<400> 28
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 29
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 组分A Y349C及T366W
<400> 29
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn Ser Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 30
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 组分B D356C, T366S, L368A及Y407V
<400> 30
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Cys Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 31
<211> 37
<212> PRT
<213> 人工序列
<220>
<223> 连接子
<400> 31
Gly Asp Pro Leu Val Thr Ala Ala Ser Val Leu Glu Phe Gly Gly Ser
1 5 10 15
Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly
20 25 30
Gly Gly Ser Asp Ile
35
<210> 32
<211> 575
<212> PRT
<213> 人工序列
<220>
<223> 人类CD155-hFcB
<400> 32
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln
20 25 30
Ala Pro Thr Gln Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro
35 40 45
Cys Tyr Leu Gln Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu
50 55 60
Thr Trp Ala Arg His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln
65 70 75 80
Thr Gln Gly Pro Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala
85 90 95
Ala Arg Leu Gly Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly
100 105 110
Leu Arg Val Glu Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe
115 120 125
Pro Gln Gly Ser Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys
130 135 140
Pro Gln Asn Thr Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro
145 150 155 160
Val Pro Met Ala Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln
165 170 175
Ile Thr Trp His Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val
180 185 190
Pro Gly Phe Leu Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu
195 200 205
Val Pro Ser Ser Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu
210 215 220
His Glu Ser Phe Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val
225 230 235 240
Tyr Tyr Pro Pro Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr
245 250 255
Leu Gly Gln Asn Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro
260 265 270
Glu Pro Thr Gly Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro
275 280 285
Phe Ala Val Ala Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys
290 295 300
Pro Ile Asn Thr Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala
305 310 315 320
Arg Gln Ala Glu Leu Thr Val Gln Val Lys Glu Gly Pro Pro Ser Glu
325 330 335
His Ser Gly Met Ser Arg Asn Glu Pro Lys Ser Ser Asp Lys Thr His
340 345 350
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
355 360 365
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
370 375 380
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
385 390 395 400
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
405 410 415
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
420 425 430
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
435 440 445
Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
450 455 460
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
465 470 475 480
Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
485 490 495
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
500 505 510
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
515 520 525
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
530 535 540
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu
545 550 555 560
His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
565 570 575
<210> 33
<211> 372
<212> PRT
<213> 人工序列
<220>
<223> 人类TIGIT-hFcB
<400> 33
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile
20 25 30
Ser Ala Glu Lys Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser
35 40 45
Thr Thr Ala Gln Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu
50 55 60
Leu Ala Ile Cys Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe
65 70 75 80
Lys Asp Arg Val Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser
85 90 95
Leu Thr Val Asn Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr
100 105 110
Pro Asp Gly Thr Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser
115 120 125
Ser Val Ala Glu His Gly Ala Arg Phe Gln Ile Pro Glu Pro Lys Ser
130 135 140
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
145 150 155 160
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
165 170 175
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
180 185 190
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
195 200 205
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
210 215 220
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
225 230 235 240
Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro
245 250 255
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
260 265 270
Val Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val
275 280 285
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
290 295 300
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
305 310 315 320
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
325 330 335
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
340 345 350
Leu His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu
355 360 365
Ser Pro Gly Lys
370
<210> 34
<211> 422
<212> PRT
<213> 人工序列
<220>
<223> 小鼠TIM-3-hFcB
<400> 34
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Leu Glu Asp Gly Tyr Lys Val Glu Val Gly Lys Asn
20 25 30
Ala Tyr Leu Pro Cys Ser Tyr Thr Leu Pro Thr Ser Gly Thr Leu Val
35 40 45
Pro Met Cys Trp Gly Lys Gly Phe Cys Pro Trp Ser Gln Cys Thr Asn
50 55 60
Glu Leu Leu Arg Thr Asp Glu Arg Asn Val Thr Tyr Gln Lys Ser Ser
65 70 75 80
Arg Tyr Gln Leu Lys Gly Asp Leu Asn Lys Gly Asp Val Ser Leu Ile
85 90 95
Ile Lys Asn Val Thr Leu Asp Asp His Gly Thr Tyr Cys Cys Arg Ile
100 105 110
Gln Phe Pro Gly Leu Met Asn Asp Lys Lys Leu Glu Leu Lys Leu Asp
115 120 125
Ile Lys Ala Ala Lys Val Thr Pro Ala Gln Thr Ala His Gly Asp Ser
130 135 140
Thr Thr Ala Ser Pro Arg Thr Leu Thr Thr Glu Arg Asn Gly Ser Glu
145 150 155 160
Thr Gln Thr Leu Val Thr Leu His Asn Asn Asn Gly Thr Lys Ile Ser
165 170 175
Thr Trp Ala Asp Glu Ile Lys Asp Ser Gly Glu Thr Ile Arg Glu Pro
180 185 190
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
195 200 205
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
210 215 220
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
225 230 235 240
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
245 250 255
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
260 265 270
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
275 280 285
Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro
290 295 300
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
305 310 315 320
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn
325 330 335
Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile
340 345 350
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
355 360 365
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys
370 375 380
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
385 390 395 400
Ser Val Leu His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu
405 410 415
Ser Leu Ser Pro Gly Lys
420
<210> 35
<211> 594
<212> PRT
<213> 人工序列
<220>
<223> 人类CD113-hFcB
<400> 35
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Pro Ile Ile Val Glu Pro His Val Thr Ala Val Trp
20 25 30
Gly Lys Asn Val Ser Leu Lys Cys Leu Ile Glu Val Asn Glu Thr Ile
35 40 45
Thr Gln Ile Ser Trp Glu Lys Ile His Gly Lys Ser Ser Gln Thr Val
50 55 60
Ala Val His His Pro Gln Tyr Gly Phe Ser Val Gln Gly Glu Tyr Gln
65 70 75 80
Gly Arg Val Leu Phe Lys Asn Tyr Ser Leu Asn Asp Ala Thr Ile Thr
85 90 95
Leu His Asn Ile Gly Phe Ser Asp Ser Gly Lys Tyr Ile Cys Lys Ala
100 105 110
Val Thr Phe Pro Leu Gly Asn Ala Gln Ser Ser Thr Thr Val Thr Val
115 120 125
Leu Val Glu Pro Thr Val Ser Leu Ile Lys Gly Pro Asp Ser Leu Ile
130 135 140
Asp Gly Gly Asn Glu Thr Val Ala Ala Ile Cys Ile Ala Ala Thr Gly
145 150 155 160
Lys Pro Val Ala His Ile Asp Trp Glu Gly Asp Leu Gly Glu Met Glu
165 170 175
Ser Thr Thr Thr Ser Phe Pro Asn Glu Thr Ala Thr Ile Ile Ser Gln
180 185 190
Tyr Lys Leu Phe Pro Thr Arg Phe Ala Arg Gly Arg Arg Ile Thr Cys
195 200 205
Val Val Lys His Pro Ala Leu Glu Lys Asp Ile Arg Tyr Ser Phe Ile
210 215 220
Leu Asp Ile Gln Tyr Ala Pro Glu Val Ser Val Thr Gly Tyr Asp Gly
225 230 235 240
Asn Trp Phe Val Gly Arg Lys Gly Val Asn Leu Lys Cys Asn Ala Asp
245 250 255
Ala Asn Pro Pro Pro Phe Lys Ser Val Trp Ser Arg Leu Asp Gly Gln
260 265 270
Trp Pro Asp Gly Leu Leu Ala Ser Asp Asn Thr Leu His Phe Val His
275 280 285
Pro Leu Thr Phe Asn Tyr Ser Gly Val Tyr Ile Cys Lys Val Thr Asn
290 295 300
Ser Leu Gly Gln Arg Ser Asp Gln Lys Val Ile Tyr Ile Ser Asp Pro
305 310 315 320
Pro Thr Thr Thr Thr Leu Gln Pro Thr Ile Gln Trp His Pro Ser Thr
325 330 335
Ala Asp Ile Glu Asp Leu Ala Thr Glu Pro Lys Lys Leu Pro Phe Pro
340 345 350
Leu Ser Thr Leu Ala Thr Ile Lys Asp Asp Glu Pro Lys Ser Ser Asp
355 360 365
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
370 375 380
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
385 390 395 400
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
405 410 415
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
420 425 430
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
435 440 445
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
450 455 460
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
465 470 475 480
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
485 490 495
Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser Leu
500 505 510
Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
515 520 525
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
530 535 540
Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp
545 550 555 560
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His
565 570 575
Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
580 585 590
Gly Lys
<210> 36
<211> 252
<212> PRT
<213> 人工序列
<220>
<223> 人类FcB
<400> 36
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Ala Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
20 25 30
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
35 40 45
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
50 55 60
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
65 70 75 80
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
85 90 95
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
100 105 110
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val
115 120 125
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
130 135 140
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
145 150 155 160
Cys Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly
165 170 175
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
180 185 190
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
195 200 205
Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
210 215 220
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His
225 230 235 240
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 37
<211> 71
<212> PRT
<213> 人类γ疱疹病毒8
<400> 37
Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Cys Leu Gly Tyr Gln
1 5 10 15
Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro Thr Ser
20 25 30
Gln Leu Cys Ser Lys Pro Gly Val Ile Phe Leu Thr Lys Arg Gly Arg
35 40 45
Gln Val Cys Ala Asp Lys Ser Lys Asp Trp Val Lys Lys Leu Met Gln
50 55 60
Gln Leu Pro Val Thr Ala Arg
65 70
<210> 38
<211> 21
<212> PRT
<213> 人类γ疱疹病毒8
<400> 38
Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Cys Leu Gly Tyr Gln
1 5 10 15
Lys Arg Pro Leu Pro
20
<210> 39
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> V1δ
<400> 39
Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Ala Leu Gly Tyr Gln
1 5 10 15
Lys Arg Pro Leu Pro
20
<210> 40
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> V1δ mut
<400> 40
Leu Gly Ala Ser Trp His Arg Pro Asp Ala Cys Ala Leu Gly Tyr Gln
1 5 10 15
Lys Arg Pro Leu Pro
20
<210> 41
<211> 34
<212> PRT
<213> 人类γR疱疹病毒8
<400> 41
Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Cys Leu Gly Tyr Gln
1 5 10 15
Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro Thr Ser
20 25 30
Gln Leu
<210> 42
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> Vp1δ
<400> 42
Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Ala Leu Gly Tyr Gln
1 5 10 15
Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro Thr Ser
20 25 30
Gln Leu
<210> 43
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> Vp1δ mut
<400> 43
Leu Gly Ala Ser Trp His Arg Pro Asp Ala Cys Ala Leu Gly Tyr Gln
1 5 10 15
Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro Thr Ser
20 25 30
Gln Leu
<210> 44
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> IgG1 Z3结构域
<400> 44
Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp
1 5 10 15
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn Ser Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 45
<211> 100
<212> PRT
<213> 人工序列
<220>
<223> 针对组分Z1最佳部分的示例序列
<220>
<221> misc_feature
<222> (100)..(100)
<223> Xaa可为任何天然发生的氨基酸
<400> 45
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
1 5 10 15
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
20 25 30
Asp Tyr Phe Pro Glu Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
35 40 45
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
50 55 60
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
65 70 75 80
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
85 90 95
Lys Lys Val Xaa
100
<210> 46
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 示例性纯化标签
<400> 46
Ala Ser His His His His His His Met
1 5
<210> 47
<211> 27
<212> PRT
<213> 人工序列
<220>
<223> 示例性三聚化序列
<400> 47
Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys
1 5 10 15
Arg Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
20 25
<210> 48
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 针对组分Z3最佳部分的示例性序列
<400> 48
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Cys
1 5 10 15
Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 49
<211> 421
<212> PRT
<213> 人工序列
<220>
<223> vMIPII-CH-hFcB
<220>
<221> misc_feature
<222> (189)..(189)
<223> Xaa可为任何天然发生的氨基酸
<400> 49
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Cys Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro
35 40 45
Thr Ser Gln Leu Cys Ser Lys Pro Gly Val Ile Phe Leu Thr Lys Arg
50 55 60
Gly Arg Gln Val Cys Ala Asp Lys Ser Lys Asp Trp Val Lys Lys Leu
65 70 75 80
Met Gln Gln Leu Pro Val Thr Ala Arg Ser Ser Ala Ser Thr Lys Gly
85 90 95
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
100 105 110
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Val Thr
115 120 125
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
130 135 140
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
145 150 155 160
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
165 170 175
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Xaa Glu Pro Lys
180 185 190
Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
195 200 205
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
210 215 220
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
225 230 235 240
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
245 250 255
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
260 265 270
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
275 280 285
Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala
290 295 300
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
305 310 315 320
Gln Val Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln
325 330 335
Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
340 345 350
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
355 360 365
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu
370 375 380
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
385 390 395 400
Val Leu His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser
405 410 415
Leu Ser Pro Gly Lys
420
<210> 50
<211> 371
<212> PRT
<213> 人工序列
<220>
<223> V1-CH-hFcB
<220>
<221> misc_feature
<222> (139)..(139)
<223> Xaa可为任何天然发生的氨基酸
<400> 50
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Cys Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Ser Ser Ala Ser Thr Lys Gly Pro Ser
35 40 45
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
50 55 60
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Val Thr Val Ser
65 70 75 80
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
85 90 95
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
100 105 110
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
115 120 125
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Xaa Glu Pro Lys Ser Ser
130 135 140
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
145 150 155 160
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
165 170 175
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
180 185 190
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
195 200 205
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
210 215 220
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
225 230 235 240
Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
245 250 255
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
260 265 270
Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser
275 280 285
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
290 295 300
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
305 310 315 320
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
325 330 335
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu
340 345 350
His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
355 360 365
Pro Gly Lys
370
<210> 51
<211> 371
<212> PRT
<213> 人工序列
<220>
<223> V1δ-CH-hFcB
<220>
<221> misc_feature
<222> (139)..(139)
<223> Xaa可为任何天然发生的氨基酸
<400> 51
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Ala Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Ser Ser Ala Ser Thr Lys Gly Pro Ser
35 40 45
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
50 55 60
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Val Thr Val Ser
65 70 75 80
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
85 90 95
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
100 105 110
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
115 120 125
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Xaa Glu Pro Lys Ser Ser
130 135 140
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
145 150 155 160
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
165 170 175
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
180 185 190
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
195 200 205
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
210 215 220
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
225 230 235 240
Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
245 250 255
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
260 265 270
Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser
275 280 285
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
290 295 300
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
305 310 315 320
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
325 330 335
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu
340 345 350
His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
355 360 365
Pro Gly Lys
370
<210> 52
<211> 371
<212> PRT
<213> 人工序列
<220>
<223> V1δ mut-CH-hFcB
<220>
<221> misc_feature
<222> (139)..(139)
<223> Xaa可为任何天然发生的氨基酸
<400> 52
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Ala Cys Ala Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Ser Ser Ala Ser Thr Lys Gly Pro Ser
35 40 45
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
50 55 60
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Val Thr Val Ser
65 70 75 80
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
85 90 95
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
100 105 110
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
115 120 125
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Xaa Glu Pro Lys Ser Ser
130 135 140
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
145 150 155 160
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
165 170 175
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
180 185 190
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
195 200 205
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
210 215 220
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
225 230 235 240
Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
245 250 255
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
260 265 270
Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser
275 280 285
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
290 295 300
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
305 310 315 320
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
325 330 335
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu
340 345 350
His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
355 360 365
Pro Gly Lys
370
<210> 53
<211> 384
<212> PRT
<213> 人工序列
<220>
<223> Vp1-CH-hFcB
<220>
<221> misc_feature
<222> (152)..(152)
<223> Xaa可为任何天然发生的氨基酸
<400> 53
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Cys Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro
35 40 45
Thr Ser Gln Leu Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
50 55 60
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
65 70 75 80
Cys Leu Val Lys Asp Tyr Phe Pro Glu Val Thr Val Ser Trp Asn Ser
85 90 95
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
100 105 110
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
115 120 125
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
130 135 140
Thr Lys Val Asp Lys Lys Val Xaa Glu Pro Lys Ser Ser Asp Lys Thr
145 150 155 160
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
165 170 175
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
180 185 190
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
195 200 205
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
210 215 220
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
225 230 235 240
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
245 250 255
Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
260 265 270
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
275 280 285
Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys
290 295 300
Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
305 310 315 320
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
325 330 335
Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser
340 345 350
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala
355 360 365
Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
370 375 380
<210> 54
<211> 384
<212> PRT
<213> 人工序列
<220>
<223> Vp1δ-CH-hFcB
<220>
<221> misc_feature
<222> (152)..(152)
<223> Xaa可为任何天然发生的氨基酸
<400> 54
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Ala Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro
35 40 45
Thr Ser Gln Leu Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
50 55 60
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
65 70 75 80
Cys Leu Val Lys Asp Tyr Phe Pro Glu Val Thr Val Ser Trp Asn Ser
85 90 95
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
100 105 110
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
115 120 125
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
130 135 140
Thr Lys Val Asp Lys Lys Val Xaa Glu Pro Lys Ser Ser Asp Lys Thr
145 150 155 160
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
165 170 175
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
180 185 190
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
195 200 205
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
210 215 220
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
225 230 235 240
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
245 250 255
Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
260 265 270
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
275 280 285
Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys
290 295 300
Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
305 310 315 320
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
325 330 335
Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser
340 345 350
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala
355 360 365
Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
370 375 380
<210> 55
<211> 384
<212> PRT
<213> 人工序列
<220>
<223> Vp1δ mut-CH-hFcB
<220>
<221> misc_feature
<222> (152)..(152)
<223> Xaa可为任何天然发生的氨基酸
<400> 55
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Ala Cys Ala Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro
35 40 45
Thr Ser Gln Leu Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
50 55 60
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
65 70 75 80
Cys Leu Val Lys Asp Tyr Phe Pro Glu Val Thr Val Ser Trp Asn Ser
85 90 95
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
100 105 110
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
115 120 125
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
130 135 140
Thr Lys Val Asp Lys Lys Val Xaa Glu Pro Lys Ser Ser Asp Lys Thr
145 150 155 160
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
165 170 175
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
180 185 190
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
195 200 205
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
210 215 220
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
225 230 235 240
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
245 250 255
Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
260 265 270
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
275 280 285
Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys
290 295 300
Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
305 310 315 320
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
325 330 335
Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser
340 345 350
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala
355 360 365
Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
370 375 380
<210> 56
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 示例性三聚体结构域
<400> 56
Val Thr Thr Leu Gln Asp Ser Ile Arg Lys Val Thr Glu Glu Asn Lys
1 5 10 15
Glu Leu Ala Asn Glu Leu Arg Arg
20
<210> 57
<211> 197
<212> PRT
<213> 人工序列
<220>
<223> vMIPII-CL最佳部分
<400> 57
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Cys Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro
35 40 45
Thr Ser Gln Leu Cys Ser Lys Pro Gly Val Ile Phe Leu Thr Lys Arg
50 55 60
Gly Arg Gln Val Cys Ala Asp Lys Ser Lys Asp Trp Val Lys Lys Leu
65 70 75 80
Met Gln Gln Leu Pro Val Thr Ala Arg Lys Arg Thr Val Ala Ala Pro
85 90 95
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
100 105 110
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
115 120 125
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
130 135 140
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
145 150 155 160
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
165 170 175
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
180 185 190
Asn Arg Gly Glu Cys
195
<210> 58
<211> 147
<212> PRT
<213> 人工序列
<220>
<223> V1-CL最佳部分
<400> 58
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Cys Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Lys Arg Thr Val Ala Ala Pro Ser Val
35 40 45
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
50 55 60
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
65 70 75 80
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
85 90 95
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
100 105 110
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
115 120 125
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
130 135 140
Gly Glu Cys
145
<210> 59
<211> 147
<212> PRT
<213> 人工序列
<220>
<223> V1δ-CL最佳部分
<400> 59
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Ala Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Lys Arg Thr Val Ala Ala Pro Ser Val
35 40 45
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
50 55 60
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
65 70 75 80
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
85 90 95
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
100 105 110
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
115 120 125
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
130 135 140
Gly Glu Cys
145
<210> 60
<211> 147
<212> PRT
<213> 人工序列
<220>
<223> V1δ mut-CL最佳部分
<400> 60
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Ala Cys Ala Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Lys Arg Thr Val Ala Ala Pro Ser Val
35 40 45
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
50 55 60
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
65 70 75 80
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
85 90 95
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
100 105 110
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
115 120 125
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
130 135 140
Gly Glu Cys
145
<210> 61
<211> 160
<212> PRT
<213> 人工序列
<220>
<223> Vp1-CL最佳部分
<400> 61
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Cys Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro
35 40 45
Thr Ser Gln Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
50 55 60
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
65 70 75 80
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
85 90 95
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
100 105 110
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
115 120 125
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
130 135 140
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
145 150 155 160
<210> 62
<211> 160
<212> PRT
<213> 人工序列
<220>
<223> Vp1δ-CL最佳部分
<400> 62
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Lys Cys Ala Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro
35 40 45
Thr Ser Gln Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
50 55 60
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
65 70 75 80
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
85 90 95
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
100 105 110
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
115 120 125
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
130 135 140
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
145 150 155 160
<210> 63
<211> 160
<212> PRT
<213> 人工序列
<220>
<223> Vp1δ mut-CL最佳部分
<400> 63
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Leu Gly Ala Ser Trp His Arg Pro Asp Ala Cys Ala Leu Gly
20 25 30
Tyr Gln Lys Arg Pro Leu Pro Gln Val Leu Leu Ser Ser Trp Tyr Pro
35 40 45
Thr Ser Gln Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
50 55 60
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
65 70 75 80
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
85 90 95
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
100 105 110
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
115 120 125
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
130 135 140
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
145 150 155 160
<210> 64
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 针对组分CL最佳部分或组分CL的示例性序列
<400> 64
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
1 5 10 15
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
20 25 30
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
35 40 45
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
50 55 60
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
65 70 75 80
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
85 90 95
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 65
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 连接子
<400> 65
Gly Gly Gly Gly Ser
1 5
<210> 66
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 连接子
<400> 66
Gly Gly Gly Ser Gly Gly Gly Ser
1 5
<210> 67
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> IgG1 Z1结构域
<400> 67
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val
<210> 68
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> IgG1铰链区
<400> 68
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly
20
<210> 69
<211> 103
<212> PRT
<213> 人工序列
<220>
<223> IgG1 Z2结构域
<400> 69
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
1 5 10 15
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
20 25 30
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
35 40 45
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
50 55 60
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
65 70 75 80
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
85 90 95
Lys Thr Ile Ser Lys Ala Lys
100
Claims (53)
1.一种融合蛋白,其特征在于:所述融合蛋白包括组分A及/或组分B;
其中组分A包括组分Y、组分Z2及组分Z3;以及
其中组分B包括组分X’、组分Z2’及组分Z3’。
2.如权利要求1所述的融合蛋白,其特征在于:组分B进一步包括组分Z1’。
3.如权利要求1所述的融合蛋白,其特征在于:组分A进一步包括组分Z1。
4.如权利要求1至3中任一项所述的融合蛋白,其特征在于:所述融合蛋白进一步包括组分C,其中组分C包括组分X及组分CL’。
5.如权利要求1至4中任一项所述的融合蛋白,其特征在于:所述融合蛋白进一步包括组分D,其中组分D包括组分Q及组分CL。
6.如权利要求1至5中任一项所述的融合蛋白,其特征在于:组分Y包括一配体结构域、一受体结构域、一scFv结构域或一脂质运载蛋白结构域。
7.如权利要求6所述的融合蛋白,其特征在于:组分Y包括PD-1、CD112R、CD113或MHC-I多肽相关的序列A(MICA)的至少一部分。
8.如权利要求7所述的融合蛋白,其特征在于:所述融合蛋白与PD-L1或PD-L2结合。
9.如权利要求1所述的融合蛋白,其特征在于:组分X’包括一病毒衍生的肽、一配体衍生的肽、一受体衍生的肽,或一HTS选择的肽。
10.如权利要求9所述的融合蛋白,其特征在于:组分X’包括vMIP-II的至少一部分。
11.如权利要求10所述的融合蛋白,其特征在于:组分X’包括V1或V1Δ。
12.如权利要求4所述的融合蛋白,其特征在于:组分X包括一病毒衍生的肽、一配体衍生的肽、一受体衍生的肽或一HTS选择的肽。
13.如权利要求12所述的融合蛋白,其特征在于:组分X包括V1或V1Δ。
14.如权利要求9至13任一项所述的融合蛋白,其特征在于:所述融合蛋白与CXCR4结合。
15.如权利要求1所述的融合蛋白,其特征在于:组分Y及组分Z2通过一铰链连接。
16.如权利要求1所述的融合蛋白,其特征在于:组分Z1’及组分Z2’通过一铰链连接。
17.如权利要求1所述的融合蛋白,其特征在于:组分X’及组分Z1’通过一连接子连接。
18.如权利要求4所述的融合蛋白,其特征在于:组分X及组分CL通过一连接子连接。
19.如权利要求5所述的融合蛋白,其特征在于:组分Q及组分CL通过一连接子连接。
20.如权利要求1至19中任一项所述的融合蛋白,其特征在于:所述融合蛋白与一免疫细胞上的一受体或配体结合。
21.如权利要求20所述的融合蛋白,其特征在于:所述受体是一Fc受体。
22.如权利要求1至21中任一项所述的融合蛋白,其特征在于:组分X’包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。
23.如权利要求1至22中任一项所述的融合蛋白,其特征在于:组分Y包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。
24.如权利要求4所述的融合蛋白,其特征在于:组分X包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。
25.如权利要求5所述的融合蛋白,其特征在于:组分Q包括PD-1、TIGIT、CD96、CD112R、CD113、CD155、CD111、CD112、MHC-I多肽相关的序列A(MICA)、NKG2A(CD94)、MICB、ULBP1-5、TIM-3、CD226、NECL2、CRTAM、CD80、CTLA-4、KIR2DL1/2/3,或CD48的至少一部分。
26.如权利要求1所述的融合蛋白,其特征在于:组分A包括如SEQ ID NOs:14至22中任一者所示的氨基酸序列。
27.如权利要求1所述的融合蛋白,其特征在于:组分B包括如SEQ ID NOs:32至35中任一者所示的氨基酸序列。
28.如权利要求1所述的融合蛋白,其特征在于:组分A包括如SEQ ID NOs:14至22中任一者所示的氨基酸序列,以及组分B包括如SEQ ID NOs:32至35中任一者所示的氨基酸序列。
29.如权利要求1所述的融合蛋白,其特征在于:组分B包括如SEQ ID NOs:49至55中任一者所示的氨基酸序列。
30.如权利要求1所述的融合蛋白,其特征在于:组分C包括如SEQ ID NOs:57至63中任一者所示的氨基酸序列。
31.如权利要求1所述的融合蛋白,其特征在于:组分B包括如SEQ ID NOs:49至55中任一者所示的氨基酸序列,以及组分C包括如SEQ ID NOs:57至63中任一者所示的氨基酸序列。
32.一种融合蛋白,其特征在于:所述融合蛋白包括组分A及/或组分B;
其中:
组分A包括组分Y、组分Z2及组分Z3;以及
组分B包括组分X’、组分Z2’及组分Z3’;以及
组分C包括组分X,以及组分C’L,
组分Y包括PD-1的至少一部分,
组分Z2及组分Z2’包括人类Fc的CH2结构域,
组分Z3及组分Z3’包括人类Fc的CH3结构域,
组分X’及组分X包括vMIP-II的至少一部分,以及
组分CL’包括人类IgG1κ的至少一CH1结构域。
33.如权利要求32所述的融合蛋白,其特征在于:所述融合蛋白能够结合(i)PD-L1或PD-L2,(ii)CXCR4,以及(iii)一免疫细胞上的一Fc受体或配体。
34.如权利要求32所述的融合蛋白,其特征在于:组分A包括如SEQ ID NO:29所示的氨基酸序列,以及组分B包括如SEQ ID NO:30所示的氨基酸序列。
35.如权利要求32所述的融合蛋白,其特征在于:组分Y包括如SEQ ID NO:1或SEQ IDNO:2所示的氨基酸序列。
36.如权利要求32所述的融合蛋白,其特征在于:组分Z2包括如SEQ ID NO:12所示的氨基酸序列及/或组分Z3包括如SEQ ID NO:13所示的氨基酸序列。
37.如权利要求32所述的融合蛋白,其特征在于:组分A包括如SEQ ID NO:14或SEQ IDNO:15所示的氨基酸序列。
38.如权利要求32所述的融合蛋白,其特征在于:组分B包括如SEQ ID NO:49所示的氨基酸序列。
39.如权利要求32所述的融合蛋白,其特征在于:组分X’包括如SEQ ID NO:37所示的氨基酸序列。
40.如权利要求32所述的融合蛋白,其特征在于:组分Z2’包括如SEQ ID NO:12所示的氨基酸序列及/或组分Z3’包括如SEQ ID NO:48所示的氨基酸序列。
41.如权利要求32所述的融合蛋白,其特征在于:组分X包括如SEQ ID NO:37所示的氨基酸序列。
42.如权利要求32所述的融合蛋白,其特征在于:组分CL’包括如SEQ ID NO:64所示的氨基酸序列。
43.如权利要求32所述的融合蛋白,其特征在于:组分B包括如SEQ ID NO:53所示的氨基酸序列。
44.如权利要求32所述的融合蛋白,其特征在于:组分C包括如SEQ ID NO:61所示的氨基酸序列。
45.如权利要求32所述的融合蛋白,其特征在于:组分A包括如SEQ ID NOs:14所示的氨基酸序列,组分B包括如SEQ ID NOs:53所示的氨基酸序列,以及组分C包括如SEQ ID NOs:61所示的氨基酸序列。
46.一种产生一融合蛋白的方法,其特征在于:所述方法包括向所述细胞施予编码人类PD-1-hFcA的一第一核酸、编码vMIPII-CH’-hFcB的一第二核酸,以及编码vMIPII-CL’的一第三核酸。
47.如权利要求46所述的方法,其特征在于:所述第一核酸编码如SEQ ID NO:14所示的氨基酸序列,及/或所述第二核酸编码如SEQ ID NO:49所示的氨基酸序列,及/或所述第三核酸编码如SEQ ID NO:57所示的氨基酸序列。
48.一种药物组合物,其特征在于:所述药物组合物包括一药学上可接受的载体及如权利要求1至45中任一项所述的融合蛋白。
49.一种治疗一患者的一增殖性疾病的方法,其特征在于:所述方法包括向有需要此种治疗的一患者施予一治疗有效量的如权利要求1至45中任一项所述的融合蛋白。
50.如权利要求49所述的方法,其特征在于:所述增殖性疾病是癌症。
51.如权利要求50所述的方法,其特征在于:所述癌症是一实体肿瘤。
52.如权利要求50所述的方法,其特征在于:所述癌症是胰腺癌、乳腺癌、卵巢癌、膀胱癌、黑色素瘤、胶质母细胞瘤、急性淋巴细胞白血病、急性髓性白血病、多发性骨髓瘤或结肠癌。
53.一种融合蛋白,其特征在于:所述融合蛋白包括如SEQ ID NO:14、SEQ ID NO:49及SEQ ID NO:57所示的氨基酸序列。
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CN110536693B (zh) | 2017-01-05 | 2023-12-22 | 卡尔医学有限公司 | Pd1-41bbl融合蛋白及使用其的方法 |
US11299530B2 (en) | 2017-01-05 | 2022-04-12 | Kahr Medical Ltd. | SIRP alpha-CD70 fusion protein and methods of use thereof |
AU2021299573A1 (en) * | 2020-07-03 | 2023-02-23 | The Trustees Of Columbia University In The City Of New York | Polyfunctional orthogonal protein chimeras |
WO2022188129A1 (zh) * | 2021-03-12 | 2022-09-15 | 利时雨 | 广谱趋化因子受体抑制剂增强新冠肺炎病毒感染的细胞免疫的分子机制及在其药物防治中的应用 |
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