CN111699195A - 具有改善的免疫治疗效果但减轻的不良作用的突变体抗ctla-4抗体 - Google Patents
具有改善的免疫治疗效果但减轻的不良作用的突变体抗ctla-4抗体 Download PDFInfo
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Abstract
本发明涉及与人CTLA‑4分子结合的抗CTLA‑4抗体组合物,以及该组合物在癌症免疫疗法中以及用于与其他免疫治疗剂相比减轻自身免疫副作用的用途。
Description
发明领域
本发明涉及具有改善的抗肿瘤活性但减轻的不良作用的突变体抗CTLA-4抗体以及制备和使用此类抗体的方法。
发明背景
抗CTLA-4单克隆抗体(单抗)赋予癌症免疫治疗效果(CITE),但是引起严重的免疫疗法相关的不良事件(irAE)。抗CTLA-4mAb在小鼠模型和黑素瘤患者中显示出CITE。抗PD-1单抗纳武单抗(Nivolumab)和抗CTLA-4单抗伊匹单抗(Ipilimumab)的组合显著提高晚期黑素瘤患者的客观响应率。此种联合疗法在晚期非小细胞肺癌(NSCLC)中也显示出有希望的结果。在II期临床试验中,在将另一种抗CTLA-4单抗(替西木单抗(Tremelimumab))与抗PD-L1单抗度伐鲁单抗(Durvalumab)组合时获得临床益处的试验性证据。
单独或组合的抗CTLA-4单抗的更广泛临床应用的主要障碍是严重不良事件(SAE)。在伊匹单抗(第一种临床抗CTLA-4单抗)试验中观察到的SAE引起免疫疗法相关的不良事件(irAE)的概念。特别地,在与伊匹单抗和纳武单抗(抗PD-1)联合疗法中,超过50%的患者形成3级和4级SAE。尽管3级和4级SAE以高比率发生,但在NSCLC中,伊匹单抗和纳武单抗联合疗法导致高的响应率。同样,尽管3级和4级SAE和患者的放弃率(drop-off rate)较高,可能是由于不可接受的毒性,但是度伐鲁单抗(抗PD-L1)和替西木单抗(抗CTLA-4单抗)的组合表明NSCLC中的临床活性。由于单一疗法和联合疗法两者中较高剂量的抗CTLA-4单抗与更好的临床结果相关,因此irAE不仅阻止许多患者继续进行免疫疗法,而且还限制了CITE的疗效。此外,大量的患者在这两种抗CTLA-4单抗的情况下放弃,这可能归因于一些临床试验中未能达到临床终点。
最近,抗PD-1单抗纳武单抗和抗CTLA-4单抗伊匹单抗作为已切除的III和IV期黑素瘤的辅助治疗的面对面比较显示了伊匹单抗具有较低的CITE,但较高的irAE,进一步使CTLA-4靶向性免疫疗法的前景黯淡。然而,存活三年的经伊匹单抗治疗的患者在十年期内没有显示存活率的进一步下降。显著持续的响应突出显示了靶向该分子进行免疫疗法的特殊好处,尤其是若可以使irAE受到控制的话。
产生安全且有效的抗CTLA-4单抗的基本问题是CITE和irAE是否是内在联系的。经典的检查点阻断假设规定抗CTLA-4单抗通过阻断B7-CTLA-4相互作用的负信号来促进淋巴样器官中的幼稚T细胞活化,从而促进癌症免疫力。根据该模型,治疗性抗体是功能上使CTLA-4-B7相互作用失活的拮抗剂。由于CTLA-4表达的基因失活导致小鼠和人类自身免疫性疾病,因此假设irAE是CITE的必要代价。另一方面,我们证明抗小鼠CTLA-4mAb的治疗作用不是阻断B7-CTLA-4相互作用,而是需要抗体介导的Treg消减,特别是在肿瘤微环境内。抗体是否能够在生理条件下阻断B7-CTLA-4相互作用以诱导CITE无关紧要。这些研究提出了一个有趣的可能性,即若可以实现局部Treg消减而不模拟CTLA-4表达的遗传失活,则可以在没有irAE的情况下实现CITE。使用人等位基因纯合或杂合的小鼠,发现irAE需要双等位参与,而CITE仅需要单等位参与。这些数据表明,irAE需要拮抗CTLA-4功能;而CITE取决于抗体的激动剂活性。
发明概述
本文提供了消除抗-CTLA-4抗体的拮抗剂活性而保留和改善它们的Fc受体激动剂活性的方法。具体公开了增加抗体结合对酸性pH的敏感性的方法,由此抗CTLA-4抗体表现出降低的与CTLA-4的结合。如本文所述,抗CTLA-4抗体结合活性的变化,例如降低,可以是特定抗体组成的两个不同pH水平之间的相对差异。在一个实施方案中,在反映细胞内内体区室的pH,与CTLA-4的结合降低。在一个优选的实施方案中,与CTLA-4的结合在5.5的内体pH相对于在中性pH(pH 7.0)的结合降低超过50%。与pH 7.0相比,此类降低在溶酶体pH4.5可达到超过75%。在pH 7.0预形成的抗体-抗原复合物在pH4.5-6.0的酸性环境下可解离。结合的降低也可以使用相同标准与pH敏感性可以相当小的参考抗体相比。参考抗体可以是本领域已知的抗体,例如伊匹单抗或替西木单抗。在工程化抗体的情况下,变化也可以使用相同标准与pH敏感性可以相当小的野生型抗体相比。
在另一方面,本文提供了鉴定具有改善的抗肿瘤功效和/或降低的毒性的抗CTLA-4抗体的方法,包括在4.5-7.0的范围内的超过1个pH(one more pH)测试或测量经板包被的CTLA-4与可溶性抗体之间的相互作用,并选择具有增加的pH敏感性的抗体,以便在酸性pH观察到降低的结合。在一个实施方案中,pH为7.0和5.5。换言之,它们是7.0和4.5,或7.0、5.5和4.5。
在另一方面,本文提供了通过抗CTLA-4抗体对细胞表面CTLA-4水平的影响来鉴定具有降低的毒性的抗CTLA-4抗体的方法。在一个优选的实施方案中,抗体可以从细胞内的CTLA-4解离并允许CTLA-4再循环回到细胞表面,这可以基于细胞表面CTLA-4的最小减少或无减少来确定。
在另一方面,本文提供了设计或修饰抗CTLA-4抗体以通过增加pH敏感性,从而在酸性pH观察到降低的与CTLA-4的结合来改善抗肿瘤作用和/或降低毒性的方法。还提供了表现出这些特征的抗CTLA-4抗体。在一个实施方案中,可以通过用组氨酸残基替换野生型抗CTLA-4抗体,例如伊匹单抗或替西木单抗的轻和/或重链可变区的一个或多个CDR区之内或附近的一个或多个酪氨酸残基来设计抗体。可以产生抗CTLA-4抗体替西木单抗或伊匹单抗的突变体形式,因此相对于野生型抗体,它们在酸性pH具有降低的与CTLA-4的结合。
在另一方面,本文提供了使用ADCC报告物测定法鉴定具有改善的抗肿瘤功效的抗体的方法,其中增强的ADCC活性用作抗肿瘤活性的读数。
本文还提供了具有增强的抗肿瘤活性和/或降低的毒性的特异性抗CTLA-4抗体、其抗体片段和前述物质的组合物。该抗体可以包含含有SEQ ID NO:1、3、5、6或8所示序列的重链和含有SEQ ID NO:2或4所示序列的轻链。抗体还可以包含含有SEQ ID NO:14-18中之一所示序列的重链和含有SEQ ID NO:10-12中之一所示序列的轻链。
本文进一步提供了进行癌症免疫疗法或治疗癌症的方法,其中本文所述的抗CTLA-4抗体组合物单独使用或与一种或多种其他抗癌疗法组合使用。一方面,其他抗癌疗法是免疫疗法。在另一方面,该免疫疗法是抗PD-1或抗PD-L1疗法。该免疫疗法可以是纳武单抗、度伐鲁单抗或派姆单抗。还提供了本文所述的抗体组合物在制备用于治疗癌症的药物中的用途。治疗癌症的方法可以包括将本文所述的组合物施用于需要癌症治疗的受试者。受试者可以是人。
附图简述
图1A-B。TremeIgG1及其变体的pH敏感性。将His-hCTLA-4(0.5μg/ml)包被在ELISA板中,并在pH范围为4.5至7.0的缓冲液中以1μg/ml添加不同的抗CTLA-4单抗。所示的pH代表结合和洗涤条件。使用辣根过氧化物酶标记的抗人IgG抗体测量与CTLA-4结合的抗体。
图2.TremeIgG1及其变体的pH敏感性结合解离。如图1中,除抗体在pH7.0与板结合的CTLA-4结合的组外,然后用所示pH的缓冲液洗涤平板。
图3。抗CTLA-4抗体对总CTLA-4水平的影响。将用人CTLA-4cDNA转染的CHO细胞与抗CTLA-4抗体在37℃下温育4小时,并通过总细胞裂解物的Western印迹测定细胞中CTLA-4的总量。TremeIgG1和mAb154诱导CTLA-4下调,但其他抗体变体的诱导少得多。
图4。内吞后在活细胞中从CTLA-4解离的抗体的pH敏感性。将表达hCTLA-4的293T稳定细胞系在4℃用抗CTLA-4单抗标记30分钟,然后洗去未结合的抗体后,将细胞转移到37℃达1h。抗体结合的表面CTLA-4被蛋白G珠捕获,并使用抗CTLA-4抗体(H-126):sc-9094(Santa Cruz biotechnology)通过western印迹检测。图4A显示了抗体在4℃的结合,并且图4B显示了在37℃温育后剩余的抗体水平。与mAb139(TremeIgG1)或其他具有较小pH敏感性的变体相比,工程化抗体,尤其是AB156和AB157在37℃在抗体诱导的内在化过程中与CTLA-4分离。
图5。抗CTLA-4抗体对细胞表面CTLA-4的影响。将表达人CTLA-4的CHO细胞用TremeIgG1及其突变体在37℃或4℃处理2小时。洗去未结合的抗体后,在4℃通过抗hIgG(H+L)-alex488检测表面CTLA-4达半小时,并通过流式细胞术进行分析。呈现的数据是相对于4℃在37℃温育的样品的MFI比率,并且已相对于HL12的比率进行标准化,所述HL12比率的平均值定义为1.0。显示的数据来自三个独立的实验,每个实验每组包含两个样品。
图6。TremeIgG1及其pH敏感性变体的ADCC活性。显示的数据是从表达FcγRIIIA的报告细胞发射的发光单位。表达人CTLA-4分子的293T细胞用作靶细胞。
图7。Ab157在肿瘤微环境中的Treg消减中表现出改善的活性。在肿瘤接种后第14天,用TremeIgG1(AB139)或其pH敏感性变体Ab157(30ug/小鼠)i.p.处理携带MC38的Ctla4h /h小鼠(n=9)。在抗体处理后16小时,通过CD4 T细胞中的%Treg细胞来测定肿瘤微环境中Treg细胞的选择性消减。*P<0.05。
图8A-E。TremeIgG1及其对pH敏感性变体的免疫治疗作用。图8A。实验设计图。图8B-E。在接受IgG-Fc(图8B)、TremeIgG1(AB139;图8C)、AB156(图8D)或AB157(图8E)的小鼠中的肿瘤生长。
图9。当用于与抗PD-1的联合疗法时,pH敏感性与抗人CTLA-4抗体的更好安全性相关。CTLA-4h/h小鼠在出生后第10、13、17和20天接受抗PD-1和以下抗CTLA-4抗体之一的联合疗法:TremeIgG1(AB139)、AB156、AB157、AB158、AB159,剂量为100μg/小鼠/注射。安全性按照随时间的存活表示。N=6。AB157相对于TremeIgG1,P=0.01;AB156相对于TremeIgG1,P=0.03。
图10。来自两个独立实验的数据的存活分析,显示与野生型抗体TremeIgG1相比,pH敏感性变体抗CTLA-4抗体AB157的更好的安全性。在出生后第10、13、17和20天以100μg/小鼠/注射的剂量施用TremeIgG1(AB139)和AB157。安全性按照随时间的存活表示。数据是两个独立实验的总结。在两个处理组之间观察到统计学显著差异。对于AB157或hIgGFc对照+抗PD-1,N=15,对于TremeIgG1+抗PD-1,N=16。P<0.0001。
发明详述
定义
如本文所用,术语“抗体”是指拥有“可变区”抗原识别位点的免疫球蛋白分子。术语“可变区”是指不同于抗体广泛共享的域(例如抗体Fc域)的免疫球蛋白域。可变区包含“高变区”,其残基负责抗原结合。高变区包含来自“互补决定区”或“CDR”的氨基酸残基(即,通常在轻链可变域的大约残基24-34(L1)、50-56(L2)和89-97(L3)处和在重链可变域中大约残基27-35(H1)、50-65(H2)和95-102(H3);参考文献44),并且可以包含来自“高变环”的那些残基(即,轻链可变域中的残基26-32(L1)、50-52(L2)和91-96(L3)以及重链可变域中的残基26-32(H1)、53-55(H2)和96-101(H3))。“框架区”或“FR”残基是除如本文所定义的高变区残基以外的那些可变域残基。本文公开的抗体可以是单克隆抗体、多特异性抗体、人抗体、人源化抗体、合成抗体、嵌合抗体、骆驼化抗体、单链抗体、二硫化物连接的Fv(sdFv)、内抗体(intrabody)或抗独特型(抗-Id)抗体(包括例如针对本发明抗体的抗-Id和抗-抗-Id抗体)。特别地,抗体可以是免疫球蛋白分子,例如IgG、IgE、IgM、IgD、IgA或IgY,或者是某个类别的抗体,例如IgG1、IgG2、IgG3、IgG4、IgA1或IgA2或某个亚类的抗体。
如本文所用,术语抗体的“抗原结合片段”是指抗体中含有抗体的互补决定区(“CDR”)以及任选地包含抗体的“可变区”抗原识别位点的框架残基并且表现出免疫特异性结合抗原的能力的一个或多个部分。此类片段包括Fab’、F(ab’)2、Fv、单链(ScFv)及其突变体,天然存在的变体以及包含抗体“可变区”抗原识别位点和异源蛋白(例如,毒素、不同抗原的抗原识别位点、酶、受体或受体配体等)的融合蛋白。如本文所用,术语“片段”是指包含至少5个连续氨基酸残基、至少10个连续氨基酸残基、至少15个连续氨基酸残基、至少20个连续氨基酸残基、至少25个连续氨基酸残基、至少40个连续氨基酸残基、至少50个连续氨基酸残基、至少60个连续氨基酸残基、至少70个连续氨基酸残基、至少80个连续氨基酸残基、至少90个连续氨基酸残基、至少100个连续氨基酸残基、至少125个连续氨基酸残基、至少150个连续氨基酸残基、至少175个连续氨基酸残基、至少200个连续氨基酸残基或至少250个连续氨基酸残基的氨基酸序列的肽或多肽。
人的、嵌合的或人源化的抗体特别优选用于人体内使用,但是,鼠抗体或其他物种的抗体可有利地用于多种用途(例如,体外或原位检测测定法、短期体内使用等)。
“嵌合抗体”是抗体的不同部分源自不同免疫球蛋白分子的分子,例如具有源自非人抗体的可变区和人免疫球蛋白恒定区的抗体。可以使用本领域已知的多种技术来产生包含来自非人类物种的一个或多个CDR和来自人类免疫球蛋白分子的框架区的嵌合抗体,所述技术包括例如CDR-嫁接(EP 239,400;国际公开号WO 91/09967;以及美国专利号5,225,539、5,530,101和5,585,089),饰面或表面重修(EP 592,106;EP 519,596;46-48)和链改组(美国专利No.5,565,332),它们全部的内容通过引用并入本文。
本文描述的抗体可以是人源化抗体。如本文所用,术语“人源化抗体”是指包含人框架区和来自非人(通常是小鼠或大鼠)免疫球蛋白的一个或多个CDR的免疫球蛋白。提供CDR的非人免疫球蛋白称为“供体”,并且提供框架的人免疫球蛋白称为“接受体”。不需要存在恒定区,但是若存在的话,则它们必须与人免疫球蛋白恒定区基本相同,即至少约85-90%,优选约95%相同或更多。因此,除可能地CDR外,人源化免疫球蛋白的所有部分与天然人免疫球蛋白序列的相应部分基本相同。人源化抗体是包含人源化轻链和人源化重链免疫球蛋白的抗体。例如,人源化抗体将不涵盖典型的嵌合抗体,因为例如嵌合抗体的整个可变区是非人的。根据“人源化”过程将供体抗体称为“人源化的”,因为预期所得的人源化抗体与提供CDR的供体抗体结合相同的抗原。人源化抗体可以是人免疫球蛋白(接受体抗体),其中接受体的高变区残基被具有期望的特异性、亲和力和能力的来自非人物种(供体抗体)诸如小鼠、大鼠、兔或非人灵长类的高变区残基替换。在一些情况下,人免疫球蛋白的框架区(FR)残基被相应的非人残基替换。此外,人源化抗体可包含在接受体抗体或供体抗体中未发现的残基。这些修饰可以进一步改善抗体性能。人源化抗体可包含至少一个,且通常两个基本上整个可变域,其中所有或基本上所有的高变区对应于非人免疫球蛋白的那些,并且所有或基本上所有的FR是人免疫球蛋白序列的那些。人源化抗体还可任选地包含免疫球蛋白恒定区的至少一部分(Fc),其可以是与FcsRIIB多肽免疫特异性结合的人免疫球蛋白的部分,其已通过引入一种或多种氨基酸残基的取代、缺失或增加(即突变)而改变。
1.抗CTLA-4抗体组合物
已经显示了针对人类CTLA-4蛋白的抗体,包括伊匹单抗和替西木单抗,作为唯一的免疫治疗剂或与另一种治疗剂如抗PD-1抗体组合增加癌症患者的存活。但是,治疗效果与明显的不良作用有关。迫切需要开发新的抗CTLA-4抗体,以获得更好的治疗效果或更少的自身免疫不良作用。发明人发现了抗CTLA-4抗体,令人惊讶地,该抗CTLA-4抗体可用于诱导癌症排斥,且还减少与免疫疗法有关的自身免疫不良作用。
本文提供了抗体及其抗原结合片段,以及包含前述物质的组合物。该组合物可以是药物组合物。该抗体可以是抗CTLA-4抗体。该抗体可以是单克隆抗体、人抗体、嵌合抗体或人源化抗体。抗体也可以是单特异性、双特异性、三特异性或多特异性的。抗体可以是可检测地标记的,并且可以包含缀合的毒素、药物、受体、酶或受体配体。
本文还提供了与CTLA-4,特别是人CTLA-4免疫特异性结合的抗体的抗原结合片段,所述CTLA-4可以以内源或转染浓度在活细胞表面上表达。抗原结合片段可以结合CTLA-4,并且活细胞可以是T细胞。
在具体的实施方案中,抗CTLA-4抗体可以有效地诱导Treg消减和Fc受体依赖性肿瘤排斥。在另一个实施方案中,抗CTLA-4抗体可以在细胞内酸性pH指示下与CTLA-4解离,从而允许CTLA-4再循环回到细胞表面。
本文进一步提供了新的抗CTLA-4抗体的设计,以及改善现有抗CTLA-4抗体的功效或毒性概况的方式,其通过掺入本文所述抗体的功能特性或属性来进行。
抗体可以包含已知抗CTLA-4抗体的氨基酸序列的突变体形式,所述抗CTLA-4抗体可以是伊匹单抗或替西木单抗。与野生型抗体序列相比,突变体序列可包含在至少一个重链或轻链的一个或多个CDR1、CDR2和CDR3区域附近或内用组氨酸对酪氨酸的一个或多个取代。抗CTLA-4抗体可包含含有SEQ ID NO:1、3、5、6和8中之一所示序列的重链和含有SEQ IDNO:2和4中之一所示序列的轻链。特别地,重链可包含SEQ ID NO:6所示的序列,并且轻链可包含SEQ ID NO:2所示的序列。重链还可包含SEQ ID NO:14-18中之一所示的序列并且轻链可包含SEQ ID NO:10-12中之一所示的序列。
2.改善抗CTLA-4抗体组合物的功效和安全性的方法
本文提供了设计(突变或工程化改造)或选择表现出改善的抗肿瘤活性和/或安全性的抗体组合物的方法。具体地,可以增加在酸性pH的抗体结合的敏感性,从而抗CTLA-4抗体在较低的pH值表现出降低的与CTLA-4的结合。在一个实施方案中,在反映内体区室的pH,与CTLA-4的结合降低。在一个优选的实施方案中,相对于中性pH(pH 7.0)的结合,在pH5.5,与CTLA-4的结合是降低的。在pH 5.5的此类降低的结合可以是在中性pH观察到的CTLA-4结合的50%或更多。本文所述的抗CTLA-4抗体活性,例如结合的变化,例如减少或增加可以与参考或野生型抗体相比。参照抗体可以是本领域已知的抗体,例如伊匹单抗或替西木单抗。该变化也可以是本文所述的特定抗体组合物的两个不同pH值之间的相对值。
可通过在4.5至7.0的pH范围内测试经板包被的CTLA-4和可溶性抗体之间的相互作用,并选择具有增加的pH敏感性的抗体,从而在酸性pH观察到降低的结合,来鉴定具有改善的抗肿瘤功效和/或降低的毒性的抗CTLA-4抗体。
具有降低的毒性的抗CTLA-4抗体可以通过其对细胞表面CTLA-4水平的影响来鉴定。在一个优选的实施方案中,抗体从细胞内的CTLA-4解离并允许CTLA-4再循环回到细胞表面,这可以基于细胞表面CTLA-4的最小降低或无降低或抗体结合的表面CTLA-4的量的减少来确定。
本文提供了设计或修饰抗CTLA-4抗体以通过增加pH敏感性,从而在酸性pH观察到降低的与CTLA-4的结合来改善抗肿瘤效果和/或降低毒性的方法。在一个实施方案中,通过用组氨酸残基替换在抗体的轻链可变区和/或重链可变区的CDR区内或附近的一个或多个酪氨酸残基来设计抗体。该方法可以包括产生在酸性pH下显示降低的与CTLA-4的结合的抗CTLA-4抗体替西木单抗或伊匹单抗的突变体形式。
可以使用ADCC报告物测定法设计或修饰抗体以得到改善的抗肿瘤功效,其中将增强的ADCC活性用作抗肿瘤活性的读数。在一个优选的实施方案中,为了增加抗肿瘤活性,CTLA-4靶向剂将选择性地消减肿瘤微环境中的Treg。在一个具体的实施方案中,抗CTLA-4单抗具有增加的Fc介导的Treg消减活性。Treg消减可通过Fc介导的效应器功能,例如抗体依赖性细胞介导的细胞毒性(ADCC)或抗体依赖性细胞介导的吞噬作用(ADCP)发生。Fc介导的效应器功能可以通过本领域已知的任何方法引入或增强。在一个实例中,抗体为IgG1同种型,其与其他同种型相比具有增强的效应器功能。Fc介导的效应器功能可通过Fc域的氨基酸序列的突变进一步增强。例如,可以将三个突变(S298A、E333A和K334A)引入Fc域的CH区域中以增加ADCC活性。用于ADCC介导的活性的抗体通常需要某种修饰,以增强其ADCC活性。有许多技术可用于这点的技术,其通常涉及对抗体进行工程化改造,以使抗体Fc区中的寡糖不具有任何岩藻糖糖单元,从而改善与FcγIIIa受体的结合。当抗体被岩藻糖基化时,作用是增加抗体依赖性细胞的细胞毒性(ADCC)。例如,Biowa的技术使用FUT8基因敲除CHO细胞系来生产100%无岩藻糖基化抗体。FUT8是唯一编码a1,6-岩藻糖基转移酶的基因,该酶催化在复杂型寡糖的a1,6-连接中岩藻糖从GDP-岩藻糖转移到GlcNAc。Probiogen已开发出CHO系,其经工程化改造以在MAb上产生较低水平的岩藻糖基化聚糖,尽管不是通过FUT敲除。Probiogen的系统引入了一种细菌酶,其将从头岩藻糖合成途径重定向到无法被细胞代谢的糖-核苷酸。作为一种替代方法,Seattle Genetics拥有专有的补料系统,该系统可在CHO(也许还有其他)细胞系中在单克隆抗体上产生较低水平的岩藻糖基化聚糖。Xencor开发了XmAb Fc域技术,其设计为改善免疫系统对肿瘤和其他病理细胞的清除。该Fc域具有两个氨基酸变化,导致大40倍的对FcγRIIIa的亲和力。它还增加对FcγRIIa的亲和力,具有募集其他效应细胞,如巨噬细胞的潜力,所述巨噬细胞通过吞噬和消化外来物质在免疫中发挥作用。
3.治疗方法
本文描述的抗体组合物或基于本文描述的方法设计的抗体可以用于上调免疫应答。免疫系统的上调在癌症和慢性感染的治疗中是特别期望的,因此本文所述的抗体组合物在此类病症的治疗中具有效用。如本文所用,术语“癌症”是指由异常的不受控制的细胞生长引起的新生物或肿瘤。“癌症”明确包括白血病和淋巴瘤。术语“癌症”还指涉及具有转移到远端部位的潜力的细胞的疾病。
本文所述的抗体组合物可用于药物的制备。该组合物也可以施用于需要治疗的受试者。受试者可以是人。该受试者可以需要治疗本文所述的疾病或病况。
因此,本文所述的方法和组合物可用于治疗或预防多种癌症或其他异常增殖性疾病中的一种或多种,所述癌症或其他异常增殖性疾病包括(但不限于)以下各项:癌,包括膀胱、乳房、结肠、肾、肝、肺、卵巢、胰腺、胃、宫颈、甲状腺和皮肤癌;包括鳞状细胞癌;淋巴样谱系的造血肿瘤,包括白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、伯基特淋巴瘤(Berketts lymphoma);髓样谱系的造血肿瘤,包括急性和慢性骨髓性白血病和前髓细胞性白血病;间充质起源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;其他肿瘤,包括黑素瘤、精原细胞瘤、tetratocarcinoma、神经母细胞瘤和神经胶质瘤;中枢和周围神经系统的肿瘤,包括星形细胞瘤、神经母细胞瘤、神经胶质瘤和许旺细胞瘤;间充质起源的肿瘤,包括纤维肉瘤、横纹肌肉瘤和骨肉瘤;以及其他肿瘤,包括黑素瘤、着色性干皮病(xenoderma pegmentosum)、角化棘皮瘤(keratoactanthoma)、精原细胞瘤、甲状腺滤泡癌和畸胎瘤。还考虑到由凋亡异常引起的癌症也可以通过本发明的方法和组合物治疗。此类癌症可包括但不限于滤泡性淋巴瘤,具有p53突变的癌,乳腺癌、前列腺癌和卵巢癌的激素依赖性肿瘤以及癌前病变,如家族性腺瘤性息肉病和骨髓增生异常综合症。在具体的实施方案中,通过本发明的方法和组合物在卵巢、膀胱、乳房、结肠、肺、皮肤、胰腺或子宫中治疗或预防恶性或异常增殖变化(例如化生和发育不良)或过度增殖性病症。在其他具体的实施方案中,通过本发明的方法和组合物治疗或预防肉瘤、黑素瘤或白血病。
抗体组合物及其抗原结合片段可以与另一种抗肿瘤疗法一起使用,该抗肿瘤疗法可以选自但不限于当前的标准和实验化学疗法、激素疗法、生物疗法、免疫疗法、放射疗法和手术。在一些实施方案中,本文所述的组合物可以与治疗或预防有效量的一种或多种本领域技术人员已知用于治疗或预防癌症、自身免疫性疾病、传染病或中毒的试剂、治疗性抗体或其他试剂组合施用。此类试剂包括例如以上讨论的生物反应修饰剂、细胞毒素、抗代谢物、烷基化剂、抗生素、抗有丝分裂剂或免疫治疗剂中的任何一种。
抗体组合物及其抗原结合片段可以与另一种抗肿瘤免疫疗法一起使用。在此类实施方案中,组合物与破坏或增强替代的免疫调节途径的分子(诸如TIM3、TIM4、OX40、CD40、GITR、4-1-BB、B7-H1、PD-1、B7-H3、B7-H4、LIGHT、BTLA、ICOS、CD27或LAG3)或调节效应分子如细胞因子(诸如IL-4、IL-7、IL-10、IL-12、IL-15、IL-17、GF-beta、IFNg、Flt3、BLys)和趋化因子(例如CCL21)的活性的分子组合施用以增强免疫调节作用。具体实施方案包括双特异性抗体,其包含本文所述的抗CTLA-4抗体或其抗原结合片段,与抗PD-1(派姆单抗(Keytruda)或纳武单抗(Opdivo)),抗B7-H1(阿特珠单抗(atezolizumab)(Tecentriq)或度伐鲁单抗(Imfinzi))、抗B7-H3、抗B7-H4、抗LIGHT、抗LAG3、抗TIM3、抗TIM4、抗CD40、抗OX40、抗GITR、抗BTLA、抗CD27、抗ICOS或抗4-1BB组合。在又一个实施方案中,将本发明的抗体或其抗原结合片段与激活免疫应答的不同阶段或方面以便实现更广泛的免疫应答的分子(例如IDO抑制剂)组合施用。在更优选的实施方案中,抗体组合物及其抗原结合片段与抗PD-1或抗4-1BB抗体组合,而不加剧自身免疫的副作用。
本文所述的组合物可包含双特异性抗体,该双特异性抗体包含桥接到结合另一种免疫刺激分子的抗体的抗CTLA-4抗体。具体实施方案包括双特异性抗体,其包含本文所述的抗CTLA-4抗体组合物和抗PD-1、抗B7-H1、抗B7-H3、抗B7-H4、抗LIGHT、抗LAG3、抗TIM3、抗TIM4抗CD40、抗OX40、抗GITR、抗BTLA、抗CD27、抗ICOS或抗4-1BB。此类抗体可以用作药物,并且可以用于治疗癌症。
4.生产
本文所述的抗CTLA-4抗体及其抗原结合片段可以使用真核表达系统制备。表达系统可需要在哺乳动物细胞如中国仓鼠卵巢(CHO)细胞中从载体表达。抗体也可以由稳定的细胞系产生,所述稳定的细胞系从已经整合到细胞基因组中的载体或载体的一部分表达抗体。
本文所述的抗CTLA-4抗体及其抗原结合片段可以使用例如层析法,诸如亲和层析、离子交换层析、疏水相互作用层析、DEAE离子交换、凝胶过滤和羟基磷灰石层析来纯化。在一些实施方案中,融合蛋白可以被工程化改造为包含含有氨基酸序列的额外域,该氨基酸序列允许多肽被捕获到亲和基质上。例如,可以使用蛋白A或蛋白G柱从细胞培养上清液或细胞质提取物中分离出包含免疫球蛋白域的Fc区的本文所述的抗体。另外,标签诸如c-myc、血凝素、聚组氨酸或Flag TM(Kodak)可用于辅助抗体纯化。此类标签可以插入多肽序列内的任何地方,包括在羧基或氨基末端。可以有用的其他融合物包括有助于检测多肽的酶,例如碱性磷酸酶。免疫亲和层析也可以用于纯化多肽。
5.药物组合物
本发明进一步涉及药物组合物,其包含治疗有效量的任何上述抗CTLA-4抗体组合物或其抗原结合片段,以及生理上可接受的载体或赋形剂。优选地,本发明的组合物包含预防或治疗有效量的抗CTLA-4抗体或其抗原结合片段和药学上可接受的载体。
在一个具体的实施方案中,术语“药学上可接受的”是指由联邦或州政府的监管机构批准或在美国药典或其他普遍认可的药典中列出的用于动物尤其是人类的。术语“载体”是指与治疗剂一起施用的稀释剂、佐剂(例如弗氏佐剂(完全和不完全)、赋形剂或媒介物。此类药物载体可以是无菌液体,例如水和油,包括石油、动物、植物或合成来源,例如花生油、大豆油、矿物油、芝麻油等的那些。当静脉内施用药物组合物时,水是优选的载体。也可以使用盐水溶液、水性右旋糖和甘油溶液作为液体载体,特别是用于注射液。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、海藻糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、干脱脂乳、甘油、丙烯、乙二醇、水、乙醇等。如果期望的话,该组合物还可以包含少量的润湿剂或乳化剂,例如Poloxamer或Polysorbate,或pH缓冲剂。这些组合物可以采取溶液、悬浮剂、乳剂、片剂、丸剂、胶囊剂、粉末、缓释制剂等形式。
通常,本发明的组合物的成分可以在密闭容器中,例如指示活性剂量的安瓿或小药囊(sachette)中在单位剂型中单独提供或混合在一起提供,例如,作为干燥的冻干粉或无水浓缩物。当组合物要通过输注施用时,它可以用含有无菌药物级水或盐水的输液瓶分配。当通过注射施用组合物时,可以提供无菌注射用水或盐水的安瓿瓶以便可以在施用之前将成分混合。
本发明的组合物可以配制成中性或盐形式。药学上可接受的盐包括但不限于与阴离子形成的盐,例如源自盐酸、磷酸、乙酸、草酸、酒石酸等的阴离子,以及与阳离子形成的盐,例如源自氢氧化钠、钾、铵、钙、铁,异丙胺、三乙胺、2-乙基氨基乙醇、组氨酸、普鲁卡因等的阳离子。
本文所述的抗CTLA-4抗体组合物或其抗原结合片段也可以被配制用于冻干以允许长期保存,特别是在室温。冻干制剂对于皮下施用特别有用。
6.施用方法
施用本文所述的组合物的方法包括但不限于肠胃外施用(例如,皮内、肌内、腹膜内、静脉内和皮下)、硬膜外和粘膜(例如,鼻内和口服途径)。在一个具体的实施方案中,肌内、静脉内或皮下施用本发明的抗体。组合物可以通过任何方便的途径施用,例如通过输注或推注,通过经由上皮或粘膜皮肤衬里(例如口腔粘膜、直肠和肠粘膜等)吸收,并且可以与其他生物活性剂一起施用。施用可以是系统的或局部的。
实施例
实施例1.在低pH时失去结合活性的替西木单抗变体的产生。
由于CTLA-4的基因失活导致严重的自发炎性淋巴增生性疾病,因此发明人认识到,拮抗或引起CTLA-4降解的抗体会是易于irAE的。考虑到许多抗原-抗体复合物可以迁移到溶酶体并被降解的事实,发明人意识到在复合物到达溶酶体之前失去与CTLA-4结合的抗体将解离并允许抗原和/或抗体分子再循环。由于溶酶体区室可具有<5.0的pH,因此通过在VL和VH CDR区域进行定点诱变,产生了在低pH时失去与CTLA-4分子的结合的替西木单抗和伊匹单抗变体。由于组氨酸侧链的pK为5.97,掺入组氨酸残基的抗体有可能在pH5.5-6.0左右发生电荷变化。为了具有最大的影响,在替西木单抗和伊匹单抗两者的CDR区域中进行了突变。
产生了包含WT或突变体替西木单抗可变区的轻链和重链的8种抗体。因为消减Treg的活性对于肿瘤排斥是重要的,所以将替西木单抗中的人IgG2恒定区替换为IgG1的恒定区,因此该产物称为TremeIgG1(AB139),并且突变体抗体称为TremeIgG1M(AB154-159)。抗体的组成和亲和力列于表1。
表1.替西木单抗变体:组成和亲和力。
抗体 | 重链 | 轻链 | KD(M) |
AB139(TremeIgG1) | SEQ IDNO:1 | SEQ ID NO:2 | 1.466E-10 |
AB154 | SEQ ID NO:3 | SEQ ID NO:2 | 1.228E-09 |
AB155 | SEQ ID NO:3 | SEQ ID NO:4 | 无结合 |
AB156 | SEQ ID NO:5 | SEQ ID NO:2 | 4.459E-09 |
AB157 | SEQ ID NO:6 | SEQ ID NO:2 | 2.322E-09 |
AB158 | SEQ ID NO:7 | SEQ ID NO:2 | 5.425E-10 |
AB159 | SEQ ID NO:8 | SEQ ID NO:2 | 3.867E-10 |
使用相似的方法,产生了伊匹单抗亲本重链(SEQ ID NO:13)和轻链(SEQ ID NO:9)的突变体。这导致具有SEQ ID NO:14-18的重链突变体和具有SEQ ID NO:9-12的轻链突变体。SEQ ID NO:1-18中列出的序列是实例,并且可以基于相同原理在CDR的区域或抗体的抗原结合位点附近进行其他突变。
为了验证该方法,评估了替西木单抗突变体抗体的活性。为了确定组氨酸向CDR区的引入是否影响抗体的pH敏感性,在pH范围内测量了抗体对其抗原,即加多组氨酸标签的CTLA-4的结合。原始数据在图1A中呈现,而标准化的结合在图1B中显示。作为对照,使用在低/酸性pH时具有降低的结合的HL12,已知HL12以pH依赖性方式结合CTLA-4。这些数据证明了,尽管TremeIgG1在所有测试的pH均与CTLA-4结合,但所有突变体在酸性pH均显示不同程度的pH敏感性。其中,Ab154、Ab158和Ab159不如HL12敏感,而Ab156和Ab157表现出较高的pH敏感度。重要的是,在晚期内体中找到的pH(pH5.5),HL12、Ab156和Ab157相对于中性pH(pH7.0)显示50%或更少的结合,而Ab158和Ab159与中性pH相比仍表现出75%或更多的结合。此外,考虑到与Ab158相比时,尽管Ab159具有更高的亲和力,但也显示出略高的pH敏感性,pH依赖性不是由于在中性pH时的低抗体亲和力所致。同样地,Ab157表现出更高的亲和力和更高的pH敏感性,Ab155不结合CTLA-4,并从此分析中排除。
由于抗CTLA-4抗体在生理条件下在中性pH下与CTLA-4结合,并且由于抗体-抗原复合物通过逐渐酸性的环境运输,因此在不同pH下测量了pH敏感性和解离性。如图2所示,通过在酸性和中性pH时结合和洗涤鉴定的pH敏感性抗体在具有相似等级的酸性pH也从CTLA-4解离。
为了在内体的酸性pH内使抗体与抗原解离,在TremeIgG1的CDR中将酪氨酸(Y)替换为组氨酸。以CDR3中的五个连续Y残基和CDR2中的两个连续Y残基的不同数目引入组氨酸。CDR3中具有两个或三个连续Y到H突变的变体(Ab157和Ab156)比CDR2中单一Y到H突变(Ab 158)或两个Y到H突变(Ab159)表现出更高的pH敏感性。Ab156和157在早期内体pH 6时开始释放CTLA-4,并且在晚期内体中找到的pH(pH5.5)时显示50%或更少的结合。而Ab158和Ab159在pH 5.5时仍显示75%或更高的结合。
也将His突变引入重链可变CDR1中的Ser31、Tyr32和Trp36处(Ab 154),或将组合突变引入轻链CDR1的Tyr32和Asp34处(Ab155)。尽管已经报道相当的突变对于pH依赖性抗原对其他抗体的结合是必要的,但它们尚未导致TremeIgG1的期望的pH敏感性:Ab154在pH5.5下仅表现出较小的CTLA-4结合丧失,而Ab 155在中性pH中没有表现出可测量的与CTLA-4的结合。数据表明,在CDR的富含酪氨酸的区域中用组氨酸替换多个酪氨酸代表了获得pH敏感性抗体,而保留在中性pH下其与抗原的结合的简单方法。
实施例2.鉴定不降低细胞表面CTLA-4水平的抗体。
为了确定抗CTLA-4抗体对总CTLA-4水平的影响,将替西木单抗抗体与用人CTLA-4cDNA转染的CHO细胞在37℃温育4小时。通过总细胞裂解物的Western印迹测定细胞中CTLA-4的总量。如图3所示,WT TremeIgG1及其变体Ab154诱导CTLA-4的显著降低。其他突变体抗体诱导少得多的降低。
为了确定抗体的pH敏感性是否引起它们与活细胞中CTLA-4的解离,首先将抗体与稳定表达人CTLA-4的293T细胞的两个重复在4℃温育。30分钟后,将等分试样切换至37℃达1小时。然后将未结合的抗体洗掉。用1%Triton X 100裂解后,使用蛋白G珠拉下抗CTLA-4抗体,并通过Western印迹进行检测。如图4A所示,在4℃,相当量的CTLA-4蛋白被抗体Ab139、Ab154、Ab156-Ab159结合。在37℃温育后,在与Ab139(TremeIgG1)或其他具有较低pH敏感性的变体相比时,与Ab156和Ab157缔合的CTLA-4少得多(图4B)。相应地,在经Mab156和157处理的细胞中,细胞裂解物中的总CTLA-4的量更高。这些数据表明,当Ab156和Ab157于37℃到达细胞内部时,它们与CTLA-4解离。
为了在TremeIgG1或其变体处理后直接评估细胞表面CTLA-4的水平,将稳定表达CTLA-4的CHO细胞与TremeIgG1(Ab139)或突变体抗体Ab154和Ab156-Ab159在4℃(无下调)或37℃温育。使用抗人CTLA-4试剂测量细胞表面的抗体结合的CTLA-4的量。HL12和伊匹单抗作为对照包括在内。如图5所示,在37℃与TremeIgG1预温育引起细胞表面CTLA-4的大大减少。Ab154和伊匹单抗诱导相似的减少。值得注意的是,Ab156和Ab157与无毒的HL12一样没有减少细胞表面CTLA-4。Ab158和Ab159引起适度降低。抗体导致细胞表面CTLA-4的减少与其结合CTLA-4分子的pH依赖性密切相关(图1)。这些数据与以下假设一致:pH敏感性是抗体介导的细胞表面抗CTLA-4分子减少的良好指示。
实施例3.pH敏感性抗CTLA-4抗体的增加的抗体依赖性细胞介导的细胞毒性(ADCC)和抗肿瘤活性。
发明人和其他人最近已经证明,抗CTLA-4抗体的ADCC活性对于体内赋予Treg消减和肿瘤排斥既必要又充分(16-18,20)。因此,使用ADCC活性的体外报告物测定法评估抗CTLA-4抗体的潜在抗肿瘤活性是令人感兴趣的。如图6所示,虽然TremeIgG1(Ab139)表现出有力的ADCC活性,但两种具有最高pH敏感性的抗体显示甚至更高的ADCC活性,尤其是在更高的抗体剂量下。
确认ADCC报告物测定法是否反映肿瘤微环境中的选择性Treg消减。将TremeIgG1和Ab157注射到在14天时接受MC38肿瘤细胞并且平均肿瘤直径为7mm的小鼠中。16小时后,收获肿瘤并通过流式细胞术确定CD4T细胞中Treg的%。如图7所示,虽然TremeIgG1在此早期时间点基本上无效,但Ab157导致Treg明显降低。
为了测试pH敏感性抗体是否有效引起肿瘤排斥,对CTLA-4h/h小鼠皮下注射MC38肿瘤细胞。7天后,当肿瘤直径达到约5mm时,用低剂量的抗CTLA-4单抗(包括TremeIgG1及其pH敏感性变体Ab156和Ab157)处理小鼠。观察到肿瘤生长或复发达6.5周(图8A)。如图8B-E所示,在3次注射后,TremeIgG1在80%的小鼠中引起完全的肿瘤排斥。值得注意的是,Ab156和Ab157实现了100%的排斥。这些数据表明,增加的pH敏感性改善抗CTLA-4抗体的抗肿瘤作用,这可能通过增加ADCC活性来实现。
实施例4.pH敏感性TremeIgG1变体的毒性小于亲代TremeIgG1抗体的毒性。
为了测试pH敏感性对TremeIgG1变体抗体的毒性的影响,比较从出生后第10天开始,第10、13、17和20天以100μg/小鼠/注射的剂量x4接受对照IgG1Fc、抗PD-1+对照IgG1Fc、抗PD-1+TremeIgG1、抗PD-1+Ab156、Ab157、Ab158、Ab159的小鼠。观察小鼠的存活。如图9所示,尽管在整个观察期内无接受对照IgG1Fc或对照IgG1Fc+抗-PD-1的小鼠死亡,但是除一只外所有接受TremeIgG1的小鼠死亡。相比之下,除一只外所有接受Ab157的小鼠幸免于整个时段。当将Ab157与TremeIgG1进行比较时,观察到存活的显著改善(P=0.01)。当使用Ab157时也观察到显著改善(P=0.03)。尽管当与TremeIgG1相比时,Ab158和Ab159也显示出略好的存活,但差异未达到统计学上的显著水平。然而,pH敏感性和安全性之间似乎存在强的相关性。当将来自涉及15只小鼠的两个实验的数据进行组合时,相对于TremeIgG1,Ab157的安全性改善甚至更为清楚(图10)。这些数据表明,pH敏感性可能是抗CTLA-4抗体安全性的良好替代标志物。
总之,已经证明了在酸性pH保持与CTLA-4结合的抗体通过靶向结合的CTLA-4进行溶酶体降解而引起细胞表面CTLA-4水平的降低。因此,这些抗体在功能上是拮抗剂并且使CTLA-4功能失活。在体内,当与抗PD-1抗体组合使用时,此类抗体表现出高毒性。相反,那些在较低pH下失去与CTLA-4结合的抗体无法通过使CTLA-4再循环到细胞表面来减少细胞表面CTLA-4,因此不能起激动剂的作用。值得注意的是,尽管这些抗体的亲和力较低,但它们在ADCC活性和肿瘤排斥方面似乎更有力。这些数据证明增加抗CTLA-4抗体的低pH敏感性作为增加肿瘤治疗效果同时减弱其毒性的新方法。
序列表
<110> 肿瘤免疫股份有限公司
马里兰大学巴尔的摩分校
Liu, Yang
Zheng, Pan
Zhang, Yan
Devenport, Martin
Du, Xuexiang
Tang, Fei
Liu, Mingyue
<120> 具有改善的免疫治疗效果但减轻的不良作用的突变体抗CTLA-4抗体
<130> 060275.0602.01PC00
<150> 62/625662
<151> 2018-02-02
<150> 62/647123
<151> 2018-03-23
<150> 62/754781
<151> 2018-11-02
<160> 18
<170> PatentIn version 3.5
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245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 4
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 4
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 Ser Ile Asn Ser His
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser 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 Ser Thr Pro Phe
85 90 95
Thr Phe Gly Pro 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> 5
<211> 455
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 5
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Asp Pro Arg Gly Ala Thr Leu His His His Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 6
<211> 455
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 6
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Asp Pro Arg Gly Ala Thr Leu Tyr His His Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 7
<211> 455
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 7
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Asp Pro Arg Gly Ala Thr Leu Tyr His Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 8
<211> 455
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 8
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys His His Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Asp Pro Arg Gly Ala Thr Leu Tyr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 9
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 9
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 10
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 10
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser
20 25 30
His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 11
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 11
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 12
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 12
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser
20 25 30
His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 13
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 13
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 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 His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln 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 Pro Gly Lys
435 440 445
<210> 14
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 14
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys His His Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 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 His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln 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 Pro Gly Lys
435 440 445
<210> 15
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 15
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 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 His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln 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 Pro Gly Lys
435 440 445
<210> 16
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 16
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 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 His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln 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 Pro Gly Lys
435 440 445
<210> 17
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 17
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr His Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 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 His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln 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 Pro Gly Lys
435 440 445
<210> 18
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 18
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 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 His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln 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 Pro Gly Lys
435 440 445
Claims (10)
1.产生在酸性pH具有降低的对CTLA-4的结合的抗CTLA-4抗体的方法,其包括在所述抗体的轻链可变区和重链可变区的至少一者的一个或多个CDR1-3区域内或附近用组氨酸替换酪氨酸。
2.在酸性pH具有降低的对CTLA-4的结合的抗CTLA-4抗体变体,其中所述抗CTLA-4抗体包含替西木单抗或伊匹单抗的氨基酸序列,其中轻链可变区和重链可变区的至少一者中的一个或多个酪氨酸残基被组氨酸替换。
3.抗CTLA-4抗体,其包含含有SEQ ID NO:1、3、5、6或8所示序列的重链和含有SEQ IDNO:2或4所示序列的轻链。
4.权利要求3的抗CTLA-4抗体,其包含含有SEQ ID NO:6所示序列的重链和含有SEQ IDNO:2所示序列的轻链。
5.抗CTLA-4抗体,其包含含有SEQ ID NO:14-18中之一所示序列的重链和含有SEQ IDNO:10-12中之一所示序列的轻链。
6.在有此需要的受试者中进行癌症免疫疗法的方法,其包括单独或与一种或多种其他疗法组合地向所述受试者施用前述权利要求中任一项的抗CTLA-4抗体。
7.权利要求6的方法,其中所述其他疗法是与PD-1或PD-L1结合的抗体。
8.权利要求7的方法,其中所述抗PD-1抗体是纳武单抗或派姆单抗。
9.前述权利要求中任一项的抗CTLA-4抗体,其用于治疗受试者中的癌症。
10.前述权利要求中任一项的抗CTLA-4抗体在制备用于治疗受试者中的癌症的药物中的用途。
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US201862625662P | 2018-02-02 | 2018-02-02 | |
US62/625,662 | 2018-02-02 | ||
US201862647123P | 2018-03-23 | 2018-03-23 | |
US62/647,123 | 2018-03-23 | ||
US201862754781P | 2018-11-02 | 2018-11-02 | |
US62/754,781 | 2018-11-02 | ||
PCT/US2019/015686 WO2019152423A1 (en) | 2018-02-02 | 2019-01-29 | Mutant anti-ctla-4 antibodies with improved immunotherapeutic effect but attenuated adverse effects |
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EP (1) | EP3746479A4 (zh) |
JP (1) | JP7490923B2 (zh) |
KR (1) | KR20200118458A (zh) |
CN (1) | CN111699195A (zh) |
AU (1) | AU2019214865A1 (zh) |
CA (1) | CA3089768A1 (zh) |
IL (1) | IL276447A (zh) |
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WO2024056049A1 (zh) * | 2022-09-16 | 2024-03-21 | 同润生物医药(上海)有限公司 | 具有pH依赖性的抗CTLA4抗体或抗原结合片段 |
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US11542332B2 (en) | 2016-03-26 | 2023-01-03 | Bioatla, Inc. | Anti-CTLA4 antibodies, antibody fragments, their immunoconjugates and uses thereof |
KR20230051630A (ko) * | 2018-10-31 | 2023-04-18 | 바이오아트라, 인코퍼레이티드 | 항-ctla4 항체, 항체 단편, 이들의 면역접합체 및 그 용도 |
EP3955960A1 (en) * | 2019-04-18 | 2022-02-23 | Bristol-Myers Squibb Company | Ipilimumab variants with enhanced specificity for binding at low ph |
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JP7490923B2 (ja) | 2024-05-28 |
IL276447A (en) | 2020-09-30 |
WO2019152423A1 (en) | 2019-08-08 |
SG11202007017PA (en) | 2020-08-28 |
JP2021512884A (ja) | 2021-05-20 |
TW201936637A (zh) | 2019-09-16 |
CA3089768A1 (en) | 2019-08-08 |
EP3746479A4 (en) | 2021-11-24 |
KR20200118458A (ko) | 2020-10-15 |
EP3746479A1 (en) | 2020-12-09 |
AU2019214865A1 (en) | 2020-09-17 |
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