CN114573701A - 抗PD-L1/TGF-β双功能抗体及其用途 - Google Patents
抗PD-L1/TGF-β双功能抗体及其用途 Download PDFInfo
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Abstract
本发明提供了一种抗PD‑L1/TGF‑β双功能抗体及其用途,具体地,本发明提供一种双功能抗体,包括:(a)抗PD‑L1的抗体或元件;和(b)与所述抗PD‑L1的抗体或元件相连接的抗TGF‑β的抗体或元件。本发明的双功能抗体可同时与TGF‑β及PD‑L1结合,从而发挥对TGF‑β和PD‑L1阳性的肿瘤细胞的治疗作用。
Description
技术领域
本发明涉及肿瘤免疫学领域,更具体地涉及抗PD-L1/TGF-β双功能抗体及其用途。
背景技术
癌症是造成人类死亡的第二大原因,仅次于心血管疾病。据世界卫生组织2018年全球癌症报告,2018年全球新增1810万例癌症病例,死亡人数达960万,相当于每6例死亡中就有1例死于癌症。其中肺癌、乳腺癌、结直肠癌、胃癌等癌症的发病和死亡人数位居前列(图1)。数据还显示,全球大约一半的新发病例和死亡病例都发生在亚洲,中国作为人口大国,更是占据了很大部分。长期以来,大部分癌症治疗都只能短暂延长患者生存期,确诊患癌如同被判死刑,导致人们“谈癌变色”。全球各医药企业不断投入抗癌药物的研发,新上市药物持续升级,经历了“杀敌一千自损八百”的化疗药、放疗,针对肿瘤相关抗原的分子靶向药、化疗药和靶向药联用,到如今非常火热的免疫治疗。癌症的发病机理逐渐明朗,肿瘤微环境中的免疫抑制是肿瘤得以形成重要因素,免疫治疗即是通过调节剂将肿瘤内免疫正常化或人为输入免疫工具,利用免疫系统杀死肿瘤细胞。肿瘤免疫治疗的惊人进展正在改变许多癌症类型的治疗标准,治愈癌症或者将癌症转化为可控的慢性病成为新时代癌症治疗的目标。
目前,已有大量新的在研品种和公司进入肿瘤免疫治疗领域,包括免疫调节剂、CAR-T细胞和双特异性抗体等。免疫细胞上同时表达激活性和抑制性分子,以保证机体的免疫平衡。肿瘤免疫逃逸是指肿瘤细胞通过多种机制逃避机体免疫系统识别和攻击,从而得以在体内生存和增殖的现象。CTLA-4、PD-1等免疫检查点就是肿瘤免疫逃逸的一种方式。PD-L1主要过表达于多种肿瘤细胞表面,与T细胞上的PD-1分子结合,诱导T细胞凋亡,从而帮助肿瘤免疫逃逸。近年来,陆续有10款靶向PD-1或PD-L1单抗药物上市,临床治疗效果明显,其中Keytruda(Pembrolizumab)和Opdivo(Nivolumab)更是顺利进入全球药物销售额Top 10榜。
TGF-β主要由免疫系统表达并分泌(包括TGF-β1/2/3),与受体TGF-βR(包括RI/RII/RIII)结合后,可调节细胞生长、增殖、分化、迁移和凋亡,影响胚胎器官发育、机体免疫等,具有重要的生理功能。TGF-β1、TGF-β2和TGF-β3三个亚型均可以结合细胞表面的受体。TGF-βRI不直接结合TGF-β,RIII可结合TGF-β,但其糖修饰过于复杂。TGF-βRII对TGF-β1/3具有极高亲和力(约5pM),对TGF-β2具有较低亲和力(约6nM)。TGF-β在肿瘤发生和发展中扮演着非常重要而且双重的角色,TGF-β在肿瘤早期可以调控几种凋亡基因的表达从而诱导肿瘤细胞的凋亡;而在肿瘤后期,大多数肿瘤细胞分泌大量TGF-β,一旦TGF-β水平过高,则转变成一个肿瘤促进因子:可抑制T和NK细胞、促进调节性T细胞、促进肿瘤血管生成、促进上皮细胞向间充质细胞转化等,从而促进肿瘤转移和发展。已有报道,TGF-β信号通路相关基因的异常调控是PD-1抗体耐药的原因之一,因此,TGF-β靶向药也成为抗癌药研发的重要方向。
PD-1/PD-L1抑制剂已经在肿瘤的治疗中初露锋芒,但是其临床平均有效率在20%-30%之间,PD-L1抑制剂的适应症仍有很大提升空间,越来越多的数据显示,PD-1/PD-L1联合化疗、靶向治疗,或者其他免疫治疗(如CTLA4抑制剂)能有效提高客观缓解率,可以使更多的患者获益。肿瘤的组织结构非常复杂,肿瘤PD-L1的表达水平是PD-1/PD-L1抑制剂无效的原因之一,此外肿瘤微环境中存在多种免疫抑制细胞(如MDSC,调节性T细胞、肿瘤相关巨噬细胞)、炎性相关因子(如IL-6、IL-10、TGF-β),共同促进肿瘤免疫逃逸、肿瘤的生长和转移。因此,除了免疫检查点调节剂“解除T细胞枷锁”外,靶向炎性相关因子的肿瘤微环境重塑的“T细胞开路者”也是抗癌药物研发的重要方向。
TGF-β是重要的肿瘤微环境调节靶点,然而TGF-β受体与TGF-β的亲和力极高,这给抗体的开发提出极大挑战。抗体亲和力必须足够高,才能与受体竞争结合TGF-β,而过高的亲和力,又容易在体内发生脱靶结合。药物的研发必须在保证安全性的前提下进行治疗,为此,只能将亲和力和剂量下调,药物有效性被迫妥协。因而,即使各大药企早已进入TGF-β靶向药领域,至今却仍未有TGF-β相关药物上市。因此开发同时阻断PD-L1和TGF-β两类分子的双靶点治疗药物具有重要意义。双抗中的PD-L1结合臂可定向到肿瘤组织,提高抗体的靶向效率,降低脱靶毒副作用。双功能抗体虽然是抗体药物研发的方向,但面临诸多挑战,比如临床前评价模型、表达量低、稳定性差、工艺复杂、质控差异性大等问题。因此,本领域迫切开发一种特异性佳、疗效好且易于制备的抗肿瘤双抗。
发明内容
本发明的目的在于提供一种抗PD-L1/TGF-β双功能抗体及其用途。
在本发明的第一方面,提供了一种双功能抗体,所述双功能抗体包括:
(a)抗PD-L1的抗体或元件;和
(b)与所述抗PD-L1的抗体或元件相连接的抗TGF-β的抗体或元件。
在另一优选例中,所述抗PD-L1的抗体或元件和所述抗TGF-β的抗体或元件通过连接肽相连。
在另一优选例中,所述抗TGF-β的抗体或元件连接到所述抗PD-L1的抗体的选自下组的区域:重链可变区、重链恒定区、轻链可变区、或其组合。
在另一优选例中,所述抗TGF-β的抗体或元件连接到所述抗PD-L1的抗体的重链可变区的起始端。
在另一优选例中,所述抗TGF-β的抗体或元件连接到所述抗PD-L1的抗体的重链恒定区的末端。
在另一优选例中,所述的抗体选自下组:纳米抗体、单链抗体、双链抗体。
在另一优选例中,所述的抗体选自下组:动物源抗体(如鼠源抗体)、嵌合抗体、人源化抗体。
在另一优选例中,所述的人源化抗体包括全人源化抗体。
在另一优选例中,所述的元件包括配体、受体或蛋白的胞外区。
在另一优选例中,所述的抗TGF-β的元件包括TGF-β受体的胞外区。
在另一优选例中,所述的TGF-β受体包括TGF-βRI、TGF-βRII、TGF-βRIII,较佳地为TGF-βRII。
在另一优选例中,所述双功能抗体中,所述的抗TGF-β元件的数量为1-4,较佳地为2。
在另一优选例中,所述双功能抗体为同源二聚体。
在另一优选例中,所述双功能抗体从N端到C端具有式Ia或Ib所示的结构:
其中,
“-”代表肽键;
“~”代表二硫键;
D为抗TGF-β的元件;
L1为无或接头元件;
VH代表抗PD-L1抗体的重链可变区;
CH代表抗PD-L1抗体的重链恒定区;
VL代表抗PD-L1抗体的轻链可变区;
CL代表抗PD-L1抗体的轻链恒定区;
其中,所述双功能抗体具有同时结合PD-L1和结合TGF-β的活性。
在另一优选例中,所述抗TGF-β的元件包括TGF-βRII胞外区,较佳地,所述TGF-βRII胞外区的氨基酸序列如SEQ ID NO:2所示。
在另一优选例中,所述接头元件为GS连接肽,较佳地,所述GS连接肽的氨基酸序列如SEQ ID NO:3所示。
在另一优选例中,所述的抗PD-L1抗体的重链可变区(VH)包括以下三个互补决定区CDR:
SEQ ID NO:12所示的CDR1,
SEQ ID NO:13所示的CDR2,和
SEQ ID NO:14所示的CDR3;和/或
所述的抗PD-L1抗体的轻链可变区(VL)包括以下三个互补决定区CDR:
SEQ ID NO:15所示的CDR1’,
氨基酸序列为GIS的CDR2’,和
SEQ ID NO:16所示的CDR3’。
在另一优选例中,所述的抗PD-L1抗体的重链可变区(VH)的氨基酸序列如SEQ IDNO:4所示。
在另一优选例中,所述的抗PD-L1抗体的重链恒定区的氨基酸序列如SEQ ID NO:5所示。
在另一优选例中,所述的抗PD-L1抗体的轻链可变区(VL)的氨基酸序列如SEQ IDNO:8所示。
在另一优选例中,所述的抗PD-L1抗体的轻链恒定区的氨基酸序列如SEQ ID NO:9所示。
在另一优选例中,所述双功能抗体具有式Ia所示的结构。
在另一优选例中,所述双功能抗体为式Ia所示结构的同源二聚体。
在另一优选例中,所述的双功能抗体为双链抗体。
在另一优选例中,所述的双功能抗体具有重链(H链)和轻链(L链)。
在另一优选例中,所述双功能抗体的H链具有如SEQ ID NO:1所示的氨基酸序列。
在另一优选例中,所述双功能抗体的L链具有如SEQ ID NO:7所示的氨基酸序列。
在另一优选例中,所述的抗体为药物偶联物形式。
在另一优选例中,所述双功能抗体偶联有肿瘤靶向标记偶联物。
在另一优选例中,所述双功能抗体还含有(优选偶联有)可检测标记物、靶向标记、药物、毒素、细胞因子、放射性核素、酶、或其组合。
在另一优选例中,所述双功能抗体还包括所述双功能抗体的活性片段和/或衍生物,其中,所述活性片段和/或所述衍生物保留了所述双功能抗体的70-100%(如70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、100%)的抗PD-L1活性和70-100%的抗TGF-β活性。
在另一优选例中,所述抗体的衍生物是本发明双功能抗体经过一个或几个氨基酸缺失、插入和/或取代后并保持至少85%的同一性的序列。
在另一优选例中,所述抗体的衍生物具有与本发明双功能抗体至少86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%的序列同一性。
在另一优选例中,所述的取代为保守性取代。
本发明的第二方面,提供了一种分离的多核苷酸(组合物),所述多核苷酸(组合物)编码本发明的第一方面所述的双功能抗体。
在另一优选例中,所述多核苷酸(组合物)具有编码所述双功能抗体L链的多核苷酸。
在另一优选例中,所述多核苷酸(组合物)具有编码所述双功能抗体H链的多核苷酸。
在另一优选例中,所述多核苷酸(组合物)中,编码L链的多核苷酸和编码H链的多核苷酸的比例为1:1。
在另一优选例中,所述多核苷酸(组合物)中,编码L链的多核苷酸和编码H链的多核苷酸各自独立存在。
本发明的第三方面,提供了一种载体,所述载体含有本发明的第二方面所述的多核苷酸。
在另一优选例中,所述载体同时含有本发明第二方面所述多核苷酸中的所有多核苷酸。
在另一优选例中,所述载体分别含有本发明第二方面所述多核苷酸中的任一多核苷酸。
在另一优选例中,所述载体为表达载体。
在另一优选例中,所述载体包括质粒、噬菌体、酵母质粒、植物细胞病毒、哺乳动物细胞病毒如腺病毒、逆转录病毒、或其他载体。
本发明的另一方面,提供了一种载体组合物,所述载体组合物包括含有本发明的第二方面所述的多核苷酸组合物中任一种多核苷酸的载体。
在另一优选例中,所述载体组合物包括含有编码L链的多核苷酸的载体和含有编码H链的多核苷酸的载体。
本发明的第四方面,提供了一种遗传工程化的宿主细胞,所述宿主细胞含有本发明的第三方面所述的载体或基因组中整合有本发明的第二方面所述的多核苷酸。
在另一优选例中,所述的宿主细胞包括原核细胞或真核细胞。
在另一优选例中,所述的宿主细胞选自下组:大肠杆菌、酵母细胞、哺乳动物细胞。
在另一优选例中,所述的宿主细胞包括CHO细胞。
本发明的第五方面,提供了一种制备本发明的第一方面所述双功能抗体的方法,包括步骤:
(i)在合适的条件下,培养本发明的第四方面所述的宿主细胞,获得含有本发明的第一方面所述的双功能抗体的混合物;和
(ii)对步骤(i)中得到的混合物进行纯化和/或分离,从而获得本发明的第一方面所述的双功能抗体。
在另一优选例中,所述纯化可以通过蛋白A亲和柱纯化分离获得目标抗体。
在另一优选例中,所述经过纯化分离后的目标抗体纯度大于95%,大于96%、大于97%、大于98%、大于99%,优选为100%。
在本发明的第六方面,提供了一种免疫偶联物,该免疫偶联物含有:
(a)本发明第一方面所述的双功能抗体;和
(b)选自下组的偶联部分:可检测标记物、药物、毒素、细胞因子、放射性核素、或酶、金纳米颗粒/纳米棒、纳米磁粒、病毒外壳蛋白或VLP、或其组合。
在另一优选例中,所述的抗体部分与所述的偶联部分通过化学键或接头进行偶联。
在另一优选例中,所述的放射性核素包括:
(i)诊断用同位素,所述的诊断用同位素选自下组:Tc-99m、Ga-68、F-18、I-123、I-125、I-131、In-111、Ga-67、Cu-64、Zr-89、C-11、Lu-177、Re-188、或其组合;和/或
(ii)治疗用同位素,所述的治疗用同位素选自下组:Lu-177、Y-90、Ac-225、As-211、Bi-212、Bi-213、Cs-137、Cr-51、Co-60、Dy-165、Er-169、Fm-255、Au-198、Ho-166、I-125、I-131、Ir-192、Fe-59、Pb-212、Mo-99、Pd-103、P-32、K-42、Re-186、Re-188、Sm-153、Ra223、Ru-106、Na24、Sr89、Tb-149、Th-227、Xe-133 Yb-169、Yb-177、或其组合。
在另一优选例中,所述偶联部分为药物或毒素。
在另一优选例中,所述的药物为细胞毒性药物。
在另一优选例中,所述的细胞毒性药物选自下组:抗微管蛋白药物、DNA小沟结合试剂、DNA复制抑制剂、烷化试剂、抗生素、叶酸拮抗物、抗代谢药物、化疗增敏剂、拓扑异构酶抑制剂、长春花生物碱、或其组合。
特别有用的细胞毒性药物类的例子包括,例如,DNA小沟结合试剂、DNA烷基化试剂、和微管蛋白抑制剂、典型的细胞毒性药物包括、例如奥瑞他汀(auristatins)、喜树碱(camptothecins)、多卡霉素/倍癌霉素(duocarmycins)、依托泊甙(etoposides)、美登木素(maytansines)和美登素类化合物(maytansinoids)(例如DM1和DM4)、紫杉烷(taxanes)、苯二氮卓类(benzodiazepines)或者含有苯二氮卓的药物(benzodiazepine containingdrugs)(例如吡咯并[1,4]苯二氮卓类(PBDs),吲哚啉苯并二氮卓类(indolinobenzodiazepines)和噁唑烷并苯并二氮卓类(oxazolidinobenzodiazepines))、长春花生物碱(vinca alkaloids)、或其组合。
在另一优选例中,所述的毒素选自下组:
耳他汀类(例如,耳他汀E、耳他汀F、MMAE和MMAF)、金霉素、类美坦西醇、篦麻毒素、篦麻毒素A-链、考布他汀、多卡米星、多拉司他汀、阿霉素、柔红霉素、紫杉醇、顺铂、cc1065、溴化乙锭、丝裂霉素、依托泊甙、替诺泊甙(tenoposide)、长春新碱、长春碱、秋水仙素、二羟基炭疽菌素二酮、放线菌素、白喉毒素、假单胞菌外毒素(PE)A、PE40、相思豆毒素、相思豆毒素A链、蒴莲根毒素A链、α-八叠球菌、白树毒素、迈托毒素(mitogellin)、局限曲菌素(retstrictocin)、酚霉素、依诺霉素、麻疯树毒蛋白(curicin)、巴豆毒素、卡奇霉素、肥皂草(Sapaonaria officinalis)抑制剂、糖皮质激素、或其组合。
在另一优选例中,所述偶联部分为可检测标记物。
在另一优选例中,所述偶联物选自:荧光或发光标记物、放射性标记物、MRI(磁共振成像)或CT(电子计算机X射线断层扫描技术)造影剂、或能够产生可检测产物的酶、放射性核素、生物毒素、细胞因子(如IL-2等)、抗体、抗体Fc片段、抗体scFv片段、金纳米颗粒/纳米棒、病毒颗粒、脂质体、纳米磁粒、前药激活酶(例如,DT-心肌黄酶(DTD)或联苯基水解酶-样蛋白质(BPHL))、化疗剂(例如,顺铂)或任何形式的纳米颗粒。
在另一优选例中,所述免疫偶联物含有:多价(如二价)的本发明第一方面所述的双功能抗体。
本发明的第七方面,提供了一种药物组合物,所述药物组合物含有:
(I)如本发明的第一方面所述的双功能抗体、或本发明第六方面所述的免疫偶联物;和
(II)药学上可接受的载体。
在另一优选例中,所述药物组合物中还含有额外的抗肿瘤剂,如细胞毒性药物。。
在另一优选例中,所述药物组合物为单元剂型。
在另一优选例中,所述抗肿瘤剂包含紫杉醇、多柔比星、环磷酰胺、阿西替尼、乐伐替尼、或派姆单抗。
在另一优选例中,所述的抗肿瘤剂可以与所述双功能抗体单独存在于独立的包装内,或所述抗肿瘤剂可以与所述双功能抗体偶联。
在另一优选例中,所述药物组合物的剂型包括胃肠给药剂型或胃肠外给药剂型。
在另一优选例中,所述的胃肠外给药剂型包括静脉注射、静脉滴注、皮下注射、局部注射、肌肉注射、瘤内注射、腹腔内注射、颅内注射、或腔内注射。
本发明的第八方面,提供了如本发明的第一方面所述双功能抗体或如本发明的第六方面所述的免疫偶联物的用途,用于制备(a)检测试剂或试剂盒;和/或(b)制备预防和/或治疗癌症或肿瘤的药物组合物。
在另一优选例中,所述肿瘤选自下组:血液肿瘤、实体瘤、或其组合。
在另一优选例中,所述肿瘤选自下组:卵巢癌、结肠癌、直肠癌、黑色素瘤(例如转移的恶性黑色素瘤)、肾癌、膀胱癌、乳腺癌、肝癌、淋巴瘤、恶性血液病、头颈癌、胶质瘤、胃癌、鼻咽癌、喉癌、宫颈癌、子宫体瘤和骨肉瘤。可以用本发明的方法治疗的其他癌症的例子包括:骨癌、膜腺癌、皮肤癌、前列腺癌、皮肤或眼内恶性黑色素瘤、子宫癌、肛区癌、睾丸癌、输卵管癌、子宫内膜癌、阴道癌、阴户癌、何杰金病、非何杰金氏淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病,包括急性髓细胞样白血病、慢性髓细胞样白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾孟癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管发生、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波因肉瘤、表皮状癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症,包括石棉诱发的癌症,以及所述癌症的组合。
在另一优选例中,所述肿瘤为直肠癌、非小细胞性肺癌、黑色素瘤、膀胱癌、或其组合。
在另一优选例中,所述肿瘤为高表达PD-L1和/或TGF-β的肿瘤。
在另一优选例中,所述药物或制剂用于制备预防和/或治疗与PD-L1和/或TGF-β(表达阳性的)相关的疾病的药物或制剂。
在另一优选例中,所述的抗体为药物偶联物(ADC)形式。
在另一优选例中,所述的检测试剂或试剂盒用于诊断PD-L1和/或TGF-β相关疾病。
在另一优选例中,所述检测试剂或试剂盒用于检测样品中PD-L1和/或TGF-β蛋白。
在另一优选例中,所述的检测试剂为检测片。
本发明的第九方面,提供了一种治疗肿瘤的方法,包括步骤:向需要的对象施用安全有效量的本发明第一方面所述的双功能抗体、或本发明第六方面所述的免疫偶联物、或本发明第七方面所述的药物组合物、或其组合。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了2018年全球癌症发病和死亡人数最多的癌症类型。
图2显示了HB0028和HB0029的结构示意图
图3显示了SDS-PAGE检测蛋白Protein A亲和柱纯化结果。其中,M表示蛋白分子量标准。
图4显示了HB0028和HB0029对人TGF-β1的结合活性。
图5显示了HB0028和HB0029对人TGF-β3的结合活性。
图6显示了HB0028和HB0029对人PD-L1的结合活性。
图7显示了HB0028和HB0029对PD-L1和TGF-β双靶点的结合活性。
图8显示了HB0028和HB0029恢复T细胞激活的作用。
图9显示了HB0028和HB0029对TGF-β/SMAD信号通路的抑制作用。
图10显示了抗体在人黑色素瘤A375混合PBMC皮下移植瘤模型中的抗肿瘤作用。
图11显示了抗体在人乳腺癌MDA-MB-231混合PBMC皮下移植瘤模型中的抗肿瘤作用。
具体实施方式
本发明人经过广泛而深入地研究,首次构建了一种抗PD-L1/TGF-β双功能抗体。具体地,在申请人自主研发的PD-L1人源化单抗HB0023(参见中国专利申请CN201910258153.9)的基础上,在单抗重链的N-末端或C-末端用柔性GS连接子连接了人源TGF-βR II的胞外区(ECD),获得2价结合PD-L1和2价结合TGF-β分子的双靶点融合单克隆抗体,分别命名为HB0028和HB0029,结构示意图如图2所示。
在前期研究中,申请人对多种不同结构不同连接方式的双特异性抗体进行了鉴定,通过比较其靶点结合活性、阻断活性、信号通路抑制功能、产品纯度、稳定性等,最终获得技术效果最好的双特异性抗体HB0028和HB0029,并确定了氨基酸序列和基因序列。其中,HB0028的结构稳定性优于HB0029,且能更好的保留TGF-βRII胞外区的结合活性。随后,将携带有HB0028基因的质粒转染至CHO宿主细胞中,通过多次单克隆筛选最终得到能高效、稳定表达HB0028的细胞株。并用该细胞株生产蛋白,进行小鼠体内抗肿瘤活性研究。
靶向TGF-β和PD-L1的双特异性抗体还没有上市产品,目前进展最快的是默克的M7824,其临床II期效果非常惊人。本申请的HB0028和HB0029的PD-L1部分的可变区序列是拥有专利保护的,GS连接子和TGF-βRII胞外区部分为公开共享序列,不同的是HB0028受体部分位于单抗N端,HB0029受体部分位于单抗C端,后者结构与默克相同。本发明的结果表明,HB0028的表达和稳定性优于HB0029和对照药900544,且能更好的保留TGF-βRII胞外区的结合活性。具体地,HB0028的体外活性与默克的M7824基本相当,并且,从体内结果看,HB0028可以通过调整剂量的方式达到与对照药M7824相当的临床效果。
术语
为了更容易理解本发明,以下具体定义了某些技术和科学术语。除非在本文中另有明确定义,本文使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
本发明所用氨基酸三字母代码和单字母代码如J.biol.chem,243,p3558(1968)中所述。
如本文所用,术语“给予”和“处理”是指外源性药物、治疗剂、诊断剂或组合物应用于动物、人、受试者、细胞、组织、器官或生物流体。“给予”和“处理”可以指治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触、以及试剂与流体的接触、流体与细胞的接触。“给予”和“处理”还意指通过试剂、诊断、结合组合物或通过另一种细胞体外和离体处理。“处理”当应用于人、动物或研究受试者时,是指治疗处理、预防或预防性措施,研究和诊断;包括抗人PD-L1抗体与人或动物、受试者、细胞、组织、生理区室或生理流体的接触。
如本文所用,术语“治疗”指给予患者内用或外用治疗剂,包含本发明的任何一种抗PD-L1/TGF-β双功能抗体及其组合物,所述患者具有一种或多种疾病症状,而已知所述治疗剂对这些症状具有治疗作用。通常,以有效缓解一种或多种疾病症状的治疗剂的量(治疗有效量)给予患者。
如本文所用,术语“任选”或“任选地”意味着随后所描述的事件或情况可以发生但不是必须发生。例如,“任选包含1-3个抗体重链可变区”是指特定序列的抗体重链可变区可以有但不是必须有,可以是1个、2个或3个。
本发明所述的“序列同一性”表示当具有适当的替换、插入或缺失等突变的情况下最佳比对和比较时,两个核酸或两个氨基酸序列之间的同一性程度。本发明中所述的序列和其具有同一性的序列之间的序列同一性可以至少为85%、90%或95%,优选至少为95%。非限制性实施例包括85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%,100%。
通常,“抗体”也称为“免疫球蛋白“其可以是天然或常规的抗体,其中两条重链通过二硫键彼此连接且每条重链与轻链通过二硫键连接。存在两种类型的轻链,λ(l)和κ(k)。存在五种主要的重链种类(或同型),其决定抗体分子的功能活性:IgM、IgD、IgG、IgA和IgE。每种链包含不同的序列结构域。轻链包括两个结构域或区,可变结构域(VL)和恒定结构域(CL)。重链包括四个结构域,重链可变区(VH)和三个恒定区(CH1、CH2和CH3,统称为CH)。轻链(VL)和重链(VH)的可变区都决定对抗原的结合识别和特异性。轻链的恒定结构域(CL)和重链的恒定区(CH)赋予重要的生物性质如抗体链结合、分泌、经胎盘的移动性、补体结合和与Fc受体(FcR)的结合。Fv片段是免疫球蛋白Fab片段的N-末端部分且由一条轻链和一条重链的可变部分组成。抗体的特异性取决于抗体结合位点和抗原决定区间的结构互补。抗体结合位点由主要来自高度可变区或互补决定区(CDR)的残基组成。偶尔,来自非高度可变或框架区(FR)的残基影响整体结构域结构且进而影响结合位点。互补决定区或CDR指共同限定结合亲和力和天然免疫球蛋白结合位点天然Fv区的特异性的氨基酸序列。免疫球蛋白的轻链和重链各具有三个CDR,分另称为CDR1-L、CDR2-L、CDR3-L和CDR1-H、CDR2-H、CDR3-H。常规抗体抗原结合位点因此包括六个CDR,包含来自每个重链和轻链v区的CDR集合。
如本文所用,术语“可变”表示抗体中可变区的某些部分在序列上有所不同,它形成了各种特定抗体对其特定抗原的结合和特异性。然而,可变性并不均匀地分布在整个抗体可变区中。它集中于轻链和重链可变区中称为互补决定区(CDR)或超变区中的三个片段中。可变区中较保守的部分称为构架区(FR)。天然重链和轻链的可变区中各自包含四个FR区,它们大致上呈β-折叠构型,由形成连接环的三个CDR相连,在某些情况下可形成部分β-折叠结构。每条链中的CDR通过FR区紧密地靠在一起并与另一链的CDR一起形成了抗体的抗原结合部位(参见Kabat等,NIH Publ.No.91-3242,卷I,647-669页(1991))。恒定区不直接参与抗体与抗原的结合,但是它们表现出不同的效应功能,例如参与抗体的依赖于抗体的细胞毒性。
如本文所用,术语“框架区”(FR)指插入CDR间的氨基酸序列,即指在单一物种中不同的免疫球蛋白间相对保守的免疫球蛋白的轻链和重链可变区的那些部分。免疫球蛋白的轻链和重链各具有四个FR,分别称为FR1-L、FR2-L、FR3-L、FR4-L和FR1-H、FR2-H、FR3-H、FR4-H。相应地,轻链可变结构域可因此称作(FR1-L)-(CDR1-L)-(FR2-L)-(CDR2-L)-(FR3-L)-(CDR3-L)-(FR4-L)且重链可变结构域可因此表示为(FR1-H)-(CDR1-H)-(FR2-H)-(CDR2-H)-(FR3-H)-(CDR3-H)-(FR4-H)。优选地,本发明的FR是人抗体FR或其衍生物,所述人抗体FR的衍生物与天然存在的人抗体FR基本相同,即序列同一性达到85%、90%、95%、96%、97%、98%或99%。
获知CDR的氨基酸序列,本领域的技术人员可轻易确定框架区FR1-L、FR2-L、FR3-L、FR4-L和/或FR1-H、FR2-H、FR3-H、FR4-H。
如本文所用,术语″人框架区″是与天然存在的人抗体的框架区基本相同的(约85%或更多,具体地90%、95%、97%、99%或100%)框架区。
如本文所用,术语“单克隆抗体”或“mAb”指针对特定抗原的具有单一氨基酸组成的抗体分子,且不应理解为需要通过任何特定方法产生该抗体。单克隆抗体可由B细胞或杂交瘤的单一克隆产生,但还可为重组的,即通过蛋白工程产生。
如本文所用,术语“抗原”或“靶抗原”指能够由抗体或抗体样结合蛋白所结合的分子或分子的部分。该术语进一步指能够用于动物以产生能够与该抗原的表位结合的抗体的分子或分子的部分。靶抗原可具有一个或多个表位。对于每种由抗体或由抗体样结合蛋白识别的靶抗原,抗体样结合蛋白能够与识别靶抗原的完整抗体竞争。
如本文所用,术语“亲和力”理论上通过完整抗体和抗原间的平衡缔合来定义。本发明双抗的亲和力可以通过KD值(解离常数)(或其它测定方式)进行评估或测定,例如生物膜层干涉技术(Bio-layer interferometry BLI),使用FortebioRed96仪器测量确定。
如本文所用,术语“接头”是指插入免疫球蛋白结构域中为轻链和重链的结构域提供足够的可动性以折叠成交换双重可变区免疫球蛋白的一个或多个氨基酸残基。优选地,本发明所述的接头元件为GS连接肽,较佳地,所述GS连接肽的氨基酸序列如SEQ ID NO:3所示。
抗PD-L1抗体
细胞程序性死亡受体-1(programmed cell death protein,PD-1)是近年来发现的一种负性共刺激分子,为CD28免疫球蛋白超家族。PD-1普遍表达于活化的T细胞,B细胞及髓系细胞,其有两个天然配体,即程序性死亡配体-1(programmed death ligand 1,PD-L1)和PD-L2,均属于B7超家族,在抗原递呈细胞中均有表达,PD-L1在多种组织也有表达。其中PD-L1是PD-1的一种重要负性免疫调节因子,又称B7-H1,其与PD-1的结合介导T细胞活化的共抑制信号,抑制T细胞活化和增殖,起到类似于CTLA-4的负调节作用,可诱导T细胞的凋亡。而且有研究报道表明肿瘤微环境也可以保护肿瘤细胞免受免疫细胞的破坏,使得肿瘤细胞不能被识别,发生免疫逃逸现象。而且肿瘤微环境可持续性表达PD-L1,使得肿瘤患者的免疫功能极度下降。
华裔科学家陈列平实验室首先发现PD-L1在肿瘤组织高表达,而且调节肿瘤浸润CD8T细胞的功能。因此,以PD-1/PD-L1为靶点的免疫调节对抗肿瘤有重要的意义。近年来,已有多种Anti-PD-1/PD-L1抗体在肿瘤免疫治疗的临床研究迅速开展。目前Pembrolizumab和Nivolumab已被FDA批准用于晚期黑色素瘤,最近Nivolumab也已被美国FDA批准用于晚期鳞状非小细胞肺癌的治疗。另外,MPDL3280A(anti-PD-L1单抗),Avelumab(anti-PD-L1单抗)等也已进入多个晚期临床研究中,覆盖非小细胞癌,黑色素瘤,膀胱癌等多个瘤种。
在另一优选例中,所述的抗PD-L1抗体的重链可变区(VH)包括以下三个互补决定区CDR:
SEQ ID NO:12所示的CDR1,
SEQ ID NO:13所示的CDR2,和
SEQ ID NO:14所示的CDR3;和/或
所述的抗PD-L1抗体的轻链可变区(VL)包括以下三个互补决定区CDR:
SEQ ID NO:15所示的CDR1’,
氨基酸序列为GIS的CDR2’,和
SEQ ID NO:16所示的CDR3’。
本领域技术人员也可以通过本领域熟知的技术对本发明抗PD-L1抗体进行修饰或改造,例如添加、缺失和/或取代一个或几个氨基酸残基,从而进一步增加抗PD-L1的亲和力或结构稳定性,并通过常规的测定方法获得修饰或改造后的结果。
TGF-β
TGF-β具有调节细胞生长、分化、凋亡、迁移和浸润、细胞外基质生成、血管形成和免疫调节等一系列生理功能,在胚胎发育和个体维持稳态过程发挥重要作用。研究发现,TGF-β基因敲除的小鼠胚胎无法正常发育,导致小鼠死亡。TGF-β在肿瘤形成的不同阶段发挥不同角色:在肿瘤形成早期,TGF-β信号通路的激活会增加周期素依赖性激酶机制剂p15和p21的表达,从而导致细胞周期阻滞和凋亡;在肿瘤形成后期,肿瘤细胞通过1)旁路途径下调p15和p21的表达;2)激活Ras/MAPK途径;3)TGF-β受体及下游分子失活突变三种途径逆转TGF-β的凋亡诱导作用。此后,肿瘤细胞大量分泌TGF-β,作用于周围细胞,通过促进基质细胞纤维化,促进肿瘤血管形成,促进表皮向间充质细胞转化和细胞转移,抑制免疫激活性细胞如T细胞、NK细胞、树突状细胞、Th1细胞、M1巨噬细胞等的活性,促进免疫抑制性细胞如T调节细胞、Th2细胞、M2巨噬细胞等的产生和活化,最终促进肿瘤发展和转移(Haque S,Morris J C.Transforming growth factor-β:A therapeutic target for cancer[J].Human Vaccines&Immunotherapeutics,2017,13(8):1741-1750.)。
由于TGF-β在肿瘤发展过程中的重要作用,TGF-β及其信号通路相关分子成为重要的治疗靶点。根据靶点所处信号通路的不同阶段,治疗性药物可分为三大类:1)TGF-β合成抑制剂;2)TGF-β与受体阻断剂;3)TGF-β下游信号通路阻断剂。反义寡核苷酸是一种有效的蛋白合成机制剂,有Antisense Pharma公司开发的Trabederson AP12009是一种18个寡核苷酸组成的反义寡核苷酸,靶向TGF-βmRNA,抑制其翻译成TGF-β蛋白。通过导管局部注射到肿瘤部位,能有效抑制肿瘤生长,延长患者生存期,已经开展了临床III期实验,但因缺少入组患者而于2014年终止实验。靶向TGF-β的单克隆抗体是研究最成熟的TGF-β与受体阻断剂,目前进展最快的有Genzyme公司的GC1008(临床II期)和CAT-192(临床I/II期),诺华的NIS793(临床II期),勃林格殷格翰和礼来共同开发的LY2382770(临床II期)和ScholarRock开发的GARP/TGF-β1双抗SRK-181(临床I期),还有许多TGF-β单抗处于临床前研究阶段,竞争十分激烈。TGF-β受体激酶抑制剂或下游分子ALK-5的机制剂如LY2157299、LY2109761、SB-431542等,都在动物模型体内或体外被证明能阻断TGF-β信号通路传导,但有的药物因耐药性或不良体内药代动力学性质而终止开发,目前仅有礼来的TGF-βRI小分子抑制剂LY2157299(Galunisertib)于2019年完成了一项临床III期实验(NCT02008318)。可溶性重组TGF-β受体II或受体III已被证明能在小鼠体内有效抑制胶质瘤、非小细胞肺癌、乳腺癌等肿瘤的生长,但研究未推上临床试验。
在本发明的一个优选例中,双功能抗体中包含的抗TGF-β的元件包括TGF-β受体的胞外区。
在另一优选例中,所述的TGF-β受体包括TGF-βRI、TGF-βRII、TGF-βRIII。
在另一优选例中,所述抗TGF-β的元件包括TGF-βRII胞外区,较佳地,所述TGF-βRII胞外区的氨基酸序列如SEQ ID NO:2所示。
优选地,本发明的TGF-βRII胞外区无论连接于抗PD-L1抗体的哪一端,均由接头连接两个相同的TGF-βRII胞外区从而以二聚体形式出现。
双功能抗体(双特异性抗体)
双特异性抗体(Bispecific Antibody,bsAb)是一种非天然抗体,它能同时靶向两种不同的抗原或蛋白,阻断两种不同的信号通路,激发具有特异性的免疫反应,其特异性和双功能性在肿瘤免疫治疗中的作用越来越重要,已成为当今世界抗体工程治疗肿瘤方面的研究热点。研究表明,双特异性抗体在肿瘤免疫治疗方面主要有介导免疫细胞对肿瘤的杀伤;结合双靶点,阻断双信号通路,发挥独特的或重叠的功能,可以有效防止耐药性;具有强特异性、靶向性和降低脱靶毒性;有效降低治疗成本等优势(摘自抗体圈),因此采用双特异性抗体药物可以降低肿瘤细胞逃逸几率,清除肿瘤细胞,提高疗效。
双特异性抗体可通过双杂交瘤细胞,化学偶联,重组基因等手段制备,其中重组基因技术在结合位点以及产量等方面灵活性强。据不完全统计,目前已有60多种双特异性抗体,根据其特点以及结构差异性,双特异性抗体结构主要有含Fc片段的双特异性抗体(IgG-like双特异性抗体,具有Fc介导的效应功能)和不含Fc片段的双特异性抗体(non-IgG-like双特异性抗体,通过抗原结合力发挥作用,具有分子量小、免疫原性低等优势)两种结构。2014年12月03日美国FDA审批安进公司研发的双特异性抗体Blincyto(Blinatumomab)上市,用于急性淋巴细胞白血病的治疗。Blinatumomab为CD19、CD3双特异性抗体,Blincyto(Blinatumomab)是美国FDA审批的第一个双特性抗体。
如本文所用,术语“双特异性抗体”、“双功能抗体”“本发明抗体”、“本发明双抗”“双抗”、“双功能融合抗体”可互换使用,是指同时结合PD-L1和TGF-β的抗PD-L1/TGF-β双特异性抗体。
在本发明中,所述双功能抗体包括:
(a)抗PD-L1的抗体或元件;和
(b)与所述抗PD-L1的抗体或元件相连接的抗TGF-β的抗体或元件。
在一优选实施方式中,所述双功能抗体从N端到C端具有式Ia或Ib所示的结构:
其中,
“-”代表肽键;
“~”代表二硫键;
D为抗TGF-β的元件;
L1为无或接头元件;
VH代表抗PD-L1抗体的重链可变区;
CH代表抗PD-L1抗体的重链恒定区;
VL代表抗PD-L1抗体的轻链可变区;
CL代表抗PD-L1抗体的轻链恒定区;
其中,所述双功能抗体具有同时结合PD-L1和结合TGF-β的活性。
式Ia或式Ib中,一种优选的H链如SEQ ID NO:1所示,一种优选地L链如SEQ ID NO:7所示。
而两条如式Ia或式Ib结构式所示的序列通过H链的二硫键相连,从而形成对称的双功能抗体结构。
本发明双抗不仅包括完整的抗体,还包括具有免疫活性的抗体的片段或抗体与其他序列形成的融合蛋白。因此,本发明还包括所述抗体的片段、衍生物和类似物。如本文所用,术语“片段”、“衍生物”和“类似物”是指基本上保持本发明抗体相同的生物学功能或活性的多肽。本发明的多肽片段、衍生物或类似物可以是(i)有一个或多个保守或非保守性氨基酸残基(优选保守性氨基酸残基)被取代的多肽,而这样的取代的氨基酸残基可以是也可以不是由遗传密码编码的,或(ii)在一个或多个氨基酸残基中具有取代基团的多肽,或(iii)成熟多肽与另一个化合物(比如延长多肽半衰期的化合物,例如聚乙二醇)融合所形成的多肽,或(iv)附加的氨基酸序列融合到此多肽序列而形成的多肽(如前导序列或分泌序列或用来纯化此多肽的序列或蛋白原序列,或与6His标签形成的融合蛋白)。根据本文的教导,这些片段、衍生物和类似物属于本领域熟练技术人员公知的范围。
本发明双抗指具有抗PD-L1以及抗TGF-β活性的、包括两条上述式I结构的抗体。该术语还包括具有与本发明双抗相同功能的、包括两条上述式I结构的抗体的变异形式。这些变异形式包括(但并不限于):一个或多个(通常为1-50个,较佳地1-30个,更佳地1-20个,最佳地1-10个)氨基酸的缺失、插入和/或取代,以及在C末端和/或N末端添加一个或数个(通常为20个以内,较佳地为10个以内,更佳地为5个以内)氨基酸。例如,在本领域中,用性能相近或相似的氨基酸进行取代时,通常不会改变蛋白质的功能。又比如,在C末端和/或N末端添加一个或数个氨基酸通常也不会改变蛋白质的功能。该术语还包括本发明双抗的活性片段和活性衍生物。
该双抗的变异形式包括:同源序列、保守性变异体、等位变异体、天然突变体、诱导突变体、在高或低的严紧度条件下能与本发明抗体的编码DNA杂交的DNA所编码的蛋白、以及利用抗本发明抗体的抗血清获得的多肽或蛋白。
在本发明中,“本发明双抗的保守性变异体”指与本发明双抗的氨基酸序列相比,有至多10个,较佳地至多8个,更佳地至多5个,最佳地至多3个氨基酸被性质相似或相近的氨基酸所替换而形成多肽。这些保守性变异多肽最好根据表A进行氨基酸替换而产生。
表A
最初的残基 | 代表性的取代 | 优选的取代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Lys;Arg | Gln |
Asp(D) | Glu | Glu |
Cys(C) | Ser | Ser |
Gln(Q) | Asn | Asn |
Glu(E) | Asp | Asp |
Gly(G) | Pro;Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe | Leu |
Leu(L) | Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Leu;Val;Ile;Ala;Tyr | Leu |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala | Leu |
编码核酸和表达载体
本发明还提供了编码上述抗体或其片段或其融合蛋白的多核苷酸分子。本发明的多核苷酸可以是DNA形式或RNA形式。DNA形式包括cDNA、基因组DNA或人工合成的DNA。DNA可以是单链的或是双链的。DNA可以是编码链或非编码链。编码本发明的成熟多肽的多核苷酸包括:只编码成熟多肽的编码序列;成熟多肽的编码序列和各种附加编码序列;成熟多肽的编码序列(和任选的附加编码序列)以及非编码序列。
术语“编码多肽的多核苷酸”可以是包括编码此多肽的多核苷酸,也可以是还包括附加编码和/或非编码序列的多核苷酸。
本发明的核酸(以及核酸组合)可用于在合适的表达系统产生本发明的重组抗体。
本发明还涉及与上述的序列杂交且两个序列之间具有至少50%,较佳地至少70%,更佳地至少80%相同性的多核苷酸。本发明特别涉及在严格条件下与本发明所述多核苷酸可杂交的多核苷酸。在本发明中,“严格条件”是指:(1)在较低离子强度和较高温度下的杂交和洗脱,如0.2×SSC,0.1%SDS,60℃;或(2)杂交时加有变性剂,如50%(v/v)甲酰胺,0.1%小牛血清/0.1%Ficoll,42℃等;或(3)仅在两条序列之间的相同性至少在90%以上,更好是95%以上时才发生杂交。并且,可杂交的多核苷酸编码的多肽与成熟多肽有相同的生物学功能和活性。
本发明的抗体的核苷酸全长序列或其片段通常可以用PCR扩增法、重组法或人工合成的方法获得。一种可行的方法是用人工合成的方法来合成有关序列,尤其是片段长度较短时。通常,通过先合成多个小片段,然后再进行连接可获得序列很长的片段。此外,还可将重链的编码序列和表达标签(如6His)融合在一起,形成融合蛋白。
一旦获得了有关的序列,就可以用重组法来大批量地获得有关序列。这通常是将其克隆入载体,再转入细胞,然后通过常规方法从增殖后的宿主细胞中分离得到有关序列。本发明所涉及的生物分子(核酸、蛋白等)包括以分离的形式存在的生物分子。
目前,已经可以完全通过化学合成来得到编码本发明蛋白(或其片段,或其衍生物)的DNA序列。然后可将该DNA序列引入本领域中已知的各种现有的DNA分子(或如载体)和细胞中。此外,还可通过化学合成将突变引入本发明蛋白序列中。
本发明还涉及包含上述的适当DNA序列以及适当启动子或者控制序列的载体。这些载体可以用于转化适当的宿主细胞,以使其能够表达蛋白质。
宿主细胞可以是原核细胞,如细菌细胞;或是低等真核细胞,如酵母细胞;或是高等真核细胞,如哺乳动物细胞。代表性例子有:大肠杆菌,链霉菌属;鼠伤寒沙门氏菌的细菌细胞;真菌细胞如酵母;果蝇S2或Sf9的昆虫细胞;CHO、COS7、293细胞的动物细胞等。
用重组DNA转化宿主细胞可用本领域技术人员熟知的常规技术进行。当宿主为原核生物如大肠杆菌时,能吸收DNA的感受态细胞可在指数生长期后收获,用CaCl2法处理,所用的步骤在本领域众所周知。另一种方法是使用MgCl2。如果需要,转化也可用电穿孔的方法进行。当宿主是真核生物,可选用如下的DNA转染方法:磷酸钙共沉淀法,常规机械方法如显微注射、电穿孔,脂质体包装等。
获得的转化子可以用常规方法培养,表达本发明的基因所编码的多肽。根据所用的宿主细胞,培养中所用的培养基可选自各种常规培养基。在适于宿主细胞生长的条件下进行培养。当宿主细胞生长到适当的细胞密度后,用合适的方法(如温度转换或化学诱导)诱导选择的启动子,将细胞再培养一段时间。
在早期培养条件中,双特异性抗体的表达量可达3.9g/L,纯度均在97%以上,且在培养过程中可以很好地代谢乳酸。
在上面的方法中的重组多肽可在细胞内、或在细胞膜上表达、或分泌到细胞外。如果需要,可利用其物理的、化学的和其它特性通过各种分离方法分离和纯化重组的蛋白。这些方法是本领域技术人员所熟知的。这些方法的例子包括但并不限于:常规的复性处理、用蛋白沉淀剂处理(盐析方法)、离心、渗透破菌、超处理、超离心、分子筛层析(凝胶过滤)、吸附层析、离子交换层析、高效液相层析(HPLC)和其它各种液相层析技术及这些方法的结合。
本发明的双抗可以单独使用,也可与可检测标记物(为诊断目的)、治疗剂、或任何以上这些物质的组合结合或偶联。
用于诊断目的可检测标记物包括但不限于:荧光或发光标记物、放射性标记物、MRI(磁共振成像)或CT(电子计算机X射线断层扫描技术)造影剂、或能够产生可检测产物的酶。
可与本发明抗体结合或偶联的治疗剂包括但不限于:1.放射性核素;2.生物毒;3.细胞因子如IL-2等;4.金纳米颗粒/纳米棒;5.病毒颗粒;6.脂质体;7.纳米磁粒;8.肿瘤治疗剂(例如,顺铂)或任何形式的抗肿瘤药物等。
药物组合物
本发明还提供了一种组合物。优选地,所述的组合物是药物组合物,它含有本发明上述的双特异性抗体或其活性片段或其融合蛋白,以及药学上可接受的载体。通常,可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中,其中pH通常约为5-8,较佳地pH约为6-8,尽管pH值可随被配制物质的性质以及待治疗的病症而有所变化。配制好的药物组合物可以通过常规途径进行给药,其中包括(但并不限于):静脉注射、静脉滴注、皮下注射、局部注射、肌肉注射、瘤内注射、腹腔内注射(如腹膜内)、颅内注射、或腔内注射。
本发明的药物组合物可直接用于结合PD-L1和/或TGF-β,因而可用于治疗肿瘤。此外,还可同时使用其他治疗剂。
本发明的药物组合物含有安全有效量(如0.001-99wt%,较佳地0.01-90wt%,更佳地0.1-80wt%)的本发明上述的纳米抗体(或其偶联物)以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。药物制剂应与给药方式相匹配。本发明的药物组合物可以被制成针剂形式,例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。药物组合物如针剂、溶液宜在无菌条件下制造。活性成分的给药量是治疗有效量,例如每天约10微克/千克体重-约50毫克/千克体重。此外,本发明的多肽还可与其他治疗剂一起使用。
在本发明中,可单独使用双特异性抗体,通过调整给药方案以获得最佳目的反应。例如,单次给药,或在一段时间内多次给药,或者可以随治疗情况的紧急程度按比例减少或增加剂量。
使用药物组合物时,是将安全有效量的免疫偶联物施用于哺乳动物,其中该安全有效量通常至少约10微克/千克体重,而且在大多数情况下不超过约50毫克/千克体重,较佳地该剂量是约10微克/千克体重-约10毫克/千克体重。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
(a)本发明的双功能抗体可以同时结合PD-L1和TGF-β,恢复T细胞激活,并抑制TGF-β/SMAD信号通路。
(b)本发明的双功能抗体HB0028具有极好的结构稳定性,且能更好的保留TGF-βRII胞外区的结合活性。
(c)本发明的双功能抗体HB0028可以在CHO宿主细胞中高效、稳定表达,易于生产。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
实施例1表达载体的构建
委托苏州金唯智生物科技有限公司(简称金唯智)合成带有人TGF-βRII胞外区(登录号:P37173)第24-159位氨基酸(ECD24-159)的N-fusion和C-fusion基因,N-fusion和C-fusion分别表示TGF-βRII ECD通过GS柔性连接子与人源化PD-L1抗体重链的N末端和C末端融合。基因合成时,在N-fusion的5’末端添加HindIII内切酶识别位点,受体ECD下游连接PD-L1抗体(HB0023)重链可变区及部分CH1基因序列,在3’末端添加NheI内切酶识别位点。C-fusion的5’末端从PD-L1抗体(HB0023)重链恒定区CH3的SexAI内切酶识别位点开始,包含部分CH3和受体ECD基因,其3’末端添加XmaI内切酶识别位点。合成好的基因由金唯智构建到pUC57载体,制备mini-scale重组质粒DNA和含有该重组质粒的穿刺菌,穿刺菌可用于扩增制备更多质粒备用。制备好的N-fusion质粒和PD-L1抗体重链表达载体(华博代号:400078)分别经过HindIII和NheI双酶切,纯化后用T4连接酶进行片段和载体连接,并将400078所用骨架人IgG1的CH2结构域上的L234A/L235A(EU编号规则)突变替换为野生型人IgG1,构建所得表达载体即为PD-L1和TGF-β双特异性抗体在N端融合的HB0028重链表达载体,编号为500054。对于C-fusion双特异性抗体HB0029的重链表达载体构建,以金唯智提供的含有C-fusion基因的质粒为模板,用引物(上游:AGGAGATGACCAAGAACCAGGTAAGTTTGACCTGCCT(SEQ ID NO:10),下游:ACCGCGAGAGCCCGGGGAGCGGGGGCTTGCCGGCCGTCGCA(SEQ ID NO:11),由金唯智合成)PCR扩增出目的基因片段,PD-L1重链表达载体400078经过SexAI和XmaI双酶切后,用In-fusion重组酶(Takara,货号639650)将PCR产物和酶切载体连接,同理将400078所用骨架人IgG1的CH2结构域上的L234A/L235A突变替换为野生型人IgG1,构建所得PD-L1和TGF-β双特异性抗体在C端融合的HB0029重链表达载体,编号为500055。双特异性抗体的轻链与亲本PD-L1人源化抗体的轻链相同,编号为400085。双特异性抗体的序列如下:
HB0028重链500054氨基酸序列:
IPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDGGGGSGGGGSGGGGSGGGGSGQVQLVQSGAEVKKPGASVKVSCKASGYAFTGYTIHWVRQAPGQRLEWMGWFYPGSGTLKYSEKFQGRVTITRDKSLSTAYMELSSLRSEDTAVYYCARHGTGTLMAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:1)
其中,TGF-βRII ECD24-159:
IPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPD(SEQ IDNO:2)
GS连接子:
GGGGSGGGGSGGGGSGGGGSG(SEQ ID NO:3)
PD-L1抗体重链可变区序列(划线部分为CDR区,以IMGT系统划分):
QVQLVQSGAEVKKPGASVKVSCKASGYAFTGYTIHWVRQAPGQRLEWMGWFYPGSGTLKYSEKFQGRVTITRDKSLSTAYMELSSLRSEDTAVYYCARHGTGTLMAMDYWGQGTLVTVSS(SEQ ID NO:4)
抗体重链恒定区序列:
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:5)
HB0029重链500055氨基酸序列(其中抗体可变区、恒定区,连接子和TGF-βRII各自的序列与HB0028相同,此处不再单独列出):
QVQLVQSGAEVKKPGASVKVSCKASGYAFTGYTIHWVRQAPGQRLEWMGWFYPGSGTLKYSEKFQGRVTITRDKSLSTAYMELSSLRSEDTAVYYCARHGTGTLMAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSGIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPD(SEQ ID NO:6)
轻链400085氨基酸序列:
DVVMTQTPLSLSVTPGQPASISCKSSQSLANSYGNTYLSWYLHKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:7)
其中,轻链可变区序列(划线部分为CDR区,以IMGT系统划分):
DVVMTQTPLSLSVTPGQPASISCKSSQSLANSYGNTYLSWYLHKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPPTFGQGTKLEIK(SEQ ID NO:8)
抗体轻链恒定区序列:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:9)
实施例2融合蛋白的表达和纯化
本发明中蛋白的表达分为瞬时转染表达和稳定转染表达两种方式,对于顺势转染表达,将构建好的重链表达载体500054和500055分别与轻链载体400085按1:1比例混合,并加入PEI(Polyetherimide,聚乙烯亚胺)预孵育后,共转染到CHO-S(赛默飞,R80007)细胞中,32℃,5%CO2,125rpm/min培养7天后,离心收集上清,纯化备用。对于稳定转染表达,将构建好的重链表达载体500054和500055分别与轻链载体400085按1:2比例混合并加入空白CHO-K1细胞中,用培养基混合,采用250~300V脉冲电压进行点击转染,MSX加压筛选稳定转染的细胞克隆,并经过有限稀释法筛选稳定高效转染HB0028和HB0029抗体的单克隆细胞株,经过扩大悬浮培养并添加细胞生长所需补料,约14天后离心收集上清。为了与德国默克公司的M7824对照药进行比较,发明人根据专利公布的M7824基因序列,合成目的基因并装载于表达载体中,用同样瞬时转染表达方法表达并纯化。收集的上清用0.45μm滤膜过滤,收集滤液。滤液经Protein A亲和柱纯化后,得到目的蛋白,其中M7824被编号为900544。纯化后的目的蛋白经SEC_UPLC检测纯度,结果显示,HB0028纯度高于95%,HB0029和900544纯度较低,存在明显降解条带。SDS-PAGE检测还原和非还原状态下的目的蛋白条带,结果如图3所示。上述结果表明,HB0028的表达和稳定性优于HB0029和对照药900544。
实施例3融合蛋白与靶点的结合活性
3.1ELISA方法检测融合蛋白对人TGF-β的结合活性
用PBS将TGF-β1(ACRO,TG1-H4212)或TGF-β3(R&D,8420-B3-025)稀释至0.5μg/ml,100μl/孔加入96孔酶标板内,4℃包被过夜,PBST洗板后用封闭液封闭1h。待测样品从30μg/ml开始,3倍梯度稀释12个梯度,以TGF-βRII-Fc(ACRO,TG2-H5252)和对照药900544(根据Merck发布专利PD-L1/TGF-β双抗M7824的序列合成基因,由华博生物自主表达)为阳性对照,900201(900201为非目的抗原靶向的人IgG1同型对照抗体,用于多项检测,作阴性对照)为阴性对照,100μl/孔加入,室温反应2h。PBST洗板后加入HRP标记抗人IgG二抗(1:5000稀释),100μl/孔加入,室温反应30min后PBST洗板,TMB显色液显色5min,硫酸终止反应,用酶标仪读取OD450值。
结果如图4和图5所示,HB0028和HB0029都能有效结合游离的TGF-β蛋白,且HB0028的结合活性强于HB0029和对照药900544。
3.2FACS方法检测融合蛋白对人PD-L1的结合活性
取过表达人PD-L1的CHO-K1细胞重悬至1×106/ml,20μl/孔加入96孔板内,待测样品从30μg/ml开始,3倍梯度稀释12个梯度,900201为阴性对照,900544为阳性对照抗体,20μl/孔加入,室温孵育30min,用1%BSA-PBS离心洗涤两次,每孔加入20μl PE荧光标记的抗人IgG二抗(Jackson Immunoresearch,109-115-098),室温孵育15min,离心洗涤三次后用流式细胞仪Canto II(BD)检测580nm处发射光强度,结果以中位荧光强度(MFI)表示。
结果如图6所示,HB0028和HB0029都能有效结合细胞膜上的人PD-L1靶蛋白,且样品间对细胞表面抗原PD-L1的结合活性相当。
3.3FACS方法检测融合蛋白对PD-L1和TGF-β双靶点的结合活性
系列稀释的待测样品和3μg/ml的TGF-β1蛋白预混合,以900201为阴性对照,900544为阳性对照抗体,孵育30min后,取过表达人PD-L1的CHO-K1细胞重悬至1×106/ml,20μl/孔加入96孔板内,混匀孵育30min。用1%BSA-PBS离心洗涤两次,每孔加入20μl PE荧光标记的抗人TGF-β1的二抗(1:100),室温孵育15min,离心洗涤三次后用流式细胞仪CantoII(BD)检测580nm处发射光强度。
结果如图7所示,融合蛋白能有效地同时结合细胞膜上人PD-L1和游离的TGF-β靶蛋白,虽然相同浓度下,HB0028双靶点结合强度弱于HB0029和对照药900544,但在饱和浓度下,HB0028分子的曲线上平台最高,即其能更高效发挥双靶点结合。
实施例4报告基因方法在体外检测融合蛋白的生物活性
4.1双功能抗体阻断PD-L1以恢复T细胞激活的作用
本检测系统由两种经基因工程改造的细胞系组成:Jurkat-NFAT-PD-1-5B8细胞(PD-1效应细胞)是稳定表达人PD-1和NFAT诱导的萤光素酶的Jurkat T细胞;CHO-K1-OS8-PD-L1-8D6细胞(PD-L1靶细胞)能稳定表达人PD-L1和TCR激活抗体OKT3单链抗体于细胞表面。当把两种类型的细胞共同培养时,PD-1/PD-L1相互作用抑制TCR信号转导以及NFAT介导的萤光素酶活性。加入可阻断PD-1或PD-L1的其中一种抗体即可解除抑制信号,从而使TCR信号通路恢复激活以及NFAT介导的萤光素酶活性增强。
待测抗体用培养基稀释至30000ng/ml后,2倍梯度稀释8个浓度,共9个浓度梯度,靶细胞Jurkat-NFAT-PD-1-5B8计数,重悬为5×105/ml,每孔30μl铺到96孔白底板中;效应细胞CHO-K1-OS8-PD-L1-8D6计数,重悬为5×105/ml,每孔30μl;加入稀释好的待测样品,每孔30μl。混匀后置于CO2培养箱,37℃孵育6小时,检测抗体的最终工作浓度为10000ng/ml、5000ng/ml、2500ng/ml、1250ng/ml、625ng/ml、312.5ng/ml、156.25ng/ml、78.125ng/ml和39.063ng/ml;孵育结束后培养板室温平衡至少15min,然后将平衡好的Bio-GloTMLuciferase Assay底物缓冲液加入96孔白板,90μl/孔,室温避光反应20min,MD酶标仪全波长读值。GraphPad Prism 8软件上,以RLU值vs.抗体工作浓度进行四参数方程拟合分析数据。
结果如图8所示,双功能抗体HB0028和HB0029能有效恢复T细胞的激活,且样品间在体外激活T细胞的能力相当。
4.2双功能抗体对TGF-β的抑制作用
TGF-β配体与细胞膜上II型受体结合后,II型受体招募并磷酸化I型受体,I型受体再磷酸化受体调控的SMAD2/SMAD3蛋白,二者与SMAD4蛋白结合,最终复合物进入细胞核内,参与目标基因的表达调控。小鼠乳腺癌细胞4T1转染Cignal Lenti SMAD Reporter(luc)(QIAGEN,CLS-017L)报告基因表达载体后,利用抗生素筛选稳定表达的细胞株,命名为4T1-SMAD细胞,可用于检测TGF-β的激活和抗体的阻断作用。
收集4T1-SMAD细胞并重悬为5×105/ml,每孔100μl铺到96孔白底板中,待测抗体、阳性对照900544和阴性对照900201用培养基稀释至500ng/ml后,1.5倍梯度稀释8个浓度,以TGF-βRII-Fc(ACRO,TG2-H5252)为阳性对照,稀释至20000ng/ml,再3倍梯度稀释8个浓度。稀释好的抗体50μl/孔加入96孔板内,孵育2h,再加入50μl 20ng/ml稀释的TGF-β1(ACRO,TG1-H4212)孵育过夜。离心去除细胞培养上清,加入30μl Bio-GloTMLuciferaseAssay底物缓冲液(Promega,G7940),室温避光反应5min,MD酶标仪酶标仪全波长读值。GraphPad Prism 8软件上,以RLU值vs.抗体工作浓度进行四参数方程拟合分析数据。
结果如图9所示,双功能抗体HB0028和HB0029能有效抑制TGF-β/SMAD信号通路的转导,且样品间的抑制活性非常接近。
实施例5 BIAcore检测HB0028与其靶点种属间亲和力
检测HB0028对不同种属PD-L1抗原亲和力时,使用偶联Anti-human IgG(Fc)芯片捕捉HB0028样品作为配体,不同种属PD-L1抗原作为分析物,进行多动力循环动力学检测。检测HB0028对不同种属TGF-β抗原亲和力时,使用Protein A芯片捕捉HB0028样品作为配体,不同种属TGF-β蛋白作为分析物,进行多动力循环动力学检测。流速:30μl/min,结合:120s,解离:600s,采用1:1结合模式,Fit local分析动力学常数。
结果如表1所示,根据多动力循环分析结果,HB0028抗体不与小鼠、大鼠、家兔的PD-L1相结合,而与猴、人的PD-L1亲和力KD值分别为5.87nM和2.45nM。在TGF-β受体端,HB0028与人、小鼠/大鼠的TGF-β1和人TGF-β3有10-11M水平的亲和力,而该分子并不与TGF-β1的前体(Human LAP,Mouse Latent TGF-β1)有结合。相较于对TGF-β1和TGF-β3的高亲和力,HB0028对TGF-β2的亲和力在10-09M的水平,且各种属间没有差异。
表1.HB0028与其靶点不同种属间亲和力
分析物 | ka(1/Ms) | kd(1/s) | KD(M) |
小鼠PD-L1 | NB | NB | NB |
大鼠PD-L1 | NB | NB | NB |
兔PD-L1 | NB | NB | NB |
猴PD-L1 | 2.17E+05 | 1.28E-03 | 5.87E-09 |
人PD-L1 | 1.90E+05 | 4.65E-04 | 2.45E-09 |
人TGF-β1 | 4.83E+07 | 5.50E-04 | 1.14E-11 |
小鼠/大鼠TGF-β1 | 9.05E+05 | 2.49E-06 | 2.75E-12 |
人LAP | NB | NB | NB |
小鼠前体TGF-β1 | NB | NB | NB |
人TGF-β2 | 5.02E+07 | 7.84E-02 | 1.56E-09 |
小鼠/大鼠TGF-β2 | 2.33E+07 | 4.60E-02 | 1.97E-09 |
人TGF-β3 | 7.17E+07 | 2.82E-03 | 3.93E-11 |
注:NB,no binding,表示没有结合。
实施例6HB0028的体内抗肿瘤活性
抗体在人黑色素瘤A375混合PBMC皮下移植瘤模型中的抗肿瘤作用:取6-8周龄的NCG小鼠,A375细胞与人PBMC共培养6天后,收取PBMC与新鲜消化下来的A375细胞,按适当比例混合,0.2ml/只,接种于小鼠右侧皮下。根据小鼠体重随机进行分组给药,详细的给药方法、给药剂量和给药途径见表2,接瘤当天开始给药,记为第0天。使用游标卡尺每周两次测量,肿瘤体积计算公式为V=0.5a×b2,a,b分别代表肿瘤的长径和短径,并计算肿瘤生长抑制率TGI(%)。
表2.huPBMC+A375移植瘤模型分组和给药
组别 | 给药组 | N | 剂量 | 给药方案 | 给药方式 |
G1 | 900201(IgG1同型对照) | 6 | 25mg/kg | BIW×4 | i.p. |
G2 | M7824 | 6 | 5mg/kg | BIW×4 | i.p. |
G3 | HB0028(LD) | 6 | 5mg/kg | BIW×4 | i.p. |
G4 | HB0028(HD) | 6 | 25mg/kg | BIW×4 | i.p. |
注:N:使用动物数量;BIW x 4:每周给药2次,4周,共8次;i.p.:腹腔注射
A375模型中抗体抗肿瘤活性结果如图10所示。结果显示,相等剂量下HB0028对肿瘤生长的抑制效果略微弱于对照药M7824(900544)(P>0.27),高剂量下HB0028的抑瘤效果增强,可与对照药相当。与阴性对照组相比,各给药组都能有效抑制肿瘤生长,实验结束时,M7824、HB0028高剂量和低剂量的抑瘤率分别为78.55%、76.74%和58.65%,组间无显著差异(P>0.27)。各组小鼠的体重以及临床前的行为学均未出现明显异常变化,表明荷瘤小鼠对测试剂量下的各受试药物具有良好的耐受性。
抗体在人乳腺癌MDA-MB-231混合PBMC皮下移植瘤模型中的抗肿瘤作用:取18-22g的雌性NCG小鼠,MDA-MB-231细胞与人PBMC共培养6天后,收取PBMC与新鲜消化下来的MDA-MB-231细胞,按适当比例混合,0.2ml/只,接种于小鼠右侧皮下。接种后,待肿瘤长至70-130mm3时,根据肿瘤体积大小随机分为3组,每组6只,详细的给药方法、给药剂量和给药途径见表3,分组给药当天为第0天。
表3.huPBMC+MDA-MB-231移植瘤模型分组和给药
注:N:使用动物数量;BIW x 4:每周给药2次,4周,共8次;i.p.:腹腔注射
MDA-MB-231模型中抗体抗肿瘤活性结果如图11所示。结果显示,相等剂量下HB0028对肿瘤生长的抑制效果与对照药M7824相当,甚至在最后两次给药时抑瘤效果表现出优于对照药的趋势。实验结束时,与阴性对照组相比,M7824、HB0028的抑瘤率分别为80.16%和91.52%。各组小鼠的体重以及临床前的行为学均未出现明显异常变化,表明荷瘤小鼠对测试剂量下的各受试药物具有良好的耐受性。
实施例7融合蛋白稳定性研究
将HB0028和HB0029样品换液至相同缓冲溶液中,并调整浓度至约1.5mg/ml。在上述条件下,对融合蛋白稳定性进行评估。在热稳定性方面进行比较,使用蛋白稳定性分析仪(UNcle,UNCHAINED LABS,US)检测两种融合蛋白的熔解温度(Tm)、聚集温度(Tagg);在加速及加压条件下比较蛋白稳定性,将两种融合蛋白在25℃恒温培养箱中放置1M、3M,在40℃恒温培养箱中放置1M,检测样品的SEC、CE纯度并比较纯度变化情况。
结果如表3所示,HB0028蛋白的Tm值(68.9℃)和HB0029蛋白的Tm值(69.7℃)接近,HB0028蛋白的Tagg值(69.5℃)比HB0029蛋白的Tagg值(64.2℃)高5℃。25℃加速3M,SEC主峰纯度HB0028降低12.3%、HB0029降低39.5%,主要表现为右肩峰及低分子的增多(疑似降解),非还原CE-SDS纯度无明显差异;40℃高温放置1M,SEC纯度HB0028降低13.4%、HB0029降低24.1%,也表现为右肩峰及低分子的增多。综上,HB0028蛋白的热聚集温度显著高于HB0029,在加速及高温条件下的降解速率显著低于HB0029,因此,HB0028蛋白的分子结构比HB0029更稳定。
表3.加速及高温条件稳定性结果
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 上海华奥泰生物药业股份有限公司
华博生物医药技术(上海)有限公司
<120> 抗PD-L1/TGF-β双功能抗体及其用途
<130> P2020-1864
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Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 6
<211> 606
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Gly Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Phe Tyr Pro Gly Ser Gly Thr Leu Lys Tyr Ser Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Lys Ser Leu Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Gly Thr Gly Thr Leu Met Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu 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 Thr 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 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser Val Asn
465 470 475 480
Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln
485 490 495
Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys
500 505 510
Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln
515 520 525
Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu
530 535 540
Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu
545 550 555 560
Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro
565 570 575
Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp
580 585 590
Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
595 600 605
<210> 7
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Ala Asn Ser
20 25 30
Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu His Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Leu Gln Gly
85 90 95
Thr His Gln Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 8
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Ala Asn Ser
20 25 30
Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu His Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Leu Gln Gly
85 90 95
Thr His Gln Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 9
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 10
<211> 37
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
aggagatgac caagaaccag gtaagtttga cctgcct 37
<210> 11
<211> 41
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
accgcgagag cccggggagc gggggcttgc cggccgtcgc a 41
<210> 12
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Gly Tyr Ala Phe Thr Gly Tyr Thr
1 5
<210> 13
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Phe Tyr Pro Gly Ser Gly Thr Leu
1 5
<210> 14
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Ala Arg His Gly Thr Gly Thr Leu Met Ala Met Asp Tyr
1 5 10
<210> 15
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Gln Ser Leu Ala Asn Ser Tyr Gly Asn Thr Tyr
1 5 10
<210> 16
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Leu Gln Gly Thr His Gln Pro Pro Thr
1 5
Claims (10)
1.一种双功能抗体,其特征在于,所述双功能抗体包括:
(a)抗PD-L1的抗体或元件;和
(b)与所述抗PD-L1的抗体或元件相连接的抗TGF-β的抗体或元件。
2.如权利要求1所述的双功能抗体,其特征在于,所述抗TGF-β的抗体或元件连接到所述抗PD-L1的抗体的重链可变区的起始端。
4.如权利要求1或3所述的双功能抗体,其特征在于,所述抗TGF-β的元件包括TGF-βRII胞外区,较佳地,所述TGF-βRII胞外区的氨基酸序列如SEQ ID NO:2所示。
5.如权利要求1或3所述的双功能抗体,其特征在于,所述的抗PD-L1抗体的重链可变区(VH)包括以下三个互补决定区CDR:
SEQ ID NO:12所示的CDR1,
SEQ ID NO:13所示的CDR2,和
SEQ ID NO:14所示的CDR3;和/或
所述的抗PD-L1抗体的轻链可变区(VL)包括以下三个互补决定区CDR:
SEQ ID NO:15所示的CDR1’,
氨基酸序列为GIS的CDR2’,和
SEQ ID NO:16所示的CDR3’。
6.一种分离的多核苷酸,其特征在于,所述多核苷酸编码权利要求1所述的双功能抗体。
7.一种载体,其特征在于,所述载体含有权利要求6所述的多核苷酸。
8.一种遗传工程化的宿主细胞,其特征在于,所述宿主细胞含有权利要求7所述的载体或基因组中整合有权利要求6所述的多核苷酸。
9.一种免疫偶联物,其特征在于,该免疫偶联物含有:
(a)权利要求1所述的双功能抗体;和
(b)选自下组的偶联部分:可检测标记物、药物、毒素、细胞因子、放射性核素、或酶、金纳米颗粒/纳米棒、纳米磁粒、病毒外壳蛋白或VLP、或其组合。
10.一种如权利要求1所述双功能抗体或如权利要求9所述的免疫偶联物的用途,其特征在于,用于制备(a)检测试剂或试剂盒;和/或(b)制备预防和/或治疗癌症或肿瘤的药物组合物。
Priority Applications (4)
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CN202011401649.6A CN114573701A (zh) | 2020-12-02 | 2020-12-02 | 抗PD-L1/TGF-β双功能抗体及其用途 |
US18/039,733 US20240026004A1 (en) | 2020-12-02 | 2021-12-01 | ANTI-PD-L1/TGF-ß BIFUNCTIONAL ANTIBODY AND USE THEREOF |
CN202180078899.7A CN116802297A (zh) | 2020-12-02 | 2021-12-01 | 抗PD-L1/TGF-β双功能抗体及其用途 |
PCT/CN2021/134824 WO2022117003A1 (zh) | 2020-12-02 | 2021-12-01 | 抗PD-L1/TGF-β双功能抗体及其用途 |
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CN202180078899.7A Pending CN116802297A (zh) | 2020-12-02 | 2021-12-01 | 抗PD-L1/TGF-β双功能抗体及其用途 |
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US (1) | US20240026004A1 (zh) |
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WO (1) | WO2022117003A1 (zh) |
Family Cites Families (5)
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JP6731346B2 (ja) * | 2014-02-10 | 2020-07-29 | メルク パテント ゲーエムベーハー | 標的TGFβ阻害 |
CN110050000B (zh) * | 2017-05-12 | 2022-07-26 | 苏州盛迪亚生物医药有限公司 | 含有TGF-β受体的融合蛋白及其医药用途 |
AU2019299318A1 (en) * | 2018-07-02 | 2021-01-21 | Merck Patent Gmbh | Combination therapy with targeted TGF-B inhibition for treatment of advanced non-small cell lung cancer |
CN109929037B (zh) * | 2019-04-01 | 2023-03-17 | 华博生物医药技术(上海)有限公司 | 针对程序性死亡配体的结合物及其应用 |
CN109942712B (zh) * | 2019-04-01 | 2022-12-20 | 华博生物医药技术(上海)有限公司 | 抗pd-l1/vegf双功能抗体及其用途 |
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2020
- 2020-12-02 CN CN202011401649.6A patent/CN114573701A/zh active Pending
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2021
- 2021-12-01 WO PCT/CN2021/134824 patent/WO2022117003A1/zh active Application Filing
- 2021-12-01 US US18/039,733 patent/US20240026004A1/en active Pending
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