CN115298217A - 结合nkg2d、cd16及flt3的蛋白质 - Google Patents
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- CN115298217A CN115298217A CN202080072319.9A CN202080072319A CN115298217A CN 115298217 A CN115298217 A CN 115298217A CN 202080072319 A CN202080072319 A CN 202080072319A CN 115298217 A CN115298217 A CN 115298217A
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Abstract
描述结合NKG2D受体、CD16及FLT3的多特异性结合蛋白,以及可用于治疗自体免疫疾病或癌症的药物组合物及治疗方法。
Description
本申请案主张2019年10月15日申请的美国临时申请案第62/915,123号的优先权,所述临时申请案整体以引用的方式并入本文中。
序列表
本申请案以引用的方式整体并入呈ASCII文本格式的序列表的计算机可读形式(CRF)。序列表文本文件标题为“14247-474-888_SEQ_LISTING”,于2020年10月5日创建,且大小为317,572字节。
技术领域
本发明涉及结合于NKG2D、CD16及FLT3的多特异性结合蛋白。
背景技术
尽管在文献中已报导用于治疗癌症的大量研究工作及科学进展,但此疾病仍然为显著健康问题。血液及骨髓癌为经常被诊断出的癌症类型,包括多发性骨髓瘤、白血病及淋巴瘤。目前针对这些癌症的治疗方案并非对所有患者皆有效和/或可能具有严重不良副作用。使用现有的治疗方案来治疗其他类型的癌症亦仍然具有挑战性。
癌症免疫疗法是理想的,因为其是高度特异性的,且可利用患者自身的免疫系统促进癌细胞的破坏。诸如双特异性T细胞衔接蛋白的融合蛋白为文献中描述的与肿瘤细胞及T细胞结合以促进肿瘤细胞破坏的癌症免疫疗法。在文献中已描述与某些肿瘤相关抗原及某些免疫细胞结合的抗体。参见例如WO 2016/134371及WO 2015/095412。
自然杀伤(NK)细胞是先天免疫系统的组成部分,约占循环淋巴细胞的15%。NK细胞实际上浸润所有组织且最初的特征为其能够有效杀死肿瘤细胞而无需预先敏化。活化的NK细胞通过类似于细胞毒性T细胞的方式,亦即经由含有穿孔素及颗粒酶的细胞溶解颗粒以及经由死亡受体路径杀死靶细胞。活化NK细胞亦分泌诸如IFN-γ的发炎细胞因子及促进其他白细胞募集至靶组织的趋化介素。
NK细胞经由其表面上的各种活化及抑制受体对信号作出反应。例如,当NK细胞遇到健康自身细胞时,其活性经由活化杀伤细胞免疫球蛋白样受体(KIR)受到抑制。可替代地,当NK细胞遇到外来细胞或癌细胞时,其经由其活化受体(例如NKG2D、NCR、DNAM1)活化。NK细胞亦通过一些免疫球蛋白的恒定区经由其表面上的CD16受体活化。NK细胞对活化的总敏感性视刺激及抑制信号总和而定。NKG2D为一种II型跨膜蛋白,基本上由NKG2D充当活化受体的所有自然杀伤细胞表表达。NKG2D亦存在于T细胞中,在T细胞中其用作共刺激受体。经由NKG2D调节NK细胞功能的能力可用于包括恶性病的多种治疗环境中。
Fms相关酪氨酸激酶3(FLT3)也称为FLK2、STK1或CD135,为一种III类受体酪氨酸激酶。FLT3为一种跨膜蛋白,其在胞外区包括多个免疫球蛋白样域。FLT3可通过结合FLT3LG来活化,从而诱导FLT3均二聚及自身磷酸化。活化的FLT3随后磷酸化且活化多个细胞质效应分子,诸如Akt、Erk及mTOR,从而促进细胞增殖且减少细胞凋亡。在急性骨髓性白血病及急性淋巴母细胞白血病中已观察到导致FLT3组成型活化的突变。
发明内容
本发明提供结合于自然杀伤细胞上的NKG2D受体及CD16受体以及肿瘤相关抗原FLT3的多特异性结合蛋白。此类蛋白质可接合超过一种NK活化受体,且可阻断天然配位体与NKG2D的结合。在某些实施方案中,蛋白质可折磨人类中的NK细胞。在一些实施方案中,蛋白质可折磨人类中及诸如啮齿动物及食蟹猕猴的其他物种中的NK细胞。亦提供含有本文所述的蛋白质中的任一种的调配物;含有一种或多种表达所述蛋白质的核酸的细胞,及使用所述蛋白质增强肿瘤细胞死亡的方法。
因此,本发明的一方面提供一种蛋白质,该蛋白质包含:
(a)结合NKG2D的第一抗原结合位点;
(b)结合FLT3的第二抗原结合位点;及
(c)足以结合CD16的抗体Fc域或其一部分,或结合CD16的第三抗原结合位点,
其中该结合FLT3的第二抗原结合位点包含:
(i)包含互补决定区1(CDR1)、互补决定区2(CDR2)及互补决定区3(CDR3)的的重链可变域(VH),该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及55的氨基酸序列;及包含CDR1、CDR2及CDR3的轻链可变域(VL),该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列;
(ii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:59、63及54的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ IDNO:86、66及67的氨基酸序列;
(iii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、88及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ IDNO:91、92及93的氨基酸序列;
(iv)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:97、99及100的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ IDNO:101、102及103的氨基酸序列;
(v)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92及93的氨基酸序列;
(vi)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:109、110及111的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:112、113及114的氨基酸序列;
(vii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:117、118及119的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:120、121及122的氨基酸序列;
(viii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ IDNO:106、92及93的氨基酸序列;
(ix)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、33及127的氨基酸序列分别;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:128、129及130的氨基酸序列;或
(x)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:132、133及134的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ IDNO:65、66及46的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及55的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及50的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ IDNO:6、7及8的氨基酸序列。在某些实施方案中,VH包含与SEQ ID NO:37至少90%一致的氨基酸序列,且VL包含与SEQ ID NO:38至少90%一致的氨基酸序列。在某些实施方案中,VH包含SEQ ID NO:53的氨基酸序列,且VL包含SEQ ID NO:42的氨基酸序列。在某些实施方案中,VH及VL包含以下氨基酸序列:SEQ ID NO:9及10;13及10;17及10;9及22;9及26;9及30;9及34;37及38;41及42;45及42;或49及42。在某些实施方案中,第二抗原结合位点呈单链可变片段(scFv)存在,且其中scFv包含选自SEQ ID NO:3、12、15、16、19、20、23、24、27、28、31、32、35、36、39、40、43、44、47、48、51及52的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:59、63及54的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:86、66及67的氨基酸序列。在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:78、63、79的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:80、66、67的氨基酸序列。在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ IDNO:62、63、64的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66、67的氨基酸序列。在某些实施方案中,VH包含与SEQ ID NO:76至少90%一致的氨基酸序列,且VL包含与SEQ ID NO:77至少90%一致的氨基酸序列。在某些实施方案中,VH包含SEQ ID NO:29的氨基酸序列,且VL包含SEQ ID NO:84的氨基酸序列。在某些实施方案中,VH及VL包含以下氨基酸序列:SEQ ID NO:68及69;72及73;或76及77。在某些实施方案中,第二抗原结合位点呈scFv存在,且其中scFv包含选自SEQ ID NO:70、71、74、75、81及82的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、88及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:91、92及93的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:97、99及100的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:101、102及103的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92及93的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:109、110及111的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:112、113及114的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:117、118及119的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:120、121及122的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92及93的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、33及127的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:128、129及130的氨基酸序列。
在某些实施方案中,结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:132、133及134的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及46的氨基酸序列。
在某些实施方案中,第二抗原结合位点以如通过表面等离子体共振(SPR)所测量的小于或等于20nM的解离常数(KD)结合人类FLT3。在某些实施方案中,第二抗原结合位点以如通过SPR所测量的小于或等于10nM的KD结合人类FLT3。在某些实施方案中,第二抗原结合位点结合食蟹猕猴FLT3。在某些实施方案中,第二抗原结合位点不与FLT3L竞争结合FLT3。
在某些实施方案中,蛋白质包含足以结合CD16的抗体Fc域或其一部分。
在某些实施方案中,结合NKG2D的第一抗原结合位点为Fab片段,且结合FLT3的第二抗原结合位点为scFv。在某些实施方案中,结合NKG2D的第一抗原结合位点为scFv,且结合FLT3的第二抗原结合位点为Fab片段。
在某些实施方案中,蛋白质进一步包含结合FLT3的额外抗原结合位点。在某些实施方案中,结合NKG2D的第一抗原结合位点为scFv,且结合FLT3的第二及额外抗原结合位点各自为Fab片段。在某些实施方案中,结合NKG2D的第一抗原结合位点为scFv,且结合FLT3的第二及额外抗原结合位点各自为scFv。
在某些实施方案中,结合FLT3的scFv和/或结合NKG2D的scFv包含重链可变域及轻链可变域。在某些实施方案中,scFv经由包含Ala-Ser或Gly-Ser的铰链连接于足以结合CD16的抗体恒定域或其一部分。在某些实施方案中,铰链进一步包含氨基酸序列Thr-Lys-Gly。在某些实施方案中,scFv的重链可变域与scFv的轻链可变域形成二硫桥键。在某些实施方案中,根据Kabat编号方案进行编号,在重链可变域的C44与轻链可变域的C100之间形成二硫桥键。在某些实施方案中,scFv的重链可变域经由可挠性接头连接于scFv的轻链可变域。在某些实施方案中,可挠性接头包含(G4S)4。在某些实施方案中,在scFv内,重链可变域位于轻链可变域的C端。在某些实施方案中,在scFv内,重链可变域位于轻链可变域的N端。
在某些实施方案中,Fab不位于抗原结合位点与Fc或其部分之间。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及270或271的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:
(i)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及255或256的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列;或
(ii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及243或244的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
在某些实施方案中,第一抗原结合位点的VH包含与SEQ ID NO:254至少90%一致的氨基酸序列,且第一抗原结合位点的VL包含与SEQ ID NO:239至少90%一致的氨基酸序列。在某些实施方案中,第一抗原结合位点的VH包含SEQ ID NO:254的氨基酸序列,且第一抗原结合位点的VL包含SEQ ID NO:239的氨基酸序列。
在某些实施方案中,抗体Fc域为人类IgG1抗体Fc域。在某些实施方案中,抗体Fc域或其部分包含与SEQ ID NO:136至少90%一致的氨基酸序列。
在某些实施方案中,根据EU编号系统进行编号,抗体Fc域的至少一个多肽链相对于SEQ ID NO:136在一个或多个位置包含一个或多个选自以下的突变:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411及K439。在某些实施方案中,根据EU编号系统进行编号,抗体Fc域的至少一个多肽链相对于SEQ ID NO:136包含一个或多个选自以下的突变:Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、T411D、T411E、K439D及K439E。在某些实施方案中,根据EU编号系统进行编号,抗体重链恒定区的一个多肽链相对于SEQ ID NO:136在一个或多个位置包含一个或多个选自以下的突变:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、K392、T394、D399、S400、D401、F405、Y407、K409、T411及K439;且抗体重链恒定区的另一个多肽链相对于SEQ ID NO:136在一个或多个位置包含一个或多个选自以下的突变:Q347、Y349、L351、S354、E356、E357、S364、T366、L368、K370、N390、K392、T394、D399、D401、F405、Y407、K409、T411及K439。在某些实施方案中,根据EU编号系统进行编号,抗体重链恒定区的一个多肽链相对于SEQ ID NO:136包含K360E及K409W取代;且抗体重链恒定区的另一个多肽链相对于SEQ ID NO:136包含Q347R、D399V及F405T取代。在某些实施方案中,根据EU编号系统进行编号,抗体重链恒定区的一个多肽链相对于SEQ ID NO:136包含Y349C取代;且抗体重链恒定区的另一个多肽链相对于SEQ ID NO:136包含S354C取代。
在另一方面中,本发明提供一种药物组合物,该药物组合物包含本文公开的蛋白质及药学上可接受的载剂。
在另一方面中,本发明提供一种细胞,该细胞包含编码本文公开的蛋白质的一种或多种核酸。
在另一方面中,本发明提供一种增强肿瘤细胞死亡的方法,该方法包括将肿瘤细胞及自然杀伤细胞暴露于有效量的本文公开的蛋白质或药物组合物。
在另一方面中,本发明提供一种治疗癌症的方法,该方法包括向有需要的患者施用有效量的本文公开的蛋白质或药物组合物。
在某些实施方案中,癌症为血液恶性病。在某些实施方案中,血液恶性病为白血病。在某些实施方案中,选自由以下组成的组:急性骨髓性白血病(AML)、急性淋巴母细胞白血病(ALL)、骨髓化生不良、急性T-淋巴母细胞白血病及急性前髓细胞白血病。在某些实施方案中,癌症表达FLT3。
下文进一步详细描述本发明的多个方面及实施方案。
附图说明
图1为异二聚体、多特异性抗体、例如三特异性结合蛋白(TriNKET)的图示。各臂可表示NKG2D结合域或与FLT3对应的结合域。在一些实施方案中,NKG2D结合域及FLT3结合域可共享共同轻链。
图2A-2E示出多特异性结合蛋白、例如三特异性结合蛋白(TriNKET)的五种示例性格式。如图2A所示,NKG2D结合域或FLT3结合域可采取scFv格式(左臂)。含有靶向NKG2D的scFv、靶向FLT3的Fab片段及异二聚的抗体恒定区的抗体在本文中称为F3-TriNKET。含有靶向FLT3的scFv、靶向NKG2D的Fab片段及结合CD16的异二聚的抗体恒定区/域的抗体在本文中称为F3'-TriNKET(图2E)。如图2B所示,NKG2D结合域与FLT3结合域均可采取scFv格式。图2C至2D示出具有三个抗原结合位点的抗体,包括结合FLT3的两个抗原结合位点,及与异二聚的抗体恒定区融合的NKG2D结合位点。这些抗体格式在本文中称为F4-TriNKET。图2C示出两个FLT3结合位点呈Fab片段格式,且NKG2D结合位点呈scFv格式。图2D示出FLT3结合位点呈scFv格式,且NKG2D结合位点呈scFv格式。图2E表示含有靶向肿瘤的scFv、靶向NKG2D的Fab片段及结合CD16的异二聚的抗体恒定区/域(“CD域”)的三特异性抗体(TriNKET)。抗体格式在本文中称为F3'-TriNKET。在某些示例性多特异性结合蛋白中,抗体恒定区上的异二聚突变包括一个恒定域上的K360E及K409W;及相对恒定域上的Q347R、D399V及F405T(显示为CD域中的三角形锁钥形状)。Fab片段的重链与轻链可变域之间的粗条表示二硫键。
图3为呈三功能抗体(Triomab)形式的TriNKET的图示,其为保持IgG样形状的三功能的双特异性抗体。此嵌合体由两个半抗体组成,各半抗体具有来源于两个亲本抗体的一个轻链及一个重链。三功能抗体形式可为含有1/2大鼠抗体及1/2小鼠抗体的异二聚体构建物。
图4为呈KiH共同轻链形式的TriNKET的图示,其涉及杵-臼(KIH)技术。KiH为含有2个结合于标靶1及2的Fab片段及由异二聚突变稳定的Fc的异二聚体。呈KiH格式的TriNKET可为具有2个结合于标靶1及标靶2的Fab片段的异二聚体构建物,其含有两个不同重链及与两个重链配对的共同轻链。
图5呈双重可变域免疫球蛋白(DVD-IgTM)形式的TriNKET的图示,其经由天然存在的可挠性接头组合两种单克隆抗体的标靶结合域且产生四价IgG样分子。DVD-IgTM为一种同二聚体构建物,其中靶向抗原2的可变域与靶向抗原1的Fab片段的可变域的N端融合。DVD-IgTM形式含有正常Fc。
图6为呈正交Fab片段界面(Ortho-Fab)形式的TriNKET的图示,其为含有与Fc融合的2个结合于标靶1及标靶2的Fab片段的异二聚体构建物。通过正交界面确保轻链(LC)-重链(HC)配对。通过Fc的突变确保异二聚。
图7为呈2合1型Ig格式的TriNKET的图示。
图8为呈ES形式的TriNKET的图示,其为含有与Fc融合的两个结合于标靶1及标靶2的不同Fab片段的异二聚体构建物。通过Fc的静电转向突变确保异二聚。
图9为呈Fab臂交换形式的TriNKET的图示:通过用来自另一分子的重链-轻链对替换重链及所附接的轻链(半分子)来交换Fab片段臂的抗体。Fab臂交换形式(cFae)为含有2个结合于标靶1及2的Fab片段及由异二聚突变稳定的Fc的异二聚体。
图10为呈SEED体形式的TriNKET的图示,其为含有2个结合于标靶1及标靶2的Fab片段及通过异二聚突变稳定的Fc的异二聚体。
图11为呈LuZ-Y形式的TriNKET的图示,其中亮氨酸拉炼用于诱导两个不同HC的异二聚。LuZ-Y形式为含有与Fc融合的两个结合于标靶1及2的不同scFab的异二聚体。经由与Fc的C端融合的亮氨酸拉炼基元来确保异二聚。
图12为呈Cov-X体形式的TriNKET的图示。
图13A-13B为呈κλ-体形式的TriNKET的图示,其为具有与通过异二聚突变稳定的Fc融合的两个不同Fab片段的异二聚体构建物:靶向抗原1的一个Fab片段含有κLC,且靶向抗原2的第二Fab片段含有λLC。图13A为κλ-体的一种形式的示例性图示;图13B为另一κλ-体的示例性图示。
图14为包括结合于标靶1的Fab片段及结合于标靶2的scFab的Oasc-Fab异二聚体构建物,Fab片段及scFab两者均与Fc域融合。通过Fc域的突变确保异二聚。
图15为一种DuetMab,其为含有两个结合于抗原1及2的不同Fab片段及通过异二聚突变稳定的Fc的异二聚体构建物。Fab片段1及2含有确保正确轻链与重链配对的差别S-S桥。
图16为一种CrossmAb,其为具有两个结合于标靶1及2的不同Fab片段及通过异二聚突变稳定的Fc的异二聚体构建物。CL及CH1域与VH及VL域切换,例如CH1与VL串联融合,而CL与VH串联融合。
图17为Fit-Ig,其为一种同二聚体构建物,其中结合于抗原2的Fab片段与结合于抗原1的Fab片段的HC的N端融合。构建物含有野生型Fc。
图18为一组传感图,其示出自鼠类杂交瘤上清液收集的结合于hFLT3的抗体的SPR概况。
图19为一组传感图,其示出自鼠类mAb子克隆收集的结合于hFLT3的抗体的SPR概况。
图20为描绘通过饱和浓度的可溶性FLT3-配位体降低候选抗体结合表达FLT3的EOL-1癌细胞的能力的条形图。
图21A-21C为展示靶向FLT3的TriNKET F3'-1158及其亲本单克隆抗体与表达FLT3的细胞株RMA-hFLT3(图21A)、RMA-cFLT3(图21B)及REH(图21C)的结合的线图。
图22A-22B为展示靶向FLT3的TriNKET F3'-1158及其亲本单克隆抗体与表达具有T227M突变的FLT3的MOLM-13细胞(图22A)及表达具有ITD突变的FLT2的MV4-11细胞的结合的线图。
图23A-23B为展示靶向FLT3的TriNKET F3'-1158及其亲本单克隆抗体内化至表达FLT3的细胞株REH(图23A)及EOL-1(图23B)中的线图。
图24A-24D为展示表达FLT3的癌细胞株EOL-1(图24A)、REH(图24B)、RS4-11(图24C)及MV4-11(图24D)在TriNKET F3'-1158及其亲本单克隆抗体存在下的NK细胞介导的溶解的条形图。
图25为描绘表达FLT3的癌细胞株REH在TriNKET F3'-1158、其NKG2D死亡变体(“F3'-1158死亡-2D”)、其Fc沉默变体(“F3'-1158si”)或其亲本单克隆抗体1158mAb存在下的NK细胞介导的溶解的线图。
图26为展示表达FLT3的急性淋巴母细胞白血病细胞株RS4-11在TriNKET F3'-1158及其亲本单克隆抗体存在下的CD8 T细胞介导的溶解的线图。
图27为一组展示TriNKET F3'-1158及其亲本单克隆抗体与血细胞的结合的直方图。
图28A-28B为展示TriNKET F3'-1158及其亲本单克隆抗体在FLT3-配位体缺乏(图28A)或存在(图28B)下的FLT3磷酸化的条形图。图7A中的FLT3-配位体样品充当阳性对照。
具体实施方式
本发明提供结合于自然杀伤细胞上的NKG2D受体及CD16受体以及肿瘤相关抗原FLT3的多特异性结合蛋白。在一些实施方案中,多特异性蛋白进一步包括结合FLT3的额外抗原结合位点。本发明亦提供包含此类多特异性结合蛋白的药物组合物,及使用此类多特异性蛋白及药物组合物的治疗方法,以达成诸如治疗自体免疫疾病及癌症的目的。本发明的多个方面在下文中分几章节阐述;然而,在一个特定章节中描述的本发明的方面不限于任何特定章节。
为帮助理解本发明,下文定义许多术语及词组。
如本文所用,术语“一种(a/an)”意谓“一种或多种”且除非上下文不相宜,否则包括复数。
如本文所用,术语“抗原结合位点”是指参与抗原结合的免疫球蛋白分子的一部分。在人类抗体中,抗原结合位点由重链(“H”)及轻(“L”)链的N端可变(“V”)区的氨基酸残基形成。重链及轻链的V区内的三个高度相异的延伸段称为“高变区”,其插入称为“构架区”或“FR”的更保守的位于两侧的延伸段之间。因此,“FR”是指在免疫球蛋白中的高变区之间天然存在且与高变区相邻的氨基酸序列。在人类抗体分子中,轻链的三个高变区及重链的三个高变区相对于彼此呈三维空间布置,形成抗原结合表面。抗原结合表面与结合抗原的三维表面互补,且重链及轻链中的每一者的三个高变区称为“互补决定区”或“CDR”。在诸如骆驼及软骨鱼的某些动物中,抗原结合位点由单个抗体链形成,提供“单域抗体”。抗原结合位点可呈完整抗体、抗体的保留抗原结合表面的抗原结合片段或诸如scFv的重组多肽存在,在单个多肽中使用肽接头将重链可变域连接至轻链可变域。
如本文所用,术语“肿瘤相关抗原”意谓包括但不限于与癌症相关的蛋白质、糖蛋白、神经节苷脂、碳水化合物、脂质的任何抗原。此类抗原可在恶性细胞上或肿瘤微环境中,诸如肿瘤相关的血管、细胞外基质、间质基质或免疫浸润物上表达。
如本文所用,术语“个体”及“患者”是指有待由本文所述的方法及组合物治疗的生物体。此类生物体优选包括(但不限于)哺乳动物(例如鼠类、猿、马、牛、猪科动物、犬科动物、猫科动物等)且更优选包括人类。
如本文所用,术语“有效量”是指化合物(例如本发明的化合物)足以实现有益或所需结果的量。有效量可分一或多次给药、施加或剂量来施用,且不意欲限于特定调配或给药途径。如本文所用,术语“治疗”包括使疾患、疾病、病症及其类似物好转或改善其症状的任何作用,例如减轻、降低、调节、改善或消除。
如本文所用,术语“药物组合物”是指活性剂与惰性或活性载剂的组合,使得组合物特别适合于体内或离体的诊断或治疗用途。
如本文所用,术语“药学上可接受的载剂”是指任何标准药物载剂,诸如磷酸盐缓冲生理食盐水溶液、水、乳液(如诸如油/水或水/油乳液)及各种类型润湿剂。组合物亦可包括稳定剂和防腐剂。关于载剂、稳定剂及佐剂的实施例,参见例如Martin,Remington'sPharmaceutical Sciences,第15版,Mack Publ.Co.,Easton,PA[1975]。
如本文所用,术语“药学上可接受的盐”是指本发明化合物的任何药学上可接受的盐(例如酸或碱),其在施用个体后,能够提供本发明的化合物或其活性代谢物或残余物。如所属领域的技术人员已知,本发明化合物的“盐”可源自于无机酸或有机酸及无机碱或有机碱。示例性酸包括(但不限于)盐酸、氢溴酸、硫酸、硝酸、过氯酸、反丁烯二酸、顺丁烯二酸、磷酸、乙醇酸、乳酸、水杨酸、丁二酸、甲苯-对磺酸、酒石酸、乙酸、柠檬酸、甲烷磺酸、乙烷磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸及其类似物。诸如草酸的其他酸虽然本身在药学上并非可接受的,但可用于制备适用作获得本发明的化合物及其药学上可接受的酸加成盐的中间体的盐。
示例性碱包括(但不限于)碱金属(例如钠)氢氧化物、碱土金属(例如镁)氢氧化物、氨及式NW4 +的化合物,其中W为C1-4烷基,及其类似物。
示例性盐包括(但不限于):乙酸盐、己二酸盐、海藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、反丁烯二酸盐、氟庚酸盐(flucoheptanoate)、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙烷磺酸盐、乳酸盐、顺丁烯二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、双羟萘酸盐(palmoate)、果胶酸盐(pectinate)、过硫酸盐、苯丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一酸盐及其类似物。盐的其他实施例包括本发明化合物的阴离子与诸如Na+、NH4 +及NW4 +(其中W为C1-4烷基)及其类似物的合适阳离子化合而成的盐。
对于治疗用途,预期本发明化合物的盐为药学上可接受的。然而,非药学上可接受的酸及碱的盐亦可用于例如制备或纯化药学上可接受的化合物。
如本文所用,“FLT3”(亦称FLK2、STK1或CD135)是指Uniprot寄存编号P36888的蛋白质及相关同功型。
如本文所用,“FLT3L”(亦称FLT3-配位体)是指Uniprot寄存编号P49771的蛋白质及相关同功型。
在整个说明书中,在组合物描述为具有、包括或包含特定组分的情况下,或者在制程及方法描述为具有、包括或包含特定步骤的情况下,预期另外存在基本上由所述组分组成或由所述组分组成的本发明的组合物,且存在基本上由所述加工步骤组成或由所述加工步骤组成的根据本发明的制程及方法。
一般而言,除非另作说明,否则指定百分比的组合物为以重量计。此外,若变量未伴有定义,则以变量的先前定义为准。
I.蛋白质
本发明提供结合于自然杀伤细胞上的NKG2D受体及CD16受体以及肿瘤相关抗原FLT3的多特异性结合蛋白。多特异性结合蛋白可用于本文所述的药物组合物及治疗方法。多特异性结合蛋白结合于自然杀伤细胞上的NKG2D受体及CD16受体可增强自然杀伤细胞破坏表达FLT3的肿瘤细胞的活性。多特异性结合蛋白结合于表达FLT3的肿瘤细胞使这些细胞接近自然杀伤细胞,此帮助对准肿瘤细胞及自然杀伤细胞对肿瘤细胞之间接破坏。结合NKG2D、CD16及另一个标靶的多特异性结合蛋白公开于国际申请公开案第WO2018148445号及第WO2019157366号中,所述公开案不以引用的方式并入本文中。下文提供一些示例性多特异性结合蛋白的其他描述。
多特异性结合蛋白的第一组分为结合于表达NKG2D受体的细胞的抗原结合位点,所述细胞可包括但不限于NK细胞、γδT细胞及CD8+αβT细胞。在NKG2D结合后,多特异性结合蛋白可阻断诸如ULBP6及MICA的天然配位体结合于NKG2D及活化NK细胞。
多特异性结合蛋白的第二组分为结合FLT3的抗原结合位点。表达FLT3的细胞可见于例如急性骨髓性白血病(AML)及急性淋巴母细胞白血病(ALL)。可发现与其他癌症及肿瘤类型,例如血液恶性病、白血病、急性骨髓性白血病(AML)、急性淋巴母细胞白血病(ALL)、骨髓化生不良、急性T淋巴母细胞性白血病及急性前髓细胞白血病相关的表达FLT3的细胞。
多特异性结合蛋白的第三组分为结合于表达CD16的细胞的抗体Fc域或其一部分或抗原结合位点,CD16为在包括自然杀伤细胞、巨噬细胞、嗜中性球、嗜酸性球、肥大细胞及滤泡树突状细胞的白细胞表面上的Fc受体。
多特异性结合蛋白的额外抗原结合位点可结合FLT3。在某些实施方案中,结合NKG2D的第一抗原结合位点为scFv,且结合FLT3的第二抗原结合位点及结合FLT3的额外抗原结合位点各自为Fab片段。在某些实施方案中,结合NKG2D的第一抗原结合位点为scFv,且结合FLT3的第二抗原结合位点及结合FLT3的额外抗原结合位点各自为scFv。
抗原结合位点各可并入抗体重链可变域及抗体轻链可变域(例如呈抗体中排列,或融合在一起,形成scFv),或抗原结合位点中的一个或多个可为单域抗体,诸如VHH抗体如骆驼科抗体,或VNAR抗体如软骨鱼中发现的VNAR抗体。
在一些实施方案中,第二抗原结合位点并入氨基酸序列与第一抗原结合位点中存在的轻链可变域的氨基酸序列一致的轻链可变域。
本文所述的多特异性结合蛋白可采取多种格式。举例而言,一种格式为包括第一免疫球蛋白重链、第一免疫球蛋白轻链、第二免疫球蛋白重链及第二免疫球蛋白轻链的异二聚体多特异性抗体(图1)。第一免疫球蛋白重链包括第一Fc(铰链-CH2-CH3)域、第一重链可变域及任选第一CH1重链域。第一免疫球蛋白轻链包括第一轻链可变域及任选第一轻链恒定域。第一免疫球蛋白轻链与第一免疫球蛋白重链一起形成结合NKG2D的抗原结合位点。第二免疫球蛋白重链包含第二Fc(铰链-CH2-CH3)域、第二重链可变域及任选第二CH1重链域。第二免疫球蛋白轻链包括第二轻链可变域及任选第二轻链恒定域。第二免疫球蛋白轻链与第二免疫球蛋白重链一起形成结合FLT3的抗原结合位点。第一Fc域及第二Fc域一起能够结合于CD16(图1)。在一些实施方案中,第一免疫球蛋白轻链与第二免疫球蛋白轻链一致。
另一种示例性格式涉及包括第一免疫球蛋白重链、第二免疫球蛋白重链及免疫球蛋白轻链的异二聚体多特异性抗体(图2A)。第一免疫球蛋白重链包括第一Fc(铰链-CH2-CH3)域,该Fc域经由接头或抗体铰链与由配对且结合NKG2D或结合FLT3的重链可变域及轻链可变域构成的单链可变片段(scFv)融合。第二免疫球蛋白重链包括第二Fc(铰链-CH2-CH3)域、第二重链可变域及CH1重链域。免疫球蛋白轻链包括轻链可变域及轻链恒定域。第二免疫球蛋白重链与免疫球蛋白轻链配对且结合于NKG2D或结合FLT3。第一Fc域及第二Fc域一起能够结合于CD16(图2A)。
另一种示例性格式涉及包括第一免疫球蛋白重链及第二免疫球蛋白重链的异二聚体多特异性抗体(图2B)。第一免疫球蛋白重链包括第一Fc(铰链-CH2-CH3)域,该Fc域经由接头或抗体铰链与由配对且结合NKG2D或结合FLT3的重链可变域及轻链可变域构成的单链可变片段(scFv)融合。第二免疫球蛋白重链包括第二Fc(铰链-CH2-CH3)域,该Fc域经由接头或抗体铰链与由配对且结合NKG2D或结合FLT3的重链可变域及轻链可变域构成的单链可变片段(scFv)融合。第一Fc域及第二Fc域一起能够结合于CD16(图2B)。
在一些实施方案中,上述单链可变片段(scFv)经由铰链序列连接于抗体恒定域。在一些实施方案中,铰链包含氨基酸Ala-Ser或Gly-Ser。在一些实施方案中,连接结合NKG2D的scFv与抗体重链恒定域的铰链包含氨基酸Ala-Ser。在一些实施方案中,连接结合FLT3的scFv与抗体重链恒定域的铰链包含氨基酸Gly-Ser。在一些其他实施方案中,铰链包含氨基酸Ala-Ser及Thr-Lys-Gly。铰链序列可提供结合于标靶抗原的可挠性及可挠性与最佳几何形状之间的平衡。
在一些实施方案中,上述单链可变片段(scFv)包括重链可变域及轻链可变域。在一些实施方案中,重链可变域与轻链可变域形成二硫桥键,以增强scFv的稳定性。举例而言,可在重链可变域的C44残基与轻链可变域的C100残基之间形成二硫桥键,氨基酸位置根据Kabat进行编号。在一些实施方案中,重链可变域经由可挠性接头连接于轻链可变域。可使用任何合适接头,例如(G4S)4接头。在scFv的一些实施方案中,重链可变域位于轻链可变域的N端。在scFv的一些实施方案中,重链可变域位于轻链可变域的C端。
本文所述的多特异性结合蛋白可进一步包括一个或多个额外抗原结合位点。额外抗原结合位点可与恒定区CH2域的N端或恒定区CH3域的C端任选经由接头序列融合。在某些实施方案中,额外抗原结合位点采取单链可变区(scFv)的形式,其任选经二硫化物稳定,产生四价或三价多特异性结合蛋白。举例而言,多特异性结合蛋白包括结合NKG2D的第一抗原结合位点、结合FLT3的第二抗原结合位点、结合FLT3的额外抗原结合位点及足以结合CD16的抗体恒定区或其一部分或结合CD16的第四抗原结合位点。这些抗原结合位点中的任一者可采取Fab片段或scFv的形式,诸如上述scFv。
在一些实施方案中,额外抗原结合位点结合与第二抗原结合位点不同的FLT3的抗原决定基。在一些实施方案中,额外抗原结合位点结合与第二抗原结合位点相同的抗原决定基。在一些实施方案中,额外抗原结合位点包含与第二抗原结合位点相同的重链及轻链CDR序列。在一些实施方案中,额外抗原结合位点包含与第二抗原结合位点相同的重链及轻链可变域序列。在一些实施方案中,额外抗原结合位点具有与第二抗原结合位点相同的氨基酸序列。示例性格式展示于图2C及2D中。因此,多特异性结合蛋白可提供FLT3的二价接合。多特异性蛋白对FLT3的二价接合可将FLT3稳定在肿瘤细胞表面上且增强NK细胞对肿瘤细胞的细胞毒性。多特异性蛋白对FLT3的二价接合可赋予更强的多特异性蛋白对肿瘤细胞的结合,由此促进更强的NK细胞对肿瘤细胞、尤其对表达低水平FLT3的肿瘤细胞的细胞毒性反应。
多特异性结合蛋白可采取额外格式。在一些实施方案中,多特异性结合蛋白呈三功能抗体形式,其为保持IgG样形状的三官能双特异性抗体。此嵌合体由两个半抗体组成,各半抗体具有来源于两个亲本抗体的一个轻链及一个重链。
在一些实施方案中,多特异性结合蛋白为KiH形式,其涉及杵-臼(KiH)技术。KiH涉及对CH3域进行工程改造,以在各重链中建立“杵”或“臼”以促进异二聚。“杵-臼(KiH)”Fc技术背后的概念为通过用体积大的残基取代小残基(例如EU编号中T366WCH3A)而在一个CH3域中引入“杵”(CH3A)。为容纳“杵”,通过用较小残基替换最邻近的残基(例如T366S/L368A/Y407VCH3B),在其他CH3域(CH3B)上建立互补“臼”表面。“臼”突变通过结构引导的噬菌体文库筛选来优化(Atwell S,Ridgway JB,Wells JA,Carter P.,Stable heterodimers fromremodeling the domain interface of a homodimer using a phage display library,J.Mol.Biol.(1997)270(1):26-35)。KiH Fc变体的X射线晶体结构(Elliott JM,Ultsch M,Lee J,Tong R,Takeda K,Spiess C等人,Antiparallel conformation of knob and holeaglycosylated half-antibody homodimers is mediated by a CH2-CH3hydrophobicinteraction.J.Mol.Biol.(2014)426(9):1947-57;Mimoto F,Kadono S,Katada H,IgawaT,Kamikawa T,Hattori K.Crystal structure of a novel asymmetrically engineeredFc variant with improved affinity for FcγRs.Mol.Immunol.(2014)58(1):132-8)显示通过CH3域间核心界面上的空间互补性推动的疏水性相互作用,在热力学上有助于异二聚,而杵-杵及臼-臼分别由于位阻及有利的相互作用的破环而不利于同二聚。
在一些实施方案中,多特异性结合蛋白呈双重可变域免疫球蛋白(DVD-IgTM)形式,其经由天然存在的可挠性接头组合两种单克隆抗体的标靶结合域且产生四价IgG样分子。
在一些实施方案中,多特异性结合蛋白呈正交Fab界面(Ortho-Fab)形式。在ortho-Fab IgG方法(Lewis SM,Wu X,Pustilnik A,Sereno A,Huang F,Rick HL等人,Generation of bispecific IgG antibodies by structure-based design of anorthogonal Fab interface.Nat.Biotechnol.(2014)32(2):191-8)中,基于结构的区域设计只在一个Fab片段中的LC及HCVH-CH1界面上引入互补突变,另一个Fab片段无任何改变。
在一些实施方案中,多特异性结合蛋白呈2合1型Ig格式。在一些实施方案中,多特异性结合蛋白呈ES形式,其为含有与Fc融合的两个结合于标靶1及标靶2的不同Fab片段的异二聚体构建物。通过Fc的静电转向突变确保异二聚。
在一些实施方案中,多特异性结合蛋白呈κλ-体形式,其为具有与通过异二聚突变稳定的Fc融合的两个不同Fab片段的异二聚体构建物:靶向抗原1的Fab片段1含有κLC,而靶向抗原2的第二Fab片段含有λLC。图13A为κλ-体的一种形式的示例性图示;图13B为另一κλ-体的示例性图示。
在一些实施方案中,多特异性结合蛋白呈Fab臂交换形式(通过用来自另一分子的重链-轻链对替换重链及所附接的轻链(半分子)来交换Fab片段臂的抗体,产生双特异性抗体)。
在一些实施方案中,多特异性结合蛋白呈SEED体形式。链交换的工程改造域(SEED)平台经设计以产生不对称及双特异性抗体样分子,能够扩大天然抗体的治疗性应用。此蛋白质工程改造平台为基于交换保守CH3域内的免疫球蛋白的结构相关序列。SEED设计允许有效产生AG/GA异二聚体,同时不支持AG及GASEED CH3域的同二聚。(Muda M.等人,Protein Eng.Des.Sel.(2011,24(5):447-54))。
在一些实施方案中,多特异性结合蛋白呈LuZ-Y形式,其中亮氨酸拉炼用于诱导两个不同HC的异二聚。(Wranik,BJ.等人,J.Biol.Chem.(2012),287:43331-9)。
在一些实施方案中,多特异性结合蛋白呈Cov-X体形式。在双特异性CovX体中,两种不同肽使用支链氮杂环丁酮接头接合在一起且与支架抗体在温和条件下以位点特异性方式融合。药效基团负责功能活性,而抗体支架给予长半衰期及Ig样分布。药效基团可在化学上优化或用其他药效基团替换以产生优化或独特的双特异性抗体。(Doppalapudi VR等人,PNAS(2010),107(52);22611-22616)。
在一些实施方案中,多特异性结合蛋白呈Oasc-Fab异二聚体形式,其包括与Fc融合的结合于标靶1的Fab片段及结合于标靶2的scFab。通过Fc的突变确保异二聚。
在一些实施方案中,多特异性结合蛋白呈DuetMab形式,其为含有两个结合于抗原1及2的不同Fab片段及通过异二聚突变稳定的Fc的异二聚体构建物。Fab片段1及2含有确保正确LC与HC配对的差别S-S桥。
在一些实施方案中,多特异性结合蛋白呈CrossmAb形式,其为具有与通过异二聚突变稳定的Fc融合的两个结合于标靶1及2的不同Fab片段的异二聚体构建物。CL及CH1域与VH及VL域切换,例如CH1与VL同框融合,而CL与VH同框融合。
在一些实施方案中,多特异性结合蛋白呈Fit-Ig形式,其为同二聚体构建物,其中结合于抗原2的Fab片段与结合于抗原1的Fab片段的HC的N端融合。构建物含有野生型Fc。
下文更详细地描述多特异性结合蛋白的个别组分。
NKG2D结合位点
在结合于自然杀伤细胞上的NKG2D受体及CD16受体以及癌细胞上的肿瘤相关抗原后,多特异性结合蛋白可接合超过一种NK活化受体,且可阻断天然配位体与NKG2D的结合。在某些实施方案中,蛋白质可折磨人类中的NK细胞。在一些实施方案中,蛋白质可折磨人类中及诸如啮齿动物及食蟹猕猴的其他物种中的NK细胞。
表1列出组合时可结合于NKG2D的重链可变域及轻链可变域的肽序列。在一些实施方案中,重链可变域及轻链可变域呈Fab格式排列。在一些实施方案中,重链可变域及轻链可变域融合在一起,形成scFv。
表1中列出的NKG2D结合位点在与NKG2D的结合亲和力方面可变化,然而,其均活化人类NK细胞。
除非另外指示,否则表1中提供的CDR序列为根据Kabat确定。
在某些实施方案中,结合NKG2D的第一抗原结合位点(例如人类NKG2D)包含:包含与表1中所公开的抗体的VH至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的抗体重链可变域(VH),及包含与表1中所公开的相同抗体的VH至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的抗体轻链可变域(VL)。在某些实施方案中,第一抗原结合位点包含表1中公开的抗体的VH及VL序列的根据Kabat或所属领域中已知的任何其他CDR确定方法确定的重链CDR1、CDR2及CDR3以及轻链CDR1、CDR2及CDR3(参见Kabat等人,(1991)Sequences of ProteinsofImmunological Interest,NIH公开案第91-3242号,Bethesda)、Chothia(参见例如Chothia C及Lesk A M,(1987),J Mol Biol 196:901-917)、MacCallum(参见MacCallum RM等人,(1996)J Mol Biol 262:732-745)。在某些实施方案中,第一抗原结合位点包含表1中公开的抗体的重链CDR1、CDR2及CDR3以及轻链CDR1、CDR2及CDR3。
在某些实施方案中,结合于NKG2D的第一抗原结合位点包含与SEQ ID NO:138相关,例如具有与SEQ ID NO:138至少90%(例如至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列,和/或并入与SEQ ID NO:138的CDR1(SEQ ID NO:140)、CDR2(SEQ ID NO:141)及CDR3(SEQID NO:142)序列一致的氨基酸序列的重链可变域。与SEQ ID NO:138相关的重链可变域可与多种轻链可变域偶合,形成NKG2D结合位点。举例而言,并入与SEQ ID NO:138相关的重链可变域的第一抗原结合位点可进一步并入选自与SEQ ID NO:139、144、146、148、150、154、156、158、160、163、165、167、169、171、173、175、177、179及181相关的序列中的任一者的轻链可变域。举例而言,第一抗原结合位点并入具有与SEQ ID NO:138至少90%(例如至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的重链可变域及具有与选自SEQ ID NO:139、144、146、148、150、154、156、158、160、163、165、167、169、171、173、175、177、179及181的序列中的任一者至少90%(例如至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的轻链可变域。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:182的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:183至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:184或185、186及189或190的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:187、188及191的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:184或185、186及189或190的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:187、188及191的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:192的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:161至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:193或194、195及196或197的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:198、199及200的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:193或194、195及196或197的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:198、199及200的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:201的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:202至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:203的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:204至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:184、205及206的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:207、188及208的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:184、205及206的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:207、188及208的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:209的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:210至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:211或212、213及214或215的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:216、217及218的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:211或212、213及214或215的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:216、217及218的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:219的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:220至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:221或222、223及224或225的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:226、217及227的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:221或222、223及224或225的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:226、217及227的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:247的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:248至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:211或212、249及250或251的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:252、199及253的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:211或212、249及250或251的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:252、199及253的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:228的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:229至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:230或231、232及233或234的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:235、236及237的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:230或231、232及233或234的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:235、236及237的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:238的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:239至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及243或244的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:276、236及245的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及243或244的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:254的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:239至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及255或256的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:276、236及245的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及255或256的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:257的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:239至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及258或259的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:276、236及245的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及258或259的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:260的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:239至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及261或262的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:276、236及245的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及261或262的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:263的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:239至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及264或265的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:276、236及245的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及264或265的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:266的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:239至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及267或268的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:276、236及245的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及267或268的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:269的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:239至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及270或271的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQID NO:276、236及245的氨基酸序列。在某些实施方案中,第一抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及270或271的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:272的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:273至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。
在某些实施方案中,结合NKG2D的第一抗原结合位点包含:包含与SEQ ID NO:274的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ IDNO:275至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。
多特异性结合蛋白可结合于表达NKG2D的细胞,包括但不限于NK细胞、γδT细胞及CD8+αβT细胞。在NKG2D结合后,多特异性结合蛋白可阻断诸如ULBP6及MICA的天然配位体结合于NKG2D及活化NK细胞。
多特异性结合蛋白结合于表达CD16的细胞,CD16为包括自然杀伤细胞、巨噬细胞、嗜中性球、嗜酸性球、肥大细胞及滤泡树突状细胞的白细胞的表面上的Fc受体。本公开案的蛋白质以KD如下的亲和力结合于NKG2D:2nM至120nM,例如2nM至110nM、2nM至100nM、2nM至90nM、2nM至80nM、2nM至70nM、2nM至60nM、2nM至50nM、2nM至40nM、2nM至30nM、2nM至20nM、2nM至10nM、约15nM、约14nM、约13nM、约12nM、约11nM、约10nM、约9nM、约8nM、约7nM、约6nM、约5nM、约4.5nM、约4nM、约3.5nM、约3nM、约2.5nM、约2nM、约1.5nM、约1nM、介于约0.5nM至约1nM、约1nM至约2nM、约2nM至3nM、约3nM至4nM,约4nM至约5nM、约5nM至约6nM、约6nM至约7nM、约7nM至约8nM、约8nM至约9nM、约9nM至约10nM、约1nM至约10nM、约2nM至约10nM、约3nM至约10nM、约4nM至约10nM、约5nM至约10nM、约6nM至约10nM、约7nM至约10nM或约8nM至约10nM之间。在一些实施方案中,NKG2D结合位点以10至62nM的KD结合于NKG2D。
FLT3结合位点
本文公开的多特异性结合蛋白的FLT3结合位点包含重链可变域及轻链可变域。表2列出组合时可结合于FLT3的重链可变域及轻链可变域的一些示例性序列。CDR序列为根据Chothia编号鉴别。
表2:结合FLT3的示例性抗原结合位点的序列
可替代地,可结合于FLT3的新颖抗原结合位点可通过针对与由SEQ ID NO:135定义的氨基酸序列、其成熟胞外片段或含有FLT3域的片段的结合筛选来鉴别(参见例如国际申请公开案第WO 2018/220584号)。
SEQ ID NO:135(成熟人类FLT3胞外域)
NQDLPVIKCVLINHKNNDSSVGKSSSYPMVSESPEDLGCALRPQSSGTVYEAAAVEVDVSASITLQVLVDAPGNISCLWVFKHSSLNCQPHFDLQNRGVVSMVILKMTETQAGEYLLFIQSEATNYTILFTVSIRNTLLYTLRRPYFRKMENQDALVCISESVPEPIVEWVLCDSQGESCKEESPAVVKKEEKVLHELFGTDIRCCARNELGRECTRLFTIDLNQTPQTTLPQLFLKVGEPLWIRCKAVHVNHGFGLTWELENKALEEGNYFEMSTYSTNRTMIRILFAFVSSVARNDTGYYTCSSSKHPSQSALVTIVEKGFINATNSSEDYEIDQYEEFCFSVRFKAYPQIRCTWTFSRKSFPCEQKGLDNGYSISKFCNHKHQPGEYIFHAENDDAQFTKMFTLNIRRKPQVLAEASASQASCFSDGYPLPSWTWKKCSDKSPNCTEEITEGVWNRKANRKVFGQWVSSSTLNMSEAIKGFLVKCCAYNSLGTSCETILLNSPGPFPFIQDNIS
在某些实施方案中,结合FLT3的第二抗原结合位点(例如人类FLT3)包含:包含与表2中所公开的抗体的VH至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的抗体重链可变域(VH),及包含与表2中所公开的相同抗体的VH至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的抗体轻链可变域(VL)。在某些实施方案中,第二抗原结合位点包含表2中所公开的抗体的VH及VL序列的根据Kabat或所属领域中已知的任何其他CDR确定方法确定的重链CDR1、CDR2及CDR3以及轻链CDR1、CDR2及CDR3(参见Kabat等人,(1991)Sequences ofProteins of Immunological Interest,NIH公开案第91-3242号,Bethesda)、Chothia(参见例如Chothia C及Lesk AM,(1987),J Mol Biol 196:901-917)、MacCallum(参见MacCallum R M等人,(1996)J Mol Biol 262:732-745)。在某些实施方案中,第二抗原结合位点包含表2中所公开的抗体的重链CDR1、CDR2及CDR3以及轻链CDR1、CDR2及CDR3。
在某些实施方案中,第二抗原结合位点与12H10.G7相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:1的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:2至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB87或GB95相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:9的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:10至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:3或12至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB88或GB96相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:13的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:10至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:15或16至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB89或GB97相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:17的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:10至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:19或20至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB90及GB98相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:9的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:22至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:23或24至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB91及GB99相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:9的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:26至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:27或28至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB92或GB100相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:9的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:30至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:31或32至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB93或GB101相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:9的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:34至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:35或36至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB94或GB102相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:37的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:38至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:39或40至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB102D101E相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:41的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:42至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及50的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:43或44至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB102M34I相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:45的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:42至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:47或48至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与GB102M34I/D101E相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:49的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:42至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及50的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQID NO:11、4及50的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:51或52至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与人源化12H10.G7相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:53的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:42至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及55的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQID NO:11、4及55的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。
在某些实施方案中,第二抗原结合位点与人源化12H10.G7相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:56的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:57至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及5的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:6、7及8的氨基酸序列。
在某些实施方案中,第二抗原结合位点与人源化12H10.G7相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:58的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:42至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及55的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQID NO:11、4及55的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。
在某些实施方案中,第二抗原结合位点与14A5.E8相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:60的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:61至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、63及64的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及67的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ IDNO:62、63及64的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及67的氨基酸序列。
在某些实施方案中,第二抗原结合位点与mAb 1551或1552相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:68的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:69至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、63及64的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及67的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、63及64的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及67的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:70或71至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与mAb 1553或1554相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:72的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:73至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、63及64的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及67的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、63及64的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及67的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:74或75至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与mAb 1689相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:76的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:77至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:78、63及79的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:80、66及67的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ IDNO:78、63及79的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:80、66及67的氨基酸序列。在某些实施方案中,第二抗原结合位点呈scFv存在,其中scFv包含与SEQ ID NO:81或82至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。
在某些实施方案中,第二抗原结合位点与人源化14A5.E8相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:29的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:84至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:59、63及54的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:86、66及67的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:59、63及54的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:86、66及67的氨基酸序列。
在某些实施方案中,第二抗原结合位点与11F4.B9相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:85的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:90至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、88及89的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:91、92及93的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ IDNO:87、88及89的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:91、92及93的氨基酸序列。
在某些实施方案中,第二抗原结合位点与人源化11F4.B9相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:14的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:94至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、88及89的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:91、92及93的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、88及89的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:91、92及93的氨基酸序列。
在某些实施方案中,第二抗原结合位点与4A4.A3相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:95的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:96至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:97、99及100的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:101、102及103的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:97、99及100的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:101、102及103的氨基酸序列。
在某些实施方案中,第二抗原结合位点与4A4.H7相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:104的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:105至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98及89的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92及93的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ IDNO:87、98及89的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92及93的氨基酸序列。
在某些实施方案中,第二抗原结合位点与15A11.C8相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:107的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:108至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:109、110及111的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:112、113及114的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:109、110及111的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:112、113及114的氨基酸序列。
在某些实施方案中,第二抗原结合位点与12C9.E5相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:115的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:116至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:117、118及119的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:120、121及122的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:117、118及119的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:120、121及122的氨基酸序列。
在某些实施方案中,第二抗原结合位点与1A2.A3相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:123的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:124至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98、89的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92、93的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ IDNO:87、98、89的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92、93的氨基酸序列。
在某些实施方案中,第二抗原结合位点与4H2.E3相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:125的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:126至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、33及127的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:128、129及130的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、33及127的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:128、129及130的氨基酸序列。
在某些实施方案中,第二抗原结合位点与14H8.E7相关。举例而言,在某些实施方案中,第二抗原结合位点包含:包含与SEQ ID NO:131的氨基酸序列至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VH,及包含与SEQ ID NO:83至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列的VL。在某些实施方案中,VH包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:132、133及134的氨基酸序列。在某些实施方案中,VL包含CDR1、CDR2及CDR3,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及46的氨基酸序列。在某些实施方案中,第二抗原结合位点包含:(a)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:132、133及134的氨基酸序列;及(b)包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及46的氨基酸序列。
在前述实施方案中的各者中,本文中预期一起结合FLT3的VH和/或VL序列可在不显著影响其结合于FLT3的能力的情况下在VH和/或VL的构架区中含有氨基酸改变(例如至少1个、2个、3个、4个、5个或10个氨基酸取代、缺失或添加)。
在某些实施方案中,本文公开的第二抗原结合位点以如通过表面等离子共振(SPR)(例如使用下文实施例1中所述的方法)或通过生物膜层干涉测量法(BLI)所测量,1nM或更低、5nM或更低或10nM或更低、15nM或更低或20nM或更低的KD(亦即解离常数)结合FLT3(例如人类FLT3),和/或结合来自个体的体液、组织和/或细胞的FLT3。在某些实施方案中,如通过(SPR)(例如使用下文实施例1中所述的方法)或通过BLI所测量,上述分离的抗体中的任一种的Kd(亦即解离速率,也称为Koff)等于或低于1×10-5、1×10-4、1×10-3、5×10-3、0.01、0.02或0.05 1/s。
在某些实施方案中,本文公开的第二抗原结合位点,例如与以上公开的12H10.G7、GB87、GB88、GB89、GB90、GB91、GB92、GB93、GB94、GB95、GB96、GB97、GB98、GB99、GB100、GB101、GB102、GB102M34I、GB102D101E、GB102M34I/D101E或人源化12H10.G7有关的抗原结合位点,结合具有T227M突变的人类FLT3变体或其胞外区。hFLT3-T227M的胞外区的氨基酸序列为NQDLPVIKCVLINHKNNDSSVGKSSSYPMVSESPEDLGCALRPQSSGTVYEAAAVEVDVSASITLQVLVDAPGNISCLWVFKHSSLNCQPHFDLQNRGVVSMVILKMTETQAGEYLLFIQSEATNYTILFTVSIRNTLLYTLRRPYFRKMENQDALVCISESVPEPIVEWVLCDSQGESCKEESPAVVKKEEKVLHELFGMDIRCCARNELGRECTRLFTIDLNQTPQTTLPQLFLKVGEPLWIRCKAVHVNHGFGLTWELENKALEEGNYFEMSTYSTNRTMIRILFAFVSSVARNDTGYYTCSSSKHPSQSALVTIVEKGFINATNSSEDYEIDQYEEFCFSVRFKAYPQIRCTWTFSRKSFPCEQKGLDNGYSISKFCNHKHQPGEYIFHAENDDAQFTKMFTLNIRRKPQVLAEASASQASCFSDGYPLPSWTWKKCSDKSPNCTEEITEGVWNRKANRKVFGQWVSSSTLNMSEAIKGFLVKCCAYNSLGTSCETILLNSPGPFPFIQDNIS(SEQ ID NO:318)。
在某些实施方案中,本文公开的第二抗原结合位点,例如与以上公开的12H10.G7、GB87、GB88、GB89、GB90、GB91、GB92、GB93、GB94、GB95、GB96、GB97、GB98、GB99、GB100、GB101、GB102、GB102M34I、GB102D101E、GB102M34I/D101E或人源化12H10.G7有关的抗原结合位点,结合具有ITD突变的人类FLT3变体或其胞外区。hFLT3-ITD的胞外区的氨基酸序列为NQDLPVIKCVLINHKNNDSSVGKSSSYPMVSESPEDLGCALRPQSSGTVYEAAAVEVDVSASITLQVLVDAPGNISCLWVFKHSSLNCQPHFDLQNRGVVSMVILKMTETQAGEYLLFIQSEATNYTILFTVSIRNTLLYTLRRPYFRKMENQDALVCISESVPEPIVEWVLCDSQGESCKEESPAVVKKEEKVLHELFGTDIRCCARNELGRECTRLFTIDLNQTPQTTLPQLFLKVGEPLWIRCKAVHVNHGFGLTWELENKALEEGNYFEMSTYSTNRTMIRILFAFVSSVARNDTGYYTCSSSKHPSQSALVTIVEKGFINATNSSEDYEIDQYEEFCFSVRFKAYPQIRCTWTFSRKSFPCEQKGLDNGYSISKFCNHKHQPGEYIFHAENDDAQFTKMFTLNIRRKPQVLAEASASQASCFSDGYPLPSWTWKKCSDKSPNCTEEITEGVWNRKANRKVFGQWVSSSTLNMSEAIKGFLVKCCAYNSLGTSCETILLNSPGPFPFIQDNIS(SEQ ID NO:319)。
在某些实施方案中,本文公开的第二抗原结合位点,例如与以上公开的12H10.G7、GB87、GB88、GB89、GB90、GB91、GB92、GB93、GB94、GB95、GB96、GB97、GB98、GB99、GB100、GB101、GB102、GB102M34I、GB102D101E、GB102M34I/D101E、人源化12H10.G7、14A5.E8、1551、1552、1553、1554、1689、人源化14A5.E8、11F4.B9、4A4.A3、4A4.H7、15A11.C8、1A2.A3、4H2.E3或14H8.E7有关的抗原结合位点,结合食蟹猕猴FLT3。
在某些实施方案中,本文公开的第二抗原结合位点,例如与以上公开的12H10.G7、GB87、GB88、GB89、GB90、GB91、GB92、GB93、GB94、GB95、GB96、GB97、GB98、GB99、GB100、GB101、GB102、GB102M34I、GB102D101E、GB102M34I/D101E、人源化12H10.G7、14A5.E8、1551、1552、1553、1554、1689、人源化14A5.E8、11F4.B9、4A4.A3、4A4.H7、12C9.E5、1A2.A3、4H2.E3或14H8.E7有关的抗原结合位点,不与FLT3L竞争结合FLT3。
在某些实施方案中,第二抗原结合位点与上述抗原结合位点竞争结合于FLT3(例如人类FLT3、食蟹猕猴FLT3)。在某些实施方案中,第二抗原结合位点与一个与以上公开的1A2.A3有关的抗原结合位点竞争结合于FLT3。在一个实施方案中,第二抗原结合位点与1A2.A3竞争结合于FLT3。在某些实施方案中,本发明的第二抗原结合位点与一个与以上公开的4A4.A3有关的抗原结合位点竞争结合于FLT3。在一个实施方案中,第二抗原结合位点与4A4.A3竞争结合于FLT3。在某些实施方案中,本发明的第二抗原结合位点与一个与以上公开的4H2.E3有关的抗原结合位点竞争结合于FLT3。在一个实施方案中,第二抗原结合位点与4H2.E3竞争结合于FLT3。在某些实施方案中,本发明的第二抗原结合位点与一个与以上公开的11F4.B9有关的抗原结合位点竞争结合于FLT3。在一个实施方案中,第二抗原结合位点与11F4.B9竞争结合于FLT3。
Fc域
在Fc域内,CD16结合通过铰链区及CH2域介导。举例而言,在人类IgG1内,与CD16的相互作用主要集中在CH2域中的氨基酸残基Asp 265-Glu 269、Asn 297-Thr 299、Ala 327-Ile 332、Leu 234-Ser 239及碳水化合物残基N-乙酰基-D-葡糖胺上(参见Sondermann等人,Nature,406(6793):267-273)。基于已知的域,诸如通过使用噬菌体呈现文库或酵母表面呈现的cDNA文库,可选择突变以增强或降低对CD16的结合亲和力,或可基于已知的相互作用的三维结构进行设计。因此,在某些实施方案中,抗体Fc域或其部分包含铰链及CH2域。
异二聚体抗体重链的组装可通过在同一细胞中表达两种不同抗体重链序列来实现,该表达可引起各抗体重链的同二聚体的组装以及异二聚体的组装。促进异二聚体的优先组装可通过将不同突变并入各抗体重链恒定区的CH3域中来实现,如US13/494870、US16/028850、US11/533709、US12/875015、US13/289934、US14/773418、US12/811207、US13/866756、US14/647480及US14/830336所示。举例而言,可基于人类IgG1且在第一多肽及第二多肽内并入允许此两个链选择性地彼此异聚的数对不同氨基酸取代,在CH3域中进行突变。以下示出的氨基酸取代的位置均根据如Kabat中的EU索引编号。
在一种情况下,第一多肽中的氨基酸取代用选自精氨酸(R)、苯丙氨酸(F)、酪氨酸(Y)或色氨酸(W)的较大氨基酸替换原始氨基酸,且第二多肽中的至少一个氨基酸取代用选自丙氨酸(A)、丝氨酸(S)、苏氨酸(T)或缬氨酸(V)的较小氨基酸替换原始氨基酸,使得较大氨基酸取代(突起)适合于较小氨基酸取代的表面(腔)。举例而言,一种多肽可并入T366W取代,且另一种多肽可并入包括T366S、L368A及Y407V的三个取代。
本发明的抗体重链可变域可任选与至少与抗体恒定区、诸如包括铰链、CH2及CH3域且有或无CH1域的IgG恒定区90%一致的氨基酸序列偶合。在一些实施方案中,恒定区的氨基酸序列与人类抗体恒定区、诸如人类IgG1恒定区、IgG2恒定区、IgG3恒定区或IgG4恒定区至少90%一致。在一个实施方案中,足以结合CD16的抗体Fc域或其一部分包含与野生型人类IgG1Fc序列DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:136)至少90%(例如至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%)一致的氨基酸序列。在一些其他实施方案中,恒定区的氨基酸序列与来自另一哺乳动物、诸如兔、犬、猫、小鼠或马的抗体恒定区至少90%一致。
在一些实施方案中,与scFv或Fab片段连接的抗体恒定域能够结合CD16。在一些实施方案中,蛋白质并入抗体Fc域的一部分(例如足以结合CD16的抗体Fc域的一部分),其中抗体Fc域包含铰链及CH2域(例如人类IgG1抗体的铰链及CH2域)和/或与人类IgG抗体的氨基酸序列234-332至少90%一致的氨基酸序列。
与人类IgG1恒定区相比,一个或多个突变可例如在Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和/或K439处并入恒定区中。示例性取代包括例如Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、T350V、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、T394W、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、K409R、T411D、T411E、K439D及K439E。
在某些实施方案中,可并入人类IgG1恒定区的CH1中的突变可在氨基酸V125、F126、P127、T135、T139、A140、F170、P171和/或V173处。在某些实施方案中,可并入人类IgG1恒定区的Cκ中的突变可在氨基酸E123、F116、S176、V163、S174和/或T164处。
可替代地,氨基酸取代可选自表3中所示的以下各组取代。
表3 | ||
第一多肽 | 第二多肽 | |
第1组 | S364E/F405A | Y349K/T394F |
第2组 | S364H/D401K | Y349T/T411E |
第3组 | S364H/T394F | Y349T/F405A |
第4组 | S364E/T394F | Y349K/F405A |
第5组 | S364E/T411E | Y349K/D401K |
第6组 | S364D/T394F | Y349K/F405A |
第7组 | S364H/F405A | Y349T/T394F |
第8组 | S364K/E357Q | L368D/K370S |
第9组 | L368D/K370S | S364K |
第10组 | L368E/K370S | S364K |
第11组 | K360E/Q362E | D401K |
第12组 | L368D/K370S | S364K/E357L |
第13组 | K370S | S364K/E357Q |
第14组 | F405L | K409R |
第15组 | K409R | F405L |
可替代地,氨基酸取代可选自表4中所示的以下各组取代。
表4 | ||
第一多肽 | 第二多肽 | |
第1组 | K409W | D399V/F405T |
第2组 | Y349S | E357W |
第3组 | K360E | Q347R |
第4组 | K360E/K409W | Q347R/D399V/F405T |
第5组 | Q347E/K360E/K409W | Q347R/D399V/F405T |
第6组 | Y349S/K409W | E357W/D399V/F405T |
可替代地,氨基酸取代可选自表5中所示的以下各组取代。
表5 | ||
第一多肽 | 第二多肽 | |
第1组 | T366K/L351K | L351D/L368E |
第2组 | T366K/L351K | L351D/Y349E |
第3组 | T366K/L351K | L351D/Y349D |
第4组 | T366K/L351K | L351D/Y349E/L368E |
第5组 | T366K/L351K | L351D/Y349D/L368E |
第6组 | E356K/D399K | K392D/K409D |
可替代地,各多肽链中的至少一个氨基酸取代可选自表6。
可替代地,至少一个氨基酸取代可选自表7中的以下各组取代,其中在第一多肽列中指示的位置经任何已知的带负电的氨基酸替换,且在第二多肽列中指示的位置经任何已知的带正电的氨基酸替换。
可替代地,至少一个氨基酸取代可选自表8中的以下各组,其中在第一多肽列中指示的位置经任何已知的带正电的氨基酸替换,且在第二多肽列中指示的位置经任何已知的带负电的氨基酸替换。
表8 | |
第一多肽 | 第二多肽 |
D399、E356或E357 | K409、K439、K370或K392 |
可替代地,氨基酸取代可选自表9中所示的以下各组。
可替代地或另外,可通过在第一或第二多肽链中的任一个上引入S354C,及在相对多肽链上引入Y349C,在两种多肽的界面内形成人工二硫桥键来增加异多聚体蛋白质的结构稳定性。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于位置T366,且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由T366、L368及Y407组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由T366、L368及Y407组成的组的一个或多个位置,且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于位置T366。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由E357、K360、Q362、S364、L368、K370、T394、D401、F405及T411组成的组的一个或多个位置且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由Y349、E357、S364、L368、K370、T394、D401、F405及T411组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由Y349、E357、S364、L368、K370、T394、D401、F405及T411组成的组的一个或多个位置且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由E357、K360、Q362、S364、L368、K370、T394、D401、F405及T411组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由L351、D399、S400及Y407组成的组的一个或多个位置且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由T366、N390、K392、K409及T411组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由T366、N390、K392、K409及T411组成的组的一个或多个位置且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由L351、D399、S400及Y407组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由Q347、Y349、K360及K409组成的组的一个或多个位置,且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由Q347、E357、D399及F405组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由Q347、E357、D399及F405组成的组的一个或多个位置,且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由Y349、K360、Q347及K409组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由K370、K392、K409及K439组成的组的一个或多个位置,且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由D356、E357及D399组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由D356、E357及D399组成的组的一个或多个位置,且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由K370、K392、K409及K439组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由L351、E356、T366及D399组成的组的一个或多个位置,且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由Y349、L351、L368、K392及K409组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由Y349、L351、L368、K392及K409组成的组的一个或多个位置,且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于选自由L351、E356、T366及D399组成的组的一个或多个位置。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于S354C取代且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于Y349C取代。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于Y349C取代且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于S354C取代。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于K360E及K409W取代且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于Q347R,D399V及F405T取代。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于Q347R、D399V及F405T取代且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于K360E及K409W取代。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于T366W取代且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于T366S、T368A及Y407V取代。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于T366S、T368A及Y407V取代且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于T366W取代。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于T350V、L351Y、F405A及Y407V取代且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于T350V、T366L、K392L及T394W取代。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于T350V、T366L、K392L及T394W取代且其中抗体恒定区的另一个多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处在于T350V、L351Y、F405A及Y407V取代。
示例性多特异性结合蛋白
以下列出包含各连接于抗体恒定区的结合FLT3的抗原结合位点及结合NKG2D的抗原结合位点的TriNKET的实施例,其中抗体恒定区包括使两个Fc链能够进行异二聚的突变。根据Chothia的CDR序列加下划线。F3-GB102呈F3格式,亦即结合FLT3的抗原结合位点为Fab,且结合NKG2D的抗原结合位点为scFv。其他TriNKET呈F3'格式,亦即结合FLT3的抗原结合位点为scFv,且结合NKG2D的抗原结合位点为Fab。在各TriNKET中,scFv包含Cys对VL的位置100及VH的位置44处的氨基酸残基的取代,由此促进scFv的VH与VL之间二硫桥键的形成。
scFv的VH及VL可经由接头、例如肽接头连接。在某些实施方案中,肽接头为可挠性接头。关于接头的氨基酸组成,选择具有赋予可挠性,不干扰本发明的蛋白质的其他域的结构与功能且抵抗蛋白酶裂解的特性的肽。举例而言,甘氨酸及丝氨酸残基通常提供蛋白酶抗性。在某些实施方案中,VL经由(GlyGlyGlyGlySer)4((G4S)4)接头(SEQ ID NO:137)在N端或C端连接至VH。
接头(例如可挠性接头)的长度可为“短的”,例如0个、1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个或12个氨基酸残基,或“长的”,例如至少13个氨基酸残基。在某些实施方案中,接头长度为10-50个、10-40个、10-30个、10-25个、10-20个、15-50个、15-40个、15-30个、15-25个、15-20个、20-50个、20-40个、20-30个或20-25个氨基酸残基。
在某些实施方案中,接头包含以下或由其组成:(GS)n(SEQ ID NO:290)、(GGS)n(SEQ ID NO:291)、(GGGS)n(SEQ ID NO:292)、(GGSG)n(SEQ ID NO:293)、(GGSGG)n(SEQ IDNO:294)及(GGGGS)n(SEQ ID NO:295)序列,其中n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。在某些实施方案中,接头包含选自以下的氨基酸序列或由其组成:SEQ ID NO:137、SEQ ID NO:201、SEQ ID NO:202、SEQ ID NO:103、SEQ ID NO:104、SEQ IDNO:83、SEQ ID NO:84、SEQ ID NO:150、SEQ ID NO:152及SEQ ID NO:154,如表10中所列出。
在F3-GB102中,结合NKG2D的scFv经由Ala-Ser接头连接于Fc的N端。在F3'-TriNKET中,结合FLT3的scFv经由Gly-Ser接头连接于Fc的N端。在肘铰链区序列处包括Ala-Ser或Gly-Ser接头以在可挠性与最佳几何形状之间达成平衡。在某些实施方案中,额外序列Thr-Lys-Gly可在铰链处在N端或C端添加至Ala-Ser或Gly-Ser序列。
如本文描述这些示例性TriNKET所用,Fc包括抗体铰链、CH2及CH3。在各示例性TriNKET中,连接于scFv的Fc域包含Q347R、D399V及F405T的突变,且连接于Fab的Fc域包含匹配突变K360E及K409W,以形成异二聚体。连接于scFv的Fc域进一步在CH3域中包括S354C取代,该取代与连接于Fab的Fc上的Y349C取代形成二硫键。这些取代为此分段中描述的序列中的粗体。
举例而言,本公开案的TriNKET为F3'-GB102。F3'-GB102包括(a)与Fc域连接的源自于GB102的结合FLT3的scFv序列;及(b)源自于A49MI的结合NKG2D的Fab片段,其包括包含重链可变域及CH1域的重链部分及包含轻链可变域及轻链恒定域的轻链部分,其中CH1域连接至Fc域。F3'-GB102包括如以下阐述的三种多肽。
GB102-VL-VH-Fc(SEQ ID NO:277)
DIVMTQSPDSLAVSLGERATINCRASESVDTYGSSFVHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEEPWTFGCGTKVEIK
GGGGSGGGGSGGGGSGGGGS
QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYVMHWVRQAPGQCLEWMGFINPYNDDTKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWRQLGSLDSWGQGTTVTVSS
GS
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPRVYTLPPCRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLVSDGSFTLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
A49MI-VH-CH1-Fc(SEQ ID NO:278)
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGAPIGAAAGWFDPWGQGTLVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTENQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSWLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
A49MI-VL-CL(SEQ ID NO:279)
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVSFPRTFGGGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
GB102-VL-VH-Fc表示结合FLT3的scFv经由包含Gly-Ser的铰链连接于Fc域的完全序列。连接于scFv的Fc域包括用于异二聚的Q347R、D399V及F405T取代,及用于与如下所述的A49MI-VH-CH1-Fc中的Y349C取代形成二硫键的S354C取代。scFv(SEQ ID NO:40)包括经由(G4S)4接头连接至GB102的轻链可变域的C端的GB102的重链可变域。作为分别VL及VH中的R100C及G44C取代的结果,scFv的重链及轻链可变域亦经由VL的C100与VH的C44之间的二硫桥键连接。
A49MI-VH-CH1-Fc表示连接至Fc域的Fab片段的重链部分,该重链部分包含结合NKG2D的A49MI的重链可变域(SEQ ID NO:254)及CH1域。A49MI-VH-CH1-Fc中的Fc域包括CH3域中的Y349C取代,其与GB102-VL-VH-Fc中的Fc上的S354C取代形成二硫键。在A49MI-VH-CH1-Fc中,Fc域亦包括K360E及K409W取代以与GB102-VL-VH-Fc中的Fc进行异二聚。
A49MI-VL-CL表示包含结合NKG2D的A49MI的轻链可变域(SEQ ID NO:239)及轻链恒定域的Fab片段的轻链部分。
本公开案的另一TriNKET为F3-GB102。F3-GB102包括:(a)连接于Fc域的源自于A49的结合NKG2D的scFv序列,及(b)源自于GB102的结合FLT3的Fab片段,其包括包含重链可变域及CH1域的重链部分,及包含轻链可变域及轻链恒定域的轻链部分,其中CH1域连接至Fc域。F3-GB102包括如以下阐述的三种多肽。
A49-VL-VH-Fc(SEQ ID NO:280)
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVSFPRTFGCGTKVEIK
GGGGSGGGGSGGGGSGGGGS
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKCLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGAPMGAAAGWFDPWGQGTLVTVSS
AS
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPRVYTLPPCRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLVSDGSFTLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
GB102-VH-CH1-Fc(SEQ ID NO:281)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYVMHWVRQAPGQGLEWMGFINPYNDDTKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWRQLGSLDSWGQGTTVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTENQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSWLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
GB102-VL-CL(SEQ ID NO:282)
DIVMTQSPDSLAVSLGERATINCRASESVDTYGSSFVHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEEPWTFGGGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
A49-VL-VH-Fc表示结合NKG2D的scFv经由包含Ala-Ser的铰链连接于Fc域的完全序列。连接于scFv的Fc域包括用于异二聚的Q347R、D399V及F405T取代,及用于与如下所述的GB102-VH-CH1-Fc中的Y349C取代形成二硫键的S354C取代。scFv(SEQ ID NO:246)包括经由(G4S)4接头连接至A49的轻链可变域的C端的A49的重链可变域。作为分别VL及VH中的Q100C及G44C取代的结果,scFv的重链及轻链可变域亦经由VL的C100与VH的C44之间的二硫桥键连接。
GB102-VH-CH1-Fc表示连接至Fc域的Fab片段的重链部分,该重链部分包含结合FLT3的GB102的重链可变域(SEQ ID NO:37)及CH1域。GB102-VH-CH1-Fc中的Fc域包括CH3域中的Y349C取代,其与A49-VL-VH-Fc中的Fc上的S354C取代形成二硫键。在GB102-VH-CH1-Fc中,Fc域亦包括K360E及K409W取代以与A49-VL-VH-Fc中的Fc进行异二聚。
GB102-VL-CL表示包含结合FLT3的GB102的轻链可变域(SEQID NO:38)及轻链恒定域的Fab片段的轻链部分。
本公开案的另一TriNKET为F3'-1553。F3'-1553包括:(a)连接于Fc域的源自于mAb1553的结合FLT3的scFv序列,及(b)源自于A49MI的结合NKG2D的Fab片段,其包括包含重链可变域及CH1域的重链部分,及包含轻链可变域及轻链恒定域的轻链部分,其中CH1域连接至Fc域。F3'-1553包括三种多肽:1553-VH-VL-Fc、A49MI-VH-CH1-Fc、A49MI-VL-CL。上文在F3'-GB102的情况下描述A49MI-VH-CH1-Fc及A49MI-VL-CL。以下阐述1553-VH-VL-Fc的多肽。
1553-VH-VL-Fc(SEQ ID NO:283)
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYWINWVRQAPGKCLEWMGNIYPGSSIINYNENFKNRVTMTEDTSTDTAYMELSSLRSEDTAVYYCARRVVYLYFDYWGQGTLVTVSS
GGGGSGGGGSGGGGSGGGGS
EIVLTQSPATLSLSPGERATLSCSASSSVSYMHWYQQKPGQAPRLLIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWTSKSPTFGCGTKVEIK
GS
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPRVYTLPPCRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLVSDGSFTLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
1553-VH-VL-Fc表示结合FLT3的scFv经由包含Gly-Ser的铰链连接于Fc域的完全序列。连接于scFv的Fc域包括用于异二聚的Q347R、D399V及F405T取代,及用于与如下所述的A49MI-VH-CH1-Fc中的Y349C取代形成二硫键的S354C取代。scFv(SEQ ID NO:74)包括经由(G4S)4接头连接至1553的轻链可变域的N端的1553的重链可变域。作为分别VL及VH中的G100C及G44C取代的结果,scFv的重链及轻链可变域亦经由VL的C100与VH的C44之间的二硫桥键连接。
本公开案的另一TriNKET为F3'-1689。F3'-1689包括:(a)连接于Fc域的源自于mAb1689的结合FLT3的scFv序列,及(b)源自于A49MI的结合NKG2D的Fab片段,其包括包含重链可变域及CH1域的重链部分,及包含轻链可变域及轻链恒定域的轻链部分,其中CH1域连接至Fc域。F3'-1689包括三种多肽:1689-VH-VL-Fc、A49MI-VH-CH1-Fc、A49MI-VL-CL。上文在F3'-GB102的情况下描述A49MI-VH-CH1-Fc及A49MI-VL-CL。以下阐述1689-VH-VL-Fc的多肽。
1689-VH-VL-Fc(SEQ ID NO:284)
QVQLVQSGAEVKKPGASVKVSCKVSGYTFPYYWINWVRQAPGKCLEWMGNIYPGSSIINYNENFKNRVTMTEDTSTDTAYMELSSLRSEDTAVYYCARRNVYLTFDYWGQGTLVTVSS
GGGGSGGGGSGGGGSGGGGS
EIVLTQSPATLSLSPGERATLSCSASSSVSYIHWYQQKPGQAPRLLIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWTSKSPTFGCGTKVEIK
GS
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPRVYTLPPCRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLVSDGSFTLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
1689-VH-VL-Fc表示结合FLT3的scFv经由包含Gly-Ser的铰链连接于Fc域的完全序列。连接于scFv的Fc域包括用于异二聚的Q347R、D399V及F405T取代,及用于与如下所述的A49MI-VH-CH1-Fc中的Y349C取代形成二硫键的S354C取代。scFv(SEQ ID NO:81)相对于1553-VH-VL-Fc中的scFv包含一组可能增加对FLT3的结合亲和力的突变。
本公开案的另一TriNKET为F3'-GB102_M34I。F3'-GB102_M34I包括:(a)连接于Fc域的源自于GB102M34I的结合FLT3的scFv序列,及(b)源自于A49MI的结合NKG2D的Fab片段,其包括包含重链可变域及CH1域的重链部分,及包含轻链可变域及轻链恒定域的轻链部分,其中CH1域连接至Fc域。F3'-GB102_M34I包括三种多肽:GB102_M34I-VL-VH-Fc、A49MI-VH-CH1-Fc、A49MI-VL-CL。上文在F3'-GB102的情况下描述A49MI-VH-CH1-Fc及A49MI-VL-CL。以下阐述GB102_M34I-VL-VH-Fc的多肽。
GB102_M34I-VL-VH-Fc(SEQ ID NO:285)
DIVMTQSPDSLAVSLGERATINCRASESVDTYGSSFVHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEEPWTFGCGTKVEIK
GGGGSGGGGSGGGGSGGGGS
QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYVIHWVRQAPGQCLEWMGFINPYNDDTKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWRQLGSLDSWGQGTTVTVSS
GS
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPRVYTLPPCRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLVSDGSFTLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
GB102_M34I-VL-VH-Fc表示结合FLT3的scFv经由包含Gly-Ser的铰链连接于Fc域的完全序列。连接于scFv的Fc域包括用于异二聚的Q347R、D399V及F405T取代,及用于与如下所述的A49MI-VH-CH1-Fc中的Y349C取代形成二硫键的S354C取代。scFv(SEQ ID NO:48)相对于GB102-VL-VH-Fc中的VH包含M34I取代以去除假定序列倾向性。
本公开案的另一TriNKET为F3'-GB102_D101E。F3'-GB102_D101E包括:(a)连接于Fc域的源自于GB102D101E的结合FLT3的scFv序列,及(b)源自于A49MI的结合NKG2D的Fab片段,其包括包含重链可变域及CH1域的重链部分,及包含轻链可变域及轻链恒定域的轻链部分,其中CH1域连接至Fc域。F3'-GB102_D101E包括三种多肽:GB102_D101E-VL-VH-Fc、A49MI-VH-CH1-Fc、A49MI-VL-CL。上文在F3'-GB102的情况下描述A49MI-VH-CH1-Fc及A49MI-VL-CL。以下阐述GB102_D101E-VL-VH-Fc的多肽。
GB102_D101E-VL-VH-Fc(SEQ ID NO:286)
DIVMTQSPDSLAVSLGERATINCRASESVDTYGSSFVHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEEPWTFGCGTKVEIK
GGGGSGGGGSGGGGSGGGGS
QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYVMHWVRQAPGQCLEWMGFINPYNDDTKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWRQLGSLESWGQGTTVTVSS
GS
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPRVYTLPPCRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLVSDGSFTLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
GB102_D101E-VL-VH-Fc表示结合FLT3的scFv经由包含Gly-Ser的铰链连接于Fc域的完全序列。连接于scFv的Fc域包括用于异二聚的Q347R、D399V及F405T取代,及用于与如下所述的A49MI-VH-CH1-Fc中的Y349C取代形成二硫键的S354C取代。scFv(SEQ ID NO:44)相对于GB102-VL-VH-Fc中的VH包含D101E取代以去除假定序列倾向性。
本公开案的另一TriNKET为F3'-GB102_M34I_D101E。F3'-GB102_M34I_D101E包括:(a)连接于Fc域的源自于GB102M34I/D101E的结合FLT3的scFv序列,及(b)源自于A49MI的结合NKG2D的Fab片段,其包括包含重链可变域及CH1域的重链部分,及包含轻链可变域及轻链恒定域的轻链部分,其中CH1域连接至Fc域。F3'-GB102_M34I_D101E包括三种多肽:GB102_M34I_D101E-VL-VH-Fc、A49MI-VH-CH1-Fc、A49MI-VL-CL。上文在F3'-GB102的情况下描述A49MI-VH-CH1-Fc及A49MI-VL-CL。以下阐述GB102_M34I_D101E-VL-VH-Fc的多肽。
GB102_M34I_D101E-VL-VH-Fc(SEQ ID NO:287)
DIVMTQSPDSLAVSLGERATINCRASESVDTYGSSFVHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEEPWTFGCGTKVEIK
GGGGSGGGGSGGGGSGGGGS
QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYVIHWVRQAPGQCLEWMGFINPYNDDTKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARWRQLGSLESWGQGTTVTVSS
GS
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPRVYTLPPCRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLVSDGSFTLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
GB102_M34I_D101E-VL-VH-Fc表示结合FLT3的scFv经由包含Gly-Ser的铰链连接于Fc域的完全序列。连接于scFv的Fc域包括用于异二聚的Q347R、D399V及F405T取代,及用于与如下所述的A49MI-VH-CH1-Fc中的Y349C取代形成二硫键的S354C取代。scFv(SEQ IDNO:52)相对于GB102-VL-VH-Fc中的VH包含M34I及D101E取代以去除假定序列倾向性。
本公开案的另一TriNKET为F3'-GB99。F3'-GB99包括:(a)连接于Fc域的源自于GB99的结合FLT3的scFv序列,及(b)源自于A49MI的结合NKG2D的Fab片段,其包括包含重链可变域及CH1域的重链部分,及包含轻链可变域及轻链恒定域的轻链部分,其中CH1域连接至Fc域。F3'-GB99包括三种多肽:GB99-VL-VH-Fc、A49MI-VH-CH1-Fc、A49MI-VL-CL。上文在F3'-GB102的情况下描述A49MI-VH-CH1-Fc及A49MI-VL-CL。以下阐述GB99-VL-VH-Fc的多肽。
GB99-VL-VH-Fc(SEQ ID NO:288)
DIVMTQSPASLAVSLGERATINCRASESVDTYGSSFVHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDAATYYCQQNNEEPWTFGCGTKVEIK
GGGGSGGGGSGGGGSGGGGS
QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYVMHWVRQAPGQCLEWMGFINPYNDDTKYNEKFKGRVTITSDTSASTAYMELSSLRSEDTAVYHCARWRQLGSLDSWGQGTTVTVSS
GS
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPRVYTLPPCRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLVSDGSFTLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
GB99-VL-VH-Fc表示结合FLT3的scFv经由包含Gly-Ser的铰链连接于Fc域的完全序列。连接于scFv的Fc域包括用于异二聚的Q347R、D399V及F405T取代,及用于与如下所述的A49MI-VH-CH1-Fc中的Y349C取代形成二硫键的S354C取代。scFv(SEQ ID NO:28)相对于GB102-VL-VH-Fc中的scFv在构架区中包含一组可能提高抗体结构及活性的回复突变。
本公开案的另一TriNKET为F3'-GB89。F3'-GB89包括:(a)连接于Fc域的源自于GB89的结合FLT3的scFv序列,及(b)源自于A49MI的结合NKG2D的Fab片段,其包括包含重链可变域及CH1域的重链部分,及包含轻链可变域及轻链恒定域的轻链部分,其中CH1域连接至Fc域。F3'-GB89包括三种多肽:GB89-VH-VL-Fc、A49MI-VH-CH1-Fc、A49MI-VL-CL。上文在F3'-GB102的情况下描述A49MI-VH-CH1-Fc及A49MI-VL-CL。以下阐述GB89-VH-VL-Fc的多肽。
GB89-VH-VL-Fc(SEQ ID NO:289)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYVMHWVRQAPGQCLEWMGFINPYNDDTKYNEKFKGRVTITSDTSASTAYMELSSLRSEDTAVYYCARWRQLGSLDSWGQGTTVTVSS
GGGGSGGGGSGGGGSGGGGS
DIVMTQSPASLAVSLGERATINCRASESVDTYGSSFVHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSRTDFTLTISSLQAEDAATYYCQQNNEEPWTFGCGTKVEIK
GS
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPRVYTLPPCRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLVSDGSFTLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
GB89-VH-VL-Fc表示结合FLT3的scFv经由包含Gly-Ser的铰链连接于Fc域的完全序列。连接于scFv的Fc域包括用于异二聚的Q347R、D399V及F405T取代,及用于与如下所述的A49MI-VH-CH1-Fc中的Y349C取代形成二硫键的S354C取代。scFv(SEQ ID NO:19)包括经由(G4S)4接头连接至GB89的轻链可变域的N端的GB89的重链可变域。作为分别VL及VH中的R100C及G44C取代的结果,scFv的重链及轻链可变域亦经由VL的C100与VH的C44之间的二硫桥键连接。scFv相对于GB102-VL-VH-Fc中的VH及VL在构架区中包含一组可能提高抗体结构及活性的回复突变。
在某一实施方案中,本公开案的TriNKET与上述示例性TriNKET中的一者一致,其除连接于结合NKG2D的Fab片段的Fc域包含Q347R、D399V及F405T的取代且连接于结合HER2的scFv的Fc域包含用于形成异二聚体的匹配取代K360E及K409W之外包括EW-RVT Fc突变。在某些实施方案中,本公开案的TriNKET与上述示例性TriNKET中的一者一致,其除连接于结合NKG2D的Fab片段的Fc域包含T366S、L368A及Y407V的“臼”取代且连接于结合HER2的scFv的Fc域包含用于形成异二聚体的T366W的“杵”取代之外包括KiH Fc突变。
在某些实施方案中,除连接于结合NKG2D的Fab片段的Fc域在CH3域中包括S354C取代且连接于结合HER2的scFv的Fc域在CH3域中包括匹配Y349C取代以形成二硫键之外,本公开案的TriNKET与上述示例性TriNKET中的一者一致。
所属领域的技术人员应了解在蛋白质产生和/或储存期间,N端谷氨酸(E)或谷氨酰胺(Q)可环化形成内酰胺(例如自发地,或由在产生和/或储存期间存在的酶催化)。因此,在多肽的氨基酸序列的N端残基为E或Q的一些实施方案中,本文中亦涵盖E或Q替换为焦谷氨酸盐的对应氨基酸序列。
所属领域的技术人员亦应了解在蛋白质蛋白质产生和/或储存期间,可移除蛋白质的C端赖氨酸(K)(例如自发地,或由在蛋白质产生和/或储存期间存在的酶催化)。在C端包含Fc域的蛋白质下常常观察到此类K移除。因此,在多肽(例如Fc域序列)的氨基酸序列的C端残基为K的一些实施方案中,本文中亦涵盖K移除的对应氨基酸序列。
上述多特异性蛋白质可使用所属领域的技术人员熟知的重组DNA技术制成。举例而言,编码第一免疫球蛋白重链的第一核酸序列可克隆至第一表达载体中;编码第二免疫球蛋白重链的第二核酸序列可克隆至第二表达载体中;编码免疫球蛋白轻链的第三核酸序列可克隆至第三表达载体中;且第一、第二及第三表达载体可稳定地一起转染至宿主细胞中以产生多聚体蛋白质。
为实现多特异性蛋白质的最高产量,可探索第一、第二及第三表达载体的不同比率以确定转染至宿主细胞的最佳比率。在转染之后,可使用所属领域中已知的方法,诸如有限稀释、ELISA、FACS、显微术或Clonepix分离单个克隆以产生细胞库。
克隆可在适合于生物反应器扩大的条件下培养且维持多特异性蛋白质的表达。多特异性蛋白质可使用所属领域中已知的方法,包括离心、深度过滤、细胞溶解、均质化、冻融、亲和力纯化、凝胶过滤、离子交换色谱法、疏水性相互作用交换色谱法及混合模式色谱法来分离及纯化。
II.多特异性蛋白质的特征
本文所述的多特异性蛋白质包括NKG2D结合位点、结合FLT3的FLT3结合位点及足以结合CD16的抗体Fc域或其一部分或结合CD16的抗原结合位点。在一些实施方案中,多特异性蛋白质含有结合于FLT3的额外抗原结合位点,如在F4-TriNKET格式中举例说明。
在一些实施方案中,多特异性蛋白质显示与对应单克隆抗体,亦即含有与多特异性蛋白质中并入的FLT3结合位点相同的FLT3结合位点的单克隆抗体类似的热稳定性。
在一些实施方案中,多特异性蛋白质同时结合于表达NKG2D和/或CD16的细胞,诸如NK细胞,及表达FLT3的细胞,诸如某些肿瘤细胞。多特异性蛋白质结合于NK细胞可增强NK细胞破坏表达FLT3的肿瘤细胞的活性。
在一些实施方案中,多特异性蛋白质以与对应抗FLT3单克隆抗体(亦即含有与多特异性蛋白质中并入的FLT3结合位点相同的FLT3结合位点的单克隆抗体)类似的亲和力结合于FLT3。在一些实施方案中,多特异性蛋白质比对应单克隆抗体更有效地杀死表达FLT3的肿瘤细胞。
在某些实施方案中,包括FLT3结合位点的本文所述的多特异性蛋白质在与表达FLT3的细胞共培养时活化初级人类NK细胞。NK细胞活化的标志为CD107a脱粒及IFN-γ细胞因子产生增加。此外,与对应抗FLT3单克隆抗体相比,多特异性蛋白质可展示在表达FLT3的细胞存在下对人类NK细胞的优良活化。
在一些实施方案中,包括FLT3结合位点的本文所述的多特异性蛋白质在与表达FLT3的细胞共培养时增强静息及IL-2活化的人类NK细胞的活性。
在一些实施方案中,与结合于FLT3的对应单克隆抗体相比,多特异性蛋白质提供靶向表达中等及低水平FLT3的肿瘤细胞的益处。
在一些实施方案中,TriNKET的二价F4格式(亦即TriNKET包括结合于FLT3的额外抗原结合位点)提高TriNKET结合于FLT3的亲合力,此实际上稳定高水平FLT3在肿瘤细胞表面上的表达及维持。在一些实施方案中,F4-TriNKET比对应F3-TriNKET或F3'-TriNKET介导更有效的肿瘤细胞杀死。
III.治疗应用
本发明提供使用本文所述的多特异性结合蛋白和/或本文所述的药物组合物治疗自体免疫疾病或癌症的方法。所述方法可用于治疗多种表达FLT3的癌症。
治疗方法可根据有待治疗的癌症表征。举例而言,在某些实施方案中,癌症为血液恶性病或白血病。在某些实施方案中,癌症为急性骨髓性白血病(AML)、急性淋巴母细胞白血病(ALL)、骨髓化生不良、骨髓发育不良综合征、急性T淋巴母细胞性白血病或急性前髓细胞白血病、慢性骨髓单核球性白血病或慢性骨髓性白血病的骨髓胚细胞危象。
靶向FLT3的多特异性结合蛋白可治疗的其他示例性癌症包括乳腺癌、卵巢癌、食道癌、膀胱或胃癌、唾液腺管癌、唾液腺管癌、肺腺癌或子宫癌的侵袭性形式,诸如子宫浆液性子宫内膜癌。在一些其他实施方案中,癌症为脑癌、乳腺癌、子宫颈癌、结肠癌、结肠直肠癌、子宫内膜癌、食道癌、白血病、肺癌、肝癌、黑色素瘤、卵巢癌、胰腺癌、直肠癌、肾癌、胃癌、睾丸癌或子宫癌。在其他实施方案中,癌症为鳞状细胞癌、腺癌、小细胞癌、黑色素瘤、神经母细胞瘤、肉瘤(例如血管肉瘤或软骨肉瘤)、喉癌、腮腺癌、胆道癌、甲状腺癌、肢端黑色素瘤、光化性角化病、急性淋巴细胞性白血病、急性骨髓性白血病、腺样囊性癌、腺瘤、腺肉瘤、腺鳞癌、肛管癌、肛门癌、肛门直肠癌、星形细胞肿瘤、大前庭腺癌、基底细胞癌、胆管癌、骨癌、骨髓癌、支气管癌、支气管腺癌、类癌瘤、胆管细胞癌、软骨肉瘤、脉络丛乳头状瘤/癌瘤、慢性淋巴细胞性白血病、慢性骨髓性白血病、透明细胞癌、结缔组织癌、囊腺瘤、消化系统癌、十二指肠癌、内分泌系统癌、内胚窦瘤、子宫内膜增生、内膜肉瘤、子宫骨膜样腺癌、内皮细胞癌、室管膜癌、上皮细胞癌、尤文氏肉瘤(Ewing's sarcoma)、眼睛及眼眶癌、女性生殖器癌、局灶性结节性增生症、胆囊癌、胃窦癌、胃底癌、胃泌素瘤、胶质母细胞瘤、胰升糖素瘤、心脏癌、血管母细胞瘤、血管内皮瘤、血管瘤、肝脏腺瘤、肝脏腺瘤病、肝胆癌、肝细胞癌、霍奇金氏病(Hodgkin's disease)、回肠癌、胰岛瘤、上皮内瘤样病变、上皮间鳞状细胞瘤形成、肝内胆管癌、侵袭性鳞状细胞癌、空肠癌、关节癌、卡波西氏肉瘤(Kaposi's sarcoma)、骨盆癌、大细胞癌、大肠癌、平滑肌肉瘤、恶性小痣黑色素瘤、淋巴瘤、男性生殖器癌、恶性黑色素瘤、恶性间皮肿瘤、髓母细胞瘤、髓上皮瘤、脑膜癌、间皮癌、转移癌、口癌、黏液表皮样癌、多发性骨髓瘤、肌肉癌、鼻道癌、神经系统癌、神经上皮腺癌结节性黑色素瘤、非上皮性皮肤癌、非霍奇金氏淋巴瘤、燕麦细胞癌、寡树突神经癌、口腔癌、骨肉瘤、乳头浆液性腺癌、阴茎癌、咽癌、垂体瘤、浆细胞瘤、假性肉瘤、肺母细胞瘤、直肠癌、肾细胞癌、呼吸系统癌、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、浆液性癌、窦癌、皮肤癌、小细胞癌、小肠癌、平滑肌癌、软组织癌、分泌生长激素抑制素的肿瘤、脊柱癌、鳞状细胞癌、横纹肌癌、间皮下癌、表浅扩散型黑色素瘤、T细胞白血病、舌癌、未分化癌、输尿管癌、尿道癌、膀胱癌、泌尿系统癌、子宫颈癌、子宫体癌、葡萄膜黑素瘤、阴道癌、疣状癌、VIP瘤、外阴癌、高分化癌或威尔姆氏肿瘤(Wilms tumor)。
在一些其他实施方案中,有待治疗的癌症为非霍奇金氏淋巴瘤,诸如B细胞淋巴瘤或T细胞淋巴瘤。在某些实施方案中,非霍奇金氏淋巴瘤为B细胞淋巴瘤,诸如弥漫性大B细胞淋巴瘤、初级纵隔的B细胞淋巴瘤、滤泡性淋巴瘤、小淋巴细胞性淋巴瘤、套细胞淋巴瘤、边缘区B细胞淋巴瘤、结外边缘区B细胞淋巴瘤、结节边缘区B细胞淋巴瘤、脾边缘区B细胞淋巴瘤、伯基特氏淋巴瘤(Burkitt lymphoma)、淋巴浆细胞性淋巴瘤、毛细胞白血病或初级中枢神经系统(CNS)淋巴瘤。在某些其他实施方案中,非霍奇金氏淋巴瘤为T细胞淋巴瘤,诸如前驱T淋巴母细胞性淋巴瘤、周边T细胞淋巴瘤、皮肤T细胞淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、结外自然杀伤/T细胞淋巴瘤、肠病型T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤、退行性大细胞淋巴瘤或周边T细胞淋巴瘤。
IV.组合疗法
本发明的另一方面提供组合疗法。本文所述的多特异性结合蛋白可与额外治疗剂组合使用来治疗自体免疫疾病或治疗癌症。
可在治疗自体免疫发炎性疾病中用作组合疗法的一部分的示例性治疗剂描述于Li等人(2017)Front.Pharmacol.,8:460中,且包括例如非类固醇消炎药(NSAID)(例如COX-2抑制剂)、糖皮质素(例如泼尼松(prednisone)/泼尼松龙(prednisolone)、甲基泼尼松龙(methylprednisolone)及氟化糖皮质素(诸如地塞米松(dexamethasone)及倍他米松(betamethasone))、改善疾病的抗风湿药(DMARD)(例如甲胺喋呤(methotrexate)、来氟米特(leflunomide)、金化合物(gold compound)、柳氮磺胺吡啶(sulfasalazine)、咪唑硫嘌呤(azathioprine)、环磷酰胺(cyclophosphamide)、抗疟疾药、D-青霉胺(D-penicillamine)及环孢霉素(cyclosporine))、抗TNF生物制剂(例如英夫利昔单抗(infliximab)、依那西普(etanercept)、阿达木单抗(adalimumab)、戈利木单抗(golimumab)、聚乙二醇结合赛妥珠单抗(Certolizumab pegol)及其生物类似药)及其他靶向CTLA-4的生物制剂(例如阿巴西普(abatacept))、IL-6受体(例如托珠单抗(tocilizumab))、IL-1(例如阿那白滞素(anakinra))、Th1免疫反应(IL-12/IL-23)(例如优特克单抗(ustekinumab))、Th17免疫反应(IL-17)(例如苏金单抗(secukinumab)及CD20(例如利妥昔单抗(rituximab))。
在治疗癌症中可用作组合疗法的一部分的示例性治疗剂包括例如放射线、丝裂霉素(mitomycin)、维甲酸(tretinoin)、瑞苯莫斯汀(ribomustin)、吉西他滨(gemcitabine)、长春新碱(vincristine)、依托泊苷(etoposide)、克拉屈滨(cladribine)、二溴甘露醇(mitobronitol)、甲胺喋呤(methotrexate)、多柔比星(doxorubicin)、卡巴醌(carboquone)、喷司他丁(pentostatin)、二胺硝吖啶(nitracrine)、净司他丁(zinostatin)、西曲瑞克(cetrorelix)、来曲唑(letrozole)、雷替曲塞(raltitrexed)、道诺霉素(daunorubicin)、法倔唑(fadrozole)、福莫司汀(fotemustine)、胸腺法新(thymalfasin)、索布佐生(sobuzoxane)、奈达铂(nedaplatin)、阿糖胞苷(cytarabine)、比卡米特(bicalutamide)、长春瑞滨(vinorelbine)、维司力农(vesnarinone)、胺鲁米特(aminoglutethimide)、安吖啶(amsacrine)、丙麸胺(proglumide)、依利醋铵(elliptiniumacetate)、酮舍林(ketanserin)、脱氧氟尿苷(doxifluridine)、阿维A酯(etretinate)、异维A酸(isotretinoin)、链脲霉素(streptozocin)、尼莫司汀(nimustine)、长春地辛(vindesine)、氟他米特(flutamide)、屈洛尼尔(drogenil)、甘胺硫嘌呤(butocin)、卡莫氟(carmofur)、雷佐生(razoxane)、西佐喃(sizofilan)、卡铂(carboplatin)、二溴卫矛醇(mitolactol)、替加氟(tegafur)、异环磷酰胺(ifosfamide)、泼尼莫司汀(prednimustine)、溶链菌制剂(picibanil)、左旋四咪唑(levamisole)、替尼泊苷(teniposide)、英丙舒凡(improsulfan)、依诺他滨(enocitabine)、麦角乙脲(lisuride)、羟甲烯龙(oxymetholone)、他莫昔芬(tamoxifen)、黄体酮(progesterone)、美雄烷(mepitiostane)、表硫雄醇(epitiostanol)、福美坦(formestane)、干扰素-α、干扰素-2α、干扰素-β、干扰素-γ(IFN-γ)、群落刺激因子-1、群落刺激因子-2、地尼白介素(denileukin diftitox)、介白素-2、促黄体激素释放因子及可展现与同源受体的差别结合或血清半衰期增加或减少的上述药剂的变体。
在治疗癌症中可用作组合疗法的一部分的其他类别药剂为免疫检查点抑制剂。示例性免疫检查点抑制剂包括抑制以下中的一或多者的药剂:(i)细胞毒性T淋巴细胞相关抗原4(CTLA4);(ii)计划性细胞死亡蛋白1(PD1);(iii)PDL1;(iv)LAG3;(v)B7-H3;(vi)B7-H4;及(vii)TIM3。CTLA4抑制剂伊匹单抗(ipilimumab)已经美国食品与药物管理局(UnitedStates Food and Drug Administration)批准用于治疗黑色素瘤。
在治疗癌症中可用作组合疗法的一部分的其他药剂为靶向非检查点标靶的单克隆抗体药剂(例如赫塞汀(herceptin))及非细胞毒性剂(例如酪氨酸激酶抑制剂)。
抗癌剂的其他类别包括例如:(i)选自ALK抑制剂、ATR抑制剂、A2A拮抗剂、碱基切除修复抑制剂、Bcr-Abl酪氨酸激酶抑制剂、布鲁顿氏酪氨酸激酶抑制剂(Bruton'sTyrosine Kinase Inhibitor)、CDC7抑制剂、CHK1抑制剂、细胞周期蛋白依赖性激酶抑制剂、DNA-PK抑制剂、DNA-PK与mTOR的抑制剂、DNMT1抑制剂、DNMT1抑制剂加2-氯-脱氧腺苷、HDAC抑制剂、刺猬信号传导路径抑制剂(Hedgehog Signaling Pathway Inhibitor)、IDO抑制剂、JAK抑制剂、mTOR抑制剂、MEK抑制剂、MELK抑制剂、MTH1抑制剂、PARP抑制剂、磷酸肌醇3-激酶抑制剂、PARP1与DHODH的抑制剂、蛋白酶体抑制剂、拓扑异构酶-II抑制剂、酪氨酸激酶抑制剂、VEGFR抑制剂及WEE1抑制剂;(ii)OX40、CD137、CD40、GITR、CD27、HVEM、TNFRSF25或ICOS的激动剂;及(iii)选自IL-12、IL-15、GM-CSF及G-CSF的细胞因子。
本发明的蛋白质亦可用作手术移除原发性病变的辅助剂。
可选择多特异性结合蛋白及额外治疗剂的量及相对施用时机以实现所需组合治疗作用。举例而言,当向需要此类施用的患者施用组合疗法时,组合中的治疗剂或包含治疗剂的药物组合物或组合物可以任何次序,诸如相继、同时、一起、同时及其类似次序施用。此外,举例而言,多特异性结合蛋白可在其他治疗剂发挥其预防或治疗作用期间施用,或反之亦然。
V.药物组合物
本公开案特征亦在于含有治疗有效量的本文所述的蛋白质的药物组合物。组合物可调配用于多种药物递送系统。一种或多种生理学上可接受的赋形剂或载剂亦可包括在组合物中以达成适当调配。用于本公开案中的合适调配物可见于Remington'sPharmaceutical Sciences,Mack Publishing Company,Philadelphia,Pa.,第17版,1985中。关于药物递送的方法的简评,参见例如Langer(Science 249:1527-1533,1990)。
本公开案的静脉内药物递送调配物可含于袋、笔或注射器中。在某些实施方案中,袋可连接至包含管和/或针的通道。在某些实施方案中,调配物可为冻干调配物或液体调配物。在某些实施方案中,调配物可冷冻干燥(冻干)且含于约12-60个小瓶中。在某些实施方案中,调配物可冷冻干燥且45mg冷冻干燥的调配物可含于一个小瓶中。在某些实施方案中,约40mg-约100mg冷冻干燥的调配物可含于一个小瓶中。在某些实施方案中,将来自12个、27个或45个小瓶的冷冻干燥调配物组合以获得静脉内药物调配物中治疗剂量的蛋白质。在某些实施方案中,调配物可为液体调配物且以约250毫克/小瓶至约1000毫克/小瓶储存。在某些实施方案中,调配物可为液体调配物且以约600毫克/小瓶储存。在某些实施方案中,调配物可为液体调配物且以约250毫克/小瓶储存。
蛋白质可存在于液体水性药物调配物中,该调配物在形成调配物的缓冲溶液中包括治疗有效量的蛋白质。
这些组合物可通过常规的灭菌技术来灭菌,或可无菌过滤。所得水溶液可经包装原样使用,或冻干,冻干制剂在施用之前与无菌水性载剂组合。制剂的pH值通常将在3与11之间,更优选5与9之间或6与8之间且最佳7与8之间,诸如7至7.5。呈固体形式的所得组合物可包装成多个单剂量单元,各含有固定量的以上提及的药剂。呈固体形式的组合物亦可包装于容器中,量灵活。
在某些实施方案中,本公开案提供一种具有延长的储存期限的调配物,其包括本公开案的蛋白质,与甘露糖醇、柠檬酸一水合物、柠檬酸钠、磷酸二钠二水合物、磷酸二氢钠二水合物、氯化钠、聚山梨醇酯80、水及氢氧化钠组合。
在某些实施方案中,制备在pH缓冲溶液中包括本公开案的蛋白质的水性调配物。本发明的缓冲液可具有在约4至约8,例如约4.5至约6.0或约4.8至约5.5的范围内的pH值,或可具有约5.0至约5.2的pH值。上述pH值中间的范围亦意欲为本公开案的一部分。举例而言,意欲包括使用上述值中的任一者的组合作为上限和/或下限的数值范围。控制pH值在此范围内的缓冲液的实施例包括乙酸盐(例如乙酸钠)、丁二酸盐(诸如丁二酸钠)、葡糖酸盐、组氨酸、柠檬酸盐及其他有机酸缓冲液。
在某些实施方案中,调配物包括含有柠檬酸盐及磷酸盐的缓冲系统以维持pH值在约4至约8范围内。在某些实施方案中,pH值范围可为约4.5至约6.0,或约pH 4.8至约5.5,或在约5.0至约5.2的pH范围内。在某些实施方案中,缓冲系统包括柠檬酸一水合物、柠檬酸钠、磷酸二钠二水合物和/或磷酸二氢钠二水合物。在某些实施方案中,缓冲系统包括约1.3mg/mL柠檬酸(例如1.305mg/mL)、约0.3mg/mL柠檬酸钠(例如0.305mg/mL)、约1.5mg/mL磷酸二钠二水合物(例如1.53mg/mL)、约0.9mg/mL磷酸二氢钠二水合物(例如0.86mg/mL)及约6.2mg/mL氯化钠(例如6.165mg/mL)。在某些实施方案中,缓冲系统包括约1至约1.5mg/mL柠檬酸、约0.25至约0.5mg/mL柠檬酸钠、约1.25至约1.75mg/mL磷酸二钠二水合物、约0.7至约1.1mg/mL磷酸二氢钠二水合物及约6.0至约6.4mg/mL氯化钠。在某些实施方案中,调配物的pH值用氢氧化钠来调整。
用作张力剂且可稳定抗体的多元醇亦可包括在调配物中。多元醇以可随调配物的所需等张性而变的量添加至调配物中。在某些实施方案中,水性调配物可为等张的。所附加的多元醇的量亦可随多元醇的分子量而改变。举例而言,与二糖(诸如海藻糖)相比,可添加较低量的单糖(例如甘露糖醇)。在某些实施方案中,在调配物中可用作张力剂的多元醇为甘露糖醇。在某些实施方案中,甘露糖醇浓度可为约5至约20mg/mL。在某些实施方案中,甘露糖醇浓度可为约7.5至约15mg/mL。在某些实施方案中,甘露糖醇浓度可为约10至约14mg/mL。在某些实施方案中,甘露糖醇浓度可为约12mg/mL。在某些实施方案中,多元醇山梨糖醇可包括在调配物中。
洗涤剂或表面活性剂亦可添加至调配物中。示例性洗涤剂包括非离子型洗涤剂,诸如聚山梨酸酯(例如聚山梨酸酯20、80等)或泊洛沙姆(poloxamer)(例如泊洛沙姆188)。所添加的洗涤剂的量使得其降低调配抗体的聚集,和/或使微粒在调配物中的形成降至最少和/或减少吸附。在某些实施方案中,调配物可包括表面活性剂聚山梨酸酯。在某些实施方案中,调配物可含有洗涤剂聚山梨醇酯80或Tween 80。Tween 80为用于描述聚氧化乙烯(20)去水山梨糖醇单油酸酯的术语(参见Fiedler,Lexikon der Hifsstoffe,EditioCantor Verlag Aulendorf,第4版,1996)。在某些实施方案中,调配物可含有约0.1mg/mL与约10mg/mL之间,或约0.5mg/mL与约5mg/mL之间的聚山梨醇酯酯80。在某些实施方案中,调配物中可添加约0.1%聚山梨醇酯酯80。
在实施方案中,本公开案的蛋白质产物调配为液体调配物。液体调配物可以10mg/mL浓度呈现于用橡皮塞封闭且用铝锯齿形密封盖密封的USP/Ph Eur I型50R小瓶中。塞子可由符合USP及Ph Eur的弹性体制成。在某些实施方案中,小瓶可装满61.2mL蛋白质产物溶液以允许60mL的可萃取体积。在某些实施方案中,液体调配物可用0.9%盐水溶液稀释。
在某些实施方案中,本公开案的液体调配物可制备成10mg/mL浓度溶液,与稳定水平的糖组合。在某些实施方案中,液体调配物可在水性载剂中制备。在某些实施方案中,稳定剂的添加量可不超过可引起对于静脉内施用而言不合需要或不适合的黏度的量。在某些实施方案中,糖可为二糖,例如蔗糖。在某些实施方案中,液体调配物亦可包括缓冲剂、表面活性剂及防腐剂中的一种或多种。
在某些实施方案中,液体调配物的pH值可通过添加药学上可接受的酸和/或碱来设定。在某些实施方案中,药学上可接受的酸可为盐酸。在某些实施方案中,碱可为氢氧化钠。
除聚集外,脱酰胺为在酦酵、收获/细胞净化、纯化、原料药/药品储存期间及在样品分析期间可能发生的肽及蛋白质的常见产物变体。脱酰胺为NH3自蛋白质损失,形成丁二酰亚胺中间体,可经历水解。丁二酰亚胺中间体引起亲本肽质量减少17道尔顿。随后水解引起质量增加18道尔顿。丁二酰亚胺中间体的分离由于在水性条件下的不稳定性而困难。因而,脱酰胺通常可检测,因为质量增加1道尔顿。天冬酰胺的脱酰胺产生天冬氨酸或异天冬氨酸。影响脱酰胺速率的参数包括pH值、温度、溶剂介电常数、离子强度、初级序列、局部多肽构象及三级结构。肽链中邻近Asn的氨基酸残基影响脱酰胺速率。蛋白质序列中在Asn后的Gly及Ser引起对脱酰胺的敏感度更高。
在某些实施方案中,本公开案的液体调配物可保存在预防蛋白质产物脱氨基的pH值及湿度的条件下。
本文中所关注的水性载剂为在药学上可接受(施用人类安全且无毒)且可用于制备液体调配物的载剂。例示性载剂包括灭菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH值缓冲溶液(例如磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液(Ringer's solution)或右旋糖溶液。
防腐剂可任选添加至本文中的调配物中以减少细菌作用。防腐剂的添加可例如促进多用途(多剂量)调配物的产生。
静脉内(IV)调配物可为特定情况下的优选给药途径,诸如当患者在医院中在移植之后经由IV途径接受所有药物时。在某些实施方案中,液体调配物在施用前用0.9%氯化钠溶液稀释。在某些实施方案中,经稀释用于注射的药品为等张的且适合于通过静脉内输注施用。
在某些实施方案中,盐或缓冲液组分可以10mM-200mM的量添加。盐和/或缓冲液为药学上可接受的,且衍生自多种已知酸(无机及有机)与“形成碱”的金属或胺。在某些实施方案中,缓冲液可为磷酸盐缓冲液。在某些实施方案中,缓冲液可为甘氨酸盐、碳酸盐、柠檬酸盐缓冲液,在此情况下钠、钾或铵离子可充当相对离子。
防腐剂可任选添加至本文中的调配物中以减少细菌作用。防腐剂的添加可例如促进多用途(多剂量)调配物的产生。
本文中所关注的水性载剂为在药学上可接受(施用人类安全且无毒)且可用于制备液体调配物的载剂。例示性载剂包括灭菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH值缓冲溶液(例如磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液或右旋糖溶液。
本公开案的蛋白质可呈包括蛋白质及冻干保护剂的冻干调配物存在。冻干保护剂可为糖,例如二糖。在某些实施方案中,冻干保护剂可为蔗糖或麦芽糖。冻干调配物亦可包括缓冲剂、表面活性剂、增积剂和/或防腐剂中的一种或多种。
可用于稳定冻干药品的蔗糖或麦芽糖的量可呈至少1:2蛋白质与蔗糖或麦芽糖的重量比。在某些实施方案中,蛋白质与蔗糖或麦芽糖重量比可为1:2至1:5。
在某些实施方案中,在冻干之前调配物的pH值可通过添加药学上可接受的酸和/或碱来设定。在某些实施方案中,药学上可接受的酸可为盐酸。在某些实施方案中,药学上可接受的碱可为氢氧化钠。
在冻干前,含有本公开案的蛋白质的溶液的pH值可调整在6至8之间。在某些实施方案中,冻干药品的pH范围可为7至8。
在某些实施方案中,盐或缓冲液组分可以10mM-200mM的量添加。盐和/或缓冲液为药学上可接受的,且衍生自多种已知酸(无机及有机)与“形成碱”的金属或胺。在某些实施方案中,缓冲液可为磷酸盐缓冲液。在某些实施方案中,缓冲液可为甘氨酸盐、碳酸盐、柠檬酸盐缓冲液,在此情况下钠、钾或铵离子可充当相对离子。
在某些实施方案中,可添加“增积剂”。“增积剂”为添加物质至冻干混合物且有助于冻干饼的物理结构(例如促进基本上均一的维持开孔结构的冻干饼的产生)的化合物。例示性填充剂包括甘露糖醇、甘氨酸、聚乙二醇及山梨糖醇。本发明的冻干调配物可含有此类增积剂。
防腐剂可任选添加至本文中的调配物中以减少细菌作用。防腐剂的添加可例如促进多用途(多剂量)调配物的产生。
在某些实施方案中,冻干药品可用水性载剂复原。本文中所关注的水性载剂为在药学上可接受(例如施用人类安全且无毒)且在冻干之后可用于制备液体调配物的载剂。例示性稀释剂包括灭菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH值缓冲溶液(例如磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液或右旋糖溶液。
在某些实施方案中,本公开案的冻干药品用USP灭菌注射用水(SWFI)或0.9%USP氯化钠注射液复原。在复原期间,冻干粉末溶于溶液中。
在某些实施方案中,本公开案的冻干蛋白质产物用约4.5mL注射用水复原且用0.9%盐水溶液(氯化钠溶液)稀释。
本发明的药物组合物中活性成分的实际剂量水平可变化,以便获得针对特定患者、组合物及施用模式,活性成分有效实现所需治疗反应且对患者无毒的量。
特定剂量可为针对每个患者的均一剂量,例如50-5000mg蛋白质。可替代地,患者的剂量可适合于患者的近似体重或表面积。确定适当剂量的其他因素可包括有待治疗或预防的疾病或疾患、疾病的严重程度、给药途径及患者的年龄、性别及医疗条件。通常通过所属领域的技术人员,尤其根据剂量信息及本文公开的分析来进行确定治疗适当剂量必需的计算的进一步修正。剂量亦可经由使用已知的与适当剂量-反应数据结合用于确定剂量的分析确定。可在监测疾病进展时调整个别患者的剂量。可测量患者中可靶向构建物或复合物的血液水平,以看是否需要调整剂量达到或维持有效浓度。药物基因组学可用于确定何种可靶向构建物和/或复合物及其剂量最可能对给定个体有效(Schmitz等人,ClinicaChimica Acta 308:43-53,2001;Steimer等人,Clinica Chimica Acta 308:33-41,2001)。
一般而言,基于体重的剂量为每公斤体重约0.01μg至约100mg,诸如约0.01μg至约100mg/kg体重、约0.01μg至约50mg/kg体重、约0.01μg至约10mg/kg体重、约0.01μg至约1mg/kg体重、约0.01μg至约100μg/kg体重、约0.01μg至约50μg/kg体重、约0.01μg至约10μg/kg体重、约0.01μg至约1μg/kg体重、约0.01μg至约0.1μg/kg体重、约0.1μg至约100mg/kg体重、约0.1μg至约50mg/kg体重、约0.1μg至约10mg/kg体重、约0.1μg至约1mg/kg体重、约0.1μg至约100μg/kg体重、约0.1μg至约10μg/kg体重、约0.1μg至约1μg/kg体重、约1μg至约100mg/kg体重、约1μg至约50mg/kg体重、约1μg至约10mg/kg体重、约1μg至约1mg/kg体重、约1μg至约100μg/kg体重、约1μg至约50μg/kg体重、约1μg至约10μg/kg体重、约10μg至约100mg/kg体重、约10μg至约50mg/kg体重、约10μg至约10mg/kg体重、约10μg至约1mg/kg体重、约10μg至约100μg/kg体重、约10μg至约50μg/kg体重、约50μg至约100mg/kg体重、约50μg至约50mg/kg体重、约50μg至约10mg/kg体重、约50μg至约1mg/kg体重、约50μg至约100μg/kg体重、约100μg至约100mg/kg体重、约100μg至约50mg/kg体重、约100μg至约10mg/kg体重、约100μg至约1mg/kg体重、约1mg至约100mg/kg体重、约1mg至约50mg/kg体重、约1mg至约10mg/kg体重、约10mg至约100mg/kg体重、约10mg至约50mg/kg体重、约50mg至约100mg/kg体重。
可每天、每周、每月或每年给予剂量一次或更多次,或甚至每2至20年一次。所属领域的普通技术人员容易基于所测量的保留时间及可靶向构建物或复合物在体液或组织中的浓度估计给药重复率。本发明的施用可为静脉内、动脉内、腹膜内、肌肉内、皮下、胸膜内、鞘内、腔内、经由导管灌注或通过直接损害内注射。此可每天施用一次或更多次,每周施用一次或更多次,每月施用一次或更多次,及每年施用一次或更多次。
以上说明描述本发明的多个方面及实施方案。专利申请案特别涵盖方面及实施方案的所有组合及变换。
实施例
参考以下实施例将更容易地理解现在概述的本发明,所述实施例仅仅出于说明本发明的某些方面及实施方案而包括且不意欲限制本发明。
实施例1.所选杂交瘤克隆的上清液的表征
通过用hFLT3-His融合蛋白对小鼠进行免疫接种来产生FLT3特异性抗体。通过酶联免疫吸附分析(ELISA)针对FLT3结合来评定228个杂交瘤的上清液,且96个杂交瘤非共价结合于hFLT3-His蛋白。基于初步生物膜层干涉测量法(BLI)结合亲和力判断、结合于表达FLT3的人类及食蟹猕猴细胞及抗原决定基多样性选择十一个克隆。通过高分辨率表面等离子共振(SPR)进一步分析此11个克隆结合hFLT3-His的能力。使用Biacore 8K仪器在37℃下进行实验以仿真生理温度。Biacore传感图及动力学参数呈现于表12中,且原始资料及拟合展示于图18中。十一个杂交瘤中的七个杂交瘤以小于10nM的KD结合,且五个显示缓慢解离速率常数(kd<5×10-4s-1)。
通过BLI使用OctetRed384(ForteBio)对与参考mAb的杂交瘤融合物进行分箱。简言之,将杂交瘤上清液负载至抗小鼠IgG捕获传感器尖端上15分钟且在PBSF中平衡5分钟。将传感器浸入200nM hFLT3-His中,且使的缔合180秒,接着浸入100nM对照IgG或200nMFTL3-配位体溶液中。反应单元的增加指示杂交瘤非参考mAb的竞争者,而信号无增加指示杂交瘤与参考mAb竞争。FL23(Amgen)及FL39(Amgen)结合于域1。EB10(ImClone)(一种已知的FLT3-配位体阻断剂)结合于域3。FL61(Amgen)亦结合于域3,但不为FLT3-配位体阻断剂。4G8(Synimmune)结合于域4。NC7(Imclone)结合于域5。这些参考抗体的VH及VL序列提供于表11中。
表11.参考抗体
观察到由杂交瘤中的五个,即4A4、11F4、1A2、4H2及13C9产生的抗体不与参考抗体中的任一者竞争结合于hFLT3-His。通过测量抗体与表达cFLT3的等基因RMA细胞的结合来评估与食蟹猕猴FLT3(cFLT3)的交叉反应性。
简言之,将RMA细胞用编码cFLT3或人类FLT3(hFLT3)的逆转录病毒载体转导。来自粗杂交瘤收获物的α-FLT3 mAb与hFLT3或cFLT3等基因细胞株以及FLT3+癌细胞株的结合如下进行。96孔圆底盘每孔添加100,000个RMA、REH或SEM细胞。将细胞短暂离心且通过旋转使团粒轻轻解离。每孔添加50μL Zombie活/死染料(PBS+1:2000染料)且在室温下在黑暗中培育20分钟。将细胞用200μL FACS缓冲液(PBS+2%FBS)洗涤。将50μL杂交瘤上清液添加至洗涤的细胞且将混合物在冰上在黑暗中培育30分钟。将细胞洗涤一次且接着添加50μL抗小鼠Fc-PE第二试剂(1:200稀释),且在冰上在黑暗中培育20分钟。洗涤细胞且用50μL 4%多聚甲醛在冰上固定15分钟。再次洗涤细胞且接着再悬浮于200μL FACS缓冲液中且储存在4℃下直至准备获取。样品在装备HTS(高通量采样器)的BD FACSCelesta上操作。
亦测量杂交瘤上清液对据报导表达FLT3的人类ALL细胞株REH癌细胞(ATCC,目录号CRL-8286)的结合亲和力。如表12所示,大部分克隆展示对表达hFLT3的癌细胞的结合亲和力及与cFLT3的交叉反应性。不收集14A5及15A11的食蟹猕猴FLT3结合数据。
表12.FLT3-His与由候选杂交瘤产生的抗体结合的动力学参数及亲和力
实施例2.经纯化的抗FLT3鼠类抗体的分析
基于实施例1中所述的分析,选择八个杂交瘤(4A4、11F4、12H10、15A11、12C09、1A2、14A5、4H2)进行次克隆及测序。产生两个来自各亲本杂交瘤的次克隆且分析。测得来自各杂交瘤的序列为独特的。自杂交瘤培养物纯化各次克隆,且通过SPR确认与hFLT3-His的结合,如图19所示。hFLT3与经纯化的鼠类次克隆mAb结合的动力学常数及亲和力展示于表13中。使用实施例1中所述的方法用参考抗体进行分箱,且四种抗体,即4A4.A3、11F4.B9、1A2.A3及4H2.E3,不与参考抗体中的任一种竞争结合于hFLT3-His。
表13:hFLT3与经纯化的鼠类次克隆的结合的动力学参数及亲和力
测试物品 | k<sub>a</sub>(1/Ms) | k<sub>d</sub>(1/s) | K<sub>D</sub>,(nM) |
1A2.A3 | 1.1×10<sup>5</sup> | 8.9×10<sup>-4</sup> | 8.5 |
4A4.A3 | 1.1×10<sup>5</sup> | 8.2×10<sup>-4</sup> | 7.3 |
4H2.E3 | 5.7×10<sup>4</sup> | 1.0×10<sup>-3</sup> | 17.6 |
11F4.B9 | 1.5×10<sup>5</sup> | 2.5×10<sup>-4</sup> | 1.7 |
12C9.E5 | 3.4×10<sup>4</sup> | 6.3×10<sup>-4</sup> | 18.7 |
12H10.G7 | 1.0×10<sup>5</sup> | 5.5×10<sup>-4</sup> | 5.4 |
14A5.E8 | 1.3×10<sup>5</sup> | 1.9×10<sup>-3</sup> | 15.1 |
15A11.C8 | 4.5×10<sup>4</sup> | 4.8×10<sup>-4</sup> | 10.5 |
用表达人类及食蟹猕猴FLT3的等基因RMA细胞株证实细胞与经纯化的次克隆mAb的结合。除12C9.E5外,所有结合于细胞表面的克隆均表达人类及食蟹猕猴FLT3(表14)。类似地,所有次克隆均以高亲和力结合于SEM(DSMZ,目录号ACC 546),SEM为据报导表达FLT3的人类ALL细胞株。
表14:经纯化的小鼠mAb与人类及食蟹猕猴FLT3RMA细胞株的细胞结合的确认
实施例3.所选抗FLT3鼠类抗体的配位体阻断特性
本实施例描述经设计以表征所选抗FLT3鼠类抗体阻断FLT3与FLT3-配位体的相互作用的能力的实验。在添加饱和浓度的可溶性FLT3-配位体之前及之后测试α-FLT3 mAb结合表达FLT3的EOL-1癌细胞(DSMZ,目录号ACC 386)的能力。对于各抗体,因是指示在FLT3-配位体存在下获得的mAb结合信号相对于在缺乏FLT3-配位体下获得的mAb结合信号下降,所以计算其配位体阻断值的百分比。已知的FLT3-配位体阻断剂EB10 mAb用作阳性对照。如图20所示,12H10.G7、11F4.B9及4A4.A3、14A5.E8抗体不干扰FLT3与FLT3-配位体的结合,而15A11.C8抗体阻断FLT3-配位体与FLT3的结合。
实施例4.假定序列倾向性分析
本实施例描述经设计以检查12H10.G7、11F4.B9及4A4.A3、14A5.E8抗体的CDR(根据Chothia鉴别)中的潜在序列倾向性的实验。考虑以下潜在倾向性:M(潜在氧化位点);NG、NS及NT序列基元(潜在脱酰胺位点);DG、DS及DT序列基元(潜在异构化位点);DP序列基元(化学水解的潜在位点)。结果概述于15表中。
表15.所选鼠类mAb的CDR中的假定序列倾向性
另外,亦鉴别在M34序列倾向性,根据Kabat,其属12H10.G7的CDRH1。这些抗体的变体经设计以移除假定序列倾向性基元。
实施例5.人源化及亲和力成熟
基于关于对重组hFLT3蛋白的动力学及亲和力、与表达人类及食蟹猕猴FLT3的细胞株的结合、与不同AML及ALL癌细胞的结合、分箱概况以及不抑制人类FLT3-配体结合所收集的数据,选择四种小鼠杂交瘤次克隆,即12H10.G7、11F4.B9、4A4.A3及14A5.E8用于人源化。虽然4A4.A3及14A5.E8显示比12H10.G7及11F4.B9略低的对hFLT3的亲和力,但这些抗体似乎分别结合于FLT3的独特抗原决定基(不与参考抗体交叉阻断)及域1,因此进行进一步分析以探索抗原决定基多样性。
将12H10.G7抗体人源化以建立如上所述的GB94及GB102,两者共享相同VH及VL序列。在构架区中引入回复突变以建立变体GB87至GB93及GB95至GB101。
将11F4.B9抗体人源化以建立如上所述的1153及1154,两者共享相同VH及VL序列。在构架区中引入回复突变以建立变体1151及1152。1153抗体亦进行亲和力成熟。简言之,设计集中于1553FLT3scFv的CDR上的文库且在酵母表面上呈现。通过将酵母与生物素化人类FLT3-His抗原一起培育,进行FACS选择两次。FACS富集的输出样品与额外CDR突变体组合以制造第二文库。通过用生物素化人类FLT3-His自100nM至1nM滴定进行两轮额外FACS选择。在10nM下进行分选,其中与亲本相比,观察到文库存在信号明显增加。涂铺分选的酵母克隆且筛选。
实施例6.TriNKET与表达人类癌症抗原的细胞的结合的评定
异位表达人类及食蟹猕猴FLT3的等基因细胞株用于评定人类与食蟹猕猴FLT3之间的交叉反应性。表达hFLT3或cFLT3的人类癌细胞株RMA用于评定靶向FLT3的TriNKET与亲本mAb的肿瘤抗原结合。人类AML细胞株MOLM-13及MV4-11及人类ALL细胞株REH用于评定TriNKET或亲本mAb的结合能力。详言之,分别表达FLT3-T227M及FLT3-ITD的MOLM-13细胞及MV4-11细胞用于评定靶向FLT3的TriNKET及亲本mAb结合突变FLT3的能力。
将呈人类IgG1格式的GB102单克隆抗体(也称为1158 mAb)及上述其对应TriNKETF3'-GB102(也称为F3'-1158)稀释且与相应细胞一起培育。接着细胞与荧光团结合的抗人类IgG二级抗体一起培育且通过流式细胞术分析。将平均荧光强度(MFI)值相对于只二级抗体的对照正规化以获得相比于背景的倍数(FOB)值。
如图21A及图21B所示,F3'-1158及1158 mAb各以同等效力结合异位表达人类及食蟹猕猴FLT3的RMA细胞。如图21C所示,F3'-1158及1158 mAb结合人类ALL细胞REH细胞。如图22A及22B所示,F3'-1158及1158 mAb各结合分别表达FLT3-T227M及FLT3-ITD的MOLM-13细胞及MV4-11细胞。
实施例7.TriNKET或mAb内化的评定
在与F3'-1158或1158 mAb一起培育之后源自于嗜酸性球白血病的EOL-1人类癌细胞株用于评定FLT3的内化。将一式两份盘中EOL-1细胞与F3'-1158、1158 mAb或hIgG1同型对照抗体一起在37℃下培育两小时。在培育之后,洗涤细胞且使用非竞争性抗FLT3抗体染色总FLT3。如下计算FLT3内化:
内化%=(1-(2小时样品MFI/2小时hIgG1同型MFI))×100%
图23A-23B展示在REH(图23A)及EOL-1(图23B)中与F3'-1158及1158 mAb一起培育之后FLT3的内化。亲本mAb诱导小于10%的FLT3内化,而靶向FLT3的TriNKET诱导小于5%的FLT3内化。
实施例8.初级人类NK细胞的细胞毒性分析
通过DELFIA细胞毒性分析测量靶细胞的溶解。简言之,自培养物中收获表达FLT3的人类癌细胞株,用HBS洗涤,且再以106/mL悬浮于生长培养基中以用BATDA试剂(PerkinElmer C136-100)标记。关于靶细胞的标记,遵循制造商说明书。在标记之后,将细胞用HBS洗涤三次,且以0.5-1.0×105/mL再悬浮于培养基中。将100μl BATDA标记的细胞添加至96孔盘的各孔。在培养基中稀释针对FLT3的单克隆抗体或TriNKET,且将50μl稀释的mAb或TriNKET添加至各孔。
为制备NK细胞,使用密度梯度离心自人类周边血液白细胞层分离PBMC,洗涤,且准备用于NK细胞分离。使用阴性选择技术利用磁性珠粒分离NK细胞。分离的NK细胞的纯度通常>90%CD3-CD56+。将分离的NK细胞静息隔夜且自培养物收获。接着洗涤细胞且以105-2.0×106/mL的浓度再悬浮于培养基中,效应与标靶(E:T)比率为5:1。将50μl NK细胞添加至盘的各孔中,总共200μl培养物体积。将盘在37℃下在5%CO2下培育2-3小时。
在培育之后,自培育箱移除盘且通过在200×g下离心5分钟将细胞团粒化。将20μl培养物上清液转移至干净微量培养盘中,且将200μl室温铕溶液(Perkin Elmer C135-100)添加至各孔中。将盘避光且在盘式震荡器上在250rpm下培育15分钟,接着使用SpectraMaxi3X仪器读取。
在缺乏NK细胞下培育的标靶细胞中测量可与铕形成荧光螯合物的物质的自发释放。在用1%Triton-X溶解的标靶细胞中测量此类物质的最大释放。如下计算特定溶解%:
特定溶解%=((实验释放–自发释放)/(最大释放–自发释放))×100%。
图24A-24D显示F3'-1158或1158 mAb增强初级NK细胞介导的人类AML或ALL细胞株EOL-1(图24A)、Reh(图24B)、RS4-11(图24C)及MV4-11(图24D)的杀死的活性。F3'-1158显示与其亲本mAb 1158 mAb相比更有效的杀死。
为评定结合NKG2D的抗原结合位点及Fc的效应功能是否有助于F3'-1158的细胞毒性,构筑两种TriNKET变体。第一变体在结合NKG2D的A49抗原结合位点的轻链可变域中含有突变。因此,此变体不结合人类NKG2D。突变轻链可变域的氨基酸序列为DIQMTQSPSTLSASVGDRVTITCRASNSISSWLAWYQQKPGKAPKLLIYEASSTKSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYDDLPTFGGGTKVEIK(SEQ ID NO:305)。此第一变体的氨基酸序列在其他方面与F3'-1158的氨基酸序列一致。第二变体在Fc域中含有突变。具体而言,Fc域的各多肽链含有L234A/L235A/P329G取代(根据EU编号系统进行编号),据报导,减少Fc与Fcγ受体的结合。此第二变体的氨基酸序列在其他方面与F3'-1158的氨基酸序列一致。
这些变体诱发NK细胞介导的标靶细胞溶解的能力使用上述DELFIA细胞毒性分析评定。如图25所示,靶向NKG2D的域及Fc域中的突变基本上降低细胞毒性。此结果表明,结合于NKG2D与结合于Fcγ受体均影响F3'-1158的细胞毒活性。
实施例9.初级人类T细胞的细胞毒性分析
除了CD8+ T细胞用作免疫效应细胞之外,通过如实施例8中所述的DELFIA细胞毒性分析测量标靶细胞的溶解。如下制备CD8+ T细胞:利用Lymphoprep及SepMate 50,根据制造商说明书,使用密度梯度离心自人类周边血白细胞层分离人类PBMC。在培养基中,在37℃下,用1μg/mL ConA(IL-2培养补充物)刺激分离的PBMC 18小时。接着移除ConA且将PBMC与25单位/毫升IL-2在37℃下培养4天。根据制造商说明书,使用阴性选择技术利用磁性珠粒(EasySepTM人类CD8+ T细胞分离试剂盒)纯化CD8+ T细胞。将CD8+ T细胞在含有10ng/mLIL-15的培养基中在37℃下培养6-13天,接着用于细胞溶解分析中。
如图26所示,F3'-1158,而非1158 mAb,显著增强CD8 T细胞溶解RS4-11标靶细胞的能力。F3'-1158以剂量依赖性方式增加CD8+ T细胞介导的RS4-11细胞溶解。
实施例10.TriNKET或mAb与人类全血的结合的评定
评定F3'-1158及1158 mAb结合不同类型血细胞的能力。简言之,将人类全血与F3'-1158、1158 mAb或人类IgG1同型对照抗体一起培育。通过流式细胞术来分析血细胞,且使用荧光团结合的抗人类IgG二级抗体检测F3'-1158、1158 mAb或同型对照抗体的结合。
如图27所示,F3'-1158及1158 mAb未显示显著结合于血液中的颗粒球、单核球、B细胞、NK细胞、CD8+ T细胞及CD4+ T细胞。
实施例11.FLT3信号传导的活化
通过pFLT3 ELISA(R&D Systems DYC368)测量FLT3的磷酸化(FLT3信号传导的标记物)。将EOL-1细胞涂铺在96孔圆底盘中。添加F3'-1158、1158 mAb和/或FLT3L。将样品在室温下培育5分钟且立即在300×g下团粒化5分钟。将细胞用PBS洗涤两次。使细胞团粒再悬浮于200μL溶解缓冲液#9中且在冰上培育15分钟。将样品在2000×g下团粒化5分钟,且将上清液转移至干净试管中。使用BCA总蛋白分析定量蛋白质浓度。任选将样品在IC稀释剂#12中稀释。根据制造商说明书测量溶解产物。通过自推导的标准曲线内插值,确定各样品中的pFLT3浓度。已知标准的光密度值相对于其相应浓度绘图且数据拟合成线性回归模型。
如图28A所示,FLT3L引起pFLT3水平增加3倍,而F3'-1158及1158 mAb不诱导显著FLT3磷酸化。图28B显示,当细胞与F3'-1158或1158 mAb以及FLT3L一起培育时,F3'-1158与1158 mAb均不抑制FLT3L诱导的FLT3磷酸化。这些结果符合1158 mAb不与FLT3L竞争结合FLT3的观察结果。
以引用的方式并入
除非相反地陈述,否则本文中提及的各专利文件及科学论文的整个公开内容均以引用的方式并入以达成所有目的。
同等物
在不脱离本发明的精神或基本特征下本发明可通过其他特定形式体现。因此,认为上述实施方案在所有方面均为说明性,而非限制本文所述的本发明。因此本发明的范畴通过随附权利要求书指示,而非通过以上描述指示,且意欲其中涵盖在权利要求书的同等含义及范畴内的所有改变。
序列表
序列表
<110> 蜻蜓疗法股份有限公司
<120> 结合NKG2D、CD16及FLT3的蛋白质
<130> 14247-474-228
<140> TBA
<141>
<150> 62/915,123
<151> 2019-10-15
<160> 319
<170> PatentIn version 3.5
<210> 1
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 12H10.G7-VH
<400> 1
Glu Val Gln Leu Gln Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Val Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr His Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 2
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 12H10.G7-VL
<400> 2
Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Ser Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 3
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB87(VH-VL)的scFv
<400> 3
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 4
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 12H10.G7-VH CDR2
<400> 4
Asn Pro Tyr Asn Asp Asp
1 5
<210> 5
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 12H10.G7-VH CDR3
<400> 5
Trp Arg Gln Leu Gly Ser Leu Asp Ser
1 5
<210> 6
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 12H10.G7-VL CDR1
<400> 6
Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
1 5 10 15
<210> 7
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 12H10.G7-VL CDR2
<400> 7
Leu Ala Ser Asn Leu Glu Ser
1 5
<210> 8
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 12H10.G7-VL CDR3
<400> 8
Gln Gln Asn Asn Glu Glu Pro Trp Thr
1 5
<210> 9
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7-VH
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 10
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7-VL
<400> 10
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 11
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB87/GB95-VH CDR1
<400> 11
Gly Tyr Thr Phe Thr Arg Tyr
1 5
<210> 12
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化12H10.G7 GB95(VL-VH)的scFv
<400> 12
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr His Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 13
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB88/GB96-VH
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 14
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 11F4.B9
<400> 14
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 Ser Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Gly Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Ile Pro Ser Thr Gly Ser Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Arg Trp Gly Asp Tyr Tyr Gly Arg Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 15
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB88(VH-VL)的scFv
<400> 15
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 16
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB96(VL-VH)的scFv
<400> 16
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr His Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 17
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB89/GB97-VH
<400> 17
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 18
<211> 517
<212> PRT
<213> 人工序列
<220>
<223> hFLT3-ITD的胞外区
<400> 18
Asn Gln Asp Leu Pro Val Ile Lys Cys Val Leu Ile Asn His Lys Asn
1 5 10 15
Asn Asp Ser Ser Val Gly Lys Ser Ser Ser Tyr Pro Met Val Ser Glu
20 25 30
Ser Pro Glu Asp Leu Gly Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr
35 40 45
Val Tyr Glu Ala Ala Ala Val Glu Val Asp Val Ser Ala Ser Ile Thr
50 55 60
Leu Gln Val Leu Val Asp Ala Pro Gly Asn Ile Ser Cys Leu Trp Val
65 70 75 80
Phe Lys His Ser Ser Leu Asn Cys Gln Pro His Phe Asp Leu Gln Asn
85 90 95
Arg Gly Val Val Ser Met Val Ile Leu Lys Met Thr Glu Thr Gln Ala
100 105 110
Gly Glu Tyr Leu Leu Phe Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile
115 120 125
Leu Phe Thr Val Ser Ile Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg
130 135 140
Pro Tyr Phe Arg Lys Met Glu Asn Gln Asp Ala Leu Val Cys Ile Ser
145 150 155 160
Glu Ser Val Pro Glu Pro Ile Val Glu Trp Val Leu Cys Asp Ser Gln
165 170 175
Gly Glu Ser Cys Lys Glu Glu Ser Pro Ala Val Val Lys Lys Glu Glu
180 185 190
Lys Val Leu His Glu Leu Phe Gly Thr Asp Ile Arg Cys Cys Ala Arg
195 200 205
Asn Glu Leu Gly Arg Glu Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn
210 215 220
Gln Thr Pro Gln Thr Thr Leu Pro Gln Leu Phe Leu Lys Val Gly Glu
225 230 235 240
Pro Leu Trp Ile Arg Cys Lys Ala Val His Val Asn His Gly Phe Gly
245 250 255
Leu Thr Trp Glu Leu Glu Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe
260 265 270
Glu Met Ser Thr Tyr Ser Thr Asn Arg Thr Met Ile Arg Ile Leu Phe
275 280 285
Ala Phe Val Ser Ser Val Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys
290 295 300
Ser Ser Ser Lys His Pro Ser Gln Ser Ala Leu Val Thr Ile Val Glu
305 310 315 320
Lys Gly Phe Ile Asn Ala Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp
325 330 335
Gln Tyr Glu Glu Phe Cys Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln
340 345 350
Ile Arg Cys Thr Trp Thr Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln
355 360 365
Lys Gly Leu Asp Asn Gly Tyr Ser Ile Ser Lys Phe Cys Asn His Lys
370 375 380
His Gln Pro Gly Glu Tyr Ile Phe His Ala Glu Asn Asp Asp Ala Gln
385 390 395 400
Phe Thr Lys Met Phe Thr Leu Asn Ile Arg Arg Lys Pro Gln Val Leu
405 410 415
Ala Glu Ala Ser Ala Ser Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro
420 425 430
Leu Pro Ser Trp Thr Trp Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys
435 440 445
Thr Glu Glu Ile Thr Glu Gly Val Trp Asn Arg Lys Ala Asn Arg Lys
450 455 460
Val Phe Gly Gln Trp Val Ser Ser Ser Thr Leu Asn Met Ser Glu Ala
465 470 475 480
Ile Lys Gly Phe Leu Val Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr
485 490 495
Ser Cys Glu Thr Ile Leu Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile
500 505 510
Gln Asp Asn Ile Ser
515
<210> 19
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB89(VH-VL)的scFv
<400> 19
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 20
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB97(VL-VH)的scFv
<400> 20
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 21
<211> 226
<212> PRT
<213> 智人
<220>
<223> 野生型人类 IgG1 Fc 序列
<400> 21
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly
225
<210> 22
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB90/GB98-VL
<400> 22
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 23
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB90(VH-VL)的scFv
<400> 23
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 24
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB98(VL-VH)的scFv
<400> 24
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr His Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 25
<211> 517
<212> PRT
<213> 人工序列
<220>
<223> hFLT3-T227M的胞外区
<400> 25
Asn Gln Asp Leu Pro Val Ile Lys Cys Val Leu Ile Asn His Lys Asn
1 5 10 15
Asn Asp Ser Ser Val Gly Lys Ser Ser Ser Tyr Pro Met Val Ser Glu
20 25 30
Ser Pro Glu Asp Leu Gly Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr
35 40 45
Val Tyr Glu Ala Ala Ala Val Glu Val Asp Val Ser Ala Ser Ile Thr
50 55 60
Leu Gln Val Leu Val Asp Ala Pro Gly Asn Ile Ser Cys Leu Trp Val
65 70 75 80
Phe Lys His Ser Ser Leu Asn Cys Gln Pro His Phe Asp Leu Gln Asn
85 90 95
Arg Gly Val Val Ser Met Val Ile Leu Lys Met Thr Glu Thr Gln Ala
100 105 110
Gly Glu Tyr Leu Leu Phe Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile
115 120 125
Leu Phe Thr Val Ser Ile Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg
130 135 140
Pro Tyr Phe Arg Lys Met Glu Asn Gln Asp Ala Leu Val Cys Ile Ser
145 150 155 160
Glu Ser Val Pro Glu Pro Ile Val Glu Trp Val Leu Cys Asp Ser Gln
165 170 175
Gly Glu Ser Cys Lys Glu Glu Ser Pro Ala Val Val Lys Lys Glu Glu
180 185 190
Lys Val Leu His Glu Leu Phe Gly Met Asp Ile Arg Cys Cys Ala Arg
195 200 205
Asn Glu Leu Gly Arg Glu Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn
210 215 220
Gln Thr Pro Gln Thr Thr Leu Pro Gln Leu Phe Leu Lys Val Gly Glu
225 230 235 240
Pro Leu Trp Ile Arg Cys Lys Ala Val His Val Asn His Gly Phe Gly
245 250 255
Leu Thr Trp Glu Leu Glu Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe
260 265 270
Glu Met Ser Thr Tyr Ser Thr Asn Arg Thr Met Ile Arg Ile Leu Phe
275 280 285
Ala Phe Val Ser Ser Val Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys
290 295 300
Ser Ser Ser Lys His Pro Ser Gln Ser Ala Leu Val Thr Ile Val Glu
305 310 315 320
Lys Gly Phe Ile Asn Ala Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp
325 330 335
Gln Tyr Glu Glu Phe Cys Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln
340 345 350
Ile Arg Cys Thr Trp Thr Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln
355 360 365
Lys Gly Leu Asp Asn Gly Tyr Ser Ile Ser Lys Phe Cys Asn His Lys
370 375 380
His Gln Pro Gly Glu Tyr Ile Phe His Ala Glu Asn Asp Asp Ala Gln
385 390 395 400
Phe Thr Lys Met Phe Thr Leu Asn Ile Arg Arg Lys Pro Gln Val Leu
405 410 415
Ala Glu Ala Ser Ala Ser Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro
420 425 430
Leu Pro Ser Trp Thr Trp Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys
435 440 445
Thr Glu Glu Ile Thr Glu Gly Val Trp Asn Arg Lys Ala Asn Arg Lys
450 455 460
Val Phe Gly Gln Trp Val Ser Ser Ser Thr Leu Asn Met Ser Glu Ala
465 470 475 480
Ile Lys Gly Phe Leu Val Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr
485 490 495
Ser Cys Glu Thr Ile Leu Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile
500 505 510
Gln Asp Asn Ile Ser
515
<210> 26
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7-VL的scFv
<400> 26
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 27
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB91(VH-VL)的scFv
<400> 27
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 28
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB99(VL-VH)的scFv
<400> 28
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr His Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 29
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 一致-VH
<220>
<221> misc_feature
<222> (30)..(30)
<223> Xaa = Phe或Thr
<220>
<221> misc_feature
<222> (31)..(31)
<223> Xaa = Ser或Tyr
<220>
<221> misc_feature
<222> (40)..(40)
<223> Xaa = Ala或Arg
<220>
<221> misc_feature
<222> (44)..(44)
<223> Xaa = Cys或Gly
<220>
<221> misc_feature
<222> (72)..(72)
<223> Xaa = Val或Glu
<220>
<221> misc_feature
<222> (76)..(76)
<223> Xaa = Ser或Tyr
<220>
<221> misc_feature
<222> (100)..(100)
<223> Xaa = Asn或Val
<220>
<221> misc_feature
<222> (104)..(104)
<223> Xaa = Thr或Tyr
<400> 29
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 Val Ser Gly Tyr Thr Phe Xaa Xaa Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Xaa Pro Gly Lys Xaa Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Xaa Asp Thr Ser Xaa Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Xaa Val Tyr Leu Xaa Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 30
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB92/GB100-VL
<400> 30
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 31
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB92(VH-VL)的scFv
<400> 31
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Val Ala Thr Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 32
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB100(VL-VH)的scFv
<400> 32
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr His Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val
245
<210> 33
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 4H2.E3-VH CDR2
<400> 33
Asn Pro Tyr Ser Asp Gly
1 5
<210> 34
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB93/GB101-VL
<400> 34
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 35
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB93(VH-VL)的scFv
<400> 35
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Ala Ala Val Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 36
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB101(VL-VH)的scFv
<400> 36
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr His Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 37
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB94/GB102-VH
<400> 37
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 38
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB94/GB102-VL
<400> 38
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 39
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB94(VH-VL)的scFv
<400> 39
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 40
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102(VL-VH)的scFv
<400> 40
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 41
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 D101E-VH
<400> 41
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Glu Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 42
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 -VL
<400> 42
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 43
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 D101E (VH-VL)的scFv
<400> 43
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Glu Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 44
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 D101E (VL-VH)的scFv
<400> 44
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Glu Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 45
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 M34I-VH
<400> 45
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 Arg Tyr
20 25 30
Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 46
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 14H8.E7-VL CDR3
<400> 46
Gln Gln Trp Ser Ser Lys Ser Pro Thr
1 5
<210> 47
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 M34I (VH-VL)的scFv
<400> 47
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 Arg Tyr
20 25 30
Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 48
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 M34I (VL-VH)的scFv
<400> 48
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 49
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 M34I/D101E-VH
<400> 49
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 Arg Tyr
20 25 30
Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Glu Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 50
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 M34I/D101E -CDR3
<400> 50
Trp Arg Gln Leu Gly Ser Leu Glu Ser
1 5
<210> 51
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 M34I/D101E (VH-VL)的scFv
<400> 51
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 Arg Tyr
20 25 30
Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Glu Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys
245
<210> 52
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 GB102 M34I/D101E (VL-VH)的scFv
<400> 52
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Glu Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245
<210> 53
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 一致 1-VH
<220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Met或Ile
<220>
<221> misc_feature
<222> (106)..(106)
<223> Xaa = Glu或Asp
<400> 53
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 Arg Tyr
20 25 30
Val Xaa His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Xaa Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 54
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 一致 VH CDR3
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Asn或Val
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = Thr或Tyr
<400> 54
Arg Xaa Val Tyr Leu Xaa Phe Asp Tyr
1 5
<210> 55
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 一致 1-VH CDR3
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa = Glu或Asp
<400> 55
Trp Arg Gln Leu Gly Ser Leu Xaa Ser
1 5
<210> 56
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 一致 2 -VH
<220>
<221> misc_feature
<222> (72)..(72)
<223> Xaa = Ser或Arg
<220>
<221> misc_feature
<222> (95)..(95)
<223> Xaa = Tyr或His
<400> 56
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Xaa Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Xaa Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 57
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 一致 2 -VL
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa = Ala或Asp
<220>
<221> misc_feature
<222> (72)..(72)
<223> Xaa = Arg或Gly
<220>
<221> misc_feature
<222> (87)..(87)
<223> Xaa = Ala或Val
<220>
<221> misc_feature
<222> (89)..(89)
<223> Xaa = Thr或Val
<400> 57
Asp Ile Val Met Thr Gln Ser Pro Xaa Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Xaa Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Xaa Ala Xaa Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 58
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 12H10.G7 一致 3-VH
<220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Met或Ile
<220>
<221> misc_feature
<222> (106)..(106)
<223> Xaa = Glu或Asp
<400> 58
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 Arg Tyr
20 25 30
Val Xaa His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Xaa Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 59
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 一致 VH CDR1
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa = Pro或Thr
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = Ser或Tyr
<400> 59
Gly Tyr Thr Phe Xaa Xaa Tyr
1 5
<210> 60
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 14A5.E8-VH
<400> 60
Glu Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Val Gln Pro Gly Ala
1 5 10 15
Ser Val Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Val Tyr Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 61
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 14A5.E8-VL
<400> 61
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 62
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 14A5.E8-VH CDR1
<400> 62
Gly Tyr Thr Phe Thr Ser Tyr
1 5
<210> 63
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 14A5.E8-VH或人源化 14A5.E8 一致 VH CDR2
<400> 63
Tyr Pro Gly Ser Ser Ile
1 5
<210> 64
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 14A5.E8-VH CDR3
<400> 64
Arg Val Val Tyr Leu Tyr Phe Asp Tyr
1 5
<210> 65
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 14A5.E8-VL CDR1
<400> 65
Ser Ala Ser Ser Ser Val Ser Tyr Met His
1 5 10
<210> 66
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 14A5.E8-VL或人源化 14A5.E8 一致 VL CDR2
<400> 66
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 67
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 14A5.E8-VL或人源化 14A5.E8 一致 VL CDR3
<400> 67
Gln Gln Trp Thr Ser Lys Ser Pro Thr
1 5
<210> 68
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1551/1552-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 Val Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Val Asp Thr Ser Ser Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Val Tyr Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 69
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1551/1552-VL
<400> 69
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Lys Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Ala Ala Val Tyr Tyr Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 70
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1551(VH-VL)的scFv
<400> 70
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 Val Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Arg Pro Gly Lys Cys Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Val Asp Thr Ser Ser Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Val Tyr Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Lys Ala Thr Leu Ser
145 150 155 160
Cys Ser Ala Ser Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Thr Ser Lys Leu Ala
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Ala Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr Phe Gly Cys Gly Thr Lys
225 230 235 240
Val Glu Ile Lys
<210> 71
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1552(VL-VH)的scFv
<400> 71
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Lys Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Ala Ala Val Tyr Tyr Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr
85 90 95
Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
115 120 125
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val
130 135 140
Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Ile
145 150 155 160
Asn Trp Val Arg Gln Arg Pro Gly Lys Cys Leu Glu Trp Met Gly Asn
165 170 175
Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe Lys Asn
180 185 190
Arg Val Thr Met Thr Val Asp Thr Ser Ser Asp Thr Ala Tyr Met Glu
195 200 205
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
210 215 220
Arg Val Val Tyr Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser
<210> 72
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1553/1554-VH
<400> 72
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 Val Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Val Tyr Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 73
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1553/1554-VL
<400> 73
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 74
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1553(VH-VL)的scFv
<400> 74
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 Val Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Val Tyr Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser
145 150 155 160
Cys Ser Ala Ser Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Thr Ser Lys Leu Ala
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr Phe Gly Cys Gly Thr Lys
225 230 235 240
Val Glu Ile Lys
<210> 75
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1554(VL-VH)的scFv
<400> 75
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr
85 90 95
Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
115 120 125
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val
130 135 140
Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Ile
145 150 155 160
Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Met Gly Asn
165 170 175
Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe Lys Asn
180 185 190
Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu
195 200 205
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
210 215 220
Arg Val Val Tyr Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser
<210> 76
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1689-VH
<400> 76
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 Val Ser Gly Tyr Thr Phe Pro Tyr Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asn Val Tyr Leu Thr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 77
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1689-VL
<400> 77
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 78
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1689-VH CDR1
<400> 78
Gly Tyr Thr Phe Pro Tyr Tyr
1 5
<210> 79
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1689-VH CDR3
<400> 79
Arg Asn Val Tyr Leu Thr Phe Asp Tyr
1 5
<210> 80
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1689-VL CDR1
<400> 80
Ser Ala Ser Ser Ser Val Ser Tyr Ile His
1 5 10
<210> 81
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1689 (VH-VL)的scFv
<400> 81
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 Val Ser Gly Tyr Thr Phe Pro Tyr Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asn Val Tyr Leu Thr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser
145 150 155 160
Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Thr Ser Lys Leu Ala
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr Phe Gly Cys Gly Thr Lys
225 230 235 240
Val Glu Ile Lys
<210> 82
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 1689 (VL-VH)的scFv
<400> 82
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr
85 90 95
Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
115 120 125
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val
130 135 140
Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Pro Tyr Tyr Trp Ile
145 150 155 160
Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Met Gly Asn
165 170 175
Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe Lys Asn
180 185 190
Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu
195 200 205
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
210 215 220
Arg Asn Val Tyr Leu Thr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser
<210> 83
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 14H8.E7-VL
<400> 83
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Thr Asn Met Glu Thr Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Lys Ser Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 84
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 一致 VL
<220>
<221> misc_feature
<222> (32)..(32)
<223> Xaa = Met或Ile
<400> 84
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Xaa
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 85
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 11F4.B9-VH
<400> 85
Glu Val Gln Leu Gln Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Gly Pro Glu Lys Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Ile Pro Ser Thr Gly Ser Thr Ile Tyr Asn Gln Lys Phe
50 55 60
Lys Ala Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Leu Gln Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Glu Arg Trp Gly Asp Tyr Tyr Gly Arg Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 86
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化 14A5.E8 一致 VL CDR1
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa = Met或Ile
<400> 86
Ser Ala Ser Ser Ser Val Ser Tyr Xaa His
1 5 10
<210> 87
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 11F4.B9-VH CDR1
<400> 87
Gly Tyr Ser Phe Thr Gly Tyr
1 5
<210> 88
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 11F4.B9-VH CDR2
<400> 88
Ile Pro Ser Thr Gly Ser
1 5
<210> 89
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 11F4.B9-VH CDR3
<400> 89
Trp Gly Asp Tyr Tyr Gly Arg Asp Tyr
1 5
<210> 90
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 11F4.B9-VL
<400> 90
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ile Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 91
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 11F4.B9-VL CDR1
<400> 91
Arg Ala Ser Glu Ser Val Asp Ile Tyr Gly Asn Ser Phe Met His
1 5 10 15
<210> 92
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 11F4.B9-VL CDR2
<400> 92
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 93
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 11F4.B9-VL CDR3
<400> 93
Gln Gln Ser Asn Glu Asp Pro Arg Thr
1 5
<210> 94
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化 11F4.B9-VL
<400> 94
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Ile Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 95
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 4A4.A3-VH
<400> 95
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala Asn Ile Trp Phe Asn Asp Asn Lys Tyr Tyr Asn Ser Thr
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Ser Ser Val Asp Thr Thr Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Gln Ile Thr Thr Val Val Gly Thr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Ser Pro Leu Thr Val Ser Pro
115 120
<210> 96
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 4A4.A3-VL
<400> 96
Arg Ile Val Met Thr Gln Ser Pro Thr Thr Met Ala Ala Ser Pro Gly
1 5 10 15
Glu Lys Ile Thr Ile Thr Cys Ser Ala Ser Ser Ser Ile Ser Ser Ile
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Phe Ser Pro Lys Leu Leu
35 40 45
Ile Phe Arg Thr Ser Asp Leu Ala Ser Gly Val Pro Pro Arg Phe Gly
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Gly Thr Met Glu
65 70 75 80
Ala Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Gly Ser Ser Phe Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 97
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 4A4.A3-VH CDR1
<400> 97
Gly Phe Ser Leu Thr Thr Tyr Gly Met
1 5
<210> 98
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 4A4.H7-VH CDR2
<400> 98
Tyr Pro Asn Thr Gly Ile
1 5
<210> 99
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 4A4.A3-VH CDR2
<400> 99
Trp Phe Asn Asp Asn
1 5
<210> 100
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 4A4.A3-VH CDR3
<400> 100
Ile Thr Thr Val Val Gly Thr Phe Asp Tyr
1 5 10
<210> 101
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 4A4.A3-VL CDR1
<400> 101
Ser Ala Ser Ser Ser Ile Ser Ser Ile Tyr Leu His
1 5 10
<210> 102
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 4A4.A3-VL CDR2
<400> 102
Arg Thr Ser Asp Leu Ala Ser
1 5
<210> 103
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 4A4.A3-VL CDR3
<400> 103
Gln Gln Gly Ser Ser Phe Pro Arg Thr
1 5
<210> 104
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 4A4.H7-VH
<400> 104
Glu Val Gln Leu Gln Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Ser Pro Glu Glu Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Asn Thr Gly Ile Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Thr Ala Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Trp Gly Asp Tyr Tyr Gly Arg Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 105
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 4A4.H7-VL
<400> 105
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Thr Val Asp Thr His
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 106
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 4A4.H7-VL CDR1
<400> 106
Arg Ala Ser Glu Thr Val Asp Thr His Gly Asn Ser Phe Met His
1 5 10 15
<210> 107
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 15A11.C8-VH
<400> 107
Glu Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Lys Thr Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg His Thr Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Val Tyr Ile Ser Ser Gly Gly Asn Thr Ile Phe Tyr Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Val Arg Gln Gly Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Ala
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 108
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 15A11.C8-VL
<400> 108
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Arg Cys Arg Ala Ser Gln Asp Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Ala Val Lys Leu Leu Ile
35 40 45
Ser Tyr Thr Ser Ile Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Gly Asp Val Ala Thr Tyr Phe Cys Gln Gln Gly Ser Ser Leu Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 109
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 15A11.C8-VH CDR1
<400> 109
Gly Phe Thr Phe Ser Asp Tyr
1 5
<210> 110
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 15A11.C8-VH CDR2
<400> 110
Ser Ser Gly Gly Asn Thr
1 5
<210> 111
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 15A11.C8-VH CDR3
<400> 111
Gln Gly Tyr Tyr Tyr Ala Met Asp Tyr
1 5
<210> 112
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 15A11.C8-VL CDR1
<400> 112
Arg Ala Ser Gln Asp Ile Thr Asn Tyr Leu Asn
1 5 10
<210> 113
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 15A11.C8-VL CDR2
<400> 113
Tyr Thr Ser Ile Leu Gln Ser
1 5
<210> 114
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 15A11.C8-VL CDR3
<400> 114
Gln Gln Gly Ser Ser Leu Pro Trp Thr
1 5
<210> 115
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 12C9.E5-VH
<400> 115
Glu Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asp Tyr
20 25 30
Glu Ile His Trp Val Lys Gln Thr Pro Val His Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Asp Pro Glu Thr Gly Ile Thr Ala Tyr Ser Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Thr Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Phe Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Gly Leu Leu Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
100 105 110
Ser Ser
<210> 116
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 12C9.E5-VL
<400> 116
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Asp Gly Glu Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Met Tyr Gln Val Ser Lys Leu Asp Pro Gly Ile Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Tyr Cys Leu Gln Gly
85 90 95
Thr Phe Tyr Pro His Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 117
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 12C9.E5-VH CDR1
<400> 117
Gly Tyr Ile Phe Thr Asp Tyr
1 5
<210> 118
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 12C9.E5-VH CDR2
<400> 118
Asp Pro Glu Thr Gly Ile
1 5
<210> 119
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 12C9.E5-VH CDR3
<400> 119
Gly Gly Leu Leu Tyr
1 5
<210> 120
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 12C9.E5-VL CDR1
<400> 120
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Asp Gly Glu Thr Tyr Leu Asn
1 5 10 15
<210> 121
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 12C9.E5-VL CDR2
<400> 121
Gln Val Ser Lys Leu Asp Pro
1 5
<210> 122
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 12C9.E5-VL CDR3
<400> 122
Leu Gln Gly Thr Phe Tyr Pro His Thr
1 5
<210> 123
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 1A2.A3 VH
<400> 123
Glu Val Gln Leu Gln Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Ser Pro Glu Glu Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Asn Thr Gly Ile Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Thr Ala Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Trp Gly Asp Tyr Tyr Gly Arg Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 124
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 1A2.A3-VL
<400> 124
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Thr Val Asp Thr His
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 125
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 4H2.E3-VH
<400> 125
Glu Val Gln Leu Gln Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Leu Met His Trp Met Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Ser Asp Gly Ile Lys Tyr Asn Glu Lys Phe
50 55 60
Arg Asp Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala His Ser Ser Gly Tyr Val Gly Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 126
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 4H2.E3-VL
<400> 126
Gly Ile Val Met Thr Gln Thr Thr Pro Ser Val Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Thr Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 127
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 4H2.E3-VH CDR3
<400> 127
Ser Ser Gly Tyr Val Gly Tyr Ala Met Asp Tyr
1 5 10
<210> 128
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 4H2.E3-VL CDR1
<400> 128
Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr
1 5 10 15
<210> 129
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 4H2.E3-VL CDR2
<400> 129
Arg Met Ser Asn Leu Ala Ser
1 5
<210> 130
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 4H2.E3-VL CDR3
<400> 130
Met Gln His Leu Glu Tyr Pro Phe Thr
1 5
<210> 131
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 14H8.E7-VH
<400> 131
Glu Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile Asn Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Thr Ile Ile Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Val Tyr Leu Tyr Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 132
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 14H8.E7-VH CDR1
<400> 132
Gly Tyr Thr Phe Thr Asn Tyr
1 5
<210> 133
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 14H8.E7-VH CDR2
<400> 133
Tyr Pro Gly Ser Thr Ile
1 5
<210> 134
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 14H8.E7-VH CDR3
<400> 134
Arg Val Val Tyr Leu Tyr Phe Asp Ser
1 5
<210> 135
<211> 517
<212> PRT
<213> 人工序列
<220>
<223> mature human FLT3 extracellular domain
<400> 135
Asn Gln Asp Leu Pro Val Ile Lys Cys Val Leu Ile Asn His Lys Asn
1 5 10 15
Asn Asp Ser Ser Val Gly Lys Ser Ser Ser Tyr Pro Met Val Ser Glu
20 25 30
Ser Pro Glu Asp Leu Gly Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr
35 40 45
Val Tyr Glu Ala Ala Ala Val Glu Val Asp Val Ser Ala Ser Ile Thr
50 55 60
Leu Gln Val Leu Val Asp Ala Pro Gly Asn Ile Ser Cys Leu Trp Val
65 70 75 80
Phe Lys His Ser Ser Leu Asn Cys Gln Pro His Phe Asp Leu Gln Asn
85 90 95
Arg Gly Val Val Ser Met Val Ile Leu Lys Met Thr Glu Thr Gln Ala
100 105 110
Gly Glu Tyr Leu Leu Phe Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile
115 120 125
Leu Phe Thr Val Ser Ile Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg
130 135 140
Pro Tyr Phe Arg Lys Met Glu Asn Gln Asp Ala Leu Val Cys Ile Ser
145 150 155 160
Glu Ser Val Pro Glu Pro Ile Val Glu Trp Val Leu Cys Asp Ser Gln
165 170 175
Gly Glu Ser Cys Lys Glu Glu Ser Pro Ala Val Val Lys Lys Glu Glu
180 185 190
Lys Val Leu His Glu Leu Phe Gly Thr Asp Ile Arg Cys Cys Ala Arg
195 200 205
Asn Glu Leu Gly Arg Glu Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn
210 215 220
Gln Thr Pro Gln Thr Thr Leu Pro Gln Leu Phe Leu Lys Val Gly Glu
225 230 235 240
Pro Leu Trp Ile Arg Cys Lys Ala Val His Val Asn His Gly Phe Gly
245 250 255
Leu Thr Trp Glu Leu Glu Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe
260 265 270
Glu Met Ser Thr Tyr Ser Thr Asn Arg Thr Met Ile Arg Ile Leu Phe
275 280 285
Ala Phe Val Ser Ser Val Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys
290 295 300
Ser Ser Ser Lys His Pro Ser Gln Ser Ala Leu Val Thr Ile Val Glu
305 310 315 320
Lys Gly Phe Ile Asn Ala Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp
325 330 335
Gln Tyr Glu Glu Phe Cys Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln
340 345 350
Ile Arg Cys Thr Trp Thr Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln
355 360 365
Lys Gly Leu Asp Asn Gly Tyr Ser Ile Ser Lys Phe Cys Asn His Lys
370 375 380
His Gln Pro Gly Glu Tyr Ile Phe His Ala Glu Asn Asp Asp Ala Gln
385 390 395 400
Phe Thr Lys Met Phe Thr Leu Asn Ile Arg Arg Lys Pro Gln Val Leu
405 410 415
Ala Glu Ala Ser Ala Ser Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro
420 425 430
Leu Pro Ser Trp Thr Trp Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys
435 440 445
Thr Glu Glu Ile Thr Glu Gly Val Trp Asn Arg Lys Ala Asn Arg Lys
450 455 460
Val Phe Gly Gln Trp Val Ser Ser Ser Thr Leu Asn Met Ser Glu Ala
465 470 475 480
Ile Lys Gly Phe Leu Val Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr
485 490 495
Ser Cys Glu Thr Ile Leu Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile
500 505 510
Gln Asp Asn Ile Ser
515
<210> 136
<211> 226
<212> PRT
<213> 人工序列
<220>
<223> 野生型人类 IgG1 Fc 序列
<400> 136
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly
225
<210> 137
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> ((G4S)4) 接头
<400> 137
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 138
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-27705-VH
<400> 138
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 139
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-27705-VL
<400> 139
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Ile
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 140
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-27705-VH CDR1
<400> 140
Gly Ser Phe Ser Gly Tyr Tyr Trp Ser
1 5
<210> 141
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> ADI-27705-VH CDR2
<400> 141
Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 142
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> ADI-27705-VH CDR3
<400> 142
Ala Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro
1 5 10
<210> 143
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-27724-VH
<400> 143
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 144
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> ADI-27724-VL
<400> 144
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 Tyr Gly Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 145
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-27740(A40)-VH
<400> 145
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 146
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-27740(A40)-VL
<400> 146
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Phe Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 147
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-27741-VH
<400> 147
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 148
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-27741-VL
<400> 148
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Ser Tyr Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 149
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-27743-VH
<400> 149
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 150
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-27743-VL
<400> 150
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 151
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-28153-VH
<400> 151
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Gly Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 152
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-28153-VL
<400> 152
Glu Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp 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 Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asp Ile Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 153
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-28226(C26)-VH
<400> 153
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 154
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-28226(C26)-VL
<400> 154
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gly Ser Phe Pro Ile
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 155
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-28154-VH
<400> 155
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 156
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-28154-VL
<400> 156
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Lys Glu Val Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 157
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29399-VH
<400> 157
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 158
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29399-VL
<400> 158
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Phe Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 159
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29401-VH
<400> 159
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 160
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29401-VL
<400> 160
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ile Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 161
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VL
<400> 161
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Asp Thr Trp Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 162
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29403-VH
<400> 162
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 163
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29403-VL
<400> 163
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 164
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29405-VH
<400> 164
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 165
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29405-VL
<400> 165
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gly Ser Phe Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 166
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29407-VH
<400> 166
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 167
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29407-VL
<400> 167
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Ser Phe Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 168
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29419-VH
<400> 168
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 169
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29419-VL
<400> 169
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Phe Ser Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 170
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29421-VH
<400> 170
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 171
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29421-VL
<400> 171
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Glu Ser Tyr Ser Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 172
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29424-VH
<400> 172
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 173
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29424-VL
<400> 173
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Phe Ile Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 174
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29425-VH
<400> 174
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 175
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29425-VL
<400> 175
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 176
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29426-VH
<400> 176
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 177
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29426-VL
<400> 177
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Phe Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 178
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29429-VH
<400> 178
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 179
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-29429-VL
<400> 179
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Glu Leu Tyr Ser Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 180
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29447(F47)-VH
<400> 180
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 181
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29447(F47)-VL
<400> 181
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Thr Phe Ile Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 182
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VH
<400> 182
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Ser Ser Ile Arg His Ala Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 183
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VL
<400> 183
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Thr Pro Ile Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 184
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VH CDR1(非-Kabat)
<400> 184
Gly Thr Phe Ser Ser Tyr Ala Ile Ser
1 5
<210> 185
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VH CDR1(非-Kabat)
<400> 185
Ser Tyr Ala Ile Ser
1 5
<210> 186
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VH CDR2
<400> 186
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 187
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VL CDR1
<400> 187
Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 188
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VL CDR2
<400> 188
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 189
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VH CDR3 (非-Kabat)
<400> 189
Ala Arg Gly Asp Ser Ser Ile Arg His Ala Tyr Tyr Tyr Tyr Gly Met
1 5 10 15
Asp Val
<210> 190
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VH CDR3 (非-Kabat)
<400> 190
Gly Asp Ser Ser Ile Arg His Ala Tyr Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 191
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-27727-VL CDR3
<400> 191
Gln Gln Tyr Tyr Ser Thr Pro Ile Thr
1 5
<210> 192
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VH
<400> 192
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Ser Asp Arg Phe His Pro Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 193
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VH CDR1(非-Kabat)
<400> 193
Gly Ser Ile Ser Ser Ser Ser Tyr Tyr Trp Gly
1 5 10
<210> 194
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VH CDR1(非-Kabat)
<400> 194
Ser Ser Ser Tyr Tyr Trp Gly
1 5
<210> 195
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VH CDR2
<400> 195
Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 196
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VH CDR3 (非-Kabat)
<400> 196
Ala Arg Gly Ser Asp Arg Phe His Pro Tyr Phe Asp Tyr
1 5 10
<210> 197
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VH CDR3 (非-Kabat)
<400> 197
Gly Ser Asp Arg Phe His Pro Tyr Phe Asp Tyr
1 5 10
<210> 198
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VL CDR1
<400> 198
Arg Ala Ser Gln Ser Val Ser Arg Tyr Leu Ala
1 5 10
<210> 199
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VL CDR2
<400> 199
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 200
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-29443(F43)-VL CDR3
<400> 200
Gln Gln Phe Asp Thr Trp Pro Pro Thr
1 5
<210> 201
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> ADI-29404(F04)-VH
<400> 201
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 202
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> ADI-29404(F04)-VL
<400> 202
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Glu Gln Tyr Asp Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 203
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> ADI-28200-VH
<400> 203
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Gly Arg Lys Ala Ser Gly Ser Phe Tyr Tyr Tyr Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 204
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> ADI-28200-VL
<400> 204
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Glu Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Pro Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 205
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-28200-VH CDR2
<400> 205
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 206
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> ADI-28200-VH CDR3
<400> 206
Ala Arg Arg Gly Arg Lys Ala Ser Gly Ser Phe Tyr Tyr Tyr Tyr Gly
1 5 10 15
Met Asp Val
<210> 207
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-28200-VH CDR1
<400> 207
Glu Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 208
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-28200-VH CDR3
<400> 208
Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr
1 5
<210> 209
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VH
<400> 209
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 Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Asn Tyr Gly Asp Thr Thr His Asp Tyr Tyr Tyr
100 105 110
Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 210
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VL
<400> 210
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val 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
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asp Trp Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 211
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VH CDR1(非-Kabat)
<400> 211
Tyr Thr Phe Thr Ser Tyr Tyr Met His
1 5
<210> 212
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VH CDR1(非-Kabat)
<400> 212
Ser Tyr Tyr Met His
1 5
<210> 213
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VH CDR2
<400> 213
Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 214
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VH CDR3(非-Kabat)
<400> 214
Ala Arg Gly Ala Pro Asn Tyr Gly Asp Thr Thr His Asp Tyr Tyr Tyr
1 5 10 15
Met Asp Val
<210> 215
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VH CDR3(非-Kabat)
<400> 215
Gly Ala Pro Asn Tyr Gly Asp Thr Thr His Asp Tyr Tyr Tyr Met Asp
1 5 10 15
Val
<210> 216
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VH CDR1
<400> 216
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 217
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VH CDR2
<400> 217
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 218
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-29379(E79)-VH CDR3
<400> 218
Gln Gln Tyr Asp Asp Trp Pro Phe Thr
1 5
<210> 219
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> ADI-29463(F63)-VH
<400> 219
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 Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Gly Glu Tyr Tyr Asp Thr Asp Asp His Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 220
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-29463(F63)-VL
<400> 220
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
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Asp Asp Tyr Trp Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 221
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-29463(F63)-VH CDR1(非-Kabat)
<400> 221
Tyr Thr Phe Thr Gly Tyr Tyr Met His
1 5
<210> 222
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> ADI-29463(F63)-VH CDR1(非-Kabat)
<400> 222
Gly Tyr Tyr Met His
1 5
<210> 223
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-29463(F63)-VH CDR2
<400> 223
Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 224
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-29463(F63)-VH CDR3(非-Kabat)
<400> 224
Ala Arg Asp Thr Gly Glu Tyr Tyr Asp Thr Asp Asp His Gly Met Asp
1 5 10 15
Val
<210> 225
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ADI-29463(F63)-VH CDR3(非-Kabat)
<400> 225
Asp Thr Gly Glu Tyr Tyr Asp Thr Asp Asp His Gly Met Asp Val
1 5 10 15
<210> 226
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> ADI-29463(F63)-VL CDR1
<400> 226
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 227
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-29463(F63)-VL CDR3
<400> 227
Gln Gln Asp Asp Tyr Trp Pro Pro Thr
1 5
<210> 228
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VH
<400> 228
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Gly Tyr Tyr Asp Ser Gly Ala Gly Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 229
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VL
<400> 229
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asp Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln 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 Val Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 230
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VH CDR1(非-Kabat)
<400> 230
Phe Thr Phe Ser Ser Tyr Ala Met Ser
1 5
<210> 231
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VH CDR1(非-Kabat)
<400> 231
Ser Tyr Ala Met Ser
1 5
<210> 232
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VH CDR2
<400> 232
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 233
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VH CDR3(非-Kabat)
<400> 233
Ala Lys Asp Gly Gly Tyr Tyr Asp Ser Gly Ala Gly Asp Tyr
1 5 10
<210> 234
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VH CDR3(非-Kabat)
<400> 234
Asp Gly Gly Tyr Tyr Asp Ser Gly Ala Gly Asp Tyr
1 5 10
<210> 235
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VL CDR1
<400> 235
Arg Ala Ser Gln Gly Ile Asp Ser Trp Leu Ala
1 5 10
<210> 236
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VL CDR2
<400> 236
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 237
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-27744(A44)-VL CDR3
<400> 237
Gln Gln Gly Val Ser Tyr Pro Arg Thr
1 5
<210> 238
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> ADI-27749(A49)-VH
<400> 238
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 239
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-27749(A49)-VL
<400> 239
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln 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 Val Ser Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 240
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-27749(A49)-VH CDR1(非-Kabat)
<400> 240
Phe Thr Phe Ser Ser Tyr Ser Met Asn
1 5
<210> 241
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> ADI-27749(A49)-VH CDR1(非-Kabat)
<400> 241
Ser Tyr Ser Met Asn
1 5
<210> 242
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-27749(A49)-VH CDR2
<400> 242
Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 243
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ADI-27749(A49)-VH CDR3(非-Kabat)
<400> 243
Ala Arg Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 244
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> ADI-27749(A49)-VH CDR3(非-Kabat)
<400> 244
Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 245
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-27749(A49)-VL CDR3
<400> 245
Gln Gln Gly Val Ser Phe Pro Arg Thr
1 5
<210> 246
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 在ADI-27749(A49)的VH中有Q44C且VL中有G100C的 scFv (VL-VH)
<400> 246
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln 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 Val Ser Phe Pro Arg
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ser
145 150 155 160
Met Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser
165 170 175
Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser
245
<210> 247
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> ADI-29378(E78)-VH
<400> 247
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 Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ala Gly Phe Ala Tyr Gly Met Asp Tyr Tyr Tyr Met
100 105 110
Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 248
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> ADI-29378(E78)-VL
<400> 248
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Asp Asn Trp Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 249
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> ADI-29378(E78)-VH CDR2
<400> 249
Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 250
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> ADI-29378(E78)-VH CDR3(非-Kabat)
<400> 250
Ala Arg Glu Gly Ala Gly Phe Ala Tyr Gly Met Asp Tyr Tyr Tyr Met
1 5 10 15
Asp Val
<210> 251
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> ADI-29378(E78)-VH CDR3(非-Kabat)
<400> 251
Glu Gly Ala Gly Phe Ala Tyr Gly Met Asp Tyr Tyr Tyr Met Asp Val
1 5 10 15
<210> 252
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> ADI-29378(E78)-VL CDR1
<400> 252
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 253
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> ADI-29378(E78)-VL CDR3
<400> 253
Gln Gln Ser Asp Asn Trp Pro Phe Thr
1 5
<210> 254
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> A49MI-VH
<400> 254
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 255
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> A49MI-VH CDR3(非-Kabat)
<400> 255
Ala Arg Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 256
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> A49MI-VH CDR3(非-Kabat)
<400> 256
Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 257
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> A49MQ-VH
<400> 257
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Gln Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 258
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> A49MQ-VH CDR3 (非-Kabat)
<400> 258
Ala Arg Gly Ala Pro Gln Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 259
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> A49MQ-VH CDR3
<400> 259
Gly Ala Pro Gln Gly Ala Ala Ala Gly Trp Phe Asp
1 5 10
<210> 260
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> A49ML-VH
<400> 260
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Leu Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 261
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> A49ML-VH CDR3 (非-Kabat)
<400> 261
Ala Arg Gly Ala Pro Leu Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 262
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> A49ML-VH CDR3
<400> 262
Gly Ala Pro Leu Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 263
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> A49MF-VH
<400> 263
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Phe Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 264
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> A49MF-VH CDR3 (非-Kabat)
<400> 264
Ala Arg Gly Ala Pro Phe Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 265
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> A49MF-VH CDR3
<400> 265
Gly Ala Pro Phe Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 266
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> A49MV-VH
<400> 266
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Val Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 267
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> A49MV-VH CDR3 (非-Kabat)
<400> 267
Ala Arg Gly Ala Pro Val Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 268
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> A49MV-VH CDR3
<400> 268
Gly Ala Pro Val Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 269
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> A49-一致-VH
<220>
<221> misc_feature
<222> (102)..(102)
<223> Xaa = Met, Leu, Ile, Val, Gln或Phe
<400> 269
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Xaa Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 270
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> A49-一致-VH CDR3 (非-Kabat)
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = Met, Leu, Ile, Val, Gln或Phe
<400> 270
Ala Arg Gly Ala Pro Xaa Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 271
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> A49-一致-VH CDR3
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa = Met, Leu, Ile, Val, Gln或Phe
<400> 271
Gly Ala Pro Xaa Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 272
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> US9,273,136-VH中的NKG2D 结合剂
<400> 272
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Gly Leu Gly Asp Gly Thr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 273
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> US9,273,136-VL中的NKG2D 结合剂
<400> 273
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Phe Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 274
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> US7,879,985-VH中的NKG2D 结合剂
<400> 274
Gln Val His Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Asp Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Ser Tyr Ser Gly Ser Ala Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Asn Trp Asp Asp Ala Phe Asn Ile Trp Gly Gln Gly Thr Met Val Thr
100 105 110
Val Ser Ser
115
<210> 275
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> US7,879,985-VL中的NKG2D 结合剂
<400> 275
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 Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 276
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> A49MI-VL CDR1
<400> 276
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 277
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> GB102-VL-VH-Fc
<400> 277
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Ser Asp Lys Thr His Thr
245 250 255
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro
370 375 380
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp
420 425 430
Gly Ser Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 278
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> A49MI-VH-CH1-Fc
<400> 278
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Glu Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Trp Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly
450
<210> 279
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> A49MI-VL-CL
<400> 279
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln 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 Val Ser Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 280
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> A49-VL-VH-Fc
<400> 280
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln 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 Val Ser Phe Pro Arg
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ser
145 150 155 160
Met Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser
165 170 175
Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Asp Lys Thr His Thr
245 250 255
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro
370 375 380
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp
420 425 430
Gly Ser Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 281
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> GB102-VH-CH1-Fc
<400> 281
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Glu Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Trp Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 282
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> GB102-VL-CL
<400> 282
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 283
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> 1553-VH-VL-Fc
<400> 283
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 Val Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Val Tyr Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser
145 150 155 160
Cys Ser Ala Ser Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Thr Ser Lys Leu Ala
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr Phe Gly Cys Gly Thr Lys
225 230 235 240
Val Glu Ile Lys Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
245 250 255
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
260 265 270
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
275 280 285
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
290 295 300
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
305 310 315 320
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
325 330 335
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
340 345 350
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
355 360 365
Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu
370 375 380
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
385 390 395 400
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
405 410 415
Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp Gly Ser Phe Thr Leu
420 425 430
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
435 440 445
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
450 455 460
Lys Ser Leu Ser Leu Ser Pro Gly
465 470
<210> 284
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> 1689-VH-VL-Fc
<400> 284
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 Val Ser Gly Tyr Thr Phe Pro Tyr Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Ser Ile Ile Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asn Val Tyr Leu Thr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser
145 150 155 160
Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Thr Ser Lys Leu Ala
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Trp Thr Ser Lys Ser Pro Thr Phe Gly Cys Gly Thr Lys
225 230 235 240
Val Glu Ile Lys Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
245 250 255
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
260 265 270
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
275 280 285
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
290 295 300
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
305 310 315 320
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
325 330 335
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
340 345 350
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
355 360 365
Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu
370 375 380
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
385 390 395 400
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
405 410 415
Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp Gly Ser Phe Thr Leu
420 425 430
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
435 440 445
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
450 455 460
Lys Ser Leu Ser Leu Ser Pro Gly
465 470
<210> 285
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> GB102_M34I-VL-VH-Fc
<400> 285
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Ser Asp Lys Thr His Thr
245 250 255
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro
370 375 380
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp
420 425 430
Gly Ser Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 286
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> GB102_D101E-VL-VH-Fc
<400> 286
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Glu Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Ser Asp Lys Thr His Thr
245 250 255
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro
370 375 380
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp
420 425 430
Gly Ser Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 287
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> GB102_M34I_D101E-VL-VH-Fc
<400> 287
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Glu Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Ser Asp Lys Thr His Thr
245 250 255
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro
370 375 380
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp
420 425 430
Gly Ser Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 288
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> GB99-VL-VH-Fc
<400> 288
Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Gly Ser Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Glu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
130 135 140
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu
165 170 175
Glu Trp Met Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn
180 185 190
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser
195 200 205
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
210 215 220
Tyr His Cys Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Ser Asp Lys Thr His Thr
245 250 255
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro
370 375 380
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp
420 425 430
Gly Ser Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 289
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> GB89-VH-VL-Fc
<400> 289
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 Arg Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Gln Leu Gly Ser Leu Asp Ser Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr Gly Ser Ser Phe Val His
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu
180 185 190
Ala Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
210 215 220
Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn Glu Glu Pro Trp Thr Phe
225 230 235 240
Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Ser Asp Lys Thr His Thr
245 250 255
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro
370 375 380
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp
420 425 430
Gly Ser Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 290
<211> 2
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<220>
<221> REPEAT
<222> (1)..(2)
<223> GS可以重复n次, n可以是1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,或20
<400> 290
Gly Ser
1
<210> 291
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<220>
<221> REPEAT
<222> (1)..(3)
<223> GGS可以重复n次, n可以是1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,或20
<400> 291
Gly Gly Ser
1
<210> 292
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<220>
<221> REPEAT
<222> (1)..(4)
<223> GGGS可以重复n次, n可以是1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,或20
<400> 292
Gly Gly Gly Ser
1
<210> 293
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<220>
<221> REPEAT
<222> (1)..(4)
<223> GGSG可以重复n次, n可以是1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,或20
<400> 293
Gly Gly Ser Gly
1
<210> 294
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<220>
<221> REPEAT
<222> (1)..(5)
<223> GGSGG可以重复n次, n可以是1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,或20
<400> 294
Gly Gly Ser Gly Gly
1 5
<210> 295
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<220>
<221> REPEAT
<222> (1)..(5)
<223> GGGGS可以重复n次, n可以是1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,或20
<400> 295
Gly Gly Gly Gly Ser
1 5
<210> 296
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 296
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10 15
Gly Ser Gly Ser
20
<210> 297
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 297
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly
1 5 10 15
Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
20 25 30
<210> 298
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 298
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
20 25 30
Gly Gly Gly Ser Gly Gly Gly Ser
35 40
<210> 299
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 299
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly
20 25 30
Gly Gly Ser Gly Gly Gly Ser Gly
35 40
<210> 300
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 300
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
1 5 10 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
20 25 30
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Gly Gly
50
<210> 301
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 301
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
35 40 45
Gly Ser
50
<210> 302
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 302
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 303
<211> 100
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 303
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
35 40 45
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
50 55 60
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
65 70 75 80
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
85 90 95
Gly Gly Gly Ser
100
<210> 304
<211> 100
<212> PRT
<213> 人工序列
<220>
<223> 接头序列
<400> 304
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
1 5 10 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
20 25 30
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
50 55 60
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
65 70 75 80
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
85 90 95
Gly Ser Gly Gly
100
<210> 305
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 具有突变轻链可变域的TriNKET变体
<400> 305
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Asn Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Ser Thr Lys Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 306
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb 4G8-Synimmune VH
<400> 306
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Leu Lys Leu Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp Pro Ser Asp Ser Tyr Lys Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met His Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Ile Thr Thr Thr Pro Phe Asp Phe Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 307
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb 4G8-Synimmune VL
<400> 307
Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Ser Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Thr
65 70 75 80
Glu Asp Phe Gly Val Tyr Phe Cys Gln Gln Ser Asn Thr Trp Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 308
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb EB10-ImClone&Lilly VH
<400> 308
Glu 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 Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Val Gly Ala His Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 309
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb EB10-ImClone&Lilly VL
<400> 309
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Asp Thr Asp Phe Thr Leu Gln Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Pro Ala Ile Ser Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 110
<210> 310
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb NC7 ImClone&Lilly VH
<400> 310
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Phe Ala Leu Phe Gly Phe Arg Glu Gln Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 311
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb NC7 ImClone&Lilly VL
<400> 311
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 Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln 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 Leu Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 312
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb FL23(Amgen) VH
<400> 312
Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Phe Arg Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val
65 70 75 80
Val Leu Thr Leu Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Phe
85 90 95
Cys Ala Arg Met Pro Glu Tyr Ser Ser Gly Trp Ser Gly Ala Phe Asp
100 105 110
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 313
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb FL23(Amgen) VL
<400> 313
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Gly Tyr Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Phe Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 314
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb FL39(Amgen) VH
<400> 314
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 315
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb FL39(Amgen) VL
<400> 315
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 Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105
<210> 316
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb FL61(Amgen) VH
<400> 316
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Glu Phe 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 Arg Gly Gly Glu Ile Thr Met Val Arg Gly Val Ile Gly Tyr Tyr
100 105 110
Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
115 120 125
Ser
<210> 317
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Alpha-FLT3 mAb FL61(Amgen) VL
<400> 317
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 Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 318
<211> 517
<212> PRT
<213> 人工序列
<220>
<223> hFLT3-T227M的胞外区
<400> 318
Asn Gln Asp Leu Pro Val Ile Lys Cys Val Leu Ile Asn His Lys Asn
1 5 10 15
Asn Asp Ser Ser Val Gly Lys Ser Ser Ser Tyr Pro Met Val Ser Glu
20 25 30
Ser Pro Glu Asp Leu Gly Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr
35 40 45
Val Tyr Glu Ala Ala Ala Val Glu Val Asp Val Ser Ala Ser Ile Thr
50 55 60
Leu Gln Val Leu Val Asp Ala Pro Gly Asn Ile Ser Cys Leu Trp Val
65 70 75 80
Phe Lys His Ser Ser Leu Asn Cys Gln Pro His Phe Asp Leu Gln Asn
85 90 95
Arg Gly Val Val Ser Met Val Ile Leu Lys Met Thr Glu Thr Gln Ala
100 105 110
Gly Glu Tyr Leu Leu Phe Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile
115 120 125
Leu Phe Thr Val Ser Ile Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg
130 135 140
Pro Tyr Phe Arg Lys Met Glu Asn Gln Asp Ala Leu Val Cys Ile Ser
145 150 155 160
Glu Ser Val Pro Glu Pro Ile Val Glu Trp Val Leu Cys Asp Ser Gln
165 170 175
Gly Glu Ser Cys Lys Glu Glu Ser Pro Ala Val Val Lys Lys Glu Glu
180 185 190
Lys Val Leu His Glu Leu Phe Gly Met Asp Ile Arg Cys Cys Ala Arg
195 200 205
Asn Glu Leu Gly Arg Glu Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn
210 215 220
Gln Thr Pro Gln Thr Thr Leu Pro Gln Leu Phe Leu Lys Val Gly Glu
225 230 235 240
Pro Leu Trp Ile Arg Cys Lys Ala Val His Val Asn His Gly Phe Gly
245 250 255
Leu Thr Trp Glu Leu Glu Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe
260 265 270
Glu Met Ser Thr Tyr Ser Thr Asn Arg Thr Met Ile Arg Ile Leu Phe
275 280 285
Ala Phe Val Ser Ser Val Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys
290 295 300
Ser Ser Ser Lys His Pro Ser Gln Ser Ala Leu Val Thr Ile Val Glu
305 310 315 320
Lys Gly Phe Ile Asn Ala Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp
325 330 335
Gln Tyr Glu Glu Phe Cys Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln
340 345 350
Ile Arg Cys Thr Trp Thr Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln
355 360 365
Lys Gly Leu Asp Asn Gly Tyr Ser Ile Ser Lys Phe Cys Asn His Lys
370 375 380
His Gln Pro Gly Glu Tyr Ile Phe His Ala Glu Asn Asp Asp Ala Gln
385 390 395 400
Phe Thr Lys Met Phe Thr Leu Asn Ile Arg Arg Lys Pro Gln Val Leu
405 410 415
Ala Glu Ala Ser Ala Ser Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro
420 425 430
Leu Pro Ser Trp Thr Trp Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys
435 440 445
Thr Glu Glu Ile Thr Glu Gly Val Trp Asn Arg Lys Ala Asn Arg Lys
450 455 460
Val Phe Gly Gln Trp Val Ser Ser Ser Thr Leu Asn Met Ser Glu Ala
465 470 475 480
Ile Lys Gly Phe Leu Val Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr
485 490 495
Ser Cys Glu Thr Ile Leu Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile
500 505 510
Gln Asp Asn Ile Ser
515
<210> 319
<211> 517
<212> PRT
<213> 人工序列
<220>
<223> hFLT3-ITD的胞外区
<400> 319
Asn Gln Asp Leu Pro Val Ile Lys Cys Val Leu Ile Asn His Lys Asn
1 5 10 15
Asn Asp Ser Ser Val Gly Lys Ser Ser Ser Tyr Pro Met Val Ser Glu
20 25 30
Ser Pro Glu Asp Leu Gly Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr
35 40 45
Val Tyr Glu Ala Ala Ala Val Glu Val Asp Val Ser Ala Ser Ile Thr
50 55 60
Leu Gln Val Leu Val Asp Ala Pro Gly Asn Ile Ser Cys Leu Trp Val
65 70 75 80
Phe Lys His Ser Ser Leu Asn Cys Gln Pro His Phe Asp Leu Gln Asn
85 90 95
Arg Gly Val Val Ser Met Val Ile Leu Lys Met Thr Glu Thr Gln Ala
100 105 110
Gly Glu Tyr Leu Leu Phe Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile
115 120 125
Leu Phe Thr Val Ser Ile Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg
130 135 140
Pro Tyr Phe Arg Lys Met Glu Asn Gln Asp Ala Leu Val Cys Ile Ser
145 150 155 160
Glu Ser Val Pro Glu Pro Ile Val Glu Trp Val Leu Cys Asp Ser Gln
165 170 175
Gly Glu Ser Cys Lys Glu Glu Ser Pro Ala Val Val Lys Lys Glu Glu
180 185 190
Lys Val Leu His Glu Leu Phe Gly Thr Asp Ile Arg Cys Cys Ala Arg
195 200 205
Asn Glu Leu Gly Arg Glu Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn
210 215 220
Gln Thr Pro Gln Thr Thr Leu Pro Gln Leu Phe Leu Lys Val Gly Glu
225 230 235 240
Pro Leu Trp Ile Arg Cys Lys Ala Val His Val Asn His Gly Phe Gly
245 250 255
Leu Thr Trp Glu Leu Glu Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe
260 265 270
Glu Met Ser Thr Tyr Ser Thr Asn Arg Thr Met Ile Arg Ile Leu Phe
275 280 285
Ala Phe Val Ser Ser Val Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys
290 295 300
Ser Ser Ser Lys His Pro Ser Gln Ser Ala Leu Val Thr Ile Val Glu
305 310 315 320
Lys Gly Phe Ile Asn Ala Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp
325 330 335
Gln Tyr Glu Glu Phe Cys Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln
340 345 350
Ile Arg Cys Thr Trp Thr Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln
355 360 365
Lys Gly Leu Asp Asn Gly Tyr Ser Ile Ser Lys Phe Cys Asn His Lys
370 375 380
His Gln Pro Gly Glu Tyr Ile Phe His Ala Glu Asn Asp Asp Ala Gln
385 390 395 400
Phe Thr Lys Met Phe Thr Leu Asn Ile Arg Arg Lys Pro Gln Val Leu
405 410 415
Ala Glu Ala Ser Ala Ser Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro
420 425 430
Leu Pro Ser Trp Thr Trp Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys
435 440 445
Thr Glu Glu Ile Thr Glu Gly Val Trp Asn Arg Lys Ala Asn Arg Lys
450 455 460
Val Phe Gly Gln Trp Val Ser Ser Ser Thr Leu Asn Met Ser Glu Ala
465 470 475 480
Ile Lys Gly Phe Leu Val Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr
485 490 495
Ser Cys Glu Thr Ile Leu Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile
500 505 510
Gln Asp Asn Ile Ser
515
Claims (66)
1.一种蛋白质,其包含:
(a)结合NKG2D的第一抗原结合位点;
(b)结合FLT3的第二抗原结合位点;及
(c)足以结合CD16的抗体Fc域或其一部分,或结合CD16的第三抗原结合位点,
其中该结合FLT3的第二抗原结合位点包含:
(i)包含互补决定区1(CDR1)、互补决定区2(CDR2)及互补决定区3(CDR3)的重链可变域(VH),该CDR1、CDR2及CDR3分别包含SEQ ID NO:11、4及55的氨基酸序列;及包含CDR1、CDR2及CDR3的轻链可变域(VL),该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列;
(ii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:59、63及54的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:86、66及67的氨基酸序列;
(iii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、88及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:91、92及93的氨基酸序列;
(iv)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:97、99及100的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:101、102及103的氨基酸序列;
(v)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92及93的氨基酸序列;
(vi)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:109、110及111的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:112、113及114的氨基酸序列;
(vii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:117、118及119的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:120、121及122的氨基酸
序列;
(viii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92及93的氨基酸序列;
(ix)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、33及127的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:128、129及130的氨基酸序列;或
(x)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:132、133及134的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及46的氨基酸序列。
2.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQID NO:11、4及55的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。
3.根据权利要求2所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQID NO:11、4及5的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。
4.根据权利要求2所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQID NO:11、4及50的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:6、7及8的氨基酸序列。
5.根据权利要求2至4中任一项所述的蛋白质,其中该VH包含与SEQ IDNO:37至少90%一致的氨基酸序列,且该VL包含与SEQ ID NO:38至少90%一致的氨基酸序列。
6.根据权利要求2至5中任一项所述的蛋白质,其中该VH包含SEQ IDNO:53的氨基酸序列,且该VL包含SEQ ID NO:42的氨基酸序列。
7.根据权利要求6的蛋白质,其中该VH及该VL分别包含以下氨基酸序列:SEQ ID NO:9及10;13及10;17及10;9及22;9及26;9及30;9及34;37及38;41及42;45及42;或49及42。
8.根据权利要求2至7中任一项所述的蛋白质,其中该第二抗原结合位点呈单链可变区片段(scFv)存在,且其中该scFv包含选自SEQ ID NO:3、12、15、16、19、20、23、24、27、28、31、32、35、36、39、40、43、44、47、48、51及52的氨基酸序列。
9.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:59、63及54的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:86、66及67的氨基酸序列。
10.根据权利要求9所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:78、63、79的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:80、66、67的氨基酸序列。
11.根据权利要求9所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、63、64的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66、67的氨基酸序列。
12.根据权利要求9至11中任一项所述的蛋白质,其中该VH包含与SEQ ID NO:76至少90%一致的氨基酸序列,且该VL包含与SEQ ID NO:77至少90%一致的氨基酸序列。
13.根据权利要求9至12中任一项所述的蛋白质,其中该VH包含SEQ ID NO:29的氨基酸序列,且该VL包含SEQ ID NO:84的氨基酸序列。
14.根据权利要求13所述的蛋白质,其中该VH及该VL分别包含以下氨基酸序列:SEQ IDNO:68及69;72及73;或76及77。
15.根据权利要求9至14中任一项所述的蛋白质,其中该第二抗原结合位点呈scFv存在,且其中该scFv包含选自SEQ ID NO:70、71、74、75、81及82的氨基酸序列。
16.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、88及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:91、92及93的氨基酸序列。
17.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:97、99及100的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:101、102及103的氨基酸序列。
18.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92及93的氨基酸序列。
19.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:109、110及111的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:112、113及114的氨基酸序列。
20.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:117、118及119的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:120、121及122的氨基酸序列。
21.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:87、98及89的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:106、92及93的氨基酸序列。
22.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:62、33及127的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:128、129及130的氨基酸序列。
23.根据权利要求1所述的蛋白质,其中该结合FLT3的第二抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:132、133及134的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:65、66及46的氨基酸序列。
24.根据前述权利要求中任一项所述的蛋白质,其中该第二抗原结合位点以如通过表面等离子共振(SPR)所测量的小于或等于20nM的解离常数(KD)结合人类FLT3。
25.根据权利要求2至8、16、17及21中任一项所述的蛋白质,其中该第二抗原结合位点以如通过SPR所测量的小于或等于10nM的KD结合人类FLT3。
26.根据权利要求2至8中任一项所述的抗原结合位点,其中该抗原结合位点结合包含SEQ ID NO:318的氨基酸序列的人类FLT3变体。
27.根据权利要求2至8中任一项所述的抗原结合位点,其中该抗原结合位点结合包含SEQ ID NO:319的氨基酸序列的人类FLT3变体。
28.根据权利要求2至21及23至27中任一项所述的蛋白质,其中该抗原结合位点结合食蟹猕猴FLT3。
29.根据权利要求2至20及22至28中任一项所述的蛋白质,其中该抗原结合位点不与FLT3L竞争结合FLT3。
30.根据前述权利要求中任一项所述的蛋白质,其中该蛋白质包含足以结合CD16的抗体Fc域或其一部分。
31.根据权利要求1至30中任一项所述的蛋白质,其中该结合NKG2D的第一抗原结合位点为Fab片段,且该结合FLT3的第二抗原结合位点为scFv。
32.根据权利要求1至30中任一项所述的蛋白质,其中该结合NKG2D的第一抗原结合位点为scFv,且该结合FLT3的第二抗原结合位点为Fab片段。
33.根据前述权利要求中任一项所述的蛋白质,其进一步包含结合FLT3的额外抗原结合位点。
34.根据权利要求1至30及32至33中任一项所述的蛋白质,其中该结合NKG2D的第一抗原结合位点为scFv,且该结合FLT3的第二抗原结合位点及该结合FLT3的额外抗原结合位点各自为Fab片段。
35.根据权利要求1至30及33中任一项所述的蛋白质,其中该结合NKG2D的第一抗原结合位点为scFv,且该结合FLT3的第二抗原结合位点及该结合FLT3的额外抗原结合位点各自为scFv。
36.根据权利要求31、32、34或35所述的蛋白质,其中该结合FLT3的scFv和/或该结合NKG2D的scFv包含重链可变域及轻链可变域。
37.根据权利要求36所述的蛋白质,其中该scFv经由包含Ala-Ser或Gly-Ser的铰链连接于足以结合CD16的抗体恒定域或其一部分。
38.根据权利要求37所述的蛋白质,其中该铰链进一步包含氨基酸序列Thr-Lys-Gly。
39.根据权利要求36至38中任一项所述的蛋白质,其中该scFv的该重链可变域与该scFv的该轻链可变域形成二硫桥键。
40.根据权利要求39所述的蛋白质,其中根据Kabat编号方案进行编号,在该重链可变域的C44与该轻链可变域的C100之间形成二硫桥键。
41.根据权利要求36至40中任一项所述的蛋白质,其中该scFv的该重链可变域经由可挠性接头连接于该scFv的该轻链可变域。
42.根据权利要求41所述的蛋白质,其中该可挠性接头包含(G4S)4。
43.根据权利要求36至42中任一项所述的蛋白质,其中在该scFv内,该重链可变域位于该轻链可变域的C端。
44.根据权利要求36至42中任一项所述的蛋白质,其中在该scFv内,该重链可变域位于该轻链可变域的N端。
45.根据权利要求31至34及36至44中任一项所述的蛋白质,其中该Fab不位于抗原结合位点与该Fc或其部分之间。
46.根据前述权利要求中任一项所述的蛋白质,其中该结合NKG2D的第一抗原结合位点包含:包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及270或271的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQID NO:276、236及245的氨基酸序列。
47.根据权利要求46所述的蛋白质,其中该结合NKG2D的第一抗原结合位点包含:
(i)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及255或256的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列;或
(ii)包含CDR1、CDR2及CDR3的VH,该CDR1、CDR2及CDR3分别包含SEQ ID NO:240或241、242及243或244的氨基酸序列;及包含CDR1、CDR2及CDR3的VL,该CDR1、CDR2及CDR3分别包含SEQ ID NO:276、236及245的氨基酸序列。
48.根据权利要求46或47所述的蛋白质,其中该第一抗原结合位点的该VH包含与SEQID NO:254至少90%一致的氨基酸序列,且该第一抗原结合位点的该VL包含与SEQ ID NO:239至少90%一致的氨基酸序列。
49.根据权利要求46至48中任一项所述的蛋白质,其中该第一抗原结合位点的该VH包含SEQ ID NO:254的氨基酸序列,且该第一抗原结合位点的该VL包含SEQ ID NO:239的氨基酸序列。
50.根据前述权利要求中任一项所述的蛋白质,其中该抗体Fc域为人类IgG1抗体Fc域。
51.根据权利要求50所述的蛋白质,其中该抗体Fc域或其部分包含与SEQ ID NO:136至少90%一致的氨基酸序列。
52.根据权利要求50或51所述的蛋白质,其中根据EU编号系统进行编号,该抗体Fc域的至少一个多肽链相对于SEQ ID NO:136在一个或多个选自以下的位置处包含一个或多个突变:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411及K439。
53.根据权利要求50至52中任一项所述的蛋白质,其中根据EU编号系统进行编号,该抗体Fc域的至少一个多肽链相对于SEQ ID NO:136包含一个或多个选自以下的突变:Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、T411D、T411E、K439D及K439E。
54.根据权利要求50至53中任一项所述的蛋白质,其中根据EU编号系统进行编号,该抗体重链恒定区的一个多肽链相对于SEQ ID NO:136在一个或多个选自以下的位置处包含一个或多个突变:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、K392、T394、D399、S400、D401、F405、Y407、K409、T411及K439;且该抗体重链恒定区的另一个多肽链相对于SEQ ID NO:136在一个或多个选自以下的位置处包含一个或多个突变:Q347、Y349、L351、S354、E356、E357、S364、T366、L368、K370、N390、K392、T394、D399、D401、F405、Y407、K409、T411及K439。
55.根据权利要求54所述的蛋白质,其中根据EU编号系统进行编号,该抗体重链恒定区的一个多肽链相对于SEQ ID NO:136包含K360E及K409W取代;且该抗体重链恒定区的另一个多肽链相对于SEQ ID NO:136包含Q347R、D399V及F405T取代。
56.根据权利要求54或55所述的蛋白质,其中根据EU编号系统进行编号,该抗体重链恒定区的一个多肽链相对于SEQ ID NO:136包含Y349C取代;且该抗体重链恒定区的另一个多肽链相对于SEQ ID NO:136包含S354C取代。
57.一种蛋白质,其包含:
(a)包含SEQ ID NO:278的氨基酸序列的第一多肽;
(b)包含SEQ ID NO:279的氨基酸序列的第二多肽;及
(c)包含选自SEQ ID NO:277、283、284、285、286、287、288及289的氨基酸序列的第三多肽。
58.一种蛋白质,其包含:
(a)包含SEQ ID NO:280的氨基酸序列的第一多肽;
(b)包含SEQ ID NO:281的氨基酸序列的第二多肽;及
(c)包含SEQ ID NO:282的氨基酸序列的第三多肽。
59.一种药物组合物,其包含根据前述权利要求中任一项所述的蛋白质及药学上可接受的载剂。
60.一种细胞,其包含编码根据权利要求1至58中任一项所述的蛋白质的一种或多种核酸。
61.一种增强肿瘤细胞死亡的方法,该方法包括将肿瘤细胞及自然杀伤细胞暴露于有效量的根据权利要求1至58中任一项所述的蛋白质或根据权利要求59的药物组合物。
62.一种治疗癌症的方法,该方法包括向有需要的患者施用有效量的根据权利要求1至58中任一项所述的蛋白质或根据权利要求59所述的药物组合物。
63.根据权利要求62所述的方法,其中该癌症为血液恶性病。
64.根据权利要求63所述的方法,其中该血液恶性病为白血病。
65.根据权利要求63或64所述的方法,其中选自由以下组成的组:急性骨髓性白血病(AML)、急性淋巴母细胞白血病(ALL)、骨髓化生不良、急性T-淋巴母细胞白血病及急性前髓细胞白血病。
66.根据权利要求62至65中任一项所述的方法,其中该癌症表达FLT3。
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