CN110621699A - Btla激动剂抗体及其用途 - Google Patents
Btla激动剂抗体及其用途 Download PDFInfo
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- CN110621699A CN110621699A CN201880033180.XA CN201880033180A CN110621699A CN 110621699 A CN110621699 A CN 110621699A CN 201880033180 A CN201880033180 A CN 201880033180A CN 110621699 A CN110621699 A CN 110621699A
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Abstract
提供了结合BTLA的抗体和使用其的方法,所述抗体可用作用于治疗与自身免疫疾病相关的病况(包括治疗狼疮)的药剂。
Description
本发明处于医药领域中。更具体地,本发明涉及针对B和T淋巴细胞衰减因子(BTLA)的抗体和其药物组合物。预期本发明的抗体可用于治疗自身免疫疾病,诸如狼疮。
狼疮是具有异质特征的自身免疫疾病,包括皮肤、口、肌肉和关节、心脏、外周血、肺、肾脏、生殖系统和CNS表现。狼疮患者处于严重且危及生命的心血管、肾和神经精神疾病的风险下。护理标准包括许多类固醇,其具有许多不利和/或危险副作用。需要疗法来管控疾病且允许减少或消除类固醇使用。
B和T淋巴细胞衰减因子(BTLA;CD272)是Ig超家族成员并且是负性调节免疫细胞活化的检查点受体家族的部分。BTLA主要表达于B细胞、T细胞和树突状细胞上。BTLA的天然配体是TNF受体超家族成员,疱疹病毒进入介体(HVEM;TNFRSF14)。
人HVEM-Fc已被报道为以112 nM的KD结合293T细胞中表达的人BTLA,如通过流式细胞术所检测(Cheung等人, PNAS, Sept. 13, 2005, 102:37;13218-13223)。HVEM与BTLA的结合导致BTLA的胞质结构域上的两个保守的基于免疫受体酪氨酸的抑制基序结构域的酪氨酸磷酸化。该磷酸化导致经由两个Src同源性2结构域募集蛋白酪氨酸磷酸酶,所述蛋白酪氨酸磷酸酶通过去磷酸化和下调阳性细胞受体信号传导(例如,T细胞受体或B细胞受体信号转导级联)而赋予BTLA的抑制活性,因此导致免疫细胞活化的抑制。在易于自发地发展狼疮样疾病的小鼠模型(MRL-lpr小鼠)中,与表达BTLA的小鼠相比,BTLA缺陷型小鼠在唾液腺、肺、胰腺、肾和关节中具有更严重的淋巴细胞浸润。因此,BTLA激动剂抗体可以为具有自身免疫疾病(诸如狼疮)的患者提供益处。
针对BTLA的激动剂抗体是本领域中已知的。例如,美国专利号8,563,694(‘694专利)公开了阻断(Mab21H6和Mab19A7)或不阻断(Mab8D5和Mab8A3) HVEM与BTLA的结合的BTLA激动剂抗体。‘694专利描述了对开发利用BTLA在淋巴细胞应答中的抑制性作用、同时允许BTLA-HVEM结合的治疗的持续需求。然而,缺乏模拟HVEM结合BTLA用于治疗自身免疫疾病的BTLA激动剂抗体。如果抗体具有显著重叠HVEM的结合位点的表位,并在抗体和HVEM之间存在结构类似性,则抗体“模拟”HVEM结合BTLA。还缺乏结合人BTLA且可用于研究自身免疫疾病的体内临床前模型(诸如鼠和食蟹猴模型)的BTLA激动剂抗体。因此,仍需要替代的BTLA激动剂抗体。
本发明的抗体试图提供替代的BTLA激动剂抗体。此类BTLA激动剂抗体可用于治疗自身免疫疾病,诸如狼疮。此类BTLA激动剂抗体能够结合来自多种物种的BTLA,诸如人、食蟹猴和/或鼠BTLA。另外,相比于具有与Mab8D5相同的重链可变区和轻链可变区的抗体,此类BTLA激动剂抗体表明增强的体外活性。本发明的抗体具有这些期望特征中的至少一种。
一种此类BTLA激动剂抗体能够结合人、食蟹猴和鼠BTLA。令人惊讶地,由于该抗体模拟结合BTLA的HVEM,因此其具有该期望的交叉反应性。相比于结合BTLA的HVEM,该抗体也对BTLA具有更高的结合亲和力。这可以为具有疾病状态与瞬时HVEM水平的患者提供益处,其中在患者具有HVEM降低的时间期间,可期望具有携带模拟BTLA的激动剂抗体。
本发明提供了结合BTLA且活化和/或增强BTLA介导的信号传导的抗体(BTLA激动剂抗体)。本发明提供了抗体,其包含轻链可变区(LCVR)和重链可变区(HCVR),其中所述LCVR包含互补决定区(CDR) LCDR1、LCDR2和LCDR3,且所述HCVR包含CDR HCDR1、HCDR2和HCDR3,且其中LCDR1的氨基酸序列是SEQ ID NO:22,LCDR2的氨基酸序列是SEQ ID NO:25,LCDR3的氨基酸序列是SEQ ID NO:28,HCDR1的氨基酸序列是SEQ ID NO:13,HCDR2的氨基酸序列是SEQ ID NO:16,且HCDR3的氨基酸序列是SEQ ID NO:19。在一个实施方案中,所述抗体包含LCVR和HCVR,且其中所述LCVR的氨基酸序列是SEQ ID NO:4,且所述HCVR的氨基酸序列是SEQ ID NO:3。在另一个实施方案中,所述抗体包含轻链(LC)和重链(HC),且其中所述LC的氨基酸序列是SEQ ID NO:2,且所述HC的氨基酸序列是SEQ ID NO:1。在又另一个实施方案中,所述抗体包含2条LC和2条HC,其中每条LC的氨基酸序列是SEQ ID NO:2,且每条HC的氨基酸序列是SEQ ID NO:1。
本发明还提供了BTLA激动剂抗体,其中LCDR1的氨基酸序列是SEQ ID NO:23,LCDR2的氨基酸序列是SEQ ID NO:26,LCDR3的氨基酸序列是SEQ ID NO:29,HCDR1的氨基酸序列是SEQ ID NO:14,HCDR2的氨基酸序列是SEQ ID NO:17,且HCDR3的氨基酸序列是SEQID NO:20。在一个实施方案中,所述LCVR的氨基酸序列是SEQ ID NO:8,且所述HCVR的氨基酸序列是SEQ ID NO:7。在另一个实施方案中,所述LC的氨基酸序列是SEQ ID NO:6,且所述HC的氨基酸序列是SEQ ID NO:5。在又另一个实施方案中,所述抗体包含2条LC和2条HC,其中每条LC的氨基酸序列是SEQ ID NO:6,且每条HC的氨基酸序列是SEQ ID NO:5。
本发明还提供了BTLA激动剂抗体,其中LCDR1的氨基酸序列是SEQ ID NO:24,LCDR2的氨基酸序列是SEQ ID NO:27,LCDR3的氨基酸序列是SEQ ID NO:30,HCDR1的氨基酸序列是SEQ ID NO:15,HCDR2的氨基酸序列是SEQ ID NO:18,且HCDR3的氨基酸序列是SEQID NO:21。在一个实施方案中,所述LCVR的氨基酸序列是SEQ ID NO:12,且所述HCVR的氨基酸序列是SEQ ID NO:11。在另一个实施方案中,所述LC的氨基酸序列是SEQ ID NO:10,且所述HC的氨基酸序列是SEQ ID NO:9。在又另一个实施方案中,所述抗体包含2条LC和2条HC,其中每条LC的氨基酸序列是SEQ ID NO:10,且每条HC的氨基酸序列是SEQ ID NO:9。
本发明还提供了结合BTLA的抗体,其中所述抗体通过包括以下的步骤生成:用Fc标记的人BTLA的胞外结构域(ECD)结构域来免疫兔;和用人和小鼠BTLA-Fc标记的蛋白加强。人BTLA ECD的氨基酸序列是SEQ ID NO:31的氨基酸31-150。
本发明提供了模拟结合BTLA的HVEM的BTLA激动剂抗体。本发明还提供了BTLA激动剂抗体,其能够结合人、食蟹猴和鼠BTLA。
本发明还提供了药物组合物,其包含本发明的抗体和一种或多种药学上可接受的载体、稀释剂或赋形剂。在一些实施方案中,本发明的药物组合物可用于治疗风湿性、神经性和皮肤病学疾病中的一种或多种,由此此类治疗包括向有需要的患者施用有效量的本发明的药物组合物。在一些具体实施方案中,所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。在其他具体实施方案中,所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。在其他具体实施方案中,所述神经性疾病是多发性硬化症。
本发明还提供了治疗具有风湿性、神经性和皮肤病学疾病中的一种或多种的患者的方法,其包括向有需要的患者施用有效量的本发明的抗体。在一些此类实施方案中,所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。在其他具体实施方案中,所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。在其他具体实施方案中,所述神经性疾病是多发性硬化症。
本发明还提供了本发明的抗体或其药物组合物,其用于疗法中。在一些实施方案中,本发明提供了本发明的抗体或其药物组合物,其用于治疗风湿性、神经性和皮肤病学疾病中的一种或多种。在一些此类实施方案中,所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。在其他具体实施方案中,所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。在其他具体实施方案中,所述神经性疾病是多发性硬化症。
本发明还提供了本发明的抗体或其药物组合物在制备用于治疗风湿性、神经性和皮肤病学疾病中的一种或多种的药物中的用途。在一些此类实施方案中,所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。在其他具体实施方案中,所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。在其他具体实施方案中,所述神经性疾病是多发性硬化症。
本发明提供了DNA分子,其包含编码具有SEQ ID NO:1、SEQ ID NO:5或SEQ ID NO:9的氨基酸序列的多肽的多核苷酸序列。本发明还提供了DNA分子,其包含编码具有SEQ IDNO:2、SEQ ID NO:6或SEQ ID NO:10的氨基酸序列的多肽的多核苷酸序列。
本发明提供了DNA分子,其包含编码具有SEQ ID NO:1的氨基酸序列的多肽的多核苷酸序列,且包含编码具有SEQ ID NO:2的氨基酸序列的多肽的多核苷酸序列。本发明还提供了包含编码具有SEQ ID NO:1的氨基酸序列的多肽的多核苷酸序列的DNA分子,和包含编码具有SEQ ID NO:2的氨基酸序列的多肽的多核苷酸序列的DNA分子。在一个具体实施方案中,编码具有SEQ ID NO:1的氨基酸序列的多肽的多核苷酸序列是SEQ ID NO:35,且编码具有SEQ ID NO:2的氨基酸序列的多肽的多核苷酸序列是SEQ ID NO:36。
本发明还提供了DNA分子,其包含编码具有SEQ ID NO:5的氨基酸序列的多肽的多核苷酸序列,且包含编码具有SEQ ID NO:6的氨基酸序列的多肽的多核苷酸序列。本发明还提供了包含编码具有SEQ ID NO:5的氨基酸序列的多肽的多核苷酸序列的DNA分子,和包含编码具有SEQ ID NO:6的氨基酸序列的多肽的多核苷酸序列的DNA分子。在一个具体实施方案中,编码具有SEQ ID NO:5的氨基酸序列的多肽的多核苷酸序列是SEQ ID NO:37,编码具有SEQ ID NO:6的氨基酸序列的多肽的多核苷酸序列是SEQ ID NO:38。
本发明还提供了DNA分子,其包含编码具有SEQ ID NO:9的氨基酸序列的多肽的多核苷酸序列,且包含编码具有SEQ ID NO:10的氨基酸序列的多肽的多核苷酸序列。本发明还提供了包含编码具有SEQ ID NO:9的氨基酸序列的多肽的多核苷酸序列的DNA分子,和包含编码具有SEQ ID NO:10的氨基酸序列的多肽的多核苷酸序列的DNA分子。在一个具体实施方案中,编码具有SEQ ID NO:9的氨基酸序列的多肽的多核苷酸序列是SEQ ID NO:39,编码具有SEQ ID NO:10的氨基酸序列的多肽的多核苷酸序列是SEQ ID NO:40。
进一步,本发明提供了哺乳动物细胞,其包含:包含编码具有SEQ ID NO:1的氨基酸序列的多肽的多核苷酸序列的DNA分子,和包含编码具有SEQ ID NO:2的氨基酸序列的多肽的多核苷酸序列的DNA分子。本发明还提供了哺乳动物细胞,其包含DNA分子,所述DNA分子包含编码具有SEQ ID NO:5的氨基酸序列的多肽和具有SEQ ID NO:6的氨基酸序列的多肽的多核苷酸序列。本发明还提供了哺乳动物细胞,其包含DNA分子,所述DNA分子包含编码具有SEQ ID NO:9的氨基酸序列的多肽和具有SEQ ID NO:10的氨基酸序列的多肽的多核苷酸序列。在一个实施方案中,所述哺乳动物细胞系是中国仓鼠卵巢(CHO)或仓鼠胚肾(HEK)细胞系。
本发明还提供了哺乳动物细胞,其包含:包含编码具有SEQ ID NO:1的氨基酸序列的多肽的多核苷酸序列的DNA分子,和/或包含编码具有SEQ ID NO:2的氨基酸序列的多肽的多核苷酸序列的DNA分子,其中所述细胞能够表达包含具有SEQ ID NO:1的氨基酸序列的HC和具有SEQ ID NO:2的氨基酸序列的LC的抗体。优选地,所述哺乳动物细胞包含DNA分子,所述DNA分子包含编码具有SEQ ID NO:1的氨基酸序列的多肽和具有SEQ ID NO:2的氨基酸序列的多肽的多核苷酸序列。在一个实施方案中,所述哺乳动物细胞系是CHO或HEK细胞系。
本发明还提供了哺乳动物细胞,其包含:包含编码具有SEQ ID NO:5的氨基酸序列的多肽的多核苷酸序列的DNA分子,和/或包含编码具有SEQ ID NO:6的氨基酸序列的多肽的多核苷酸序列的DNA分子,其中所述细胞能够表达包含具有SEQ ID NO:5的氨基酸序列的HC和具有SEQ ID NO:6的氨基酸序列的LC的抗体。优选地,所述哺乳动物细胞包含DNA分子,所述DNA分子包含编码具有SEQ ID NO:5的氨基酸序列的多肽和具有SEQ ID NO:6的氨基酸序列的多肽的多核苷酸序列。在一个实施方案中,所述哺乳动物细胞系是CHO或HEK细胞系。
本发明还提供了哺乳动物细胞,其包含:包含编码具有SEQ ID NO:9的氨基酸序列的多肽的多核苷酸序列的DNA分子,和/或包含编码具有SEQ ID NO:10的氨基酸序列的多肽的多核苷酸序列的DNA分子,其中所述细胞能够表达包含具有SEQ ID NO:9的氨基酸序列的HC和具有SEQ ID NO:10的氨基酸序列的LC的抗体。优选地,所述哺乳动物细胞包含DNA分子,所述DNA分子包含编码具有SEQ ID NO:9的氨基酸序列的多肽和具有SEQ ID NO:10的氨基酸序列的多肽的多核苷酸序列。在一个实施方案中,所述哺乳动物细胞系是CHO或HEK细胞系。
在另一个实施方案中,本发明提供了用于产生抗体的方法,所述抗体包含具有SEQID NO:2的氨基酸序列的LC和具有SEQ ID NO:1的氨基酸序列的HC,其中所述方法包括:在使得表达所述抗体的条件下培养包含DNA的哺乳动物细胞,所述DNA编码具有SEQ ID NO:2的氨基酸序列的LC和/或具有SEQ ID NO:1的氨基酸序列的HC;和回收表达的抗体。本发明包括可通过如上文刚刚描述的本发明的方法获得的抗体。
本发明还提供了用于产生抗体的方法,所述抗体包含具有SEQ ID NO:6的氨基酸序列的LC和具有SEQ ID NO:5的氨基酸序列的HC,其中所述方法包括:在使得表达所述抗体的条件下培养包含DNA的哺乳动物细胞,所述DNA编码具有SEQ ID NO:6的氨基酸序列的LC和/或具有SEQ ID NO:5的氨基酸序列的HC;和回收表达的抗体。本发明包括可通过如上文刚刚描述的本发明的方法获得的抗体。
本发明还提供了用于产生抗体的方法,所述抗体包含具有SEQ ID NO:10的氨基酸序列的LC和具有SEQ ID NO:9的氨基酸序列的HC,其中所述方法包括:在使得表达所述抗体的条件下培养包含DNA的哺乳动物细胞,所述DNA编码具有SEQ ID NO:10的氨基酸序列的LC和/或具有SEQ ID NO:9的氨基酸序列的HC;和回收表达的抗体。本发明包括可通过如上文刚刚描述的本发明的方法获得的抗体。
本发明包括用于产生抗体的方法,所述抗体包含两条HC和两条LC,其中两条HC各自的氨基酸序列是SEQ ID NO:1,且两条LC各自的氨基酸序列是SEQ ID NO:2,且所述方法包括:a)在使得表达所述抗体的条件下培养如上文所述的本发明的哺乳动物细胞,和b)回收表达的抗体。本发明包括可通过如上文刚刚描述的本发明的方法获得的抗体。
本发明还包括用于产生抗体的方法,所述抗体包含两条HC和两条LC,其中两条HC各自的氨基酸序列是SEQ ID NO:5,且两条LC各自的氨基酸序列是SEQ ID NO:6,且所述方法包括:a)在使得表达所述抗体的条件下培养如上文所述的本发明的哺乳动物细胞,和b)回收表达的抗体。本发明包括可通过如上文刚刚描述的本发明的方法获得的抗体。
本发明还包括用于产生抗体的方法,所述抗体包含两条HC和两条LC,其中两条HC各自的氨基酸序列是SEQ ID NO:9,且两条LC各自的氨基酸序列是SEQ ID NO:10,且所述方法包括:a)在使得表达所述抗体的条件下培养如上文所述的本发明的哺乳动物细胞,和b)回收表达的抗体。本发明包括可通过如上文刚刚描述的本发明的方法获得的抗体。
本发明提供了抗体,其在具有以下SEQ ID NO:31的残基的结构性和功能性表位处接触人BTLA:位置42处的Arg和位置127处的His。本发明还提供了抗体,其在包含由SEQ IDNO:31给出的氨基酸序列的位置42处的Arg的结构性和功能性表位处接触人BTLA。
本发明提供了抗体,其在具有以下SEQ ID NO:31的残基的新型结构表位处接触人BTLA:位置35处的Asp、位置37处的Gln、位置42处的Arg、位置74处的Leu、位置76处的Gly、位置79处的Cys、位置114处的Arg、位置119处的Phe、位置120处的Gln、位置122处的Asn、位置128处的Ser。在一个优选实施方案中,抗体22B3被称为模拟结合BTLA的HVEM,因为抗体22B3的HCDR3结构上类似于HVEM。优选地,当在程序诸如PyMOL™中BTLA:抗体晶体结构与BTLA:HVEM晶体结构对齐时,抗体CDR环采用类似于HVEM环的构型,所述HVEM环包含氨基酸残基69至72 (SEQ ID NO:41的氨基酸ELTG)。
本发明提供了抗体,其在具有SEQ ID NO:31的位置52处的Asp的功能性表位处接触人BTLA。所述抗体接触具有以下SEQ ID NO:31的残基的新型结构性表位:位置46处的His、位置55处的Glu、位置103处的Glu、位置104处的Pro、位置106处的Leu、位置107处的Pro、位置134处的Thr、位置139处的Ala。
本发明提供了抗体,其在具有SEQ ID NO:31的位置68处的His和位置81处的Lys的功能性表位处接触人BTLA。在一个实施方案中,所述抗体接触具有以下SEQ ID NO:31的残基的新型结构性表位:位置62处的Tyr、位置64处的Ala、位置68处的His、位置85处的Arg、位置91处的Glu、位置98处的Phe、位置118处的Asn。
本发明提供了抗体,其在具有以下SEQ ID NO:31的残基的新型结构表位处接触人BTLA:位置35处的Asp、位置37处的Gln、位置42处的Arg、位置74处的Leu、位置76处的Gly、位置79处的Cys、位置114处的Arg、位置119处的Phe、位置120处的Gln、位置122处的Asn以及位置124处的Ile、位置128处的Ser。
如本文所用,“抗体”是包含通过二硫键互联的2条HC和2条LC的免疫球蛋白分子。每条LC和HC的氨基端部分包括约100-120个氨基酸的可变区,其主要负责经由其中所含有的CDR来识别抗原。CDR与更保守的称为框架区(“FR”)的区域相交替。每条LCVR和HCVR由3个CDR和4个FR构成,其从氨基端至羧基端以以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。LC的3个CDR称为“LCDR1、LCDR2和LCDR3”,且HC的3个CDR称为“HCDR1、HCDR2和HCDR3”。CDR含有与抗原形成特异性相互作用的大多数残基。也就是说,CDR含有与抗原的残基接触(在4.5Å内)的大多数残基。抗体结合具体抗原的功能性能力因此主要受6个CDR内的氨基酸残基影响。基于众所周知的Kabat编号惯例(Kabat, 等人, Ann. NY Acad. Sci. 190:382-93 (1971); Kabat等人, Sequences of Proteins of Immunological Interest, 第五版, U.S. Department of Health and Human Services, NIH Publication No. 91-3242(1991))和Chothia惯例(Chothia C, Lesk AM. Canonical structures for thehypervariable regions of immunoglobulins. J. Mol. Biol. 1987;196:901–17.Chothia C, Lesk AM, Tramontano A, Levitt M, Smith-Gill SJ, Air G, Sheriff S,Padlan EA, Davies D, Tulip WR, 等人Conformations of immunoglobulinhypervariable regions. Nature. 1989;342:877–83),将氨基酸指定至本发明抗体的LCVR和HCVR区内的CDR结构域。HCDR1的起始氨基酸残基由Chothia定义且HCDR1的终止氨基酸残基由Kabat定义。HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的起始和终止氨基酸残基由Kabat定义。
如本文所用,术语“表位”可指结构性表位(与抗体的可变区接触的抗原的位点)和/或功能性表位(可与或可不与抗体的可变区接触且对于抗体结合必要的抗原的位点)。通过X-射线结晶学测定结构性表位,其中将结合的Fab上的另一个残基的4.5Å内的人BTLA上的任何残基被视为接触位点。
本发明的抗体可使用已知方法来制备并纯化。例如,编码HC(例如由SEQ ID NO:1给出的氨基酸序列)和LC(例如由SEQ ID NO:2给出的氨基酸序列)的cDNA序列可经克隆并工程改造至GS(谷氨酰胺合成酶)表达载体中。然后,工程改造的免疫球蛋白表达载体可稳定转染至CHO细胞中。如本领域技术人员将理解,抗体的哺乳动物表达将导致通常在Fc区中的高度保守的N-糖基化位点处的糖基化。稳定克隆可针对特异性结合BTLA的抗体的表达来验证。可在生物反应器中将阳性克隆扩展至用于抗体产生的无血清培养基中。抗体已分泌至其中的培养基可通过常规技术来纯化。例如,培养基可方便地施加至已用相容缓冲液诸如磷酸盐缓冲盐水来平衡的蛋白A或G琼脂糖FF柱。洗涤柱以移除非特异性结合组分。将结合的抗体例如通过pH梯度来洗脱,且抗体级分诸如通过SDS-PAGE来检测且然后合并。抗体可使用常用技术浓缩和/或无菌过滤。可溶性聚集物和多聚体可通过常用技术有效移除,所述技术包括大小排阻、疏水相互作用、离子交换或羟磷灰石色谱。产物可立刻冷冻(例如在-70℃下)或可冻干。
本发明的抗体可并入药物组合物中,所述药物组合物可通过本领域众所周知的方法制备且包含本发明的抗体和一种或多种药学上可接受的载体、稀释剂或赋形剂。
包含有效量的本发明的抗体的药物组合物可通过肠胃外途径(例如皮下、静脉内、腹膜内、肌内或经皮)施用于处于如本文所述的疾病或病症的风险中或展现如本文所述的疾病或病症的患者。“有效量”是指实现期望治疗结果的必需量(在剂量下且对于时间段且对于施用方式)。抗体的有效量可根据因素而变化,所述因素诸如疾病状态、个体的年龄、性别和重量以及抗体在个体内诱发期望应答的能力。有效量也是治疗有益效应胜过本发明的抗体的任何毒性或有害效应的量。
本发明的抗体可用于患者的治疗中。更具体地,预期本发明抗体治疗风湿性、神经性和皮肤病学疾病中的一种或多种。风湿性疾病的特征在于炎症,其可影响人的关节、肌肉和/或器官。一种此类风湿性疾病是全身性红斑狼疮(SLE)。
如本文可互换使用,“治疗(treatment)”和/或“治疗(treating)”和/或“治疗(treat)”意指其中可减缓、中断、阻止、控制、停止或逆转本文所述病症的进展的所有过程,但不一定指示所有病症症状的完全消除。治疗包括施用本发明的抗体用于治疗会受益于BTLA活性增加的人的疾病或病况,且包括:(a)抑制疾病的进一步进展;和(b)减轻疾病,即引起疾病或病症的消退或缓解其症状或并发症。
抗体工程改造
通过用Fc标记的人BTLA的胞外结构域(ECD)结构域来免疫兔并用小鼠BTLA-Fc标记的蛋白(25F7)或替代地用人和小鼠BTLA-Fc标记的蛋白(22B3和23C8)加强来生成本发明的抗体。用组氨酸标记的人、小鼠和食蟹猴BTLA完成筛选以鉴定交叉反应性。人BTLA的氨基酸序列由SEQ ID NO:31给出,Balbc小鼠BTLA的氨基酸序列由SEQ ID NO:32给出,C57BL6的氨基酸序列由SEQ ID NO:33给出,且食蟹猴BTLA的氨基酸序列由SEQ ID NO:34给出。然后将抗体人源化并亲和力成熟。
实施例
工程改造的BTLA激动剂抗体的表达和纯化
本发明的BTLA激动剂抗体可以基本上如下表达和纯化。可用用于分泌抗体的表达系统使用最佳预定HC:LC载体比率(诸如1:3或1:2)或编码HC和LC两者的单一载体系统瞬时或稳定转染适当宿主细胞(诸如HEK 293或CHO)。可使用许多常用技术中的任一者纯化其中已分泌抗体的经澄清培养基。例如,可将培养基便利地施加至已用相容缓冲液(诸如磷酸盐缓冲盐水(pH 7.4))平衡的MabSelect柱(GE Healthcare)或KappaSelect柱(GE Healthcare)(用于Fab片段)。可洗涤该柱以去除非特异性结合组分。可例如通过pH梯度(诸如20mM Tris缓冲液(pH 7.0)至10mM柠檬酸钠缓冲液(pH 3.0)或磷酸盐缓冲盐水(pH 7.4)至100mM甘氨酸缓冲液(pH 3.0))洗脱结合抗体。可诸如通过SDS-PAGE检测抗体级分,且然后可合并。根据预期用途,进一步纯化是任选的。可使用常用技术浓缩和/或无菌过滤抗体。可通过常用技术(包括大小排阻、疏水性相互作用、离子交换、多态或羟磷灰石色谱)有效去除可溶性聚集物和多聚体。抗体在这些色谱步骤之后的纯度为约95%至约99%。产物可保持冷藏,立即在-70℃下冷冻或可冻干。下面显示本发明的示例性抗体的氨基酸SEQ ID NO。
表1. 示例性BTLA激动剂抗体的氨基酸序列。
结合亲和力和动力学
通过表面等离子共振使用Biacore® 3000 (GE Healthcare)来测量本发明的BTLA激动剂抗体(22B3、23C8和25F7)对BTLA的结合亲和力和动力学。通过经由胺偶联将约120 RUBTLA蛋白(人、大鼠、鼠(Balbc或C57BL6)或食蟹猴BTLA)固定在Biacore® CM5芯片上,且使BTLA激动剂抗体流动来测量结合亲和力,从500 nM开始,以2倍连续稀释降至15.6 nM。实验在25℃下在HBS-EP缓冲液(GE Healthcare BR100669;10 mM HEPES,150 mM NaCl,3 mMEDTA,0.05%表面活性剂P20,pH 7.4)中实施。对于每个循环,250 μL抗体样品以50 μl/min流过流动室1和2,且然后解离10分钟。通过以10 μL/mL流速注射5 μL的pH 1.5的甘氨酸缓冲液来再生芯片表面。将数据拟合至1:1 Langmiur结合模型以推导kon、koff,并计算KD。遵循基本上如上所述的程序,观察到以下参数(显示于表2中)。下文显示的数据是人、食蟹猴、大鼠和鼠对于22B3的三次实验的平均值。
表2. 结合亲和力和动力学。
如上表2中所示,本发明的BTLA激动剂抗体结合BTLA。具体地,抗体22B3能够结合人、鼠和食蟹猴BTLA。
与原代细胞的结合
通过FACS来测定本发明的BTLA抗体(22B3、23C8和25F7)结合来自不同物种的原代细胞的能力。根据制造商的方案,使用Ficoll (GE #17-1440-02)和SepMate管(STEMCELL #15450)从供体血液样品(San Diego Blood Bank, #LRS-WBC)分离人外周血单核细胞(PBMC)。食蟹猴PBMC (全世界灵长类动物 # CA-10)从液氮解冻并用FACS缓冲液洗涤一次(与上文相同)。
从雄性C57BL6小鼠(JAX)或雌性Sprague Dawley大鼠(Harlan)收集脾脏,合并,并在用完全RPMI 1640冲洗的50 mL锥形管上使用细胞过滤器和注射器栓塞解离成单细胞悬浮液,所述完全RPMI 1640具有10%热灭活的FBS和2 mM EDTA。在用完全RPMI淬灭之前,将细胞沉淀,移除培养基,并通过将沉淀物再悬浮于2 ml ACK裂解缓冲液(gibco #A10492-01)中近似2分钟来裂解红血细胞。可将裂解的细胞沉淀且在FACS缓冲液(含有3% FBS、20 mMHEPES和2 mM EDTA的DPBS 1X)中洗涤一次。
使用Countess细胞计数器定量分离的原代细胞,且以2 x106个细胞/ml再悬浮于FACS缓冲液中。在细胞分离的同一天通过将50 µl (~0.1 x106个)细胞铺板至96孔板(Greiner #650101)中来进行流式细胞术实验。通过在4℃下添加1 µl Fc封闭剂(例如,来自BD # 553142) 15分钟且不洗涤来阻止非特异性抗体结合。
通过在FACS缓冲液中连续稀释,在不同浓度下测试BTLA抗体结合。例如,将以不同浓度开始的纯化抗体和对照首先稀释至30 µg/mL,且进行起始材料的连续1:3稀释,以得到总共10种滴定物(加上未处理对照)。抗体滴定物在4℃下与细胞一起孵育20分钟,并在染色之前用FACS缓冲液洗涤。细胞使用荧光染料缀合的抗体染色以鉴定特定细胞类型(例如,CD19 B细胞、CD4 T细胞或CD8 T细胞)或使用二抗染色以鉴定结合该子集的抗体的存在或不存在。在流式细胞仪上分析之前,在4℃下进行染色20分钟并用FACS缓冲液洗涤3次。结果使用标准FACS分析软件(例如,FACSDiva)分析且报导为每种滴定物的二抗的平均荧光强度。通过高于背景的平均荧光强度染色确定指示结合的阳性结果。
遵循基本上如上所述的程序,抗体22B3结合表达人、食蟹猴、大鼠和小鼠BTLA的细胞,抗体23C8结合表达人和食蟹猴BTLA的细胞,且抗体25F7结合表达人、食蟹猴和小鼠BTLA的细胞。
BTLA激动剂抗体诱导的磷酸化
为了测定本发明的BTLA激动剂抗体(22B3和25F7)在人B细胞系中诱导酪氨酸磷酸化的能力,在37℃下使BTLA抗体以10 μg/mL结合至24孔培养板一小时。用PBS洗涤板以移除任何未结合的抗体。可以将表达人BTLA的B细胞系(诸如Ramos.2G6.4C10人B淋巴细胞细胞系(ATCC))以10x10^6个细胞/mL添加至孔并在37℃下孵育30 min。将细胞移取且裂解于完全裂解缓冲液(MSD)中,并在-80℃下冷冻至少30 min。
通过Meso Sector S 600检测磷酸化的BTLA。通过在室温下在封闭溶液(MSD)中孵育一小时来制备链霉抗生物素蛋白检测板。在室温下将生物素化的BTLA捕获抗体(5A5)包被至板上一小时,随后为三个或更多个Tris洗涤步骤。将细胞裂解物在室温下孵育两小时。用SULFO-TAG抗BTLA抗体(ANC6E9)检测总BTLA,并用SULFO-TAG抗磷酸酪氨酸抗体(PY20;MSD)、随后三个或更多个Tris洗涤步骤来测量磷酸化BTLA。然后在临使用Meso Sector S600分析之前将2x读取缓冲液T (MSD)的添加物添加至孔。
遵循基本上如上所述的程序,抗体22B3导致超过背景的BTLA的酪氨酸磷酸化相比于阴性对照增加2.41倍,并且抗体25F7导致超过背景的BTLA的酪氨酸磷酸化相比于阴性对照增加1.47倍。这些数据表明BTLA激动剂抗体22B3和25F7能够在人B细胞系中诱导BTLA磷酸化。
人原代B细胞增殖的抑制
通过抑制人原代B细胞增殖的能力来评估本发明的BTLA激动剂抗体的体外功效。使用人B细胞分离试剂盒(EasySep)从健康人外周血单核细胞分离人原代B细胞并将其再悬浮于适当的人原代细胞培养基中。将抗IgM与同种型对照或BTLA抗体的滴定物一起包被至板并在37℃下孵育一小时,随后为PBS洗涤步骤。将分离的人B细胞添加至各孔并在37℃下与5%CO2一起孵育72小时,随后为[3H]-胸苷脉冲最后18小时。孵育后,移取板并将其置于干冰上30分钟且然后在-20℃下储存直至准备好收获。细胞通过解冻裂解且用Harvester9600(Tomtec)收获。通过用MicroBeta2 2450微板计数器(Perkin Elmer)测量[3H]-胸苷掺入来评价增殖。
使用计数来评价该测定中的相对增殖应答,并使用等式[%抑制=AVG最大信号-样品信号)/AVG最大信号 x 100]来计算百分比抑制,所述等式可用于使用绘图软件(GraphPad Prism)来测定IC50值。
遵循基本上如上所述的程序,BTLA激动剂抗体22B3能够以计算的0.32 + /-0.1nM的IC50体外抑制原代B细胞增殖,抗体23C8能够以计算的0.14 nM的IC50体外抑制原代B细胞增殖,且抗体25F7能够以计算的0.17 nM的IC50体外抑制原代B细胞增殖。在类似的实验中,抗体22B3能够以计算的0.32 nM的IC50抑制原代B细胞增殖,且具有与Mab8D5相同的HCVR和LCVR (分别为‘694专利的SEQ ID NO:11和18)的抗体以计算的6.38 nM的IC50抑制原代B细胞增殖。这些数据表明BTLA激动剂抗体22B3、23C8和25F7能够体外抑制B细胞增殖,且抗体22B3相比于Mab8D5具有更大的体外活性。
GvHD的人源化NSG小鼠模型
体内测定人PBMC驱动的移植物抗宿主疾病(GvHD)的预防。
简言之,将雌性NSG小鼠(JAX Labs,Stock # 05557)(近似8-10周龄)标准化且基于基线体重测量值分至处理组中(n=8只小鼠/处理组)。根据制造商的方案,使用Ficoll(GE #17-1440-02)和SepMate管(STEMCELL # 15450)从血液供体计划(San Diego BloodBank, #LRS-WBC)分离外周血单核细胞(PBMC)。将PBMC以近似150 x106个细胞/ml PBS再悬浮。处理组在给药之前是不知情的。
在第1天,将悬浮于PBS中的100 µl (15 x106个细胞)的PBMC (如上所述) (或用于非移植对照的100 µl PBS)静脉内(IV)注射至每只小鼠的尾部中。通过皮下(SQ)注射向小鼠每周给药(QW) PBS媒介物中的不同浓度的本发明的抗体(22B3或23C8)或对照。三次独立研究基本上如本文所述进行。用于各研究的给药浓度为[研究1 (抗体22B3):0.1、1.0、5.0、10.0和20.0 mg/kg;研究2 (抗体22B3或23C8):0.001、0.01、10.0和100 mpk;以及研究3:0.001、0.005、0.01、0.1、0.5和1.0 mpk]。
终止研究,并在同种型对照动物失去基线体重的20%损失(研究1和2)或第28天(研究3)之前,对小鼠进行安乐死。记录重量(研究1和研究2),收集血清用于细胞因子分析(研究1;通过MSD ELISA进行分析;分析的细胞因子为TNFα、IL-10、IL-6、IL-4、IL12p70、IL-13、IL-2和IL-8),并收获脾脏用于表型分析/药效学分析(通过CD 8 T细胞群体的减少来测量;研究1和研究3)。
遵循基本上如上所述的程序,获得以下数据。
研究1中的抗体22B3处理的动物表明以下(呈0.1、1.0、5.0、10.0或20.0 mg/kg剂量的抗体):(i)在研究结束时的体重与未移植对照动物的体重相比类似;(ii)细胞因子TNFα、IL-10、IL-6、IL-4和IL-12p70与同种型对照动物相比减少;和(iii) CD 8 T细胞群体与同种型对照动物相比减少(表型分析/药效学分析)。
来自研究2的数据表明用0.01 mg/kg抗体22B3或1.0、5.0或10.0 mg/kg抗体23C8处理的小鼠在研究结束时,与未移植对照动物的体重相比,具有类似体重。研究2未表明22B3在10.0 mg/kg下对体重的活性,其可反映该模型的天然供体可变性。在研究3中,抗体22B3表明以下剂量的抗体的体内药效学活性:0.01、0.1、0.5和1.0 mg/kg。综上,这些数据表明抗体22B3和抗体23C8在体内有效预防GvHD。
mIFNα诱导的狼疮性肾炎
干扰素α (IFNα)诱导的狼疮性肾炎模型是全身性红斑狼疮(SLE)的小鼠模型,其中IFNα用于与新西兰黑小鼠和新西兰白(NZB/W)小鼠的杂交鼠中同步发病且加速疾病进展。NZB/W小鼠模型是自发狼疮性肾炎的经典模型。可以用使用腺病毒载体外源性施用IFNα来加速这些小鼠中的疾病进展。该狼疮性肾炎模型用于表明本发明的BTLA激动剂抗体的活性。
研究开始前一天,基于体重随机地分选十一周龄的雌性NZB/W小鼠。将小鼠分布至以下处理组中:(1) LacZ腺相关病毒(AAV + 10 mg/kg人IgG4 PAA同种型对照(PAA为S228P、F234A和L235A突变);(2) IFNα AAV + 10 mg/kg人IgG4 PAA同种型对照;(3) IFNαAAV + 3 mg/kg 22B3抗体;(4) IFNα AAV + 10 mg/kg 22B3抗体;或(5) IFNα AAV + 50mg/kg环磷酰胺。在研究开始之日(第0天),向小鼠静脉内一次施用PBS中的表达LacZ基因(非患病)或小鼠IFNα (患病)的AAV的1011个基因组拷贝(GC)。在组1-4中,将小鼠在第0天开始每周一次用PBS中的同种型对照或22B3抗体皮下处理。在组5中,将小鼠每10天用PBS中的环磷酰胺腹膜内处理。每2周从小鼠收集尿液样品,直至处理开始后6周研究终止。KamiyaBiomedical™小鼠微量白蛋白ELISA用于定量尿液白蛋白水平。通过使用酶促肌酐测定(Roche Diagnostics)来测量尿液肌酐。将白蛋白尿(肾功能的生物标志物)定义为尿液中检测到的大于300 µg白蛋白/mg肌酐。
遵循基本上如上所述的程序,到第4周,同种型处理的患病组(IFNα AAV + hIgG4PAA)中的白蛋白尿的发生率达到100%且保持升高直至研究结束,而LacZ AAV处理(非患病)的小鼠未显示任何白蛋白尿的发生率。可以是急性肾毒性的环磷酰胺引起患病小鼠中的白蛋白尿的瞬时增加,但环磷酰胺组中的白蛋白尿的发生率到研究结束时降至零。3 mg/kg和10 mg/kg的抗体22B3能够在第28天时将白蛋白尿的发生率分别降低至50%和20%,并在第42天时分别降低至60%和70%。这些结果表明抗体22B3能够保留模型中的肾功能。
研究期间百分比存活率的Kaplan-Meier图(数据未显示)显示,同种型处理的患病组中的肾机能不全导致在第28天时开始的死亡。到研究结束,同种型处理的患病组中的存活率为60%。未患病且环磷酰胺处理的组具有100%的存活率。在研究结束时,用10 mg/kg抗体22B3处理的小鼠也显示100%存活率,而用3 mg/kg处理的小鼠显示80%存活率。这些结果表明抗体22B3能够在该模型中预防疾病相关的死亡。
咪喹莫特诱导的牛皮癣的模型
测试本发明的抗体限制通过应用TLR7/8激动剂咪喹莫特(IMQ)诱导的牛皮癣样皮炎的严重程度的能力。在第0天,将七周龄的雌性B6.SJL-Ptprc a Pepc b/BoyJ小鼠(JAX储存号:002014)或HVEM-/-小鼠(描述于Wang等人, J. Clin. Invest., 115:3, 711-717, 2005年3月)分别用3 mg/kg或1 mg/kg的抗体22B3或抗体25F7腹膜内注射,且将小鼠的背部剃毛。用hIgG4同种型对照注射的动物充当对照。在第1-3天,将小鼠用吸入的异氟醚(VetOne)麻醉,且然后将5% IMQ乳霜(50 mg,Fougera)应用至经剃毛皮肤的限定区域。在第4天,切除皮肤的处理区域并分析疾病严重程度和炎症相关基因表达。
遵循基本上如上所述的程序,组织学分析表明,在用hIgG4同种型对照或1 mg/kg抗体22B3处理的组中的表皮层的增厚,伴有角化不全和角化过度。用3 mg/kg抗体22B3或3mg/kg抗体25F7处理的小鼠显示表皮厚度的显著减小,其中一些区域看起来组织学正常。通过qPCR使用iTaq Universal SYBR Green Supermix (Bio-Rad)分析皮肤中的基因表达。用3 mg/kg抗体22B3处理的小鼠表现出I型IFN (IFNα、IFNβ)和IFNγ以及IFN应答基因(Isg15、Mx1、Mx2、Oas2)的表达的显著减少。参与建立IMQ诱导的皮炎的细胞因子的分析还表明3 mg/kg抗体22B3处理组中的IL-22和IL-23表达的显著减少。这些数据表明BTLA激动剂抗体22B3和25F7能够减小牛皮癣样皮炎的小鼠模型中的表皮厚度。
表位测定
通过ELISA测定本发明的BTLA激动剂抗体的功能性表位,并通过x-射线结晶学测定结构性表位。
方法
ELISA:功能性表位
将BTLA的表面突变的以下集合单独地引入与(人)Fc融合的人BTLA蛋白中:D35R、Q37R、Y39E、R42D、Q43A、E45R、S47H、L49R、D52R、E55R、E57R、D84R、N65R、H68A、V80R、K81E、E83R、S88H、K90H、E91H、I95R、E103H、L106R、N108R、R114V、S121Y、N122R、E125H、H127E、T130R、Y132R和T134H。
使用ELISA测定22B3和23C8的结合,其中待绘制表位的抗体由固定的抗兔抗体捕获,并在洗涤之后,将每种BTLA突变体作为4点4倍稀释系列与捕获的抗体孵育并用酶联抗人Fc试剂检测。将所得信号在抗体间比较并与对照抗体比较。功能性表位通常通过针对一种或两种突变体的信号的显著减少来指示自身。对于25F7抗体,进行夹心ELISA,其中固定人源化22B3,捕获BTLA突变体且其由兔25F7结合。这得到强得多的信号且可在消除22B3表位之后鉴定25F7表位。
X-射线结晶学:结构性表位
为了测定各种抗体的相互作用界面且因此测定各种抗体在BTLA上的物理表位,将人BTLA与本发明的抗体的Fab部分共结晶并测定晶体结构。从所得的晶体结构,将任何抗体原子的4.5Å内的BTLA残基计数为表位的部分(使用Pymol可视化软件)。4.5埃从原子中心至原子中心测量。具有以4.5埃接近抗体中的任何原子的至少一个原子的任何残基是表位的部分。
在具有人BTLA的复合物中测定两种22B3结构。首先利用亲本兔22B3抗体Fab,用组氨酸标记并与表达为Fc融合体的人BTLA的S47H突变体(稳定突变)一起纯化,且然后切割和纯化。这两种蛋白以近似等摩尔比混合并在市售的筛网中筛选结晶。获得晶体并在高级光子源(Advanced Photon Source)处收集衍射数据。该数据通过分子置换减少并解析且精化以得到在22B3和BTLA之间的复合物的高分辨率结构。第二复合物在人源化22B3 (Fab部分)的亲和力成熟版本(具有HC突变I56Q/T57H/G98A和LC S95H)和人BTLA之间。将这些共表达,纯化为复合物并类似地筛选。所得的结构和表位类似于第一结构。
以与第一22B3复合物相同的方式,即通过纯化His标记的兔亲本Fab,与单体S47H人BTLA混合和结晶,来获得复合物中的23C8的结构。
根据第二22B3复合物,即通过共表达、共纯化和结晶,来获得具有人BTLA的复合物中的25F7的结构。利用具有与人BTLA的改进结合的人源化25F7的双突变体(用于表位测定的人源化25F7在HC S30W/LC E27R处具有突变)。
结果
22B3抗体:在一组BTLA表面突变体中,R42D和H127E对与兔22B3抗体(包含与22B3相同的CDR,但具有兔框架)的结合具有显著负面影响。功能性表位包含人BTLA (SEQ ID NO:31)的位置42处的Arg和位置127处的His。在人BTLA和兔22B3 Fab之间的晶体结构复合物中的22B3的4.5埃内并且是结构性表位的BTLA残基是SEQ ID NO:31的以下残基:位置35处的Asp、位置37处的Gln、位置42处的Arg、位置74处的Leu、位置76处的Gly、位置79处的Cys、位置114处的Arg、位置119处的Phe、位置120处的Gln和位置122处的Asn、位置128处的Ser。人BTLA和人22B3变体(HC I56Q/T57H/G98A LC S95H) Fab之间的晶体结构复合物中的22B3的4.5埃内的BTLA残基是SEQ ID NO:31的位置35处的Asp、位置37处的Gln、位置42处的Arg、位置74处的Leu、位置76处的Gly、位置79处的Cys、位置114处的Arg、位置119处的Phe、位置120处的Gln、位置122处的Asn以及位置124处的Ile、位置128处的Ser。
在类似研究中,HVEM结合BTLA的结构性表位是BTLA的以下氨基酸:位置37处的Gln、位置42处的Arg、位置74处的Leu、位置76处的Gly、位置77处的Thr、位置112处的Ser、位置114处的Arg、位置118处的Asn、位置121处的Ser、位置128处的Ser和位置130处的Thr。通过将抗体:BTLA晶体结构叠加至HVEM:BTLA晶体结构上、对齐BTLA分子来评价抗体22B3和HVEM之间的结构类似性。含有氨基酸残基69-72的HVEM区和对应抗体区中的骨架均方根偏差被测定为1.4埃。
23C8抗体:D52R在ELISA中阻断兔23C8 (包含与23C8相同的HCDR1、HCDR2、HCDR3、LCDR1和LCDR2,具有QCTYGGVVGSTSDDNP的LCDR3且具有兔框架)与人BTLA的结合。功能性表位包含人BTLA (SEQ ID NO:31)的位置52处的Asp。在人BTLA (S47H)和兔23C8 Fab之间的晶体结构复合物中的23C8的4.5埃内并且是结构性表位的BTLA残基是SEQ ID NO:31的位置46处的His、位置55处的Glu、位置103处的Glu、位置104处的Pro、位置106处的Leu、位置107处的Pro、位置134处的Thr以及位置139处的Ala。抗体23C8不模拟HVEM结合。
25F7抗体:在一组BTLA表面突变体中,H68A和K61E对与兔25F7抗体(包含与25F7相同的CDR,但具有兔框架)的结合具有显著负面影响。功能性表位包含人BTLA (SEQ ID NO:31)的位置68处的His和位置81处的Lys。人BTLA和人源化25F7 Fab变体(HC S30W,LC E27R)之间的晶体结构复合物中的25F7的4.5埃内且为结构性表位的BTLA残基为SEQ ID NO:31的位置62处的Tyr、位置64处的Ala、位置68处的His、位置85处的Arg、位置91处的Glu、位置98处的Phe和位置118处的Asn。抗体25F7不模拟HVEM结合。
序列
序列表
<110> Eli Lilly and Company
<120> BTLA激动剂抗体及其用途
<130> X21261
<140> 62/508510
<141> 2017-05-19
<160> 41
<170> PatentIn version 3.5
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<213> 人工序列
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100 105 110
Ile Lys
<210> 9
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 9
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 Ser Leu Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Ser Asp Asp Gly Thr Thr Tyr Tyr Ala Thr Trp Ala Lys
50 55 60
Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met
65 70 75 80
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Ala Gly Ala Gly Gly Val Gln Asp Tyr Leu Thr Leu Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 10
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 10
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Gln Ala Ser Glu Asn Ile Tyr Asn Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Gly Ser Ser Asn Ser Asn
85 90 95
Ile Asp Asn Pro Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 11
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 11
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 Ser Leu Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Ser Asp Asp Gly Thr Thr Tyr Tyr Ala Thr Trp Ala Lys
50 55 60
Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met
65 70 75 80
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Ala Gly Ala Gly Gly Val Gln Asp Tyr Leu Thr Leu Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 12
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 12
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Gln Ala Ser Glu Asn Ile Tyr Asn Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Gly Ser Ser Asn Ser Asn
85 90 95
Ile Asp Asn Pro Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 13
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 13
Gly Phe Ser Leu Ser Ser Tyr Gly Val Ser
1 5 10
<210> 14
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 14
Gly Phe Asp Ile Ser Lys Tyr Asn Ile Gln
1 5 10
<210> 15
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 15
Gly Phe Ser Leu Ser Thr Tyr Ala Met Asn
1 5 10
<210> 16
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 16
Ala Ile Ser Tyr Asp Gly Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Ser
1 5 10 15
<210> 17
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 17
Phe Ile Asn Tyr Gly Gly Ser Ala Tyr Tyr Ala Ser Arg Ala Lys Gly
1 5 10 15
<210> 18
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 18
Ile Ile Ser Asp Asp Gly Thr Thr Tyr Tyr Ala Thr Trp Ala Lys Gly
1 5 10 15
<210> 19
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 19
Gly Asp Tyr Tyr Asp Asp Tyr Val Tyr Val Tyr Ala Leu Asp Ile
1 5 10 15
<210> 20
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 20
Gly Leu Ser Asn Ser Asp Leu
1 5
<210> 21
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 21
Asp Ala Gly Ala Gly Gly Val Gln Asp Tyr Leu Thr Leu
1 5 10
<210> 22
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 22
Gln Ala Ser Gln Ser Ile Ser Thr Ala Leu Ala
1 5 10
<210> 23
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 23
Gln Ala Ser Gln Ser Ile Ser Ser Trp Leu Ser
1 5 10
<210> 24
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 24
Gln Ala Ser Glu Asn Ile Tyr Asn Phe Leu Ala
1 5 10
<210> 25
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 25
Ala Ala Ser Thr Leu Ala Ser
1 5
<210> 26
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 26
Arg Ala Ser Thr Leu Ala Ser
1 5
<210> 27
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 27
Ser Ala Ser Thr Leu Ala Ser
1 5
<210> 28
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 28
Gln Gln Gly Tyr Ser Ser Ser Asn Leu Asp Asn Val
1 5 10
<210> 29
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 29
Gln Ser Thr Tyr Gly Gly Val Val Gly Ser Thr Ser Asp Asp Asn Pro
1 5 10 15
<210> 30
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 30
Gln Gln Gly Ser Ser Asn Ser Asn Ile Asp Asn Pro
1 5 10
<210> 31
<211> 289
<212> PRT
<213> 智人
<400> 31
Met Lys Thr Leu Pro Ala Met Leu Gly Thr Gly Lys Leu Phe Trp Val
1 5 10 15
Phe Phe Leu Ile Pro Tyr Leu Asp Ile Trp Asn Ile His Gly Lys Glu
20 25 30
Ser Cys Asp Val Gln Leu Tyr Ile Lys Arg Gln Ser Glu His Ser Ile
35 40 45
Leu Ala Gly Asp Pro Phe Glu Leu Glu Cys Pro Val Lys Tyr Cys Ala
50 55 60
Asn Arg Pro His Val Thr Trp Cys Lys Leu Asn Gly Thr Thr Cys Val
65 70 75 80
Lys Leu Glu Asp Arg Gln Thr Ser Trp Lys Glu Glu Lys Asn Ile Ser
85 90 95
Phe Phe Ile Leu His Phe Glu Pro Val Leu Pro Asn Asp Asn Gly Ser
100 105 110
Tyr Arg Cys Ser Ala Asn Phe Gln Ser Asn Leu Ile Glu Ser His Ser
115 120 125
Thr Thr Leu Tyr Val Thr Asp Val Lys Ser Ala Ser Glu Arg Pro Ser
130 135 140
Lys Asp Glu Met Ala Ser Arg Pro Trp Leu Leu Tyr Arg Leu Leu Pro
145 150 155 160
Leu Gly Gly Leu Pro Leu Leu Ile Thr Thr Cys Phe Cys Leu Phe Cys
165 170 175
Cys Leu Arg Arg His Gln Gly Lys Gln Asn Glu Leu Ser Asp Thr Ala
180 185 190
Gly Arg Glu Ile Asn Leu Val Asp Ala His Leu Lys Ser Glu Gln Thr
195 200 205
Glu Ala Ser Thr Arg Gln Asn Ser Gln Val Leu Leu Ser Glu Thr Gly
210 215 220
Ile Tyr Asp Asn Asp Pro Asp Leu Cys Phe Arg Met Gln Glu Gly Ser
225 230 235 240
Glu Val Tyr Ser Asn Pro Cys Leu Glu Glu Asn Lys Pro Gly Ile Val
245 250 255
Tyr Ala Ser Leu Asn His Ser Val Ile Gly Pro Asn Ser Arg Leu Ala
260 265 270
Arg Asn Val Lys Glu Ala Pro Thr Glu Tyr Ala Ser Ile Cys Val Arg
275 280 285
Ser
<210> 32
<211> 306
<212> PRT
<213> 小家鼠
<400> 32
Met Lys Thr Val Pro Ala Met Leu Gly Thr Pro Arg Leu Phe Arg Glu
1 5 10 15
Phe Phe Ile Leu His Leu Gly Leu Trp Ser Ile Leu Cys Glu Lys Ala
20 25 30
Thr Lys Arg Asn Asp Glu Glu Cys Glu Val Gln Leu Asn Ile Lys Arg
35 40 45
Asn Ser Lys His Ser Ala Trp Thr Gly Glu Leu Phe Lys Ile Glu Cys
50 55 60
Pro Val Lys Tyr Cys Val His Arg Pro Asn Val Thr Trp Cys Lys His
65 70 75 80
Asn Gly Thr Ile Trp Val Pro Leu Glu Val Gly Pro Gln Leu Tyr Thr
85 90 95
Ser Trp Glu Glu Asn Arg Ser Val Pro Val Phe Val Leu His Phe Lys
100 105 110
Pro Ile His Leu Ser Asp Asn Gly Ser Tyr Ser Cys Ser Thr Asn Phe
115 120 125
Asn Ser Gln Val Ile Asn Ser His Ser Val Thr Ile His Val Arg Glu
130 135 140
Arg Thr Gln Asn Ser Ser Glu His Pro Leu Ile Thr Val Ser Asp Ile
145 150 155 160
Pro Asp Ala Thr Asn Ala Ser Gly Pro Ser Thr Met Glu Glu Arg Pro
165 170 175
Gly Arg Thr Trp Leu Leu Tyr Thr Leu Leu Pro Leu Gly Ala Leu Leu
180 185 190
Leu Leu Leu Ala Cys Val Cys Leu Leu Cys Phe Leu Lys Arg Ile Gln
195 200 205
Gly Lys Glu Lys Lys Pro Ser Asp Leu Ala Gly Arg Asp Thr Asn Leu
210 215 220
Val Asp Ile Pro Ala Ser Ser Arg Thr Asn His Gln Ala Leu Pro Ser
225 230 235 240
Gly Thr Gly Ile Tyr Asp Asn Asp Pro Trp Ser Ser Met Gln Asp Glu
245 250 255
Ser Glu Leu Thr Ile Ser Leu Gln Ser Glu Arg Asn Asn Gln Gly Ile
260 265 270
Val Tyr Ala Ser Leu Asn His Cys Val Ile Gly Arg Asn Pro Arg Gln
275 280 285
Glu Asn Asn Met Gln Glu Ala Pro Thr Glu Tyr Ala Ser Ile Cys Val
290 295 300
Arg Ser
305
<210> 33
<211> 306
<212> PRT
<213> 小家鼠
<400> 33
Met Lys Thr Val Pro Ala Met Leu Gly Thr Pro Arg Leu Phe Arg Glu
1 5 10 15
Phe Phe Ile Leu His Leu Gly Leu Trp Ser Ile Leu Cys Glu Lys Ala
20 25 30
Thr Lys Arg Asn Asp Glu Glu Cys Pro Val Gln Leu Thr Ile Thr Arg
35 40 45
Asn Ser Lys Gln Ser Ala Arg Thr Gly Glu Leu Phe Lys Ile Gln Cys
50 55 60
Pro Val Lys Tyr Cys Val His Arg Pro Asn Val Thr Trp Cys Lys His
65 70 75 80
Asn Gly Thr Ile Cys Val Pro Leu Glu Val Ser Pro Gln Leu Tyr Thr
85 90 95
Ser Trp Glu Glu Asn Gln Ser Val Pro Val Phe Val Leu His Phe Lys
100 105 110
Pro Ile His Leu Ser Asp Asn Gly Ser Tyr Ser Cys Ser Thr Asn Phe
115 120 125
Asn Ser Gln Val Ile Asn Ser His Ser Val Thr Ile His Val Thr Glu
130 135 140
Arg Thr Gln Asn Ser Ser Glu His Pro Leu Ile Thr Val Ser Asp Ile
145 150 155 160
Pro Asp Ala Thr Asn Ala Ser Gly Pro Ser Thr Met Glu Glu Arg Pro
165 170 175
Gly Arg Thr Trp Leu Leu Tyr Thr Leu Leu Pro Leu Gly Ala Leu Leu
180 185 190
Leu Leu Leu Ala Cys Val Cys Leu Leu Cys Phe Leu Lys Arg Ile Gln
195 200 205
Gly Lys Glu Lys Lys Pro Ser Asp Leu Ala Gly Arg Asp Thr Asn Leu
210 215 220
Val Asp Ile Pro Ala Ser Ser Arg Thr Asn His Gln Ala Leu Pro Ser
225 230 235 240
Gly Thr Gly Ile Tyr Asp Asn Asp Pro Trp Ser Ser Met Gln Asp Glu
245 250 255
Ser Glu Leu Thr Ile Ser Leu Gln Ser Glu Arg Asn Asn Gln Gly Ile
260 265 270
Val Tyr Ala Ser Leu Asn His Cys Val Ile Gly Arg Asn Pro Arg Gln
275 280 285
Glu Asn Asn Met Gln Glu Ala Pro Thr Glu Tyr Ala Ser Ile Cys Val
290 295 300
Arg Ser
305
<210> 34
<211> 289
<212> PRT
<213> 食蟹猴
<400> 34
Met Lys Thr Leu Pro Ala Met Leu Gly Ser Gly Arg Leu Phe Trp Val
1 5 10 15
Val Phe Leu Ile Pro Tyr Leu Asp Ile Trp Asn Ile His Gly Lys Glu
20 25 30
Ser Cys Asp Val Gln Leu Tyr Ile Lys Arg Gln Ser Tyr His Ser Ile
35 40 45
Phe Ala Gly Asp Pro Phe Lys Leu Glu Cys Pro Val Lys Tyr Cys Ala
50 55 60
His Arg Pro Gln Val Thr Trp Cys Lys Leu Asn Gly Thr Thr Cys Val
65 70 75 80
Lys Leu Glu Gly Arg His Thr Ser Trp Lys Gln Glu Lys Asn Leu Ser
85 90 95
Phe Phe Ile Leu His Phe Glu Pro Val Leu Pro Ser Asp Asn Gly Ser
100 105 110
Tyr Arg Cys Ser Ala Asn Phe Leu Ser Ala Ile Ile Glu Ser His Ser
115 120 125
Thr Thr Leu Tyr Val Thr Asp Val Lys Ser Ala Ser Glu Arg Pro Ser
130 135 140
Lys Asp Glu Met Ala Ser Arg Pro Trp Leu Leu Tyr Ser Leu Leu Pro
145 150 155 160
Leu Gly Gly Leu Pro Leu Leu Ile Thr Thr Cys Phe Cys Leu Phe Cys
165 170 175
Phe Leu Arg Arg His Gln Gly Lys Gln Asn Glu Leu Ser Asp Thr Thr
180 185 190
Gly Arg Glu Ile Thr Leu Val Asp Val Pro Phe Lys Ser Glu Gln Thr
195 200 205
Glu Ala Ser Thr Arg Gln Asn Ser Gln Val Leu Leu Ser Glu Thr Gly
210 215 220
Ile Tyr Asp Asn Glu Pro Asp Phe Cys Phe Arg Met Gln Glu Gly Ser
225 230 235 240
Glu Val Tyr Ser Asn Pro Cys Leu Glu Glu Asn Lys Pro Gly Ile Ile
245 250 255
Tyr Ala Ser Leu Asn His Ser Ile Ile Gly Leu Asn Ser Arg Gln Ala
260 265 270
Arg Asn Val Lys Glu Ala Pro Thr Glu Tyr Ala Ser Ile Cys Val Arg
275 280 285
Ser
<210> 35
<211> 1347
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 35
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg catctggatt ctccctcagt agctatggag tgagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggagcc attagttatg atggtattac atactacgcg 180
agctgggcga aaagcagagt caccatgacc agggacacgt ccacgagcac agtctacatg 240
gagctgagca gcctgagatc tgaggacacg gccgtgtatt actgtgcgag aggggactac 300
tacgatgatt atgtttatgt ttatgcttta gacatctggg gccagggcac cctggtcacc 360
gtctcctcag cttctaccaa gggcccatcg gtcttcccgc tagcgccctg ctccaggagc 420
acctccgaga gcacagccgc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 480
acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 540
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 600
acgaagacct acacctgcaa cgtagatcac aagcccagca acaccaaggt ggacaagaga 660
gttgagtcca aatatggtcc cccatgccca ccctgcccag cacctgaggc cgccggggga 720
ccatcagtct tcctgttccc cccaaaaccc aaggacactc tcatgatctc ccggacccct 780
gaggtcacgt gcgtggtggt ggacgtgagc caggaagacc ccgaggtcca gttcaactgg 840
tacgtggatg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagttcaac 900
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaacggcaag 960
gagtacaagt gcaaggtctc caacaaaggc ctcccgtcct ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agagccacag gtgtacaccc tgcccccatc ccaggaggag 1080
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 1140
gccgtggagt gggaaagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200
ctggactccg acggctcctt cttcctctac agcaggctaa ccgtggacaa gagcaggtgg 1260
caggagggga atgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacaca 1320
cagaagagcc tctccctgtc tctgggt 1347
<210> 36
<211> 651
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 36
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgcc aggccagtca gagcattagt actgcattag cctggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctatgct gcatccactc tggcatctgg catcccagac 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag actggagcct 240
gaagattttg cagtgtatta ctgtcaacag ggttatagta gtagtaatct tgataatgtt 300
ttcggcggag ggaccaaggt ggagatcaaa cggaccgtgg ctgcaccatc tgtcttcatc 360
ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420
aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480
aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540
accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600
catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg c 651
<210> 37
<211> 1323
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 37
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cgacatcagt aagtacaaca tccaatgggt ccgccaggct 120
ccagggaagg ggctggagtg ggttggcttc attaattatg gtggtagcgc atactacgcg 180
agccgggcga aaggcagatt caccatctca agagatgatt caaagaactc actgtatctg 240
caaatgaaca gcctgaaaac cgaggacacg gccgtgtatt actgtgctag aggactaagt 300
aatagcgacc tctggggcca gggcaccctg gtcaccgtct cctcagcttc taccaagggc 360
ccatcggtct tcccgctagc gccctgctcc aggagcacct ccgagagcac agccgccctg 420
ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480
ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540
agcagcgtgg tgaccgtgcc ctccagcagc ttgggcacga agacctacac ctgcaacgta 600
gatcacaagc ccagcaacac caaggtggac aagagagttg agtccaaata tggtccccca 660
tgcccaccct gcccagcacc tgaggccgcc gggggaccat cagtcttcct gttcccccca 720
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 780
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 840
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 900
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 960
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 1020
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 1080
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga aagcaatggg 1140
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1200
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 1260
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 1320
ggt 1323
<210> 38
<211> 663
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 38
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggccagtca gagcattagt agttggttat cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctacagg gcatccactc tggcatctgg ggtcccatca 180
aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240
gaagatattg caacatatta ctgtcaatcc acttatggtg gtgttgttgg cagtactagt 300
gatgataatc ctttcggcgg agggaccaag gtggagatca aacggaccgt ggctgcacca 360
tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg 420
tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc 480
ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac 540
agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 600
tgcgaagtca cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag 660
tgc 663
<210> 39
<211> 1341
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 39
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg catctggatt ctccctcagt acctatgcaa tgaactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaatc attagtgatg atggtaccac atactacgcg 180
acctgggcga aaggcagagt caccatgacc agggacacgt ccacgagcac agtctacatg 240
gagctgagca gcctgagatc tgaggacacg gccgtgtatt actgtgcgag agatgctggt 300
gctggtggtg tccaagacta cttaaccttg tggggccagg gcaccctggt caccgtctcc 360
tcagcttcta ccaagggccc atcggtcttc ccgctagcgc cctgctccag gagcacctcc 420
gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 600
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 660
tccaaatatg gtcccccatg cccaccctgc ccagcacctg aggccgccgg gggaccatca 720
gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 780
acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 840
gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 960
aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1140
gagtgggaaa gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1260
gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1320
agcctctccc tgtctctggg t 1341
<210> 40
<211> 651
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 40
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60
atcaactgcc aggccagtga gaatatttac aactttttgg cctggtacca gcagaaacca 120
ggacagcctc ctaagctgct catttactct gcatccactc tggcatctgg ggtccctgac 180
cgattcagtg gcagcgggtc tgggacagat ttcactctca ccatcagcag cctgcaggct 240
gaagatgtgg cagtttatta ctgtcaacag ggttctagta atagtaatat tgataatcct 300
ttcggcggag ggaccaaggt ggagatcaaa cggaccgtgg ctgcaccatc tgtcttcatc 360
ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420
aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480
aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540
accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600
catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg c 651
<210> 41
<211> 283
<212> PRT
<213> 智人
<400> 41
Met Glu Pro Pro Gly Asp Trp Gly Pro Pro Pro Trp Arg Ser Thr Pro
1 5 10 15
Lys Thr Asp Val Leu Arg Leu Val Leu Tyr Leu Thr Phe Leu Gly Ala
20 25 30
Pro Cys Tyr Ala Pro Ala Leu Pro Ser Cys Lys Glu Asp Glu Tyr Pro
35 40 45
Val Gly Ser Glu Cys Cys Pro Lys Cys Ser Pro Gly Tyr Arg Val Lys
50 55 60
Glu Ala Cys Gly Glu Leu Thr Gly Thr Val Cys Glu Pro Cys Pro Pro
65 70 75 80
Gly Thr Tyr Ile Ala His Leu Asn Gly Leu Ser Lys Cys Leu Gln Cys
85 90 95
Gln Met Cys Asp Pro Ala Met Gly Leu Arg Ala Ser Arg Asn Cys Ser
100 105 110
Arg Thr Glu Asn Ala Val Cys Gly Cys Ser Pro Gly His Phe Cys Ile
115 120 125
Val Gln Asp Gly Asp His Cys Ala Ala Cys Arg Ala Tyr Ala Thr Ser
130 135 140
Ser Pro Gly Gln Arg Val Gln Lys Gly Gly Thr Glu Ser Gln Asp Thr
145 150 155 160
Leu Cys Gln Asn Cys Pro Pro Gly Thr Phe Ser Pro Asn Gly Thr Leu
165 170 175
Glu Glu Cys Gln His Gln Thr Lys Cys Ser Trp Leu Val Thr Lys Ala
180 185 190
Gly Ala Gly Thr Ser Ser Ser His Trp Val Trp Trp Phe Leu Ser Gly
195 200 205
Ser Leu Val Ile Val Ile Val Cys Ser Thr Val Gly Leu Ile Ile Cys
210 215 220
Val Lys Arg Arg Lys Pro Arg Gly Asp Val Val Lys Val Ile Val Ser
225 230 235 240
Val Gln Arg Lys Arg Gln Glu Ala Glu Gly Glu Ala Thr Val Ile Glu
245 250 255
Ala Leu Gln Ala Pro Pro Asp Val Thr Thr Val Ala Val Glu Glu Thr
260 265 270
Ile Pro Ser Phe Thr Gly Arg Ser Pro Asn His
275 280
Claims (87)
1.结合BTLA的抗体,其包含具有SEQ ID NO:13的氨基酸序列的HCDR1、具有SEQ ID NO:16的氨基酸序列的HCDR2、具有SEQ ID NO:19的氨基酸序列的HCDR3、具有SEQ ID NO:22的氨基酸序列的LCDR1、具有SEQ ID NO:25的氨基酸序列的LCDR2和具有SEQ ID NO:28的氨基酸序列的LCDR3。
2.权利要求1的抗体,其包含具有SEQ ID NO:3的氨基酸序列的重链可变区(HCVR)和具有SEQ ID NO:4的氨基酸序列的轻链可变区(LCVR)。
3.权利要求1或2的抗体,其包含具有SEQ ID NO:1的氨基酸序列的重链(HC)和具有SEQID NO:2的氨基酸序列的轻链(LC)。
4.权利要求1至3中任一项的抗体,其包含两条HC和两条LC,其中每条HC具有SEQ IDNO:1的氨基酸序列,且每条轻链(LC)具有SEQ ID NO:2的氨基酸序列。
5.药物组合物,其包含权利要求1至4中任一项的抗体和一种或多种药学上可接受的载体、稀释剂或赋形剂。
6.治疗具有风湿性、神经性和/或皮肤病学疾病的患者的方法,其包括施用有效量的权利要求1-4中任一项的抗体。
7.权利要求6的方法,其中所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。
8.权利要求6的方法,其中所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。
9.权利要求6的方法,其中所述神经性疾病是多发性硬化症。
10.权利要求1至4中任一项的抗体,其用于疗法中。
11.权利要求1至4中任一项的抗体,其用于治疗风湿性、神经性和皮肤病学疾病中的一种或多种。
12.权利要求11的抗体,其中所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。
13.权利要求11的抗体,其中所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。
14.权利要求11的抗体,其中所述神经性疾病是多发性硬化症。
15.权利要求1至4中任一项的抗体在制备用于治疗风湿性、神经性和皮肤病学疾病中的一种或多种的药物中的用途。
16.权利要求15的抗体的用途,其中所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。
17.权利要求15的抗体的用途,其中所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。
18.权利要求15的抗体的用途,其中所述神经性疾病是多发性硬化症。
19.药物组合物,其用于治疗选自狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎的病况,所述药物组合物包含有效量的权利要求1至4中任一项的抗体。
20.药物组合物,其用于治疗选自特应性皮炎和牛皮癣的病况,所述药物组合物包含有效量的权利要求1至4中任一项的抗体。
21.药物组合物,其用于治疗多发性硬化症,所述药物组合物包含有效量的权利要求1至4中任一项的抗体。
22.DNA分子,其包含编码由SEQ ID NO:1的氨基酸序列给出的抗体重链的多核苷酸。
23.DNA分子,其包含编码由SEQ ID NO:2的氨基酸序列给出的抗体轻链的多核苷酸。
24.DNA分子,其包含编码具有SEQ ID NO:1的氨基酸序列的抗体重链的多核苷酸序列和编码具有SEQ ID NO:2的氨基酸序列的抗体轻链的多核苷酸序列。
25.权利要求24的DNA分子,其中编码抗体重链的多核苷酸序列是SEQ ID NO:35,且编码抗体轻链的多核苷酸序列是SEQ ID NO:36。
26.哺乳动物细胞,其包含权利要求22的DNA分子和权利要求23的DNA分子,其中所述细胞能够表达包含两条重链和两条轻链的抗体,其中每条重链的氨基酸序列由SEQ ID NO:1给出,且每条轻链的氨基酸序列由SEQ ID NO:2给出。
27.哺乳动物细胞,其包含权利要求24或25的DNA分子,其中所述细胞能够表达包含两条重链和两条轻链的抗体,其中每条重链的氨基酸序列由SEQ ID NO:1给出,且每条轻链的氨基酸序列由SEQ ID NO:2给出。
28.用于产生抗体的方法,其中两条HC各自的氨基酸序列为SEQ ID NO:1,且两条LC各自的氨基酸序列为SEQ ID NO:2,且其中所述方法包括:a)在使得表达所述抗体的条件下培养权利要求26或27的哺乳动物细胞,和b)回收表达的抗体。
29.可通过权利要求28的方法获得的抗体。
30.结合BTLA的抗体,其包含具有SEQ ID NO:14的氨基酸序列的HCDR1、具有SEQ IDNO:17的氨基酸序列的HCDR2、具有SEQ ID NO:20的氨基酸序列的HCDR3、具有SEQ ID NO:23的氨基酸序列的LCDR1、具有SEQ ID NO:26的氨基酸序列的LCDR2和具有SEQ ID NO:29的氨基酸序列的LCDR3。
31.权利要求30的抗体,其包含具有SEQ ID NO:7的氨基酸序列的重链可变区(HCVR)和具有SEQ ID NO:8的氨基酸序列的轻链可变区(LCVR)。
32.权利要求30或31的抗体,其包含具有SEQ ID NO:5的氨基酸序列的重链(HC)和具有SEQ ID NO:6的氨基酸序列的轻链(LC)。
33.权利要求30至32中任一项的抗体,其包含两条HC和两条LC,其中每条HC具有SEQ IDNO:5的氨基酸序列,且每条轻链(LC)具有SEQ ID NO:6的氨基酸序列。
34.药物组合物,其包含权利要求30至33中任一项的抗体和一种或多种药学上可接受的载体、稀释剂或赋形剂。
35.治疗具有风湿性、神经性和/或皮肤病学疾病的患者的方法,其包括施用有效量的权利要求30至33中任一项的抗体。
36.权利要求35的方法,其中所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。
37.权利要求35的方法,其中所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。
38.权利要求35的方法,其中所述神经性疾病是多发性硬化症。
39.权利要求30至33中任一项的抗体,其用于疗法中。
40.权利要求30至33中任一项的抗体,其用于治疗风湿性、神经性和皮肤病学疾病中的一种或多种。
41.权利要求40的抗体,其中所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。
42.权利要求40的抗体,其中所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。
43.权利要求40的抗体,其中所述神经性疾病是多发性硬化症。
44.权利要求30至33中任一项的抗体在制备用于治疗风湿性、神经性和皮肤病学疾病中的一种或多种的药物中的用途。
45.权利要求44的抗体的用途,其中所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。
46.权利要求44的抗体的用途,其中所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。
47.权利要求44的抗体的用途,其中所述神经性疾病是多发性硬化症。
48.药物组合物,其用于治疗选自狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎的病况,所述药物组合物包含有效量的权利要求30至33中任一项的抗体。
49.药物组合物,其用于治疗选自特应性皮炎和牛皮癣的病况,所述药物组合物包含有效量的权利要求30至33中任一项的抗体。
50.药物组合物,其用于治疗多发性硬化症,所述药物组合物包含有效量的权利要求30至33中任一项的抗体。
51.DNA分子,其包含编码由SEQ ID NO:5的氨基酸序列给出的抗体重链的多核苷酸。
52.DNA分子,其包含编码由SEQ ID NO:6的氨基酸序列给出的抗体轻链的多核苷酸。
53.DNA分子,其包含编码具有SEQ ID NO:5的氨基酸序列的抗体重链的多核苷酸序列和编码具有SEQ ID NO:6的氨基酸序列的抗体轻链的多核苷酸序列。
54.权利要求53的DNA分子,其中编码抗体重链的多核苷酸序列是SEQ ID NO:37,且编码抗体轻链的多核苷酸序列是SEQ ID NO:38。
55.哺乳动物细胞,其包含权利要求51的DNA分子和权利要求52的DNA分子,其中所述细胞能够表达包含两条重链和两条轻链的抗体,其中每条重链的氨基酸序列由SEQ ID NO:5给出,且每条轻链的氨基酸序列由SEQ ID NO:6给出。
56.哺乳动物细胞,其包含权利要求53或54的DNA分子,其中所述细胞能够表达包含两条重链和两条轻链的抗体,其中每条重链的氨基酸序列由SEQ ID NO:5给出,且每条轻链的氨基酸序列由SEQ ID NO:6给出。
57.用于产生抗体的方法,其中两条HC各自的氨基酸序列为SEQ ID NO:5,且两条LC各自的氨基酸序列为SEQ ID NO:6,且其中所述方法包括:a)在使得表达所述抗体的条件下培养权利要求55或56的哺乳动物细胞,和b)回收表达的抗体。
58.可通过权利要求57的方法获得的抗体。
59.结合BTLA的抗体,其包含具有SEQ ID NO:15的氨基酸序列的HCDR1、具有SEQ IDNO:18的氨基酸序列的HCDR2、具有SEQ ID NO:21的氨基酸序列的HCDR3、具有SEQ ID NO:24的氨基酸序列的LCDR1、具有SEQ ID NO:27的氨基酸序列的LCDR2和具有SEQ ID NO:30的氨基酸序列的LCDR3。
60.权利要求59的抗体,其包含具有SEQ ID NO:11的氨基酸序列的重链可变区(HCVR)和具有SEQ ID NO:12的氨基酸序列的轻链可变区(LCVR)。
61.权利要求59或60的抗体,其包含具有SEQ ID NO:9的氨基酸序列的重链(HC)和具有SEQ ID NO:10的氨基酸序列的轻链(LC)。
62.权利要求59至61中任一项的抗体,其包含两条HC和两条LC,其中每条HC具有SEQ IDNO:9的氨基酸序列,且每条轻链(LC)具有SEQ ID NO:10的氨基酸序列。
63.药物组合物,其包含权利要求59至62中任一项的抗体和一种或多种药学上可接受的载体、稀释剂或赋形剂。
64.治疗具有风湿性、神经性和/或皮肤病学疾病的患者的方法,其包括施用有效量的权利要求59至62中任一项的抗体。
65.权利要求64的方法,其中所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。
66.权利要求64的方法,其中所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。
67.权利要求64的方法,其中所述神经性疾病是多发性硬化症。
68.权利要求59至62中任一项的抗体,其用于疗法中。
69.权利要求59至62中任一项的抗体,其用于治疗风湿性、神经性和皮肤病学疾病中的一种或多种。
70.权利要求69的抗体,其中所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。
71.权利要求69的抗体,其中所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。
72.权利要求69的抗体,其中所述神经性疾病是多发性硬化症。
73.权利要求59至62中任一项的抗体在制备用于治疗风湿性、神经性和皮肤病学疾病中的一种或多种的药物中的用途。
74.权利要求73的抗体的用途,其中所述风湿性疾病是狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎中的至少一种。
75.权利要求73的抗体的用途,其中所述皮肤病学疾病是特应性皮炎和牛皮癣中的至少一种。
76.权利要求73的抗体的用途,其中所述神经性疾病是多发性硬化症。
77.药物组合物,其用于治疗选自狼疮性肾炎、全身性红斑狼疮和类风湿性关节炎的病况,所述药物组合物包含有效量的权利要求59至62中任一项的抗体。
78.药物组合物,其用于治疗选自特应性皮炎和牛皮癣的病况,所述药物组合物包含有效量的权利要求59至62中任一项的抗体。
79.药物组合物,其用于治疗多发性硬化症,所述药物组合物包含有效量的权利要求59至62中任一项的抗体。
80.DNA分子,其包含编码由SEQ ID NO:9的氨基酸序列给出的抗体重链的多核苷酸。
81.DNA分子,其包含编码由SEQ ID NO:10的氨基酸序列给出的抗体轻链的多核苷酸。
82.DNA分子,其包含编码具有SEQ ID NO:9的氨基酸序列的抗体重链的多核苷酸序列和编码具有SEQ ID NO:10的氨基酸序列的抗体轻链的多核苷酸序列。
83.权利要求82的DNA分子,其中编码抗体重链的多核苷酸序列是SEQ ID NO:39,且编码抗体轻链的多核苷酸序列是SEQ ID NO:40。
84.哺乳动物细胞,其包含权利要求80的DNA分子和权利要求81的DNA分子,其中所述细胞能够表达包含两条重链和两条轻链的抗体,其中每条重链的氨基酸序列由SEQ ID NO:9给出,且每条轻链的氨基酸序列由SEQ ID NO:10给出。
85.哺乳动物细胞,其包含权利要求82或83的DNA分子,其中所述细胞能够表达包含两条重链和两条轻链的抗体,其中每条重链的氨基酸序列由SEQ ID NO:9给出,且每条轻链的氨基酸序列由SEQ ID NO:10给出。
86.用于产生抗体的方法,其中两条HC各自的氨基酸序列为SEQ ID NO:9,且两条LC各自的氨基酸序列为SEQ ID NO:10,且其中所述方法包括:a)在使得表达所述抗体的条件下培养权利要求84或85的哺乳动物细胞,和b)回收表达的抗体。
87.可通过权利要求86的方法获得的抗体。
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GB201820554D0 (en) * | 2018-12-17 | 2019-01-30 | Univ Oxford Innovation Ltd | BTLA antibodies |
JP2022552323A (ja) | 2019-10-15 | 2022-12-15 | イーライ リリー アンド カンパニー | 組換え操作された、リパーゼ/エステラーゼ欠損哺乳動物細胞株 |
GB202008860D0 (en) | 2020-06-11 | 2020-07-29 | Univ Oxford Innovation Ltd | BTLA antibodies |
JP2023546713A (ja) * | 2020-10-23 | 2023-11-07 | アナプティスバイオ インコーポレイティッド | B及びtリンパ球アテニュエータ(btla)調節因子及びその使用方法 |
WO2023143565A1 (en) * | 2022-01-29 | 2023-08-03 | Hifibio (Hk) Limited | Anti-btla antibodies and uses thereof in treating cancer |
WO2024040195A1 (en) | 2022-08-17 | 2024-02-22 | Capstan Therapeutics, Inc. | Conditioning for in vivo immune cell engineering |
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WO2017096017A1 (en) * | 2015-12-02 | 2017-06-08 | Stsciences, Inc. | Antibodies specific to glycosylated btla (b- and t- lymphocyte attenuator) |
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