CN116368152A - 通过受体tac技术的膜结合蛋白的下调 - Google Patents
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Abstract
提供了新颖的融合蛋白，编码所述蛋白的核酸，包含所述核酸的载体，包含所述核酸或载体的组合物，包含所述核酸、载体或组合物或药物组合物的宿主细胞。还提供了降低(下调)细胞中靶膜结合蛋白(MBP)水平的方法，产生具有降低的靶膜结合蛋白水平的细胞的方法，或治疗疾病的方法，或降低或预防与向受试者施用一个或多个CAR T细胞相关的该受试者的GvHD的方法。
Description
本申请要求于2020年9月13日提交的名称为“通过受体TAC技术的膜结合蛋白的下调”的美国临时专利申请号63/077,658，于2021年2月2日提交的名称为“通过受体TAC技术的膜结合蛋白的下调”的美国临时专利申请号63/144,945，以及于2021年4月11日提交的名称为“通过受体TAC技术的膜结合蛋白的下调”的美国临时专利申请号63/173,476的权益；其内容通过引用以其整体并入本文中。
本发明是根据山东博安生物技术股份有限公司(SHANDONG BOAN BIOTECHNOLOGYCO.,LTD.)和博安波士顿有限责任公司(Boan Boston LLC)之间的联合研究协议完成的。
技术领域
本申请涉及膜结合蛋白(MBP)的下调，并且特别地，涉及通过受体TAC技术的膜结合蛋白的下调。本申请提供了新颖的融合蛋白，编码所述蛋白质的核酸，包含所述核酸的载体，包含所述核酸或载体的组合物，包含所述核酸、载体或组合物或药物组合物的宿主细胞。本申请还提供了降低(下调)细胞中靶膜结合蛋白(MBP)水平的方法，产生具有降低的靶膜结合蛋白水平的细胞的方法，或治疗疾病的方法，或降低或预防与向受试者施用一个或多个CAR T细胞相关的该受试者的GvHD的方法。
背景技术
嵌合抗原受体(CAR)T细胞疗法在治疗血液恶性肿瘤中的初步成功预示了免疫治疗策略的新领域的快速成长(Seledtsov,V.I.,Goncharov等人,Human Vaccines andImmunotherapeutics[人类疫苗和免疫治疗]11,851–869(2015))。CAR是设计者受体，通常具有源自CD3ζITAM基序和共刺激结构域(例如源自4-1BB或CD28)的模块激活结构域(Weinkove,R.,George,P.等人,Clin.Transl.Immunol.[临床与转化免疫学]8,e1049(2019))。尽管也设计了替代方法，但这些受体的靶识别通常通过在CAR的细胞外末端上的scFv结构域提供(Kuhn,N.F.等人Cancer Cell[癌症细胞]35,473-488.e6(2019))。
两种批准的CD19 CAR-T药物(Kymriah和Yescarta)以及Abecma(BCMA CAR-T)都是自体产物。它们由每个单独患者的自身T细胞制成。虽然自体CD19 CAR-T在难治性和复发性癌症患者中显示了前所未有的功效，但它们确实代表了未来的重大挑战：它们需要复杂的制造；由于患者差异，CAR-T细胞的质量通常存在显著差异，并且这导致产物质量差异甚至生产失败(失败率高达14％)(Bersenev,A.Transfusion[输液](2017).doi:10.1111/trf.14110)，(Dai,X.,Mei等人,Biotechnology Journal[生物技术杂志](2019))。然而，制造产物需要的交付周期是大约3-4周，所以由于疾病进展不能等待那么长时间的患者将不能加入临床试验；成本也太高，大多数患者群体负担不起。对于Kymriah，每个患者的成本是$475,000，而对于Yescarta为$373,000。
另一方面，同种异体(现成的)CAR-T将提供许多优势。细胞可以提前批量制备，并且可以提供数千剂；将产物冷冻、储存并且分配用于现成的使用；CAR-T细胞将由具有更好细胞质量的健康供体制备；每个批次的细胞将具有统一的质量；这将使针对患者的交付周期最小化；并且商品的成本可以显著降低(Rafiq,S.等人,Nature Reviews ClinicalOncology[自然评论：临床肿瘤学](2020))，(Depil,S.等人,Nature Reviews DrugDiscovery[自然综述：药物发现](2020))。
目前，有几种方法来制备不会引起患者移植物抗宿主病(GvHD)的同种异体产物：它们可以通过基因编辑技术(例如CRISPR(成簇的规律间隔的短回文重复序列)介导的TCR敲低)制备，或它们可以通过TCR的siRNA下调制备，或它们可以用天然不触发GvHD的细胞(例如脐带血或PBMC来源的NK细胞(Li,Y.等人,Cell Stem Cell[细胞干细胞](2018))、NK92细胞系、或γδT细胞等)制备(Marcus,A.等人,Expert Opinion on BiologicalTherapy[生物治疗专家意见](2014))，(Depil,S.等人,Nature Reviews Drug Discovery[自然综述：药物发现](2020))，(Themeli,M.,Rivière等人,Cell Stem Cell[细胞干细胞](2015))，(Rezvani,K.等人,Molecular Therapy[分子疗法](2017))。
用基因编辑技术的重大挑战是始终存在脱靶修饰的风险。脱靶修饰率可以高达50％(Zhang,X.H.等人,Molecular Therapy-Nucleic Acids[分子疗法-核酸](2015))，这可能导致不需要的突变，并且对患者构成重大风险。此外，制造过程复杂，因为它需要两个修饰步骤：第一步骤是将CAR转染至T细胞中，第二步骤是引入CRISPR机制以敲除TCR。
另一方面，NK细胞和γδT细胞与体内持久性和增殖较差相关，这将显著影响其效力。它们也很难在体外扩增(Li,Y.,Cell Stem Cell[细胞干细胞](2018))，(Rezvani,K.,等人,Molecular Therapy[分子疗法](2017))，(Shimasaki,N.等人,Nature Reviews DrugDiscovery[自然综述：药物发现](2020))。
如何在避免以上提及的缺陷的同时下调T细胞或其他细胞中的膜结合蛋白(MBP)是一个需要解决的问题。
发明内容
本申请提供了新颖的融合蛋白、编码所述蛋白质的核酸、包含所述核酸的载体、包含所述核酸或载体的组合物、包含所述核酸、载体或组合物或药物组合物的细胞(例如宿主细胞)。本申请还提供了降低(下调)细胞中靶膜结合蛋白(MBP)水平的方法，产生具有降低的靶膜结合蛋白水平的细胞的方法，或治疗疾病的方法，或降低或预防与向受试者施用一个或多个CAR T细胞相关的该受试者的GvHD的方法。
在本申请中，膜结合蛋白(MBP)的下调是通过降解标签蛋白介导的降解实现的，其中该降解标签蛋白包含泛素连接酶和/或介导降解的细胞表面受体的结构域(例如IL2Rβ亚结构域、L2Rβjm结构域)。降解标签蛋白(例如泛素连接酶或IL2Rβ)对待降解的MBP的标签特异性或靶向特异性(或识别特异性)是通过待降解的MBP的抗体(或抗原结合片段)介导的(即抗体介导的底物识别)，或由具有跨膜结构域(即，跨膜结构域介导的底物识别)的待降解的膜结合蛋白或复合物的亚基或结构域介导的。本申请的技术方案可以应用于细胞表面上的任何靶标，与细胞类型无关。
在一方面，本申请的融合蛋白包含：
介导膜结合蛋白(MBP)降解的降解标签蛋白，其中该降解标签蛋白选自泛素连接酶或其变体中的一个或多个，或介导降解的细胞表面受体的一个或多个亚基或结构域；以及
跨膜连接结构域，其包含：
1)第一跨膜连接结构域，其包含第一跨膜结构域和第一连接蛋白；
其中该第一跨膜结构域选自CD8α、CD4、CD3、CD28、4-1BB或IL2R或其变体的一个或多个亚基或结构域的跨膜结构域；该第一连接蛋白选自该待降解的MBP的抗体或抗原结合片段中的一个或多个；并且该第一跨膜结构域与该第一连接蛋白直接或间接连接；
优选地，包含上述1)的该跨膜连接结构域的融合蛋白进一步包含第一信号肽；或者
2)第二跨膜连接结构域，其包含该待降解的MBP或其变体的跨膜结构域。
在特定实施例中，优选地，MBP是膜结合受体；更优选地，哺乳动物来源膜结合受体，最优选地人膜结合受体；
优选地，泛素连接酶包含E3泛素连接酶或其变体的一个或多个亚基或结构域；
优选地，介导降解的细胞表面受体包含白细胞介素受体或其变体的一个或多个亚基或结构域；
优选地，上述1)中的待降解的MBP的抗原结合片段包含与该MBP或其变体特异性结合的scFv或纳米抗体；
优选地，上述2)中的待降解的MBP或其变体的跨膜结构域包含CD3ζ、CD3γ、CD3δ、CD3ε、CD3α、CD3β或其变体中的一个或多个的跨膜结构域；
更优选地，上述2)中的第二跨膜连接结构域包含CD3ζ、CD3γ、CD3δ、CD3ε、CD3α、CD3β或其变体中的一个或多个的细胞外结构域和跨膜结构域；
更优选地，上述2)中的第二跨膜连接结构域包含CD3ζ、CD3γ、CD3δ、CD3ε、CD3α、CD3β或其变体中的一个或多个的第二信号肽、细胞外结构域和跨膜结构域。
在另一特定实施例中，优选地，膜结合受体选自CD3、TCR、CD5、CD7、PD-L1和CD47或其变体的一个或多个亚基或结构域；
该E3泛素连接酶选自以下蛋白质或其截短形式：Hsc70相互作用蛋白(CHIP)的C末端、CHIP.dTPR、含有F盒WD40的蛋白7(FBW7)、FBW7.2-293、希佩尔-林道(VHL)、VHL.152-213、斑点型BTB-POZ蛋白(SPOP)、SPOP.167-374、SOCS2、SOCS2.143-198、泛素蛋白连接酶E3A(UBE3A)、小鼠双微体2同源物(MDM2)、后期促进复合物(APC)、UBR5、LNX、卡西塔斯B谱系淋巴瘤转化序列样蛋白1(CBLL1)、含有HECT结构域和锚蛋白重复序列的E3泛素蛋白连接酶1(HACE1)，含有HECT、C2和WW结构域的E3泛素蛋白连接酶1(HECW1)，含有HECT、C2和WW结构域的E3泛素蛋白连接酶2(HECW2)，含有HECT和RLD结构域的E3泛素蛋白连接酶1(HERC1)，HERC2、HERC3、HERC4、HERC5、HERC6、HUWE1、ITCH、神经前体细胞表达的发育下调蛋白4(NEDD4)、神经前体细胞表达的发育下调基因4样蛋白(NEDD4L)、肽基脯氨酰异构酶(亲环蛋白)样2(PPIL2)、PIAS1、PIAS2、PIAS3、PIAS4、RANBP2、RNF4、RBX1、SMURF1、SMURF2、STUB1、TOPORS、TRIP12、UBE3A、UBE3B、UBE3C、UBE3D、UBE4A、UBE4B、UBOX5、UBR5、WWP1、WWP2、Parkin、MKRN1、GRAIL.IC、RNF133.IC、RNF122.rIC或RNF152.rIC；优选地，该E3泛素连接酶包含CHIP、CHIP.dTPR、FBW7.2-293、VHL.152-213、SPOP.167-374、SOCS2.143-198、GRAIL.IC、RNF133.IC、RNF122.rIC或RNF152.rIC；并且更优选地，该CHIP、CHIP.dTPR、FBW7.2-293、VHL.152-213、SPOP.167-374、SOCS2.143-198、GRAIL.IC、RNF133.IC、RNF122.rIC或RNF152.rIC分别包含与SEQ ID NO.21-26、62、79、81或83中任一项所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
白细胞介素受体的亚基或结构域包含IL-2R的溶酶体靶向基序；优选地，该IL-2R的溶酶体靶向基序包含L2Rβjm结构域；更优选地，该L2Rβjm结构域(IL2Rβjm)包含与SEQ IDNO.58中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
上述1)中的该第一跨膜结构域选自CD3、CD8α、CD4、或其变体的跨膜结构域；优选地，CD3ζ跨膜结构域变体、CD8α跨膜结构域、或CD4跨膜结构域分别包含与SEQ ID NO.89、18或15中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
该第一信号肽分别选自与SEQ ID NO.19或20中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
上述1)中MBP的抗体或抗原结合片段选自CD3、CD5、CD7、PD-L1或CD47的抗体或抗原结合片段；优选地，CD3的抗原结合片段包含SP34 scFv、OKT3 scFv、UCHT1 scFv、UCHT1.Y177T scFv、L2K scFv、F6A scFv、BMA031 scFv、或BMA031.H6L12 scFv；CD5的抗原结合片段包含αCD5.14 scFv；CD7的抗原结合片段包含αCD7.TH69 scFv；PD-L1的抗原结合片段包含αPD-L1 scFv；CD47的抗原结合片段包含αCD47 scFv；更优选地，该SP34 scFv、OKT3 scFv、UCHT1 scFv、UCHT1.Y177T scFv、L2K scFv、F6A scFv、BMA031 scFv、BMA031.H6L12 scFv、αCD5.14 scFv、αCD7.TH69 scFv、αPD-L1 scFv或αCD47 scFv分别包含与SEQ ID NO.2-13中任一项所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
上述2)中的第二跨膜连接结构域包含CD3ζ或CD3ε的跨膜结构域，优选地，CD3ζ或CD3ε的细胞外结构域和跨膜结构域，更优选地，CD3ζ或CD3ε的第二信号肽、细胞外结构域和跨膜结构域；更优选地，该CD3ζ或CD3ε的跨膜结构域(TM)分别包含与SEQ ID NO.67、70中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该CD3ζ或CD3ε的细胞外结构域(EM)分别包含与SEQ ID NO.66、69中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该CD3ζ或CD3ε的第二信号肽分别包含与SEQ ID NO.65、68中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该CD3ζ(CD3ζ.ΔIC)的第二信号肽、细胞外结构域和跨膜结构域以及该CD3ε(CD3ε.ΔIC)的第二信号肽、细胞外结构域和跨膜结构域分别包含与SEQ ID NO.61、64中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在特定实施例中，所述融合蛋白进一步包含铰链或P2A-GFP中的一个或多个；
优选地，该铰链选自CD8α铰链或CD4铰链；更优选地，CD8α铰链或CD4铰链分别包含与SEQ ID NO.16或14中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该铰链与该第一跨膜结构域的N末端相邻，
优选地，P2A-GFP包含与SEQ ID NO.57中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该P2A-GFP序列位于该融合蛋白的C末端。
在另一特定实施例中，所述融合蛋白从N末端至C末端包含：
a)第一连接蛋白、降解标签蛋白、第一跨膜结构域；
优选地，该第一连接蛋白包含待降解的MBP的抗体或抗原结合片段；更优选地，该待降解的MBP的抗体或抗原结合片段包含CD3、CD5、CD7、PD-L1或CD47的抗体或抗原结合片段；更优选地，CD3的抗原结合片段包含SP34 scFv、OKT3 scFv、UCHT1 scFv、UCHT1.Y177TscFv、L2K scFv、F6A scFv、BMA031 scFv、或BMA031.H6L12 scFv；CD5的抗原结合片段包含αCD5.14 scFv；CD7的抗原结合片段包含αCD7.TH69 scFv；PD-L1的抗原结合片段包含αPD-L1scFv；CD47的抗原结合片段包含αCD47 scFv；
优选地，该降解标签蛋白包含E3泛素连接酶；更优选地，该E3泛素连接酶包含CHIP.dTPR、FBW7.2-293、VHL.152-213、SPOP.167-374、或SOCS2.143-198；
优选地，该第一跨膜结构域包含CD8α跨膜结构域；
b)第一连接蛋白、第一跨膜结构域、降解标签蛋白；
优选地，该第一连接蛋白包含该待降解的MBP的抗体或抗原结合片段；更优选地，该待降解的MBP的抗体或抗原结合片段包含CD3的抗体或抗原结合片段；更优选地，CD3的抗原结合片段包含SP34 scFv；
优选地，该降解标签蛋白包含E3泛素连接酶；更优选地，E3泛素连接酶包含GRAIL.IC；
优选地，该第一跨膜结构域选自CD3ζ跨膜结构域变体、CD8α跨膜结构域、和CD4跨膜结构域中的一个或多个；
c)上述2)中的第二跨膜连接结构域、介导降解的细胞表面受体；
优选地，上述2)中的该第二跨膜连接结构域包含CD3ζ.ΔIC或CD3ε.ΔIC；
优选地，所述介导降解的细胞表面受体包含IL2Rβjm；或者
d)上述2)中的第二跨膜连接结构域、E3泛素连接酶或其变体中的一个或多个；
优选地，上述2)中的该第二跨膜连接结构域包含CD3ζ.ΔIC；
优选地，该E3泛素连接酶或其变体中的一个或多个包含GRAIL.IC、CHIP.dTPR、RNF133.IC、RNF122.rIC、RNF152.rIC。
在另外的特定实施例中，融合蛋白从N末端至C末端包含：
a)：
LG112，SP-OKT3 scFv-CHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG114，SP-OKT3 scFv-FBW7-CD8α铰链/TM-P2A-eGFP；
LG115，SP-OKT3 scFv-VHL-CD8α铰链/TM-P2A-eGFP；
LG116，SP-OKT3 scFv-SPOP-CD8α铰链/TM-P2A-eGFP；
LG117，SP-OKT3 scFv-SOCS2-CD8α铰链/TM-P2A-eGFP；
LG118，SP-SP34 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG123，SP-UCHT1 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG124，SP-UCHT1.Y177T scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG125，SP-L2K scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG126，SP-F6A scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG119，SP-BMA031.wt scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG120，SP-BMA031.H6L12 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG137，SP-αCD5.14 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG138，SP-αCD7.TH69 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
MLB052，SP-αPD-L1 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
MLB053，SP-αCD47 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
b)：
LG222，SP-SP34-CD3ζ.ΔIC-1-GRAIL.IC-P2A-eGFP；
LG222.1，SP-SP34-CD8α铰链/TM-GRAIL.IC-P2A-eGFP；
LG222.2，SP-SP34-CD4铰链/TM-GRAIL.IC-P2A-eGFP；
c)：
MLB014，CD3ζ.ΔIC-IL2Rβjm-P2A-eGFP；
MLB046，CD3ε.ΔIC-IL2Rβjm-P2A-eGFP；
d)：
LG171，CD3ζ.ΔIC-GRAIL.IC-P2A-eGFP；
LG171p1、CAG-CD3ζ.ΔIC-GRAIL.IC-P2A-eGFP；
LG213，CD3ζ.ΔIC-CHIP.dTPR-P2A-GFP；
LG174，CD3ζ.ΔIC-RNF133.IC-P2A-GFP；
LG180，CD3ζ.ΔIC-RNF122.rIC-P2A-GFP；
LG183，CD3ζ.ΔIC-RNF152.rIC-P2A-GFP；
任选地，该融合蛋白不包括P2A-eGFP(即P2A-GFP)和/或SP。
在另一方面，本申请提供了核酸，其中该核酸包含编码本申请的融合蛋白的多核苷酸。
在另一方面，本申请提供了载体，其中该载体包含本申请的核酸。
在特定实施例中，优选地，融合蛋白的表达启动子包含CAG或EF1a；
更优选地，CAG或EF1a分别包含与SEQ ID NO.72或88中所示的核酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的核酸序列；
更优选地，a)融合蛋白的表达启动子是EF1a；
更优选地，b)融合蛋白的表达启动子是EF1a；
更优选地，c)融合蛋白的表达启动子是EF1a；
更优选地，d)融合蛋白中的LG171p1的表达启动子是CAG，更优选地，d)融合蛋白中的其他融合蛋白的表达启动子是EF1a。
在另一方面，本申请提供了组合物，该组合物包含本申请的核酸或载体。
在另一方面，组合物包含第一核酸和第二核酸；或包含具有第一核酸的第一载体以及具有第二核酸的第二载体；或包含具有第一核酸和第二核酸的载体，其中
(1)该第一核酸编码本申请的融合蛋白；
(2)该第二核酸编码包含以下的嵌合抗原受体(CAR)：
(a)细胞外配体结合结构域，其包含与预定抗原特异性结合的单链可变片段(scFv)；
(b)跨膜结构域；以及
(c)细胞质区段，其包含一个或多个信号传导结构域，优选地其包含4-1BB信号传导结构域和CD3ζ信号传导结构域。
在特定实施例中，组合物中的融合蛋白选自上述a)-d)融合蛋白中的一个或多个，该组合物包含第一核酸和第二核酸；或包含具有第一核酸的第一载体以及具有第二核酸的第二载体；或包含具有第一核酸和第二核酸的载体。
在特定实施例中，预定抗原是肿瘤相关抗原。
在另外的特定实施例中，肿瘤相关抗原选自以下组：CEA、密封蛋白18.2、GPC3、受体酪氨酸激酶样孤儿受体1(ROR1)、CD38、CD19、CD20、CD22、BCMA、CAIX、CD446、CD133、EGFR、EGFRvIII、EpCam、GD2、EphA2、Her1、Her2、ICAM-1、IL13Ra2、间皮素、MUC1、MUC16、NKG2D、PSCA、NY-ESO-1、MART-1、WT1、MAGE-A10、MAGE-A3、MAGE-A4、EBV、NKG2D、PD1、PD-L1、CD25、IL-2或CD3。
在另外的特定实施例中，肿瘤相关抗原是CEA。
在另一方面，本申请提供了细胞(例如宿主细胞)，该细胞包含本申请的核酸或载体或组合物。
在特定实施例中，宿主细胞是哺乳动物细胞，优选地人细胞。
在另外的特定实施例中，宿主细胞是T细胞或原代T细胞、γδT细胞、NK细胞、NKT细胞、巨噬细胞、B细胞、或非免疫细胞。
在另外的特定实施例中，宿主细胞是同种异体细胞。
在另一方面，本申请提供了药物组合物，该药物组合物包含本申请的融合蛋白、核酸、载体、组合物或细胞。
在特定实施例中，组合物进一步包含一种或多种药学上可接受的赋形剂。
在另一方面，本申请提供了降低细胞中靶膜结合蛋白水平的方法，该方法包括将本申请的核酸、载体、或组合物引入细胞中。
在特定实施例中，细胞(例如宿主细胞)是哺乳动物细胞，优选地人细胞。
在另外的实施例中，宿主细胞是T细胞或原代T细胞、γδT细胞、NK细胞、NKT细胞、巨噬细胞、B细胞、或非免疫细胞。
在另外的实施例中，宿主细胞是同种异体细胞。
在另一方面，本申请提供了产生具有降低的靶膜结合蛋白水平的细胞的方法，该方法包括将本申请的核酸、载体、或组合物引入细胞中。优选地，细胞是哺乳动物细胞，更优选地人细胞；更优选地，细胞是T细胞或原代T细胞、γδT细胞、NK细胞、NKT细胞、巨噬细胞、B细胞、或非免疫细胞；最优选地，细胞是同种异体细胞。
在另一方面，本申请提供了治疗疾病的方法，该方法包括向有需要的受试者施用治疗有效量的具有本申请的组合物的同种异体细胞或向有需要的受试者施用治疗有效量的本申请的细胞，其中优选地，该受试者具有减少的移植物抗宿主疾病(GvHD)。优选地，细胞是哺乳动物细胞，更优选地人细胞；更优选地，细胞是T细胞或原代T细胞、γδT细胞、NK细胞、NKT细胞、巨噬细胞、B细胞、或非免疫细胞；最优选地，细胞是同种异体细胞。
在另一方面，本申请提供了降低或预防与向受试者施用一个或多个CAR T细胞相关的该受试者的GvHD的方法，该方法包括
(1)用本申请的核酸或载体或组合物转染一个或多个CAR T细胞，以及
(2)向该受试者施用所述CAR T细胞。
在另一方面，本申请提供了下调细胞群中的膜结合蛋白(MBP)的方法，该方法包括向所述细胞群添加本申请的宿主细胞，其中该宿主细胞表达包含与所述MBP特异性结合的scFv的融合蛋白，和/或该宿主细胞表达包含具有跨膜结构域的MBP的组分或其片段的融合蛋白。
在另外的方面，宿主细胞群是T细胞群，优选地人原代T细胞群。
在另外的方面，MBP是CD3，优选地人CD3。
本申请具有以下优点：
1)本申请的融合蛋白可以降低(下调)细胞中的靶膜结合蛋白(MBP)水平；以及
2)本申请的CAR T细胞可以降低或预防受试者的GvHD。
附图说明
本申请的新颖的特征在所附权利要求书中特别阐述。在以下具体实施方式中以实施例和实例的方式进行了解释，可以更好地理解本申请的特征和优点。
图1产生同种异体CAR-T宿主细胞以避免对受体组织的潜在GvHD应答的图。由于T细胞、供体T细胞的不同发育/成熟经历，当注入不同的受体中时，可以潜在引发对外源抗原(GvHD)的强免疫应答，例如细胞毒性、细胞因子释放综合征和神经毒性。通过降解供体细胞中的TCR/CD3复合物，此类不利影响可能大大消除。
图2TCR/CD3降解构建体和参考构建体的示意图。出于TCR/CD3复合物降解目的，一系列E3连接酶或其变体(E3连接酶的功能结构域)(例如FBW7、VHL、SPOP和CHIP.dTPR)通过连接至针对人CD3的scFv进行测试。采用克隆SP34或OKT3用于scFv产生。这些构建体中的一些通过CD8α铰链/跨膜结构域在细胞膜上进一步锚定。本文采用LS008构建体(CD19 CAR)用作阴性对照。通过将CD3的抗体或抗原结合片段接合至E3连接酶/泛素获得细胞质构建体(LG089、LG091、LG092、LG085构建体)，但该细胞质构建体没有SP序列和铰链/TM序列，并且在细胞的细胞质中表达。细胞质或膜锚定的构建体(LG021、LG022、LG023、LG024构建体)没有E3连接酶/泛素序列，只有CD3的抗体或抗原结合片段。通过将CD3的抗体或抗原结合片段接合至E3连接酶/泛素获得TCR/CD3降解构建体(LG112、LG113)，并且该构建体具有SP序列和铰链/TM序列两者。
图3A-3E细胞质构建体(LG089、LG091、LG092、LG085)对人原代T细胞中的TCR/CD3复合物的影响。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司(StemCell)Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集激活的原代T细胞，并且在表达用于TCR/CD3降解的细胞质构建体之一的质粒存在的情况下进行电穿孔。两天后，收获细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。图3A示出了系统对照pmaxGFP和LS008在原代T细胞中具有良好的转染效率，并且在这两种构建体的任一种中没有TCRα/β和CD3的下调。图3B-3E的FACS结果显示当抗CD3 scFv(例如SP34 scFv或OKT3 scFv)缀合的E3连接酶(包括FBW7(图3B)、VHL(图3C)、SPOP(图3D)和hCHIP.dTPR(图3E))在细胞质中表达时，没有明显的TCR/CD3复合物降解。
图4A-4D膜锚定的OKT3构建体(LG021、LG022、LG023、LG024)赋予人原代T细胞中TCR/CD3复合物的下调。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集细胞，并且用表达用于TCR/CD3降解的细胞质/膜锚定的构建体之一的1μg DNA质粒进行电穿孔。两天后，收获细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。当SP34 scFv(LG021)(图4A)或OKT3scFv(LG023)(图4C)依赖性构建体在细胞质中表达时，没有显著的TCR/CD3复合物下调。相似地，膜锚定的SP34 scFv构建体(LG022)也没有显示任何影响(图4B)。然而，当以膜锚定的形式采用OKT3scFv序列时，观察到显著的TCR/CD3复合物下调(LG024)(图4D)。
图5膜锚定的OKT3构建体赋予Jurkat细胞中TCR/CD3复合物的下调。用PiggyBac转座酶mRNA和表达膜锚定的OKT3构建体(LG024)的转座子两者电穿孔Jurkat细胞。维持Jurkat细胞直到第57天，并且用CD3(PE)和TCRα/β(APC)染色后进行流式细胞术测试，显示在具有稳定整合转座子(表达膜锚定的OKT3构建体(LG024))的细胞中TCR/CD3复合物的显著的降解(GFP阳性)。
图6A-6D E3连接酶与OKT3 scFv构建体的膜外连接(LG112)比E3连接酶与OKT3scFv构建体的细胞质连接(LG113)赋予对Jurkat细胞系中TCR/CD3复合物的更好的下调。用PiggyBac转座酶mRNA和表达不同膜锚定的OKT3构建体(LG112、LG113)的转座子两者电穿孔Jurkat细胞。在第3天收获Jurkat细胞并且用CD3(PE)和TCRα/β(APC)染色后进行流式细胞术分析。图6A示出了系统对照pmaxGFP和LS008在Jurkat细胞中具有良好的转染效率，并且在这两种构建体的任一种中没有TCRα/β和CD3的下调。没有E3泛素连接酶的膜锚定的OKT3scFv构建体(LG024)显示了Jurkat细胞中TCR-CD3复合物显著的下调(图6B)。当hCHIP.dTPR以外膜方式(近端连接)(LG112)(图6C)而非细胞质方式(LG113)(图6D)与OKT3 scFv连接时，获得甚至更强的TCR/CD3复合物下调。
图7A-7D E3连接酶与OKT3构建体的膜外连接(LG112)比E3连接酶与OKT3scFv构建体的细胞质连接(LG113)赋予对人原代T细胞中TCR/CD3复合物更好的下调。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集已激活的原代T细胞，并且用PiggyBac转座酶mRNA和表达不同膜锚定的OKT3构建体的转座子两者进行电穿孔。三天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。图7A示出了系统对照pmaxGFP和LS008在原代T细胞中具有良好的转染效率，并且在这两种构建体的任一种中没有TCRα/β和CD3的下调。与我们在Jurkat细胞系中发现的相似，当hCHIP.dTPR以外膜方式(近端连接)(LG112)(图7C)而非细胞质方式(LG113)(图7D)与OKT3 scFv连接时，降解可以是更显著的。发现与没有E3泛素连接酶的膜锚定的OKT3 scFv构建体(LG024)(图7B)相比，当E3泛素连接酶(CHIP.dTPR)位于整个构建体的细胞质部分(LG113，图7D)时，TCR/CD3降解没有显著的变化。
图8A-8E具有不同E3连接酶的TCR/CD3降解构建体。(图8A)设计并合成一系列具有与膜锚定的OKT3 scFv连接的不同E3连接酶(包括FBW7、VHL、SPOP和SOCS2)的构建体。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集原代T细胞，并且用PiggyBac转座酶mRNA和表达不同膜锚定的OKT3构建体的转座子两者进行电穿孔。三天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。测试FBW7(图8B)、VHL(图8C)、SPOP(图8D)和SOCS2(图8E)的TCR/CD3下调影响。
图9A-9F具有靶向不同CD3的scFv的TCR/CD3降解构建体。(图9A)设计并合成一系列具有靶向不同TCR-CD3的scFv(包括SP34、UCHT1、UCHT1.Y177T、L2K和F6A)的TCR/CD3降解构建体。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集原代T细胞，并且用PiggyBac转座酶mRNA和转座子DNA构建体两者进行电穿孔。三天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。测试通过SP34(图9B)、UCHT1(图9C)、UCHT1.Y177T(图9D)、L2K(图9E)和F6A(图9F)的TCR/CD3下调影响。
图10A-10E E3连接酶(CHIP.dTPR)是优化人原代T细胞中的TCR/CD3下调所必需的。(图10A)在存在或不存在CHIP.dTPR的情况下，设计并合成一系列具有靶向TCR的scFv(BMA031或BMA031.H6L12)的TCR降解构建体。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集细胞，并且用PiggyBac转座酶mRNA和转座子DNA构建体两者进行电穿孔。三天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。在存在(图10B)(图10C)或不存在(图10D)(图10E)CHIP.dTPR的情况下，测试通过BMA031(LG119，图10B)(LG133，图10D)或BMA031.H6L12(LG120，图10C)(LG134，图10E)的TCR/CD3下调影响。
图11A-图11B示出了CD3下调通过CD3/CD28/CD2刺激赋予较低的Jurkat细胞激活。图11A示出了在基线时所有细胞的CD69(T细胞激活标志物)表达水平低；图11B示出了与T细胞LS008转染的细胞相比，在LG024或LG112转染的GFP+细胞中的CD69表达水平在刺激后4小时显著降低。
图12A-12C CD5或CD7下调构建体和验证。图12A示出了设计并合成一系列CD5或CD7降解构建体。图12B示出了αCD5.14 scFv赋予了对CD5的强下调；图12C示出了αCD7.TH69scFv(靶向CD7的scFv)在人原代T细胞中也显示显著的下调影响。
图13A-13B PD-L1和CD47通过E3 CHIP构建体的下调。图13A示出了分别对PD-L1和CD47特异性的E3构建体MLB052和MLB053的示意图。每个构建体是由对靶向抗原特异性的N末端ScFv结构域和缺乏TPR结构域的E3连接酶CHIP的截短形式组成。E3降解剂构建体(MLB052或MLB053)是通过柔性铰链和跨膜锚定对膜进行锚定。对于PD-L1，1)显示Jurkat细胞的两种不同群体(GFP+和GFP-)的代表性流式细胞术图(即图13B的左列的上小图)，Jurkat细胞用PE缀合的抗PD-L1抗体进行染色；2)相对于未转染的Jurkat亲本细胞(即图13B的右列的上小图的虚线标记区域)，在GFP+表达上进行门控的表达E3-CHIP的细胞上的PD-L1表达的直方图(即图13B的右列的上小图中的虚线标记区域)。对于CD 47，1)用抗CD47E3CHIP转染的Jurkat细胞(GFP+)(即图13B的左列的下小图)以及用APC缀合的抗CD47一抗染色的Jurkat细胞的代表性流式细胞术图；2)显示相对于未转染的亲本对照细胞(图13B的右列的下小图)，在GFP+表达上进行门控的E3 CHIP转染的Jurkat细胞的CD47表达的直方图。
图14A-图14B通过E3 CHIP连接的靶向CD3的构建体(LG024)的TCR表达的旁分泌下调。图14A示出了用于显示TCR表达的旁分泌下调的共培养测定的门控策略。对CellTrace紫色阳性细胞(即没有LG024转染的Cell Trace+细胞)和CellTrace紫色阴性细胞(即LG024转染的Cell Trace–细胞)进行的门控允许表征这些不同群体(图14A的左列)。将LG024转染的细胞(即Cell Trace–细胞)进一步门控至表达E3连接酶构建体的GFP阳性群体以及未转染的GFP阴性群体中(图14A的中间列)。用PE缀合的αCD3(克隆Hit3a)对细胞进行染色以评估TCR表面表达(图14A的左列)。图14B示出了用CellTrace紫色标记的亲本储备Jurkat细胞(即没有LG024转染的Cell Trace+细胞)对用LG024电穿孔的Jurkat细胞(即LG024转染的Cell Trace–细胞)进行连续稀释。对表达E3连接酶的细胞部分的连续稀释显示非表达细胞上表面分子的抗原特异性下调。用CellTrace紫色标记的亲本细胞对LG024转染的Jurkat细胞连续稀释以使得E3连接酶阳性细胞的总比例为：78％、57％、44％、31％、22％、16％、11％、和0％。亲本群体(即未转染的群体)显示为灰色阴影直方图(即填充区域)。将转染的群体进一步门控为GFP阳性(黑实线标记区域)和GFP阴性(黑虚线标记区域)。使用PE缀合的CD3抗体(克隆Hit3a)对细胞进行染色以确定TCR表面表达。
图15A-图15D不同的铰链/跨膜结构域对由靶向CD3的scFv(即SP34)和GRAIL.IC两者介导的Jurkat中的TCR/CD3下调的影响。图15A示出了LG222、LG222.1和LG222.2的构建体图；图15B-D示出了用表达LG222、LG222.1或LG222.2的PiggyBac载体与PiggyBac转座酶mRNA的组合电穿孔Jurkat细胞。在电穿孔后第3天，通过CD3和TCRα/β染色评估TCR表面表达。
图16A-图16C不同的铰链/跨膜结构域对由靶向CD3的scFv(即SP34)和GRAIL.IC两者介导的人原代T细胞中的TCR/CD3下调的影响。图16A-16C示出了用表达LG222、LG222.1或LG222.2的PiggyBac载体与PiggyBac转座酶mRNA的组合预激活并电穿孔人原代T细胞。在电穿孔后第3天，通过CD3和TCRα/β染色评估TCR表面表达。
图17受体内吞作用的概述。细胞表面受体经由网格蛋白介导的内吞作用或经由网格蛋白非依赖性内吞作用进行内吞，其中将它们内化为细胞内囊泡。将在其内腔内含有表面受体胞外结构域的囊泡经由衔接蛋白运输至早期内体用于进一步分选。通过再循环内体可以将表面受体从早期内体运输至细胞表面，或在多泡体内聚集。分选至表面或可替代的细胞内途径依赖于这些表面受体的跨膜结构域和胞内结构域中的基序。将受体从多泡体进一步加工至晚期内体中并且最终至溶酶体中，其中内腔的低pH，以及溶酶体蛋白酶导致细胞表面受体及其相关货物的降解。
图18A CD3ζ.ΔIC-IL2Rβjm(MLB014)和CD3ε.ΔIC-IL2Rβjm(MLB046)嵌合蛋白(即融合蛋白)的示意图。我们的设计基于将CD3ζ(MLB014)和CD3ε(MLB046)的细胞外序列和跨膜序列直接融合至IL2Rβ胞内结构域(即IL2Rβjm)的前27个氨基酸，这些氨基酸具有其溶酶体靶向基序。包括CD3ζ和CD3ε跨膜结构域使我们的构建体掺入至多亚基TCR复合物中。
图18B CD3ζ.ΔIC-IL2Rβjm和CD3ε.ΔIC-IL2Rβjm嵌合蛋白(即融合蛋白)的表达导致Jurkat E6.1 NFAT荧光素酶报告细胞中的TCR下调。用表达CD3融合蛋白的PiggyBac载体和PiggyBac转座酶mRNA电穿孔Jurkat细胞以诱导CD3ζ.ΔIC-IL2Rβjm(MLB014)或CD3ε.ΔIC-IL2Rβjm(MLB046)的表达。在电穿孔后第5天，通过CD3染色评估TCR表面表达。由于TCR是专性异聚复合物，CD3的下调表明整体TCR下调。这些数据表明将MLB014/(CD3ζ.ΔIC-IL2Rβjm)构建体或MLB046/(CD3ε.ΔIC-IL2Rβjm)掺入至TCR复合物中促进整个复合物内化的增加。
图18C CD3ζ.ΔIC-IL2Rβjm和CD3ε.ΔIC-IL2Rβjm嵌合蛋白的表达导致供体来源的细胞中的TCR下调。与Jurkat报告细胞一样，用PiggyBac载体和PiggyBac转座酶mRNA电穿孔原代T细胞以诱导CD3ζ.ΔIC-IL2Rβjm(MLB014)或CD3ε.ΔIC-IL2Rβjm(MLB046)的表达。在电穿孔后第5天，通过针对CD3(上小图)和TCRα/β(下小图)进行的染色评估TCR表达。这些数据表明相同的潜在机制在原代T细胞和Jurkat细胞中起作用，但在原代T细胞中TCR下调的效率有所降低。
图19CD3ζ.ΔIC-GRAIL.IC(LG171)的示意图。我们的设计基于CD3ζ(即CD3ζ.ΔIC或CD3ζ截短(截短形式))的细胞外序列和跨膜序列以及膜锚定的E3连接酶GRAIL(GRAIL.IC)的细胞内结构域。包括CD3ζ跨膜结构域可以使我们的构建体掺入至多亚基TCR复合物中。
图20LG171嵌合蛋白的表达导致Jurkat细胞中的TCR/CD3下调。用表达CD3融合蛋白的PiggyBac载体(即LG171)和PiggyBac转座酶mRNA电穿孔Jurkat细胞以诱导CD3ζ.ΔIC-GRAIL.IC(LG171)的表达。在电穿孔后第3天，通过CD3和TCRα/β染色评估TCR表面表达。
图21LG171嵌合蛋白的表达导致人原代T细胞中的TCR/CD3下调。与Jurkat报告细胞一样，用PiggyBac载体LG171和PiggyBac转座酶电穿孔原代T细胞以诱导CD3ζ.ΔIC-GRAIL.IC(LG171)的表达。在电穿孔后第3天，通过针对CD3和TCRα/β进行的染色评估TCR表达。相似地，TCR/CD3表达的下调在GFP+部分中是显著的。
图22LG212(没有E3连接酶)不能降低人原代T细胞中的TCR表达。用PiggyBac载体LG212和PiggyBac转座酶电穿孔原代T细胞。在电穿孔后第3天，通过针对CD3和TCRα/β进行的染色评估TCR表达。当在人原代T细胞中仅采用CD3ζ(即CD3ζ.ΔIC)时，可以看到没有TCR/CD3的下调。
图23A-23C GRAIL细胞内结构域中的突变或结构域开关在LG171中赋予与LG212(CD3ζ.ΔIC)中相似的TCR下调。LG171.ZF(含有结构域开关)、LG171.H2N2(含有点突变)构建体在图23A中显示。FACS(图23B)和蛋白质印迹(图23C)测试两者表明GRAIL的功能锌指结构域对LG171中更好的TCR/CD3下调是必需的(图21)。
图24LG171嵌合蛋白的表达不能赋予对CD5或CD7的非特异性的下调。LG171在原代T细胞中的下调作用是TCR/CD3特异性的，因为CD5和CD7都没有受到影响。
图25A-25C具有CAG启动子的LG171p1赋予对T细胞上TCR/CD3的下调。LG171p1融合蛋白构建体在图25A中显示。图25A示出了通过用CAG启动子替换LG171中的EF1a启动子产生构建体LG171p1；图25B示出了CAG启动子赋予对Jurkat细胞上的TCR/CD3的下调。用表达LG171p1融合蛋白的PiggyBac载体和PiggyBac转座酶mRNA电穿孔Jurkat细胞。在电穿孔后第3天，通过CD3和TCRα/β染色评估TCR表面表达。图25C示出了CAG启动子赋予对人原代T细胞上的TCR/CD3的持续下调。与Jurkat报告细胞一样，用PiggyBac载体LG171p1和PiggyBac转座酶预激活并电穿孔原代T细胞。在电穿孔后第3、7和13天，通过CD3和TCRα/β染色评估TCR表面表达。
图26A-26B LG213中的下调主要由CD3ζ截短引起。将CHIP.ΔTPR与全长CD3ζ或CD3ζ.ΔIC连接以产生新嵌合体(LG132，LG213)用于靶向TCR(图26A)。用LG132或LG213转染的原代T细胞中的TCR水平的FACS数据。与具有全长CD3ζ的LG132的无影响相比，LG213中的下调主要由CD3ζ截短引起(图26B)。
图27A-27C.基于CD3ζ截短的另外的E3嵌合体及其在TCR下调中的功效。图27A示出了基于CD3ζ截短的另外的E3连接酶及其嵌合体构建体的构建体设计。图27B另外的E3连接酶及其嵌合体构建体在TCR下调中的FACS数据。图27C蛋白质印迹数据显示使用β-肌动蛋白作为标志物，在基于CD3ζ的另外的E3嵌合体构建体中TCR的显著降低。
图28A-图28B用LG171转染的Jurkat细胞中的激活降低。图28A示出了用LG171转染的Jurkat细胞中的激活降低(CD69上调减弱)，图28B示出了用LG171转染的Jurkat细胞中的激活降低(ppERK上调减弱)。用αCD3/CD28短暂刺激用所指出的构建体转染的Jurkat细胞。通过FACS检查CD69(图28A)和ppERK(图28B)。
图29A-29C用LG171和LG171p1转染的原代T细胞中的激活降低。用OKT3(抗CD3抗体)刺激用所指出的构建体转染的人原代T细胞用于CD69上调和IFN-γ细胞因子分泌。通过FACS检查CD69上调(图29A)。24小时后，收集上清液并且测试IFN-γ水平(图29B)。在使用ELISA测试IFN-γ水平前，将模拟T细胞(未处理的T细胞)或LG171p1转染的T细胞与同种异体mDC细胞共培养5天(图29C)。图29A示出了用LG171(CD69)转染的原代T细胞中的激活降低。图29B示出了用LG171和LG171p1(IFN-γ)转染的原代T细胞中的激活降低。图29C示出了用LG171p1(IFN-γ)转染的原代T细胞中的激活降低。
图30A-图30C LG171.CldnCar的表达和杀伤效率。LG171.CldnCar和CldnCar融合蛋白构建体在图30A中显示。图30B示出了在用所指出的构建体转染的T细胞中的TCR/CAR表达。图30C示出了通过用亲本HEK细胞(即HEK)或过表达CLDN18.2的HEK细胞(即HEK-CLDN18.2)共培养工程化T细胞24小时来测定细胞毒性。
具体实施方式
除非另外定义，否则本文所用的技术与科学术语具有如本申请所属领域通常所用的相同含义。出于解释本说明书的目的，以下定义将适用并且在适当时，以单数形式使用的术语也包括复数并且反之亦然。如本文和所附权利要求书中所用，除非上下文另有明确规定，否则单数形式“一个/种(a/an)”和“该(the)”也指复数形式，例如，提及“宿主细胞”包括多个此类宿主细胞。
如本文所用，“T细胞受体(TCR)复合物”(也称为TCR/CD3复合物)是T细胞表面的多聚体复合物，其激活导致T细胞的活化。该复合物包含(i)TCR，和(ii)CD3 T细胞共受体。如下文所示，TCR包含α链和β链。CD3 T细胞共受体包含CD3γ链、CD3δ链、两条CD3ε链和两条ζ链作为辅助分子。
TCR允许T细胞的抗原特异性激活。每个T细胞都表达克隆性TCR，这些克隆性TCR在T细胞与抗原呈递细胞APC(经由MHC II类)或任何其他细胞类型(经由MHC I类)之间的物理接触期间识别特异性肽/MHC复合物。TCR是二硫键连接的膜锚定异二聚体蛋白，其通常由高可变α和β链组成。TCR的每条链包含两个细胞外结构域：可变(V)区和恒定(C)区，两者均为形成反平行β折叠的免疫球蛋白超家族(IgSF)结构域。恒定区位于细胞膜的近端，随后是跨膜区和短的细胞质尾部，而可变区与肽/MHC复合物结合。TCRα链和TCRβ链的可变结构域各具有三个高变区或互补决定区(CDR)，这有助于TCR对特定肽/MHC复合物的特异性。β链的可变区还具有通常不接触抗原的另外的高变区域(HV4)。
“单链可变片段(scFv)”是抗体的重链可变区(VH)和轻链可变区(VL)的融合蛋白，用十至约25个氨基酸的短接头肽连接。该接头通常富含甘氨酸(针对灵活性)，以及丝氨酸或苏氨酸(针对溶解度)，并且可以将VH的N末端和VL的C末端连接起来，或反之亦然。尽管去除了恒定区并引入了接头，但该蛋白质仍保留了原始抗体的特异性。scFv抗体例如在Houston,J.S.,Methods in Enzymol.[酶学方法]203(1991)46-96中描述。另外，抗体片段包含单链多肽，这些单链多肽具有VH结构域的特征，即能够与VL结构域一起组装到功能性抗原结合位点；或这些单链多肽具有VL结构域的特征，即能够与VH结构域一起组装到功能性抗原结合位点，从而提供全长抗体的抗原结合特性。
如本文所用，“治疗(treatment)”(及其语法变体，例如治疗(“treat”或“treating”))是指试图改变被治疗个体的自然过程的临床干预，并且可以用于预防或在临床病理过程期间进行。治疗的期望效果包括但不限于预防疾病的发生或复发、减轻症状、减少疾病的任何直接或间接病理后果、预防转移、降低疾病进展速率、改善或缓和疾病状态、以及缓解或改善预后。在一些实施例中，本申请的分子用于延迟疾病的发展或减缓疾病的进展。
如本文所用，术语“癌症”或“肿瘤”是指增殖性疾病，例如卵巢癌、胰腺癌、结肠癌、结直肠癌、淋巴瘤、淋巴细胞白血病、肺癌、非小细胞肺(NSCL)癌、细支气管肺泡细胞肺癌、骨癌、皮肤癌、头颈癌、皮肤或眼内黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃部癌症(stomach cancer)、胃癌(gastric cancer)、乳腺癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、膀胱癌、肾癌或输尿管癌、肾细胞癌、肾盂癌、间皮瘤、肝细胞癌、胆管癌、中枢神经系统(CNS)肿瘤、脊髓轴肿瘤、脑干神经胶质瘤、多形性胶质母细胞瘤、星形细胞瘤、神经鞘瘤、室管膜瘤、髓母细胞瘤、脑膜瘤、鳞状细胞癌、垂体腺瘤和尤文氏肉瘤，包括上述癌症中的任一种的难治性型式，或上述癌症中的一种或多种的组合。
在描述各种实施例之前，应当理解，本公开的教导并不限于所描述的特定实施例，并且因此当然是可以改变的。还应当理解，本文中使用的术语仅用于描述特定实施例的目的，并且不旨在是限制性的，因为本教导的范围将仅由所附权利要求书限制。
本申请提供了具有特定有利特性(例如当在宿主细胞中表达时降低膜结合蛋白(MBP)水平)的新颖的融合蛋白。
在本申请中，膜结合蛋白(MBP)的下调是通过降解标签蛋白介导的降解实现的，其中该降解标签蛋白包含泛素连接酶和/或介导降解的细胞表面受体的结构域(例如IL2Rβ亚结构域)。降解标签蛋白(例如泛素连接酶或IL2Rβ)对待降解的MBP的标签特异性或靶向特异性(或识别特异性)是通过待降解的MBP的抗体(或其抗原结合片段)介导的(即抗体介导的底物识别)，或由具有跨膜结构域(即，跨膜结构域介导的底物识别)的待降解的膜结合蛋白或复合物的亚基或结构域介导的。本申请的技术方案可以应用于细胞表面上的任何靶标，与细胞类型无关。优选地，待降解的MBP可以是膜结合受体或受体复合物；更优选地，膜结合受体可以是T细胞受体(TCR)。因此，优选地，本申请涉及由受体TAC(靶向受体的嵌合体)靶向的泛素介导的降解来下调TCR产生同种异体嵌合抗原受体T细胞(CAR-T)、或涉及融合蛋白(例如融合蛋白，其包含与降解标签蛋白(例如E3泛素连接酶和/或介导降解的细胞表面受体的结构域)融合的具有跨膜结构域的待降解的膜结合蛋白组分或其片段)的产生，降解标签蛋白可以在TCR复合物形成过程中掺入至多亚基TCR复合物中以导致TCR复合物的下调。特别地，将抗体(例如抗CD3抗体)或其抗原结合片段与E3泛素连接酶(例如与Hsc70相互作用的蛋白质的C末端(CHIP))细胞外融合，然后连接跨膜域，或将E3泛素连接酶或介导降解的细胞表面受体细胞内融合至具有跨膜结构域的待降解的膜结合蛋白或复合物的组分或其片段。当在宿主细胞(例如原代T细胞)中表达时，MBP(例如TCR复合物)被显著下调。这是基于蛋白质降解的新颖的MBP下调技术。这一技术可以是应用于任何MBP，尤其是表面受体，用于治疗性用途或研究目的。
(1)本申请的融合蛋白
1.融合蛋白a)：
本申请公开了融合蛋白a)，其包含：第一连接蛋白、降解标签蛋白、第一跨膜结构域。
在一些实施例中，融合蛋白从N末端至C末端包含：第一连接蛋白、降解标签蛋白、第一跨膜结构域。
在一些实施例中，第一连接蛋白包含待降解的MBP的抗体或抗原结合片段；更优选地，该待降解的MBP的抗体或抗原结合片段包含CD3、CD5、CD7、PD-L1或CD47的抗体或抗原结合片段；更优选地，CD3的抗原结合片段包含SP34 scFv、OKT3scFv、UCHT1 scFv、UCHT1.Y177T scFv、L2K scFv、F6A scFv、BMA031 scFv、或BMA031.H6L12 scFv；CD5的抗原结合片段包含αCD5.14 scFv；CD7的抗原结合片段包含αCD7.TH69 scFv；PD-L1的抗原结合片段包含αPD-L1 scFv；CD47的抗原结合片段包含αCD47 scFv。
在一些实施例中，降解标签蛋白包含E3泛素连接酶；更优选地，该E3泛素连接酶包含CHIP.dTPR、FBW7.2-293、VHL.152-213、SPOP.167-374、SOCS2.143-198；
在一些实施例中，第一跨膜结构域包含CD8α跨膜结构域。
在一些实施例中，融合蛋白a)进一步包含第一信号肽。
任选地，也可以是scFv与E3连接酶之间的接头(例如SEQ ID No.91)。
任选地，也可以是CD8α跨膜结构域(CD8 TM)与E3连接酶之间的接头(例如SEQ IDNo.91)。
2.融合蛋白b)：
本申请公开了融合蛋白b)，其包含：第一连接蛋白、第一跨膜结构域、降解标签蛋白。
在一些实施例中，融合蛋白从N末端至C末端包含：第一连接蛋白、第一跨膜结构域、降解标签蛋白。
在一些实施例中，第一连接蛋白包含待降解的MBP的抗体或抗原结合片段；更优选地，该待降解的MBP的抗体或抗原结合片段包含CD3的抗体或抗原结合片段；更优选地，CD3的抗原结合片段包含SP34 scFv；
在一些实施例中，降解标签蛋白包含E3泛素连接酶；更优选地，E3泛素连接酶包含GRAIL.IC；
在一些实施例中，第一跨膜结构域选自CD3ζ跨膜结构域变体、CD8α跨膜结构域、和CD4跨膜结构域中的一个或多个。
在一些实施例中，融合蛋白b)进一步包含第一信号肽。
任选地，也可以是与融合蛋白b)(例如LG222、LG222.1、LG222.2)的TM结构域的C末端连接的细胞内结构域(例如SEQ ID No.90)。
3.融合蛋白c)：
本申请公开了融合蛋白c)，其包含：上述2)中的第二跨膜连接结构域、介导降解的细胞表面受体。
在一些实施例中，融合蛋白从N末端至C末端包含：上述2)中的第二跨膜连接结构域、介导降解的细胞表面受体。
在一些实施例中，上述2)中的第二跨膜连接结构域包含CD3ζ.ΔIC或CD3ε.ΔIC；
在一些实施例中，介导降解的细胞表面受体包含IL2Rβjm。
4.融合蛋白d)：
本申请公开了融合蛋白d)，其包含：上述2)中的第二跨膜连接结构域、E3泛素连接酶或其变体中的一个或多个。
在一些实施例中，融合蛋白从N末端至C末端包含：上述2)中的第二跨膜连接结构域、E3泛素连接酶或其变体中的一个或多个。
在一些实施例中，上述2)中的第二跨膜连接结构域包含CD3ζ.ΔIC。
在一些实施例中，E3泛素连接酶或其变体中的一个或多个包含GRAIL.IC、CHIP.dTPR、RNF133.IC、RNF122.rIC、RNF152.rIC。
5.融合蛋白中使用的序列
在一些实施例中，SP34 scFv、OKT3 scFv、UCHT1 scFv、UCHT1.Y177T scFv、L2KscFv、F6AscFv、BMA031 scFv、BMA031.H6L12 scFv、αCD5.14 scFv、αCD7.TH69scFv、αPD-L1scFv或αCD47 scFv分别包含与SEQ ID NO.2-13中任一项所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在一些实施例中，CHIP、CHIP.dTPR、FBW7.2-293、VHL.152-213、SPOP.167-374、SOCS2.143-198、GRAIL.IC、RNF133.IC、RNF122.rIC或RNF152.rIC分别包含与SEQ IDNO.21-26、62、79、81或83中任一项所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在一些实施例中，CD3ζ跨膜结构域变体、CD8α跨膜结构域、或CD4跨膜结构域分别包含与SEQ ID NO.89、18或15中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在一些实施例中，融合蛋白a)进一步包含第一信号肽；优选地，第一信号肽分别选自与SEQ ID NO.19或20中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在一些实施例中，融合蛋白b)进一步包含第一信号肽；优选地，第一信号肽选自与SEQ ID NO.19中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在一些实施例中，CD3ζ.ΔIC和CD3ε.ΔIC分别包含与SEQ ID NO.61、64中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。更优选地，CD3ζ或CD3ε的跨膜结构域(TM)分别包含与SEQ ID NO.67、70中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，CD3ζ或CD3ε的细胞外结构域(EM)分别包含与SEQ ID NO.66、69中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，CD3ζ或CD3ε的第二信号肽分别包含与SEQ ID NO.65、68中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在一些实施例中，L2Rβjm结构域(IL2Rβjm)包含与SEQ ID NO.58中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在非限制性实例中，本申请的融合蛋白进一步包含铰链或P2A-GFP中的一个或多个。
在一些实施例中，铰链选自CD8α铰链、或CD4铰链；更优选地，CD8α铰链或CD4铰链分别包含与SEQ ID NO.16或14中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，铰链与第一跨膜结构域的N末端相邻。
在一些实施例中，P2A-GFP包含与SEQ ID NO.57中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，P2A-GFP序列位于融合蛋白的C末端。
6.第一跨膜连接结构域包含第一跨膜结构域和第一连接蛋白
第一连接蛋白：膜结合蛋白的抗体或其抗原结合片段(例如scFv)
膜结合蛋白的抗体或其抗原结合片段(例如scFv)可以用作介导降解标签蛋白与膜结合蛋白结合(或特异性结合，特异性识别)的连接蛋白(即抗体介导的底物识别)。
单链可变片段
本申请的scFv是与膜结合蛋白(包括但不限于CD3、CD5、CD7、PD-1、PD-L1或CD47)特异性结合的那些，优选地与那些膜结合蛋白的细胞外部分结合。优选地，scFv是与TCR/CD3复合物的组分(或亚基)特异性结合的那些。
因此，在一些实施例中，scFv与CD3特异性结合；例如，CD3是哺乳动物来源CD3，优选地人CD3。
第一跨膜结构域：
第一跨膜结构域选自CD8α、CD4、CD3、CD28、4-1BB和IL2R或其变体的一个或多个亚基或结构域的跨膜结构域。
7.第二跨膜连接结构域包含待降解的MBP或其变体的跨膜结构域
待降解的MBP或其变体(连接蛋白2)的跨膜结构域
在一些实施例中，具有跨膜结构域的待降解膜结合蛋白或其变体的一个或多个亚基或结构域(或片段)可以用作连接蛋白以介导降解标签蛋白至膜结合蛋白的掺入(或通过掺入的特异性识别)，例如，在膜结合蛋白形成期间降解标签蛋白至膜结合蛋白的掺入(即跨膜结构域介导的底物识别)。
在一些实施例中，待降解的膜结合蛋白是膜结合受体。
在一些实施例中，膜结合受体是CD3，优选地哺乳动物来源CD3，更优选地人CD3。
在一些实施例中，连接蛋白2包含CD3ζ、CD3γ、CD3δ、CD3ε、CD3α、CD3β或其变体中的一个或多个的跨膜结构域。
在一些实施例中，连接蛋白2包含CD3ζ、CD3γ、CD3δ、CD3ε、CD3α、CD3β或其变体中的一个或多个的细胞外结构域和跨膜结构域。
在一些实施例中，连接蛋白2包含CD3ζ、CD3γ、CD3δ、CD3ε、CD3α、CD3β或其变体中的一个或多个的第二信号肽、细胞外结构域和跨膜结构域。
8.降解标签蛋白1：E3泛素连接酶
“E3泛素连接酶”或“E3连接酶”或“泛素连接酶”(UL)在本文中用于描述根据本申请的双功能化合物中的泛素连接酶部分的一个或多个靶酶结合位点。E3 UL是与E2泛素缀合酶组合导致泛素连接至靶蛋白上的赖氨酸的蛋白质；E3泛素连接酶靶向通过蛋白酶体降解的特定蛋白底物。因此，E3泛素连接酶单独或与E2泛素缀合酶复合负责将泛素转移至靶蛋白。一般而言，泛素连接酶参与多泛素化，使得第二泛素连接至第一泛素，第三泛素连接至第二泛素等。多泛素化标记蛋白质以通过蛋白酶体降解。然而，存在一些泛素化事件限于单泛素化，其中泛素连接酶仅将单个泛素添加到底物分子中。单泛素化蛋白不是靶向蛋白酶体进行降解，而是可以替代地改变其细胞位置或功能，例如经由结合具有能够结合泛素的结构域的其他蛋白质。更复杂的是，泛素上的不同赖氨酸可以被E3靶向以成链。最常见的赖氨酸是泛素链上的Lys48。这是用于制造多泛素的赖氨酸，它被蛋白酶体识别。
在一些实施例中，E3泛素连接酶选自以下蛋白质或其截短形式：GRAIL、Hsc70相互作用蛋白(CHIP)的C末端、CHIP.dTPR、含有F盒WD40的蛋白7(FBW7)、FBW7.2-293、希佩尔-林道(VHL)、VHL.152-213、斑点型BTB-POZ蛋白(SPOP)、SPOP.167-374、泛素蛋白连接酶E3A(UBE3A)、小鼠双微体2同源物(MDM2)、后期促进复合物(APC)、UBR5、LNX、卡西塔斯B谱系淋巴瘤转化序列样蛋白1(CBLL1)、含有HECT结构域和锚蛋白重复序列的E3泛素蛋白连接酶1(HACE1)，含有HECT、C2和WW结构域的E3泛素蛋白连接酶1(HECW1)，含有HECT、C2和WW结构域的E3泛素蛋白连接酶2(HECW2)，含有HECT和RLD结构域的E3泛素蛋白连接酶1(HERC1)，HERC2、HERC3、HERC4、HERC5、HERC6、HUWE1、ITCH、神经前体细胞表达的发育下调蛋白4(NEDD4)、神经前体细胞表达的发育下调基因4样蛋白(NEDD4L)、肽基脯氨酰异构酶(亲环蛋白)样2(PPIL2)、PIAS1、PIAS2、PIAS3、PIAS4、RANBP2、RNF4、RBX1、SMURF1、SMURF2、STUB1、TOPORS、TRIP12、UBE3A、UBE3B、UBE3C、UBE3D、UBE4A、UBE4B、UBOX5、UBR5、WWP1、WWP2、Parkin、MKRN1、GRAIL.IC、RNF133.IC、RNF122.rIC或RNF152.rIC。
在本申请中，E3泛素连接酶用作降解标签蛋白，并且E3泛素连接酶介导的MBP降解也可以在细胞外和/或细胞内实现。
降解标签蛋白2：介导降解的细胞表面受体的一个或多个亚基或结构域
介导降解的细胞表面受体的一个或多个亚基或结构域(即降解标签蛋白)可以是介导MBP或其组分的降解(或内吞作用和降解、内吞作用后降解)的蛋白质，并且例如，由细胞表面受体的一个或多个亚基或结构域介导的MBP或其组分的降解可以在细胞内通过E3泛素连接酶、溶酶体或其他降解途径来实现，并且可能在MBP或其组分的内吞作用后实现。
在膜结合蛋白(MBP)形成期间通过与用于形成MBP的MBP的组分融合将介导降解的细胞表面受体的一个或多个亚基或结构域特异性掺入至MBP或其组分中。另外，用于形成MBP的MBP的组分可以是MBP的一个或多个结构域，任选地，CD3ε或CD3ζ的一个或多个结构域。
尽管细胞表面受体也可以属于MBP，但介导降解的细胞表面受体通常与待降解的MBP不同。
在一些实施例中，介导降解并且用作本申请的降解标签蛋白的细胞表面受体包含白细胞介素受体、或由其衍生的变体。
在一些实施例中，白细胞介素受体的亚基或结构域包含IL-2R的溶酶体靶向基序；优选地，IL-2R的溶酶体靶向基序包含L2Rβjm结构域。
9.跨膜结构域
“跨膜结构域”包括跨越质膜的约15个氨基酸残基长度的氨基酸序列。更优选地，跨膜结构域包括约至少20、25、30、35、40、或45个氨基酸残基并且跨越质膜。跨膜结构域富含疏水残基，并且通常具有α螺旋结构。在优选的实施例中，跨膜结构域的至少50％、60％、70％、80％、90％、95％或更多的氨基酸是疏水性的，例如，亮氨酸、异亮氨酸、酪氨酸或色氨酸。跨膜结构域描述于例如，Zagotta,W.N.等人(1996)Annu.Rev.Neurosci.[神经科学年鉴]19:235-263，其内容通过引用并入本文。
融合蛋白中跨膜结构域的功能是将所述融合蛋白锚定至细胞表面，并且因此任何实现该功能的跨膜结构域都可用于本申请。
适用于本申请的跨膜结构域可以选自以下：CD8α、CD28、4-1BB或IL2R跨膜结构域，即上文6中的第一跨膜结构域。
适用于本申请的跨膜结构域也可以是连接蛋白本身的结构域的跨膜结构域，即上文7中的跨膜结构域。
(2)编码融合蛋白、CAR的核酸、包含所述核酸的载体、以及包含所述核酸或载体的组合物
本申请提供了编码本文所述的融合蛋白的核酸。编码融合蛋白的核酸可以通过常规方法容易地从特定融合蛋白的氨基酸序列中制备。编码氨基酸序列的核苷酸序列可以是从前述NCBI RefSeq ID或GenBank的登录号中获得，用于每个结构域的氨基酸序列，并且本申请的核酸可以使用标准分子生物学和/或化学程序制备。例如，可以基于核苷酸序列合成核酸，并且本申请的核酸可以通过使用聚合酶链式反应(PCR)将从cDNA文库获得的DNA片段进行组合来制备。
本申请的核酸可以与另一种核酸连接，以便在合适的启动子的控制下表达。启动子的实例包括通过药物(例如四环素或多柔比星)等作用组成型促进基因或可操作地连接的构建体的表达的启动子、诱导基因或可操作地的连接构建体的表达的启动子。为了获得核酸的有效转录，本申请的核酸还可以与和启动子或转录起始位点配合的其他调节元件连接，例如包含增强子序列、或终止子序列的核酸。除了本申请的核酸之外，可以掺入可以为用于确认核酸表达的标记物的基因(例如，药物抗性基因、编码报告酶的基因、或编码荧光蛋白的基因)。
在实施例中，核酸是用于在特定宿主中表达的密码子优化的核酸。
本申请进一步提供了载体，其包含编码本文所述的融合蛋白的核酸。术语“载体”、“表达载体”、和“表达构建体”或“构建体”可互换使用，并且均定义为被设计为用于细胞中蛋白质表达的质粒、病毒或其他核酸。载体或构建体用于将基因引入宿主细胞，由此载体将与细胞中的聚合酶相互作用以表达该载体/构建体中编码的蛋白质。表达载体和/或表达构建体可以存在于染色体外或整合到染色体中的细胞中。当整合到染色体中时，包含表达载体或表达构建体的核酸将是表达载体或表达构建体。
本申请进一步提供组合物，其包含本文所述的至少一种核酸或至少一种载体。
本申请进一步提供了组合物，其包含第一核酸和第二核酸，包含具有第一核酸的第一载体以及具有第二核酸的第二载体、或包含具有第一核酸和第二核酸的载体，其中
(1)该第一核酸编码本文所述的融合蛋白，
(2)该第二核酸编码包含以下的嵌合抗原受体(CAR)：
(a)细胞外配体结合结构域，其包含与预定抗原特异性结合的单链可变片段(scFv)；
(b)跨膜结构域，以及
(c)细胞质区段，其包含一个或多个信号传导结构域，优选地其包含4-1BB信号传导结构域和CD3ζ信号传导结构域。
在一些实施例中，预定抗原是肿瘤相关抗原。
在一些实施例中，肿瘤相关抗原选自以下组：CEA、密封蛋白18.2、GPC3、受体酪氨酸激酶样孤儿受体1(ROR1)、CD38、CD19、CD20、CD22、BCMA、CAIX、CD446、CD133、EGFR、EGFRvIII、EpCam、GD2、EphA2、Her1、Her2、ICAM-1、IL13Ra2、间皮素、MUC1、MUC16、NKG2D、PSCA、NY-ESO-1、MART-1、WT1、MAGE-A10、MAGE-A3、MAGE-A4、EBV、NKG2D、PD1、PD-L1、CD25、IL-2和CD3。
在一些实施例中，肿瘤相关抗原是CEA。
(3)宿主细胞
本申请提供了宿主细胞，其包含本文所述的核酸或载体或组合物。因此，当表达时，本文所述的融合蛋白将在用于细胞疗法的宿主细胞的表面上表达。
在一些实施例中，宿主细胞是同种异体细胞。
在一些实施例中，宿主细胞是哺乳动物细胞，优选地灵长类动物细胞，更优选地人细胞。
在一些实施例中，宿主细胞选自T细胞、或原代T细胞、γδT细胞、NK细胞、NKT细胞、巨噬细胞、B细胞、或非免疫细胞。
(4)药物组合物
本申请的药物组合物包含表达融合蛋白的细胞，优选地表达融合蛋白和CAR的细胞，如本文所述的，与一种或多种药学上或生理学上可接受的载剂、稀释剂或赋形剂组合。此类组合物可以包含缓冲液，如中性缓冲盐水、磷酸盐缓冲盐水等；碳水化合物，如葡萄糖、甘露糖、蔗糖、葡聚糖、或甘露醇；蛋白质、多肽或氨基酸，如甘氨酸；抗氧化剂；螯合剂，如EDTA或谷胱甘肽；佐剂(例如氢氧化铝)；以及防腐剂。在一方面，本申请的组合物被配制用于静脉内施用。
本申请的药物组合物能以适合于待治疗(或预防)的疾病的方式施用。施用的总量和频率将由如患者的状况以及患者的疾病的类型和严重程度等因素来确定，然而适当的剂量可以通过临床试验来确定。
适合的药学上可接受的赋形剂是本领域技术人员熟知的。药学上可接受的赋形剂的实例包括磷酸盐缓冲盐水(例如0.01M磷酸盐、0.138M NaCl、0.0027M KCI，pH 7.4)、含有无机酸盐(例如盐酸盐、氢溴酸盐、磷酸盐、或硫酸盐)的水溶液、盐水、乙二醇或乙醇溶液、以及有机酸的盐(例如醋酸盐、丙酸盐、丙二酸盐或苯甲酸盐)。在一些实施例中，也可以使用佐剂，如润湿剂或乳化剂、和pH缓冲剂。在一些实施例中，可以适当使用在Remington’sPharmaceutical Sciences[雷明顿药物科学](Mack Pub.Co.[马克出版公司],新泽西州1991)(出于所有目的，其通过引用以其整体并入本文)中描述的药学上可接受的赋形剂。本申请的组合物可以配制成适用于肠胃外施用的已知形式，例如，注射或输注。在一些实施例中，本申请的组合物可以包含配制品添加剂，例如悬浮剂、防腐剂、稳定剂和/或分散剂、以及在储存期间延长有效期的保存剂。
(5)治疗方法
本申请提供了治疗有需要的受试者的疾病的方法，该方法包括向该受试者施用有效量的本文所述的药物组合物。
在一些实施例中，疾病是癌症。
在一些实施例中，癌症是恶性血液病或实体瘤。
在一些实施例中，癌症是卵巢癌、胰腺癌、结肠癌、结直肠癌、淋巴瘤、食管癌、肺癌、卵巢癌、肝癌、头颈癌、或胆囊癌。
(6)产生具有降低的靶膜结合蛋白水平的细胞的方法
本申请提供了产生具有降低的靶膜结合蛋白水平的细胞的方法，该方法包括将本文所述的核酸、载体、或组合物引入细胞中。
(7)降低或预防GvHD的方法
本申请提供了降低或预防与向受试者施用一个或多个CAR T细胞相关的该受试者的GvHD的方法，该方法包括：
(1)用本文所述的核酸或载体转染一个或多个CAR T细胞，以及
(2)向该受试者施用所述CAR T细胞。
(8)下调细胞群中的膜结合蛋白(MBP)的方法
本申请提供了下调细胞群中的膜结合蛋白(MBP)的方法，该方法包括向所述细胞群添加本申请的宿主细胞，其中该宿主细胞表达包含与所述MBP特异性结合的scFv的融合蛋白，和/或该宿主细胞表达包含具有跨膜结构域的MBP的组分或其片段的融合蛋白。
优选地，宿主细胞群是T细胞群，优选地人原代T细胞群。
优选地，MBP是CD3，优选地人CD3。
本申请中的示例序列
*不包括P2A-GFP(即P2A-eGFP)序列；**斜体表明P2A序列。
实例1
I.系统对照构建体
LS008，SP-αCD19 scFv-CD8α铰链/TM-P2A-eGFP(图2)、CD19 CAR，即本文采用LS008作为阴性对照。
II.实例2-3中使用的构建体
实例2：
LG089，与SP34 scFv的N末端连接的E3连接酶FBW7片段(2-293)(FBW7-SP34 scFv-P2A-eGFP)；
LG091，与SP34 scFv的C末端连接的E3连接酶VHL片段(152-213)(SP34 scFv-VHL-P2A-eGFP)；
LG092，与SP34 scFv的C末端连接的E3连接酶SPOP片段(167-374)(SP34 scFv-SPOP-P2A-eGFP)；
LG085，与OKT3 scFv的C末端连接的E3连接酶CHIP片段(128-303、CHIP.dTPR)(OKT3 scFv-hCHIP.dTPR-P2A-eGFP)；
实例3：
LG021，SP34 scFv-CD8α铰链/TM-P2A-eGFP；
LG022，膜锚定的信号肽(SP)-SP34 scFv-CD8α铰链/TM-P2A-eGFP；
LG023，细胞质OKT3 scFv-CD8α铰链/TM-P2A-eGFP；
LG024，SP-OKT3 scFv-CD8α铰链/TM-P2A-eGFP；
III.实例4-17中使用的构建体
实例4：
LG112，SP-OKT3 scFv-CHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG113，SP-OKT3 scFv-CD8α铰链/TM-CHIP.dTPR-P2A-eGFP；
实例5：
LG114，SP-OKT3 scFv-FBW7-CD8α铰链/TM-P2A-eGFP；
LG115，SP-OKT3 scFv-VHL-CD8α铰链/TM-P2A-eGFP；
LG116，SP-OKT3 scFv-SPOP-CD8α铰链/TM-P2A-eGFP；
LG117，SP-OKT3 scFv-SOCS2-CD8α铰链/TM-P2A-eGFP；
实例6：
LG118，SP-SP34 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG123，SP-UCHT1 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG124，SP-UCHT1.Y177T scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG125，SP-L2K scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG126，SP-F6A scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
实例7：
LG119，SP-BMA031.wt scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG120，SP-BMA031.H6L12 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP
LG133，SP-BMA031.wt scFv-CD8α铰链/TM-P2A-eGFP
LG134，SP-BMA031.H6L12 scFv-CD8α铰链/TM-P2A-eGFP
实例9-10：
CD5、CD7、PD-L1、CD47下调构建体
LG137，SP-αCD5.14 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG138，SP-αCD7.TH69 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
MLB052，SP-αPD-L1 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
MLB053，SP-αCD47 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
任选地，也可以是scFv与E3连接酶之间的接头(例如SEQ ID No.91)。
任选地，也可以是CD8 TM与E3连接酶之间的接头(例如SEQ ID No.91)。
实例12：
LG222，SP-SP34-CD3ζ.ΔIC-1-GRAIL.IC-P2A-eGFP
LG222.1，SP-SP34-CD8α铰链/TM-GRAIL.IC-P2A-eGFP
LG222.2，SP-SP34-CD4铰链/TM-GRAIL.IC-P2A-Egfp
任选地，也可以是与LG222、LG222.1、LG222.2的TM结构域的C末端连接的细胞内结构域(例如SEQ ID No.90)。
实例13：
MLB014，CD3ζ.ΔIC-IL2Rβjm-P2A-eGFP；
MLB046，CD3ε.ΔIC-IL2Rβjm-P2A-eGFP；
实例14：
LG171，CD3ζ.ΔIC-GRAIL.IC-P2A-eGFP
LG212，CD3ζ.ΔIC-P2A-eGFP
LG171.ZF、CD3ζ.ΔIC-GRAIL.ZF突变体-P2A-GFP
LG171.H2N2、CD3ζ.ΔIC-GRAIL.IC.H2N2突变体-P2A-GFP
LG171p1、CAG-CD3ζ.ΔIC-GRAIL.IC-P2A-eGFP
实例15：
LG132，CD3ζ-CHIP.DTPR-P2A-GFP
LG213，CD3ζ.ΔIC-CHIP.DTPR-P2A-GFP
RNF133，RNF133-P2A-GFP
LG174，CD3ζ.ΔIC-RNF133.IC-P2A-GFP
RNF122，RNF122-P2A-GFP
LG180，CD3ζ.ΔIC-RNF122.rIC-P2A-GFP
RNF152，RNF152-P2A-GFP
LG183，CD3ζ.ΔIC-RNF152.rIC-P2A-GFP。
实例2
细胞质构建体(LG089、LG091、LG092、LG085)对人原代T细胞中的TCR/CD3复合物的验证。
在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂(干细胞技术公司(StemCell Technologies))将人分离的原代T细胞体外激活3天。然后收集激活的原代T细胞，并且用表达用于TCR/CD3降解的细胞质构建体(LG089、LG091、LG092、LG085构建体)之一的pBluescript II SK(+)-PB供体质粒进行电穿孔。两天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)(博奇公司(Biolegend))两者进行染色。pmaxGFP(仅表达GFP的质粒)和LS008两者均表明在原代T细胞中的良好转染效率，并且在这两个构建体中均没有TCRα/β和CD3的下调(图3A)。然而，当采用SP34 scFv和OKT3 scFv促进TCR/CD3复合物与E3连接酶(包括FBW7(图3B)、VHL(图3C)、SPOP(图3D)和hCHIP.dTPR(图3E))的接合时，GFP+细胞中仍然没有明显的TCR/CD3复合物的降解，表明当前系统潜在的错误靶向影响。
实例3
膜锚定的构建体(LG021、LG022、LG023、LG024)对人原代T细胞和Jurkat细胞系中的TCR/CD3复合物的验证。
在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集激活的原代T细胞，并且用表达用于TCR/CD3降解的细胞质/膜锚定的构建体(LG021、LG022、LG023、LG024)之一的质粒进行电穿孔。两天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。结果显示使用没有E3连接酶/泛素的SP34 scFv不能引发TCR/CD3的任何下调，无论它是在细胞质中表达(LG021)(图4A)或是在细胞膜上表达(LG022)(图4B)。虽然OKT3 scFv(LG023)的细胞质表达(图4C)显示与SP34 scFv(LG021)相似的影响，但当表达在细胞膜上锚定时(LG024)，它的确引发GFP+细胞中的TCR/CD3复合物的下调(图4D)。
用PiggyBac转座酶mRNA和表达膜锚定的OKT3构建体(LG024)的转座子两者电穿孔Jurkat细胞。维持Jurkat细胞直到第57天，并且用CD3(PE)和TCRα/β(APC)染色后进行流式细胞术测试，显示在具有稳定整合转座子(表达膜锚定的OKT3构建体(LG024))的细胞中TCR/CD3复合物的显著的降解(GFP阳性>85％，图5)。
实例4
E3泛素连接酶与膜锚定的OKT3构建体(LG112，LG113)的连接对Jurkat细胞系和人原代T细胞中的TCR/CD3复合物的验证
1.使用Jurkat细胞验证构建体(LG112、LG113)
用PiggyBac转座酶mRNA和以不同的方式与E3泛素连接酶连接的表达膜锚定的OKT3构建体(LG112，LG113)的转座子两者电穿孔Jurkat细胞。在第3天收获Jurkat细胞并且用CD3(PE)和TCRα/β(APC)染色后进行流式细胞术分析。图6A示出了系统对照pmaxGFP和LS008在Jurkat细胞中具有良好的转染效率，并且在这两种构建体的任一种中没有TCRα/β和CD3的下调。图6B示出了没有E3泛素连接酶的膜锚定的OKT3 scFv构建体(LG024)显示了Jurkat细胞中TCR-CD3复合物显著的下调。当hCHIP.dTPR以外膜方式(近端连接)(LG112)(图6C)而非细胞质方式(LG113)(图6D)与OKT3 scFv连接时，获得甚至更强的TCR/CD3复合物下调。
2.使用人分离的原代T细胞验证构建体(LG112、LG113)
在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集原代T细胞，并且用PiggyBac转座酶mRNA和表达不同膜锚定的OKT3构建体的转座子两者进行电穿孔。三天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。图7A示出了系统对照pmaxGFP和LS008在原代T细胞中具有良好的转染效率，并且在这两种构建体的任一种中没有TCRα/β和CD3的下调。与我们在Jurkat细胞系中发现的相似，当hCHIP.dTPR以外膜方式(近端连接)(LG112)(图7C)而非细胞质方式(LG113)(图7D)与OKT3 scFv连接时，降解可以是更显著的。发现与没有E3泛素连接酶的膜锚定的OKT3 scFv构建体(LG024)(图7B)相比，当E3泛素连接酶(CHIP.dTPR)位于整个构建体的细胞质部分(LG113，图7D)时，TCR/CD3降解没有显著的变化。
实例5人原代T细胞中不同E3连接酶与的膜锚定的OKT3构建体连接对TCR/CD3复合物下调影响的验证
设计并合成一系列具有与膜锚定的OKT3 scFv连接的不同E3连接酶(包括FBW7、VHL、SPOP和SOCS2)的构建体(图8A)。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集原代T细胞，并且用表达用于TCR/CD3降解的膜锚定的构建体之一的质粒进行电穿孔。三天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。结果显示，当采用OKT3 scFv时，E3连接酶(包括FBW7(图8B)、VHL(图8C)和SOCS2(图8E))可能引发TCR/CD3的轻微下调。有趣的是，SPOP在人原代T细胞中可以赋予TCR/CD3的更强的下调(图8D)。
实例6由靶向不同CD3的scFv介导的TCR/CD3降解的验证
设计并合成一系列具有靶向不同CD3的scFv(包括SP34、UCHT1、UCHT1.Y177T、L2K和F6A)的TCR/CD3降解构建体(图9A)。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集原代T细胞，并且用PiggyBac转座酶mRNA和转座子DNA构建体两者进行电穿孔。三天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。结果显示，通过在构建体中以外膜方式与CHIP.dTPR直接连接，SP34scfv(图9B)和F6A scfv(图9F)可能引发TCR/CD3的下调；然而UCHT1 scfv(图9C)、UCHT1.Y177T scfv(图9D)、和L2K scfv(图9E)在人原代T细胞中可以赋予TCR/CD3的更强的下调(图9B-9F)。
实例7E3连接酶(CHIP.dTPR)是优化人原代T细胞中的TCR/CD3下调所必需的。
在存在或不存在CHIP.dTPR的情况下，设计并合成一系列具有靶向TCR的scFv(BMA031或BMA031.H6L12)的TCR降解构建体(图10A)。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集细胞，并且用PiggyBac转座酶mRNA和转座子DNA构建体两者进行电穿孔。三天后，收获原代T细胞并且针对CD3(PE)和TCRα/β(APC)两者进行染色。结果显示，在CHIP.dTPR存在的情况下，靶向TCR的scFv(BMA031和BMA031.H6L12)两者均导致强转染和TCR/CD3复合物的明显下调(图10B-图10C)。然而，在不存在CHIP.dTPR的情况下，原代T细胞可能无法在转染过程中存活，在这种情况下，只有一小部分细胞显示出目的基因的成功表达(图10D-图10E)。此外，LG024(没有E3连接酶的另一TCR/CD3下调构建体)在人原代T细胞中不能实现良好的转染(图4D)或TCR/CD3下调(图7B)。因此，E3连接酶似乎是优化人原代T细胞中的TCR/CD3下调所必需的。
实例8在Jurkat细胞中通过CD3/CD28刺激CD3下调赋予较低的激活。
用PiggyBac转座酶mRNA和表达不同膜锚定的OKT3构建体(LG024、LG112)的转座子或对照LS008两者电穿孔Jurkat-NFAT细胞。将细胞维持14天，并且检查在CD3/CD28/CD2Immunocult/激活剂再刺激之前和之后的激活状态。构建体LG024、LG112的表达是通过转导的Jurkat细胞(即转导的Jurkat细胞)中的联合GFP表达(图11A-11B中的右小图的纵坐标)推断的；CD69(图11A-11B中的右小图的横坐标)是在T细胞激活的数小时内上调的激活标志物，使用PE缀合的抗CD69一抗(博奇公司，加利福尼亚州圣地亚哥)评估CD69表达。结果显示在基线时所有细胞的CD69(T细胞激活标志物)表达水平低(图11A)。然而，与来自LS008转染的细胞的T细胞相比，在LG024或LG112转染的GFP+细胞中的CD69表达水平在刺激后显著降低(图11B)。这一发现表明TCR/CD3下调通过CD3/CD28/CD2刺激赋予对T细胞激活的较低应答性。
实例9CD5或CD7下调构建体和验证。
设计并合成一系列CD5或CD7降解构建体(图12A)。在人IL-2、IL-7和IL-15存在的情况下，使用干细胞公司Immunocult-XF/激活剂将人分离的原代T细胞体外激活3天。然后收集原代T细胞，并且用PiggyBac转座酶mRNA和转座子DNA构建体两者进行电穿孔。四天后，收获细胞并且针对CD5(PE)和CD7(APC)两者的表达进行染色(图12B-图12C)。结果显示αCD5.14 scFv赋予CD5的强下调(图12B)。对于CD7，αCD7.TH69 scFv(靶向CD7的scFv)在人原代T细胞中也显示显著的下调影响(图12C)。
实例10PD-L1和CD47通过E3 CHIP构建体的下调
转座子介导的E3连接酶构建体的递送在Jurkat细胞中用于修饰表面分子的表达(图13B)。EF1α启动子用于驱动抗原特异性ScFv-E3连接酶嵌合融合蛋白的表达。P2A序列用于驱动同时GFP表达，以鉴定和表征表达E3连接酶系统的细胞(图13A)。用表达MLB052或MLB053的PiggyBac载体和Piggy Bac转座酶mRNA电穿孔Jurkat细胞。在转座子稳定整合至Jurkat细胞基因组中后，在电穿孔后第5天通过流式细胞术评估PD-L1和CD47的降解。对GFP阳性细胞(即，表达E3连接酶构建体的那些)的门控显示PD-L1表面表达的边际下调(即图13B右列的上小图中的黑线标记区域稍微向左移动到虚线标记区域)。在标准细胞培养条件下(5％ CO2，在补充有5mM HEPES和10％ FBS的RPMI培养基中)，Jurkat细胞不强烈表达PD-L1。表达MLB053的Jurkat细胞上的相同门控策略在表达E3连接酶构建体的那些细胞中显示CD47表达的强下调(即图13B右列的下小图中的黑线标记区域显著向左移动到虚线标记区域)。如预期的，亲本Jurkat细胞显示出CD47的明亮染色(虚线标记区域)。
实例11通过E3 CHIP连接的靶向CD3的构建体(LG112)的TCR表达的旁分泌下调。
为了证实E3连接酶构建体能以抗原特异性方式下调在邻近细胞上的表面分子，我们设计了经转导表达LG112的Jurkat细胞与亲本储备细胞之间的共培养试验。为了区分两种群体，用CellTrace紫色染料标记亲本Jurkat细胞。
图14A提供了门控策略的概述，显示CellTrace紫色阳性亲本细胞(即没有LG024转染的Cell Trace+细胞)与CellTrace紫色阴性E3连接酶转染的细胞(即LG024转染的CellTrace–细胞)之间的描述。在图14A左列的上小图中，CellTrace紫色阴性群体(即LG024转染的Cell Trace–细胞)进一步细分为表达E3连接酶构建体的GFP阳性群体(图14A中间列的右填充区域)和不表达E3连接酶构建体的GFP阴性群体(图14A中间列的左填充区域)。在E3连接酶阳性细胞(即GFP阳性群体，77.8％)与E3连接酶阴性细胞(即GFP阴性群体，22.2％)的高比率下，发现整个细胞群的TCR表达低，如通过CD3染色确定的(即图14A右列的上小图)。
图14B示出了由于E3连接酶阳性细胞的百分比通过用亲本Jurkat细胞的连续稀释而降低，从约78％阳性降低至11％阳性，我们观察到CellTrace紫色阳性亲本细胞群中TCR表面表达增加。因此，在这一系统中，在邻近细胞上的TCR表达与群体中表达E3连接酶的细胞数量呈负相关。这些结果显示我们的E3连接酶构建体以旁分泌方式促进表达非E3连接酶的细胞中的靶分子的抗原特异性下调。值得注意的是，表达E3连接酶的细胞中TCR下调的程度也依赖于邻近细胞的表达谱，其中当表达E3连接酶的细胞部分更高时敲低更完全。稀释E3连接酶阳性细胞的数量也挽救了转染细胞群中CellTrace紫色阴性GFP阴性细胞的表型，如该群体中TCR阳性细胞的增加所示。
实例12铰链/跨膜结构域(TM)选择影响由SP34和GRAIL.IC两者介导的TCR/CD3复合物的下调。
为了增强CD3与GRAIL.IC(E3功能结构域)之间的特异性接合，采用靶向CD3的scFv、SP34并且通过如图15A中列出的不同的铰链/跨膜结构域与GRAIL.IC连接。在Jurkat和人原代T细胞两者中测试所有三个构建体LG222、LG222.1和LG222.2。
1.在Jurkat细胞中测试LG222、LG222.1和LG222.2。
在电穿孔后第3天，收获Jurkat细胞并且使用αCD3和αTCRα/β抗体针对TCR表达进行染色。基于在融合蛋白构建体上的GFP共表达鉴定表达构建体的细胞。结果显示CD3ζ.ΔIC(LG222)(图15B)和CD4铰链/TM(LG222.2)(图15D)两者均优于CD8a铰链/TM(LG222.1)(图15C)，后者仅较少部分GFP+细胞显示细胞表面上的TCR/CD3下调(图15C从左至右第三和第四小图中的左上区域)。
2.在人原代T细胞中测试LG222、LG222.1和LG222.2。
在电穿孔后第3天，收获经电穿孔用于表达LG222、LG222.1或LG222.2构建体的预激活的原代T细胞，并且使用αCD3和αTCRα/β抗体评估TCR/CD3表达(图16A-16C)。与Jurkat细胞相似，使用CD3ζ.ΔIC结构域的构建体实现TCR/CD3表达的显著的下调(图16A，LG222)。使用CD8a铰链/TM结构域仅在一小部分GFP+细胞中赋予TCR/CD3下调(图16B，LG222.1)。然而，构建体LG222.2的多个重复没有实现良好的GFP表达，而无法得出TCR/CD3下调的可靠结论(图16C，LG222.2)。
实例13CD3-IL2Rβ近膜融合蛋白的表达促进TCR复合物表面不稳定性
MLB014/(CD3ζ.ΔIC-IL2Rβjm)构建体和MLB046/(CD3ε.ΔIC-IL2Rβjm)构建体在图18A中显示。
1.用MLB014或MLB046转染的Jurkat细胞
在用MLB014/(CD3ζ.ΔIC-IL2Rβjm)构建体或MLB046/(CD3ε.ΔIC-IL2Rβjm)构建体电穿孔后第5天，收获Jurkat细胞，并且使用αCD3抗体(即抗CD3抗体)针对TCR表达进行染色。基于在融合蛋白构建体上的GFP共表达鉴定表达构建体的细胞。对GFP阳性群体的门控表明，可检测的TCR表面表达存在大的阴性移动(图18B从左到右第二和第三小图中的左上区域)。这些数据表明将MLB014/(CD3ζ.ΔIC-IL2Rβjm)构建体或MLB046/(CD3ε.ΔIC-IL2Rβjm)掺入至TCR复合物中促进整个复合物内化的增加(图18B)。
2.用MLB014或MLB046转染的原代T细胞
在电穿孔后第5天，收获经电穿孔用于表达MLB014/(CD3ζ.ΔIC-IL2Rβjm)构建体或MLB046/(CD3ε.ΔIC-IL2Rβjm)的原代T细胞，并且使用αCD3和αTCRα/β抗体评估TCR表达(图18C)。此处，原代T细胞中TCR表达的下调没有Jurkat细胞明显，但仍可观察到GFP表达与TCR或CD3表达之间的负相关(图18C从左到右第二和第三列的每个小图中的左上区域)。这些数据表明相同的潜在机制在原代T细胞和Jurkat细胞中起作用，但在原代T细胞中TCR下调的效率有所降低。
实例14LG171/(CD3ζ.ΔIC/GRAIL.IC)融合蛋白的表达显著促进Jurkat细胞和人原代T细胞两者中的TCR/CD3复合物表达下调
1.用LG171转染的Jurkat细胞
LG171/(CD3ζ.ΔIC/GRAIL.IC)融合蛋白构建体在图19中显示。
在用LG171(即CD3ζ.ΔIC-GRAIL.IC)融合蛋白构建体电穿孔后第3天，收获Jurkat细胞，并且使用αCD3抗体和αTCRα/β抗体针对TCR表达进行染色。基于在融合蛋白构建体上的GFP共表达鉴定表达构建体的细胞。对GFP阳性群体的门控表明大多数移动为不可检测的TCR表面表达。这些数据表明将CD3ζ.ΔIC/GRAIL.IC构建体掺入至TCR复合物中促进整个复合物的不稳定性的增加(图20)。
2.用LG171转染的原代T细胞
在电穿孔后第3天，收获经电穿孔用于表达LG171(即CD3ζ.ΔIC-GRAIL.IC)构建体的原代T细胞，并且使用αCD3和αTCRα/β抗体评估TCR/CD3表达(图21)。相似地，TCR/CD3表达的下调在GFP+部分中是显著的。这些数据表明使用CD3ζ.ΔIC-GRAIL.IC融合蛋白的相同的潜在机制在原代T细胞和Jurkat细胞两者中都是有效的。
3.LG212(没有E3连接酶)
用PiggyBac载体LG212和PiggyBac转座酶电穿孔原代T细胞。在电穿孔后第3天，通过针对CD3和TCRα/β进行的染色评估TCR表达。当在人原代T细胞中仅采用截短的CD3ζ(即CD3ζ.ΔIC)时，我们不能看到任何TCR/CD3下调(图22)。
4.用构建体LG171.ZF(含有结构域开关)或LG171.H2N2(含有点突变)转染的原代T细胞
在具有CD8α铰链(SEQ ID NO.85)的GRAIL中通过切换锌指结构域(SEQ ID NO.84)或将点突变引入锌指结构域产生两种以上构建体LG171.ZF、LG171.H2N2(图23A)。FACS(图23B)和蛋白质印迹(图23C)测试两者表明GRAIL的功能锌指结构域对LG171中更好的TCR/CD3下调是必需的(图21)。
5.LG171嵌合蛋白不能赋予CD5或CD7的非特异性下调
与Jurkat报告细胞一样，用PiggyBac载体LG171和PiggyBac转座酶电穿孔原代T细胞。在电穿孔后第3天，通过流式细胞术评估CD5和CD7表达两者。LG171在原代T细胞中的下调作用是TCR/CD3特异性的，因为CD5和CD7都没有受到影响(图24)。
6.用LG171p1/(CAG/CD3ζ.ΔIC/GRAIL.IC)转染的T细胞
CAG启动子在Jurkat细胞和人原代T细胞两者中是赋予对TCR/CD3复合物显著的且持续的下调的良好的可替代物。
除了在其他实例中测试的EF1a启动子之外，还基于LG171设计研究了CAG启动子。为了实现这一目的，在Jurkat和人原代T细胞两者中设计(图25A)并测试新构建体LG171p1。
6.1用LG171p1转染的Jurkat细胞
在用LG171p1/(CAG/CD3ζ.ΔIC/GRAIL.IC)融合蛋白构建体电穿孔后第3天(图25B)，收获Jurkat细胞，并且使用αCD3和αTCRα/β抗体针对TCR表达进行染色。基于在融合蛋白构建体上的GFP共表达鉴定表达构建体的细胞。对GFP阳性群体的门控表明在Jurkat中大多数移动为不可检测的TCR表面表达(图25B从左到右第三和第四小图中的左上区域)。这些数据表明CAG启动子可能是Jurkat中赋予显著的基因表达水平的EF1a的良好替代物。
6.2用LG171p1转染的原代T细胞
在电穿孔后第3天，收获经电穿孔用于表达LG171p1构建体的预激活的原代T细胞，并且使用αCD3和αTCRα/β抗体评估TCR/CD3表达(图25C)。相似地，TCR/CD3表达的下调在GFP+部分中是显著的(图25C从左至右第三和第四列的每个小图中的左上区域)。这些数据表明使用LG171p1融合蛋白的相同的潜在机制在原代T细胞和Jurkat细胞两者中都是起作用的。更显著地，长期随访表明TCR/CD3的下调不能维持到第13天。(图25C)
实例15具有不同E3连接酶的TCR/CD3降解构建体(具有除GRAIL.IC之外的不同E3连接酶的CD3ζ.ΔIC)。
1.我们还以与LG171相似的设计测试了用于TCR下调的CHIP(图26A)。与具有全长CD3ζ的LG132的无影响相比，LG213中的下调主要由CD3ζ截短(即CD3ζ.ΔIC)引起(图26B)。
2.还以与LG171相似的设计测试了其他E3连接酶(包括RNF133、RNF122和RNF152)(图27A)。FACS和蛋白质印迹两者显示一致的结果，当E3连接酶功能结构域与CD3ζ截短连接时TCR下调(图27B-27C)。
实例16用LG171(CD69、ppERK、IFN-γ)转染的细胞中的激活降低
1.用所指出的构建体转染的Jurkat细胞中的CD69、ppERK水平
为了检查激活的影响，由CD3/CD28(抗CD3/CD28抗体)短暂刺激用所指出的构建体转染的Jurkat细胞，并且然后测试CD69上调和细胞内ERK磷酸化(即ppERK或ERK)水平。两种测定显示LG171显著减弱CD69的上调以及ERK磷酸化(图28A-图28B)。尽管CD3z截短(即CD3ζ.ΔIC)可以在比GFP、CD3ζ、GRAIL更短的时间刺激(20min，图28B)中延迟ERK磷酸化(填充区域向左移动至黑线标记区域)，但当细胞被刺激4小时时，它仍然不能降低CD69上调(图28A)。然而，在LG171中CD69、ppERK的上调两者是显著延迟的/抑制的，表明CD3ζ截短(即CD3ζ.ΔIC)与GRAIL之间的协同影响。
2.用所指出的构建体转染的原代T细胞中的IFN-γ水平
我们还测试了对人原代T细胞激活的影响。用所指出的构建体转染预激活的原代T细胞。几天后，用OKT3(抗CD3抗体)再刺激T细胞用于CD69上调和IFN-γ细胞因子分泌。与我们在Jurkat中发现的相似，用LG171或LG171p1(CAG启动子)转染的人原代T细胞显示CD69上调(图29A)和IFN-γ分泌(图29B)显著较低。当采用更强的TCR交联化学物质PHA-L(图29B)时，与GFP对照相比，LG171和LG171p1也赋予较低的IFN-γ分泌，这表明在同种异体T细胞输注期间避免潜在GvHD应答的更安全的策略。
为了进一步证实这一发现，采用MLR测定(图29C)。详细地说，将模拟T细胞或用LG171p1转染的T细胞与体外衍生的同种异体成熟DC细胞共培养5天。然后，通过ELISA测试上清液中的IFN-γ水平。相似地，当用来自两种不同供体的成熟DC测试时，LG171p1显著降低IFN-γ分泌。
实例17LG171.CldnCar的表达和杀伤效率
迄今为止，目前批准用于临床使用的所有CAR T细胞疗法都依赖于自体T细胞工程化和再植入。为了标准化跨供体的疗法并降低CAR T细胞疗法的成本，需要开发强大的同种异体T细胞技术。
1.CldnCar和LG171.CldnCar融合蛋白构建体在图30A中显示。我们将编码基于GRAIL的受体TAC的第一核酸(即LG171或CD3ζ-GRAIL.IC)与编码CAR(密封蛋白18.2CAR)的第二核酸组合至单个转座子载体中以产生LG171.CldnCar(即LG171/密封蛋白18.2CAR联合表达构建体)。
2.通过αCD3ε(抗CD3抗体，用于CD3表达)检测TCR下调，以及通过αF(ab’)2染色(用于scFv表达)检测CAR表达；结果在图30B中显示。
表达受体TAC/CAR构建体的T细胞在GFP表达上进行门控(图30B的左小图和右小图中从上到下的第一个峰)。从图30B的左小图可以是看到，与用CldnCar(从上到下的第三个峰)转染的T细胞相比，用LG171.CldnCar(最低峰)和LG171(从上到下的第二个峰)转染的T细胞缺乏TCR表达。从图30B的右小图可以是看到，用LG171转染的T细胞缺乏scFv表达(从上到下的第二峰)，然而与用CldnCar转染的T细胞相比(从上到下的第三峰)，用LG171.CldnCar转染的T细胞具有正常的scFv表达(最低峰)。
3.为了测试TCR缺陷型T细胞中的CAR功能性，我们测定了其对HEK-cldn18.2细胞(这些细胞经转导以过表达CLDN18.2)和HEK293T细胞(即亲本HEK细胞)(这些细胞是密封蛋白18.2阴性的)的细胞毒性潜力，结果在图30C中显示。
从图30C的左小图可以是看到，没有检测到针对密封蛋白18.2阴性的亲本HEK细胞系(即HEK)的细胞毒性。从图30C的右小图可以是看到，表达LG171/密封蛋白18.2CAR联合表达构建体(即LG171.CldnCar)的T细胞显示与表达密封蛋白18.2CAR(即CldnCar)对照质粒(即HEK-CLDN 18.2)的细胞相同的抗原特异性细胞毒性。抗原特异性细胞裂解随着E:T比率的增加而增加。单独表达LG171的T细胞显示对表达密封蛋白18.2的靶细胞应答的细胞毒性最小，表明这一影响的确由CAR介导。
4.综合而言，我们已经证明E3连接酶融合蛋白可以用于下调TCR表达以及预防T细胞激活，并且这一影响是TCR特异性的并且在共表达系统中不影响CAR功效。因此，我们相信受体TAC平台代表了在蛋白质水平下通过操作TCR表达产生同种异体CAR T细胞的新颖的方式。
其他实施例
应当理解，虽然已经结合具体实施方式对本申请进行了描述，但前面的描述旨在说明而非限制本申请的范围，本申请的范围由所附的权利要求的范围限定。其他方面、优点以及修改在随附权利要求的范围内。
上述描述的各种实施例可以进行组合以提供另外的实施例。本说明书中提及的和/或申请数据表中列出的所有美国专利、美国专利申请出版物、美国专利申请、国外专利、国外专利申请和非专利出版物，均通过引用以其整体并入本文。如果需要采用各种专利、申请和出版物的概念来提供又另外的实施例，则可以修改这些实施例的各方面。
鉴于以上详细描述，可以对实施例做出这些和其他改变。总的来说，在以下权利要求中，所使用的术语不应被解释为将权利要求限制于说明书和权利要求中申请的特别实施例，而是应被解释为包括所有可能的实施例以及这些权利要求有权具有的等同物的全部范围。因此，权利要求不受本申请的限制。
序列表
<110> 山东博安生物技术股份有限公司（SHANDONG BOAN BIOTECHNOLOGY CO.,LTD.）
博安波士顿有限责任公司（Boan Boston LLC）
<120> 通过受体TAC技术的膜结合蛋白的下调
<130> BA13
<150> US 63/077,658
<151> 2020-09-13
<150> US 63/144,945
<151> 2021-02-02
<150> US 63/173,476
<151> 2021-04-11
<160> 91
<170> PatentIn 3.5版
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<220>
<223> CD19 CAR scFv
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Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
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Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
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Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
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Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
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Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser
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Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu
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Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys
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Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
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Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser
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Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile
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Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
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Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
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Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
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<212> PRT
<213> 人工序列
<220>
<223> SP34 scFv
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
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Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
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Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
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Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
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Arg
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<223> UCHT1 scFv
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Met Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu
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<210> 5
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<223> UCHT1.Y177T scFv
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Met Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
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Val Thr Val Ser Ser
245
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<212> PRT
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<223> L2K scFv
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Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
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Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys
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Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln
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Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr
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Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
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<210> 7
<211> 249
<212> PRT
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<220>
<223> F6A scFv
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Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
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Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
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Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
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Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
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Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly
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Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
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Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
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Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ile Tyr Ala Met Asn Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
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Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Ser
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Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
195 200 205
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
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His Gly Asn Phe Gly Asn Ser Tyr Val Ser Phe Phe Ala Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser
245
<210> 8
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> BMA031 scFv（即 BMA031.wt scFv)
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Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
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Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr
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Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
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Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu Lys Phe
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Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
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Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val His Tyr Cys
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Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
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Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly
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Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala
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Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala
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Thr Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser Gly Thr
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Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val
180 185 190
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr
195 200 205
Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln
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Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
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Lys
<210> 9
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> BMA031.H6L12 scFv
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys
85 90 95
Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala
130 135 140
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala
145 150 155 160
Thr Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Lys
165 170 175
Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val
180 185 190
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
195 200 205
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
210 215 220
Trp Ser Ser Asn Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys
<210> 10
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> αCD5.14 scFv
<400> 10
Ile Asp Ala Met Gly Asn Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
1 5 10 15
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
20 25 30
Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
35 40 45
Gly Leu Arg Trp Met Gly Trp Ile Asn Thr His Thr Gly Glu Pro Thr
50 55 60
Tyr Ala Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
65 70 75 80
Ala Ser Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr
85 90 95
Ala Thr Tyr Phe Cys Thr Arg Arg Gly Tyr Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Met Thr Gln
130 135 140
Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly Glu Arg Val Thr Ile Thr
145 150 155 160
Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser Trp Phe His His
165 170 175
Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile Tyr Arg Ala Asn Arg Leu
180 185 190
Val Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp
195 200 205
Tyr Ser Leu Thr Ile Ser Ser Leu Asp Tyr Glu Asp Met Gly Ile Tyr
210 215 220
Tyr Cys Gln Gln Tyr Asp Glu Ser Pro Trp Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Met Lys Gly Ser Gly Asp Pro Ala
245 250
<210> 11
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> αCD7.TH69 scFv
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Phe Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Asp Glu Val Arg Gly Tyr Leu Asp Val Trp Gly Ala Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ala Tyr Lys Asp Ile Gln Met Thr Gln Thr Thr
130 135 140
Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Ser
145 150 155 160
Ala Ser Gln Gly Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Ser Leu His Ser
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser
195 200 205
Leu Thr Ile Ser Asn Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Ser Lys Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Arg
<210> 12
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> αPD-L1 scFv
<400> 12
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Thr Tyr Ala Gly Ser Asn Glu Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Trp Val Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val
130 135 140
Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val
145 150 155 160
Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Glu Ile Lys
<210> 13
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> αCD47 ScFv
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro
130 135 140
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
145 150 155 160
Ile Val Tyr Ser Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys
165 170 175
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys
<210> 14
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> CD4铰链
<400> 14
Asp Ser Gly Gln Val Leu Leu Glu Ser Asn Ile Lys Val Leu Pro Thr
1 5 10 15
Trp Ser Thr Pro Val Gln Pro
20
<210> 15
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> CD4跨膜结构域
<400> 15
Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile
1 5 10 15
Gly Leu Gly Ile Phe Phe
20
<210> 16
<211> 46
<212> PRT
<213> 人工序列
<220>
<223> CD8α铰链
<400> 16
Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
1 5 10 15
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
20 25 30
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 17
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> CD8α跨膜结构域（用于LS008*）
<400> 17
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 18
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> CD8α跨膜结构域
<400> 18
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr
20
<210> 19
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 信号肽（CD8α）
<400> 19
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 20
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 信号肽（IGHV3-23）
<400> 20
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 21
<211> 303
<212> PRT
<213> 人工序列
<220>
<223> CHIP
<400> 21
Met Lys Gly Lys Glu Glu Lys Glu Gly Gly Ala Arg Leu Gly Ala Gly
1 5 10 15
Gly Gly Ser Pro Glu Lys Ser Pro Ser Ala Gln Glu Leu Lys Glu Gln
20 25 30
Gly Asn Arg Leu Phe Val Gly Arg Lys Tyr Pro Glu Ala Ala Ala Cys
35 40 45
Tyr Gly Arg Ala Ile Thr Arg Asn Pro Leu Val Ala Val Tyr Tyr Thr
50 55 60
Asn Arg Ala Leu Cys Tyr Leu Lys Met Gln Gln His Glu Gln Ala Leu
65 70 75 80
Ala Asp Cys Arg Arg Ala Leu Glu Leu Asp Gly Gln Ser Val Lys Ala
85 90 95
His Phe Phe Leu Gly Gln Cys Gln Leu Glu Met Glu Ser Tyr Asp Glu
100 105 110
Ala Ile Ala Asn Leu Gln Arg Ala Tyr Ser Leu Ala Lys Glu Gln Arg
115 120 125
Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys
130 135 140
Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu
145 150 155 160
Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu
165 170 175
Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His
180 185 190
Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met
195 200 205
Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys
210 215 220
Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met
225 230 235 240
Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp
245 250 255
Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg
260 265 270
Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu
275 280 285
Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr
290 295 300
<210> 22
<211> 176
<212> PRT
<213> 人工序列
<220>
<223> CHIP.dTPR（即h CHIP.dTPR或hCHIP. ΔTPR）
<400> 22
Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys
1 5 10 15
Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser
20 25 30
Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg
35 40 45
Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser
50 55 60
His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr
65 70 75 80
Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys
85 90 95
Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu
100 105 110
Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys
115 120 125
Asp Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr
130 135 140
Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys
145 150 155 160
Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr
165 170 175
<210> 23
<211> 292
<212> PRT
<213> 人工序列
<220>
<223> FBW7.2-293（即FBW7）
<400> 23
Cys Val Pro Arg Ser Gly Leu Ile Leu Ser Cys Ile Cys Leu Tyr Cys
1 5 10 15
Gly Val Leu Leu Pro Val Leu Leu Pro Asn Leu Pro Phe Leu Thr Cys
20 25 30
Leu Ser Met Ser Thr Leu Glu Ser Val Thr Tyr Leu Pro Glu Lys Gly
35 40 45
Leu Tyr Cys Gln Arg Leu Pro Ser Ser Arg Thr His Gly Gly Thr Glu
50 55 60
Ser Leu Lys Gly Lys Asn Thr Glu Asn Met Gly Phe Tyr Gly Thr Leu
65 70 75 80
Lys Met Ile Phe Tyr Lys Met Lys Arg Lys Leu Asp His Gly Ser Glu
85 90 95
Val Arg Ser Phe Ser Leu Gly Lys Lys Pro Cys Lys Val Ser Glu Tyr
100 105 110
Thr Ser Thr Thr Gly Leu Val Pro Cys Ser Ala Thr Pro Thr Thr Phe
115 120 125
Gly Asp Leu Arg Ala Ala Asn Gly Gln Gly Gln Gln Arg Arg Arg Ile
130 135 140
Thr Ser Val Gln Pro Pro Thr Gly Leu Gln Glu Trp Leu Lys Met Phe
145 150 155 160
Gln Ser Trp Ser Gly Pro Glu Lys Leu Leu Ala Leu Asp Glu Leu Ile
165 170 175
Asp Ser Cys Glu Pro Thr Gln Val Lys His Met Met Gln Val Ile Glu
180 185 190
Pro Gln Phe Gln Arg Asp Phe Ile Ser Leu Leu Pro Lys Glu Leu Ala
195 200 205
Leu Tyr Val Leu Ser Phe Leu Glu Pro Lys Asp Leu Leu Gln Ala Ala
210 215 220
Gln Thr Cys Arg Tyr Trp Arg Ile Leu Ala Glu Asp Asn Leu Leu Trp
225 230 235 240
Arg Glu Lys Cys Lys Glu Glu Gly Ile Asp Glu Pro Leu His Ile Lys
245 250 255
Arg Arg Lys Val Ile Lys Pro Gly Phe Ile His Ser Pro Trp Lys Ser
260 265 270
Ala Tyr Ile Arg Gln His Arg Ile Asp Thr Asn Trp Arg Arg Gly Glu
275 280 285
Leu Lys Ser Pro
290
<210> 24
<211> 62
<212> PRT
<213> 人工序列
<220>
<223> VHL.152-213（即VHL）
<400> 24
Thr Leu Pro Val Tyr Thr Leu Lys Glu Arg Cys Leu Gln Val Val Arg
1 5 10 15
Ser Leu Val Lys Pro Glu Asn Tyr Arg Arg Leu Asp Ile Val Arg Ser
20 25 30
Leu Tyr Glu Asp Leu Glu Asp His Pro Asn Val Gln Lys Asp Leu Glu
35 40 45
Arg Leu Thr Gln Glu Arg Ile Ala His Gln Arg Met Gly Asp
50 55 60
<210> 25
<211> 208
<212> PRT
<213> 人工序列
<220>
<223> SPOP.167-374（即SPOP）
<400> 25
Ser Val Asn Ile Ser Gly Gln Asn Thr Met Asn Met Val Lys Val Pro
1 5 10 15
Glu Cys Arg Leu Ala Asp Glu Leu Gly Gly Leu Trp Glu Asn Ser Arg
20 25 30
Phe Thr Asp Cys Cys Leu Cys Val Ala Gly Gln Glu Phe Gln Ala His
35 40 45
Lys Ala Ile Leu Ala Ala Arg Ser Pro Val Phe Ser Ala Met Phe Glu
50 55 60
His Glu Met Glu Glu Ser Lys Lys Asn Arg Val Glu Ile Asn Asp Val
65 70 75 80
Glu Pro Glu Val Phe Lys Glu Met Met Cys Phe Ile Tyr Thr Gly Lys
85 90 95
Ala Pro Asn Leu Asp Lys Met Ala Asp Asp Leu Leu Ala Ala Ala Asp
100 105 110
Lys Tyr Ala Leu Glu Arg Leu Lys Val Met Cys Glu Asp Ala Leu Cys
115 120 125
Ser Asn Leu Ser Val Glu Asn Ala Ala Glu Ile Leu Ile Leu Ala Asp
130 135 140
Leu His Ser Ala Asp Gln Leu Lys Thr Gln Ala Val Asp Phe Ile Asn
145 150 155 160
Tyr His Ala Ser Asp Val Leu Glu Thr Ser Gly Trp Lys Ser Met Val
165 170 175
Val Ser His Pro His Leu Val Ala Glu Ala Tyr Arg Ser Leu Ala Ser
180 185 190
Ala Gln Cys Pro Phe Leu Gly Pro Pro Arg Lys Arg Leu Lys Gln Ser
195 200 205
<210> 26
<211> 56
<212> PRT
<213> 人工序列
<220>
<223> SOCS2.143-198（即 SOCS2）
<400> 26
Pro Arg Asn Gly Thr Val His Leu Tyr Leu Thr Lys Pro Leu Tyr Thr
1 5 10 15
Ser Ala Pro Ser Leu Gln His Leu Cys Arg Leu Thr Ile Asn Lys Cys
20 25 30
Thr Gly Ala Ile Trp Gly Leu Pro Leu Pro Thr Arg Leu Lys Asp Tyr
35 40 45
Leu Glu Glu Tyr Lys Phe Gln Val
50 55
<210> 27
<211> 486
<212> PRT
<213> 人工序列
<220>
<223> LS008*（αCD19 CAR）
<400> 27
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
145 150 155 160
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
180 185 190
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
195 200 205
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
210 215 220
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
305 310 315 320
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
325 330 335
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
340 345 350
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
355 360 365
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
370 375 380
Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
385 390 395 400
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
405 410 415
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
420 425 430
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
435 440 445
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
450 455 460
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
465 470 475 480
Gln Ala Leu Pro Pro Arg
485
<210> 28
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> LG024*
<400> 28
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn
65 70 75 80
Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Lys Asn Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr
100 105 110
Gly Val Tyr Phe Cys Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
145 150 155 160
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
165 170 175
Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln
180 185 190
Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu
195 200 205
Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
210 215 220
Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr
245 250 255
Lys Leu Gln Ile Thr Arg Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
305 310 315 320
Val Leu Leu Leu Ser Leu Val Ile Thr
325
<210> 29
<211> 424
<212> PRT
<213> 人工序列
<220>
<223> LG085*
<400> 29
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser
145 150 155 160
Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala
165 170 175
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro
180 185 190
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile
195 200 205
Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp
210 215 220
Ser Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr
225 230 235 240
Arg Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly Asp Asp Ile
245 250 255
Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn Ser Ile Glu
260 265 270
Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr Leu Ser Arg
275 280 285
Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys Gln Arg Asn
290 295 300
His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln Gln Ala Cys
305 310 315 320
Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp Glu Leu Phe
325 330 335
Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro Asp Tyr Leu
340 345 350
Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys Ile Thr Pro
355 360 365
Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His Leu Gln Arg
370 375 380
Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr Gln Glu Gln
385 390 395 400
Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala Phe Ile Ser
405 410 415
Glu Asn Gly Trp Val Glu Asp Tyr
420
<210> 30
<211> 553
<212> PRT
<213> 人工序列
<220>
<223> LG089*
<400> 30
Cys Val Pro Arg Ser Gly Leu Ile Leu Ser Cys Ile Cys Leu Tyr Cys
1 5 10 15
Gly Val Leu Leu Pro Val Leu Leu Pro Asn Leu Pro Phe Leu Thr Cys
20 25 30
Leu Ser Met Ser Thr Leu Glu Ser Val Thr Tyr Leu Pro Glu Lys Gly
35 40 45
Leu Tyr Cys Gln Arg Leu Pro Ser Ser Arg Thr His Gly Gly Thr Glu
50 55 60
Ser Leu Lys Gly Lys Asn Thr Glu Asn Met Gly Phe Tyr Gly Thr Leu
65 70 75 80
Lys Met Ile Phe Tyr Lys Met Lys Arg Lys Leu Asp His Gly Ser Glu
85 90 95
Val Arg Ser Phe Ser Leu Gly Lys Lys Pro Cys Lys Val Ser Glu Tyr
100 105 110
Thr Ser Thr Thr Gly Leu Val Pro Cys Ser Ala Thr Pro Thr Thr Phe
115 120 125
Gly Asp Leu Arg Ala Ala Asn Gly Gln Gly Gln Gln Arg Arg Arg Ile
130 135 140
Thr Ser Val Gln Pro Pro Thr Gly Leu Gln Glu Trp Leu Lys Met Phe
145 150 155 160
Gln Ser Trp Ser Gly Pro Glu Lys Leu Leu Ala Leu Asp Glu Leu Ile
165 170 175
Asp Ser Cys Glu Pro Thr Gln Val Lys His Met Met Gln Val Ile Glu
180 185 190
Pro Gln Phe Gln Arg Asp Phe Ile Ser Leu Leu Pro Lys Glu Leu Ala
195 200 205
Leu Tyr Val Leu Ser Phe Leu Glu Pro Lys Asp Leu Leu Gln Ala Ala
210 215 220
Gln Thr Cys Arg Tyr Trp Arg Ile Leu Ala Glu Asp Asn Leu Leu Trp
225 230 235 240
Arg Glu Lys Cys Lys Glu Glu Gly Ile Asp Glu Pro Leu His Ile Lys
245 250 255
Arg Arg Lys Val Ile Lys Pro Gly Phe Ile His Ser Pro Trp Lys Ser
260 265 270
Ala Tyr Ile Arg Gln His Arg Ile Asp Thr Asn Trp Arg Arg Gly Glu
275 280 285
Leu Lys Ser Pro Gly Ser Gly Ser Gly Ser Gly Glu Val Gln Leu Val
290 295 300
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
305 310 315 320
Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val
325 330 335
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
340 345 350
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
355 360 365
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
370 375 380
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
385 390 395 400
Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln
405 410 415
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
420 425 430
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
435 440 445
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
450 455 460
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn
465 470 475 480
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
485 490 495
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
500 505 510
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
515 520 525
Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Arg Trp Val Phe
530 535 540
Gly Gly Gly Thr Lys Leu Thr Val Leu
545 550
<210> 31
<211> 323
<212> PRT
<213> 人工序列
<220>
<223> LG091*
<400> 31
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
145 150 155 160
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
165 170 175
Gly Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
180 185 190
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
195 200 205
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
210 215 220
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser
225 230 235 240
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ser
245 250 255
Gly Ser Gly Ser Gly Thr Leu Pro Val Tyr Thr Leu Lys Glu Arg Cys
260 265 270
Leu Gln Val Val Arg Ser Leu Val Lys Pro Glu Asn Tyr Arg Arg Leu
275 280 285
Asp Ile Val Arg Ser Leu Tyr Glu Asp Leu Glu Asp His Pro Asn Val
290 295 300
Gln Lys Asp Leu Glu Arg Leu Thr Gln Glu Arg Ile Ala His Gln Arg
305 310 315 320
Met Gly Asp
<210> 32
<211> 469
<212> PRT
<213> 人工序列
<220>
<223> LG092*
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
145 150 155 160
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
165 170 175
Gly Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
180 185 190
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
195 200 205
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
210 215 220
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser
225 230 235 240
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ser
245 250 255
Gly Ser Gly Ser Gly Ser Val Asn Ile Ser Gly Gln Asn Thr Met Asn
260 265 270
Met Val Lys Val Pro Glu Cys Arg Leu Ala Asp Glu Leu Gly Gly Leu
275 280 285
Trp Glu Asn Ser Arg Phe Thr Asp Cys Cys Leu Cys Val Ala Gly Gln
290 295 300
Glu Phe Gln Ala His Lys Ala Ile Leu Ala Ala Arg Ser Pro Val Phe
305 310 315 320
Ser Ala Met Phe Glu His Glu Met Glu Glu Ser Lys Lys Asn Arg Val
325 330 335
Glu Ile Asn Asp Val Glu Pro Glu Val Phe Lys Glu Met Met Cys Phe
340 345 350
Ile Tyr Thr Gly Lys Ala Pro Asn Leu Asp Lys Met Ala Asp Asp Leu
355 360 365
Leu Ala Ala Ala Asp Lys Tyr Ala Leu Glu Arg Leu Lys Val Met Cys
370 375 380
Glu Asp Ala Leu Cys Ser Asn Leu Ser Val Glu Asn Ala Ala Glu Ile
385 390 395 400
Leu Ile Leu Ala Asp Leu His Ser Ala Asp Gln Leu Lys Thr Gln Ala
405 410 415
Val Asp Phe Ile Asn Tyr His Ala Ser Asp Val Leu Glu Thr Ser Gly
420 425 430
Trp Lys Ser Met Val Val Ser His Pro His Leu Val Ala Glu Ala Tyr
435 440 445
Arg Ser Leu Ala Ser Ala Gln Cys Pro Phe Leu Gly Pro Pro Arg Lys
450 455 460
Arg Leu Lys Gln Ser
465
<210> 33
<211> 512
<212> PRT
<213> 人工序列
<220>
<223> LG112*
<400> 33
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn
65 70 75 80
Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Lys Asn Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr
100 105 110
Gly Val Tyr Phe Cys Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
145 150 155 160
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
165 170 175
Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln
180 185 190
Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu
195 200 205
Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
210 215 220
Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr
245 250 255
Lys Leu Gln Ile Thr Arg Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn
260 265 270
Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg
275 280 285
Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His
290 295 300
Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu
305 310 315 320
Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg
325 330 335
Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp
340 345 350
Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp
355 360 365
Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu
370 375 380
Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu
385 390 395 400
Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro
405 410 415
Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile
420 425 430
Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr
435 440 445
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln
450 455 460
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
465 470 475 480
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
485 490 495
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
500 505 510
<210> 34
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> LG112*△SP
<400> 34
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser
145 150 155 160
Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala
165 170 175
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro
180 185 190
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile
195 200 205
Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp
210 215 220
Ser Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr
225 230 235 240
Arg Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly Asp Asp Ile
245 250 255
Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn Ser Ile Glu
260 265 270
Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr Leu Ser Arg
275 280 285
Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys Gln Arg Asn
290 295 300
His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln Gln Ala Cys
305 310 315 320
Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp Glu Leu Phe
325 330 335
Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro Asp Tyr Leu
340 345 350
Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys Ile Thr Pro
355 360 365
Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His Leu Gln Arg
370 375 380
Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr Gln Glu Gln
385 390 395 400
Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala Phe Ile Ser
405 410 415
Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro Ala Pro Arg
420 425 430
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
435 440 445
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
450 455 460
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
465 470 475 480
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
485 490
<210> 35
<211> 512
<212> PRT
<213> 人工序列
<220>
<223> LG113*
<400> 35
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn
65 70 75 80
Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Lys Asn Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr
100 105 110
Gly Val Tyr Phe Cys Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
145 150 155 160
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
165 170 175
Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln
180 185 190
Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu
195 200 205
Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
210 215 220
Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr
245 250 255
Lys Leu Gln Ile Thr Arg Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
305 310 315 320
Val Leu Leu Leu Ser Leu Val Ile Thr Gly Ser Gly Ser Gly Ser Gly
325 330 335
Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys
340 345 350
Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser
355 360 365
Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg
370 375 380
Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser
385 390 395 400
His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr
405 410 415
Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys
420 425 430
Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu
435 440 445
Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys
450 455 460
Asp Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr
465 470 475 480
Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys
485 490 495
Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr
500 505 510
<210> 36
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> LG113*△SP
<400> 36
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser
145 150 155 160
Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala
165 170 175
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro
180 185 190
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile
195 200 205
Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp
210 215 220
Ser Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr
225 230 235 240
Arg Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
245 250 255
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
260 265 270
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
275 280 285
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
290 295 300
Leu Val Ile Thr Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly
305 310 315 320
Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn
325 330 335
Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr
340 345 350
Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys
355 360 365
Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln
370 375 380
Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp
385 390 395 400
Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro
405 410 415
Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys
420 425 430
Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His
435 440 445
Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr
450 455 460
Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala
465 470 475 480
Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr
485 490
<210> 37
<211> 521
<212> PRT
<213> 人工序列
<220>
<223> LG123*
<400> 37
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Met Asp Ile Gln Met Thr Gln Thr Thr Ser Ser
20 25 30
Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser
35 40 45
Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly
50 55 60
Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val
65 70 75 80
Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr
85 90 95
Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln
100 105 110
Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile
115 120 125
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu
145 150 155 160
Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr
165 170 175
Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys
180 185 190
Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr
195 200 205
Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser
210 215 220
Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp
245 250 255
Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Gly
260 265 270
Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser
275 280 285
Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg
290 295 300
Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr Leu Ser Arg Leu Ile
305 310 315 320
Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys Gln Arg Asn His Glu
325 330 335
Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln Gln Ala Cys Ile Glu
340 345 350
Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp Glu Leu Phe Ser Gln
355 360 365
Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly
370 375 380
Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys Ile Thr Pro Ser Gly
385 390 395 400
Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His Leu Gln Arg Val Gly
405 410 415
His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile
420 425 430
Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala Phe Ile Ser Glu Asn
435 440 445
Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro
450 455 460
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
465 470 475 480
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
485 490 495
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
500 505 510
Val Leu Leu Leu Ser Leu Val Ile Thr
515 520
<210> 38
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> LG123*△SP
<400> 38
Met Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu
1 5 10 15
Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn
20 25 30
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu
35 40 45
Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu
65 70 75 80
Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro
85 90 95
Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
130 135 140
Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
145 150 155 160
Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Met
165 170 175
Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
180 185 190
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
195 200 205
Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
210 215 220
Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
225 230 235 240
Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Gly Ser Gly Ser Gly Ser
245 250 255
Gly Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala
260 265 270
Lys Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu
275 280 285
Ser Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu
290 295 300
Arg Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp
305 310 315 320
Ser His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys
325 330 335
Tyr Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg
340 345 350
Lys Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu
355 360 365
Leu Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg
370 375 380
Lys Asp Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val
385 390 395 400
Thr Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met
405 410 415
Lys Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp
420 425 430
Tyr Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
435 440 445
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
450 455 460
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
465 470 475 480
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
485 490 495
Leu Val Ile Thr
500
<210> 39
<211> 516
<212> PRT
<213> 人工序列
<220>
<223> LG124*
<400> 39
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Met Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
115 120 125
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
145 150 155 160
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
165 170 175
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
180 185 190
Ala Leu Ile Asn Pro Thr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
195 200 205
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr
210 215 220
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
225 230 235 240
Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
245 250 255
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Gly Ser Gly Ser
260 265 270
Gly Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala
275 280 285
Lys Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu
290 295 300
Ser Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu
305 310 315 320
Arg Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp
325 330 335
Ser His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys
340 345 350
Tyr Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg
355 360 365
Lys Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu
370 375 380
Leu Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg
385 390 395 400
Lys Asp Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val
405 410 415
Thr Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met
420 425 430
Lys Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp
435 440 445
Tyr Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
450 455 460
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
465 470 475 480
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
485 490 495
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
500 505 510
Leu Val Ile Thr
515
<210> 40
<211> 495
<212> PRT
<213> 人工序列
<220>
<223> LG124*△SP
<400> 40
Met Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
1 5 10 15
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn
20 25 30
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
115 120 125
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
130 135 140
Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Leu Ile Asn Pro
165 170 175
Thr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr
180 185 190
Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
195 200 205
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr
210 215 220
Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu
225 230 235 240
Val Thr Val Ser Ser Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe
245 250 255
Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp
260 265 270
Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser
275 280 285
Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu
290 295 300
Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala
305 310 315 320
Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met
325 330 335
Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile
340 345 350
Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro
355 360 365
Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu
370 375 380
His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu
385 390 395 400
Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp
405 410 415
Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr
420 425 430
Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro
435 440 445
Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val
450 455 460
His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro
465 470 475 480
Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
485 490 495
<210> 41
<211> 511
<212> PRT
<213> 人工序列
<220>
<223> LG125*
<400> 41
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met
20 25 30
Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser
35 40 45
Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro
50 55 60
Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser
85 90 95
Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser
100 105 110
Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val
145 150 155 160
Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met
165 170 175
His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr
180 185 190
Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp
195 200 205
Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
210 215 220
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
225 230 235 240
Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr
245 250 255
Leu Thr Val Ser Ser Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe
260 265 270
Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp
275 280 285
Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser
290 295 300
Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu
305 310 315 320
Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala
325 330 335
Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met
340 345 350
Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile
355 360 365
Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro
370 375 380
Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu
385 390 395 400
His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu
405 410 415
Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp
420 425 430
Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr
435 440 445
Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro
450 455 460
Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val
465 470 475 480
His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro
485 490 495
Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
500 505 510
<210> 42
<211> 490
<212> PRT
<213> 人工序列
<220>
<223> LG125*△SP
<400> 42
Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser
115 120 125
Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys
130 135 140
Thr Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln
145 150 155 160
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg
165 170 175
Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr
180 185 190
Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr
195 200 205
Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His
210 215 220
Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
225 230 235 240
Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly Asp Asp Ile Pro
245 250 255
Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn Ser Ile Glu Glu
260 265 270
Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr Leu Ser Arg Leu
275 280 285
Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys Gln Arg Asn His
290 295 300
Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln Gln Ala Cys Ile
305 310 315 320
Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp Glu Leu Phe Ser
325 330 335
Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro Asp Tyr Leu Cys
340 345 350
Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys Ile Thr Pro Ser
355 360 365
Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His Leu Gln Arg Val
370 375 380
Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr Gln Glu Gln Leu
385 390 395 400
Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala Phe Ile Ser Glu
405 410 415
Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro Ala Pro Arg Pro
420 425 430
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
435 440 445
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
450 455 460
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
465 470 475 480
Gly Val Leu Leu Leu Ser Leu Val Ile Thr
485 490
<210> 43
<211> 520
<212> PRT
<213> 人工序列
<220>
<223> LG126*
<400> 43
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
20 25 30
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
35 40 45
Ala Val Thr Ser Gly Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
50 55 60
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
65 70 75 80
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
85 90 95
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala
100 105 110
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
145 150 155 160
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ile
165 170 175
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
180 185 190
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
195 200 205
Asp Ser Val Lys Ser Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
210 215 220
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Phe
245 250 255
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser
260 265 270
Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala
275 280 285
Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg
290 295 300
Ile His Gln Glu Ser Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala
305 310 315 320
Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly
325 330 335
Asp Glu Asp Asp Ser His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala
340 345 350
Lys His Asp Lys Tyr Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val
355 360 365
Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys
370 375 380
Ile Ser Phe Glu Leu Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile
385 390 395 400
Thr Tyr Asp Arg Lys Asp Ile Glu Glu His Leu Gln Arg Val Gly His
405 410 415
Phe Asp Pro Val Thr Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro
420 425 430
Asn Leu Ala Met Lys Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly
435 440 445
Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
450 455 460
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
465 470 475 480
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
485 490 495
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
500 505 510
Leu Leu Leu Ser Leu Val Ile Thr
515 520
<210> 44
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> LG126*△SP
<400> 44
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
20 25 30
Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ile Tyr Ala Met Asn Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
165 170 175
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Ser
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
195 200 205
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
210 215 220
His Gly Asn Phe Gly Asn Ser Tyr Val Ser Phe Phe Ala Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Gly Ser Gly Ser Gly
245 250 255
Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys
260 265 270
Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser
275 280 285
Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg
290 295 300
Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser
305 310 315 320
His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr
325 330 335
Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys
340 345 350
Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu
355 360 365
Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys
370 375 380
Asp Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr
385 390 395 400
Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys
405 410 415
Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr
420 425 430
Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
435 440 445
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
450 455 460
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
465 470 475 480
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
485 490 495
Val Ile Thr
<210> 45
<211> 512
<212> PRT
<213> 人工序列
<220>
<223> LG119*
<400> 45
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu
20 25 30
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Lys Phe Thr Ser Tyr Val Met His Trp Val Lys Gln Lys Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys
65 70 75 80
Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser
85 90 95
Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser
100 105 110
Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe
115 120 125
Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu
145 150 155 160
Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr
165 170 175
Met Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met His Trp Tyr Gln
180 185 190
Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys
195 200 205
Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr
210 215 220
Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr
225 230 235 240
Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly
245 250 255
Thr Lys Leu Glu Leu Lys Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn
260 265 270
Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg
275 280 285
Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His
290 295 300
Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu
305 310 315 320
Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg
325 330 335
Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp
340 345 350
Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp
355 360 365
Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu
370 375 380
Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu
385 390 395 400
Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro
405 410 415
Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile
420 425 430
Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr
435 440 445
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln
450 455 460
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
465 470 475 480
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
485 490 495
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
500 505 510
<210> 46
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> LG119*△SP
<400> 46
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val His Tyr Cys
85 90 95
Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala
130 135 140
Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala
145 150 155 160
Thr Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser Gly Thr
165 170 175
Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val
180 185 190
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr
195 200 205
Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln
210 215 220
Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
225 230 235 240
Lys Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly Asp Asp Ile
245 250 255
Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn Ser Ile Glu
260 265 270
Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr Leu Ser Arg
275 280 285
Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys Gln Arg Asn
290 295 300
His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln Gln Ala Cys
305 310 315 320
Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp Glu Leu Phe
325 330 335
Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro Asp Tyr Leu
340 345 350
Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys Ile Thr Pro
355 360 365
Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His Leu Gln Arg
370 375 380
Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr Gln Glu Gln
385 390 395 400
Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala Phe Ile Ser
405 410 415
Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro Ala Pro Arg
420 425 430
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
435 440 445
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
450 455 460
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
465 470 475 480
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
485 490
<210> 47
<211> 512
<212> PRT
<213> 人工序列
<220>
<223> LG120*
<400> 47
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys
65 70 75 80
Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser
85 90 95
Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
100 105 110
Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe
115 120 125
Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu
145 150 155 160
Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
165 170 175
Leu Ser Cys Ser Ala Thr Ser Ser Val Ser Tyr Met His Trp Tyr Gln
180 185 190
Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys
195 200 205
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
210 215 220
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
225 230 235 240
Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Gln Gly
245 250 255
Thr Lys Leu Glu Ile Lys Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn
260 265 270
Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg
275 280 285
Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His
290 295 300
Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu
305 310 315 320
Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg
325 330 335
Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp
340 345 350
Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp
355 360 365
Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu
370 375 380
Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu
385 390 395 400
Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro
405 410 415
Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile
420 425 430
Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr
435 440 445
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln
450 455 460
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
465 470 475 480
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
485 490 495
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
500 505 510
<210> 48
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> LG120*△SP
<400> 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys
85 90 95
Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala
130 135 140
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala
145 150 155 160
Thr Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Lys
165 170 175
Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val
180 185 190
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
195 200 205
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
210 215 220
Trp Ser Ser Asn Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly Asp Asp Ile
245 250 255
Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn Ser Ile Glu
260 265 270
Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr Leu Ser Arg
275 280 285
Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys Gln Arg Asn
290 295 300
His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln Gln Ala Cys
305 310 315 320
Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp Glu Leu Phe
325 330 335
Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro Asp Tyr Leu
340 345 350
Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys Ile Thr Pro
355 360 365
Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His Leu Gln Arg
370 375 380
Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr Gln Glu Gln
385 390 395 400
Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala Phe Ile Ser
405 410 415
Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro Ala Pro Arg
420 425 430
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
435 440 445
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
450 455 460
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
465 470 475 480
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
485 490
<210> 49
<211> 520
<212> PRT
<213> 人工序列
<220>
<223> LG137*
<400> 49
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys Ile Asp Ala Met Gly Asn Ile Gln Leu Val Gln Ser Gly
20 25 30
Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala
35 40 45
Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala
50 55 60
Pro Gly Lys Gly Leu Arg Trp Met Gly Trp Ile Asn Thr His Thr Gly
65 70 75 80
Glu Pro Thr Tyr Ala Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu
85 90 95
Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn
100 105 110
Glu Asp Thr Ala Thr Tyr Phe Cys Thr Arg Arg Gly Tyr Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys
145 150 155 160
Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly Glu Arg Val
165 170 175
Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser Trp
180 185 190
Phe His His Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile Tyr Arg Ala
195 200 205
Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Asp Tyr Glu Asp Met
225 230 235 240
Gly Ile Tyr Tyr Cys Gln Gln Tyr Asp Glu Ser Pro Trp Thr Phe Gly
245 250 255
Gly Gly Thr Lys Leu Glu Met Lys Gly Ser Gly Asp Pro Ala Gly Ser
260 265 270
Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala
275 280 285
Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg
290 295 300
Ile His Gln Glu Ser Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala
305 310 315 320
Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly
325 330 335
Asp Glu Asp Asp Ser His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala
340 345 350
Lys His Asp Lys Tyr Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val
355 360 365
Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys
370 375 380
Ile Ser Phe Glu Leu Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile
385 390 395 400
Thr Tyr Asp Arg Lys Asp Ile Glu Glu His Leu Gln Arg Val Gly His
405 410 415
Phe Asp Pro Val Thr Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro
420 425 430
Asn Leu Ala Met Lys Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly
435 440 445
Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
450 455 460
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
465 470 475 480
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
485 490 495
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
500 505 510
Leu Leu Leu Ser Leu Val Ile Thr
515 520
<210> 50
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> LG137*△SP
<400> 50
Asp Ala Met Gly Asn Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys
1 5 10 15
Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr
20 25 30
Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly
35 40 45
Leu Arg Trp Met Gly Trp Ile Asn Thr His Thr Gly Glu Pro Thr Tyr
50 55 60
Ala Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala
65 70 75 80
Ser Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala
85 90 95
Thr Tyr Phe Cys Thr Arg Arg Gly Tyr Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Met Thr Gln Ser
130 135 140
Pro Ser Ser Met Tyr Ala Ser Leu Gly Glu Arg Val Thr Ile Thr Cys
145 150 155 160
Lys Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser Trp Phe His His Lys
165 170 175
Pro Gly Lys Ser Pro Lys Thr Leu Ile Tyr Arg Ala Asn Arg Leu Val
180 185 190
Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Tyr
195 200 205
Ser Leu Thr Ile Ser Ser Leu Asp Tyr Glu Asp Met Gly Ile Tyr Tyr
210 215 220
Cys Gln Gln Tyr Asp Glu Ser Pro Trp Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Leu Glu Met Lys Gly Ser Gly Asp Pro Ala Gly Ser Gly Ser Gly Ser
245 250 255
Gly Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala
260 265 270
Lys Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu
275 280 285
Ser Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu
290 295 300
Arg Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp
305 310 315 320
Ser His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys
325 330 335
Tyr Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg
340 345 350
Lys Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu
355 360 365
Leu Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg
370 375 380
Lys Asp Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val
385 390 395 400
Thr Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met
405 410 415
Lys Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp
420 425 430
Tyr Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
435 440 445
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
450 455 460
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
465 470 475 480
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
485 490 495
Leu Val Ile Thr
500
<210> 51
<211> 515
<212> PRT
<213> 人工序列
<220>
<223> LG138*
<400> 51
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu
35 40 45
Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys
50 55 60
Arg Leu Glu Trp Val Ala Ser Ile Ser Ser Gly Gly Phe Thr Tyr Tyr
65 70 75 80
Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg
85 90 95
Asn Ile Leu Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala
100 105 110
Met Tyr Tyr Cys Ala Arg Asp Glu Val Arg Gly Tyr Leu Asp Val Trp
115 120 125
Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ala Tyr Lys Asp Ile Gln
145 150 155 160
Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val
165 170 175
Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Ser Asn Tyr Leu Asn Trp
180 185 190
Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr
195 200 205
Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro Glu Asp Ile
225 230 235 240
Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Lys Leu Pro Tyr Thr Phe Gly
245 250 255
Gly Gly Thr Lys Leu Glu Ile Lys Arg Gly Ser Gly Ser Gly Ser Gly
260 265 270
Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys
275 280 285
Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser
290 295 300
Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg
305 310 315 320
Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser
325 330 335
His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr
340 345 350
Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys
355 360 365
Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu
370 375 380
Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys
385 390 395 400
Asp Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr
405 410 415
Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys
420 425 430
Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr
435 440 445
Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
450 455 460
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
465 470 475 480
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
485 490 495
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
500 505 510
Val Ile Thr
515
<210> 52
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> LG138*△SP
<400> 52
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Phe Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Asp Glu Val Arg Gly Tyr Leu Asp Val Trp Gly Ala Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Ala Ala Tyr Lys Asp Ile Gln Met Thr Gln Thr Thr
130 135 140
Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Ser
145 150 155 160
Ala Ser Gln Gly Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Ser Leu His Ser
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser
195 200 205
Leu Thr Ile Ser Asn Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Ser Lys Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Arg Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly
245 250 255
Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn
260 265 270
Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr
275 280 285
Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys
290 295 300
Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln
305 310 315 320
Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp
325 330 335
Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro
340 345 350
Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys
355 360 365
Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His
370 375 380
Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr
385 390 395 400
Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala
405 410 415
Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro
420 425 430
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
435 440 445
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
450 455 460
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
465 470 475 480
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
485 490
<210> 53
<211> 515
<212> PRT
<213> 人工序列
<220>
<223> MLB052*
<400> 53
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Ser Asn Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ala Ile Ile Thr Tyr Ala Gly Ser Asn Glu Tyr
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Asp Arg Ile Trp Val Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
145 150 155 160
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys
165 170 175
Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu Ala
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp
195 200 205
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
210 215 220
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
225 230 235 240
Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Leu Thr Phe
245 250 255
Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Ser Gly Ser Gly Ser Gly
260 265 270
Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys
275 280 285
Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser
290 295 300
Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg
305 310 315 320
Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser
325 330 335
His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr
340 345 350
Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys
355 360 365
Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu
370 375 380
Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys
385 390 395 400
Asp Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr
405 410 415
Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys
420 425 430
Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr
435 440 445
Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
450 455 460
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
465 470 475 480
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
485 490 495
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
500 505 510
Val Ile Thr
515
<210> 54
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> MLB052*△SP
<400> 54
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Thr Tyr Ala Gly Ser Asn Glu Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Trp Val Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val
130 135 140
Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val
145 150 155 160
Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Glu Ile Lys Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly
245 250 255
Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn
260 265 270
Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr
275 280 285
Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys
290 295 300
Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln
305 310 315 320
Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp
325 330 335
Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro
340 345 350
Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys
355 360 365
Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His
370 375 380
Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr
385 390 395 400
Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala
405 410 415
Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro
420 425 430
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
435 440 445
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
450 455 460
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
465 470 475 480
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
485 490
<210> 55
<211> 515
<212> PRT
<213> 人工序列
<220>
<223> MLB053*
<400> 55
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Asn Tyr Asn Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Arg Leu Glu Trp Met Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser
65 70 75 80
Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Arg Ala Met Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
145 150 155 160
Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys
165 170 175
Arg Ser Ser Gln Ser Ile Val Tyr Ser Asn Gly Asn Thr Tyr Leu Gly
180 185 190
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys
195 200 205
Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
210 215 220
Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp
225 230 235 240
Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe
245 250 255
Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Ser Gly Ser Gly Ser Gly
260 265 270
Arg Leu Asn Phe Gly Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys
275 280 285
Lys Lys Arg Trp Asn Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser
290 295 300
Glu Leu His Ser Tyr Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg
305 310 315 320
Glu Leu Glu Glu Cys Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser
325 330 335
His Val Arg Ala Gln Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr
340 345 350
Met Ala Asp Met Asp Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys
355 360 365
Lys Arg Asp Ile Pro Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu
370 375 380
Met Arg Glu Pro Cys Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys
385 390 395 400
Asp Ile Glu Glu His Leu Gln Arg Val Gly His Phe Asp Pro Val Thr
405 410 415
Arg Ser Pro Leu Thr Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys
420 425 430
Glu Val Ile Asp Ala Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr
435 440 445
Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
450 455 460
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
465 470 475 480
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
485 490 495
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
500 505 510
Val Ile Thr
515
<210> 56
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> MLB053*△SP
<400> 56
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro
130 135 140
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
145 150 155 160
Ile Val Tyr Ser Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys
165 170 175
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly
245 250 255
Asp Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn
260 265 270
Ser Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr
275 280 285
Leu Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys
290 295 300
Gln Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln
305 310 315 320
Gln Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp
325 330 335
Glu Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro
340 345 350
Asp Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys
355 360 365
Ile Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His
370 375 380
Leu Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr
385 390 395 400
Gln Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala
405 410 415
Phe Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro
420 425 430
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
435 440 445
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
450 455 460
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
465 470 475 480
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
485 490
<210> 57
<211> 258
<212> PRT
<213> 人工序列
<220>
<223> P2A-GFP**（即 P2A-eGFP)
<400> 57
Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn
1 5 10 15
Pro Gly Pro Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val
20 25 30
Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser
35 40 45
Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu
50 55 60
Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu
65 70 75 80
Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp
85 90 95
His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr
100 105 110
Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr
115 120 125
Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu
130 135 140
Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys
145 150 155 160
Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile Met Ala Asp Lys
165 170 175
Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile Glu
180 185 190
Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile
195 200 205
Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln
210 215 220
Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu
225 230 235 240
Leu Glu Phe Val Thr Ala Ala Gly Ile Thr Leu Gly Met Asp Glu Leu
245 250 255
Tyr Lys
<210> 58
<211> 27
<212> PRT
<213> 人工序列
<220>
<223> IL2Rβjm（即 IL2Rβ jm DT或L2Rβ jm结构域）
<400> 58
Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys Asn
1 5 10 15
Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu
20 25
<210> 59
<211> 78
<212> PRT
<213> 人工序列
<220>
<223> MLB014*（CD3ζ.△IC-IL2Rβjm）
<400> 59
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala
35 40 45
Leu Phe Leu Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu
50 55 60
Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu
65 70 75
<210> 60
<211> 179
<212> PRT
<213> 人工序列
<220>
<223> MLB046 *（CD3ε.△IC -IL2Rβjm）
<400> 60
Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser
1 5 10 15
Val Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Gly Ile Thr
20 25 30
Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr
35 40 45
Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys
50 55 60
Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp
65 70 75 80
His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr
85 90 95
Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu
100 105 110
Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met
115 120 125
Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu
130 135 140
Leu Leu Leu Val Tyr Tyr Trp Ser Asn Cys Arg Asn Thr Gly Pro Trp
145 150 155 160
Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe
165 170 175
Ser Gln Leu
<210> 61
<211> 51
<212> PRT
<213> 人工序列
<220>
<223> CD3ζ.△IC
<400> 61
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala
35 40 45
Leu Phe Leu
50
<210> 62
<211> 200
<212> PRT
<213> 人工序列
<220>
<223> GRAIL.IC
<400> 62
Tyr Ser Ala Arg Arg Leu Arg Asn Ala Arg Ala Gln Ser Arg Lys Gln
1 5 10 15
Arg Gln Leu Lys Ala Asp Ala Lys Lys Ala Ile Gly Arg Leu Gln Leu
20 25 30
Arg Thr Leu Lys Gln Gly Asp Lys Glu Ile Gly Pro Asp Gly Asp Ser
35 40 45
Cys Ala Val Cys Ile Glu Leu Tyr Lys Pro Asn Asp Leu Val Arg Ile
50 55 60
Leu Thr Cys Asn His Ile Phe His Lys Thr Cys Val Asp Pro Trp Leu
65 70 75 80
Leu Glu His Arg Thr Cys Pro Met Cys Lys Cys Asp Ile Leu Lys Ala
85 90 95
Leu Gly Ile Glu Val Asp Val Glu Asp Gly Ser Val Ser Leu Gln Val
100 105 110
Pro Val Ser Asn Glu Ile Ser Asn Ser Ala Ser Ser His Glu Glu Asp
115 120 125
Asn Arg Ser Glu Thr Ala Ser Ser Gly Tyr Ala Ser Val Gln Gly Thr
130 135 140
Asp Glu Pro Pro Leu Glu Glu His Val Gln Ser Thr Asn Glu Ser Leu
145 150 155 160
Gln Leu Val Asn His Glu Ala Asn Ser Val Ala Val Asp Val Ile Pro
165 170 175
His Val Asp Asn Pro Thr Phe Glu Glu Asp Glu Thr Pro Asn Gln Glu
180 185 190
Thr Ala Val Arg Glu Ile Lys Ser
195 200
<210> 63
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> LG171 *（CD3ζ.△IC-GRAIL.IC）
<400> 63
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala
35 40 45
Leu Phe Leu Tyr Ser Ala Arg Arg Leu Arg Asn Ala Arg Ala Gln Ser
50 55 60
Arg Lys Gln Arg Gln Leu Lys Ala Asp Ala Lys Lys Ala Ile Gly Arg
65 70 75 80
Leu Gln Leu Arg Thr Leu Lys Gln Gly Asp Lys Glu Ile Gly Pro Asp
85 90 95
Gly Asp Ser Cys Ala Val Cys Ile Glu Leu Tyr Lys Pro Asn Asp Leu
100 105 110
Val Arg Ile Leu Thr Cys Asn His Ile Phe His Lys Thr Cys Val Asp
115 120 125
Pro Trp Leu Leu Glu His Arg Thr Cys Pro Met Cys Lys Cys Asp Ile
130 135 140
Leu Lys Ala Leu Gly Ile Glu Val Asp Val Glu Asp Gly Ser Val Ser
145 150 155 160
Leu Gln Val Pro Val Ser Asn Glu Ile Ser Asn Ser Ala Ser Ser His
165 170 175
Glu Glu Asp Asn Arg Ser Glu Thr Ala Ser Ser Gly Tyr Ala Ser Val
180 185 190
Gln Gly Thr Asp Glu Pro Pro Leu Glu Glu His Val Gln Ser Thr Asn
195 200 205
Glu Ser Leu Gln Leu Val Asn His Glu Ala Asn Ser Val Ala Val Asp
210 215 220
Val Ile Pro His Val Asp Asn Pro Thr Phe Glu Glu Asp Glu Thr Pro
225 230 235 240
Asn Gln Glu Thr Ala Val Arg Glu Ile Lys Ser
245 250
<210> 64
<211> 152
<212> PRT
<213> 人工序列
<220>
<223> CD3ε.△IC
<400> 64
Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser
1 5 10 15
Val Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Gly Ile Thr
20 25 30
Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr
35 40 45
Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys
50 55 60
Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp
65 70 75 80
His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr
85 90 95
Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu
100 105 110
Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met
115 120 125
Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu
130 135 140
Leu Leu Leu Val Tyr Tyr Trp Ser
145 150
<210> 65
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> MLB014.SP （即CD3ζ的信号肽）
<400> 65
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala
20
<210> 66
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> MLB014.EM
<400> 66
Gln Ser Phe Gly Leu Leu Asp Pro Lys
1 5
<210> 67
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> MLB014.TM（即CD3ζ的跨膜结构域）
<400> 67
Leu Cys Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu
1 5 10 15
Thr Ala Leu Phe Leu
20
<210> 68
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> MLB046.SP（即CD3ε的信号肽）
<400> 68
Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser
1 5 10 15
Val Gly Val Trp Gly Gln
20
<210> 69
<211> 104
<212> PRT
<213> 人工序列
<220>
<223> MLB046.EM（即CD3ε的细胞外结构域）
<400> 69
Asp Gly Asn Glu Glu Met Gly Gly Ile Thr Gln Thr Pro Tyr Lys Val
1 5 10 15
Ser Ile Ser Gly Thr Thr Val Ile Leu Thr Cys Pro Gln Tyr Pro Gly
20 25 30
Ser Glu Ile Leu Trp Gln His Asn Asp Lys Asn Ile Gly Gly Asp Glu
35 40 45
Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp His Leu Ser Leu Lys Glu
50 55 60
Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly
65 70 75 80
Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu Arg Ala Arg Val
85 90 95
Cys Glu Asn Cys Met Glu Met Asp
100
<210> 70
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> MLB046.TM（即CD3ε的跨膜结构域）
<400> 70
Val Met Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly
1 5 10 15
Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser
20 25
<210> 71
<211> 152
<212> PRT
<213> 人工序列
<220>
<223> LG212 *（CD3ε.△IC）
<400> 71
Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser
1 5 10 15
Val Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Gly Ile Thr
20 25 30
Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr
35 40 45
Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys
50 55 60
Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp
65 70 75 80
His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr
85 90 95
Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu
100 105 110
Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met
115 120 125
Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu
130 135 140
Leu Leu Leu Val Tyr Tyr Trp Ser
145 150
<210> 72
<211> 1733
<212> DNA
<213> 人工序列
<220>
<223> CAG启动子
<400> 72
ctcgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60
gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120
ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180
ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240
atcaagtgta tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg 300
cctggcatta tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg 360
tattagtcat cgctattacc atggtcgagg tgagccccac gttctgcttc actctcccca 420
tctccccccc ctccccaccc ccaattttgt atttatttat tttttaatta ttttgtgcag 480
cgatgggggc gggggggggg ggggggcgcg cgccaggcgg ggcggggcgg ggcgaggggc 540
ggggcggggc gaggcggaga ggtgcggcgg cagccaatca gagcggcgcg ctccgaaagt 600
ttccttttat ggcgaggcgg cggcggcggc ggccctataa aaagcgaagc gcgcggcggg 660
cgggagtcgc tgcgcgctgc cttcgccccg tgccccgctc cgccgccgcc tcgcgccgcc 720
cgccccggct ctgactgacc gcgttactcc cacaggtgag cgggcgggac ggcccttctc 780
ctccgggctg taattagcgc ttggtttaat gacggcttgt ttcttttctg tggctgcgtg 840
aaagccttga ggggctccgg gagggccctt tgtgcggggg gagcggctcg gggggtgcgt 900
gcgtgtgtgt gtgcgtgggg agcgccgcgt gcggctccgc gctgcccggc ggctgtgagc 960
gctgcgggcg cggcgcgggg ctttgtgcgc tccgcagtgt gcgcgagggg agcgcggccg 1020
ggggcggtgc cccgcggtgc ggggggggct gcgaggggaa caaaggctgc gtgcggggtg 1080
tgtgcgtggg ggggtgagca gggggtgtgg gcgcgtcggt cgggctgcaa ccccccctgc 1140
acccccctcc ccgagttgct gagcacggcc cggcttcggg tgcggggctc cgtacggggc 1200
gtggcgcggg gctcgccgtg ccgggcgggg ggtggcggca ggtgggggtg ccgggcgggg 1260
cggggccgcc tcgggccggg gagggctcgg gggaggggcg cggcggcccc cggagcgccg 1320
gcggctgtcg aggcgcggcg agccgcagcc attgcctttt atggtaatcg tgcgagaggg 1380
cgcagggact tcctttgtcc caaatctgtg cggagccgaa atctgggagg cgccgccgca 1440
ccccctctag cgggcgcggg gcgaagcggt gcggcgccgg caggaaggaa atgggcgggg 1500
agggccttcg tgcgtcgccg cgccgccgtc cccttctccc tctccagcct cggggctgtc 1560
cgcgggggga cggctgcctt cgggggggac ggggcagggc ggggttcggc ttctggcgtg 1620
tgaccggcgg ctctagagcc tctgctaacc atgttcatgc cttcttcttt ttcctacagc 1680
tcctgggcaa cgtgctggtt attgtgctgt ctcatcattt tggcaaagaa ttg 1733
<210> 73
<211> 514
<212> PRT
<213> 人工序列
<220>
<223> LG222*
<400> 73
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
65 70 75 80
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
115 120 125
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
130 135 140
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu
165 170 175
Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr
180 185 190
Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro
195 200 205
Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro
210 215 220
Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala
225 230 235 240
Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys
245 250 255
Ala Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu
260 265 270
Thr Val Leu Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys Tyr Leu
275 280 285
Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe
290 295 300
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Tyr Ser Ala Arg Arg Leu
305 310 315 320
Arg Asn Ala Arg Ala Gln Ser Arg Lys Gln Arg Gln Leu Lys Ala Asp
325 330 335
Ala Lys Lys Ala Ile Gly Arg Leu Gln Leu Arg Thr Leu Lys Gln Gly
340 345 350
Asp Lys Glu Ile Gly Pro Asp Gly Asp Ser Cys Ala Val Cys Ile Glu
355 360 365
Leu Tyr Lys Pro Asn Asp Leu Val Arg Ile Leu Thr Cys Asn His Ile
370 375 380
Phe His Lys Thr Cys Val Asp Pro Trp Leu Leu Glu His Arg Thr Cys
385 390 395 400
Pro Met Cys Lys Cys Asp Ile Leu Lys Ala Leu Gly Ile Glu Val Asp
405 410 415
Val Glu Asp Gly Ser Val Ser Leu Gln Val Pro Val Ser Asn Glu Ile
420 425 430
Ser Asn Ser Ala Ser Ser His Glu Glu Asp Asn Arg Ser Glu Thr Ala
435 440 445
Ser Ser Gly Tyr Ala Ser Val Gln Gly Thr Asp Glu Pro Pro Leu Glu
450 455 460
Glu His Val Gln Ser Thr Asn Glu Ser Leu Gln Leu Val Asn His Glu
465 470 475 480
Ala Asn Ser Val Ala Val Asp Val Ile Pro His Val Asp Asn Pro Thr
485 490 495
Phe Glu Glu Asp Glu Thr Pro Asn Gln Glu Thr Ala Val Arg Glu Ile
500 505 510
Lys Ser
<210> 74
<211> 551
<212> PRT
<213> 人工序列
<220>
<223> LG222.1*
<400> 74
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
65 70 75 80
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
115 120 125
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
130 135 140
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu
165 170 175
Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr
180 185 190
Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro
195 200 205
Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro
210 215 220
Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala
225 230 235 240
Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys
245 250 255
Ala Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu
260 265 270
Thr Val Leu Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Arg Val Lys Phe Ser Arg Ser Ala Asp Tyr
340 345 350
Ser Ala Arg Arg Leu Arg Asn Ala Arg Ala Gln Ser Arg Lys Gln Arg
355 360 365
Gln Leu Lys Ala Asp Ala Lys Lys Ala Ile Gly Arg Leu Gln Leu Arg
370 375 380
Thr Leu Lys Gln Gly Asp Lys Glu Ile Gly Pro Asp Gly Asp Ser Cys
385 390 395 400
Ala Val Cys Ile Glu Leu Tyr Lys Pro Asn Asp Leu Val Arg Ile Leu
405 410 415
Thr Cys Asn His Ile Phe His Lys Thr Cys Val Asp Pro Trp Leu Leu
420 425 430
Glu His Arg Thr Cys Pro Met Cys Lys Cys Asp Ile Leu Lys Ala Leu
435 440 445
Gly Ile Glu Val Asp Val Glu Asp Gly Ser Val Ser Leu Gln Val Pro
450 455 460
Val Ser Asn Glu Ile Ser Asn Ser Ala Ser Ser His Glu Glu Asp Asn
465 470 475 480
Arg Ser Glu Thr Ala Ser Ser Gly Tyr Ala Ser Val Gln Gly Thr Asp
485 490 495
Glu Pro Pro Leu Glu Glu His Val Gln Ser Thr Asn Glu Ser Leu Gln
500 505 510
Leu Val Asn His Glu Ala Asn Ser Val Ala Val Asp Val Ile Pro His
515 520 525
Val Asp Asn Pro Thr Phe Glu Glu Asp Glu Thr Pro Asn Gln Glu Thr
530 535 540
Ala Val Arg Glu Ile Lys Ser
545 550
<210> 75
<211> 529
<212> PRT
<213> 人工序列
<220>
<223> LG222.2*
<400> 75
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
65 70 75 80
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
115 120 125
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
130 135 140
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu
165 170 175
Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr
180 185 190
Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro
195 200 205
Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro
210 215 220
Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala
225 230 235 240
Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys
245 250 255
Ala Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu
260 265 270
Thr Val Leu Asp Ser Gly Gln Val Leu Leu Glu Ser Asn Ile Lys Val
275 280 285
Leu Pro Thr Trp Ser Thr Pro Val Gln Pro Met Ala Leu Ile Val Leu
290 295 300
Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe
305 310 315 320
Arg Val Lys Phe Ser Arg Ser Ala Asp Tyr Ser Ala Arg Arg Leu Arg
325 330 335
Asn Ala Arg Ala Gln Ser Arg Lys Gln Arg Gln Leu Lys Ala Asp Ala
340 345 350
Lys Lys Ala Ile Gly Arg Leu Gln Leu Arg Thr Leu Lys Gln Gly Asp
355 360 365
Lys Glu Ile Gly Pro Asp Gly Asp Ser Cys Ala Val Cys Ile Glu Leu
370 375 380
Tyr Lys Pro Asn Asp Leu Val Arg Ile Leu Thr Cys Asn His Ile Phe
385 390 395 400
His Lys Thr Cys Val Asp Pro Trp Leu Leu Glu His Arg Thr Cys Pro
405 410 415
Met Cys Lys Cys Asp Ile Leu Lys Ala Leu Gly Ile Glu Val Asp Val
420 425 430
Glu Asp Gly Ser Val Ser Leu Gln Val Pro Val Ser Asn Glu Ile Ser
435 440 445
Asn Ser Ala Ser Ser His Glu Glu Asp Asn Arg Ser Glu Thr Ala Ser
450 455 460
Ser Gly Tyr Ala Ser Val Gln Gly Thr Asp Glu Pro Pro Leu Glu Glu
465 470 475 480
His Val Gln Ser Thr Asn Glu Ser Leu Gln Leu Val Asn His Glu Ala
485 490 495
Asn Ser Val Ala Val Asp Val Ile Pro His Val Asp Asn Pro Thr Phe
500 505 510
Glu Glu Asp Glu Thr Pro Asn Gln Glu Thr Ala Val Arg Glu Ile Lys
515 520 525
Ser
<210> 76
<211> 204
<212> PRT
<213> 人工序列
<220>
<223> GRAIL.IC.ZF突变体（锌指→CD8a铰链）
<400> 76
Tyr Ser Ala Arg Arg Leu Arg Asn Ala Arg Ala Gln Ser Arg Lys Gln
1 5 10 15
Arg Gln Leu Lys Ala Asp Ala Lys Lys Ala Ile Gly Arg Leu Gln Leu
20 25 30
Arg Thr Leu Lys Gln Gly Asp Lys Glu Ile Gly Pro Asp Gly Asp Ser
35 40 45
Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
50 55 60
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
65 70 75 80
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Cys Asp
85 90 95
Ile Leu Lys Ala Leu Gly Ile Glu Val Asp Val Glu Asp Gly Ser Val
100 105 110
Ser Leu Gln Val Pro Val Ser Asn Glu Ile Ser Asn Ser Ala Ser Ser
115 120 125
His Glu Glu Asp Asn Arg Ser Glu Thr Ala Ser Ser Gly Tyr Ala Ser
130 135 140
Val Gln Gly Thr Asp Glu Pro Pro Leu Glu Glu His Val Gln Ser Thr
145 150 155 160
Asn Glu Ser Leu Gln Leu Val Asn His Glu Ala Asn Ser Val Ala Val
165 170 175
Asp Val Ile Pro His Val Asp Asn Pro Thr Phe Glu Glu Asp Glu Thr
180 185 190
Pro Asn Gln Glu Thr Ala Val Arg Glu Ile Lys Ser
195 200
<210> 77
<211> 200
<212> PRT
<213> 人工序列
<220>
<223> GRAIL.IC.H2N2突变体
<400> 77
Tyr Ser Ala Arg Arg Leu Arg Asn Ala Arg Ala Gln Ser Arg Lys Gln
1 5 10 15
Arg Gln Leu Lys Ala Asp Ala Lys Lys Ala Ile Gly Arg Leu Gln Leu
20 25 30
Arg Thr Leu Lys Gln Gly Asp Lys Glu Ile Gly Pro Asp Gly Asp Ser
35 40 45
Cys Ala Val Cys Ile Glu Leu Tyr Lys Pro Asn Asp Leu Val Arg Ile
50 55 60
Leu Thr Cys Asn Arg Ile Phe Arg Lys Thr Cys Val Asp Pro Trp Leu
65 70 75 80
Leu Glu His Arg Thr Cys Pro Met Cys Lys Cys Asp Ile Leu Lys Ala
85 90 95
Leu Gly Ile Glu Val Asp Val Glu Asp Gly Ser Val Ser Leu Gln Val
100 105 110
Pro Val Ser Asn Glu Ile Ser Asn Ser Ala Ser Ser His Glu Glu Asp
115 120 125
Asn Arg Ser Glu Thr Ala Ser Ser Gly Tyr Ala Ser Val Gln Gly Thr
130 135 140
Asp Glu Pro Pro Leu Glu Glu His Val Gln Ser Thr Asn Glu Ser Leu
145 150 155 160
Gln Leu Val Asn His Glu Ala Asn Ser Val Ala Val Asp Val Ile Pro
165 170 175
His Val Asp Asn Pro Thr Phe Glu Glu Asp Glu Thr Pro Asn Gln Glu
180 185 190
Thr Ala Val Arg Glu Ile Lys Ser
195 200
<210> 78
<211> 376
<212> PRT
<213> 人工序列
<220>
<223> RNF133
<400> 78
Met His Leu Leu Lys Val Gly Thr Trp Arg Asn Asn Thr Ala Ser Ser
1 5 10 15
Trp Leu Met Lys Phe Ser Val Leu Trp Leu Val Ser Gln Asn Cys Cys
20 25 30
Arg Ala Ser Val Val Trp Met Ala Tyr Met Asn Ile Ser Phe His Val
35 40 45
Gly Asn His Val Leu Ser Glu Leu Gly Glu Thr Gly Val Phe Gly Arg
50 55 60
Ser Ser Thr Leu Lys Arg Val Ala Gly Val Ile Val Pro Pro Glu Gly
65 70 75 80
Lys Ile Gln Asn Ala Cys Asn Pro Asn Thr Ile Phe Ser Arg Ser Lys
85 90 95
Tyr Ser Glu Thr Trp Leu Ala Leu Ile Glu Arg Gly Gly Cys Thr Phe
100 105 110
Thr Gln Lys Ile Lys Val Ala Thr Glu Lys Gly Ala Ser Gly Val Ile
115 120 125
Ile Tyr Asn Val Pro Gly Thr Gly Asn Gln Val Phe Pro Met Phe His
130 135 140
Gln Ala Phe Glu Asp Val Val Val Val Met Ile Gly Asn Leu Lys Gly
145 150 155 160
Thr Glu Ile Phe His Leu Ile Lys Lys Gly Val Leu Ile Thr Ala Val
165 170 175
Val Glu Val Gly Arg Lys His Ile Ile Trp Met Asn His Tyr Leu Val
180 185 190
Ser Phe Val Ile Val Thr Thr Ala Thr Leu Ala Tyr Phe Ile Phe Tyr
195 200 205
His Ile His Arg Leu Cys Leu Ala Arg Ile Gln Asn Arg Arg Trp Gln
210 215 220
Arg Leu Thr Thr Asp Leu Gln Asn Thr Phe Gly Gln Leu Gln Leu Arg
225 230 235 240
Val Val Lys Glu Gly Asp Glu Glu Ile Asn Pro Asn Gly Asp Ser Cys
245 250 255
Val Ile Cys Phe Glu Arg Tyr Lys Pro Asn Asp Ile Val Arg Ile Leu
260 265 270
Thr Cys Lys His Phe Phe His Lys Asn Cys Ile Asp Pro Trp Ile Leu
275 280 285
Pro His Gly Thr Cys Pro Ile Cys Lys Cys Asp Ile Leu Lys Val Leu
290 295 300
Gly Ile Gln Val Val Val Glu Asn Gly Thr Glu Pro Leu Gln Val Leu
305 310 315 320
Met Ser Asn Glu Leu Pro Glu Thr Leu Ser Pro Ser Glu Glu Glu Thr
325 330 335
Asn Asn Glu Val Ser Pro Ala Gly Thr Ser Asp Lys Val Ile His Val
340 345 350
Glu Glu Asn Pro Thr Ser Gln Asn Asn Asp Ile Gln Pro His Ser Val
355 360 365
Val Glu Asp Val His Pro Ser Pro
370 375
<210> 79
<211> 166
<212> PRT
<213> 人工序列
<220>
<223> RNF133.IC
<400> 79
His Arg Leu Cys Leu Ala Arg Ile Gln Asn Arg Arg Trp Gln Arg Leu
1 5 10 15
Thr Thr Asp Leu Gln Asn Thr Phe Gly Gln Leu Gln Leu Arg Val Val
20 25 30
Lys Glu Gly Asp Glu Glu Ile Asn Pro Asn Gly Asp Ser Cys Val Ile
35 40 45
Cys Phe Glu Arg Tyr Lys Pro Asn Asp Ile Val Arg Ile Leu Thr Cys
50 55 60
Lys His Phe Phe His Lys Asn Cys Ile Asp Pro Trp Ile Leu Pro His
65 70 75 80
Gly Thr Cys Pro Ile Cys Lys Cys Asp Ile Leu Lys Val Leu Gly Ile
85 90 95
Gln Val Val Val Glu Asn Gly Thr Glu Pro Leu Gln Val Leu Met Ser
100 105 110
Asn Glu Leu Pro Glu Thr Leu Ser Pro Ser Glu Glu Glu Thr Asn Asn
115 120 125
Glu Val Ser Pro Ala Gly Thr Ser Asp Lys Val Ile His Val Glu Glu
130 135 140
Asn Pro Thr Ser Gln Asn Asn Asp Ile Gln Pro His Ser Val Val Glu
145 150 155 160
Asp Val His Pro Ser Pro
165
<210> 80
<211> 155
<212> PRT
<213> 人工序列
<220>
<223> RNF122
<400> 80
Met His Pro Phe Gln Trp Cys Asn Gly Cys Phe Cys Gly Leu Gly Leu
1 5 10 15
Val Ser Thr Asn Lys Ser Cys Ser Met Pro Pro Ile Ser Phe Gln Asp
20 25 30
Leu Pro Leu Asn Ile Tyr Met Val Ile Phe Gly Thr Gly Ile Phe Val
35 40 45
Phe Met Leu Ser Leu Ile Phe Cys Cys Tyr Phe Ile Ser Lys Leu Arg
50 55 60
Asn Gln Ala Gln Ser Glu Arg Tyr Gly Tyr Lys Glu Val Val Leu Lys
65 70 75 80
Gly Asp Ala Lys Lys Leu Gln Leu Tyr Gly Gln Thr Cys Ala Val Cys
85 90 95
Leu Glu Asp Phe Lys Gly Lys Asp Glu Leu Gly Val Leu Pro Cys Gln
100 105 110
His Ala Phe His Arg Lys Cys Leu Val Lys Trp Leu Glu Val Arg Cys
115 120 125
Val Cys Pro Met Cys Asn Lys Pro Ile Ala Ser Pro Ser Glu Ala Thr
130 135 140
Gln Asn Ile Gly Ile Leu Leu Asp Glu Leu Val
145 150 155
<210> 81
<211> 95
<212> PRT
<213> 人工序列
<220>
<223> RNF122.rIC
<400> 81
Ser Lys Leu Arg Asn Gln Ala Gln Ser Glu Arg Tyr Gly Tyr Lys Glu
1 5 10 15
Val Val Leu Lys Gly Asp Ala Lys Lys Leu Gln Leu Tyr Gly Gln Thr
20 25 30
Cys Ala Val Cys Leu Glu Asp Phe Lys Gly Lys Asp Glu Leu Gly Val
35 40 45
Leu Pro Cys Gln His Ala Phe His Arg Lys Cys Leu Val Lys Trp Leu
50 55 60
Glu Val Arg Cys Val Cys Pro Met Cys Asn Lys Pro Ile Ala Ser Pro
65 70 75 80
Ser Glu Ala Thr Gln Asn Ile Gly Ile Leu Leu Asp Glu Leu Val
85 90 95
<210> 82
<211> 203
<212> PRT
<213> 人工序列
<220>
<223> RNF152
<400> 82
Met Glu Thr Leu Ser Gln Asp Ser Leu Leu Glu Cys Gln Ile Cys Phe
1 5 10 15
Asn Tyr Tyr Ser Pro Arg Arg Arg Pro Lys Leu Leu Asp Cys Lys His
20 25 30
Thr Cys Cys Ser Val Cys Leu Gln Gln Met Arg Thr Ser Gln Lys Asp
35 40 45
Val Arg Cys Pro Trp Cys Arg Gly Val Thr Lys Leu Pro Pro Gly Phe
50 55 60
Ser Val Ser Gln Leu Pro Asp Asp Pro Glu Val Leu Ala Val Ile Ala
65 70 75 80
Ile Pro His Thr Ser Glu His Thr Pro Val Phe Ile Lys Leu Pro Ser
85 90 95
Asn Gly Cys Tyr Met Leu Pro Leu Pro Ile Ser Lys Glu Arg Ala Leu
100 105 110
Leu Pro Gly Asp Met Gly Cys Arg Leu Leu Pro Gly Ser Gln Gln Lys
115 120 125
Ser Val Thr Val Val Thr Ile Pro Ala Glu Gln Gln Pro Leu Gln Gly
130 135 140
Gly Ala Pro Gln Glu Ala Val Glu Glu Glu Gln Asp Arg Arg Gly Val
145 150 155 160
Val Lys Ser Ser Thr Trp Ser Gly Val Cys Thr Val Ile Leu Val Ala
165 170 175
Cys Val Leu Val Phe Leu Leu Gly Ile Val Leu His Asn Met Ser Cys
180 185 190
Ile Ser Lys Arg Phe Thr Val Ile Ser Cys Gly
195 200
<210> 83
<211> 165
<212> PRT
<213> 人工序列
<220>
<223> RNF152.rIC
<400> 83
Trp Thr Ser Ser Lys Val Val Gly Arg Arg Asp Gln Glu Glu Glu Val
1 5 10 15
Ala Glu Gln Pro Ala Gly Gly Gln Leu Pro Gln Gln Glu Ala Pro Ile
20 25 30
Thr Val Val Thr Val Ser Lys Gln Gln Ser Gly Pro Leu Leu Arg Cys
35 40 45
Gly Met Asp Gly Pro Leu Leu Ala Arg Glu Lys Ser Ile Pro Leu Pro
50 55 60
Leu Met Tyr Cys Gly Asn Ser Pro Leu Lys Ile Phe Val Pro Thr His
65 70 75 80
Glu Ser Thr His Pro Ile Ala Ile Val Ala Leu Val Glu Pro Asp Asp
85 90 95
Pro Leu Gln Ser Val Ser Phe Gly Pro Pro Leu Lys Thr Val Gly Arg
100 105 110
Cys Trp Pro Cys Arg Val Asp Lys Gln Ser Thr Arg Met Gln Gln Leu
115 120 125
Cys Val Ser Cys Cys Thr His Lys Cys Asp Leu Leu Lys Pro Arg Arg
130 135 140
Arg Pro Ser Tyr Tyr Asn Phe Cys Ile Gln Cys Glu Leu Leu Ser Asp
145 150 155 160
Gln Ser Leu Thr Glu
165
<210> 84
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> GRAIL- 锌指结构域
<400> 84
Cys Ala Val Cys Ile Glu Leu Tyr Lys Pro Asn Asp Leu Val Arg Ile
1 5 10 15
Leu Thr Cys Asn His Ile Phe His Lys Thr Cys Val Asp Pro Trp Leu
20 25 30
Leu Glu His Arg Thr Cys Pro Met Cys Lys
35 40
<210> 85
<211> 46
<212> PRT
<213> 人工序列
<220>
<223> CD8铰链
<400> 85
Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
1 5 10 15
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
20 25 30
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 86
<211> 544
<212> PRT
<213> 人工序列
<220>
<223> LG116*
<400> 86
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn
65 70 75 80
Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Lys Asn Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr
100 105 110
Gly Val Tyr Phe Cys Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
145 150 155 160
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
165 170 175
Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln
180 185 190
Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu
195 200 205
Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
210 215 220
Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr
245 250 255
Lys Leu Gln Ile Thr Arg Gly Ser Gly Ser Gly Ser Gly Ser Val Asn
260 265 270
Ile Ser Gly Gln Asn Thr Met Asn Met Val Lys Val Pro Glu Cys Arg
275 280 285
Leu Ala Asp Glu Leu Gly Gly Leu Trp Glu Asn Ser Arg Phe Thr Asp
290 295 300
Cys Cys Leu Cys Val Ala Gly Gln Glu Phe Gln Ala His Lys Ala Ile
305 310 315 320
Leu Ala Ala Arg Ser Pro Val Phe Ser Ala Met Phe Glu His Glu Met
325 330 335
Glu Glu Ser Lys Lys Asn Arg Val Glu Ile Asn Asp Val Glu Pro Glu
340 345 350
Val Phe Lys Glu Met Met Cys Phe Ile Tyr Thr Gly Lys Ala Pro Asn
355 360 365
Leu Asp Lys Met Ala Asp Asp Leu Leu Ala Ala Ala Asp Lys Tyr Ala
370 375 380
Leu Glu Arg Leu Lys Val Met Cys Glu Asp Ala Leu Cys Ser Asn Leu
385 390 395 400
Ser Val Glu Asn Ala Ala Glu Ile Leu Ile Leu Ala Asp Leu His Ser
405 410 415
Ala Asp Gln Leu Lys Thr Gln Ala Val Asp Phe Ile Asn Tyr His Ala
420 425 430
Ser Asp Val Leu Glu Thr Ser Gly Trp Lys Ser Met Val Val Ser His
435 440 445
Pro His Leu Val Ala Glu Ala Tyr Arg Ser Leu Ala Ser Ala Gln Cys
450 455 460
Pro Phe Leu Gly Pro Pro Arg Lys Arg Leu Lys Gln Ser Gly Thr Thr
465 470 475 480
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln
485 490 495
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
500 505 510
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
515 520 525
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
530 535 540
<210> 87
<211> 525
<212> PRT
<213> 人工序列
<220>
<223> LG118*
<400> 87
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
65 70 75 80
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
115 120 125
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
130 135 140
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu
165 170 175
Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr
180 185 190
Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro
195 200 205
Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro
210 215 220
Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala
225 230 235 240
Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys
245 250 255
Ala Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu
260 265 270
Thr Val Leu Gly Ser Gly Ser Gly Ser Gly Arg Leu Asn Phe Gly Asp
275 280 285
Asp Ile Pro Ser Ala Leu Arg Ile Ala Lys Lys Lys Arg Trp Asn Ser
290 295 300
Ile Glu Glu Arg Arg Ile His Gln Glu Ser Glu Leu His Ser Tyr Leu
305 310 315 320
Ser Arg Leu Ile Ala Ala Glu Arg Glu Arg Glu Leu Glu Glu Cys Gln
325 330 335
Arg Asn His Glu Gly Asp Glu Asp Asp Ser His Val Arg Ala Gln Gln
340 345 350
Ala Cys Ile Glu Ala Lys His Asp Lys Tyr Met Ala Asp Met Asp Glu
355 360 365
Leu Phe Ser Gln Val Asp Glu Lys Arg Lys Lys Arg Asp Ile Pro Asp
370 375 380
Tyr Leu Cys Gly Lys Ile Ser Phe Glu Leu Met Arg Glu Pro Cys Ile
385 390 395 400
Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His Leu
405 410 415
Gln Arg Val Gly His Phe Asp Pro Val Thr Arg Ser Pro Leu Thr Gln
420 425 430
Glu Gln Leu Ile Pro Asn Leu Ala Met Lys Glu Val Ile Asp Ala Phe
435 440 445
Ile Ser Glu Asn Gly Trp Val Glu Asp Tyr Gly Thr Thr Thr Pro Ala
450 455 460
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
465 470 475 480
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
485 490 495
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
500 505 510
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
<210> 88
<211> 1149
<212> DNA
<213> 人工序列
<220>
<223> EF1α启动子
<400> 88
gggcagagcg cacatcgccc acagtccccg agaagttggg gggaggggtc ggcaattgaa 60
ccggtgccta gagaaggtgg cgcggggtaa actgggaaag tgatgtcgtg tactggctcc 120
gcctttttcc cgagggtggg ggagaaccgt atataagtgc agtagtcgcc gtgaacgttc 180
tttttcgcaa cgggtttgcc gccagaacac aggtaagtgc cgtgtgtggt tcccgcgggc 240
ctggcctctt tacgggttat ggcccttgcg tgccttgaat tacttccacg cccctggctg 300
cagtacgtga ttcttgatcc cgagcttcgg gttggaagtg ggtgggagag ttcgaggcct 360
tgcgcttaag gagccccttc gcctcgtgct tgagttgagg cctggcctgg gcgctggggc 420
cgccgcgtgc gaatctggtg gcaccttcgc gcctgtctcg ctgctttcga taagtctcta 480
gccatttaaa atttttgatg acctgctgcg acgctttttt tctggcaaga tagtcttgta 540
aatgcgggcc aagatctgca cactggtatt tcggtttttg gggccgcggg cggcgacggg 600
gcccgtgcgt cccagcgcac atgttcggcg aggcggggcc tgcgagcgcg gccaccgaga 660
atcggacggg ggtagtctca agctggccgg cctgctctgg tgcctggcct cgcgccgccg 720
tgtatcgccc cgccctgggc ggcaaggctg gcccggtcgg caccagttgc gtgagcggaa 780
agatggccgc ttcccggccc tgctgcaggg agctcaaaat ggaggacgcg gcgctcggga 840
gagcgggcgg gtgagtcacc cacacaaagg aaaagggcct ttccgtcctc agccgtcgct 900
tcatgtgact ccacggagta ccgggcgccg tccaggcacc tcgattagtt cttttggagt 960
acgtcgtctt taggttgggg ggaggggttt tatgcgatgg agtttcccca cactgagtgg 1020
gtggagactg aagttaggcc agcttggcac ttgatgtaat tctccttgga atttgccctt 1080
tttgagtttg gatcttggtt cattctcaag cctcagacag tggttcaaag tttttttctt 1140
ccatttcag 1149
<210> 89
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> CD3ζ跨膜结构域变体（用于LG222，即
CD3ζ.ΔIC-1）
<400> 89
Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys Tyr Leu Leu Asp Gly
1 5 10 15
Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu
20 25 30
<210> 90
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 细胞内结构域（用于LG222、LG222.1、LG222.2）
<400> 90
Arg Val Lys Phe Ser Arg Ser Ala Asp
1 5
<210> 91
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> scFv与E3连接酶之间或CD8 TM与E3连接酶之间的接头
<400> 91
Gly Ser Gly Ser Gly Ser Gly
1 5
Claims (14)
1.一种融合蛋白，其包含：
介导膜结合蛋白(MBP)降解的降解标签蛋白，其中该降解标签蛋白选自泛素连接酶或其变体中的一个或多个，或介导降解的细胞表面受体的一个或多个亚基或结构域；以及
跨膜连接结构域，其包含：
1)第一跨膜连接结构域，其包含第一跨膜结构域和第一连接蛋白；
其中该第一跨膜结构域选自CD8α、CD4、CD3、CD28、4-1BB和IL2R或其变体的一个或多个亚基或结构域的跨膜结构域；该第一连接蛋白选自该待降解的MBP的抗体或抗原结合片段中的一个或多个；并且该第一跨膜结构域与该第一连接蛋白直接或间接连接；
优选地，具有上述1)的跨膜连接结构域的融合蛋白进一步包含第一信号肽；或者
2)第二跨膜连接结构域，其包含该待降解的MBP或其变体的跨膜结构域；
优选地，该MBP是膜结合受体；更优选地，哺乳动物来源膜结合受体，最优选地人膜结合受体；
优选地，该泛素连接酶包含E3泛素连接酶或其变体的一个或多个亚基或结构域；
优选地，所述介导降解的细胞表面受体包含白细胞介素受体或其变体的一个或多个亚基或结构域；
优选地，上述1)中的该待降解的MBP的抗原结合片段包含与该MBP或其变体特异性结合的scFv、纳米抗体；
优选地，上述2)中的该待降解的MBP或其变体的跨膜结构域包含CD3ζ、CD3γ、CD3δ、CD3ε、CD3α、CD3β或其变体中的一个或多个的跨膜结构域；
更优选地，上述2)中的第二跨膜连接结构域包含CD3ζ、CD3γ、CD3δ、CD3ε、CD3α、CD3β或其变体中的一个或多个的细胞外结构域和跨膜结构域；
更优选地，上述2)中的第二跨膜连接结构域包含CD3ζ、CD3γ、CD3δ、CD3ε、CD3α、CD3β或其变体中的一个或多个的第二信号肽、细胞外结构域和跨膜结构域。
2.如权利要求1所述的融合蛋白，其中，
该膜结合受体选自CD3、TCR、CD5、CD7、PD-L1和CD47或其变体的一个或多个亚基或结构域；
该E3泛素连接酶选自以下蛋白质或其截短形式：Hsc70相互作用蛋白(CHIP)的C末端、CHIP.dTPR、含有F盒WD40的蛋白7(FBW7)、FBW7.2-293、希佩尔-林道(VHL)、VHL.152-213、斑点型BTB-POZ蛋白(SPOP)、SPOP.167-374、SOCS2、SOCS2.143-198、泛素蛋白连接酶E3A(UBE3A)、小鼠双微体2同源物(MDM2)、后期促进复合物(APC)、UBR5、LNX、卡西塔斯B谱系淋巴瘤转化序列样蛋白1(CBLL1)、含有HECT结构域和锚蛋白重复序列的E3泛素蛋白连接酶1(HACE1)，含有HECT、C2和WW结构域的E3泛素蛋白连接酶1(HECW1)，含有HECT、C2和WW结构域的E3泛素蛋白连接酶2(HECW2)，含有HECT和RLD结构域的E3泛素蛋白连接酶1(HERC1)，HERC2、HERC3、HERC4、HERC5、HERC6、HUWE1、ITCH、神经前体细胞表达的发育下调蛋白4(NEDD4)、神经前体细胞表达的发育下调基因4样蛋白(NEDD4L)、肽基脯氨酰异构酶(亲环蛋白)样2(PPIL2)、PIAS1、PIAS2、PIAS3、PIAS4、RANBP2、RNF4、RBX1、SMURF1、SMURF2、STUB1、TOPORS、TRIP12、UBE3A、UBE3B、UBE3C、UBE3D、UBE4A、UBE4B、UBOX5、UBR5、WWP1、WWP2、Parkin、MKRN1、GRAIL.IC、RNF133.IC、RNF122.rIC或RNF152.rIC；优选地，该E3泛素连接酶包含CHIP、CHIP.dTPR、FBW7.2-293、VHL.152-213、SPOP.167-374、SOCS2.143-198、GRAIL.IC、RNF133.IC、RNF122.rIC或RNF152.rIC；并且更优选地，该CHIP、CHIP.dTPR、FBW7.2-293、VHL.152-213、SPOP.167-374、SOCS2.143-198、GRAIL.IC、RNF133.IC、RNF122.rIC或RNF152.rIC分别包含与SEQ ID NO.21-26、62、79、81或83中任一项所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
白细胞介素受体的所述亚基或结构域包含IL-2R的溶酶体靶向基序；优选地，该IL-2R的溶酶体靶向基序包含L2Rβjm结构域；更优选地，该L2Rβjm结构域(IL2Rβjm)包含与SEQ IDNO.58中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
上述1)中的该第一跨膜结构域选自CD3、CD8α、CD4、或其变体的跨膜结构域；优选地，CD3ζ跨膜结构域变体、CD8α跨膜结构域、或CD4跨膜结构域分别包含与SEQ ID NO.89、18或15中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
该第一信号肽分别选自与SEQ ID NO.19或20中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
上述1)中该MBP的该抗体或抗原结合片段选自CD3、CD5、CD7、PD-L1或CD47的抗体或抗原结合片段；优选地，CD3的抗原结合片段包含SP34 scFv、OKT3 scFv、UCHT1 scFv、UCHT1.Y177T scFv、L2K scFv、F6A scFv、BMA031 scFv、或BMA031.H6L12 scFv；CD5的抗原结合片段包含αCD5.14 scFv；CD7的抗原结合片段包含αCD7.TH69 scFv；PD-L1的抗原结合片段包含αPD-L1 scFv；CD47的抗原结合片段包含αCD47 scFv；更优选地，该SP34 scFv、OKT3 scFv、UCHT1 scFv、UCHT1.Y177T scFv、L2K scFv、F6A scFv、BMA031 scFv、BMA031.H6L12 scFv、αCD5.14 scFv、αCD7.TH69 scFv、αPD-L1 scFv或αCD47 scFv分别包含与SEQ ID NO.2-13中任一项所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；
上述2)中的第二跨膜连接结构域包含CD3ζ或CD3ε的跨膜结构域，优选地，CD3ζ或CD3ε的细胞外结构域和跨膜结构域，更优选地，CD3ζ或CD3ε的第二信号肽、细胞外结构域和跨膜结构域；更优选地，该CD3ζ或CD3ε的跨膜结构域(TM)分别包含与SEQ ID NO.67、70中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该CD3ζ或CD3ε的细胞外结构域(EM)分别包含与SEQ ID NO.66、69中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该CD3ζ或CD3ε的第二信号肽分别包含与SEQ ID NO.65、68中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该CD3ζ(CD3ζ.ΔIC)的第二信号肽、细胞外结构域和跨膜结构域以及该CD3ε(CD3ε.ΔIC)的第二信号肽、细胞外结构域和跨膜结构域分别包含与SEQ ID NO.61、64中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
3.如权利要求1-2中任一项所述的融合蛋白，其中
该融合蛋白进一步包含铰链或P2A-GFP中的一个或多个；
优选地，该铰链选自CD8α铰链或CD4铰链；更优选地，CD8α铰链或CD4铰链分别包含与SEQ ID NO.16或14中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该铰链与该第一跨膜结构域的N末端相邻，
优选地，P2A-GFP包含与SEQ ID NO.57中所示的氨基酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的氨基酸序列；更优选地，该P2A-GFP序列位于该融合蛋白的C末端。
4.如权利要求1-3中任一项所述的融合蛋白，其中该融合蛋白从N末端至C末端包含：
a)该第一连接蛋白、该降解标签蛋白、该第一跨膜结构域；
优选地，该第一连接蛋白包含该待降解的MBP的抗体或抗原结合片段；更优选地，该待降解的MBP的抗体或抗原结合片段包含CD3、CD5、CD7、PD-L1或CD47的抗体或抗原结合片段；更优选地，CD3的抗原结合片段包含SP34 scFv、OKT3 scFv、UCHT1 scFv、UCHT1.Y177TscFv、L2K scFv、F6A scFv、BMA031 scFv、或BMA031.H6L12 scFv；CD5的抗原结合片段包含αCD5.14 scFv；CD7的抗原结合片段包含αCD7.TH69 scFv；PD-L1的抗原结合片段包含αPD-L1scFv；CD47的抗原结合片段包含αCD47 scFv；
优选地，该降解标签蛋白包含该E3泛素连接酶；更优选地，该E3泛素连接酶包含CHIP.dTPR、FBW7.2-293、VHL.152-213、SPOP.167-374、SOCS2.143-198；
优选地，该第一跨膜结构域包含CD8α跨膜结构域；
b)该第一连接蛋白、该第一跨膜结构域、该降解标签蛋白；
优选地，该第一连接蛋白包含该待降解的MBP的抗体或抗原结合片段；更优选地，该待降解的MBP的抗体或抗原结合片段包含CD3的抗体或抗原结合片段；更优选地，CD3的抗原结合片段包含SP34 scFv；
优选地，该降解标签蛋白包含该E3泛素连接酶；更优选地，E3泛素连接酶包含GRAIL.IC；
优选地，该第一跨膜结构域选自CD3ζ跨膜结构域变体、CD8α跨膜结构域、和CD4跨膜结构域中的一个或多个；
c)上述2)中的该第二跨膜连接结构域、所述介导降解的细胞表面受体；
优选地，上述2)中的该第二跨膜连接结构域包含CD3ζ.ΔIC或CD3ε.ΔIC；
优选地，所述介导降解的细胞表面受体包含IL2Rβjm；或者
d)上述2)中的该第二跨膜连接结构域、E3泛素连接酶或其变体中的一个或多个；
优选地，上述2)中的该第二跨膜连接结构域包含CD3ζ.ΔIC；
优选地，该E3泛素连接酶或其变体中的一个或多个包含GRAIL.IC、CHIP.dTPR、RNF133.IC、RNF122.rIC、RNF152.rIC。
5.如权利要求4所述的融合蛋白，其中该融合蛋白从N末端至C末端包含：
a)：
LG112，SP-OKT3 scFv-CHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG114，SP-OKT3 scFv-FBW7-CD8α铰链/TM-P2A-eGFP；
LG115，SP-OKT3 scFv-VHL-CD8α铰链/TM-P2A-eGFP；
LG116，SP-OKT3 scFv-SPOP-CD8α铰链/TM-P2A-eGFP；
LG117，SP-OKT3 scFv-SOCS2-CD8α铰链/TM-P2A-eGFP；
LG118，SP-SP34 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG123，SP-UCHT1 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG124，SP-UCHT1.Y177T scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG125，SP-L2K scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG126，SP-F6A scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG119，SP-BMA031.wt scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG120，SP-BMA031.H6L12 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG137，SP-αCD5.14 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
LG138，SP-αCD7.TH69 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
MLB052，SP-αPD-L1 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
MLB053，SP-αCD47 scFv-hCHIP.dTPR-CD8α铰链/TM-P2A-eGFP；
b)：
LG222，SP-SP34-CD3ζ.ΔIC-1-GRAIL.IC-P2A-eGFP；
LG222.1，SP-SP34-CD8α铰链/TM-GRAIL.IC-P2A-eGFP；
LG222.2，SP-SP34-CD4铰链/TM-GRAIL.IC-P2A-eGFP；
c)：
MLB014，CD3ζ.ΔIC-IL2Rβjm-P2A-eGFP；
MLB046，CD3ε.ΔIC-IL2Rβjm-P2A-eGFP；
d)：
LG171，CD3ζ.ΔIC-GRAIL.IC-P2A-eGFP；
LG171p1、CAG-CD3ζ.ΔIC-GRAIL.IC-P2A-eGFP；
LG213，CD3ζ.ΔIC-CHIP.dTPR-P2A-GFP；
LG174，CD3ζ.ΔIC-RNF133.IC-P2A-GFP；
LG180，CD3ζ.ΔIC-RNF122.rIC-P2A-GFP；
LG183，CD3ζ.ΔIC-RNF152.rIC-P2A-GFP；
任选地，该融合蛋白不包括P2A-eGFP和/或SP。
6.一种核酸，其包含编码如权利要求1-5中任一项所述的融合蛋白的多核苷酸。
7.一种载体，其包含如权利要求6所述的核酸；
优选地，其进一步包含该融合蛋白的表达启动子，该表达启动子包含CAG或EF1a；
更优选地，该CAG或EF1a分别包含与SEQ ID NO.72或88中所示的核酸序列具有至少约95％、96％、97％、98％、99％或100％同一性的核酸序列；
更优选地，该a)融合蛋白的表达启动子是EF1a；
更优选地，该b)融合蛋白的表达启动子是EF1a；
更优选地，该c)融合蛋白的表达启动子是EF1a；
更优选地，该d)融合蛋白中的该LG171p1的表达启动子是CAG，更优选地，该d)融合蛋白中的其他融合蛋白的表达启动子是EF1a。
8.一种组合物，其包含如权利要求6所述的核酸或如权利要求7所述的载体。
9.一种组合物，其包含第一核酸和第二核酸；或包含具有第一核酸的第一载体以及具有第二核酸的第二载体；或包含具有第一核酸和第二核酸的载体，其中
(1)该第一核酸编码如权利要求1-5中任一项所述的融合蛋白，以及(2)该第二核酸编码包含以下的嵌合抗原受体(CAR)：
(a)细胞外配体结合结构域，其包含与预定抗原特异性结合的单链可变片段(scFv)；
(b)跨膜结构域，优选地CD8α、CD28、4-1BB或IL2R跨膜结构域，更优选地CD8α跨膜结构域，以及
(c)细胞质区段，其包含一个或多个信号传导结构域，优选地其包含4-1BB信号传导结构域和CD3ζ信号传导结构域；
优选地，该预定抗原是肿瘤相关抗原；更优选地，该肿瘤相关抗原选自以下组：CEA、密封蛋白18.2、GPC3、受体酪氨酸激酶样孤儿受体1(ROR1)、CD38、CD19、CD20、CD22、BCMA、CAIX、CD446、CD133、EGFR、EGFRvIII、EpCam、GD2、EphA2、Her1、Her2、ICAM-1、IL13Ra2、间皮素、MUC1、MUC16、NKG2D、PSCA、NY-ESO-1、MART-1、WT1、MAGE-A10、MAGE-A3、MAGE-A4、EBV、NKG2D、PD1、PD-L1、CD25、IL-2或CD3；最优选地，该肿瘤相关抗原是CEA。
10.一种细胞，其包含如权利要求6所述的核酸或如权利要求7所述的载体或如权利要求8-9中任一项所述的组合物；优选地，该细胞是哺乳动物细胞，更优选地人细胞；更优选地，该细胞是T细胞或原代T细胞、γδT细胞、NK细胞、NKT细胞、巨噬细胞、B细胞、或非免疫细胞；最优选地，该细胞是同种异体细胞。
11.一种药物组合物，其包含如权利要求1-5中任一项所述的融合蛋白，如权利要求6所述的核酸或如权利要求7所述的载体或如权利要求8-9中任一项所述的组合物或如权利要求10所述的细胞。
12.一种降低细胞中靶膜结合蛋白水平的方法，该方法包括将如权利要求6所述的核酸，如权利要求7所述的载体，或如权利要求8-9中任一项所述的组合物引入细胞；优选地，该细胞是哺乳动物细胞，更优选地人细胞；更优选地，该细胞是T细胞或原代T细胞、γδT细胞、NK细胞、NKT细胞、巨噬细胞、B细胞、或非免疫细胞；最优选地，该细胞是同种异体细胞。
13.一种治疗疾病的方法，该方法包括向有需要的受试者施用治疗有效量的具有如权利要求8-9中任一项所述的组合物的同种异体细胞或向有需要的受试者施用治疗有效量的如权利要求10所述的细胞；优选地，该细胞是T细胞或原代T细胞、γδT细胞、NK细胞、NKT细胞、巨噬细胞、B细胞、或非免疫细胞；优选地，该受试者具有减少的移植物抗宿主疾病(GvHD)。
14.一种下调细胞群中膜结合蛋白(MBP)的方法，该方法包括将如权利要求10所述的细胞添加至该细胞群，其中该细胞表达包含与所述MBP特异性结合的scFv的融合蛋白，和/或该细胞表达包含具有跨膜结构域的该MBP的组分或其片段的融合蛋白；优选地，该细胞群是T细胞群，优选地人原代T细胞群，并且其中该MBP是CD3，优选地人CD3。
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