CN106794245A - 肿瘤靶向性il‑2变体免疫细胞因子和针对人pd‑l1的抗体的组合疗法 - Google Patents
肿瘤靶向性il‑2变体免疫细胞因子和针对人pd‑l1的抗体的组合疗法 Download PDFInfo
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Abstract
本发明涉及特定的肿瘤靶向性IL‑2变体免疫细胞因子与特定的结合人PD‑L1的抗体的组合疗法。
Description
本发明涉及特定的肿瘤靶向性IL-2变体免疫细胞因子与特定的结合人PD-L1的抗体的组合疗法。
发明背景
癌症是经济发达国家中死亡的首位原因和发展中国家中死亡的第二位原因。尽管有化疗的最新进展和目标在于在分子水平上干预癌细胞中生长信号的转导和调节的药剂的开发,具有晚期癌症的患者的预后一般仍然较差。因此,对于开发能添加至现有治疗以在没有引起不可接受的毒性的情况下延长存活的新疗法存在持续且迫切的医学需求。
IL-2和基于肿瘤靶向性IL-2的免疫细胞因子
白介素2(IL-2)是一种活化淋巴细胞和天然杀伤(NK)细胞的细胞因子。IL-2已经显示出具有抗肿瘤活性;然而,高水平的IL-2引起肺毒性,而且IL-2的抗肿瘤活性受到多种抑制性反馈环限制。
基于它的抗肿瘤功效,高剂量IL-2(阿地白介素,以销售)治疗已经在美国批准用于具有转移性肾细胞癌(RCC)和恶性黑素瘤的患者,以及在欧盟用于具有转移性RCC的患者。然而,作为IL-2的作用模式的后果,IL-2的系统性和非靶向性应用可能经由诱导T调节细胞和AICD而可观地损害抗肿瘤免疫力。系统性IL-2治疗的另一项担忧涉及静脉内施用后的严重副作用,包括严重的心血管,肺水肿,肝,胃肠(GI),神经学,和血液学事件(Proleukin(aldesleukin)Summary of Product Characteristics[SmPC]:http://www.medicines.org.uk/emc/medicine/19322/SPC/(accessed May 27,2013))。尽管以亚最佳的治疗结果为代价,已经在患者中测试了低剂量IL-2方案。总之,如果能克服与其应用有关的缺点的话,利用IL-2的治疗性办法对于癌症疗法可能是有用的。包含肿瘤靶向性抗原结合模块和基于IL-2的效应器模块的免疫缀合物记载于例如WO 2012/146628和WO2012/107417。
PD-L1和PD-L1抗体
对T细胞共刺激或提供两种截然不同的信号是一种关于抗原呈递细胞(APC)对静息T淋巴细胞的淋巴细胞活化的广泛公认的模型。Lafferty等人,Aust.J.Exp.Biol.Med.Sci.53:27-42(1975)。
此模型进一步提供了自身与非自身的辨别和免疫耐受性。Bretscher等人,Science 169:1042-1049(1970);Bretscher,P.A.,P.N.A.S.USA 96:185-190(1999);Jenkins等人,J.Exp.Med.165:302-319(1987)。在主要组织相容性复合体(MHC)的背景中呈递的外来抗原肽的识别后,第一信号,或抗原特异性信号经由T细胞受体(TCR)转导。第二或共刺激信号通过抗原呈递细胞(APC)上表达的共刺激分子投递至T细胞,并且诱导T细胞以促进克隆扩充,细胞因子分泌和效应器功能。Lenschow等人,Ann.Rev.Immunol.14:233(1996)。在缺乏共刺激的情况中,T细胞能对抗原刺激变得不应,不发起有效的免疫应答,并且进一步可以导致对外来抗原的耐受性或耗竭。
简单的两信号模型可能过度简化,因为TCR信号的强度实际上对T细胞活化和分化具有定量影响。Viola等人,Science 273:104-106(1996);Sloan-Lancaster,Nature 363:156-159(1993)。而且,如果TCR信号强度高的话,T细胞活化甚至能在共刺激信号缺失下发生。更为重要的是,T细胞接受正和负第二共刺激信号两者。此类正和负信号的调节对于在维持免疫耐受性和防止自身免疫的同时使宿主的保护性免疫应答最大化是至关重要的。
负第二信号对于诱导T细胞耐受性似乎是必需的,而正信号促进T细胞活化。虽然简单的两信号模型仍然为未免疫淋巴细胞提供有效解释,但是宿主的免疫应答是一个动态过程,并且也可以对抗原暴露的T细胞提供共刺激信号。
共刺激的机制是治疗学方面感兴趣的,因为已经显示了共刺激信号的操作提供增强或终止基于细胞的免疫应答的手段。最近,已经发现了T细胞功能障碍或无反应性与抑制性受体(编程性死亡1多肽(PD-1))的诱导且持续的表达并行发生。因此,靶向PD-1和经由与PD-1的相互作用发信号的其它分子,诸如编程性死亡配体1(PD-Ll)和编程性死亡配体2(PD-L2)的治疗剂是强烈感兴趣的领域。已经提出抑制PD-1信号传导作为增强T细胞免疫以治疗癌症(例如肿瘤免疫)和感染(包括急性和慢性感染二者,例如持久的)的手段。然而,既然针对此途径中的靶物的最佳治疗剂仍然有待商品化,那么存在重大的未满足的医疗需求。针对PD-L1的抗体记载于例如WO 2010/077634。
发明概述
本发明包含肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体的组合疗法,用于治疗癌症或肿瘤,用于预防或治疗转移,用于治疗炎性疾病,用于治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于刺激免疫应答或功能,诸如T细胞活性。
本发明包含肿瘤靶向性IL-2变体免疫细胞因子制造用于治疗癌症或肿瘤,用于预防或治疗转移,用于治疗炎性疾病,用于治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于刺激免疫应答或功能,诸如T细胞活性的药物的用途,其中该肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用。
本发明包含结合人PD-L1的抗体制造用于治疗癌症或肿瘤,用于预防或治疗转移,用于治疗炎性疾病,用于治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于刺激免疫应答或功能,诸如T细胞活性的药物的用途,其中该结合人PD-L1的抗体与肿瘤靶向性IL-2变体免疫细胞因子组合施用。
本发明包含治疗癌症或肿瘤的方法,预防或治疗转移的方法,治疗炎性疾病的方法,治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展的方法,或刺激免疫应答或功能,诸如T细胞活性的方法,该方法包括施用肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体的组合疗法。
组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体或其抗原结合片段,和具有降低的对IL-2受体的α亚基的结合亲和力(与野生型IL-2,例如SEQ ID NO:2所示人IL-2相比)的IL-2突变体,特别是人IL-2的突变体,诸如包含下述各项的IL-2:
i)选自与SEQ ID NO:2所示人IL-2的残基42,45和72对应的位置的1,2或3个位置处的1,2或3处氨基酸替代,例如3个位置处的3处替代,例如具体的氨基酸替代F42A,Y45A和L72G;或
ii)i)中所列特征加上与SEQ ID NO:2所示人IL-2残基3对应的位置处的氨基酸替代,例如具体的氨基酸替代T3A;或
iii)与SEQ ID NO:2所示人IL-2残基3,42,45和72对应的位置处的4处氨基酸替代,例如具体的氨基酸替代T3A,F42A,Y45A和L72G。
组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体的重链可变域和轻链可变域和由两个亚基组成且包含促进两条不相同多肽链异二聚化的修饰的Fc域,和
具有降低的对IL-2受体的α亚基的结合亲和力(与野生型IL-2,例如SEQ ID NO:2所示人IL-2相比)的IL-2突变体,特别是人IL-2的突变体,诸如包含下述各项的IL-2:
i)选自与SEQ ID NO:2所示人IL-2残基42,45和72对应的位置的1,2或3个位置处的1,2或3处氨基酸替代,例如3个位置处的3处替代,例如具体的氨基酸替代F42A,Y45A和L72G;或
ii)i)中所列特征加上与SEQ ID NO:2所示人IL-2残基3对应的位置处的氨基酸替代,例如具体的氨基酸替代T3A;或
iii)与SEQ ID NO:2所示人IL-2残基3,42,45和72对应的位置处的4处氨基酸替代,例如具体的氨基酸替代T3A,F42A,Y45A和L72G。
该抗体可结合癌胚抗原(CEA)或成纤维细胞活化蛋白(FAP)作为该抗体的靶物,使得该肿瘤靶向性IL-2变体免疫细胞因子是CEA靶向性IL-2变体免疫细胞因子或FAP靶向性IL-2变体免疫细胞因子,如此具有免疫细胞因子的抗CEA抗体或抗FAP抗体构件。
促进异二聚化的Fc域修饰可以是节-入-穴修饰,包含Fc域的亚基之一中的节修饰和Fc域的两个亚基之另一中的穴修饰,或介导静电操纵效应(electrostatic steeringeffect)的修饰,包含将两条多肽链的界面处的一个或多个氨基酸残基用带电荷的氨基酸残基替换,例如一个亚基上的DD突变(例如K392D,K409D;EU编号方式)和另一个亚基上的KK突变(例如D356K,D399K;EU编号方式)。人IgG1 Fc区的一种例示性序列如SEQ ID NO:1所示。
组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子可以是CEA靶向性IL-2变体免疫细胞因子,其可以包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列;或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,
或FAP靶向性IL-2变体免疫细胞因子,其可以包含
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列。
组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
在多个实施方案中,组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子是
CEA靶向性IL-2变体免疫细胞因子,其特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,
或是FAP靶向性IL-2变体免疫细胞因子,其特征在于包含
a)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
c)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列,
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
在一个实施方案中,组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子的特征在于包含
a)SEQ ID NO:84,SEQ ID NO:86和SEQ ID NO:88的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
在一个实施方案中,组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
在一个实施方案中,上文所述肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体的组合疗法用于治疗癌症或肿瘤。所述癌症或肿瘤可以呈递肿瘤细胞上或肿瘤细胞环境中的抗原。所述组合疗法的靶物可以是肿瘤细胞上或肿瘤细胞环境中呈递的。所述癌症或肿瘤可以表达或过表达CEA或FAP。所述治疗可以是实体瘤的。所述实体瘤可以表达或过表达CEA或FAP。所述治疗可以是癌症的。所述癌症可以表达或过表达CEA或FAP。所述癌症可以选自下组:结直肠癌,头和颈癌,非小细胞肺癌,乳腺癌,胰腺癌,肝癌和胃癌。所述癌症可以选自下组:肺癌,结肠癌,胃癌,乳腺癌,头和颈癌,皮肤癌,肝癌,肾癌,前列腺癌,胰腺癌,脑癌和骨骼肌癌。
在一个实施方案中,上文所述肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体的组合疗法用于预防或治疗转移。
在一个实施方案中,上文所述肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体的组合疗法用于治疗炎性疾病。
在一个实施方案中,上文所述肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体的组合疗法用于治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展。
在一个实施方案中,上文所述肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体的组合疗法用于刺激免疫应答或功能,诸如T细胞活性。
本发明包含一种肿瘤靶向性IL-2变体免疫细胞因子,其中如上所述该免疫细胞因子与结合人PD-L1的抗体组合施用,用于
i)在表达该免疫细胞因子的靶物的肿瘤中抑制肿瘤生长;
ii)增强具有表达该免疫细胞因子的靶物的肿瘤的受试者的中值和/或总体存活,
其中该靶物可以是在肿瘤细胞上或肿瘤细胞环境中呈递的。
本发明包含一种CEA靶向性IL-2变体免疫细胞因子,其中该免疫细胞因子与结合人PD-L1的抗体组合施用,用于
i)在表达CEA的肿瘤中抑制肿瘤生长;
ii)增强具有表达CEA的肿瘤的受试者的中值和/或总体存活;
其中组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列;或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
本发明包含一种FAP靶向性IL-2变体免疫细胞因子,其中该免疫细胞因子与结合人PD-L1的抗体组合施用,用于
i)在表达FAP的肿瘤中抑制肿瘤生长;
ii)增强具有表达FAP的肿瘤的受试者的中值和/或总体存活;
其中组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列;或
b)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
c)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
d)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列,
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
本发明包含一种肿瘤靶向性IL-2变体免疫细胞因子,其用于治疗具有表达CEA的肿瘤或特征在于表达或过表达CEA的肿瘤,具有表达FAP的肿瘤或特征在于表达或过表达FAP的肿瘤或具有与表达或过表达CEA或FAP有关的肿瘤的患者,且其中该免疫细胞因子与结合人PD-L1的抗体组合施用,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列,
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
在一个实施方案中,免疫细胞因子的抗体成分或抗体属于人IgG1亚类或人IgG4亚类。
本发明包含:
A)一种用于
i)在表达CEA的肿瘤中或在表达FAP的肿瘤中抑制肿瘤生长;
ii)增强具有表达CEA的肿瘤或表达FAP的肿瘤的受试者的中值和/或总体存活的方法,其中CEA靶向性IL-2变体免疫细胞因子或FAP靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用,
或
B)一种治疗具有表达CEA的肿瘤或特征在于表达或过表达CEA的肿瘤,或表达FAP的肿瘤或特征在于表达或过表达FAP的肿瘤的患者的方法,且其中CEA靶向性IL-2变体免疫细胞因子或FAP靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用,
其中组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列;或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,
或其中组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子特征在于包含
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列,
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
本文所述抗体和肿瘤靶向性IL-2变体免疫细胞因子的组合疗法对于需要靶向肿瘤细胞上或肿瘤细胞环境中呈递的抗原的疗法的患者显示好处。本文所述抗体和CEA靶向性IL-2变体免疫细胞因子的组合疗法对于需要CEA靶向性疗法的患者显示好处。本文所述抗体和FAP靶向性IL-2变体免疫细胞因子的组合疗法对于需要FAP靶向性疗法的患者显示好处。依照本发明的肿瘤靶向性IL-2变体免疫细胞因子在针对表达靶物的肿瘤的肿瘤生长抑制性活性方面显示功效且格外在与本文所述抗PD-L1抗体组合治疗癌症和转移方面尤其有用。依照本发明的肿瘤靶向性IL-2变体免疫细胞因子在增强具有表达靶物的肿瘤的受试者的中值和/或总体存活方面显示功效且格外在与本文所述抗PD-L1抗体组合治疗癌症和转移方面尤其有用。依照本发明的特定的CEA靶向性IL-2变体免疫细胞因子在针对表达CEA的肿瘤的肿瘤生长抑制性活性方面显示功效且格外在与本文所述特定的抗PD-L1抗体组合治疗癌症和转移方面尤其有用。依照本发明的特定的CEA靶向性IL-2变体免疫细胞因子在增强具有表达CEA的肿瘤的受试者的中值和/或总体存活方面显示功效且格外在与本文所述特定抗PD-L1抗体组合治疗癌症和转移方面尤其有用。依照本发明的特定的FAP靶向性IL-2变体免疫细胞因子在针对表达FAP的肿瘤的肿瘤生长抑制性活性方面显示功效且格外在与本文所述特定的抗PD-L1抗体组合治疗癌症和转移方面尤其有用。依照本发明的特定的FAP靶向性IL-2变体免疫细胞因子在增强具有表达FAP的肿瘤的受试者的中值和/或总体存活方面显示功效且格外在与本文所述特定的抗PD-L1抗体组合治疗癌症和转移方面尤其有用。依照本发明的特定的结合人PD-L1的抗体在增强具有表达CEA的肿瘤或表达FAP的肿瘤的受试者的中值和/或总体存活方面显示功效且格外在分别与本文所述特定的CEA靶向性IL-2变体免疫细胞因子或FAP靶向性IL-2变体免疫细胞因子组合治疗癌症和转移方面尤其有用。
附图说明
图1。呈现CEA-IL2v和PD-L1单抗作为单一药剂及在组合设置中的一项功效实验的结果。将MC38-CEA转染子结直肠癌细胞系注射入Black 6-huCEA-hu FcγRIII tg小鼠中的门静脉以研究肝转移性模型中的存活。图例中指出以mg/kg计的每只小鼠注射的抗体的量。
图2。呈现CEA-IL2v和PD-L1单抗作为单一药剂及在组合设置中的一项功效实验的结果。将MC38-CEA转染子结直肠癌细胞系皮下注射入Black 6-huCEA-huFcγRIII tg小鼠以研究皮下模型中的肿瘤生长抑制,使用测径器测量肿瘤尺寸。图例中指出以mg/kg计的每只小鼠注射的抗体的量。
图3。呈现CEA-IL2v和PD-L1单抗作为单一药剂及在组合设置中的一项功效实验的结果。将Panc02-H7-CEA转染子胰腺癌细胞系注射入Black 6-huCEA-huFcγRIII tg小鼠中的胰腺以研究胰腺原位同基因模型中的存活。图例中指出以mg/kg计的每只小鼠注射的抗体的量。
图4。呈现(A)CEA靶向性CEA-IL2v和PD-L1单抗或非靶向性DP47-IL2v和PD-L1单抗作为单一药剂及在组合设置中的一项功效实验的结果。将Panc02-H7-CEA转染子胰腺癌细胞系注射入Black 6-huCEA-huFcγRIII tg小鼠中的胰腺以研究胰腺原位同基因模型中的存活。图例中指出以mg/kg计的每只小鼠注射的抗体的量。(B)对不同处理组显示第一次施用后IL2v的血清水平。
图5。呈现体外研究的结果,显示人PMBC和人A549肺癌细胞系的共培养物,CEA-IL2v处理以浓度依赖性方式诱导A549细胞上的PD-L1上调。在单独(A)或以1:1(B)或10:1(C)的E:T比在PBMC存在下用10nM或100nM CEA-IL2v处理后通过流式细胞术分析A549肿瘤细胞上的PD-L1表达。
图6。呈现FAP-IL2v和PD-L1单抗作为单一药剂及在组合设置中的一项功效实验的结果。将MC38-FAP转染子结直肠癌细胞系皮下注射入Black 6小鼠以研究皮下模型中的肿瘤生长抑制。(A)肿瘤尺寸(使用测径器测量);(B)存活。n=14。
发明详述
IL-2途径
IL-2在体外及在体内扩充及活化淋巴细胞和NK细胞群体的能力解释了IL-2的抗肿瘤效果。然而,作为防止过度免疫应答和潜在自身免疫的一种调节机制,IL-2导致活化诱导的细胞死亡(AICD)且使得活化的T细胞对Fas介导的凋亡易感。
而且,IL-2牵涉外周CD4+CD25+T调节细胞的维持和扩充(Fontenot JD,RasmussenJP,Gavin MA等人,A function for interleukin 2 in Foxp3 expressing regulatory Tcells.Nat Immunol.2005;6:1142-1151;D'Cruz LM,Klein L,Development and functionof agonist-induced CD25+Foxp3+regulatory T cells in the absence ofinterleukin 2 signaling.Nat Immunol.2005;6:1152-1159;Maloy KJ,Powrie F,Fueling regulation:IL-2 keeps CD4+Treg cells fit.Nat Immunol.2005;6:1071-1072)。这些细胞阻抑效应T细胞或是经由细胞-细胞接触或是经由免疫阻抑性细胞因子,诸如IL-10或转化生长因子(TGF)-β的释放来破坏自身或靶物。T调节细胞的消减显示出增强IL-2诱导的抗肿瘤免疫力(Imai H,Saio M,Nonaka K等人,Depletion of CD4+CD25+regulatory T cells enhances interleukin-2-induced antitumor immunity in amouse model of colon adenocarcinoma.Cancer Sci.2007;98:416-423)。
IL-2还在CD8+T细胞的初次和二次扩充(primary and secondary expansion)期间在记忆CD8+T-细胞分化中发挥重大作用。IL-2看来负责初次抗原攻击后效应器功能的最佳扩充和生成。在大多数抗原特异性CD8+T细胞通过凋亡而消失的免疫应答的收缩阶段期间,IL-2信号能够挽救CD8+T细胞免于细胞死亡及提供记忆CD8+T-细胞的持久增多。在记忆阶段,可以通过施用外源IL-2来提高CD8+T细胞频率。而且,只有在初始引发期间接受了IL-2信号的CD8+T细胞能够在更新的抗原攻击后介导有效的二次扩充。如此,免疫应答的不同阶段期间的IL-2信号在优化CD8+T细胞功能方面是关键的,由此影响这些T细胞的初次和二次应答二者(Adv Exp Med Biol.2010;684:28-41.The role of interleukin-2 inmemory CD8 cell differentiation.Boyman O1,Cho JH,Sprent J)。
基于它的抗肿瘤功效,高剂量IL-2(阿地白介素,以销售)治疗已经在美国批准用于具有转移性肾细胞癌(RCC)和恶性黑素瘤的患者,以及在欧盟用于具有转移性RCC的患者。然而,作为IL-2的作用模式的后果,IL-2的系统性和非靶向性应用可能经由诱导T调节细胞和AICD而可观地损害抗肿瘤免疫力。系统性IL-2治疗的另一项担忧涉及静脉内施用后的严重副作用,包括严重的心血管,肺水肿,肝,胃肠(GI),神经学,和血液学事件(Proleukin(aldesleukin)Summary of Product Characteristics[SmPC]:http://www.medicines.org.uk/emc/medicine/19322/SPC/(accessed May 27,2013))。尽管以亚最佳的治疗结果为代价,已经在患者中测试了低剂量IL-2方案。总之,如果能克服与其应用有关的缺点的话,利用IL-2的治疗性办法对于癌症疗法可能是有用的。
包含肿瘤靶向性抗原结合模块(例如针对肿瘤细胞上或肿瘤细胞环境中呈递的抗原,包括癌胚抗原(CEA)和成纤维细胞活化蛋白(FAP)的)和基于IL-2的效应器模块(例如包括突变体IL-2)的免疫缀合物记载于例如WO 2012/146628和WO 2012/107417。
特别地,已经设计了突变体IL-2(例如称作IL-2qm的四重突变体),通过消除对IL-2Rα亚基(CD25)的结合来克服野生型IL-2(例如阿地白介素)或第一代基于IL-2的免疫细胞因子的限制。已经将此突变体IL-2qm偶联至多种肿瘤靶向性抗体,诸如针对CEA的人源化抗体和针对FAP的抗体。另外,已经修饰抗体的Fc区以阻止结合Fcγ受体和C1q复合物。所得肿瘤靶向性IL-2变体免疫细胞因子(例如CEA靶向性IL-2变体免疫细胞因子和FAP靶向性IL-2变体免疫细胞因子)已经在非临床体外和体内实验中显示出能够消除肿瘤细胞。
如此,所得免疫细胞因子代表一类肿瘤靶向性IL-2变体免疫细胞因子,它们通过消除对IL-2Rα亚基(CD25)的结合而解决了IL-2的缺点:
野生型IL-2和IL-2变体的特性
术语“IL-2”或“人IL-2”指人IL-2蛋白,包括野生型和在野生型IL-2的氨基酸序列中包含一处或多处突变的变体,例如如SEQ ID NO:2中所示,具有C125A替代以避免形成二硫化物桥接的IL-2二聚体。也可以突变IL-2来去除N-和/或O-糖基化位点。
术语“CEA”指癌胚抗原,包括它的免疫原性表位CAP-1和CAP-2,一种在多种肿瘤类型的细胞表面上高表达的蛋白质。
术语“FAP”指成纤维细胞活化蛋白,一种在细胞表面上表达且在多种肿瘤类型的肿瘤细胞上或在多种肿瘤类型的肿瘤细胞环境中呈递的蛋白质。
PD-1/PD-L1/PD-L2途径
一种调节T细胞活化的重要负共刺激信号是由编程性死亡-1受体(PD-1)(CD279)及其配体结合配偶PD-L1(B7-H1,CD274;SEQ ID NO:88)和PD-L2(B7-DC,CD273)提供的。PD-1的负调节作用是通过PD-1敲除(Pdcd1-/-)揭示的,其倾向于自身免疫。Nishimura等人,Immunity 11:141-51(1999);Nishimura等人,Science 291:319-22(2001)。PD-1与CD28和CTLA-4有关,但是缺少容许同二聚化的近膜半胱氨酸。PD-1的胞质域含有基于免疫受体酪氨酸的抑制性基序(ITIM,V/IxYxxL/V)。PD-1只结合PD-L1和PD-L2。Freeman等人,J.Exp.Med.192:1-9(2000);Dong等人,Nature Med.5:1365-1369(1999);Latchman等人,Nature Immunol.2:261-268(2001);Tseng等人,J.Exp.Med.193:839-846(2001)。
PD-1能在T细胞,B细胞,天然杀伤T细胞,活化的单核细胞和树突细胞(DC)上表达。PD-1由活化的但不由未刺激的人CD4+和CD8+T细胞,B细胞和髓样细胞表达。这与更受局限的CD28和CTLA-4表达形成对比。Nishimura等人,Int.Immunol.8:773-80(1996);Boettler等人,J.Virol.80:3532-40(2006)。已经自活化的人T细胞克隆了PD-1的至少4种变体,包括缺少(i)外显子2,(ii)外显子3,(iii)外显子2和3,或(iv)外显子2至4的转录物。Nielsen等人,Cell.Immunol.235:109-16(2005)。除PD-1Δex3外,在静息外周血单个核细胞(PBMC)中所有变体以与全长PD-1相似的水平表达。所有变体的表达在用抗CD3和抗CD28活化人T细胞后显著诱导。PD-1Δex3变体缺少跨膜域,且类似可溶性CTLA-4,其在自身免疫中发挥重要作用。Ueda等人,Nature 423:506-11(2003)。此变体在具有类风湿性关节炎的患者的滑液和血清中富集。Wan等人,J.Immunol.177:8844-50(2006)。
两种PD-1配体区别在于它们的表达样式。PD-L1在小鼠T和B细胞,CD,巨噬细胞,间充质干细胞和骨髓衍生肥大细胞上组成性表达。Yamazaki等人,J.Immunol.169:5538-45(2002)。PD-L1在广泛的非造血细胞(例如角膜,肺,血管上皮,肝非实质细胞,间充质干细胞,胰岛,胎盘合胞滋养层,角质形成细胞,等)上表达[Keir等人,Annu.Rev.Immunol.26:677-704(2008)],而且在活化后在多种细胞类型上上调。I型和II型干扰素IFN均上调PD-L1。Eppihimer等人,Microcirculation 9:133-45(2002);Schreiner等人,J.Neuroimmunol.155:172-82(2004)。细胞系中的PD-L1表达在MyD88,TRAF6和MEK受到抑制时降低。Liu等人,Blood 110:296-304(2007)。JAK2也已经与PD-L1诱导联系起来。Lee等人,FEBS Lett.580:755-62(2006);Liu等人,Blood 110:296-304(2007)。磷酸酶和张力蛋白同系物(PTEN)(一种修饰磷脂酰肌醇3-激酶(PI3K)和Akt信号传导的细胞磷酸酶)的丧失或抑制提高癌症中的转录后PD-L1表达。Parsa等人,Nat.Med.13:84-88(2007)。
PD-L2表达比PD-L1更受局限。PD-L2在DC,巨噬细胞,和骨髓衍生肥大细胞上可诱导表达。PD-L2还在约二分之一至三分之二的静息腹膜B1细胞上表达,但是不在常规B2B细胞上表达。Zhong等人,Eur.J.Immunol.37:2405-10(2007)。PD-L2+B1细胞结合磷脂酰胆碱,而且对于针对细菌抗原的先天免疫应答可能是重要的。IFN-γ对PD-L2的诱导部分依赖于NF-κB。Liang等人,Eur.J.Immunol.33:2706-16(2003)。PD-L2还可以在单核细胞和巨噬细胞上受GM-CF,IL-4和IFN-γ诱导。Yamazaki等人,J.Immunol.169:5538-45(2002);Loke等人,PNAS 100:5336-41(2003)。
PD-1信号传导通常具有比对细胞增殖要大的对细胞因子生成的影响,对IFN-γ,TNF-α和IL-2生成有显著影响。PD-1介导的抑制性信号传导还依赖于TCR信号传导的强度,在低水平的TCR刺激投递较大的抑制。这种降低可以通过经由CD28的共刺激[Freeman等人,J.Exp.Med.192:1027-34(2000)]或IL-2的存在[Carter等人,Eur.J.Immunol.32:634-43(2002)]来克服。
越来越多的证据说明经由PD-L1和PD-L2的信号传导可能是双向的。就是说,在修饰TCR或BCR信号传导以外,信号传导还可以投递回到表达PD-L1和PD-L2的细胞。虽然用自具有瓦尔登斯特伦(Waldenstrom)氏巨球蛋白血症的患者分离的天然人抗PD-L2抗体处理树突细胞未发现上调MHC II或B7共刺激分子,但是此类细胞确实生成极大量的促炎症细胞因子,特别是TNF-α和IL-6,且刺激T细胞增殖。Nguyen等人,J.Exp.Med.196:1393-98(2002)。用这种抗体处理小鼠还(1)增强对移植的b16黑素瘤抗性和快速诱导肿瘤特异性CTL。Radhakrishnan等人,J.Immunol.170:1830-38(2003);Radhakrishnan等人,CancerRes.64:4965-72(2004);Heckman等人,Eur.J.Immunol.37:1827-35(2007);(2)阻断变应性哮喘小鼠模型中气道炎性疾病发生。Radhakrishnan等人,J.Immunol.173:1360-65(2004);Radhakrishnan等人,J.Allergy Clin.Immunol.116:668-74(2005)。
关于逆信号传导入树突细胞(“DC”)的进一步证据源自用可溶性PD-1(与Ig恒定区融合的PD-1EC域-“s-PD-1”)培养的骨髓衍生DC的研究。Kuipers等人,Eur.J.Immunol.36:2472-82(2006)。此sPD-1以通过施用抗PD-1可逆的方式抑制DC活化且提高IL-10生成。
另外,数项研究显示了PD-L1或PD-L2的一种不依赖于PD-1的受体。B7.1早就鉴定为PD-L1的结合配偶。Butte等人,Immunity 27:111-22(2007)。化学交联研究提示PD-L1和B7.1能经由它们的IgV样域相互作用。B7.1:PD-L1相互作用能诱导进入T细胞的抑制性信号。通过B7.1连接CD4+T细胞上的PD-L1或通过PD-L1连接CD4+T细胞上的B7.1投递抑制性信号。缺少CD28和CTLA-4的T细胞显示在通过抗CD3加B7.1包被珠刺激时降低的增殖和细胞因子生成。在缺少B7.1的所有受体(即CD28,CTLA-4和PD-L1)的T细胞中,T细胞增殖和细胞因子生成不再受抗CD3加B7.1包被珠抑制。这指示B7.1在CD28和CTLA-4缺失下经由T细胞上的PD-L1特异性起作用。类似地,缺少PD-1的T细胞在抗CD3加PD-L1包被珠存在下刺激时显示降低的增殖和细胞因子生成,证明PD-L1连接T细胞上的B7.1的抑制效果。当T细胞缺少PD-L1的所有已知受体(即没有PD-1和B7.1)时,T细胞增殖不再受抗CD3加PD-L1包被珠削弱。如此,PD-L1能经由B7.1或PD-1任一对T细胞发挥抑制效果。
B7.1和PD-L1之间的直接相互作用提示当前关于共刺激的理解是不全面的,而且强调对这些分子在T细胞上的表达的意义。关于PD-L1-/-T细胞的研究指出T细胞上的PD-L1能下调T细胞的细胞因子生成。Latchman等人,Proc.Natl.Acad.Sci.USA 101:10691-96(2004)。因为PD-L1和B7.1均在T细胞,B细胞,DC和巨噬细胞上表达,所以这些细胞类型上的B7.1和PD-L1之间的定向相互作用是有可能的。另外,非造血细胞上的PD-L1可能与B7.1以及T细胞上的PD-1相互作用,这提出了PD-L1是否参与它们的调节的问题。关于B7.1:PD-L1相互作用的抑制性作用的一种可能的解释是T细胞PD-L1可能诱捕或隔离APC B7.1,不得与CD28相互作用。
结果是,拮抗经由PD-L1的信号传导(包括阻断PD-L1与PD-1,B7.1任一或二者相互作用,由此阻止PD-L1将负共刺激信号发送至T细胞和其它抗原呈递细胞)很可能增强响应感染(例如急性和慢性)的免疫和肿瘤免疫。另外,本发明的抗PD-L1抗体可以与PD-1:PD-L1信号传导的其它成分的拮抗剂(例如拮抗性抗PD-1和抗PD-L2抗体)组合。
术语“人PD-L1”指人蛋白质PD-L1(SEQ ID NO:4,PD-1信号传导,通常)。如本文中使用的,“结合人PD-L1”或“特异性结合人PD-L1”或“抗PD-L1抗体”指抗体以KD值1.0x10- 8mol/l或更低(在一个实施方案中,以KD值1.0x10-9mol/l或更低)的结合亲和力特异性结合人PD-L1抗原。结合亲和力用标准结合测定法测定,诸如表面等离振子共振技术(GE-Healthcare,Uppsala,Sweden)。如此,如本文中使用的,“结合人PD-L1的抗体”指以KD 1.0x10-8mol/l或更低(在一个实施方案中,1.0x10-8mol/l-1.0x10-13mol/l),在一个实施方案中,以KD 1.0x10-9mol/l或更低(在一个实施方案中,1.0x10-9mol/l-1.0x10- 13mol/l)的结合亲和力特异性结合人PD-L1抗原的抗体。
如本文中详细描述的,发明人发现肿瘤靶向性突变体IL-2在与PD-1/PD-L1途径拮抗剂组合使用时在体内提供卓越的治疗效果。特别地,发明人发现肿瘤靶向性突变体IL-2诸如CEA靶向性IL-2变体免疫细胞因子(称作CEA-IL2v或CEA靶向性IgG-IL-2qm)或FAP靶向性IL-2变体免疫细胞因子(称作FAP-IL2v或FAP靶向性IgG-IL-2qm)在与结合人PD-L1的抗体组合使用时在体内提供卓越的治疗效果。
IL-2扩充及活化淋巴细胞和天然杀伤(NK)细胞的能力支撑IL-2的抗肿瘤活性。设计成消除IL-2对IL-2α亚基(CD25)的结合的IL-2突变体克服IL-2的限制,而且作为肿瘤靶向性IL-2变体免疫细胞因子诸如CEA靶向性IL-2变体免疫细胞因子或FAP靶向性IL-2变体免疫细胞因子的一部分已经显示出能够消除肿瘤细胞。
如本文中描述的,发明人发现肿瘤靶向性IL-2变体免疫细胞因子的体外处理诱导肿瘤细胞上的PD-L1上调。例如,人PBMC和人A549肺癌细胞系的共培养物显示CEA靶向性IL-2变体免疫细胞因子以浓度依赖性方式诱导A549细胞上的PD-L1上调,最有可能是经由IFNγ释放介导的。使用称作“CEA-IL2v”的CEA靶向性IL-2变体免疫细胞因子(对应于具有WO2012/146628,实施例1和2中记载的SEQ ID NO:84,86和88所示序列的基于抗CEA抗体CH1A1A 98/99 2F1和IL-2四重突变体(IL-2qm,SEQ ID NO:3)的CEA靶向性IgG-IL-2qm融合蛋白),CEA-IL2v自身不能够诱导A549肿瘤细胞上的PD-L1(图4)。然而,在PBMC存在下,A549细胞上的PD-L1上调,指示该效果是经由免疫细胞介导的,最有可能是经由IFNγ释放介导的。PD-L1的表达水平随CEA-IL2v浓度升高以及更高的E:T比而升高。已知PD-L1上调经由与PD-1相互作用对NK和T细胞的活性有负面影响。因此通过添加PD-L1阻断性抗体能消除此负反馈环。
如本文中描述的,发明人进一步发现肿瘤靶向性IL-2变体免疫细胞因子的体内处理和PD-L1抑制i)在小鼠肿瘤细胞系的同基因模型中导致与相应的单一药剂疗法相比卓越的肿瘤生长抑制,和ii)在小鼠肿瘤细胞系的同基因模型中导致卓越的组合中值和/或总体存活,特别是在伴随应用时。发起了多项临床前研究来评估肿瘤靶向性IL-2变体免疫细胞因子的鼠源化替代分子与抗小鼠PD-L1替代抗体的组合的体内抗肿瘤功效。例如,发起了临床前研究来评估CEA靶向性IL-2变体免疫细胞因子CEA-IL2v的鼠源化替代分子(称作muCEA-muIL2v)或FAP靶向性IL-2变体免疫细胞因子FAP-IL2v的鼠源化替代分子(称作muFAP-muIL2v)与抗小鼠PD-L1替代抗体(例如具有图11中所示序列的WO 2010/077634中记载的YW243.55.S70 PD-L1muIgG1,其含有DAPG突变以消除FcγR相互作用,或人/小鼠交叉反应性抗PD-L1抗体)的组合的体内抗肿瘤功效。
免疫细胞因子和抗体
本文所述组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子包含结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体或其抗原结合片段,和IL-2突变体,特别是人IL-2的突变体,具有降低的对IL-2受体的α亚基的结合亲和力(与野生型IL-2,例如SEQ ID NO:2所示人IL-2相比),诸如包含下述各项的IL-2:
i)选自与SEQ ID NO:2所示人IL-2残基42,45和72对应的位置的1,2或3个位置处的1,2或3处氨基酸替代,例如3个位置处的3处替代,例如具体的氨基酸替代F42A,Y45A和L72G;或
ii)i)中所列特征加上与SEQ ID NO:2所示人IL-2残基3对应的位置处的氨基酸替代,例如具体的氨基酸替代T3A;或
iii)与SEQ ID NO:2所示人IL-2残基3,42,45和72对应的位置处的4处氨基酸替代,例如具体的氨基酸替代T3A,F42A,Y45A和L72G。
本文所述组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子可以包含结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体的重链可变域和轻链可变域和由两个亚基组成且包含促进两条不相同多肽链异二聚化的修饰的Fc域,和
IL-2突变体,特别是人IL-2的突变体,具有降低的对IL-2受体的α亚基的结合亲和力(与野生型IL-2,例如SEQ ID NO:2所示人IL-2相比),诸如包含下述各项的IL-2:
i)选自与SEQ ID NO:2所示人IL-2残基42,45和72对应的位置的1,2或3个位置处的1,2或3处氨基酸替代,例如3个位置处的3处替代,例如具体的氨基酸替代F42A,Y45A和L72G;或
ii)i)中所列特征加上与SEQ ID NO:2所示人IL-2残基3对应的位置处的氨基酸替代,例如具体的氨基酸替代T3A;或
iii)与SEQ ID NO:2所示人IL-2残基3,42,45和72对应的位置处的4处氨基酸替代,例如具体的氨基酸替代T3A,F42A,Y45A和L72G。
组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子可以包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列;或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列。
在一些实施方案中,组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子包含SEQID NO:84,SEQ ID NO:86和SEQ ID NO:88的多肽序列。
组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子可以包含
a)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
c)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
d)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列。
在一些实施方案中,组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子包含SEQID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列。
这些肿瘤靶向性IL-2变体免疫细胞因子,连同它们的构成部分抗原结合模块,Fc域和效应器模块,作为WO 2012/146628和WO 2012/107417中记载的免疫缀合物的例子描述。例如,具有SEQ ID NOs:84和86和88所示序列的基于抗CEA抗体CH1A1A 98/99 2F1和IL-2四重突变体(qm)(SEQ ID NO:3)的特定免疫细胞因子‘CEA靶向性IgG-IL-2qm融合蛋白’记载于例如WO 2012/146628的实施例1和2。例如,具有SEQ ID NO:79和80和81所示序列的基于抗FAP抗体4B9和IL-2四重突变体(IL-2qm,SEQ ID NO:3)的特定免疫细胞因子‘FAP靶向性IgG-IL-2qm融合蛋白’记载于例如WO 2012/146628的实施例1和2和WO 2012/107417的实施例1。
WO 2012/146628中记载的特定CEA靶向性IL-2变体免疫细胞因子特征在于包含下述本文所述多肽序列:
IL-2突变体 | 氨基酸序列,SEQ ID NO: |
IL-2qm | 3 |
WO 2012/146628和WO 2012/107417中记载的特定FAP靶向性IL-2变体免疫细胞因子特征在于包含下述本文所述多肽序列:
IL-2突变体 | 氨基酸序列,SEQ ID NO: |
IL-2qm | 3 |
如WO 2012/146628中记载的,IL-2突变体具有降低的对IL-2受体α亚基的结合亲和力。α亚基(也称为CD25)与β和γ亚基(也分别称为CD122和CD132)一起形成异二聚体高亲和力IL-2受体,而仅由β-和γ亚基组成的二聚体受体称为中等亲和力IL-2受体。如WO2012/146628中记载的,与野生型IL-2多肽相比,具有降低的对IL-2受体α亚基的结合的IL-2突变体多肽具有降低的诱导调节性T细胞中IL-2信号传导的能力,诱导T细胞中更少的激活诱导的细胞死亡(AICD),且具有降低的体内毒性概况。在肿瘤靶向性IL-2变体免疫细胞因子中使用具有降低毒性的此类IL-2突变体特别有利,其由于存在Fc域具有较长的血清半衰期。与野生型IL-2相比,IL-2突变体可包含至少一处氨基酸突变,该氨基酸突变降低或消除IL-2突变体对IL-2受体α亚基(CD25)的亲和力但保留该IL-2突变体对中等亲和力IL-2受体(由IL-2受体β和γ亚基组成)的亲和力。所述一处或多处氨基酸突变可以是氨基酸替代。IL-2突变体可包含在选自与人IL-2(如SEQ ID NO:2所示)残基42,45和72对应的位置的一个,两个或三个位置处的一处,两处或三处氨基酸替代。IL-2突变体可包含在与人IL-2残基42,45和72对应的位置处的三处氨基酸取代。IL-2突变体可以是人IL2突变体。IL-2突变体可以是包含氨基酸替代F42A,Y45A和L72G的人IL-2。IL-2突变体可另外在与人IL-2第3位对应的位置处包含氨基酸突变,其消除IL-2的O-糖基化位点。特别地,所述另外的氨基酸突变是由丙氨酸残基替换苏氨酸残基的氨基酸替代。可用于本发明的具体的IL-2突变体包含在与人IL-2(如SEQ ID NO:2所示)残基3,42,45和72对应的位置处的四处氨基酸取代。具体的氨基酸替代为T3A,F42A,Y45A和L72G。如WO 2012/146628的实施例中显示的,所述四重突变体IL-2多肽(IL-2qm)展现出没有对CD25的可检测的结合,降低的诱导T细胞中凋亡的能力,降低的诱导T调节细胞中IL-2信号传导的能力,和降低的体内毒性概况。然而,它保留激活效应细胞中IL-2信号传导,诱导效应细胞的增殖和通过NK细胞生成IFN-γ作为次生细胞因子的能力。依照任何上文描述的IL-2突变体可包含另外的突变,其提供别的优点,诸如升高的表达或稳定性。例如,位置125处的半胱氨酸可用中性氨基酸诸如丙氨酸替换以避免形成二硫化物桥接的IL-2二聚体。如此,IL-2突变体可以在与人IL-2的残基125对应的位置处包含另外的氨基酸突变。所述另外的氨基酸突变可以是氨基酸替代C125A。IL-2突变体可包含SEQ ID NO:3的多肽序列。
如WO 2012/146628和WO 2012/107417中记载的,肿瘤靶向性IL-2变体免疫细胞因子的肿瘤靶向可以通过靶向肿瘤细胞上或肿瘤细胞环境中呈递的抗原来实现。如此,所述免疫细胞因子具有抗原结合模块。所述抗原结合模块一般是结合特定抗原决定簇且能够指导其所附接的实体(例如效应器模块和Fc域)到达靶部位,例如到达携带该抗原决定簇的特定类型的肿瘤细胞或肿瘤基质的多肽分子。所述免疫细胞因子能结合例如在肿瘤细胞的表面上,在其它患病细胞的表面上,游离于血液血清中和/或在胞外基质(ECM)中找到的抗原决定簇。所述抗原结合模块可以针对与病理学状况有关的抗原,诸如肿瘤细胞上或肿瘤细胞环境中或在炎症部位呈递的抗原。
肿瘤抗原的非限制性例子包括MAGE,MART-1/Melan-A,gp100,二肽基肽酶IV(DPPIV),腺苷脱氨酶结合蛋白(ADAbp),亲环蛋白(cyclophilin)b,结直肠相关抗原(CRC)-C017-1A/GA733,癌胚抗原(CEA)及其免疫原性表位CAP-1和CAP-2,etv6,aml1,前列腺特异性抗原(PSA)及其免疫原性表位PSA-1,PSA-2和PSA-3,前列腺特异性膜抗原(PSMA),前列腺干细胞抗原(PSCA),MAGE肿瘤抗原家族(例如MAGE-A1,MAGE-A2,MAGE-A3,MAGE-A4,MAGE-A5,MAGE-A6,MAGE-A7,MAGE-A8,MAGE-A9,MAGE-A10,MAGE-A11,MAGE-A12,MAGE-Xp2(MAGE-B2),MAGE-Xp3(MAGE-B3),MAGE-Xp4(MAGE-B4),MAGE-C1,MAGE-C2,MAGE-C3,MAGE-C4,MAGE-C5),GAGE肿瘤抗原家族(例如GAGE-1,GAGE-2,GAGE-3,GAGE-4,GAGE-5,GAGE-6,GAGE-7,GAGE-8,GAGE-9),BAGE,RAGE,LAGE-1,NAG,GnT-V,MUM-1,CDK4,酪氨酸酶,p53,MUC家族,HER2/neu,p21ras,RCAS1,α-胎蛋白,E-钙粘蛋白,α-连环蛋白(catenin),β-连环蛋白和γ-连环蛋白,p120ctn,gp100Pmel117,PRAME,NY-ESO-1,cdc27,腺瘤样结肠息肉蛋白(adenomatous polyposis coli protein,APC),胞衬蛋白(fodrin),连接蛋白(Connexin)37,Ig独特型,p15,gp75,GM2和GD2神经节苷脂,病毒产物诸如人乳头状瘤病毒蛋白,Smad肿瘤抗原家族,lmp-1,P1A,EBV编码的核抗原(EBNA)-1,脑糖原磷酸化酶,SSX-1,SSX-2(HOM-MEL-40),SSX-1,SSX-4,SSX-5,SCP-1和CT-7,以及c-erbB-2。ECM抗原的非限制性例子包括多配体聚糖(syndecan),类肝素酶(heparanase),整联蛋白,骨桥蛋白(osteopontin),link,钙粘蛋白,层粘连蛋白,EGF型层粘连蛋白,凝集素,纤连蛋白,刻缺蛋白(notch),生腱蛋白和matrixin。细胞表面抗原的非限制性例子包括:FAP,Her2,EGFR,IGF-1R,CD22(B细胞受体),CD23(低亲和力IgE受体),CD30(细胞因子受体),CD33(髓样细胞表面抗原),CD40(肿瘤坏死因子受体),IL-6R(IL6受体),CD20,MCSP,和PDGFβR(β血小板衍生的生长因子受体)。在特定的实施方案中,抗原是人抗原。
在某些实施方案中,抗原结合模块针对肿瘤细胞上或肿瘤细胞环境中呈现的抗原。在一个具体的实施方案中,抗原结合模块针对选自下组的抗原:成纤维细胞活化蛋白(FAP)和癌胚抗原(CEA)。免疫缀合物可包含两个或更多个抗原结合模块,其中这些抗原结合模块的每一个特异性结合同一抗原决定簇。
所述抗原结合模块可以是保留对抗原决定簇的特异性结合的任何类型的抗体或其片段。抗体片段包括但不限于VH片段,VL片段,Fab片段,F(ab’)2片段,scFv片段,Fv片段,微型抗体,双抗体,三抗体和四抗体(参见例如Hudson和Souriau,Nature Med 9,129-134(2003))。在一个特定的实施方案中,所述抗原结合模块是Fab分子。在一个实施方案中,所述Fab分子是人的。在另一个实施方案中,所述Fab分子是人源化的。在还有另一个实施方案中,所述Fab分子包含人重链和轻链恒定区。
在优选的实施方案中,肿瘤靶向性IL-2变体免疫细胞因子的肿瘤靶向可以通过靶向癌胚抗原(CEA)来实现,如WO 2012/146628中记载的。CEA靶向可以用抗CEA抗体或其抗原结合片段实现。抗CEA抗体可以包含与SEQ ID NO:66或SEQ ID NO:68的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的重链可变区序列,或其保留功能性的变体。抗CEA抗体可以包含与SEQ ID NO:65或SEQ ID NO:67的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的轻链可变区序列,或其保留功能性的变体。抗CEA抗体可以包含与SEQ ID NO:66的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的重链可变区序列,或其保留功能性的变体,和与SEQ ID NO:65的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的轻链可变区序列,或其保留功能性的变体。抗CEA抗体可以包含与SEQ ID NO:68的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的重链可变区序列,或其保留功能性的变体,和与SEQ ID NO:67的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的轻链可变区序列,或其保留功能性的变体。抗CEA抗体可以包含SEQ ID NO:66的重链可变区序列和SEQ ID NO:65的轻链可变区序列。抗CEA抗体可以包含SEQ ID NO:68的重链可变区序列和SEQ ID NO:67的轻链可变区序列。
如WO 2012/146628中记载的,CEA靶向性IL-2变体免疫细胞因子可以包含如下的多肽序列,其中对CEA特异性的Fab重链与包含节修饰的Fc域亚基共享羧基末端肽键,该包含节修饰的Fc域亚基继而与IL-2多肽共享羧基末端肽键。CEA靶向性IL-2变体免疫细胞因子可以包含选自下组的多肽序列:SEQ ID NO:82,SEQ ID NO:83和SEQ ID NO:84,或其保留功能性的变体。CEA靶向性IL-2变体免疫细胞因子可以包含如下的多肽序列,其中对CEA特异性的Fab重链与包含穴修饰的Fc域亚基共享羧基末端肽键。CEA靶向性IL-2变体免疫细胞因子可以包含SEQ ID NO:85或SEQ ID NO:86的多肽序列,或其保留功能性的变体。CEA靶向性IL-2变体免疫细胞因子可以包含对CEA特异性的Fab轻链。CEA靶向性IL-2变体免疫细胞因子可以包含SEQ ID NO:87或SEQ ID NO:88的多肽序列,或其保留功能性的变体。CEA靶向性IL-2变体免疫细胞因子可以包含SEQ ID NO:85,SEQ ID NO:82和SEQ ID NO:87的多肽序列,或其保留功能性的变体。CEA靶向性IL-2变体免疫细胞因子可以包含SEQ ID NO:84,SEQID NO:86和SEQ ID NO:88的多肽序列,或其保留功能性的变体。所述多肽可以共价连接,例如通过二硫键。所述Fc域多肽链可以包含氨基酸替代L234A,L235A,和P329G(其可称作LALAP329G)。
如WO 2012/146628中记载的,CEA靶向性IL-2变体免疫细胞因子可以是具有SEQID NO:84,86和88所示序列的基于抗CEA抗体CH1A1A 98/99 2F1和IL-2四重突变体(IL-2qm,SEQ ID NO:3)的CEA靶向性IgG-IL-2qm融合蛋白(如例如WO 2012/146628实施例1和2中记载的)。具有SEQ ID NO:84,86和88所示序列的CEA靶向性IL-2变体免疫细胞因子在本文中称作“CEA-IL2v”。
在优选的实施方案中,肿瘤靶向性IL-2变体免疫细胞因子的肿瘤靶向可以通过靶向成纤维细胞活化蛋白(FAP)来实现,如WO 2012/146628和WO 2012/107417中记载的。FAP靶向可以用抗FAP抗体或其抗原结合片段来实现。抗FAP抗体可以包含与选自下组的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的重链可变区序列:SEQ IDNO:7,SEQ ID NO:9,SEQ ID NO:10,SEQ ID NO:12,SEQ ID NO:14,SEQ ID NO:16,SEQ IDNO:18,SEQ ID NO:20,SEQ ID NO:22,SEQ ID NO:24,SEQ ID NO:26,SEQ ID NO:28,SEQ IDNO:30,SEQ ID NO:32,SEQ ID NO:34,SEQ ID NO:36,SEQ ID NO:38,SEQ ID NO:40,SEQ IDNO:42,SEQ ID NO:44,SEQ ID NO:46,SEQ ID NO:48,SEQ ID NO:50,SEQ ID NO:52,SEQ IDNO:54,SEQ ID NO:56,SEQ ID NO:58,SEQ ID NO:60,SEQ ID NO:62和SEQ ID NO:64,或其保留功能性的变体。抗FAP抗体可以包含与选自下组的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的轻链可变区序列:SEQ ID NO:5,SEQ ID NO:6,SEQ IDNO:8,SEQ ID NO:11,SEQ ID NO:13,SEQ ID NO:15,SEQ ID NO:17,SEQ ID NO:19,SEQ IDNO:21,SEQ ID NO:23,SEQ ID NO:25,SEQ ID NO:27,SEQ ID NO:29,SEQ ID NO:31,SEQ IDNO:33,SEQ ID NO:35,SEQ ID NO:37,SEQ ID NO:39,SEQ ID NO:41,SEQ ID NO:43,SEQ IDNO:45,SEQ ID NO:47,SEQ ID NO:49,SEQ ID NO:51,SEQ ID NO:53,SEQ ID NO:55,SEQ IDNO:57,SEQ ID NO:59,SEQ ID NO:61和SEQ ID NO:63,或其保留功能性的变体。抗FAP抗体可以包含与选自下组的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的重链可变区序列:SEQ ID NO:7,SEQ ID NO:9,SEQ ID NO:10,SEQ ID NO:12,SEQ IDNO:14,SEQ ID NO:16,SEQ ID NO:18,SEQ ID NO:20,SEQ ID NO:22,SEQ ID NO:24,SEQ IDNO:26,SEQ ID NO:28,SEQ ID NO:30,SEQ ID NO:32,SEQ ID NO:34,SEQ ID NO:36,SEQ IDNO:38,SEQ ID NO:40,SEQ ID NO:42,SEQ ID NO:44,SEQ ID NO:46,SEQ ID NO:48,SEQ IDNO:50,SEQ ID NO:52,SEQ ID NO:54,SEQ ID NO:56,SEQ ID NO:58,SEQ ID NO:60,SEQ IDNO:62和SEQ ID NO:64,或其保留功能性的变体,和与选自下组的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的轻链可变区序列:SEQ ID NO:5,SEQ IDNO:6,SEQ ID NO:8,SEQ ID NO:11,SEQ ID NO:13,SEQ ID NO:15,SEQ ID NO:17,SEQ IDNO:19,SEQ ID NO:21,SEQ ID NO:23,SEQ ID NO:25,SEQ ID NO:27,SEQ ID NO:29,SEQ IDNO:31,SEQ ID NO:33,SEQ ID NO:35,SEQ ID NO:37,SEQ ID NO:39,SEQ ID NO:41,SEQ IDNO:43,SEQ ID NO:45,SEQ ID NO:47,SEQ ID NO:49,SEQ ID NO:51,SEQ ID NO:53,SEQ IDNO:55,SEQ ID NO:57,SEQ ID NO:59,SEQ ID NO:61和SEQ ID NO:63,或其保留功能性的变体。抗FAP抗体可以包含与SEQ ID NO:42的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的重链可变区序列和与SEQ ID NO:41的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的轻链可变区序列。抗FAP抗体可以包含与SEQ ID NO:58的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的重链可变区序列和与SEQ ID NO:57的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的轻链可变区序列。抗FAP抗体可以包含与SEQ ID NO:12的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的重链可变区序列和与SEQ IDNO:11的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的轻链可变区序列。抗FAP抗体可以包含与SEQ ID NO:7的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的重链可变区序列和与SEQ ID NO:6的序列至少约80%,85%,90%,95%,96%,97%,98%,99%或100%相同的轻链可变区序列。抗FAP抗体可以包含SEQ ID NO:42的重链可变区序列和SEQ ID NO:41的轻链可变区序列。抗FAP抗体可以包含SEQ ID NO:58的重链可变区序列和SEQ ID NO:57的轻链可变区序列。抗FAP抗体可以包含SEQ ID NO:12的重链可变区序列和SEQ ID NO:11的轻链可变区序列。抗FAP抗体可以包含SEQ ID NO:7的重链可变区序列和SEQ ID NO:6的轻链可变区序列。
如WO 2012/146628和WO 2012/107417中记载的,FAP靶向性IL-2变体免疫细胞因子可以包含如下的多肽序列,其中对FAP特异性的Fab重链与包含节修饰的Fc域亚基共享羧基末端肽键,该包含节修饰的Fc域亚基继而与IL-2多肽共享羧基末端肽键。FAP靶向性IL-2变体免疫细胞因子可以包含选自下组的多肽序列:SEQ ID NO:69,SEQ ID NO:70,SEQ IDNO:71,SEQ ID NO:72和SEQ ID NO:73,或其保留功能性的变体。FAP靶向性IL-2变体免疫细胞因子可以包含如下的多肽序列,其中对FAP特异性的Fab重链与包含穴修饰的Fc域亚基共享羧基末端肽键。FAP靶向性IL-2变体免疫细胞因子可以包含选自下组的多肽序列:SEQ IDNO:74,SEQ ID NO:75和SEQ ID NO:76,或其保留功能性的变体。FAP靶向性IL-2变体免疫细胞因子可以包含对FAP特异性的Fab轻链。FAP靶向性IL-2变体免疫细胞因子可以包含SEQID NO:77或SEQ ID NO:78的多肽序列,或其保留功能性的变体。FAP靶向性IL-2变体免疫细胞因子可以包含SEQ ID NO:77的多肽序列,SEQ ID NO:74的多肽序列,和选自下组的多肽序列:SEQ ID NO:69和SEQ ID NO:72,或其保留功能性的变体。FAP靶向性IL-2变体免疫细胞因子可以包含SEQ ID NO:75,SEQ ID NO:70和SEQ ID NO:77的多肽序列,或其保留功能性的变体。FAP靶向性IL-2变体免疫细胞因子可以包含SEQ ID NO:76,SEQ ID NO:71和SEQID NO:78的多肽序列,或其保留功能性的变体。FAP靶向性IL-2变体免疫细胞因子可以包含SEQ ID NO:77,SEQ ID NO:74和SEQ ID NO:72的多肽序列,或其保留功能性的变体。FAP靶向性IL-2变体免疫细胞因子可以包含SEQ ID NO:78,SEQ ID NO:76和SEQ ID NO:73的多肽序列,或其保留功能性的变体。所述多肽是共价连接的,例如通过二硫键。所述Fc域亚基可以各自包含氨基酸替代L234A,L235A,和P329G(其可称作LALA P329G)。
如WO 2012/146628和WO 2012/107417中记载的,FAP靶向性IL-2变体免疫细胞因子可以是具有SEQ ID NO:79,80和81所示序列的基于抗FAP抗体4B9和IL-2四重突变体(IL-2qm,SEQ ID NO:3)的FAP靶向性IgG-IL-2qm融合蛋白(如例如WO 2012/146628实施例1和2和WO 2012/107417实施例1中记载的)。具有SEQ ID NO:79,80和81所示序列的FAP靶向性IL-2变体免疫细胞因子在本文中称作“FAP-IL2v”。
本文所述组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子可以包含结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体,和IL-2突变体具有降低的对IL-2受体亚基的结合亲和力。肿瘤靶向性IL-2变体免疫细胞因子可以基本上由结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体,和具有降低的对IL-2受体亚基的结合亲和力的IL-2突变体组成。所述抗体可以是IgG抗体,特别是IgG1抗体。肿瘤靶向性IL-2变体免疫细胞因子可以包含单个具有降低的对IL-2受体亚基的结合亲和力的IL-2突变体(即存在不超过一个IL-2突变体模块)。
如本文中描述的,本文所述组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子可以包含结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体的重链可变域和轻链可变域和由两个亚基组成且包含促进两条不相同多肽链异二聚化的修饰的Fc域。本文所述组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子可以包含结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体的重链可变域和包含节突变的Fc域亚基,结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体的重链可变域和包含穴突变的Fc域亚基,和结合肿瘤细胞上或肿瘤细胞环境中呈递的抗原的抗体的轻链可变域,和具有降低的对IL-2受体亚基的结合亲和力的IL-2突变体。如此,免疫细胞因子可以包含包含促进两条不相同多肽链异二聚化的修饰的Fc域。“促进异二聚化的修饰”是降低或防止多肽与相同多肽联合以形成同二聚体的肽主链操作或多肽的翻译后修饰。如本文中使用的,具体地,促进异二聚化的修饰包括对期望形成二聚体的两个多肽中的每一个进行的分开的修饰,其中所述修饰彼此互补,从而促进两个多肽的联合。例如,促进异二聚化的修饰可以改变期望形成二聚体的一个或两个多肽的结构或电荷,从而在立体或静电上分别促进它们的联合。异二聚化在两个不相同的多肽如Fc域的两个亚基之间发生,其中与每个亚基融合的别的免疫缀合物组分(例如抗原结合模块,效应器模块)是不相同的。在依照本发明的免疫缀合物中,促进异二聚化的修饰在Fc域中。在一些实施方案中,促进异二聚化的修饰包含氨基酸突变,具体为氨基酸替代。在一个具体的实施方案中,促进异二聚化的修饰包含Fc域的两个亚基的每一个中分开的氨基酸突变,具体为氨基酸替代。人IgG Fc域的两条多肽链之间最广泛的蛋白质-蛋白质相互作用的位点在Fc域的CH3域中。如此,在一个实施方案中,所述修饰在Fc域的CH3域中。在一个具体的实施方案中,所述修饰是节-入-穴修饰,其包含在Fc域的两个亚基之一中的节修饰和在Fc域的两个亚基的另一个中的穴修饰。
节-入-穴技术记载于例如US 5,731,168;US 7,695,936;Ridgway等,Prot Eng 9,617-621(1996)和Carter,J Immunol Meth 248,7-15(2001)。一般地,该方法牵涉在第一多肽的界面处引入隆起(“节”)并在第二多肽的界面处引入相应的空腔(“穴”),从而使得隆起可以置于空腔中以促进异二聚体形成并阻碍同二聚体形成。通过将来自第一多肽界面的小氨基酸侧链用更大的侧链(例如酪氨酸或色氨酸)替换来构建隆起。在第二多肽的界面中创建具有与隆起相同或相似大小的互补性空腔,其通过将大氨基酸侧链用更小的氨基酸侧链(例如丙氨酸或苏氨酸)替换得到。可以通过改变编码多肽的核酸,例如通过位点特异性诱变或通过肽合成来制备隆起和空腔。在一个具体的实施方案中,节修饰包含在Fc域的两个亚基之一中的氨基酸替代T366W,而穴修饰包含在Fc域的两个亚基的另一个中的氨基酸替代T366S,L368A和Y407V。在又一个具体的实施方案中,包含节修饰的Fc域亚基另外包含氨基酸替代S354C,且包含穴修饰的Fc域亚基另外包含氨基酸替代Y349C。引入这两个半胱氨酸残基导致在Fc区的两个亚基之间形成二硫桥,从而进一步稳定二聚体(Carter,JImmunol Methods 248,7-15(2001))。Fc区中氨基酸残基的编号方式依照EU编号系统,也称为EU索引,如记载于Kabat等,Sequences of Proteins of Immunological Interest,第5版Public Health Service,National Institutes of Health,Bethesda,MD,1991的。如本文中使用的,Fc域的“亚基”指形成二聚体Fc域的两条多肽之一,即包含免疫球蛋白重链中能够稳定自身联合的C端恒定区的多肽。例如,IgG Fc域的亚基包含IgG CH2和IgG CH3恒定域。
在一个备选的实施方案中,促进两条不相同多肽链的异二聚化的修饰包含介导静电操纵效应(electrostatic steering effect)的修饰,例如如记载于WO 2009/089004的。一般地,此方法涉及将在两条多肽链界面处的一个或多个氨基酸残基替换为带电荷的氨基酸残基,从而在静电上不利于同二聚体形成而在静电上有利于异二聚化。
可以将具有降低的对IL-2受体亚基的结合亲和力的IL-2突变体融合至包含节修饰的Fc域亚基的羧基端氨基酸。不希望受理论束缚,IL-2突变体与Fc域的含有节的Fc域亚基的融合会进一步使包含两个IL-2突变体多肽的同二聚体免疫细胞因子的生成(两个含有节的多肽的空间对撞)最小化。
可以将免疫细胞因子的Fc域工程化改造为与非工程化Fc域相比,具有改变的对Fc受体的结合亲和力,尤其是改变的对Fcγ受体的结合亲和力,如WO 2012/146628中记载的。可以改变Fc域对补体成分,尤其是对C1q的结合,如WO 2012/146628中记载的。Fc域赋予免疫缀合物以有利的药动学特性,包括长血清半衰期,其有助于在靶组织中的较好累积和有利的组织-血液分配比。然而,同时它可能导致不想要的免疫缀合物对表达Fc受体的细胞而非优选的携带抗原的细胞的靶向。而且,Fc受体信号传导途径的共激活可能导致细胞因子释放,其与效应器模块及免疫缀合物的长半衰期组合,在系统性施用后引起细胞因子受体的过度激活和严重的副作用。与此相符的是,常规的IgG-IL-2免疫缀合物已被描述为与输注反应有关(参见例如King等,J Clin Oncol 22,4463-4473(2004))。
因此,可以将免疫细胞因子的Fc域工程化改造为具有降低的对Fc受体的结合亲和力。在一个此类实施方案中,所述Fc域包含一处或多处氨基酸突变,其降低Fc域对Fc受体的结合亲和力。典型地,Fc域的两个亚基的每一个中存在相同的一处或多处氨基酸突变。在一个实施方案中,所述氨基酸突变将Fc域对Fc受体的结合亲和力降低至少2倍,至少5倍,或至少10倍。在有超过一处降低Fc域对Fc受体的结合亲和力的氨基酸突变的实施方案中,这些氨基酸突变的组合可以将Fc域对Fc受体的亲和力降低至少10倍,至少20倍,或甚至至少50倍。在一个实施方案中,包含工程化Fc域的免疫缀合物与包含非工程化Fc域的免疫缀合物相比,展现出低于20%,特别是低于10%,更特别地低于5%的对Fc受体的结合亲和力。在一个实施方案中,Fc受体是活化性Fc受体。在一个具体的实施方案中,Fc受体是Fcγ受体,更具体的是FcγRIIIa,FcγRI或FcγRIIa受体。优选地,降低对这些受体的每一种的结合。在一些实施方案中,还降低对补体成分的结合亲和力,尤其是对C1q的结合亲和力。在一个实施方案中,不降低对新生儿Fc受体(FcRn)的结合亲和力。当Fc域(或包含所述Fc域的免疫缀合物)展现出非工程化形式的Fc域(或包含所述非工程化形式的Fc域的免疫缀合物)对FcRn的结合亲和力的超过约70%时,就实现实质性相似的对FcRn的结合,即保留该Fc域对所述受体的结合亲和力。Fc域或包含所述Fc域的本发明的免疫缀合物可以展现出高于约80%和甚至高于约90%的此类亲和力。在一个实施方案中,所述氨基酸突变是氨基酸替代。在一个实施方案中,Fc域包含在第P329位的氨基酸替代。在一个更具体的实施方案中,所述氨基酸替代是P329A或P329G,特别是P329G。在一个实施方案中,Fc域在选自S228,E233,L234,L235,N297和P331的位置处包含别的氨基酸替代。在一个更具体的实施方案中,别的氨基酸替代是S228P,E233P,L234A,L235A,L235E,N297A,N297D或P331S。在一个具体的实施方案中,Fc域在位置P329,L234和L235处包含氨基酸替代。在一个更具体的实施方案中,Fc域包含氨基酸突变L234A,L235A和P329G(LALA P329G)。此氨基酸替代的组合几乎完全消除Fcγ受体对人IgG Fc域的结合,如WO 2012/130831中记载的,通过援引完整收入本文。WO 2012/130831还描述了制备此类突变体Fc域的方法和用于测定其特性诸如Fc受体结合或效应器功能的方法。Fc区中氨基酸残基的编号方式依照EU编号系统,也称为EU索引,如记载于Kabat等,Sequences of Proteins of Immunological Interest,第5版Public HealthService,National Institutes of Health,Bethesda,MD,1991的。
可以使用本领域中公知的及如WO 2012/146628中记载的遗传或化学方法通过氨基酸删除,替代,插入或修饰来制备突变体Fc域。遗传方法可以包括对编码DNA序列的位点特异性诱变,PCR,基因合成,等等。正确的核苷酸变化可以通过例如测序来验证。
在一个实施方案中,将Fc域工程化改造为与非工程化Fc域相比具有降低的效应器功能,如WO 2012/146628中记载的。所述降低的效应器功能可包括但不限于下列一种或多种:降低的补体依赖性细胞毒性(CDC),降低的抗体依赖性细胞介导的细胞毒性(ADCC),降低的抗体依赖性细胞吞噬作用(ADCP),降低的细胞因子分泌,降低的免疫复合物介导的抗原呈递细胞的抗原摄取,降低的对NK细胞的结合,降低的对巨噬细胞的结合,降低的对单核细胞的结合,降低的对多形核细胞的结合,降低的诱导凋亡的直接信号传导,降低的靶物结合的抗体的交联,降低的树突细胞成熟,或降低的T细胞引发。
IgG4抗体展现出与IgG1抗体相比降低的对Fc受体的结合亲和力和降低的效应器功能。因此,在一些实施方案中,本发明的T细胞激活性双特异性抗原结合分子的Fc域是IgG4Fc域,特别是人IgG4 Fc域。在一个实施方案中,IgG4 Fc域包含在位置S228处的氨基酸替代,具体是氨基酸替代S228P。为了进一步降低其对Fc受体的结合亲和力和/或其效应器功能,在一个实施方案中,IgG4 Fc域包含在位置L235处的氨基酸替代,具体是氨基酸替代L235E。在另一个实施方案中,IgG4 Fc域包含在位置P329处的氨基酸替代,具体是氨基酸替代P329G。在一个特定的实施方案中,IgG4 Fc域包含在位置S228,L235和P329处的氨基酸替代,具体是氨基酸替代S228P,L235E和P329G。此类IgG4 Fc域突变体及其Fcγ受体结合特性记载于欧洲专利申请no.WO 2012/130831,通过援引完整收入本文。
本文所述组合疗法中使用的结合人PD-L1的抗体选自下组:243.55.S70,243.55.H1,243.55.H12,243.55.H37,243.55.H70,243.55.H89,243.55.S1,243.55.5,243.55.8,243.55.30,243.55.34,243.55.S37,243.55.49,243.55.51,243.55.62,和243.55.84。
这些抗体记载于WO 2010/77634(序列显示于WO 2010/77634的图11)且特征在于包含本文所述下述VH和VL序列:
在本发明的一个实施方案中,本文所述组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列;或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列;或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列
且
组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
在本发明的一个实施方案中,本文所述组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
c)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
d)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列,
且
组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
在一个实施方案中,本文所述组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子特征在于包含SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ IDNO:3的多肽序列。
在一个实施方案中,本文所述组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子特征在于包含SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列。
在一个实施方案中,本文所述组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子特征在于包含SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列。
在一个实施方案中,本文所述组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子特征在于包含SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ IDNO:3的多肽序列。
在一个实施方案中,本文所述组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子特征在于包含SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL。
在一个实施方案中,组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ IDNO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
在本发明的一个优选的实施方案中,本文所述组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子特征在于包含SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,且
组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
在本发明的一个优选的实施方案中,本文所述组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子特征在于包含SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,且
组合疗法中使用的结合人PD-L1的抗体特征在于包含SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
术语“抗体”在本文中以最广义使用且涵盖各种抗体结构,包括但不限于单克隆抗体,多克隆抗体和抗体片段,只要它们展现出期望的抗原结合活性。
“抗体片段”指完整抗体外的分子,其包含完整抗体中结合与完整抗体结合的抗原的一部分。抗体片段的例子包括但不限于Fv,Fab,Fab’,Fab’-SH,F(ab’)2,双抗体,线性抗体,单链抗体分子(例如scFv),和单域抗体。对于某些抗体片段的综述,参见Hudson等,NatMed 9,129-134(2003)。对于scFv片段的综述,参见例如Plückthun,于The Pharmacologyof Monoclonal Antibodies,vol.113,Rosenburg和Moore编,Springer-Verlag,New York,pp.269-315(1994);亦参见WO 93/16185;和美国专利No.5,571,894和5,587,458。对包含补救受体结合表位残基且具有延长的体内半衰期的Fab和F(ab’)2片段的论述,参见美国专利No.5,869,046。双抗体是具有两个抗原结合位点的抗体片段,其可以是二价或双特异性的。参见,例如EP 404,097;WO 1993/01161;Hudson等,Nat Med 9,129-134(2003);和Hollinger等,Proc Natl Acad Sci USA 90,6444-6448(1993)。三抗体和四抗体也记载于Hudson等,Nat Med 9,129-134(2003)。单域抗体是包含抗体的整个或部分重链可变域,或整个或部分轻链可变域的抗体片段。在某些实施方案中,单域抗体是人单域抗体(Domantis,Inc.,Waltham,MA;参见例如美国专利No.6,248,516 B1)。可以通过各种技术来制备抗体片段,包括但不限于对完整抗体的蛋白水解消化以及通过重组宿主细胞(例如大肠杆菌或噬菌体)产生,如本文中描述的。
术语“抗原结合域”或“抗体的抗原结合部分”在本文中使用时指包含特异性结合部分或整个抗原且与其互补的区域的抗体部分。如此,该术语指抗体中负责抗原结合的氨基酸残基。抗原结合域可由例如一个或多个抗体可变域(也称为抗体可变区)提供。特别地,抗原结合域包含抗体轻链可变区(VL)和抗体重链可变区(VH)。抗体的抗原结合部分包含来自“互补决定区”或“CDR”的氨基酸残基。“框架”或“FR”区是可变域中那些与本文中定义的高变区残基不同的区。因此,抗体的轻和重链可变域自N至C端包含域FR1,CDR1,FR2,CDR2,FR3,CDR3,和FR4。尤其地,重链的CDR3是对抗原结合贡献最大且限定抗体特性的区。CDR和FR区依照Kabat等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991)的标准定义和/或那些来自“高变环”的残基来确定。
术语“可变区”或“可变域”指牵涉抗体对抗原结合的抗体重链或轻链的域。天然抗体的重链和轻链的可变域(分别为VH和VL)一般具有类似的结构,每个域包含4个保守的框架区(FR)和3个高变区(HVR)。参见,例如Kindt等,Kuby Immunology,第6版,W.H.Freemanand Co.,第91页(2007)。单个VH或VL域可能足以赋予抗原结合特异性。
术语“表位”表示抗原诸如CEA或人PD-L1中能够特异性结合抗体的蛋白质决定簇。表位通常由分子诸如氨基酸或糖侧链的化学活性表面聚组组成,而且表位通常具有特定的三维结构特征,以及特定的电荷特征。构象性和非构象性表位的区别在于对前者而非后者的结合在变性溶剂存在下丧失。
本文中术语“Fc域”或“Fc区”用于定义免疫球蛋白重链中至少含有恒定区的一部分的C端区域。该术语包括天然序列Fc区和变体Fc区。虽然IgG重链的Fc区的边界可以略微变化,但是人IgG重链Fc区通常定义为自Cys226或Pro230延伸至重链的羧基端。然而,可以存在或不存在Fc区的C端赖氨酸(Lys447)。除非本文中另外指定,Fc区或恒定区中氨基酸残基的编号方式依照EU编号系统,也称为EU索引,如记载于Kabat等,Sequences of Proteinsof Immunological Interest,第5版Public Health Service,National Institutes ofHealth,Bethesda,MD,1991的。抗体的Fc域不直接涉及抗体对抗原的结合,但是展现出多种效应器功能。“抗体的Fc域”是熟练技术人员公知的术语,而且基于木瓜蛋白酶对抗体的切割定义。根据其重链恒定区的氨基酸序列,抗体或免疫球蛋白分成类:IgA,IgD,IgE,IgG和IgM,并且这些中的数种可以进一步分成亚类(同种型),例如IgG1,IgG2,IgG3,和IgG4,IgA1,和IgA2。依照重链恒定区,不同类的免疫球蛋白分别称作α,δ,ε,γ,和μ。抗体的Fc域直接涉及基于补体激活,C1q结合和Fc受体结合的ADCC(抗体依赖性细胞介导的细胞毒性)和CDC(补体依赖性细胞毒性)。补体激活(CDC)是通过补体因子C1q结合大多数IgG抗体亚类的Fc域启动的。虽然抗体对补体系统的影响依赖于某些条件,但是对C1q的结合是由Fc域中的限定结合位点引起的。此类结合位点是本领域现有技术中已知的,而且记载于例如Boackle,R.J.等人,Nature 282(1979)742-743;Lukas,T.J.等人,J.Immunol.127(1981)2555-2560;Brunhouse,R.和Cebra,J.J.,Mol.Immunol.16(1979)907-917;Burton,D.R.等人,Nature 288(1980)338-344;Thommesen,J.E.等人,Mol.Immunol.37(2000)995-1004;Idusogie,E.E.等人,J.Immunol.164(2000)4178-4184;Hezareh,M.等人,J.Virology 75(2001)12161-12168;Morgan,A.等人,Immunology 86(1995)319-324;EP 0307434。此类结合位点是例如L234,L235,D270,N297,E318,K320,K322,P331和P329(依照Kabat,E.A.的EU索引的编号方式,参见上文)。亚类IgG1,IgG2和IgG3的抗体通常显示补体激活及C1q和C3结合,而IgG4不激活补体系统,而且不结合C1q和C3。
在一个实施方案中,本文所述免疫细胞因子的抗体构件或抗体包含自人起源衍生的Fc域和优选地,人恒定区的所有其它部分。如本文中使用的,术语“自人起源衍生的Fc域”表示如下的Fc域,其是属于亚类IgG1,IgG2,IgG3或IgG4的人抗体的Fc域,优选来自人IgG1亚类的Fc域,来自人IgG1亚类的突变型Fc域(在一个实施方案中具有L234A+L235A上的突变),来自人IgG4亚类的Fc域或来自人IgG4亚类的突变型Fc域(在一个实施方案中具有S228P上的突变)。在一个优选实施方案中,人重链恒定区是SEQ ID NO:58(人IgG1亚类),在另一个优选实施方案中,人重链恒定区是SEQ ID NO:59(具有突变L234A和L235A的人IgG1亚类),在另一个优选实施方案中,人重链恒定区是SEQ ID NO:60(人IgG4亚类),而在另一个优选实施方案中,人重链恒定区是SEQ ID NO:61(具有突变S228P的人IgG4亚类)。在一个实施方案中,所述抗体具有降低的或最小限度的效应器功能。在一个实施方案中,所述最小限度的效应器功能源自效应器降低性Fc突变。在一个实施方案中,所述效应器降低性Fc突变为L234A/L235A或L234A/L235A/P329G或N297A或D265A/N297A。在一个实施方案中,为每种抗体选择的所述效应器降低性Fc突变彼此独立地选自包含L234A/L235A,L234A/L235A/P329G,N297A和D265A/N297A(EU编号方式)的组(由L234A/L235A,L234A/L235A/P329G,N297A和D265A/N297A组成的组)。
在一个实施方案中,本文所述免疫细胞因子的抗体构件或抗体属于人IgG类(即属于IgG1亚类,IgG2亚类,IgG3亚类或IgG4亚类)。
在一个优选实施方案中,本文所述免疫细胞因子的抗体构件或抗体属于人IgG1亚类或人IgG4亚类。在一个实施方案中,本文所述免疫细胞因子的抗体构件或抗体属于人IgG1亚类。在一个实施方案中,本文所述免疫细胞因子的抗体构件或抗体属于人IgG4亚类。
在一个实施方案中,本文所述免疫细胞因子的抗体构件或抗体特征在于恒定链是人起源的。此类恒定链是本领域现有技术公知的,而且记载于例如Kabat,E.A.,(参见例如Johnson,G.和Wu,T.T.,Nucleic Acids Res.28(2000)214-218)。例如,一种有用的人重链恒定区包含氨基酸序列SEQ ID NO:114。例如,一种有用的人轻链恒定区包含κ轻链恒定区氨基酸序列SEQ ID NO:113。
如本文中使用的,术语“核酸”或“核酸分子”意图包括DNA分子和RNA分子。核酸分子可以是单链的或双链的,但是优选是双链DNA。
如本申请内使用的,术语“氨基酸”表示天然存在的羧基α-氨基酸组,包括丙氨酸(三字母代码:ala,单字母代码:A),精氨酸(arg,R),天冬酰胺(asn,N),天冬氨酸(asp,D),半胱氨酸(cys,C),谷氨酰胺(gln,Q),谷氨酸(glu,E),甘氨酸(gly,G),组氨酸(his,H),异亮氨酸(ile,I),亮氨酸(leu,L),赖氨酸(lys,K),甲硫氨酸(met,M),苯丙氨酸(phe,F),脯氨酸(pro,P),丝氨酸(ser,S),苏氨酸(thr,T),色氨酸(trp,W),酪氨酸(tyr,Y),和缬氨酸(val,V)。
关于参照多肽序列的“百分比(%)氨基酸序列同一性”定义为在比对序列并在必要时引入缺口以获取最大百分比序列同一性后,且不将任何保守性替代视为序列同一性的一部分时,候选序列中与参照多肽序列中的氨基酸残基相同的氨基酸残基的百分比。为测定百分比氨基酸序列同一性目的比对可以以本领域技术范围内的多种方式进行,例如使用公众可得到的计算机软件,如BLAST,BLAST-2,ALIGN或Megalign(DNASTAR)软件。本领域技术人员可决定用于比对序列的适宜参数,包括在比较序列的全长里获得最大比对需要的任何算法。然而,就本文中目的而言,使用序列比较计算机程序ALIGN-2来生成%氨基酸序列同一性值。ALIGN-2序列比较计算机程序由Genentech,Inc.创作,并且源代码已与用户文档一起提交到美国版权局(U.S.Copyright Office),Washington D.C.,20559,其在美国版权注册No.TXU510087下注册。ALIGN-2程序可从Genentech,Inc.,South San Francisco,California公开获得,或可从源代码汇编。ALIGN-2程序应当汇编用于UNIX操作系统,包括数字UNIX V4.0D。所有序列比较参数均由ALIGN-2程序设定且不改变。在采用ALIGN-2进行氨基酸序列比较的情况下,给定的氨基酸序列A对/与/相对给定的氨基酸序列B的%氨基酸序列同一性(或其可以用短语表示为对/与/相对给定的氨基酸序列B具有或包含特定%氨基酸序列同一性的给定氨基酸序列A)如下计算:
分数X/Y的100倍
其中X是由序列比对程序ALIGN-2在所述程序对A和B的比对中评为相同匹配的氨基酸残基数,而其中Y是B中氨基酸残基的总数。会领会的是,当氨基酸序列A的长度不等于氨基酸序列B的长度时,A对B的%氨基酸序列同一性将不等于B对A的%氨基酸序列同一性。除非另外明确说明,本文中使用的所有%氨基酸序列同一性值如在上一段中描述的那样使用ALIGN-2计算机程序获得。与本发明的参照核苷酸序列具有至少例如95%“相同的”核苷酸序列的核酸或多核苷酸意指该多核苷酸的核苷酸序列与参照序列相同,只不过按照参照核苷酸序列的每100个核苷酸,该多核苷酸序列可以包含多达5处点突变。换言之,为了获得与参照核苷酸序列具有至少95%相同的核苷酸序列的多核苷酸,可以删除或用另一种核苷酸替代参照序列中高达5%的核苷酸,或者可以将参照序列中占总核苷酸的高达5%的数目的核苷酸插入到参照序列中。参照序列的这些变更可以发生在参照核苷酸序列的5’或3’端位置或那些末端位置之间的任意地方,个别分散在参照序列中的残基中或分散在参照序列内的一或多个连续组中。作为一个实际问题,可以使用已知的计算机程序,如上文针对多肽论述的程序(例如ALIGN-2)来常规确定任何特定的多核苷酸序列是否与本发明的核苷酸序列为至少80%,85%,90%,95%,96%,97%,98%或99%相同。
术语“表达盒”指重组或合成生成的,具有一系列允许特定核酸在靶细胞中转录的指定核酸元件的多核苷酸。可以将重组表达盒掺入质粒,染色体,线粒体DNA,质体DNA,病毒或核酸片段中。通常,表达载体的重组表达盒部分包含要转录的核酸序列和启动子等。在某些实施方案中,本发明的表达盒包含编码本文所述多肽或其片段的多核苷酸序列。
术语“载体”或“表达载体”与“表达构建体”同义,并指用于在靶细胞中导入与其可操作联合的特定基因及指导表达的DNA分子。该术语包括作为自主复制核酸结构的载体以及掺入到已经接受其导入的宿主细胞的基因组中的载体。表达载体包含表达盒。表达盒允许转录大量稳定的mRNA。一旦表达载体在靶细胞内,就通过细胞转录和/或翻译装置生成基因编码的核糖核酸分子或蛋白质。在一个实施方案中,表达载体包含表达盒,其包含编码本文所述多肽或其片段的多核苷酸序列。
术语“人工的”指合成的或非宿主细胞衍生的组合物,例如化学合成的寡核苷酸。
术语“宿主细胞”,“宿主细胞系”和“宿主细胞培养物”可交换使用并指已引入外源核酸的细胞,包括此类细胞的后代。宿主细胞包括“转化体”和“经转化的细胞”,其包括初始转化的细胞和自其衍生的后代(不考虑传代数)。后代在核酸内含物上可能与亲本细胞不完全相同,但可以含有突变。本文中包括具有如原始转化细胞中筛选或选择的相同的功能或生物学活性的突变体后代。宿主细胞是能用于生成本文所述多肽的任意类型的细胞系统。在一个实施方案中,将宿主细胞工程化为允许生成在其Fc区中具有经修饰寡糖的多肽。在某些实施方案中,操作宿主细胞为表达升高水平的一种或多种具有β(1,4)-N-乙酰葡糖胺基转移酶III(GnTIII)活性的多肽。在某些实施方案中,还操作宿主细胞为表达升高水平的一种或多种具有α-甘露糖苷酶II(ManII)活性的多肽。宿主细胞包括培养的细胞,例如哺乳动物培养细胞如CHO细胞,BHK细胞,NS0细胞,SP2/0细胞,YO骨髓瘤细胞,P3X63小鼠骨髓瘤细胞,PER细胞,PER.C6细胞或杂交瘤细胞,酵母细胞,昆虫细胞和植物细胞等,而且还包括在转基因动物,转基因植物或培养的植物或动物组织中包含的细胞。
可以例如通过固相肽合成(例如Merrifield固相肽合成)或重组生成来获得本文所述肿瘤靶向性IL-2变体免疫细胞因子。对于重组生成,分离一种或多种编码所述免疫细胞因子(片段)的多核苷酸(例如如上文描述的),并将其插入一种或多种载体中用于在宿主细胞中进一步克隆和/或表达。可以使用常规规程容易分离并测序此类多核苷酸。在一个实施方案中,提供包含一种或多种多核苷酸的载体(优选为表达载体)。可以使用本领域技术人员公知的方法来构建含有免疫缀合物(片段)的编码序列以及适宜的转录/翻译控制信号的表达载体。这些方法包括体外重组DNA技术,合成技术和体内重组/遗传重组。参见,例如记载于Maniatis等,MOLECULAR CLONING:A LABORATORY MANUAL,Cold Spring HarborLaboratory,N.Y.(1989);和Ausubel等,CURRENT PROTOCOLS IN MOLECULAR BIOLOGY,Greene Publishing Associates and Wiley Interscience,N.Y(1989)的技术。表达载体可以是质粒,病毒的一部分或可以是核酸片段。表达载体包含表达盒,对其中在与启动子和/或其它转录或翻译控制元件的可操作联合中克隆编码免疫细胞因子(片段)的多核苷酸(即编码区)。如本文中使用的,“编码区”是核酸中由翻译成氨基酸的密码子组成的一部分。尽管“终止密码子”(TAG,TGA或TAA)不翻译成氨基酸,但可将其视为编码区的一部分(若存在的话),但任何侧翼序列例如启动子,核糖体结合位点,转录终止子,内含子,5’和3’非翻译区等,不是编码区的一部分。两个或更多个编码区可以存在于单一的多核苷酸构建体中(例如单一的载体上),或存在于分开的多核苷酸构建体中,例如在分开的(不同的)载体上。此外,任何载体可含有单个编码区,或可包含两个或更多个编码区,例如载体可以编码一种或多种多肽,其经由蛋白水解切割在翻译后或共翻译分开成最终蛋白质。另外,载体,多核苷酸或核酸可以编码异源编码区,其与编码免疫细胞因子(片段)或其变体或衍生物的多核苷酸融合或未融合。异源编码区包括但不限于特殊化的元件或基序,如分泌信号肽或异源功能域。当基因产物例如多肽的编码区与一种或多种调节序列以某种方式联合从而使得该基因产物的表达置于该调节序列的影响或控制下时,即为可操作联合。若诱导启动子功能导致编码期望的基因产物的mRNA的转录并且如果两个DNA片段之间的连接的性质不干扰表达调节序列指导该基因产物表达的能力或不干扰DNA模板被转录的能力,则两个DNA片段(如多肽编码区和与其联合的启动子)为“可操作联合的”。如此,如果启动子能够实现编码多肽的核酸的转录,那么该启动子区将是与该核酸可操作联合。所述启动子可以是细胞特异性启动子,其仅指导预先确定的细胞中的DNA的实质性转录。除启动子以外,其它转录控制元件例如增强子,操纵基因,阻遏物和转录终止信号能与多核苷酸可操作联合以指导细胞特异性转录。在本文中公开了合适的启动子和其它转录控制区。多种转录控制区是本领域技术人员已知的。这些包括但不限于在脊椎动物细胞中发挥功能的转录控制区,如但不限于来自巨细胞病毒的启动子和增强子区段(例如立即早期启动子,以及内含子-A),猿病毒40(例如早期启动子)和逆转录病毒(如例如劳斯(Rous)肉瘤病毒)。其它转录控制区包括那些自脊椎动物基因如肌动蛋白,热休克蛋白,牛生长激素和家兔β球蛋白衍生的,以及能够控制真核细胞中基因表达的其它序列。另外的合适的转录控制区包括组织特异性启动子和增强子以及诱导型启动子(例如四环素诱导型启动子)。类似地,多种翻译控制元件是本领域普通技术人员已知的。这些包括但不限于核糖体结合位点,翻译起始和终止密码子以及自病毒系统衍生的元件(具体地,内部核糖体进入位点或IRES,亦称为CITE序列)。表达盒还可以包含其它特征,如复制起点和/或染色体整合元件,如逆转录病毒长末端重复(LTR)或腺伴随病毒(AAV)反向末端重复(ITR)。
本文所述多核苷酸和核酸编码区可以与编码分泌或信号肽的另外的编码区联合,所述分泌或信号肽指导由多核苷酸编码的多肽的分泌。例如,如果期望分泌所述免疫细胞因子,那么可以将编码信号序列的DNA置于编码免疫细胞因子或其片段的核酸上游。依照信号假说,由哺乳动物细胞分泌的蛋白质具有信号肽或分泌前导序列,一旦启动将生长的蛋白质链跨越粗面内质网输出,就将该信号肽或分泌前导序列从成熟的蛋白质切去。本领域中普通技术人员知晓由脊椎动物细胞分泌的多肽一般具有融合至多肽N端的信号肽,其从所翻译的多肽切去以生成分泌的或“成熟的”多肽形式。在某些实施方案中,使用天然的信号肽,例如免疫球蛋白重链或轻链信号肽,或该序列的保留指导与其可操作联合的多肽分泌的能力的功能性衍生物。或者,可以使用异源哺乳动物信号肽或其功能性衍生物。例如,可以将野生型前导序列用人组织血纤维蛋白溶酶原激活剂(TPA)或小鼠β-葡糖醛酸糖苷酶的前导序列替代。分泌性信号肽的例示性氨基酸和相应的多核苷酸序列显示于SEQ ID NO:115-123。
可以将编码能用于促进后期纯化(例如组氨酸标签)或辅助标记免疫细胞因子的短蛋白序列的DNA纳入编码免疫细胞因子(片段)的多核苷酸内或其末端。
在一个别的实施方案中,提供包含一种或多种本文所述多核苷酸的宿主细胞。在某些实施方案中,提供包含一种或多种本文所述载体的宿主细胞。多核苷酸和载体可以单独地或组合地纳入本文中分别关于多核苷酸和载体所描述的任何特征。在一个此类实施方案中,宿主细胞包含载体(例如已用该载体转化或转染),所述载体包含编码本文所述免疫细胞因子(一部分)的多核苷酸。如本文中使用的,术语“宿主细胞”指任何能工程化以生成免疫细胞因子或其片段的细胞系统种类。适用于复制并支持免疫细胞因子表达的宿主细胞是本领域中公知的。在适当时,可用特定的表达载体转染或转导此类细胞,并且可以培养大量的含载体细胞以用于接种大规模发酵罐,从而获得充足量的免疫细胞因子用于临床应用。合适的宿主细胞包括原核微生物如大肠杆菌,或各种真核细胞,如中国仓鼠卵巢细胞(CHO),昆虫细胞等。例如,可以在细菌中生成多肽,尤其在不需要糖基化时。在表达后,可以将多肽在可溶性级分中从细菌细胞糊分离并可以进一步纯化。除了原核生物外,真核微生物如丝状真菌或酵母也是适合编码多肽的载体的克隆或表达宿主,包括其糖基化途径已被“人源化”,导致生成具有部分或完全人的糖基化模式的多肽的真菌和酵母菌株。参见Gerngross,Nat Biotech 22,1409-1414(2004),和Li等,Nat Biotech 24,210-215(2006)。适用于表达(糖基化)多肽的宿主细胞还自多细胞生物体(无脊椎动物和脊椎动物)衍生。无脊椎动物细胞的例子包括植物和昆虫细胞。已鉴定出可与昆虫细胞一起使用的大量杆状病毒株,特别是用于转染草地贪夜蛾(Spodoptera frugiperda)细胞。也可以将植物细胞培养物用作宿主。参见例如美国专利No.5,959,177,6,040,498,6,420,548,7,125,978和6,417,429(描述用于在转基因植物中生成抗体的PLANTIBODIESTM技术)。脊椎动物细胞也可以用作宿主。例如,适应于在悬液中生长的哺乳动物细胞系可以是有用的。可用的哺乳动物宿主细胞系的其它例子是由SV40转化的猴肾CV1系(COS-7);人胚肾系(293或293T细胞,如例如记载于Graham等,J Gen Virol 36,59(1977)),幼仓鼠肾细胞(BHK),小鼠塞托利(sertoli)细胞(TM4细胞,如例如记载于Mather,Biol Reprod 23,243-251(1980)的),猴肾细胞(CV1),非洲绿猴肾细胞(VERO-76),人宫颈癌细胞(HELA),犬肾细胞(MDCK),buffalo大鼠肝细胞(BRL 3A),人肺细胞(W138),人肝细胞(Hep G2),小鼠乳房肿瘤细胞(MMT 060562),TRI细胞(如例如记载于Mather等,Annals N.Y.Acad Sci 383,44-68(1982)的),MRC 5细胞和FS4细胞。其它可用的哺乳动物宿主细胞系包括中国仓鼠卵巢(CHO)细胞,包括dhfr-CHO细胞(Urlaub等,Proc Natl Acad Sci USA 77,4216(1980));和骨髓瘤细胞系如YO,NS0,P3X63和Sp2/0。对于某些适用于蛋白质生产的哺乳动物宿主细胞系的综述,参见例如Yazaki和Wu,Methods in Molecular Biology,第248卷(B.K.C.Lo编,Humana Press,Totowa,NJ),pp.255-268(2003)。宿主细胞包括培养的细胞,例如哺乳动物培养细胞,酵母细胞,昆虫细胞,细菌细胞和植物细胞等,但还包括在转基因动物,转基因植物或培养的植物或动物组织中包含的细胞。在一个实施方案中,宿主细胞是真核细胞,优选为哺乳动物细胞如中国仓鼠卵巢(CHO)细胞,人胚肾(HEK)细胞或淋巴样细胞(例如Y0,NS0,Sp20细胞)。
本领域中已知在这些系统中表达外来基因的标准技术。可以将表达包含抗体的重链或轻链的多肽的细胞工程化改造为使得还表达另一抗体链,从而使得表达的产物是具有重链和轻链两者的抗体。
提供了生成本文所述免疫细胞因子的方法,其中所述方法包括在适合所述免疫细胞因子表达的条件下培养包含编码免疫细胞因子的多核苷酸的宿主细胞(如本文中提供的),并从宿主细胞(或宿主细胞培养基)回收所述免疫细胞因子。
所述免疫细胞因子的组分彼此遗传融合。免疫细胞因子可设计为使其组分直接彼此融合或经由接头序列间接融合。可依照本领域中公知的方法测定接头的组成和长度,并可以测试功效。效应器模块和Fc域之间的接头序列的例子见于以下显示的序列:SEQ IDNO:69,70,71,72,73,79,82,83和84。还包含另外的序列以纳入切割位点来分开融合物的各个组分(若期望的话),例如内肽酶识别序列。
免疫细胞因子至少包含能结合抗原决定簇的抗体可变区。可变区可形成天然或非天然存在的抗体及其片段的一部分和自其衍生。生成多克隆抗体和单克隆抗体的方法是本领域中公知的(参见例如Harlow和Lane,"Antibodies,a laboratory manual",ColdSpring Harbor Laboratory,1988)。非天然存在的抗体可以使用固相肽合成构建生成,可以重组生成(例如如记载于美国专利No.4,186,567的)或可通过例如筛选包含可变重链和可变轻链的组合库获得(参见例如McCafferty的美国专利No.5,969,108)。抗原结合模块以及其生成方法还详细记载于PCT公开文本No.WO 2011/020783,其完整内容通过提述并入本文。
可以将抗体,抗体片段,抗原结合域或可变区的任何动物种类用于本文所述免疫细胞因子。可用于本发明的非限制性抗体,抗体片段,抗原结合域或可变区可以是鼠,灵长类或人起源的。在免疫细胞因子意图供人使用的情况中,那么可以使用嵌合形式的抗体,其中抗体的恒定区来自人。也可以依照本领域中公知的方法制备人源化或全人形式的抗体(参见例如Winter的美国专利No.5,565,332)。人源化可以通过各种方法实现,包括但不限于(a)将非人(例如供体抗体)CDR嫁接到人(例如受体抗体)框架和恒定区上,保留或不保留关键的框架残基(例如那些对于保留较好的抗原结合亲和力或抗体功能重要的残基),(b)仅将非人特异性决定区(SDR或a-CDR;对于抗体-抗原相互作用关键的残基)嫁接到人框架和恒定区上,或(c)移植完整的非人可变域,但通过替换表面残基用人样部分来“掩饰(cloak)”它们。人源化的抗体及其制备方法综述于例如Almagro和Fransson,Front Biosci13,1619-1633(2008),并且还记载于例如Riechmann等,Nature 332,323-329(1988);Queen等,Proc Natl Acad Sci USA 86,10029-10033(1989);美国专利No.5,821,337,7,527,791,6,982,321和7,087,409;Jones等,Nature 321,522-525(1986);Morrison等,ProcNatl Acad Sci 81,6851-6855(1984);Morrison和Oi,Adv Immunol 44,65-92(1988);Verhoeyen等,Science 239,1534-1536(1988);Padlan,Molec Immun 31(3),169-217(1994);Kashmiri等,Methods 36,25-34(2005)(描述SDR(a-CDR)嫁接);Padlan,MolImmunol 28,489-498(1991)(描述“表面重建”);Dall’Acqua等,Methods 36,43-60(2005)(描述“FR改组”);和Osbourn等,Methods 36,61-68(2005)以及Klimka等,Br J Cancer 83,252-260(2000)(描述了FR改组的“引导选择”办法)。可以使用本领域中已知的各种技术来生成人抗体和人可变区。人抗体一般记载于van Dijk和van de Winkel,Curr OpinPharmacol 5,368-74(2001)以及Lonberg,Curr Opin Immunol 20,450-459(2008)。人可变区能形成通过杂交瘤方法制备的人单克隆抗体的一部分和自其衍生(参见例如MonoclonalAntibody Production Techniques and Applications,pp.51-63(Marcel Dekker,Inc.,New York,1987))。还可以通过对转基因动物施用免疫原来制备人抗体和人可变区,所述转基因动物已经过修饰以应答抗原激发而生成完整的人抗体或具有人可变区的完整抗体(参见例如Lonberg,Nat Biotech 23,1117-1125(2005)。还可以通过分离选自人衍生的噬菌体展示库的Fv克隆可变区序列来生成人抗体和人可变区(参见例如Hoogenboom等,于Methodsin Molecular Biology 178,1-37(O’Brien等编,Human Press,Totowa,NJ,2001);和McCafferty等,Nature 348,552-554;Clackson等,Nature 352,624-628(1991))。噬菌体通常展示抗体片段,作为单链Fv(scFv)片段或作为Fab片段。通过噬菌体展示来制备免疫缀合物的抗原结合模块的详细描述可见于PCT公开文本No.WO 2011/020783所附的实施例。
在某些实施方案中,将抗体工程化改造为具有增强的结合亲和力,其依照例如公开于PCT公开文本No.WO 2011/020783(参见涉及亲和力成熟的实施例)或美国专利申请公开文本No.2004/0132066的方法进行,其完整内容通过提述据此并入。可以经由酶联免疫吸附测定法(ELISA)或本领域技术人员熟知的其它技术来测量免疫细胞因子结合特定抗原决定簇的能力,所述其它技术例如表面等离振子共振技术(在BIACORE T100系统上分析)(Liljeblad等,Glyco J 17,323-329(2000))和传统的结合测定法(Heeley,Endocr Res28,217-229(2002))。可以使用竞争测定法来鉴定与参照抗体竞争对特定抗原的结合的抗体,抗体片段,抗原结合域或可变域,例如与CH1A1A 98/99 2F1抗体竞争对CEA的结合的抗体。在某些实施方案中,此类竞争性抗体结合由参照抗体结合的相同表位(例如线性或构象性表位)。用于定位抗体结合的表位的详细的例示性方法在Morris(1996)“EpitopeMapping Protocols,”于Methods in Molecular Biology vol.66(Humana Press,Totowa,NJ)中提供。在一种例示性竞争测定法中,将固定化的抗原(例如CEA)在溶液中温育,所述溶液包含结合该抗原的第一标记抗体(例如CH1A1A 98/99 2F1抗体)和测试其与第一抗体竞争对抗原的结合的能力的第二未标记抗体。第二抗体可以存在于杂交瘤上清液中。作为对照,将固定化的抗原在溶液中温育,所述溶液包含第一标记抗体但没有第二未标记抗体。在允许第一抗体结合抗原的条件下温育后,除去过量的未结合的抗体,并测量与固定化抗原联合的标记物的量。如果与固定化抗原联合的标记物的量在测试样品中相对于对照样品实质性降低,那么这指示第二抗体在与第一抗体竞争对抗原的结合。参见Harlow和Lane(1988)Antibodies:A Laboratory Manual ch.14(Cold Spring Harbor Laboratory,ColdSpring Harbor,NY)。
可以通过本领域已知的技术来纯化如本文中描述的那样制备的免疫细胞因子,所述技术如高效液相层析,离子交换层析,凝胶电泳,亲和层析,大小排阻层析等。用于纯化具体蛋白质的实际条件将部分取决于因素,如净电荷,疏水性,亲水性等,而且对于本领域中的技术人员将是明显的。对于亲和层析纯化,能使用免疫细胞因子结合的抗体,配体,受体或抗原。例如,对于免疫细胞因子的亲和层析纯化,可以使用具有蛋白A或蛋白G的基质。可以使用连续的蛋白A或G亲和层析和大小排阻层析来分离免疫细胞因子,基本如WO 2012/146628实施例中描述的。可以通过多种公知的分析方法中的任一种来测定免疫细胞因子的纯度,包括凝胶电泳,高压液相层析等。例如,免疫细胞因子可以显示为完整且适当装配的,如通过还原性SDS-PAGE证明的。
可以如WO 2012/146628和WO 2012/107417实施例中记载的那样来制备本文所述肿瘤靶向性IL-2变体免疫细胞因子,诸如CEA靶向性IL-2变体免疫细胞因子和FAP靶向性IL-2变体免疫细胞因子。
优选通过重组手段来生产本文所述抗体。此类方法是现有技术广泛知道的,而且包括原核和真核细胞中的蛋白质表达,随后分离抗体多肽且通常纯化至药学可接受纯度。为了蛋白质表达,通过标准方法将编码轻和重链或其片段的核酸插入表达载体中。在适宜的原核或真核宿主细胞中实施表达,诸如CHO细胞,NS0细胞,SP2/0细胞,HEK293细胞,COS细胞,酵母,或大肠杆菌细胞,并自细胞(自上清液或在细胞裂解后)回收抗体。
抗体的重组生产是现有技术公知的,而且记载于例如综述性论文Makrides,S.C.,Protein Expr.Purif.17(1999)183-202;Geisse,S.等人,Protein Expr.Purif.8(1996)271-282;Kaufman,R.J.,Mol.Biotechnol.16(2000)151-161;Werner,R.G.,Drug Res.48(1998)870-880。
抗体可以存在于完整细胞中,细胞裂解物中,或部分纯化的或实质性纯的形式。通过标准技术实施纯化以消除其它细胞成分或其它污染物,例如其它细胞核酸或蛋白质,标准技术包括碱/SDS处理,CsCl成带,柱层析,琼脂糖凝胶电泳,和本领域公知的其它技术。参见Ausubel,F.等人编,Current Protocols in Molecular Biology,Greene Publishingand Wiley Interscience,New York(1987)。
NS0细胞中的表达记载于例如Barnes,L.M.等人,Cytotechnology 32(2000)109-123;Barnes,L.M.等人,Biotech.Bioeng.73(2001)261-270。瞬时表达记载于例如Durocher,Y.等人,Nucl.Acids.Res.30(2002)E9。可变域的克隆记载于Orlandi,R.等人,Proc.Natl.Acad.Sci.USA 86(1989)3833-3837;Carter,P.等人,Proc.Natl.Acad.Sci.USA89(1992)4285-4289;Norderhaug,L.等人,J.Immunol.Methods 204(1997)77-87。一种优选的瞬时表达系统(HEK 293)记载于Schlaeger,E.-J.和Christensen,K.,Cytotechnology30(1999)71-83,及Schlaeger,E.-J.,J.Immunol.Methods 194(1996)191-199。
将依照本发明的重和轻链可变域与启动子,翻译起始,恒定区,3'非翻译区,聚腺苷酸化,和翻译终止的序列组合以形成表达载体构建物。可以将重和轻链表达构建物组合入单一载体中,共转染,序贯转染,或分开转染入宿主细胞中,然后融合以形成表达双链的单一宿主细胞。
适合于原核生物的控制序列包括例如启动子,任选的操纵基因序列,和核糖体结合位点。已知真核细胞利用启动子,增强子和聚腺苷酸化信号。
在将核酸放置在与另一种核酸序列的功能性关系中时,它是“可操作连接的”。例如,若前序列或分泌前导的DNA以参与多肽分泌的前蛋白表达,则它与多肽的DNA可操作连接;若启动子或增强子影响序列的转录,则它与编码序列可操作连接;或者若核糖体结合位点定位为使得便于翻译,则它与编码序列可操作连接。一般而言,“可操作连接的”意指所连接的DNA序列是连续的,而且在分泌前导的情况中,是连续的且在读码框中。然而,增强子不必是连续的。通过在方便的限制性位点处的连接来实现连接。若不存在此类位点,则依照常规的实践使用合成的寡核苷酸衔接头或接头。
通过常规免疫球蛋白纯化规程,诸如例如蛋白A-Sepharose,羟磷灰石层析,凝胶电泳,透析,或亲和层析,恰当地将单克隆抗体与培养液分开。使用常规规程,容易分离编码单克隆抗体的DNA和RNA及测序。杂交瘤细胞可充当此类DNA和RNA的来源。一旦分离,可以将该DNA插入表达载体中,然后将该表达载体转染入不另外生成免疫球蛋白蛋白质的宿主细胞(诸如HEK 293细胞,CHO细胞,或骨髓瘤细胞)中,以获得该宿主细胞中重组单克隆抗体的合成。
如本文中使用的,表述“细胞”,“细胞系”,和“细胞培养物”可互换使用,而且所有此类名称包括后代。如此,词语“转化子”和“经转化细胞”包括原代受试细胞及自其衍生的培养物,不管转移的次数。还理解,由于有意的或无意的突变,所有后代的DNA内容可以不是精确相同的。包括具有与在初始转化细胞中所筛选的相同的功能或生物学活性的变异后代。
治疗方法和组合物
本发明包含用于治疗需要治疗的患者的方法,其特征在于对该患者施用治疗有效量的依照本发明的肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体的组合疗法。
本发明包含依照本发明的肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体用于所描述的组合疗法的用途。
本发明的一个优选的实施方案是本发明的肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体的组合疗法,其用于治疗癌症或肿瘤。
如此,本发明的一个实施方案是本文所述肿瘤靶向性IL-2变体免疫细胞因子,其用于与本文所述抗PD-L1抗体组合治疗癌症或肿瘤。
本发明的另一个实施方案是本文所述抗PD-L1抗体,其用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合治疗癌症或肿瘤。
肿瘤靶向性IL-2变体免疫细胞因子可以是依照本文所述发明的CEA靶向性IL-2变体免疫细胞因子或FAP靶向性IL-2变体免疫细胞因子。
癌症或肿瘤可以呈递肿瘤细胞上或肿瘤细胞环境中的抗原。组合疗法的靶物可以是在肿瘤细胞上或在肿瘤细胞环境中呈递的。癌症或肿瘤可以表达或过表达CEA或FAP。治疗可以是实体瘤的。实体瘤可以表达或过表达CEA或FAP。治疗可以是癌症的。癌症可以表达或过表达CEA或FAP。癌症可以选自下组:结直肠癌,头和颈癌,非小细胞肺癌,乳腺癌,胰腺癌,肝癌和胃癌。癌症可以选自下组:肺癌,结肠癌,胃癌,乳腺癌,头和颈癌,皮肤癌,肝癌,肾癌,前列腺癌,胰腺癌,脑癌和骨骼肌癌。
如本文中使用的,术语“癌症”可以是例如肺癌,非小细胞肺(NSCL)癌,支气管肺泡细胞肺癌,骨癌,胰腺癌,皮肤癌,头和颈癌,皮肤或眼内黑素瘤,子宫癌,卵巢癌,直肠癌,肛门区癌,胃癌,胃的癌,结肠癌,乳腺癌,子宫的癌,输卵管癌,子宫内膜癌,宫颈癌,阴道癌,阴门癌,何杰金(Hodgkin)氏病,食管癌,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,肾或输尿管癌,肾细胞癌,肾盂癌,间皮瘤,肝细胞癌,胆囊癌,中枢神经系统(CNS)新生物,脊柱轴肿瘤,脑干胶质瘤,多形性成胶质细胞瘤,星形细胞瘤,施旺细胞瘤,室管膜瘤,髓母细胞瘤,脑脊膜瘤,鳞状细胞癌,垂体腺瘤,淋巴瘤,淋巴细胞性白血病,包括任何上述癌症的顽固形式,或一种或多种上述癌症的组合。在一个优选的实施方案中,此类癌症是乳腺癌,结直肠癌,黑素瘤,头和颈癌,肺癌或前列腺癌。在一个优选的实施方案中,此类癌症是乳腺癌,卵巢癌,宫颈癌,肺癌或前列腺癌。在另一个优选的实施方案中,此类癌症是乳腺癌,肺癌,结肠癌,卵巢癌,黑素瘤癌,膀胱癌,肾的癌,肾癌,肝癌,头和颈癌,结直肠癌,胰腺癌,胃癌癌,食道癌,间皮瘤,前列腺癌,白血病,淋巴瘤,骨髓瘤。在一个优选的实施方案中,此类癌症进一步特征在于CEA或FAP表达或过表达。
本发明的一个实施方案是与本文所述抗PD-L1抗体组合的本文所述肿瘤靶向性IL-2变体免疫细胞因子,其用于治疗任何上文所述癌症或肿瘤。
本发明的另一个实施方案是与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合的本文所述抗PD-L1抗体,其用于治疗任何上文所述癌症或肿瘤。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子与本文所述抗PD-L1抗体的组合疗法,其用于治疗癌症。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子与本文所述抗PD-L1抗体的组合疗法,其用于预防或治疗转移。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子与本文所述抗PD-L1抗体的组合疗法,其用于治疗炎性疾病。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子与本文所述抗PD-L1抗体的组合疗法,其用于治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子与本文所述抗PD-L1抗体的组合疗法,其用于刺激免疫应答或功能,诸如T细胞活性。
本发明包含用于在有所需要的患者中治疗癌症的方法,其特征在于对该患者施用本文所述肿瘤靶向性IL-2变体免疫细胞因子和本文所述抗PD-L1抗体。
本发明包含用于在有所需要的患者中预防或治疗转移的方法,其特征在于对该患者施用本文所述肿瘤靶向性IL-2变体免疫细胞因子和本文所述抗PD-L1抗体。
本发明包含用于在有所需要的患者中治疗炎性疾病的的方法,其特征在于对该患者施用本文所述肿瘤靶向性IL-2变体免疫细胞因子和本文所述抗PD-L1抗体。
本发明包含用于在有所需要的患者中治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展的方法,其特征在于对该患者施用本文所述肿瘤靶向性IL-2变体免疫细胞因子和本文所述抗PD-L1抗体
本发明包含用于在有所需要的患者中刺激免疫应答或功能,诸如T细胞活性的方法,其特征在于对该患者施用本文所述肿瘤靶向性IL-2变体免疫细胞因子和本文所述抗PD-L1抗体。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子,其用于与本文所述抗PD-L1抗体组合治疗癌症,或者用于制造用于与本文所述抗PD-L1抗体组合治疗癌症的药物。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子,其用于与本文所述抗PD-L1抗体组合预防或治疗转移,或者用于制造用于与本文所述抗PD-L1抗体组合预防或治疗转移的药物。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子,其用于与本文所述抗PD-L1抗体组合治疗炎性疾病,或者用于制造用于与本文所述抗PD-L1抗体组合治疗炎性疾病的药物。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子,其用于与本文所述抗PD-L1抗体组合治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或者用于制造用于与本文所述抗PD-L1抗体组合治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展的药物。
本发明包含本文所述肿瘤靶向性IL-2变体免疫细胞因子,其用于与本文所述抗PD-L1抗体组合刺激免疫应答或功能,诸如T细胞活性,或者用于制造用于与本文所述抗PD-L1抗体组合刺激免疫应答或功能,诸如T细胞活性的药物。
本发明包含本文所述抗PD-L1抗体,其用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合治疗癌症,或者用于制造用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合治疗癌症的药物。
本发明包含本文所述抗PD-L1抗体,其用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合预防或治疗转移,或者用于制造用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合预防或治疗转移的药物。
本发明包含本文所述抗PD-L1抗体,其用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合治疗炎性疾病,或者用于制造用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合治疗炎性疾病的药物。
本发明包含本文所述抗PD-L1抗体,其用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或者用于制造用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展的药物。
本发明包含本文所述抗PD-L1抗体,其用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合刺激免疫应答或功能,诸如T细胞活性,或者用于制造用于与本文所述肿瘤靶向性IL-2变体免疫细胞因子组合刺激免疫应答或功能,诸如T细胞活性的药物。
在本发明的一个优选的实施方案中,上文所述不同疾病的组合治疗和医药用途中使用的肿瘤靶向性IL-2变体免疫细胞因子是CEA靶向性IL-2变体免疫细胞因子,其特征在于包含SEQ ID NO:84,SEQ ID NO:86和SEQ ID NO:88的多肽序列,且
此类组合治疗中使用的结合人PD-L1的抗体特征在于包含SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
在本发明的一个优选的实施方案中,上文所述不同疾病的组合治疗和医药用途中使用的肿瘤靶向性IL-2变体免疫细胞因子是FAP靶向性IL-2变体免疫细胞因子,其特征在于包含SEQ ID NO:79,SEQ ID NO:80和SEQ ID NO:81的多肽序列,且
此类组合治疗中使用的结合人PD-L1的抗体特征在于包含SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
在另一个方面,本发明提供一种组合物,例如一种药物组合物,其含有与药学可接受载剂一起配制的本文所述肿瘤靶向性IL-2变体免疫细胞因子和本文所述结合人PD-L1的抗体或其抗原结合部分。
如本文中使用的,“药学可接受载体”包括任何和所有生理学相容的溶剂,分散介质,涂层,抗细菌和抗真菌剂,等张和吸收/再吸收延迟剂,等等。优选地,载体适合于注射或输注。
可以通过本领域已知的多种方法来施用本发明的组合物。正如技术人员会领会的,施用的路径和/或模式会随期望的结果而变化。
药学可接受载体包括无菌水溶液或分散体和用于制备无菌可注射溶液或分散体的无菌粉末。此类介质和药剂对药学活性物质的使用是本领域已知的。在水之外,载体可以是例如等张缓冲盐水溶液。
不管选择的施用路径,通过本领域技术人员知道的常规方法将可以以合适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配制成药学可接受剂量形式。
本发明的药物组合物中活性组分的实际剂量水平可以变化以获得对特定患者,组合物,和施用模式有效实现期望治疗响应,对患者没有毒性的活性组分量(有效量)。选择的剂量水平会取决于多种药动学因素,包括采用的本发明特定组合物或其酯,盐或酰胺的活性,施用路径,施用时间,采用的特定化合物的排泄速率,与采用的特定组合物组合使用的其它药物,化合物和/或材料,治疗的患者的年龄,性别,重量,状况,一般健康和在先医学史,及医学领域公知的类似因素。
在一个方面,本发明提供一种意图用于治疗疾病的试剂盒,其在相同的容器中或在分开的容器中包含(a)本文所述肿瘤靶向性IL-2变体免疫细胞因子,和(b)本文所述结合人PD-L1的抗体,且任选进一步包含(c)包装插页,其包括指导作为治疗疾病的方法使用该组合治疗的印刷说明书。此外,所述试剂盒可以包含(a)其中装有如下组合物的第一容器,其中所述组合物包含本文所述结合人PD-L1的抗体;(b)其中装有如下组合物的第二容器,其中所述组合物包含本文所述肿瘤靶向性IL-2变体免疫细胞因子;和任选的(c)其中装有如下组合物的第三容器,其中所述组合物包含别的细胞毒性剂或其它方面治疗剂。本发明的这一实施方案中的试剂盒可以进一步包含包装插页,其指示该组合物可用于治疗特定状况。或者/另外地,所述试剂盒可以进一步包含第三(或第四)容器,其装有药学可接受的缓冲液,诸如抑菌性注射用水(BWFI),磷酸盐缓冲盐水,林格(Ringer)氏溶液和右旋糖溶液。它可以进一步包括从商业和用户立场看期望的其它材料,包括其它缓冲液,稀释剂,滤器,针,和注射器。
在一个方面,本发明提供一种意图用于治疗疾病的试剂盒,其包含(a)装有本文所述肿瘤靶向性IL-2变体免疫细胞因子的容器,和(b)包装插页,其包括指导作为治疗疾病的方法与本文所述抗PD-L1抗体一起在组合疗法中使用该肿瘤靶向性IL-2变体免疫细胞因子的说明书。
在另一个方面,本发明提供一种意图用于治疗疾病的试剂盒,其包含(a)装有本文所述抗PD-L1抗体的容器,和(b)包装插页,其包括指导作为治疗疾病的方法与本文所述肿瘤靶向性IL-2变体免疫细胞因子一起在组合疗法中使用该抗PD-L1抗体的说明书。
在又一个方面,本发明提供一种意图用于治疗疾病的药物,其包含本文所述肿瘤靶向性IL-2变体免疫细胞因子,其中所述药物与本文所述结合人PD-L1的抗体一起用于组合疗法,且任选包含包装插页,其包括指导作为治疗疾病的方法使用所述组合治疗的印刷说明书。
在仍有又一个方面,本发明提供一种意图用于治疗疾病的药物,其包含本文所述结合人PD-L1的抗体,其中所述药物与本文所述肿瘤靶向性IL-2变体免疫细胞因子一起用于组合疗法,且任选包含包装插页,其包括指导作为治疗疾病的方法使用所述组合治疗的印刷说明书。
术语“治疗方法”或其等同用语在应用于例如癌症时指设计为降低或消除患者中的癌细胞数目,或者减轻癌症症状的规程或作用过程。癌症或另一种增殖性病症的“治疗方法”不必意味着实际上会消除癌细胞或其它病症,实际上会降低细胞数目或病症,或实际上会减轻癌症或其它病症的症状。经常,甚至会实施具有较低的成功概率,但是然而鉴于医学史和估计的患者存活预期认为诱导总体有益的作用过程的治疗癌症的方法。
术语“与……组合施用”,“共施用”,“组合疗法”或“组合治疗”指例如作为分开的配制剂/应用(或者作为一种单一配制剂/应用)施用本文所述肿瘤靶向性IL-2变体免疫细胞因子和本文所述结合人PD-L1的抗体。共施用可以是同时的或者以任意次序序贯的,其中优选地,存在着所有活性剂同时施加其生物学活性的时段。同时或序贯(例如静脉内(i.v.)经由连续输注)共施用所述活性剂。在序贯共施用这两种治疗剂时,在同一天在两次分开的施用中施用剂量,或者在第1天施用药剂之一,而在第2天至第7天,优选在第2天至第4天共施用第二种。如此,在一个实施方案中,术语“序贯地”意指在第一组分的剂量后7天内,优选在第一组分的剂量后4天内;而术语“同时地”意指同一时间。术语“共施用”就肿瘤靶向性IL-2变体免疫细胞因子和/或抗PD-L1抗体的维持剂量而言意指若治疗周期对于这两种药物都是合适的,例如每周,则可以同时共施用维持剂量。或者,序贯共施用维持剂量,例如在交替的周给予肿瘤靶向性IL-2变体免疫细胞因子和抗PD-L1抗体的剂量。
不证自明的是,以“治疗有效量”(或仅为“有效量”)对患者施用抗体,所述治疗有效量是相应化合物或组合会引发研究人员,兽医,医学医生或其它临床医生寻找的组织,系统,动物或人的生物学或医学应答的量。
共施用量和共施用时机会取决于所治疗患者的类型(物种,性别,年龄,重量,等)和状况和所治疗疾病或状况的严重性。可以一次或在一系列治疗里,例如在同一天或在次日或以每周间隔对患者适当地共施用所述肿瘤靶向性IL-2变体免疫细胞因子和/或抗PD-L1抗体。
例如,可以在第1周中同时共施用肿瘤靶向性IL-2变体免疫细胞因子和/或抗PD-L1抗体,隔周交替肿瘤靶向性IL-2变体免疫细胞因子和抗PD-L1抗体的维持剂,例如以肿瘤靶向性IL2变体免疫细胞因子开始,例如持续3周。例如,可以在第1周中同时共施用肿瘤靶向性IL-2变体免疫细胞因子和/或抗PD-L1抗体,同时共施用肿瘤靶向性IL-2变体免疫细胞因子和抗PD-L1抗体的维持剂,例如每周,例如持续例如2周的总治疗时间。例如,可以在第1周中同时共施用肿瘤靶向性IL-2变体免疫细胞因子和/或抗PD-L1抗体,同时共施用肿瘤靶向性IL-2变体免疫细胞因子和抗PD-L1抗体的维持剂,例如每周,例如持续例如5周的总治疗时间(也可以描述为持续5周一周一次同时共施用肿瘤靶向性IL-2变体免疫细胞因子和抗PD-L1抗体的治疗方案)。在一个实施方案中,每两周一次,每三周一次或每四周一次施用肿瘤靶向性IL-2变体免疫细胞因子。在一个实施方案中,每两周一次或每三周一次施用抗PD-L1抗体。在一个实施方案中,在治疗周期的第一天序贯进行肿瘤靶向性IL-2变体免疫细胞因子和抗PD-L1抗体的第一次施用。
根据疾病的类型和严重性,约0.1mg/kg至50mg/kg(例如0.1-20mg/kg)所述肿瘤靶向性IL-2变体免疫细胞因子和/或抗PD-L1抗体是将两种药物共施用于患者的初始候选剂量。此外,所述肿瘤靶向性IL-2变体免疫细胞因子和/或抗PD-L1抗体的剂量可以是平坦-固定剂量,不管患者的重量。例如,可以为肿瘤靶向性IL-2变体免疫细胞因子选择最大剂量平坦1mg/kg或40mg;起始剂量平坦10mg,一周一次或隔周一次或0.05-0.5mg/kg一周一次或隔周一次。在一个实施方案中,每两周,每三周,或每四周施用平坦-固定剂量5-50mg,例如5mg,6mg,10mg,15mg,20mg,25mg,30mg,35mg,40mg,45mg或50mg肿瘤靶向性IL-2变体免疫细胞因子。例如,可以为抗PD-L1抗体选择最大剂量20mg/kg q3w;如果降低的话,10mg/kg。在一个实施方案中,每两周施用平坦-固定剂量800mg抗PD-L1抗体。在另一个实施方案中,每三周施用平坦-固定剂量1200mg抗PD-L1抗体。本发明包含依照本发明的肿瘤靶向性IL-2变体免疫细胞因子和抗PD-L1抗体用于治疗罹患癌症,例如结直肠,肝或胰腺癌的患者的用途。
在与抗PD-L1抗体组合的肿瘤靶向性IL-2变体免疫细胞因子以外,还可以施用化疗剂。
在一个实施方案中,此类可以与本文所述肿瘤靶向性IL-2变体免疫细胞因子和本文所述抗PD-L1抗体一起施用的另外的化疗剂包括但不限于抗肿瘤剂,包括烷化剂,包括:氮芥,诸如二氯甲基二乙胺(mechlorethamine),环磷酰胺(cyclophosphamide),异环磷酰胺(ifosfamide),美法仑(melphalan)和苯丁酸氮芥(chlorambucil);亚硝基脲(nitrosourea),诸如卡莫司汀(carmustine)(BCNU),洛莫司汀(lomustine)(CCNU),和司莫司汀(semustine)(methyl-CCNU);TemodalTM(替莫唑胺(temozolamide)),乙撑亚胺/甲基蜜胺诸如三乙撑蜜胺(TEM),三乙烯硫代磷酰胺(塞替派(thiotepa)),六甲基蜜胺(HMM,六甲蜜胺(altretamine));烃基磺酸酯,诸如白消安(busulfan);三嗪,诸如达卡巴嗪(dacarbazine)(DTIC);抗代谢物,包括叶酸类似物,诸如甲氨喋呤(methotrexate)和三甲曲沙(trimetrexate),嘧啶类似物,诸如5-氟尿嘧啶(5FU),氟脱氧尿苷,吉西他滨(gemcitabine),胞嘧啶阿拉伯糖苷(AraC,阿糖胞苷(cytarabine)),5-氮胞苷,2,2'-二氟脱氧胞苷,嘌呤类似物,诸如6-巯基嘌呤,6-硫鸟嘌呤,硫唑嘌呤(azathioprine),T-脱氧柯福霉素(喷司他丁(pentostatin)),erythrohydroxynonyladenine(EHNA),磷酸氟达拉滨(fludarabine phosphate),和2-氯脱氧腺苷(克拉屈滨(cladribine),2-CdA);天然产物,包括抗有丝分裂药物,诸如帕利他赛(paclitaxel),长春花生物碱(包括长春碱(vinblastine)(VLB),长春新碱(vincristine),和长春瑞滨(vinorelbine)),泰索帝(taxotere),雌莫司汀(estramustine),和磷酸雌莫司汀;表鬼臼毒素(pipodophylotoxin),诸如依托泊苷(etoposide)和替尼泊苷(teniposide);抗生素,诸如放线菌素D(actinomycin D),道诺霉素(daunomycin)(柔红霉素(rubidomycin)),多柔比星(doxorubicin),米托蒽醌(mitoxantrone),伊达比星(idarubicin),博来霉素(bleomycin),普卡霉素(plicamycin)(光辉霉素(mithramycin)),丝裂霉素C(mitomycinC),和放线菌素(actinomycin);酶,诸如L-天冬酰胺酶;生物学应答改性剂,诸如干扰素-α,IL-2,G-CSF和GM-CSF;包括铂配位复合物的混杂剂,诸如奥沙利铂(oxaliplatin),顺铂(cisplatin)和卡铂(carboplatin),蒽二酮,诸如米托蒽醌(mitoxantrone),取代的脲,诸如羟基脲,甲基肼衍生物,包括N-甲基肼(MIH)和丙卡巴肼(procarbazine),肾上腺皮质阻抑剂,诸如米托坦(mitotane)(o,p-DDD)和氨鲁米特(aminoglutethimide);激素和拮抗剂,包括肾上腺皮质类固醇拮抗剂,诸如强的松(prednisone)及等效物,地塞米松(dexamethasone)和氨鲁米特(aminoglutethimide);GemzarTM(吉西他滨(gemcitabine)),妊娠素,诸如己酸羟基孕酮(hydroxyprogesterone caproate),乙酸甲羟孕酮(medroxyprogesterone acetate)和乙酸甲地孕酮(megestrol acetate);雌激素,诸如己烯雌酚(diethylstilbestrol)和乙炔雌二醇等效物;抗雌激素,诸如他莫昔芬(tamoxifen);雄激素,包括丙酸睾酮(testosterone propionate)和氟甲睾酮(fluoxymesterone)/等效物;抗雄激素,诸如氟他胺(flutamide),促性腺激素释放激素类似物和亮丙瑞林(leuprolide);和非类固醇抗雄激素,诸如氟他胺(flutamide)。靶向后成机制的疗法包括但不限于组蛋白脱乙酰基酶抑制剂,脱甲基化剂(例如Vidaza)和释放转录阻抑(ATRA)疗法也可以与抗原结合蛋白质组合。在一个实施方案中,化疗剂选自下组:紫杉烷(像例如帕利他赛(Taxol),多西他赛(Taxotere),经修饰的帕利他赛(例如Abraxane和Opaxio),多柔比星,舒尼替尼(Sutent),索拉非尼(Nexavar),和其它多激酶抑制剂,奥沙利铂,顺铂和卡铂,依托泊苷,吉西他滨,和长春碱。在一个实施方案中,化疗剂选自下组:紫杉烷(像例如帕利他赛(Taxol),多西他赛(Taxotere),经修饰的帕利他赛(例如Abraxane和Opaxio)。在一个实施方案中,别的化疗剂选自5-氟尿嘧啶(5-FU),亚叶酸,伊立替康,或奥沙利铂。在一个实施方案中,化疗剂为5-氟尿嘧啶,亚叶酸和伊立替康(FOLFIRI)。在一个实施方案中,化疗剂为5-氟尿嘧啶和奥沙利铂(FOLFOX)。
与别的化疗剂的组合疗法的具体例子包括例如与紫杉烷(例如多西他赛或帕利他赛)或经修饰的帕利他赛(例如Abraxane或Opaxio),多柔比星,卡培他滨和/或贝伐单抗(Avastin)用于治疗乳腺癌的疗法;与卡铂,奥沙利铂,顺铂,帕利他赛,多柔比星(或经修饰的多柔比星(Caelyx或Doxil)),或拓扑替康(Hycamtin)用于卵巢癌的疗法;与多激酶抑制剂MKI(Sutent,Nexavar,或706)和/或多柔比星用于治疗肾癌的疗法;与奥沙利铂,顺铂和/或放射用于治疗鳞状细胞癌的疗法;与Taxol和/或卡铂用于治疗肺癌的疗法。
因此,在一个实施方案中,别的化疗剂选自下组:紫杉烷(多西他赛或帕利他赛)或经修饰的帕利他赛(Abraxane或Opaxio),多柔比星,卡培他滨和/或贝伐单抗(用于治疗乳腺癌)。
在一个实施方案中,肿瘤靶向性IL-2变体免疫细胞因子/PD-L1抗体组合疗法是不施用化疗剂的。
本发明还包含一种用于治疗患有诸如本文所述疾病的患者的方法。
本发明进一步提供一种用于制备包含有效量的依照本文所述发明的肿瘤靶向性IL-2变体免疫细胞因子和依照本文所述发明的抗PD-L1抗体以及药学可接受载体的药物组合物的方法及依照本文所述发明的肿瘤靶向性IL-2变体免疫细胞因子和抗PD-L1抗体对此类方法的用途。
本发明进一步提供有效量的依照本文所述发明的肿瘤靶向性IL-2变体免疫细胞因子和依照本文所述发明的抗PD-L1抗体用于制备药物制剂的用途,优选地,与药学可接受载体一起,用于治疗患有癌症的患者。
提供下面的实施例,序列表和附图来帮助理解本发明,所附权利要求书列出本发明的真实范围。理解的是,可以在所列规程中进行更改而不偏离本发明的精神。
序列说明
SEQ ID NO:1 例示性人IgG1 Fc区
SEQ ID NO:2 人IL-2(C125A)
SEQ ID NO:3 四重突变体人IL-2(IL-2qm)
SEQ ID NO:4 人PD-L1(包括信号序列)
SEQ ID NO:5 轻链可变域,Mab 3F2
SEQ ID NO:6 轻链可变域,Mab 3F2(YS)
SEQ ID NO:7 重链可变域,Mab 3F2
SEQ ID NO:8 轻链可变域,Mab 3D9
SEQ ID NO:9 重链可变域,Mab 3D9
SEQ ID NO:10 重链可变域,Mab 3D9(TA)
SEQ ID NO:11 轻链可变域,Mab 4G8
SEQ ID NO:12 重链可变域,Mab 4G8
SEQ ID NO:13 轻链可变域,Mab 4B3
SEQ ID NO:14 重链可变域,Mab 4B3
SEQ ID NO:15 轻链可变域,Mab 4D6
SEQ ID NO:16 重链可变域,Mab 4D6
SEQ ID NO:17 轻链可变域,Mab 2C6
SEQ ID NO:18 重链可变域,Mab 2C6
SEQ ID NO:19 轻链可变域,Mab 5H5
SEQ ID NO:20 重链可变域,Mab 5H5
SEQ ID NO:21 轻链可变域,Mab 2C4
SEQ ID NO:22 重链可变域,Mab 2C4
SEQ ID NO:23 轻链可变域,Mab 2D9
SEQ ID NO:24 重链可变域,Mab 2D9
SEQ ID NO:25 轻链可变域,Mab 4B8
SEQ ID NO:26 重链可变域,Mab 4B8
SEQ ID NO:27 轻链可变域,Mab 7A1
SEQ ID NO:28 重链可变域,Mab 7A1
SEQ ID NO:29 轻链可变域,Mab 13C2
SEQ ID NO:30 重链可变域,Mab 13C2
SEQ ID NO:31 轻链可变域,Mab 13E8
SEQ ID NO:32 重链可变域,Mab 13E8
SEQ ID NO:33 轻链可变域,Mab 14C10
SEQ ID NO:34 重链可变域,Mab 14C10
SEQ ID NO:35 轻链可变域,Mab 17A11
SEQ ID NO:36 重链可变域,Mab 17A11
SEQ ID NO:37 轻链可变域,Mab 19G1
SEQ ID NO:38 重链可变域,Mab 19G1
SEQ ID NO:39 轻链可变域,Mab 20G8
SEQ ID NO:40 重链可变域,Mab 20G8
SEQ ID NO:41 轻链可变域,Mab 4B9
SEQ ID NO:42 重链可变域,Mab 4B9
SEQ ID NO:43 轻链可变域,Mab 5B8
SEQ ID NO:44 重链可变域,Mab 5B8
SEQ ID NO:45 轻链可变域,Mab 5F1
SEQ ID NO:46 重链可变域,Mab 5F1
SEQ ID NO:47 轻链可变域,Mab 14B3
SEQ ID NO:48 重链可变域,Mab 14B3
SEQ ID NO:49 轻链可变域,Mab 16F1
SEQ ID NO:50 重链可变域,Mab 16F1
SEQ ID NO:51 轻链可变域,Mab 16F8
SEQ ID NO:52 重链可变域,Mab 16F8
SEQ ID NO:53 轻链可变域,Mab O3C9
SEQ ID NO:54 重链可变域,Mab O3C9
SEQ ID NO:55 轻链可变域,Mab O2D7
SEQ ID NO:56 重链可变域,Mab O2D7
SEQ ID NO:57 轻链可变域,Mab 28H1
SEQ ID NO:58 重链可变域,Mab 28H1
SEQ ID NO:59 轻链可变域,Mab 22A3
SEQ ID NO:60 重链可变域,Mab 22A3
SEQ ID NO:61 轻链可变域,Mab 29B11
SEQ ID NO:62 重链可变域,Mab 29B11
SEQ ID NO:63 轻链可变域,Mab 23C10
SEQ ID NO:64 重链可变域,Mab 23C10
SEQ ID NO:65 轻链可变域,Mab CH1A1A 98/99 2F1
SEQ ID NO:66 重链可变域,Mab CH1A1A 98/99 2F1
SEQ ID NO:67 轻链可变域,Mab CH1A1A 98/99 2F1
SEQ ID NO:68 重链可变域,Mab CH1A1A 98/99 2F1
SEQ ID NO:69 28H1 Fab HC-Fc节(LALA P329G)-IL-2qm
SEQ ID NO:70 4G8 Fab HC-Fc节(LALA P329G)-IL-2qm
SEQ ID NO:71 4B9 Fab HC-Fc节(LALA P329G)-IL-2qm
SEQ ID NO:72 28H1 Fab HC-Fc节(LALA P329G)-IL-2qm(2)
SEQ ID NO:73 4B9 Fab HC-Fc节(LALA P329G)-IL-2qm(2)
SEQ ID NO:74 28H1 Fab HC-Fc穴(LALA P329G)
SEQ ID NO:75 4G8 Fab HC-Fc穴(LALA P329G)
SEQ ID NO:76 4B9 Fab HC-Fc穴(LALA P329G)
SEQ ID NO:77 4G8 Fab LC
SEQ ID NO:78 3F2 Fab LC
SEQ ID NO:79 4B9 Fab HC-Fc节(LALA P329G)-IL-2qm(2)
SEQ ID NO:80 4B9 Fab HC-Fc穴(LALA P329G)
SEQ ID NO:81 3F2 Fab LC
SEQ ID NO:82 CH1A1A 98/99 2F1 Fab HC-Fc节(wt)-IL-2qm
SEQ ID NO:83 CH1A1A 98/99 2F1 Fab HC-Fc节(wt)-IL-2qm
SEQ ID NO:84 CH1A1A 98/99 2F1 Fab HC-Fc节(LALA P329G)-IL-2qm
SEQ ID NO:85 CH1A1A 98/99 2F1 Fab HC-Fc穴(wt)
SEQ ID NO:86 CH1A1A 98/99 2F1 Fab HC-Fc穴(LALA P329G)
SEQ ID NO:87 CH1A1A 98/99 2F1 Fab LC
SEQ ID NO:88 CH1A1A 98/99 2F1 Fab LC
SEQ ID NO:89 重链可变域VH变体1,抗PD-L1 243.55
SEQ ID NO:90 重链可变域VH变体2,抗PD-L1 243.55
SEQ ID NO:91 重链可变域VH变体3,抗PD-L1 243.55
SEQ ID NO:92 轻链可变域VL变体1,抗PD-L1 243.55
SEQ ID NO:93 轻链可变域VL变体2,抗PD-L1 243.55
SEQ ID NO:94 轻链可变域VL变体3,抗PD-L1 243.55
SEQ ID NO:95 轻链可变域VL变体4,抗PD-L1 243.55
SEQ ID NO:96 轻链可变域VL变体5,抗PD-L1 243.55
SEQ ID NO:97 轻链可变域VL变体6,抗PD-L1 243.55
SEQ ID NO:98 轻链可变域VL变体7,抗PD-L1 243.55
SEQ ID NO:99 轻链可变域VL变体8,抗PD-L1 243.55
SEQ ID NO:100 轻链可变域VL变体9,抗PD-L1 243.55
SEQ ID NO:101 轻链可变域VL变体10,抗PD-L1 243.55
SEQ ID NO:102 轻链可变域VL变体11,抗PD-L1 243.55
SEQ ID NO:103 轻链可变域VL变体12,抗PD-L1 243.55
SEQ ID NO:104 轻链可变域VL变体13,抗PD-L1 243.55
SEQ ID NO:105 轻链可变域VL变体14,抗PD-L1 243.55
SEQ ID NO:106 轻链可变域VL变体15,抗PD-L1 243.55
SEQ ID NO:107 轻链可变域VL变体16,抗PD-L1 243.55
SEQ ID NO:108 muCEA HC-Fc(DD)-muIL2v
SEQ ID NO:109 muCEA HC-Fc(KK)
SEQ ID NO:110 muCEA LC
SEQ ID NO:111 YW243.55.S70 PD-L1 muIgG1 DAPG HC
SEQ ID NO:112 YW243.55.S70 PD-L1 muIgG1 DAPG LC
SEQ ID NO:113 人卡帕轻链恒定区
SEQ ID NO:114 自IgG1衍生的人重链恒定区
SEQ ID NO:115 前导序列
SEQ ID NO:116 前导序列
SEQ ID NO:117 前导序列
SEQ ID NO:118 前导序列
SEQ ID NO:119 前导序列
SEQ ID NO:120 前导序列
SEQ ID NO:121 前导序列
SEQ ID NO:122 前导序列
SEQ ID NO:123 前导序列
SEQ ID NO:124 muFAP HC-Fc(DD)-muIL2v
SEQ ID NO:125 muFAP HC-Fc(KK)
SEQ ID NO:126 muFAP LC
在下面的陈述中,描述了本发明的实施方案:
1.A)与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用作治疗癌症的组合疗法,用作预防或治疗转移的组合疗法,用作治疗炎性疾病的组合疗法,用作治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展的组合疗法,或用作刺激免疫应答或功能,诸如T细胞活性的组合疗法;或
B)肿瘤靶向性IL-2变体免疫细胞因子制造用于治疗癌症,用于预防或治疗转移,用于治疗炎性疾病,用于治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于刺激免疫应答或功能,诸如T细胞活性的药物的用途,其中该肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用;或
C)肿瘤靶向性IL-2变体免疫细胞因子,其用于治疗癌症,用于预防或治疗转移,用于治疗炎性疾病,用于治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于刺激免疫应答或功能,诸如T细胞活性,其中该肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用;
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
2.依照实施方案1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,用于治疗癌症。
3.依照实施方案2的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,用于治疗乳腺癌,肺癌,结肠癌,卵巢癌,黑素瘤癌,膀胱癌,肾的癌,肾癌,肝癌,头和颈癌,结直肠癌,黑素瘤,胰腺癌,胃癌瘤癌,食道癌,间皮瘤,前列腺癌,白血病,淋巴瘤,骨髓瘤。
4.依照实施方案1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,用于预防或治疗转移。
5.依照实施方案1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,用于治疗炎性疾病。
6.依照实施方案1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,用于治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展。
7.依照实施方案1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,用于刺激免疫应答或功能,诸如T细胞活性。
8.A)与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用于
i)在表达该免疫细胞因子的靶物的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达该免疫细胞因子的靶物的肿瘤的受试者的中值和/或总体存活,
其中该靶物是在肿瘤细胞上或肿瘤细胞环境中呈递的;或
B)肿瘤靶向性IL-2变体免疫细胞因子制造用于
i)在表达该免疫细胞因子的靶物的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达该免疫细胞因子的靶物的肿瘤的受试者的中值和/或总体存活的药物的用途,其中该靶物是在肿瘤细胞上或肿瘤细胞环境中呈递的,其中该肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用;或
C)肿瘤靶向性IL-2变体免疫细胞因子用于
i)在表达该免疫细胞因子的靶物的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达该免疫细胞因子的靶物的肿瘤的受试者的中值和/或总体存活的用途,其中该靶物是在肿瘤细胞上或肿瘤细胞环境中呈递的,其中该肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
9.A)与结合人PD-L1的抗体组合的CEA靶向性IL-2变体免疫细胞因子,其用于
i)在表达CEA的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达CEA的肿瘤的受试者的中值和/或总体存活;或
B)CEA靶向性IL-2变体免疫细胞因子制造用于
i)在表达CEA的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达CEA的肿瘤的受试者的中值和/或总体存活的药物的用途;或
C)CEA靶向性IL-2变体免疫细胞因子用于
i)在表达CEA的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达CEA的肿瘤的受试者的中值和/或总体存活的用途,其中该CEA靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用,
其中组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
10.A)与结合人PD-L1的抗体组合的FAP靶向性IL-2变体免疫细胞因子,其用于
i)在表达FAP的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达FAP的肿瘤的受试者的中值和/或总体存活;或
B)FAP靶向性IL-2变体免疫细胞因子制造用于
i)在表达FAP的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达FAP的肿瘤的受试者的中值和/或总体存活的药物的用途;或
C)FAP靶向性IL-2变体免疫细胞因子用于
i)在表达FAP的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达FAP的肿瘤的受试者的中值和/或总体存活的用途,其中该FAP靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用,
其中组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
c)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
d)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
11.A)一种肿瘤靶向性IL-2变体免疫细胞因子,其用于治疗具有表达CEA的肿瘤或特征在于表达或过表达CEA的肿瘤,具有表达FAP的肿瘤或特征在于表达或过表达FAP的肿瘤或具有与表达或过表达CEA或FAP有关的肿瘤的患者,且其中该免疫细胞因子与结合人PD-L1的抗体组合施用,或
B)肿瘤靶向性IL-2变体免疫细胞因子制造用于治疗具有表达CEA的肿瘤或特征在于表达或过表达CEA的肿瘤,具有表达FAP的肿瘤或特征在于表达或过表达FAP的肿瘤或具有与表达或过表达CEA或FAP有关的肿瘤的患者的药物的用途,且其中该免疫细胞因子与结合人PD-L1的抗体组合施用,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
12.依照前述实施方案任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
SEQ ID NO:84,SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
SEQ ID NO:79,SEQ ID NO:80和SEQ ID NO:81的多肽序列,
且其中组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
13.依照前述实施方案任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,其特征在于所述免疫细胞因子的抗体构件和所述抗体是人IgG1亚类或人IgG4亚类的。
14.依照前述实施方案任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,其特征在于所述抗体具有降低的或最小限度的效应器功能。
15.依照前述实施方案任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,其中所述最小限度的效应器功能源自效应器降低性Fc突变。
16.依照前述实施方案任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子或用途,其中所述效应器降低性Fc突变为L234A/L235A或L234A/L235A/P329G或N297A或D265A/N297A(EU编号方式)。
17.A)一种用于
i)在表达该免疫细胞因子的靶物的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达该免疫细胞因子的靶物的肿瘤的受试者的中值和/或总体存活的方法,其中该靶物是在肿瘤细胞上或肿瘤细胞环境中呈递的,其中肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用,或
B)一种治疗具有表达CEA的肿瘤或特征在于表达或过表达CEA的肿瘤,具有表达FAP的肿瘤或特征在于表达或过表达FAP的肿瘤或具有与表达或过表达CEA或FAP有关的肿瘤的患者的方法,其中肿瘤靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
18.一种用于在有所需要的患者中治疗癌症,用于在有所需要的患者中预防或治疗转移,用于在有所需要的患者中治疗炎性疾病,用于在有所需要的患者中治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于在有所需要的患者中刺激免疫应答或功能,诸如T细胞活性的方法,
其包括对该患者施用肿瘤靶向性IL-2变体免疫细胞因子和抗PD-L1抗体,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
19.依照实施方案18的方法,其用于治疗癌症。
20.依照实施方案19的方法,其用于治疗乳腺癌,肺癌,结肠癌,卵巢癌,黑素瘤癌,膀胱癌,肾的癌,肾癌,肝癌,头和颈癌,结直肠癌,黑素瘤,胰腺癌,胃癌瘤癌,食道癌,间皮瘤,前列腺癌,白血病,淋巴瘤,骨髓瘤。
21.依照实施方案17至20任一项的方法,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
SEQ ID NO:84,SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
SEQ ID NO:79,SEQ ID NO:80和SEQ ID NO:81的多肽序列,
且其中组合疗法中使用的结合人PD-L1的抗体特征在于包含
SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
22.依照实施方案17至21任一项的方法,其特征在于所述免疫细胞因子的抗体构件和所述抗体是人IgG1亚类或人IgG4亚类的。
23.依照实施方案17至22任一项的方法,其特征在于所述抗体具有降低的或最小限度的效应器功能。
24.依照实施方案17至23任一项的方法,其中所述最小限度的效应器功能源自效应器降低性Fc突变。
25.依照实施方案17至24任一项的方法,其中所述效应器降低性Fc突变为L234A/L235A或L234A/L235A/P329G或N297A或D265A/N297A(EU编号方式)。
26.依照实施方案17至25任一项的方法,其中所述肿瘤靶向性IL-2变体免疫细胞因子和结合人PD-L1的抗体同时或序贯施用。
27.依照实施方案17至26任一项的方法,其进一步包括对所述患者施用化疗剂。
28.一种意图用于在有所需要的患者中治疗癌症,用于在有所需要的患者中预防或治疗转移,用于在有所需要的患者中治疗炎性疾病,用于在有所需要的患者中治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于刺激免疫应答或功能,诸如T细胞活性的试剂盒,
其在相同的容器中或在分开的容器中包含(a)肿瘤靶向性IL-2变体免疫细胞因子,(b)结合人PD-L1的抗体,和(c)任选的包装插页,其包括指导在组合治疗中使用该肿瘤靶向性IL-2变体免疫细胞因子和结合人PD-L1的抗体的印刷说明书,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
29.一种意图用于在有所需要的患者中治疗癌症,用于在有所需要的患者中预防或治疗转移,用于在有所需要的患者中治疗炎性疾病,用于在有所需要的患者中治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于刺激免疫应答或功能,诸如T细胞活性的试剂盒,
其包含(a)装有肿瘤靶向性IL-2变体免疫细胞因子的容器,和(b)包装插页,其包括指导作为治疗疾病的方法与结合人PD-L1的抗体一起在组合疗法中使用该肿瘤靶向性IL-2变体免疫细胞因子的说明书,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
30.一种意图用于在有所需要的患者中治疗癌症,用于在有所需要的患者中预防或治疗转移,用于在有所需要的患者中治疗炎性疾病,用于在有所需要的患者中治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于刺激免疫应答或功能,诸如T细胞活性的试剂盒,
其包含(a)装有结合人PD-L1的抗体的容器,和(b)包装插页,其包括指导作为治疗疾病的方法与肿瘤靶向性IL-2变体免疫细胞因子一起在组合疗法中使用该结合人PD-L1的抗体的说明书,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
31.依照实施方案28至30的试剂盒,其用于治疗癌症。
32.依照实施方案31的试剂盒,其用于治疗乳腺癌,肺癌,结肠癌,卵巢癌,黑素瘤癌,膀胱癌,肾的癌,肾癌,肝癌,头和颈癌,结直肠癌,黑素瘤,胰腺癌,胃癌瘤癌,食道癌,间皮瘤,前列腺癌,白血病,淋巴瘤,骨髓瘤。
33.依照实施方案28至32任一项的试剂盒,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
SEQ ID NO:84,SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
SEQ ID NO:79,SEQ ID NO:80和SEQ ID NO:81的多肽序列,
且其中组合疗法中使用的结合人PD-L1的抗体特征在于包含
SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
34.依照实施方案28至33任一项的试剂盒,其特征在于所述免疫细胞因子的抗体构件和所述抗体是人IgG1亚类或人IgG4亚类的。
35.依照实施方案28至34任一项的试剂盒,其特征在于所述抗体具有降低的或最小限度的效应器功能。
36.依照实施方案28至35任一项的试剂盒,其中所述最小限度的效应器功能源自效应器降低性Fc突变。
37.依照实施方案28至36任一项的试剂盒,其中所述效应器降低性Fc突变为L234A/L235A或L234A/L235A/P329G或N297A或D265A/N297A(EU编号方式)。
38.一种意图用于在有所需要的患者中治疗癌症,用于在有所需要的患者中预防或治疗转移,用于在有所需要的患者中治疗炎性疾病,用于在有所需要的患者中治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展,或用于刺激免疫应答或功能,诸如T细胞活性的药物,
其包含肿瘤靶向性IL-2变体免疫细胞因子,
其中所述药物与结合人PD-L1的抗体一起用于组合疗法,且任何包含包装插页,其包括指导在组合治疗中使用该肿瘤靶向性IL-2变体免疫细胞因子和结合人PD-L1的抗体的印刷说明书,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
39.依照实施方案38的药物,其用于治疗癌症。
40.依照实施方案39的药物,其用于治疗乳腺癌,肺癌,结肠癌,卵巢癌,黑素瘤癌,膀胱癌,肾的癌,肾癌,肝癌,头和颈癌,结直肠癌,黑素瘤,胰腺癌,胃癌瘤癌,食道癌,间皮瘤,前列腺癌,白血病,淋巴瘤,骨髓瘤。
41.依照实施方案38至40任一项的药物,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
SEQ ID NO:84,SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
SEQ ID NO:79,SEQ ID NO:80和SEQ ID NO:81的多肽序列,
且其中组合疗法中使用的结合人PD-L1的抗体特征在于包含
SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
42.依照实施方案38至41任一项的药物,其特征在于所述免疫细胞因子的抗体构件和所述抗体是人IgG1亚类或人IgG4亚类的。
43.依照实施方案38至42任一项的药物,其特征在于所述抗体具有降低的或最小限度的效应器功能。
44.依照实施方案38至43任一项的药物,其中所述最小限度的效应器功能源自效应器降低性Fc突变。
45.依照实施方案38至44任一项的药物,其中所述效应器降低性Fc突变为L234A/L235A或L234A/L235A/P329G或N297A或D265A/N297A(EU编号方式)。
实施例
单独的和与抗PD-L1Mab组合的针对CEA的靶向性IL2v免疫缀合物在小鼠肿瘤细胞系的同基因模型中的体内功效。
在数种同基因模型中对单独和与PD-L1Mab组合的针对CEA的靶向性IL2v免疫缀合物测试它们的抗肿瘤功效。
材料
研究中使用的分子如下。生成CEA靶向性IL-2变体免疫细胞因子CEA-IL2v的鼠源化替代分子,称作muCEA-muIL2v,用于完全免疫胜任小鼠中的体内肿瘤模型以降低抗药物抗体(ADA)的形成。另外,生成FAP靶向性IL-2变体免疫细胞因子FAP-IL2v的鼠源化嵌合型式,称作muFAP-muIL2v,用于完全免疫胜任小鼠中的体内肿瘤模型以降低抗药物抗体(ADA)的形成。在鼠源化替代分子中,Fc域节-入-穴突变用muIgG1上的DDKK突变替换并LALAP329G突变用muIgG1上的DAPG突变替换。
例如,muCEA-muIL2v特征在于下述特征。作为亲本抗体,应用具有人(人源化)可变区,而非鼠恒定区的人-小鼠嵌合IgG1抗体。为了避免潜在的免疫原性,使用对应的Black 6同种异型(小鼠基因组计划发表序列)。通过与人IL-2v中鉴定的那些同源的三处突变消除对muIL2Rα的结合并去除各自的O-糖基化位点:T23A(O-Glyco),F76A,Y79A,L106G。另外,与阿地白介素中一样,通过C160A突变(编号方式基于UniProt ID P04351,包括信号肽)突变半胱氨酸残基以避免聚集。虽然muIgG1早就具有降低的FcγR结合,但是通过引入DAPG突变(D265A,P329G)完全消除对鼠FcγR的结合,而muFcRn结合得到保留。muIL-2v经由非免疫原性(G4S)2-连接头仅仅融合至muIgG1抗体的一条重链的C末端。为了实现这一点,使用静电操纵经由Fc域中的DDKK突变改造免疫细胞因子以容许小鼠背景中的异二聚化。
muCEA-muIL2v的多肽序列如下:
具有DD突变且具有融合的muIL2v的重链(SEQ ID NO:108):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLEWMGWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCARWDFAYYVEAMDYWGQGTTVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSQTVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVAISKDDPEVQFSWFVDDVEVHTAQTKPREEQINSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFGAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITNFFPEDITVEWQWNGQPAENYDNTQPIMDTDGSYFVYSDLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGGGGGSGGGGSGGGGSAPASSSTSSSTAEAQQQQQQQQQQQQHLEQLLMDLQELLSRMENYRNLKLPRMLTAKFALPKQATELKDLQCLEDELGPLRHVLDGTQSKSFQLEDAENFISNIRVTVVKLKGSDNTFECQFDDESATVVDFLRRWIAFAQSIISTSPQ
具有KK突变的重链(SEQ ID NO:109):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLEWMGWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCARWDFAYYVEAMDYWGQGTTVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSQTVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVAISKDDPEVQFSWFVDDVEVHTAQTKPREEQINSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFGAPIEKTISKTKGRPKAPQVYTIPPPKKQMAKDKVSLTCMITNFFPEDITVEWQWNGQPAENYKNTQPIMKTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK
轻链(SEQ ID NO:110):
DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPGKAPKLLIYSASYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYYTYPLFTFGQGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
muFAP-muIL2v的多肽序列如下:
具有DD突变且具有融合的muIL2v的重链(SEQ ID NO:124):
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAIIGSGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGWFGGFNYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSQTVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVAISKDDPEVQFSWFVDDVEVHTAQTKPREEQINSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFGAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITNFFPEDITVEWQWNGQPAENYDNTQPIMDTDGSYFVYSDLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGGGGGSGGGGSGGGGSAPASSSTSSSTAEAQQQQQQQQQQQQHLEQLLMDLQELLSRMENYRNLKLPRMLTAKFALPKQATELKDLQCLEDELGPLRHVLDGTQSKSFQLEDAENFISNIRVTVVKLKGSDNTFECQFDDESATVVDFLRRWIAFAQSIISTSPQ
具有KK突变的重链(SEQ ID NO:125):
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAIIGSGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGWFGGFNYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSQTVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVAISKDDPEVQFSWFVDDVEVHTAQTKPREEQINSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFGAPIEKTISKTKGRPKAPQVYTIPPPKKQMAKDKVSLTCMITNFFPEDITVEWQWNGQPAENYKNTQPIMKTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK
轻链(SEQ ID NO:126):
EIVLTQSPGTLSLSPGERATLSCRASQSVTSSYLAWYQQKPGQAPRLLINVGSRRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQGIMLPPTFGQGTKVEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
研究中使用人/小鼠交叉反应性抗PD-L1抗体。例如,生成了称作YW243.55.S70PD-L1 muIgG1的抗小鼠PD-L1替代抗体以用于体内肿瘤模型,该抗小鼠PD-L1替代抗体基于WO 2010/077634中记载的YW243.55.S70 PD-L1抗体(序列显示于图11中)。此抗体含有DAPG突变以消除FcγR相互作用。将YW243.55.S70的可变区附着至具有DAPG Fc突变的鼠IgG1恒定域。
YW243.55.S70 PD-L1 muIgG1的多肽序列如下:
YW243.55.S70 PD-L1 muIgG1 DAPG HC(SEQ ID NO:111):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSAAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDAPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFGAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK
YW243.55.S70 PD-L1 muIgG1 LC(SEQ ID NO:112):
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
实施例1
MC38-CEA肝转移性同基因模型
通过门静脉内注射入Black 6-huCEA-huFcγRIII双重转基因小鼠,在小鼠转染子结直肠细胞系MC38-CEA中测试CEA靶向性IL2v免疫缀合物的鼠替代物。这项研究中使用人/小鼠交叉反应性抗PD-L1抗体YW243.55.S70 PD-L1 muIgG1。
MC38-CEA结直肠癌细胞最初是自City of Hope(California,USA)获得的,并在扩充后保藏于Roche-Glycart内部细胞库。在5%CO2的水饱和气氛中在含有10%FCS(Gibco)和G418(Geniticin;Gibco)的DMEM中于37℃例行培养肿瘤细胞系。将存活率96.3%的第9代用于移植。使用0.3ml结核菌素注射器(BD Biosciences,Germany)将5x105个细胞/动物注射入小鼠门静脉。为此,在麻醉的Black 6-CEA-FcγRIII转基因小鼠的腹部的中膜中做一小切口。打开腹膜壁并小心挤压肠。将100μl(RPMI培养基中的5x105个MC38-CEA细胞)细胞悬浮液注射入门静脉。使用5/0可溶解缝合线关闭腹膜壁和皮肤伤口。
依照承诺的方针(GV-Solas;Felasa;TierschG)以12小时光照/12小时黑暗的日周期在无特定病原体的条件下维持实验开始时8-9周龄的雌性Black 6-CEA-FcγRIII小鼠(Roche-Glycart;Switzerland)(在Charles Rivers,Lyon,France处繁殖)。实验性研究方案得到了当地政府的审查和批准(P 2011/128)。达到后,将动物维持一周以适应新的环境和进行观察。定期进行连续健康监测。
在研究第0天对小鼠门静脉注射5x105个MC38-huCEA细胞,随机化并称重。肿瘤细胞注射后1周,对小鼠静脉内注射CEA-IL-2v,PD-L1单抗或CEA-IL-2v+PD-L1单抗的组合一次。第一次施用组合组PD-L1+CEA-IL2v后1天(第1周)发现1只动物死亡。其余小鼠呈现竖毛,弓背和减少运动的临床体征,在2天中解决。对于最终的存活评估,自实验中取出第一次疗法施用后24小时发现死亡的小鼠。第2至4周,交替周给予CEA-IL2v和PD-L1,而且小鼠对于这种新的剂量给药方案不显示临床体征。对所有小鼠静脉内注射200μl适宜溶液。对媒介组中的小鼠注射组氨酸缓冲液,并对治疗组注射CEA-IL-2v构建体或PD-L1单抗或CEA-IL-2v+PD-L1单抗组合。为了获得适当量的免疫缀合物/200μl,在必要时用组氨酸缓冲液稀释储液。
图1和表1A显示CEA-IL-2v+PD-L1单抗组合与单独的CEA-IL-2v和PD-L1单抗相比就增强的中值和总体存活而言介导卓越的功效。
表1A
表1B
实施例2
MC38-CEA皮下同基因模型
通过皮下注射入Black 6-CEA-FcγRIII转基因小鼠,在小鼠转染子结直肠细胞系MC38-CEA中测试CEA靶向性IL2v免疫缀合物的鼠替代物。这项研究中使用人/小鼠交叉反应性抗PD-L1抗体。
MC38-CEA结直肠癌细胞最初是自City of Hope(California,USA)获得的,并在扩充后保藏于Roche-Glycart内部细胞库。在5%CO2的水饱和气氛中在含有10%FCS(Gibco)和G418(Geniticin;Gibco)的DMEM中于37℃例行培养肿瘤细胞系。将存活率97.9%的第6代用于移植。使用1ml结核菌素注射器(BD Biosciences,Germany)在100μl RPMI细胞培养基(Gibco)中将5x105个细胞/动物皮下注射入小鼠体侧。
依照承诺的方针(GV-Solas;Felasa;TierschG)以12小时光照/12小时黑暗的日周期在无特定病原体的条件下维持实验开始时8-9周龄的雌性Black 6-CEA-FcγRIII小鼠(Roche-Glycart;Switzerland)(在Charles Rivers,Lyon,France处繁殖)。实验性研究方案得到了当地政府的审查和批准(P 2011/128)。达到后,将动物维持一周以适应新的环境和进行观察。定期进行连续健康监测。
在研究第0天对小鼠皮下注射5x105个MC38-CEA细胞,随机化并称重。肿瘤细胞注射后2周(肿瘤体积>200mm3),一周一次对小鼠静脉内注射CEA-IL-2v,PD-L1单抗或CEA-IL-2v+PD-L1单抗的组合,持续2周。对所有小鼠静脉内注射200μl适宜溶液。对媒介组中的小鼠注射组氨酸缓冲液,并对治疗组注射CEA-IL-2v构建体或PD-L1单抗或CEA-IL-2v+PD-L1单抗组合。为了获得适当量的免疫缀合物/200μl,在必要时用组氨酸缓冲液稀释储液。
图2和表2A显示CEA-IL-2v 0.5mg/kg+PD-L1单抗的组合与单独的CEA-IL-2v和PD-L1单抗和更低剂量CEA-IL2v的组合相比就肿瘤生长抑制而言介导卓越的功效。
表2A
表2B
实施例3
Panc02-CEA胰腺同基因模型
通过胰腺内注射入Black 6-CEA-FcγRIII转基因小鼠,在小鼠胰腺Panc02-CEA转染子细胞系中测试CEA靶向性CEA-IL2v免疫缀合物的鼠替代物。这项研究中使用人/小鼠交叉反应性抗PD-L1抗体。
Panc02-H7细胞(小鼠胰腺癌)最初是自MD Anderson癌症中心(Texas,USA)获得的,并在扩充后保藏于Roche-Glycart内部细胞库。通过钙转染和亚克隆技术内部生成Panc02-H7-huCEA细胞。在含有10%FCS(Sigma),4μg/ml嘌呤霉素和1%Glutamax的RPMI培养基中培养Panc02-H7-huCEA。在5%CO2的水饱和气氛中于37℃培养细胞。将第21代用于移植。细胞存活率为93.1%。使用0.3ml结核菌素注射器(BD Biosciences,Germany)将1x105个细胞/动物注射入小鼠胰腺。为此,在麻醉的Black 6-CEA-FcγRIII转基因小鼠的左腹部位做一小切口。打开腹膜壁并用镊子小心分离胰腺。将10μl(RPMI培养基中的1x105个Panc02-H7-huCEA细胞)细胞悬浮液注射入胰尾。使用5/0可溶解缝合线关闭腹膜壁和皮肤伤口。
依照承诺的方针(GV-Solas;Felasa;TierschG)以12小时光照/12小时黑暗的日周期在无特定病原体的条件下维持实验开始时8-9周龄的雌性Black 6-CEA-FcγRIII小鼠(Roche-Glycart;Switzerland)(在Charles Rivers,Lyon,France处繁殖)。实验性研究方案得到了当地政府的审查和批准(P 2011/128)。达到后,将动物维持一周以适应新的环境和进行观察。定期进行连续健康监测。
在研究第0天对小鼠胰腺内注射1x105个Panc02-CEA细胞,随机化并称重。肿瘤细胞注射后1周,一周一次对小鼠静脉内注射CEA-IL-2v,PD-L1单抗或CEA-IL-2v+PD-L1单抗的组合,持续5周。
对所有小鼠静脉内注射200μl适宜溶液。对媒介组中的小鼠注射组氨酸缓冲液,并对治疗组注射CEA-IL-2v构建体或PD-L1单抗或CEA-IL-2v+PD-L1单抗组合。为了获得适当量的免疫缀合物/200μl,在必要时用组氨酸缓冲液稀释储液。
图3和表3A显示CEA-IL-2v+PD-L1单抗组合与单独的CEA-IL-2v和PD-L1单抗相比就增强的中值和总体存活而言介导卓越的功效。
表3A
表3B
实施例4
Panc02-CEA胰腺同基因模型
通过胰腺内注射入Black 6-CEA-FcγRIII转基因小鼠,在小鼠胰腺Panc02-CEA转染子细胞系中针对非靶向性DP47-IL2v免疫缀合物测试CEA靶向性CEA-IL2v免疫缀合物的鼠替代物。这项研究中使用人/小鼠交叉反应性抗PD-L1抗体。
Panc02-H7细胞(小鼠胰腺癌)最初是自MD Anderson癌症中心(Texas,USA)获得的,并在扩充后保藏于Roche-Glycart内部细胞库。通过钙转染和亚克隆技术内部生成Panc02-H7-huCEA细胞。在含有10%FCS(Sigma),4μg/ml嘌呤霉素和1%Glutamax的RPMI培养基中培养Panc02-H7-huCEA。在5%CO2的水饱和气氛中于37℃培养细胞。将第12代用于移植。细胞存活率为94%。使用0.3ml结核菌素注射器(BD Biosciences,Germany)将1x105个细胞/动物注射入小鼠胰腺。为此,在麻醉的Black 6-CEA-FcγRIII转基因小鼠的左腹部位做一小切口。打开腹膜壁并用镊子小心分离胰腺。将10μl(RPMI培养基中的1x105个Panc02-H7-huCEA细胞)细胞悬浮液注射入胰尾。使用5/0可溶解缝合线关闭腹膜壁和皮肤伤口。
依照承诺的方针(GV-Solas;Felasa;TierschG)以12小时光照/12小时黑暗的日周期在无特定病原体的条件下维持实验开始时8-9周龄的雌性Black 6-CEA-FcγRIII小鼠(Roche-Glycart;Switzerland)(在Charles Rivers,Lyon,France处繁殖)。实验性研究方案得到了当地政府的审查和批准(P ZH193/2014)。达到后,将动物维持一周以适应新的环境和进行观察。定期进行连续健康监测。
在研究第0天对小鼠胰腺内注射1x105个Panc02-CEA细胞,随机化并称重。肿瘤细胞注射后1周,一周一次对小鼠静脉内注射CEA-IL-2v,PD-L1单抗或CEA-IL-2v+PD-L1单抗的组合,持续4周。
对所有小鼠静脉内注射200μl适宜溶液。对媒介组中的小鼠注射组氨酸缓冲液,并对治疗组注射CEA-IL2v构建体或DP47-IL2v或PD-L1单抗或CEA-IL2v+PD-L1单抗和DP47-IL2v+PD-L1单抗组合。为了获得适当量的免疫缀合物/200μl,在必要时用组氨酸缓冲液稀释储液。选择CEA-IL2v和DP47-IL2v的剂量来匹配相似水平的它们施用后24小时的暴露,如通过IL2受体ELISA测定法测量的(显示于图4B)。
图4A和表4A显示CEA-IL-2v+PD-L1单抗组合与单独的CEA-IL-2v,DP47-IL2v,PD-L1单抗和DP47-IL2v+PD-L1单抗组合相比就增强的中值和总体存活而言介导卓越的功效。
表4A
表4B。成对时序检验(多重检验水平=0.00333)。
表4C
实施例5
CEA-IL2v处理后的PD-L1上调
自新鲜血液分离PBMC。简言之,用PBS 3:1稀释血液。将约30ml血液/PBS混合物堆在15ml Histopaque(Sigma)上并以450x g无中断离心30分钟。用5ml移液器将淋巴细胞收集入装有PBS的50ml管。将管用PBS装满至50ml并以350x g离心10分钟。丢弃上清液,在50mlPBS中重悬浮团粒并以300x g离心10分钟。重复清洗步骤一次。在含有10%FCS和1%谷氨酰胺的RPMI中重悬浮细胞。
A549(ECACC 86012804)是一种人高加索肺癌(腺癌;原发性肿瘤)细胞系。在含有10%FCS和1%谷氨酰胺的DMEM中培养细胞。在达到汇合之前每2至4天分拆细胞。
在测定法开始前一天收获A549细胞并在1ml培养基中以1x106个细胞每孔的密度接种入6孔板。次日去除培养基并添加PBMC(得到10:1或1:1的最终E:T比)或单独的培养基。在温箱中用100nM CEA-IL2v,10nM CEA-IL2v或仅培养基处理细胞48小时。处理后用细胞解离缓冲液收获A549并通过流式细胞术分析PD-L1表达。
48小时后用细胞解离缓冲液收获A549并用于FACS分析。将细胞以400g离心4分钟并用含有0.1%BSA的PBS(FACS缓冲液)清洗一次。然后将40μl/孔稀释的抗PD-L1抗体(BioLegend,5μl,在40μl FACS缓冲液中)或相应的同种型对照添加至细胞。将细胞在电冰箱中温育30分钟。之后将细胞用FACS缓冲液清洗两次并在200μl/孔含有2%PFA的FACS缓冲液中重悬浮。使用BD FACS Fortessa实施分析。
图5显示单独用CEA-IL2v处理A549肿瘤细胞不引起A549细胞上PD-L1表达的诱导。然而,在PBMC存在下用CEA-IL2v处理A549细胞时,检测到A549细胞上PD-L1的浓度依赖性上调。PD-L1上调还依赖于共培养物中存在的PBMC的量。
实施例6
MC38-FAP同基因皮下肿瘤模型
通过皮下注射入Black 6小鼠,在小鼠结肠腺癌MC38-FAP转染子细胞系中测试FAP靶向性FAP-IL2v免疫缀合物的鼠替代物。这项研究中使用人/小鼠交叉反应性抗PD-L1抗体YW243.55.S70 PD-L1 muIgG1。
MC38-FAP invipa(体内传代)细胞是在Roche-Glycart生成的,并在扩充后保藏于Glycart内部细胞库。在5%CO2的水饱和气氛中在补充有10%胎牛血清(Invitrogen,Switzerland),1mM丙酮酸盐和1%NEAA加6μg/ml嘌呤霉素的DMEM培养基(GIBCO,Switzerland)中于37℃例行培养这些细胞。通过每两天用胰蛋白酶/EDTA 1x(GIBCO,Switzerland)分拆来实施培养物传代。在注射那天,使用胰蛋白酶-EDTA (Gibco,Switzerland)自培养瓶(Greiner Bio-One)收获肿瘤细胞并转移入50ml培养基,清洗并在RPMI无血清培养基(Gibco,Switzerland)中重悬浮。用RPMI再次清洗后,使用细胞计数器测定细胞浓度。对于注射,将最终滴度调节至20x106个细胞/mL,100μl RPMI细胞培养基中有2x106个细胞。
Black 6雌性小鼠购自Charles Rivers,依照承诺的方针(GV-Solas;Felasa;TierschG)以12小时光照/12小时黑暗的日周期在无特定病原体的条件下维持。实验性研究方案得到了当地政府的审查和批准(P ZH193/2014)。达到后,将动物维持一周以适应新的环境和进行观察。定期进行连续健康监测。
在研究第0天对小鼠皮下注射MC38-muFAP细胞(2x106个细胞/100μl/小鼠);存活率94.4%的第7代。在第x天(肿瘤超过100mm3),第x+7天,第x+14天,第x+21天,等静脉内注射媒介和抗体疗法(2mg/kg剂量的muFAP-IL2v和10mg/kg剂量的muPD-L1,以及它们的组合)。用于小鼠的最大治疗次数为5。
对所有小鼠静脉内注射200μl适宜溶液。对媒介组中的小鼠注射组氨酸缓冲液,并对治疗组注射抗体。为了获得适当量的抗体/200μl,在必要时用组氨酸缓冲液稀释抗体溶液。
图6A和6B和表5A显示FAP-IL-2v+PD-L1单抗的组合与单独的FAP-IL-2v和PD-L1单抗相比就肿瘤生长抑制以及增强的中值和总体存活而言介导卓越的功效。
表5A
组 | 以天计的中值存活 | 与对照比较的p值 |
媒介 | 30 | 1.0000 |
muFAP-IL-2v | 40 | 0.2190 |
抗PDL1 | 48 | 0.0351* |
muFAP-IL-2v+抗PDL1 | 64 | 0.0066** |
表5B
序列表
<110> 豪夫迈·罗氏有限公司(F. HOFFMANN-LA ROCHE AG)
<120> 肿瘤靶向性IL-2变体免疫细胞因子和针对人PD-L1的抗体的组合疗法
<130> 32228
<150> EP 14182778.2
<151> 2014-08-29
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<170> PatentIn version 3.5
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Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
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Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
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Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
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Ile Ser Thr Leu Thr
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Asp Leu Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile
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Ile Gln Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser
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Ala Ala Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr
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Arg Cys Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val
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Asp Pro Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr
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Pro Lys Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser
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Cys Thr Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu
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Val Ile Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr His
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Leu Val Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala Leu Thr
245 250 255
Phe Ile Phe Arg Leu Arg Lys Gly Arg Met Met Asp Val Lys Lys Cys
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Gly Ile Gln Asp Thr Asn Ser Lys Lys Gln Ser Asp Thr His Leu Glu
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Glu Thr
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Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Tyr Pro Gly
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Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
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Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
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Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
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Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
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Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
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115
<210> 8
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1 5 10 15
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35 40 45
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Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
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50 55 60
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65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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100 105 110
Val Thr Val Ser Ser
115
<210> 10
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<213> 人工序列
<220>
<223> 3D9(TA); VH
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Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
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Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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50 55 60
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65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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100 105 110
Val Thr Val Ser Ser
115
<210> 11
<211> 108
<212> PRT
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<220>
<223> 4G8; VL
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35 40 45
Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
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Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
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Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 12
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<212> PRT
<213> 人工序列
<220>
<223> 4G8; VH
<400> 12
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
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65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 13
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 4B3; VL
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Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
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Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Tyr Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
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Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 14
<211> 117
<212> PRT
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<220>
<223> 4B3; VH
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Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
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Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
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65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 15
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 4D6; VL
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Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Gln Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
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85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 16
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 4D6; VH
<400> 16
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 17
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 2C6; VL
<400> 17
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Gln Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 18
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 2C6; VH
<400> 18
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Ala Gly Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 19
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 5H5; VL
<400> 19
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Asn Gln Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 20
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 5H5; VH
<400> 20
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Gly Trp Phe Thr Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 21
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 2C4; VL
<400> 21
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Asn Gln Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 22
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 2C4; VH
<400> 22
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Thr Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 23
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 2D9; VL
<400> 23
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Asn Gln Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 24
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 2D9; VH
<400> 24
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Thr Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 25
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 4B8; VL
<400> 25
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 26
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 4B8; VH
<400> 26
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 27
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 7A1; VL
<400> 27
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Gln Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 28
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 7A1; VH
<400> 28
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 29
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 13C2; VL
<400> 29
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Leu Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 30
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 13C2; VH
<400> 30
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 31
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 13E8; VL
<400> 31
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Leu Asn Ile Pro
85 90 95
Ser Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 32
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 13E8; VH
<400> 32
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 33
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 14C10; VL
<400> 33
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly His Ile Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 34
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 14C10; VH
<400> 34
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Trp Met Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 35
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 17A11; VL
<400> 35
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Leu Asn Ile Pro
85 90 95
Ser Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 36
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 17A11; VH
<400> 36
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 37
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 19G1; VL
<400> 37
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 38
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 19G1; VH
<400> 38
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Ser Ser Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 39
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 20G8; VL
<400> 39
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 40
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 20G8; VH
<400> 40
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ser Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 41
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 4B9; VL
<400> 41
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 4B9; VH
<400> 42
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 43
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 5B8; VL
<400> 43
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 44
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 5B8; VH
<400> 44
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Trp Gly Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 45
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 5F1; VL
<400> 45
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 5F1; VH
<400> 46
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Ser Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 47
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 14B3; VL
<400> 47
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 48
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 14B3; VH
<400> 48
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ala Ser Gly Ala Ile Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 49
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 16F1; VL
<400> 49
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 50
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 16F1; VH
<400> 50
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 51
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 16F8; VL
<400> 51
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 52
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 16F8; VH
<400> 52
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 53
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> O3C9; VL
<400> 53
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 54
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> O3C9; VH
<400> 54
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 55
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> O2D7; VL
<400> 55
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Thr Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ala Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 56
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> O2D7; VH
<400> 56
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 57
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 28H1; VL
<400> 57
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 58
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 28H1; VH
<400> 58
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Trp Ala Ser Gly Glu Gln Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 59
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 22A3; VL
<400> 59
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 60
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 22A3; VH
<400> 60
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ser Ile Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 61
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 29B11; VL
<400> 61
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 62
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 29B11; VH
<400> 62
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 63
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 23C10; VL
<400> 63
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 64
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 23C10; VH
<400> 64
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Thr Asn Gly Asn Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 65
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1; VL
<400> 65
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 Lys Ala Ser Ala Ala Val Gly Thr Tyr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Lys Arg 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 His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 66
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1; VH
<400> 66
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 67
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1; VL
<400> 67
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 Lys Ala Ser Ala Ala Val Gly Thr Tyr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Lys Arg 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 His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 68
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1; VH
<400> 68
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 69
<211> 592
<212> PRT
<213> 人工序列
<220>
<223> 28H1 Fab HC-Fc 节 (LALA P329G)-IL-2 qm
<400> 69
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Trp Ala Ser Gly Glu Gln Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ala Pro Ala Ser Ser
450 455 460
Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu
465 470 475 480
Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr
485 490 495
Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu Leu
500 505 510
Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val
515 520 525
Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu
530 535 540
Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr
545 550 555 560
Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe
565 570 575
Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr Leu Thr
580 585 590
<210> 70
<211> 593
<212> PRT
<213> 人工序列
<220>
<223> 4G8 Fab HC-Fc 节 (LALA P329G)-IL-2 qm
<400> 70
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ala Pro Ala Ser
450 455 460
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp
465 470 475 480
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
485 490 495
Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu
500 505 510
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
515 520 525
Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
530 535 540
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
545 550 555 560
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
565 570 575
Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr Leu
580 585 590
Thr
<210> 71
<211> 593
<212> PRT
<213> 人工序列
<220>
<223> 4B9 Fab HC-Fc 节 (LALA P329G)-IL-2 qm
<400> 71
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ala Pro Ala Ser
450 455 460
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp
465 470 475 480
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
485 490 495
Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu
500 505 510
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
515 520 525
Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
530 535 540
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
545 550 555 560
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
565 570 575
Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr Leu
580 585 590
Thr
<210> 72
<211> 593
<212> PRT
<213> 人工序列
<220>
<223> 28H1 Fab HC-Fc 节 (LALA P329G)-IL-2 qm (2)
<400> 72
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Trp Ala Ser Gly Glu Gln Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Ser
450 455 460
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp
465 470 475 480
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
485 490 495
Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu
500 505 510
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
515 520 525
Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
530 535 540
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
545 550 555 560
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
565 570 575
Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr Leu
580 585 590
Thr
<210> 73
<211> 594
<212> PRT
<213> 人工序列
<220>
<223> 4B9 Fab HC-Fc 节 (LALA P329G)-IL-2 qm (2)
<400> 73
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala
450 455 460
Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu
465 470 475 480
Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys
485 490 495
Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys Lys Ala Thr
500 505 510
Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu
515 520 525
Glu Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg
530 535 540
Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser
545 550 555 560
Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val
565 570 575
Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr
580 585 590
Leu Thr
<210> 74
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 28H1 Fab HC-Fc 穴 (LALA P329G)
<400> 74
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Trp Ala Ser Gly Glu Gln Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 75
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 4G8 Fab HC-Fc 穴 (LALA P329G)
<400> 75
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 76
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 4B9 Fab HC-Fc 穴 (LALA P329G)
<400> 76
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 77
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 4G8 Fab LC
<400> 77
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 78
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 3F2 Fab LC
<400> 78
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 79
<211> 594
<212> PRT
<213> 人工序列
<220>
<223> 4B9 Fab HC-Fc 节 (LALA P329G)-IL-2 qm (2)
<400> 79
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala
450 455 460
Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu
465 470 475 480
Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys
485 490 495
Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys Lys Ala Thr
500 505 510
Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu
515 520 525
Glu Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg
530 535 540
Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser
545 550 555 560
Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val
565 570 575
Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr
580 585 590
Leu Thr
<210> 80
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 4B9 Fab HC-Fc 穴 (LALA P329G)
<400> 80
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 81
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 3F2 Fab LC
<400> 81
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 82
<211> 599
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1 Fab HC-Fc 节 (wt)-IL-2 qm
<400> 82
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
450 455 460
Gly Gly Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Gly Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 83
<211> 599
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1 Fab HC-Fc 节 (wt)-IL-2 qm
<400> 83
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
450 455 460
Gly Gly Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Gly Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 84
<211> 598
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1 Fab HC-Fc 节 (LALA P329G)-IL-2 qm
<400> 84
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
465 470 475 480
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
485 490 495
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro
500 505 510
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
515 520 525
Lys Pro Leu Glu Glu Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His
530 535 540
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
545 550 555 560
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
565 570 575
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser
580 585 590
Ile Ile Ser Thr Leu Thr
595
<210> 85
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A Fab HC-Fc 穴 (wt)
<400> 85
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 86
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1 Fab HC-Fc 穴 (wt)
<400> 86
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 87
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1 Fab LC
<400> 87
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 Lys Ala Ser Ala Ala Val Gly Thr Tyr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Lys Arg 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 His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 88
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> CH1A1A 98/99 2F1 Fab LC
<400> 88
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 Lys Ala Ser Ala Ala Val Gly Thr Tyr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Lys Arg 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 His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 89
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 89
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 90
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 90
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 91
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 91
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Leu Pro Tyr Gly Gly Ser Ser Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 92
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 92
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 93
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 93
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Tyr Asn Val Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 94
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 94
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Tyr Ala Pro Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 95
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 95
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Tyr Thr Val Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 96
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 96
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Asn Thr Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser 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 Tyr Tyr Thr Val Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 97
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 97
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Gly Val Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 98
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 98
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Leu Phe Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 99
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 99
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Phe Ile Thr Pro Thr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 100
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 100
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Tyr Tyr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 101
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 101
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Phe Phe Tyr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 102
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 102
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Ser Leu Phe Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 103
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 103
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Ser Leu Tyr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 104
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 104
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Ser Trp Tyr His Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 105
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 105
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Phe Tyr Ile Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 106
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 106
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Trp Tyr Thr Pro Thr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 107
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 序列是合成的
<400> 107
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Ser Tyr Phe Ile Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 108
<211> 608
<212> PRT
<213> 人工序列
<220>
<223> muCEA HC-Fc (DD)-muIL2v
<400> 108
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
180 185 190
Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
210 215 220
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
245 250 255
Val Thr Cys Val Val Val Ala Ile Ser Lys Asp Asp Pro Glu Val Gln
260 265 270
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Lys
275 280 285
Pro Arg Glu Glu Gln Ile Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
290 295 300
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
305 310 315 320
Val Asn Ser Ala Ala Phe Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
340 345 350
Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
355 360 365
Asn Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
370 375 380
Pro Ala Glu Asn Tyr Asp Asn Thr Gln Pro Ile Met Asp Thr Asp Gly
385 390 395 400
Ser Tyr Phe Val Tyr Ser Asp Leu Asn Val Gln Lys Ser Asn Trp Glu
405 410 415
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
420 425 430
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Gly Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Ser Ser
450 455 460
Ser Thr Ser Ser Ser Thr Ala Glu Ala Gln Gln Gln Gln Gln Gln Gln
465 470 475 480
Gln Gln Gln Gln Gln His Leu Glu Gln Leu Leu Met Asp Leu Gln Glu
485 490 495
Leu Leu Ser Arg Met Glu Asn Tyr Arg Asn Leu Lys Leu Pro Arg Met
500 505 510
Leu Thr Ala Lys Phe Ala Leu Pro Lys Gln Ala Thr Glu Leu Lys Asp
515 520 525
Leu Gln Cys Leu Glu Asp Glu Leu Gly Pro Leu Arg His Val Leu Asp
530 535 540
Gly Thr Gln Ser Lys Ser Phe Gln Leu Glu Asp Ala Glu Asn Phe Ile
545 550 555 560
Ser Asn Ile Arg Val Thr Val Val Lys Leu Lys Gly Ser Asp Asn Thr
565 570 575
Phe Glu Cys Gln Phe Asp Asp Glu Ser Ala Thr Val Val Asp Phe Leu
580 585 590
Arg Arg Trp Ile Ala Phe Ala Gln Ser Ile Ile Ser Thr Ser Pro Gln
595 600 605
<210> 109
<211> 445
<212> PRT
<213> 人工序列
<220>
<223> muCEA HC-Fc (KK)
<400> 109
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
180 185 190
Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
210 215 220
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
245 250 255
Val Thr Cys Val Val Val Ala Ile Ser Lys Asp Asp Pro Glu Val Gln
260 265 270
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Lys
275 280 285
Pro Arg Glu Glu Gln Ile Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
290 295 300
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
305 310 315 320
Val Asn Ser Ala Ala Phe Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
340 345 350
Lys Lys Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
355 360 365
Asn Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
370 375 380
Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Lys Thr Asp Gly
385 390 395 400
Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu
405 410 415
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
420 425 430
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 110
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> muCEA LC
<400> 110
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 Lys Ala Ser Ala Ala Val Gly Thr Tyr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Lys Arg 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 His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala
100 105 110
Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser
115 120 125
Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp
130 135 140
Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val
145 150 155 160
Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met
165 170 175
Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser
180 185 190
Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys
195 200 205
Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 111
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> YW243.55.S70 PD-L1 muIgG1 DAPG HC
<400> 111
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
115 120 125
Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly
130 135 140
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn
145 150 155 160
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr
180 185 190
Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser
195 200 205
Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro
210 215 220
Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro
225 230 235 240
Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys
245 250 255
Val Val Val Asp Ile Ser Lys Asp Ala Pro Glu Val Gln Phe Ser Trp
260 265 270
Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu
275 280 285
Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met
290 295 300
His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser
305 310 315 320
Ala Ala Phe Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
325 330 335
Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln
340 345 350
Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe
355 360 365
Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu
370 375 380
Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe
385 390 395 400
Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn
405 410 415
Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr
420 425 430
Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440
<210> 112
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> YW243.55.S70 PD-L1 muIgG1 DAPG LC
<400> 112
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 113
<211> 107
<212> PRT
<213> 人(Homo sapiens)
<400> 113
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> 114
<211> 330
<212> PRT
<213> 人(Homo sapiens)
<400> 114
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 115
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 前导序列
<400> 115
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210> 116
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 前导序列
<400> 116
atggactgga cctggagaat cctcttcttg gtggcagcag ccacaggagc ccactcc 57
<210> 117
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 前导序列
<400> 117
atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactcc 57
<210> 118
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 前导序列
<400> 118
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210> 119
<211> 66
<212> DNA
<213> 人工序列
<220>
<223> 前导序列
<400> 119
atggacatga gggtccccgc tcagctcctg ggcctcctgc tgctctggtt cccaggtgcc 60
aggtgt 66
<210> 120
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 前导序列
<400> 120
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 121
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 前导序列
<400> 121
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctaccggtgt gcattcc 57
<210> 122
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 前导序列
<400> 122
atgggctggt cctgcatcat cctgtttctg gtggctaccg ccactggagt gcattcc 57
<210> 123
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 前导序列
<400> 123
atgggctggt cctgcatcat cctgtttctg gtcgccacag ccaccggcgt gcactct 57
<210> 124
<211> 604
<212> PRT
<213> 人工序列
<220>
<223> muFAP HC-Fc (DD)-muIL2v
<400> 124
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp
180 185 190
Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys
210 215 220
Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val
245 250 255
Val Val Ala Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe
260 265 270
Val Asp Asp Val Glu Val His Thr Ala Gln Thr Lys Pro Arg Glu Glu
275 280 285
Gln Ile Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala
305 310 315 320
Ala Phe Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg
325 330 335
Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met
340 345 350
Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asn Phe Phe Pro
355 360 365
Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn
370 375 380
Tyr Asp Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val
385 390 395 400
Tyr Ser Asp Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr
405 410 415
Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu
420 425 430
Lys Ser Leu Ser His Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Ser Ser
450 455 460
Ser Thr Ala Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
465 470 475 480
Gln His Leu Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser Arg
485 490 495
Met Glu Asn Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Ala Lys
500 505 510
Phe Ala Leu Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys Leu
515 520 525
Glu Asp Glu Leu Gly Pro Leu Arg His Val Leu Asp Gly Thr Gln Ser
530 535 540
Lys Ser Phe Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile Arg
545 550 555 560
Val Thr Val Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys Gln
565 570 575
Phe Asp Asp Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp Ile
580 585 590
Ala Phe Ala Gln Ser Ile Ile Ser Thr Ser Pro Gln
595 600
<210> 125
<211> 441
<212> PRT
<213> 人工序列
<220>
<223> muFAP HC-Fc (KK)
<400> 125
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp
180 185 190
Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys
210 215 220
Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val
245 250 255
Val Val Ala Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe
260 265 270
Val Asp Asp Val Glu Val His Thr Ala Gln Thr Lys Pro Arg Glu Glu
275 280 285
Gln Ile Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala
305 310 315 320
Ala Phe Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg
325 330 335
Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Lys Gln Met
340 345 350
Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asn Phe Phe Pro
355 360 365
Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn
370 375 380
Tyr Lys Asn Thr Gln Pro Ile Met Lys Thr Asp Gly Ser Tyr Phe Val
385 390 395 400
Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr
405 410 415
Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu
420 425 430
Lys Ser Leu Ser His Ser Pro Gly Lys
435 440
<210> 126
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> muFAP LC
<400> 126
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala Asp Ala
100 105 110
Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser
115 120 125
Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp
130 135 140
Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val
145 150 155 160
Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met
165 170 175
Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser
180 185 190
Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys
195 200 205
Ser Phe Asn Arg Asn Glu Cys
210 215
Claims (16)
1.与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用作治疗癌症的组合疗法,用作预防或治疗转移的组合疗法,用作治疗炎性疾病的组合疗法,用作治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展的组合疗法,或用作刺激免疫应答或功能,诸如T细胞活性的组合疗法,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
2.依照权利要求1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用于治疗癌症。
3.依照权利要求2的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用于治疗乳腺癌,肺癌,结肠癌,卵巢癌,黑素瘤癌,膀胱癌,肾的癌,肾癌,肝癌,头和颈癌,结直肠癌,黑素瘤,胰腺癌,胃癌瘤癌,食道癌,间皮瘤,前列腺癌,白血病,淋巴瘤,骨髓瘤。
4.依照权利要求1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用于预防或治疗转移。
5.依照权利要求1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用于治疗炎性疾病。
6.依照权利要求1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用于治疗免疫相关疾病诸如肿瘤免疫力或延迟其进展。
7.依照权利要求1的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用于刺激免疫应答或功能,诸如T细胞活性。
8.与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其用于
i)在表达该免疫细胞因子的靶物的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达该免疫细胞因子的靶物的肿瘤的受试者的中值和/或总体存活,
其中该靶物是在肿瘤细胞上或肿瘤细胞环境中呈递的,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
9.与结合人PD-L1的抗体组合的CEA靶向性IL-2变体免疫细胞因子,其用于
i)在表达CEA的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达CEA的肿瘤的受试者的中值和/或总体存活,
其中该CEA靶向性IL-2变体免疫细胞因子与结合人PD-L1的抗体组合施用,
其中组合疗法中使用的CEA靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
10.与结合人PD-L1的抗体组合的FAP靶向性IL-2变体免疫细胞因子,其用于
i)在表达FAP的肿瘤中抑制肿瘤生长;和/或
ii)增强具有表达FAP的肿瘤的受试者的中值和/或总体存活,
其中组合疗法中使用的FAP靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
c)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
d)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
11.一种肿瘤靶向性IL-2变体免疫细胞因子,其用于治疗具有表达CEA的肿瘤或特征在于表达或过表达CEA的肿瘤,具有表达FAP的肿瘤或特征在于表达或过表达FAP的肿瘤或具有与表达或过表达CEA或FAP有关的肿瘤的患者,且其中该免疫细胞因子与结合人PD-L1的抗体组合施用,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
a)SEQ ID NO:68的重链可变域VH和SEQ ID NO:67的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
b)SEQ ID NO:84或SEQ ID NO:86或SEQ ID NO:88的多肽序列,或
c)SEQ ID NO:84,和SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
d)SEQ ID NO:108,和SEQ ID NO:109和SEQ ID NO:110的多肽序列,或
e)SEQ ID NO:42的重链可变域VH和SEQ ID NO:41的轻链可变域VL,和SEQ ID NO:3的多肽序列,或
f)SEQ ID NO:79或SEQ ID NO:80或SEQ ID NO:81的多肽序列,或
g)SEQ ID NO:79,和SEQ ID NO:80和SEQ ID NO:81的多肽序列,或
h)SEQ ID NO:124,和SEQ ID NO:125和SEQ ID NO:126的多肽序列;
且组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL,或
b)SEQ ID NO:90的重链可变域VH和SEQ ID NO:93的轻链可变域VL,或
c)SEQ ID NO:90的重链可变域VH和SEQ ID NO:94的轻链可变域VL,或
d)SEQ ID NO:90的重链可变域VH和SEQ ID NO:95的轻链可变域VL,或
e)SEQ ID NO:90的重链可变域VH和SEQ ID NO:96的轻链可变域VL,或
f)SEQ ID NO:90的重链可变域VH和SEQ ID NO:97的轻链可变域VL,或
g)SEQ ID NO:90的重链可变域VH和SEQ ID NO:98的轻链可变域VL,或
h)SEQ ID NO:90的重链可变域VH和SEQ ID NO:99的轻链可变域VL,或
i)SEQ ID NO:90的重链可变域VH和SEQ ID NO:100的轻链可变域VL,或
j)SEQ ID NO:90的重链可变域VH和SEQ ID NO:101的轻链可变域VL,或
k)SEQ ID NO:90的重链可变域VH和SEQ ID NO:102的轻链可变域VL,或
l)SEQ ID NO:90的重链可变域VH和SEQ ID NO:103的轻链可变域VL,或
m)SEQ ID NO:90的重链可变域VH和SEQ ID NO:104的轻链可变域VL,或
n)SEQ ID NO:90的重链可变域VH和SEQ ID NO:105的轻链可变域VL,或
o)SEQ ID NO:90的重链可变域VH和SEQ ID NO:106的轻链可变域VL,或
p)SEQ ID NO:91的重链可变域VH和SEQ ID NO:107的轻链可变域VL。
12.依照前述权利要求任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,
其中组合疗法中使用的肿瘤靶向性IL-2变体免疫细胞因子特征在于包含
SEQ ID NO:84,SEQ ID NO:86和SEQ ID NO:88的多肽序列,或
SEQ ID NO:79,SEQ ID NO:80和SEQ ID NO:81的多肽序列,
且其中组合疗法中使用的结合人PD-L1的抗体特征在于包含
a)SEQ ID NO:89的重链可变域VH和SEQ ID NO:92的轻链可变域VL。
13.依照前述权利要求任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其特征在于所述免疫细胞因子的抗体构件和所述抗体是人IgG1亚类或人IgG4亚类的。
14.依照前述权利要求任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其特征在于所述抗体具有降低的或最小限度的效应器功能。
15.依照前述权利要求任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其中所述最小限度的效应器功能源自效应器降低性Fc突变。
16.依照前述权利要求任一项的与结合人PD-L1的抗体组合的肿瘤靶向性IL-2变体免疫细胞因子,其中所述效应器降低性Fc突变为L234A/L235A或L234A/L235A/P329G或N297A或D265A/N297A。
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