CN117180420A - 一种稳定的抗cldn18.2和cd47双特异性抗体的液体制剂及其应用 - Google Patents
一种稳定的抗cldn18.2和cd47双特异性抗体的液体制剂及其应用 Download PDFInfo
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Abstract
本发明公开了一种稳定的抗CLDN18.2和CD47双特异性抗体的液体制剂,所述的液体制剂包括如下浓度的组分:抗CLDN18.2和CD47双特异性抗体15~25mg/mL、缓冲剂10~40mM和稳定剂125~260mM;所述的液体制剂的pH值为4.5~7.5。本发明还公开了上述液体制剂在制备预防和/或治疗肿瘤的药物中的应用。本发明的抗CLDN18.2和CD47双特异性抗体的液体制剂,其稳定性好,在40℃剧烈条件下,可以稳定保存1个月,且SEC纯度检测结果显示所述的液体制剂中抗CLDN18.2和CD47双特异性抗体的纯度仍高达93.0%以上。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种稳定的抗CLDN18.2和CD47双特异性抗体的液体制剂及其应用。
背景技术
CLDN18.2属于紧密连接蛋白(Claudins/CLDNs)家族成员,主要在机体的上皮细胞中表达。CLDN蛋白异常可导致上皮细胞结构破坏及功能受损,造成细胞间黏附力下降、极性丧失,使细胞的正常分化缺失并获得侵袭性,导致多种肿瘤的发生和发展,也与肿瘤的侵袭和转移存在一定的关系。CLDN18是CLDN蛋白家族成员之一,在人体中CLDN18.1和CLDN18.2的表达具有组织特异性,CLDN18.1主要表达在肺组织中,CLDN18.2作为一个高度特异性的细胞表面分子,在正常的组织中仅表达在分化的胃粘膜和小肠上皮细胞上,其构成了细胞旁屏障,控制细胞间分子的流动。该分子具有四个跨膜结构域,NH2端和COOH端位于胞内。在原发性胃癌及其转移后癌症中大部分都表达CLDN18.2分子,另外在胰腺癌、食管癌、卵巢癌、胆管癌中也常常观察到CLDN18.2被激活表达。CLDN18.2的激活表达依赖于转录因子环腺苷酸应答元件结合蛋白结合到其基因未甲基化的蛋白结合位点上。由于CLDN18.2在正常组织表达的高度特异性及在多种癌症中被激活表达,因此CLDN18.2成为极具潜力的治疗靶点。
CD47是一个具有胞外N-末端IgV结构域、5个跨膜结构域和胞内C-末端的跨膜蛋白,也被称为整合素相关蛋白(IAP),属于免疫球蛋白超家族,广泛表达于多种正常细胞表面,介导凋亡、增殖、免疫等一系列反应,而且还在免疫和血管新生响应中发挥着重要作用。SIRPα(信号调节蛋白α,signal regulated protein alpha)是一种在巨噬细胞和其他髓系免疫细胞上表达的抑制性受体。CD47通过与巨噬细胞表面的SIRPα连接,使SIRPα胞内ITIM发生磷酸化,并产生一系列的级联反应抑制巨噬细胞的吞噬作用,从而避免误伤正常细胞。CD47在多种实体瘤细胞及恶性血液瘤细胞上呈现高表达,而且其表达水平与疾病进展呈正相关。肿瘤细胞上高表达的CD47结合SIRPα后能够避免巨噬细胞吞噬清除,发生免疫逃逸。因此,阻断CD47-SIRPα信号通路能够避免免疫逃逸,解除免疫抑制,激活巨噬细胞、T细胞,恢复肿瘤细胞杀伤能力。
CLDN18.2与CD47两个靶点前者特异存在于肿瘤细胞表面,后者于免疫微环境高度相关,同时攻击两者在抗肿瘤靶向治疗方面存在可预见的协同作用。抗CLDN18.2和CD47双特异性抗体可以选择性地靶向表达CLDN18.2和CD47的癌细胞,可通过ADCC、ADCP等Fc端功能对肿瘤细胞进行杀伤,并阻断靶细胞上的CD47/SIRPα相互作用,激活针对该细胞的先天免疫系统,进一步杀伤靶细胞。并且一条臂与CLDN18.2结合且另一臂与CD47结合的双特异性抗体在选择性靶向表达两种抗原的细胞时,在亲和力方面,与任一臂相比,双特异性抗体与同时表达两者抗原的细胞上的两种抗原结合可导致亲和力增加。且预计双特异性抗体可对仅表达CD47(但不表达CLDN18.2)的细胞具有较弱的活性。这可以帮助避免靶向表达某些CD47但不表达CLDN18.2的正常细胞,可以增加抗CLDN18.2和CD47双特异性抗体的安全性和/或耐受性。
专利WO2021003082就公开了一种抗CLDN18.2与CD47的双特异性抗体,该抗体能够结合表达CLDN18.2和CD47的癌细胞,诱导ADCC作用,并阻断CD47与SIRPα的结合,诱导巨噬细胞介导的吞噬作用,且与人类红细胞的结合极少,毒性较低,与上述猜测相符合。但未知此类双特异性抗体在体内抗肿瘤效果如何,在体内的复杂环境中是否还能维持体外实验的结果。
抗体的本质是蛋白质,具有确定的一级、二级、三级和高级结构,这些特定的结构使蛋白质药物在体内发挥生物学功能。与传统化药小分子药物相比,复杂大分子蛋白药物的稳定性差,易导致结构和功能改变,进而影响药物的有效性和安全性。而双特异性抗体相对于普通抗体的特异性及靶向性均具有优势,但因其结构复杂,在生产及存储中容易发生聚集变性或氧化、脱酰胺等化学反应,导致产品的安全性和有效性受到影响。因此,开发稳定的制剂配方,是蛋白类药物开发的重要环节。
发明内容
本申请的发明人经过广泛的研究发现,抗CLDN18.2和CD47双特异性抗体与特定浓度的缓冲剂、稳定剂、抗氧剂、表面活性剂组成的液体制剂在pH为5.0~6.0的条件下,在外观、不溶性微粒检测、40℃下放置4周后的SEC纯度、以及25℃下以及2~8℃条件下分别放置6个月后的SEC纯度等方面均具有优异的稳定性。因此,本发明的首要目的是提供一种稳定的抗CLDN18.2和CD47双特异性抗体的液体制剂及其应用,以解决现有的抗CLDN18.2和CD47双特异性抗体的稳定性差、容易导致结构和功能改变的问题。
为解决上述技术问题,本发明提供的技术方案之一为:一种稳定的抗CLDN18.2和CD47双特异性抗体的液体制剂,所述的液体制剂包括:抗CLDN18.2和CD47双特异性抗体、缓冲剂和稳定剂;其中,
所述抗CLDN18.2和CD47双特异性抗体的浓度为15~25mg/mL,较佳地为18~22mg/mL,更佳地为19~21mg/mL,非限制性实施例包括19mg/mL、20mg/mL、21mg/mL;
所述缓冲剂的浓度为10~40mM,较佳地为15~35mM,更佳地为15~30mM,非限制性实施例包括15mM、20mM、25mM、30mM;和,
所述稳定剂的浓度为125~260mM,较佳地为180~250mM,更佳地为210~230mM,非限制性实施例包括210mM、215mM、220mM、225mM、230mM;
所述的液体制剂的pH值为4.5~7.5,较佳地为5.0~6.5,更佳地为5.0~6.0,非限制性实施例包括5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0。
在本发明的实施方案中,所述的双特异性抗体包含特异性结合CD47的第一抗原结合域和特异性结合CLDN 18.2的第二抗原结合域;其中,
所述第一抗原结合域的LCDR1的氨基酸序列如SEQ ID NO:1所示,LCDR2的氨基酸序列如SEQ ID NO:2所示,LCDR3的氨基酸序列如SEQ ID NO:3所示,HCDR1的氨基酸序列如SEQ ID NO:4所示,HCDR2的氨基酸序列如SEQ ID NO:5所示,以及HCDR3的氨基酸序列如SEQID NO:6所示;
较佳地,所述第二抗原结合域包含免疫球蛋白单可变结构域VHH;优选地,所述第二抗原结合域的HCDR1的氨基酸序列如SEQ ID NO:7所示,HCDR2的氨基酸序列如SEQ IDNO:8所示,以及HCDR3的氨基酸序列如SEQ ID NO:9所示;
较佳地,所述第一抗原结合域和第二抗原结合域的轻链可变区和/或重链可变区的框架区为人源框架区;优选地,
所述第一抗原结合域的轻链可变区的氨基酸序列如SEQ ID NO:10所示;和/或,
所述第一抗原结合域的重链可变区的氨基酸序列如SEQ ID NO:12所示;和/或,
所述第二抗原结合域的重链可变区的氨基酸序列如SEQ ID NO:14所示;
较佳地,所述第一抗原结合域的轻链恒定区为人κ轻链恒定区,和/或,所述第一抗原结合域的重链恒定区为人IgG1的重链恒定区;优选地,
所述第一抗原结合域的轻链恒定区的氨基酸序列如SEQ ID NO:11所示;和/或,
所述第一抗原结合域的重链恒定区的氨基酸序列如SEQ ID NO:13所示;
所述第一抗原结合域的重链和所述第二抗原结合域的重链可变区之间用接头连接;
较佳地,所述第二抗原结合域的重链可变区用接头连接在所述第一抗原结合域的重链的C端;
更佳地,第一抗原结合域的重链的氨基酸序列如SEQ ID NO:16所示,和/或,所述接头的氨基酸序列如SEQ ID NO:18所示;
在本发明一较佳实施例中,所述双特异性抗体包含长链和短链,所述短链包含如SEQ ID NO:15所示的氨基酸序列,所述长链包含如SEQ ID NO:17所示的氨基酸序列。
在本发明的实施方案中,所述的缓冲剂选自醋酸盐缓冲剂、琥珀酸盐缓冲剂、枸椽酸盐缓冲剂、组氨酸盐酸盐缓冲剂、组氨酸醋酸盐缓冲剂和磷酸盐缓冲剂中的一种或多种;
较佳地,所述的缓冲剂为组氨酸盐酸盐缓冲剂。
在本发明的实施方案中,所述的稳定剂选自以下组中的一种或多种:糖、多元醇和氨基酸;
较佳地,所述的糖选自麦芽糖、蔗糖和海藻糖中的一种或多种;所述的多元醇为山梨醇;所述的氨基酸为脯氨酸或甘氨酸;
更佳地,所述的糖为海藻糖;所述的氨基酸为脯氨酸。
在一些实施方案中,所述的液体制剂还包括2~70mM的抗氧剂,较佳地为2~20mM,非限制性实施例包括2mM、10mM、15mM、20mM、45mM;所述的抗氧剂选自盐酸精氨酸、甲硫氨酸和氯化钠中的一种或多种;
较佳地,所述的抗氧剂为甲硫氨酸。
在一些实施方案中,所述的液体制剂包括0.01~0.5mg/mL的表面活性剂,较佳地为0.01~0.15mM,更佳地为0.05~0.15mM,非限制性实施例包括0.05mM、0.10mM、0.15mM、0.2mM、0.25mM、0.3mM、0.4mM、0.5mM;所述的表面活性剂为聚山梨酯20或聚山梨酯80;
较佳地,所述的表面活性剂为聚山梨酯80。
在一些实施方案中,所述的液体制剂选自以下组中的一组或多组:
(1)抗CLDN18.2和CD47双特异性抗体和组氨酸盐酸盐缓冲剂;
(2)抗CLDN18.2和CD47双特异性抗体和组氨酸醋酸盐缓冲剂;
(3)抗CLDN18.2和CD47双特异性抗体、组氨酸盐酸盐缓冲剂、蔗糖和聚山梨酯80;
(4)抗CLDN18.2和CD47双特异性抗体、组氨酸盐酸盐缓冲剂、山梨醇、甲硫氨酸和聚山梨酯80;
(5)抗CLDN18.2和CD47双特异性抗体、组氨酸盐酸盐缓冲剂、海藻糖、甲硫氨酸和聚山梨酯80。
在一些实施方案中,所述的液体制剂包括如下浓度的组分:
所述的液体制剂的pH值为5.0~6.0;
其中,在非限制性实施例中:
组氨酸盐酸盐缓冲剂浓度包括10mM、15mM、20mM、25mM、30mM、35mM、40mM;
海藻糖浓度包括210mM、215mM、220mM、225mM、228mM、230mM。
pH值包括5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0。
较佳地,所述的甲硫氨酸浓度为5~10mM(即0.745mg/mL~1.49mg/mL),非限制性实施例包括5mM、6mM、7mM、8mM、9mM、10mM;
所述的聚山梨酯80浓度为0.05~0.1mg/mL,非限制性实施例包括0.05mg/mL、0.06mg/mL、0.07mg/mL、0.08mg/mL、0.09mg/mL、0.1mg/mL;
所述的液体制剂的pH值为5.0。
在一优选实施方案中,所述液体制剂包括如下浓度的组分:
所述的液体制剂的pH值为5.0。
本发明提供的技术方案之二为:如技术方案之一所述的抗CLDN18.2和CD47双特异性抗体的液体制剂在制备预防和/或治疗肿瘤的药物中的应用;
较佳地,所述的肿瘤为CLDN18.2阳性肿瘤;
更佳地,所述的肿瘤为消化系统肿瘤;进一步更佳地,所述消化系统肿瘤选自消化道肿瘤例如胃癌、结直肠癌,以及胰腺癌。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明的积极进步效果在于:
本发明提供的稳定的抗CLDN18.2和CD47双特异性抗体的液体制剂,其有益效果为:稳定性好,在40℃剧烈条件下,可以稳定保存4周,且SEC纯度检测结果显示该制剂中抗CLDN18.2和CD47双特异性抗体的纯度高达93.0%以上。因此,本发明的抗CLDN18.2和CD47双特异性抗体的液体制剂能够保证抗CLDN18.2和CD47双特异性抗体的储存与用药稳定性,具有广阔的工业应用前景。
附图说明
图1a为抗CLDN18.2和CD47双特异性抗体(简称:双抗A)与CLDN18.2亲和力测定Global Fitting 1:1拟合曲线。
图1b为双抗A与CD47亲和力测定。
图1c为ELISA法测定双抗A与CD47的结合活性。
图2a为双抗A在NUGC-4细胞上的阻断人CD47与受体SIRPα结合的能力。
图2b为双抗A在hCLDN18.2-NUGC-4细胞上的阻断人CD47与受体SIRPα结合的能力。
图3a和图3b为双抗A在小鼠体内对肿瘤生长的抑制作用。
图4a为双抗A对BxPC3-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤体积。
图4b为双抗A对BxPC3-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤展示图。
图4c为双抗A对BxPC3-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤重量。
图5为双抗A对BxPC3-hCLDN18.2荷瘤小鼠体重的影响。
图6为双抗A对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤体积。
图7为双抗A对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤展示图。
图8为双抗A对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤重量。
图9为双抗A对HT29-hCLDN18.2荷瘤小鼠体重的影响。
图10为双抗A对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤体积。
图11为双抗A对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤展示图(X表示该小鼠肿瘤完全消除)。
图12为双抗A对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤重量。
图13为双抗A对NUGC-4-hCLDN18.2荷瘤小鼠体重的影响。
图14为给药抗体对HT29-hCLDN18.2小鼠移植瘤的疗效-肿瘤体积。
图15为给药抗体对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤展示图。
图16为给药抗体对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤重量。
图17为给药抗体对HT29-hCLDN18.2荷瘤小鼠体重的影响。
具体实施方式
在本发明中,上述所列CDR的氨基酸序列均是按照Kabat定义规则所示出的。但是,本领域人员公知,在本领域中可以通过多种方法来定义抗体的CDR,例如基于抗体的三维结构和CDR环的拓扑学的Chothia(Chothia等人.(1989)Nature 342:877-883,Al-Lazikani等人,Journal of Molecular Biology,273,927-948(1997))、基于抗体序列可变性的Kabat(Kabat等人,U.S.Department of Health and Human Services,National Institutes ofHealth(1987))、AbM(University of Bath),Contact(University College London)、国际ImMunoGeneTics database(IMGT)(万维网imgt.cines.fr/),以及基于利用大量晶体结构的近邻传播聚类(affinity propagation clustering)的North CDR定义。本领域技术人员应当理解的是,除非另有规定,否则术语给定抗体或其区(例如可变区)的“CDR”及“互补决定区”应理解为涵盖如通过本发明描述的上述已知方案中的任何一种界定的互补决定区。
本发明所用氨基酸三字母代码和单字母代码如本领域技术人员知晓,或参见文献(J.Biol.Chem,243,p3558(1968))中所述。
如本发明所用,“载体”表示构建体,其能够将一种或多种所关注的基因或序列递送入宿主细胞并且优选在宿主细胞中表达所述基因或序列。载体的实例包括但不限于病毒载体、裸DNA或RNA表达载体、质粒、粘粒或噬菌体载体、与阳离子凝聚剂相关的DNA或RNA表达载体、包囊化于脂质体中的DNA或RNA表达载体以及某些真核细胞,例如生产细胞。
在本发明实施例中,实验结束时将各组小鼠安乐处死。使用Excel统计软件:平均值以AVE计算;SD值以STDEV计算;SEM值以STDEV/SQRT(每组动物数)计算;使用GraphPadPrism 6.0软件作图,组间差异P值以Student's t test分析。
在本发明实施例中,肿瘤体积(TV)计算公式为:TV=0.5×长径×短径2。
抑瘤率TGItv(%):用于评价药物抗肿瘤活性的作用,抑瘤率(%)=[1-(TVt-TVinitial)/(CVt-CVinitial)]×100%,其中,TVt表示治疗组每次测量时的肿瘤体积;TVinitial表示分组给药时治疗组的肿瘤体积;CVt表示对照组每次测量时的肿瘤体积;CVinitial表示分组给药时对照组的肿瘤体积。
为进一步阐述本发明所采取的技术手段及其效果,以下结合实施例和附图对本发明作进一步地说明,以下实施例中“双抗A”即为本发明的抗CLDN18.2和CD47的双特异性抗体,本申请人在先专利申请202111214360.8及PCT/CN2022/082008全文为本申请引用和参考。可以理解的是,此处所描述的具体实施方式仅仅用于解释本发明,而非对本发明的限定。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本发明使用的实验材料和试剂如表1所示:
表1:物料信息
物料名称 | 生产厂家 | 货号 |
双抗A | 宝船生物医药科技(上海)有限公司 | N/A |
醋酸 | 湖南尔康制药股份有限公司 | 000320181001 |
醋酸钠(无水) | 南京化学试剂股份有限公司 | 190212019C |
琥珀酸 | 默克化工技术(上海)有限公司 | K50186881829 |
琥珀酸钠 | 默克化工技术(上海)有限公司 | N/A |
枸橼酸 | 湖南华日制药有限公司 | 20180307 |
枸橼酸钠 | 湖南华日制药有限公司 | 20180803 |
磷酸二氢钠(一水) | 湖南九典制药股份有限公司 | 201905I01 |
磷酸氢二钠(无水) | 湖南九典制药股份有限公司 | 201904G01 |
组氨酸 | 上海味之素氨基酸有限公司 | 18HB12A003 |
盐酸组氨酸 | 上海味之素氨基酸有限公司 | 19HH12B035 |
麦芽糖 | 湖南九典宏阳制药股份有限公司 | TF03190701 |
蔗糖 | Pfanstiehl,Inc. | 35793A |
海藻糖 | Pfanstiehl.Inc. | 36831A |
山梨醇 | 罗盖特(中国)精细化工有限公司 | E165F |
脯氨酸 | Avantor | 194152 |
甘氨酸 | 湖北省八峰药化股份有限公司 | 201903051 |
氯化钠 | 江苏勤奋药业有限公司 | 20180122 |
盐酸精氨酸 | 默克化工技术(上海)有限公司 | K48810044 721 |
甲硫氨酸 | 湖北省八峰药化股份有限公司 | 201912271 |
聚山梨酯80(II) | 南京威尔药业股份有限公司 | 20190502-2 |
制备实施例1:
1.抗CLDN18.2和CD47双特异性抗体(简称:双抗A)的制备
(1)抗体表达质粒的构建
将抗体重链和轻链基因分别连接到克隆T载体并经测序确认,利用限制性内切酶NheⅠ和SalⅠ将轻链和重链基因分别亚克隆到Mu-H和/>Mu-P表达载体并经测序和酶切确认后,最终获得重组质粒。
(2)抗体的表达
重组质粒通过电穿孔方式共转染至CHO-K1宿主细胞以表达,并用本领域常规方法进行亲和纯化。
双抗A的序列和结构
结合CLDN18.2的臂采用一种特异性识别人CLDN18.2而不识别CLDN18.1的抗CLDN18.2单域抗体NA3S-H1(CDR1、CDR2和CDR3的氨基酸序列分别示于SEQ ID NO:7、8和9;VHH的氨基酸序列示于SEQ ID NO:14),结合CD47的臂采用抗CD47人源化抗体A7H3L3的抗原结合结构域(HCDR1、HCDR2和HCDR3的氨基酸序列分别示于SEQ ID NO:4、5和6;LCDR1、LCDR2和LCDR3的氨基酸序列分别示于SEQ ID NO:1、2和3;重链可变区的氨基酸序列示于SEQ IDNO:12,轻链可变区的氨基酸序列示于SEQ ID NO:10)。将抗体A7H3L3的重链可变区融合至人IgG1重链恒定区(SEQ ID NO:13)形成抗体A7H3L3的重链(SEQ ID NO:16),轻链可变区融合至人κ轻链恒定区(SEQ ID NO:11)形成抗体A7H3L3的轻链(SEQ ID NO:15)。
抗CLDN18.2单域抗体NA3S-H1已经公布于WO2020238730A1,其体外ADCC和CDC的细胞杀伤效应以及在人CLDN18.2-HEK29T-SCID肿瘤移植模型上的肿瘤抑制试验都表现出了极好的药效。人源化抗体A7H3L3与红细胞上的CD47结合很弱,是比较理想用于双特异性抗体的候选抗体,同时双特异性抗体的设计因为结合CLDN18.2会使得抗CD47抗体A7H3L3结合臂更好的结合表达双靶点的肿瘤细胞,同时更好的阻断SIRPα抑制性信号。
本发明的双抗A的结构如下:
长链结构(从N端至C端):
VHCD47-CH1-Hinge-CH2-CH3-Linker-VHHCLDN18.2;
短链结构(从N端至C端):
VLCD47-CL(即:SEQ ID NO:15);
其中,Linker(接头)序列为(SEQ ID NO:18):GGGGSGGGGS
完整的双抗A的长链全长序列如SEQ ID NO:17所示。
实施例1:双抗A的体外药效学检验
1.抗原亲和力、结合活性、特异性
使用BLI(生物膜干涉)技术进行抗原亲和力研究,结果显示,双抗A与人CLDN18.2的亲和力较高,亲和力常数KD=1.87×10-9M,参见图1a;与人CD47的亲和力较低,亲和力常数KD=2.18×10-8M,参见图1b。
用ELISA法进行抗原结合活性研究,结果显示,双抗A可以特异性结合CLDN18.2(EC50=121ng/mL)和CD47(EC50=46.2ng/mL),并呈现典型的量效关系曲线,参见图1c。
竞争结合试验显示,双抗A可以在ELISA和细胞水平显著抑制CD47与配体SIRPα的结合,结合活性结果为IC50=2.2μg/mL。
2.红细胞凝集试验
红细胞凝集试验结果显示,双抗A与阴性对照均不会引起人红细胞凝集,显著优于CD47靶点的阳性对照药Hu5F9-G4(对照药为按照专利US20200283520A1中报道的抗体序列进行自制获得),说明其对人红细胞安全性较好。
实施例2:双抗A在表达单靶点和双靶点的肿瘤细胞上阻断CD47与SIRPα结合的能力
通过流式细胞术测定了双抗A阻断NUGC-4细胞(表达内源CD47,购自BNCC菌种库,编号BNCC341962)和hCLDN18.2-NUGC-4细胞上(采用慢病毒转染的方式构建过表达外源人CLDN18.2的胃癌细胞株NUGC-4)的CD47与SIRPα结合的能力。作为比较,还测定了抗体1F8(WO2018075857A1中1F8抗体)、F4AM4-IgG1(在附图中简称为F4AM4;重链的氨基酸序列如SEQ ID NO:19所示,轻链的氨基酸序列如SEQ ID NO:20所示)和A7H3L3阻断NUGC-4和hCLDN18.2-NUGC-4肿瘤细胞上CD47与SIRPα结合的能力。
具体方法如下:取1×105个NUGC-4细胞或hCLDN18.2-NUGC-4细胞,低速离心(300g)去上清。将离心管底部的细胞通过配制好的FACS缓冲液(含2%FBS的1×PBS缓冲液)润洗一次;然后向润洗后的细胞中加入梯度稀释的待测抗体,孵育1h;用FACS缓冲液润洗细胞两次后加入100μL的1μg/mL SIRPα-mFc(ACRO,SIA-H52A8),在4℃孵育1h;经FACS缓冲液润洗三次,加入100μL 1:200稀释的PE标记的羊抗鼠Fc二抗(Abcam,ab98742),在4℃孵育1h后离心去上清,向细胞中加入200μL FACS缓冲液重悬细胞,最后通过流式细胞仪(Beckman,CytoFLEX AOO-1-1102)检测结合至细胞上的SIRPα-mFc的量(表示为平均荧光强度(MFI))。
在NUGC-4细胞上的结果如图2a所示:抗体F4AM4-IgG1能够有效的阻断CD47与SIRPα的结合,IC50为0.033μg/mL(0.226nM);抗体1F8具有较弱的阻断效果,IC50为15.36μg/mL(105.6nM);而双抗A几乎没有阻断能力。
在hCLDN18.2-NUGC-4细胞上的结果如图2b所示:抗体F4AM4-IgG1在此肿瘤细胞上依然具有强的阻断能力,IC50为0.056μg/mL(0.383nM);相比于在NUGC-4细胞上的阻断能力,双抗A在hCLDN18.2-NUGC-4细胞上的阻断能力显著提高,并且优于抗体1F8;双抗A和1F8阻断hCLDN18.2-NUGC-4上CD47与SIRPα结合的IC50分别为0.765μg/mL(4.476nM)和1.98μg/mL(82.34nM);另外,抗CLDN18.2单域抗体NA3S-H1因为只结合CLDN18.2,因而没有任何阻断效果。基于此,双抗A虽然在CD47单靶点表达的细胞上的阻断活性弱于抗体1F8,然而在CD47和CLDN18.2双靶点表达的细胞上阻断活性明显优于抗体1F8,将发挥更强的阻断CD47与受体SIRPα结合的能力。
实施例3:双抗A的体内抑瘤实验
1.体内抑瘤实验1
6-7周龄雌性裸鼠(16-18g)饲养在恒温恒湿的独立通风盒内,饲养室温度21-24℃,湿度30-53%。将3×106个hCLDN18.2-NUGC-4细胞对裸鼠进行左侧腋窝皮下注射(第0天),待小鼠皮下荷瘤体积达到300-400mm3左右时(第20天),剔除肿瘤体积差异较大的小鼠样本,然后依据肿瘤体积进行随机分组(每组8只小鼠):分别是PBS处理组、NA3S-H1单抗给药组、A7H3L3单抗给药组、NA3S-H1+A7H3L3联合给药组和双抗A给药组。以NA3S-H1单抗5mg/kg作为标准,其它所有药物均采用等摩尔剂量进行给药,即分别为A7H3L3单抗9.4mg/kg、NA3S-H1+A7H3L3联合5mg/kg+9.4mg/kg、双抗A10.6mg/kg。每个星期两次给药,分别是腹膜内注射(i.p.)和静脉注射(i.v.)两种方式交替给药。随时观察和记录肿瘤长(mm)和宽(mm),计算其肿瘤体积(V),计算方式为:V=(长×宽2)/2,抑瘤率TGI(%)=(1-给药组肿瘤平均体积/PBS处理组肿瘤平均体积)×100%。
抗体抑瘤的结果如图3a和表2所示,从中可以看出:在此等摩尔剂量下,NA3S-H1单抗给药组几乎没有表现出肿瘤抑制效果,其它组都表现出一定的肿瘤抑制效果,其中,双抗A的效果最好,在第39天之前达到接近54.54%的抑瘤率,肿瘤大小接近第20天肿瘤初始体积,且优于联合用药(A7H3L3+NA3S-H1(9.4+5mpk))的结果,这表明双抗A对CLDN18.2的结合可以增强其对CD47和SIRPα结合的阻断效果。
表2双特异性抗体在小鼠体内的抑瘤率
天数 | NA3S-H1 | A7H3L3 | 双抗A | A7H3L3+NA3S-H1 |
25 | 2.96% | -1.31% | 3.41% | 12.73% |
28 | 8.76% | 2.17% | 27.69% | 18.40% |
32 | -5.33% | 3.73% | 40.26% | 19.30% |
35 | -6.94% | 2.10% | 44.31% | 19.49% |
39 | 2.01% | 15.00% | 54.54% | 33.71% |
42 | -7.26% | 14.65% | 51.45% | 30.84% |
46 | -8.69% | 24.65% | 48.33% | 32.59% |
49 | -5.94% | 25.18% | 45.12% | 25.62% |
2.体内抑瘤实验2
随机分组(每组8只小鼠):分别是PBS处理组,单抗NA3S-H1给药组,双抗A。在接种当天(第0天)进行首次给药,每个星期给药两次,以NA3S-H1单抗2.5mg/kg作为标准,双抗A采用等摩尔剂量进行给药,即5.3mg/kg。其余方法与实施例3的第1点一致。结果如图3b所示,在此等摩尔剂量下,NA3S-H1单抗给药组表现出一定的肿瘤抑制效果,抑瘤率约为54.99%(第34天);双抗A组所有小鼠中的肿瘤被完全抑制,抑瘤率接近100%(第34天)。该结果证明了双抗A的肿瘤抑制效果显著优于抗CLDN18.2单抗NA3S-H1。
实施例4:评价双抗A在皮下移植BxPC-3-hCLDN18.2胰腺癌细胞的CB-17SCID小鼠模型中评价抗肿瘤作用
将表达hCLDN18.2的BxPC3细胞(购自康源博创生物科技(北京)有限公司)皮下接种于39只CB-17SCID小鼠(购自北京维通利华实验动物技术有限公司上海分公司),每只小鼠接种1×107个细胞。接种细胞后第10天,根据动物肿瘤体积和动物体重,挑取32只小鼠随机分成4组,每组8只,包括PBS对照组、双抗A低剂量组(1mg/kg)、双抗A中剂量组(3mg/kg)和双抗A高剂量组(10mg/kg)。分组当天定义为D1天,并于D1开始给药,尾静脉注射和腹腔注射交替给药,一周给药两次。试验过程中每天进行动物一般状态观察,并一周进行两次肿瘤体积和体重测量。
本次试验给药至D50,D54试验结束,将小鼠安乐处死,并剖取肿瘤进行称重。
本试验结束时各组瘤体积、瘤重及相应抑瘤率如表3-1所示。根据试验过程中肿瘤体积绘制肿瘤生长曲线,如图4a所示。与PBS对照组相比,双抗A各给药组可不同程度抑制BxPC3-hCLDN18.2肿瘤的生长,根据瘤体积进行抑瘤率TGItv计算,1、3、10mg/kg三个剂量组TGItv分别为47.12%、85.90%、86.48%。将各组小鼠的D54肿瘤体积进行统计学差异比较,与PBS对照组相比,3mg/kg剂量组和10mg/kg剂量组瘤体积的降低差异极显著(P<0.01)。
本次试验肿瘤展示图和小鼠的肿瘤重量见图4b和图4c所示。根据肿瘤重量进行抑瘤率TGItw计算,各组TGItw及P值统计分析如表3-1所示。与PBS对照组相比,本发明抗体能够剂量依赖性地降低BxPC3-hCLDN18.2肿瘤的重量,1、3、10mg/kg三个剂量组TGItw分别为44.16%、80.00%、74.46%。10mg/kg剂量组瘤重抑瘤率低于3mg/kg剂量组可能是由于给药时间较长,使得药效已达到饱和。将各组小鼠的D54肿瘤重量进行统计学差异比较,与PBS对照组相比,3mg/kg剂量组和10mg/kg剂量组瘤重量的降低差异极显著(P<0.01)。
表3-1:双抗A对BxPC3-hCLDN18.2荷瘤小鼠移植瘤的疗效
给药过程中,各组小鼠体重呈正常增长趋势,如图5所示。各给药组小鼠一般观察未见明显异常,提示目前给药剂量动物耐受良好。各组小鼠体重数据如表3-2所示。
表3-2:BxPC3-hCLDN18.2荷瘤小鼠体重数据(g)
实施例5:评价双抗A在皮下移植HT29-hCLDN18.2结直肠癌细胞的CB-17SCID小鼠模型中评价抗肿瘤作用
将表达hCLDN18.2的HT29细胞(购自康源博创生物科技(北京)有限公司)皮下接种于39只CB-17SCID小鼠,每只小鼠接种5×106个细胞。接种细胞后第6天,根据动物肿瘤体积和动物体重,挑取32只小鼠随机分成4组,每组8只,包括PBS对照组、双抗A低剂量组(1mg/kg)、双抗A中剂量组(3mg/kg)和双抗A高剂量组(10mg/kg)。分组当天定义为D1天,并于D1开始给药,尾静脉注射和腹腔注射交替给药,一周给药两次。试验过程中每天进行动物一般状态观察,并一周进行两次肿瘤体积和体重测量。
本次试验给药至D32,D36试验结束,将小鼠安乐处死,并剖取肿瘤进行称重。
本试验结束时各组瘤体积、瘤重及相应抑瘤率如表4所示。根据试验过程中肿瘤体积绘制肿瘤生长曲线,如图6所示。与PBS对照组相比,双抗A各给药组可不同程度抑制HT29-hCLDN18.2肿瘤的生长,根据瘤体积进行抑瘤率TGItv计算,1、3、10mg/kg三个剂量组TGItv分别为39.30%、48.54%、82.27%。将各组小鼠的D36肿瘤体积进行统计学差异比较,与PBS对照组相比,1mg/kg剂量组、3mg/kg剂量组和10mg/kg剂量组瘤体积的降低差异极显著(P<0.01)。
本次试验肿瘤展示图和小鼠的肿瘤重量见图7和图8所示。根据肿瘤重量进行抑瘤率TGItw计算,各组TGItw及P值统计分析如表4所示。与PBS对照组相比,本发明抗体能够剂量依赖性地降低HT29-hCLDN18.2肿瘤的重量,1、3、10mg/kg三个剂量组TGItw分别为23.29%、31.53%、73.46%。将各组小鼠的D36肿瘤重量进行统计学差异比较,与PBS对照组相比,3mg/kg剂量组瘤重量的降低差异显著(P<0.05),10mg/kg剂量组瘤重量的降低差异极显著(P<0.01)。
表4:双抗A对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效
给药过程中,各给药组小鼠体重呈正常增长趋势,在D29后,对照组小鼠由于受肿瘤体积的影响,身体状况变差,体重降低,如图9所示。各给药组小鼠一般观察未见明显异常,提示目前给药剂量动物耐受良好。各组小鼠体重数据如表5所示。
表5:HT29-hCLDN18.2荷瘤小鼠体重数据(g)
实施例6:
评价双抗A在皮下移植NUGC-4-hCLDN18.2胃癌细胞的CB-17SCID小鼠模型中评价抗肿瘤作用
将上述表达hCLDN18.2的NUGC-4细胞皮下接种于44只CB-17SCID小鼠,每只小鼠接种3×106个细胞。接种细胞后第6天,根据动物肿瘤体积,挑取28只小鼠随机分成4组,每组7只,包括PBS对照组、双抗A低剂量组(3mg/kg)、双抗A中剂量组(10mg/kg)和双抗A高剂量组(20mg/kg)。分组当天定义为D1天,并于D1开始给药,尾静脉注射给药,一周给药两次。试验过程中每天进行动物一般状态观察,并一周进行两次肿瘤体积和体重测量。
本次试验给药至D27,D29试验结束,将小鼠安乐处死,并剖取肿瘤进行称重。
本试验结束时各组瘤体积、瘤重及相应抑瘤率如表6所示。根据试验过程中肿瘤体积绘制肿瘤生长曲线,如图10所示。与PBS对照组相比,双抗A各给药组可不同程度抑制NUGC-4-hCLDN18.2肿瘤的生长,根据瘤体积进行抑瘤率TGItv计算,3、10、20mg/kg三个剂量组TGItv分别为32.28%、90.07%、106.32%。将各组小鼠的D29肿瘤体积进行统计学差异比较,与PBS对照组相比,10mg/kg剂量组和20mg/kg剂量组瘤体积的降低均差异极显著(P<0.01)。在本次试验中,截至D29试验结束,双抗A中剂量10mg/kg组有1只小鼠肿瘤全部缓解(肿瘤消失),3只小鼠肿瘤部分缓解(肿瘤体积小于分组体积);双抗A高剂量20mg/kg组动物肿瘤全部缓解。
本次试验肿瘤展示图和小鼠的肿瘤重量见图11和图12所示。根据肿瘤重量进行抑瘤率TGItw计算,各组TGItw及P值统计分析如表6所示。与PBS对照组相比,双抗A抗体能够剂量依赖性地降低NUGC-4-hCLDN18.2肿瘤的重量,3、10、20mg/kg三个剂量组TGItw分别为29.23%、86.15%、100.00%。将各组小鼠的D29肿瘤重量进行统计学差异比较,与PBS对照组相比,10mg/kg剂量组和20mg/kg剂量组瘤重量的降低差异极显著(P<0.01)。
表6:双抗A对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效
给药至D8,PBS对照组体重出现异常下降,原因是这组中有一笼小鼠的水瓶发生漏水,导致小鼠缺水体重下降,更换水瓶后小鼠体重迅速恢复正常。给药过程中,各组小鼠体重呈正常增长趋势,如图13所示,一般观察未见明显异常,提示在目前给药剂量下动物耐受良好。各试验组小鼠体重数据如表7所示。
表7:NUGC-4-hCLDN18.2荷瘤小鼠体重数据(g)
分组 | D1 | D5 | D8 | D12 | D15 | D19 | D22 | D27 | D29 |
G1-PBS | 18.52 | 18.53 | 17.41 | 17.99 | 18.56 | 19.00 | 18.68 | 19.42 | 19.09 |
G2-双抗A-3mg/kg,BIW | 18.73 | 18.59 | 18.69 | 18.60 | 18.85 | 19.14 | 19.19 | 19.59 | 19.51 |
G3-双抗A-10mg/kg,BIW | 19.02 | 19.05 | 19.01 | 19.03 | 19.22 | 19.74 | 19.56 | 19.54 | 19.65 |
G4-双抗A-20mg/kg,BIW | 18.27 | 18.41 | 18.32 | 18.26 | 18.44 | 18.78 | 18.80 | 19.40 | 19.14 |
实施例7:评价双抗A对比单靶点抗体在皮下移植HT29-hCLDN18.2结直肠癌细胞的CB-17SCID小鼠模型中评价抗肿瘤作用
将上述表达hCLDN18.2的HT29-hCLDN18.2细胞皮下接种于34只CB-17SCID小鼠,每只小鼠接种5×106个细胞。接种细胞后第7天,根据动物肿瘤体积和动物体重,挑取28只随机分成4组,每组7只,包括PBS对照组、CLDN18.2单抗(IMAB362)组(10mg/kg)、CD47单抗(Hu5F9-G4)组(10mg/kg)和双抗A组(10mg/kg)。分组当天定义为D1,并于分组当天开始给药,CLDN18.2单抗(IMAB362)、CD47单抗(Hu5F9-G4)和双抗A抗体均为尾静脉注射和腹腔注射交替给药,每周给药两次。试验过程中每天进行动物一般状态观察,并一周进行两次肿瘤体积和体重测量。
本次试验给药至D26,D29试验结束,将小鼠安乐处死,并剖取肿瘤进行称重。
根据试验过程中肿瘤体积绘制肿瘤生长曲线如图14所示。根据终末瘤体积进行TGItv计算,如表8所示。与PBS对照组相比,各给药组均可不同程度抑制HT29-hCLDN18.2肿瘤的生长。其中,CLDN18.2单抗(IMAB362)组、CD47单抗(Hu5F9-G4)组、双抗A组TGItv分别为26.60%、21.07%、84.99%。与PBS对照组相比,CLDN18.2单抗(IMAB362)组和CD47单抗(Hu5F9-G4)组瘤体积的降低无显著性差异(P>0.05),双抗A组瘤体积的降低均具有统计学意义。且双抗A组瘤体积分别与CLDN18.2单抗(IMAB362)组、CD47单抗(Hu5F9-G4)组相比,均显著性降低,具有统计学意义。
表8:给药抗体对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效(TGItv)
本次试验肿瘤展示图和小鼠的肿瘤重量见图15和图16,根据瘤重进行TGItw计算,如表9所示。CLDN18.2单抗(IMAB362)组、CD47单抗(Hu5F9-G4)组、双抗A组TGItw分别为20.59%、16.30%、78.67%。与PBS对照组相比,CLDN18.2单抗(IMAB362)组和CD47单抗(Hu5F9-G4)组瘤重的降低无显著性差异(P>0.05),双抗A组瘤重的降低均具有统计学意义。且双抗A组瘤重分别与CLDN18.2单抗(IMAB362)组、CD47单抗(Hu5F9-G4)组相比,均显著性降低,具有统计学意义。
表9:给药抗体对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效(TGItw)
给药过程中,各组小鼠体重呈正常平稳增长趋势,个别小鼠因肿瘤体积较大,导致后期小鼠体重稍有下降,如图17所示,一般观察未见明显异常,提示所有小鼠在目前的给药剂量下均耐受良好。各组小鼠体重数据如表10所示。
表10:HT29-hCLDN18.2荷瘤小鼠不同组别小鼠体重数据(g)
实施例8:缓冲剂对液体制剂稳定性的影响
本实施例的主要目的为评估本发明的双抗A的液体制剂A使用不同缓冲剂(醋酸盐缓冲剂、琥珀酸盐缓冲剂、枸椽酸盐缓冲剂、组氨酸盐酸盐缓冲剂、组氨酸醋酸盐缓冲剂或磷酸盐缓冲剂)和不同pH值的缓冲剂对液体制剂稳定性的影响。
对表11所示的配方在-20℃(24h)→5℃(24h)条件下进行5个循环(FT5)、垂直翻转3周后(Agi-W3)、40℃条件下放置4周(40℃-M1)、5℃条件下放置一个月(5℃-M1)和光照12天后(SI-D12)的五种条件下平行考察,然后对其进行SEC-HPLC(分子排阻色谱,简称SEC)分析,评估其中双抗A的SEC纯度的变化,测试结果如表12、13和14所示。
表11:缓冲剂选择实验条件
表12:缓冲剂选择实验外观结果
如表12中的数据所示,对于双抗A的液体制剂而言,在5℃条件下放置一个月(5℃-M1)、光照12天(SI-D12)和垂直翻转3周后(Agi-W3)的三个平行条件下,使用琥珀酸盐缓冲剂(A5-A8)、枸椽酸盐缓冲剂(A9-A12)以及磷酸盐缓冲剂(A22-A25)的液体制剂出现蛋白析出物。
表13:缓冲剂选择实验检测结果
如表13中的数据所示,在40℃条件下放置一个月后(40℃-M1),使用组氨酸盐酸盐缓冲剂(A13、A14、A15、A16)和组氨酸醋酸盐缓冲剂(A17、A18、A19、A20)的液体制剂相较于使用醋酸盐缓冲剂(A1、A2、A3、A4)的液体制剂中双抗A的SEC、CEX、CE-SDS NR纯度更高,具有更佳的稳定性。
表14:缓冲剂选择实验抗原结合活性检测结果
组氨酸盐酸盐缓冲剂(A13和A14)和组氨酸醋酸盐缓冲剂(A17-A19)体系所示的液体制剂在40℃下放置四周后(40℃-M1),对其样品进行了抗原结合活性检测,结果如表14所示。
对于组氨酸盐酸盐缓冲剂和组氨酸醋酸盐缓冲剂体系,如表14中的数据所示,使用组氨酸盐酸盐缓冲剂(A13和A14)的液体制剂的抗原结合活性更佳。根据以上检测结果,优选组氨酸盐酸盐缓冲体系进行后续实验。
实施例9:稳定剂和抗氧剂对液体制剂稳定性的影响
本实施例的主要目的为评估本发明的双抗A的液体制剂使用不同浓度和组成的稳定剂(麦芽糖、蔗糖、海藻糖、山梨醇、脯氨酸、甘氨酸)和抗氧剂(盐酸精氨酸、甲硫氨酸、氯化钠)对液体制剂稳定性的影响。
将表15所示的配方在-20℃(24h)→5℃(24h)条件下进行6个循环(FT6)、40℃条件下放置4周(40℃-M1)、垂直翻转3周后(Agi-W3)的三个条件下平行考察,并进行SEC-HPLC检测,分析其中双抗A纯度的变化,测试结果如表16所示。
表15:稳定剂实验条件
表16:稳定剂筛选实验SEC纯度检测结果
如表16中的数据所示,对于双抗A的液体制剂而言,稳定剂配方(B1~B7)冻融六轮后(FT6),B7表现差于其他六个处方;在40℃下放置4周后(40℃-M1),B1表现差于其他六个配方,B2略优于其他六配方,而其他四个配方中双抗A的SEC纯度无明显差异。
抗氧剂配方中(B8~B10),在40℃下放置4周后(40℃-M1),B9表现明显优于其他两个配方,因而优选甲硫氨酸进行后续实验。
表17:稳定剂筛选实验不溶性微粒检测结果
注:单位名称“P/mL”中“P”代表微粒个数。
B1~B7所示的液体制剂在40℃下放置四周后,对B1~B7样品进行了不溶性微粒检测,结果如表17所示。
如表17中的数据所示,B4在40℃下放置4周后,其不溶性微粒明显少于其他六组处方因而优选海藻糖进行后续实验。
实施例10:配方组分的浓度优化实验
本实施例的目的是在确定配方组分后评估一定浓度范围内的各组分即双抗A、组氨酸盐酸盐缓冲剂、海藻糖、甲硫氨酸、聚山梨酯80以及一定范围内pH对本发明双抗A的液体制剂配方C1-C15稳定性的影响。
以双抗A、组氨酸盐酸盐缓冲剂、海藻糖、甲硫氨酸、聚山梨酯80组合为配方,围绕抗体浓度(20mg/mL)、缓冲液浓度(10~40mM)、海藻糖浓度(210~230mM)、甲硫氨酸(0~20mM)、聚山梨酯80浓度(0~0.2mg/mL)以及pH范围(pH 5.0~6.0)设计实验。
将表18所示配方在40℃下放置2周(40℃-W2)和4周(40℃-W4)和光照5天后(SI-D5)的两个平行条件下,检测一个月后液体制剂中双抗A的SEC纯度的变化,测试结果如表19所示。
表18:优化实验条件
表19:优化实验检测结果
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如表19中的数据所示,C1~C15的液体制剂经过40℃下放置2周(40℃-W2)和4周(40℃-W4),光照5天后(SI-D5)的两个平行条件下,液体制剂中双抗A的SEC纯度都大于93%。表明在上述实施例的组分浓度范围内,双抗A的液体制剂的稳定性较好。
实施例11:配方的加速稳定性与长期稳定性
本实施例的主要目的为评估25℃和2~8℃条件下本发明双抗A液体制剂配方D1的长期稳定性。
将表20所示配方在25℃下以及2~8℃条件下,分别放置6个月;在各取样点取样检测液体制剂中双抗A的SEC纯度的变化,测试结果如表21所示。
表20:加速稳定性与长期稳定性
表21:加速稳定性与长期稳定性实验结果
如表20中的数据所示,用含83.2mg/mL海藻糖、1.49mg/mL甲硫氨酸、20mM组氨酸盐酸盐缓冲剂和0.1mg/mL聚山梨酯80的制剂体系对本发明的液体制剂中的双抗A有很好的保护作用,因此,表21所示的液体制剂配方能够保证双抗A较好的物理和化学稳定性,具有广泛的工业应用前景。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰。这些改进和润饰也应视为本发明的保护范围。
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Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn His
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Ile His Ser Gly Val Pro Ser Ser Phe Arg Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Tyr Thr Leu Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 11
<211> 107
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 抗CD47抗体的轻链恒定区
<400> 11
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> 12
<211> 117
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 抗CD47抗体的重链可变区
<400> 12
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 Phe Asn Ile Lys Asp Ile
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Gln Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 13
<211> 330
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 抗CD47抗体的重链恒定区
<400> 13
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
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 Lys
325 330
<210> 14
<211> 120
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 抗CLDN18.2抗体的重链可变区
<400> 14
Gln 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 Ser Ile Phe Asn Ile Pro
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Val Ser Gly Ile Gly Ser Thr Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 15
<211> 234
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 双抗A的短链
<220>
<221> SIGNAL
<222> (1)..(20)
<223> 信号肽
<400> 15
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn His Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Ile His Ser Gly Val Pro Ser
65 70 75 80
Ser Phe Arg Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Tyr
100 105 110
Thr Leu Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 16
<211> 467
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 抗CD47抗体的重链
<220>
<221> SIGNAL
<222> (1)..(20)
<223> 信号肽
<400> 16
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
20 25 30
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn
35 40 45
Ile Lys Asp Ile Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly
50 55 60
Leu Glu Trp Ile Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr
65 70 75 80
Asp Gln Lys Phe Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr
85 90 95
Asn Thr Ala Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Gly Tyr Gly Ser Gly Phe Ala Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 17
<211> 597
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 双抗A的长链
<220>
<221> SIGNAL
<222> (1)..(20)
<223> 信号肽
<400> 17
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
20 25 30
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn
35 40 45
Ile Lys Asp Ile Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly
50 55 60
Leu Glu Trp Ile Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr
65 70 75 80
Asp Gln Lys Phe Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr
85 90 95
Asn Thr Ala Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Gly Tyr Gly Ser Gly Phe Ala Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln
465 470 475 480
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
485 490 495
Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Asn Ile Pro Val Met Gly
500 505 510
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Gly Ile
515 520 525
Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe
530 535 540
Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn
545 550 555 560
Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Leu Val
565 570 575
Val Ser Gly Ile Gly Ser Thr Leu Glu Val Trp Gly Gln Gly Thr Leu
580 585 590
Val Thr Val Ser Ser
595
<210> 18
<211> 10
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 接头
<400> 18
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 19
<211> 452
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> F4AM4-IgG1重链
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Thr Asp Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Phe Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Gly Arg Pro Tyr Tyr Gly Thr Arg Tyr Gly Ser Trp Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 20
<211> 214
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> F4AM4-IgG1 轻链
<400> 20
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Asn Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Lys Asn Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu 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
Claims (10)
1.一种稳定的抗CLDN18.2和CD47双特异性抗体的液体制剂,其特征在于,所述的液体制剂包括如下浓度的组分:
抗CLDN18.2和CD47双特异性抗体 15~25mg/mL;较佳地为18~22mg/mL;
缓冲剂 10~40mM;和
稳定剂 125~260mM;
所述的液体制剂的pH值为4.5~7.5,较佳地为5.0~6.5。
2.如权利要求1所述的抗CLDN18.2和CD47双特异性抗体的液体制剂,其特征在于,所述的双特异性抗体包含特异性结合CD47的第一抗原结合域和特异性结合CLDN18.2的第二抗原结合域;其中,
所述第一抗原结合域的LCDR1的氨基酸序列如SEQ ID NO:1所示,LCDR2的氨基酸序列如SEQ ID NO:2所示,LCDR3的氨基酸序列如SEQ ID NO:3所示,HCDR1的氨基酸序列如SEQID NO:4所示,HCDR2的氨基酸序列如SEQ ID NO:5所示,以及HCDR3的氨基酸序列如SEQ IDNO:6所示;
所述第二抗原结合域包含免疫球蛋白单可变结构域VHH;优选地,所述第二抗原结合域的HCDR1的氨基酸序列如SEQ ID NO:7所示,HCDR2的氨基酸序列如SEQ ID NO:8所示,以及HCDR3的氨基酸序列如SEQ ID NO:9所示;
所述第一抗原结合域和第二抗原结合域的轻链可变区和/或重链可变区的框架区为人源框架区;优选地,
所述第一抗原结合域的轻链可变区的氨基酸序列如SEQ ID NO:10所示;和/或,
所述第一抗原结合域的重链可变区的氨基酸序列如SEQ ID NO:12所示;和/或,
所述第二抗原结合域的重链可变区的氨基酸序列如SEQ ID NO:14所示;
所述第一抗原结合域的轻链恒定区为人κ轻链恒定区,和/或,所述第一抗原结合域的重链恒定区为人IgG1的重链恒定区;优选地,
所述第一抗原结合域的轻链恒定区的氨基酸序列如SEQ ID NO:11所示;和/或,
所述第一抗原结合域的重链恒定区的氨基酸序列如SEQ ID NO:13所示;
所述第一抗原结合域的重链和所述第二抗原结合域的重链可变区之间用接头连接;
较佳地,所述第二抗原结合域的重链可变区用接头连接在所述第一抗原结合域的重链的C端;
更佳地,第一抗原结合域的重链的氨基酸序列如SEQ ID NO:16所示,和/或,所述接头的氨基酸序列如SEQ ID NO:18所示;
所述双特异性抗体包含长链和短链,所述短链包含如SEQ ID NO:15所示的氨基酸序列,所述长链包含如SEQ ID NO:17所示的氨基酸序列。
3.如权利要求1或2所述的抗CLDN18.2和CD47双特异性抗体的液体制剂,其特征在于,所述的缓冲剂选自醋酸盐缓冲剂、琥珀酸盐缓冲剂、枸椽酸盐缓冲剂、组氨酸盐酸盐缓冲剂、组氨酸醋酸盐缓冲剂和磷酸盐缓冲剂中的一种或多种;
较佳地,所述的缓冲剂为组氨酸盐酸盐缓冲剂。
4.如权利要求1~3任一项所述的抗CLDN18.2和CD47双特异性抗体的液体制剂,其特征在于,所述的稳定剂选自以下组中的一种或多种:糖、多元醇和氨基酸;
较佳地,所述的糖选自麦芽糖、蔗糖和海藻糖中的一种或多种;所述的多元醇为山梨醇;所述的氨基酸为脯氨酸或甘氨酸;
更佳地,所述的糖为海藻糖;所述的氨基酸为脯氨酸。
5.如权利要求1~4任一项所述的抗CLDN18.2和CD47双特异性抗体的液体制剂,其特征在于,所述的液体制剂还包括2~70mM的抗氧剂;所述的抗氧剂选自盐酸精氨酸、甲硫氨酸和氯化钠中的一种或多种;
较佳地,所述的抗氧剂为甲硫氨酸。
6.如权利要求1~5任一项所述的抗CLDN18.2和CD47双特异性抗体的液体制剂,其特征在于,所述的液体制剂还包括0.01~0.5mg/mL的表面活性剂;所述的表面活性剂优选为聚山梨酯20或聚山梨酯80;
较佳地,所述的表面活性剂为聚山梨酯80。
7.如权利要求1~6任一项中所述的抗CLDN18.2和CD47双特异性抗体的液体制剂,其特征在于,所述的液体制剂选自以下组中的一组或多组:
(1)抗CLDN18.2和CD47双特异性抗体和组氨酸盐酸盐缓冲剂;
(2)抗CLDN18.2和CD47双特异性抗体和组氨酸醋酸盐缓冲剂;
(3)抗CLDN18.2和CD47双特异性抗体、组氨酸盐酸盐缓冲剂、蔗糖和聚山梨酯80;
(4)抗CLDN18.2和CD47双特异性抗体、组氨酸盐酸盐缓冲剂、山梨醇、甲硫氨酸和聚山梨酯80;
(5)抗CLDN18.2和CD47双特异性抗体、组氨酸盐酸盐缓冲剂、海藻糖、甲硫氨酸和聚山梨酯80。
8.如权利要求1~7任一项中所述的抗CLDN18.2和CD47双特异性抗体的液体制剂,其特征在于,所述的液体制剂包括如下浓度的组分:
所述的液体制剂的pH值为5.0~6.0;
较佳地,所述的甲硫氨酸浓度为5~10mM,即0.745mg/mL~1.49mg/mL;所述的聚山梨酯80浓度为0.05~0.1mg/mL;和/或,所述的液体制剂的pH值为5.0。
9.如权利要求8所述的抗CLDN18.2和CD47双特异性抗体的液体制剂,其特征在于,所述的液体制剂包括如下浓度的组分:
所述的液体制剂的pH值为5.0。
10.如权利要求1~9任一项中所述的抗CLDN18.2和CD47双特异性抗体的液体制剂在制备预防和/或治疗肿瘤的药物中的应用;
较佳地,所述的肿瘤为CLDN18.2阳性肿瘤;
更佳地,所述的肿瘤为消化系统肿瘤;进一步更佳地,所述消化系统肿瘤选自消化道肿瘤例如胃癌、结直肠癌,以及胰腺癌。
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