CN117003871A - 结合bcma和cd3的抗体及其用途 - Google Patents
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Abstract
本申请涉及一种与BCMA特异结合的单克隆抗体或其抗原结合片段,及其在治疗肿瘤例如多发骨髓瘤中的用途,以及一种与CD3特异结合的单克隆抗体或其抗原结合片段,及其在治疗或减缓炎性疾病、自身免疫疾病或移植物排斥中的用途。本申请还涉及一种包含上述单克隆抗体或其抗原结合片段的同时靶向BCMA和CD3的双特异性抗体,及其在肿瘤等疾病治疗中的用途。
Description
发明领域
本申请涉及一种与人和猴BCMA特异性结合的抗体或其抗原结合片段,及其在治疗或缓解肿瘤例如多发性骨髓瘤中的用途;以及一种结合人CD3,特别是CD3 δ&ε复合体,的抗体或其抗原结合片段,及其在治疗或缓解炎性疾病、自免疫疾病或移植物排斥中的用途。本申请还涉及一种包含本申请抗体或其抗原结合片段的靶向BCMA和CD3的双特异性抗体,及其在治疗肿瘤等疾病中的用途。
背景技术
多发性骨髓瘤(MM)是浆细胞恶性增殖性疾病,其疾病特征是骨髓中的浆细胞像肿瘤细胞一样无限制地增殖,并且大部分情况下伴有单克隆免疫球蛋白分泌,最终导致器官或组织损伤。例如,MM常伴有多发性溶骨性损害、高钙血症、贫血、肾脏损害等。MM多发于中老年人,在性别分布上有明显差异,男性患病比例高于女性。MM约占血液系统恶性肿瘤的10%,是继白血病、淋巴瘤之后第三多发的血液系统肿瘤。
近年来,尽管化疗、蛋白酶体抑制剂、免疫调节剂和CD38靶向抗体等治疗方法在MM领域取得了很大进展,但相当一部分的患者对这些疗法没有反应、或反应期很短。而且,MM几乎无法治愈,患者逐渐对既有疗法产生抗性,导致复发。因此,该领域对新药的需求仍然迫切。
B细胞成熟抗原是一种较为热门的MM治疗靶点。
BCMA和BCMA靶向疗法
B细胞成熟抗原,又称BCMA、CD269或TNFRSF17,是一种I型跨膜蛋白,为肿瘤坏死因子受体(TNFR)超家族的一员。其与同为TNFR超家族的BAFF受体(BAFFR)和跨膜激活剂及钙调亲环素配体相互作用分子(TACI),在不同发育阶段的B细胞存活中发挥着重要的作用(Rickert R.C et al.,(2011)Immunological Reviews 244(1):115-133)。
BCMA主要表达于成熟B淋巴细胞及浆细胞表面,少量表达于造血干细胞或非造血组织。其配体包括B细胞活化因子(BAFF)和增殖诱导因子(APRIL),其中后者的BCMA亲和性更高。通过与BAFF和APRIL结合,BCMA启动NF-κB 和MAPK8/JNK信号通路,促进骨髓浆细胞和浆母细胞的存活,特别为长寿命骨髓浆细胞存活所必需,支持着体液免疫应答。膜结合BCMA可以经γ-分泌酶作用而从细胞表面脱落,成为游离的可溶性BCMA(sBCMA),进入体液循环,减少膜表面BCMA的信号转导(Laurent SAet al.,(2015)Nat Commun.6:7333)。
除在正常生理中发挥重要作用外,BCMA还被发现在MM患者的骨髓恶性浆细胞的表面过表达。BCMA可促进恶性浆细胞在骨髓环境中的成活,恶性浆细胞的APRIL-BCMA信号通路会促进恶性肿瘤细胞的增殖、凋亡逃逸,还使其产生强效的免疫抑制分子,比如IL-10、PD-L1和TGF-β(Tai Y-T et al.,(2016)Blood. 127(25):3225-3236)。在大量的动物模型和人体患者中,BCMA的过表达和激活均表现出与MM进展的相关性(TaiY-T et al.,(2016)Supra;Sanchez E et al.,(2016) Clin CancerRes.22:3383-3397)。此外,sBCMA可通过复合体的形成而抑制BAFF 的活性,引发例如MM患者体内的免疫缺陷。
相比于特异表达于浆细胞却很快从细胞表面消失的CD138,膜BCMA是更好的MM恶性浆细胞的生物标记物,其可以在冰冻样本中可以方便地检测到,可用于MM的诊断、病情进程的监控、疗法应答的监控、以及预后。sBCMA也是很好的MM标记物,可用于监控患者对疗法的反应,且可用于病情预后,含量越高,预后越差(Shah N et al.,(2020),Leukemia 34(4):985-1005)。
由于BCMA的选择性表达/分布特点,即广泛存在于MM细胞表面,但在其他正常组织细胞上表达很低或不表达,以及BCMA的较长血清半衰期,使其成为 MM和其他血液系统恶性肿瘤的一个非常热门的免疫治疗靶点。
目前靶向BCMA的疗法主要分为以下三类:双特异性抗体、抗体药物偶联物 (ADC)、和嵌合抗原抗体(CAR)-T细胞疗法。
在双特异性抗体中,有一类双特异性T细胞衔接器,同时具有靶细胞结合特异性和T细胞结合特异性。这类抗体可以拉近T细胞和靶细胞之间的距离,促进T细胞和靶细胞之间的相互作用。
T细胞和CD3
CD3分子是T细胞表面的一种标记分子,与T细胞受体(TCR)组成TCR-CD3 复合体,在抗原识别和免疫信号传导过程中具有重要的作用。TCR由α和β链组成,或由γ和δ链组成,各链的胞内域没有信号转导的功能,T细胞胞内信号通路完全由 CD3蛋白负责。CD3分子由一条γ链、一条δ链、两条ε和两条ζ链构成,在TCR/CD3 复合体中形成为三个二聚体εγ、εδ、和ζζ。ε、γ和δ均为I型跨膜蛋白,具有类似免疫球蛋白胞外功能域,ε、γ、δ和ζ的胞内域共含有10个免疫受体酪氨酸活化基序 (ITAM),当ITAM磷酸化后会与激酶ZAP70结合,向下游转导T细胞激活信号。
靶向CD3的抗体可以通过与靶向疾病相关抗原(如肿瘤相关抗原)的功能基团形成双特异性分子,如上所述,建立T细胞与疾病相关抗原的物理连接,引起T 细胞的活化和由T细胞介导的对疾病相关细胞的杀伤。例如,靶向CD3和肿瘤相关抗原的双特异性抗体在拉近T细胞与肿瘤细胞后,可活化T细胞,向肿瘤细胞释放包含有280多种蛋白的超分子攻击粒子(SMAP)。在SMAP的核心区带有穿孔素和颗粒酶,穿孔素可以刺穿肿瘤细胞的外膜,而颗粒酶会诱导肿瘤细胞凋亡(Bálint et al.,(2020)Science 368(6493):897-901)。
CD3抗体可通过在T细胞表面聚集CD3,模拟TCR识别MHC-抗原肽的过程,从而激活T细胞的TCR复合体信号通路,释放IL-2、IFN-r和TNF-α等细胞因子,激活T细胞的增殖和分化。T细胞的增殖和分化在肿瘤治疗中是一把双刃剑,一方面可以产生更多的T细胞来杀伤肿瘤细胞,但在另一方面也会在受试者体内产生很大的毒性反应,即细胞因子释放综合征(“CRS”)。在临床上,与CRS相关的副作用不仅包括疲劳、呕吐、心动过速、高血压、背痛,还包括如癫痫发作、脑病、脑水肿、无菌性脑膜炎和头痛的中枢神经系统(CNS)反应。例如,在CD3单特异性抗体如OKT3的治疗中观察到CRS,且被认为是抗体在体内结合Fc受体 (FcR)时形成的抗体交联而引起的(Herold KC et al.,(2003)J Clin Invest. 111(3):409-418)。因此,在后续的抗体研发中,CD3抗体的Fc区经改造而呈现弱的FcR结合力,比如Tepizumab。
同理,在靶向CD3的双特异性抗体的治疗中,也不免出现CRS。例如,在 CD19/CD3 T细胞双特异性药剂博纳吐单抗的临床试验中,频繁观察到重度CRS 和CNS毒性。对于CD3单特异性抗体的Fc区改造,并不足以改善CD3双特异性抗体引起的CRS,因为双特异性抗体中靶向疾病相关抗原的功能基团与靶细胞的结合会引起抗体的交联,并从而引起T细胞释放大量的细胞因子。
靶向BCMA和CD3的双特异抗体
靶向BCMA和CD3的双特异性抗体,一方面可结合MM细胞表面表达的 BCMA抗原,另一方面结合T细胞表面的CD3受体,将患者的T细胞募集到MM 细胞周围,并且激活T细胞消灭MM细胞。
然而,如上所述,CD3双特异性抗体的毒性不容忽视。2021年上半年,多个 BCMA×CD3双特异抗体(AMG701、Elranatamab等)因为安全性问题暂停临床试验。
因而,亟需构建一种既有强大的肿瘤杀伤力、又引起较小的毒性反应的 BCMA×CD3双特异性抗体。而这种双特异性抗体的构建,不仅需要对于CD3有能引起较少细胞因子释放的CD3抗体或其抗原结合片段,还需要优化CD3结合抗体或抗原结合片段与BCMA结合抗体或其抗原结合片段的组合,从而找到较好的治疗窗口。
对于本申请中任何文件的引用,并不等同于承认这些文件是本申请的现有技术。
发明内容
本申请的发明人通过研究,找到了一种与人和猴BCMA特异结合的抗体或其抗原结合片段。其与现有技术如EM801中的BCMA结合部分相比,具有相当或更好的人/猴BCMA结合活性/亲和力,且结合几乎不受环境中sBCMA的影响。
本申请的发明人还发现了一种CD3抗体或其抗原结合片段。该抗体或其抗原结合片段不结合单独的CD3δ或CD3ε,而仅与CD3δ&ε复合体结合。与现有技术例如EM801中的CD3结合部分相比,其在游离情况下几乎没有T细胞激活能力,且在用于双特异性抗体构建时,在高浓度时具有相当的靶细胞杀伤活性,而毒副作用更低。
因而,在第一个方面,本申请提供一种分离的单克隆抗体(例如,人源抗体)、或其抗原结合片段,其与BCMA结合,可以含有(i)重链可变区,该重链可变区可以含有VH CDR1区、VH CDR2区和VH CDR3区,其中,VH CDR1区、VH CDR2 区和VH CDR3区可以分别包含如SEQID NOs:1、2和3所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列;和/或(ii)轻链可变区,该轻链可变区可以含有VL CDR1区、VLCDR2区和VL CDR3区,其中,VL CDR1区、VL CDR2区和VL CDR3区可以分别包含如SEQ IDNOs:4、5和6所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、95%、 98%或99%同一性的氨基酸序列。
本申请BCMA抗体或其抗原结合片段的重链可变区可以包含如SEQ ID NO:7 所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列。
本申请BCMA抗体或其抗原结合片段的轻链可变区可以包含如SEQ ID NO:8 (X1=I、X2=V、X3=E、X4=I、X5=无;或X1=E、X2=L、X3=T、X4=A、X5=R) 所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列。
在一些实施方式中,本申请的抗体或其抗原结合片段可以包含重链可变区和轻链可变区,该重链可变区和轻链可变区可以分别包含如SEQ ID NOs:7和8 (X1=I、X2=V、X3=E、X4=I、X5=无;或X1=E、X2=L、X3=T、X4=A、X5=R) 所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列。
本申请的抗体或其抗原结合片段可以包含重链恒定区和/或轻链恒定区。重链恒定区可以是具有FcR结合力的重链恒定区,例如IgG1重链恒定区,例如具有 SEQ ID NO:17(X1=L、X2=L、X3=N、X4=T、X5=L、X6=Y)所示氨基酸的人 IgG1重链恒定区。轻链恒定区可以是κ或λ轻链恒定区,例如人κ或λ轻链恒定区,如SEQ ID NO:18所示的人κ恒定区。
在一些实施方式中,本申请的抗体或其结合片段可以是IgG1、IgG2、IgG3或 IgG4亚型。在一些实施方式中,本申请的抗体或其结合片段可以是scFv、Fab、F (ab')2等片段。本申请的抗体或其结合片段可以是人源的或者人源化的。
本申请还提供包含本申请BCMA抗体或其抗原结合部片段的免疫偶联物,其中该抗体或其抗原结合部分与治疗剂例如细胞毒素或抗癌剂相连接。本申请还提供含有本申请BCMA抗体或其抗原结合部分的双特异性分子,该抗体或其抗原结合部分连接有第二功能基团,例如,第二抗体,该第二功能基团具有不同于本申请抗体或其结合部分的结合特异性。在另一方面,本申请的抗体或其抗原结合部分可以是嵌合抗原受体(CAR)或基因改造T细胞受体(TCR)的一部分。本申请还提供具有上述CAR和/或TCR的免疫细胞,包括T细胞、NK细胞等。本发明的抗体或其抗原结合部分还可以由溶瘤病毒编码或由溶瘤病毒承载。
在第二个方面,本申请提供一种分离的单克隆抗体(例如,人源抗体)、或其抗原结合片段,其与CD3特别是CD3δ&ε复合体特异结合,可以含有(i)重链可变区,该重链可变区可以含有VH CDR1区、VH CDR2区和VH CDR3区,其中,VH CDR1区、VH CDR2区和VH CDR3区可以分别包含如1)SEQ ID NOs:9、 10和11;2)SEQ ID NOs:26(X1=D,X2=T)、27(X1=T,X2=T,X3=I)和28 (X1=N,X2=F);3)SEQ ID NOs:26(X1=S,X2=S)、27(X1=S,X2=S,X3=L)和28(X1=R,X2=Y);或4)SEQ ID NOs:26(X1=D,X2=A)、27(X1=H, X2=H,X3=I)和28(X1=N,X2=Y)所示的氨基酸序列,或与上述序列具有至少 80%、85%、90%、95%、98%或99%同一性的氨基酸序列;和/或(ii)轻链可变区,该轻链可变区可以含有VL CDR1区、VLCDR2区和VL CDR3区,其中,VL CDR1区、VL CDR2区和VL CDR3区可以分别包含如1)SEQ IDNOs:12、13和 14;2)SEQ ID NOs:29(X1=Q,X2=R,X3=V)、30(X1=R,X2=Q)、和31 (X1=S,X2=I,X3=Q);3)SEQ ID NOs:29(X1=R,X2=L,X3=V)、30(X1=K, X2=Y)、和31(X1=Q,X2=I,X3=T);或4)SEQ ID NOs:29(X1=R,X2=R, X3=L)、30(X1=K,X2=P)、和31(X1=H,X2=T,X3=R)所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列。
本申请的CD3抗体或其抗原结合片段可以包含重链可变区和轻链可变区,其中VHCDR1区、VH CDR2区、VH CDR3区、VL CDR1区、VL CDR2区、和VL CDR3区可以包含1)SEQ IDNOs:9、10、11、12、13和14;2)SEQ ID NOs:26 (X1=D,X2=T)、27(X1=T,X2=T,X3=I)、28(X1=N,X2=F)、29(X1=Q, X2=R,X3=V)、30(X1=R,X2=Q)、和31(X1=S,X2=I,X3=Q);3)SEQ ID NOs:26(X1=S,X2=S)、27(X1=S,X2=S,X3=L)、28(X1=R,X2=Y)、 29(X1=R,X2=L,X3=V)、30(X1=K,X2=Y)、和31(X1=Q,X2=I,X3=T);或4)SEQ ID NOs:26(X1=D,X2=A)、27(X1=H,X2=H,X3=I)、28(X1=N, X2=Y)、29(X1=R,X2=R,X3=L)、30(X1=K,X2=P)、和31(X1=H,X2=T, X3=R)所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列。
本申请CD3抗体或其抗原结合片段的重链可变区可以包含如SEQ ID NOs:15 或32(X1=S,X2=D,X3=T,X4=T,X5=T,X6=I,X7=N,X8=F;X1=D,X2=S,X3=S,X4=S,X5=S,X6=L,X7=R,X8=Y;或X1=G,X2=D,X3=A,X4=H, X5=H,X6=I,X7=N,X8=Y)所示的氨基酸序列,或与上述序列具有至少80%、 85%、90%、95%、98%或99%同一性的氨基酸序列。
本申请CD3抗体或其抗原结合片段的轻链可变区可以包含如SEQ ID NOs:16 或33(X1=Q,X2=R,X3=V,X4=R,X5=Q,X6=S,X7=I,X8=Q;X1=R,X2=L, X3=V,X4=K,X5=Y,X6=Q,X7=I,X8=T;或X1=R,X2=R,X3=L,X4=K, X5=P,X6=H,X7=T,X8=R)所示的氨基酸序列,或与上述序列具有至少80%、 85%、90%、95%、98%或99%同一性的氨基酸序列。
在一些实施方式中,本申请的抗体或其抗原结合片段可以包含重链可变区和轻链可变区,该重链可变区和轻链可变区可以分别包含1)SEQ ID NOs:15和16; 2)SEQ ID NOs:32(X1=S,X2=D,X3=T,X4=T,X5=T,X6=I,X7=N,X8=F) 33(X1=Q,X2=R,X3=V,X4=R,X5=Q,X6=S,X7=I,X8=Q);3)SEQ ID NOs: 32(X1=D,X2=S,X3=S,X4=S,X5=S,X6=L,X7=R,X8=Y)和33(X1=R, X2=L,X3=V,X4=K,X5=Y,X6=Q,X7=I,X8=T);或4)SEQ ID NOs:32(X1=G, X2=D,X3=A,X4=H,X5=H,X6=I,X7=N,X8=Y)和33(X1=R,X2=R,X3=L, X4=K,X5=P,X6=H,X7=T,X8=R)所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列。
本申请的CD3抗体或其抗原结合片段可以包含重链恒定区和/或轻链恒定区。在一些实施方式中,本申请的CD3抗体或其抗原结合片段包含具有FcR弱结合的重链恒定区、和/或轻链恒定区。在一些实施方式中,本申请的CD3抗体或其抗原结合片段包含不结合FcR的重链恒定区、和/或轻链恒定区。弱结合或不结合FcR 的重链恒定区可以是人IgG1(N297A)、人IgG1(L234A+L235A)、人IgG1 (L234A+L235A+P329G)、人IgG1(L234A+L235A+N297A)(如SEQ ID NO:17 (X1=A、X2=A、X3=A、X4=T、X5=L、X6=Y)所示)、人IgG1 (L234A+L235A+N297A+P329G)、人IgG2(V234A+V237A)、人IgG1 (L234A+V235E)的重链恒定区,或其功能片段。轻链恒定区可以是κ或λ轻链恒定区,例如人κ或λ轻链恒定区,如SEQ ID NO:18所示的人κ轻链恒定区。
在一些实施方式中,本申请的抗体或其结合片段可以是scFv、Fab、F(ab')2等片段。本申请的抗体或其结合片段可以是人源的或者人源化的。
本申请还提供含有本申请CD3抗体或其抗原结合片段的双特异性分子,该抗体或其抗原结合片段连接有第二功能基团,例如,第二抗体,该第二功能基团具有不同于本申请抗体或其结合部分的结合特异性,例如具有疾病相关抗原的结合特异性。
在一些实施方式中,该双特异性分子可以靶向CD3ε和疾病相关抗原。在一些实施方式中,疾病相关抗原为肿瘤相关抗原,例如CD20、CD19、CD22、CD4、 CD24、CD38、CD123、CD228、CD138、BCMA、GPC3、CEA、CD276、gp100、5T4、GD2、EGFR、MUC-1、PSMA、EpCAM、MCSP、SM5-1、MICA、MICB、 ULBP、和HER-2。在一些实施方式中,疾病相关抗原为感染疾病相关抗原,例如 CD4、HBsAg、LMP-1和LMP2。在一些实施方式中,疾病相关抗原为炎性疾病相关抗原,例如IL17R和CD6。在一个实施方式中,疾病相关抗原为BCMA。
在第三个方面,本申请提供一种靶向BCMA和CD3的双特异性分子,包含 BCMA抗原结合域、和CD3抗原结合域,其中BCMA抗原结合域包含本申请的 BCMA抗体或其抗原结合片段,CD3抗原结合域包含本申请的CD3抗体或其抗原结合片段。
在一些实施方式中,该双特异性分子可以是两个抗原结合域经接头连接的融合蛋白。在一些实施方式中,该双特异性分子可以例如以scFv-scFv、Fab-Fab、 Fv-Fv、scFv-Fab(Fv)等形式存在的双特异性抗体,两个单特异性部分之间直接连接或通过接头等连接。
本申请的双特异性分子可以包含1个CD3抗原结合域、和1-4个BCMA抗原结合域。在一个实施方式中,双特异抗体可以包含1个CD3抗原结合域、和2个 BCMA抗原结合域。在一个实施方式中,BCMA抗原结合域是特异结合BCMA的抗体或其抗原结合片段,如Fv和/或scFv。在一个实施方式中,CD3抗原结合域为本申请中的CD3抗体或其抗原结合片段,如Fv或Fab。包含在双特异性分子中的2个BCMA抗原结合域可以具有相同或不同的抗原结合片段的形式。
本申请的靶向CD3和BCMA的双特异性分子可以为IgG样抗体。
在一个实施方式中,该双特异性分子可以包含:
i)第一多肽链,含有特异结合BCMA的重链可变区、和重链恒定区;
ii)第二多肽链,含有特异结合BCMA的轻链可变区;
iii)第三多肽链,含有特异结合BCMA的重链可变区、特异结合BCMA的轻链可变区、特异结合CD3的重链可变区、和重链恒定区;以及
iv)第四多肽链,含有特异结合CD3的轻链可变区,
其中第一多肽链中特异结合BCMA的重链可变区和第二多肽链中特异结合 BCMA的轻链可变区结合形成能够特异结合BCMA的抗原结合片段,第三多肽链中特异结合BCMA的重链可变区和特异结合BCMA的轻链可变区形成能够特异结合BCMA的抗原结合片段,第三多肽链中特异结合CD3的重链可变区与第四多肽链中特异结合CD3的轻链可变区结合形成能够特异地结合CD3的抗原结合片段,且第一多肽链的重链恒定区与第三多肽链的重链恒定区通过例如杵-臼、共价或二硫键等作用结合在一起。
第一多肽链的重链恒定区可以为带有臼结构的重链恒定区,例如带有 T366S/L368A/Y407V突变的人IgG1重链恒定区或其片段。第一多肽链的重链恒定区可以为带有臼结构且弱结合或不结合FcR的重链恒定区,如具有SEQ ID NO:17 (X1=A、X2=A、X3=A、X4=S、X5=A、X6=V)的人IgG1重链恒定区。第三多肽链的重链恒定区可以为带有杵结构的重链恒定区,例如带有T366W突变的人 IgG1重链恒定区或其片段。第三多肽链的重链恒定区可以为带有杵结构且弱结合或不结合FcR的重链恒定区,如具有SEQ ID NO:17(X1=A、X2=A、X3=A、X4=W、 X5=L、X6=Y)的人IgG1重链恒定区。
或者,第一多肽链的重链恒定区可以为带有杵结构的重链恒定区,例如带有T366W突变的人IgG1重链恒定区或其片段。第一多肽链的重链恒定区可以为带有杵结构且弱结合或不结合FcR的重链恒定区,如具有SEQ ID NO:17(X1=A、 X2=A、X3=A、X4=W、X5=L、X6=Y)的人IgG1重链恒定区。第三多肽链的重链恒定区可以为带有臼结构的重链恒定区,例如带有T366S/L368A/Y407V突变的人IgG1重链恒定区或其片段。第三多肽链的重链恒定区可以为带有臼结构且弱结合或不结合FcR的重链恒定区,如具有SEQ ID NO:17(X1=A、X2=A、X3=A、 X4=S、X5=A、X6=V)的人IgG1重链恒定区。
第三多肽链中特异结合BCMA的重链可变区可以经接头与特异结合BCMA的抗体轻链可变区连接。在一个实施方式中,接头可以是约5-30氨基酸长度的肽。在一个实施方式中,接头可以是约10-30氨基酸长度的肽。在一个实施方式中,接头可以是约10-20氨基酸长度的肽。在一个实施方式中,该接头可以是GS接头,例如包含SEQ ID NO:19的氨基酸序列的GS接头。
在第三多肽链中,特异结合BCMA的轻链可变区或特异结合BCMA的重链可变区可以经接头与特异结合CD3的重链可变区连接。在一个实施方式中,接头可以是约5-30氨基酸长度的肽。在一个实施方式中,接头可以是约10-30氨基酸长度的肽。在一个实施方式中,接头可以是约10-15氨基酸长度的肽。在一个实施方式中,该接头可以是GS接头,例如包含SEQID NO:20的氨基酸序列的GS接头。
在一个实施方式中,第一多肽链从N端至C端含有特异结合BCMA的重链可变区、和重链恒定区。第一多肽链的重链恒定区可以为带臼结构的重链恒定区。第三多肽链从N端至C端含有特异结合BCMA的重链可变区、特异结合BCMA 的轻链可变区、特异结合CD3的重链可变区、和重链恒定区;或者特异结合BCMA 的轻链可变区、特异结合BCMA的重链可变区、特异结合CD3的重链可变区、和重链恒定区。第三多肽链的重链恒定区可以为带杵结构的重链恒定区。
第二多肽链还可以在C端包含轻链恒定区,例如SEQ ID NO:18所示的人κ恒定区。
第四多肽链还可以在C端包含轻链恒定区,例如SEQ ID NO:18所示的人κ恒定区。
第一多肽链、第二多肽链、第三多肽链、和第四多肽链,在一些实施方式中,可以分别包含1)SEQ ID NOs:38、39、34、和35;2)SEQ ID NOs:38、39、36 (X1=S,X2=D,X3=T,X4=T,X5=T,X6=I,X7=N,X8=F)、和37(X1=Q, X2=R,X3=V,X4=R,X5=Q,X6=S,X7=I,X8=Q);3)SEQ ID NOs:38、39、36(X1=D,X2=S,X3=S,X4=S,X5=S,X6=L,X7=R,X8=Y)、和37(X1=R, X2=L,X3=V,X4=K,X5=Y,X6=Q,X7=I,X8=T);或4)SEQ ID NOs:38、39、36(X1=G,X2=D,X3=A,X4=H,X5=H,X6=I,X7=N,X8=Y)、和37 (X1=R,X2=R,X3=L,X4=K,X5=P,X6=H,X7=T,X8=R)所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列。
在另一实施方式中,双特异抗体可以包含:
i)第一多肽链,含有特异结合BCMA的重链可变区、和重链恒定区;
ii)第二多肽链,含有特异结合BCMA的轻链可变区;
iii)第三多肽链,含有特异结合CD3的重链可变区、和重链恒定区;以及
iv)第四多肽链,含有特异结合BCMA的重链可变区、特异结合BCMA的轻链可变区、和特异结合CD3的轻链可变区,
其中第一多肽链中特异结合BCMA的重链可变区和第二多肽链中特异结合 BCMA的轻链可变区结合形成能够特异结合BCMA的抗原结合片段,第三多肽链中特异结合CD3的重链可变区与第四多肽链中特异结合CD3的轻链可变区结合形成能够特异地结合CD3的抗原结合片段,第四多肽链中特异结合BCMA的重链可变区和特异结合BCMA的轻链可变区形成能够特异结合BCMA的抗原结合片段,且第一多肽链的重链恒定区与第三多肽链的重链恒定区通过例如杵-臼、共价或二硫键等作用结合在一起。
在一个实施方式中,第一多肽链从N端至C端含有特异结合BCMA的重链可变区、和重链恒定区。第三多肽链从N端至C端含有特异结合CD3的重链可变区、和重链恒定区。第四多肽链从N端到C端包含特异结合BCMA的重链可变区、特异结合BCMA的轻链可变区、和特异结合CD3的轻链可变区;特异结合BCMA 的轻链可变区、特异结合BCMA的重链可变区、和特异结合CD3的轻链可变区;特异结合CD3的轻链可变区、特异结合BCMA的轻链可变区、和特异结合BCMA 的重链可变区;或者特异结合CD3的轻链可变区、特异结合BCMA的重链可变区、和特异结合BCMA的轻链可变区。
第一多肽链的重链恒定区和第三多肽链的重链恒定区的其中之一可以为带有杵结构的重链恒定区,例如带有T366W突变的人IgG1重链恒定区或其片段,如带有杵结构且弱结合或不结合FcR的重链恒定区,如具有SEQ ID NO:17(X1=A、 X2=A、X3=A、X4=W、X5=L、X6=Y)的人IgG1重链恒定区;另一重链恒定区可以为带有臼结构的重链恒定区,例如带有T366S/L368A/Y407V突变的人IgG1 重链恒定区或其片段,如带有臼结构且弱结合或不结合FcR的重链恒定区,如具有SEQ ID NO:17(X1=A、X2=A、X3=A、X4=S、X5=A、X6=V)的人IgG1重链恒定区。
第四多肽链中特异结合BCMA的重链可变区可以经接头与特异结合BCMA的轻链可变区连接。第四多肽链中特异结合BCMA的重链可变区或特异结合BCMA 的抗体轻链可变区可以经接头与特异结合CD3的轻链可变区连接在一起。在一个实施方式中,接头可以是约5-30氨基酸长度的肽。在一个实施方式中,接头可以是约10-30氨基酸长度的肽。在一个实施方式中,接头可以是约10-15氨基酸长度的肽。在一个实施方式中,连接BCMA重链可变区与BCMA轻链可变区的接头可以是GS接头,例如包含SEQ ID NO:19的氨基酸序列的GS接头。在一个实施方式中,连接BCMA重链或轻链可变区与CD3轻链可变区的接头可以是GS接头,例如包含SEQ ID NO:20的氨基酸序列的GS接头。
双特异抗体可以含有在特异结合BCMA的轻链可变区的C端的轻链恒定区、和/或在特异结合CD3的轻链可变区的C端的轻链恒定区。在特异结合BCMA的轻链可变区的C端的轻链恒定区可以是人λ轻链恒定区,如含有SEQ ID NO:18的轻链恒定区。在特异结合CD3的轻链可变区的C端的轻链恒定区可以是人λ轻链恒定区,如含有SEQ ID NO:18的轻链恒定区。
本申请还保护构成双特异性分子的第一多肽链、第二多肽链、第三多肽链、和第四多肽链,以及由其中多肽链构成的半抗体。
本申请的BCMA×CD3双特异性抗体,相比于现有技术抗体例如EM801,在具有更高CD3结合活性和相当疾病细胞杀伤力的情况下,引起更低的细胞因子释放。
本申请还包括编码本申请BCMA抗体或其抗原结合片段、含有本申请BCMA 抗体或其抗原结合片段的免疫偶联物、含有本申请BCMA抗体或其抗原结合片段的CAR或TCR、本申请的CD3抗体或其抗原结合片段、或含有本申请BCMA和 /或CD3抗体或其抗原结合片段的双特异性分子的核酸分子,以及包含该核酸的表达载体以及包含该表达载体的宿主细胞。本申请还提供使用含有上述表达载体的宿主细胞来制备上述各分子的方法,包括:(i)在宿主细胞中表达抗体,以及(ii) 从宿主细胞或其培养物中分离抗体。
本申请还提供药物组合物,其包含本申请的BCMA抗体或其抗原结合片段、含有本申请BCMA抗体或其抗原结合片段的免疫偶联物、含有本申请BCMA抗体或其抗原结合片段的CAR或TCR-免疫细胞、本申请的CD3抗体或其抗原结合片段、含有本申请BCMA和/或CD3抗体或其抗原结合片段的双特异性分子、核酸分子、表达载体、或宿主细胞,以及药学上可接受的载体。
在第三个方面,本申请提供在受试者中治疗或减缓BCMA相关疾病的方法,包括向受试者施用治疗有效量的与本申请BCMA抗体或其抗原结合片段相关的药物组合物。BCMA相关疾病包括,但不限于,多发性骨髓瘤,和其他血液系统恶性肿瘤,如浆细胞瘤、浆细胞白血病、巨球蛋白血症、孤立性骨浆细胞瘤、髓外浆细胞瘤等。
在第四个方面,本申请提供在受试者中治疗或减缓炎性疾病、自身免疫疾病或移植物排斥的方法,包括向受试者施用治疗有效量的与本申请CD3抗体或其抗原结合片段相关的药物组合物。在一些实施方式中,炎性疾病为多发性硬化症 (MS)、和炎性肠道疾病(IBD)(如克罗恩病)。在一些实施方式中,自身免疫疾病为I型糖尿病。在一些实施方式中,通过经口方式向受试者施用本申请的抗体或其抗原结合片段。
本申请还提供本申请的CD3抗体或其抗原结合片段在制备靶向CD3和疾病相关抗原的双特异性分子中的用途。疾病相关抗原可以为肿瘤相关抗原,例如 BCMA、CD19、CD22、CD4、CD24、CD38、CD123、CD228、CD138、BCMA、 GPC3、CEA、CD276、gp100、5T4、GD2、EGFR、MUC-1、PSMA、EpCAM、 MCSP、SM5-1、MICA、MICB、ULBP、和HER-2。疾病相关抗原为感染疾病相关抗原,例如CD4、HBsAg、LMP-1和LMP2。在一些实施方式中,疾病相关抗原为炎性疾病相关抗原,例如IL17R和CD6。
本申请还提供使用本申请靶向CD3和疾病相关抗原的双特异性分子在受试者中治疗或减缓相关疾病的方法,包括向受试者施用治疗有效量的与本申请CD3双特异性分子相关的药物组合物。相关疾病可以为肿瘤、感染性疾病、或炎性疾病,根据双特异性分子中的疾病相关抗原而定。
在第五个方面,本申请提供在受试者中治疗或减缓BCMA相关疾病的方法,包括向受试者施用治疗有效量的与本申请靶向BCMA和CD3的双特异性分子相关的药物组合物。BCMA相关疾病包括,但不限于,多发性骨髓瘤,和其他血液系统恶性肿瘤,如浆细胞瘤、浆细胞白血病、巨球蛋白血症、孤立性骨浆细胞瘤、髓外浆细胞瘤等。
在本申请中引用或提及的所有文件(包括但不限于本文引用的所有文献、专利、公开的专利申请)(“本申请引用文件”),在本申请引用文件中引用或提及的所有文件,以及本申请或任意本申请引用文件中提及的任何产品的制造商手册、说明书、产品规格和产品页,均通过引用的方式并入本申请,且可能在实施本发明时采用。更具体而言,所有参考文件均通过引用的方式并入本申请,如同各文件通过引用的方式并入。在本文中提及的任何Genbank序列通过引用的方式并入本申请。
应当注意的是,在本申请中,特别是在权利要求中,术语例如“包含”、“包括”等可以具有中国专利法所赋予的意义;而术语例如“基本由……组成”具有中国专利法所赋予的意义,例如允许没有明确表述的元素的存在,但将现有技术中存在的元素、或影响本发明的基本或新的特性的元素排除在外。
附图说明
以下以示例方式给出但不意在将本发明限制于具体实施方式的具体描述,可以结合附图更好地进行理解。
图1示出噬菌体BCMA抗体A6-3与BCMA蛋白的结合活性。
图2示出BCMA抗体与BCMA蛋白的结合活性。
图3示出BCMA抗体与BCMA蛋白的亲和力。
图4示出BCMA抗体与293A/人BCMA(A)、293A/猴BCMA(B)、293A/ 小鼠BCMA(C)、以及BAFFR和TACI(D)的结合活性。
图5示出游离BCMA(sBCMA)对BCMA抗体与膜表面BCMA结合的影响。
图6示出噬菌体CD3抗体D1E9(A)、D8E5(B)、D12A4(C)以及7-1A12 (D)与CD3D&E复合体的结合活性。
图7示出CD3抗体D1E9(A)、7-1A12(B)、D8E5(C)以及D12A4(D) 与CD3D&E复合体的结合活性。
图8示出CD3抗体与CD3E(A)、以及CD3D(B)的结合活性。
图9示出CD3抗体与Jurkat细胞的结合活性。
图10示出CD3抗体在经二抗结合而呈交联状态下对人原代分离的T细胞的活化能力,具体表现为T细胞干扰素γ的分泌(A和B),以及T细胞早期激活标志物CD69的表达(C和D)。
图11示出本申请示例性CD3×BCMA双特异抗体的结构。
图12示出CD3×BCMA双特异性抗体305-H1 KIH、305-H2 KIH、305-M KIH (A)、和305-L-KIH(B)与CD3D&E的结合活性。
图13示出CD3×BCMA双特异性抗体305-H1 KIH、305-H2 KIH、305-M KIH (A)、和305-L-KIH(B)与人BCMA的结合活性。
图14示出CD3×BCMA双特异性抗体与293A/人BCMA(A、B)、293A/猴 BCMA(C、D)、以及293A/小鼠BCMA(E、F)的结合活性。
图15示出CD3×BCMA双特异性抗体305-H1 KIH、305-H2 KIH、305-M KIH (A)、和305-L-KIH(B)与Jurkat细胞的结合活性。
图16示出CD3×BCMA双特异性抗体对人PBMC中T细胞的活化,具体表现为IFN-γ(A)、IL-6(B)和TNF-α(C)的分泌。
图17示出CD3×BCMA双特异性抗体介导PBMC杀伤BCMA阳性肿瘤细胞的活性(A),以及杀伤体系下刺激T细胞分泌IL-6(B)和TNF-α(C)的能力。
具体实施方式
为更好理解本申请,首先定义一些术语。其他定义则贯穿具体实施方式部分而列出。
术语“CD3”是指分化簇3,包含γ链、δ链、ε链和ζ链等。术语“CD3ε”或“CD3E”是指CD3的ε链。术语“CD3δ”或“CD3D”是指CD3的δ链。术语“CD3D&E”或“CD3δ&ε”是指δ链和ε链形成的εδ复合体。以上术语包括变体、同源物、直向同源物和平行同源物。
术语“BCMA”是指B细胞成熟抗原,大量选择性地表达于恶性浆细胞。“人 BCMA”是指具有人氨基酸序列的BCMA蛋白,例如具有SEQ ID NO:21所示的氨基酸序列。“猴BCMA”是指具有猴氨基酸序列的BCMA蛋白,例如具有SEQ ID NO: 22所示的氨基酸序列。“小鼠BCMA”是指具有小鼠氨基酸序列的BCMA蛋白,例如具有SEQ ID NO:23所示的氨基酸序列。
本文中的术语“抗体”意在包括IgG、IgA、IgD、IgE和IgM全长抗体及其任何抗原结合片段(即,抗原结合片段)。全长抗体是包含至少两条重(H)链和两条轻(L)链的糖蛋白,重链和轻链由二硫键连接。各重链由重链可变区(简称VH) 和重链恒定区构成。重链恒定区由三个结构域构成,即CH1、CH2和CH3。各轻链由轻链可变区(简称VL)和轻链恒定区构成。轻链恒定区由一个结构域CL构成。 VH和VL区还可以划分为称作互补决定区(CDR)的高变区,其由较为保守的骨架区(FR)区分隔开。各VH和VL由三个CDR以及四个FR构成,从氨基端到羧基端以FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4的顺序排布。重链和轻链的可变区包含与抗原相互作用的结合域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合,包括多种免疫系统细胞(例如,效应细胞)和传统补体系统的第一组分(C1q)。本申请中的单特异性BCMA抗体可以包含具有结合免疫系统细胞和补体系统蛋白的恒定区,其恒定区片段是指保持有免疫系统细胞和补体系统蛋白结合力并发挥效应功能的部分。本申请中的单特异性CD3抗体以及双特异性CD3抗体,包括靶向CD3和BCMA的抗体,可以包含弱结合或不结合免疫系统细胞和补体系统蛋白的恒定区,其恒定区片段是指保持有弱结合或不结合免疫系统细胞和补体系统蛋白能力的部分。“IgG样抗体”是指在IgG抗体的结构基础上略加修饰的分子,如在IgG抗体的重链和/或轻链的N端或C端连接有多肽,如scFv,的抗体分子。
本文中的术语,抗体的“抗原结合片段”(或简称为抗体部分),是指抗体的保持有特异结合抗原(例如,CD3蛋白)能力的一个或多个片段。已证实,抗体的抗原结合功能可以通过全长抗体的片段来实施。包含在抗体的“抗原结合片段”中的结合片段的例子包括(i)Fab片段,由VL、VH、CL和CH1构成的单价片段;(ii) F(ab')2片段,包含铰链区二硫桥连接的两个Fab片段的二价片段;(iii)由VH和CH1构成的Fd片段;(iv)由抗体单臂VL和VH构成的Fv片段;(v)由VH构成的dAb片段(Ward et al.,(1989)Nature 341:544-546);(vi)分离的互补决定区(CDR);(vii)纳米抗体,一种包含单可变结构域和两个恒定结构域的重链可变区;以及(viii)单链Fc(scFv),包含由接头(如短肽)连接的VL和VH,其中VL和VH区配对形成单价分子(参见例如Bird et al.,(1988)Science 242:423-426; Huston et al.,(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。这些单链抗体也意在包括在术语涵义中。这些抗体片段可以通过本领域技术人员已知的常用技术而得到,且片段可以通过与完整抗体相同的方式进行功能筛选。
术语“FcR”是指在一些细胞,如B淋巴细胞、天然杀伤细胞、巨噬细胞等表面表达的蛋白,可以被抗体的Fc部分其结合,引发对靶细胞的吞噬和毒性等,在免疫系统中发挥重要作用。FcR包括Fcα受体、Fcε受体、和Fcγ受体,其中Fcγ受体术语免疫球蛋白超家族,是引发对微生物的吞噬作用的最重要的FcR,包括FcγRI (CD64)、FcγRIIA(CD32A)、FcγRIIB(CD32B)、和FcγRIIIA(CD16A)等。
本文所用的术语“分离的抗体”是指基本不含具有不同抗原特异性的其他抗体的抗体。例如,与CD3蛋白特异结合的分离抗体基本不含特异结合CD3蛋白之外抗原的抗体。但是,特异结合人CD3蛋白的分离抗体可能对其他抗原例如其他物种的CD3蛋白具有交叉结合性。此外,分离的抗体基本不含其他细胞材料和/或化学物质。
术语“单克隆抗体”或“单抗”或“单克隆抗体组成”是指单一分子组成的抗体分子制品。单克隆抗体组成呈现出对于特定表位的单一结合特异性和亲和力。
术语“双特异性”或“双特异”分子是指特异性结合两个靶分子、或同一靶分子上两个不同表位的分子。双特异性分子包括本申请中特异结合CD3和一种疾病相关抗原(例如BCMA)的双特异抗体。相对而言,“单特异性”分子是指特异结合某一个靶分子,尤其是某一个靶分子上一个表位的分子,例如本申请中结合CD3或 BCMA的抗体。
术语“人源抗体”是指可变区骨架和CDR区得自人种系免疫球蛋白序列的抗体。此外,如果抗体包含恒定区,其也得自人种系免疫球蛋白序列。本申请的人源抗体可以包含不由人种系免疫球蛋白序列编码的氨基酸残基,例如通过体外随机突变或点突变或通过体内体细胞突变而导入的突变。然而,术语“人源抗体”不包括在小鼠骨架序列中插入得自其他哺乳动物物种的CDR序列的抗体。
术语“人源化抗体”是指来源于非人物种但其蛋白序列已经被修改以增加其与人天然生成抗体的相似度的抗体。
在本文中,“特异结合”CD3或BCMA的抗体是指与人CD3(还可能是其他非人物种的CD3)或人BCMA(以及其他非人BCMA,如猴BCMA)结合但是基本不与非CD3/BCMA蛋白结合的抗体。
术语“基本不结合”是指,不与蛋白或细胞结合,或者不以高亲和力与其结合,即结合蛋白或细胞的KD为1.0x10-6M以上,更优选1.0x10-5M以上,更优选1.0 x10-4M以上、1.0x10-3M以上,更优选1.0x10-2M以上。
术语“EC50”,又叫半最大效应浓度,是指引起50%最大效应的抗体浓度。
术语“IC50”,又称为半抑制浓度,是指对指定的生物过程抑制一半时所需的药物或抑制剂的浓度。
本申请中的术语“交联”是指由抗体的Fc区结合免疫细胞上FcR等而引起的抗体聚集或相互作用,或者由双特异性CD3抗体上靶向疾病相关抗原的部分结合疾病相关抗原而引起的抗体聚集或相互作用。在体外实验中,可以通过抗体Fc结合二抗而形成抗体交联。本申请的CD3抗体或其抗原结合片段仅有在交联状态下才具有T细胞激活活性。相对的,本申请中的术语“游离”是指抗体之间或者抗体与其他分子之间不会产生相互作用而产生二聚化或者多聚化。本申请的CD3抗体或其抗原结合片段在游离状态下不会激活T细胞。
术语“受试者”包括任何人或非人动物。术语“非人动物”包括所有脊椎动物,例如哺乳类和非哺乳类,例如非人灵长类、羊、狗、猫、牛、马、鸡、两栖类、和爬行类,尽管优选哺乳动物,例如非人灵长类、羊、狗、猫、牛和马。
术语“治疗有效量”是指足以防止或减缓与疾病或病症(例如肿瘤)相关的症状的本申请抗体量。治疗有效量与被治疗的疾病相关,其中本领域技术人员可以方便地判别出实际的有效量。
本申请的多个方面在以下更加具体地加以描述。
本申请的BCMA抗体
本申请的BCMA抗体或其抗原结合片段可以与人和猴BCMA特异结合。其与现有技术如EM801中的BCMA结合部分相比,具有相当或更好的人/猴BCMA结合活性/亲和力,且结合几乎不受环境中sBCMA的影响。
本申请的BCMA抗体或其抗原结合片段的重链可变区CDR和轻链可变区 CDR通过Kabat编号系统确定。领域内熟知,重链可变区和轻链可变区CDR可以通过例如Chothia、IMGT、AbM或Contact编号系统/方法确定。
本申请的CD3抗体
本申请的CD3抗体或其抗原结合片段可以与人CD3,特别是人CD3δ&ε复合体,特异性结合。
本申请的CD3抗体或其抗原结合片段的重链可变区CDR和轻链可变区CDR 通过Kabat编号系统确定。领域内熟知,重链可变区和轻链可变区CDR可以通过例如Chothia、IMGT、AbM或Contact编号系统/方法确定。
本申请的CD3抗体或其抗原结合片段在游离状态下能够结合CD3,但不激活 T细胞;在交联状态下,能结合CD3,并激活T细胞。因而,当本申请的CD3抗体及其抗原结合片段制备成弱FcR结合或非FcR结合时,可以在体内呈游离、或基本游离的状态,用于治疗炎性疾病和自免疫疾病。
另一方面,本申请的CD3抗体或其抗原结合片段可以制备为靶向CD3和另一靶点(比如,肿瘤相关抗原或其他疾病如感染疾病或炎性疾病相关抗原)的非FcR 结合的双特异抗体,当抗体因CD3外靶点的结合而呈现交联状态时,激活T细胞,通过释放SMAP等方式杀伤靶细胞。例如,本申请的CD3抗体或其抗原结合片段可以制备为靶向CD3和肿瘤相关抗原的非FcR结合的双特异抗体,该双特异抗体只有在肿瘤处结合肿瘤相关抗原时才呈现交联状态,激活T细胞,达到杀伤肿瘤细胞的效果。与现有CD3抗体相比,交联状态的本申请抗体在引发细胞因子释放方面的活性更低,即,所引发的毒性较低。
本申请的双特异性分子引发较高的靶细胞特异杀伤、以及较低的T细胞活化和细
胞因子释放
本申请涉及包含一种或多种本申请抗体或其抗原结合片段与至少一个其他功能分子如另一种肽或蛋白(例如,另一抗体或受体配体)相连接的双特异性分子,以生成与至少两个不同结合位点或靶向分子相结合的双特异性分子。术语“双特异性分子”包括具有三种或更多种特异性的分子。双特异性分子可以以多种形式和尺寸出现。在尺寸谱的一端,双特异性分子保持传统抗体形式,除其具有两个结合臂且各臂具有不同特异性外,替代具有两个特异性相同的结合臂的情况。在另一极端的是双特异性分子,由两个经肽链连接的单链抗体片段(scFv)构成,称为 Bs(scFv)2构建体。中间尺寸的双特异性分子例如包括由肽类接头连接的两个不同的F(ab)片段,又例如包括经由肽链连接的F(ab)与单链抗体片段(scFv)。这些和其他形式的双特异性分子可以通过基因改造、体细胞杂交或化学法进行制备。
在本申请中,除CD3结合特异性外,双特异性分子还特异结合疾病相关抗原。在一些实施方式中,该双特异性分子可以靶向CD3和疾病相关抗原。优选疾病相关抗原在病灶区细胞上独特地表达,或在病灶区细胞上大量表达而在正常细胞上少量表达。
在一些实施方式中,疾病相关抗原为肿瘤相关抗原,例如BCMA、CD19、CD22、 CD4、CD24、CD38、CD123、CD228、CD138、BCMA、GPC3、CEA、CD276、 gp100、5T4、GD2、EGFR、MUC-1、PSMA、EpCAM、MCSP、SM5-1、MICA、MICB、ULBP、和HER-2。
在一些实施方式中,疾病相关抗原为感染疾病相关抗原,例如在病原体上的标记蛋白,或在感染细胞表面上的标记蛋白。感染疾病相关抗原为例如CD4、 HBsAg、LMP-1和LMP2。其中CD4为AIDS治疗的靶向蛋白。
在一些实施方式中,疾病相关抗原为炎性疾病相关抗原,例如在造成炎症的活化免疫细胞上表达的标记蛋白,例如IL17R和CD6。
双特异性分子可以以多种形式和尺寸出现。在尺寸谱的一端,双特异性分子保持传统抗体形式,除其具有两个结合臂且各臂具有不同特异性外,替代具有两个特异性相同的结合臂的情况。在另一极端的是双特异性分子,由两个经肽链连接的单链抗体片段(scFv)构成,称为Bs(scFv)2构建体。中间尺寸的双特异性分子包括由肽类接头连接的两个不同的F(ab)片段。这些和其他形式的双特异性分子可以通过基因改造、体细胞杂交或化学法进行制备。参见,例如Kufer et al,cited supra;Cao and Suresh,BioconjugateChemistry,9(6),635-644(1998);和van Spriel et al.,Immunology Today,21(8),391-397(2000)。
CD3双特异分子上将T细胞与靶细胞拉近。多个CD3双特异分子因为结合疾病相关抗原而处于交联状态,从而激活T细胞,杀灭靶细胞。
本申请的BCMA×CD3双特异性分子
在一些实施方式中,疾病相关抗原为BCMA,其为选择性地高表达于恶性浆细胞的分子标记物,是诊断和/或治疗多发性骨髓瘤或其他血液恶性肿瘤的理想靶抗原。
本申请的BCMA×CD3双特异性分子可以包含1个CD3抗原结合域、和1-4 个BCMA抗原结合域。在一个实施方式中,双特异性分子可以包含1个CD3抗原结合域、和2个BCMA抗原结合域。在一个实施方式中,BCMA抗原结合域是本申请的BCMA抗体或其抗原结合片段,如Fv和/或scFv。在一个实施方式中,CD3 抗原结合域为本申请中的CD3抗体或其抗原结合片段,如Fv。包含在双特异性分子中的2个BCMA抗原结合域可以相同或者不同,例如结合相同或不同的抗原表位、具有相同或不同的抗原结合片段的序列、和/或相同或不同的抗原结合片段的形式。
在一个实施方式中,双特异性分子包含1个特异结合CD3的Fv、1个特异结合BCMA的Fv、和1个特异结合BCMA的scFv。在一个实施方式中,特异结合 BCMA的Fv和特异结合BCMA的scFv具有本申请BCMA抗体的重链可变区和轻链可变区。
本申请的BCMA×CD3双特异性分子可以为IgG样抗体。在一个实施方式中,该双特异抗体包含特异结合CD3的IgG半抗体、特异结合BCMA的IgG半抗体、以及与特异结合CD3的IgG半抗体的重链可变区或轻链可变区的N端连接的特异结合BCMA的scFv。
在一个实施方式中,该双特异抗体可以包含:
i)第一多肽链,含有特异结合BCMA的重链可变区、和重链恒定区;
ii)第二多肽链,含有特异结合BCMA的轻链可变区;
iii)第三多肽链,含有特异结合BCMA的重链可变区、特异结合BCMA的轻链可变区、特异结合CD3的重链可变区、和重链恒定区;以及
iv)第四多肽链,含有特异结合CD3的轻链可变区,
其中第一多肽链中特异结合BCMA的重链可变区和第二多肽链中特异结合 BCMA的轻链可变区结合形成能够特异地结合BCMA的抗原结合片段,第三多肽链中特异结合BCMA的重链可变区和特异结合BCMA的轻链可变区形成能够特异结合BCMA的抗原结合片段,第三多肽链中特异结合CD3的重链可变区与第四多肽链中特异结合CD3的轻链可变区结合形成能够特异地结合CD3的抗原结合片段,且第一多肽链的重链恒定区与第三多肽链的重链恒定区通过例如杵-臼、共价或二硫键等作用结合在一起。
在一个实施方式中,第一多肽链从N端至C端含有特异结合BCMA的重链可变区、和重链恒定区。第一多肽链的重链恒定区可以为带臼结构的重链恒定区。第三多肽链从N端至C端含有特异结合BCMA的重链可变区、特异结合BCMA 的轻链可变区、特异结合CD3的重链可变区、和重链恒定区;特异结合BCMA的轻链可变区、特异结合BCMA的重链可变区、特异结合CD3的重链可变区、和重链恒定区;特异结合CD3的重链可变区、重链恒定区、特异结合BCMA的重链可变区、和特异结合BCMA的轻链可变区;或者特异结合CD3的重链可变区、重链恒定区、特异结合BCMA的轻链可变区、和特异结合BCMA的重链可变区。第三多肽链的重链恒定区可以为带杵结构的重链恒定区。
在另一实施方式中,双特异抗体可以包含:
i)第一多肽链,含有特异结合BCMA的重链可变区、和重链恒定区;
ii)第二多肽链,含有特异结合BCMA的轻链可变区;
iii)第三多肽链,含有特异结合CD3的重链可变区、和重链恒定区;以及
iv)第四多肽链,含有特异结合BCMA的重链可变区、特异结合BCMA的轻链可变区、和特异结合CD3的轻链可变区,
其中第一多肽链中特异结合BCMA的重链可变区和第二多肽链中特异结合 BCMA的轻链可变区结合形成能够特异地结合BCMA的抗原结合片段,第三多肽链中特异结合CD3的重链可变区与第四多肽链中特异结合CD3的轻链可变区结合形成能够特异地结合CD3的抗原结合片段,第四多肽链中特异结合BCMA的重链可变区和特异结合BCMA的轻链可变区形成能够特异结合BCMA的抗原结合片段,且第一多肽链的重链恒定区与第三多肽链的重链恒定区通过例如杵-臼、共价或二硫键等作用结合在一起。
在一个实施方式中,第一多肽链从N端至C端含有特异结合BCMA的重链可变区、和重链恒定区。第三多肽链从N端至C端含有特异结合CD3的重链可变区、和重链恒定区。第四多肽链从N端到C端包含特异结合BCMA的重链可变区、特异结合BCMA的轻链可变区、和特异结合CD3的轻链可变区;特异结合BCMA的轻链可变区、特异结合BCMA的重链可变区、和特异结合CD3ε的轻链可变区;特异结合CD3的轻链可变区、特异结合BCMA的轻链可变区、和特异结合BCMA 的重链可变区;或者特异结合CD3的轻链可变区、特异结合BCMA的重链可变区、和特异结合BCMA的轻链可变区。接头
在双特异抗体中,特异结合BCMA的重链可变区可以经接头与特异结合 BCMA的轻链可变区连接,以形成scFv。特异结合BCMA的重链可变区或特异结合BCMA的轻链可变区可以经接头与特异结合CD3的抗体或抗原结合片段连接。
接头可以由肽键连接的氨基酸构成,优选肽键连接的5-30个氨基酸,其中氨基酸选自20种天然存在的氨基酸。这些氨基酸中的一种或多种可以糖基化,如本领域技术人员所了解的。在一个实施方式中,5-30个氨基酸可以选自甘氨酸、丙氨酸、脯氨酸、天冬酰胺、谷氨酰胺、丝氨酸和赖氨酸。在一个实施方式中,接头由大部分有空键位阻的氨基酸构成,例如甘氨酸和丙氨酸。示例性的接头为多聚甘氨酸,特别是多聚(Gly-Ala)、以及多聚丙氨酸。本申请中用于scFv构建的示例性接头可以如SEQ ID NO:19所示。本申请中用于连接BCMA抗体片段与CD3 抗体片段的示例性接头可以如SEQ ID NO:20所示。
接头也可以是非肽类接头。例如,可以使用烷基接头,例如-NH-、-(CH2)s-C(O)-,其中s=2-20。这些烷基接头还可以经任何非空间位阻基团例如低级烷基(例如C1-6低级酰基)、卤素(例如Cl、Br)、CN、NH2、苯基等进行取代。
保守修饰
在另一实施方式中,本申请的抗体,包括CD3抗体、BCMA抗体、和 BCMA×CD3双特异抗体,包含与本申请抗体存在一个或多个保守修饰的重链和/ 或轻链可变区序列或CDR1、CDR2和CDR3序列。本领域知道,一些保守序列修改不会使抗原结合性消失。参见,例如,Brummell et al.,(1993)Biochem 32:1180-8; de Wildt et al.,(1997)Prot.Eng.10:835-41;Komissarov et al.,(1997)J.Biol.Chem. 272:26864-26870;Hall et al.,(1992)J.Immunol.149:1605-12;Kelley and O'Connell (1993)Biochem.32:6862-35;Adib-Conquy et al.,(1998)Int.Immunol.10:341-6and Beers et al.,(2000)Clin.Can.Res.6:2835-43。
本文所用的术语“保守序列修饰”是指不会显著影响或改变抗体结合特性的氨基酸修饰。这样的保守修饰包括氨基酸替换、添加和删除。可以通过领域内已知的标准技术,例如点突变和PCR介导的突变,将修饰引入本申请抗体中。保守氨基酸替换是氨基酸残基用具有相似侧链的氨基酸残基进行替换。具有相似侧链的氨基酸残基组在领域内已知。这些氨基酸残基组包括具有碱性侧链(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链(例如,天冬氨酸、谷氨酸)、不带电极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此,本申请抗体的CDR区中的一个或多个氨基酸残基可以用同侧链组的其他氨基酸残基替换,且得到的抗体可以使用本文所述的功能检测对其进行保留功能(即,上述的功能)的测试。
基因修饰的抗体
本申请的抗体,包括CD3抗体、BCMA抗体、和BCMA×CD3双特异抗体,可以以具备本申请抗体的一个或多个VH/VL序列的抗体作为起始材料,制备成基因修饰的抗体。抗体可以通过修饰一个或两个可变区(即,VH和/或VL)内(例如,在一个或多个CDR区和/或一个或多个骨架区)的一个或多个残基来进行基因修饰,以改善结合亲和力和/或增加与某些物种天然产生的抗体的相似性。例如,抗体可以通过修饰恒定区中的残基进行基因修饰,例如改变抗体的效应功能。
在某些实施方式中,CDR区植入可以用来基因修饰抗体的可变区。抗体主要通过位于六个重链和轻链互补决定区(CDR)中的氨基酸残基与靶标抗原进行相互作用。出于这个原因,CDR内的氨基酸残基比起CDR外的序列在个体抗体之间更加地多样。因为CDR序列负责主要的抗体-抗原相互作用,可以通过构建含有特定天然抗体的CDR序列植入到不同特性的不同抗体的骨架序列的表达载体,来表达模拟特定天然抗体的特性的重组抗体(Riechmannet al.,(1998)Nature 332:323-327;Jones et al.,(1986)Nature 321:522-525;Queenet al.,(1989)Proc.Natl. Acad;U.S.A.86:10029-10033)。
因此,本申请的另一实施方式涉及分离的单克隆抗体或其抗原结合片段、和/ 或双特异抗体,包含重链可变区和/或轻链可变区,重链可变区包含具有本申请序列的CDR1、CDR2和CDR3,轻链可变区包含具有本申请序列的CDR1、CDR2 和CDR3。尽管这些抗体包含本申请抗体的VH和VLCDR序列,它们可以含有不同的骨架序列。
这样的骨架序列可以从包括种系抗体基因序列的公开DNA数据库或公开参考文献中获得。例如,用于人重链和轻链可变区基因的种系DNA序列可以在Vbase 人种系序列数据库(www.mrc-cpe.cam.ac.uk/vbase)以及Kabat et al.,(1991),同上;Tomlinson et al.,(1992)J.Mol.Biol.227:776-798;和Cox et al.,(1994)Eur.J. Immunol.24:827-836中获得。作为另一实施方式,用于人重链和轻链可变区基因的种系DNA序列可以在Genbank数据库中得到。
通过使用本领域公知的称为空格(gap)BLAST的序列相似性搜索方法之一(Altschul et al.,(1997)),将抗体蛋白序列与蛋白序列数据库进行比较。
用于本申请抗体的优选骨架序列是结构上与本申请抗体所用的骨架序列相似的那些。VH CDR1、CDR2、和CDR3序列可以植入到与得到该骨架序列的种系免疫球蛋白基因具有相同序列的骨架区中,或者CDR序列可以植入到包含有与种系序列相比具有一个或多个突变的骨架区中。例如,在一些情况下,将骨架区中的残基进行突变是有益的,以保持或增强抗体的抗原结合性(参见例如U.S.Pat.Nos. 5,530,101;5,585,089;5,693,762和6,180,370)。
另一类的可变区修饰是将VH和/或VLCDR1、CDR2和/或CDR3区内的氨基酸残基进行突变,从而改进目标抗体的一种或多种结合特性(例如,亲和力)。可以进行点突变或PCR介导的突变来引入突变,且其对于抗体结合或其他功能特性的影响可以在本领域所知的体外或体内检测中进行评价。优选地,引入本领域所知的保守修饰。突变可以是氨基酸替换、添加或缺失,但优选为替换。此外,通常改变CDR区内的不多于一个、两个、三个、四个或五个的残基。
本申请的基因改造抗体包括在VH和/或VL的骨架残基中做出基因修饰以例如改变抗体特性的那些。骨架修饰包括对骨架区的、或者甚至一个或多个CDR区的一个或多个残基进行突变,以去除T细胞表位,从而减少抗体的可能导致的免疫原性。该方法也称为“去免疫化”,在美国专利公开20030153043中有更加详细的描述。此外,作为骨架或CDR区内修饰之外的另一种选择,本申请的抗体可以基因改造成在Fc区包括基因修饰,通常来改变抗体的一个或多个功能特性,例如血清半衰期、补体结合、Fc受体结合、和/或抗体依赖的细胞毒性。此外,本申请的抗体可以进行化学修饰(例如,可以向抗体附加一个或多个化学功能基团),或者修饰成改变其糖基化,来改变抗体的一个或多个功能特性。
在一个实施方式中,CH1的铰链区进行修饰,改变,例如增加或减少铰链区的半胱氨酸残基的数量。改变CH1铰链区的半胱氨酸残基,来例如促进重链轻链的组装或增加/降低抗体的稳定性。
在另一个实施方式中,对抗体的Fc铰链区进行突变,以降低抗体的生物半衰期。更加具体地,将一个或多个氨基酸突变引入Fc铰链片段的CH2-CH3连接区,从而抗体相对于天然Fc-铰链结构域SpA结合而言,具有减弱的SpA结合力。该方法在美国专利6,165,745中有更详细的描述。
在另一实施方式中,修饰抗体的糖基化。例如,可以制备去糖基化的抗体(即,抗体缺少糖基化)。可以改变糖基化,来例如增加抗体对抗原的亲和性。这样的糖化修饰可以通过例如改变抗体序列中的一个或多个糖基化位点来达成。例如,可以做出一个或多个氨基酸替换,以消除一个或多个可变区骨架糖基化位点,从而消除该位置的糖基化。这样的去糖基化可以增加抗体对抗原的亲和性。参见,例如美国专利5,714,350和6,350,861。
此外,可以制备具有改变的糖基化类型的抗体,例如岩藻糖残基量减少的低岩藻糖基抗体,或者具有增加的平分型GlcNac结构的抗体。改变的糖基化形式被证明能增加抗体的ADCC活性。这样的糖化修饰可以通过例如在糖基化系统改变的宿主细胞中表达抗体而进行。具有改变的糖基化系统的细胞在领域中已知,且可以用作表达本申请重组抗体的宿主细胞,以制备具有改变的糖基化的抗体。例如,细胞系Ms704、Ms705和Ms709缺少岩藻糖基转移酶基因FUT8(α(1,6)-岩藻糖基转移酶),从而在Ms704、Ms705和Ms709细胞系中表达的抗体在其糖中缺失岩藻糖。Ms704、Ms705和Ms709 FUT8-/-细胞系通过在CHO/DG44细胞中使用两种替换载体定向破坏FUT8基因而制备(参见美国专利公开20040110704 和Yamane-Ohnuki et al.,(2004)BiotechnolBioeng 87:614-22)。作为另一个例子, EP 1,176,195记载了FUT8基因功能破坏的细胞系,其编码岩藻糖基转移酶,从而在该细胞系中表达的抗体通过降低或消除α-1,6键相关酶而表现出低岩藻糖基化。 EP 1,176,195也描述了一种细胞系,其具有较低的用于向结合抗体Fc区的N-乙酰葡糖胺添加岩藻糖的酶活性,或者不具有这种酶的活性,例如大鼠骨髓瘤细胞系 YB2/0(ATCC CRL 1662)。
本文抗体的另一修饰是聚乙二醇化(PEG化)。抗体可以PEG化,例如来增加抗体的生物(例如,血清)半衰期。为使抗体PEG化,抗体或其片段通常与聚乙二醇(PEG),例如PEG的反应性酯或醛类衍生物,在使一个或多个PEG基团附于抗体或抗体片段的条件下反应。优选地,PEG化通过与反应性PEG分子(或类似的有反应性的水溶性聚合物)的酰化反应或烷化反应进行。本文中所用的术语“聚乙二醇”包括任何形式的用于衍生其他蛋白的PEG,例如单(C1-C10)烷氧基 -或芳氧基聚乙二醇或聚乙二醇马来酰亚胺。在某些实施方式中,需要PEG化的抗体是去糖基化的抗体。PEG化蛋白的方法在领域内已知,且可以应用到本申请的抗体。参见,例如EPO 154316和EP 0401384。
本申请抗体的制备
本申请的CD30和BCMA单特异性抗体可以使用噬菌体展示技术进行制备。此外,也可以通过体细胞杂交(杂交瘤)技术、B淋巴细胞的病毒或致癌性转化等进行制备。在一个实施方式中,将由标准分子生物技术得到的编码部分或全长轻链和重链的DNA插入一个或多个表达载体中,从而基因与转录和翻译调控序列可操作地连接。在该情况下,术语“可操作地连接”是指抗体基因连接到载体中,从而载体内的转录和翻译控制序列行使它们既定的调控抗体基因转录和翻译的功能。
本申请的双特异抗体,特别是BCMA×CD3双特异抗体,的制备可以通过i) 将编码双特异抗体的各多肽链的序列插入一个或多个表达载体,其中一个或多个表达载体与转录和翻译调控序列可操作地连接;ii)用表达载体转导或转染宿主细胞,以及iii)表达多肽链以形成本申请的双特异抗体。
术语“调控序列”包括控制抗体基因转录或翻译的启动子、增强子和其他表达控制元件(例如,多腺苷酸化信号)。优选的用于哺乳动物宿主细胞表达的调控序列包括引导在哺乳动物细胞中的高水平蛋白表达的病毒元件,例如得自巨细胞病毒(CMV)、猿猴病毒40(SV40)、腺病毒的启动子和/或增强子,如腺病毒主要晚期启动子(AdMLP)和多瘤病毒。或者,可以使用非病毒调控序列,例如泛素启动子或β-珠蛋白启动子。另外,调控元件由不同来源的序列构成,例如SRα启动子系统,其包含来自SV40早期启动子的序列和人T细胞白血病I型病毒的长末端重复。表达载体和表达控制序列选为与所使用的表达宿主细胞相容。
表达载体可以编码促进抗体链从宿主细胞分泌的信号肽。抗体链基因可以克隆到载体中,从而信号肽在阅读框内连接到抗体链基因的氨基端。信号肽可以是免疫球蛋白信号肽或异源信号肽(即,来自非免疫球蛋白的信号肽)。
除抗体链基因和调控序列外,本申请的表达载体可以携带其他序列,例如调控载体在宿主细胞中复制的序列(例如,复制起始点)和可选择标记物基因。可选择标记物基因可用于选择已导入载体的宿主细胞(参见,例如,美国专利 4,399,216;4,634,665和5,179,017)。例如,通常可选择标记物基因赋予已导入载体的宿主细胞以药物抗性,例如G418、潮霉素、或氨甲喋呤抗性。优选的可选择标记物基因包括二氢叶酸还原酶(DHFR)基因(用于dhfr宿主细胞的氨甲喋呤选择/扩增)和neo基因(用于G418选择)。
编码CD3抗体重链和轻链、或双特异抗体不同多肽链的表达载体通过标准技术转染到宿主细胞中。多个形式的术语“转染”包括多种常用于将外源DNA导入原核或真核宿主细胞的技术,例如,电穿孔、磷酸钙沉淀、DEAE-右旋糖转染等。尽管在原核或真核宿主细胞中表达本申请抗体在理论上是可行的,优选抗体在真核细胞中表达,最优选在哺乳动物宿主细胞中表达,因为真核细胞,特别是哺乳动物细胞,比原核细胞更可能组装并分泌适当折叠且有免疫活性的抗体。
本申请可用的表达载体的例子包括但不限于质粒、病毒载体、酵母人工染色体(YAC)、细菌人工染色体(BAC)、可转化人工染色体(TAC)、哺乳动物人工染色体(MAC)和人工附加染色体(HAEC)。
免疫偶联物
本申请的BCMA抗体或其抗原结合部分可以与治疗剂偶联,形成免疫偶联物,例如抗体-药物偶联物(ADC)。合适的治疗剂包括细胞毒素、烷化剂、DNA小沟结合分子、DNA嵌入剂、DNA交联剂、组蛋白去乙酰化酶抑制剂、核输出抑制剂、蛋白酶体抑制剂、拓扑异构酶I或II的抑制剂、热激蛋白抑制剂、酪氨酸激酶抑制剂、抗生素和抗有丝分裂剂。在ADC中,抗体和治疗剂优选地通过接头偶联,该接头可切割,例如肽类接头、二硫类接头或腙类接头。
嵌合抗原受体
本申请还提供包含BCMA单链抗体scFv的嵌合抗原受体,该scFv包含本申请BCMA抗体的重链和轻链CDR、或重链和轻链可变区。
嵌合抗原受体可以包含(a)含有BCMA scFv的胞外抗原结合域;(b)跨膜结构域;和(c)胞内信号转导结构域。
编码抗体或携带抗体的溶瘤病毒
溶瘤病毒偏好地侵染并杀灭癌细胞。本申请的BCMA或BCMA×CD3抗体可以与溶瘤病毒一起使用。此外,编码本申请抗体的溶瘤病毒可以引入人体中。
本申请的核酸分子
在另一方面,本申请提供编码本申请CD3或BCMA抗体或其抗原结合片段(如其中的重链/轻链可变区或CDR等)的核酸分子,编码本申请双特异抗体或其片段 (如其中的BCMA重链可变区-接头-BCMA轻链可变区-接头-CD3重链可变区、 BCMA轻链可变区-接头-BCMA重链可变区-接头-CD3重链可变区等)的核酸分子,以及编码本申请免疫交联物、本申请CAR或TCR等的核酸分子。核酸可以存在整细胞中,在细胞裂解液中,或处于部分纯化或基本纯的形式。当通过标准技术从其他细胞组分或其他污染物例如其他细胞核酸或蛋白中纯化出来后,核酸是“分离的”或“基本纯的”。本申请的核酸可以为例如DNA或RNA,且可能包含或可能不包含内含子序列。在优选实施方式中,核酸是cDNA分子。
本申请的核酸可以使用标准的分子生物学技术获得。对于使用噬菌体展示技术从免疫球蛋白基因库获得的抗体,编码这类抗体的核酸可以从基因库中收集。
优选的本申请核酸分子包括编码CD3或BCMA单克隆抗体的VH和VL序列或CDR的那些。一旦获得了编码VH和VL的DNA片段,这些DNA片段可以进一步通过标准的重组DNA技术进行操作,例如将可变区基因转变为全长抗体链基因、Fab片段基因或scFv基因。在这些操作中,编码VH或VL的DNA片段与编码另一蛋白的另一DNA片段,例如抗体恒定区或柔性接头,可操作地连接。术语“可操作地连接”是指两个DNA片段连接在一起,从而两个DNA片段编码的氨基酸序列都在阅读框内。
编码VH区的分离DNA可以通过可操作地连接VH编码DNA与编码重链恒定区(CH1、CH2和CH3)的另一DNA分子而转变成全长重链基因。人重链恒定区基因的序列在领域内已知,且包括这些区域的DNA片段可以通过标准PCR扩增而获得。重链恒定区可以是IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM或IgD恒定区,但是优选为IgG1或IgG4恒定区。对于Fab片段重链基因,编码VH区的DNA 可以可操作地与仅编码重链CH1恒定区的另一DNA分子连接。
编码VL区的分离DNA可以通过可操作地连接VL编码DNA与编码轻链恒定区CL的另一DNA分子而转变成全长轻链基因。人轻链恒定区基因的序列在领域内已知,且包括这些区域的DNA片段可以通过标准PCR扩增而获得。在优选实施方式中,轻链恒定区可以是κ和λ恒定区。
为创建scFv基因,编码VH和VL的DNA片段可以可操作地与编码柔性接头例如编码氨基酸序列(Gly4-Ser)3的另一片段连接,从而VH和VL序列可以作为连续的单链蛋白进行表达,其中VH和VL区域通过该柔性接头连接。
对于本申请中的双特异抗体,可以先获得编码CD3抗体的CDR、VH和VL、靶向疾病相关抗原(如BCMA)抗体的VH和VL、以及接头等的序列,然后根据所需的双特异抗体的形式来组合这些序列。
药物组合物
在另一方面,本申请提供一种药物组合物,其包含本申请的BCMA抗体或其抗原结合片段、含有本申请BCMA抗体或其抗原结合片段的免疫偶联物、含有本申请BCMA抗体或其抗原结合片段的CAR或TCR-免疫细胞、本申请的CD3抗体或其抗原结合片段、含有本申请BCMA和/或CD3抗体或其抗原结合片段的双特异性分子、核酸分子、表达载体、或宿主细胞,与药学上可接受的载体配制在一起。组合物可以任选地包含一种或多种其他药学上的有效成分,例如另一抗肿瘤抗体、抗感染抗体、免疫增强抗体、或自身免疫疾病治疗抗体,或者非抗体类抗肿瘤剂、抗感染剂、免疫增强剂、或自身免疫疾病治疗剂。本申请的药学组合物可以与例如另一抗癌剂、另一抗感染剂、另一免疫增强剂、或另一自身免疫疾病治疗剂联合使用。
药学组合物可以包含任何数量的赋形剂。可以使用的赋形剂包括载体、表面活性剂、增稠或乳化剂、固体粘合剂、分散或混悬剂、增溶剂、染色剂、矫味剂、涂层、崩解剂、润滑剂、甜味剂、防腐剂、等渗剂及其组合。
药物组合物适合于经口、静脉内、肌内、皮下、肠道外、脊柱或表皮施用(例如通过注射或推注)。基于施用途径的不同,有效成分可以包在材料中,以保护其不受酸和可能使其失活的其他自然条件的影响。“肠道外施用”是指不同于肠道和局部外用的方式,通常通过注射进行,包括但不限于静脉内、肌内、动脉内、膜内、囊内、眶内、心脏内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬脑膜上和胸骨内注射和推注。或者,本申请的抗体可以通过非肠道外路径施用,例如外用、表皮施用或粘膜施用,例如鼻内、经口、阴道、直肠、舌下、或局部外用。优选地,本申请的药物组合物经口施用。
药物组合物可以为无菌水溶液或分散液的形式。它们也可以配制在微乳剂、脂质体或其他适于高浓度药物的有序结构中。
与载体材料一起制备成单剂型的有效成分的量将随着治疗主体和特定施用模式而变,且基本上而言是产生疗效的组合物的量。以百分比计,该量为约0.01-约 99%的与药学上可接受载体结合的有效成分。
给药方案经调整提供最佳的所需反应(例如,治疗反应)。例如,可以施用快速灌注剂,可以随时间推移施用多个分剂量,或者剂量可以随治疗情况的危急程度成比例降低或提高。特别有利的是,以方便施用和剂量均匀的剂量单位型配置肠道外组合物。剂量单位型是指物理上分开的单位,适于治疗主体的单次给药;各单位包含计算出来与药学载体一起产生所需疗效的预定量的有效成分。或者,抗体可以以缓释剂施用,这种情况下所需的施用频率降低。
对于本申请CD3抗体的施用,可以部分地参照OKT3的FDA批准剂量,但最终由医学工作者,如医生,根据受试者的具体情况,如性别、年龄、既往病史等进行确定。对于本申请BCMA×CD3双特异抗体的施用,可以部分地参照EM801 的剂量,具体可以由医学工作者,如医生,根据受试者的具体情况,如性别、年龄、既往病史等进行确定。
“治疗有效量”的本申请CD3抗体、BCMA×CD3双特异抗体,或引起疾病症状严重程度的降低、或无症状期频率和持续时间的增加。例如,对于肿瘤患者,“治疗有效量”优选地,与对照受试者相比,将肿瘤减少至少约20%、更优选至少约40%,甚至更优选至少约60%,且更优选地至少约80%,甚至完全消除肿瘤。
药物组合物可以是缓释试剂,包括植入体、和微胶囊递送系统。可以使用生物可降解、生物相容的聚合物,例如乙烯-醋酸乙烯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯、和聚乳酸。参见,例如,Sustained and ControlledRelease Drug Delivery Systems,J.R.Robinson,ed.,Marcel Dekker,Inc.,New York,1978。药学组合物可以经医学设备来给药,例如(1)无针皮下注射设备(例如,美国专利5,399,163; 5,383,851;5,312,335;5,064,413;4,941,880;4,790,824;和4,596,556);(2)微量输液泵(美国专利4,487,603);(3)经皮给药设备(美国专利4,486,194);(4) 推注设备(美国专利4,447,233和4,447,224);和(5)渗透设备(美国专利4,439,196 和4,475,196)。
在某些实施方式中,本申请的抗体经配制,以确保合适的体内分布。例如,为确保本申请的治疗抗体穿越血脑屏障,抗体可以配制在脂质体中,其还可以额外地包含靶向功能基团,以增强对特定细胞或器官的选择性输送。
本申请的用途和方法
本申请的药物组合物具有多种体外和外内应用。例如,本申请中与CD3单特异性抗体相关的药物组合物可以用于炎性疾病、自免疫疾病和移植物排斥的治疗和缓解。而本申请中的BCMA抗体,例如可以用于BCMA样本的体外检测,以进行多发性骨髓瘤或其他恶性血液肿瘤的诊断、病情进程的监控、疗法应答的监控、以及预后等。
在一个方面,本申请的与CD3抗体或其抗原结合片段相关的药物组合物可以用于炎性疾病、自免疫疾病和移植物排斥的治疗和缓解。本申请的CD3抗体或其抗原结合片段具有弱结合或不结合FcR的重链恒定区。在一些实施方式中,炎性疾病为多发性硬化症(MS)、和炎性肠道疾病(IBD)(如克罗恩病)。在一些实施方式中,自身免疫疾病为I型糖尿病。
在一个方面,本申请的与BCMA抗体或其抗原结合片段相关的药物组合物可以用于多发性骨髓瘤或其他BCMA相关疾病的治疗或缓解。其他BCMA相关疾病可以包括,但不限于,浆细胞瘤、浆细胞白血病、巨球蛋白血症、淀粉样变性、华氏巨球蛋白血症、孤立性骨浆细胞瘤、髓外浆细胞瘤、骨硬化性骨髓瘤、重链病、意义不明确的单克隆丙种球蛋白病以及郁积型多发性骨髓瘤。
在另一方面,本申请的与双特异性分子相关的药物组合物可以用于治疗相关疾病,以靶向CD3和疾病相关抗原,其中双特异性分子不具有Fc区,或者具有 Fc区但弱结合或不结合FcR。根据疾病相关抗原的不同,该药物组合物可以治疗各种肿瘤,比如肠腺癌、乳腺癌、肾细胞癌、黑色素瘤、胰腺癌、非小细胞肺癌、成胶质细胞瘤和胃癌,原发或转移的;感染性疾病,如AIDS;以及各种炎性疾病或自免疫疾病。
在一个实施方式中,本申请的药物组合物包含BCMA×CD3双特异抗体、和/ 或编码该双特异抗体的核酸分子、表达载体或宿主细胞。该药物组合物可以用于在受试者中治疗或减缓BCMA相关疾病的治疗或缓解。BCMA相关疾病包括,但不限于,多发性骨髓瘤、浆细胞瘤、浆细胞白血病、巨球蛋白血症、淀粉样变性、华氏巨球蛋白血症、孤立性骨浆细胞瘤、髓外浆细胞瘤、骨硬化性骨髓瘤、重链病、意义不明确的单克隆丙种球蛋白病以及郁积型多发性骨髓瘤。
本申请提供本申请药物组合物与一种或多种其他抗体或非抗体类治疗剂一起施用的联合疗法,其能有效治疗或减缓相关疾病。
本文讨论的治疗剂的组合可以作为在药学可接受载体中的单一组合物同时施用,或者作为分开的组合物同时施用,其中各药剂处于药学可接受载体中。在另一个实施方式中,治疗剂的组合可以按序施用。
此外,如果进行多次联合疗法施用,且药剂按序施用,则在各时间点的按序施用的次序可以反转或保持相同,按序施用可以与同时施用或其任何组合相结合。
本申请的各方面和实施方式将参照附图和以下实施例进行讨论。其他方面和实施方式对于本领域技术人员是清楚的。在本文中描述的所有文献通过引用的方式全部并入本文。尽管本申请已经结合示例性实施方式进行了描述,很多等同修改和变化在给出本申请时对于本领域技术人员是清楚的。因而,本申请的示例性实施方式是示例性的,非限制性的。可以对所述实施方式做出多种变化,而不脱离本申请的宗旨和范围。
实施例
实施例1.稳定表达人BCMA、猴BCMA、小鼠BCMA、人BAFFR、或人TACI的HEK293A细胞
株的构建
使用HEK293A细胞来构建分别稳定过表达人BCMA、猴BCMA、小鼠BCMA、人BAFFR和人TACI的细胞系。简单而言,合成编码人BCMA、猴BCMA、小鼠 BCMA、人BAFFR、人TACI(氨基酸序列分别如SEQ ID NOs:21-25所示)的cDNA 序列,并经酶切分别克隆到pLV-EGFP(2A)-Puro载体(北京英茂盛业生物科技有限公司,中国)的BamH1和EcoR1酶切位点中。将得到的pLV-EGFP(2A)-Puro-人 BCMA、pLV-EGFP(2A)-Puro-猴BCMA、pLV-EGFP(2A)-Puro-小鼠BCMA、pLV-EGFP(2A)-Puro-BAFFR、或pLV-EGFP(2A)-Puro-TACI与psPAX和pMD2.G质粒通过脂质体转染的方式转染到HEK293T细胞(南京科佰公司,中国)中,产生慢病毒,具体转染方法与Lipofectamine 3000试剂盒(Thermo Fisher Scientific,美国)说明书步骤完全一致。转染三天后,从HEK293T细胞的细胞培养基(DMEM 培养基(Cat#:SH30022.01,Gibco),补充有10%FBS(Cat#:FND500,Excell)) 中收获慢病毒。然后用慢病毒转染HEK293A细胞(南京科佰公司,中国),得到稳定表达人、猴或小鼠BCMA、人BAFFR、或人TACI的HEK293A细胞(分别称为 HEK293A/人BCMA、HEK293A/猴BCMA、HEK293A/小鼠BCMA、HEK293A/人 BAFFR、HEK293A/人TACI细胞)。转染的HEK293A细胞培养在含有0.2μg/ml嘌呤毒素(Cat#:A11138-03,Gibco)的DMEM+10%FBS培养基中7天。人和猴BCMA 的表达使用市售可得的BCMA抗体(PE-抗人BCMA抗体,Cat#:357503,Biolegend,美国)通过流式分析仪经FACS分析。相似地,小鼠BCMA的表达通过市售可得的小鼠BCMA抗体(抗小鼠BCMA抗体,Cat#:O88472,Novus,美国),人BAFFR 的表达使用市售可得的BAFFR抗体(PE-抗人BAFFR抗体,Cat#:316905,Biolegend,美国),人TACI的表达使用市售可得的TACI抗体(PE-抗人TACI抗体,Cat#:133403, Biolegend,美国),经FACS确证。
实施例2.BCMA单克隆抗体的筛选
无菌PBS稀释抗原BCMA-his蛋白(Cat#:BCA-H522y,ACRO)至终浓度为 10μg/mL,吸取500μL加入到免疫管中,4℃包被过夜,同时设置阴性对照,即PBS包被免疫管。采用含4%脱脂奶粉的PBST分别封闭免疫管和噬菌体抗体库(实验室自己制备),37℃1h。将封闭后的噬菌体抗体库加入免疫管中进行抗体抗原结合,噬菌体的投入量约为3×1012,37℃孵育1h。PBS(T)洗去未结合的噬菌体, 0.1M HCL-甘氨酸洗脱结合的噬菌体,用1.5M Tris-HCL(pH8.8)中和洗脱下来的噬菌体。
取550μl中和后的噬菌体感染约10mL生长至对数生长期的TG1菌液,37℃静置30min。取出适量菌液铺板测定CFU,其余细菌离心涂布于2YTAG大平板上,37℃培养过夜。次日,将菌落从2YTAG平板上刮下,重悬于50ml 2YTGA 培养基中。培养至对数生长期后,加入2mL辅助病毒M13(pfu=1×1013),30℃振荡培养过夜。次日回收上清,常规PEG沉淀,所得次级噬菌体抗体库可进行下一轮的筛选。共进行三轮亲和淘选,步骤同上。
挑取经过三轮筛选后产出的分隔良好的单克隆菌落,接种至1mL 2YTAG(含 100μg/ml氨苄和2%葡萄糖)培养基中,37℃、220rpm培养过夜。第二天转接至新的96孔深孔板,培养至其对数生长期,每孔加入约1010的辅助噬菌体M13。37 ℃静止感染30min后,4000rpm、4℃离心15min,弃去上清,菌体用2YTAK(含 100μg/ml氨苄和70μg/ml卡那霉素)重悬沉淀,28℃、220rpm培养过夜。吸取扩增后的噬菌体上清进行ELISA鉴定。对获得的阳性克隆进行测序,获得1种抗体序列,命名为A6-3,其VH-CDR1、VH-CDR2、VH-CDR3、VL-CDR1、VL-CDR2、VL-CDR3、VH和VL的氨基酸序列分别如SEQ ID NOs:1-7和8(X1=I、X2=V、 X3=E、X4=I、X5=无)所示。
将测序正确的这1个抗体,进行噬菌体展示,沉淀,获得高纯度的噬菌体scFv 抗体。利用梯度稀释ELISA法检测噬菌体抗体与BCMA蛋白的结合能力。具体地,将噬菌体抗体从0.1mg/ml开始进行3倍梯度稀释,然后与BCMA蛋白 (Cat#:BCA-H522y,ACRO)结合。HRP标记的小鼠抗M13单克隆抗体(义翘神州,11973-MM05T-H)检测噬菌体抗体与BCMA蛋白的结合情况。实验结果显示在图1中。
如图1所示,噬菌体抗体A6-3与BCMA蛋白特异结合,呈剂量依赖关系。
实施例3.全长BCMA抗体的表达和纯化
将上述筛选出的A6-3 scFv抗体以全长单克隆抗体的形式表达在HEK293F细胞(Cobioer,中国)中,进行进一步表征研究。简单而言,将重链/轻链可变区分别加上人IgG1/κ恒定区(氨基酸序列如SEQ ID NOs:17(X1=L、X2=L、X3=N、X4=T、X5=L、X6=Y)和18)的编码序列克隆到pCDNA3.1(Invitrogen,Carlsbad,美国)的EcoRI/BamHI限制性内切酶位点中,构建表达载体,其中重链可变区的 C端接重链恒定区的N端,轻链可变区的C端接轻链恒定区的N端。
采用天根无内毒素质粒大提试剂盒(Cat#:DP117,天根)提取pCDNA3.1-A6-3 质粒。采用5mLFreeStyle F17细胞培养基重悬pCDNA3.1-A6-3质粒,同时吸取3 倍质粒体积的转染试剂(PEI)重悬在5mL FreeStyle F17细胞培养基中。将PEI 缓慢地加入到质粒中,充分混合,室温放置约15min。将上述混合液加入到100ml 293F细胞中(细胞密度为1×106/mL),37℃细胞摇床培养6-7天。3000rpm离心 15min收取细胞上清,然后将细胞上清流经protein-A亲和柱(Cat#:17040501, GE,美国)进行亲和纯化。用PBS清洗protein-A柱子3-4次,最后使用0.2M pH2.4 的甘氨酸-HCl洗脱抗体,然后用1.5M Tris-HCl(pH9.1)将洗脱液中和至pH7.4。采用30K超滤管对洗脱后的抗体进行换液和浓缩。抗体保存在PBS缓冲液中(pH 7.4),其浓度通过NanoDrop仪确定。纯化的单克隆抗体进行进一步表征。
实施例4.BCMA抗体与BCMA蛋白的结合活性检测
PBS包被液稀释抗原BCMA蛋白(Cat#:BCA-H522y,ACRO)至终浓度为1 μg/mL,将稀释后的BCMA蛋白溶液加入到96孔ELISA板中,每孔100μL,4℃包被过夜。用含4%脱脂奶粉的PBST封闭ELISA板,250μL/孔,室温封闭1h。 PBST洗涤ELISA板,200μL/孔,洗涤3次。用PBST稀释A6-3抗体,从10μg/mL 开始进行三倍梯度稀释,共设置11个稀释梯度。将稀释后的样品加入到封闭好的 ELISA板中,100μL/孔,37℃孵育1h,最后一孔做为阴性对照,即只有稀释液 PBST。PBST洗涤ELISA板,200μL/孔,洗涤3次。向ELISA板中加入100μL HRP 标记的山羊抗人IgG单克隆抗体(1:7000稀释,Cat#:31413,thermofisher),室温孵育1h。PBST洗涤ELISA板,200μL/孔,洗涤4次。向ELISA板中加入100 μLTMB底物显色液(Cat#:555214,BD),静置显色,然后用50μL 10%硫酸终止显色。450nm波长处测定光吸收值。采用GraphPad软件处理分析数据。实验结果显示在图2中。
如图2所示,A6-3抗体与BCMA蛋白有很强的结合力,并且呈剂量依赖关系。采用GraphPad软件分析ELISA数据,抗体与BCMA结合的EC50值为7.332 ng/ml。
实施例5.BCMA抗体的亲和力检测
采用捕获法(BIAcore 8K)测定A6-3抗体和BCMA蛋白的结合亲和力。将鼠抗人Fc段的抗体(Cat#:BR100839,cytiva)偶联至芯片CM5的表面。HBS-EP 缓冲液(Cat#:BR-1006-69,GE Life Sciences)稀释A6-3抗体至1μg/mL,保证约100RU抗体被抗人Fc的抗体捕获。BCMA抗原(Cat#:BCA-H522y,ACRO) 用HBS-EP缓冲液稀释至不同浓度(0.5、0.25、0.125、0.0625、0.03125、0.015625、 0.0078125、0.003900625μg/ml),将不同浓度的BCMA蛋白流经固定相表面。采用3M MgCl2溶液对芯片进行再生。用Biacore 8K控制软件中的动力学分析Wizard进行动力学实验。根据Biacore 8K评估软件进行拟合,获得A6-3抗体的 KD值,示于图3和表1中。
从表1和图3可知,A6-3抗体与BCMA蛋白有很强的结合亲和力。
表1.BCMA抗体对人BCMA的结合亲和力
Ka | Kd | KD(M) | |
A6-3 | 1.37E+06 | 1.82E-04 | 1.32E-10 |
实施例6.BCMA抗体对细胞表面BCMA的结合活性和结合特异性
通过FACS检测BCMA抗体对细胞表面表达的BCMA的结合活性。利用胰酶消化收集生长状态良好的HEK293A/人BCMA、HEK293A/猴BCMA和HEK293A/ 小鼠BCMA细胞(实施例1中制备),300g离心5min去除培养基。PBS重悬计数后再次离心去除上清。利用2%FBS-PBS溶液重悬细胞,调整细胞浓度为4×106个/ml。将细胞加入U型底96孔板中,50μl/孔。用2%FBS-PBS稀释A6-3抗体,从20μg/ml(用于HEK293A/人BCMA和HEK293A/小鼠BCMA的结合)或40μg/ml(用于HEK293A/猴BCMA的结合)开始进行5倍梯度稀释,共设置12个稀释梯度。在上述96孔板中加入50μl A6-3抗体稀释液,吹打混匀,室温孵育1h。 2%FBS-PBS洗板,200μL/孔,洗涤3次。向板中加入PE标记的山羊抗人IgG(H+L) 二抗,1:500稀释,50μl/孔,室温结合45min。2%FBS-PBS洗板,200μL/孔,洗涤3次。最后向板中加入150μL 2%FBS-PBS以重悬细胞,并经流式细胞仪检测, FlowJo软件进行数据处理,GraphPad软件进行数据分析。
同时,检测A6-3抗体对于BMCA同家族蛋白BAFFR和TACI蛋白的结合情况,实验方法与上述检测类似,不同之处在于,仅设置两个抗体检测浓度,100μg/ml 和10μg/ml。
如图4(A、B、C)所示,A6-3抗体与HEK293A/人BCMA、HEK293A/猴 BCMA细胞有很强的结合力,并且呈剂量依赖关系,但不与HEK293A/小鼠BCMA 细胞结合。A6-3抗体与HEK293A/人BCMA、HEK293A/猴BCMA细胞结合的EC50值分别为41.52ng/ml和98.57ng/ml。
图4(D)显示出,A6-3与BCMA同家族蛋白BAFFR和TACI完全没有结合力,说明其与BCMA的结合是高度特异的。
实施例7.sBCMA对BCMA抗体与膜表面BCMA结合的影响
为了检测游离BCMA蛋白(sBCMA)是否会影响A6-3抗体与BCMA阳性细胞的结合,采用实施例1构建的人BCMA过表达的HEK293A细胞进行FACS结合力检测。简而言之,将100μl培养基中的105个HEK293A/人BCMA细胞在96 孔板上铺板,加入50μl梯度稀释的抗体或50μlPBS,再加入人BCMA-his游离抗原(Cat#:10620-H08H,义翘神州),使其终浓度为1μg/ml。4℃孵育1h后,96 孔板用PBST清洗3遍。之后,加入500倍稀释的APC-山羊抗小鼠IgG(Cat#:405308,BioLegend,美国)。4℃孵育1h后,96孔板用PBS清洗3遍,然后使用FACS检测仪(BD)检测细胞荧光强度。
实验结果如图5所示,游离的BCMA蛋白只是略微降低了A6-3对HEK293A/ 人BCMA细胞的结合力,对抗体结合BCMA阳性细胞不造成显著影响。
实施例8.CD3单克隆抗体的筛选和制备
CD3D即为CD3的δ链,CD3E即为CD3的ε链。
表2.CD3D&E单克隆抗体的可变区序列ID NO.
根据实施例2中的方法步骤,筛选与CD3D&E结合的单克隆抗体,共获得4 种抗体序列,分别命名为D1E9、7-1A12、D8E5、D12A4,其可变区的氨基酸序列ID NO.示于表2。
将4种抗体分别进行噬菌体展示,沉淀,获得高纯度的噬菌体scFv抗体。利用梯度稀释ELISA法检测噬菌体抗体与CD3D&E蛋白的结合能力。简单而言,将噬菌体抗体从0.1mg/ml或者1mg/ml开始进行3倍梯度稀释,然后与CD3D&E 蛋白(Cat#:CT038-H2508H,义翘神州)结合。加入HRP标记的小鼠抗M13单克隆抗体(Cat#:11973-MM05T-H,义翘神州)检测噬菌体抗体与CD3D&E蛋白的结合情况。实验结果显示在图6中。
如图6所示,4种噬菌体抗体可以与CD3D&E蛋白特异结合,呈剂量依赖关系。
根据实施例3中的方法步骤,分别将上述D1E9、7-1A12、D8E5和D12A4的 scFv抗体以全长单克隆抗体的形式表达在HEK293F细胞(Cobioer,中国)中,其中人IgG1和κ恒定区的氨基酸序列分别如SEQ ID NO:17(X1=A、X2=A、X3=A、 X4=T、X5=L、X6=Y)和18所示。然后利用protein-A亲和柱进行纯化,获得的抗体进一步表征研究。
实施例9.CD3抗体与CD3D&E蛋白的结合活性检测
根据实施例4中的方法步骤,检测D1E9、7-1A12、D8E5和D12A4与CD3D&E 蛋白(Cat#:CT038-H2508H,义翘神州)的结合活性。实验结果显示在图7中。
如图7所示,D1E9等4种抗体与CD3D&E蛋白有很强的结合力,并且呈剂量依赖关系。采用GraphPad软件分析ELISA数据,抗体与CD3D&E结合的EC50值示于表3。
表3.CD3抗体对CD3D&E抗原的结合活性
D1E9 | 7-1A12 | D8E5 | D12A4 | |
EC50(ng/ml) | 87.92 | 4.02 | 8.16 | 22.58 |
根据实施例4中的方法步骤,检测D1E9、7-1A12、D8E5和D12A4与CD3D (Cat#:10981-H08H,义翘神州)、CD3E蛋白(Cat#:10977-H08S,义翘神州) 的结合活性,ACD3抗体作为阳性对照,ACD3抗体的重链可变区和轻链可变区序列为专利WO2022056455A1中的氨基酸序列7、8,重链恒定区与轻链恒定区分别为人IgG1和κ轻链恒定区,氨基酸序列分别如SEQID NO:17(X1=A、X2=A、 X3=A、X4=T、X5=L、X6=Y)和18所示。本实施例与实施例4的不同之处在于,抗体不进行梯度稀释,只采用10μg/ml进行检测。实验结果显示在图8中。图8示出CD3抗体与CD3E(A)、以及CD3D(B)
如图8所示,D1E9等4种抗体均不与CD3E(A)或CD3D(B)蛋白结合。
实施例10.CD3抗体的亲和力检测
采用捕获法(BIAcore 8K)分别测定D1E9、7-1A12、D8E5和D12A4抗体与 CD3D&E、CD3E和CD3D蛋白的亲和力。将鼠抗人Fc段的抗体偶联至芯片CM5 的表面上。HBS-EP缓冲液(Cat#:BR-1006-69,GE Life Sciences)稀释D1E9、7-1A12、D8E5和D12A4抗体至1μg/mL,保证约100响应值(响应单元,RU) 抗体被抗人Fc的抗体捕获。CD3D&E(Cat#:CT038-H2508H,义翘神州)蛋白用 HBS-EP缓冲液(Cat#:BR-1006-69,GE Life Sciences)从20μg/ml开始进行对倍稀释,共设置6个稀释梯度,将不同浓度的CD3D&E蛋白流经固定相表面。采用 3M MgCl2溶液对芯片进行再生。用Biacore 8K控制软件中的动力学分析Wizard 进行动力学实验。根据Biacore 8K评估软件进行拟合,获得D1E9等抗体与 CD3D&E的KD值,示于表4中。
如表4所示,D1E9等抗体均能与CD3D&E复合体结合,亲和力处于357~6.54 nM。
表4.D1E9、7-1A12、D8E5和D12A4抗体对人CD3D&E的亲和力
Ka | Kd | KD(M) | |
D1E9 | 4.98E+04 | 5.97E-03 | 1.20E-07 |
7-1A12 | 7.18E+04 | 4.7E-04 | 6.54E-09 |
D8E5 | 5.17E+04 | 1.55E-03 | 3.00E-08 |
D12A4 | 3.49E+04 | 1.25E-02 | 3.57E-07 |
采用捕获法(BIAcore 8K)分别测定D1E9、7-1A12、D8E5和D12A4抗体与 CD3D的亲和力。将鼠抗His段的抗体偶联至芯片CM5的表面上,CD3D-his (Cat#:10981-H08H,义翘神州)蛋白用HBS-EP缓冲液稀释(Cat#:BR-1006-69,GE Life Sciences)至2μg/ml,保证约50RU蛋白被抗His的抗体捕获。HBS-EP 缓冲液(Cat#:BR-1006-69,GE Life Sciences)稀释D1E9、7-1A12、D8E5和D12A4 抗体至120μg/mL,分别将抗体流经固定相表面。采用3M MgCl2溶液对芯片进行再生。用Biacore 8K控制软件中的动力学分析Wizard进行动力学实验。实验发现,D1E9、7-1A12、D8E5和D12A4等抗体均不与CD3D蛋白结合。
采用固定抗原法检测D1E9、7-1A12、D8E5和D12A4抗体与CD3E(Cat#: 10977-H08S,义翘神州)的亲和力。将CD3E蛋白偶联至芯片CM5的表面上,保证约200RU的蛋白被固定在芯片上。HBS-EP缓冲液(Cat#:BR-1006-69,GE Life Sciences)稀释D1E9、7-1A12、D8E5和D12A4抗体至120μg/mL,分别将抗体流经固定相表面。采用pH1.5 Gly-Hcl溶液对芯片进行再生。用Biacore 8K控制软件中的动力学分析Wizard进行动力学实验。实验发现,D1E9、7-1A12、D8E5和 D12A4等抗体均不与CD3E蛋白结合。
以上结果表明,D1E9、7-1A12、D8E5和D12A4仅识别CD3D&E复合体。实施例11.CD3D& E抗体对Jurkat细胞的结合活性
收集生长状态良好的Jurkat细胞,300g离心5min去除培养基。PBS重悬计数后再次离心去除上清。利用2%FBS-PBS溶液重悬细胞,调整细胞浓度为3×106个/ml。将细胞加入U型底96孔板中,50μl/孔。用2%FBS-PBS分别稀释D1E9、 7-1A12、D8E5和D12A4抗体,从20μg/ml开始进行4倍梯度稀释,共设置12个稀释梯度。分别向上述96孔板加入50μl稀释后的抗体,吹打混匀,室温孵育1h。 2%FBS-PBS洗板,200μL/孔,洗涤3次。分别向细胞悬液中加入PE标记的山羊抗人IgG(H+L)二抗,1:500稀释,50μl/孔,室温结合45min。2%FBS-PBS洗板,200μL/孔,洗涤3次。最后向板中加入150μL 2%FBS-PBS,重悬细胞,经流式细胞仪检测,FlowJo软件进行数据处理,GraphPad分析数据。实验结果显示在图9 中。
如图9所示,D1E9、7-1A12、D8E5和D12A4抗体与Jurkat细胞有很强的结合力,并且呈剂量依赖关系,结合的EC50值示于表5中。
表5.CD3抗体对Jurkat细胞的结合活性
D1E9 | 7-1A12 | D8E5 | D12A4 | |
EC50(ng/ml) | 83.67 | 119.1 | 41.08 | 110.0 |
实施例12.CD3D&E抗体对T细胞活性的激活
为进一步确定本申请CD3D&E抗体在交联状态下对CD3/TCR信号通路的激动性,进行人原代T细胞激活检测。
简单而言,将96孔细胞培养板用100μl 5μg/ml Fab‘2山羊抗人Fc的二抗(Invitrogen,美国,Cat#:31163)4度包被过夜。PBS洗2遍后加入100μl不同浓度的本申请CD3抗体,37℃孵育2小时。同时通过梯度密度离心的方式获得健康人供体血样中的PBMC,CD4+T细胞通过Invitrogen Dynabeads非接触人CD4+T 细胞分离试剂盒(Cat#:11346D,Thermal Fisher Scientific,美国)从PBMC中分离出来,具体分离步骤跟试剂盒提供的说明书完全一致。将细胞密度调整成2.5×105活细胞/ml。将200μl上述T细胞悬液加入包被好CD3抗体的细胞培养板中,37 ℃、5%CO2孵育24小时后,吸取50μl细胞培养基上清,用于IFN-γ分泌量检测。使用制造商的方法步骤,经ELISA(Cat#:SIF50,R&D,美国)确定IFN-γ浓度。细胞继续培养48小时后,收集细胞,经PBS洗3次,加入2μl PE-鼠抗人CD69 抗体(Cat#:555531,BD,美国),常温孵育30分钟后,离心,PBS洗3次。通过流式检测CD4+T细胞中CD69+T细胞的比例,来确定交联的CD3抗体对T细胞激活的作用。
实验结果如图10所示,D1E9、7-1A12、D8E5和D12A4抗体能显著激活T 细胞,增加T细胞的IFN-γ分泌(A,B),并剂量依赖性地激活T细胞表面CD69 的表达(C,D)。
实施例13.CD3×BCMA双特异性抗体的构建和表达
采用不对称(BCMA:CD3为2:1)的全抗体组装形式进行双特异性抗体构建,具体双抗结构如图11所示。以GS载体(具体信息见ZL200510064335.0)为表达载体,构建CD3×BCMA双特异性抗体的5个半抗体305-H1杵、305-H2杵、 305-M杵、305-L杵和305臼。其中,305-H2杵的长链包含BCMA scFv-接头-D1E9 抗体重链可变区-重链恒定区,氨基酸序列如SEQ IDNO:34所示,短链包含D1E9 抗体轻链可变区-轻链恒定区,氨基酸序列如SEQ ID NO:35所示;305-H1杵的结构同305-H2,除使用7-1-A12抗体可变区外,其长链和短链的氨基酸序列分别如 SEQ ID NOs:36(X1=S,X2=D,X3=T,X4=T,X5=T,X6=I,X7=N,X8=F)和 37(X1=Q,X2=R,X3=V,X4=R,X5=Q,X6=S,X7=I,X8=Q)所示;305-M 杵的结构同305-H2,除使用的D8E5抗体可变区外,其长链和短链的氨基酸序列分别如SEQ ID NOs:36(X1=D,X2=S,X3=S,X4=S,X5=S,X6=L,X7=R, X8=Y)和37(X1=R,X2=L,X3=V,X4=K,X5=Y,X6=Q,X7=I,X8=T)所示;305-L杵的结构同305-H2,除使用D12A4抗体可变区外,其长链和短链的氨基酸序列分别如SEQ ID NOs:36(X1=G,X2=D,X3=A,X4=H,X5=H,X6=I, X7=N,X8=Y)和37(X1=R,X2=R,X3=L,X4=K,X5=P,X6=H,X7=T,X8=R) 所示;305臼的长链包含BCMA抗体重链可变区-重链恒定区,氨基酸序列如SEQ ID NO:38所示,短链包含BCMA抗体轻链可变区-轻链恒定区,氨基酸序列如SEQ ID NO:39所示。在靶向BCMA的scFv中,轻链可变区的骨架做了一定的改造,以使scFv的结构更加稳定。
全基因合成305-H1杵、305-H2杵、305-M杵、305-L杵中的BCMA scFv-接头-CD3抗体重链可变区、以及305臼中的BCMA抗体重链可变区的DNA序列,利用限制性内切酶EcoRI和Nhe I分别对上述两个片段进行双酶切,并将酶切后的基因片段克隆至含各自重链恒定区的载体中,完成5个半抗重链全长基因的装配。全基因合成305-H1杵、305-H2杵、305-M杵、305-L杵中的CD3抗体轻链可变区、以及305臼中的BCMA抗体轻链可变区的DNA序列,利用限制性内切酶Cla I和 BsiW I分别对2个片段进行双酶切,并将酶切后的基因片段克隆至含轻链恒定区的载体中,完成5个半抗轻链全长基因的装配。分别采用Cla I和Hind III酶切半抗轻链全长基因,采用EcoRI和XhoI酶切半抗重链全长基因,HindIII和EcoR I 酶切pCMV-cofragment质粒,ClaI和XhoI酶切GS-载体。将回收的4个DNA片段进行连接、转化并挑取单克隆进行测序,获得含有正确序列的半抗表达载体,分别命名为MBS305-H1杵、MBS305-H2杵、MBS305-M杵、MBS305-L杵表达载体、和MBS305臼表达载体。将上述获得的表达载体通过PEI转染HEK-293F 细胞(Cobioer,中国),具体实验方法参考实施例3。转染后的HEK-293F细胞在 37℃、5%CO2的培养箱中以120RPM转速培养。10-12天后,收集细胞培养上清,3500rpm离心5分钟,并通过0.22μm滤膜过滤除去细胞碎片。单克隆抗体通过预平衡的protein-A亲和柱(Cat#:17040501,GE,美国)来富集纯化。后用洗脱缓冲液(20mM柠檬酸,pH3.0-pH3.5)进行洗脱。之后,抗体保存在PBS(pH 7.0) 中,并通过NanoDrop检测抗体浓度。
实施例14.CD3×BCMA双特异性抗体的组装
将纯化的半抗体进一步通过体外方式进行组装,分别将MBS305-H1杵、 MBS305-H2杵、MBS305-M杵、MBS305-L杵和MBS305臼半抗体以1:1的摩尔比混合,用Tris碱缓冲溶液调节至pH 8.0,添加一定量的还原型谷胱甘肽溶液,在25℃反应并低速搅拌过夜。反应结束后用2M醋酸溶液调节pH值至5.5。通过超滤去除还原剂,终止反应。装配后的抗体调至低盐Tris缓冲溶液(pH 8.0)中,用0.2μm的过滤膜过滤。首先采用低盐Tris缓冲溶液(pH8.0)平衡阴离子层析柱,然后将样品装载到阴离子层析柱,收集流穿组分,随后使用低盐Tris缓冲溶液 (pH8.0)进行冲洗直至UV280趋向于基线。用醋酸溶液将收集的流穿样品pH调至5.5。将阴离子收集的样品用30kDa超滤管浓缩至1mL,用0.2μm的过滤膜过滤。采用低浓度乙酸盐缓冲溶液(pH 5.5)平衡阳离子层析柱,将样品上样到阳离子层析柱中。上样完毕后,再用低浓度乙酸盐缓冲溶液(pH 5.5)平衡柱子,然后进行线性梯度洗脱,0-100%高浓度醋酸盐(pH 5.5),20CV,收集洗脱组分。
由MBS305-H1杵、MBS305-H2杵、MBS305-M杵、MBS305-L杵和MBS305 臼组装好的双抗命名为MBS305-H1-KIH、MBS305-H2-KIH、MBS305-M-KIH和 MBS305-L-KIH,纯化后的抗体经过质谱鉴定纯度高于90%,用于后续功能检测。
实施例15.CD3×BCMA双特异性抗体与人CD3以及人BCMA的结合活性
纯化的双特异性抗体首先通过ELISA检测来确定其与重组人CD3蛋白和人 BCMA蛋白的结合力,按照实施例4和实施例9中的步骤进行。CD3×BCMA抗体 EM801根据公开专利WO2016020332A1中的氨基酸序列43、44、45和46制备,用作参照。实验结果分别显示在图12和图13中。
如图12所示,MBS305-H1-KIH、MBS305-H2-KIH、MBS305-M-KIH、 MBS305-L-KIH和EM801均具有很强的CD3D&E蛋白结合活性,并且呈剂量依赖关系。采用GraphPad软件分析ELISA数据,抗体与CD3D&E结合的EC50值示于表6中。
如图13所示,MBS305-H1-KIH、MBS305-H2-KIH、MBS305-M-KIH、 MBS305-L-KIH和EM801均与人BCMA蛋白有着很强的结合力,并且呈剂量依赖关系。采用GraphPad软件分析ELISA数据,抗体与人BCMA结合的EC50值示于表6中。
表6.CD3-BCMA双特异抗体对CD3D&E以及BCMA的结合活性
根据实施例5和实施例10中的方法步骤,检测CD3×BCMA双特异性抗体 MBS305-H1-KIH、MBS305-H2-KIH、MBS305-M-KIH、MBS305-L-KIH和EM801 与CD3D&E蛋白以及人BCMA的亲和力。根据Biacore 8K评估软件进行拟合,获得CD3-BCMA双特异抗体结合KD值,示于表7和表8中。
从表7可知,MBS305-H1-KIH、MBS305-H2-KIH、MBS305-M-KIH、 MBS305-L-KIH和EM801均能与CD3D&E复合体蛋白结合。
由表8可知,MBS305-H1-KIH、MBS305-H2-KIH、MBS305-M-KIH、 MBS305-L-KIH和EM801均与人BCMA有着很强的亲和力,且MBS305系列双抗的亲和力高于EM801。
表7.CD3-BCMA双特异抗体对人CD3D&E复合体的亲和力
Ka | Kd | KD | |
305-H1-KIH | 4.74E+04 | 3.84E-04 | 8.09E-09 |
305-H2-KIH | 3.03E+04 | 7.76E-03 | 2.56E-07 |
305-M-KIH | 4.36E+04 | 1.65E-03 | 3.79E-08 |
305-L-KIH | 1.79E+04 | 1.03E-02 | 6.75E-07 |
EM801 | 1.38E+05 | 6.82E-03 | 4.93E-08 |
表8.MBS305-H2-KIH和EM801对人BCMA的亲和力
Ka | Kd | KD | |
305-H1-KIH | 8.07E+05 | 1.36E-04 | 1.68E-10 |
305-H2-KIH | 7.14E+05 | 1.47E-04 | 2.06E-10 |
305-M-KIH | 9.40E+05 | 9.89E-05 | 1.05E-10 |
305-L-KIH | 8.77E+05 | 2.32E-04 | 2.32E-10 |
EM801 | 1.36E+06 | 3.22E-03 | 2.37E-09 |
实施例16.CD3×BCMA双特异性抗体与293A-BCMA细胞以及Jurkat细胞的结合力
根据实施例6中的方法步骤,经FACS检测CD3×BCMA双特异性抗体MBS305-H1-KIH、MBS305-H2-KIH、MBS305-M-KIH、MBS305-L-KIH以及EM801 与HEK293A/人BCMA、HEK293A/猴BCMA、以及HEK293A/小鼠BCMA(实施例1制备)的结合力。实验结果显示在图14中。
如图14(A-D)所示,MBS305系列双特异抗体和EM801与HEK293A/人BCMA 以及HEK293A/猴BCMA细胞有很强的结合力,并且呈剂量依赖关系。MBS305 系列双特异抗体和EM801与HEK293A/人BCMA的结合活性相当,MBS305系列双特异抗体与HEK293A/猴BCMA的结合活性高于EM801。采用GraphPad软件分析数据,MBS305系列双特异抗体和EM801与HEK293A/人BCMA、HEK293A/ 猴BCMA细胞和HEK293A/小鼠BCMA细胞结合的EC50值示于表9中。
表9.MBS305-H2-KIH和EM801与表达BCMA的293A细胞的结合活性
根据实施例11中的方法步骤,检测CD3×BCMA双特异性抗体 MBS305-H1-KIH、MBS305-H2-KIH、MBS305-M-KIH、MBS305-L-KIH和EM801 与Jurkat细胞的结合力。实验结果显示在图15中。
如图15所示,MBS305系列双特异抗体和EM801与Jurket细胞有很强的结合力,并且呈剂量依赖关系。采用GraphPad软件分析数据,MBS305系列双特异抗体和EM801与Jurkat细胞结合的EC50值示于表10中。
表10.MBS305-H2-KIH和EM801与Jurkat细胞的结合活性
实施例17.CD3×BCMA双特异性抗体对人PBMC中T细胞的活化
为进一步确定游离的CD3×BCMA双特异性抗体对PBMC中CD3/TCR信号通路的激动性,进行人原代PBMC细胞激活检测。通过梯度密度离心的方式获得健康人供体血样中的PBMC,PBMC细胞用完全RPMI培养基(RPMI1640+10%FBS) 重悬,调整细胞密度为2.5×105/ml,将上述细胞悬液加入96孔细胞培养板(200μl/ 孔),并加入50μl不同浓度的本申请双特异性抗体,37℃、5%CO2孵育48小时后,收集上清。使用制造商的方法步骤,经ELISA试剂盒(Cat#:430107,Biolegend,美国;Cat#:430504,Biolegend,美国;Cat#:430207,Biolegend,美国)分别确定上清中的IFN-γ浓度、IL-6浓度和TNF-α浓度。EM801作为实验的阳性对照抗体。
实验结果如图16所示,EM801显著诱导PBMC分泌IFN-γ(A)、IL-6(B) 和TNF-α(C),而MBS305系列双特异抗体处理的上清中没有检测到上述细胞因子的释放,表明EM801在临床应用中引起细胞因子风暴的风险远远高于 MBS305-H2-KIH。
实施例18.CD3×BCMA双特异性抗体介导PBMC杀伤BCMA阳性肿瘤细胞以及在杀伤
体系下活化T细胞的能力
对双特异性抗体进一步分析其诱导人PBMC对BCMA阳性HEK293A/人 BCMA细胞的杀伤能力,其中实施例1中构建的HEK293A/人BCMA细胞本底表达GFP的绿色荧光蛋白。
具体而言,将HEK293A/人BCMA细胞重悬于RPMI完全培养基(RPMI +10%FBS)中,并将细胞密度调整成2.5×105活细胞/ml。人PBMC使用淋巴分离液通过密度梯度离心而获得,细胞密度调整成5×105活细胞/ml,重悬于完全培养基(RIPM1640+10%FBS)中。将上述细胞各100μl加入96孔板(效应细胞和靶细胞比例2:1),并加入100μl不同浓度的双特异性抗体。细胞和抗体的混合物在37℃、5%CO2的培养箱中培养48小时。之后,各吸取50μl细胞培养基上清,按照制造商的方法步骤,经两个试剂盒(Cat#:430504,Biolegend,美国;Cat#:430207,Biolegend,美国)确定IL-6、和TNF-α的分泌浓度。
抗体介导的对于靶细胞HEK293A/人BCMA的杀伤效果经LIVE/DEAD可固定死细胞染色试剂盒(Thermo Fisher,USA,Cat#:L34964)检测。将上述培养的细胞混合物用PBS洗3遍,然后与LIVE/DEAD可固定死细胞染料于37℃孵育30 分钟。细胞用PBS洗3遍,用FACS进行检测。计算出绿色荧光阳性细胞(HEK293A/ 人BCMA细胞)的细胞死亡率。
实验结果如图17(A)所示,低浓度(1ng/ml)的EM801对靶细胞HEK293A/ 人BCMA的杀伤效果好于MBS305系列双特异抗体,但是当抗体浓度升高到10 ng/ml以后,EM801和MBS305系列双特异抗体有着相当的肿瘤杀伤效果。而不同浓度的MBS305系列双特异抗体诱导产生的细胞因子(包括IL-6(B)和TNF-α (C))浓度都显著低于EM801。因此,在高于10ng/ml的抗体浓度下,MBS305 系列双特异抗体有着与EM801相当的BCMA肿瘤细胞杀伤能力,但其诱导产生的细胞因子水平更低,保持相当药效的情况下,其安全性更高。
本申请的示例性序列如下所示。
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尽管本申请已经结合一个或多个实施方式进行了描述,应当理解的是,本发明不限于这些实施方式,且上述描述意在涵盖包含在所附权利要求的精神和范围内的所有其他可选形式、修饰和等同物。本文中应用的文献均通过引用的方式全部并入本文。
序列表
<110> 北京天广实生物技术股份有限公司
<120> 结合BCMA和CD3的抗体及其用途
<130> 55556 00071
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<170> PatentIn版本3.5
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Asn His Ile Ile His
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<212> PRT
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Tyr Ile Asn Pro Tyr Pro Gly Tyr His Gly Tyr Asn Asp Lys Phe Ser
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Gly
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Asp Gly Tyr Tyr Arg Asp Gln Asp Val Leu Asp Tyr
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<212> PRT
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Lys Ala Ser Gln Asp Ile Ser Gln Tyr Leu Asn
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Tyr Thr Ser Gly Leu His Pro
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Gln Gln Gly Tyr Ala Leu Pro Trp Thr
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<223> BCMA抗体A6-3的VH
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
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Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Gly Tyr Asn Asp Lys Phe
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Ser Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Asp Gly Tyr Tyr Arg Asp Gln Asp Val Leu Asp Tyr Trp Gly
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Gln Gly Thr Leu Val Thr Val Ser Ser
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<223> BCMA抗体A6-3的VL
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<221> 其他特征
<222> (83)..(83)
<223> Xaa可以是Ile或Glu
<220>
<221> 其他特征
<222> (104)..(104)
<223> Xaa可以是Val或Leu
<220>
<221> 其他特征
<222> (105)..(105)
<223> Xaa可以是Glu或Thr
<220>
<221> 其他特征
<222> (106)..(106)
<223> Xaa可以是Ile或Ala
<220>
<221> 其他特征
<222> (108)..(108)
<223> Xaa可以是无或Arg
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
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Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Ser Gln Tyr
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Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
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Tyr Tyr Thr Ser Gly Leu His Pro Gly Val Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Pro
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Glu Asp Xaa Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Leu Pro Trp
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Thr Phe Gly Gln Gly Thr Lys Xaa Xaa Xaa Lys Xaa
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<212> PRT
<213> 人工序列
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<223> CD3D&E抗体D1E9的VH-CDR1
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Asp Phe Ala Met His
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<213> 人工序列
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<223> CD3D&E抗体D1E9的VH-CDR2
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Gly Ile Thr Trp Asn Ser Gly Ser Val Gly Tyr Ala Asp Ser Val Lys
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Gly
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<213> 人工序列
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<223> CD3D&E抗体D1E9的VH-CDR3
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Asp Arg Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val
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<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体D1E9的VL-CDR1
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Arg Ala Ser Thr Ser Val Ser His Asn Val Ala
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<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体D1E9的VL-CDR2
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Gly Ala Ser Thr Lys Val Thr
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<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体D1E9的VL-CDR3
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Gln His Tyr Ile Asn Trp Pro Leu Thr
1 5
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<213> 人工序列
<220>
<223> CD3D&E抗体D1E9的VH
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Phe
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Ser Gly Ile Thr Trp Asn Ser Gly Ser Val Gly Tyr Ala Asp Ser Val
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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
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Ala Lys Asp Arg Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ala Ser
115 120
<210> 16
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体D1E9的VL
<400> 16
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 Thr Ser Val Ser His Asn
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Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
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Tyr Gly Ala Ser Thr Lys Val Thr Gly Ile Pro Ala Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
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Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Ile Asn Trp Pro Leu
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Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
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<210> 17
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 人IgG1 Fc-野生型/IgG1 Fc L234A/L235A/N297A/带杵长链中的IgG1 Fc
L234A/L235A/N297A/T366W/带臼长链中的IgG1 Fc
<220>
<221> 其他特征
<222> (117)..(117)
<223> Xaa可以是Leu或Ala
<220>
<221> 其他特征
<222> (118)..(118)
<223> Xaa可以是Leu或Ala
<220>
<221> 其他特征
<222> (180)..(180)
<223> Xaa可以是Asn或Ala
<220>
<221> 其他特征
<222> (249)..(249)
<223> Xaa可以是Thr、Trp或Ser
<220>
<221> 其他特征
<222> (251)..(251)
<223> Xaa可以是Leu或Ala
<220>
<221> 其他特征
<222> (290)..(290)
<223> Xaa可以是Tyr或Val
<400> 17
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
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Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
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Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
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Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
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Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
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Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Xaa Xaa Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Xaa Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
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His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Xaa Cys Xaa Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Xaa Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 18
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> κ轻链恒定区
<400> 18
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
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Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
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Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 19
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 19
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> 20
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 20
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 21
<211> 184
<212> PRT
<213> 智人(Homo sapiens)
<400> 21
Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser
1 5 10 15
Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr
20 25 30
Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser
35 40 45
Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu
50 55 60
Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile
65 70 75 80
Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu
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Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu
100 105 110
Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys
115 120 125
Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe
130 135 140
Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys
145 150 155 160
Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu
165 170 175
Ile Glu Lys Ser Ile Ser Ala Arg
180
<210> 22
<211> 183
<212> PRT
<213> 豚尾猴(Macaca nemestrina)
<400> 22
Met Leu Gln Met Ala Arg Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser
1 5 10 15
Leu Leu His Asp Cys Lys Pro Cys Gln Leu Arg Cys Ser Ser Thr Pro
20 25 30
Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Met Thr Asn Ser Val
35 40 45
Lys Gly Met Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu Ile
50 55 60
Ile Ser Leu Ala Val Phe Val Leu Thr Phe Leu Leu Arg Lys Met Ser
65 70 75 80
Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu Leu
85 90 95
Gly Met Ala Asn Ile Asp Leu Glu Lys Gly Arg Thr Gly Asp Glu Ile
100 105 110
Val Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys Glu
115 120 125
Asp Cys Ile Lys Asn Lys Pro Lys Val Asp Ser Asp His Cys Phe Pro
130 135 140
Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys Thr
145 150 155 160
Asn Asp Tyr Cys Asn Ser Leu Ser Ala Ala Leu Ser Val Thr Glu Ile
165 170 175
Glu Lys Ser Ile Ser Ala Arg
180
<210> 23
<211> 185
<212> PRT
<213> 小鼠(Mus musculus)
<400> 23
Met Ala Gln Gln Cys Phe His Ser Glu Tyr Phe Asp Ser Leu Leu His
1 5 10 15
Ala Cys Lys Pro Cys His Leu Arg Cys Ser Asn Pro Pro Ala Thr Cys
20 25 30
Gln Pro Tyr Cys Asp Pro Ser Val Thr Ser Ser Val Lys Gly Thr Tyr
35 40 45
Thr Val Leu Trp Ile Phe Leu Gly Leu Thr Leu Val Leu Ser Leu Ala
50 55 60
Leu Phe Thr Ile Ser Phe Leu Leu Arg Lys Met Asn Pro Glu Ala Leu
65 70 75 80
Lys Asp Glu Pro Gln Ser Pro Gly Gln Leu Asp Gly Ser Ala Gln Leu
85 90 95
Asp Lys Ala Asp Thr Glu Leu Thr Arg Ile Arg Ala Gly Asp Asp Arg
100 105 110
Ile Phe Pro Arg Ser Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys Glu
115 120 125
Asp Cys Val Lys Ser Lys Pro Lys Gly Asp Ser Asp His Phe Phe Pro
130 135 140
Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys Thr
145 150 155 160
Gly Asp Tyr Gly Lys Ser Ser Val Pro Thr Ala Leu Gln Ser Val Met
165 170 175
Gly Met Glu Lys Pro Thr His Thr Arg
180 185
<210> 24
<211> 184
<212> PRT
<213> 智人
<400> 24
Met Arg Arg Gly Pro Arg Ser Leu Arg Gly Arg Asp Ala Pro Ala Pro
1 5 10 15
Thr Pro Cys Val Pro Ala Glu Cys Phe Asp Leu Leu Val Arg His Cys
20 25 30
Val Ala Cys Gly Leu Leu Arg Thr Pro Arg Pro Lys Pro Ala Gly Ala
35 40 45
Ser Ser Pro Ala Pro Arg Thr Ala Leu Gln Pro Gln Glu Ser Val Gly
50 55 60
Ala Gly Ala Gly Glu Ala Ala Leu Pro Leu Pro Gly Leu Leu Phe Gly
65 70 75 80
Ala Pro Ala Leu Leu Gly Leu Ala Leu Val Leu Ala Leu Val Leu Val
85 90 95
Gly Leu Val Ser Trp Arg Arg Arg Gln Arg Arg Leu Arg Gly Ala Ser
100 105 110
Ser Ala Glu Ala Pro Asp Gly Asp Lys Asp Ala Pro Glu Pro Leu Asp
115 120 125
Lys Val Ile Ile Leu Ser Pro Gly Ile Ser Asp Ala Thr Ala Pro Ala
130 135 140
Trp Pro Pro Pro Gly Glu Asp Pro Gly Thr Thr Pro Pro Gly His Ser
145 150 155 160
Val Pro Val Pro Ala Thr Glu Leu Gly Ser Thr Glu Leu Val Thr Thr
165 170 175
Lys Thr Ala Gly Pro Glu Gln Gln
180
<210> 25
<211> 293
<212> PRT
<213> 智人
<400> 25
Met Ser Gly Leu Gly Arg Ser Arg Arg Gly Gly Arg Ser Arg Val Asp
1 5 10 15
Gln Glu Glu Arg Phe Pro Gln Gly Leu Trp Thr Gly Val Ala Met Arg
20 25 30
Ser Cys Pro Glu Glu Gln Tyr Trp Asp Pro Leu Leu Gly Thr Cys Met
35 40 45
Ser Cys Lys Thr Ile Cys Asn His Gln Ser Gln Arg Thr Cys Ala Ala
50 55 60
Phe Cys Arg Ser Leu Ser Cys Arg Lys Glu Gln Gly Lys Phe Tyr Asp
65 70 75 80
His Leu Leu Arg Asp Cys Ile Ser Cys Ala Ser Ile Cys Gly Gln His
85 90 95
Pro Lys Gln Cys Ala Tyr Phe Cys Glu Asn Lys Leu Arg Ser Pro Val
100 105 110
Asn Leu Pro Pro Glu Leu Arg Arg Gln Arg Ser Gly Glu Val Glu Asn
115 120 125
Asn Ser Asp Asn Ser Gly Arg Tyr Gln Gly Leu Glu His Arg Gly Ser
130 135 140
Glu Ala Ser Pro Ala Leu Pro Gly Leu Lys Leu Ser Ala Asp Gln Val
145 150 155 160
Ala Leu Val Tyr Ser Thr Leu Gly Leu Cys Leu Cys Ala Val Leu Cys
165 170 175
Cys Phe Leu Val Ala Val Ala Cys Phe Leu Lys Lys Arg Gly Asp Pro
180 185 190
Cys Ser Cys Gln Pro Arg Ser Arg Pro Arg Gln Ser Pro Ala Lys Ser
195 200 205
Ser Gln Asp His Ala Met Glu Ala Gly Ser Pro Val Ser Thr Ser Pro
210 215 220
Glu Pro Val Glu Thr Cys Ser Phe Cys Phe Pro Glu Cys Arg Ala Pro
225 230 235 240
Thr Gln Glu Ser Ala Val Thr Pro Gly Thr Pro Asp Pro Thr Cys Ala
245 250 255
Gly Arg Trp Gly Cys His Thr Arg Thr Thr Val Leu Gln Pro Cys Pro
260 265 270
His Ile Pro Asp Ser Gly Leu Gly Ile Val Cys Val Pro Ala Gln Glu
275 280 285
Gly Gly Pro Gly Ala
290
<210> 26
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体7-1-A12、D8E5、D12A4的VH-CDR1
<220>
<221> 其他特征
<222> (1)..(1)
<223> Xaa可以是Asp或Ser
<220>
<221> 其他特征
<222> (3)..(3)
<223> Xaa可以是Thr、Ser或Ala
<400> 26
Xaa Tyr Xaa Met His
1 5
<210> 27
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体7-1-A12、D8E5、D12A4的VH-CDR2
<220>
<221> 其他特征
<222> (6)..(6)
<223> Xaa可以是Thr、Ser或His
<220>
<221> 其他特征
<222> (8)..(8)
<223> Xaa可以是Thr、Ser或His
<220>
<221> 其他特征
<222> (9)..(9)
<223> Xaa可以是Ile或Leu
<400> 27
Gly Ile Ser Trp Asn Xaa Gly Xaa Xaa Gly Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 28
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体7-1-A12、D8E5、D12A4的VH-CDR3
<220>
<221> 其他特征
<222> (2)..(2)
<223> Xaa可以是Asn或Arg
<220>
<221> 其他特征
<222> (10)..(10)
<223> Xaa可以是Phe或Tyr
<400> 28
Asp Xaa Ser Gly Tyr Gly His Tyr Tyr Xaa Gly Met Asp Val
1 5 10
<210> 29
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体7-1-A12、D8E5、D12A4的VL-CDR1
<220>
<221> 其他特征
<222> (4)..(4)
<223> Xaa可以是Gln或Arg
<220>
<221> 其他特征
<222> (8)..(8)
<223> Xaa可以是Arg或Leu
<220>
<221> 其他特征
<222> (10)..(10)
<223> Xaa可以是Val或Leu
<400> 29
Arg Ala Ser Xaa Ser Val Ser Xaa Asn Xaa Ala
1 5 10
<210> 30
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体7-1-A12、D8E5、D12A4的VL-CDR2
<220>
<221> 其他特征
<222> (5)..(5)
<223> Xaa可以是Arg或Lys
<220>
<221> 其他特征
<222> (6)..(6)
<223> Xaa可以是Gln、Tyr或Pro
<400> 30
Gly Ala Ser Thr Xaa Xaa Thr
1 5
<210> 31
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体7-1-A12、D8E5、D12A4的VL-CDR2
<220>
<221> 其他特征
<222> (2)..(2)
<223> Xaa可以是Ser、Gln或His
<220>
<221> 其他特征
<222> (4)..(4)
<223> Xaa可以是Ile或Thr
<220>
<221> 其他特征
<222> (9)..(9)
<223> Xaa可以是Gln、Thr或Arg
<400> 31
Gln Xaa Tyr Xaa Asn Trp Pro Leu Xaa
1 5
<210> 32
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体7-1-A12、D8E5、D12A4 的VH
<220>
<221> 其他特征
<222> (30)..(30)
<223> Xaa可以是Ser、Asp或Gly
<220>
<221> 其他特征
<222> (31)..(31)
<223> Xaa可以是Asp或Ser
<220>
<221> 其他特征
<222> (33)..(33)
<223> Xaa可以是Thr、Ser或Ala
<220>
<221> 其他特征
<222> (55)..(55)
<223> Xaa可以是Thr、Ser或His
<220>
<221> 其他特征
<222> (57)..(57)
<223> Xaa可以是Thr、Ser或His
<220>
<221> 其他特征
<222> (58)..(58)
<223> Xaa可以是Ile或Leu
<220>
<221> 其他特征
<222> (100)..(100)
<223> Xaa可以是Asn或Arg
<220>
<221> 其他特征
<222> (108)..(108)
<223> Xaa可以是Phe或Tyr
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Xaa Tyr
20 25 30
Xaa Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Xaa Gly Xaa Xaa Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Xaa Ser Gly Tyr Gly His Tyr Tyr Xaa Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ala Ser
115 120
<210> 33
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> CD3D&E抗体7-1-A12、D8E5、D12A4 的VL
<220>
<221> 其他特征
<222> (27)..(27)
<223> Xaa可以是Gln或Arg
<220>
<221> 其他特征
<222> (31)..(31)
<223> Xaa可以是Arg或Leu
<220>
<221> 其他特征
<222> (33)..(33)
<223> Xaa可以是Val或Leu
<220>
<221> 其他特征
<222> (54)..(54)
<223> Xaa可以是Arg或Lys
<220>
<221> 其他特征
<222> (55)..(55)
<223> Xaa可以是Gln、Tyr或Pro
<220>
<221> 其他特征
<222> (90)..(90)
<223> Xaa可以是Ser、Gln或His
<220>
<221> 其他特征
<222> (92)..(92)
<223> Xaa可以是Ile或Thr
<220>
<221> 其他特征
<222> (97)..(97)
<223> Xaa可以是Gln、Thr或Arg
<400> 33
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 Xaa Ser Val Ser Xaa Asn
20 25 30
Xaa Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Xaa Xaa 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 Xaa Tyr Xaa Asn Trp Pro Leu
85 90 95
Xaa Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 34
<211> 717
<212> PRT
<213> 人工序列
<220>
<223> 305-H2杵长链
<400> 34
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Gly Tyr Asn Asp Lys Phe
50 55 60
Ser Gly Arg Ala Thr Met Thr Ser 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 Asp Gly Tyr Tyr Arg Asp Gln Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Ser Gln Tyr Leu Asn Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr
180 185 190
Ser Gly Leu His Pro Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Glu
210 215 220
Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Leu Pro Trp Thr Phe Gly
225 230 235 240
Gln Gly Thr Lys Leu Thr Ala Lys Arg Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
260 265 270
Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala
275 280 285
Ser Gly Phe Thr Phe Asp Asp Phe Ala Met His Trp Val Arg Gln Ala
290 295 300
Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Thr Trp Asn Ser Gly
305 310 315 320
Ser Val Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
325 330 335
Asp Asn Ala Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
340 345 350
Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Arg Ser Gly Tyr Gly
355 360 365
His Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
370 375 380
Val Ala Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
385 390 395 400
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
405 410 415
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
420 425 430
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
435 440 445
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
450 455 460
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
465 470 475 480
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
485 490 495
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu
500 505 510
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
515 520 525
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
530 535 540
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
545 550 555 560
Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu
565 570 575
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
580 585 590
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
595 600 605
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
610 615 620
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys
625 630 635 640
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
645 650 655
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
660 665 670
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
675 680 685
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
690 695 700
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
705 710 715
<210> 35
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 305-H2杵短链
<400> 35
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 Thr Ser Val Ser His Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Lys Val 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 His Tyr Ile Asn Trp Pro Leu
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> 36
<211> 717
<212> PRT
<213> 人工序列
<220>
<223> 305-H1、305-M、305-L杵长链
<220>
<221> 其他特征
<222> (294)..(294)
<223> Xaa可以是Ser、Asp或Gly
<220>
<221> 其他特征
<222> (295)..(295)
<223> Xaa可以是Asp或Ser
<220>
<221> 其他特征
<222> (297)..(297)
<223> Xaa可以是Thr、Ser或Ala
<220>
<221> 其他特征
<222> (319)..(319)
<223> Xaa可以是Thr、Ser或His
<220>
<221> 其他特征
<222> (321)..(321)
<223> Xaa可以是Thr、Ser或His
<220>
<221> 其他特征
<222> (322)..(322)
<223> Xaa可以是Ile或Leu
<220>
<221> 其他特征
<222> (364)..(364)
<223> Xaa可以是Asn或Arg
<220>
<221> 其他特征
<222> (372)..(372)
<223> Xaa可以是Phe或Tyr
<400> 36
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Gly Tyr Asn Asp Lys Phe
50 55 60
Ser Gly Arg Ala Thr Met Thr Ser 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 Asp Gly Tyr Tyr Arg Asp Gln Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Ser Gln Tyr Leu Asn Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr
180 185 190
Ser Gly Leu His Pro Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Glu
210 215 220
Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Leu Pro Trp Thr Phe Gly
225 230 235 240
Gln Gly Thr Lys Leu Thr Ala Lys Arg Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
260 265 270
Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala
275 280 285
Ser Gly Phe Thr Phe Xaa Xaa Tyr Xaa Met His Trp Val Arg Gln Ala
290 295 300
Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Ser Trp Asn Xaa Gly
305 310 315 320
Xaa Xaa Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
325 330 335
Asp Asn Ala Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
340 345 350
Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Xaa Ser Gly Tyr Gly
355 360 365
His Tyr Tyr Xaa Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
370 375 380
Val Ala Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
385 390 395 400
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
405 410 415
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
420 425 430
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
435 440 445
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
450 455 460
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
465 470 475 480
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
485 490 495
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu
500 505 510
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
515 520 525
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
530 535 540
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
545 550 555 560
Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu
565 570 575
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
580 585 590
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
595 600 605
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
610 615 620
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys
625 630 635 640
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
645 650 655
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
660 665 670
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
675 680 685
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
690 695 700
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
705 710 715
<210> 37
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 305-H1、305-M、305-L杵短链
<220>
<221> 其他特征
<222> (27)..(27)
<223> Xaa可以是Gln或Arg
<220>
<221> 其他特征
<222> (31)..(31)
<223> Xaa可以是Arg或Leu
<220>
<221> 其他特征
<222> (33)..(33)
<223> Xaa可以是Val或Leu
<220>
<221> 其他特征
<222> (54)..(54)
<223> Xaa可以是Arg或Lys
<220>
<221> 其他特征
<222> (55)..(55)
<223> Xaa可以是Gln、Tyr或Pro
<220>
<221> 其他特征
<222> (90)..(90)
<223> Xaa可以是Ser、Gln或His
<220>
<221> 其他特征
<222> (92)..(92)
<223> Xaa可以是Ile或Thr
<220>
<221> 其他特征
<222> (97)..(97)
<223> Xaa可以是Gln、Thr或Arg
<400> 37
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 Xaa Ser Val Ser Xaa Asn
20 25 30
Xaa Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Xaa Xaa 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 Xaa Tyr Xaa Asn Trp Pro Leu
85 90 95
Xaa 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> 38
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 305-H1、305-H2、305-M、305-L臼长链
<400> 38
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Gly Tyr Asn Asp Lys Phe
50 55 60
Ser Gly Arg Ala Thr Met Thr Ser 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 Asp Gly Tyr Tyr Arg Asp Gln Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 39
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 305-H1、305-H2、305-M、305-L臼短链
<400> 39
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Ser Gln Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Gly Leu His Pro Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Leu Pro Trp
85 90 95
Thr Phe Gly Gln 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
Claims (18)
1.一种分离的单克隆抗体或其抗原结合片段,与BCMA特异结合,包含重链可变区和轻链可变区,该重链可变区包含VH CDR1区、VH CDR2区和VH CDR3区,该轻链可变区包含VLCDR1区、VL CDR2区和VL CDR3区,其中VH CDR1区、VH CDR2区、VH CDR3区、VL CDR1区、VLCDR2区和VL CDR3区的氨基酸序列分别如SEQ ID NOs:1、2、3、4、5和6所示。
2.根据权利要求1所述的分离的单克隆抗体或其抗原结合片段,其中所述重链可变区包含SEQ ID NO:7所示的氨基酸序列。
3.根据权利要求1所述的分离的单克隆抗体或其抗原结合片段,其中,所述轻链可变区包含SEQ ID NO:8(X1=I、X2=V、X3=E、X4=I、X5=无;或X1=E、X2=L、X3=T、X4=A、X5=R)所示的氨基酸序列。
4.根据权利要求2所述的分离的单克隆抗体或其抗原结合片段,其中所述重链可变区和所述轻链可变区分别包含(1)SEQ ID NOs:7和8(X1=I、X2=V、X3=E、X4=I、X5=无);或(2)SEQ ID NOs:7和8(X1=E、X2=L、X3=T、X4=A、X5=R)所示的氨基酸序列。
5.根据权利要求1所述的分离的单克隆抗体或其抗原结合片段,包含重链恒定区和轻链恒定区,其中重链恒定区包含SEQ ID NO:17(X1=L、X2=L、X3=N、X4=T、X5=L、X6=Y)的氨基酸序列,轻链恒定区包含SEQ ID NO:18所示的氨基酸序列。
6.一种免疫偶联物、嵌合抗原受体(CAR)、或基因改造T细胞受体(TCR),包含权利要求1-5中任一项所述的分离的单克隆抗体或其抗原结合片段。
7.一种双特异性分子,包含
i)与CD3特异结合的抗原结合域,其包含与CD3特异结合的抗体或其抗原结合片段,其中该抗体或其抗原结合片段包含重链可变区和轻链可变区,该重链可变区包含VH CDR1区、VH CDR2区和VH CDR3区,该轻链可变区包含VL CDR1区、VL CDR2区和VL CDR3区,其中VHCDR1区、VH CDR2区、VH CDR3区、VL CDR1区、VL CDR2区和VL CDR3区的氨基酸序列分别如1)SEQ ID NOs:9、10、11、12、13和14;2)SEQ ID NOs:26(X1=D,X2=T)、27(X1=T,X2=T,X3=I)、28(X1=N,X2=F)、29(X1=Q,X2=R,X3=V)、30(X1=R,X2=Q)、和31(X1=S,X2=I,X3=Q);3)SEQ ID NOs:26(X1=S,X2=S)、27(X1=S,X2=S,X3=L)、28(X1=R,X2=Y)、29(X1=R,X2=L,X3=V)、30(X1=K,X2=Y)、和31(X1=Q,X2=I,X3=T);或4)SEQ ID NOs:26(X1=D,X2=A)、27(X1=H,X2=H,X3=I)、28(X1=N,X2=Y)、29(X1=R,X2=R,X3=L)、30(X1=K,X2=P)、和31(X1=H,X2=T,X3=R)所示,以及
ii)与BCMA特异结合的抗原结合域,其包含权利要求1-5中任一项所述的分离的单克隆抗体或其抗原结合片段。
8.如权利要求7所述的双特异性分子,包含一个与CD3特异结合的抗原结合域、以及两个与BCMA特异结合的抗原结合域。
9.如权利要求8所述的双特异性分子,包含
i)第一多肽链,含有特异结合BCMA的重链可变区、和重链恒定区;
ii)第二多肽链,含有特异结合BCMA的轻链可变区;
iii)第三多肽链,含有特异结合BCMA的重链可变区、特异结合BCMA的轻链可变区、特异结合CD3的重链可变区、和重链恒定区;以及
iv)第四多肽链,含有特异结合CD3的轻链可变区,
其中第一多肽链中特异结合BCMA的重链可变区和第二多肽链的轻链可变区结合形成能够特异结合BCMA的抗原结合片段,第三多肽链中特异结合BCMA的重链可变区和特异结合BCMA的轻链可变区结合形成能够特异结合BCMA的抗原结合片段,第三多肽链中特异结合CD3的重链可变区与第四多肽链中特异结合CD3的轻链可变区结合形成能够特异地结合CD3的抗原结合片段,且第一多肽链的重链恒定区与第三多肽链的重链恒定区结合在一起。
10.如权利要求9所述的双特异性分子,其中与CD3特异结合的抗体或其抗原结合片段的重链可变区和轻链可变区分别包含1)SEQ ID NOs:15和16;2)SEQ ID NOs:32(X1=S,X2=D,X3=T,X4=T,X5=T,X6=I,X7=N,X8=F)和33(X1=Q,X2=R,X3=V,X4=R,X5=Q,X6=S,X7=I,X8=Q);3)SEQ ID NOs:32(X1=D,X2=S,X3=S,X4=S,X5=S,X6=L,X7=R,X8=Y)和33(X1=R,X2=L,X3=V,X4=K,X5=Y,X6=Q,X7=I,X8=T);或4)SEQ ID NOs:32(X1=G,X2=D,X3=A,X4=H,X5=H,X6=I,X7=N,X8=Y)和33(X1=R,X2=R,X3=L,X4=K,X5=P,X6=H,X7=T,X8=R)所示的氨基酸序列。
11.如权利要求9所述的双特异性分子,其中,第一多肽链的重链恒定区含有SEQ IDNO:17(X1=A、X2=A、X3=A、X4=S、X5=A、X6=V)所示的氨基酸序列,第三多肽链的重链恒定区含有SEQ ID NO:17(X1=A、X2=A、X3=A、X4=W、X5=L、X6=Y)所示的氨基酸序列。
12.如权利要求9所述的双特异性分子,其中,第一多肽链从N端至C端含有特异结合BCMA的重链可变区和重链恒定区,第三多肽链从N端至C端含有特异结合BCMA的重链可变区、特异结合BCMA的轻链可变区、特异结合CD3的重链可变区、和重链恒定区。
13.如权利要求12所述的双特异性分子,其中,在第三多肽链中,特异结合BCMA的重链可变区经SEQ ID NO:19所示的接头与特异结合BCMA的轻链可变区连接,且特异结合BCMA的轻链可变区经SEQ ID NO:20所示的接头与特异结合CD3的重链可变区连接。
14.如权利要求9所述的双特异性分子,其中第一多肽链、第二多肽链、第三多肽链、和第四多肽链,分别包含1)SEQ ID NOs:38、39、34、和35;2)SEQ ID NOs:38、39、36(X1=S,X2=D,X3=T,X4=T,X5=T,X6=I,X7=N,X8=F)、和37(X1=Q,X2=R,X3=V,X4=R,X5=Q,X6=S,X7=I,X8=Q);3)SEQ ID NOs:38、39、36(X1=D,X2=S,X3=S,X4=S,X5=S,X6=L,X7=R,X8=Y)、和37(X1=R,X2=L,X3=V,X4=K,X5=Y,X6=Q,X7=I,X8=T);或4)SEQ IDNOs:38、39、36(X1=G,X2=D,X3=A,X4=H,X5=H,X6=I,X7=N,X8=Y)、和37(X1=R,X2=R,X3=L,X4=K,X5=P,X6=H,X7=T,X8=R)所示的氨基酸序列。
15.一种核酸,编码权利要求1-5中任一项所述的分离的单克隆抗体或其抗原结合部分、或权利要求7-14中任一项所述的双特异性分子。
16.一种药物组合物,包含权利要求1-5中任一项所述的分离的单克隆抗体或其抗原结合部分、权利要求6中所述的免疫偶联物、嵌合抗原受体(CAR)、或基因改造T细胞受体(TCR)、或权利要求7-14中任一项所述的双特异性分子,以及药学上可接受的载体。
17.权利要求16所述的药物组合物在制备治疗或缓解BCMA相关疾病的药物中的用途。
18.如权利要求16所述的用途,其中BCMA相关疾病为多发性骨髓瘤、浆细胞瘤、浆细胞白血病、巨球蛋白血症、淀粉样变性、孤立性骨浆细胞瘤、髓外浆细胞瘤、骨硬化性骨髓瘤、重链病、或意义不明确的单克隆丙种球蛋白病。
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