CN109415442A - 人源化抗il-1r3抗体 - Google Patents
人源化抗il-1r3抗体 Download PDFInfo
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- CN109415442A CN109415442A CN201780041725.7A CN201780041725A CN109415442A CN 109415442 A CN109415442 A CN 109415442A CN 201780041725 A CN201780041725 A CN 201780041725A CN 109415442 A CN109415442 A CN 109415442A
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Abstract
本公开涉及特异性结合IL‑1R3的人源化抗体或者其片段或衍生物或多肽,所述片段或衍生物或多肽含有足以赋予IL‑1R3结合特异性的、所述抗体的至少一部分。所述抗体抑制IL‑1R3诱导的NFkB活性。其还抑制IL‑1α、IL‑1β、IL‑33、和/或IL‑36刺激的NFkB活性。本公开进一步涉及所述人源化抗体在治疗IL‑1R3介导的疾病如癌症中的用途。最后,本公开涵盖药物组合物,其包含药学可接受的载体和治疗有效量的根据本发明的抗体。所述药物组合物可用于治疗IL‑1R3介导的疾病如癌症。
Description
技术领域
本发明涉及人源化抗IL-1R3抗体和其用途。
背景技术
白细胞介素1受体辅助蛋白(interleukin 1receptor accessory protein,IL1RAP),也称为IL1R3,是1型白细胞介素1受体(IL1R1)的共同受体,并且对于IL-1信号的传导来说是不可缺少的。在IL-1的结合时,IL-1R1与IL-1RAcP缔合,形成功能性信号受体复合物,其刺激NFkB活性。
IL-33、其受体ST2、和IL-1RAcP也形成具有就NFkB激活而言与IL-1β/IL-1R1/IL-1RAcP复合物相似的活性的复合物(IL-33/ST2/IL-1RAcP)。IL-36(IL-36α(IL-1F6)、IL-36β(IL-1F8)、和IL-36γ(IL-1F9)),它们的受体IL-36R,和IL-1RAcP也形成具有就NFkB激活而言与IL-1β/IL-1R1/IL-1RAcP复合物相似的活性的复合物。
人NF-kB是参与炎症、免疫反应和细胞凋亡的几种基因的表达的重要调节因子。因此,在包括自身免疫疾病、神经变性疾病、炎症和癌症等多种疾病的病理学中涉及NFkB的功能异常。例如,在治疗骨关节炎(OA)中,NF-kB途径是重要的靶标。因此,通过抑制人IL-1R1/IL-1RAcP复合物的信号传导活性来调节人NFkB途径的试剂代表多种人类疾病的可能治疗。特别地,高亲和力中和抗体可制成优异的治疗剂。
自从超过15年以来,已进行尝试生成针对人IL1RAcP的功能性单克隆抗体。然而,很多尝试都失败了,并且现存的抗体仍显示各种缺点。
WO199623067涉及IL-1RAcP抗体,其特异性结合鼠IL-1受体辅助蛋白。实施例15和16描述了生成中和IL-1生物活性的抗人IL-1RAcP抗体的尝试。然而,WO199623067并没有提供此类抗体,并且描述IL-1诱导的IL-6分析的实施例16仅为假设性的。Do-Young Yoon D-Y和Charles A.Dinarello CA在J.Immunol.1998;160:3170-3179中描述了针对鼠IL-1RAcP的结构域II和III的多克隆抗体,其抑制IL-1β活性但并不结合。然而,在较高浓度的IL-1β(1000pg/ml)下,该多克隆抗血清不阻断D10S细胞的增殖。(D10S是鼠D10.G4.1辅助性T细胞的亚克隆,其针对亚飞摩尔(subfemtomolar)(渺摩尔(attomolar))浓度的IL-1β或α在没有促分裂原的情况下增殖,参见Orencole SF和Dinarello CA;Cytokine 1(1989)14-22)。Jaras M.等人,PNAS107(2010)16280-16285描述了兔多克隆抗IL1RAcP抗体KMT-1用于杀死CML干细胞的用途。该抗体以其兔Fc部分引起的IL1RAcP非依赖性方式来诱导ADCC。Jaras等人预期“潜在的未来治疗性IL1RAP靶向抗体预计对正常造血细胞显示低毒性”。针对鼠IL-1RAcP的多克隆兔抗体还在Do-Young Yoon和Charles A.Dinarello,Journal ofBiochemistry and Molecular Biology,Vol.40,No.4,July 2007,pp.562-570中提及。
WO2002064630也涉及IL-1RAcP和其用途,但没有描述针对IL-1RAcP的抗体。WO2004022718和WO2009120903理论上地提及针对CSF1R、IL13RA1、IL1RAP、IFNAR1、IL5R、INSR、IL1RL1、LTK、和TACSTD1的抗体可根据本领域现有技术生成。然而,在此也没有提及针对IL-1RAcP的抗体。WO2011021014和WO 2012098407(US20140017167)涉及多克隆兔抗人IL-1RAcP抗血清KMT-1(参见Jaras等人2010)和其用途。WO2014100772涉及与IL-1RAcP结合的抗IL-1RAcP抗体。然而,没有描述关于刺激NFkB活性的任何功能性信号受体复合物(如IL-1β/IL-1R1/IL-1RAcP)的抑制的活性。US6280955涉及IL-1RAcP和其用途,但同样没有描述针对IL-1RAcP的抗体。US7390880提及IL1RAcP的N末端片段,但是也没有描述针对IL-1RAcP的抗体。
WO2004100987涉及白细胞介素-l(IL-1)拮抗剂在制备用于治疗新内膜(neointimal)增生的药物中的用途,并且涉及IL-1拮抗剂用于治疗新内膜增生的用途。作为此类拮抗剂,提及抗IL-1RAcP抗体,但未进一步描述。US2003026806涉及与IL-1结合的抗体。WO2002064630也涉及针对IL-1RAcP蛋白的IL-1拮抗剂。虽然提及了IL-1RAcP用于筛选IL-1RAcP拮抗剂的用途,但未公开此类方法或拮抗剂。
这显示,识别具有高亲和力、高特异性、和针对IL-1R3的有效的中和活性的单克隆抗体是非常困难的。本发明包含人源化IL-1R3抗体,其具有对IL-1R3的高亲和力和特异性,具有有效的IL-1R3中和活性、和改善的稳定性。
发明内容
本发明涉及特异性结合IL-1R3的人源化IgG1LALA抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物或多肽。所述抗体抑制IL-1R3诱导的NFkB活性。其还抑制IL-1α、IL-1β、IL-33、和/或IL-36刺激的NFkB活性。
本发明进一步涉及根据本发明的抗体用于治疗IL-1R3介导的疾病。
本发明进一步包含治疗患者中IL-1R3介导的疾病的方法,其包括给予患者药学有效量的所述抗体。
本发明还包括药物组合物,其包含药学可接受的载体和治疗有效量的所述抗体。
具体实施方式
定义
根据本发明的术语“兔”意为分类目兔形目(Lagomorpha)的成员的动物,所述兔形目包括科(野兔(hares)和家兔(rabbits))和鼠兔科(Ochotonidae)(鼠兔(pikas)),优选属穴兔属(Oryctolagus)。
术语"抗体"涵盖各种形式的抗体结构,包括但不限于,完整抗体和抗体片段,只要其示出根据本发明的性质即可。
根据本发明的术语"兔单克隆抗体"意为通过免疫兔并从所述兔的抗原生成细胞中分离而产生的单克隆抗体、以及进一步修饰的此类抗体,优选人源化抗体、嵌合抗体、其片段、或进一步遗传工程或重组生产的抗体,只要保留根据本发明的特征性质即可。优选抗体来自所述兔的B细胞或兔杂交瘤细胞。
根据本发明的术语"抗体生成细胞(antibody producing cell)”意为兔B细胞,其生成抗体,优选B细胞或兔杂交瘤细胞。
"天然抗体"通常为由两条相同的轻(L)链和两条相同的重(H)链组成的异四聚体糖蛋白。各轻链通过一个共价二硫键连接至重链,而二硫键的数量在不同免疫球蛋白同种型的重链之间不同。各重链和轻链还具有规则间隔的链内二硫桥。各重链在一端具有可变结构域(VH),接着是多个恒定结构域。各轻链在一端具有可变结构域(VL),并在其另一端具有恒定结构域。轻链的恒定结构域与重链的第一恒定结构域对齐,并且轻链可变结构域与重链可变结构域对齐。认为特定的氨基酸残基在轻链和重链可变结构域之间形成界面。
对于肽或多肽序列的"百分比(%)氨基酸序列同一性"定义为,在根据需要比对序列并引入空位(gap)以实现最大百分比序列同一性并且不将任何保守替换考虑为序列同一性的一部分后,候选序列中与特定肽或多肽序列中的氨基酸残基相同的氨基酸残基的百分比。为了测定百分比氨基酸序列同一性的目的的比对可以以在本领域技术范围内的各种方式实现,例如,使用公众可获得的计算机软件,例如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。
术语"VL(或VH)区"与VL(或VH)结构域具有相同含义。
根据本发明的术语"Fc受体"或"FcR"指的是与抗体的Fc区结合的人类受体。FcR结合IgG抗体,并且包括FcγRI、FcγRII、和FcγRIII亚类的受体,包括等位基因变体和这些受体的可选剪接形式。FcγRII受体包括FcγRIIA("激活受体")和FcγRIIB("抑制受体"),其具有主要在其细胞质结构域中不同的相似氨基酸序列。激活受体FcγRIIA在其细胞质结构域中含有基于免疫受体酪氨酸的激活基序(ITAM)。抑制受体FcγRIIB在其细胞质结构域中含有基于免疫受体酪氨酸的抑制基序(ITIM)(参见综述M.in Daeron,Annu.Rev.Immunol.15:203-234(1997))。FcRIIIA(CD16a)调节ADCC。FcR在Ravetch和Kinet,Annu.Rev.Immunol 9:457-92(1991);Capel等人,Immunomethods 4:25-34(1994);和de Haas等人,J.Lab.CHn.Med.126:330-41(1995)中综述。这些和所有其他FcR在本文中由术语"FcR"涵盖。该术语还包括新生儿受体FcRn,其负责母体IgG至胎儿的转移(Guyer等人,J.Immunol.117:587(1976)和Kim等人,J.Immunol.24:249(1994)),并且调节较慢的分解代谢,由此延长半衰期。
如本文所用的术语"抗体效应子功能"或"效应子功能"指的是由IgG的一个(或多个)Fc效应子结构域(例如,免疫球蛋白的Fc区)提供的功能。此类功能可通过例如一个(或多个)Fc效应子结构域与具有吞噬或裂解活性的免疫细胞上的Fc受体的结合、或者通过一个(或多个)Fc效应子结构域与补体系统的组分的结合来实现。典型的效应子功能为ADCC、ADCP和CDC。
"抗体片段"指的是除了完整抗体以外的分子,其包含与完整抗体所结合的抗原结合的完整抗体的一部分。抗体片段的实例包括但不限于Fv、Fab、Fab'、Fab'-SH、F(ab')2;双抗体;线性抗体;单链抗体分子(例如scFv);和从抗体片段形成的多特异性抗体。
与参考抗体"结合相同表位的抗体"指的是在竞争分析中阻断参考抗体与其抗原的结合50%以上的抗体,反之,参考抗体在竞争分析中阻断抗体与其抗原的结合50%以上。本文提供示例性的竞争分析。
"抗体依赖性的细胞介导的细胞毒性"和"ADCC"指的是细胞介导的反应,其中表达FcR的非特异性细胞毒性细胞(例如天然杀伤(NK)细胞、嗜中性粒细胞、和巨噬细胞)识别靶细胞上结合的抗体,并且随后引起靶细胞的裂解。调节ADCC的原代细胞、NK细胞仅表达FcyRIII,而单核细胞表达FcyRI、FcyRII和FCYRIII。
术语"抗体依赖性细胞吞噬作用"和"ADCP"指的是抗体包被的细胞全部或部分由与免疫球蛋白Fc区结合的吞噬免疫细胞(例如,巨噬细胞、嗜中性粒细胞和树突细胞)内在化的过程。
"C1q"是包括免疫球蛋白的Fc区的结合位点的多肽。C1q与两个丝氨酸蛋白酶C1r和C1s一起,形成复合物C1,即补体依赖性细胞毒性(CDC)途径的第一组分。人C1q可商购自例如Quidel,San Diego,Calif。
抗体的"类"指的是其重链具有的恒定结构域或恒定区的类型。存在5大类抗体:IgA、IgD、IgE、IgG、和IgM,并且这些中的几类可进一步分为亚类(同种型),例如,IgGi、IgG2、IgG3、IgG4、IgAi、和IgA2。对应于不同类的免疫球蛋白的重链恒定结构域分别称为a、δ、ε、γ、和μ。
例如药物制剂等的试剂的"有效量"指的是在需要的剂量和时间段下,有效实现期望的治疗或预防结果的量。
本文中术语"Fc区"用于定义免疫球蛋白重链的C末端区域,其包含恒定区的至少一部分。该术语包括天然序列Fc区和变体Fc区。除非本文另有说明,否则在Fc区或恒定区中氨基酸残基的编号根据EU编号系统,也称为EU索引,其如Kabat,等人,Sequences ofProteins of Immunological Interest,第5版.Public Health Service,NationalInstitutes of Health,Bethesda,MD(1991)所述。
"变体Fc区"包含凭借至少一个如本文所述的"氨基酸修饰"与"天然"或"野生型"序列Fc区的氨基酸序列不同的氨基酸序列。如本文所用的术语"Fc-变体"指的是包含Fc结构域中的修饰的多肽。本发明的Fc变体根据组成其的氨基酸修饰来定义。因此,例如,P329G是含有在相对于亲本Fc多肽的329位处用甘氨酸取代脯氨酸的Fc变体,其中编号根据EU索引。野生型氨基酸的特性可为未指定的,在该情况下前述变体称为P329G。对于本发明中讨论的所有位置,编号根据EU索引。EU索引或如Kabat或EU编号方案中的EU索引指的是EU抗体的编号(Edelman,等人,Proc Natl Acad Sci USA 63(1969)78-85,其通过引用整体并入本文。)修饰可为添加、删除、或取代。取代可包括天然存在的氨基酸或非天然存在的氨基酸。变体可包括非天然氨基酸。实例包括美国专利号6,586,207;WO 98/48032;WO 03/073238;US 2004/0214988 A1;WO 05/35727 A2;WO 05/74524 A2;Chin,J.W.,等人,Journal ofthe American Chemical Society 124(2002)9026-9027;Chin,J.W.,和Schultz,P.G.,ChemBioChem 11(2002)1135-1137;Chin,J.W.,等人,PICAS United States of America99(2002)11020-11024;以及Wang,L.,和Schultz,P.G.,Chem.(2002)1-10,其全部通过引用整体并入。
术语"含有Fc区的多肽"指的是包含Fc区的多肽例如抗体或免疫黏附素(参见下述定义)。
术语"Fc受体"或"FcR"用于描述与抗体的Fc区结合的受体。结合IgG抗体的FcR(γ受体)包括FcyRI、FcyRII、和FcyRIII亚类的受体,包括等位基因变体和这些受体的可选地剪接的形式。FcyRII受体包括FcyRIIA("激活受体")和FcyRIIB("抑制受体"),其具有主要在其细胞质结构域中不同的相似的氨基酸序列。激活受体FcyRIIA在其细胞质结构域中含有基于免疫受体酪氨酸的激活基序(ITAM)。抑制受体FcyRIIB在其细胞质结构域中含有基于免疫受体酪氨酸的抑制基序(ITIM)(参见Daeron,M.,Annu.Rev.Immunol.15(1997)203-234中的综述)。FcR在Ravetch,和Kinet,Annu.Rev.Immunol 9(1991)457-492;Capel,等人,Immunomethods 4(1994)25-34;和de Haas,等人,J.Lab.Clin.Med.126(1995)330-41中综述。其他FcR,包括未来将识别的那些,在本文中由术语"FcR"涵盖。该术语还包括新生儿受体FcRn,其负责母体IgG至胎儿的转移(Guyer,等人,J.Immunol.117(1976)587和Kim,等人,J.Immunol.24(1994)249)。
如本文使用的"IgG Fc配体"意为来自任何生物体的、与IgG抗体的Fc区结合从而形成Fc/Fc配体复合物的分子,优选多肽。Fc配体包括但不限于FcyRs、FcyRs、FcyRs、FcRn、Clq、C3、甘露聚糖结合性凝集素、甘露糖受体、葡萄球菌A蛋白、链球菌G蛋白、和病毒FcyR。Fc配体还包括Fc受体同源物(FcRH),其为与FcyR同源的Fc受体的家族(Davis,等人,Immunological Reviews 190(2002)123-136,其通过引用整体并入)。Fc配体可包括结合Fc的未发现的分子。具体的IgG Fc配体为FcRn和Fcγ受体。如本文所用的"Fc配体"意为来自任何生物体的、与抗体的Fc区结合从而形成Fc/Fc配体复合物的分子,优选多肽。
如本文所用的"Fcγ受体"、"FcyR"或"FcγR"意为结合IgG抗体Fc区并由FcyR基因编码的蛋白质家族的任何成员。在人类中,该家族包括但不限于,FcyRI(CD64),包括同种型FcyRIA、FcyRIB、和FcyRIC;FcyRII(CD32),包括同种型FcyRIIA(包括同种异型H131和R131)、FcyRIIB(包括FcyRIIB-l和FcyRIIB-2)、和FcyRIIc;以及FcyRIII(CD 16),包括同种型FcyRIIIA(包括同种异型VI 58和F158)和FcyRIIIb(包括同种异型FcyRIIB-NA1和FcyRIIB-NA2)(Jefferis,等人,Immunol Lett 82(2002)57-65,其通过引用整体并入),以及任何未发现的人FcyR或者FcyR同种型或同种异型。FcyR可来自任何生物体,包括但不限于人、小鼠、大鼠、兔、和猴。小鼠FcyR包括但不限于FcyRI(CD64)、FcyRII(CD32)、FcyRIII(CD 16)、和FCYRIII-2(CD 16-2),以及任何未发现的小鼠FcyR或者FcyR同种型或同种异型。
如本文所用的"FcRn"或"新生儿Fc受体"意为结合IgG抗体Fc区并至少部分由FcRn基因编码的蛋白质。FcRn可来自任何生物体,包括但不限于人、小鼠、大鼠、兔、和猴。如本领域已知的,功能性FcRn蛋白包括两种多肽,通常称为重链和轻链。轻链为β-2-微球蛋白并且重链由FcRn基因编码。除非本文另有说明,FcRn或FcRn蛋白指的是FcRn重链与β-2-微球蛋白的复合物。
“免疫缀合物"意为与一种或多种细胞毒性剂例如化学治疗剂、药物、生长抑制剂、毒素、其他抗体或放射性同位素缀合的抗体。
"抗体片段"包含全长抗体的一部分,优选其可变区,或至少其抗原结合位点。抗体片段的实例包括双抗体、Fab片段、和单链抗体分子。scFv抗体例如描述于Huston,J.S.,Methods in Enzymol.203(1991)46-88。
如本文所用的术语"单克隆抗体"或"单克隆抗体组合物"指的是单一氨基酸组成的抗体分子的制剂。
术语"人源化抗体"或"抗体的人源化形式(version)"指的是其中已修饰人可变区从而包含根据本发明的抗体的CDR的抗体。在优选的实施方案中,将VH和VL的CDR移植到人抗体的框架区从而制备"人源化抗体"。参见例如Riechmann,L.,等人,Nature 332(1988)323-327;和Neuberger,M.S.,等人,Nature 314(1985)268-270。重链和轻链可变框架区可源自相同或不同的人抗体序列。人抗体序列可为天然存在的人抗体的序列。人重链和轻链可变框架区列于例如Lefranc,M.-P.,Current Protocols in Immunology(2000)–附录IPA.1P.1-A.1P.37,并且可通过IMGT即国际ImMunoGeneTics(http://imgt.cines.fr)或通过http://vbase.mrc-cpe.cam.ac.uk获得。
如本文所用的术语"特异性结合,针对靶标,或抗靶标抗体"指的是通过ELISA测量的抗体与相应抗原(靶标)的结合,其中所述ELISA优选包含将相应抗原涂覆至固体支持体(support)上,在允许与相应抗原或蛋白质形成免疫复合物的条件下加入所述抗体,通过使用与根据本发明的抗体结合的二抗和使用过氧化物酶介导的显色测量光密度值(OD)来检测所述免疫复合物。
根据本发明的术语"抗原”指的是用于免疫的抗原或包含所述抗原作为其蛋白序列的一部分的蛋白质。例如,对于免疫,可以使用蛋白质的细胞外结构域的片段(例如前20个氨基酸),对于检测/分析等,可以使用蛋白质的细胞外结构域或全长蛋白质。
本文中的术语"特异性结合”或“特异性识别”意为抗体对抗原显示明显的(appreciable)亲和力,并且优选不显示显著的交叉反应性。
“明显的”结合亲和力包括以至少10exp7M-1、特别地至少10exp8M-1、更特别地至少10exp9M-1、或甚至更特别地至少10exp10M-1的亲和力结合。
“不显示显著的交叉反应性”的抗体是不会明显地结合不期望的其他蛋白质的抗体。对根据本发明的表位特异性的抗体将例如不与IL-1R3上的其他表位交叉反应。特异性结合可以根据用于测定这类结合的任何领域公知的方法、例如通过竞争性结合分析(例如ELISA)来测定。
如本文所用的所有蛋白质术语指的是人蛋白质。如果意指来自其他物种的蛋白质,则将明确提及。
如本文所用的术语"IL-1α”指的是人IL-1(UniProtKB P01583)。如本文所用的术语"IL-1β”指的是人IL-1β(UniProtKB P01584)。IL-1通过诱导IL-2释放、B细胞成熟和增殖、以及成纤维细胞生长因子活性来刺激胸腺细胞增殖。IL-1蛋白质参与炎症反应,识别为内源性热原(UniProtKB)。
如本文所用的术语"IL-33”指的是人IL-33(UniProtKB O95760),即与IL1RL1/ST2受体结合并通过IL1RL1/ST2受体信号传导的细胞因子,所述IL1RL1/ST2受体反过来激活靶细胞中的NF-κ-B和MAPK信号传导途径(UniProtKB)。
本文所用的术语"IL-36”指的是人IL-36α(UniProtKB Q9UHA7)、IL-36β(UniProtKB Q9NZH7)和/或IL-36γ(UniProtKB Q9NZH8)。IL-36是与IL1RL2/IL-36R受体结合并通过IL1RL2/IL-36R受体信号传导的细胞因子,所述IL1RL2/IL-36R受体反过来激活与促炎症反应相关的靶细胞中NF-κ-B和MAPK信号传导途径。IL-36似乎通过作用于角质形成细胞、树突细胞和间接作用于T细胞从而驱动组织浸润、细胞成熟和细胞增殖来参与皮肤炎症反应(UniProtKB)。
如本文所用的术语"NFkB”指的是人核因子NF-κ-B,其由p105亚基(P19838)和p100亚基(Q00653)组成。
“NFkB的抑制”根据本发明测量为人细胞中NFkB依赖性荧光素酶基因表达的抑制。这类方法例如描述于Windheim M.等人,Mol.Cell.Biol.28(2008)1783-1791;Huang J.等人PNAS USA 94(1997)12829-12832;Xiaoxia L.等人,Mol.Cell,Biol.19(1999)4643-4652。如果本文中意指成熟NFkB,则明确提及。
如本文所用的"根据本发明的抗体的可变区(或结构域)"(轻链(VL)的可变区、重链(VH)的可变区)表示直接参与抗体与抗原结合的该对轻链和重链区中的每个。可变轻链和重链区具有相同的一般结构,并且各区包含序列广泛保守、通过三个互补决定区CDR连接的4个框架(FR)区。根据本发明的抗体包含VH区和VL区或其部分,它们一起足以特异性结合相应抗原。
当本文使用时,术语"抗体的抗原结合部分"指的是负责抗原结合的抗体的氨基酸残基。抗体的抗原结合部分优选包括来自"互补决定区"或"CDR"的氨基酸残基。CDR序列根据Kabat等人,Sequences of Proteins of Immunological Interest,第五版.PublicHealth Service,National Institutes of Health,Bethesda,Md.(1991)定义。使用该编号系统,实际的线性氨基酸序列可包含对应于可变区的FR或CDR的缩短或插入的更少或额外的氨基酸。
如本文所用的短语"肠胃外给药"和"肠胃外给予"意为除了肠内和局部给药以外的给药模式,通常通过注射,并且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内(intraorbital)、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注。
如本文所用的术语"癌症"可为例如肺癌、非小细胞肺(NSCL)癌、细支气管肺泡细胞肺癌(bronchioloalveolar cell lung cancer)、骨癌、胰腺癌、皮肤癌、头颈癌(cancerof the head or neck)、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌症、肠胃癌(stomach cancer)、胃癌(gastric cancer)、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、何杰金病、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、胆癌(biliary cancer)、中枢神经系统(CNS)肿瘤、脊柱轴肿瘤(spinal axis tumors)、脑干胶质瘤、多形性成胶质细胞瘤、星形细胞瘤、神经鞘瘤、室管膜瘤、成神经管细胞瘤、脑膜瘤、鳞状细胞癌、垂体腺瘤、淋巴瘤、淋巴细胞性白血病,包括任意上述癌症的顽固性形式,或上述癌症中的一种或多种的组合。
发明详述
当源自免疫哺乳动物的抗体意欲用作人类治疗剂时,所述抗体的人源化需要作为开发中的质量特征。人源化的目标是尽可能保持抗体的原始特征(结合特异性、活性),同时降低当源自其他生物体的非人源化抗体引入人时可发生的免疫副作用。本发明基于已知的CDR移植的人源化策略。在此,平行地生产大量的活性人源化抗体,并且选择最佳候选物用于进一步评估。
如在本申请的背景技术部分概述的,非常难以识别具有针对IL-1R3的高亲和力、高特异性、和有效的中和活性的单克隆抗体。本发明包含人源化IL-1R3抗体,其对IL-1R 3具有高亲和力和特异性,具有有效的IL-1R3中和活性,和改善的稳定性。
特别地,本发明涉及特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物,所述人源化抗体或者其片段或衍生物包含:
a)重链可变区(VH),其包含含有CDR-H1、CDR-H2、和CDR-H3的互补决定区
其中CDR-H1区包含选自SEQ ID NO:69-85的组的氨基酸序列,
其中CDR-H2区包含选自SEQ ID NO:86-102的组的氨基酸序列,
和其中CDR-H3区包含选自SEQ ID NO:103-119的组的氨基酸序列;和
b)轻链可变区(VL),其包含含有CDR-L1、CDR-L2、和CDR-L3的互补决定区
其中CDR-L1区包含选自SEQ ID NO:120-136的组的氨基酸序列,
其中CDR-L2区包含选自SEQ ID NO:137-153的组的氨基酸序列,和
其中CDR-L3区包含选自SEQ ID NO:154-170和175的组的氨基酸序列。
在一个实施方案中,本发明的抗体包含CDR-L3的2位处的取代。所述取代可为半胱氨酸向丝氨酸取代。
另外,本发明包含特异性结合IL-1R3的人源化抗体或者其包含足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物,其中所述抗体包含与选自由SEQ IDNO:1至34和SEQ ID NO:173的VH区组成的组的VH区至少60%相同、优选至少70%相同、更优选至少80%相同、更优选至少90%相同的重链可变(VH)区。
在一个实施方案中,特异性结合IL-1R3的人源化抗体或者其包含足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物包含重链可变区(VH)序列,所述重链可变区(VH)序列具有与选自根据本发明的VH序列的组的氨基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、或100%的序列同一性。
在某些实施方案中,相对于参考序列,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、或99%的同一性的VH序列含有取代(例如保守取代)、插入、或删除,借此抗体保留根据本发明特异性结合相应抗原的能力。
本发明还涉及特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物,其中所述抗体包含与选自由SEQ IDNO:35至68和174的VL区组成的组的VL区至少60%相同、优选至少70%相同、更优选至少80%相同、更优选至少90%相同的轻链可变(VL)区。
在另一实施方案中,特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物包含轻链可变区(VL),所述轻链可变区(VL)具有与根据本发明的VL序列的氨基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、或100%的序列同一性。
在某些实施方案中,相对于参考序列,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、或99%的同一性的VL序列含有取代(例如保守取代)、插入、或删除,借此抗体保留特异性结合相应抗原的能力。
在某些实施方案中,在所述VL序列中已取代、插入和/或删除总共1至10个氨基酸。在某些实施方案中,取代、插入、或删除发生于CDR以外的区域(即,FR中)。本发明还包含亲和力成熟的抗体,其可根据本领域已知的方法生产。Marks等人Bio/Technology 10:779-783(1992)描述了通过VH和VL结构域改组的亲和力成熟。CDR和/或框架残基的随机诱变描述于:Barbas等人,Proc Nat.Acad.Sci,USA 91:3809-3813(1994);Schier等人,Gene 169:147-155(1995);Yelton等人,J.Immunol.1 55:1994-2004(1995);Jackson等人,J.Immunol.1 54(7):3310-9(1995);和Hawkins等人,J.Mol.Biol.226:889-896(1992)以及WO2010108127。
在某些实施方案中,在各所述VH或VL序列中已取代、插入和/或删除总共1至10个氨基酸。在一个实施方案中,本发明的抗体包含VH或VL序列的90位处的取代。优选90位处的氨基酸由丝氨酸取代。该取代优选在轻链可变区(VL)的90位处。在优选实施方案中,SEQID.NO:62的90位处的半胱氨酸由丝氨酸取代。然而,本发明的抗体不限于90位处的氨基酸取代,但可含有导致具有本发明的抗体的性质的功能性抗体的任何取代、删除或插入。因此,本发明的抗体的VL和VH序列还可包含不同位置处的其他突变。
在某些实施方案中,取代、插入、或删除发生于CDR以外的区域(即,FR中)。
在其他实施方案中,取代、插入、或删除发生于CDR内部的区域。在一个优选的实施方案中,本发明的抗体包含CDR-L3的2位处的取代。优选该取代为半胱氨酸向丝氨酸。在一个实施方案中,所述取代在SEQ ID NO:164中。
本发明还包括特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物,其中所述抗体包含含有选自SEQ IDNO:1至34和173的组的氨基酸序列的重链可变区(VH)。
优选地,重链可变区(VH)序列为SEQ ID NO:1,可选地SEQ ID NO:2、或SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQID NO:28、或SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、或者可选地SEQ ID NO:34或173。
此外,本发明涉及特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物,其中所述抗体包含含有选自SEQ IDNO:35至68和174的组的氨基酸序列的轻链可变区(VL)。
甚至更优选的,轻链可变区(VL)序列为SEQ ID NO:35、或SEQ ID NO:36、SEQ IDNO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42、SEQ IDNO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ IDNO:49、SEQ ID NO:50、SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ IDNO:55、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、SEQ ID NO:60、SEQ IDNO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ IDNO:67、或者可选地SEQ ID NO:68或174。
根据本发明的特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物还包含VH区和VL区,所述VH区和VL区包含选自由MAB-15-0139、MAB-15-0106MAB-15-0108、MAB-15-0110、MAB-15-0117、MAB-15-0121、MAB-15-0140、MAB-15-0115、MAB-15-0125、MAB-15-0119、MAB-15-0109、MAB-15-0097、MAB-15-0135、MAB-15-0133、MAB-15-0107、MAB-15-0128、MAB-15-0116、MAB-16-0004、MAB-16-0009、MAB-16-0028、MAB-16-0031、MAB-16-0043、MAB-16-0049、MAB-16-0045、MAB-16-0040、MAB-16-0036、MAB-16-0046、MAB-16-0030、MAB-16-0021、MAB-16-0019、MAB-16-0015、MAB-16-0027、MAB-16-0048、MAB-16-0041、MAB-16-0149、MAB-16-0150组成的组的抗体的各自的CDR1、CDR2和CDR3区。
在一个实施方案中,特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物包含SEQ ID NO.:1和35、或SEQ IDNO.:2和36。根据本发明的抗体还可含有SEQ ID NO.:3和37、或SEQ ID NO.:4和38、或SEQID NO.:5和39、或SEQ ID NO.:6和40、或SEQ ID NO.:7和41、或SEQ ID NO.:8和42、或SEQID NO.:9和43、或SEQ ID NO.:10和44、或SEQ ID NO.:11和45、或SEQ ID NO.:12和46。可选地,根据本发明的抗体包含SEQ ID NO.:13和47、或SEQ ID NO.:14和48、或SEQ ID NO.:15和49、或SEQ ID NO.:16和50、或SEQ ID NO.:17和51、或SEQ ID NO.:18和52、或SEQ IDNO.:19和53、或SEQ ID NO.:20和54、或SEQ ID NO.:21和55、或SEQ ID NO.:22和56、或SEQID NO.:23和57、或SEQ ID NO.:24和58、或SEQ ID NO.:25和59、或SEQ ID NO.:26和60、或SEQ ID NO.:27和61。
可选地,根据本发明的抗体包含SEQ ID NO.:28和62、或SEQ ID NO.:29和63、或SEQ ID NO.:30和64、或SEQ ID NO.:31和65、或SEQ ID NO.:32和66、或SEQ ID NO.:33和67、或SEQ ID NO.:34和68。
更优选地,特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物含有恒定区序列CR-H(SEQ ID NO.172)和CR-L(SEQ ID NO.171)以及选自SEQ ID NO:1至34和173的组的VH区和选自SEQ ID NO:35至68和174的组的VL区。
特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物还含有恒定区序列CR-H(SEQ ID NO.172)和CR-L(SEQID NO.171)以及VH区和VL区,所述VH区和VL区包含选自由MAB-15-0139、MAB-15-0106、MAB-15-0108、MAB-15-0110、MAB-15-0117、MAB-15-0121、MAB-15-0140、MAB-15-0115、MAB-15-0125、MAB-15-0119、MAB-15-0109、MAB-15-0097、MAB-15-0135、MAB-15-0133、MAB-15-0107、MAB-15-0128、MAB-15-0116、MAB-16-0004、MAB-16-0009、MAB-16-0028、MAB-16-0031、MAB-16-0043、MAB-16-0049、MAB-16-0045、MAB-16-0040、MAB-16-0036、MAB-16-0046、MAB-16-0030、MAB-16-0021、MAB-16-0019、MAB-16-0015、MAB-16-0027、MAB-16-0048、MAB-16-0041、MAB-16-0149和MAB-16-150组成的组的抗体的各自CDR1、CDR2和CDR3区。
按照根据本发明的抗体的优选的治疗应用,本发明的抗体的效应子功能(例如ADCC)减少或缺乏。与现有技术的其他抗体如CAN04(例如WO 2015/132602 A1)相对,本发明的抗体不显示增加的效应子功能并且不包括ADCC。
优选地,根据本发明的人源化抗体显示减少的或不显示Fcγ-受体信号传导。
因此,本发明还涉及人源化抗体,其中所述抗体至少包含在人IgG1 Fc区的L234A和L235A或人IgG4 Fc区的S228P和L235E处的氨基酸取代。
在根据本发明的一个实施方案中,抗体为人源化IgG1LALA抗体。
在根据本发明的一个实施方案中,特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物抑制IL-1R3诱导的NFkB活性。
在另一实施方案中,特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物与选自以下的组的抗体相同的表位结合:抗体MAB-15-0139、MAB-15-0106、MAB-15-0108、MAB-15-0110、MAB-15-0117、MAB-15-0121、MAB-15-0140、MAB-15-0115、MAB-15-0125、MAB-15-0119、MAB-15-0109、MAB-15-0097、MAB-15-0135、MAB-15-0133、MAB-15-0107、MAB-15-0128、MAB-15-0116、MAB-16-0004、MAB-16-0009、MAB-16-0028、MAB-16-0031、MAB-16-0043、MAB-16-0049、MAB-16-0045、MAB-16-0040、MAB-16-0036、MAB-16-0046、MAB-16-0030、MAB-16-0021、MAB-16-0019、MAB-16-0015、MAB-16-0027、MAB-16-0048、MAB-16-0041、MAB-16-0149和MAB-16-150。
根据本发明的抗体具有当涉及结合其靶标时非常有效的优点。它们显示对其抗原IL1R3的强结合能力,但对其他受体并没有。抗体的结合性质在生化酶联免疫吸附测定(ELISA)和细胞结合分析(流式细胞术)中研究并且在图2、6和7中例示。
根据本发明的优选的抗体,其显示小于30ng/ml、优选小于20ng/ml的半数最大有效浓度(EC50)。在其他实施方案中,它们显示小于15ng/ml、10ng/ml或者小于5ng/ml的EC50。根据本发明的优选的抗体在生物化学ELISA实验中显示16.3ng/ml的EC50(参见图7)。
根据本发明的抗体还在其中在不同细胞系中表达人IL1R3的实验中显示与其抗原的非常强的结合,同时抗体不结合不表达人IL1R3的细胞系(例如NIH-3T3,参见图5)。
在IL1R3高表达细胞系SK-MEL-30(参见图6,实施例8)中,抗体显示优选小于400ng/ml、更优选小于350ng/ml、和小于310ng/ml的EC50。
在本发明包含的一个优选的实施方案中,根据本发明的抗体抑制IL-1α和/或IL-1β刺激的NFkB活性。图3、4和8例示根据本发明的抗体的强抑制活性。
在一个实施方案中,特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物抑制IL-1α刺激的NFkB活性。
在另一实施方案中,特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物抑制IL-1β刺激的NFkB活性。
优选在HEK293T/17-FR细胞中,根据本发明的抗体以小于100ng/ml,优选小于95ng/ml、85ng/ml、75ng/ml、65ng/ml、55ng/ml、45ng/ml、35ng/ml、25ng/ml、20ng/ml和最优选小于15ng/ml的EC50抑制IL-1β刺激的NFkB活性(例如参见图3)。
进一步优选在A549-NFkB-RE-Luc细胞中,根据本发明的抗体以小于1000ng/ml,优选小于500ng/ml、300ng/ml、200ng/ml,和最优选小于100ng/ml的EC50抑制IL-1α刺激的NFkB活性(例如参见图8)。
进一步优选在A549-NFkB-RE-Luc细胞中,根据本发明的抗体以小于700ng/ml,优选小于600ng/ml、300ng/ml、200ng/ml、100ng/ml和最优选小于50ng/ml的EC50抑制IL-1β刺激的NFkB活性(例如参见图8)。
本发明还包含人源化抗体,其中所述抗体抑制由选自由IL-1β/IL-1R1/IL-1RAcP、IL-1α/IL-1R1/IL-1RAcP IL-33/ST2/IL-1RAcP、和/或IL-36/Il-36R/IL-1RAcP组成的组的复合物刺激的NFkB活性。
另外,相对于不存在根据本发明所述的抗体的相同分析,在A549-NFkB-RE-Luc细胞裂解物中,根据本发明的人源化抗体以10μg/m的浓度(兔IgG同种型具有150KD的分子量)使得用0.1ng/ml人IL-1α、人IL-1β、IL-33和/或IL-36(分子量参见UniProtKB/Swiss-Prot)刺激的NFkB表达(Steady-GloTM荧光素酶分析系统;Promega;Cat.No.E2510)抑制50%以上、优选70%以上、优选80%以上、更优选90%以上、并且更优选95%以上。
在一个实施方案中,在HEK 293T/17细胞(用NF-kB报道基因控制下的荧光素酶转染的HEK 293T/17-FR细胞)、HEK-Blue-IL33TM细胞(Invivogen)或HEK-293/17-IF细胞中,根据本发明的人源化抗体分别抑制IL-1α、IL-1β、IL-33、和/或IL-36刺激的荧光素酶活性。
优选地,所述IL-1α刺激的荧光素酶活性被抑制50%以上、优选70%以上、优选80%以上、优选90%以上、更优选95%以上。优选地,所述IL-1α刺激的荧光素酶活性被抑制95%。
优选地,所述IL-1β刺激的荧光素酶活性被抑制50%以上、优选70%以上、优选80%以上、优选90%以上、更优选95%以上。优选地,所述IL-1β刺激的荧光素酶活性被抑制95%。
优选地,所述IL-33刺激的荧光素酶活性被抑制50%以上、优选70%以上、优选80%以上、优选90%以上、更优选95%以上。优选地,所述IL-33刺激的荧光素酶活性被抑制95%。
优选地,所述IL-36刺激的荧光素酶活性被抑制50%以上、优选70%以上、优选80%以上、优选90%以上、更优选95%以上。优选地,所述IL-36刺激的荧光素酶活性被抑制95%。
另外,根据本发明的抗体抑制人IL-1a和IL-1b介导的IL-6释放,并且优于多克隆抗体。该有效的抑制活性示于并例示于图9。在这些实验中,EC50值表明人源化抗IL-1R3IgG1-LALA抗体优于山羊抗人IL1-R3多克隆抗体AF676(R&D Systems)。在本发明的优选实施方案中,抗体以小于2500ng/ml,优选小于1500ng/ml、小于1000ng/ml、小于600ng/ml、小于400ng/ml、和小于300ng/ml的EC50抑制人IL-a介导的IL-6释放。还优选本发明的抗体以小于500ng/ml,优选小于400ng/ml、小于300ng/ml、小于200ng/ml、和小于150ng/ml的EC50抑制人IL-1b介导的IL-6释放。
在本发明的另一实施方案中,抗体抑制人IL-33介导的NfkB信号传导。图10例示根据本发明所选的抗体在HEK-Blue-IL33TM细胞中的抑制活性,并且说明其优于多克隆抗体。在本发明的优选实施方案中,抗体以20000ng/ml,优选小于18000ng/ml、小于3000ng/ml、小于1000ng/ml、小于500ng/ml、和小于400ng/ml的EC50抑制人IL-33介导的NfkB信号传导。
本发明的抗体还可以抑制人IL-36介导的NfkB信号传导(图11)。优选地,它们以小于100ng/ml,优选小于50ng/ml、小于40ng/ml、小于30ng/ml、小于20ng/ml、和小于15ng/ml的EC50抑制人IL-36介导的NfkB信号传导。
显著地,本发明人发现根据本发明的抗体抑制由各种不同的刺激介导的细胞因子释放。例如,抗体抑制由IL-1a、IL-33和IL-36a介导的细胞因子释放。所选抗体的结果示于图12。例如,抗体MAB-16-0030抑制由所有三种刺激介导的细胞因子释放,而IL-1Ra仅影响IL-1a介导的细胞因子释放。
与急性或慢性炎症相关的疾病通过多种细胞因子的作用同时或连续地维持或建立。早期“警报素(alarmins)”例如IL-1a和IL-33可引发其他细胞因子包括IL-1b和IL-36,从而建立强的炎症环境。因此,对多种细胞因子介导的信号传导的伴随抑制(concomitantinhibition)发挥对炎症过程的有效控制。本发明抗体的一个关键方面是它们通过阻断IL1R3受体来抑制多细胞因子信号传导。
抗体与免疫细胞的结合,例如通过直接诱导细胞凋亡信号传导途径、刺激过度的细胞因子释放或抗体效应子功能介导的抗体依赖性细胞毒性抗体(antibody dependentcellular cytotoxicity,ADCC),可导致细胞清除(cell depleting)和有害作用。
因此,本发明的抗体的另一个方面是它们不诱导通过直接诱导细胞凋亡信号传导途径、刺激过量的细胞因子释放或抗体效应子功能介导的抗体依赖性细胞毒性抗体介导的免疫细胞清除。
重要地,根据本发明的抗体不影响免疫细胞的生存力。例如,它们不影响人外周血单核细胞(PBMC)的生存力,并且它们不在PBMC中诱导IL-6释放(参见图13)。
根据本发明的抗体不仅抑制如上所述的不同细胞系中的细胞因子释放的功能性激活,而且还在来自供体的PMBC或全血细胞中的细胞因子释放的功能性激活。它们抑制通过不同的特定或复杂刺激介导的细胞因子释放。例如,它们抑制由LPS、热灭活的白色念珠菌(Candida albicans)、IL-12/IL-33或抗CD3/CD28抗体刺激的PBMC的激活(参见图14和15)。
另外,在一个实施方案中,根据本发明的人源化抗IL-1R3 IgG1-LALA抗体能够在混合白细胞反应中抑制IFNg、IL-6、TNF-a、IL-13、IL-17和IL-10的释放(参见图16)。
此外,根据本发明的抗体特别有用于治疗其中靶标即IL1R3的失调是潜在原因的疾病。
因此,本发明进一步涉及特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物用于治疗IL-1R3介导的疾病。
本发明还包含治疗患者中IL-1R3介导的疾病的方法,其包括给予患者药学有效量的根据本发明的抗体、和其衍生物或片段。
本发明还涉及药物组合物,其包含药学可接受的载体和治疗有效量的根据本发明的特异性结合IL-1R3的人源化抗体或者其含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分的片段或衍生物。
如本文所用的,"药学载体"包括生理上相容的任意的和所有的溶剂、分散介质、包衣、抗细菌和抗真菌剂、以及等渗和延迟吸收剂等。优选地,载体适用于静脉内、肌内、皮下、肠胃外、脊柱或表皮给药(例如注射或输注)。
本发明的组合物可通过本领域已知的各种方法给予。如本领域技术人员将理解的,给药途径和/或模式将根据期望的结果而不同。为了通过某些给药途径给予本发明的化合物,可需要用材料包衣化合物、或共同给予化合物与材料,从而防止化合物失活。例如,化合物可在合适的载体例如脂质体和稀释剂中给予受试者。药学可接受的稀释剂包括盐水和水性缓冲溶液。药学载体包括用于临时制备无菌可注射溶液或分散液的无菌水溶液或分散液和无菌粉末。这类介质和试剂用于药学活性物质的用途是本领域已知的。
如本文使用的短语"肠胃外给药"和"肠胃外给予"意为除了肠内和局部给药以外的给药模式,通常通过注射,并且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内(intraorbital)、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注。
这些组合物还可包括佐剂例如防腐剂、湿润剂、乳化剂和分散剂。可以通过上文的灭菌程序、以及通过包括各种抗细菌和抗真菌剂如对羟基苯甲酸酯、氯丁醇、苯酚、和山梨酸等来确保防止存在微生物。还可期望在组合物中包含等渗剂,例如糖和氯化钠等。此外,可注射药学形式的延长吸收可通过包含延迟吸收的试剂例如单硬脂酸铝和明胶来进行。无论所选的给药途径如何,可以以合适的水合形式使用的本发明的化合物和/或本发明的药物组合物通过本领域技术人员已知的常规方法配制为药学可接受的剂型。可改变本发明的药物组合物中的活性成分的实际剂量水平从而获得有效实现对于特定患者、组合物、和给药模式的期望的治疗反应而不对患者有毒性的活性成分量。所选剂量水平将取决于各种药物代谢动力学因素,包括使用的本发明的特定组合物的活性,给药途径,给药时间,使用的特定化合物的排泄速率,治疗时长,与使用的特定组合物组合使用的其他药物、化合物和/或材料,治疗的患者的年龄、性别、体重、状况、一般健康和先前病史,以及医学领域广泛公知的类似因素。
本发明的一个方面是根据本发明的药物组合物用于治疗如本申请中所定义的癌症。
本发明的另一方面是治疗患者中IL-1R3介导的疾病的方法,其包括给予患者根据本发明的药物组合物。
此类IL-1R3介导的疾病可包括癌症。在文献中描述了癌症中的负面预后和进展与IL-1α、IL-1β、IL-33、IL-36的增加水平和/或IL-1R3的增加表达有关。
如本文所用的术语"癌症"可为例如肺癌、非小细胞肺(NSCL)癌、细支气管肺泡细胞肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌症、肠胃癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、何杰金病、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、胆癌、中枢神经系统(CNS)肿瘤、脊柱轴肿瘤、脑干胶质瘤、多形性成胶质细胞瘤、星形细胞瘤、神经鞘瘤、室管膜瘤、成神经管细胞瘤、脑膜瘤、鳞状细胞癌、垂体腺瘤、淋巴瘤、淋巴细胞性白血病,包括任意上述癌症的顽固性形式,或上述癌症中的一种或多种的组合。优选此类癌症为白血病、乳腺癌、结肠癌、肺癌、和胰腺癌。更优选癌症为白血病。
在一个实施方案中,IL-1R3介导的疾病选自由以下组成的组:白血病、乳腺癌、结肠癌、肺癌、胰腺癌、肝癌、非小细胞肺癌、结直肠癌、肠胃癌、胃癌、雌激素受体阳性乳腺癌、头颈部鳞状细胞癌、间皮瘤、胆囊癌、卵巢癌、膀胱癌、前列腺癌、甲状腺癌、何杰金病、MALT淋巴瘤、唾液腺癌、或黑素瘤。
一些肿瘤由分泌炎性细胞因子例如IL-1α、IL-1β、IL-33、IL-36的肿瘤微环境细胞引起或促进。在某些情况下,此类细胞因子的表达引起肿瘤抗性的形成。细胞因子抑制剂和抗癌化合物的伴随使用(concomitant use)显著改善此类治疗的反应率或可破坏肿瘤抗性。这由本发明提供,是因为实现细胞因子诱导的信号传导的广谱抑制。癌症指征的此类活性不通过癌细胞的直接清除活性实现,但通过借由调节IL1R3信号传导途径抑制癌症相关炎症来实现。本发明的抗体提供非常优选的活性特征,这是因为它们使得能够有效抑制癌症相关的慢性炎症,同时避免不期望的副作用,因为它们不显示抗体效应子功能,因此不影响表达IL-1R3的靶细胞的生存力。
因此,在本发明的一个实施方案中,抗体或药物组合物用于治疗患者,其中所述患者包括肿瘤,例如实体瘤,并且显示对细胞毒性、细胞抑制或靶向/免疫治疗的不足反应或肿瘤抗性。
在本发明的一方面中,根据本发明的人源化抗体和/或药物组合物旨在用于与一种或多种细胞毒性、细胞抑制或靶向的抗癌化合物组合来治疗癌症。使用细胞因子抑制剂和细胞毒性、细胞抑制或靶向的抗癌化合物显著改善此类治疗的反应率或可破坏肿瘤抗性。
在本发明的这些方面,癌症优选选自由以下组成的组:胰腺癌、肝癌、肺癌(与石棉、感染、吸烟、二氧化硅引起的炎症相关)、非小细胞肺癌、结直肠癌/结肠炎相关癌症(与炎性肠病相关)、肠胃癌、胃癌、慢性胃炎相关胃癌、雌激素受体阳性乳腺癌、头颈部鳞状细胞癌、间皮瘤、胆囊癌(胆囊结石相关的慢性胆囊炎相关)、卵巢癌、膀胱癌、前列腺癌、大肠杆菌感染相关前列腺癌、甲状腺癌、何杰金病、MALT淋巴瘤、唾液腺癌、黑素瘤、子宫内膜异位症相关子宫内膜癌、巴雷特食管炎(Barrett’s esophagitis)相关食管癌。
在本发明的方法的一方面中,根据本发明的IL1R3抗体或药物组合物与一种或多种细胞毒性、细胞抑制或靶向抗癌剂同时给予。另一方面,抗体或药物组合物与一种或多种细胞毒性、细胞抑制或靶向抗癌剂顺序给予。
在后一情况下,优选在用一种或多种细胞毒性、细胞抑制或靶向抗癌剂治疗后给予抗体。
根据本发明的细胞毒性或细胞抑制剂可为紫杉烷、蒽环类抗生素、烷基化剂、组蛋白脱乙酰酶抑制剂、拓扑异构酶抑制剂、激酶抑制剂、核苷酸类似物、肽抗生素、铂基试剂和检查点抑制剂(checkpoint inhibitor)。
优选靶向抗癌剂选自以下之一或其组合:抗EGFR化合物例如西妥昔单抗(cetuximab)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、拉帕替尼(lapatinib)、帕尼单抗(panitumumab),和抗HER2化合物例如曲妥单抗(trastuzumab)、曲妥珠单抗-美坦新偶联物(ado-trastuzumab emtansine)、帕妥珠单抗(pertuzumab)。
进一步优选靶向抗癌剂为检查点抑制剂。这些可为但不限于:抗PD1化合物例如派姆单抗(pembrolizumab)、和纳武单抗(nivolumab),以及抗PDL1化合物例如阿特珠单抗(atezolizumab)、阿维鲁单抗(Avelumab)、和度伐鲁单抗(Durvalumab),以及抗CTLA-4化合物例如伊匹单抗(Ipilimumab)和曲美目单抗(Tremelimumab)。
实施例
以下实施例与附图和表格结合使用以说明本发明。
实施例1:B细胞上清液中的P013_03(人IL-1R3)特异性抗体的测定
分析原理:
用P013_03涂布NUNC Maxisorp 384孔微量滴定板。在封闭过程后,来自B细胞上清液的特异性抗体与抗原结合,然后通过POD标记的抗体检测。样品以1:2稀释进行试验。
材料:
板: 384孔NUNC Maxisorp板;目录号464718
蛋白质: P013-03(浓度1.5mg/ml;分析浓度0.5μg/ml)
标准抗体: P013-02(浓度1mg/ml;起始分析浓度2μg/ml)
检测抗体: 抗兔IgG,过氧化物酶连接的物种特异性完整抗体(来自驴)(ECL);GE;目录号NA9340;分析稀释:1:5000
PBS: 盒中的缓冲液,预混PBS缓冲液,10x;Roche Applied Sciences;目录号11666789001
BSA: 来自牛血清的牛血清白蛋白级分V;Roche Applied Sciences;目录号10735086001
Tween 20: Tween 20;Carl Roth;目录号9127.2
TMB: TMB溶液;Life Technologies;目录号SB02
HCl: 1M Titripur盐酸;Merck;目录号1090571000
ELISA缓冲液: PBS,0.5%BSA,0.05%Tween
洗涤缓冲液: PBS,0.1%Tween
封闭缓冲液: PBS,2%BSA,0.05%Tween
样品: Elisa缓冲液中的1:2稀释
步骤:
1.添加12.5μLPBS中的P013-03(0.5μg/ml)至384孔NUNC Maxisorp板并在室温(RT)下温育1h。
2.用90μl洗涤缓冲液洗涤3x。
3.添加90μL封闭缓冲液至各孔并在室温下温育1h。
4.用洗涤缓冲液洗涤3x。
5.添加1:2稀释的12.5μL标准抗体或在Elisa缓冲液中1:2稀释的样品并在室温下温育1h。
6.用洗涤缓冲液洗涤3x。
7.添加12.5μL Elisa缓冲液中的1:5000POD-抗体并在室温下温育1h。
8.用洗涤缓冲液洗涤6x。
9.添加15μL TMB。
10.充分显色后添加15μL HCl。
11.读取450nm/620nm下的吸光度。
实施例2:通过荧光素酶报道基因实验识别抑制P013报道基因的P013特异性抗体
分析原理:
将表达NF-kB-RE萤火虫荧光素酶报道基因的293T/17-FR细胞接种至多聚-D-赖氨酸-细胞培养板。在P013的刺激后,使用Steady-Glo荧光素酶分析试剂盒试验293T/17-FR裂解物的激活的NF-kB。具有功能性抗体的上清液结合P013并抑制NF-kB激活,以低信号显示。样品在P013溶液中以1:2稀释进行试验。
材料:
板: 细胞板:384孔PDL Costar细胞培养板;目录号3844
分析板: 384孔lumitrac白色板;Corning;目录号3572
细胞: 293T/17-FR;分析浓度250,000个细胞/ml
细胞传代越多信号越低!
蛋白质: P013_05(浓度0.03mg/ml;分析浓度115pg/ml;工作浓度230pg/ml)
标准抗体: P013_06(浓度0.2mg/ml;起始工作浓度6μg/ml)
试剂盒: Steady-Glo荧光素酶分析系统;Promega;目录号E2510
细胞培养基: DMEM培养基;PAN Biotech;目录号P04-04510
FCS: 胎牛血清,HyClone;Thermo;目录号St30070.03
293T/17-FR培养基: DMEM培养基,10%FCS,(+20μg/ml潮霉素-B,仅用于培养)
条件B细胞培养基(MAB Discovery)
样品: 用DMEM培养基+10%FCS中的P013_05来1:2稀释
步骤:
1.细胞培养步骤:
使用胰蛋白酶/EDTA每周一(接种出:5x106个细胞/T175烧瓶)和周五(接种出:3x106个细胞/T175烧瓶)分瓶汇合的293T/17-FR细胞(仅在室温下温育30秒)。
2.接种25μl DMEM+10%FCS中的细胞(0.25x106个细胞/ml)至384孔PDL板(Corning cat#3844)并在37℃和5%CO2下过夜温育。
3.吸取培养基,并添加12.5μl样品或在条件培养基中1:3稀释的P013_06或仅条件培养基,并在37℃和5%CO2下温育30min(程序:3吸取和样品转移)
4.添加12.5μl DMEM+10%FCS中的P013_05并在37℃和5%CO2下温育5小时(程序:4_添加P013_05)。
5.平衡培养的细胞至室温10min。
6.添加25μl Steady-Glo试剂并用移液管混合多次(程序:6_Steady Glo)
7.等待5分钟,然后将45μl上清液转移至384孔lumitrac白色板(Corning Cat#3572)(程序:7_转移45μl)
8.在Tecan读板器中测量发光:积分时间:0.5秒
实施例3:B细胞上清液中的huIL1RaP、msIL1RaP、CD134和CD137特异性抗体的测定
分析原理:
用靶蛋白包被NUNC Maxisorp 384孔微量滴定板。在封闭过程后,来自B细胞上清液的特异性抗体与靶标结合,然后通过POD标记的抗体检测。
材料:
板:384孔NUNC Maxisorp板;目录号464718
蛋白质:切割的huIL1RaP(P026_12;浓度0.96mg/mL;分析浓度0.25μg/mL)
切割的muIL1RaP(P026_13;浓度0.93mg/mL;分析浓度0.25μg/mL)
切割的CD134(P026_14;浓度0.51mg/mL;分析浓度0.25μg/mL)
切割的CD137(P026_15;批次2;浓度1.1mg/mL;分析浓度1μg/mL)
标准抗体:人IL-1 RAcP/IL-1 R3抗体(P013_6/P026_08;浓度0.2mg/mL或0.399mg/mL;起始分析浓度2μg/mL;用于huIL1RaP和msIL1RaP)
MAB-14-0283(浓度0.6mg/mL;起始分析浓度2μg/mL;用于CD134)
MAB-14-0285(浓度1mg/mL;起始分析浓度2μg/mL;用于CD137)
检测抗体:样品:抗兔IgG,过氧化物酶连接的物种特异性Fab2片段(来自驴)(ECL);GE;目录号NA9340;分析稀释:ELISA缓冲液中的1:5000
对于MAB-14-0283和MAB-0285:抗人IgG过氧化物酶连接的物种特异性Fab2片段(来自山羊)(HRP);AbD Serotec;目录号STAR126P;分析稀释:ELISA缓冲液中的1:5000对于huIL1RaP和msIL1RaP:过氧化物酶缀合的AffiniPure驴抗山羊IgG(H+L);Jackson ImmunoResearch;目录号705-035-003;分析稀释:ELISA缓冲液中的1:5000
PBS:盒中的缓冲液,预混PBS缓冲液,10x;Roche Applied Sciences;目录号11666789001
BSA:来自牛血清的牛血清白蛋白级分V;Roche Applied Sciences目录号10735086001
Tween 20:Tween 20;Carl Roth;目录号9127.2
TMB:TMB溶液;Invitrogen;目录号SB02
HCl:1M Titripur盐酸;Merck;目录号1090571000
ELISA缓冲液:PBS,0.5%BSA,0.05%Tween
洗涤缓冲液:PBS,0.1%Tween
封闭缓冲液:PBS,2%BSA,0.05%Tween
样品:ELISA缓冲液中的1:4稀释
步骤:
1.添加12.5μL PBS中稀释的0.25μg/mL或1μg/mL蛋白质至384孔NUNC Maxisorp板并在室温下温育1h。
2.用90μL洗涤缓冲液洗涤3x。
3.添加90μL封闭缓冲液至各孔并在室温下温育1h。
4.用90μL洗涤缓冲液洗涤3x。板可以以干燥状态在-20℃下用铝箔密封来保存长达6周。
5.添加在1:2稀释步骤中的12.5μL标准抗体或样品(在ELISA缓冲液中稀释)并在室温下温育1h。
6.用90μL洗涤缓冲液洗涤3x。
7.添加12.5μL ELISA缓冲液中的1:5000POD抗体并在室温下温育1h。
8.用90μL洗涤缓冲液洗涤6x。
9.添加15μL TMB。
10.15min显色后添加15μL HCl。
11.读取450nm/620nm下的吸光度
实施例4:用IL-1(α/β)刺激后A549-NFκB-RE-Luc稳定转染细胞的NFκB表达的抑制
分析原理:
将A549-NFκB-RE-Luc稳定转染细胞(Signosis)移液至384孔板并过夜温育。第2天,使抗IL1R3抗体与A549-NFkB-RE-Luc稳定转染细胞结合,然后通过加入IL-1(α或β)刺激所述细胞。由于NFκB信号传导途径激活,这导致荧光素酶基因的转录,并且可通过细胞裂解和添加荧光素来测量。
试验抗体是否可抑制NFkB途径的激活并因此降低发光信号。
材料:
板:384孔低边白色平底聚苯乙烯TC处理的无菌微量培养板;Corning;目录号3570
蛋白质:IL-1α(P026_09);重组人IL-1α/IL-1F1;10μg/mL;R&D Systems;目录号200-LA-002
IL-1β(P026_10);重组人IL-1β/IL-1F2;25μg/mL;R&D Systems;目录号200-LB-005
标准抗体:MAB-15-0115;MAB Discovery GmbH;2.51mg/ml;工作浓度10μg/ml
细胞:A549-NFκB-RE-Luc稳定转染细胞;Signosis;目录号SL-0014
培养基:DMEM;PAN;目录号P04-04510
FCS:胎牛血清南非低IgG(Fetal Bovine Serum South Africa Low IgG);PAN;目录号1552-P120909
青霉素(Pen)/链霉素(Strep):10,000U青霉素/ml;10mg链霉素/ml;PAN Biotech;目录号P06-07100
分离剂:胰蛋白酶-EDTA 1x;PAN;目录号P10-023100(4mL用于T175/2mL用于T75;~8min 37℃)
细胞培养基:DMEM,10%FCS,1%青霉素/链霉素
检测试剂盒:Steady-GloTM荧光素酶分析系统;Promega;目录号E2510
步骤:
1.在细胞培养基中培养A549-NFκB-RE-Luc稳定转染细胞(1,7E+04个细胞/cm2培养3天;2,28E+04个细胞/cm2培养2天)。不要超过10次传代!
2.每孔涂板25μL培养基中的40,000个A549-NFκB-RE-Luc稳定转染细胞(浓度=1.6x106个细胞/mL)至具有平底的白色的细胞培养处理的384孔板。
在37℃/5%CO2下过夜温育。
3.从板吸取培养基,并使用CyBio移液机械臂将10μL培养基中的样品或者标准样品(standard)添加至板(程序:文件夹P026/NFκB中的“培养基移除和样品转移”)。在37℃/5%CO2下温育1h。
4.使用CyBio移液机器人将10μL培养基中的IL-1(α或β)添加至板(程序:文件夹P026/NFκB中的“从储存容器(reservoir)转移”)(工作浓度:0.2ng/mL;分析浓度:0.1ng/mL)并在37℃/5%CO2下温育5h。
在进行步骤4前,根据Steady-Glo实验方案在Steady-Glo缓冲液中溶解Steady-Glo底物,并平衡该溶液和分析板至室温。
5.添加20μL Steady-Glo混合物,充分混合从而保证适当的细胞裂解。在室温下温育10min。
6.使用设置为500ms积分时间的微量培养板读板器(程序:Lumineszenz-384)测定各孔的相对发光单位。
实施例5:用IL-1(α/β)刺激后A549细胞的IL-6分泌
分析原理:
将A549细胞移液至384孔板并用抗IL1R3抗体温育。然后,用IL-1(α或β)刺激细胞并分泌IL-6至分析培养基中。通过IL-6ELISA测量IL-6的量。
材料:
分析试剂盒:DuoSet ELISA人IL-6;目录号DY206-05(R&D Systems);
DuoSet由人IL-6捕获抗体(部分840113)、人IL-6检测抗体(部分840114)、人IL-6(部分840115)和链霉菌抗生素蛋白-HRP(部分8939755)组成
板:384孔透明细胞培养处理板;Corning;目录号3701 384孔Maxisorp板;NUNC;目录号464718
PP板:120μL 384深孔“钻石”板,透明;Axygen(Corning);目录号P-384-120SQ-C
蛋白质:IL-1α;重组人IL-1α/IL-1F1;R&D Systems;目录号200-LA-002
IL-1β;重组人IL-1β/IL-1F2;R&D Systems;目录号200-LB-005
rhIL1-ra/IL-1F3;R&D Systems;目录号280-RA-010
标准抗体:人IL-1RAcP/IL-1R3抗体;R&D Systems;目录号AF676或AF676-SP
培养基:DMEM;PAN;目录号P04-04510
FCS:胎牛血清南非低IgG;PAN;目录号1552-P120909
青霉素/链霉素:10,000U青霉素/ml;10mg链霉素/ml;PAN Biotech;目录号P06-07100
PBS:盒中的缓冲液,预混PBS缓冲液,10x;Roche Applied Sciences;目录号11666789001
BSA:来自牛血清的牛血清白蛋白级分V;Roche Applied Sciences;目录号10735086001
Tween 20:Tween 20;Carl Roth;目录号9127.2
TMB:TMB溶液;Invitrogen;目录号SB02
HCl:1M Titripur盐酸;Merck;目录号1090571000
ELISA缓冲液:PBS,0.5%BSA,0.05%Tween
洗涤缓冲液:PBS,0.1%Tween
封闭缓冲液:PBS,2%BSA,0.05%Tween
细胞培养基:DMEM,10%FCS,1%青霉素/链霉素
步骤:
细胞刺激
1.每孔涂板25μL培养基中的6,000个A549细胞(浓度=2.4x105个细胞/mL)至细胞培养板。在37℃/5%CO2下过夜温育。
2.从板吸取培养基并添加12.5μL培养基中的样品或标准样品至板。在37℃/5%CO2下温育3h。
3.添加12.5μL IL-1(α或β)至板(工作浓度:0.2ng/mL;分析浓度:0.1ng/mL)并在37℃/5%CO2下温育48h。
4.吸取培养基并转移至包被和封闭的Elisa板(步骤9)。可选地,上清液可在-80℃下储存于PP板中长达一周。
Elisa板制备
5.将捕获抗体在PBS中稀释至2μg/mL的浓度。立即用每孔12.5μL的稀释的捕获抗体包被384孔Maxisorp板。密封板并在室温下温育1h。
6.吸取各孔并用洗涤缓冲液洗涤,重复过程两次,总共三次洗涤。使用自动洗涤器用洗涤缓冲液(90μL)填充各孔来洗涤。在各步骤完全除去液体对良好的性能来说是必不可少的。最后的洗涤之后,通过吸取或通过翻转板并用干净的纸巾吸干来除去任何残留的洗涤缓冲液。
7.通过添加90μL封闭缓冲液至各孔来封闭板。在室温下温育最少1h。
8.重复如步骤6中的吸取/洗涤。板现在已准备好用于样品添加。包被和封闭的板可在-20℃下以干燥状态储存长达一个月。
分析步骤9.每孔添加12.5μL的在ELISA缓冲液(EB)中稀释的纯样品或IL-6标准样品。覆盖并在室温下温育1h。
10.重复如Elisa板制备的步骤6的吸取/洗涤。
11.向各孔添加12.5μL在EB中稀释的检测抗体。覆盖并在室温下温育1h。
12.重复如Elisa板制备的步骤6的吸取/洗涤。
13.向各孔添加12.5μL的在ELISA缓冲液中1:40稀释的链霉菌抗生素蛋白-HRP。覆盖板并在室温下温育20分钟。避免将板放置在直接光线下。
14.重复如Elisa板制备的步骤6的吸取/洗涤。
15.向各孔添加15μL底物溶液(TMB)。在室温下温育20分钟。
16.向各孔添加15μL的终止溶液(HCl,1M)。轻轻敲打板从而确保充分混合。
17.使用设置为450nm的微量培养板读板器立即测定各孔的光学密度。如果可用波长校正,设定为540nm或570nm(程序:TMB终止384细胞因子)。在450nm下直接作出而不校正的读数可能较高且较不准确。
实施例6:通过竞争分析的huIL1RaP特异性抗体的结合特征的测定
分析原理:
用参考抗体Can04包被NUNC Maxisorp 384孔微量滴定板。在此期间,用待试验的二抗和抗HIS-POD抗体预温育His标记的靶蛋白。然后将该预温育混合物添加至分析板,并在足够的显色时间(development time)后测量450nm/620nm下的吸光度。
材料:
板:384孔NUNC Maxisorp板;目录号464718
包被抗体:Can04(MAB Discovery GmbH;CEP Ab no.184;浓度1mg/ml;分析浓度100ng/ml)
蛋白质:huIL1RaP-His蛋白(P026_01;融合_1_链_A同型二聚体huIL1RaP-His标记的;GeneArt;浓度3mg/ml;分析浓度62.5ng/ml)
标准抗体:Can04(参见:“包被抗体”;起始工作浓度3μg/ml)
阴性对照:Her2抗体(Lifespan;目录号LS-C95808/26358;浓度225μg/mL;起始工作浓度3μg/ml)
检测抗体:抗HIS POD抗体(单克隆抗多聚组氨酸过氧化物酶缀合物;Sigma;目录号A7058;浓度7.5mg/ml;分析浓度:3.33μg/ml)
PBS:盒中的缓冲液,预混PBS缓冲液,10x;Roche Applied Sciences;目录号11666789001
BSA:来自牛血清的牛血清白蛋白级分V;Roche Applied Sciences;目录号10735086001
Tween 20:Tween 20;Sigma-Aldrich;目录号P1379
TMB:TMB溶液;Merck;目录号CL07
HCl:1M Titripur盐酸;Merck;目录号1090571000
ELISA缓冲液:PBS,0.5%BSA,0.05%Tween
洗涤缓冲液:PBS,0.05%Tween
封闭缓冲液:PBS,2%BSA,0.05%Tween
步骤:
12.制备预温育混合物并在室温下温育2h。
a.预温育(在384孔板中)
i.将10μl在ELISA缓冲液中的二抗稀释系列(1:2稀释;起始工作浓度:3μg/ml)或空白样品(BLANK)与
ii.10μl His标记的蛋白质(分析浓度62.5ng/ml)和
iii.10μl抗HIS POD抗体(分析浓度:3.33μg/mL)混合,并在室温下温育1h。
13.同时,用20μl PBS中的包被抗体(Can04;分析浓度100ng/ml)包被NUNCMaxisorp板,并在室温下温育1h。
14.用90μL洗涤缓冲液洗涤3x。
15.用90μl封闭缓冲液在室温下封闭1h。
16.用洗涤缓冲液洗涤3x。
17.在室温下添加20μl ELISA缓冲液中的预温育混合物1h。
18.用洗涤缓冲液洗涤6x。
19.添加25μL TMB.
20.充分显色后添加25μL HCl。
21.读取450nm/620nm下的吸光度。
实施例7:IL12反向筛选(Counter screen)
分析原理:
IL12结合用作反向筛选。如IL12蛋白那样用接头(linker)、huFc和His(HER1不具有His标签)标记HER蛋白。结合标签的抗体在两种分析中都为阳性,而抗原特异性抗体仅与HER蛋白结合而不与IL12结合。
材料:
板:384孔NUNC Maxisorp板;目录号464718
蛋白质:重组人IL-12Rβ1Fc嵌合体;R&D Systems;目录号839-B1;分析浓度0.5μg/mL
标准抗体:IL-12Rβ1抗体;GeneTex;目录号GTX103917;1mg/mL;起始分析浓度500ng/mL(然后1:2稀释)
检测抗体:抗兔IgG,过氧化物酶连接的物种特异性Fab2片段(来自驴)(ECL);GE;目录号NA9340;分析稀释:1:5000
样品:在ELISA缓冲液中的稀释是项目依赖的(project dependent)(对于高浓度的IgG,推荐1:2稀释)
步骤:
1.添加12.5μL PBS中的0.5μg/mL HER蛋白质至384孔NUNC Maxisorp板中并在室温下温育1h。
2.用洗涤缓冲液洗涤3x。
3.向各孔添加90μL封闭缓冲液并在室温下温育1h。
4.用洗涤缓冲液洗涤3x。板可在-20℃下用铝箔密封冷冻数周。
5.添加12.5μL 1:2稀释的标准抗体或ELISA缓冲液中稀释的样品,并在室温下温育1h(冷冻的板应在样品施加前不久解冻)。
6.用洗涤缓冲液洗涤3x。
7.添加12.5μL Elisa缓冲液中的1:5000POD抗体并在室温下温育1h。
8.用洗涤缓冲液洗涤6x。
9.添加15μL TMB。
10.充分显色后添加15μL HCl(项目依赖的;IL12分析不短于其他分析)。
11.读取450nm/620nm下的吸光度。
实施例8:细胞结合分析
A549和NIH-3T3细胞在DMEM+10%FCS中培养。HEK-293细胞在DMEM+15%FCS中培养,SK-MEL-30在RPMI+10%FBS中培养。使用Accumax(Sigma)收获细胞,用PBS洗涤,并重悬于染色缓冲液(BD Pharmingen)。抗IL-1R3抗体与细胞在4℃下以10μg/ml的浓度在染色缓冲液中温育30分钟。对于EC50 SK-MEL-30细胞结合分析,以20μg/ml开始的1:2稀释系列温育细胞。细胞用染色缓冲液洗涤并在4℃下用Alexa-488标记的山羊抗人二抗(Dianova)温育30分钟。细胞用染色缓冲液洗涤并重悬于含有1:100稀释的DRAQ7(Abcam)死细胞染剂的缓冲液中。使用BD Accuri C6 Sampler流式细胞仪分析细胞。使用Excel(Microsoft)和XLfit(IDBS)进行拟合曲线和EC50计算。
实施例9:生物化学人IL-1R3 ELISA
用PBS中的浓度0.25μg/ml的重组Fc标记的hIL-1R3(Ser21-Glu359)在室温下包被Nunc 384孔Maxisorp板60分钟。用洗涤缓冲液(PBS 0.1%Tween)洗涤三次板并用PBS、0.2%BSA、0.05%Tween在室温下封闭60分钟。在用洗涤缓冲液洗涤三次后,将抗体以6至0.03μg/ml(1:3稀释系列)的浓度范围添加至ELISA缓冲液(PBS、0.5%BSA、0.05%Tween)中,并在室温下温育60min。用洗涤缓冲液洗涤三次板,然后用ELISA缓冲液中的1:5000稀释的抗人IgG过氧化物酶连接的物种特异性F(ab)2片段(山羊,AbD Serotec)在室温下温育60分钟。在添加TMB底物溶液(Invitrogen,15μl/孔)前,用洗涤缓冲液洗涤六次板。5分钟温育后,添加终止溶液(1M HCl,15μl/孔),并使用Tecan M1000读板器测量吸光度(450nm/620nm)。使用Excel(Microsoft)和XLfit(IDBS)进行拟合曲线和EC50计算。
实施例10:IL-1α和IL-1β功能中和分析
在DMEM、10%FCS、1%青霉素/链霉素中培养A-549-NFκB-RE-Luc(Signosis)5天,然后将其以25μl培养基中的40,000细胞/孔的细胞密度接种于384孔白色平底聚苯乙烯组织培养处理的微量培养板(Corning)中。在37℃/5%CO2下过夜温育细胞。通过吸取除去培养基,并以10μl培养基的体积、各种浓度添加单克隆或多克隆(山羊抗人IL-1R3,AF676,R&DSystems)抗体,并且在37℃/5%CO2下温育60分钟。添加10μl培养基中的重组人IL-1α或IL-1β(R&D Systems)蛋白至0.1ng/ml的终浓度,并且在37℃/5%CO2下温育板5小时。将20μlSteady-GloTM(Promega)溶液添加至各板,充分混合并在室温下温育板10分钟,然后使用Tecan M1000读板器测量发光。使用Excel(Microsoft)和XLfit(IDBS)进行拟合曲线和EC50计算。
实施例11:IL-1α和IL-1β功能中和分析–A-549IL6-释放分析
将A549细胞以25μl培养基中6,000细胞/孔的密度接种于384-孔透明细胞培养处理板(Corning)中的DMEM、10%FCS、1%青霉素/链霉素中。在37℃/5%CO2下过夜温育细胞。通过吸取除去培养基,并以12.5μl培养基的体积、各种浓度添加单克隆或多克隆(山羊抗人IL-1R3,AF676,R&D Systems)抗体,并且在37℃/5%CO2下温育3小时。添加12.5μl培养基中的重组人IL-1α或IL-1β(R&D Systems)蛋白至0.1ng/ml的终浓度,并且在37℃/5%CO2下温育板48小时。使用DuoSet人IL-6ELISA试剂盒(R&D Systems,登录号DY206-05)根据生产商的说明测量细胞上清液中的分泌的人IL-6水平。使用Excel(Microsoft)和XLfit(IDBS)进行拟合曲线和EC50计算。
实施例12:IL-33功能中和分析
将HEK-BlueTMIL-33细胞(InvivoGen)在DMEM,10%FCS中培养5天,然后将其以15μl培养基中的25,000细胞/孔的细胞密度接种于384孔透明、平底、细胞培养处理的微量培养板(Corning)中。以5μl培养基的体积添加各种浓度的单克隆或多克隆(山羊抗人IL-1R3,AF676,R&D Systems)抗体并在37℃/5%CO2下温育板60分钟。添加5μl培养基中的重组人IL-33(R&D Systems)蛋白至5ng/ml的终浓度,并在37℃/5%CO2下过夜温育板。将5μl细胞上清液转移至含有20μl 2xQUANTI-Blue试剂(InvivoGen)的透明、平底聚苯乙烯NBSTM微量培养板(Corning)。板在37℃下温育45分钟并使用Tecan M1000读板器在655nm处测量光学密度。使用Excel(Microsoft)和XLfit(IDBS)进行拟合曲线和EC50计算。
实施例13:IL-36功能中和分析
将HEK293/17-IF细胞(MAB Discovery GmbH)在DMEM、10%FCS、20μg/ml潮霉素中培养5天,然后将其以20μl培养基中的30,000细胞/孔的细胞密度接种于384孔白色、平底、细胞培养处理板(Corning)中。在37℃/5%CO2下过夜培养细胞。通过吸取除去培养基并以10μl培养基的体积添加各种浓度的单克隆或多克隆(山羊抗人IL-1R3,AF676,R&DSystems)抗体。在37℃/5%CO2下温育板60分钟。添加10μl培养基中的重组人IL-36g(R&DSystems)蛋白至15ng/ml的终浓度,并在37℃/5%CO2下温育板5小时。将20μl Steady-GloTM(Promega)溶液添加至各孔,充分混合,并在室温下温育板10分钟,然后使用Tecan M1000读板器读取发光。使用Excel(Microsoft)和XLfit(IDBS)进行拟合曲线和EC50计算。
实施例14:IL-1α、IL-33和IL-36α的中和
对含有IL-1α、IL-33或IL-36α的三种不同的细胞系试验抗IL-1R3抗体的功能,从而测定对依赖于IL-1R3进行信号传导的涉及三种IL-1受体(IL-1R1、-R4或–R6)的信号传导途径的影响。
用IL-1α刺激人上皮肺细胞系A549作为IL-1依赖性疾病例如自身免疫疾病的模型。在T75烧瓶(37℃,5%CO2)、完全F-12K培养基(10%FCS,1%青霉素/链霉素)中培养细胞系,并平均2次/周分瓶,在分析前不超过15次传代。将A549细胞接种(50,000/孔)于96平底板中,静置3小时,然后用MAB-16-0030(20μg/mL–1μg/mL)或IL-1Ra(10μg/mL)预温育1小时。然后用重组人IL-1α(50pg/mL,Peprotech)刺激细胞24小时,然后收获上清液并分析IL-6生产(Duoset ELISA,RnD Systems)。
研究人肥大细胞系(HMC-1)的IL-8生产的IL-33依赖性诱导。在T75烧瓶(37℃,5%CO2)、完全Iscove′s改良的Dulbeccos′s培养基(IMDM,10%FCS,1%青霉素/链霉素)中培养细胞系,并平均3次/周分瓶,在分析前不具有高于2*106/mL的细胞密度或超过15次传代。将HMC-1细胞接种(30,000/孔)于96平底板中,静置3小时,然后用MAB-16-0030(20μg/mL–1μg/mL)或IL-1Ra(10μg/mL)预温育1小时。然后用重组人IL-33(20ng/mL,RnD systems)刺激细胞24小时,然后收获上清液并分析IL-8生产(Duoset ELISA,RnD Systems)。
使用人角质细胞系(HaCaT)研究对IL-36信号传导的影响。在T75烧瓶(37℃,5%CO2)、完全DMEM培养基(10%FCS,1%青霉素/链霉素)中培养细胞系,并且平均3次/周分瓶,在分析前不超过15次传代。将HaCaT细胞接种(50,000/孔)于96平底板中,静置3小时,然后用MAB-16-0030(20μg/mL–1μg/mL)或IL-1Ra(10μg/mL)预温育1小时。然后用重组人IL-36α(50ng/mL,RnD systems)刺激细胞24小时,然后收获上清液并分析IL-8生产(DuosetELISA,RnD Systems)。
实施例15:PBMC的生存力和IL-6释放
使用常规的MTT还原分析试验抗hIL-1R3抗体MAB-16-0030对来自三名健康供体的未刺激的PBMC(500,000/孔)的生存力的影响。简而言之,用仅培养基或MAB-16-0030(20μg/mL)温育PBMC(200μL)。24小时、3和5天后,用MTT(20μL)温育PBMC 2小时,然后在ELISA读板器上测量570nM处的吸光度。利用吸光度和转化MTT的存活细胞之间的已知线性,使用仅培养基作为对照设置为100%来计算存活细胞数。在MTT分析的同一天,收获来自在相同条件下温育且来自相同供体的PBMC的上清液,并随后分析IL-6生产(Duoset ELISA,RnDsystems),从而评价仅MAB-16-0030的任何可能的刺激作用。
实施例16:PBMC的功能封闭
来自健康供体的新鲜分离的PBMC用于评价MAB-16-0030对用不同抗原刺激的人类细胞的影响。对所有刺激,使用500,000个PBMC/孔进行实验,以200μL的总体积进行刺激。接种细胞并在刺激前用仅培养基、MAB-16-0030(20–0.1μg/mL)或IL-1Ra(10μg/mL)温育细胞1小时。使用以下刺激:LPS(10ng/mL,24小时,RPMI无FCS),抗人CD3/CD28(1.25μg/mL;0.5μg/mL(eBioscience)3天,RPMI 10%FCS),IL-12/-33(2ng/mL;20ng/mL(Peprotech;RnDSystems)),3天,RPMI 10%FCS)或热灭活的白色念珠菌(0.5*106/mL,5天,RPMI 10%FCS)。刺激后,收获上清液并使用Duoset ELISA(RnD Systems)根据生产商的实验方案分析细胞因子生产。
实施例17:全血中的免疫细胞的功能封闭
热灭活的白色念珠菌用于刺激全血。来自健康供体的新鲜收获的血液(EDTA管)分配于微量离心管(250μL/管)中,并用仅培养基(RPMI,无FCS)、MAB-16-0030(20–0.1μg/mL)或IL-1Ra(10μg/mL)预温育1小时,然后用白色念珠菌(0.5*106/mL)至1mL的终体积进行刺激。24小时温育(37℃,5%CO2)后,收获上清液并通过ELISA(Duoset,RnD Systems)分析细胞因子生产。
实施例18:混合淋巴细胞反应(MLR)
来自健康、非匹配供体的PBMC以1:1比例(250,000/供体)混合,并用仅培养基、MAB-16-0030(20–1μg/mL)或IL-1Ra(10μg/mL)温育5天(RPMI,10%FCS)。使用Quansys多路复用平台(Quansys multiplex platform)根据生产商的实验方案分析细胞因子生产。
附图说明
图1:序列(氨基酸为单字母码)
可变区(VR)的完整序列:
重链:VH完整:SEQ ID NO:1-34和SEQ ID NO:173
轻链:VL完整:SEQ ID NO:35-68和SEQ ID NO:174
互补决定区(CDR):
重链:CDRH1:SEQ ID NO:69-85
CDRH2:SEQ ID NO:86-102
CDRH3:SEQ ID NO:103-119
轻链:CDRL1:SEQ ID NO:120-136
CDRL2:SEQ ID NO:137-153
CDRL3:SEQ ID NO:154-170和175
恒定区(CR):
轻链:CR-L:SEQ ID NO:171
重链:CR-H:SEQ ID NO:172
在以下附图中,AF676为购自以下链接的商购的多克隆抗体制剂:https:// www.rndsystems.com/products/human-il-1-racp-il-1-r3-antibody_af676
图2:人IL-1R3 ELISA
用代表IL-1R3的人细胞外结构域的人Il-1R3蛋白包被384微量滴定板(0.5mg/ml,至少1h)。在强洗涤步骤接着封闭步骤后,添加抗体(每孔12.5μl)并在室温下温育1h。彻底地洗去未结合的抗体。结合的抗体量通过用过氧化物酶标记的抗人检测抗体温育微量滴定板(室温下1h)来识别。通过添加TMB引发过氧化物酶反应,并在450nm/620nm下测量吸光度。
为了确保与人IL-1R3的结合特异性,平行进行使用具有相同特征的IL12蛋白的反向筛选。分析的设置与上述相同。与人IL-1R3结合、但不与IL12结合的B细胞上清液视为活性的。
图3:HEK293报道基因分析
HEK293T/17-FR细胞用pGL4.32[luc2P/NF-κB-RE/Hygro]载体(Promega)稳定转染并接种于384孔PDL Costar细胞培养板中,接着用抗体30min温育。然后用IL-1β刺激细胞5小时,然后使用Steady-Glo荧光素酶分析试剂盒(Promega)根据生产商的实验方案测定NF-kB活性。
图4:使用A549稳定细胞系的NFκB荧光素酶报道基因分析
A549-NFkB-RE-Luc稳定转染细胞(购自Signosis)已培养3天(1,7E+04个细胞/cm3)。用每孔4x104个细胞填充384孔低边白色平底聚苯乙烯TC处理的微量滴定板(Corning)。10h的培养期后,用抗体温育细胞1h,然后用10μl IL-1β刺激细胞另外5h。已通过测定相对于未刺激细胞的各孔的相对发光单位的Steady-GloTM荧光素酶分析系统(Promega)测量NFkB调节。
图5:细胞结合分析:与IL-1R3表达细胞结合
使用流式细胞术试验人源化抗IL-1R3 IgG1-LALA抗体的与具有不同IL-1R3受体密度的细胞系的结合。人源化抗IL-1R3 IgG1-LALA抗体与低和高IL-1R3表达细胞系结合。抗体不与小鼠NIH-3T3细胞结合。根据实施例8中描述的方法进行实验。
图6:细胞结合分析:人IL-1R3高表达细胞系SK-MEL-30上的细胞结合使用流式细胞术通过与高IL-1R3表达细胞系SK-MEL-30结合来测定人源化抗IL-1R3 IgG1-LALA抗体的EC50细胞结合值。人源化抗IL-1R3 IgG1-LALA抗体MAB-16-0030和MAB-16-0149分别显示307和306ng/ml的细胞结合。根据实施例8中描述的方法进行实验。
图7:人IL-1R3生物化学ELISA
在生化ELISA中试验人源化抗IL-1R3 IgG1-LALA抗体与重组人IL-1R3蛋白的结合。例示的抗体分别显示16.3ng/ml和29.1ng/ml的EC50结合值。根据实施例9中描述的方法进行实验。
图8:A549-NFkB-RE-Luc细胞中人IL-1a和IL-1b介导的NfKB信号传导的抑制
分别使用以0.1ng/ml IL-1a和IL-1b刺激的A549-NFkB-RE-Luc细胞在基于细胞的基因报道子分析中试验IL-1a和IL-1b的功能中和。人源化抗IL-1R3 IgG1-LALA抗体显示比山羊抗人IL1-R3多克隆抗体AF676(R&D Systems)更优异的EC50值。根据实施例10中描述的方法进行实验。
图9:IL-1α和IL-1β功能中和分析—A-549细胞的人IL-1a和IL-1b介导的IL-6释放的抑制
使用A-549细胞试验人源化抗IL-1R3 IgG1-LALA抗体对IL-1a和IL-1b介导的IL-6细胞释放的中和。EC50值表明人源化抗IL-1R3 IgG1-LALA抗体比山羊抗人IL1-R3多克隆抗体AF676(R&D Systems)更优异。根据实施例11中描述的方法进行实验。
图10:IL-33功能中和分析—HEK-Blue-IL33TM细胞中人IL-33介导的NfkB信号传导的抑制
使用IL-33刺激的基因报道子HEK-Blue-IL33TM细胞(InvivoGen)试验人源化抗IL-1R3 IgG1-LALA抗体对IL-33介导的信号传导的中和。EC50值表明人源化抗IL-1R3 IgG1-LALA抗体比山羊抗人IL1-R3多克隆抗体AF676(R&D Systems)更优异。根据实施例12中描述的方法进行实验。
图11:IL-36功能中和分析—HEK-293/17-IF细胞中人IL-36介导的NfkB信号传导的抑制
使用IL-36g刺激的基因报道子HEK-293/17-IF细胞试验人源化抗IL-1R3 IgG1-LALA抗体对IL-36介导的信号传导的中和。典型的人源化抗IL-1R3 IgG1-LALA抗体显示比山羊抗人IL1-R3多克隆抗体AF676(R&D Systems)更优异的EC50值。根据实施例13中描述的方法进行实验。
图12:IL-1a、IL-33和IL-36a介导的细胞的细胞因子释放的中和
使用特异性IL-1a、IL-33和IL-36a依赖性细胞系统试验IL-1a、IL-33和IL-36a介导的细胞的细胞因子释放的中和。试验了根据本发明的代表性人源化抗IL-1R3 IgG1-LALA抗体(MAB-16-0030)对细胞因子释放的抑制,并与IL-1Ra比较。尽管根据本发明的抗体能够抑制通过全部三种刺激介导的细胞因子释放,但IL-1Ra仅影响IL-1a介导的细胞因子释放。根据实施例14中描述的方法进行实验。
图13:用人源化抗IL-1R3 IgG1-LALA抗体处理的未刺激的PBMC的生存力和IL-6释放
抗体与免疫细胞的结合可导致细胞清除和有害作用,例如通过直接诱导细胞凋亡信号传导途径、刺激过度的细胞因子释放或抗体依赖性细胞毒性(ADCC)。为了排除人源化抗IL-1R3 IgG1-LALA抗体直接影响PBMC的生存力,在用不同浓度的根据本发明的代表性人源化抗IL-1R3 IgG1-LALA抗体(MAB-16-0030)温育1、3和5天后,研究三名供体的PBMC的生存力和IL-6释放。存活力或IL-6释放均未受MAB-16-0030影响。这些结果支持人源化抗IL-1R3 IgG1-LALA抗体封闭在免疫细胞上的IL-1R3功能,而没有偶然性的细胞清除和诱导细胞有害作用。根据实施例15中描述的方法进行实验。
图14:用不同刺激激活的PBMC的功能封闭
为了试验人源化抗IL-1R3 IgG1-LALA抗体是否抑制用特异性或复合刺激来刺激的PBMC的激活,用LPS、热灭活的白色念珠菌、IL-12/IL-33或CD3/CD28抗体刺激10名供体的PBMC。根据本发明的代表性人源化抗IL-1R3 IgG1-LALA抗体能够抑制由全部试验的刺激介导的细胞因子释放。根据实施例16中描述的方法进行实验。
图15:用白色念珠菌激活的全血中免疫细胞的功能封闭
为了试验人源化抗IL-1R3 IgG1-LALA抗体是否抑制全血中免疫细胞的激活,用热灭活的白色念珠菌刺激8名供体的全血。图中所示的根据本发明的代表性人源化抗IL-1R3IgG1-LALA抗体能够抑制白色念珠菌(Candida)诱导的IL-6细胞因子释放。根据实施例17中描述的方法进行实验。
图16:混合淋巴细胞反应(MLR)中细胞因子释放的封闭
使用健康、无匹配的供体的PBMC在混合淋巴细胞反应(MLR)中试验人源化抗IL-1R3 IgG1-LALA抗体封闭不同细胞因子的释放的能力。图中所示的根据本发明的代表性人源化抗IL-1R3 IgG1-LALA抗体能够抑制IFNg、IL-6、TNF-a、IL-13、IL-17和IL-10的释放。根据实施例18中描述的方法进行实验。
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<120> 人源化抗IL-1R3抗体
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Glu Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Pro Gly Tyr Ser Ser Trp Leu Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 19
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 19
Glu Val Gln Leu Glu Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Ala
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Ser
20 25 30
His Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ala Cys Ile Tyr Ala Gly Ser Ser Gly Asn Thr Tyr Tyr Ala Asn
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Phe Cys Ala Arg Val Asp Ala Ser Ser Ser Gly Ser Trp Asp Leu Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 20
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 20
Glu Val Gln Leu Leu Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Thr
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser Ser Tyr
20 25 30
Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Gly Val Ile Thr Ser Ser Ala Thr Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg
85 90 95
Gly Gly Pro Gly Tyr Ser Thr Asn Thr His Tyr Ala Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 21
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 21
Glu Val Gln Leu Glu Glu Ser Gly Gly Arg Val Val Gln Pro Gly Thr
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Asp Asn Tyr
20 25 30
Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ala Val Ile Ser Ser Asp Gly Phe Phe Tyr Asp Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Ala Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Asp Arg Gly Thr Ser Thr Gly Ser Leu Asp Leu Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 22
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 22
Gln Val Gln Leu Glu Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Thr
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Gly Ser Ala Ser Thr Tyr Tyr Ala Thr Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Leu Tyr Leu Gln Met
65 70 75 80
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg Thr
85 90 95
His Tyr Ala Ala Val Ala Gly Tyr Gly Tyr Ala Ser Arg Leu Asp Leu
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 23
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 23
Gln Val Gln Leu Gln Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Asn
20 25 30
Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu
35 40 45
Val Ala Cys Ile Tyr Thr Ser Thr Gly Asn Thr Trp Tyr Ala Ser Trp
50 55 60
Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
85 90 95
Cys Ala Arg Asp Leu Leu Val Val Thr Ser Phe Asn Leu Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 24
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 24
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Ala
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Ser
20 25 30
Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ala Cys Ile Tyr Ala Gly Ser Ser Gly Val Thr Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Asp Thr Ser Ser Thr Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
85 90 95
Cys Ala Ser Glu Thr Asp Gly Asn Tyr Phe Asn Leu Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 25
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 25
Glu Val Gln Leu Glu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Tyr Trp Arg Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ala Cys Ile Tyr Ala Gly Ser Gly Asp Val Thr Tyr Tyr Ala Asn
50 55 60
Trp Val Asn Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ser Gly Val Gly Phe Gly Tyr Phe Asn Leu Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 26
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 26
Glu Val Gln Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Asp Phe Ser Ser Tyr
20 25 30
Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ala Cys Ile Phe Ile Gly Tyr Gly Asp Val Thr Trp Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Ala Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Phe Cys Ala Arg Ala Leu Gly Ser Ser Gly Tyr Arg Val Asn Leu Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 27
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 27
Gln Val Gln Leu Glu Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Ala
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Met Ile Tyr Gly Ser Gly Tyr Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Thr Thr Ser Thr Thr Leu Tyr Leu Gln Met
65 70 75 80
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg Asp
85 90 95
Pro Gln Tyr Phe Ile Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 28
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 28
Glu Val Gln Leu Glu Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Thr
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Tyr Ile Gly Gly Thr Thr Ala Tyr Ala Ser Trp Pro Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Thr Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Leu Gln Gly Ala Asn Tyr Tyr Asn Ser Leu Ala Leu Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 29
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 29
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Ser Asn
20 25 30
Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu
35 40 45
Val Ala Cys Ile Tyr Thr Asn Ser Gly Asn Thr Trp Ser Ala Ser Trp
50 55 60
Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Asn Ser Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Leu Asn Tyr Pro Asp Thr Ser Asn Leu Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 30
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 30
Glu Val Gln Leu Glu Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Phe Gly
20 25 30
Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ala Cys Ile Tyr Gly Asp Ser Ser Asp Thr Leu Tyr Ala Asn Trp
50 55 60
Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Asn Ser Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
85 90 95
Cys Ala Arg Tyr Pro Gly Gly Ser Tyr Tyr Asn Leu Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 31
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 31
Gln Val Gln Leu Gln Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Ala
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Thr
20 25 30
Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ala Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Asn Ser Ser Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Val Asp Gly Ser Ser Ser Gly Ser Trp Asp Leu Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 32
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 32
Glu Val Gln Leu Glu Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Ala
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Ser Phe Ser Ser Ser
20 25 30
Asp Phe Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ala Cys Ile Tyr Ala Gly Ser Ser Val Ser Ile Tyr Tyr Ala Thr
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Ala Ser Ser Thr Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
85 90 95
Cys Ala Arg Ser Thr Gly Ser Val Gly Arg Gly Phe Asn Leu Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 33
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Ile
20 25 30
Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Cys Ile Tyr Thr Gly Asn Ser Asp Phe Thr Tyr Tyr Ala Asn
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Phe Cys Ala Arg Phe Arg Asp Asp Tyr Ala Ser Leu Lys Leu Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 34
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 34
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Gly
20 25 30
Tyr Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Cys Ile Tyr Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asn Trp
50 55 60
Ala Lys Gly Arg Phe Thr Ile Ser Lys Asp Asn Ser Lys Thr Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
85 90 95
Cys Ala Arg Asn Ser Asn Asp Trp Met Tyr Phe Asn Leu Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 35
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 35
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Trp Trp Val Ile Glu His
85 90 95
Asn Gly Ala Ala Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 36
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 36
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Leu Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Ala Ser Tyr Ser Thr Gly
85 90 95
Pro Asp Trp Thr Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 37
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 37
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Tyr Ile Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Ala Thr Thr Tyr Asn
85 90 95
Val Asp Asn Val Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 38
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 38
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asn Ile Gly Asn Gly
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Cys Thr Tyr Trp Asn Pro Asp
85 90 95
Tyr Ile Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 39
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 39
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Ser Gly
20 25 30
Ile Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Tyr Ser Tyr Ser Asn
85 90 95
Thr Gly Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 40
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 40
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Val Cys Thr Asp Ile Ser
85 90 95
Thr Asp Asp Leu Tyr Asn Ala Phe Gly Gln Gly Thr Lys Val Val Ile
100 105 110
Lys
<210> 41
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 41
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Val Tyr Thr Tyr Ser Thr
85 90 95
Asp Ile His Ala Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 42
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 42
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Val Tyr Thr His Ile Ser
85 90 95
Ala Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 43
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 43
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asn Ile Tyr Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Tyr Ser Gly Gly
85 90 95
Thr Asp Asn Asp Val Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 44
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 44
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser Val Asp Gly Asn
20 25 30
Asn Leu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Asp Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Ser Tyr Tyr Ser
85 90 95
Ser Ser Trp Tyr Asn Val Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 45
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Tyr Ser Phe
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asp Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Cys Asn Tyr Ile Ile Asp Tyr
85 90 95
Gly Ala Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105
<210> 46
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Gly Tyr Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Asn Ser Asp Ser
85 90 95
Asp Ala Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105
<210> 47
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 47
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Thr Ile Ser Ile Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Thr Glu Asp Asn
85 90 95
Ile Asp Asn Thr Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 48
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Leu Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Ala Val Tyr Ser Gly Asn
85 90 95
Thr Glu Trp Ala Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 49
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 49
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Val Tyr Asn Ser
20 25 30
Asn His Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Glu Phe Ser Cys
85 90 95
Val Ser Ala Asp Cys Ile Ala Phe Gly Gly Gly Thr Lys Val Val Ile
100 105 110
Lys
<210> 50
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Cys Thr Tyr Tyr Asp Asn Asn
85 90 95
Tyr Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 51
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 51
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Ala Asn
20 25 30
Tyr Trp Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Ser Trp Tyr Tyr Ser Gly
85 90 95
Ser Gly Ser Tyr His Ser Trp Ala Phe Gly Gln Gly Thr Lys Val Val
100 105 110
Ile Lys
<210> 52
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 52
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Trp Trp Val Ile Glu His
85 90 95
Asn Gly Ala Ala Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 53
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 53
Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Leu Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Ala Ser Tyr Ser Thr Gly
85 90 95
Pro Asp Trp Thr Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 54
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 54
Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Tyr Ile Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Ala Thr Thr Tyr Asn
85 90 95
Val Asp Asn Val Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 55
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 55
Glu Leu Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asn Ile Gly Asn Gly
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Cys Thr Tyr Trp Asn Pro Asp
85 90 95
Tyr Ile Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 56
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 56
Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Ser Gly
20 25 30
Ile Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Tyr Ser Tyr Ser Asn
85 90 95
Thr Gly Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 57
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 57
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Val Cys Thr Asp Ile Ser
85 90 95
Thr Asp Asp Leu Tyr Asn Ala Phe Gly Gln Gly Thr Lys Val Val Ile
100 105 110
Lys
<210> 58
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 58
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Val Tyr Thr Tyr Ser Thr
85 90 95
Asp Ile His Ala Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 59
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 59
Glu Leu Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Val Tyr Thr His Ile Ser
85 90 95
Ala Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 60
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 60
Ala Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asn Ile Tyr Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Tyr Ser Gly Gly
85 90 95
Thr Asp Asn Asp Val Phe Gly Gly Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 61
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 61
Asn Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser Val Asp Gly Asn
20 25 30
Asn Leu Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Asp Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Ser Tyr Tyr Ser
85 90 95
Ser Ser Trp Tyr Asn Val Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 62
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 62
Asp Val Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Tyr Ser Phe
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asp Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Cys Asn Tyr Ile Ile Asp Tyr
85 90 95
Gly Ala Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105
<210> 63
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 63
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Gly Tyr Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Asn Ser Asp Ser
85 90 95
Asp Ala Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105
<210> 64
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 64
Ala Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Thr Ile Ser Ile Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Thr Glu Asp Asn
85 90 95
Ile Asp Asn Thr Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 65
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 65
Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Leu Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Ala Val Tyr Ser Gly Asn
85 90 95
Thr Glu Trp Ala Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105 110
<210> 66
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 66
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Val Tyr Asn Ser
20 25 30
Asn His Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Glu Phe Ser Cys
85 90 95
Val Ser Ala Asp Cys Ile Ala Phe Gly Gly Gly Thr Lys Val Val Ile
100 105 110
Lys
<210> 67
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 67
Asp Val Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Cys Thr Tyr Tyr Asp Asn Asn
85 90 95
Tyr Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 68
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 68
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Ala Asn
20 25 30
Tyr Trp Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Ser Trp Tyr Tyr Ser Gly
85 90 95
Ser Gly Ser Tyr His Ser Trp Ala Phe Gly Gln Gly Thr Lys Val Val
100 105 110
Ile Lys
<210> 69
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 69
Ser Ser Tyr Trp Ile Cys
1 5
<210> 70
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 70
Ser Ser His Tyr Met Cys
1 5
<210> 71
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 71
Ser Tyr Ala Met Gly
1 5
<210> 72
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 72
Asn Tyr Ala Met Gly
1 5
<210> 73
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 73
Ser Tyr Tyr Met Ser
1 5
<210> 74
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 74
Ser Asn Tyr Trp Ile Cys
1 5
<210> 75
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 75
Ser Ser Tyr Tyr Met Cys
1 5
<210> 76
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 76
Thr Ser Tyr Trp Arg Cys
1 5
<210> 77
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 77
Ser Tyr Tyr Tyr Met Cys
1 5
<210> 78
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 78
Ser Tyr Trp Met Ser
1 5
<210> 79
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 79
Ser Tyr Asp Met Ser
1 5
<210> 80
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 80
Ser Asn Tyr Tyr Met Cys
1 5
<210> 81
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 81
Phe Gly Tyr Tyr Met Cys
1 5
<210> 82
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 82
Ser Thr Tyr Tyr Met Cys
1 5
<210> 83
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 83
Ser Ser Asp Phe Met Cys
1 5
<210> 84
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 84
Ser Ile Tyr Tyr Met Cys
1 5
<210> 85
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 85
Ser Gly Tyr Asp Met Cys
1 5
<210> 86
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 86
Cys Ile Tyr Thr Gly Ser Gly Gly Thr Tyr Tyr Ala Ser Trp Glu Lys
1 5 10 15
Gly
<210> 87
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 87
Cys Ile Tyr Ala Gly Ser Ser Gly Asn Thr Tyr Tyr Ala Asn Trp Ala
1 5 10 15
Lys Gly
<210> 88
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 88
Val Ile Thr Ser Ser Ala Thr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 89
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 89
Val Ile Ser Ser Asp Gly Phe Phe Tyr Asp Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 90
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 90
Ile Ile Ser Gly Ser Ala Ser Thr Tyr Tyr Ala Thr Trp Ala Lys Gly
1 5 10 15
<210> 91
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 91
Cys Ile Tyr Thr Ser Thr Gly Asn Thr Trp Tyr Ala Ser Trp Ala Lys
1 5 10 15
Gly
<210> 92
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 92
Cys Ile Tyr Ala Gly Ser Ser Gly Val Thr Tyr Tyr Ala Ser Trp Ala
1 5 10 15
Lys Gly
<210> 93
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 93
Cys Ile Tyr Ala Gly Ser Gly Asp Val Thr Tyr Tyr Ala Asn Trp Val
1 5 10 15
Asn Gly
<210> 94
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 94
Cys Ile Phe Ile Gly Tyr Gly Asp Val Thr Trp Tyr Ala Ser Trp Ala
1 5 10 15
Lys Gly
<210> 95
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 95
Met Ile Tyr Gly Ser Gly Tyr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 96
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 96
Thr Ile Tyr Ile Gly Gly Thr Thr Ala Tyr Ala Ser Trp Pro Lys Gly
1 5 10 15
<210> 97
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 97
Cys Ile Tyr Thr Asn Ser Gly Asn Thr Trp Ser Ala Ser Trp Ala Lys
1 5 10 15
Gly
<210> 98
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 98
Cys Ile Tyr Gly Asp Ser Ser Asp Thr Leu Tyr Ala Asn Trp Ala Lys
1 5 10 15
Gly
<210> 99
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 99
Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser Trp Ala
1 5 10 15
Lys Gly
<210> 100
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 100
Cys Ile Tyr Ala Gly Ser Ser Val Ser Ile Tyr Tyr Ala Thr Trp Ala
1 5 10 15
Lys Gly
<210> 101
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 101
Cys Ile Tyr Thr Gly Asn Ser Asp Phe Thr Tyr Tyr Ala Asn Trp Ala
1 5 10 15
Lys Gly
<210> 102
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 102
Cys Ile Tyr Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asn Trp Ala Lys
1 5 10 15
Gly
<210> 103
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 103
Asp Pro Gly Tyr Ser Ser Trp Leu
1 5
<210> 104
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 104
Val Asp Ala Ser Ser Ser Gly Ser Trp Asp Leu
1 5 10
<210> 105
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 105
Gly Gly Pro Gly Tyr Ser Thr Asn Thr His Tyr Ala Phe Asp Pro
1 5 10 15
<210> 106
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 106
Asp Arg Gly Thr Ser Thr Gly Ser Leu Asp Leu
1 5 10
<210> 107
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 107
Thr His Tyr Ala Ala Val Ala Gly Tyr Gly Tyr Ala Ser Arg Leu Asp
1 5 10 15
Leu
<210> 108
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 108
Asp Leu Leu Val Val Thr Ser Phe Asn Leu
1 5 10
<210> 109
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 109
Glu Thr Asp Gly Asn Tyr Phe Asn Leu
1 5
<210> 110
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 110
Gly Val Gly Phe Gly Tyr Phe Asn Leu
1 5
<210> 111
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 111
Ala Leu Gly Ser Ser Gly Tyr Arg Val Asn Leu
1 5 10
<210> 112
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 112
Asp Pro Gln Tyr Phe Ile Leu
1 5
<210> 113
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 113
Leu Gln Gly Ala Asn Tyr Tyr Asn Ser Leu Ala Leu
1 5 10
<210> 114
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 114
Asp Leu Asn Tyr Pro Asp Thr Ser Asn Leu
1 5 10
<210> 115
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 115
Tyr Pro Gly Gly Ser Tyr Tyr Asn Leu
1 5
<210> 116
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 116
Val Asp Gly Ser Ser Ser Gly Ser Trp Asp Leu
1 5 10
<210> 117
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 117
Ser Thr Gly Ser Val Gly Arg Gly Phe Asn Leu
1 5 10
<210> 118
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 118
Phe Arg Asp Asp Tyr Ala Ser Leu Lys Leu
1 5 10
<210> 119
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 119
Asn Ser Asn Asp Trp Met Tyr Phe Asn Leu
1 5 10
<210> 120
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 120
Gln Ala Ser Glu Ser Ile Ser Asn Tyr Leu Ser
1 5 10
<210> 121
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 121
Gln Ala Ser Glu Ser Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 122
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 122
Gln Ala Ser Gln Ser Ile Tyr Ile Tyr Leu Ser
1 5 10
<210> 123
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 123
Gln Ala Ser Glu Asn Ile Gly Asn Gly Leu Ala
1 5 10
<210> 124
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 124
Leu Ala Ser Glu Asp Ile Tyr Ser Gly Ile Ser
1 5 10
<210> 125
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 125
Gln Ala Ser Glu Asp Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 126
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 126
Gln Ala Ser Glu Asp Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 127
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 127
Gln Ala Ser Glu Asp Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 128
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 128
Gln Ala Ser Glu Asn Ile Tyr Ser Ser Leu Ala
1 5 10
<210> 129
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 129
Gln Ser Ser Gln Ser Val Asp Gly Asn Asn Leu Leu Ser
1 5 10
<210> 130
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 130
Gln Ala Ser Gln Ser Ile Tyr Ser Phe Leu Ser
1 5 10
<210> 131
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 131
Gln Ala Ser Gln Ser Ile Gly Tyr Tyr Leu Ala
1 5 10
<210> 132
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 132
Gln Ala Ser Gln Thr Ile Ser Ile Asn Leu Ala
1 5 10
<210> 133
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 133
Gln Ala Ser Gln Asn Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 134
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 134
Gln Ala Ser Gln Ser Val Tyr Asn Ser Asn His Leu Ser
1 5 10
<210> 135
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 135
Gln Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ser
1 5 10
<210> 136
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 136
Gln Ala Ser Glu Ser Ile Ser Ala Asn Tyr Trp Ser
1 5 10
<210> 137
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 137
Leu Ala Ser Thr Leu Ala Ser
1 5
<210> 138
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 138
Ala Ala Ser Leu Leu Ala Ser
1 5
<210> 139
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 139
Asp Ala Ser Lys Leu Ala Ser
1 5
<210> 140
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 140
Gly Ala Ser Thr Leu Ala Ser
1 5
<210> 141
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 141
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 142
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 142
Gly Ala Ser Thr Leu Ala Ser
1 5
<210> 143
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 143
Arg Ala Ser Thr Leu Ala Ser
1 5
<210> 144
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 144
Asp Ala Ser Thr Leu Ala Ser
1 5
<210> 145
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 145
Asp Ala Ser Asp Leu Ala Ser
1 5
<210> 146
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 146
Asp Ala Ser Asn Leu Ala Ser
1 5
<210> 147
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 147
Ala Ala Ser Asp Leu Glu Ser
1 5
<210> 148
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 148
Arg Ala Ser Thr Leu Ala Ser
1 5
<210> 149
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 149
Tyr Ala Ser Thr Leu Ala Ser
1 5
<210> 150
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 150
Ala Ala Ser Leu Leu Ala Ser
1 5
<210> 151
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 151
Ser Ala Ser Thr Leu Ala Ser
1 5
<210> 152
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 152
Gly Ala Ser Asn Leu Ala Ser
1 5
<210> 153
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 153
Gly Ala Ser Thr Leu Ala Ser
1 5
<210> 154
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 154
Gln Asn Trp Trp Val Ile Glu His Asn Gly Ala Ala
1 5 10
<210> 155
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 155
Gln Ser Ala Ser Tyr Ser Thr Gly Pro Asp Trp Thr
1 5 10
<210> 156
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 156
Gln Gln Gly Ala Thr Thr Tyr Asn Val Asp Asn Val
1 5 10
<210> 157
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 157
Gln Cys Thr Tyr Trp Asn Pro Asp Tyr Ile Gly Gly Ala
1 5 10
<210> 158
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 158
Leu Gly Gly Tyr Ser Tyr Ser Asn Thr Gly Pro Thr
1 5 10
<210> 159
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 159
Leu Gly Val Cys Thr Asp Ile Ser Thr Asp Asp Leu Tyr Asn Ala
1 5 10 15
<210> 160
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 160
Leu Gly Val Tyr Thr Tyr Ser Thr Asp Ile His Ala
1 5 10
<210> 161
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 161
Leu Gly Val Tyr Thr His Ile Ser Ala Asp Asn Ala
1 5 10
<210> 162
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 162
Gln Gln Gly Tyr Tyr Ser Gly Gly Thr Asp Asn Asp Val
1 5 10
<210> 163
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 163
Gln Gly Ser Tyr Tyr Ser Ser Ser Trp Tyr Asn Val
1 5 10
<210> 164
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 164
Gln Cys Asn Tyr Ile Ile Asp Tyr Gly Ala
1 5 10
<210> 165
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 165
Gln Ser Tyr Tyr Asn Ser Asp Ser Asp Ala
1 5 10
<210> 166
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 166
Gln Gln Gly Tyr Thr Glu Asp Asn Ile Asp Asn Thr
1 5 10
<210> 167
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 167
Gln Gly Ala Val Tyr Ser Gly Asn Thr Glu Trp Ala
1 5 10
<210> 168
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 168
Gln Gly Glu Phe Ser Cys Val Ser Ala Asp Cys Ile Ala
1 5 10
<210> 169
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 169
Gln Cys Thr Tyr Tyr Asp Asn Asn Tyr Gly Gly Ala
1 5 10
<210> 170
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 170
Gln Ser Trp Tyr Tyr Ser Gly Ser Gly Ser Tyr His Ser Trp Ala
1 5 10 15
<210> 171
<211> 107
<212> PRT
<213> 智人(Homo sapiens)
<400> 171
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 172
<211> 329
<212> PRT
<213> 智人
<400> 172
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 173
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 173
Glu Val Gln Leu Leu Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Thr
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser Ser Tyr
20 25 30
Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Gly Val Ile Thr Ser Ser Ala Thr Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Gly Gly Pro Gly Tyr Ser Thr Asn Thr His Tyr Ala Phe Asp Pro
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 174
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 174
Asp Val Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Tyr Ser Phe
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asp Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Asn Tyr Ile Ile Asp Tyr
85 90 95
Gly Ala Phe Gly Gln Gly Thr Lys Val Val Ile Lys
100 105
<210> 175
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 175
Gln Ser Asn Tyr Ile Ile Asp Tyr Gly Ala
1 5 10
Claims (19)
1.一种特异性结合IL-1R3的人源化抗体或者其片段或衍生物,所述片段或衍生物含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分,所述特异性结合IL-1R3的人源化抗体或者其片段或衍生物包含:
a)重链可变区(VH),其包含含有CDR-H1、CDR-H2、和CDR-H3的互补决定区,
其中所述CDR-H1区包含选自SEQ ID NO:69-85的组的氨基酸序列,
其中所述CDR-H2区包含选自SEQ ID NO:86-102的组的氨基酸序列,
和其中所述CDR-H3区包含选自SEQ ID NO:103-119的组的氨基酸序列;和
b)轻链可变区(VL),其包含含有CDR-L1、CDR-L2、和CDR-L3的互补决定区
其中所述CDR-L1区包含选自SEQ ID NO:120-136的组的氨基酸序列,
其中所述CDR-L2区包含选自SEQ ID NO:137-153的组的氨基酸序列,和
其中所述CDR-L3区包含选自SEQ ID NO:154-170和SEQ ID NO:175的组的氨基酸序列。
2.一种特异性结合IL-1R3的人源化抗体或者其片段或衍生物,其中所述抗体包含与选自由SEQ ID NO:1至34和173的VH区组成的组的VH区至少90%相同的重链可变(VH)区。
3.一种特异性结合IL-1R3的人源化抗体或者其片段或衍生物,其中所述抗体包含与选自由SEQ ID NO:35至68和SEQ ID NO:174的VL区组成的组的VL区至少90%相同的轻链可变(VL)区。
4.根据权利要求2所述的特异性结合IL-1R3的人源化抗体或者其片段或衍生物,其中所述抗体包含含有选自SEQ ID NO:1至34和173的组的氨基酸序列的重链可变区(VH)。
5.根据权利要求3所述的特异性结合IL-1R3的人源化抗体或者其片段或衍生物,其中所述抗体包含含有选自SEQ ID NO:35至68和174的组的氨基酸序列的轻链可变区(VL)。
6.根据权利要求1至5任一项所述的特异性结合IL-1R3的人源化抗体或者其片段或衍生物,其包含VH区和VL区,所述VH区和VL区含有选自由以下组成的组的抗体的各自的CDR1、CDR2和CDR3区:MAB-15-0139、MAB-15-0106、MAB-15-0108、MAB-15-0110、MAB-15-0117、MAB-15-0121、MAB-15-0140、MAB-15-0115、MAB-15-0125、MAB-15-0119、MAB-15-0109、MAB-15-0097、MAB-15-0135、MAB-15-0133、MAB-15-0107、MAB-15-0128、MAB-15-0116、MAB-16-0004、MAB-16-0009、MAB-16-0028、MAB-16-0031、MAB-16-0043、MAB-16-0049、MAB-16-0045、MAB-16-0040、MAB-16-0036、MAB-16-0046、MAB-16-0030、MAB-16-0021、MAB-16-0019、MAB-16-0015、MAB-16-0027、MAB-16-0048、MAB-16-0041、MAB-16-0149、MAB-16-150。
7.一种特异性结合IL-1R3的人源化抗体或者其片段或衍生物,其抑制IL-1R3诱导的NFkB活性,所述片段或衍生物含有足以赋予IL-1R3结合特异性的、所述抗体的至少一部分。
8.根据前述权利要求任一项所述的人源化抗体、其片段或衍生物,其中所述抗体与选自由以下组成的组的抗体结合相同的表位:抗体MAB-15-0139、MAB-15-0106、MAB-15-0108、MAB-15-0110、MAB-15-0117、MAB-15-0121、MAB-15-0140、MAB-15-0115、MAB-15-0125、MAB-15-0119、MAB-15-0109、MAB-15-0097、MAB-15-0135、MAB-15-0133、MAB-15-0107、MAB-15-0128、MAB-15-0116、MAB-16-0004、MAB-16-0009、MAB-16-0028、MAB-16-0031、MAB-16-0043、MAB-16-0049、MAB-16-0045、MAB-16-0040、MAB-16-0036、MAB-16-0046、MAB-16-0030、MAB-16-0021、MAB-16-0019、MAB-16-0015、MAB-16-0027、MAB-16-0048、MAB-16-0041、MAB-16-0149、MAB-16-150。
9.根据前述权利要求任一项所述的人源化抗体,其中所述抗体抑制IL-1α、IL-1β、IL-33、和/或IL-36刺激的NFkB活性。
10.根据前述权利要求任一项所述的人源化抗体,其中所述抗体抑制由选自以下组成的组的复合物刺激的NFkB活性:IL-1β/IL-1R1/IL-1RAcP、IL-1α/IL-1R1/IL-1RAcP、IL-33/ST2/IL-1RAcP、和/或IL-36/Il-36R/IL-1RAcP。
11.根据前述权利要求任一项所述的人源化IgG1LALA抗体,其中相对于不存在根据本发明所述的抗体的相同分析,所述抗体以10μg/ml的浓度使得用0.1ng/ml人IL-1α、人IL-1β、IL-33和/或IL-36刺激的A549-NFkB-RE-Luc细胞裂解物中的NFkB表达抑制50%以上、优选60%以上、优选70%以上、优选80%以上、优选90%以上、更优选95%以上。
12.根据前述权利要求任一项所述的人源化抗体,其中所述抗体分别抑制IL-1α、IL-1β、IL-33、和/或IL-36刺激的在用NF-kB报道基因控制下的荧光素酶转染的HEK293T/17细胞中的荧光素酶活性。
13.根据前述权利要求任一项所述的人源化抗体,其中所述抗体至少包含在人IgG1 Fc区的L234A和L235A或者人IgG4 Fc区的S228P和L235E处的氨基酸取代。
14.根据前述权利要求任一项所述的人源化抗体,其用于治疗IL-1R3介导的疾病。
15.根据权利要求14所述的人源化抗体,其中所述IL-1R3介导的疾病选自由肺癌、非小细胞肺(NSCL)癌、细支气管肺泡细胞肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌症、肠胃癌、胃癌、结肠癌、乳腺癌、或子宫癌组成的组。
16.一种药物组合物,其包含药学可接受的载体和治疗有效量的根据前述权利要求任一项所述的抗体。
17.根据权利要求16所述的药物组合物,其用于治疗IL-1R3介导的疾病。
18.根据权利要求16或17所述的药物组合物,其中所述IL-1R3介导的疾病选自由肺癌、非小细胞肺(NSCL)癌、细支气管肺泡细胞肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌症、肠胃癌、胃癌、结肠癌、乳腺癌、或子宫癌组成的组。
19.根据权利要求1至15任一项所述的人源化抗体或根据权利要求16至18任一项所述的药物组合物,其用于与一种或多种细胞毒性、细胞抑制或靶向的抗癌化合物组合来治疗癌症。
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Publication number | Priority date | Publication date | Assignee | Title |
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Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3401332A1 (en) | 2017-05-08 | 2018-11-14 | MAB Discovery GmbH | Anti-il-1r3 antibodies for use in inflammatory conditions |
WO2018231827A1 (en) | 2017-06-12 | 2018-12-20 | Bluefin Biomedicine, Inc. | Anti-il1rap antibodies and antibody drug conjugates |
TW202021618A (zh) | 2018-08-17 | 2020-06-16 | 美商23與我有限公司 | 抗il1rap抗體及其使用方法 |
TW202227496A (zh) | 2020-09-14 | 2022-07-16 | 瑞士商伊克諾斯科學公司 | 結合至il1rap之抗體及其用途 |
EP4288457A2 (en) * | 2021-02-05 | 2023-12-13 | Boehringer Ingelheim International GmbH | Anti-il1rap antibodies |
CA3220913A1 (en) | 2021-05-21 | 2022-11-24 | Leo Pharma A/S | Anti il-1 receptor accessory protein antibodies |
US20240101691A1 (en) * | 2022-09-21 | 2024-03-28 | Sanofi Biotechnology | Humanized anti-il-1r3 antibody and methods of use |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1934072A (zh) * | 2004-01-30 | 2007-03-21 | 派普林生物脂股份有限公司 | 治疗和载体分子 |
CN102639565A (zh) * | 2009-08-21 | 2012-08-15 | 坎塔吉亚有限责任公司 | Il1rap在急性和慢性髓细胞样白血病细胞上的表达 |
WO2012177595A1 (en) * | 2011-06-21 | 2012-12-27 | Oncofactor Corporation | Compositions and methods for the therapy and diagnosis of cancer |
CN102939304A (zh) * | 2010-04-09 | 2013-02-20 | 诺维信生物制药丹麦公司 | 白蛋白衍生物和变体 |
CN103459424A (zh) * | 2011-01-19 | 2013-12-18 | 坎塔吉亚有限责任公司 | 抗il1rap抗体及其治疗人类的用途 |
CN103492416A (zh) * | 2011-04-15 | 2014-01-01 | 默克专利股份公司 | 用于癌症中使用的抗il-1r1抑制剂 |
WO2015132602A1 (en) * | 2014-03-05 | 2015-09-11 | Cantargia Ab | Anti human interleukin-1 receptor accessory protein (il1 rap) antibodies and uses thereof |
Family Cites Families (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5204244A (en) | 1987-10-27 | 1993-04-20 | Oncogen | Production of chimeric antibodies by homologous recombination |
US5202238A (en) | 1987-10-27 | 1993-04-13 | Oncogen | Production of chimeric antibodies by homologous recombination |
US5283179A (en) | 1990-09-10 | 1994-02-01 | Promega Corporation | Luciferase assay method |
ES2103770T3 (es) | 1990-11-26 | 1997-10-01 | Akzo Nobel Nv | Procedimiento de produccion de anticuerpos monoclonales. |
PE64396A1 (es) | 1995-01-23 | 1997-01-28 | Hoffmann La Roche | Proteina accesoria del receptor de la interleucina 1 |
US6974682B1 (en) | 1996-08-26 | 2005-12-13 | Human Genome Sciences, Inc. | Soluble interleukin-1 receptor accessory molecule |
EP0915987A2 (en) | 1997-04-21 | 1999-05-19 | Donlar Corporation | POLY-($g(a)-L-ASPARTIC ACID), POLY-($g(a)-L-GLUTAMIC ACID) AND COPOLYMERS OF L-ASP AND L-GLU, METHOD FOR THEIR PRODUCTION AND THEIR USE |
US6280955B1 (en) | 1997-12-16 | 2001-08-28 | Tularik Inc. | Interleukin-1 receptor accessory proteins, nucleic acids and methods |
WO1999054342A1 (en) | 1998-04-20 | 1999-10-28 | Pablo Umana | Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity |
US6541225B1 (en) | 2000-01-26 | 2003-04-01 | Raven Biotechnologies, Inc. | Methods and compositions for generating human monoclonal antibodies |
US7449443B2 (en) | 2000-03-23 | 2008-11-11 | California Institute Of Technology | Method for stabilization of proteins using non-natural amino acids |
US6586207B2 (en) | 2000-05-26 | 2003-07-01 | California Institute Of Technology | Overexpression of aminoacyl-tRNA synthetases for efficient production of engineered proteins containing amino acid analogues |
US20030026806A1 (en) | 2000-10-27 | 2003-02-06 | Amgen Inc. | Antibodies and other selective IL-1 binding agents that allow binding to IL-1 receptor but not activation thereof |
AU2002253842A1 (en) | 2000-10-31 | 2002-08-28 | Immunex Corporation | Il-1 receptor accessory protein |
WO2003014309A2 (en) | 2001-08-07 | 2003-02-20 | Immunex Corporation | Interleukin-1 receptors in the treatment of diseases |
US7139665B2 (en) | 2002-02-27 | 2006-11-21 | California Institute Of Technology | Computational method for designing enzymes for incorporation of non natural amino acids into proteins |
ATE549033T1 (de) | 2002-09-06 | 2012-03-15 | Amgen Inc | Therapeutischer menschlicher monoklonaler anti-il-1r1-antikörper |
KR101498588B1 (ko) | 2003-01-22 | 2015-03-05 | 로슈 글리카트 아게 | 융합 구성체와 Fc 수용체 결합 친화도 및 이펙터 기능이 증가된 항체를 생성하기 위한 이의 용도 |
WO2004100987A2 (en) | 2003-05-06 | 2004-11-25 | Regeneron Pharmaceuticals, Inc. | Methods of using il-1 antagonists to treat neointimal hyperplasia |
GB0312481D0 (en) | 2003-05-30 | 2003-07-09 | Celltech R&D Ltd | Antibodies |
EP1675620B1 (en) | 2003-10-09 | 2019-05-08 | Ambrx, Inc. | Polymer derivatives |
TR201809892T4 (tr) | 2003-11-05 | 2018-07-23 | Roche Glycart Ag | Fc reseptörüne bağlanma afinitesi ve artırılmış efektör fonksiyonu bulunan antijen bağlayan moleküller. |
JP4889505B2 (ja) | 2004-02-02 | 2012-03-07 | アンブレツクス・インコーポレイテツド | 被修飾されたヒト成長ホルモンポリペプチドおよびこれらの使用 |
WO2007003041A1 (en) | 2005-07-01 | 2007-01-11 | John Schrader | Methods of isolating cells and generating monoclonal antibodies |
KR101460932B1 (ko) | 2005-08-26 | 2014-11-12 | 로슈 글리카트 아게 | 변형된 세포 신호 활성을 가진 개질된 항원 결합 분자 |
MX2008014692A (es) | 2006-05-19 | 2009-08-18 | Alder Biopharmaceuticals Inc | Metodo de cultivo para obtener una poblacion clonal de celulas b especificas de antigeno. |
EP2271673B1 (en) | 2008-03-26 | 2016-02-24 | Cellerant Therapeutics, Inc. | Cytokine receptors associated with myelogenous haematological proliferative disorders and uses thereof |
MA33198B1 (fr) | 2009-03-20 | 2012-04-02 | Genentech Inc | Anticorps anti-her di-spécifiques |
EP2400298B1 (en) | 2010-05-28 | 2013-08-14 | F.Hoffmann-La Roche Ag | Single B-cell cultivation method and specific antibody production |
US9873918B2 (en) | 2011-08-11 | 2018-01-23 | Albert Einstein College Of Medicine, Inc. | Treatment of acute myeloid leukemia and myelodysplastic syndromes |
US20150315279A1 (en) * | 2012-12-21 | 2015-11-05 | Cellerant Therapeutics, Inc. | Antibodies that bind membrane-bound il1rap |
US10126304B2 (en) | 2013-01-16 | 2018-11-13 | George Mason Research Foundation, Inc. | Binding domain mapping |
GB201413913D0 (en) * | 2014-08-06 | 2014-09-17 | Cantargia Ab | Novel antibodies and uses thereof |
EP3313887A2 (en) | 2015-06-26 | 2018-05-02 | MAB Discovery GmbH | Monoclonal anti-il-1racp antibodies |
EP3401332A1 (en) | 2017-05-08 | 2018-11-14 | MAB Discovery GmbH | Anti-il-1r3 antibodies for use in inflammatory conditions |
-
2016
- 2016-05-06 EP EP16168617.5A patent/EP3241845A1/en not_active Withdrawn
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- 2017-05-08 CN CN201780041725.7A patent/CN109415442B/zh active Active
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- 2017-05-08 SG SG11201809764XA patent/SG11201809764XA/en unknown
- 2017-05-08 MX MX2018013517A patent/MX2018013517A/es unknown
- 2017-05-08 CN CN202211533197.6A patent/CN116178548A/zh active Pending
-
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- 2018-10-26 ZA ZA2018/07167A patent/ZA201807167B/en unknown
- 2018-11-05 MX MX2023002554A patent/MX2023002554A/es unknown
-
2021
- 2021-08-24 US US17/410,153 patent/US20220089751A1/en active Pending
-
2022
- 2022-03-03 JP JP2022032317A patent/JP7480199B2/ja active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1934072A (zh) * | 2004-01-30 | 2007-03-21 | 派普林生物脂股份有限公司 | 治疗和载体分子 |
CN102639565A (zh) * | 2009-08-21 | 2012-08-15 | 坎塔吉亚有限责任公司 | Il1rap在急性和慢性髓细胞样白血病细胞上的表达 |
CN102939304A (zh) * | 2010-04-09 | 2013-02-20 | 诺维信生物制药丹麦公司 | 白蛋白衍生物和变体 |
CN103459424A (zh) * | 2011-01-19 | 2013-12-18 | 坎塔吉亚有限责任公司 | 抗il1rap抗体及其治疗人类的用途 |
CN103492416A (zh) * | 2011-04-15 | 2014-01-01 | 默克专利股份公司 | 用于癌症中使用的抗il-1r1抑制剂 |
WO2012177595A1 (en) * | 2011-06-21 | 2012-12-27 | Oncofactor Corporation | Compositions and methods for the therapy and diagnosis of cancer |
WO2015132602A1 (en) * | 2014-03-05 | 2015-09-11 | Cantargia Ab | Anti human interleukin-1 receptor accessory protein (il1 rap) antibodies and uses thereof |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110382002A (zh) * | 2017-03-09 | 2019-10-25 | Mab发现股份有限公司 | 特异性结合人il-1r7的抗体 |
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