CN116710556A - 抗pd-l1/抗4-1bb天然抗体结构样异源二聚体形式双特异抗体及其制备 - Google Patents
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Abstract
提供了抗PD‑L1/抗4‑1BB天然抗体结构样异源二聚体形式双特异抗体及其制备。具体而言,提供了一种具有天然IgG特点、并且没有重轻链错配的高度稳定的异源二聚体形式的抗PD‑L1/抗4‑1BB双特异抗体及其制备方法。该双特异抗体能同时结合两种靶分子并且在治疗复杂疾病方面更有效且副作用更小。
Description
本发明涉及抗PD-L1/抗4-1BB天然抗体结构样异源二聚体形式双特异抗体及其制备。具体而言,本发明提供了一种具有天然IgG特点、并且没有重轻链错配的高度稳定的异源二聚体形式的抗PD-L1/抗4-1BB双特异抗体及其制备方法。
程序性死亡配体-1(programmed death ligand 1,PD-L1)是免疫检查点程序性死亡受体-1(programmed death-1,PD-1)的配体,属于B7家族,诱导性表达于多种免疫细胞表面,包括T细胞、B细胞、单核细胞、巨噬细胞、DC细胞以及内皮细胞、表皮细胞等。PD-L1与PD-1结合后,主要参与T细胞活化的负调控,可以调节免疫应答的强弱程度和持续时间。PD-L1除了作为PD-1的配体以外,还能作为CD80的配体,向T细胞传递负调控信号,诱导T细胞免疫耐受(Autoimmun Rev,2013,12(11):1091-1100.Front Immunol,2013,4:481.Nat Rev Cancer,2012,12(4):252-264.Trends Mol Med.2015 Jan;21(1):24-33.Clin Cancer Res.2012 Dec 15;18(24):6580-7.)。在正常情况下,PD-L1和PD-1可以介导和维持机体组织的自身免疫耐受,防止在炎症反应过程中免疫系统过度活化伤害自身组织,对避免自身免疫性疾病的发生具有积极作用;在病理情况下,其参与肿瘤免疫以及多种自身免疫病的发生发展过程。多项研究报道,PD-L1在多种肿瘤组织中高表达,PD-1在肿瘤浸润淋巴细胞中高表达,且PD-L1和PD-1的过表达与肿瘤不良临床预后密切相关(Anticancer Agents Med Chem.2015;15(3):307-13.Hematol Oncol Stem Cell Ther.2014 Mar;7(1):1-17.Trends Mol Med.2015Jan;21(1):24-33.Immunity.2013 Jul 25;39(1):61-73.J Clin Oncol.2015 Jun 10;33(17):1974-82.)。利用PD-L1单克隆抗体阻断PD-L1/PD-1以及CD80/PD-L1的相互作用,在临床前实验研究和临床中都显示出了良好的抗肿瘤效果。目前PD-L1单克隆抗体已经被批准用于治疗非小细胞肺癌和尿路上皮癌等多种肿瘤。
4-1BB(也称作CD137,TNFRSF9等)是肿瘤坏死因子受体超家族(TNFRS)的一种跨膜蛋白质。4-1BB在DC、活化的单核细胞、NK细胞、中性粒细胞、嗜酸性粒细胞和肥大细胞上表达。4-1BBL(CD137L)是TNF超家族的糖蛋白成员,主要在活化的B细 胞、巨噬细胞、树突状细胞、髓系细胞上表达。4-1BB是CD8+和CD4+T细胞、调节性T细胞(Treg)、自然杀伤T细胞(NK(T)细胞)、B细胞和嗜中性粒细胞上的共刺激分子。4-1BB与4-1BBL结合后激活胞内的信号通路。研究表明一些4-1BB激动剂mAb在许多模型中增加共刺激分子表达,并且显著增强细胞溶解性T淋巴细胞应答,引起抗肿瘤功效。
因此,本领域仍然有必要研究一种同时阻断PD-L1和4-1BB信号通路的新型治疗药物。
发明内容
本发明提供了一种新的具有天然IgG结构特点、并且没有重轻链错配的高度稳定的异源二聚体形式的能同时阻断PD-L1和4-1BB的双功能抗体及其制备方法,该双功能抗体倾向于选择性结合同时高表达PD-L1和4-1BB的肿瘤细胞,从而发挥高效、特异的杀伤效果,同时具有较低的毒副作用。
本发明的第一方面涉及一种双特异性抗体,其包含特异性结合PD-L1的第一抗原结合功能区和特异性结合4-1BB的第二抗原结合功能区,其中所述特异性结合PD-L1的第一抗原结合功能区包含:
(A)重链可变区,所述重链可变区包含
(a)HCDR1,其包含SEQ ID NO:15所示的氨基酸序列,
(b)HCDR2,其包含SEQ ID NO:16所示的氨基酸序列,以及
(c)HCDR3,其包含SEQ ID NO:17所示的氨基酸序列;以及
(B)轻链可变区,所述轻链可变区包含
(a)LCDR1,其包含SEQ ID NO:18所示的氨基酸序列,
(b)LCDR2,其包含SEQ ID NO:19所示的氨基酸序列,以及
(c)LCDR3,其包含SEQ ID NO:20所示的氨基酸序列。
在一些实施方案中,所述双特异性抗体的特异性结合4-1BB的第二抗原结合功能区包含
(A)重链可变区,所述重链可变区包含
(a)HCDR1,其包含SEQ ID NO:21所示的氨基酸序列,
(b)HCDR2,其包含SEQ ID NO:22所示的氨基酸序列,以及
(c)HCDR3,其包含SEQ ID NO:23所示的氨基酸序列;以及
(B)轻链可变区,所述轻链可变区包含
(a)LCDR1,其包含SEQ ID NO:24所示的氨基酸序列,
(b)LCDR2,其包含SEQ ID NO:25所示的氨基酸序列,以及
(c)LCDR3,其包含SEQ ID NO:26所示的氨基酸序列。
在一些实施方案中,所述双特异性抗体的特异性结合PD-L1的第一抗原结合功能区包含
(A)重链可变区,所述重链可变区包含
(a)HCDR1,其包含SEQ ID NO:15所示的氨基酸序列,
(b)HCDR2,其包含SEQ ID NO:16所示的氨基酸序列,以及
(c)HCDR3,其包含SEQ ID NO:17所示的氨基酸序列;以及
(B)轻链可变区,所述轻链可变区包含
(a)LCDR1,其包含SEQ ID NO:18所示的氨基酸序列,
(b)LCDR2,其包含SEQ ID NO:19所示的氨基酸序列,以及
(c)LCDR3,其包含SEQ ID NO:20所示的氨基酸序列;并且
所述特异性结合4-1BB的第二抗原结合功能区包含
(A)重链可变区,所述重链可变区包含
(a)HCDR1,其包含SEQ ID NO:21所示的氨基酸序列,
(b)HCDR2,其包含SEQ ID NO:22所示的氨基酸序列,以及
(c)HCDR3,其包含SEQ ID NO:23所示的氨基酸序列;以及
(B)轻链可变区,所述轻链可变区包含
(a)LCDR1,其包含SEQ ID NO:24所示的氨基酸序列,
(b)LCDR2,其包含SEQ ID NO:25所示的氨基酸序列,以及
(c)LCDR3,其包含SEQ ID NO:26所示的氨基酸序列。
如SEQ ID NO.15-20所示的特异性结合PD-L1的第一抗原结合功能区的6个CDR序列和如SEQ ID NO.21-26所示的特异性结合4-1BB的第二抗原结合功能区的6个CDR序列分别是本发明人以人PD-L1和4-1BB为抗原,利用杂交瘤技术获得的单克隆抗体的重轻链可变区的CDR,所述单克隆抗体不同于现有技术已知的PD-L1抗体和4-1BB抗体且具有更高的生物活性,如更高的结合特异性、抗肿瘤活性等。
特异性结合PD-L1的第一抗原结合功能区的6个CDR序列,分别与SEQ ID NO.15-20所示序列具有至少70%的同一性且保留相应母体序列生物活性,例如至少75%、80%、 85%、90%、95%或更高的同一性;或者分别为SEQ ID NO.15-20所示序列经删除、替换和/或添加一个或多个氨基酸残基后获得的保留相应母体序列生物活性,例如1个、2个、3个或更多个;
特异性结合4-1BB的第二抗原结合功能区的6个CDR序列,分别与SEQ ID NO.21-26所示序列具有至少70%的同一性且保留相应母体序列生物活性,例如至少75%、80%、85%、90%、95%或更高的同一性;或者分别为SEQ ID NO.21-26所示序列经删除、替换和/或添加一个或多个氨基酸残基后获得的保留相应母体序列生物活性,例如1个、2个、3个或更多个。
在一些实施方案中,所述双特异性抗体的特异性结合PD-L1的第一抗原结合功能区包含重链可变区和轻链可变区,所述重链可变区包含SEQ ID NO:6所示的氨基酸序列;或与SEQ ID No.6所示序列具有至少70%的同一性且保留相应母体序列生物活性,例如至少75%、80%、85%、90%、95%、96%、97%、98%、99%或更高的同一性;或为SEQ ID NO.6所示序列经删除、替换和/或添加一个或多个氨基酸残基后获得的保留相应母体序列生物活性的变体序列,例如1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、15个、20个或更多个。所述轻链可变区包含SEQ ID NO:2所示的氨基酸序列;或与SEQ ID No.2所示序列具有至少70%的同一性且保留相应母体序列生物活性,例如至少75%、80%、85%、90%、95%、96%、97%、98%、99%或更高的同一性;或为SEQ ID NO.2所示序列经删除、替换和/或添加一个或多个氨基酸残基后获得的保留相应母体序列生物活性的变体序列,例如1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、15个、20个或更多个。
在一些实施方案中,所述双特异性抗体的特异性结合4-1BB的第二抗原结合功能区包含重链可变区和轻链可变区,所述重链可变区包含如SEQ ID NO:12所示的氨基酸序列;或与SEQ ID No.12所示序列具有至少70%的同一性且保留相应母体序列生物活性,例如至少75%、80%、85%、90%、95%、96%、97%、98%、99%或更高的同一性;或为SEQ ID NO.12所示序列经删除、替换和/或添加一个或多个氨基酸残基后获得的保留相应母体序列生物活性的变体序列,例如1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、15个、20个或更多个。所述轻链可变区包含如SEQ ID NO:10所示的氨基酸序列;或与SEQ ID No.10所示序列具有至少70%的同一性且保留相应母体序列生物活性,例如至少75%、80%、85%、90%、95%、96%、97%、98%、99%或更高的同一性;或为SEQ ID NO.10所示序列经删除、替换和/或添加一个或多个氨基酸残基后获得的保留 相应母体序列生物活性的变体序列,例如1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、15个、20个或更多个。
在一些实施方案中,所述双特异性抗体的特异性结合PD-L1的第一抗原结合功能区包含重链可变区和轻链可变区,所述重链可变区包含SEQ ID NO:6所示的氨基酸序列,所述轻链可变区包含SEQ ID NO:2所示的氨基酸序列;并且其中特异性结合4-1BB的所述第二抗原结合功能区包含重链可变区和轻链可变区,所述重链可变区包含如SEQ ID NO:12所示的氨基酸序列,所述轻链可变区包含如SEQ ID NO:10所示的氨基酸序列。
本领域技术人员知晓,对于所述氨基酸序列的组合方式应符合生物学规律,即,轻重链或轻重链的可变区、抗原结合片段要相互匹配,如SEQ ID NO:6和SEQ ID NO:2相互匹配,SEQ ID NO:12和SEQ ID NO:10相互匹配。
在一些实施方案中,所述双特异抗体的第一个抗原结合功能区和第二个抗原结合功能区选自Fab片段、scFv片段和可变结构域片段Fv。
在一些实施方案中,所述双特异抗体的第一个抗原结合功能区和第二个抗原结合功能区都是Fab片段。
在一些实施方案中,所述双特异抗体的Fab片段包含不同的第一重链可变区及第二重链可变区,以及不同的第一轻链可变区及第二轻链可变区。
在一些实施方案中,所述双特异抗体的第一个抗原结合功能区和第二个抗原结合功能区中一个是Fab片段,另一个是scFv。
在一些实施方案中,所述双特异性抗体包含第一Fc链和第二Fc链,以及能与PD-L1特异性结合的第一个抗原结合功能区和能与4-1BB特异性结合的第二个抗原结合功能区;
其中所述第一Fc链和第二Fc链均为包含氨基酸替换的免疫球蛋白G Fc片段,并且所述第一Fc链及第二Fc链共同构成可以与Fc受体结合的异源二聚体;
其中所述第一Fc链和第二Fc链通过共价键或连接体分别连接到所述第一抗原结合功能区和第二抗原结合功能区;
并且其中所述第一Fc链和第二Fc链中的任意一条在366位及399位上包含氨基酸替换,另一条在351位、407位及409位上包含氨基酸替换,其中氨基酸位置根据Kabat EU指数编号系统编号。
在一些实施方案中,所述双特异抗体的第一Fc链及第二Fc链氨基酸替换如下,
a)L351G、L351Y、L351V、L351P、L351D、L351E、L351K或L351W;
b)T366L、T366P、T366W或T366V;
c)D399C、D399N、D399I、D399G、D399R、D399T或D399A;
d)Y407L、Y407A、Y407P、Y407F、Y407T或Y407H;和
e)K409C、K409P、K409S、K409F、K409V、K409Q或K409R。
在一些实施方案中,所述双特异抗体的氨基酸替换包括:
a)第一Fc链和第二Fc链中的任意一条为T366L及D399R替换,另一条为L351E、Y407L及K409V替换;
b)第一Fc链和第二Fc链中的任意一条为T366L及D399C替换,另一条为L351G、Y407L及K409C替换;
c)第一Fc链和第二Fc链中的任意一条为T366L及D399C替换,另一条为L351Y、Y407A及K409P替换;
d)第一Fc链和第二Fc链中的任意一条为T366P及D399N替换,另一条为L351V、Y407P及K409S替换;
e)第一Fc链和第二Fc链中的任意一条为T366W及D399G替换,另一条为L351D、Y407P及K409S替换;
f)第一Fc链和第二Fc链中的任意一条为T366P及D399I替换,另一条为L351P、Y407F及K409F替换;
g)第一Fc链和第二Fc链中的任意一条为T366V及D399T替换,另一条为L351K、Y407T及K409Q替换;
h)第一Fc链和第二Fc链中的任意一条为T366L及D399A替换,另一条为L351W、Y407H及K409R替换。
在一些实施方案中,所述双特异抗体的氨基酸替换包括:
a)第一Fc链和第二Fc链中的任意一条为T366L及K409V替换,另一条为L351E、Y407L及D399R替换;
b)第一Fc链和第二Fc链中的任意一条为T366L及K409C替换,另一条为L351G、Y407L及D399C替换;
c)第一Fc链和第二Fc链中的任意一条为T366L及K409P替换,另一条为L351Y、Y407A及D399C替换;
d)第一Fc链和第二Fc链中的任意一条为T366P及K409S替换,另一条为L351V、Y407P及D399N替换;
e)第一Fc链和第二Fc链中的任意一条为T366W及K409S替换,另一条为L351D、Y407P及D399G替换;
f)第一Fc链和第二Fc链中的任意一条为T366P及K409F替换,另一条为L351P、Y407F及D399I替换;
g)第一Fc链和第二Fc链中的任意一条为T366V及K409Q替换,另一条为L351K、Y407T及D399T替换;
h)第一Fc链和第二Fc链中的任意一条为T366L及K409R替换,另一条为L351W、Y407H及D399A替换。
在一些实施方案中,所述双特异抗体的第一Fc链和第二Fc链中的任意一条的氨基酸替换为T366L和D399R,另一条的氨基酸替换为L351E、Y407L和K409V。
在一些实施方案中,所述双特异抗体的第一Fc链及与其共价相连的第一抗原结合功能区,和第二Fc链及与其共价相连的第二抗原结合功能区,在存在还原剂的溶液中且所述溶液中除所述第一Fc链及与其共价相连的第一抗原结合功能区和第二Fc链及与其共价相连的第二抗原结合功能区以外不含其它多肽时,其形成同源二聚体的基于所有多肽链的重量比例均低于50%,如均低于45%、40%、35%、30%、25%、20%或更低。
在一些实施方案中,所述双特异性抗体包含特异性结合PD-L1的第一重链/第一轻链对,其中所述第一重链具有包含SEQ ID NO:6所示的氨基酸序列的重链可变区,以及包含SEQ ID NO:8所示的氨基酸序列的重链恒定区;所述第一轻链具有包含如SEQ ID NO:2所示的氨基酸序列的轻链可变区,以及包含如SEQ ID NO:4所示的氨基酸序列的轻链恒定区。
在一些实施方案中,所述双特异性抗体包含特异性结合4-1BB的第二重链/第二轻链对,其中所述第二重链具有包含SEQ ID NO:12所示的氨基酸序列的重链可变区,以及包含SEQ ID NO:13所示的氨基酸序列的重链恒定区;所述第一轻链具有包含如SEQ ID NO:10所示的氨基酸序列的轻链可变区,以及包含如SEQ ID NO:3所示的氨基酸序列的轻链恒定区。
本发明的第二方面涉及一种分离的多核苷酸,其编码如上所述的异源二聚体形式的双特异抗体。
在一些实施方案中,编码第一抗原结合功能区氨基酸的核苷酸序列包含SEQ ID NO:1和5的核苷酸序列。
在一些实施方案中,编码第二抗原结合功能区氨基酸的核苷酸序列包含SEQ ID NO: 11和9的核苷酸序列。
在一些实施方案中,编码第一轻链和第二轻链氨基酸的核苷酸序列均包含SEQ ID NO:3的核苷酸序列。
在一些实施方案中,编码第一重链和第二重链中的任意一条氨基酸的核苷酸序列包含SEQ ID NO:7的核苷酸序列,编码另一条的核苷酸序列包含SEQ ID NO:13的核苷酸序列。
本发明的第三方面涉及一种重组表达载体,其包含如上所述的分离的多核苷酸。
在一些实施方案中,表达载体为基于pCDNA改造得到的质粒载体X0GC。
本发明的第四方面涉及一种宿主细胞,其包含如上所述的分离的多核苷酸,或如上所述的重组表达载体。
在一些实施方案中,所述的宿主细胞选自人胚肾细胞HEK293或以HEK293细胞为基础改造而得到的HEK293T、HEK293E、HEK293F;仓鼠卵巢细胞CHO或以CHO细胞为基础改造而得到的CHO-S、CHO-dhfr
-、CHO/DG44、ExpiCHO;大肠杆菌或以大肠杆菌为基础改造得到的大肠杆菌BL21、BL21(DE3)、Rosetta、Origami;酵母菌或以酵母为基础改造得到的毕赤酵母、酿酒酵母、乳酸克鲁维亚酵母、多形汉逊酵母;昆虫细胞或以昆虫细胞为基础改造得到的细胞High5、SF9;植物细胞;哺乳动物乳腺细胞、体细胞。
本发明的第五方面涉及一种组合物,其包含如上所述双特异抗体或如上所述的分离的多核苷酸或如上所述的重组表达载体或如上所述的宿主细胞,及药学上可接受的载体。在进一步的实施方案中,所述组合物还包含至少一种第二治疗剂,优选地,所述第二治疗剂与所述双特异抗体、分离的多核苷酸、重组表达载体或宿主细胞处于所述组合物的不同的部分中,优选地,第二治疗剂是抗PD-1抗体和/或STING激动剂。
本发明的第六方面涉及一种生产如上所述双特异抗体的方法,其包括步骤:
1)将如上所述的分离的多核苷酸或如上所述的重组表达载体分别在宿主细胞中进行表达;
2)将在宿主细胞中分别表达的蛋白进行还原;以及
3)将还原的蛋白混合,然后将混合物进行氧化。
在一些实施方案中,宿主细胞选自人胚肾细胞HEK293或以HEK293细胞为基础改造而得到的HEK293T、HEK293F、HEK293F;仓鼠卵巢细胞CHO或以CHO细胞为基础改造而得到的CHO-S、CHO-dhfr
-、CHO/DG44、ExpiCHO;大肠杆菌或以大肠杆菌为基础改造得到的大肠杆菌BL21、BL21(DE3)、Rosetta、Origami;酵母菌或以酵母为基础 改造得到的毕赤酵母、酿酒酵母、乳酸克鲁维亚酵母、多形汉逊酵母;昆虫细胞或以昆虫细胞为基础改造得到的细胞High5、SF9;植物细胞;哺乳动物乳腺细胞、体细胞。
在一些实施方案中,还原步骤包括1)在还原剂存在下进行还原反应,所述还原剂选自:2-巯基乙胺、二硫苏糖醇、三(2-羧乙基)膦或其他化学衍生物;2)去除还原剂。在一些实施方案中,还原剂为0.1mM或更高浓度二硫苏糖醇,反应条件为4℃下反应至少3小时,如0.1mM、0.2mM、0.3mM、0.4mM、0.5mM或更高,如3.5小时、4小时、4.5小时、5小时、5.5小时、6小时,或更长。
在一些实施方案中,氧化步骤为在空气中氧化,也包括在氧化剂存在下进行氧化反应,所述氧化剂选自:L-脱氢抗坏血酸或其化学衍生物。在一些实施方案中,氧化剂为0.5mM或更高浓度L-脱氢抗坏血酸,反应条件为4℃下反应至少5小时,如0.6mM、0.7mM、0.8mM、0.9mM、1.0mM、1.2mM、1.5mM或更高,如5小时、6小时、7小时、8小时、9小时,或更长。
在一些实施方案中,所述的方法还包括分离纯化的步骤。在一些实施方案中,所述分离纯化包括阳离子树脂交换、阴离子树脂交换、反相层析、亲和层析、尺寸排阻层析及其组合。
本发明的第七方面涉及如上所述双特异抗体和/或如上所述的分离的多核苷酸和/或如上所述的重组表达载体和/或如上所述的宿主细胞和/或如上所述的组合物在制备用于预防和/或治疗受试者疾病的药物中的用途。
本发明的第八方面涉及如上所述双特异抗体和/或如上所述的分离的多核苷酸和/或如上所述的重组表达载体和/或如上所述的宿主细胞和/或如上所述的组合物,其用做用于预防和/或治疗受试者疾病的药物。
本发明的第九方面涉及一种预防和/或治疗疾病的方法,包括将如上所述的双特异抗体和/或如上所述的分离的多核苷酸和/或如上所述的重组表达载体和/或如上所述的宿主细胞和/或如上所述的组合物施予有需求的受试者。
在一些实施方案中,受试者是哺乳动物,优选地,人类受试者。
在一些实施方案中,所述疾病选自如下肿瘤:白血病、淋巴瘤、骨髓瘤、脑肿瘤、头颈部鳞状细胞癌、非小细胞肺癌、鼻咽癌、食道癌、胃癌、胰腺癌、胆囊癌、肝癌、结直肠癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、膀胱癌、肾细胞癌、黑色素瘤、小细胞肺癌、骨癌。
换言之,本发明设计了一种全新的抗PD-L1/抗4-1BB天然抗体结构样异源二聚体形 式双特异抗体,其具有天然IgG特点,并且没有重轻链错配,是高度稳定的异源二聚体形式的抗PD-L1/抗4-1BB双特异抗体。本发明制备的双特异抗体能同时结合两种靶分子PD-L1和4-1BB,将其应用于复杂疾病治疗时可发挥比单一治疗剂更好的效果且副作用更小。同时,相对于多个药物的组合治疗,该双特异抗体作为单一治疗分子不仅方便了患者和医疗工作者的使用,也简化了复杂的新药开发流程。
图1:示出了抗PD-L1表达产物的洗脱峰色谱图。
图2:示出了抗4-1BB表达产物的洗脱峰色谱图。
图3:示出了抗PD-L1/抗4-1BB双特异抗体分子的结构。
图4.示出了含一条重链和一条轻链的半抗体分子结构。
图5.示出了含一条重链和一条轻链的半抗体分子的SEC-HPLC分析结果。其中A图和B图分别表示抗PD-L1半抗体分子和抗4-1BB半抗体分子的结果。
图6.示出了抗PD-L1/抗4-1BB双特异抗体分子的SEC-HPLC分析结果。
图7.示出了抗PD-L1/抗4-1BB双特异抗体分子的CE分析结果。
图8.A图示出了抗PD-L1/抗4-1BB双特异抗体对PD-L1的亲和力,B图示出了抗PD-L1/抗4-1BB双特异抗体对4-1BB的亲和力,C图示出了抗PD-L1/抗4-1BB双特异抗体对4-1BB的亲和力。
图9.A图示出了抗PD-L1/抗4-1BB双特异抗体阻断PD-L1/PD-1结合的活性,B图示出了抗PD-L1/抗4-1BB双特异抗体阻断PD-L1/CD80结合的活性。
图10.示出了抗PD-L1/抗4-1BB双特异抗体的T细胞调控活性。
图11.示出了抗PD-L1/抗4-1BB双特异抗体介导的4-1BB受体激动活性。
图12.示出了抗PD-L1/抗4-1BB双特异抗体在基因敲入小鼠同源肿瘤模型中的抗肿瘤药效。
图13.示出了BALB/c-hPD1/hPDL1/hCD137小鼠的肿瘤体积变化。
图14.示出了h4-1BB/hPD-1小鼠的肿瘤体积数据。
定义:
在本文中,术语“抗体”以最广意义使用,指包含抗原结合位点的蛋白质,涵盖各 种结构的天然抗体和人工抗体,包括但不限于完整抗体和抗体的抗原结合片段。
在本文中,术语“双特异性抗体”包含与两种不同生物分子上的表位特异性结合的抗原结合结构域。除非另外说明,否则列出的双特异性抗体名称中双特异性抗体结合的抗原的顺序是任意的。即,在一些实施方案中,术语“抗PD-L1/4-1BB双特异性抗体”和“抗4-1BB/PD-L1双特异性抗体”可以互换使用。在一些实施方案中,双特异性抗体包含两个半抗体,其中每个半抗体包含单个重链可变区和任选地重链恒定区的至少一部分以及单个轻链可变区和任选地轻链恒定区的至少一部分。在一些实施方案中,双特异性抗体包含两个半抗体,其中每个半抗体包含单个重链可变区和单个轻链可变区并且不包含多于一个单个重链可变区且不包含多于一个单个轻链可变区。在一些实施方案中,双特异性抗体包含两个半抗体,其中每个半抗体包含单个重链可变区和单个轻链可变区,并且其中第一半抗体与第一抗原结合且不与第二抗原结合并且第二半抗体与第二抗原结合且不与第一抗原结合。
术语“互补决定区”或“CDR区”或“CDR”(在本文中与超变区“HVR”可以互换使用)指抗体可变结构域中在序列上高变并且形成在结构上确定的环(“超变环”)和/或含有抗原接触残基(“抗原接触点”)的区域。CDR主要负责与抗原表位结合。在本文中,重链的三个CDR称为HCDR1、HCDR2和HCDR3,轻链的三个CDR称为LCDR1、LCDR2和LCDR3。
应该注意,基于不同的指派系统获得的同一抗体的可变区的CDR的边界可能有所差异。即不同指派系统下定义的同一抗体可变区的CDR序列有所不同。因此,在涉及用本发明定义的具体CDR序列限定抗体时,所述抗体的范围还涵盖了这样的抗体,其可变区序列包含所述的具体CDR序列,但是由于应用了不同的方案(例如不同的指派系统规则或组合)而导致其所声称的CDR边界与本发明所定义的具体CDR边界不同。
共价连接是指异源二聚体形式的双特异抗体中,两个Fc链之间,任一个Fc链及与其相连接的抗原结合功能区之间,是通过共价键而连接成为一个分子。其中Fc链包含通过一个或多个通过共价连接(如二硫键链)而连接的第一抗原结合功能区及第二抗原结合功能区;该第一Fc链及第二Fc链分别通过共价连接(如亚胺键或酰胺键)而连接到一个抗原结合功能区上;
抗原结合功能区是指可以与目标分子如抗原发生特异性相互作用的区域,其作用具有高度选择性,识别一种目标分子的序列通常不能识别其他分子序列。代表性的抗原结合功能区包括:抗体的可变区、抗体可变区的结构变构体、受体的结合域、配体结合域 或酶结合域。
一个或多个二硫键链间连接是指第一Fc链及第二Fc链通过一个或多个二硫键链间连接,形成异源二聚体片段。在本发明中,一个或多个二硫键的形成可以是第一Fc链及第二Fc链或者第一Fc链及第二Fc链及其相连接的抗原结合功能区在同一个细胞内合成时形成,也可以是第一Fc链及第二Fc链或者第一Fc链及第二Fc链及其相连接的抗原结合功能区在不同细胞内分别合成,之后通过体外还原氧化的方法形成。
第一Fc链及第二Fc链是指通过共价连接而组成结合片段,共价连接包括二硫键,每条链至少包含免疫球蛋白重链恒定区的一部分;并且该第一Fc链及第二Fc链在氨基酸序列上是不同的,至少包括了一位氨基酸的不同。在此发明中的第一Fc链及第二Fc链,相同链之间存在强烈的相互排斥作用,而不同链之间存在吸引作用,因此当在细胞内共同表达时,第一Fc链及第二Fc链,或者第一Fc链及第二Fc链及其相连接的抗原结合功能区,更倾向于形成异源二聚体。将第一Fc链及第二Fc链,或者第一Fc链及第二Fc链及其相连接的抗原结合功能区分别在两个宿主细胞内表达时,第一Fc链或者第一Fc链及其相连接的抗原结合功能区不倾向于形成同源二聚体,第二Fc链或者第二Fc链及其相连接的抗原结合功能区不倾向于形成同源二聚体。在本发明中,当第一Fc链及第二Fc链,或者第一Fc链及第二Fc链及其相连接的抗原结合功能区分别在两个宿主细胞内表达时,并且在存在还原剂时,同源二聚体的比例低于50%,即单体(一条Fc链或者一条Fc链及其相连接的抗原结合功能区)比例大于50%。
免疫球蛋白是具有四条多肽链的对称结构,其中两条较长、相对分子量较大的相同的重链,含450~550个氨基酸残基,相对分子质量在55000~70000Da之间;两条较短、相对分子量较小的相同的轻链(L链),含约210个氨基酸残基,相对分子质量约24000Da。不同的免疫球蛋白重链和轻链在靠近N端的约110个氨基酸的序列变化很大,称为可变区(variable region,V区),而靠近C端的其余氨基酸序列相对稳定,称为恒定区(constant region,C区)。抗体的每条重链由重链可变区(本文中简称为VH)和重链恒定区(本文中简称为CH)构成,每条轻链由轻链可变区(本文中简称为VL)和轻链恒定区(本文中简称为CL)组成。重链中可变区约占重链长度的1/4,恒定区约占重链长度的3/4。对于已知五种Ig来说,IgG(γ)、IgA(α)、IgD(δ)、IgM(μ)和IgE(ε),其中前三类Ig的H链内有三个恒定区,即CH1、CH2和CH3组成。后两类(IgM和IgE)的H链中有一个VH区和四个恒定区,即CH1至CH4。恒定区既是免疫球蛋白分子的骨架,又是激活免疫反应的部位之一。虽然本发明实施例涉及IgG,但本领域技术 人员知晓,如果希望的话,可以通过已知方法转换本发明的抗体的类别。例如,最初是IgM的本发明抗体可以类别转换为本发明的IgG抗体。此外,类别转换技术可以用来将一个IgG亚类转化成另一亚类,例如从IgGl转换到IgG2。因此,本发明的抗体的效应子功能可以通过同种型切换变为例如IgG1、IgG2、IgG3、IgG4、IgD、IgA、IgE或IgM抗体,用于各种治疗用途。在一个实施例中,本发明的抗体是IgG1抗体,例如IgG1,κ。
本发明中的恒定区一部分至少包括了第一Fc链和第二Fc链相互作用的区域,该区域对于IgG来说,是位于CH3区域的一部分氨基酸,至少包括GLN347、TYR349、THR 350、LEU 351、SER 354、ARG 355、ASP 356、GLU 357、LYS 360、SER 364、THR 366、LEU 368、LYS 370、ASN390、LYS392、THR394、PRO395、VAL 397、ASP399、SER400、PHE405、TYR407、LYS409、LYS439。
第一Fc链及第二Fc链分别通过共价键或连接体连接到一个抗原结合功能区上是指第一Fc链及第二Fc链分别通过共价键或连接体连接到一个抗体的抗原结合片段,或可以识别抗原的单链抗体,或可以识别抗原的其他抗体片段变构体,或可以识别配体的受体,或可以识别受体的配体,其中所述共价键是指是化学键的一种,两个或多个原子共同使用它们的外层电子,在理想情况下达到电子饱和的状态,由此组成比较稳定的化学结构叫做共价键,或者说共价键是原子间通过共用电子对所形成的相互作用。同一种的元素的原子或不同元素的都可以通过共价键结合,对于本发明的第一Fc链及第二Fc链间的共价键,包括但不限于一分子氨基酸的氨基与另一分子氨基酸的羧基脱水反应形成的酰胺键,或者乙二醇或聚乙二醇或其他化合物或其多聚物的醛基与一分子氨基酸的氨基形成酰胺键或亚胺键,其中连接体是可以将两条多肽链通过共价键连接起来的一段氨基酸序列或者一种化合物或者一种化合物的多聚体,其中一段氨基酸序列包括但不限于一段小肽,如GGGGSGGGGSGGGGS,通过酰胺键将第一Fc链或第二Fc链,以及可以识别抗原的单链抗体,或可以识别抗原的其他抗体片段结构变构体连接起来
第一Fc链与第二Fc链更倾向于形成异源二聚体而不倾向于各自形成同源二聚体是指,由于在第一Fc链与第二Fc链中,相同的多肽链间存在互相排斥的作用,而不同的多肽链间存在吸引作用,因此当在细胞内共同表达时,第一Fc链及第二Fc链,或者第一Fc链及第二Fc链及其相连接的抗原结合功能区,更倾向于形成异源二聚体。将第一Fc链及第二Fc链,或者第一Fc链及第二Fc链及其相连接的抗原结合功能区分别在两个宿主细胞内表达时,第一Fc链或者第一Fc链及其相连接的抗原结合功能区不倾向于形成同源二聚体,第二Fc链或者第二Fc链及其相连接的抗原结合功能区不倾向于形成同 源二聚体。
Kabat EU指数编号系统是指,Kabat利用一种方法将一个编号指定给抗体序列的每个氨基酸并且这种指定每个残基的编号的方法已经成为本领域的标准方法。Kabat方案可以延伸到不存在于他的研究中的其它抗体,基于保守的氨基酸,将目标抗体与Kabat鉴定的共有序列之一进行比对。在本文中,如无特殊说明,抗体的氨基酸位置均根据Kabat EU指数编号系统编号。
Fc结构域是指可结晶段(fragment crystallizable,Fc),相当于Ig的CH2和CH3结构域,是Ig与效应分子或者细胞相互作用的部位。
IgG是免疫球蛋白G(Immunoglobulin G,IgG)的缩写,是血清主要的抗体成分,根据IgG分子中的r链抗原性差异,人IgG有四个亚型:IgG1、IgG2、IgG3、IgG4。
半抗体分子是指抗体的一条重链与一条轻链形成的结构,其中重链与轻链间可以通过共价键连接,也可以不通过共价键连接,是一种识别抗原的单价抗体结构。
Fab片段是一种分子识别序列,是抗原结合片段(fragment of antigen binding,Fab),相当于抗体分子的两个臂,由一个完整的轻链和重链的VH和CH1结构域组成。scFv是一种分子识别序列,是一种由抗体的轻链可变区与重链可变区通过基因工程改造而得到的抗体片段的结构异构体。膜受体的细胞外区是一种分子识别序列,膜受体通常包括位于细胞外部的可以识别并结合相应抗原或者配体的细胞外区域,将受体锚定在细胞表面的跨膜区,以及在胞内的具有激酶活性或者可以传递信号通路的胞内区。细胞膜受体的配体是指能被膜受体胞外区识别并结合的蛋白质,小肽或化合物。细胞因子是免疫原、丝裂原或其他刺激剂诱导多种细胞产生的低分子量可溶性蛋白质,具有调节固有免疫和适应性免疫、血细胞生成、细胞生长、APSC多能细胞以及损伤组织修复等多种功能。细胞因子可被分为白细胞介素、干扰素、肿瘤坏死因子超家族、集落刺激因子、趋化因子、生长因子等。蛋白表达标签指在目标蛋白的N端或C端加入的一段氨基酸序列,可以是小肽也可以是长的氨基酸,标签的加入可以有利于蛋白质的正确折叠,可以有利于蛋白质的分离纯化,可以有利于降低蛋白质在胞内的降解,常用的标签包括但不限于HA、SUMO、His、GST、GFP、Flag。
可应用于本发明的异源二聚体形式的双特性抗体中的抗体并无任何限制。优选地,现有技术中已知可以用于治疗和/或预防疾病的抗体均可以用于本发明。
本发明的异源二聚体形式的双特性抗体可具有一个或多个替换、缺失、添加和/或插 入。例如,某些氨基酸可以替换在蛋白质结构中的其它氨基酸而没有明显损失与其它多肽(如抗原)或细胞结合的能力。由于结合能力和蛋白性质决定了蛋白的生物功能活性,可以在蛋白序列上进行某些氨基酸序列的替换而不会明显损失它们的生物效用或活性。
在许多情况中,多肽变体含有一个或多个保守替换。“保守替换”是指其中氨基酸被其它具有类似性质的氨基酸所替换,使得肽化学领域中技术人员可预期多肽的二级结构和亲水性质基本上不发生变化。
氨基酸替换通常是基于氨基酸侧链取代基的相对相似性,如它们的疏水性、亲水性、电荷、大小等。考虑了各种前述特征的示例性替换是本领域技术人员公知的并包括:精氨酸和赖氨酸;谷氨酸和天冬氨酸;丝氨酸和苏氨酸;谷氨酰胺和天冬酰胺;以及缬氨酸、亮氨酸和异亮氨酸。
本发明使用的术语“同一性”具有本领域通常已知的含义,本领域技术人员也熟知测定不同序列间同一性的规则、标准,是指在序列比对和引入缺口(如果必要的话,以获得最大百分比同源性)后,多核苷酸或多肽序列变体的残基与非变体序列的相同的百分比。在本发明中,在满足同一性限定的情况下,还需要所获得的变体序列具有母体序列所具有的生物活性。本领域技术人员公知如何利用上述活性筛选变体序列的方法和手段。本领域技术人员可以在本申请公开内容的教导下容易地获得这样的变体序列。在具体实施方式中,多核苷酸和多肽变体与本文所述的多核苷酸或多肽具有至少约70%、至少约75%、至少约80%、至少约90%、至少约95%、至少约98%、或至少约99%,或至少约99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%的多核苷酸或多肽同一性。由于遗传密码的冗余性,将存在编码相同氨基酸序列的这些序列的变体。
本发明的另一个实施方式中,提供了能够在中度至高度严格条件下与本发明提供的多核苷酸序列或其片段或其互补序列相杂交的多核苷酸组合物。杂交技术是分子生物学领域公知的。为了说明的目的,用于测试本发明的多核苷酸与其他多核苷酸杂交的合适中等严格条件包括在5×SSC、0.5%SDS、1.0mM EDTA(pH8.0)的溶液中预洗;在50-60℃、5×SSC、过夜的条件下杂交;再于65℃下20分钟用含0.1%SDS的2×、0.5×和0.2×的SSC各洗涤两次。本领域技术人员理解,可容易地操纵杂交的严格性,例如通过改变杂交溶液的盐含量和/或进行杂交的温度。例如,在另一个实施方式中,合适的高严格杂交条件包括上述的条件,所不同的是杂交温度升高了,例如达到60-65℃或65-70℃。
本发明的宿主细胞可以是用于外源基因表达的所有细胞,包括但不限于大肠杆菌,酵母,昆虫细胞,植物细胞,哺乳动物细胞。
本发明的载体包括可以在任何类型的细胞或生物体中进行复制的载体,包括如质粒、噬菌体、粘粒和迷你染色体。在一些实施方式中,包括本发明多核苷酸的载体是适合于多核苷酸繁殖或复制的载体,或者是适合于表达本发明多肽的载体。这样的载体是本领域已知并可以购买的。
“载体”包括穿梭载体和表达载体。通常,质粒构建体也包括分别用于细菌中质粒复制和选择的复制起点(如复制的ColE1起点)和选择标记(如氨苄青霉素或四环素抗性)。“表达载体”是指包含用于在细菌或真核细胞中表达本发明的抗体包括抗体片段所需要的控制序列或调控元件的载体。
本发明的载体可以是用于外源基因表达的所有载体,包括但不限于质粒载体,其中质粒载体至少包含复制起始位点、启动子、目的基因、多克隆位点、筛选标记基因,优选地,本发明所述载体包括但不限于基于pCDNA改造得到的质粒载体,比如X0GC载体。
其还包含至少一种第二治疗剂,优选地,所述第二治疗剂与所述双特异抗体、分离的多核苷酸、重组表达载体或宿主细胞处于所述组合物的不同的部分中,优选地,第二治疗剂是抗PD-1抗体和/或STING激动剂。
本发明的组合物中包含的第二治疗剂并无特别限制,只要其与本发明的双特异抗体分离的多核苷酸、重组表达载体或宿主细胞生理学上相容即可。生理学上相容是指施用于受试者时不产生过度的刺激、毒性等不良反应。在一些实施方案中,所述第二治疗剂与所述双特异抗体、分离的多核苷酸、重组表达载体或宿主细胞作为混合物处于所述组合物中。在一些实施方案中,所述第二治疗剂与所述双特异抗体、分离的多核苷酸、重组表达载体或宿主细胞处于所述组合物的不同的部分中,处于所述组合物的不同的部分中是指,所述组合物由相互分离的部分组成,所述相互分离的部分可以处于不同的容器中或同一容器的相互隔离的不同隔断中,如不同的小瓶、注射器、小管。所述相互分离的部分可以在施用前混合在一起共同施用,或在一定时间间隔内顺序施用,如间隔5分钟、10分钟、20分钟、30分钟、1小时、5小时、12小时、24小时、48小时、1周、1个月或更久。所述第二治疗剂可以是用于与所述双特异抗体、分离的多核苷酸、重组表达载体或宿主细胞治疗相同或不同疾病的药物,例如,都是用于治疗白血病的药物,或者一种用于治疗白血病而另一种用于治疗结肠瘤。在一些实施方案中,第二治疗剂包括抗炎剂,例如IL-6抑制剂、肿瘤坏死因子α(TNF-α)抑制剂、干扰素γ(IFN-γ)抑制剂、皮质类固醇、抗组织胺药、退热剂和/或抗生素。在一些实施方案中,第二治疗剂选自由以下组成的组:第二抗体、免疫治疗剂、靶向治疗剂或化学治疗剂,
在一些实施方案中第二治疗剂为抗体,该抗体的靶标选自:CD47、CD70、CD200、CD154、CD223(LAG-3)、KIR(杀伤细胞免疫球蛋白样受体)、GITR、CD20、CD28、CD40、CD86、CD160、CD258、CD270、CD275、CD276、OX40L、B7-H4、GITRL、4-1BBL、CD3、CD25、CD48、CD66a、CD80、CD94、CD96、CD112、CD115、CD205、CD226、CD244、CD262、CD284、CD288、白血病抑制因子(LIF)、TNFSF15、TDO2、IGF-1R、GD2、TMIGD2、RGMB、VISTA、BTNL2、Btn、TIGIT、Siglecs(唾液酸结合Ig样凝集素,即SIGLEC 15)、VEGFR、ILT家族、MICA、TGFβ、STING途径(干扰素基因途径的刺激因子)、精氨酸酶、EGFRvIII、HHLA2、PD-1、PD-L1、PD-L2、CTLA-4、BTLA、吲哚胺2,3加双氧酶(IDO,IDO1)、TIM3、A2A腺苷受体(ADO受体)、CD39、CD73、CD27、ICOS(CD278)、CD137(4-1BB)、OX40、TNFSF25、IL-10、半乳凝素、NKp30、NKp40、NKp44、NKp46、NKG2A、NKG2D、DNAM1、DAP10、CD16(CD16a、CD16b或二者)、CRTAM、CD27、PSGL1、CD96、CD100(也称SEMA4D)、NKp80、CD244(也称SLAMF4或2B4)、SLAMF6、SLAMF7、KIR2DS2、KIR2DS4、KIR3DS1、KIR2DS3、KIR2DS5、KIR2DS1、CD94、NKG2C、NKG2E或CD160。
在一些实施方案中,抗体是抗PD-1抗体。在一些实施方案中,抗PD-1抗体是纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、西米普利单抗(cemiplimab)、卡瑞利珠单抗(Camrelizumab)、特瑞普利单抗(Toripalimab)、信迪利单抗(sintilimab)、替雷利珠单抗(tislelizumab)、派安普利单抗(Penpulimab)或赛帕利单抗(zimberelimab)。
在一些实施方案中,第二治疗剂为免疫治疗剂。免疫治疗剂的非限制性实例包含:抗体、小分子免疫调节剂、嵌合抗原受体(CAR)T细胞、NK细胞、树突细胞(DC)、过继性细胞转移(ACT)、免疫检查点调节剂、细胞因子、癌症疫苗、佐剂、溶瘤病毒或其组合。在一些实施方案中,免疫治疗剂为STING激动剂。
在一些实施方案中,第二治疗剂为靶向治疗剂。“靶向治疗剂”是指特异性靶向和抑制一种或多种致癌信号传导蛋白(例如,参与细胞生长和存活的那些)的分子。这种靶向治疗剂的非限制性实例包含:酪氨酸激酶抑制剂(例如伊马替尼
吉非替尼
厄洛替尼
索拉非尼
舒尼替尼
达沙替尼
拉帕替尼
尼罗替尼
硼替佐米
他莫昔芬
托法替尼
ALK抑制剂(例如克唑替尼)、Bcl-2抑制剂(例如奥巴曲拉、纳维曲拉、棉酚)、PARP抑制剂(例如iniparib、奥拉帕尼)、PI3K抑制剂(例如哌立福辛)、阿帕替尼、AN-152、Braf抑制剂(例 如曲美替尼、MEK162)、CDK抑制剂(例如PD-0332991、LEE011)、Hsp90抑制剂(沙利霉素、VAL-083));小分子药物缀合物(例如,vintafolide);丝氨酸-苏氨酸激酶抑制剂(例如,替西罗莫司
依维莫司
威罗菲尼
曲美替尼
达拉菲尼
抗体(例如,抗CD20抗体(例如,利妥昔单抗
抗HER2/neu抗体(例如,曲妥珠单抗
)、alemtuxumab
抗EGFR抗体(例如,西妥昔单抗、帕尼单抗)、抗VEGF抗体(例如,贝伐单抗
);抗体偶联物,例如抗体药物偶联物(antibody drug conjugates,ADC)、抗体免疫刺激偶联药物(Immune-stimulating Antibody Conjugate,ISAC)、抗体寡核苷酸偶联物(Antibody-oligonucleotide conjugates,AOC)。在一些实施方案中,抗体偶联物是ADC类药物。ADC类药物的非限制性实例包括:Her2-ADC、Trop2-ADC、CD22-ADC、BCMA-ADC、CD19-ADC、Nectin-4-ADC。
在一些实施例中,第二治疗剂为化学治疗剂,化学治疗剂的非限制性实例包括:烷化剂,如塞替派和
环磷酰胺;替莫唑胺;烷基磺酸酯,如白消安、英丙舒凡和哌泊舒凡;氮丙啶类,如苯唑多巴、卡波醌、美妥替哌和乌瑞替派;乙烯亚胺类和甲基蜜胺类,包括六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基三聚氰胺;多聚乙酰(特别是布拉他辛和布拉他辛酮);喜树碱(包括合成类似物拓扑替康);苔藓虫素;海洋抑素;CC-1065(包括其阿多来新、卡折来新和比折来新合成类似物);念珠藻素(特别是念珠藻素1和念珠藻素8);海兔毒素;多卡霉素(包括合成类似物KW-2189和CB1-TM1);软珊瑚醇;水鬼蕉碱;匍枝珊瑚醇;海绵抑素;氮芥,如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、双氯乙基甲胺、盐酸氧氮芥、美法仑、新氮芥、苯芥胆固醇、泼尼莫司汀、曲磷胺、尿嘧啶氮芥;亚硝基脲类,诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;生素类,诸如烯二炔类抗生素(例如,加利车霉素,尤其是加利车霉素γ11和加利车霉素ω11(参见例如,Agnew,Chem.Intl.Ed.Engl.,33:183-186(1994));达内霉素,包括达内霉素A;二膦酸盐类,诸如氯膦酸盐;埃斯波霉素;以及新制癌菌素生色团和相关色蛋白烯二炔类抗生素生色团)、阿克拉霉素类、放线菌素、氨茴霉素、重氮丝氨酸、博来霉素、放线菌素C、卡拉比辛、洋红霉素、嗜癌霉素、色霉素、更生霉素、柔红霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、
多柔比星(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯啉基-多柔比星和脱氧多柔比星)、表柔比星、依索比星、依达比星、麻西罗霉素、丝裂霉素诸如丝裂霉素C、霉酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊 非霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢物类,诸如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸、甲氨喋呤、蝶罗呤、三甲曲沙;嘌呤类似物,诸如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,诸如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷;雄激素类,诸如卡鲁睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷、睾内酯;抗肾上腺类,诸如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂,诸如亚叶酸;醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;氨苯吖啶;bestrabucil;比生群;依达曲沙;defofamine;地美可辛;地吖醌;依氟鸟氨酸;依利醋铵;埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明;美登木素生物碱类,诸如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇;二胺硝吖啶;喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基酰肼;丙卡巴肼;
多糖复合物(JHS Natural Products,Eugene,Oreg.);雷佐生;根霉素;西佐喃;锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2’,2”-三氯三乙胺;单端孢菌烯类(尤其是T-2毒素、verracurin A、杆孢菌素A和蛇形菌素);乌拉坦;长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;gacytosine;阿糖胞苷(“Ara-C”);环磷酰胺;噻替哌;类紫杉醇,例如
(紫杉醇;Bristol-Myers Squibb Oncology,Princeton,N.J.)、
(不含克列莫佛、紫杉醇的白蛋白工程化纳米颗粒制剂(American Pharmaceutical Partners,Schaumberg,111.)和
多西他塞(Rhone-Poulenc Rorer,Antony,法国);苯丁酸氮芥;
吉西他滨;6-硫鸟嘌呤;巯基嘌呤;甲氨喋呤;铂类似物,诸如顺铂、奥沙利铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;NAVELBINE,长春瑞滨;能灭瘤;替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;希罗达;伊班膦酸盐;伊立替康(Camptosar,CPT-11)(包括伊立替康与5-FU和甲酰四氢叶酸的治疗方案);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄醇,诸如视黄酸;卡培他滨;考布他丁;甲酰四氢叶酸(LV);奥沙利铂,包括奥沙利铂治疗方案(FOLFOX);拉帕替尼(TYKERB);PKC-α、Raf、H-Ras、EGFR的抑制剂(例如,厄洛替尼
和减少细胞增殖的VEGF-A以及上述任何物质的药学上可接受的盐、酸或衍生物。
本发明的受试者包括禽类、爬行动物、哺乳动物等。优选地,哺乳动物包括啮齿类动物、灵长类动物,优选地,灵长类动物包括人。
本发明所涉及的疾病的范围包括但不限于肿瘤,优选的,所述肿瘤包括:白血病、 淋巴瘤、骨髓瘤、脑肿瘤、头颈部鳞状细胞癌、非小细胞肺癌、鼻咽癌、食道癌、胃癌、胰腺癌、胆囊癌、肝癌、结直肠癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、膀胱癌、肾细胞癌、黑色素瘤、小细胞肺癌、骨癌。
药学上可接受的载体是指是指药学领域常规的药物载体,例如:稀释剂、赋形剂和水等,填充剂如淀粉、蔗糖,乳糖、微晶纤维素等;粘合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;润湿剂如甘油;崩解剂如羧甲基淀粉钠,羟丙纤维素,交联羧甲基纤维素,琼脂、碳酸钙和碳酸氢钠;吸收促进剂如季铵化合物;表面活性剂如十六烷醇,十二烷基硫酸钠;吸附载体如高龄土和皂粘土;润滑剂如滑石粉、硬脂酸钙和镁、微粉硅胶和聚乙二醇等。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
下面将通过下述非限制性实施例进一步说明本发明,本领域技术人员公知,在不背离本发明精神的情况下,可以对本发明做出许多修改,这样的修改也落入本发明的范围。
下述实验方法如无特别说明,均为常规方法,所使用的实验材料如无特别说明,均可容易地从商业公司获取。本发明下述实施例中使用的各种抗体均来源于商业途径的标准抗体。
实施例
实施例1抗PD-L1/抗4-1BB异源二聚体抗体分子的载体构建
构建分别含抗人PD-L1抗体的重链和轻链的X0GC表达载体。轻链可变区核苷酸序列如SEQ ID NO.1所示,氨基酸序列如SEQ ID NO:2所示;轻链恒定区核苷酸序列如SEQ ID NO.3所示,氨基酸序列如SEQ ID NO:4所示;重链可变区核苷酸序列如SEQ ID NO.5所示,氨基酸序列如SEQ ID NO:6所示;重链恒定区核苷酸序列如SEQ ID NO.7所示,氨基酸序列如SEQ ID NO:8所示。通过PCR的方法分别扩增轻链可变区以及轻链恒定区,重链可变区以及重链恒定区。本申请中所有PCR反应均使用NEB公司的Phusion超保真DNA聚合酶(F-530L)。PCR引物根据碱基互补原则以及酶切位点的需要进行常规设计。反应体系均为:H
2O 8.9μl,5×Phusion超保真DNA聚合酶缓冲液4μl,1mM dNTP 4μl,上游引物1μl,下游引物1μl,Phusion超保真DNA聚合酶0.1μl,模板1μl。将可变区及恒定区PCR产物,经1.5%琼脂糖凝胶电泳后用DNA回收试剂盒(Promega,A9282,下同)回收相应片段。以回收的可变区片段与恒定区片段作为模板,使用可变区上游引物及 恒定区下游引物,再进行一轮PCR反应,然后再回收相应片段,得到轻链或者重链的全长片段。将X0GC载体及全长片段,用EcoRI(Thermo,货号FD0275)及HindIII(Thermo,货号FD0505)酶切,酶切反应体系为:10×缓冲液6μl,EcoRI及HindIII各2μl,胶回收获得的全长片段40μl,H
2O 10μl,酶切体系于37℃条件下反应1小时。将酶切产物用T4DNA连接酶(Thermo,货号EL0011)连接(下同),反应体系为:10×连接酶缓冲液1μl,连接酶0.5μl,胶回收获得的全长片段7.5μl,胶回收获得的X0GC载体1μl,连接于22℃反应30min。将连接产物转化大肠杆菌感受态细胞DH5α(天根,CB104,下同)。获得抗人PD-L1抗体重链和轻链的X0GC表达载体,分别用于在真核细胞中表达抗人PD-L1抗体的重链和轻链。
本发明同时构建了分别含抗人4-1BB抗体的重链和轻链可变区序列的X0GC表达载体。轻链可变区核苷酸序列如SEQ ID NO.9所示,氨基酸序列如SEQ ID NO:10所示;轻链恒定区核苷酸序列如SEQ ID NO.3所示,氨基酸序列如SEQ ID NO:4所示;重链可变区核苷酸序列如SEQ ID NO.11所示,氨基酸序列如SEQ ID NO:12所示;重链恒定区核苷酸序列如SEQ ID NO.13所示,氨基酸序列如SEQ ID NO:14所示。获得抗人4-1BB抗体重链和轻链的X0GC表达载体,分别用于在真核细胞中表达抗人4-1BB抗体的重链和轻链。
实施例2抗PD-L1/抗4-1BB异源二聚体抗体分子的表达
分别将含抗人PD-L1抗体的重链和轻链的表达载体共转染ExpiCHO细胞(ExpiCHOTM Cells,货号A29127,invitrogen)。另外分别将含抗人4-1BB的抗体的重链和轻链的表达载体也共转染ExpiCHO细胞。
转染前一天接种细胞,接种密度为3.5×10
6细胞/mL。转染当天用新鲜的ExpiCHO表达培养基(ExpiCHOTM Expression Medium,货号A29100-01,invitrogen)将细胞稀释,稀释密度为6×10
6细胞/mL。按照转染体积取出质粒,质粒的终浓度为0.5ug/ml,用OptiPROMSFM培养基(OptiPROMSFM,货号12309-019,invitrogen)将质粒稀释至转染体积的4%,颠倒混匀。取出6.4倍质粒量的ExpiFectamineTM转染试剂(ExpiFectamineTM CHO Transfection Kit,货号A29129,invitrogen),用OptiPROMSFM培养基将转染试剂稀释至转染体积的4%,颠倒混匀。将稀释后的转染试剂加入到稀释的质粒中,轻轻混匀,室温静置1~5min,慢慢滴加到细胞中。之后放入细胞培养箱(CO
2浓度为8%),125rpm摇床37℃培养20小时。向细胞中慢慢滴加0.006倍转染体积的ExpiCHOTMEnhancer(ExpiFectamineTMCHO Transfection Kit,货号A29129,invitrogen)和0.24倍转染体积的 ExpiCHOTMFeed(ExpiCHOTMFeed,货号A29101-02,invitrogen)。放入125rpm摇床32℃培养。离心收集转染10天的细胞培养上清。
通过Protein A的方法测定表达量。在应用层析柱纯化之前,以0.22μm滤膜过滤以去除沉淀物。此步骤在4℃下进行。
实施例3抗PD-L1/抗4-1BB异源二聚体抗体分子表达产物的纯化
采用AKTA explorer 100型蛋白纯化系统(GE Healthcare)以及亲和色谱柱MabSelect SuRe(GE Healthcare)于室温下进行纯化。首先以流动相A(20mM磷酸钠缓冲液,pH7.4)平衡色谱柱,在基线稳定后将经过上述处理的细胞上清液进行上样,并在上样后以流动相A进行平衡。样品分别为抗PD-L1表达产物和抗4-1BB表达产物。之后,首先以流动相B(含有1M氯化钠的流动相A)冲洗2-3个柱体积;然后再以流动相A冲洗2-3个柱体积,然后以流动相C(100mM甘氨酸,pH 3.5)洗脱5个柱体积,收集洗脱峰即为目的蛋白峰。抗PD-L1表达产物的洗脱峰色谱图如图1所示,抗4-1BB表达产物的洗脱峰如图2所示。收集标示的洗脱峰(图示灰色区域),并通过滴加1M Tris碱溶液将pH调至7.2,添加NaCl使其终浓度为0.15M,无菌过滤后放2~8℃储存。
实施例4抗PD-L1/抗4-1BB异源二聚体抗体分子的制备和纯化
抗PD-L1/抗4-1BB异源二聚体抗体分子的结构如图3所示。
将上述MabSelect SuRe(GE Healthcare)方法纯化获得的产物进行体外重组以获得异源二聚体。首先将上述纯化收集的蛋白溶液通过半胱氨酸还原的过程,二硫键被打开,抗PD-L1以及抗4-1BB产物中含有的抗体同源二聚体分子铰链区二硫键也打开,形成了含有一条重链和一条轻链的半抗体分子,结构如图4所示。还原的样品经流动相缓冲液中包含1mM DTT还原剂的SEC-HPLC(shodex,protein kw-803)分析,结果分别如图5的A和B图所示,抗PD-L1和抗4-1BB的同源二聚体分子比例均小于10%,半抗体分子比例均大于90%。
然后将还原的抗PD-L1以及抗4-1BB半抗体分子等摩尔比例混合,在室温条件下进行重组反应0.5小时,在重组的过程中,抗PD-L1及抗4-1BB半抗体分子通过CH2以及CH3间的非共价作用力形成了同时含有抗PD-L1以及抗4-1BB半抗体分子的异源二聚体的双特异抗体,之后将蛋白溶液通过超滤浓缩(标称截留分子量10KDa),将溶液置换为20mM磷酸盐缓冲液,0.15M NaCl,0.1mM胱氨酸,室温过夜进行氧化反应,使 异源二聚体的双特异抗体的二硫键重新形成。
上述抗PD-L1以及抗4-1BB表达产物经还原氧化得到的抗PD-L1/抗4-1BB异源二聚体抗体分子通过超滤浓缩(标称截留分子量10KDa),将溶液置换为20mM柠檬酸缓冲液,pH 6.0。采用AKTA explorer 100型蛋白纯化系统(GE Healthcare)以及离子色谱柱Poros XS(ThermoFisher)于室温下进行纯化。首先以流动相A(20mM柠檬酸,pH6.0)平衡色谱柱,在基线稳定后将经过上述处理的蛋白溶液进行上样,并在上样后以流动相A进行平衡,之后以A(20mM柠檬酸,pH6.0)到B(20mM柠檬酸,200mM精氨酸,pH 6.0)梯度冲洗15个柱体积(0%B-100%B,80min),收集洗脱主峰,收集的蛋白溶液通过超滤浓缩(标称截留分子量10KDa),将溶液置换为20mM柠檬酸,140mM精氨酸,pH 6.0,过滤除菌,加入0.02%Tween80,4℃保存。将纯化得到的抗PD-L1/抗4-1BB的异源二聚体抗体分子BH3120h通过SEC-HPLC进行纯度分析,结果如图6所示,纯度为98.54%;进行CE分析,结果如图7所示,纯度为96.44%。
实施例5抗PD-L1/抗4-1BB异源二聚体抗体的靶点结合活性
用酶联免疫吸附试验(ELISA)测定抗PD-L1/抗4-1BB异源二聚体抗体与单个抗原的结合能力。具体实施过程如下:用pH=9.6的碳酸盐缓冲溶液在96孔高吸附酶标板(Costar,货号42592)上包被重组人PD-L1(北京义翘神州,货号10084-H08H)或者人4-1BB(北京义翘神州,货号10041-H08H),包被浓度为1μg/mL,每孔100μL,包被在4℃过夜进行。PBST洗涤5次。用含1%BSA的PBST按300μL/孔封闭,25℃孵育1小时。PBST洗涤5次。加入序列稀释在含1%BSA的PBST里的异源二聚体抗体样品以及对照,每孔加入100μL,25℃孵育1小时。PBST洗涤5次。然后加入1:10000稀释在含1%BSA的PBST里的辣根过氧化物酶标记的抗人IgG抗体(Chemicon,货号AP309P),每孔加入100μL,25℃孵育1小时。PBST洗涤5次。加入比色底物TMB,100μL/孔,室温显色10分钟。加入1M H
2SO
4,100μL/孔,终止显色。在酶标仪上读取450nm处的吸光度。
同时使用GS-H2/4-1BB细胞测定抗PD-L1/抗4-1BB异源二聚体抗体与4-1BB抗原的结合能力。具体实施过程如下:收集GS-H2/4-1BB细胞(购自金斯瑞),用含2%FBS(Hyclone,货号SH30084.03)的冷DPBS(GIBCO,货号14190-136)洗涤一次。将GS-H2/4-1BB重悬于含2%FBS的冷DPBS中,密度为5×10
6个细胞/mL,每个流式管中加入100μL细胞悬液,同时加入100μL序列稀释的异源二聚体抗体样品以及对照。流式管于冰上孵育30分钟。用含2%FBS的DPBS洗涤两次。再重悬于200μL含2%FBS的488A-Fab- 抗人IgG(终浓度5μg/mL)的冷DPBS中。冰上避光孵育30分钟。用含2%FBS的DPBS洗涤两次。再重悬于500μL冷DPBS中,该细胞悬液于流式细胞仪(BD,FACS Calibur)上进行检测分析,读取细胞中的荧光强度。
结果如图8的A图所示,抗PD-L1/抗4-1BB异源二聚体抗体BH3120h对PD-L1具有高亲和力,略弱于PD-L1双价单抗的抗原结合活性;如图8的B图所示,抗PD-L1/抗4-1BB异源二聚体抗体BH3120h对4-1BB亲和力较低,弱于4-1BB双价单抗的抗原结合活性;如图8的C图所示,抗PD-L1/抗4-1BB异源二聚体抗体BH3120h对4-1BB亲和力较高,强于抗4-1BB双价单抗的抗原结合活性。
实施例6抗PD-L1/抗4-1BB异源二聚体抗体的配体-受体结合阻断活性
PD-L1与PD-1,CD80结合的阻断活性检测实施过程如下:用pH=9.6的碳酸盐缓冲溶液在96孔高吸附酶标板上包被重组人PD-L1-Fc(北京百普赛斯,货号PD1-H5258),包被浓度为1μg/mL,包被量为100μL每孔,包被在4℃过夜进行。PBST洗涤5次。用含1%BSA的PBST按300μL/孔封闭,25℃孵育1小时。PBST洗涤5次。加入序列稀释在含1%BSA的PBST里的异源二聚体抗体样品以及对照,每孔加入50μL,并加入50μL生物素标记的PD-1-Fc(北京韩美药品),浓度为40nM(终浓度20nM),或者加入50μL生物素标记的CD80-Fc(北京百普赛斯,货号B71-H82F2),浓度为100nM(终浓度50nM),25℃孵育90分钟。PBST洗涤5次。然后加入1:1000稀释在含1%BSA的PBST里的Streptavidin-HRP(BD Pharmingen,货号554066),每孔加入100μL,25℃孵育1小时。PBST洗涤5次。加入比色底物TMB,100μL/孔,室温显色10分钟。加入1M H
2SO
4,100μL/孔,终止显色。在酶标仪上读取450nm处的吸光度。
结果如图9的A图所示,抗PD-L1/抗4-1BB异源二聚体抗体BH3120h能够阻断PD-L1与PD-1的结合,略弱于抗PD-L1双价单抗;如图9的B图所示,抗PD-L1/抗4-1BB异源二聚体抗体BH3120h能够阻断PD-L1与CD80的结合。
实施例7抗PD-L1/抗4-1BB异源二聚体抗体的T细胞调控活性
用混合淋巴细胞反应(MLR)测定抗PD-L1/抗4-1BB异源二聚体抗体对T细胞免疫反应的调控活性。
人树突状细胞(DC)的获取:参照Monocyte细胞分离试剂盒(Miltenyi Biotech,货 号130091153)使用说明书分离人单核细胞。简要的说,先用DPBS(GIBCO,货号14190-136)洗涤PBMC(Allcells,货号PB0005-C)一次,再将PBMC按10
7细胞每40μL分离缓冲液(PBS含2mM EDTA,0.5%BSA,pH=7.2)重悬(以下使用量均按10
7细胞计),并加入10μL FcR封闭试剂和10μL Biotin Antibody Cocktail(生物素抗体混合物),在4℃孵育5分钟。再加入30μL分离缓冲液和20μL Anti-Biotin MicroBeads(抗生物素微珠),在4℃孵育10分钟。过MACS分离柱,即得人单核细胞。将人单核细胞按细胞密度为5×10
6/mL重悬于无血清的RPMI 1640培养基(GIBCO,货号22400-089)并接种在细胞培养瓶中,在完全培养基(RPMI 1640含10%FBS)中培养,并加入200ng/ml GM-CSF(北京义翘神州,货号10015-HNAH)和100ng/ml IL-4(北京义翘神州,货号11846-HNAE)。孵育3天,换液,再孵育3天。然后将培养基更换为完全培养基(RPMI 1640含10%FBS)
中含200ng/ml GM-CSF、100ng/ml IL-4以及20ng/ml TNF-α(北京义翘神州,货号10602-HNAE),孵育1天。即得DC细胞。
人T细胞的获取:复苏收集人PBMC细胞,保证此PBMC与诱导DC细胞的PBMC来自不同个体。参照Pan T细胞分离试剂盒(Miltenyi Biotech,货号130096535)使用说明书分离人T细胞。简要的说,先用DPBS洗涤PBMC一次,再将PBMC按10
7细胞每40μL分离缓冲液(PBS含2mM EDTA,0.5%BSA,pH=7.2)重悬(以下使用量均按10
7细胞计),并加入10μL Pan T cell Biotin Antibody Cocktail(Pan T细胞生物素抗体混合物),在4℃孵育5分钟。再加入30μL分离缓冲液和20μL Pan T cell MicroBead Cocktail(Pan T细胞微珠混合物),在4℃孵育10分钟。过MACS分离柱,即得T细胞。
将收集到的人DC细胞和人T细胞重悬于完全培养基(RPMI 1640含10%FBS)中,接种于96孔板,接种的DC细胞和T细胞分别为1×10
4个细胞/孔,1×10
5个细胞/孔,混合培养。并加入用完全培养基序列稀释的异源二聚体抗体样品以及对照。将培养板置于37℃二氧化碳培养箱中孵育5天。孵育结束之后,取出孔内上清,用IL-2检测试剂盒(RayBiotech,货号ELH-IL2)按照说明书检测细胞因子的含量。简要的说,将100μL的标准品和稀释好的样品加入到样品检测板中,25℃孵育2.5小时,PBST洗板5次,加入100μL生物素标记的检测抗体,25℃孵育1小时,PBST洗板5次,然后加入100μL/well辣根过氧化物酶标记的链霉亲和素,25℃孵育45分钟,PBST洗涤5次。加入比色底物TMB,100μL/孔,室温显色10分钟。加入1M H
2SO
4,100μL/孔,终止显色。在酶标仪上读取450nm处的吸光度。
结果如图10所示,人T细胞在同种异体DC细胞的刺激下,会活化分泌IL-2。加入 抗PD-L1和抗4-1BB双价抗体都会增强T细胞的活化,促进细胞因子的分泌。抗PD-L1/抗4-1BB异源二聚体抗体BH3120h也显示了很强的T细胞调控活性,显著地促进细胞因子IL-2的分泌。
实施例8抗PD-L1/抗4-1BB异源二聚体抗体介导的4-1BB受体激动活性
收集GS-H2/4-1BB细胞(购自金斯瑞),用含2%FBS(Hyclone,货号SH30084.03)的MEM+Glu培养基(GIBCO,货号41090101)洗涤一次。将GS-H2/4-1BB重悬于含2%FBS的MEM+Glu培养基中,密度为1×10
5个细胞/mL,取96-well平底细胞培养板(Costar,货号3599),每孔加入100μL细胞悬液,将培养板置于37℃二氧化碳培养箱中孵育2小时,使细胞贴附到培养板。将异源二聚体抗体样品以及对照稀释于含2%FBS的MEM+Glu培养基中,取50μL加入到铺好GS-H2/4-1BB细胞的细胞培养板中。同时收集DLD-1/PD-L1细胞(DLD-1购自中国科学院),用含2%FBS的MEM+Glu培养基制成1×10
5个细胞/mL的细胞悬液,取50μL加入到铺好GS-H2/4-1BB细胞的并加入异源二聚体抗体样品以及对照的细胞培养板中。将细胞培养板置于37℃二氧化碳培养箱中孵育24小时,取细胞培养上清,用IL-8检测试剂盒(达科为,货号1110802)按照说明书检测细胞因子的含量。简要的说,将100μL的标准品和稀释好的样品加入到样品检测板中,同时加入50μL生物素标记的检测抗体,25℃孵育1小时,PBST洗板5次,然后加入100μL/well辣根过氧化物酶标记的链霉亲和素,25℃孵育1小时,PBST洗涤5次。加入比色底物TMB,100μL/孔,室温显色10分钟。加入1M H
2SO
4,100μL/孔,终止显色。在酶标仪上读取450nm处的吸光度。
结果如图11所示,加入抗4-1BB双价单抗可以介导一定程度的GS-H2/4-1BB细胞活化,并分泌少量IL-8,加入抗PD-L1双价抗体不能活化GS-H2/4-1BB细胞。而抗PD-L1/抗4-1BB异源二聚体抗体BH3120h可以交联DLD-1/PD-L1细胞上PD-L1和GS-H2/4-1BB细胞上的4-1BB,从而导致4-1BB发生簇集进而强烈活化GS-H2/4-1BB细胞,并产生大量的IL-8。
实施例9抗PD-L1/抗4-1BB异源二聚体抗体在基因敲入小鼠体内的抗MC38肿瘤药效研究
实验材料选用hPD-L1/h4-1BB双人源化小鼠(敲除了鼠源的PD-L1和4-1BB,过表达人源的PD-L1和4-1BB,江苏百奥赛图),雌性,6-8周龄。小鼠适应环境一周后,每 只小鼠于右侧背部皮下接种5×10
5个MC38/hPD-L1小鼠结肠瘤细胞(MC38购自上海舜冉)。待肿瘤体积长至约100mm
3时,根据肿瘤体积进行分组,每组6只荷瘤小鼠。分别给予溶媒(DPBS,GIBCO,货号14190-136)、抗PD-L1单抗35nmol/kg、抗4-1BB单抗35nmol/kg以及抗PD-L1/抗4-1BB异源二聚体抗体70nmol/kg(考虑单抗为双价抗体,双特异抗体的抗PD-L1、抗4-1BB均为单价),每周给药3次,连续给药2周,给药方式为腹腔注射。自给药之日起,每周测量2次肿瘤体积,测量其长径a,短径b,肿瘤体积计算公式为:肿瘤体积(mm3)=(a×b
2)/2。肿瘤体积测量持续时间为4周,即停药后,再观察2周。
结果如图12所示,在同源肿瘤模型中,抗PD-L1/抗4-1BB异源二聚体抗体BH3120h具有比抗PD-L1双价抗体和抗4-1BB双价抗体更强的抗肿瘤药效。
实施例10抗PD-L1/抗4-1BB异源二聚体抗体与抗PD-1抗体联合应用在基因敲入小鼠体内的抗CT-26肿瘤药效研究
动物选用hPD1/hPDL1/hCD137三人源化小鼠(江苏集萃药康),雌性,6-8周龄。小鼠适应环境一周后,每只小鼠于右颈背部皮下接种5×10
5个CT-26/hPD-L1小鼠结肠瘤细胞(江苏集萃药康)。待肿瘤体积长至约100mm
3时,根据肿瘤体积进行随机分组。分别给予溶媒(DPBS)、抗PD-L1/4-1BB双抗10mg/kg、抗PD-1单抗(BH2917b)5mg/kg以及合用组(10+5mg/kg),每2天给药1次连续给药4次,给药方式为腹腔注射。自给药之日起,每周三次测量肿瘤体积并记录长短径值,按照下列公式进行瘤体积计算:瘤体积=[(短径^2×长径)/2]。肿瘤生长抑制率计算按照:肿瘤生长抑制率=[1-RTV(实验组)/RTV(对照组)]×100%。RTV:相对肿瘤体积,RTV=V
t/V
0,V
t:时间t时的肿瘤体积,V
0:初始肿瘤体积。结果如图13所示,在同源肿瘤模型中,抗PD-L1/抗4-1BB异源二聚体抗体BH3120与抗PD-1抗体合用体现出更好的抗肿瘤活性协同效应。接种CT-26-hPD-L1细胞20天后,和对照组相比,BH2917b(5mg/kg)和BH3120(10mg/kg)瘤体积均减小,肿瘤生长抑制率分别为44.1%和37.3%。BH3120+BH2917b(10+5mg/kg)能显著抑制肿瘤增殖,肿瘤生长抑制率为79.6%。采用t检验分析与BH3120(10mg/kg)相比,联合治疗组的瘤体积明显减小,且差异有统计学意义(P<0.05);与BH2917b(5mg/kg)组相比,联合治疗组的瘤体积减小但无统计学意义(P>0.05)。
实施例11抗PD-L1/抗4-1BB异源二聚体抗体与抗PD-1抗体联合应用在基因敲入 小鼠体内的抗MC38肿瘤药效研究
动物选用hPD1/hCD137双人源化小鼠(江苏集萃药康和百奥赛图),雌性,6-8周龄。小鼠适应环境一周后,每只小鼠于右颈背部皮下接种1×10
6个MC38/hPD-L1小鼠结肠瘤细胞(江苏集萃药康)。待肿瘤体积长至约100mm
3时,根据肿瘤体积进行随机分组。分别给予溶媒(DPBS)、抗PD-L1/4-1BB双抗1和3mg/kg,抗PD-1单抗(BH2917b)5mg/kg以及合用组(1+5mg/kg),每周给药2次连续给药6次,给药方式为腹腔注射。自给药之日起,每周三次测量肿瘤体积并记录长短径值,按照下列公式进行瘤体积计算:瘤体积=[(短径^2×长径)/2]。肿瘤生长抑制率计算按照:肿瘤生长抑制率=[1-RTV(实验组)/RTV(对照组)]×100%。RTV:相对肿瘤体积,RTV=V
t/V
0,V
t:时间t时的肿瘤体积,V
0:初始肿瘤体积。结果如图14所示,在同源肿瘤模型中,抗PD-L1/抗4-1BB异源二聚体抗体BH3120与抗PD-1抗体合用体现出更好的抗肿瘤活性协同效应。接种hPD-L1/MC38细胞33天后,抗体单用组有一定的抑瘤作用且有剂量依赖性,肿瘤生长抑制率分别为:BH2917b(5mg/kg)76.58%,BH3120(3mg/kg)47.07%,BH3120(1mg/kg)30.95%。BH3120+BH2917b(1+5mg/kg)联合用药能显著抑制肿瘤增殖,TGI
TV%为122.40%。采用t检验分析与BH3120(1mg/kg)组相比差异有统计学意义(P<0.05);与BH2917b(5mg/kg)组相比差异有统计学意义(P<0.01)。
Claims (29)
- 一种双特异性抗体,所述双特异性抗体包含特异性结合PD-L1的第一抗原结合功能区和特异性结合4-1BB的第二抗原结合功能区,其中所述特异性结合PD-L1的第一抗原结合功能区包含:(A)重链可变区,所述重链可变区包含(a)HCDR1,其包含SEQ ID NO:15所示的氨基酸序列,(b)HCDR2,其包含SEQ ID NO:16所示的氨基酸序列,以及(c)HCDR3,其包含SEQ ID NO:17所示的氨基酸序列;以及(B)轻链可变区,所述轻链可变区包含(a)LCDR1,其包含SEQ ID NO:18所示的氨基酸序列,(b)LCDR2,其包含SEQ ID NO:19所示的氨基酸序列,以及(c)LCDR3,其包含SEQ ID NO:20所示的氨基酸序列。
- 根据权利要求1所述的双特异性抗体,其中特异性结合4-1BB的所述第二抗原结合功能区包含(A)重链可变区,所述重链可变区包含(a)HCDR1,其包含SEQ ID NO:21所示的氨基酸序列,(b)HCDR2,其包含SEQ ID NO:22所示的氨基酸序列,以及(c)HCDR3,其包含SEQ ID NO:23所示的氨基酸序列;以及(B)轻链可变区,所述轻链可变区包含(a)LCDR1,其包含SEQ ID NO:24所示的氨基酸序列,(b)LCDR2,其包含SEQ ID NO:25所示的氨基酸序列,以及(c)LCDR3,其包含SEQ ID NO:26所示的氨基酸序列。
- 根据权利要求1或权利要求2所述的双特异性抗体,其中所述特异性结合PD-L1的第一抗原结合功能区包含(A)重链可变区,所述重链可变区包含(a)HCDR1,其包含SEQ ID NO:15所示的氨基酸序列,(b)HCDR2,其包含SEQ ID NO:16所示的氨基酸序列,以及(c)HCDR3,其包含SEQ ID NO:17所示的氨基酸序列;以及(B)轻链可变区,所述轻链可变区包含(a)LCDR1,其包含SEQ ID NO:18所示的氨基酸序列,(b)LCDR2,其包含SEQ ID NO:19所示的氨基酸序列,以及(c)LCDR3,其包含SEQ ID NO:20所示的氨基酸序列;并且所述特异性结合4-1BB的第二抗原结合功能区包含(A)重链可变区,所述重链可变区包含(a)HCDR1,其包含SEQ ID NO:21所示的氨基酸序列,(b)HCDR2,其包含SEQ ID NO:22所示的氨基酸序列,以及(c)HCDR3,其包含SEQ ID NO:23所示的氨基酸序列;以及(B)轻链可变区,所述轻链可变区包含(a)LCDR1,其包含SEQ ID NO:24所示的氨基酸序列,(b)LCDR2,其包含SEQ ID NO:25所示的氨基酸序列,以及(c)LCDR3,其包含SEQ ID NO:26所示的氨基酸序列。
- 根据权利要求1-3任一项所述的双特异性抗体,其中特异性结合PD-L1的所述第一抗原结合功能区包含重链可变区和轻链可变区,所述重链可变区包含SEQ ID NO:6所示的氨基酸序列,所述轻链可变区包含SEQ ID NO:2所示的氨基酸序列。
- 根据权利要求1-4任一项所述的双特异性抗体,其中特异性结合4-1BB的所述第二抗原结合功能区包含重链可变区和轻链可变区,所述重链可变区包含如SEQ ID NO:12所示的氨基酸序列,所述轻链可变区包含如SEQ ID NO:10所示的氨基酸序列。
- 根据权利要求1-5任一项所述的双特异性抗体,其中特异性结合PD-L1的所述第一抗原结合功能区包含重链可变区和轻链可变区,所述重链可变区包含SEQ ID NO:6所示的氨基酸序列,所述轻链可变区包含SEQ ID NO:2所示的氨基酸序列;并且其中特异性结合4-1BB的所述第二抗原结合功能区包含重链可变区和轻链可变区,所述重链可变区包含如SEQ ID NO:12所示的氨基酸序列,所述轻链可变区包含如SEQ ID NO:10所示的氨基酸序列。
- 如权利要求1-6任一项所述的双特异抗体,其中第一个抗原结合功能区和第二个抗原结合功能区选自Fab片段、scFv片段、可变结构域片段Fv。
- 如权利要求1-7任一项所述的双特异抗体,其中第一个抗原结合功能区和第二个 抗原结合功能区都是Fab片段。
- 如权利要求1-8任一项所述的双特异抗体,其Fab片段包含不同的第一重链可变区及第二重链可变区,以及不同的第一轻链可变区及第二轻链可变区。
- 如权利要求1-9任一项所述的双特异抗体,其中第一个抗原结合功能区和第二个抗原结合功能区中一个是Fab片段,另一个是scFv。
- 根据权利要求1-10所述的双特异性抗体,其包含第一Fc链和第二Fc链,其中所述第一Fc链和第二Fc链均为包含氨基酸替换的免疫球蛋白G Fc片段,并且所述第一Fc链及第二Fc链共同构成可以与Fc受体结合的异源二聚体;其中所述第一Fc链和第二Fc链通过共价键或连接体分别连接到所述第一抗原结合功能区和第二抗原结合功能区;并且其中所述第一Fc链和第二Fc链中的任意一条在366位及399位上包含T366L和D399R氨基酸替换,另一条在351位、407位及409位上包含L351E、Y407L和K409V氨基酸替换,其中氨基酸位置根据Kabat EU指数编号系统编号。
- 如权利要求1-11任一项所述的双特异抗体,其中第一Fc链及与其共价相连的第一抗原结合功能区,和第二Fc链及与其共价相连的第二抗原结合功能区,在存在还原剂的溶液中且所述溶液中除所述第一Fc链及与其共价相连的第一抗原结合功能区和第二Fc链及与其共价相连的第二抗原结合功能区以外不含其它多肽时,其形成同源二聚体的基于所有多肽链的重量比例均低于50%。
- 根据权利要求1-12所述的双特异性抗体,其包含特异性结合PD-L1的第一重链/第一轻链对,其中所述第一重链具有包含SEQ ID NO:6所示的氨基酸序列的重链可变区,以及包含SEQ ID NO:8所示的氨基酸序列的重链恒定区;所述第一轻链具有包含如SEQ ID NO:2所示的氨基酸序列的轻链可变区,以及包含如SEQ ID NO:4所示的氨基酸序列的轻链恒定区。
- 根据权利要求1-13所述的双特异性抗体,其包含特异性结合4-1BB的第二重链/第二轻链对,其中所述第二重链具有包含SEQ ID NO:12所示的氨基酸序列的重链可变区,以及包含SEQ ID NO:14所示的氨基酸序列的重链恒定区;所述第一轻链具有包含如SEQ ID NO:10所示的氨基酸序列的轻链可变区,以及包含如SEQ ID NO:4所示的氨基酸序列的轻链恒定区。
- 一种分离的多核苷酸,其编码如权利要求1-14任一项所述的双特异抗体。
- 一种重组表达载体,其包含权利要求15所述的分离的多核苷酸。
- 一种宿主细胞,其包含权利要求15所述的分离的多核苷酸,或权利要求16所述的重组表达载体。
- 如权利要求17所述的宿主细胞,其选自人胚肾细胞HEK293或以HEK293细胞为基础改造而得到的HEK293T、HEK293E、HEK293F;仓鼠卵巢细胞CHO或以CHO细胞为基础改造而得到的CHO-S、CHO-dhfr -、CHO/DG44、ExpiCHO;大肠杆菌或以大肠杆菌为基础改造得到的大肠杆菌BL21、BL21(DE3)、Rosetta、Origami;酵母菌或以酵母为基础改造得到的毕赤酵母、酿酒酵母、乳酸克鲁维亚酵母、多形汉逊酵母;昆虫细胞或以昆虫细胞为基础改造得到的细胞High5、SF9;植物细胞;哺乳动物乳腺细胞、体细胞。
- 一种组合物,其包含权利要求1-14任一项所述的双特异抗体或权利要求15所述的分离的多核苷酸或权利要求16所述的重组表达载体或权利要求17或18所述的宿主细胞,及药学上可接受的载体。
- 如权利要求19所述的组合物,其还包含至少一种第二治疗剂,优选地,所述第二治疗剂与所述双特异抗体、分离的多核苷酸、重组表达载体或宿主细胞处于所述组合物的不同的部分中,优选地,第二治疗剂选自由以下组成的组:第二抗体,免疫治疗剂、靶向治疗剂或化学治疗剂,优选地,所述第二治疗剂为抗PD-1抗体和/或STING激动剂。
- 一种生产如权利要求1-14任一项所述的双特异抗体的方法,其包括步骤:1)将权利要求15所述的分离的多核苷酸或权利要求16所述的重组表达载体分别在宿主细胞中进行表达;2)将在宿主细胞中分别表达的蛋白进行还原;以及3)将还原的蛋白混合,然后将混合物进行氧化。
- 如权利要求21所述的方法,其中还原步骤包括1)在还原剂存在下进行还原反应,所述还原剂选自:2-巯基乙胺、二硫苏糖醇、三(2-羧乙基)膦或其他化学衍生物;2)去除还原剂。
- 如权利要求21或22所述的方法,其中氧化步骤为在空气中氧化,也包括在氧化剂存在下进行氧化反应,所述氧化剂选自:L-脱氢抗坏血酸或其化学衍生物。
- 如权利要求21-23任一项所述的方法,其还包括分离纯化的步骤。
- 权利要求1-14任一项所述的双特异抗体和/或权利要求15任一项所述的分离的多核苷酸和/或权利要求16所述的重组表达载体和/或权利要求17或18所述的宿主细胞和/或权利要求19或20所述的组合物在制备用于预防和/或治疗受试者疾病的药物中的用途。
- 权利要求1-14任一项所述的双特异抗体和/或权利要求15任一项所述的分离的多核苷酸和/或权利要求16述的重组表达载体和/或权利要求17或18所述的宿主细胞和/或权利要求19或20所述的组合物,其用做用于预防和/或治疗受试者疾病的药物。
- 一种预防和/或治疗疾病的方法,包括将权利要求1-14任一项所述的异源二聚体形式的双特异抗体和/或权利要求15任一项所述的分离的多核苷酸和/或权利要求16所述的重组表达载体和/或权利要求17或18所述的宿主细胞和/或权利要求19或20所述的组合物施予有需求的受试者。
- 如权利要求25所述的用途,权利要求26所述的异源二聚体形式的双特异抗体、分离的多核苷酸、重组表达载体、宿主细胞或组合物,或权利要求27所述的方法,其中受试者是哺乳动物,优选地,人类受试者。
- 如权利要求25所述的用途,权利要求26所述的异源二聚体形式的双特异抗体、分离的多核苷酸、重组表达载体、宿主细胞或组合物,或权利要求27所述的方法,其中所述疾病选自如下肿瘤:白血病、淋巴瘤、骨髓瘤、脑肿瘤、头颈部鳞状细胞癌、非小细胞肺癌、鼻咽癌、食道癌、胃癌、胰腺癌、胆囊癌、肝癌、结直肠癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、膀胱癌、肾细胞癌、黑色素瘤、小细胞肺癌、骨癌。
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