CN113999313A - 抗her2抗体及其应用 - Google Patents
抗her2抗体及其应用 Download PDFInfo
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- CN113999313A CN113999313A CN202110852970.4A CN202110852970A CN113999313A CN 113999313 A CN113999313 A CN 113999313A CN 202110852970 A CN202110852970 A CN 202110852970A CN 113999313 A CN113999313 A CN 113999313A
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Abstract
本发明提供了抗HER2抗体及其应用,本发明提供的抗体可以用于治疗HER2阳性疾病,也可以用于诊断或预后HER2阳性疾病。本发明抗体BAT0303F是由敲除岩藻糖转移酶的宿主细胞表达,可增强抗体的ADCC效应。
Description
技术领域
本发明属于生物医药技术领域,尤其涉及抗HER2抗体及其应用。
背景技术
人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2,又称ErbB-2)是一种单链跨膜糖蛋白,分子量为185KD;胞外部分为配体结合区,其包含I-IV四个子区域,静息状态下的胞外段的空间位置表现为类似配体结合后的活化状态,在缺乏高亲和力的天然配体下使其成为二聚体分子,胞内部分具有酪氨酸激酶活性。HER2(即HER-2)是HER/erbB家族成员之一,该家族还包括HER1(即ErbB1或EGFR)、HER3(ErbB3)和HER4(ErbB4)。HER2编码基因位于17号染色体,其编码I型跨膜生长因子受体酪氨酸激酶。在HER/erbB家族受体活化过程中,其胞外段与配体结合后,诱导受体二聚体形成,激活胞内酪氨酸激酶,活化以Ras/Raf/MEK/Erk及P13K/Akt为主的下游信号通路,并参与细胞增殖、凋亡调控等生物学功能。肿瘤中过表达的HER2可与自身,或在配体缺失的情况下与家族其他成员形成二聚体或异二聚体,导致肿瘤细胞内信号通路的异常活化。
正常机体组织中,HER2受体主要在胚胎发育期表达,成年后只在少数成熟机体组织中低表达。研究发现,25%-30%乳腺癌、约20%胃癌、约10%的卵巢癌细胞中过表达HER2。
曲妥珠单抗可以选择性地作用于HER-2蛋白的细胞外IV区,并抑制肿瘤血管的形成,延缓肿瘤生长和进展。目前研究认为曲妥珠单抗的作用机制为:(1)结合Fc-γ受体,从而激活抗体介导细胞的细胞毒作用(antibody dependent cell mediated cytotoxicity,ADCC),产生机体免疫,杀伤HER-2阳性的肿瘤细胞;(2)通过作用于HER-2受体的胞外结构域,抑制HER-2受体自身的同源二聚化,从而阻断受体下游信号的转导,抑制肿瘤细胞存活与增殖;(3)通过抑制肿瘤血管表皮生长因子的形成,降低肿瘤血管的密度;(4)诱导HER-2阳性的癌细胞的自身降解死亡;(5)作用于PI3K-AKT信号途径,从而阻断肿瘤细胞下游信号的转导;(6)通过抑制P27kipl的形成来减少细胞周期蛋白D1的表达,促进细胞凋亡并使细胞周期停滞。帕妥珠单抗作为一种新型的人源化单克隆抗体,与曲妥珠单抗的作用位点(IV区)不同,帕妥珠单抗与HER-2受体胞外结构域Ⅱ区进行结合,阻断HER-2与其他EGFR受体家族的异源二聚化作用,抑制与HER-2受体活性相关的肿瘤细胞的增殖与生存。
发明内容
本发明提供了可以特异性结合HER2的抗体。本发明提供的抗体可以用于治疗HER2阳性疾病,也可以用于诊断或预后HER2阳性疾病。
在一些实施方案中,所述抗体为ADCC效应增强的抗HER2抗体,用于靶向病患的细胞或组织,增强药物的抗肿瘤疗效。在一些实施方案中,所述抗体中岩藻糖基化水平不高于10%。在一些实施方案中,所述抗体中岩藻糖基化水平为约0、约1%、约2%、约3%、约6%、约7%、约8%、约9%、约10%,或这些数值中的任何两个之间的范围(包括端点)或其中任何值。
一些实施方案中提供了一种抗体,所述抗体特异性结合HER2,并且包含:(a)HCDR1,其包含SEQ ID NO:1所示的序列,或与SEQ ID NO:1所示序列相比具有1个或2个保守氨基酸取代的序列;(b)HCDR2,其包含SEQ ID NO:2所示的序列,或与SEQ ID NO:2所示序列相比具有1个或2个保守氨基酸取代的序列;(c)HCDR3,其包含SEQ ID NO:3所示的序列,或与SEQ ID NO:3所示序列相比具有1个或2个保守氨基酸取代的序列;(d)LCDR1,其包含SEQID NO:4所示的序列,或与SEQ ID NO:4所示序列相比具有1个或2个保守氨基酸取代的序列;(e)LCDR2,其包含SEQ ID NO:5所示的序列,或与SEQ ID NO:5所示序列相比具有1个或2个保守氨基酸取代的序列;(f)LCDR3,其包含SEQ ID NO:6所示的序列,或与SEQ ID NO:6所示序列相比具有1个或2个保守氨基酸取代的序列;
所述抗体的岩藻糖基化水平为0%-5%。
在一些实施方案中,所述抗体包含:(a)HCDR1,其包含SEQ ID NO:1所示的序列,(b)HCDR2,其包含SEQ ID NO:2所示的序列,(c)HCDR3,其包含SEQ ID NO:3所示的序列,(d)LCDR1,其包含SEQ ID NO:4所示的序列,(e)LCDR2,其包含SEQ ID NO:5所示的序列,(f)LCDR3,其包含SEQ ID NO:6所示的序列。
在一些实施方案中,所述抗体的重链可变区包含如SEQ ID NO:7所示的序列,与SEQ ID NO:7所示序列具有至少80%同一性的序列,或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链可变区包含SEQ ID NO:8所示的序列,与SEQ ID NO:8所示序列具有至少80%同一性的序列,或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的序列。
在一些实施方案中,所述抗体的重链可变区包含如SEQ ID NO:7所示的序列,所述抗体的轻链可变区包含SEQ ID NO:8所示的序列。
在一些实施方案中,所述抗体的重链包含如SEQ ID NO:9所示的序列,与SEQ IDNO:9所示序列具有至少80%同一性的序列,或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链包含SEQ ID NO:10所示的序列,与SEQ ID NO:10序列具有至少80%同一性的序列,或与SEQ ID NO:10序列相比具有一个或多个保守氨基酸取代的序列。
在一些实施方案中,所述抗体的重链包含如SEQ ID NO:9所示的序列,所述抗体的轻链包含SEQ ID NO:10所示的序列。
在一些实施方案中,所述抗体的岩藻糖基化水平为约0、约1%、约2%、约3%、约4%、约5%,或这些数值中的任何两个之间的范围(包括端点)或其中任何值。在一些实施方案中,所述抗体的岩藻糖基化水平为约0。在一些实施方案中,所述抗体没有结合岩藻糖。
在一些实施方案中,所述抗体为单克隆抗体。在一些实施方案中,所述抗体为重组人源化单克隆抗体。在一些实施方案中,所述抗体为重组人源化的IgG1单克隆抗体。
在一些实施方案中,所述抗体由CHO细胞、HEK293F细胞、Cos1细胞、Cos7细胞、CV1细胞或鼠L细胞表达。在一些实施方案中,所述抗体由敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞、HEK293F细胞、Cos1细胞、Cos7细胞、CV1细胞或鼠L细胞表达。在一些实施方案中,所述抗体由敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞表达。抗HER2抗体可通过常规方法进行纯化,如低速离心使细胞和培养基分离,高速离心上清液,并依次进行蛋白A亲和纯化和离子交换纯化。
本发明还提供一种抗体,并且包含:(a)HCDR1,其包含SEQ ID NO:1所示的序列,或与SEQ ID NO:1所示序列相比具有1个或2个保守氨基酸取代的序列;(b)HCDR2,其包含SEQID NO:2所示的序列,或与SEQ ID NO:2所示序列相比具有1个或2个保守氨基酸取代的序列;(c)HCDR3,其包含SEQ ID NO:3所示的序列,或与SEQ ID NO:3所示序列相比具有1个或2个保守氨基酸取代的序列;(d)LCDR1,其包含SEQ ID NO:4所示的序列,或与SEQ ID NO:4所示序列相比具有1个或2个保守氨基酸取代的序列;(e)LCDR2,其包含SEQ ID NO:5所示的序列,或与SEQ ID NO:5所示序列相比具有1个或2个保守氨基酸取代的序列;(f)LCDR3,其包含SEQ ID NO:6所示的序列,或与SEQ ID NO:6所示序列相比具有1个或2个保守氨基酸取代的序列;
所述抗体包含不低于60%的G0。
在一些实施方案中,所述抗体包含:(a)HCDR1,其包含SEQ ID NO:1所示的序列,(b)HCDR2,其包含SEQ ID NO:2所示的序列,(c)HCDR3,其包含SEQ ID NO:3所示的序列,(d)LCDR1,其包含SEQ ID NO:4所示的序列,(e)LCDR2,其包含SEQ ID NO:5所示的序列,(f)LCDR3,其包含SEQ ID NO:6所示的序列。
在一些实施方案中,所述抗体的重链可变区包含如SEQ ID NO:7所示的序列,与SEQ ID NO:7所示序列具有至少80%同一性的序列,或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链可变区包含SEQ ID NO:8所示的序列,与SEQ ID NO:8所示序列具有至少80%同一性的序列,或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的序列。
在一些实施方案中,所述抗体的重链可变区包含如SEQ ID NO:7所示的序列,所述抗体的轻链可变区包含SEQ ID NO:8所示的序列。
在一些实施方案中,所述抗体的重链包含如SEQ ID NO:9所示的序列,与SEQ IDNO:9所示序列具有至少80%同一性的序列,或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链包含SEQ ID NO:10所示的序列,与SEQ ID NO:10序列具有至少80%同一性的序列,或与SEQ ID NO:10序列相比具有一个或多个保守氨基酸取代的序列。
在一些实施方案中,所述抗体的重链包含如SEQ ID NO:9所示的序列,所述抗体的轻链包含SEQ ID NO:10所示的序列。
在一些实施方案中,所述抗体包含不低于60%的G0。在一些实施方案中,G0糖型的含量为约61%、约62%、约63%、约65%、约68%、约71%、约72%、约73%、约74%、约75%,或这些数值中任何两个之间的范围(包括端点)或其中任何值。在一些实施方案中,G0糖型的含量为61%-75%。在一些实施方案中,G0糖型的含量为约72%-73%。
在一些实施方案中,G0-GN糖型的含量为4%-7%。在一些实施方案中,G0-GN糖型的含量为约4%、约5%、约6%、约7%,或这些数值中任何两个之间的范围(包括端点)或其中任何值。在一些实施方案中,G0-GN糖型的含量为5%-6%。
在一些实施方案中,G1糖型的含量为8%-12%。在一些实施方案中,G1糖型的含量为约8%、约9%、约10%、约11%、约12%,或这些数值中任何两个之间的范围(包括端点点)或其中任何值。在一些实施方案中,G1糖型的含量为8%-9%。
在一些实施方案中,G1'糖型的含量为6%-12%。在一些实施方案中,G1'糖型的含量为约6%、约7%、约8%、约9%、约10%、约11%、约12%,或这些数值中任何两个之间的范围(包括端点)或其中任何值。在一些实施方案中,G1'糖型的含量为8%-9%。
在一些实施方案中,G2糖型的含量不高于3%。在一些实施方案中,G2糖型的含量为不高于2%、不高于1%。在一些实施方案中,G2糖型的含量为约0-1%。
在一些实施方案中,G0糖型的含量为61%-75%,G0-GN糖型的含量为4%-7%,G1'糖型的含量为6%-12%,G1糖型的含量为8%-12%,G2糖型的含量不高于3%。在一些实施方案中,G0糖型的含量为约72%-73%,G0-GN糖型的含量为约5%-6%,G1糖型的含量为8%-9%,G1'糖型的含量为8%-9%,G2糖型的含量为约0-1%。
在一些实施方案中,所述抗体由CHO细胞、HEK293F细胞、Cos1细胞、Cos7细胞、CV1细胞或鼠L细胞表达。在一些实施方案中,所述抗体由敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞、HEK293F细胞、Cos1细胞、Cos7细胞、CV1细胞或鼠L细胞表达。在一些实施方案中,所述抗体由敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞表达。抗HER2抗体可通过常规方法进行纯化,如低速离心使细胞和培养基分离,高速离心上清液,并依次进行蛋白A亲和纯化和离子交换纯化。
本发明还提供了一种抗体组合物,抗体组合物中抗体特异性结合HER2,并且包含:(a)HCDR1,其包含SEQ ID NO:1所示的序列,或与SEQ ID NO:1所示序列相比具有1个或2个保守氨基酸取代的序列;(b)HCDR2,其包含SEQ ID NO:2所示的序列,或与SEQ ID NO:2所示序列相比具有1个或2个保守氨基酸取代的序列;(c)HCDR3,其包含SEQ ID NO:3所示的序列,或与SEQ ID NO:3所示序列相比具有1个或2个保守氨基酸取代的序列;(d)LCDR1,其包含SEQ ID NO:4所示的序列,或与SEQ ID NO:4所示序列相比具有1个或2个保守氨基酸取代的序列;(e)LCDR2,其包含SEQ ID NO:5所示的序列,或与SEQ ID NO:5所示序列相比具有1个或2个保守氨基酸取代的序列;(f)LCDR3,其包含SEQ ID NO:6所示的序列,或与SEQ IDNO:6所示序列相比具有1个或2个保守氨基酸取代的序列;
所述抗体组合物中主峰的含量至少为72%。
在一些实施方案中,抗体组合物中抗体包含:(a)HCDR1,其包含SEQ ID NO:1所示的序列,(b)HCDR2,其包含SEQ ID NO:2所示的序列,(c)HCDR3,其包含SEQ ID NO:3所示的序列,(d)LCDR1,其包含SEQ ID NO:4所示的序列,(e)LCDR2,其包含SEQ ID NO:5所示的序列,(f)LCDR3,其包含SEQ ID NO:6所示的序列。
在一些实施方案中,所述抗体的重链可变区包含如SEQ ID NO:7所示的序列,与SEQ ID NO:7所示序列具有至少80%同一性的序列,或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链可变区包含SEQ ID NO:8所示的序列,与SEQ ID NO:8所示序列具有至少80%同一性的序列,或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的序列。
在一些实施方案中,所述抗体的重链可变区包含如SEQ ID NO:7所示的序列,所述抗体的轻链可变区包含SEQ ID NO:8所示的序列。
在一些实施方案中,所述抗体的重链包含如SEQ ID NO:9所示的序列,与SEQ IDNO:9所示序列具有至少80%同一性的序列,或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链包含SEQ ID NO:10所示的序列,与SEQ ID NO:10序列具有至少80%同一性的序列,或与SEQ ID NO:10序列相比具有一个或多个保守氨基酸取代的序列。
在一些实施方案中,所述抗体的重链包含如SEQ ID NO:9所示的序列,所述抗体的轻链包含SEQ ID NO:10所示的序列。
在一些实施方案中,抗体组合物中主峰的含量为73%-82%。在一些实施方案中,抗体组合物中主峰的含量为约73%、约74%、约75%、约76%、约77%、约78%、约79%、约80%、约81%、约82%,或这些数值中任何两个之间的范围(包括端点)或其中任何值。在一些实施方案中,抗体组合物中主峰的含量为77%-81%。
在一些实施方案中,所述抗体组合物中碱性变异体的含量不高于8%或6%。在一些实施方案中,所述抗体组合物中碱性变异体的含量为约1%、约2%、约3%、约4%、约5%、约6%、约7%、约8%,或这些数值中任何两个之间的范围(包括端点)或其中任何值。在一些实施方案中,所述抗体组合物中碱性变异体的含量为1%-6%。在一些实施方案中,所述抗体组合物中碱性变异体的含量为2%-5%。在一些实施方案中,所述抗体组合物中碱性变异体的含量为1%-4%。
在一些实施方案中,所述抗体由CHO细胞、HEK293F细胞、Cos1细胞、Cos7细胞、CV1细胞或鼠L细胞表达。在一些实施方案中,所述抗体由敲除了α-(1,6)-岩藻糖转移酶的CHO细胞、HEK293F细胞、Cos1细胞、Cos7细胞、CV1细胞或鼠L细胞表达。在一些实施方案中,所述抗体由敲除了α-(1,6)-岩藻糖转移酶的CHO细胞表达。抗HER2抗体可通过常规方法进行纯化,如低速离心使细胞和培养基分离,高速离心上清液,并依次进行蛋白A亲和纯化和离子交换纯化。
在一些实施方案中,所述抗体为BAT0303F,是糖基化修饰的重组人源化抗HER-2单克隆抗体,其抗体序列与帕妥珠序列一致;此外,抗体BAT0303F是由敲除岩藻糖的CHO细胞表达,有增强的ADCC效应、进一步提高药效。
在一些实施方案中,所述抗体为分离的抗HER2抗体。
本发明还提供了一种编码所述的抗体的核酸。在一些实施方案中,所述核酸分子为分离的核酸。
本发明还提供了一种包含所述的核酸的载体。在一些实施方案中,所述载体为分离的载体。
本发明还提供了一种包含所述的核酸分子或载体的宿主细胞。在一些实施方案中,所述宿主细胞为分离的宿主细胞。在一些实施方案中,所述宿主细胞为CHO细胞、HEK293F细胞、Cos1细胞、Cos7细胞、CV1细胞或鼠L细胞。
本发明还提供了治疗方法和用途。在一些实施方案中,提供了用于治疗或改善细胞增殖性疾病的方法,所述方法包括向患者施用有效量的所述的抗体。在一些实施方案中,提供了所述的抗体、所述的核酸分子、所述的载体或宿主细胞在制备用于治疗或改善细胞增殖性疾病的药物中的应用。
本发明还提供了诊断方法和用途。在一些实施方案中,提供了检测样品中HER2表达量的方法:样品与所述的抗体进行接触,使得所述的抗体结合HER2,并检测其结合,即样品中HER2蛋白的含量。在一些实施方案中,提供了所述抗体在制备用于诊断细胞增殖性疾病试剂盒中的应用。在一些实施方案中,提供一种包含所述的抗体的诊断试剂盒。
本发明还提供了一种所述药物组合物,其包含所述的抗体或抗体组合物,以及药学上可接受的载体。
附图说明
图1为实施例2中pHC质粒图谱;其中,intron A表示为干扰素α-2b基因,SV40E和hCMV表示为启动子,polyA表示为poly尾,heavy chain Gene表示为重链基因,GS DNA表示为谷氨酰胺合成酶基因,beta-lactamse表示为氨苄抗生素筛选标记基因。
图2为实施例2中pLC质粒图谱;light chain Gene表示为轻链基因。
图4为实施例8中抗HER2抗体对肿瘤细胞增殖的抑制效果曲线图;其中横坐标concentration表示浓度。
图5显示实施例9中抗HER2抗体对HCC1954细胞的ADCC效应。
图6显示实施例9中抗HER2抗体对NCI-N87细胞的ADCC效应;其中,横坐标表示浓度。
图7显示实施例10中抗HER2抗体均能抑制NCI-N87的生长。
图8显示实施例12中抗HER2抗体对荷瘤小鼠体重的影响。
定义
除非另作说明,否则下列的每一个术语应当具有下文所述的含义。
应当注意的是,术语“一种”实体是指一种或多种该实体,例如“一种抗体”应当被理解为一种或多种抗体,因此,术语“一种”(或“一个”)、“一种或多种”和“至少一种”可以在本文中互换使用。
本文所用的术语“包含”或“包括”意味着组合物和方法等包括所列举的元素,例如组份或步骤,但不排除其它。“基本上由……组成”意味着组合物和方法排除对组合的特征有根本影响的其它元素,但不排除对组合物或方法无本质上影响的元素。“由……组成”意味着排除未特别列举的元素。
术语“多肽”旨在涵盖单数的“多肽”以及复数的“多肽”,并且是指由通过酰胺键(也称为肽键)线性连接的氨基酸单体构成的分子。术语“多肽”是指两个或更多个氨基酸的任何单条链或多条链,并且不涉及产物的特定长度。因此,“多肽”的定义中包括肽、二肽、三肽、寡肽、“蛋白质”、“氨基酸链”或用于指两个或多个氨基酸链的任何其他术语,并且术语“多肽”可以用来代替上述任何一个术语,或者与上述任何一个术语交替使用。术语“多肽”也意在指多肽表达后修饰的产物,包括但不限于糖基化、乙酰化、磷酸化、酰胺化、通过已知的保护/封闭基团衍生化、蛋白水解切割或非天然发生的氨基酸修饰。多肽可以源自天然生物来源或通过重组技术产生,但其不必从指定的核酸序列翻译所得,它可能以包括化学合成的任何方式产生。
“氨基酸”是指既含氨基又含羧基的有机化合物,比如α-氨基酸,其可直接或以前体的形式由核酸编码。单个氨基酸由三个核苷酸(所谓的密码子或碱基三联体)组成的核酸编码。每一个氨基酸由至少一个密码子编码。相同氨基酸由不同密码子编码称为“遗传密码的简并性”。氨基酸包括天然氨基酸和非天然氨基酸。天然氨基酸包括丙氨酸(三字母代码:ala,一字母代码:A)、精氨酸(arg,R)、天冬酰胺(asn,N)、天冬氨酸(asp,D)、半胱氨酸(cys,C)、谷氨酰胺(gln,Q)、谷氨酸(glu,E)、甘氨酸(gly,G)、组氨酸(his,H)、异亮氨酸(ile,I)、亮氨酸(leu,L)、赖氨酸(lys,K)、甲硫氨酸(met,M)、苯丙氨酸(phe,F)、脯氨酸(pro,P)、丝氨酸(ser,S)、苏氨酸(thr,T)、色氨酸(trp,W)、酪氨酸(tyr,Y)和缬氨酸(val,V)。
“保守氨基酸取代”是指一个氨基酸残基被另一个含有化学性质(例如电荷或疏水性)相似的侧链(R基团)的氨基酸残基所取代。一般而言,保守氨基酸取代不大会在实质上改变蛋白质的功能性质。含有化学性质相似侧链的氨基酸类别的实例包括:1)脂族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;2)脂族羟基侧链:丝氨酸和苏氨酸;3)含酰胺的侧链:天冬酰胺和谷氨酰胺;4)芳族侧链:苯丙氨酸、酪氨酸和色氨酸;5)碱性侧链:赖氨酸、精氨酸和组氨酸;6)酸性侧链:天冬氨酸和谷氨酸。本发明中“轻链可变区、重链可变区、轻链和重链的保守氨基酸取代”的氨基酸数目为约1个、约2个、约3个、约4个、约7个、约9个、约11个、约20个、约22个、约24个、约28个、约31个、约33个、约36个、约39个、约43个、约45个保守氨基酸取代,或这些数值中的任何两个之间的范围(包括端点)或其中任何值。
本发明中关于细胞、核酸、多肽、抗体等所使用的术语“分离的”,例如“分离的”DNA、RNA、多肽、抗体是指分别于细胞天然环境中的其它组分如DNA或RNA中的一种或多种所分离的分子。本发明使用的术语“分离的”还指当通过重组DNA技术产生时基本上不含细胞材料、病毒材料或细胞培养基的核酸或肽,或化学合成时的化学前体或其他化学品。此外,“分离的核酸”意在包括不以天然状态存在的核酸片段,并且不会以天然状态存在。术语“分离的”在本发明中也用于指从其他细胞蛋白质或组织分离的细胞或多肽。分离的多肽意在包括纯化的和重组的多肽。分离的多肽、抗体等通常通过至少一个纯化步骤制备。在一些实施方案中,分离的核酸、多肽、抗体等的纯度至少为约50%、约60%、约70%、约80%、约90%、约95%、约99%,或这些数值中的任何两个值之间的范围(包括终点)或其中任何值。
术语“重组”涉及多肽或多聚核苷酸,意指天然不存在的多肽或多聚核苷酸的形式,不受限制的实施例可以通过组合产生通常并不天然存在的多聚核苷酸或多肽。
“同源性”、“同一性”或“相似性”是指两个肽之间或两个核酸分子之间的序列相似性。可以通过比较每个序列中可以比对的位置来确定同源性。当被比较的序列中的位置被相同的碱基或氨基酸占据时,则分子在该位置是同源的。序列之间的同源程度是由序列共有的匹配或同源位置的数目组成的一个函数。
在一些实施方案中,至少80%同一性为约80%同一性、约81%同一性、约82%同一性、约83%同一性、约85%同一性、约87%同一性、约89%同一性、约90%同一性、约91%同一性、约92%同一性、约93%同一性、约94%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、约99%同一性,或这些数值中的任何两个之间的范围(包括端点)或其中任何值。
多聚核苷酸或多聚核苷酸序列(或多肽或抗体序列)与另一序列有具有一定百分比(例如90%、95%、98%或者99%)的“同一性或序列同一性”是指当序列比对时,所比较的两个序列中该百分比的碱基(或氨基酸)相同。可以使用目测或本领域已知的软件程序来确定该比对和同一性百分比或序列同一性,比如Ausubel et al.eds.(2007)在CurrentProtocols in Molecular Biology中所述的软件程序。优选使用默认参数进行比对。其中一种比对程序是使用默认参数的BLAST,例如BLASTN和BLASTP,两者使用下列默认参数:Geneticcode=standard;filter=none;strand=both;cutoff=60;expect=10;Matrix=BLOSUM62;Descriptions=50sequences;sortby=HIGHSCORE;Databases=non-redundant;GenBank+EMBL+DDBJ+PDB+GenBankCDStranslations+Swi ssProtein+SPupdate+PIR。生物学上等同的多聚核苷酸是具有上述指定百分比的同一性并编码具有相同或相似生物学活性的多肽的多聚核苷酸。
多聚核苷酸是由四个核苷酸碱基的特定序列组成:腺嘌呤(A)、胞嘧啶(C)、鸟嘌呤(G)、胸腺嘧啶(T),或当多聚核苷酸是RNA时胸腺嘧啶换为尿嘧啶(U)。“多聚核苷酸序列”可以以多聚核苷酸分子的字母表示。该字母表示可以被输入到具有中央处理单元的计算机中的数据库中,并用于生物信息学应用,例如用于功能基因组学和同源性搜索。
术语“多聚核苷酸”和“寡核苷酸”可互换使用,是指任何长度的核苷酸的聚合形式,无论是脱氧核糖核苷酸还是核糖核苷酸或其类似物。多聚核苷酸可以具有任何三维结构并且可以执行已知或未知的任何功能。以下是不受限制的多聚核苷酸的实施例:基因或基因片段(例如探针、引物、EST或SAGE标签)、外显子、内含子、信使RNA(mRNA)、转运RNA、核糖体RNA、核糖酶、cDNA、dsRNA、siRNA、miRNA、重组多聚核苷酸、分支的多聚核苷酸、质粒、载体、任何序列的分离的DNA、任何序列的分离的RNA、核酸探针和引物。多聚核苷酸可以包含修饰的核苷酸,例如甲基化的核苷酸和核苷酸类似物。如果存在该修饰,则对核苷酸的结构修饰可以在组装多聚核苷酸之前或之后进行。核苷酸的序列可以被非核苷酸组分中断。聚合后可以进一步修饰多聚核苷酸,例如通过与标记组分缀合。这个术语也指双链和单链分子。除另有说明或要求外,本公开的任何多聚核苷酸的实施例包括双链形式和已知或预测构成双链形式的两种可互补单链形式中的每一种。
术语“编码”应用于多聚核苷酸时,是指被称为“编码”多肽的多聚核苷酸,在其天然状态或当通过本领域技术人员公知的方法操作时,经转录和/或翻译可以产生该多肽和/或其片段。
“抗体”是指特异性识别和结合抗原的多肽或多肽复合物。抗体可以是完整的抗体及其任何抗原结合片段或其单链。因此术语“抗体”包括分子中含有具有与抗原结合的生物学活性的免疫球蛋白分子的至少一部分的任何蛋白质或肽。抗体和抗原结合片段包括但不局限重链或轻链或其配体结合部分的互补决定区(CDR)、重链可变区(VH)、轻链可变区(VL)、重链恒定区(CH)、轻链恒定区(CL)、框架区(FR)或其任何部分,或结合蛋白的至少一部分。CDR区包括轻链的CDR区(LCDR1-3)和重链的CDR区(HCDR1-3)。
“单克隆抗体”(mAb)是由相同的免疫细胞制备的抗体,所述免疫细胞是单一亲本细胞的所有克隆。单克隆抗体可以具有单价亲和力,因为它们结合相同的表位(抗体识别的抗原部分)。相反,多克隆抗体与多个表位结合,并且通常由几种不同的浆细胞分泌。单克隆抗体可以通过杂交瘤、重组、转基因或本领域技术人员已知的其他技术制备。
术语“抗体”包括可以在生物化学上区分的各种广泛种类的多肽。本领域技术人员将会理解,重链的类别包括gamma、mu、alpha、delta或epsilon(γ、μ、α、δ、ε),其中还有一些亚类(例如γ1-γ4)。该链的性质决定了抗体的“种类”分别为IgG、IgM、IgA、IgG或IgE。免疫球蛋白亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgG5等已被充分表征并且赋予的功能特异性也已知。所有的免疫球蛋白种类都在本发明公开的保护范围内。在一些实施方案中,免疫球蛋白分子为IgG种类。IgG通常包含分子量约23,000道尔顿的两条相同的轻链多肽和分子量约为53,000-70,000的两条相同的重链多肽。这四条链通过二硫键以“Y”构型连接,其中轻链从“Y”口开始并延续通过可变区包围重链。
轻链可以分为kappa(κ)或lambda(λ)。每个重链可以与κ或λ轻链结合。一般来说,当由杂交瘤,B细胞或基因工程宿主细胞生产免疫球蛋白时,其轻链和重链通过共价键结合,两条重链的“尾巴”部分通过共价二硫键或非共价键结合。在重链中,氨基酸序列从Y构型的叉状末端的N末端延伸至每条链底部的C末端。免疫球蛋白κ轻链可变区为Vκ;免疫球蛋白λ轻链可变区为Vλ。
轻链和重链都分成结构和功能同源性的区域。术语“恒定的”和“可变的”根据功能被使用。轻链(VL)和重链(VH)链部分的可变区决定了抗原识别和特异性。轻链和重链的恒定区赋予重要的生物学性质,如分泌、经胎盘移动、Fc受体结合、补体结合等。按照惯例,恒定区的编号随着它们变得更远离抗体的抗原结合位点或氨基末端而增加。N端部分是可变区,C端部分是恒定区;CH3和CL结构域分别包含重链和轻链的羧基端。
在天然存在的抗体中,假设抗体在含水环境中呈现其三维构型时,存在于每个抗原结合域中的六个“互补决定区”或“CDR”是形成抗原结合结构域的短的、非连续的与抗原特异性结合的氨基酸序列。抗原结合结构域中被称为“构架”区域的剩余其它氨基酸显示出较小的分子间可变性。构架区大部分采用β-折叠构象,CDR形成与之连接的环状结构,或在某些情况下形成β折叠结构的一部分。因此,框架区通过形成支架从而通过链间非共价相互作用使CDR定位在正确的方位上。具有特定位置的CDR的抗原结合域形成了与抗原上的表位互补的表面,该互补表面促进抗体和其抗原表位的非共价结合。对于给定的重链或轻链可变区,本领域普通技术人员都可以通过已知方法鉴定出包含CDR和框架区的氨基酸(参见Kabat,E.,et al.,U.S.Department of Health and Human Services,Sequences ofProteins of Immunological Interest,(1983)和Chothia and Lesk,J.Mol.Biol.,196:901-917(1987))。
在本领域中使用和/或接受的术语有两个或多个定义的情况下,除非明确地对立指出,否则本文使用的术语的定义包括所有这些含义。一个具体的例子是使用“互补决定区”(“CDR”)一词来描述在重链和轻链多肽的可变区内发现的非连续的抗原结合位点。这一特定区域在Kabat et al.,U.S.Dept.of Health and Human Services,Sequences ofProteins of Immunological Interest(1983)和Chothia等在J.Mol.Biol.196:901-917(1987)有相关描述,其通过引用全部并入本文。
根据Kabat和Chothia定义的CDR包括相互比较时的氨基酸残基的重叠或子集。尽管如此,应用任一定义来指代抗体或其变体的CDR都在本发明范围内。包含特定CDR的确切残基编号将根据CDR的序列和大小而变化。本领域技术人员通常可以根据抗体的可变区氨基酸序列确定出CDR包含哪些特定的残基。
Kabat等人还定义了适用于任何抗体的可变区序列的编号系统。本领域普通技术人员可以不依赖于序列本身以外的其他实验数据将该“Kabat编号”系统应用到任何可变区序列。“Kabat编号”是指由Kabat et al.,U.S.Dept.of Health and Human Services在“Sequence of Proteinsof Immunological Interest”(1983)提出的编号系统。抗体还可以采用EU编号系统。
“轻链恒定区”包括来自抗体轻链的一部分氨基酸序列。较佳地,轻链恒定区(CL)包含恒定κ结构域或恒定λ结构域中的至少一个。“轻链-重链对”是指可通过轻链的CL结构域和重链的CH1结构域之间的二硫键形成二聚体的轻链和重链的集合。
“VH结构域”包括免疫球蛋白重链的氨基末端可变结构域,“CH1结构域”包括免疫球蛋白重链的第一个(大部分氨基末端)恒定区。CH2结构域不与其它结构域紧密配对,而是在完整的天然IgG分子的两个CH2结构域之间插入两个N-连接的分支碳水化合物链。还有文献记载,CH3结构域从CH2结构域开始延伸到IgG分子的C-末端,大约包含108个残基。“铰链区”包括连接CH1结构域和CH2结构域的部分重链区域。所述铰链区包含约25个残基并且是有韧性的,从而使得两个N端抗原结合区能够独立移动。铰链区可以被细分为三个不同的结构域:上、中和下铰链结构域(Rouxetal.,J.Immunol 161:4083(1998))。
“二硫键”指两个硫原子之间形成的共价键。半胱氨酸的硫醇基团可以与第二个硫醇基团形成二硫键或桥接。在大多数天然存在的IgG分子中,CH1和CL区通过二硫键连接。
“特异性结合”或“对……具有特异性”通常是指抗体或抗原结合片段与特定抗原通过其抗原结合结构域与表位互补性结合形成相对稳定的复合物。“特异性”可以用抗体或抗原结合片段与特定抗原或表位结合的相对亲和力表达。例如,如果抗体“A”比抗体“B”与同一抗原的相对亲和力大,可以认为抗体“A”比抗体“B”对该抗原具有更高的特异性。特异性结合可以用平衡解离常数(KD)来描述,较小的KD意味着较紧密的结合。确定两个分子是否特异性结合的方法是本领域内众所周知的,并包括例如平衡透析、表面等离子共振、生物膜层光学干涉测量法等。“特异性结合”抗原a的抗体包括与抗原a平衡解离常数KD小于或等于约100nM、小于或等于约10nM、小于或等于约5nM、小于或等于约1nM的抗体。
“抗体依赖性细胞介导的细胞毒性”(ADCC)是细胞介导的免疫防御机制,机理是:效应细胞的膜表面受体与抗体特异性结合,主动裂解靶细胞。它是体液免疫反应的一部分,可以通过其作用来限制和控制感染。
ADCC需要一种效应细胞,通常是与IgG抗体相互作用的天然杀伤(NK)细胞。然而,巨噬细胞、中性粒细胞和嗜酸性粒细胞也可以介导ADCC,例如嗜酸性粒细胞通过IgE抗体杀死某些被称为蠕虫的寄生虫。另外,ADCC是适应性免疫应答的一部分,因为它依赖于先前的抗体应答。
“Fc区”是抗体的尾区,其与细胞表面受体和补体系统的一些蛋白质相互作用。该特性允许抗体激活免疫系统。在IgG、IgA和IgD抗体同种型中,Fc区由两个相同的蛋白质片段组成,衍生自抗体的两条重链的第二和第三恒定区;在IgM和IgE抗体同种型中,Fc区含有三个重链恒定结构域(CH2-4);IgG的Fc区具有高度保守的N-糖基化位点。Fc片段的糖基化对于Fc受体介导的活性是必需的,且不同的糖型对治疗性抗体的药学性质有不同的影响。
“Fc受体”或“FcR”是在某些细胞表面发现的蛋白质,这些细胞包括B淋巴细胞、滤泡树突细胞、自然杀伤细胞、巨噬细胞、中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、人血小板和肥大细胞等,它们都有助于保护免疫系统的功能。Fc受体的名称来源于其对抗体的Fc区域的结合特异性。Fc受体与附着于受感染细胞或入侵病原体的抗体结合。它们的活性通过吞噬细胞和细胞毒性细胞破坏微生物、或通过抗体介导的吞噬作用去除感染细胞、或通过抗体依赖性细胞介导的细胞毒性去发挥作用。一些病毒如黄病毒通过称为抗体依赖性感染增强的机制使用Fc受体来帮助它们感染细胞。
不同类型的Fc受体是基于它们识别的抗体类型进行分类。例如,结合抗体IgG的那些称为Fc-γ受体(FcγR),结合IgA的那些称为Fc-α受体(FcαR),结合IgE的那些称为Fc-ε受体(FcεR)。FcR的类别还可通过表达它们的细胞(巨噬细胞、粒细胞、天然杀伤细胞、T细胞和B细胞)和每种受体的信号传导特性来区分。
所有Fcγ受体(FcγR)都属于免疫球蛋白超家族,是诱导微生物吞噬作用的最重要的Fc受体。该家族包括几个成员:FcγRI(CD64),FcγRIIA(CD32),FcγRIIB(CD32),FcγRIIIA(CD16a),FcγRIIIB(CD16b),由于它们的分子结构不同,它们的抗体亲和力不同。例如,FcγRI比FcγRII或FcγRIII更强地结合IgG。FcγRI还具有由三个免疫球蛋白(Ig)样结构域组成的细胞外部分,比FcγRII或FcγRIII具有更多的结构域。这种性质允许FcγRI结合唯一的IgG分子(或单体),但所有Fcγ受体必须结合免疫复合物中的多个IgG分子才能被激活。Fc-γ受体对IgG的亲和力不同,而不同的IgG亚类对每种Fcγ受体具有独特的亲和力。这些相互作用通过IgG的位置CH2-84.4处的聚糖(寡糖)进一步调节。例如,通过产生空间位阻,含有CH2-84.4聚糖的岩藻糖降低了对FcγRIIIA的IgG亲和力。
“治疗”是指治疗性治疗和预防性或防治性措施,其目的是预防、减缓、改善或停止不良的生理改变或紊乱,例如疾病的进程,包括但不限于以下无论是可检测还是不可检测的结果,症状的缓解、疾病程度的减小、疾病状态的稳定(即不恶化)、疾病进展的延迟或减缓、疾病状态的改善、缓和、减轻或消失(无论是部分还是全部)、延长与不接受治疗时预期的生存期限等。需要治疗的患者包括已经患有病症或紊乱的患者,容易患有病症或紊乱的患者,或者需要预防该病症或紊乱的患者,可以或预期从施用本发明公开的抗体或药物组合物用于检测、诊断过程和/或治疗中受益的患者。
“患者”指需要诊断、预后或治疗的任何哺乳动物,包括人类、狗、猫、兔子、鼠、马、牛等。
“约”指相关技术领域技术人员容易知道的相应数值的常规误差范围。在一些实施方式中,本文中提到“约”指所描述的数值以及其±10%、±5%或±1%的范围。
基于单克隆抗体所带电荷可对其进行分离,进而可对电荷异质体进行分析,常用的分析方法有等电聚焦凝胶电泳(IEF)、毛细管等电聚焦凝胶电泳(cIEF)、阳离子交换色谱法(CEX)和阴离子交换色谱法(AEX)。与主峰相比,这些变异体通常被称为酸性变异体和碱性变异体,即酸峰和碱峰。采用CEX分析时,酸峰早于主峰洗脱出来,而碱峰晚于主峰洗脱出来。
抗HER2抗体
本发明提供了抗HER2抗体,受测抗体表现出有效的结合活性、生物活性(ADCC效应增强),并可用于治疗和诊断用途。
在一些实施方案中,所述抗体的重链包含如SEQ ID NO:9所示的序列,所述抗体的轻链包含SEQ ID NO:10所示的序列。在一些实施方案中,所述抗体为单克隆抗体。
在一些实施方案中,所述抗体为单克隆抗体,抗体的岩藻糖基化水平为0%-5%。在一些实施方案中,所述抗体为单克隆抗体,抗体的岩藻糖基化水平为0。
在一些实施方案中,所述抗体为单克隆抗体有以下一种或几种特征,G0糖型的含量为61%-75%,G0-GN糖型的含量为4%-7%,G1'糖型的含量为6%-12%,G1糖型的含量为8%-12%,G2糖型的含量不高于3%。在一些实施方案中,G0糖型的含量为约72%-73%,G0-GN糖型的含量为约5%-6%,G1糖型的含量为8%-9%,G1'糖型的含量为8%-9%,G2糖型的含量为约0-1%。
在一些实施方案中,所述抗体为单克隆抗体,抗体组合物中主峰的含量至少为72%,比如73%-82%。在一些实施方案中,所述抗体为单克隆抗体,所述抗体组合物中碱性变异体的含量不高于8%或6%。在一些实施方案中,所述抗体为单克隆抗体,抗体组合物中主峰的含量为77%-81%,所述抗体组合物中碱性变异体的含量为1%-6%。在一些实施方案中,所述抗体为单克隆抗体,抗体组合物中主峰的含量为77%-78%,所述抗体组合物中碱性变异体的含量为2%-5%。在一些实施方案中,所述抗体为单克隆抗体,抗体组合物中主峰的含量为79%-81%,所述抗体组合物中碱性变异体的含量为1%-4%。
在一些实施方案中,所述抗体由敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞、HEK293F细胞、Cos1细胞、Cos7细胞、CV1细胞或鼠L细胞表达。在一些实施方案中,所述抗体由敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞表达。
本领域普通技术人员还应当理解,本发明所公开抗体是可以被替换的,替换后其氨基酸序列不同于该抗体的天然存在的氨基酸序列。例如,替换后的氨基酸序列可以是与起始序列相似的,比如与起始序列具有一定比例的同一性,比如它可以与起始序列的同一性为约80%、约85%、约90%、约95%、约98%、约99%,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。
在某些实施方案中,抗体包含的氨基酸序列具有一个或多个修饰基团。例如,本发明公开的抗HER2抗体可以包含有韧性的接头序列,或者可以被修饰以添加功能性基团(例如PEG、药物、毒素或标签)。
本发明公开的抗体包括被修饰的衍生物,即通过任何类型的分子与抗体的共价连接进行修饰,其中共价连接不会阻止抗体与抗原表位结合。包括但不限制以下实例,抗体可以被糖基化、乙酰化、聚乙二醇化、磷酸化、酰胺化、通过已知的保护/封闭基团衍生化、蛋白水解切割、连接至细胞配体或其他蛋白质等。众多化学修饰中的任一种修饰可以通过现有技术进行,包括但不限于特异性化学裂解、乙酰化、甲酰化、衣霉素的代谢合成等。
在一些实施方案中,抗体可以与治疗剂、药物前体、肽、蛋白质、酶、病毒、脂类、生物反应调节剂、药剂或PEG缀合。
抗体可以与治疗剂缀合或融合,所述治疗剂包括可检测标记(如放射性标记)、免疫调节剂、激素、酶、寡核苷酸、光敏治疗剂、细胞毒性剂、超声增强剂、非放射性标记物及其组合物,和本领域已知的其它此类试剂。
抗体可通过将其偶联至化学发光化合物来被可检测地标记。然后通过检测在化学反应过程中出现的发光从而确定化学发光标记的抗体的存在。化学发光标记化合物的实例包括鲁米诺、异鲁米诺、芳香吖啶酯、咪唑、吖啶盐和草酸酯。
抗体和编码抗体的多聚核苷酸的制备方法
本发明还公开了编码本发明所述抗体及其衍生物的多聚核苷酸或核酸分子。本发明公开的多聚核苷酸可以编码重链可变区、轻链可变区、Fc区、部分重链可变区或部分轻链可变区。制备抗体的方法是本领域公知的并且在本发明中有所描述。在某些实施方案中,本发明公开的抗体包括的可变区和恒定区都是全人源的。全人源抗体可以使用本领域中公开的技术和本发明所述的技术制备。例如,针对特定抗原的全人源抗体可以通过将抗原施用于转基因动物中来制备,所述转基因动物已经被改良过以响应抗原攻击而产生全人源抗体。可用于制备这类抗体的示例性技术参见美国专利6,458,592;6,420,140,其全部内容通过引用并入本文。
本发明公开的抗HER2抗体的结合特异性可以通过体外实验,例如免疫共沉淀、放射免疫实验(RIA)或酶联免疫吸附实验(ELISA)来检测。
此外,使用常规重组DNA技术,可将本发明的抗体的一个或多个CDR插入框架区,例如插入到人类框架区以构建人源化非全人源抗体。框架区可以是天然存在的或共有的框架区,优选人类框架区(参见Chothia et al.,J.Mol.Biol.278:457-479(1998),其列出一系列人类框架区)。一些多核苷酸可以编码框架区和CDR组合产生的与目标抗原的至少一个表位特异性结合的抗体。在框架区内可以进行一个或多个氨基酸取代,可以选择能够改善抗体与其抗原结合的氨基酸取代。另外,可用此法进行参与链间二硫键形成的一个或多个可变区中半胱氨酸残基的取代或缺失,从而产生缺少一个或多个链间二硫键的抗体分子。本领域技术范围内的对多核苷酸进行的其他改变也涵盖于本发明中。
抗体可以通过使用常规重组DNA技术制备。使用本领域技术人员公知的技术可以选择、构建和培养生产抗体的细胞系。这些技术在各种实验室手册和主要出版物中均有描述。在这方面,下文描述的适合本发明使用的技术参考文献如Current Protocols inImmunology,Coligan et al.,Eds.,Green Publishing Associates and Wiley-Interscience,John Wiley and Sons,New York(1991),Recombinant DNA Technologyfor Production of Protein Therapeutics in Cultured Mammalian Cells,D.L.Hacker,F.M.Wurm,in Reference Module in Life Sciences,2017;其全部内容包括补充内容通过引用并入全文。
在一些实施方案中,可以按常规方法根据本文所述抗体氨基酸序列设计合成编码抗体的DNA,将其置入表达载体中,然后转染宿主细胞,在培养基中培养被转染的宿主细胞产生单克隆抗体。在一些实施方案中,表达抗体载体包括至少一个启动子元件,抗体编码序列,转录终止信号和polyA尾。其他元件包括增强子,Kozak序列及插入序列两侧RNA剪接的供体和受体位点。可以通过SV40的前期和后期启动子,来自逆转录病毒的长末端重复序列如RSV、HTLV1、HIVI及巨细胞病毒的早期启动子来获得高效的转录,也可应用其它一些细胞的启动子如肌动蛋白启动子。合适的表达载体可包括pIRES1neo,pRetro-Off,pRetro-On,PLXSN,或者Plncx,pcDNA3.1(+/-),pcDNA/Zeo(+/-),pcDNA3.1/Hygro(+/-),PSVL,PMSG,pRSVcat,pSV2dhfr,pBC12MI和pCS2等。常使用的哺乳动物细胞包括293细胞,Cos1细胞,Cos7细胞,CV1细胞,鼠L细胞和CHO细胞等。
在一些实施方案中,插入基因片段需含有筛选标记,常见的筛选标记包括二氢叶酸还原酶,谷氨酰胺合成酶,新霉素抗性,潮霉素抗性等筛选基因,以便于转染成功的细胞的筛选分离。将构建好的质粒转染到无上述基因的宿主细胞,经过选择性培养基培养,转染成功的细胞大量生长,产生想要获得的目的蛋白。
在一些实施方案中,本文所述取代为保守氨基酸取代。
治疗方法
本发明还提供了治疗方法和用途。在一些实施方案中,提供了用于治疗细胞增殖性疾病的方法,所述方法包括向患者施用有效剂量的所述抗HER2抗体。在一些实施方案中,提供了所述抗HER2抗体在治疗细胞增殖性疾病中的应用。在一些实施方案中,提供了所述抗HER2抗体在制备用于治疗细胞增殖性疾病的药物中的应用。
在一些实施方案中,所述细胞增殖性疾病为癌症。在一些实施方案中,所述癌症为HER2阳性癌症。在一些实施方案中,所述癌症包括但不限于淋巴瘤、母细胞瘤、肉瘤、白血病和淋巴样恶性肿瘤。此类癌症的更具体例子包括但不限于鳞状细胞癌(例如上皮鳞状细胞癌),肺癌(包括小细胞肺癌、非小细胞肺癌),腹膜癌,肝细胞癌,胃癌,胰腺癌,成胶质细胞瘤,宫颈癌,卵巢癌,肝癌,膀胱癌,尿道癌,肝瘤,乳腺癌,结肠癌,直肠癌,结肠直肠癌,子宫内膜癌,子宫癌,唾液腺癌,肾癌,前列腺癌,外阴癌,甲状腺癌,肛门癌,阴茎癌,黑素瘤,浅表扩散性黑素瘤,恶性雀斑样痣黑素瘤,肢端黑素瘤,结节性黑素瘤,多发性骨髓瘤,B细胞淋巴瘤(包括低级/滤泡性非何杰金(Hodgkin)氏淋巴瘤(NHL),小淋巴细胞性(SL)NHL,中级/滤泡性NHL,中级弥漫性NHL,高级成免疫细胞性NHL,高级成淋巴细胞性NHL,高级小无核裂细胞性NHL,贮积病(bulky disease)NHL,套细胞淋巴瘤,AIDS相关淋巴瘤和瓦尔登斯特伦氏(Waldenstrom)巨球蛋白血症),慢性淋巴细胞性白血病(CLL),急性成淋巴细胞性白血病(ALL),毛细胞性白血病,慢性成髓细胞性白血病,移植后淋巴增殖性病症(PTLD),以及与瘢痣病(phakomatoses),水肿(诸如与脑瘤有关的)和梅格斯氏(Meigs)综合征有关的异常血管增殖,脑癌、头癌和颈癌及相关转移。在一些实施方案中,所述癌症为乳腺癌、腹膜癌、输卵管癌、肺癌、结肠直肠癌、胆道癌、膀胱癌、卵巢癌、前列腺癌或胃癌。
对于任何特定患者的具体剂量和治疗方案将取决于各种因素,包括所使用的特定抗体或衍生物、患者的年龄和体重、一般健康状况、性别和饮食,以及给药时间、排泄频率、药物组合,以及所治疗的特定疾病的严重程度。由包括在本领域普通技术人员范围内的医疗护理人员对这些因素进行判断。所述剂量还将取决于待治疗的个体患者、给药途径、制剂类型、所用化合物的特性、疾病的严重程度以及所需的效果。所用剂量可以通过本领域熟知的药理学和药代动力学原理确定。
在一些实施方案中,所述抗体的重链包含如SEQ ID NO:9所示的序列,所述抗体的轻链包含SEQ ID NO:10所示的序列。在一些实施方案中,所述抗HER2抗体由敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞表达。
在一些实施方案中,所述方法或用途包括:向有需要的患者给药包含有效量的抗体的药物组合物。在一些实施方案中,所述有效剂量为每剂50mg至1000mg。在一些实施方案中,患者患有HER2阳性晚期实体瘤。在一些实施方案中,实体瘤源自乳腺癌或胃癌。在一些实施方案中,本发明公开了一种用于治疗有需要患者的HER2阳性晚期实体瘤的方法,其包括施用有效量的抗HER2抗体(或制剂),其中有效量为50mg至1000mg每个治疗周期。在一些实施方案中,一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周、约8周,或这些数值值中的任何两个值之间的范围(包括端点)或其中任何值。
在一些实施方案中,可以将抗HER2抗体配制成药物组合物,并以适合于所选给药途径的多种形式向患者给药,例如通过肠胃外,静脉内(iv),肌肉内,局部或皮下途径进行给药。在一些实施方案中,可以将抗HER2抗体(或制剂)静脉输注。抗HER2抗体(或制剂)的量将取决于药物的性质,细胞表面触发药物的内在化,运输和释放的程度,所治疗的疾病,患者的状况(如年龄,性别,体重等)。在一些实施方案中,本发明抗HER2体(或制剂)的施用方法为静脉输液。
在一些实施方案中,患者每个治疗周期内施用本发明抗HER2体为1-15mg/kg。在一些实施方案中,每次施用本发明抗HER2抗体为约1mg/kg、约2mg/kg、约3mg/kg、约4mg/kg、约5mg/kg、约6mg/kg、约7mg/kg、约8mg/kg、约9mg/kg、约10mg/kg、约11mg/kg、约12mg/kg、约13mg/kg、约14mg/kg、约15mg/kg,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,一个治疗周期为1周至14周给药1次或多次。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2抗体为1-15mg/kg;其中,一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周、约8周,或这些数值值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2抗体为约1mg/kg;其中,一个治疗周期为约2周给药1次。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2抗体为约3mg/kg;其中,一个治疗周期为约2周给药1次。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2抗体为约6mg/kg;其中,一个治疗周期为约2周给药1次。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2抗体为约10mg/kg;其中,一个治疗周期为约2周给药1次。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2抗体为约15mg/kg;其中,一个治疗周期为约2周给药1次。
在一些实施方案中,患者每个治疗周期内施用本发明抗HER2体为1-15mg/kg;其中,患者进行多个治疗周期。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2体为1-15mg/kg;其中,患者进行约2个、约3个、约4个、约5个、约6个,或约7个治疗周期。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2体为1mg/kg、约2mg/kg、约3mg/kg、约4mg/kg、约5mg/kg、约6mg/kg、约7mg/kg、约8mg/kg、约9mg/kg、约10mg/kg、约11mg/kg、约12mg/kg、约13mg/kg、约14mg/kg、约15mg/kg,其中,患者进行约2个、约3个、约4个、约5个或约6个治疗周期。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2体为1mg/kg;其中,患者进行约2个、约3个、约4个、约5个或约6个治疗周期。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2体为约3mg/kg;其中,患者进行约2个、约3个、约4个、约5个或约6个治疗周期。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2体为6mg/kg;其中,患者进行约2个、约3个、约4个、约5个或约6个治疗周期。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2体为约10mg/kg;其中,患者进行约2个、约3个、约4个、约5个或约6个治疗周期。在一些实施方案中,患者每个治疗周期内施用本发明抗HER2体为约15mg/kg,其中,患者进行约2个、约3个、约4个、约5个或约6个治疗周期。在一些实施方案中,患者每个治疗周期内给药一次。在一些实施方案中,每个治疗周期内多次给药,例如2次、3次、4次或5次。在一些实施方案中,患者每个治疗周期只能施用1次或4次。
在一些实施方案中,患者接受一个治疗周期治疗。在一些实施方案中,患者接受多个(例如2个、3个或4个)治疗周期治疗。在一些实施方案中,患者接受治疗直至病症得到缓解而不再需要治疗。
在一些实施方案中,本发明公开了一种治疗HER2阳性晚期实体瘤的方法,其包括向有需要患者施用有效量的抗体(或制剂);其中,有效量为单次给药50mg至1000mg。剂量时间表和给药方式取决于某些患者群中的抗体(或制剂)的获益风险评估和一般临床实践指南。
在一些实施方案中,患者每个治疗治疗周期的有效量是60mg至900mg抗体(或制剂)。在一些实施方案中,患者每个治疗周期内的有效量是约60mg、约100mg、约120mg、约180mg、约240mg、约300mg、约360mg、约420mg、约600mg、约700mg、约800mg、约900mg,或者这些数值中任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,一个治疗周期为1周至8周给药1次。在一些实施方案中,每个治疗周期内的有效量是60mg至900mg;其中,一个治疗周期为约1周、约2周、约3周、约5周、约6周、约7周、约8周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,一个治疗周期为2周。在一些治疗方案中,患者每个治疗周期内的有效量是60mg至900mg;其中一个治疗周期为2周。在一些实施方案中,患者每个治疗周期内的有效量为约60mg、约100mg、约120mg、约180mg、约240mg、约300mg、约360mg、约420mg、约600mg、约700mg、约800mg、约900mg,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值;其中,一个治疗周期为约2周。
在一些实施方案中,患者每个治疗周期内的有效量为约60mg;其中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,患者每个治疗周期内的有效量为50mg至80mg,比如约60mg给药1次。
在一些实施方案中,患者每个治疗周期内的有效量为约180mg;其中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,患者每个治疗周期内的有效量为150mg至200mg,比如约180mg给药1次。
在一些实施方案中,患者每个治疗周期内的有效量为约300mg;其中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,患者每个治疗周期内的有效量为250mg至320mg,比如约300mg给药1次。
在一些实施方案中,患者每个治疗周期内的有效量为约600mg;其中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,患者每个治疗周期内的有效量为570mg至680mg,比如约600mg给药1次。
在一些实施方案中,患者每个治疗周期内的有效量为约900mg;其中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,患者每个治疗周期内的有效量为880mg至940mg,比如约900mg给药1次。
在一些实施方案中,单剂量给药后,患者的症状得到缓解。在一些实施方案中,单剂量给药后,患者后的症状未得到预期缓解,再对患者给药。
在一些实施方案中,起始剂量为600-1000mg,静脉输液的时间为50-70min。在一些实施方案中,起始剂量为约600mg、约630mg、约700mg、约800mg、约840mg、约870mg、约920mg、约980mg、约1000mg,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,静脉输液的时间为约50min、约53min、约56min、约60min、约63min、约67min、约70min,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。
在一些实施方案中,本发明抗HER2抗体首次给药后的治疗周期为1-4周,维持剂量为200-500mg,静脉输液的时间为30-60min。在一些实施方案中,首次给药后的治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,每个治疗周期给药1次或2次。在一些实施方案中,维持剂量为约200mg、约240mg、约310mg、约380mg、约400mg、约420mg、约460mg、约500mg,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,静脉输液的时间为约30min、约33min、约42min、约49min、约54min、约60min,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。
在一些实施方案中,治疗HER2阳性晚期实体瘤的方法包括向有需要患者施用起始剂量为700-900mg的本发明抗HER2抗体,之后约每3周向该患者施用约200-500mg的本发明抗HER2抗体。
联合疗法
在一些实施方案中,本发明抗体可以结合其它治疗或预防方案,包括施用一种或多种本发明抗体以及一种或多种其它治疗剂或方法一起使用或组合使用。对于组合治疗,抗体可以与其它治疗剂可同时或分开施用。当分开施用时,可以在施用另一种其它治疗剂之前或之后施用本发明抗体。
在一些实施方案中,本发明抗体与曲妥珠单抗联合给药。在一些实施方案中,曲妥珠单抗的起始剂量为4-10mg/kg,静脉输液的时间为80-100min。在一些实施方案中,曲妥珠单抗的起始剂量为约4mg/kg、约5mg/kg、约6mg/kg、约7mg/kg、约8mg/kg、约9mg/kg、约10mg/kg,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,静脉输液的时间为约80min、约81min、约84min、约87min、约90min、约92min、约95min、约97min、约98min、约100min,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,曲妥珠单抗首次给药后的治疗周期为1-4周,维持剂量为2-8mg/kg,静脉输液的时间为30-90min。在一些实施方案中,曲妥珠单抗首次给药后的治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,每个治疗周期给药1次或2次。在一些实施方案中,维持剂量为约2mg/kg、约3mg/kg、约4mg/kg、约5mg/kg、约6mg/kg、约7mg/kg、约8mg/kg,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,静脉输液的时间为约30min、约40min、约50min、约60min、约70min、约80min、约90min,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。
在一些实施方案中,本发明抗HER2抗体与曲妥珠单抗-透明质酸酶联合给药。在一些实施方案中,曲妥珠单抗-透明质酸酶的施用方法为皮下给药,皮下给药的时间为2-5min。在一些实施方案中个,皮下给药的时间为约2min、约3min、约4min、约5min,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,曲妥珠单抗-透明质酸酶的起始剂量为500mg/1000units-700mg/1000units。
在一些实施方案中,曲妥珠单抗-透明质酸酶的起始剂量为约500mg/1000、约540mg/1000units、约580mg/1000units、约600mg/1000units、约640mg/1000units、约700mg/1000units,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,曲妥珠单抗-透明质酸酶的治疗周期为1-4周。在一些实施方案中,曲妥珠单抗-透明质酸酶给药的治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,每个治疗周期给药1次或2次。
在一些实施方案中,本发明抗HER2抗体可用于治疗转移性乳腺癌。在一些实施方案中,本发明抗HER2抗体与多西他赛(docetaxel)联合用于治疗转移性乳腺癌。
在一些实施方案中,多西他赛的起始剂量为60-70mg/m2,并采取静脉输液的方式进行给药。在一些实施方案中,多西他赛的起始剂量为约60mg/m2、约62mg/m2、约65mg/m2、约68mg/m2、约70mg/m2,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,患者对起始剂量的耐受性良好,多西他赛的维持剂量为80-100mg/m2,治疗周期为1-4周。在一些实施方案中,多西他赛的维持剂量为约80mg/m2、约83mg/m2、约85mg/m2、约87mg/m2、约90mg/m2、约92mg/m2、约98mg/m2、约100mg/m2,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,本发明抗HER2抗体与化疗剂组合施用。在一些实施方案中,可与本发明抗体一起施用的化疗剂包括但不限于抗生素衍生物(例如阿霉素、博来霉素、柔红霉素和放线菌素D)、抗雌激素药(如他莫昔芬)、抗代谢物(如氟尿嘧啶、5-FU、甲氨蝶呤、氟尿苷、干扰素α-2b、谷氨酸、光神霉素,巯基嘌呤和6-硫基鸟嘌呤)、细胞毒性剂(如卡莫司汀、BCNU、洛莫司汀、CCNU、阿糖胞苷、环磷酰胺、雌莫司汀、羟基脲、甲基苄肼、丝裂霉素、白消安、顺铂和硫酸长春新碱)、激素(如甲羟孕酮、雌莫司汀磷酸钠、炔雌醇、雌二醇、醋酸甲地孕酮、甲睾酮、己烯雌酚二磷酸、氯烯雌醚和睾内酯)、氮芥衍生物(例美法仑、苯丁酸氮芥、二氯甲基二乙铵(氮芥)和噻替哌)、类固醇及其组合(如倍他米松磷酸钠),以及其它化合物(如氮烯唑胺、天冬酰胺酶、米托坦、硫酸长春新碱、硫酸长春碱和依托泊苷)。
在一些实施方案中,本发明抗体与细胞因子联合施用。可以与本发明抗体一起施用的细胞因子包括但不限于IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-10、IL-12、IL-13、和IL-15等。
药物组合物
本发明还提供了药物组合物。这样的组合物包含有效剂量的抗体和药学上可接受的载体。在一些实施方案中,药物组合物还包含抗癌剂(例如免疫检查点抑制剂)。在一些实施方案中,药物组合物中含1%-90%的本发明抗体。
在一些实施方案中,术语“药学上可接受的”是指由政府的监管机构批准的或公认药典中列出的用于动物,特别是用于人类的物质。此外,“药学上可接受的载体”通常指是任何类型的无毒固体、半固体或液体填充剂、稀释剂、包封材料或制剂助剂等。
术语“载体”是指施用于可以与活性成分一起施用于患者的稀释剂、佐剂、赋形剂或载体。这此类药物载体可以是无菌液体,如水和油,包括石油、动植物或合成来源的油,如花生油、大豆油、矿物油、芝麻油等。当药物组合物静脉内给药时,水是优选的载体。盐水溶液和葡萄糖水溶液和甘油溶液也可用作液体载体,特别是用于注射溶液。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。如有需要,组合物还可以含有少量的润湿剂或乳化剂,或pH缓冲剂如乙酸盐、柠檬酸盐或磷酸盐。抗菌剂如苯甲醇或对羟基苯甲酸甲酯、抗氧化剂如抗坏血酸或亚硫酸氢钠、螯合剂如乙二胺四乙酸,以及调节张力的试剂如氯化钠或右旋葡萄糖也是可以预见的。这些组合物可以采取溶液、悬液、乳剂、片剂、丸剂、胶囊、散剂、缓释制剂等形式。该组合物可以用传统的粘合剂和载体如甘油三酯配制成栓剂。口服制剂可以包括标准载体,例如药物等级的甘露糖醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。合适的药物载体的实例在E.W.Martin的Remington'sPharmaceutical Sciences中有描述,在此通过引用并入本发明。此类组合物将含有临床有效剂量的抗体或抗原结合片段,优选以纯化后的形式,连同合适数量的载体,以提供适合于患者的给药形式。该制剂应该适用于给药模式。亲本制剂可以封装在安瓿瓶、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。
在一些实施方案中,根据常规步骤将组合物配制成适合静脉内注射于人体的药物组合物。用于静脉内给药的组合物通常是在无菌等渗水性缓冲液中的溶液。组合物还可包含增溶剂和局部麻醉剂如利多卡因,从而缓解注射部位的疼痛。一般而言,有效成分以单位剂量形式单独供给或混在一起供给,如以干燥的冻干粉末或无水浓缩物的形式装在可指示活性剂份量的密封容器(如安瓿瓶或小袋)中。在通过输注施用组合物的情况下,可以用含有无菌药用级水或盐水的输液瓶来分装组合物。在通过注射施用组合物的情况下,可以使用注射用的无菌水或盐水的安瓿瓶,使得可以在施用之前混合有效成分。
本发明的化合物可以配制成中性的或盐的形式。药学上可接受的盐包括衍生自如盐酸、磷酸、乙酸、草酸、酒石酸等的与阴离子形成的盐,以及衍生自如钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁卡因等的与阳离子形成的盐。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案,具体实施例不代表对本发明保护范围的限制。其他人根据本发明理念所做出的一些非本质的修改和调整仍属于本发明的保护范围。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到,或者可根据已知方法制备。
实施例1 HER2抗原表达
从NCBI获取HER2胞外区蛋白序列,并添加His标签便于纯化;HER2抗原的序列如SEQ ID NO:11所示(见表1)。根据密码子偏好特点优化并合成HER2抗原的核酸序列,将HER2抗原的核酸序列构建至表达载体pcDNA3.1中,稳转入CHO细胞中,再筛选高表达的细胞株。收获细胞上清,镍柱纯化蛋白即得HER2抗原。
实施例2重组人源化抗HER2抗体的载体的构建
根据密码子偏好特点优化并合成抗体轻链和抗体重链的核酸序列。参照Wood etal.,High level synthesis of immunoglobulins in Chinese hamster ovary cells,JImmunol.145(9):3011(1990)等方法,分别将抗体轻链和抗体重链的核酸序列构建至表达载体中:含有重链核酸序列的质粒为pHC(如图1所示),含有轻链核酸序列的质粒为pLC(如图2所示);其中,抗HER2抗体的重链序列如SEQ ID NO:9所示,抗HER2抗体的轻链序列如SEQID NO:10所示。采用常规的分子生物学方法,通过酶切将两个质粒pHC和pLC合并成完整的质粒,即得到质粒pHL。本发明涉及的氨基酸序列见表1,对应的核酸序列见表2。
表1抗原或抗体的氨基酸序列
表2抗体的核酸酸序列
实施例3稳定细胞系的构建
酶切质粒pHL,得到线性化的质粒。准备CHO(如CHO-k1细胞)和敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞,采用电穿孔方法将线性化的pHL质粒分别转染两株细胞。电转染之后分别将两种细胞重悬入含有1×GS(Specialty Media,货号为GSS1016-C)的CHO-AGT(Gibco,货号为12490025)培养基中,以每孔2500个细胞的密度均匀分到40块96孔板中,每孔体积为100μL。将细胞培养板放入8%CO2、37℃培养箱培养中,48小时后补加100μL CHO-AGT培养基(含有1×GS和终浓度为50μM的MSX(甲硫氨酸亚砜胺))继续培养。16-20天后,96孔细胞培养板中的细胞约形成肉眼可见的细胞克隆团。采用ELISA方法技术筛选出高表达的多株细胞,并逐级扩大培养,获得目的蛋白。CHO细胞表达的抗体命名为BAT0303,敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞表达的抗体命名为BAT0303F。其中,CHO的α-(1,6)-岩藻糖转移酶基因FUT8的敲除方法可参考专利WO2019029713A。细胞培养液上清经Protein A、阴离子、阳离子层析等步骤得到纯化后的抗体。
实施例4抗体分子量的测定
将抗体稀释到1mg/ml,采用C4色谱柱进行有效地分离,采用LC-MS进行定性检测。流动相为:A相为0.1%FA(甲酸)/超纯水,B相为0.1%FA/乙腈;色谱柱为Waters ACQUITYC4(2.1×100mm,1.7μm),柱温为70℃,流速为0.3ml/min,进样量:5μl(即5μg)。采用UNIFI处理UNIFI采集的数据。
如表3所示,抗体BAT0303F的分子量与理论值差异在2Da左右,属于正常误差范围内,符合要求。
表3 BAT0303F完整分子量结果
实施例5糖基化修饰检测
表4仅列出了一组抗体BAT0303F的部分糖型百分含量;其中,G0糖型的含量不低于60%,G0-GN糖型的含量为4%-7%,G1糖型的含量为8%-12%,G1'糖型的含量为6%-12%,G2糖型的含量不高于3%。
表4部分糖型百分含量
注:表中ND表示未检测到。
实施例6酸碱峰测定
1)采用ProPacTM WCX-10色谱柱(4×250mm,10μm),流动相A:20mmol/L磷酸钠缓冲液,pH7.0,流动相B:20mmol/L磷酸钠缓冲液,100mmol/L NaCl,pH7.0,流速:0.8ml/min,保留时间为5-35min:10%-50%流动相B,280nm进行离子交换色谱分析。分别选择两批次BAT0303F和两批次进行检测,BAT0303F与的检测结果如表5所示。
表5峰值百分含量
注:表中数据是通过电脑积分,保留小数点后两位。
2)CBP酶切鉴定:取待测样品适量,用流动相A(20mmol/L磷酸钠缓冲液)稀释,加入5mg/mL CBP(上海雅心生物技术有限公司重组羧肽酶B,RCPB01),使待测样品与CBP的质量比为50:1,抗体终浓度为1mg/mL,混匀,37℃水浴孵化30min,采用上述的离子交换色谱进行分析,BAT0303F与的检测结果如表6所示(碱峰含量减少是相对于表5中碱峰)。
表6峰值百分含量
注:表中数据是通过电脑积分,保留小数点后两位。
实施例6抗体的结合活性
采用PBS配置0.75μg/mL Her2抗原包被液,每孔铺100μL,4℃包被过夜。随后采用3%BSA 37℃封闭2h,梯度稀释BAT0303F和BAT0303抗体的起始浓度为2μg/mL,共9个梯度。按1:10000加入HRP标记的anti-Fc二抗(sigma,货号为A7164-1ML),37℃孵育1h。去除上清,PBST(含0.05%Tween-20的PBS缓冲液)洗多遍,加入TMB显色液,37℃孵育5-10min,随后加入2M H2SO4终止显色。采用酶标仪测定,同时读取各孔的吸光度值,检测波长为450nm。
实施例7亲和力的测定
采用BIAcore(GE Healthcare,T200)检测抗体BAT0303F与HER2抗原的体外结合活性。将待测抗体用HBS-EP(0.01M HEPES,0.15M NaCl,3mM EDTA,0.005%P20,pH 7.4)稀释至5μg/mL,HER2-His抗原采用HBS-EP稀释至100nM,并以此为起始浓度作2倍梯度稀释,获得100、50、25、12.5、6.25、3.125nM的HER2-His稀释液。采用Protein A(GE Healthcare,货号为29127555)芯片进行检测,5μg/ml抗体稀释液以10μl/min的流速通过实验流路(Fc2、Fc4),捕获15s使捕获量约为600RU;之后流速调为30μl/min,依次进不同浓度的抗原稀释液(0、3.125、6.25、12.5、25、50、100nM),同时经过实验流路(Fc2、Fc4)和参比流路(Fc1、Fc3)表面,结合时间180s,解离时间600s,最后进Glycine 1.5缓冲液60s对芯片进行再生并进入下一个循环。采用数据分析软件Evaluation Software3.1对试验结果进行分析,将样品试验流路采集所得传感信号进行参比流路、样品空白双扣减,并选用动力学“1:1”模型进行拟合,得出各抗体样品对HER2亲和结合的动力学参数。
表7亲和结合的动力学参数
注:ka为结合速率;kd为解离速率;KD为结合解离平衡常数,也即亲和力。
实施例8细胞增殖抑制作用
提前培养细胞MDA-MB-175VII细胞(来自国家实验细胞资源共享服务平台),当细胞铺满培养板至60%-80%时,消化细胞,用含10%FBS的培养基终止消化,使用含2%FBS的培养基将细胞密度调整至6×104个/mL,按照6000个/孔的密度将细胞铺于96孔细胞培养板。培养箱培养12-24h后,加入待检抗体测样品梯度稀释,培养箱培养三天后,弃上清,加入含10%CCK8(厂家为DOJINDO,CK04)的培养基后培养箱显色2-4h,酶标仪读取OD450值。
如图4所示,抗体BAT0303F和BAT0303能特异性地结合HER2胞外结构域II,从而抑制MDA-MB-175VII细胞的增殖。
实施例9体外ADCC效应测定
HCC1954细胞(南京科佰)和NCI-N87细胞(来自中国科学院典型培养物保藏委员会细胞库)均为HER2抗原高表达的细胞株,当细胞生长状态较佳时,消化细胞并按照6000个/孔的密度铺板,同时按照PBMC(外周血单个细胞)30000个/孔的密度与靶细胞(HCC1954细胞和NCI-N87细胞)共培养3-4个小时,随后梯度稀释抗体BAT0303和BAT0303F,以及曲妥珠的类似药BAT-Her(BAT-Her抗体序列与曲妥珠单抗的序列相同,BAT-Her由CHO细胞表达),37℃培养箱孵育3天,去上清,加入含10%CCK8的培养基,孵育2-4h,酶标仪读取OD450值。
如图5和图6所示,抗体BAT0303与BAT-Her的ADCC效应较为类似,但抗体BAT0303F对靶细胞的杀伤作用远强于抗体BAT0303和BAT-Her。
实施例10与BAT-Her的协同药效测定
BAT0303F和BAT-Her分别靶向HER2的结构域II和结构域IV,二者通过不同的作用机理抑制细胞增殖,本实施例中探究BAT0303F是否与BAT-Her有协同作用。在NCI-N87细胞中,提前铺板,分别加入BAT0303F、BAT-Her和BAT0303F+BAT-Her的抗体梯度稀释液。培养箱培养3天后,去上清、并分别加入含10%CCK8的培养基,显色3-5h后酶标仪读取OD450值。
如图7所示,抗体BAT0303F和BAT-Her均能抑制NCI-N87的生长,抗体BAT0303F和BAT-Her二者联合给药能显著抑制NCI-N87的生长。
实施例11受体亲和力检测
为了测定抗体BAT0303F与Fc受体及补体C1q亲和力,采用BLI(Bio-LayerInterferometry,生物膜层表面干涉)技术,检测并比较了抗体BAT0303F、与新生儿Fc受体蛋白Rn(FcRn,ACROBiosystems公司的Cat#FCM-H82W4)、Fc受体蛋白gamma IIIa(FcγRIIIa,ACROBiosystems公司的Cat#CDA-H82E9)、FcγRIIa(ACROBiosystems公司的Cat#CDA-H82E6)及补体C1q(quidel公司的Cat#A-400)的亲和力的异同。采集数据后,用仪器的数据分析软件Acquisition 8.2对数据进行分析,以Baseline采集所得信号为基线、扣减参比信号,对所得数据进行群组分析并进行拟合。
如表8所示,与相比,抗体BAT0303F与受体FcγRIIIa(V158)的亲和力有显著的提升,但对其他几个受体的亲和力没有显著差异;抗体敲除岩藻糖后,特异性地提高抗体与FcγRIIIa(V158)的亲和力。
表8 BAT0303F与Fc受体及C1q亲和力结果
实施例12移植瘤药效
Calu-3细胞(人非小细胞肺癌细胞)培养在含10%胎牛血清的MEM培养液(添加有0.01mM NEAA)培养中,收集指数生长期的Calu-3细胞,PBS重悬至适合浓度后用于BALB/cnude裸鼠(北京安凯毅博生物技术有限公司)皮下肿瘤接种。
实验小鼠于右侧背部前肩胛骨皮下接种1×107Calu-3细胞,细胞重悬在1:1的PBS与基质胶中(0.2mL/只),并定期观察肿瘤生长情况;待肿瘤生长至平均体积约为185mm3时,根据肿瘤大小和小鼠体重随机分组给药。分组当天设定为Day 0,给药开始于Day 0。每周给药一次,共给药四次,在第21天时停止给药,给药结束后继续观察其抑瘤作用,直到D35天;肿瘤抑制作用的结果见表9和图8。
表9
注:a.数据以“平均值±标准误差”表示;b.停止给药周期后(Day28)平均肿瘤体积;c.TGI%=[1-(Ti-T0)/(Ci-C0)]×100,其中T0及C0分别是给药组及溶媒对照组分组当天Day 0的平均肿瘤体积,Ti及Ci分别是给药组及溶媒对照组Day 53时的平均肿瘤体积;d.*P<0.05,**P<0.01,***P<0.001,nsP>0.05与溶媒对照组肿瘤体积相比(第53天)。
如表9所示,抗体BAT0303F给药组能显著抑制肿瘤细胞的生长,抗体BAT0303F在5mg/kg的给药剂量下,即能最大程度抑制移植瘤的生长,达到饱和剂量;如图8所示,荷瘤小鼠在抗体BAT0303F所有测试剂量下耐受良好。
实施例13临床研究
本研究是一项开放、剂量递增的研究BAT0303F抗体用于局部晚期/转移性HER2阳性实体瘤患者的安全性、耐受性和药代动力学特征的I期临床试验。
本研究采用的给药方式为:静脉输液,每周期第一天给药,每周期14天。剂量依次设置为1mg/kg、3mg/kg、6mg/kg、10mg/kg、15mg/kg,1mg/kg和3mg/kg剂量组采用快速爬坡方式,6mg/kg剂量组开始按“3+3”方式爬坡方式。
抗肿瘤疗效的评价指标包括:
最佳整体应答(Best Overall Response,BOR):完全缓解(CR)、部分缓解(PR)、疾病稳定(SD)和疾病进展(PD);
客观缓解率(Objective Response Rate,ORR):完全缓解(CR)和部分缓解(PR)占受试者的比率;
缓解持续时间(Duration of Response,DOR);
疾病进展时间:给药期间的无进展生存期(PFS)。
入选标准
受试者需要满足以下全部标准方可入选:
1)经组织病理学和/或细胞学确诊为HER2阳性的晚期实体瘤患者(优选乳腺癌、胃癌)。HER2阳性(HER2阳性定义为FISH+、或IHC3+、或IHC2+且进行基因扩增检测结果为阳性);
2)按照RECIST(实体瘤疗效评价标准)1.1版的标准具有至少1个可测量病灶的肿瘤;
3)美国东部肿瘤协作组(ECOG)体力状况评分0-1分;
4)具备足够的骨髓、肝、肾及凝血功能,定义如下:
5)超声心动检查左心室射血分数(LVEF)≥50%。
退出标准
若受试者在治疗期间出现以下任一情况,可考虑让其退出本研究:
1)任何AE导致受试者不能继续参与本研究;
2)任何原因导致受试者研究治疗延迟21天以上;
3)并发疾病或者受试者病情改变,研究者认为受试者不再适合研究治疗;
4)哺乳或怀孕;
5)受试者对于研究程序和研究治疗的依从性差;
6)受试者或研究者要求停止研究治疗;
7)受试者因任何原因,要求采取其他抗肿瘤药物或措施;
8)疾病进展,需要采取其他抗肿瘤治疗;
9)其它原因。
序列表
<110> 百奥泰生物制药股份有限公司
<120> 抗HER2抗体及其应用
<150> CN202010739418.X
<151> 2020-07-28
<160> 13
<170> SIPOSequenceListing 1.0
<210> 1
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Gly Phe Thr Phe Thr Asp Tyr Thr
1 5
<210> 2
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe Lys
1 5 10 15
<210> 3
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Leu Gly Pro Ser Phe Tyr Phe Asp Tyr
1 5
<210> 4
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Lys Ala Ser Gln Asp Val Ser Ile Gly Val Ala
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Ala Ser Tyr Arg Tyr Thr Gly
1 5
<210> 6
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Gln Tyr Tyr Ile Tyr Pro Tyr Thr Phe
1 5 10
<210> 7
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 8
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 9
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 10
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 11
<211> 636
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Thr Gln Val Cys Thr Gly Thr Asp Met Lys Leu Arg Leu Pro Ala Ser
1 5 10 15
Pro Glu Thr His Leu Asp Met Leu Arg His Leu Tyr Gln Gly Cys Gln
20 25 30
Val Val Gln Gly Asn Leu Glu Leu Thr Tyr Leu Pro Thr Asn Ala Ser
35 40 45
Leu Ser Phe Leu Gln Asp Ile Gln Glu Val Gln Gly Tyr Val Leu Ile
50 55 60
Ala His Asn Gln Val Arg Gln Val Pro Leu Gln Arg Leu Arg Ile Val
65 70 75 80
Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr Ala Leu Ala Val Leu Asp
85 90 95
Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro Val Thr Gly Ala Ser Pro
100 105 110
Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser Leu Thr Glu Ile Leu Lys
115 120 125
Gly Gly Val Leu Ile Gln Arg Asn Pro Gln Leu Cys Tyr Gln Asp Thr
130 135 140
Ile Leu Trp Lys Asp Ile Phe His Lys Asn Asn Gln Leu Ala Leu Thr
145 150 155 160
Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys His Pro Cys Ser Pro Met
165 170 175
Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser Ser Glu Asp Cys Gln Ser
180 185 190
Leu Thr Arg Thr Val Cys Ala Gly Gly Cys Ala Arg Cys Lys Gly Pro
195 200 205
Leu Pro Thr Asp Cys Cys His Glu Gln Cys Ala Ala Gly Cys Thr Gly
210 215 220
Pro Lys His Ser Asp Cys Leu Ala Cys Leu His Phe Asn His Ser Gly
225 230 235 240
Ile Cys Glu Leu His Cys Pro Ala Leu Val Thr Tyr Asn Thr Asp Thr
245 250 255
Phe Glu Ser Met Pro Asn Pro Glu Gly Arg Tyr Thr Phe Gly Ala Ser
260 265 270
Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu Ser Thr Asp Val Gly Ser
275 280 285
Cys Thr Leu Val Cys Pro Leu His Asn Gln Glu Val Thr Ala Glu Asp
290 295 300
Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys Pro Cys Ala Arg Val Cys
305 310 315 320
Tyr Gly Leu Gly Met Glu His Leu Arg Glu Val Arg Ala Val Thr Ser
325 330 335
Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys Lys Ile Phe Gly Ser Leu
340 345 350
Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp Pro Ala Ser Asn Thr Ala
355 360 365
Pro Leu Gln Pro Glu Gln Leu Gln Val Phe Glu Thr Leu Glu Glu Ile
370 375 380
Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro Asp Ser Leu Pro Asp Leu
385 390 395 400
Ser Val Phe Gln Asn Leu Gln Val Ile Arg Gly Arg Ile Leu His Asn
405 410 415
Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu Gly Ile Ser Trp Leu Gly
420 425 430
Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly Leu Ala Leu Ile His His
435 440 445
Asn Thr His Leu Cys Phe Val His Thr Val Pro Trp Asp Gln Leu Phe
450 455 460
Arg Asn Pro His Gln Ala Leu Leu His Thr Ala Asn Arg Pro Glu Asp
465 470 475 480
Glu Cys Val Gly Glu Gly Leu Ala Cys His Gln Leu Cys Ala Arg Gly
485 490 495
His Cys Trp Gly Pro Gly Pro Thr Gln Cys Val Asn Cys Ser Gln Phe
500 505 510
Leu Arg Gly Gln Glu Cys Val Glu Glu Cys Arg Val Leu Gln Gly Leu
515 520 525
Pro Arg Glu Tyr Val Asn Ala Arg His Cys Leu Pro Cys His Pro Glu
530 535 540
Cys Gln Pro Gln Asn Gly Ser Val Thr Cys Phe Gly Pro Glu Ala Asp
545 550 555 560
Gln Cys Val Ala Cys Ala His Tyr Lys Asp Pro Pro Phe Cys Val Ala
565 570 575
Arg Cys Pro Ser Gly Val Lys Pro Asp Leu Ser Tyr Met Pro Ile Trp
580 585 590
Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln Pro Cys Pro Ile Asn Cys
595 600 605
Thr His Ser Cys Val Asp Leu Asp Asp Lys Gly Cys Pro Ala Glu Gln
610 615 620
Arg Ala Ser Pro Leu Thr His His His His His His
625 630 635
<210> 12
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
gatatccaga tgacccagag cccttcctcc ctgagcgcta gcgtgggcga ccgggtgacc 60
atcacctgca aggctagcca ggacgtgtcc atcggcgtgg cctggtacca gcagaagccc 120
ggcaaggccc ccaagctgct gatctactcc gcttcctatc ggtataccgg cgtgccttcc 180
aggttctccg gcagcggctc cggcaccgac ttcaccctga ccatctcctc cctgcagcct 240
gaggacttcg ccacctacta ctgtcagcag tactacatct acccttacac cttcggccag 300
ggcaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 13
<211> 1347
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
gaggtgcagc tggtggagtc cggcggcgga ctggtgcagc caggaggaag cctgaggctg 60
tcctgcgccg ctagcggctt caccttcacc gattacacca tggactgggt gaggcaggcc 120
cctggcaagg gcctggagtg ggtggctgac gtgaatccca atagcggcgg ctccatctac 180
aatcagaggt tcaagggcag gtttaccctg tccgtggata ggagcaagaa taccctgtac 240
ctgcagatga actccctgag ggccgaggac accgccgtgt attattgtgc tcggaatctg 300
ggccctagct tttatttcga ttattggggc cagggtaccc tggtcaccgt gtctagtgct 360
agtactaagg ggccttcagt gtttccactg gcaccctcat ccaaatccac cagcggcgga 420
acagcagccc tgggttgtct ggtgaaggac tacttcccag aacccgtcac cgtgtcatgg 480
aactccggcg cactgacatc tggagtccac acttttcctg ccgtgctgca gagctctggg 540
ctgtactccc tgagttcagt ggtcactgtc ccatccagct ctctgggtac acagacttat 600
atctgcaacg tgaatcacaa gccaagtaat accaaagtcg acaagaaagt ggagcccaag 660
tcatgtgata aaacccatac atgcccccct tgtcctgcac cagaactgct gggaggtcca 720
agcgtgttcc tgtttccacc caagcctaaa gacacactga tgattagtag gactcccgag 780
gtcacctgcg tggtcgtgga cgtgtcccac gaggatcctg aagtcaagtt taactggtac 840
gtggatggcg tcgaagtgca taatgctaag accaaaccaa gagaggaaca gtacaactcc 900
acttatcgcg tcgtgagcgt cctgaccgtg ctgcatcagg attggctgaa cggcaaggag 960
tataagtgca aagtgagcaa taaggctctg cccgcaccta tcgagaaaac catttctaag 1020
gcaaaaggac agcctcgaga accacaggtg tacacactgc ctccaagccg tgaggaaatg 1080
accaagaacc aggtctctct gacatgtctg gtgaaaggct tctatccttc agacattgct 1140
gtggagtggg aatccaatgg acagccagag aacaattaca agaccacacc ccctgtgctg 1200
gacagcgatg gctctttctt tctgtattct aagctgaccg tggataaaag tcggtggcag 1260
cagggaaatg tcttttcttg tagtgtgatg cacgaagcac tgcacaacca ctacacccag 1320
aaatcactgt cactgtctcc agggaag 1347
Claims (17)
1.一种抗体,其特征在于,所述抗体特异性结合HER2,并且包含:(a)HCDR1,其包含SEQID NO:1所示的序列,(b)HCDR2,其包含SEQ ID NO:2所示的序列,(c)HCDR3,其包含SEQ IDNO:3所示的序列,(d)LCDR1,其包含SEQ ID NO:4所示的序列,(e)LCDR2,其包含SEQ ID NO:5所示的序列,(f)LCDR3,其包含SEQ ID NO:6所示的序列;
所述抗体的岩藻糖基化水平为0%-5%。
2.如权利要求1所述的抗体,其特征在于,所述抗体的岩藻糖基化水平为0%。
3.一种抗体,其特征在于,所述抗体特异性结合HER2,并且包含:(a)HCDR1,其包含SEQID NO:1所示的序列,(b)HCDR2,其包含SEQ ID NO:2所示的序列,(c)HCDR3,其包含SEQ IDNO:3所示的序列,(d)LCDR1,其包含SEQ ID NO:4所示的序列,(e)LCDR2,其包含SEQ ID NO:5所示的序列,(f)LCDR3,其包含SEQ ID NO:6所示的序列;
所述抗体包含不低于60%的G0。
4.如权利要求3所述的抗体,其特征在于,所述抗体的G0糖型的含量为61%-75%。
5.如权利要求3所述的抗体,其特征在于,所述抗体的G0糖型的含量为72%-73%。
6.如权利要求1-5任一项所述的抗体,其特征在于,G0-GN糖型的含量为3%-7%,G1糖型的含量为6%-12%,G1'糖型的含量为6%-12%,G2糖型的含量不高于3%。
7.如权利要求6所述的抗体,其特征在于,G0-GN糖型的含量为5%-6%,G1糖型的含量为8%-9%,G1'糖型的含量为8%-9%,G2糖型的含量为0-1%。
8.如权利要求1-7任一项所述的抗体,其特征在于,所述抗体的重链可变区包含如SEQID NO:7所示的序列,与SEQ ID NO:7所示序列具有至少80%同一性的序列,或与SEQ IDNO:7所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链可变区包含SEQ ID NO:8所示的序列,与SEQ ID NO:8所示序列具有至少80%同一性的序列,或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的序列。
9.如权利要求8所述的抗体,其特征在于,所述抗体的重链包含如SEQ ID NO:9所示的序列,与SEQ ID NO:9所示序列具有至少80%同一性的序列,或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链包含SEQ ID NO:10所示的序列,与SEQ ID NO:10序列具有至少80%同一性的序列,或与SEQ ID NO:10序列相比具有一个或多个保守氨基酸取代的序列。
10.如权利要求1-9任一项所述的抗体,其特征在于,所述抗体由敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞表达。
11.一种抗体组合物,其特征在于,所述抗体组合物中抗体特异性结合HER2,并且包含:(a)HCDR1,其包含SEQ ID NO:1所示的序列,(b)HCDR2,其包含SEQ ID NO:2所示的序列,(c)HCDR3,其包含SEQ ID NO:3所示的序列,(d)LCDR1,其包含SEQ ID NO:4所示的序列,(e)LCDR2,其包含SEQ ID NO:5所示的序列,(f)LCDR3,其包含SEQ ID NO:6所示的序列;
所述抗体组合物中主峰的含量至少为72%。
12.如权利要求11所述的抗体组合物,其特征在于,所述抗体组合物中主峰的含量为73%-82%。
13.如权利要求11或12所述的抗体组合物,其特征在于,所述抗体组合物中碱性变异体的含量不高于6%。
14.如权利要求11-13任一项所述的抗体组合物,其特征在于,所述抗体的重链可变区包含如SEQ ID NO:7所示的序列,与SEQ ID NO:7所示序列具有至少80%同一性的序列,或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链可变区包含SEQ ID NO:8所示的序列,与SEQ ID NO:8所示序列具有至少80%同一性的序列,或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的序列。
15.如权利要求14所述的抗体,其特征在于,所述抗体的重链包含如SEQ ID NO:9所示的序列,与SEQ ID NO:9所示序列具有至少80%同一性的序列,或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的序列;和/或
所述抗体的轻链包含SEQ ID NO:10所示的序列,与SEQ ID NO:10序列具有至少80%同一性的序列,或与SEQ ID NO:10序列相比具有一个或多个保守氨基酸取代的序列。
16.如权利要求11-15任一项所述的抗体组合物,其特征在于,所述抗体由敲除了α-(1,6)-岩藻糖转移酶基因FUT8的CHO细胞表达。
17.一种药物组合物,其特征在于,所述药物组合物包含权利要求1-10任一项所述的抗体或权利要求11-16任一项所述的抗体组合物,以及药学上可接受的载体。
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US (1) | US20230279144A1 (zh) |
EP (1) | EP4190818A1 (zh) |
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US6130364A (en) | 1995-03-29 | 2000-10-10 | Abgenix, Inc. | Production of antibodies using Cre-mediated site-specific recombination |
US6420140B1 (en) | 1996-10-11 | 2002-07-16 | Abgenix, Inc. | Production of multimeric protein by cell fusion method |
CN104394887A (zh) * | 2012-07-18 | 2015-03-04 | 葛莱高托普有限公司 | 采用具有低岩藻糖化的抗her2抗体的新治疗性疗法 |
AR094781A1 (es) * | 2013-02-13 | 2015-08-26 | Laboratoire Français Du Fractionnement Et Des Biotechnologies | Anticuerpos anti-her2 (receptor 2 del factor de crecimiento epidérmico humano) altamente galactosilados y sus usos |
CN107446045A (zh) * | 2016-07-22 | 2017-12-08 | 北京天广实生物技术股份有限公司 | 一种抗her2的抗体、其药物组合物及用途 |
CN106543286A (zh) * | 2016-12-07 | 2017-03-29 | 上海邦耀生物科技有限公司 | 一种去岩藻糖抗her2抗体及其应用 |
CN107881160A (zh) | 2017-08-11 | 2018-04-06 | 百奥泰生物科技(广州)有限公司 | 一种由基因组被编辑的cho宿主细胞产生的具有独特糖谱的重组抗体及其制备方法 |
CN112153988A (zh) * | 2018-05-17 | 2020-12-29 | 博尔特生物治疗药物有限公司 | 免疫缀合物 |
CN110522909B (zh) * | 2019-09-30 | 2024-02-20 | 安徽省立医院 | 一种协同增强抗her2阳性肿瘤效果的药物组合 |
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2021
- 2021-07-27 WO PCT/CN2021/108724 patent/WO2022022526A1/zh active Application Filing
- 2021-07-27 EP EP21850196.3A patent/EP4190818A1/en active Pending
- 2021-07-27 US US18/007,262 patent/US20230279144A1/en active Pending
- 2021-07-27 CN CN202110852970.4A patent/CN113999313A/zh active Pending
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