CN116323657B - 同时靶向PD-L1和TGFβ的双功能分子及其医药用途 - Google Patents
同时靶向PD-L1和TGFβ的双功能分子及其医药用途 Download PDFInfo
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Abstract
提供了一种同时靶向PD‑L1和TGFβ的双功能分子及包含所述双功能分子的药物组合物,还提供了所述同时靶向PD‑L1和TGFβ的双功能分子治疗和预防癌症的用途。
Description
技术领域
本发明属于生物医药领域,具体的涉及一种同时靶向PD-L1和TGFβ的双功能分子及其医药用途。
背景技术
继化疗、放疗和靶向治疗之后,免疫治疗成为日益重要的一种新型的肿瘤治疗方式,代表了这一领域思维方式的转化。程序性死亡受体1(programmed death 1,PD-1)和程序性死亡配体1(programmed death ligand 1,PD-L1)是免疫检查信号通路的核心蛋白,在正常情况下可以保护自身组织不受T细胞的攻击,但是也会被肿瘤细胞利用来逃避免疫系统的清除。针对PD-1或者PD-L1的抗体药物能够显著抑制肿瘤的生长,多个癌种的对PD-1/PD-L1治疗响应的病人都有显著的生存获益。然而,肿瘤病人对于PD-1/PD-L1治疗发生响应的比率并不高,原因之一在于肿瘤复杂的微环境,存在多条免疫抑制的信号通路。因此,同时针对PD-1/PD-L1和另一免疫检查点的双特异性抗体就更加具备治疗潜力。
研究显示,在对PD-1/PD-L1治疗不响应的肿瘤组织中,常常伴随着转化生长因子β(TGFβ)高表达。在正常生理条件下,TGFβ作为免疫调节因子可以保护自身组织免于免疫系统的攻击,但是在肿瘤微环境中,TGFβ通过作用于免疫系统,帮助肿瘤细胞实现免疫逃逸,加速肿瘤进展。TGFβ有三种亚型,分别为TGFβ1,TGFβ2和TGFβ3,均在多种肿瘤组织中高表达,且它们在血清中的高表达也与不良预后相关。与此同时,TGFβ1还能直接阻止T细胞的分化,抑制T细胞和NK细胞杀伤癌细胞的功能。
因此,同时阻断PD-1/PD-L1信号通路和TGFβ信号通路的药物,比起针对单一信号通路的药物有望进一步提高免疫治疗的响应率。
目前已有PD-L1抗体和TGFβRII融合蛋白组成的双功能分子公开,如WO2015118175A2,WO2018205985A1等。但仍存在着半衰期较短等问题,本发明提供了一种体内、外稳定性更优的技术方案。
发明内容
本发明提供一种同时靶向PD-L1和TGFβ的双功能分子,包含靶向PD-L1的部分和TGF-β受体部分,所述的靶向PD-L1的部分为PD-L1抗体,所述的TGF-β受体部分为TGFβRII(TGF-beta receptor type-2)胞外区的N端截短形式,所述PD-L1抗体的每个重链C端均连接一个TGFβRII胞外区的N端截短形式,所述PD-L1抗体的轻链和重链可变区CDR序列如下:
LCDR1的序列如SEQ ID NO:9所示;
LCDR2的序列如SEQ ID NO:10所示;
LCDR3的序列如SEQ ID NO:11所示;
HCDR1的序列如SEQ ID NO:12所示;
HCDR2的序列如SEQ ID NO:13所示;
HCDR3的序列如SEQ ID NO:14所示。
优选的,所述的TGFβRII胞外区的全长序列如SEQ ID NO:1所示,N端截短形式为17-27个氨基酸的截短。
优选的,所述的TGF-β受体部分的序列如SEQ ID NO:2所示。
优选的,所述PD-L1抗体的轻链可变区序列如SEQ ID NO:15所示;重链可变区序列如SEQ ID NO:16所示。
优选的,所述PD-L1抗体的轻链序列如SEQ ID NO:5所示;重链序列如SEQ ID NO:6所示,并且重链C末端最后一位的K突变成A。
优选的,所述PD-L1抗体的重链C端通过连接肽连接TGFβRII胞外区的N端截短形式。
优选的,所述连接肽为(G4S)XG,所述x为3-6,优选为4-5。
优选的,所述PD-L1抗体的轻链序列如SEQ ID NO:7所示,重链与TGFβRII胞外区的N端截短形式整体的序列如SEQ ID NO:8所示。
本发明还提供一种药物组合物,其包含上述的双功能分子以及药学上可接受载体。
本发明还提供一种核酸分子,其编码上述的双功能分子。
本发明还提供一种表达载体,其含有上述的核酸分子。
本发明还提供一种宿主细胞,其包含上述的表达载体,所述宿主细胞选自细菌、酵母菌和哺乳动物细胞;优选为哺乳动物细胞;更优选为HEK293E细胞、expi293细胞或CHO细胞。
本发明还提供上述的双功能分子在用于制备治疗癌症的药物中的用途。
优选的,所述癌症为PD-L1阳性的肿瘤。
优选的,所述癌症选自肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌和头颈肿瘤。
本发明还提供一种治疗和预防肿瘤的方法,包括给予所需患者治疗有效量的上述的双功能分子或上述的药物组合物。
附图说明
图1:双功能分子结构示意图。
图2:双功能分子体外结合人源PD-L1的结果。
图3:双功能分子体外结合人源TGFβ1的结果。
图4:使用SPR技术检测双功能分子6与人源PD-L1和人源TGFβ1的结合。
图5:在细胞水平检测双功能分子阻断PD-1/PD-L1信号通路的能力。
图6:在细胞水平检测双功能分子阻断TGFβ/SMAD信号通路的能力。
图7:在MDA-MB-231模型中双功能分子对肿瘤重量的影响。
图8:在人源化MC-38模型中双功能分子对肿瘤体积和肿瘤重量的影响。
具体实施方式
术语
本说明书中提及的所有公布、专利和专利申请都以引用的方式并入本文,所述引用的程度就如同已特定地和个别地指示将各个别公布、专利或专利申请以引用的方式并入本文。
在下文详细描述本发明前,应理解本发明不限于本文中描述的特定方法学、方案和试剂,因为这些可以变化。还应理解本文中使用的术语仅为了描述具体实施方案,而并不意图限制本发明的范围。除非另外定义,本文中使用的所有技术和科学术语与本发明所属领域中普通技术人员通常的理解具有相同的含义。
本文所公开的某些实施方案包含了数值范围,并且本发明的某些方面可采用范围的方式描述。除非另有说明,应当理解数值范围或者以范围描述的方式仅是出于简洁、便利的目的,并不应当认为是对本发明的范围的严格限定。因此,采用范围方式的描述应当被认为具体地公开了所有可能的子范围以及在该范围内的所有可能的具体数值点,正如这些子范围和数值点在本文中已经明确写出。不论所述数值的宽窄,上述原则均同等适用。当采用范围描述时,该范围包括范围的端点。
当涉及可测量值比如量、暂时持续时间等时,术语“约”是指包括指定值的±20%、或在某些情况下±10%、或在某些情况下±5%、或在某些情况下±1%、或在某些情况下±0.1%的变化。
本文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。
本文所用的术语“抗体”,典型是指包含通过共价二硫键和非共价相互作用保持在一起的两条重(H)多肽链和两条轻(L)多肽链的Y型四聚蛋白。天然IgG抗体即具有这样的结构。每条轻链由一个可变结构域(VL)和一个恒定结构域(CL)组成。每条重链包含一个可变结构域(VH)和恒定区。
本领域已知五个主要类别的抗体:IgA,IgD,IgE,IgG和IgM,对应的重链恒定结构域分别被称为α,δ,ε,γ和μ,IgG和IgA可以进一步分为不同的亚类,例如IgG可分为IgG1,IgG2,IgG3,IgG4,IgA可分为IgA1和IgA2。来自任何脊椎动物物种的抗体的轻链基于其恒定结构域的氨基酸序列可以被分配到两种明显相异的类型之一,称为κ和λ。
在IgG、IgA和IgD抗体的情形中,该恒定区包含称为CH1、CH2和CH3的三个结构域(IgM和IgE具有第四结构域CH4)。在IgG、IgA和IgD类别中,CH1和CH2结构域被柔性铰链区分离,该铰链区是可变长度的富含脯氨酸和半胱氨酸的区段。每类抗体进一步包含由配对半胱氨酸残基形成的链间和链内二硫键。
术语“可变区”或“可变结构域”显示出从一种抗体到另一种抗体的氨基酸组成的显著变化,并且主要负责抗原识别和结合。每个轻链/重链对的可变区形成抗体结合位点,使得完整的IgG抗体具有两个结合位点(即它是二价的)。重链的可变区(VH)和轻链的可变区(VL)结构域各包含具有极端变异性的三个区域,被称为高变区(HVR),或更通常地,被称为互补决定区(CDR),VH和VL各有4个骨架区FR,分别用FR1,FR2,FR3,FR4表示。因此,CDR和FR序列通常出现在重链可变结构域(或轻链可变结构域)的以下序列中:FR1-HCDR1(LCDR1)-FR2-HCDR2(LCDR2)-FR3-HCDR3(LCDR3)-FR4。
术语“Fc”用于定义免疫球蛋白重链的C端区域,所述区域包含至少一部分的恒定区。该术语包括天然序列Fc区和变体Fc区。
如在此使用的,广义上的“抗体”的类型可包括如多克隆抗体(polyclonalantibodies)、单克隆抗体、嵌合抗体、人源化抗体及灵长类化抗体、CDR移植抗体(CDR-grafted antibody)、人类抗体(包括重组产生的人类抗体)、重组产生的抗体、胞内抗体、多特异性抗体、双特异性抗体、单价抗体、多价抗体、抗个体基因型抗体、合成抗体(包括突变蛋白及其变体)等等。
术语“单克隆抗体”(或称“单抗”)指由单一细胞克隆产生的基本均质、仅针对某一特定抗原表位的抗体。单克隆抗体可以使用本领域中已知的多种技术制备,包括杂交瘤技术、重组技术、噬菌体展示技术、转基因动物、合成技术或上述技术的组合等。
需说明的是,本发明的单克隆抗体可变区的CDR和FR的划分是根据Kabat定义确定的。而其他命名和编号系统,例如Chothia、IMGT或AHo等,也是本领域技术人员已知的。因此,以本发明的单抗序列为基础,包含任何命名系统衍生的一种或多种CDR的人源化抗体均明确地保持在本发明的范围内。
术语“抗体片段”包含完整抗体的至少一部分。如在此所使用,抗体分子的“片段”包括抗体的“抗原结合片段”,并且术语“抗原结合片段”是指免疫球蛋白或抗体中与所选抗原或其免疫原性决定部分特异性结合或反应的多肽片段,或由此片段进一步衍生的融合蛋白产物,例如单链抗体,嵌合抗原受体中的胞外结合区等。示例性的抗体片段或其抗原结合片段包括但不限于:可变轻链片段、可变重链片段、Fab片段、F(ab')2片段、Fd片段、Fv片段、单结构域抗体、线性抗体、单链抗体(scFv)及由抗体片段形成的双特异性抗体或多特异性抗体等。
术语“抗原”是指被抗体或抗体结合片段识别并特异性结合的物质,广义上,抗原可以包括所选靶标的任何免疫原性片段或决定簇,包括单表位、多表位、单结构域、多结构域、完整的胞外结构域(ECD)或蛋白质。肽、蛋白质、糖蛋白、多糖和脂质,其部分及其组合均可构成抗原。非限制性示例性抗原包括肿瘤抗原或病原体抗原等。“抗原”也可以指引发免疫反应的分子。任何形式的抗原或含有该抗原的细胞或制剂都可以用于生成对抗原决定簇具有特异性的抗体。抗原可以是分离的全长蛋白质、细胞表面蛋白(例如,用在其表面上表达至少一部分抗原的细胞进行免疫的)、或可溶性蛋白质(例如,仅用该蛋白质的ECD部分进行免疫的)或蛋白质构建体(例如,Fc抗原)。该抗原可以在基因修饰的细胞中产生。前述任何抗原可以单独或与本领域已知的一种或多种免疫原性增强佐剂组合使用。编码该抗原的DNA可以是基因组的或非基因组的(例如,cDNA),并且可以编码足以引起免疫原性应答的至少一部分ECD。可以使用任何载体来转化其中表达抗原的细胞,所述载体包括但不限于腺病毒载体、慢病毒载体、质粒以及非病毒载体如阳离子脂质。
术语“表位”是指抗原上与免疫球蛋白或抗体特异性结合的位点。表位可以由相邻的氨基酸、或通过蛋白质的三级折叠而并列的不相邻的氨基酸形成。由相邻的氨基酸形成的表位通常在暴露于变性溶剂后保持,而通过三级折叠形成的表位通常在变性溶剂处理后丧失。表位通常以独特的空间构象存在并且包括至少3-15个氨基酸。由给定的抗体确定其结合的表位的方法是本领域熟知的,包括免疫印迹和免疫沉淀检测分析等。确定表位的空间构象的方法包括本领域中的技术,例如X射线晶体分析法和二维核磁共振等。
术语“亲和力”或“结合亲和力”指分子(例如抗体)的单一结合位点与其结合配偶体(例如抗原)之间全部非共价相互作用总和的强度。术语“KD”是指特定的抗体-抗原相互作用的解离常数。可以使用本领域已知的各种技术来确定结合亲和力,例如表面等离子体共振、生物层干涉法、双极化干涉法、静态光散射、动态光散射、等温滴定量热法、ELISA、分析超速离心和流式细胞术等。
术语“生物学活性”指抗体结合抗原并导致可测量的生物学反应的能力,所述生物学反应可以在体外或体内进行测量。
术语“药物制剂”或“制剂”或“制剂处方”,表示这样的制品:其存在形式允许活性成分的生物学活性有效,并且不含有对所述制剂要施用的受试者有毒的其他组分。
术语“溶液制剂”表示,在大气压下至少约2℃至约8℃的温度为液体的制剂。
术语“脱酰胺”表示,抗体中的一个或多个天冬酰胺残基已经被衍生成,例如,天冬氨酸或异-天冬氨酸。
术语“聚集”的抗体是这样一种抗体,其已经被发现与其它抗体分子一起聚集,特别是在冷冻和/或搅动之后。
术语“稳定的”制剂是这样的制剂,其中的蛋白质在保存后基本上保持其物理稳定性和/或化学稳定性和/或生物学活性。优选地,该制剂在保存后基本上保持其物理和化学稳定性,以及其生物学活性。一般基于制剂保质期来选择贮存期。用来测量蛋白质稳定性的各种分析技术是本领域已有的。可以在选定的温度下测量稳定性持续选定的时间。稳定性能够以许多不同的方式进行定性和/或定量地评估,包括评估聚集物形成(例如利用大小排阻层析,通过测量浊度,和/或通过肉眼观察);通过利用阳离子交换层析或毛细管分区电泳评估电荷异质性;氨基末端或羧基末端序列分析;质谱分析;SDS-PAGE分析以比较减小的和完整的抗体;肽图谱分析;评估生物学活性或抗体的抗原结合功能;等等。不稳定性可以包括下列的任一种或多种:聚集,脱酰胺作用(例如Asn脱酰胺作用),氧化作用(例如Met氧化作用),异构化作用(例如Asp异构化作用),剪切/水解/片段化(例如铰链区片段化),琥珀酰亚胺形成,未配对的半胱氨酸,N-末端延伸,C-末端加工,糖基化作用差异,等等。
术语“缓冲剂”或“缓冲液”表示稳定药物制剂pH的药学上可接受的赋形剂。合适的缓冲剂是本领域公知的,且可以在文献中找到的。优选的药学上可接受的缓冲液包括但不限于:组氨酸缓冲液、柠檬酸盐缓冲液、琥珀酸盐缓冲液、醋酸盐缓冲液、精氨酸缓冲液、磷酸盐缓冲液或其混合物等等。缓冲液用本领域已知的酸或碱进行pH调节,可以将pH调至在4.5-6.0范围内的值,特别是调至在4.5-5.5范围内的值,最特别地是调至pH5.2。
术语“稳定剂”表示药学可接受的赋形剂,其在制造,储存和应用过程中保护活性药物成分和/或制剂免受化学和/或物理降解。稳定剂包括但不限于糖,氨基酸,多元醇,环糊精等。
术语“表面活性剂”表示,用于保护蛋白制剂抵抗物理应力(如搅拌和剪切)的药学上可接受的赋形剂。药学上可接受的表面活性剂包括:聚氧乙烯脱水山梨糖醇脂肪酸酯(吐温)、聚氧乙烯烷基醚(例如在商标BrijTM下销售的那些)和聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆,Pluronic)。聚氧乙烯脱水山梨糖醇-脂肪酸酯包括聚山梨酯20(在商标吐温20TM下销售)和聚山梨酯80(在商标吐温80TM下销售)。
术语“联合用药物”指包含各自具有活性成分的两种或两种以上药物制剂的组合,在施用于受试者时需要联合使用。活性成分可以混合在一起形成单一的给药单元,也可分别独立成为给药单元,分别使用。
术语“有效量”指本发明的抗体或片段的药物制剂的剂量,其以单一或多次剂量施用患者后,在治疗的患者中产生预期效果。有效量可以由作为本领域技术人员的主治医师通过考虑以下多种因素来容易地确定:诸如人种差异;体重、年龄和健康状况;涉及的具体疾病;疾病的严重程度;个体患者的应答;施用的具体抗体;施用模式;施用制剂的生物利用率特征;选择的给药方案;和任何伴随疗法的使用。
术语“药盒”包括有效量的一种或多种单位剂型的本发明的药物制剂或联合用药物。在一些实施方案中,药盒可含有治疗或预防性组合物的无菌容器;这样的容器可以是盒、安瓿、瓶、小瓶、管、袋、泡罩包装或本领域已知的其它合适的容器形式。这种容器可以由塑料、玻璃、层压纸、金属箔或其他适合于保持药物的材料制成。此外,药盒还包括将本发明的药物制剂或联合用药物给予个体的说明书。说明书中通常包含使用本发明的药物制剂或联合用药物来治疗或预防疾病的方法。
生产和纯化抗体和抗原结合片段的方法在现有技术中能够熟知和获得,如冷泉港的抗体实验技术指南,5-8章和15章。
本发明工程化的抗体或其抗原结合片段可用常规方法制备和纯化。比如,编码重链和轻链的cDNA序列,可以克隆并重组至表达载体。重组的免疫球蛋白表达载体可以稳定地转染CHO细胞。作为一种更推荐的现有技术,哺乳动物类表达系统会导致抗体的糖基化,特别是在Fc区的高度保守N端。通过表达与人源抗原特异性结合的抗体得到稳定的克隆。阳性的克隆在生物反应器的无血清培养基中扩大培养以生产抗体。分泌了抗体的培养液可以用常规技术纯化、收集。抗体可用常规方法进行过滤浓缩。可溶的混合物和多聚体,也可以用常规方法去除,比如分子筛、离子交换。
本文所用的术语“个体”或“受试者”是指任何动物,例如哺乳动物或有袋动物。本发明的个体包括但不限于人类、非人类灵长类动物(例如食蟹猴或恒河猴或其他类型的猕猴)、小鼠、猪、马、驴、牛、绵羊、大鼠和任何种类的家禽。
本文所用的术语“肿瘤”指的是一种以细胞或组织的病理性增生为特征的疾病,及其随后的迁移或侵袭其他组织或器官。肿瘤生长通常是不受控制的和进行性的,不诱导或抑制正常细胞增殖。肿瘤可影响多种细胞、组织或器官,包括但不限于选自膀胱、骨、脑、乳腺、软骨、神经胶质细胞、食管、输卵管、胆囊、心脏、肠、肾、肝、肺、淋巴结、神经组织、卵巢、胰腺、前列腺、骨骼肌、皮肤、脊髓、脾、胃、睾丸、胸腺、甲状腺、气管、输尿管、尿道、子宫、阴道器官,或组织或相应的细胞。肿瘤包括癌症,如肉瘤,癌,或浆细胞瘤(浆细胞的恶性肿瘤)。本发明所述的肿瘤,可包括,但不限于白血病(如急性白血病、急性淋巴细胞白血病、急性髓细胞性白血病,急性粒细胞白血病,急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、慢性白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、真性红细胞增多症),淋巴瘤(霍奇金病、非霍奇金病)、原发性巨球蛋白血症,重链病,实体瘤如肉瘤和癌症(如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、血管肉瘤、淋巴管内皮肉瘤,间皮瘤,尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、癌、支气管癌、髓样癌、肾细胞癌、肝癌,尼罗河管癌,绒癌、精原细胞瘤、胚胎癌、肾母细胞瘤、宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、髓母细胞瘤,颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤,听神经瘤,少突胶质瘤、神经鞘瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤)、食管癌、胆囊癌、肾癌、多发性骨髓瘤。较佳地,所述的“肿瘤”包括但不限于:胰腺癌、肝癌、肺癌、胃癌、食管癌、头颈部鳞状细胞癌、前列腺癌、结肠癌、乳腺癌、淋巴瘤、胆囊癌、肾癌、白血病、多发性骨髓瘤、卵巢癌、宫颈癌和胶质瘤。
本文所用的术语“疾病”或“病症”或“紊乱”等是指任何损害或干扰细胞、组织或器官的正常功能的改变或失调。例如,所述的“疾病”包括但不限于:肿瘤、病原体感染、自身免疫性疾病、T细胞功能障碍性疾病、或免疫耐受能力缺陷(如移植排斥)。
本文所用的术语“治疗”是指在试图改变个人或处理细胞引起的的疾病过程中的临床干预,既可以进行预防也可以在临床病理过程干预。治疗效果包括但不限于,防止疾病的发生或复发、减轻症状、减少任何疾病直接或间接的病理后果、防止转移、减慢疾病的进展速度、改善或缓解病情、缓解或改善预后等。
本文所用的术语“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,所述其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
实施例
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,通常按照常规条件或按照制造厂商所建议的条件。
实施例1:PD-L1/TGFβ双功能分子的克隆和表达
双功能分子的结构是在PD-L1抗体的重链C端连接TGFβRII蛋白的胞外区,如附图1所示。TGFβRII蛋白的胞外区全长由136个氨基酸组成,经研究发现,截短其N端的27个以下氨基酸不会影响与TGFβ细胞因子的结合能力,也不会影响其功能,并且可以改善双功能分子的稳定性,因此,优选17-27个氨基酸的截短,更优选N端截短22个氨基酸的形式,其中TGFβRII蛋白胞外区全长序列ECD(1-136)如SEQ ID NO:1所示,TGFβRII蛋白胞外区N端截短22个氨基酸序列ECD(23-136)如SEQ ID NO:2所示。
其中PD-L1抗体的轻链和重链可变区CDR序列如下:
LCDR1的序列如SEQ ID NO:9所示;
LCDR2的序列如SEQ ID NO:10所示;
LCDR3的序列如SEQ ID NO:11所示;
HCDR1的序列如SEQ ID NO:12所示;
HCDR2的序列如SEQ ID NO:13所示;
HCDR3的序列如SEQ ID NO:14所示。
PD-L1抗体的轻链可变区序列如SEQ ID NO:15所示;重链可变区序列如SEQ IDNO:16所示。
PD-L1抗体的轻链序列如SEQ ID NO:5所示;重链序列如SEQ ID NO:6所示。
不同截短形式的TGFβRII蛋白胞外区通过(G4S)xG连接到PD-L1抗体的重链C端,并且把原先抗体重链C端最后一位的K突变成A,与轻链一起,通过HEK293E或expi293细胞系统表达,得到如下表1所示的双功能分子:
表1各双功能分子结构描述
双功能分子例 | 序列描述 | N端截短氨基酸数 |
双功能分子1 | anti-PDL1-(G4S)4G-ECD(18-136,N19S) | 17 |
双功能分子2 | anti-PDL1-(G4S)4G-ECD(19-136,N19S) | 18 |
双功能分子3 | anti-PDL1-(G4S)4G-ECD(20-136) | 19 |
双功能分子4 | anti-PDL1-(G4S)4G-ECD(21-136) | 20 |
双功能分子5 | anti-PDL1-(G4S)5G-ECD(21-136) | 20 |
双功能分子6 | anti-PDL1-(G4S)5G-ECD(23-136) | 22 |
双功能分子7 | anti-PDL1-(G4S)5G-ECD(26-136) | 25 |
双功能分子8 | anti-PDL1-(G4S)5G-ECD(28-136) | 27 |
注:序列中ECD(n-136)为TGFβRII蛋白胞外区的截短形式,n为截短后起始氨基酸的序号;N19S表示第19位氨基酸突变为S。
上述双功能分子6的轻链序列如SEQ ID NO:7所示,重链与TGFβRII胞外区的N端截短形式整体的序列如SEQ ID NO:8所示。
在细胞中表达的双功能分子通过实施例2进行纯化,所得蛋白可用于下述各实验中。
实施例2:PD-L1/TGFβ双功能分子的纯化
细胞培养液4500g离心30min收集上清,并用0.22μm滤膜过滤。使用MabSelectSuRe Protein A柱子(GE Healthcare)纯化上清;平衡缓冲液为1×PBS,平衡10个柱体积,将细胞上清上样与Protein A结合,上样结束后,用含有0.1%Triton X100和0.1%TritonX114的1×PBS冲洗10个柱体积的柱子,后用1×PBS冲洗10个柱体积的柱子,然后用100mM醋酸钠(pH3.5)洗脱缓冲液冲洗柱子,根据A280紫外吸收峰来收集洗脱样品,收集的洗脱样品用1M Tris-HCl(pH9.0)中和。
将中和后的洗脱样品用0.22μm滤膜过滤、超滤浓缩后用HiLoadTM26/600SuperdexTM200pg(GE Healthcare)进行分子筛层析,缓冲液为1×PBS,据A280紫外吸收合并目的蛋白峰。收集的蛋白样品经SEC-HPLC鉴定纯度大于95%;收集的蛋白样品采用LAL(Endosafe nexgen-PTS)法检测内毒素,结果小于1EU/mg。
另外下述实验中的PD-L1单抗的轻链序列如SEQ ID NO:5所示;重链序列如SEQ IDNO:6所示。下述实验中阳性对照分子为SHR-1701,其为恒瑞医药的靶向PD-L1和TGFβ的双功能分子,序列参见专利WO2018205985A1,具体来说,其轻链序列如SEQ ID NO:3所示,重链与TGFβRII胞外区的N端截短形式整体的序列如SEQ ID NO:4所示。也按照上述方法进行表达纯化。
以下实施例3-5为结合活性评价实验,实施例6-7为细胞功能评价实验,实施例8为药代动力学评价实验,实施例9-10为体内药效评价实验。
实施例3:ELISA检测PD-L1/TGFβ双功能分子结合人源PD-L1实验
实验过程描述如下:
a)使用人源PD-L1蛋白(购自sinobiological,货号10084-H08H)按1μg/mL的浓度包被96孔板,每孔100μL,4℃放置过夜;
b)每孔200μLPBST洗板3次,加入200μL封闭试剂1%BSA,37℃孵育1.5小时;
c)每孔200μLPBST洗板3次,加入100μL逐级梯度稀释的PD-L1/TGFβ双功能分子、阳性对照SHR-1701和PD-L1单抗,室温孵育2小时;
d)每孔300μLPBST洗板3次,加入100μL羊抗人Fc(HRP)二抗(购自abcam,货号ab98624),1:20000稀释,室温孵育1小时;
e)每孔300μLPBST洗板6次,加入100μLTMB,避光放置6分钟后,加入100μL终止液停止显色反应;
f)MD公司的M5读板仪检测450nm波长的吸光度值,并使用softmax软件处理数据。
ELISA结合的实验结果如图2所示,双功能分子6保留了对人源PD-L1的结合活性,并且与阳性对照分子结合能力相当。
实施例4:ELISA检测PD-L1/TGFβ双功能分子结合人源TGFβ1实验
实验过程描述如下:
a)使用人源TGFβ1蛋白(购自CST,货号#8915)按1μg/mL的浓度包被96孔板,每孔100μL,4℃放置过夜;
b)每孔200μLPBST洗板3次,加入200μL封闭试剂1%BSA,37℃孵育1.5小时;
c)每孔200μLPBST洗板3次,加入100μL逐级梯度稀释的PD-L1/TGFβ双功能分子、阳性对照SHR-1701和PD-L1单抗,室温孵育2小时;
d)每孔300μLPBST洗板3次,加入100μL羊抗人Fc(HRP)二抗(购自abcam,货号ab98624),1:20000稀释,室温孵育1小时;
e)每孔300μLPBST洗板6次,加入100μLTMB,避光放置6分钟后,加入100μL终止液停止显色反应;
f)MD公司的M5读板仪检测450nm波长的吸光度值,并使用softmax软件处理数据。
ELISA结合的实验结果如图3所示,双功能分子6结合人源TGFβ1蛋白的能力与阳性对照分子相当。
实施例5:Biacore检测PD-L1/TGFβ双功能分子与抗原的亲和力和动力学性质
使用Biacore 8K仪器分析双功能分子与人源PD-L1和人源TGFβ1的亲和力和动力学性质。CM5芯片先用EDC和NHS活化,然后固定抗人Fc的鼠单抗,再用乙醇胺封闭。
为测定与人源PD-L1的亲和力与动力学性质,双功能分子用HBS-EP+(10mM HEPES,pH 7.4,150mM NaCl,3mM EDTA,0.05%P20)缓冲液稀释至5μg/mL,以10μL/min的流速捕获30s。人源PD-L1两倍逐级稀释至系列浓度(5nM-0.078nM),以30μL/min的流速结合180s,解离300s。
为测定与人源TGFβ1的亲和力与动力学性质,双功能分子用HBS-EP+缓冲液稀释至1μg/mL,以10μL/min的流速捕获60s。人源TGFβ1两倍逐级稀释至系列浓度(2nM-0.00156nM),以30μL/min的流速结合120s,解离1200s。
每一轮实验结束后,使用3M MgCl2溶液冲洗以30μL/min的流速冲洗30s,将捕获的抗体连同抗原一起去除,完成芯片的再生。原始数据使用Biacore Insight EvaluationSoftware(version 2.0.15.12933)软件进行分析,拟合模型使用1:1,实验数据如图4所示,得到的亲和力和动力学性质如下表2所示,结果显示双功能分子6对于人源PD-L1和人源TGFβ1有很高的亲和力。
表2双功能分子6各项亲和力数据
Ligand(配体) | Analyte(分析物) | ka(1/Ms) | kd(1/s) | KD(M) |
双功能分子6 | 人源PD-L1 | 1.41E+06 | 7.44E-04 | 5.26E-10 |
双功能分子6 | 人源TGFβ1 | 7.44E+08 | 3.65E-04 | 4.90E-13 |
实施例6:检测双功能分子阻断PD-1/PD-L1信号通路的实验
通过报告基因法检测分子的生物学活性,以转染了PD-L1和anti-CD3-单链抗体片段(scFv)的CHO细胞作为靶细胞,以转染了PD-1和受NFAT元件调控的荧光素酶(luciferase)基因的Jurkat细胞作为效应细胞。CHO细胞膜上的anti-CD3-scFv与Jurkat细胞表面的CD3结合后,会向Jurkat细胞呈递激活信号,从而表达荧光素酶;CHO细胞表面的PD-L1在与Jurkat细胞表面的PD-1结合后向Jurkat细胞递送抑制信号,抑制荧光素酶的表达;而双功能分子可以阻断PD-1与PD-L1的结合,从而解除抑制信号的递送,恢复荧光素酶的表达,产生荧光信号。
实验过程描述如下:
a)收取CHO-PDL1-CD3L细胞,清洗并重悬至4E5个细胞/mL;
b)在96孔板中每孔加入100μL细胞悬液,在37℃,5%CO2细胞培养箱中孵育过夜;
c)将待测分子从200nM起两倍逐级稀释10个浓度点;
d)收取Jurkat-PD1-NFAT细胞,清洗并重悬至1E6个细胞/mL;
e)把放置CHO-PDL1-CD3L细胞的96孔板从培养箱中取出,每孔移除95μL上清,加入50μL待测分子溶液;
f)加入50μL Jurkat-PD1-NFAT细胞,在37℃,5%CO2细胞培养箱中孵育6h;
g)每孔加入50μL Bio-Glo Luciferase染色液,读取化学发光信号。
结果如图5所示,双功能分子6对于PD-1/PD-L1的阻断能力与阳性对照分子SHR-1701相当,也与PD-L1单抗的阻断能力相当。
实施例7:检测双功能分子阻断TGFβ/SMAD信号通路的实验
购自BPS Bioscience公司的SBE Reporter-HEK293细胞系用于TGFβ/SMAD信号通路的活性监控。TGFβ蛋白与细胞表面受体结合,启动信号级联反应,导致SMAD2和SMAD3磷酸化和活化,然后与SMAD4形成复合物。SMAD复合物随后转移到细胞核并与细胞核中的SMAD结合元件(SBE)结合,导致TGFβ/SMAD反应基因的转录和表达,其中就包括转染进细胞的荧光素酶基因,从而产生荧光信号。双功能分子含有TGFβRII融合蛋白,能够阻止TGFβ蛋白与细胞表面受体结合,进而抑制荧光信号的表达。
实验过程描述如下:
a)在96孔板的每个孔内加入25,000个SBEReporter-HEK293细胞;
b)在37℃,5%CO2细胞培养箱中孵育24h;
c)加入逐级稀释的不同浓度的抗体分子;
d)4个小时后加入TGFβ蛋白,终浓度10ng/mL;
e)在37℃,5%CO2细胞培养箱中孵育过夜
f)每孔加入100μL ONE-StepTM Luciferase试剂,在室温震荡15-30min,读取荧光信号。
结果如图6所示,多个双功能分子对TGFβ/SMAD信号通路的阻断能力相似,且与阳性对照分子SHR-1701相当。
实施例8:食蟹猴药代动力学实验
每个分子的药代实验均使用从未给过药物的食蟹猴两只,一雌一雄,给药前禁食12小时以上,给药后禁食4小时,自由饮水。双功能分子和阳性对照的给药剂量为10mg/kg,30min完成静脉输注。采血时间点为Pre-dose,30min,1hr,6hr,24hr,2d,4d,7d,10d,14d,21d,28d,35d,42d。采集全血后常温静置半小时,离心取上清(6000转,8分钟,4℃)收集血清,离心后将血清分装,-80℃冻存。
采用ELISA法检测血清中药物分子的浓度,检测过程描述如下:
a)使用人源PD-L1蛋白按1μg/mL的浓度包被96孔板,每孔100μL,4℃放置过夜;
b)每孔200μL PBST洗板3次,加入300μL封闭试剂5%奶粉,37℃孵育1小时;
c)每孔200μL PBST洗板3次,加入100μL标准品、QC和待测样品,37℃孵育1小时;
d)每孔300μL PBST洗板6次,加入100μL anti-human TGFβRII biotinylatedantibody(购自R&D,货号BAF241),1:5000稀释,37℃孵育1小时;
e)每孔300μL PBST洗板6次,加入100μL Streptavidin HRP(购自BD,货号554066),1:10000稀释,37℃孵育1小时;
f)每孔300μL PBST洗板6次,加入100μL TMB,避光放置6分钟后,加入100μL终止液停止显色反应;
g)MD公司的M5读板仪检测450nm波长的吸光度值,并使用softmax软件处理数据。
采用Phoenix Winnolin软件对测得的的猴血清浓度进行计算,得到药代参数,如下表3所示。
表3双功能分子6的猴血清浓度和PK参数
表中浓度的单位均为μg/mL,BLQ为低于检测限。
表4阳性对照的猴血清浓度和PK参数
上表中浓度的单位均为μg/mL,BLQ为低于检测限。
结果显示双功能分子在猴体内的半衰期约为164小时,由于PD-L1是一个内化速率比较快的靶点,双功能分子在体内存在靶点介导的药物清除,且存在一定的免疫原性,因此双功能分子药代性质良好,在食蟹猴体内性质稳定,不存在明显的脱靶结合。
同时,我们发现双功能分子6在猴体内的半衰期是阳性对照分子SHR-1701(见表4)的两倍。原因可能在于,双功能分子6是IgG1亚型,而阳性对照是IgG4亚型,而一般认为,IgG1亚型的抗体比IgG4亚型的抗体在体内的性质更加稳定。因此,双功能分子6有望在后续的临床实验中取得比阳性对照更长的半衰期,进一步降低给药频率和用药成本。
实施例9:人乳腺癌MDA-MB-231小鼠皮下移植瘤模型评价双功能分子的抑瘤率实验
本实验评价受试药物在人乳腺癌细胞MDA-MB-231混合PBMC皮下移植NCG小鼠中的抗肿瘤作用。
MDA-MB-231细胞培养在含10%胎牛血清(FBS)的L-15培养液中。收集对数生长期的MDA-MB-231细胞,HBSS重悬至适合浓度用于NCG小鼠皮下肿瘤接种。取正常人外周血,用密度梯度离心法分离人PBMC,将分离的PBMC加入经MitomycinC处理的MDA-MB-231细胞中,PBMC与MDA-MB-231细胞共培养6天,培养液为含IL-2和10%FBS的RPMI1640培养液。培养6天后,收取培养的PBMC,将PBMC与新鲜消化下来的MDA-MB-231细胞混合接种于64只NCG小鼠(江苏集萃药康生物科技有限公司)右侧皮下,每组8只,共8组。接种后,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5,分组给药当天为第0天。
表5各组给药方案
每周两次使用游标卡尺测量肿瘤体积,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。肿瘤生长抑制率TGI(%)=[1-(Ti-T0)/(Vi-V0)]×100,其中Ti为化合物组开始给药后的平均肿瘤体积,T0为化合物组首次给药时的平均肿瘤体积,V0为溶媒对照组首次给药时的平均肿瘤体积,Vi为溶媒对照组开始给药后的平均肿瘤体积。所有荷瘤鼠体重每周测量两次。同时计算给药后小鼠体重增长变化率:体重变化用公式RCBW%=(BWi–BW0)/BW0×100%,BWi是小鼠当前体重,BW0是分组当日的小鼠体重。实验结束后,称量肿瘤块的重量,并拍照。结果见下表6:
表6各组实验结果
肿瘤称重的结果如图7所示。可以看到,双功能分子6有明显的抑瘤作用,5mg/kg、10mg/kg和20mg/kg的剂量下,抑瘤率分别为59.92%、62.78%和71.48%,抑瘤率随着剂量的增加而提高。在等摩尔剂量的水平,双功能分子6的药效优于PD-L1单抗,也优于PD-L1单抗与TGFbRII融合蛋白的联用。同时,双功能分子6给药组没有出现小鼠的死亡,且小鼠的体重稳步增长,显示双功能分子6在小鼠体内安全性良好。
实施例10:人结肠癌MC-38小鼠皮下移植瘤模型评价双功能分子的抑瘤率实验
本实验评价双功能分子对PD-L1人源化小鼠MC38(人源化PD-L1)结肠癌模型的肿瘤抑制作用,并与阳性对照抗体SHR-1701进行对比。
将MC38(人源化PDL1)细胞以1×106个/0.1mL接种于PD-L1人源化小鼠的右侧腋窝皮下,共60只。当平均肿瘤体积达到60-120mm3时,挑选40只肿瘤体积适中小鼠入组,按照肿瘤体积大小随机分为5组(每组8只):第一组为IgG1同型抗体(20mg/kg)、第二组为双功能分子6(5mg/kg)、第三组为双功能分子6(10mg/kg)、第四组为双功能分子6(20mg/kg)、第五组为阳性对照SHR-1701(20mg/kg)。动物分组当天开始给药,给药体积均为10mL/kg,给药方式为腹腔注射(ip)。每周给药2次,共给药6次。
试验过程中,持续观察实验动物体重及肿瘤生长状态,每周两次测量肿瘤并称量体重,计算肿瘤体积及肿瘤生长抑制率。试验终点(末次给药后第4天)时采集肿瘤组织并拍照,称量肿瘤组织重量并计算瘤重抑制率(见图8)。
结果显示,试验期间各组动物体重稳定增长,未观察到受试药物对动物的日常活动和体重有明显的影响。如图8所示,肿瘤生长曲线表明,双功能分子6在5、10和20mg/kg剂量下均可以显著抑制MC38肿瘤模型的生长(P<0.01),且表现出明显的剂量依赖性,试验终点时的肿瘤生长抑制率分别为41.0%、52.9%和60.8%。同时双功能分子6与阳性对照抗体SHR-1701在同等剂量(20mg/kg)下,肿瘤抑制作用相当(P>0.05),其TGI分别为60.8%和63.2%。
试验终点时肿瘤组织重量表明,双功能分子6在5、10和20mg/kg剂量下均可以显著肿瘤组织的生长(P<0.01),且表现出明显的剂量依赖性,其肿瘤重量抑制率分别为43.2%、54.4%和64.8%。同时,双功能分子6与阳性对照抗体SHR-1701在同等剂量(20mg/kg)下表现出相似的抗肿瘤活性(P>0.05),其肿瘤重量抑制率(IR%)分别为64.8%和61.0%。
序列表
<110> 上海齐鲁制药研究中心有限公司
<120> 同时靶向PD-L1和TGFβ的双功能分子及其医药用途
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Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Phe
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 4
<211> 584
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 4
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Gly Pro Asn Ser Gly Phe Thr Ser Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Gly Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp
465 470 475 480
Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys
485 490 495
Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val
500 505 510
Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp
515 520 525
Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro
530 535 540
Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met
545 550 555 560
Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu
565 570 575
Glu Tyr Asn Thr Ser Asn Pro Asp
580
<210> 5
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 5
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile His Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Leu Leu Val
35 40 45
Tyr Gly Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Gln Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
85 90 95
Tyr Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser 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 Asn 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> 6
<211> 445
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Phe
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Gly Thr Ile Asn Tyr Asp Glu Lys Phe
50 55 60
Arg Ser Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Gly Trp Asp Gly Glu His Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 7
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 7
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile His Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Leu Leu Val
35 40 45
Tyr Gly Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Gln Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
85 90 95
Tyr Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser 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 Asn 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> 8
<211> 585
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 8
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Phe
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Gly Thr Ile Asn Tyr Asp Glu Lys Phe
50 55 60
Arg Ser Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Gly Trp Asp Gly Glu His Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Lys Phe Pro Gln Leu Cys Lys Phe Cys
465 470 475 480
Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn
485 490 495
Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala
500 505 510
Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His
515 520 525
Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser
530 535 540
Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe
545 550 555 560
Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser
565 570 575
Glu Glu Tyr Asn Thr Ser Asn Pro Asp
580 585
<210> 9
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 9
Arg Ala Ser Glu Asn Ile His Ser Asn Leu Ala
1 5 10
<210> 10
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 10
Gly Ala Thr Asn Leu Ala Asp
1 5
<210> 11
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 11
Gln His Phe Trp Gly Thr Pro Pro Tyr Ala
1 5 10
<210> 12
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 12
Thr Phe Trp Met His
1 5
<210> 13
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 13
Asn Ile Tyr Pro Gly Ser Gly Thr Ile Asn Tyr Asp Glu Lys Phe Arg
1 5 10 15
Ser
<210> 14
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 14
Gly Trp Asp Gly Glu His
1 5
<210> 15
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 15
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile His Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Leu Leu Val
35 40 45
Tyr Gly Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Gln Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Pro
85 90 95
Tyr Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 16
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的蛋白
<400> 16
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Phe
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Gly Ser Gly Thr Ile Asn Tyr Asp Glu Lys Phe
50 55 60
Arg Ser Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Gly Trp Asp Gly Glu His Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
Claims (14)
1.一种同时靶向PD-L1和TGFβ的双功能分子,其特征在于:包含靶向PD-L1的部分和TGF-β受体部分,所述的靶向PD-L1的部分为PD-L1抗体,所述的TGF-β受体部分为TGF-β受体2TGFβRII胞外区的N端截短形式,所述PD-L1抗体的每个重链C端均连接一个TGFβRII胞外区的N端截短形式,所述PD-L1抗体的轻链和重链可变区CDR序列如下:
LCDR1的序列如SEQ ID NO:9所示;
LCDR2的序列如SEQ ID NO:10所示;
LCDR3的序列如SEQ ID NO:11所示;
HCDR1的序列如SEQ ID NO:12所示;
HCDR2的序列如SEQ ID NO:13所示;
HCDR3的序列如SEQ ID NO:14所示;
所述的TGFβRII胞外区的全长序列如SEQ ID NO:1所示,N端截短形式为17-27个氨基酸的截短。
2.如权利要求1所述的双功能分子,其特征在于:所述的TGF-β受体部分的序列如SEQID NO:2所示。
3.如权利要求1-2任一项所述的双功能分子,其特征在于:所述PD-L1抗体的轻链可变区序列如SEQ ID NO:15所示;重链可变区序列如SEQ ID NO:16所示。
4.如权利要求1-2任一项所述的双功能分子,其特征在于:所述PD-L1抗体的轻链序列如SEQ ID NO:5所示;重链序列如SEQ ID NO:6所示,并且重链C末端最后一位的K突变成A。
5.如权利要求1-2任一项所述的双功能分子,其特征在于:所述PD-L1抗体的重链C端通过连接肽连接TGFβRII胞外区的N端截短形式。
6.如权利要求5所述的双功能分子,其特征在于:所述连接肽为(G4S)XG,所述x为3-6。
7.如权利要求1-2任一项所述的双功能分子,其特征在于:所述PD-L1抗体的轻链序列如SEQ ID NO:7所示,重链与TGFβRII胞外区的N端截短形式整体的序列如SEQ ID NO:8所示。
8.一种药物组合物,其特征在于:包含权利要求1-7任一项所述的双功能分子以及药学上可接受载体。
9.一种核酸分子,其特征在于:编码权利要求1-7任一项所述的双功能分子。
10.一种表达载体,其特征在于:其含有权利要求9所述的核酸分子。
11.一种宿主细胞,其特征在于:其包含权利要求10所述的表达载体,所述宿主细胞选自细菌、酵母菌和哺乳动物细胞。
12.如权利要求11所述的宿主细胞,其特征在于:所述宿主细胞选自HEK293E细胞、expi293或CHO细胞。
13.权利要求1-7任一项所述的双功能分子在用于制备治疗癌症的药物中的用途;所述癌症为PD-L1阳性的肿瘤。
14.如权利要求13所述的用途,其特征在于:所述癌症选自肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌和头颈肿瘤。
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WO2016161410A2 (en) * | 2015-04-03 | 2016-10-06 | Xoma Technology Ltd. | Treatment of cancer using inhibitors of tgf-beta and pd-1 |
CN106103488A (zh) * | 2014-02-10 | 2016-11-09 | 默克专利有限公司 | 靶向TGFβ抑制 |
CN109641963A (zh) * | 2016-08-12 | 2019-04-16 | 默克专利有限公司 | 癌症的联合治疗 |
CN110050000A (zh) * | 2017-05-12 | 2019-07-23 | 江苏恒瑞医药股份有限公司 | 含有TGF-β受体的融合蛋白及其医药用途 |
WO2020127369A1 (en) * | 2018-12-21 | 2020-06-25 | Ose Immunotherapeutics | Bifunctional molecule directed against human pd-1 |
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CN106103488A (zh) * | 2014-02-10 | 2016-11-09 | 默克专利有限公司 | 靶向TGFβ抑制 |
WO2016161410A2 (en) * | 2015-04-03 | 2016-10-06 | Xoma Technology Ltd. | Treatment of cancer using inhibitors of tgf-beta and pd-1 |
CN108136001A (zh) * | 2015-04-03 | 2018-06-08 | 佐马技术有限公司 | 使用TGF-β抑制剂和PD-1抑制剂治疗癌症 |
CN109641963A (zh) * | 2016-08-12 | 2019-04-16 | 默克专利有限公司 | 癌症的联合治疗 |
CN110050000A (zh) * | 2017-05-12 | 2019-07-23 | 江苏恒瑞医药股份有限公司 | 含有TGF-β受体的融合蛋白及其医药用途 |
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