CN109476741A - 与cd38和pd-l1结合的分子 - Google Patents
与cd38和pd-l1结合的分子 Download PDFInfo
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- CN109476741A CN109476741A CN201780028279.6A CN201780028279A CN109476741A CN 109476741 A CN109476741 A CN 109476741A CN 201780028279 A CN201780028279 A CN 201780028279A CN 109476741 A CN109476741 A CN 109476741A
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Abstract
本发明涉及一种双特异性分子,所述双特异性分子包含至少一个抗‑CD38结构域和至少一个抗‑PD‑L1结构域,其能够同时分别结合至CD38和PD‑L1抗原。
Description
本发明涉及CD38/PD-L1结合分子,特别是靶向CD38和PD-L1的抗体,用于生产这些分子的方法,以及其组合物和用途。
背景技术
多发性骨髓瘤(MM)是第三常见的血液系统恶性肿瘤,每年全球有114,000例患者。尽管取得了治疗进展,但是MM仍是为数不多的具有未满足的医疗需求的血液系统恶性肿瘤之一。一旦患者在经过一线治疗后出现疾病进展,且患有复发性或难治性(r/r)疾病,治疗选择是非常有限的。然而,近年来已开发出抗-MM肿瘤靶抗原(TAA)抗体。一种抗-CD38抗体达雷木单抗(daratumumab)已被批准用于治疗患有复发性MM的患者,其他抗-CD38抗体目前正在开发中(isatuximab和MOR-202,在美国专利US 8,263,746中对其进行了描述)。然而,需要改善目前在30-35%范围内的应答。已证实可以通过免疫调节疗法(例如,来那度胺)增强抗-CD38抗体的活性,免疫调节疗法刺激患者的免疫系统。而且,已证实MM肿瘤细胞对抗体疗法耐受的机制之一与检验点抑制剂通路(例如,PD-1/PD-L1)信号增强有关。因此,有机会增强抗-CD38抗体对MM肿瘤细胞的细胞毒性,同时通过抑制检验点抑制剂通路(例如,PD-1/PD-L1)激活免疫系统。
在生理条件下,PD-L1通过下调免疫系统起到防止自身免疫的重要作用。其在“APC样”免疫细胞(T细胞、NK细胞、巨噬细胞、髓样DC、B细胞、上皮细胞、血管内皮细胞)和肿瘤细胞上表达。PD-L1与其同源受体PD-1和B7-结合,并且通过抑制其增殖和活化负向调控免疫细胞(T细胞、NK细胞等)。
在病理条件下,PD-L1由肿瘤细胞高表达(>90%MM患者)并且与预后不良相关。已证实靶向免疫检验点通路的阻断抗体(抗-PD-1、抗-CTLA-4、抗-PD-L1等)在多种不同类型的癌症中(肺癌、黑色素瘤等)显示出显著的活性。已在MM中观察到了有效性的迹象,但是这类有希望治疗剂的活性在MM中仍是欠佳的。其中的一个原因可能是具有有益活性/副作用性质的分子(例如,抗-PD-L1)需要接近化学计量的阻断/饱和其靶点以便对T细胞激发最大的免疫刺激作用。
因此,将抗-PD-L1抗体特异性靶向肿瘤部位(例如,靶向CD38+癌细胞)可能有助于将抗-PD-L1治疗剂递送至需要免疫刺激的部位,并且可以产生使得肿瘤和微环境细胞中的PD-L1完全阻断的最大免疫细胞刺激。在肿瘤部位的这种靶向免疫细胞活化还可以降低免疫细胞的系统活化、防止不良副作用以及允许更高剂量的治疗性抗体。
发明内容
为了利用T细胞、BK细胞和其他免疫细胞的细胞毒性能力治疗多发性骨髓瘤(MM)和其他癌症(优选CD38+癌症),设计了具有两个结合位点(分别特异性针对CD38和PD-L1)的双特异性分子。本发明的双特异性分子消除了与T细胞和NK细胞上的PD-1与在肿瘤和肿瘤微环境细胞上表达的PD-L1的相互作用相关的免疫系统抑制。这种分子在治疗癌症中是有用的,特别是多发性骨髓瘤或者任意CD38+癌症,其过表达PD-L1并且在表达PD-L1的免疫细胞(浆细胞样树突状细胞,髓细胞来源的抑制细胞)微环境中生长,在这种微环境中进一步抑制T细胞和NK细胞。本发明的分子促进CD38+/PD-L1+肿瘤细胞以及肿瘤微环境细胞中的PD-L1+细胞的抗体依赖性细胞介导的细胞毒性(ADCC)、吞噬作用以及补体依赖性细胞毒性(CDC)。
在本发明的一个实施方式中,工程化改造了若干包含抗-CD38和抗-PD-L1结构域的双特异性CD38/PD-L1分子。这些双特异性CD38/PD-L1分子能够同时与这两个抗原结合。
更具体地,工程化改造了包含抗-CD38和抗-PD-L1结构域的双特异性CD38/PD-L1抗体。这些双特异性CD38/PD-L1抗体能够同时与这两个抗原结合。
在一个优选的实施方式中,在CHO细胞中表达双特异性CD38/PD-L1抗体,并通过使用蛋白A树脂的亲和层析对其进行纯化。在体外测定中表征抗体结合性质。其在ELISA测定中同时结合CD38和PD-L1。
将具有图1A或1B结构的双特异性四价四Fab抗体称为,其为BiomunexTherapeutics公司的商标。
本发明的抗体是针对CD38和PD-L1双特异性的和二价的。本发明的抗原结合双特异性抗体是由连续的“复合重链”(由mAb IgG的天然重链,随后为接头以及mAb2的Fab重链构成)组成的全长双特异性抗体,所述“复合重链”由Fc(铰链-CH2-CH3),然后是抗体1的Fab重链(CH1-VH)和抗体2连续的Fab重链(CH1-VH)构成,后者通过铰链来源的多肽接头序列连接在一起,在蛋白表达过程中产生的复合重链与相同的另一条复合重链结合,同时共表达的抗体2和抗体1的Fab轻链(LC)与其同源重链结构域结合以形成最终的串联F(ab')2-Fc分子;抗体1(Ab1)和抗体2(Ab2)是不同的并且选自由抗-CD38抗体(达雷木单抗、isatuximab、MOR-202或任意其他抗-CD38抗体)或其突变衍生物和抗-PD-L1抗体(阿特珠单抗、durvalumab、avelumab、MDX-1105或任意其他抗-PD-L1抗体)或其突变衍生物组成的组。
抗体能够与CD38和PD-L1双价结合。
进一步描述了由如上文所述的双特异性抗体的重链构成的多肽,以及包含编码所述多肽的序列的多核苷酸。
还描述了使用包含所述多肽核苷酸的表达载体转染的宿主细胞。
本发明的又一个目的是提供一种用于制备本发明的双特异性抗体的方法。
因此,提供了一种用于生产本发明的双特异性抗体的方法,所述方法包括下述步骤:a)在适宜培养基中和培养条件下培养宿主细胞,所述宿主细胞表达如上文所定义的抗体重链以及如上文所定义的抗体轻链,以及b)从所述培养基中或从所述所培养的细胞中回收所述所生产的抗体。
本发明利用重组载体,特别是表达载体,所述表达载体包含编码本申请所定义的重链和轻链的多核苷酸以及在所选择的宿主细胞中具有活性的转录和翻译控制元件。能够用于构建根据本发明的表达载体的载体本身是已知的,并且将根据意欲使用的宿主细胞的功能特别地对其进行选择。优选地,使用编码重链的多核苷酸以及编码两条不同轻链的两个多核苷酸转化所述宿主细胞。可以将所述多核苷酸插入相同的表达载体中或者单独的表达载体中。用于生产本发明抗体的方法包括培养此类宿主细胞以及从所述培养物中回收所述抗原结合片段或抗体。
附图说明
图1A和1B是本发明的双特异性抗体的示意图,所述双特异性抗体包含两条重链和四条轻链。
图2显示了在还原条件下双特异性抗体BiXAbs 4218、4219和5104的SDS聚丙烯酰胺凝胶电泳图。
图3显示了在非还原条件下双特异性抗体BiXAbs 4218、4219和5104的SDS聚丙烯酰胺凝胶电泳图。
图4显示了BiXAbs 4218和4219的ELISA结合试验。
图5显示了在还原和非还原条件下BiXAb-6567的SDS聚丙烯酰胺凝胶电泳图。第1道:在还原条件下BiXAb-6567的迁移情况;第2道:以每个条带的重量表示的分子量标记物;第3道:在非还原条件下BiXAb-6567的迁移情况。
图6显示了BiXAb-6567的体积排阻色谱分析结果。
图7显示了通过数字扫描量热法测定的两个母体抗体(抗-CD38和抗-PD-L1)以及BiXAb-6567的解链曲线。
图8A显示了在直接CD38抗原结合ELISA中两个母体抗体(抗-CD38和抗-PD-L1)以及BiXAb-6567的结合曲线。图8B显示了在直接PD-L1抗原结合ELISA中两个母体抗体(抗-CD38和抗-PD-L1)以及BiXAb-6567的结合曲线。图8C显示了在双抗原(PD-L1和CD38)结合ELISA中BiXAb-6567的结合曲线。
Figures9A至9C显示了两个母体mAb(抗-CD38和抗-PD-L1)和BiXAb-6567在三种不同细胞系中的荧光激活细胞分选曲线,9A:多发性骨髓瘤RPMI-8226,9B:稳定转染全长CD38的CHO细胞,以及9C:卵巢癌细胞系SKOV-3。
图10显示了两个母体mAb(抗-CD38和抗-PD-L1)、BiXAb-6567以及阴性对照抗-CD20抗体在CHO-CD38细胞系上的滴定结合曲线。
图11显示了在使用多发性骨髓瘤细胞系RPMI-8226作为靶细胞以及未分级分离的非预活化单核细胞作为效应细胞的ADCC测定中两个母体抗体(抗-CD38和抗-PD-L1)、BiXAb-6567以及两个阴性对照抗体抗-CD20和抗-HER2的细胞毒活性曲线。
图12显示了在使用CHO-CD38细胞系作为靶细胞以及未分级分离的非预活化单核细胞作为效应细胞的ADCC测定中两个母体抗体(抗-CD38和抗-PD-L1)、BiXAb-6567以及两个阴性对照抗体抗-CD20和抗-HER2的细胞毒活性曲线。
图13显示了在使用SKOV-3细胞系作为靶细胞以及富集的IL-12预活化NK细胞作为效应细胞的ADCC测定中两个母体抗体(抗-CD38和抗-PD-L1)、BiXAb-6567以及两个阴性对照抗体抗-CD20和抗-HER2的细胞毒活性曲线。
图14显示了在使用SKOV-3细胞系作为靶细胞以及富集的IL-15预活化NK细胞作为效应细胞的ADCC测定中两个母体抗体(抗-CD38和抗-PD-L1)、BiXAb-6567以及两个阴性对照抗体抗-CD20和抗-HER2的细胞毒活性曲线。
具体实施方式
定义:
天然存在的抗体分子的基本结构是Y型四聚体四元结构,其由两条相同的重链和两条相同的轻链组成,通过非共价相互作用以及链间二硫键结合在一起。
在哺乳动物物种中,有五种类型的重链:α、δ、ε、γ和μ,其决定了免疫球蛋白的类型(同种型)分别为:IgA、IgD、IgE、IgG和IgM。重链N-末端可变结构域(VH)之后,在重链γ、α和δ中是含有3个结构域(从N-末端至C-末端的编号为CH1、CH2和CH3)的恒定区,而重链μ和ε的恒定区由4个结构域(从N-末端至C-末端的编号为CH1、CH2、CH3和CH4)组成。IgA、IgG和IgD的CH1和CH2结构域由柔性铰链分隔,所述柔性铰链的长度在不同类型之间不同,在IgA和IgG的情况下,在不同亚型之间:IgG1、IgG2、IgG3和IgG4的铰链分别有15、12、62(或77)和12个氨基酸,以及IgA1和IgA2的铰链分别有20和7个氨基酸。
有两种类型的轻链:λ和κ,其能够与任意重链同种型结合,但是在给定抗体分子中的两条轻链是相同类型。两条轻链在功能上是相同的。其N-末端可变结构域(VL)之后是由称为CL的单一结构域构成的恒定区。
重链和轻链通过CH1和CL结构域之间的蛋白/蛋白相互作用和通过VH/VL相互作用配对,以及两条重链通过其CH3结构域之间的蛋白/蛋白相互作用结合。免疫球蛋白分子的结构通常通过CH1和CL结构域之间以及铰链之间的链间二硫键来稳定。
抗原结合区对应于Y型结构的臂,其由每一个与重链的VH和CH1结构域配对的完整轻链构成,并且将其称为Fab片段(用于片段的抗原结合)。Fab片段最初由木瓜蛋白酶消化天然免疫球蛋白分子产生,其在铰链区链间二硫键的氨基末端侧切割抗体分子,从而释放两个相同的抗原结合臂。其他蛋白酶如胃蛋白酶也在铰链区切割抗体分子,但在链间二硫键的羧基末端侧,释放由两个相同Fab片段组成的片段,并且其仍通过二硫键保持连接;在F(ab')2片段中的二硫键还原产生Fab'片段。
将与VH和VL结构域对应的抗原结合区的部分称为Fv片段(用于片段的可变性);其含有CDR(互补性决定区),所述CDR形成抗原结合位点(也称为互补位)。
负责其与效应分子或细胞结合的抗体的效应区对应于Y型结构的茎,并且含有重链成对的CH2和CH3结构域(或者CH2、CH3和CH4结构域,取决于抗体的类型),并且将其称为Fc(用于片段的可结晶性)区。
由于两条重链以及两条轻链是相同的,因而天然存在的抗体分子具有两个相同的抗原结合位点,因此其同时与两个相同的表位结合。
如果相比于其与其他物质结合,其以更高的亲和性、亲合力、更容易和/或以更长的持续时间结合,则称为抗体“特异性结合”至其靶抗原。“特异性结合”或“优先结合”不一定需要(尽管其可以包括)排他性结合。通常但不是必须地,提及结合指优先结合。
术语“对象”、“个体”和“患者”在本申请中可以互换使用,指针对治疗进行评估的和/或所治疗的哺乳动物。对象可以是人,但还包括其他哺乳动物,特别是作为人类疾病的实验室模型使用的那些哺乳动物,例如小鼠、大鼠、家兔、犬等。
术语“治疗(treatment)”或“治疗(treating)”指某种行动、应用或疗法,其中向包括人在内的对象施与以直接地或间接地改善对象的病况为目的的医疗救助。特别地,在一些实施方式中该术语指降低发病率或减轻症状、消除复发、预防复发、预防发病、改善症状、改善预后或者其组合。本领域技术人员将理解的是治疗不一定导致症状完全消除或除去。例如,对于癌症而言,“治疗(treatment)”或“治疗(treating)”可以指延缓赘生物或恶性细胞生长、增殖或转移,阻止或推迟赘生物或恶性细胞生长、增殖或转移的进展或者其某些组合。
优选的双特异性抗体的设计:
本发明提供了双特异性四价抗体,所述双特异性四价抗体包含针对每个其靶点的两个结合位点,以及能够激活效应功能(如抗体依赖性细胞介导的细胞毒性(ADCC)、吞噬作用和补体依赖性细胞毒性(CDC))的功能性Fc结构域。
本发明的抗体是全长抗体。其优选地包含来自人免疫球蛋白优选IgG更优选IgG1的重链和轻链。
轻链优选κ轻链。
在一个优选的实施方式中,本发明的接头以四-Fab双特异性抗体形式连接两对IgG Fab结构域,所述四-Fab双特异性抗体的氨基酸序列包含通过接头连接的至少两个Fab的重链序列,之后是天然铰链序列,之后是IgG Fc序列,其与适宜的IgG轻链序列共表达。
在图1A和1B中显示了本发明抗体的一个实例,其具有IgG-样结构。
本发明的双特异性抗体通常包含
-由Fc(铰链-CH2-CH3)构成的连续重链
-之后是抗体1的Fab重链(CH1-VH)和抗体2连续的Fab重链(CH1-VH),后者通过铰链来源的多肽接头序列连接在一起,
-以及在蛋白表达过程中所得到的重链组装成二聚体,同时共表达的抗体1和抗体2的轻链(VL-CL)与其同源重链结合以形成最终的串联F(ab)’2-Fc分子,
抗体1(Ab1)和抗体2(Ab2)是不同的。
Ab1和Ab2是不同的,其独立地选自由抗-CD38抗体(如达雷木单抗)和抗-PD-L1抗体(如阿特珠单抗)组成的组。
达雷木单抗结合人CD38的C-末端区域独特的CD38表位,氨基酸233至246和267至280,272和274位的氨基酸对结合是特别重要的。有利地,Ab1和/或Ab2可以是与达雷木单抗结合至相同表位或重叠表位(例如,具有至少4个氨基酸的重叠)的抗体。
在另一个实施方式中,Ab1和/或Ab2可以是与阿特珠单抗结合至相同表位或重叠表位的抗体。
在一个特定的实施方式中,双特异性分子是双特异性抗体,所述双特异性抗体包含优选地由a)两条重链和b)四条轻链组成,每条重链包含优选地由SEQ ID NO:1组成,以及两条轻链包含优选地由SEQ ID NO:2组成和另外两条轻链包含优选地由SEQ ID NO:3组成。将这种双特异性抗体称为BiXAb-4218。
在另一个特定的实施方式中,双特异性分子是双特异性抗体,所述双特异性抗体包含优选地由a)两条重链和b)四条轻链组成,每条重链包含优选地由SEQ ID NO:4组成,以及两条轻链包含优选地由SEQ ID NO:5组成和另外两条轻链包含优选地由SEQ ID NO:6组成。将这种双特异性抗体称为BiXAb-4219。
在另一个特定的实施方式中,双特异性分子是双特异性抗体,所述双特异性抗体包含优选地由a)两条重链和b)四条轻链组成,每条重链包含优选地由SEQ ID NO:7组成,以及两条轻链包含优选地由SEQ ID NO:8组成和另外两条轻链包含优选地由SEQ ID NO:9组成。将这种双特异性抗体称为BiXAb-5104。
在一个优选的实施方式中,双特异性分子是双特异性抗体,所述双特异性抗体包含优选地由a)两条重链和b)四条轻链组成,每条重链包含优选地由SEQ ID NO:10组成,以及两条轻链包含优选地由SEQ ID NO:11组成和另外两条轻链包含优选地由SEQ ID NO:12组成。将这种双特异性抗体称为BiXAb-6567。
重链(SEQ ID NO:10)包含
-达雷木单抗的VH(SEQ ID NO:22)
-达雷木单抗Fab的CH1结构域(具有突变L124Q和S188V的G1m(3)同种异型的人IgG1)(SEQ ID NO:23)
-AP接头(SEQ ID NO:15)
-阿特珠单抗的VH(SEQ ID NO:24)
-阿特珠单抗Fab的CH1结构域(具有突变T192D的G1m(3)同种异型的人IgG1)(SEQID NO:25)
-人IgG1的铰链(SEQ ID NO:26)
-人IgG1的CH2结构域(SEQ ID NO:27)
-G1m(3)同种异型的人IgG1的CH3结构域(SEQ ID NO:28)
轻链SEQ ID NO:11包含
-达雷木单抗的VH(SEQ ID NO:29)
-具有突变V133T和S176V的达雷木单抗的Cκ结构域(SEQ ID NO:30)
轻链SEQ IDNO:12包含
-阿特珠单抗的VL(SEQ ID NO:31)
-具有突变S114A和N137K的阿特珠单抗的Cκ结构域(SEQ ID NO:32)
还描述了具有改善的性质的双特异性抗体,其显示出与CD38和/或PD-L1更高的结合亲和性。例如,针对CD38和/或PD-L1,这种双特异性抗体能够显示出低于1 x 10-7M、10- 8M,优选地低于1 x 10-9或1 x 10-10M的Kd。
接头的设计
多肽接头,也称为“铰链来源的多肽接头序列”或“假铰链接头”包含选自IgA、IgG和IgD的(优选人源的)一种或多种免疫球蛋白铰链区的全部或部分序列。所述多肽接头可以仅包含一种免疫球蛋白铰链区的全部或部分序列。在这种情况下,所述免疫球蛋白可以与同其相邻的CH1结构域的免疫球蛋白来源属于相同同种型和亚类或者不同同种型或亚类。或者,所述多肽接头可以包含不同同种型或亚类的至少两种免疫球蛋白铰链区的全部或部分序列。在这种情况下,直接在CH1结构域之后的多肽接头的N-末端部分优选地由与所述CH1结构域的免疫球蛋白来源属于相同同种型和亚类的免疫球蛋白铰链区的全部或部分组成。
任选地,所述多肽接头还可以包含免疫球蛋白CH2结构域的2至15个优选地5至10个N-末端氨基酸的序列。
多肽接头序列通常由少于80个氨基酸,优选地少于60个氨基酸以及更优选地少于40个氨基酸组成。
在一些情况下,可以使用来自天然铰链的序列;在其他情况下,可以对这些序列进行点突变,特别是使用丙氨酸或丝氨酸取代天然IgG1、IgG2或IgG3铰链序列中的一个或多个半胱氨酸残基,以避免产生不需要的链内或链间二硫键。
在一个特定的实施方式中,多肽接头序列包含或由下述氨基酸序列组成EPKX1CDKX2HX3X4PPX5PAPELLGGPX6X7PPX8PX9PX10GG(SEQ ID NO:13),其中X1、X2、X3、X4、X5、X6、X7、X8、X9、X10是相同的或不同的任意氨基酸。特别地,多肽接头序列可以包含或由选自下组的序列组成
EPKSCDKTHTSPPAPAPELLGGPGGPPGPGPGGG(SEQ ID NO:14);
EPKSCDKTHTSPPAPAPELLGGPAAPPAPAPAGG(SEQ ID NO:15);
EPKSCDKTHTSPPAPAPELLGGPAAPPGPAPGGG(SEQ ID NO:16);
EPKSCDKTHTCPPCPAPELLGGPSTPPTPSPSGG(SEQ ID NO:17)和EPKSCDKTHTSPPSPAPELLGGPSTPPTPSPSGG(SEQ ID NO:18)。
能够用在本发明的多特异性抗原结合片段中的铰链来源多肽接头的一个非限制性实例是具有SEQ ID NO:17的多肽。所述多肽由人IgG1铰链的全长序列,之后是人IgG1CH2的9个N-末端氨基酸(APELLGGPS,SEQ ID NO:19),人IgA1铰链的一部分序列(TPPTPSPS,SEQID NO:20)以及二肽GG构成,加入二肽GG以便为接头提供附加的柔性。在另一个优选的实施方式中,铰链来源多肽接头序列是SEQ ID NO:15或SEQ ID NO:18。
在一个特定的实施方式中,X1、X2和X3,相同地或不同地,是苏氨酸(T)或丝氨酸(S)。
在另一个特定的实施方式中,X1、X2和X3,相同地或不同地,选自下组:Ala(A)、Gly(G)、Val(V)、Asn(N)、Asp(D)和Ile(I),更优选地,X1、X2和X3,相同地或不同地,可以是Ala(A)或Gly(G)。
或者,X1、X2和X3,相同地或不同地,可以是Leu(L)、Glu(E)、Gln(Q)、Met(M)、Lys(K)、Arg(R)、Phe(F)、Tyr(T)、His(H)、Trp(W),优选地是Leu(L)、Glu(E)或Gln(Q)。
在一个特定的实施方式中,X4和X5,相同地或不同地,可以是选自下组的氨基酸:丝氨酸(S)、半胱氨酸(C)、丙氨酸(A)和甘氨酸(G)。
在一个优选的实施方式中,X4是丝氨酸(S)或半胱氨酸(C)。
在一个优选的方面中,X5是丙氨酸(A)或半胱氨酸(C)。
在一个特定的实施方式中,X6、X7、X8、X9、X10,相同地或不同地,是苏氨酸(T)或丝氨酸(S)之外的任意氨基酸。优选地,X6、X7、X8、X9、X10,相同地或不同地,选自下组:Ala(A)、Gly(G)、Val(V)、Asn(N)、Asp(D)和Ile(I)。
或者,X6、X7、X8、X9、X10,相同地或不同地,可以是Leu(L)、Glu(E)、Gln(Q)、Met(M)、Lys(K)、Arg(R)、Phe(F)、Tyr(T)、His(H)、Trp(W),优选地是Leu(L)、Glu(E)或Gln(Q)。
在一个优选的实施方式中,X6、X7、X8、X9、X10,相同地或不同地,选自下组:Ala(A)和Gly(G)。
在又一个优选的实施方式中,X6和X7是相同的并且优选地选自下组:Ala(A)和Gly(G)。
在一个优选的实施方式中,多肽接头序列包含或者由序列SEQ ID NO:13组成,其中
X1、X2和X3,相同地或不同地,是苏氨酸(T)、丝氨酸(S);
X4是丝氨酸(S)或半胱氨酸(C);
X5是丙氨酸(A)或半胱氨酸(C);
X6、X7、X8、X9、X10,相同地或不同地,选自下组:Ala(A)和Gly(G)。
在另一个优选的实施方式中,多肽接头序列包含或由SEQ ID NO:13序列组成,其中
X1、X2和X3,相同地或不同地,是Ala(A)或Gly(G);
X4是丝氨酸(S)或半胱氨酸(C);
X5是丙氨酸(A)或半胱氨酸(C);
X6、X7、X8、X9、X10,相同地或不同地,选自下组:Ala(A)和Gly(G)。双特异性抗体的生产:
对于表达多特异性抗体的一般技术,本领域技术人员可以参见国际专利申请WO2013/005194,其通过引用并入本申请。
本申请还描述了一种多核苷酸,所述多核苷酸包含编码本发明分子或抗体的蛋白链的序列。所述多核苷酸还可以包含附加序列:特别是其可以有利地包含编码能够使所述蛋白链分泌的先导序列或信号肽的序列。还公开了使用所述多核苷酸转化的宿主细胞。
通常地,将不同抗-CD38和抗-PD-L1单克隆抗体的氨基酸序列用于设计DNA序列,其任选地在用于哺乳动物表达的密码子优化之后。对于重链而言,合成编码信号肽、后接铰链接头的Fab1的可变区和恒定CH1结构域以及具有用于限制性酶酶切的翼侧序列的Fab2的可变区和恒定CH1结构域的DNA。对于轻链而言,合成编码信号肽以及可变和恒定κ区的DNA。
将编码本发明抗体的重链和轻链的核酸插入表达载体。可以将轻链和重链克隆进入相同的或不同的表达载体。编码免疫球蛋白链的DNA区段在表达载体中与控制序列可操作地连接以确保免疫球蛋白多肽的表达。此类控制序列包括信号序列、启动子、增强子以及转录终止序列。表达载体通常作为附加体或作为宿主染色体DNA的组成部分在宿主生物中复制。通常,表达载体将含有选择标记物(例如,四环素或新霉素)以使得能够检测被所需DNA序列转化的那些细胞。
在一个实例中,重链和轻链编码序列(例如,编码VH和VL、VH-CH1和VL-CL或者全长重链和全长轻链的序列)均包含在一个表达载体中。在另一个实例中,将抗体的每条重链和轻链克隆到单独的载体中。在后一种情况下,可以将编码重链和轻链的表达载体共同转染至同一宿主细胞中以表达这两条链,其能够在体内或在体外组装以形成完整的抗体。或者,可以将编码重链的表达载体以及编码轻链的表达载体引不同宿主细胞中以分别表达每条重链和轻链,然后可以对其进行纯化和组装以便在体外形成完整的抗体。
在一个特定的实施方式中,使用三个独立的表达载体(如质粒)共转染宿主细胞以便共同产生所有三种链(即分别为重链HC,以及两条轻链LC1和LC2)并分泌双特异性抗体。
更特别地,可以有利地以下述分子比2:1:1(HC:LC1:LC2)使用三种载体。
用于表达本申请所述抗体的重组载体通常含有与组成型或诱导型启动子可操作地连接的编码抗体氨基酸序列的核酸。载体可适于在原核生物、真核生物或者在这两者中的复制和整合。典型的载体含有用于调控编码抗体的核酸表达的转录和翻译终止子、起始序列和启动子。载体任选地含有通用表达盒,所述通用表达盒至少含有一条独立的终止子序列,使得表达盒能够在原核生物和真核生物中复制的序列(即,穿梭载体)以及用于原核和真核系统的选择标记物。
可以在原核或真核表达系统中生产如本申请所述的双特异性抗体,如细菌、酵母、丝状真菌、植物、昆虫(例如,使用杆状病毒载体)和哺乳动物细胞。本发明的重组抗体不必在真核细胞中糖基化或表达;然而,在哺乳动物细胞中表达通常是优选的。有用的哺乳动物宿主细胞系的实例是人胚肾细胞系(293细胞)、幼仓鼠肾细胞(BHK细胞)、中国仓鼠卵巢细胞/-或+DHFR(CHO、CHO-S、CHO-DG44、Flp-in CHO细胞)、非洲绿猴肾细胞(VERO细胞)和人肝细胞(Hep G2细胞)。
优选使用哺乳动物组织细胞培养物表达和生产多肽,因为在本领域中已开发了多种能够分泌完整免疫球蛋白的适宜宿主细胞系,包括CHO细胞系、各种Cos细胞系、HeLa细胞、优选骨髓瘤细胞系(如NS0)或转化的B细胞或杂交瘤。
在一个最优选的实施方式中,通过使用CHO细胞系(最有利地CHO-S或CHO-DG-44细胞系或其衍生物)生产本发明的双特异性抗体。
这些细胞的表达载体可以包含表达控制序列(如复制原点、启动子和增强子),必要的加工信息位点(如核糖体结合位点、RNA剪接位点、多腺苷酸化位点)和转录终止子序列。优选的表达控制序列是来自免疫球蛋白基因、SV40、腺病毒、牛乳头瘤病毒、巨细胞病毒等的启动子。
可以采用本领域熟知的方法将含有所关注的多核苷酸序列(例如,重链和轻链编码序列以及表达控制序列)的载体转染进入宿主细胞,这些方法根据细胞宿主的类型而改变。例如,可以将磷酸钙处理或电穿孔用于其他细胞宿主。(一般地参见Sambrook等,Molecular Cloning:A Laboratory Manual(Cold Spring Harbor Press,2nd ed.,1989))。当将重链和轻链克隆至单独的表达载体上时,将载体共转染以获得完整免疫球蛋白的表达和组装。
用载体转化或转染宿主细胞(例如,通过化学转染或电穿孔法)并在常规(或根据需要经改良的)营养培养基中培养,以诱导启动子、选择转化子或扩增编码所需序列的基因。
抗体的表达可以是瞬时的或稳定的。
优选地,双特异性抗体通过稳定表达的方法生产,其中使用编码双特异性抗体(如BiXAb-6567)所有多肽链的DNA稳定转染的细胞系能够持续表达,这使得能够生产治疗剂。例如,在CHO细胞中的稳定表达是特别有利的。
本发明的全抗体、其二聚体、单个轻链和重链或其他免疫球蛋白形式一旦表达可以对其进行进一步的分离或纯化以获得用于进一步测定和应用的基本上均匀的制备物。可以使用本领域公知的标准蛋白纯化方法。例如,适宜的纯化方法可以包括在免疫亲和或离子交换柱上的分级分离、乙醇沉淀、高效液相色谱(HPLC)、十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)、硫酸铵沉淀和凝胶过滤(一般地参见Scopes,Protein Purification(Springer-Verlag,N.Y.,1982))。对于药物用途而言,优选具有至少约90至95%同质性以及最优选具有98至99%或更高同质性的基本上纯的免疫球蛋白。
体外生产允许按比例放大以生产大量所需的本发明的双特异性抗体。这些方法可以使用均相悬浮培养,例如在气升式反应器中或在连续搅拌反应器中,或者固化或捕获细胞培养物,例如在中空纤维、微囊、琼脂糖微珠或陶瓷盒中。
突变衍生物和突变:
与CD38结合的多肽序列可以来自任意抗-CD38抗体,例如选自下组:达雷木单抗、isatuximab、MOR-202或其突变衍生物。
与PD-L1结合的多肽序列可以来自任意抗-PD-L1抗体,例如选自下组:阿特珠单抗、durvalumab、avelumab、MDX-1105或其突变衍生物。
术语“突变的衍生物”、“突变体”或“功能性变体”指通过缺失、取代或插入一个或若干个氨基酸而与其所示母体序列不同的序列。优选地,突变衍生物与天然序列优选地显示出至少80%、优选地至少85%、更优选地至少90%的同源序列。在一个特定的实施方式中,突变基本上不影响抗体的功能。
突变的衍生物或功能性变体可以含有VH链,所述VH链含有与本申请所述的任意参照序列至少85%(例如,90%、92%、94%、95%、96%、97%、98%或99%)相同的氨基酸序列,VL链,所述VL链具有与本申请所述的任意参照序列至少85%(例如,90%、92%、94%、95%、96%、97%、98%或99%)相同的氨基酸序列,或者这两者。这些变体能够与CD38和PD-L1结合。在一些实例中,变体与上文所述的参照抗体具有相似的抗原结合亲和性(例如,具有小于1 x 10-7M、10-8M,优选地小于1 x 10-9或1 x 10-10M的KD)。
使用术语ka(结合速率常数)、kd(解离速率常数)或KD(平衡解离)定义结合亲和性。通常地,针对抗体当使用特异性结合时,指抗体以小于10-7M,优选地小于10-8M(例如,小于10-9M或10-10M)的亲和性(KD)值与其靶点特异性结合(“识别”)。较低的KD值表示具有较高的结合亲和性(即,更强的结合),这样KD值为10-9表示其与KD值10-8相比具有更高的结合亲和性。
使用经Karlin和Altschul Proc.Natl.Acad.Sci.USA 90:5873-77,1993修订的Karlin和Altschul Proc.Natl.Acad.Sci.USA 87:2264-68,1990的算法确定两条氨基酸序列的“同一性百分比”。这种算法已被嵌入NBLAST和XBLAST程序(2.0版),Altschul等,J.Mol.Biol.215:403-10,1990。可以使用XBLAST程序(评分=50,字长=3)进行BLAST蛋白检索,以获得与所关注蛋白分子的氨基酸序列同源性。当在两条序列之间存在空位时,可以使用如Altschul等,Nucleic Acids Res.25(17):3389-3402,1997中所述的空位BLAST。当使用BLAST和空位BLAST程序时,可以使用各程序(例如,XBLAST和NBLAST)的缺省参数。
在其他实施方式中,本申请所述的功能性变体可以含有一个或多个突变(例如,保守性取代),其优选地不出现在预计与一个或多个CDR相互作用的残基。
本申请描述了基本上与参照抗体是相同的突变的衍生物或功能性变体。
术语“基本上相同的”或“无实质性的”指变体的相关氨基酸序列(例如,在框架区(FR)、CDR、VH或VL结构域中)与参照抗体相比不存在实质性的不同(例如,包括保守性氨基酸取代),这样变体与参照抗体相比具有基本上相似的结合活性(例如,亲和性、特异性或者这两者)和生物活性。此类变体可以包含微小的氨基酸改变,例如在特定区域的5个氨基酸序列中有1或2个取代。在通常情况下,与CDR区相比,在FR区中可以有更多取代,只要其对抗体的结合功能不具有负面影响(如与原始抗体相比结合亲和性降低50%以上)即可。在一些实施方式中,在原始抗体与经修饰抗体之间的序列同一性可以是约85%、90%、95%、96%、97%、98%、99%或更高。在一些实施方式中,经修饰抗体具有相同的结合特异性,并且具有原始抗体至少50%的亲和性。
保守性取代将产生具有与进行此类修饰的分子类似的功能和化学特征的分子。例如,“保守性氨基酸取代”可以是使用另一残基对天然氨基酸残基的取代,所述取代使得对该位置氨基酸残基的极性或电荷几乎没有影响。本领域技术人员能够确定所需的氨基酸取代(无论是保守性的还是非保守性的)。例如,可以使用氨基酸取代鉴定分子序列的重要残基,或者提高或降低本申请所述分子的亲和性。可以采用本领域普通技术人员公知的改变多肽序列的方法制备含有一个或多个保守性氨基酸取代的变体,例如可以参见汇编了此类方法的参考文献,例如Molecular Cloning:A Laboratory Manual,J.Sambrook等编著,第2版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,New York,1989,或Current Protocols in Molecular Biology,F.M.Ausubel等编著,John Wiley&Sons,Inc.,New York。氨基酸的保守性取代包括在下组中的氨基酸之间的取代:(a)M、I、L、V;(b)F、Y、W;(c)K、R、H;(d)A、G;(e)S、T;(f)Q、N;和(g)E、D。
本公开内容还提供了具有改善的抗体生物学性质的抗体变体,如具有更高或更低的结合亲和性,或者对表达CD38和/或PD-L1的细胞具有改变的ADCC性质。
可以通过将适当的核苷酸改变引入抗体核酸或通过肽合成制备抗体的氨基酸序列变体。此类修饰包括例如从抗体的氨基酸序列中缺失残基和/或插入和/或取代残基。可以进行缺失、插入和取代的任意组合以获得最终的构建体,即提供具有所需特征的最终的构建体。可以采用本领域公知的各种方法制备编码抗体氨基酸序列变体的核酸分子。这些方法包括但不限于对此前制备的抗体变体或非变体(天然)版本的寡核苷酸介导的(或位点定向)诱变、PCR诱变和表达盒诱变。在一个实施方式中,本发明抗体的平衡解离常数(KD)值小于10-7M,特别地小于10-8M、10-9M或10-10M。可以采用本领域公知的技术确定结合亲和性,如ELISA或双特异性相互作用分析(例如,使用表面等离子体共振),或者本领域公知的其他技术。
可以采用常规方法对本申请所述的任意分子进行检测以确定其性质,如抗原结合活性、抗原结合特异性和生物功能。
可以对本申请所述的任意分子进行修饰以使其含有本领域公知且易于获得的其他非蛋白部分,例如通过PEG化、高糖基化等。能够延长血清半衰期的修饰是值得关注的。
在整个本说明书中,根据Kabat等,Sequences of Proteins of ImmunologicalInterest,第5版,Public Health Service,National Institutes of Health,Bethesda,Md.(1991)对氨基酸序列进行定义。
突变可以位于恒定结构域中。双特异性抗体确实有利地包含在CH1和CL结构域的界面处具有突变的Fab片段,所述突变有利于重链/轻链的同源配对并防止其错配。
在一个优选的实施方式中,本申请所述的双特异性抗体包含:
·具有不同的突变CH1和突变CL结构域的两个Fab片段,其由下述组成
a)具有来自人IgG1/κ的突变CH1和突变C-κ结构域以及Ab1的VH和VL结构域的Fab片段,
b)具有来自人IgG1/κ的突变CH1和突变C-κ结构域以及Ab2的VH和VL结构域的Fab片段,
c)来自人κ恒定结构域的突变轻链恒定结构域,
以下列顺序串联排布Fab片段
-Ab1Fab片段突变CH1结构域的C-末端通过多肽接头与Ab2Fab片段VH结构域的N-末端连接,
-通过人IgG1的铰链区将Ab2片段突变CH1结构域的C-末端与CH2结构域的N-末端连接,
-人IgG1的二聚化CH2和CH3结构域。
在特定的实例中,描述了双特异性抗体,其中Ab1或Ab2之一的Fab CH1结构域是突变结构域,其来自于CH1结构域192位的苏氨酸残基被天冬氨酸残基取代的免疫球蛋白的CH1结构域,以及同源CL结构域是突变结构域,其来自于CL结构域137位的天冬酰胺残基被赖氨酸残基取代和CL结构域114位的丝氨酸残基被丙氨酸残基取代的免疫球蛋白的CL结构域,和/或其中Ab1或Ab2的一个或另一个的Fab CH1结构域是突变结构域,其来自于CH1结构域124位的亮氨酸残基被谷氨酰胺残基取代和CH1结构域188位的丝氨酸残基被缬氨酸残基取代的免疫球蛋白的CH1结构域,以及同源CL结构域是突变结构域,其来自于CL结构域133位的缬氨酸残基被苏氨酸残基取代和CL结构域176位的丝氨酸残基被缬氨酸残基取代的免疫球蛋白的CL结构域。
本发明的抗体可以是糖基化的或非糖基化的,或者可以显示出多种糖基化特征。在一个优选的实施方式中,抗体在重链可变区是非糖基化的,但是在Fc区是糖基化的。
某些突变衍生物可以使用参照抗体的人源化形式。在人源化方法中,将来自供体小鼠可变区的互补性决定区(CDR)和某些其他氨基酸移植入人受体可变区,然后将其与人恒定区连接。参见例如,Riechmann等,Nature 332:323-327(1988);美国专利号5,225,539。
治疗用途:
可以将本发明的双特异性分子(优选抗体)用作药物,特别是治疗癌症的药物。
如在本申请中所使用的,术语“癌症”包括任何癌症,特别是血液系统恶性肿瘤,以及以CD38或PD-L1的表达或过表达为特征的任何其他癌症,尤其是以CD38和PD-L1共表达为特征的那些癌症。
癌症的实例是淋巴瘤或白血病,如非霍奇金氏淋巴瘤(NHL)、急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)或多发性骨髓瘤(MM)、乳腺癌、卵巢癌、头颈癌、膀胱癌、黑色素瘤、结直肠癌、胰腺癌、肺癌、平滑肌瘤。
因此,描述了一种通过向需要此类治疗的所述患者施用根据本发明的双特异性分子治疗罹患癌症的患者的方法。因此,本发明的另一个方面是根据本发明的双特异性分子在制备用于治疗癌症的药物中的用途。
本发明一个方面是一种药物组合物,所述药物组合物包含根据本发明的双特异性分子。本发明的另一个方面是根据本发明的双特异性分子在制备药物组合物中的用途。本发明的又一个方面是一种用于制备药物组合物的方法,所述药物组合物包含根据本发明的双特异性分子。
在另一个方面中,本发明提供了一种组合物(例如,药物组合物),所述组合物包含与药物载体一起制剂的本申请所定义的双特异性分子。
如在本申请中所使用的,“药物载体”包括生理上相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。优选地,载体适于静脉内、肌内、皮下、胃肠外、脊柱或表皮施用(例如,通过注射或输注)。
可以通过本领域公知的各种方法施用本发明的组合物。施用途径和/或方式将根据所需的结果而改变。
为了通过某些施用途径给予本发明的双特异性分子或抗体,可能需要使用某种材料对本发明的双特异性分子或抗体进行包覆或将本发明的双特异性分子或抗体与某种材料共同施用以防止其失活。例如,本发明的双特异性分子或抗体可以在适宜载体(例如,脂质体或稀释剂)中向对象施用。药学上可接受的稀释剂包括盐水和水性缓冲溶液。药物载体包括用于无菌可注射溶液或分散液临时制备的无菌水溶液或分散液和无菌粉末。用于药物活性物质的此类介质和药剂的使用是本领域公知的。
这些组合物还可以含有助剂如防腐剂、润湿剂、乳化剂和分散剂。可以通过灭菌方法和包含各种抗细菌剂和抗真菌剂(例如,尼泊金、氯丁醇、苯酚、山梨酸等)确保阻止存在微生物。将等渗剂(如氯化钠)加入组合物中也可能是需要的。此外,可以通过加入延迟吸收的药剂使可注射药物形式的吸收延迟。
可以改变本发明药物组合物中活性成分的实际剂量水平以获得能够针对特定患者、组分和施用方式达到所需的治疗应答且对患者不具有毒性的活性成分的量。
所选择的剂量水平将取决于多种药代动力学因素,包括所使用的本发明特定组合物的活性,施用途径,施用时间,治疗持续时间,与所使用的特定组合物联用的其他药物、化合物和/或物质,所治疗患者的年龄、性别、体重、状况、一般健康情况和既往病史以及医疗领域熟知的类似因素。例如,可以每周3次至每月1次以0.2-20mg/kg的剂量施用本发明的双特异性分子或抗体。
因此,通过参考下述实施例将更易于理解通常如上文所述的本发明,这些实施例是以举例说明方式提供的并且并非旨在限制本发明。
实施例
实施例1:双特异性抗体BiXAb-4218、BiXAb-4219和BiXAb-5104的制备
基因合成
使用GeneScript程序,在进行用于哺乳动物表达的密码子优化之后,将不同抗-CD38和抗-PD-L1单克隆抗体的氨基酸序列用于设计DNA序列。对于重链而言,利用GeneScript合成编码信号肽、后接铰链接头的Fab1的可变区和恒定CH1结构域以及具有用于限制性酶酶切的翼侧序列的Fab2的可变区和恒定CH1结构域的DNA。对于轻链而言,利用GeneScript合成编码信号肽以及可变和恒定κ区的DNA。
使用PfuTurbo Hot Start进行PCR反应以扩增插入物,然后分别用NotI+ApaI和NotI+HindIII酶切重链和轻链。将经双重酶切的重链片段与NotI+ApaI酶切的Evitria专利表达载体连接,该表达载体中已经插入了人IgG1CH1+铰链+CH2+CH3结构域。将经双重酶切的轻链片段与经NotI+HindIII处理的Evitria专利载体连接。通过双链DNA测序对质粒DNA进行验证。
表达、纯化和表征
对于50mL规模的表达,将在Evitria专利载体中的共计50μg质粒DNA(重链25μg+每条轻链(LC1和LC2)12.5μg)在1.5mL Eppendorf管中混合,加入1mL含有25μL 3mg/mL PEIpH7.0的CHO SFM培养基,在RT下孵育20min。将DNA-PEI混合物加入在125mL摇瓶中的49mL1-2 x 106个细胞/mL的FreeStyleTM CHO-S细胞中。将细胞再振荡6天。将细胞3,000rpm离心15min收集上清液。通过蛋白A树脂对收集得到的上清液进行纯化。使用Gel Biorad Stain-Free 4–15%凝胶和相应的电泳缓冲液在还原条件下和非还原条件下进行电泳。通过将纯化的抗体与2X SDS上样缓冲液混合并在95℃下加热5min制备样品。还原样品的制备包括在加热前加入NuPAGE还原剂。使用Ladder Precision Plus蛋白未染色标准品(Biorad)确定表观MW。图2表示在还原条件下CD38/PD-L1抗体的SDS-PAGE图。观察到对应于复合重链和两个共迁移轻链的两个条带并且其具有预期的分子量。图3表示在非还原条件下CD38/PD-L1抗体的SDS-PAGE图。与预期一致,250kDa的显著条带对应于完整的CD38/PD-L1分子。
对于双抗原结合培养板ELISA测定,使用下述试剂:重组人CD38,Fc-标记的(Creative BioMart);生物素化的人PD-L1,Avi Tag(AcroBiosystems);链霉亲和素-HRP(Biotechne RD-Systems)。使用含2μg/mL人CD38-Fc融合蛋白的1X PBS pH7.4(100μL/孔)将Maxisorp培养板在4℃下包被过夜。使用含0.05%吐温-20的1X PBS(1X PBST)洗板5次,然后使用3%脱脂奶粉/1X PBST在RT下振荡1hr进行封闭(200μL/孔)。加入先使用1X PBS按照1/500的稀释度对1mg/ml4218和4219的储备液进行稀释再按照1:3系列稀释的稀释液(100μL/孔)。将板在RT下振荡孵育1hr,随后使用1X PBST洗板5次。加入含1μg/mL生物素-人PD-L1蛋白的1X PBS(100μL/孔),并将板在RT下振荡1hr。使用1X PBST洗涤5次后,加入含0.1μg/mL与链霉亲和素偶联的HRP的1XPBS(100μL/孔)。将板在RT下振荡1hr,随后使用1X PBST洗涤5次。加入含TMB底物的1X PBS(100μL/孔)进行显色。使用VictorII多功能酶标仪在405nm下采集数据(每孔0.1秒)。图4表明两种CD38/PD-L1具有双抗原结合性质。该图确证了这些分子这两种类型的结合结构域(抗-CD38结构域和抗-PD-L1结构域)与其同源抗原靶点结合。
实施例2:本发明的双特异性抗体BiXAb-6567的制备
基因合成
使用GeneScript程序,在进行用于哺乳动物表达的密码子优化之后,将抗-CD38(达雷木单抗)和抗-PD-L1(阿特珠单抗)抗体的氨基酸序列用于设计DNA序列。将这些抗体称为“母体”抗-CD38和“母体”抗-PD-L1 mAb。
重链的DNA构建体设计如下:信号肽(SEQ ID NO:21),之后是序列SEQ ID NO:10[组成为:可变区,之后是Fab1的恒定CH1结构域(抗-CD38),其中在Kabat 124位和188位分别引入突变Leu至Gln和Ser至Val,之后是接头,之后是可变区,之后是Fab2的恒定CH1结构域(抗-PD-L1),其中在Kabat 192位引入突变Thr至Asp];在重链DNA构建体的两端引入用于限制性酶酶切的翼侧序列。轻链的DNA构建体设计如下:信号肽(SEQ ID NO:21),之后是可变区,之后是恒定κ区。对于抗-CD38轻链,在恒定κ结构域的Kabat 143位(Leu至Gln)和188位(Ser至Val)引入突变。对于抗-PDL1轻链,在恒定κ结构域的Kabat 133位(Val至Thr)和176位(Ser至Val)引入突变。所有DNA构建体均由Gene Art合成。
使用PfuTurbo Hot Start进行PCR反应以扩增插入物,然后分别用NotI和ApaI以及NotI和HindIII酶切重链和轻链。将经双重酶切的重链片段与经NotI和ApaI处理的pcDNA3.1表达载体(Invitrogen)连接,该表达载体中已经插入了人IgG1铰链后接CH2-CH3结构域。将经双重酶切的轻链片段与经NotI和HindIII处理的pcDNA3.1表达载体(Invitrogen)连接。通过双链DNA测序对质粒DNA进行验证。
表达和纯化
使用瞬时基因表达在适于悬浮于无血清培养基中的CHO-S细胞中(CHO SFM-II培养基,Life TechnologiesTM)通过以2:1:1=HC:LC1:LC2的分子比(1条连续的重链(HC)和2条轻链(LC))将在单独载体上编码的3个基因共转染生产双特异性抗体BiXAb-6567。通常地,对于50mL规模的表达,将共计50μg质粒DNA(重链25μg,12.5μg抗-CD38轻链和12.5μg抗-PD-L1轻链)在1.5mL Eppendorf管中混合,然后加入1mL含有25μL 3mg/mL PEI转化试剂pH7.0(Polyplus)的CHO SFM培养基,并在室温下孵育反应物20min。将DNA-PEI混合物加入在125mL摇瓶中的49mL 1-2 x 106个细胞/mL的Life Technologies’InvitrogenFreeStyleTM CHO-S细胞中。将细胞振荡6天。将细胞3,000rpm离心15min收集上清液。使用ForteBio蛋白A生物传感器(Systems)确定上清液中BiXAb-6567的表达滴度。然后,在蛋白A亲和树脂(MabSelect SuRe,GE Healthcare Life Sciences)上纯化BiXAb-6567。使用0.1M甘氨酸pH 3.5从蛋白A上洗脱抗体,并使用1M TRIS中和洗脱物。对在DulbeccoPBS(Lonza)中的纯化抗体进行无菌过滤(0.2μM无菌滤器,Techno Plastic Products AG),并通过在280nm下读取的光密度(OD)确定抗体的终浓度。
BiXAab-6567通常在瞬时CHO表达中显示出良好的表达滴度(>180mg/升)。该表达水平与在常规单克隆抗体中所见的表达水平相当。
SDS聚丙烯酰胺凝胶电泳
为评估纯化BiXAb-6567的质量,我们进行了SDS-PAGE(ExperionTM自动电泳系统,BioRad)。在电泳缓冲液中存在十二烷基硫酸钠(SDS)的情况下,抗体在凝胶中的迁移速率主要取决于其尺寸,从而能够确定分子量。在非还原条件下和在还原条件下进行该测定;后者将二硫键破坏,从而能够观察单个多肽链(轻链和重链)。
SDS-PAGE数据见图5。在非还原条件下,保持了抗体的四级结构,所观察到的分子量应表示不同重链和轻链的分子量之和。本发明的双特异性抗体(BiXAb-6567)由6条链组成:两条重链和四条轻链。BiXab-6567的理论分子量是244.40kDa,其没有考虑翻译后修饰(PTM),例如在Fc的天冬酰胺297中的N-糖基化。使用已知分子量的标准品的混合物对凝胶进行校正。非还原数据显示出在250kDa分子量标准品附近有一主要条带,该条带与计算得到的分子量以及预计在Fc结构域中297位的两个天冬酰胺上具有糖基化一致。在还原条件下,二硫苏糖醇(DTT)通过还原二硫键和破坏四级结构进一步使BiXAb-6567变性,因此6条多肽链将根据其分子量在凝胶中单独迁移。BiXAb-6567的两条相同重链作为单一条带共迁移,两对轻链由于其具有几乎相同的分子量而作为第二个条带共迁移。因此,根据分子量标准品的迁移性,数据显示出在约75kDa和25kDa处有两个主要条带。每条重链在天冬酰胺297处具有一个N-糖基化位点,这解释了为什么较高分子量的条带较宽以及观察到的分子量略高于计算得到的分子量(75.44kDa);这种变宽是糖基化蛋白的典型特征。抗-CD38(23.40kDa)和抗-PD-L1(23.36kDa)的计算分子量非常接近,因此导致其共迁移。
总而言之,在非还原和还原条件下,BiXAb-6567的SDS-PAGE均显示出预期性质,并且当考虑在重链中存在N-糖基化位点时,其与计算得到的理论分子量一致。
体积排阻色谱分析
在经工程化改造的蛋白分子中经常会观察到蛋白聚集。我们进行了体积排阻色谱(SEC)分析以测定一步亲和纯化BiXAb-6567制备(参见变体的表达和纯化)的高分子量物质的含量。我们使用了SEC-s3000(300x 7.8mm)柱(BioSep)和Aktapurifier 10系统(GEHealthcare);使用PBS缓冲液pH 7.4,流速为1mL/min。
图6中所示的SEC色谱图显示了与单体BiXAb-6567的预计尺寸对应的主峰;该峰占样品总量的98.2%。此外,观察到了与较高分子量物质(可能是二聚体)对应的小峰;该峰占样品总量的1.8%。因此,我们得出较高分子量物质的含量百分比较低,且与在CHO表达系统中生产的常规单克隆抗体接近。单体峰窄且对称的峰型表明BiXAb-6567被正确组装且是单一物质。
实施例3:通过差示扫描量热法表征BiXAb-6567
使用差示扫描量热法(DSC)对BiXAb-6567、母体抗-CD38mAb和母体抗-PD-L1 mAb的热稳定性进行比较。使用MicrocalTM VP-毛细管DSC系统(Malvern Instruments)进行差示扫描量热法实验。
对所有样品进行离心(20,000x g,5min,4℃),并且在进行DSC分析之前使用Nanodrop ND-1000分光光度计(Thermo Scientific)的IgG分析程序对其蛋白含量进行定量。为了进行测定,使用PBS将所有样品稀释为终浓度1mg/mL。
预平衡时间为3min,所得到的热分析图在扫描速率60℃/h、过滤期25秒和基质反馈条件下在20至110℃之间采集。在样品分析之前,测量5次缓冲液/缓冲液扫描以稳定仪器,在每次蛋白/缓冲液扫描之间进行缓冲液/缓冲液扫描。使用非-2-态解折叠模型对数据进行拟合,通过扣除基线对转变前和转变后进行校正。
图7中所示的DSC曲线(覆盖50至100℃范围)显示了单个Fv区能够导致不同Fab解折叠性质的方式;该实验还表明Fv区决定了Fab的表观稳定性。抗-CD38mAb的DSC曲线显示出两个转变:Cp max为170Kcal/摩尔/℃和Tm1为70.9℃的大峰,其对应于解折叠的CH2和Fab结构域,以及Cp max为20Kcal/摩尔/℃和Tm2为81.5℃的小峰,其对应于解折叠的CH3结构域。抗-PD-L1 mAb的DSC曲线显示出两个转变:Cp max为20Kcal/摩尔/℃和Tm1为69.9℃的小峰,其对应于解折叠的CH2结构域,以及Cp max为160Kcal/摩尔/℃和Tm2为83.4℃的大峰,其对应于解折叠的CH3和Fab结构域。
BiXAb-6567的DSC曲线也显示出了具有两个大峰的两个转变。第一个峰的Cp max为130Kcal/摩尔/℃和Tm1为71.5℃,其对应于解折叠的抗-CD38 mAb的CH2和Fab结构域;第二个峰的Cp max为170Kcal/摩尔/℃和Tm2为81.5℃,其对应于解折叠的抗-PD-L1 mAb的CH3和Fab结构域。因而,BiXAb-6567的DSC曲线类似于两个母体mAb的两个DSC曲线的叠加,并且其说明了BiXAb-6567具有极好的组装和稳定性。BiXAb-6567的T起始(63.3℃)与母体mAb相似(抗-CD38T起始=63.5℃和抗-PD-L1T起始=63.2℃),表明BiXAb-6567与母体抗体具有相似的稳定性性质。BiXAb-6567计算得到的ΔH为1560kcal/摩尔,这反应了双特异性分子与两个母体抗体(抗-CD38ΔH=963kcal/摩尔和抗-PD-L1ΔH=820kcal/摩尔)相比具有更大的尺寸。定义:
Tm或变性/熔化温度是解折叠和折叠物质的浓度相等的点,并且其是展开转变的终点。作为一个参数,其描述了蛋白对热变性的敏感性,因此其与蛋白的稳定性相关。Tm越高,蛋白越稳定。
T起始是展开转变开始时的温度。该参数的值通常比Tm低5至10℃。其也是描述蛋白稳定性的参数,但是是与对热变性的耐受性相关的。
ΔH是解折叠的量热焓,反映了蛋白中分子内相互作用的破坏情况(即,结构域内和结构域间相互作用的破坏)。热解折叠过程是吸热的,因此产生正焓值。量热焓(ΔH)是热解折叠转变峰下的面积。
实施例4:BiXAb-6567的无细胞结合性质
直接CD38抗原结合培养板ELISA测定
分别使用100μL由PBS pH 7.4稀释制备的浓度为3μg/mL的母体mAb(抗-CD38或抗-PDL1)将Maxisorp培养板在4℃下包被过夜。还使用由PBS pH 7.4稀释制备的浓度为5μg/mL的BiXAb-6567将Maxisorp培养板在4℃下包被过夜。使用含0.05%吐温-20的1X PBS(PBST)洗板5次,然后使用含1%BSA的1x PBS在室温下封闭2hr(200μL/孔)。随后使用1x PBST洗板5次。使用1x PBS以1μg/mL的初始浓度进行3倍系列稀释制备7个点的重组CD38His/Flag-标签(Creative Biomart);每个稀释步骤在各测定孔中加入100μL。将板在室温下孵育1hr,并使用1x PBST洗涤5次。加入使用1x PBS进行10,000倍稀释的与抗-Flag标签抗体偶联的HRP(Abcam)(100μL/孔),并将板在室温下孵育1hr。使用1x PBST洗涤5次后,加入含TMB底物的1x PBS(100μL/孔)进行比色读数,并将板在室温下孵育15min进行显色。使用Victor2酶标仪(Perkin Elmer)在650nm下采集测定数据。
BiXAb-6567显示出与母体抗-CD38抗体非常类似的剂量依赖性结合曲线(图8A)。两种抗体与CD38结合的EC50如下所示:EC50[BiXAb-6567]=171ng/mL和EC50[抗-CD38]=199ng/mL。该结果表明BiXAb-6567具有正确组装的抗-CD38Fab结构域,因为其显示出与母体抗-CD38mAb相似的结合。与预期一致,作为阴性对照的母体抗-PDL1 mAb未显示出任何结合。
直接PDL1抗原结合培养板ELISA测定
使用100μL由1x PBS pH 7.4稀释制备的浓度为1μg/mL的生物素化的人PD-L1蛋白(AcroBiosystems)将Maxisorp培养板在4℃下包被过夜。使用PBST洗板5次,然后使用含1%BSA的1x PBS在室温下封闭2hr(200μL/孔)。随后使用1x PBST洗板5次。使用1x PBS进行3倍系列稀释制备7个点的抗-CD38mAb(初始浓度0.3mg/mL),或抗-PD-L1 mAb(初始浓度0.3mg/mL),或BiXAb-6567(初始浓度0.5mg/mL);每个稀释步骤在各测定孔中加入100μL。将板在室温下孵育1hr,并使用1x PBST洗涤5次。加入使用1x PBS进行5,000倍稀释的与抗-人抗体(IgG H&L)偶联的HRP(Abliance)(100μL/孔),并将板在室温下孵育1hr。使用1x PBST洗涤5次后,加入含TMB底物的1x PBS(100μL/孔)进行比色读数,并将板在室温下孵育15min进行显色。使用Victor2酶标仪(Perkin Elmer)在650nm下采集测定数据。
BiXAb-6567显示出与母体抗-PD-L1非常类似的剂量依赖性结合曲线(图8B)。两种抗体与PD-L1结合的EC50如下所示:EC50[BiXAb-6567]=93ng/mL和EC50[抗-PD-L1]=72ng/mL。该结果表明BiXAb-6567具有正确组装的抗-PD-L1Fab结构域,因为其显示出与母体抗-PD-L1 mAb相似的结合。与预期一致,作为阴性对照的母体抗-CD38mAb未显示出任何结合。
双抗原结合ELISA测定
使用100μL由1x PBS pH 7.4稀释制备的浓度为2μg/mL的重组人Fc-标签CD38(Creative BioMart)将Maxisorp培养板在4℃下包被过夜。使用1x PBST洗板5次,然后使用含1%BSA的1x PBS在室温下封闭2hr(200μL/孔)。使用1x PBST洗板5次。使用1x PBS进行3倍系列稀释制备7个点的BiXAb-6567(初始浓度1μg/mL);每个稀释步骤在各测定孔中加入100μL。将板在室温下孵育1hr,并随后使用1x PBST洗涤5次。加入含1μg/mL生物素化人PD-L1(AcroBiosystems的1x PBS(100μL/孔),并将板在室温下孵育1hr。使用1x PBST洗涤5次后,加入使用1x PBS稀释制备的0.1μg/mL与链霉亲和素偶联的HRP(Biotechne)(100μL/孔)。将板在室温下孵育1hr。使用1x PBST洗涤5次后,加入含TMB底物的1x PBS(100μL/孔)进行比色读数,并将板在室温下孵育15min进行显色。使用Victor2酶标仪(Perkin Elmer)在650nm下采集测定数据。
在双ELISA形式中BiXAb-6567显示出剂量依赖性结合曲线,表明该抗体具有正确组装的抗-CD38和抗-PD-L1Fab结构域(图8C)。这表明BiXAb-6567是能够以EC50=144ng/mL同时结合CD38和PD-L1的双特异性抗体。与预期一致,两种母体mAb抗-CD38或抗-PDL1在该双ELISA形式中均未显示出任何结合。
实施例5:通过荧光激活细胞分选(FACS)确定相对结合活性
在补充了100μg/ml青霉素、100μg/ml链霉素、10%胎牛血清和500μg/ml遗传霉素的DMEM-Glutamax-I培养基中培养CHO-CD38细胞(稳定转染了全长人CD38的CHO细胞)。在补充了100μg/ml青霉素、100μg/ml链霉素和10%胎牛血清的RPMI 1640-Glutamax-I培养基中培养SKOV-3细胞和RPMI-8226细胞。
每个样品使用3x105个细胞(CHO-CD38,或SKOV-3,或RPMI-8226)。使用PBA溶液(补充了1%BSA和0.05%叠氮钠的PBS)洗涤细胞1次。为了确定FACS曲线,使用体积为30μl和浓度为50μg/ml的各抗体对细胞染色。为了测定BiXAb-6567和母体抗-CD38抗体的滴度,以及随后测定结合参数,使用体积为30μl和所示浓度的各抗体对CHO-CD38细胞染色。将细胞在冰上孵育30min,然后使用1ml PBA溶液洗涤2次。使用荧光标记的抗-人κ或抗-人IgG Fcγ特异性二抗在冰上避光孵育细胞30min,然后使用1ml PBA溶液洗涤2次;最后,将细胞重悬于终体积500μl PBA溶液中。使用Epics-XL或Navios流式细胞仪(Beckman Coulter)测定样品。每次实验采集10.000个事件。
BiXAb-6567以及抗-CD38和抗-PD-L1母体抗体的结合曲线见图9A-C。我们选择检测了多发性骨髓瘤细胞系RPMI-8226,其表达较高水平的CD38和可忽略不计水平的PD-L1(图9A);CHO-CD38细胞系,由于其稳定转染了全长CD38因此表达极高水平的CD38(图9B);以及卵巢癌细胞系SKOV-3,已知其表达PD-L1(图9C)。在3个细胞系中,对于BiXAb-6567这些曲线显示与两种母体抗体的曲线非常类似的单峰。这表明BiXAb-6567正确的折叠并具有与母体抗体类似的结合性质。与预期一致,CHO-CD38仅表达CD38且不表达PD-L1,而SKOV-3仅表达PD-L1且不表达CD38。
为了定量确证BiXAb-6567具有与母体抗-CD38抗体类似的结合性质,使用CHO-CD38细胞测定了BiXAb-6567和抗-CD38母体抗体的滴度,结果如图10所示。经测定BiXAb-6567的EC50为17.1nM,而母体抗-CD38为8.5nM,这证实了BiXAb-6567中的抗-CD38Fab结构域与母体抗-CD38抗体中的该结构域具有类似的结合性质。与预期一致,在该实验中的阴性对照抗-PD-L1和抗-CD20抗体未显示出与CHO-CD38细胞的结合。
实施例6:使用未分级分离的非预活化单核细胞(MNC)的抗体依赖性细胞介导的细胞毒性(ADCC)
如上述实施例5中所述培养CHO-CD38、SKOV-3和RPMI-8226细胞。
采用下述程序制备MNC。使用枸橼酸盐对新抽取的外周血进行抗凝处理。随后,使用5ml Ficoll-Paque PLUS溶液对6ml抗凝全血分层。将样品在RT下以2,500rpm离心20min,随后不进行离心破碎。从血浆/Ficoll界面处收集MNC。使用PBS按照1:10对MNC细胞悬液进行稀释,并在室温下1,800rpm离心5分钟。除去上清液,通过向细胞悬液中加入45ml冰冷的蒸馏水裂解红细胞30秒,随后加入5ml 10x PBS。将细胞在室温下1,800rpm离心5分钟,并使用1x PBS洗涤3次以除去血小板。最后,将细胞重悬于5ml细胞培养基中。在ADCC测定中,将细胞数调整至达到40:1=效应细胞:肿瘤细胞的比例。
对于ADCC51铬释放测定,在37℃和5%CO2条件下,将1x106个靶细胞(RPMI 8226、SKOV-3或CHO-CD38)在含100μCi51铬的200μl PBS中孵育2小时。孵育2小时后,使用7ml培养基洗涤细胞3次,最后以0.1 x 106个细胞/ml的浓度重悬。在存在抗体的情况下,在37℃和5%CO2条件下,将靶细胞(5,000个细胞/孔)和MNC在96孔微量培养板(200μl测定体积)中孵育3小时。为了测定最大靶细胞裂解(=最大cpm),加入Triton X-100。为测定基础51铬释放(=基础cpm),不再对靶细胞进行进一步处理。在孵育4hr后,将微量培养板在2000rpm下离心5min,并将25μl上清液与125μl Optiphase Supermix(Perkin Elmer)混合并在振荡培养箱中孵育1min。在MicroBeta TriLux(Perkin Elmer)β计数器中测定样品。使用下述公式计算靶细胞的裂解:
裂解%=(实验cpm-基础cpm)/(最大cpm-基础cpm)x 100。
所有检测均重复进行3次。
使用非预活化MNC作为效应细胞进行CD38+细胞(RPMI-8226和CHO-CD38)的ADCC测定(图11和图12)。测定结果表明,BiXAb-6567和抗-CD38抗体对RPMI-8226细胞具有较强的细胞毒性,其EC50分别为0.8nM和0.3nM;BiXAb-6567和抗-CD38抗体对CHO-CD38细胞具有细胞毒性,其EC50分别为0.2nM和0.07nM。与预期一致,抗-PD-L1对这两种细胞系均显示出最低活性;两种阴性对照mAb抗-CD20和抗-HER2不促进任何裂解。这些结果表明BMX-6567对CD38+细胞具有较强的ADCC活性,这与其母体抗-CD38抗体是类似的。
实施例7:使用富集的预活化NK细胞的ADCC
如实施例5中所述培养SKOV3细胞、RPMI 8226和CHO-CD38细胞。如实施例6中所述制备MNC。根据生产厂商的说明书,使用“人NK细胞分离试剂盒”(Miltenyi),通过负性选择从MNC中分离NK细胞。以2x106个细胞的接种密度,在补充了10%胎牛血清的RPMI培养基中将NK细胞培养过夜。加入IL-12或IL-15至终浓度为10ng/ml。如实施例5中所述进行ADCC测定,但不同之处为效应细胞与肿瘤细胞的比例为10:1和反应持续时间降至3hr。
使用IL-12或IL-15预活化富集NK细胞,在PD-L1+细胞系上测定BiXAb-6567的抗-PD-L1部分的ADCC性质。结果如图13和图14中所示。该实验对BiXAb-6567与其母体抗-PD-L1抗体的ADCC性质进行比较;使用抗-HER2抗体作为阳性对照,以及使用抗-CD20抗体和母体抗-CD38抗体作为阴性对照,因为SKOV-3细胞是PD-L1+/HER2+/CD20-/CD38-。图13和图14表明BiXAb-6567和母体抗-PD-L1抗体具有较强的ADCC活性,其不依赖于在培养NK细胞时是否使用IL-12或IL-15。当使用IL-12时,BiXAb-6567和母体抗-PD-L1抗体的EC50分别为0.007nM和0.03nM。当使用IL-15时,曲线甚至更加相似;但是曲线拟合不是收敛的,因此妨碍了对EC50值的计算。这些结果表明BMX-6567对PD-L1+细胞具有较强的ADCC活性,这与其母体抗-PD-L1抗体是类似的。
序列表
<110> 拜奥穆尼克斯制药
<120> 与CD38和PD-L1结合的分子
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<223> LC1
<400> 2
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 Arg Ser Asn Trp Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ala 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 Glu 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> 3
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> LC2
<400> 3
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ala 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 Lys 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> 4
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> BiXAb 4219重链
<400> 4
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser 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 Glu 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 Arg 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
Thr Pro Pro Thr Pro Ser Pro Ser Gly Gly Glu Asn Leu Tyr Phe Gln
245 250 255
Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asn Ser
275 280 285
Phe Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser
305 310 315 320
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
325 330 335
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
340 345 350
Cys Ala Lys Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr
355 360 365
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
370 375 380
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
385 390 395 400
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
405 410 415
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
420 425 430
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
435 440 445
Lys Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
450 455 460
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
465 470 475 480
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
485 490 495
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
500 505 510
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
515 520 525
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
530 535 540
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
545 550 555 560
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
565 570 575
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
580 585 590
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
595 600 605
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
610 615 620
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
625 630 635 640
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
645 650 655
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
660 665 670
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
675 680 685
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
690 695 700
Leu Ser Pro Gly Lys
705
<210> 5
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> LC1
<400> 5
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ala 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 Lys 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> 6
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> LC2
<400> 6
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 Arg Ser Asn Trp Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ala 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 Glu 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> 7
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> BiXAb 5104重链
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Ala Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Thr Ile Tyr Gly Pro Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Lys Thr Val Tyr
65 70 75 80
Met His Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Tyr Tyr Gly Ser Asn Ser Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Lys Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser Gly Gly Glu Asn Leu Tyr
245 250 255
Phe Gln Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
260 265 270
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
275 280 285
Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
290 295 300
Glu Trp Val Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val
305 310 315 320
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
325 330 335
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp
355 360 365
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
370 375 380
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
385 390 395 400
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
405 410 415
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
420 425 430
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
435 440 445
Val Glu Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
450 455 460
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
465 470 475 480
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
485 490 495
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
500 505 510
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
515 520 525
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
530 535 540
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
545 550 555 560
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
565 570 575
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
580 585 590
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
595 600 605
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
610 615 620
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
625 630 635 640
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
645 650 655
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
660 665 670
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
675 680 685
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
690 695 700
Ser Leu Ser Pro Gly Lys
705 710
<210> 8
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> LC1
<400> 8
Asp Ile Val Met Thr Gln Ser His Leu Ser Met Ser Thr Ser Leu Gly
1 5 10 15
Asp Pro Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Val
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Arg Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ala Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ala 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 Glu 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> 9
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> LC2
<400> 9
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 Arg 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 Asp 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 Leu Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ala Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Lys Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 10
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> BiXAB BMX101-AP-ML1-CC1
<400> 10
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 Val Ser Gly Phe Thr Phe Asn Ser Phe
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 Gly 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 Phe Cys
85 90 95
Ala Lys Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr 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 Gln 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 Val 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 Arg Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Ser Pro Pro Ala Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ala Ala Pro Pro Ala Pro Ala Pro Ala Gly Gly Glu Val
245 250 255
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
260 265 270
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser Trp Ile
275 280 285
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Trp
290 295 300
Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
305 310 315 320
Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
340 345 350
Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
370 375 380
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
385 390 395 400
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
405 410 415
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
420 425 430
Gly Leu Tyr Ser Leu Ser Ser Val Val Asp Val Pro Ser Ser Ser Leu
435 440 445
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
450 455 460
Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
465 470 475 480
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
485 490 495
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
500 505 510
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
515 520 525
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
530 535 540
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
545 550 555 560
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
565 570 575
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
580 585 590
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
595 600 605
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
610 615 620
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
625 630 635 640
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
645 650 655
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
660 665 670
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
675 680 685
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
690 695 700
<210> 11
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 达雷木单抗LC
<400> 11
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 Arg Ser Asn Trp Pro Pro
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 Thr 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 Val
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> 12
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 阿特珠单抗-LC
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ala 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 Lys 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> 13
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> 接头1
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa可以是任意天然存在的氨基酸
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa可以是任意天然存在的氨基酸
<220>
<221> misc_feature
<222> (10)..(11)
<223> Xaa可以是任意天然存在的氨基酸
<220>
<221> misc_feature
<222> (14)..(14)
<223> Xaa可以是任意天然存在的氨基酸
<220>
<221> misc_feature
<222> (24)..(25)
<223> Xaa可以是任意天然存在的氨基酸
<220>
<221> misc_feature
<222> (28)..(28)
<223> Xaa可以是任意天然存在的氨基酸
<220>
<221> misc_feature
<222> (30)..(30)
<223> Xaa可以是任意天然存在的氨基酸
<220>
<221> misc_feature
<222> (32)..(32)
<223> Xaa可以是任意天然存在的氨基酸
<400> 13
Glu Pro Lys Xaa Cys Asp Lys Xaa His Xaa Xaa Pro Pro Xaa Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Xaa Xaa Pro Pro Xaa Pro Xaa Pro Xaa
20 25 30
Gly Gly
<210> 14
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> 接头2
<400> 14
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Ala Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Gly Gly Pro Pro Gly Pro Gly Pro Gly
20 25 30
Gly Gly
<210> 15
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> 接头2
<400> 15
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Ala Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ala Ala Pro Pro Ala Pro Ala Pro Ala
20 25 30
Gly Gly
<210> 16
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> 接头3
<400> 16
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Ala Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ala Ala Pro Pro Gly Pro Ala Pro Gly
20 25 30
Gly Gly
<210> 17
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> 接头4
<400> 17
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser
20 25 30
Gly Gly
<210> 18
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> 接头6
<400> 18
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser
20 25 30
Gly Gly
<210> 19
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Nter IgG1 CH2
<400> 19
Ala Pro Glu Leu Leu Gly Gly Pro Ser
1 5
<210> 20
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人IgA1铰链部分
<400> 20
Thr Pro Pro Thr Pro Ser Pro Ser
1 5
<210> 21
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 信号肽
<400> 21
Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 22
<211> 122
<212> PRT
<213> 智人
<400> 22
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asn Ser Phe
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 Gly 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 Phe Cys
85 90 95
Ala Lys Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 23
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> 达雷木单抗的CH1结构域
<400> 23
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Gln Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Val Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val
<210> 24
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 阿特珠单抗的VH
<400> 24
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 25
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> 阿特珠单抗的CH1结构域
<400> 25
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Asp Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val
<210> 26
<211> 15
<212> PRT
<213> 智人
<400> 26
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 27
<211> 110
<212> PRT
<213> 智人
<400> 27
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 28
<211> 107
<212> PRT
<213> 智人
<400> 28
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 29
<211> 107
<212> PRT
<213> 智人
<400> 29
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 Arg Ser Asn Trp Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 30
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 达雷木单抗的CKappa结构域
<400> 30
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 Thr Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Val Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 31
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 阿特珠单抗的VL
<400> 31
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 32
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 阿特珠单抗的CKappa结构域
<400> 32
Arg Thr Val Ala Ala Pro Ala 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 Lys Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
Claims (16)
1.一种双特异性分子,所述双特异性分子包含至少一个抗-CD38结构域和至少一个抗-PD-L1结构域,其能够同时分别结合至CD38和PD-L1抗原。
2.根据权利要求1所述的双特异性分子,所述双特异性分子是抗体或其片段。
3.根据权利要求2所述的双特异性分子,所述双特异性分子是全长抗体,所述抗体包含两条重链和四条轻链,
其中每条重链包含
a.含有铰链-CH2-CH3结构域的Fc区,
b.其Fc区与抗体1(Ab1)的Fab重链(CH1-VH)连接,
c.其还通过来自铰链的多肽接头序列与抗体2(Ab2)的Fab重链(CH1-VH)连接,其中所述多肽接头序列将所述Ab1的Fab重链VH结构域的N-末端与所述Ab2的CH1结构域的C-末端连接,
以及所述四条轻链包含Ab1的Fab轻链(CL-VL)和与其同源重链结构域结合的Ab2的Fab轻链(CL-VL);
Ab1和Ab2是不同的,并且选自由抗-CD38抗体和抗-PD-L1抗体组成的组。
4.根据权利要求3所述的双特异性分子,其中Ab1是抗-CD38抗体和Ab2是抗-PD-L1抗体。
5.根据权利要求3所述的双特异性分子,其中Ab1是抗-PD-L1抗体和Ab2是抗-CD38抗体。
6.根据权利要求3至5中任意一项所述的双特异性分子,其中所述抗-CD38抗体选自下组:达雷木单抗(daratumumab)、isatuximab、MOR-202或其突变衍生物。
7.根据权利要求3至6中任意一项所述的双特异性分子,其中所述抗-PD-L1抗体选自下组:阿特珠单抗(atezolizumab)、durvalumab、avelumab、MDX-1105或其突变衍生物。
8.根据权利要求3至7中任意一项所述的双特异性分子,其中所述Ab1的CH1和CL结构域具有与所述Ab2的CH1和CL结构域不同的序列。
9.根据权利要求3至7中任意一项所述的双特异性分子,其中所述Ab1或Ab2之一的FabCH1结构域是突变结构域,其来自于所述CH1结构域192位的苏氨酸残基被天冬氨酸残基取代的免疫球蛋白的CH1结构域,以及所述同源CL结构域是突变结构域,其来自于所述CL结构域137位的天冬酰胺残基被赖氨酸残基取代和所述CL结构域114位的丝氨酸残基被丙氨酸残基取代的免疫球蛋白的CL结构域,和/或其中所述Ab1或Ab2的一个或另一个的Fab CH1结构域是突变结构域,其来自于所述CH1结构域124位的亮氨酸残基被谷氨酰胺残基取代和所述CH1结构域188位的丝氨酸残基被缬氨酸残基取代的免疫球蛋白的CH1结构域,以及所述同源CL结构域是突变结构域,其来自于所述CL结构域133位的缬氨酸残基被苏氨酸残基取代和所述CL结构域176位的丝氨酸残基被缬氨酸残基取代的免疫球蛋白的CL结构域。
10.根据权利要求1至9中任意一项所述的双特异性分子,所述双特异性分子包含优选地由a)两条重链和b)四条轻链组成,每条重链包含优选地由SEQ ID NO:10组成,以及两条轻链包含优选地由SEQ ID NO:11组成和另外两条轻链包含优选地由SEQ ID NO:12组成。
11.一种多肽,所述多肽包含优选地由权利要求1至10中任意一项所定义的双特异性分子的重链组成。
12.一种多核苷酸,所述多核苷酸包含编码权利要求11所述的多肽的序列。
13.一种转染了表达载体的宿主细胞,所述表达载体包含权利要求12所述的多核苷酸。
14.一种用于生产权利要求1至10中任意一项所述的双特异性分子的方法,所述方法包括下述步骤:
a.在适宜培养基中和培养条件下培养宿主细胞,所述宿主细胞表达如权利要求1至10中任意一项所定义的抗体重链以及如权利要求1至10中任意一项所定义的抗体轻链,以及
b.从所述培养基中或从所述所培养的细胞中回收所述所生产的抗体。
15.权利要求1至10中任意一项所述的双特异性分子用作药物。
16.权利要求1至10中任意一项所述的双特异性分子用于治疗癌症,优选地多发性骨髓瘤、淋巴瘤或白血病。
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US11505616B2 (en) | 2022-11-22 |
CN109476741B (zh) | 2023-02-24 |
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EP3433273B1 (en) | 2021-12-29 |
EP3433273A1 (en) | 2019-01-30 |
RU2018137419A3 (zh) | 2020-08-17 |
KR20190016942A (ko) | 2019-02-19 |
WO2017162890A1 (en) | 2017-09-28 |
ES2906639T3 (es) | 2022-04-19 |
JP2019516396A (ja) | 2019-06-20 |
HUE057657T2 (hu) | 2022-06-28 |
PL3433273T3 (pl) | 2022-04-04 |
CN116284428A (zh) | 2023-06-23 |
KR102361412B1 (ko) | 2022-02-09 |
EP3998285A1 (en) | 2022-05-18 |
AU2017236183A1 (en) | 2018-11-15 |
SG11201808289SA (en) | 2018-10-30 |
RU2764201C2 (ru) | 2022-01-14 |
AU2017236183B2 (en) | 2024-03-07 |
CA3022143A1 (en) | 2017-09-28 |
PT3433273T (pt) | 2022-02-21 |
JP2022116166A (ja) | 2022-08-09 |
US20230146591A1 (en) | 2023-05-11 |
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