CN113861294B - 针对犬白介素-4受体α的抗体 - Google Patents
针对犬白介素-4受体α的抗体 Download PDFInfo
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Abstract
本发明涉及针对犬白介素‑4受体α的抗体。具体地,本发明公开了针对犬IL‑4受体α的抗体和阻断抗体,所述抗体具有特定序列和对犬IL‑4受体α的高结合亲和力。本发明也公开了本发明的抗体在治疗狗的特应性皮炎中的用途。本发明还公开了结合针对犬IL‑4受体α的抗体的独特表位。
Description
本申请是申请日为2016年4月1日的中国专利申请201680032086.3 “针对犬白介素-4受体α的抗体”的分案申请。
相关申请的交叉引用
本申请根据35 U.S.C. § 119(e)要求以下申请的优先权:2015年4月2日提交的临时申请美国系列号62/142,108,2015年12月18日提交的临时申请美国系列号62/269,486,和2016年3月18日提交的临时申请美国系列号62/310,250,它们全部的内容特此通过引用整体并入。
技术领域
本发明涉及针对犬IL-4受体α的抗体,所述抗体具有特定序列、对犬IL-4受体α的高结合亲和力,包括可以阻断犬IL-4与犬IL-4受体α的结合的抗体。本发明还涉及结合针对犬IL-4受体α的抗体的独特表位。本发明也涉及本发明的抗体和表位在狗的特应性皮炎的治疗中的用途。
背景技术
免疫系统包含驻留的和再循环的特化细胞的网络,所述特化细胞共同起作用以保护宿主免于感染性疾病和癌症。免疫系统的执行该功能的能力在较大程度上依赖于由白细胞分泌且被统称为白介素的一组蛋白的生物活性。充分研究的白介素包括两种被鉴别为白介素-4 (IL-4)和白介素-13 (IL-13)的重要分子。IL-4和IL-13是可以由许多细胞类型分泌的两种密切相关的蛋白,所述细胞类型包括CD4+ Th2细胞、天然杀伤T细胞(NKT)、巨噬细胞、肥大细胞和嗜碱性粒细胞。IL-4和IL-13表现出许多重叠的功能,且对于T细胞依赖性的体液免疫应答的发展是关键性的。尽管它们在总体结构、细胞来源和生物学功能上具有相似性,但是这些细胞因子中的每一种介导某些特化功能,这已经刺激了相当多的研究,所述研究的目的在于鉴别这些白介素用于介导它们的共同和独特生物活性的受体和下游信号传递途径。
现在已知IL-4以高亲和力结合两种受体,即,I型和II型IL-4受体。I型IL-4受体由IL-4受体α链和共同的γC链组成,所述γC链也是几种其它白介素(包括IL-2、IL-7、IL-9和IL-15)的受体的组成部分。II型IL-4受体由IL-4受体α链和IL-13受体α1链组成。另一方面,IL-13结合II型IL-4受体和被命名为IL-13受体α2的独特受体。IL-13与IL-13受体α2的结合不会转导信号,且该受体也以可溶形式分泌。因此,IL-13受体α2经常被称作诱饵受体。
已经在细菌和哺乳动物细胞中克隆并表达来自多个物种的编码IL-4蛋白的基因。例如,编码人IL-4的cDNA表明,成熟的人IL-4是129个氨基酸的分泌型多肽,具有15 Kd的预测分子量[Yokota等人,Proc Natl Acad Sci U S A. 83(16): 5894-5898 (1986)]。还已经鉴别出编码犬IL-4蛋白的cDNA,并证实其编码与人IL-4具有40%同一性的132氨基酸多肽[van der Kaaij等人,Immunogenetics 49:142-143(1999)]。已经在多种宿主系统中克隆和表达编码人IL-13的基因[Minty等人,Nature 362:248-50 (1993)]。编码人IL-13的cDNA表明,成熟的IL-13是具有12.4 Kd表观分子量的分泌型多肽。还已经鉴别出编码犬IL-13的cDNA[Yang等人,J. Interferon and Cytokine Research 20:779-785 (2000)]。预测的犬IL-13成熟多肽由111个氨基酸组成,且与人IL-13具有61.8%同一性。
已经在多种宿主系统中克隆和表达编码人和小鼠IL-4受体α链的基因。例如,Galizzi等人已经描述了编码人IL-4受体α链的cDNA [International Immunology 2(7):669-675 (1990)],Mosley等人已经描述了编码鼠IL-4受体α链的cDNA[Cell,59(2):335-348 (1989)]。人IL-4受体α链的cDNA编码825个氨基酸残基,包括24氨基酸残基信号序列。尽管鼠蛋白比人受体短15个氨基酸残基,但是两种蛋白密切相关,在氨基酸水平具有50%的总序列同一性。
还已经公开了编码马、犬和猫IL-4受体α链的基因[参见,US 7,208,579 B2]。另外,可以在Genbank数据库中发现据预测与犬IL-4受体α的一种异形体对应的cDNA(SEQ IDNO: 1)。因此,利用该发明来确定IL-4受体α链cDNA和最终确定它编码的多肽序列。
尽管IL-4和IL-13是对抗细胞外病原体(例如,居留于组织或腔的寄生虫)的保护所需的Th2免疫应答的发生的关键细胞因子,但是两种细胞因子已经牵涉进人类和动物的多种变态反应性疾病(包括哮喘和特应性皮炎)的发病机制中。哮喘是人类中的一种常见呼吸系统疾病。该疾病的特征在于肺部炎症、支气管气道对外部刺激的高反应性、和支气管壁组织的结构改变。Vatrella等人已经综述了变应性哮喘的病理生理学[Journal of Asthma and Allergy 7:123-130 (2014)]。哮喘由CD4+ Th2细胞支持,所述CD4+ Th2细胞产生大量IL-4和IL-13并在变应性气道中引起免疫炎症应答。理解哮喘应答的新近进展强调了IL-4和IL-13在疾病发病机制中所起的重要作用。例如,两种细胞因子会刺激B细胞中从IgM至IgE的免疫球蛋白同种型转换,且该变应原-特异性的IgE会促进肥大细胞去粒作用和炎症介质在气道中的释放。另外,IL-4和IL-13都会增加支气管平滑肌收缩和刺激嗜酸性粒细胞的气道募集,所述嗜酸性粒细胞还可以响应于变应原结合的IgE与嗜酸性粒细胞上的其受体的交联而去粒。另外,IL-13也会通过刺激杯形细胞增生、胶原沉积和气道平滑肌细胞增殖而刺激粘液分泌并促进气道重塑。因而,现在清楚,IL-4和IL-13密切参与导致哮喘事件表达的病理学变化,包括支气管收缩和增加的气道活动过度。
特应性皮炎(AD)是一种特征在于免疫系统调节异常和表皮屏障异常的复发性的、有瘙痒的、炎症性的皮肤疾病。AD的病理学和免疫学属性已经成为广泛研究的主题[综述在Rahman等人.Inflammation & Allergy-drug target 10:486-496(2011)和Harskamp等人, Seminar in Cutaneous Medicine and Surgery 32:132-139 (2013)中]。AD是人类中最常见的皮肤疾病,影响2-10%的美国成年人口和世界上约25%的儿童。在人类中,AD皮肤病灶的特征在于Th2细胞、嗜酸性粒细胞、肥大细胞和树突细胞的渗入。在AD的急性期中,这些病灶表现出Th2-型细胞因子(包括IL-4和IL-13)的优势表达。AD也特征在于升高的IgE循环水平,并且与皮肤中CD4+ Th2细胞的IL-4和IL-13表达正相关。尽管已经将AD归类为Th2疾病,但是其它T细胞子集(诸如Th1、Th22和Th17)也可能促进疾病发病机制。尽管AD的全世界发病率逐渐增加,但是其症状没有被局部药剂充分控制的患者可用的治疗选择限于口服皮质类固醇、口服环孢菌素和窄带UVB光疗。这些疗法不总是有效的,且它们的应用与多种安全性效应有关。近年来,已经开发了对人IL-4 Rα特异性的单克隆抗体,且这些抗体中的一些已经针对它们在人类中用于治疗特应性皮炎的治疗效用进行了广泛测试[参见,例如,US20150017176 A1]。
AD也是伴侣动物、特别是狗中的一种常见疾病,据估计它在其中的发病率为犬群体的大约10-15%。AD在狗和猫中的发病机制[综述在Nuttall等人, Veterinary Records 172(8):201-207 (2013)中]与AD在人类中的发病机制具有显著相似性,包括多种免疫细胞的皮肤渗入和CD4+ Th2极化的细胞因子环境,包括IL-4和IL-13细胞因子的优势。如在人类中一样,狗和猫的特应性皮炎的当前疗法依赖于姑息疗法(诸如洗发剂和湿润剂)或针对症状疗法(通过使用口服或全身性皮质类固醇和口服环孢菌素)。与人AD一样,这些疗法没有解决疾病的根本机制且具有显著的安全性和效力问题。因而,对安全且有效的伴侣动物AD的治疗选择存在未得到满足的医学需要。这样的治疗应当优选地干扰疾病的根本机制。
本文中对任何参考文献的引用不应解释为承认:这样的参考文献可作为本申请的“背景技术”得到。
发明内容
本发明涉及对犬IL-4Rα具有高结合亲和力的抗-犬白介素-4受体α(IL-4Rα)抗体。在更具体的实施方案中,所述抗-犬白介素-4受体α(IL-4Rα)抗体还具有阻断犬IL-4和犬IL-13与I型或II型IL-4受体的结合并相应抑制来自犬IL-4和IL-13的信号传递的能力。在具体实施方案中,这样的抗-犬IL-4Rα抗体是鼠抗-犬IL-4Rα抗体。在更具体的实施方案中,所述抗-犬IL-4Rα抗体具有对犬IL-4Rα的高结合亲和力,以及具有阻断犬IL-4和犬IL-13与I型和II型IL-4受体的结合的能力。
此外,本发明涉及这些抗体所包含的互补决定区(CDR)和这些CDR(例如,得自鼠抗-犬IL-4Rα抗体)在犬框架中的组合以形成犬化抗-犬IL-4Rα抗体。本发明也涉及这样的抗体在治疗病症诸如特应性皮炎和/或其它不利病症中的用途,所述其它不利病症归因于来自犬IL-4和/或犬IL-13与I型和/或II型IL-4受体的结合的信号传递的下游效应。
因此,本发明提供了来自十四(14)种举例说明的鼠抗-犬IL-4Rα抗体的独特CDR集合。所述14种举例说明的鼠抗-犬IL-4Rα抗体具有独特CDR集合,即,三个轻链CDR:CDR轻1(CDRL1),CDR轻2(CDRL2),和CDR轻3(CDRL3);和三个重链CDR:CDR重1(CDRH1),CDR重2(CDRH2)和CDR重3(CDRH3)。如下面详述的,在每个CDR集合内存在实质序列同源性,和甚至某种冗余,例如,参见,下面CDRL1的集合。因此,本发明不仅提供了来自14种举例说明的鼠抗-犬IL-4Rα抗体的六个CDR的氨基酸序列,而且还提供了这些CDR的保守修饰的变体、以及这样的变体:其包含(例如,共享)相同规范结构和/或结合被犬IL-4Rα的表位包含的犬IL-4Rα的氨基酸残基中的一个或多个(例如,1-4个或更多个)。
因此,本发明提供了特异性地结合IL-4Rα的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:含有SEQ ID NO: 47、SEQ ID NO: 48、SEQ ID NO: 49、SEQ ID NO:50、SEQ ID NO: 51、SEQ ID NO: 52、SEQ ID NO: 53、SEQ ID NO: 54、SEQ ID NO: 55、SEQID NO: 129、SEQ ID NO: 130或SEQ ID NO: 131的氨基酸序列的轻链互补决定区1 (VLCDR1),和/或含有SEQ ID NO: 56、SEQ ID NO: 57、SEQ ID NO: 58、SEQ ID NO: 59、SEQ IDNO: 60、SEQ ID NO: 61、SEQ ID NO: 62、SEQ ID NO: 63、SEQ ID NO: 64、SEQ ID NO:132、SEQ ID NO: 133或SEQ ID NO: 134的氨基酸序列的轻链互补决定区2 (VL CDR2),和/或含有SEQ ID NO: 65、SEQ ID NO: 66、SEQ ID NO: 67、SEQ ID NO: 68、SEQ ID NO: 69、SEQ ID NO: 70、SEQ ID NO: 71、SEQ ID NO: 72、SEQ ID NO: 73、SEQ ID NO: 135、SEQ IDNO: 136、SEQ ID NO: 137、SEQ ID NO: 138或SEQ ID NO: 139的氨基酸序列的轻链互补决定区3 (VL CDR3),和/或重链互补决定区1 (VH CDR1),其中所述CDRH1含有SEQ ID NO:74、SEQ ID NO: 75、SEQ ID NO: 76、SEQ ID NO: 77、SEQ ID NO: 78、SEQ ID NO: 79、SEQID NO: 80、SEQ ID NO: 81、SEQ ID NO: 82、SEQ ID NO: 140、SEQ ID NO: 141、SEQ IDNO: 142或SEQ ID NO: 143的氨基酸序列,和/或含有SEQ ID NO: 83、SEQ ID NO: 84、SEQID NO: 85、SEQ ID NO: 86、SEQ ID NO: 87、SEQ ID NO: 88、SEQ ID NO: 89、SEQ ID NO:90、SEQ ID NO: 91、SEQ ID NO: 144、SEQ ID NO: 145、SEQ ID NO: 146、SEQ ID NO: 147或SEQ ID NO: 148的氨基酸序列的重链互补决定区2 (VH CDR2),和/或含有SEQ ID NO:92、SEQ ID NO: 93、SEQ ID NO: 94、SEQ ID NO: 95、SEQ ID NO: 96、SEQ ID NO: 97、SEQID NO: 98、SEQ ID NO: 99、SEQ ID NO: 100、SEQ ID NO: 149、SEQ ID NO: 150、SEQ IDNO: 151、SEQ ID NO: 152或SEQ ID NO: 153的氨基酸序列的重链互补决定区3 (VHCDR3)。在具体实施方案中,所述抗体是哺乳动物抗体。在更具体的实施方案中,所述抗体是犬化抗体。
因此,本发明的犬化抗体或其抗原结合片段包含一个或多个具有SEQ ID NO: 74、SEQ ID NO: 75、SEQ ID NO: 76、SEQ ID NO: 77、SEQ ID NO: 78、SEQ ID NO: 79、SEQ IDNO: 80、SEQ ID NO: 81、SEQ ID NO: 82、SEQ ID NO: 140、SEQ ID NO: 141、SEQ ID NO:142或SEQ ID NO: 143的氨基酸序列的重链互补决定区1 (VH CDR1)。在另一个实施方案中,所述重链互补决定区2 (VH CDR2)包含SEQ ID NO: 83、SEQ ID NO: 84、SEQ ID NO:85、SEQ ID NO: 86、SEQ ID NO: 87、SEQ ID NO: 88、SEQ ID NO: 89、SEQ ID NO: 90、SEQID NO: 91、SEQ ID NO: 144、SEQ ID NO: 145、SEQ ID NO: 146、SEQ ID NO: 147或SEQ IDNO: 148的氨基酸序列。在另一个实施方案中,所述重链互补决定区3 (VH CDR3)包含SEQID NO: 92、SEQ ID NO: 93、SEQ ID NO: 94、SEQ ID NO: 95、SEQ ID NO: 96、SEQ ID NO:97、SEQ ID NO: 98、SEQ ID NO: 99、SEQ ID NO: 100、SEQ ID NO: 149、SEQ ID NO: 150、SEQ ID NO: 151、SEQ ID NO: 152或SEQ ID NO: 153的氨基酸序列。在这类的一个具体实施方案中,所述犬化抗体或抗原结合片段包含:含有SEQ ID NO: 74、SEQ ID NO: 75、SEQID NO: 76、SEQ ID NO: 77、SEQ ID NO: 78、SEQ ID NO: 79、SEQ ID NO: 80、SEQ ID NO:81、SEQ ID NO: 82、SEQ ID NO: 140、SEQ ID NO: 141、SEQ ID NO: 142或SEQ ID NO: 143的氨基酸序列的VH CDR1,和含有SEQ ID NO: 83、SEQ ID NO: 84、SEQ ID NO: 85、SEQ IDNO: 86、SEQ ID NO: 87、SEQ ID NO: 88、SEQ ID NO: 89、SEQ ID NO: 90、SEQ ID NO: 91、SEQ ID NO: 144、SEQ ID NO: 145、SEQ ID NO: 146、SEQ ID NO: 147或SEQ ID NO: 148的氨基酸序列的VH CDR2。在另一个这样的实施方案中,所述犬化抗体或抗原结合片段包含:含有SEQ ID NO: 74、SEQ ID NO: 75、SEQ ID NO: 76、SEQ ID NO: 77、SEQ ID NO: 78、SEQID NO: 79、SEQ ID NO: 80、SEQ ID NO: 81、SEQ ID NO: 82、SEQ ID NO: 140、SEQ ID NO:141、SEQ ID NO: 142或SEQ ID NO: 143的氨基酸序列的VH CDR1,和含有SEQ ID NO: 92、SEQ ID NO: 93、SEQ ID NO: 94、SEQ ID NO: 95、SEQ ID NO: 96、SEQ ID NO: 97、SEQ IDNO: 98、SEQ ID NO: 99或SEQ ID NO: 100、SEQ ID NO: 149、SEQ ID NO: 150、SEQ ID NO:151、SEQ ID NO: 152或SEQ ID NO: 153的氨基酸序列的VH CDR3。在另一个这样的实施方案中,所述犬化抗体或抗原结合片段包含:含有SEQ ID NO: 83、SEQ ID NO: 84、SEQ IDNO: 85、SEQ ID NO: 86、SEQ ID NO: 87、SEQ ID NO: 88、SEQ ID NO: 89、SEQ ID NO: 90、SEQ ID NO: 91、SEQ ID NO: 144、SEQ ID NO: 145、SEQ ID NO: 146、SEQ ID NO: 147或SEQ ID NO: 148的氨基酸序列的VH CDR2,和含有SEQ ID NO: 92、SEQ ID NO: 93、SEQ IDNO: 94、SEQ ID NO: 95、SEQ ID NO: 96、SEQ ID NO: 97、SEQ ID NO: 98、SEQ ID NO: 99或SEQ ID NO: 100、SEQ ID NO: 149、SEQ ID NO: 150、SEQ ID NO: 151、SEQ ID NO: 152或SEQ ID NO: 153的氨基酸序列的VH CDR3。在另一个这样的实施方案中,所述犬化抗体或抗原结合片段包含:含有SEQ ID NO: 74、SEQ ID NO: 75、SEQ ID NO: 76、SEQ ID NO: 77、SEQ ID NO: 78、SEQ ID NO: 79、SEQ ID NO: 80、SEQ ID NO: 81、SEQ ID NO: 82、SEQ IDNO: 140、SEQ ID NO: 141、SEQ ID NO: 142或SEQ ID NO: 143的氨基酸序列的VH CDR1,含有SEQ ID NO: 83、SEQ ID NO: 84、SEQ ID NO: 85、SEQ ID NO: 86、SEQ ID NO: 87、SEQID NO: 88、SEQ ID NO: 89、SEQ ID NO: 90、SEQ ID NO: 91、SEQ ID NO: 144、SEQ ID NO:145、SEQ ID NO: 146、SEQ ID NO: 147或SEQ ID NO: 148的氨基酸序列的VH CDR2,和含有SEQ ID NO: 92、SEQ ID NO: 93、SEQ ID NO: 94、SEQ ID NO: 95、SEQ ID NO: 96、SEQ IDNO: 97、SEQ ID NO: 98、SEQ ID NO: 99或SEQ ID NO: 100、SEQ ID NO: 149、SEQ ID NO:150、SEQ ID NO: 151、SEQ ID NO: 152或SEQ ID NO: 153的氨基酸序列的VH CDR3。
在具体实施方案中,所述犬化抗体或抗原结合片段还包含含有SEQ ID NO: 47、SEQ ID NO: 48、SEQ ID NO: 49、SEQ ID NO: 50、SEQ ID NO: 51、SEQ ID NO: 52、SEQ IDNO: 53、SEQ ID NO: 54、SEQ ID NO: 55、SEQ ID NO: 129、SEQ ID NO: 130或SEQ ID NO:131的氨基酸序列的轻链互补决定区1 (VL CDR1)。在有关的实施方案中,所述轻链互补决定区2 (VL CDR2)包含SEQ ID NO: 56、SEQ ID NO: 57、SEQ ID NO: 58、SEQ ID NO: 59、SEQ ID NO: 60、SEQ ID NO: 61、SEQ ID NO: 62、SEQ ID NO: 63、SEQ ID NO: 64、SEQ IDNO: 132、SEQ ID NO: 133或SEQ ID NO: 134的氨基酸序列。在另一个实施方案中,所述轻链互补决定区3 (VL CDR3)包含SEQ ID NO: 65、SEQ ID NO: 66、SEQ ID NO: 67、SEQ IDNO: 68、SEQ ID NO: 69、SEQ ID NO: 70、SEQ ID NO: 71、SEQ ID NO: 72、SEQ ID NO: 73、SEQ ID NO: 135、SEQ ID NO: 136、SEQ ID NO: 137、SEQ ID NO: 138或SEQ ID NO: 139的氨基酸序列。在这类的一个具体实施方案中,所述犬化抗体或抗原结合片段包含:含有SEQID NO: 47、SEQ ID NO: 48、SEQ ID NO: 49、SEQ ID NO: 50、SEQ ID NO: 51、SEQ ID NO:52、SEQ ID NO: 53、SEQ ID NO: 54、SEQ ID NO: 55、SEQ ID NO: 129、SEQ ID NO: 130或SEQ ID NO: 131的氨基酸序列的VL CDR1,和含有SEQ ID NO: 56、SEQ ID NO: 57、SEQ IDNO: 58、SEQ ID NO: 59、SEQ ID NO: 60、SEQ ID NO: 61、SEQ ID NO: 62、SEQ ID NO: 63、SEQ ID NO: 64、SEQ ID NO: 132、SEQ ID NO: 133或SEQ ID NO: 134的氨基酸序列的VLCDR2。
在其它这样的实施方案中,所述犬化抗体或抗原结合片段包含:含有SEQ ID NO:47、SEQ ID NO: 48、SEQ ID NO: 49、SEQ ID NO: 50、SEQ ID NO: 51、SEQ ID NO: 52、SEQID NO: 53、SEQ ID NO: 54、SEQ ID NO: 55、SEQ ID NO: 129、SEQ ID NO: 130或SEQ IDNO: 131的氨基酸序列的VL CDR1,和含有SEQ ID NO: 65、SEQ ID NO: 66、SEQ ID NO: 67、SEQ ID NO: 68、SEQ ID NO: 69、SEQ ID NO: 70、SEQ ID NO: 71、SEQ ID NO: 72、SEQ IDNO: 73、SEQ ID NO: 135、SEQ ID NO: 136、SEQ ID NO: 137、SEQ ID NO: 138或SEQ IDNO: 139的氨基酸序列的VL CDR3。在另一个这样的实施方案中,所述犬化抗体或抗原结合片段包含:含有SEQ ID NO: 56、SEQ ID NO: 57、SEQ ID NO: 58、SEQ ID NO: 59、SEQ IDNO: 60、SEQ ID NO: 61、SEQ ID NO: 62、SEQ ID NO: 63、SEQ ID NO: 64、SEQ ID NO:132、SEQ ID NO: 133或SEQ ID NO: 134的氨基酸序列的VL CDR2,和含有SEQ ID NO: 65、SEQ ID NO: 66、SEQ ID NO: 67、SEQ ID NO: 68、SEQ ID NO: 69、SEQ ID NO: 70、SEQ IDNO: 71、SEQ ID NO: 72、SEQ ID NO: 73、SEQ ID NO: 135、SEQ ID NO: 136、SEQ ID NO:137、SEQ ID NO: 138或SEQ ID NO: 139的氨基酸序列的VL CDR3。
在其它这样的实施方案中,所述犬化抗体或抗原结合片段包含:含有SEQ ID NO:47、SEQ ID NO: 48、SEQ ID NO: 49、SEQ ID NO: 50、SEQ ID NO: 51、SEQ ID NO: 52、SEQID NO: 53、SEQ ID NO: 54、SEQ ID NO: 55、SEQ ID NO: 129、SEQ ID NO: 130或SEQ IDNO: 131的氨基酸序列的VL CDR1,含有SEQ ID NO: 56、SEQ ID NO: 57、SEQ ID NO: 58、SEQ ID NO: 59、SEQ ID NO: 60、SEQ ID NO: 61、SEQ ID NO: 62、SEQ ID NO: 63、SEQ IDNO: 64、SEQ ID NO: 132、SEQ ID NO: 133或SEQ ID NO: 134的氨基酸序列的VL CDR2,和含有SEQ ID NO: 65、SEQ ID NO: 66、SEQ ID NO: 67、SEQ ID NO: 68、SEQ ID NO: 69、SEQID NO: 70、SEQ ID NO: 71、SEQ ID NO: 72、SEQ ID NO: 73、SEQ ID NO: 135、SEQ ID NO:136、SEQ ID NO: 137、SEQ ID NO: 138或SEQ ID NO: 139的氨基酸序列的VL CDR3。
在具体实施方案中,所述犬化抗-犬IL-4Rα抗体包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-3A和H3-12,即,重链的CDR1具有规范结构类别1,重链的CDR2具有规范结构类别3A,且重链的CDR3具有规范结构类别12。在甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-1、L2-1和L3-1。在其它实施方案中,所述犬化抗-犬IL-4Rα抗体包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-2A和H3-7。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-2A、L2-1和L3-1。在其它的实施方案中,所述犬化抗-犬IL-4Rα抗体还包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-2B和H3-15。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-4、L2-1和L3-1。在其它的实施方案中,所述犬化抗-犬IL-4Rα抗体还包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-1和H3-15。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-3、L2-1和L3-1。在其它的实施方案中,所述犬化抗-犬IL-4Rα抗体还包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-2B和H3-6。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-2A、L2-1和L3-1。
在其它的实施方案中,所述犬化抗-犬IL-4Rα抗体还包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-2B和H3-4。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-6、L2-1和L3-1。在其它的实施方案中,所述犬化抗-犬IL-4Rα抗体还包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-1和H3-13。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-1、L2-1和L3-1。在其它的实施方案中,所述犬化抗-犬IL-4Rα抗体还包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-2A和H3-6。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-2A、L2-1和L3-1。
在其它的实施方案中,所述犬化抗-犬IL-4Rα抗体还包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-3A和H3-15或可选地H3-13。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-6、L2-1和L3-1。在其它的实施方案中,所述犬化抗-犬IL-4Rα抗体还包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-2A和H3-10。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-6、L2-1和L3-1。在其它的实施方案中,所述犬化抗-犬IL-4Rα抗体还包含互补决定区(CDR),其中所述CDR具有以下规范结构:对于重链的CDR1、CDR2和CDR3,分别为H1-1、H2-3A和H3-9。在这类的甚至更具体的实施方案中,对应轻链的CDR具有以下规范结构:对于轻链的CDR1、CDR2和CDR3,分别为L1-3、L2-1和L3-3。
本发明还提供了一种分离的特异性地结合IL-4Rα的、包含犬IgG重链和犬κ或λ轻链的犬化抗体或其抗原结合片段。在这类的具体实施方案中,从鼠抗-犬IL-4Rα抗体得到犬κ或λ轻链和犬IgG重链,所述犬κ或λ轻链包含三个轻链互补决定区(CDR):CDR轻1 (CDRL1)、CDR轻2 (CDRL2)和CDR轻3 (CDRL3),所述犬IgG重链包含三个重链CDR:CDR重1 (CDRH1)、CDR重2 (CDRH2)和CDR重3 (CDRH3)。本发明的犬化抗体和其抗原结合片段的具体实施方案结合犬IL-4Rα和/或阻断犬IL-4Rα与犬IL-4的结合。
在具体实施方案中,本发明提供了一种分离的特异性地结合犬白介素-4受体α(IL-4Rα)的哺乳动物抗体或其抗原结合片段,其包含三个轻链互补决定区(CDR):CDR轻1(CDRL1)、CDR轻2 (CDRL2)和CDR轻3 (CDRL3);和三个重链CDR:CDR重1 (CDRH1)、CDR重2(CDRH2)和CDR重3 (CDRH3)。在某些实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 47、SEQ ID NO: 47的变体、SEQ ID NO: 47的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 47的变体、SEQ ID NO: 48、SEQ ID NO: 48的变体、SEQ ID NO: 48的保守修饰的变体、包含规范结构类别2A的SEQ ID NO: 48的变体、SEQ ID NO: 49、SEQ IDNO: 49的变体、SEQ ID NO: 49的保守修饰的变体、包含规范结构类别4的SEQ ID NO: 49的变体、SEQ ID NO: 50、SEQ ID NO: 50的变体、SEQ ID NO: 50的保守修饰的变体、包含规范结构类别3的SEQ ID NO: 50的变体、SEQ ID NO: 51、SEQ ID NO: 51的变体、SEQ ID NO:51的保守修饰的变体、包含规范结构类别3的SEQ ID NO: 51的变体、SEQ ID NO: 52、SEQID NO: 52的变体、SEQ ID NO: 52的保守修饰的变体、包含规范结构类别2A的SEQ ID NO:52的变体、SEQ ID NO: 53、SEQ ID NO: 53的变体、SEQ ID NO: 53的保守修饰的变体、包含规范结构类别6的SEQ ID NO: 53的变体、SEQ ID NO: 54、SEQ ID NO: 54的变体、SEQ IDNO: 54的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 54的变体、SEQ ID NO: 55、SEQ ID NO: 55的变体、SEQ ID NO: 55的保守修饰的变体、包含规范结构类别2A的SEQ IDNO: 55的变体、SEQ ID NO: 129、SEQ ID NO: 129的变体、SEQ ID NO: 129的保守修饰的变体、包含规范结构类别6的SEQ ID NO: 129的变体、SEQ ID NO: 130、SEQ ID NO: 130的变体、SEQ ID NO: 130的保守修饰的变体、包含规范结构类别6的SEQ ID NO: 130的变体、SEQID NO: 131、SEQ ID NO: 131的变体、SEQ ID NO: 131的保守修饰的变体或包含规范结构类别3的SEQ ID NO: 131的变体。
对应的CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 56、SEQ ID NO: 56的变体、SEQ ID NO: 56的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 56的变体、SEQID NO: 57、SEQ ID NO: 57的变体、SEQ ID NO: 57的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 57的变体、SEQ ID NO: 58、SEQ ID NO: 58的变体、SEQ ID NO: 58的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 58的变体、SEQ ID NO: 59、SEQ ID NO: 59的变体、SEQ ID NO: 59的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 59的变体、SEQID NO: 60、SEQ ID NO: 60的变体、SEQ ID NO: 60的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 60的变体、SEQ ID NO: 61、SEQ ID NO: 61的变体、SEQ ID NO: 61的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 61的变体、SEQ ID NO: 62、SEQ ID NO: 62的变体、SEQ ID NO: 62的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 62的变体、SEQID NO: 63、SEQ ID NO: 63的变体、SEQ ID NO: 63的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 63的变体、SEQ ID NO: 64、SEQ ID NO: 64的变体、SEQ ID NO: 64的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 64的变体、SEQ ID NO: 132、SEQ ID NO:132的变体、SEQ ID NO: 132的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 132的变体、SEQ ID NO: 133、SEQ ID NO: 133的变体、SEQ ID NO: 133的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 133的变体、SEQ ID NO: 134、SEQ ID NO: 134的变体、SEQID NO: 134的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 134的变体。
对应的CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 65、SEQ ID NO: 65的变体、SEQ ID NO: 65的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 65的变体、SEQID NO: 66、SEQ ID NO: 66的变体、SEQ ID NO: 66的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 66的变体、SEQ ID NO: 67、SEQ ID NO: 67的变体、SEQ ID NO: 67的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 67的变体、SEQ ID NO: 68、SEQ ID NO: 68的变体、SEQ ID NO: 68的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 68的变体、SEQID NO: 69、SEQ ID NO: 69的变体、SEQ ID NO: 69的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 69的变体、SEQ ID NO: 70、SEQ ID NO: 70的变体、SEQ ID NO: 70的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 70的变体、SEQ ID NO: 71、SEQ ID NO: 71的变体、SEQ ID NO: 71的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 71的变体、SEQID NO: 72、SEQ ID NO: 72的变体、SEQ ID NO: 72的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 72的变体、SEQ ID NO: 73、SEQ ID NO: 73的变体、SEQ ID NO: 73的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 73的变体、SEQ ID NO: 135、SEQ ID NO: 135的变体、SEQ ID NO: 135的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 135的变体、SEQ ID NO: 136、SEQ ID NO: 136的变体、SEQ ID NO: 136的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 136的变体、SEQ ID NO: 137、SEQ ID NO: 137的变体、SEQ IDNO: 137的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 137的变体、SEQ ID NO:138、SEQ ID NO: 138的变体、SEQ ID NO: 138的保守修饰的变体、包含规范结构类别3的SEQ ID NO: 138的变体、SEQ ID NO: 139、SEQ ID NO: 139的变体、SEQ ID NO: 139的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 139的变体。
对应的CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 74、SEQ ID NO: 74的变体、SEQ ID NO: 74的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 74的变体、SEQID NO: 75、SEQ ID NO: 75的变体、SEQ ID NO: 75的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 75的变体、SEQ ID NO: 76、SEQ ID NO: 76的变体、SEQ ID NO: 76的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 76的变体、SEQ ID NO: 77、SEQ ID NO: 77的变体、SEQ ID NO: 77的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 77的变体、SEQ ID NO: 78、SEQ ID NO: 78的变体、SEQ ID NO: 78的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 78的变体、SEQ ID NO: 79、SEQ ID NO: 79的变体、SEQ ID NO: 79的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 79的变体、SEQ ID NO: 80、SEQ IDNO: 80的变体、SEQ ID NO: 80的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 80的变体、SEQ ID NO: 81、SEQ ID NO: 81的变体、SEQ ID NO: 81的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 81的变体、SEQ ID NO: 82、SEQ ID NO: 82的变体、SEQ ID NO:82的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 82的变体、SEQ ID NO: 140、SEQID NO: 140的变体、SEQ ID NO: 140的保守修饰的变体、包含规范结构类别1的SEQ ID NO:140的变体、SEQ ID NO: 141、SEQ ID NO: 141的变体、SEQ ID NO: 141的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 141的变体、SEQ ID NO: 142、SEQ ID NO: 142的变体、SEQ ID NO: 142的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 142的变体、SEQ IDNO: 143、SEQ ID NO: 143的变体、SEQ ID NO: 143的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 143的变体。
对应的CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 83、SEQ ID NO: 83的变体、SEQ ID NO: 83的保守修饰的变体、包含规范结构类别3A的SEQ ID NO: 83的变体、SEQID NO: 84、SEQ ID NO: 84的变体、SEQ ID NO: 84的保守修饰的变体、包含规范结构类别2A的SEQ ID NO: 84的变体、SEQ ID NO: 85、SEQ ID NO: 85的变体、SEQ ID NO: 85的保守修饰的变体或包含规范结构类别2B的SEQ ID NO: 85的变体、SEQ ID NO: 86、SEQ ID NO:86的变体、SEQ ID NO: 86的保守修饰的变体、SEQ ID NO: 87、SEQ ID NO: 87的变体、SEQID NO: 87的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 87的变体、SEQ ID NO:88、SEQ ID NO: 88的变体、SEQ ID NO: 88的保守修饰的变体、包含规范结构类别2B的SEQID NO: 88的变体、SEQ ID NO: 89、SEQ ID NO: 89的变体、SEQ ID NO: 89的保守修饰的变体、包含规范结构类别2B的SEQ ID NO: 89的变体、SEQ ID NO: 90、SEQ ID NO: 90的变体、SEQ ID NO: 90的保守修饰的变体、包含规范结构类别1的SEQ ID NO: 90的变体、SEQ IDNO: 91、SEQ ID NO: 91的变体、SEQ ID NO: 91的保守修饰的变体、包含规范结构类别2A的SEQ ID NO: 91的变体、SEQ ID NO: 144、SEQ ID NO: 144的变体、SEQ ID NO: 144的保守修饰的变体、包含规范结构类别3A的SEQ ID NO: 144的变体、SEQ ID NO: 145、SEQ ID NO:145的变体、SEQ ID NO: 145的保守修饰的变体、包含规范结构类别2A的SEQ ID NO: 145的变体、SEQ ID NO: 146、SEQ ID NO: 146的变体、SEQ ID NO: 146的保守修饰的变体、包含规范结构类别3A的SEQ ID NO: 146的变体、SEQ ID NO: 147、SEQ ID NO: 147的变体、SEQID NO: 147的保守修饰的变体、包含规范结构类别3A的SEQ ID NO: 147的变体、SEQ IDNO: 148、SEQ ID NO: 148的变体、SEQ ID NO: 148的保守修饰的变体或包含规范结构类别3A的SEQ ID NO: 148的变体。
对应的CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 92、SEQ ID NO: 92的变体、SEQ ID NO: 92的保守修饰的变体、包含规范结构类别12的SEQ ID NO: 92的变体、SEQID NO: 93、SEQ ID NO: 93的变体、SEQ ID NO: 93的保守修饰的变体、包含规范结构类别7的SEQ ID NO: 93的变体、SEQ ID NO: 94、SEQ ID NO: 94的变体、SEQ ID NO: 94的保守修饰的变体或包含规范结构类别15的SEQ ID NO: 94的变体、SEQ ID NO: 95、SEQ ID NO: 95的变体、SEQ ID NO: 95的保守修饰的变体或包含规范结构类别11的SEQ ID NO: 95的变体、SEQ ID NO: 96、SEQ ID NO: 96的变体、SEQ ID NO: 96的保守修饰的变体、包含规范结构类别15的SEQ ID NO: 96的变体、SEQ ID NO: 97、SEQ ID NO: 97的变体、SEQ ID NO: 97的保守修饰的变体、包含规范结构类别6的SEQ ID NO: 97的变体、SEQ ID NO: 98、SEQ IDNO: 98的变体、SEQ ID NO: 98的保守修饰的变体、包含规范结构类别4的SEQ ID NO: 98的变体、SEQ ID NO: 99、SEQ ID NO: 99的变体、SEQ ID NO: 99的保守修饰的变体、包含规范结构类别13的SEQ ID NO: 99的变体、SEQ ID NO: 100、SEQ ID NO: 100的变体、SEQ IDNO: 100的保守修饰的变体或包含规范结构类别6的SEQ ID NO: 100的变体、SEQ ID NO:149、SEQ ID NO: 149的变体、SEQ ID NO: 149的保守修饰的变体、包含规范结构类别15的SEQ ID NO: 149的变体、SEQ ID NO: 150、SEQ ID NO: 150的变体、SEQ ID NO: 150的保守修饰的变体、包含规范结构类别10的SEQ ID NO: 150的变体、SEQ ID NO: 151、SEQ ID NO:151的变体、SEQ ID NO: 151的保守修饰的变体、包含规范结构类别15的SEQ ID NO: 151的变体、SEQ ID NO: 152、SEQ ID NO: 152的变体、SEQ ID NO: 152的保守修饰的变体、包含规范结构类别9的SEQ ID NO: 152的变体、SEQ ID NO: 153、SEQ ID NO: 153的变体、SEQID NO: 153的保守修饰的变体或包含规范结构类别13的SEQ ID NO: 153的变体。
在具体实施方案中,本发明的哺乳动物抗体(包括嵌合的哺乳动物抗体)和/或其抗原结合片段结合犬白介素-4受体α(IL-4Rα)和/或阻断犬IL-4Rα与犬IL-4和/或犬IL-13的结合。在有关的实施方案中,本发明的哺乳动物抗体和/或其抗原结合片段阻断犬IL-4和/或犬IL-13与IL-4 I型受体和/或IL-4 II型受体的结合。在具体实施方案中,所述哺乳动物抗体(无论是否分离)是犬化抗体。
因此,在哺乳动物抗体(包括犬化抗体)的某些实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 47、SEQ ID NO: 47的变体、SEQ ID NO: 47的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 47的变体;所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 56、SEQ ID NO: 56的变体、SEQ ID NO: 56的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 56的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 65、SEQ ID NO: 65的变体、SEQ ID NO: 65的保守修饰的变体或包含规范结构类别1的SEQ IDNO: 65的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 74、SEQ ID NO: 74的变体、SEQ ID NO: 74的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 74的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 83、SEQ ID NO: 83的变体、SEQ ID NO:83的保守修饰的变体和包含规范结构类别3A的SEQ ID NO: 83的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 92、SEQ ID NO: 92的变体、SEQ ID NO: 92的保守修饰的变体或包含规范结构类别12的SEQ ID NO: 92的变体。
在哺乳动物抗体(包括犬化抗体)的其它实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 48、SEQ ID NO: 48的变体、SEQ ID NO: 48的保守修饰的变体或包含规范结构类别2A的SEQ ID NO: 48的变体;所述CDRL2包含选自以下的氨基酸序列:SEQID NO: 57、SEQ ID NO: 57的变体、SEQ ID NO: 57的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 57的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 66、SEQ IDNO: 66的变体、SEQ ID NO: 66的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 66的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 75、SEQ ID NO: 75的变体、SEQ ID NO: 75的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 75的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 84、SEQ ID NO: 84的变体、SEQ ID NO: 84的保守修饰的变体和包含规范结构类别2A的SEQ ID NO: 84的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 93、SEQ ID NO: 93的变体、SEQ ID NO: 93的保守修饰的变体或包含规范结构类别7的SEQ ID NO: 93的变体。
在哺乳动物抗体(包括犬化抗体)的其它的实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 49、SEQ ID NO: 49的变体、SEQ ID NO: 49的保守修饰的变体或包含规范结构类别4的SEQ ID NO: 49的变体;所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 58、SEQ ID NO: 58的变体、SEQ ID NO: 58的保守修饰的变体或包含规范结构类别4的SEQ ID NO: 58的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 67、SEQ ID NO: 67的变体、SEQ ID NO: 67的保守修饰的变体或包含规范结构类别1的SEQ IDNO: 67的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 76、SEQ ID NO: 76的变体、SEQ ID NO: 76的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 76的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 85、SEQ ID NO: 85的变体、SEQ ID NO:85的保守修饰的变体和包含规范结构类别2B的SEQ ID NO: 85的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 94、SEQ ID NO: 94的变体、SEQ ID NO: 94的保守修饰的变体或包含规范结构类别15的SEQ ID NO: 94的变体。
在哺乳动物抗体(包括犬化抗体)的其它实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 51、SEQ ID NO: 51的变体、SEQ ID NO: 51的保守修饰的变体或包含规范结构类别3的SEQ ID NO: 51的变体;所述CDRL2包含选自以下的氨基酸序列:SEQID NO: 60、SEQ ID NO: 60的变体、SEQ ID NO: 60的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 60的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 69、SEQ IDNO: 69的变体、SEQ ID NO: 69的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 69的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 78、SEQ ID NO: 78的变体、SEQ ID NO: 78的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 78的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 87、SEQ ID NO: 87的变体、SEQ ID NO: 87的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 87的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 96、SEQ ID NO: 96的变体、SEQ ID NO: 96的保守修饰的变体或包含规范结构类别15的SEQ ID NO: 96的变体。
在哺乳动物抗体(包括犬化抗体)的其它的实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 52、SEQ ID NO: 52的变体、SEQ ID NO: 52的保守修饰的变体或包含规范结构类别2A的SEQ ID NO: 52的变体;所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 61、SEQ ID NO: 61的变体、SEQ ID NO: 61的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 61的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 70、SEQ ID NO: 70的变体、SEQ ID NO: 70的保守修饰的变体或包含规范结构类别1的SEQ IDNO: 70的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 79、SEQ ID NO: 79的变体、SEQ ID NO: 79的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 79的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 88、SEQ ID NO: 88的变体、SEQ ID NO:88的保守修饰的变体和包含规范结构类别2B的SEQ ID NO: 88的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 97、SEQ ID NO: 97的变体、SEQ ID NO: 97的保守修饰的变体或包含规范结构类别6的SEQ ID NO: 97的变体。
在哺乳动物抗体(包括犬化抗体)的其它实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 53、SEQ ID NO: 53的变体、SEQ ID NO: 53的保守修饰的变体或包含规范结构类别6的SEQ ID NO: 53的变体;所述CDRL2包含选自以下的氨基酸序列:SEQID NO: 62、SEQ ID NO: 62的变体、SEQ ID NO: 62的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 62的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 71、SEQ IDNO: 71的变体、SEQ ID NO: 71的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 71的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 80、SEQ ID NO: 80的变体、SEQ ID NO: 80的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 80的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 89、SEQ ID NO: 89的变体、SEQ ID NO: 89的保守修饰的变体和包含规范结构类别2B的SEQ ID NO: 89的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 98、SEQ ID NO: 98的变体、SEQ ID NO: 98的保守修饰的变体或包含规范结构类别4的SEQ ID NO: 98的变体。
在哺乳动物抗体(包括犬化抗体)的其它的实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 54、SEQ ID NO: 54的变体、SEQ ID NO: 54的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 54的变体;所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 63、SEQ ID NO: 63的变体、SEQ ID NO: 63的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 63的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 72、SEQ ID NO: 72的变体、SEQ ID NO: 72的保守修饰的变体或包含规范结构类别1的SEQ IDNO: 72的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 81、SEQ ID NO: 81的变体、SEQ ID NO: 81的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 81的变体;所述CDRH2选自以下的氨基酸序列:包含SEQ ID NO: 90、SEQ ID NO: 90的变体、SEQ ID NO:90的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 90的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 99、SEQ ID NO: 99的变体、SEQ ID NO: 99的保守修饰的变体或包含规范结构类别13的SEQ ID NO: 99的变体。在这类的具体实施方案中,当所述抗体(或其抗原结合片段)结合犬白介素-4受体α(IL-4Rα)时,所述抗体结合SEQ ID NO: 157或SEQ ID NO: 158的氨基酸序列内或SEQ ID NO: 157和SEQ ID NO: 158二者内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个氨基酸残基或更多。
在哺乳动物抗体(包括犬化抗体)的其它实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 55、SEQ ID NO: 55的变体、SEQ ID NO: 55的保守修饰的变体或包含规范结构类别2A的SEQ ID NO: 55的变体;所述CDRL2包含选自以下的氨基酸序列:SEQID NO: 64、SEQ ID NO: 64的变体、SEQ ID NO: 64的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 64的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 73、SEQ IDNO: 73的变体、SEQ ID NO: 73的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 73的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 82、SEQ ID NO: 82的变体、SEQ ID NO: 82的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 82的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 91、SEQ ID NO: 91的变体、SEQ ID NO: 91的保守修饰的变体和包含规范结构类别2A的SEQ ID NO: 91的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 100、SEQ ID NO: 100的变体、SEQ ID NO: 100的保守修饰的变体或包含规范结构类别6的SEQ ID NO: 100的变体。
在哺乳动物抗体(包括犬化抗体)的其它的实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 129、SEQ ID NO: 129的变体、SEQ ID NO: 129的保守修饰的变体或包含规范结构类别6的SEQ ID NO: 129的变体;所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 132、SEQ ID NO: 132的变体、SEQ ID NO: 132的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 132的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ IDNO: 135、SEQ ID NO: 135的变体、SEQ ID NO: 135的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 135的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 140、SEQID NO: 140的变体、SEQ ID NO: 140的保守修饰的变体或包含规范结构类别1的SEQ IDNO: 140的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 144、SEQ ID NO: 144的变体、SEQ ID NO: 144的保守修饰的变体和包含规范结构类别3A的SEQ ID NO: 144的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 149、SEQ ID NO: 149的变体、SEQID NO: 149的保守修饰的变体或包含规范结构类别15的SEQ ID NO: 149的变体。在这类的具体实施方案中,当所述抗体(或其抗原结合片段)结合犬白介素-4受体α(IL-4Rα)时,所述抗体结合SEQ ID NO: 127或SEQ ID NO: 128的氨基酸序列内或SEQ ID NO: 127和SEQ IDNO: 128二者内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个氨基酸残基或更多。
在哺乳动物抗体(包括犬化抗体)的其它实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 130、SEQ ID NO: 130的变体、SEQ ID NO: 130的保守修饰的变体或包含规范结构类别6的SEQ ID NO: 130的变体;所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 133、SEQ ID NO: 133的变体、SEQ ID NO: 133的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 133的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO:136、SEQ ID NO: 136的变体、SEQ ID NO: 136的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 136的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 141、SEQ IDNO: 141的变体、SEQ ID NO: 141的保守修饰的变体或包含规范结构类别1的SEQ ID NO:141的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 145、SEQ ID NO: 145的变体、SEQ ID NO: 145的保守修饰的变体和包含规范结构类别2A的SEQ ID NO: 145的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 150、SEQ ID NO: 150的变体、SEQ IDNO: 150的保守修饰的变体或包含规范结构类别10的SEQ ID NO: 150的变体。在这类的具体实施方案中,当所述抗体(或其抗原结合片段)结合犬白介素-4受体α(IL-4Rα)时,所述抗体结合SEQ ID NO: 158或SEQ ID NO: 162的氨基酸序列内或SEQ ID NO: 158和SEQ IDNO: 162二者内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个氨基酸残基或更多。
在哺乳动物抗体(包括犬化抗体)的其它的实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 129、SEQ ID NO: 129的变体、SEQ ID NO: 129的保守修饰的变体或包含规范结构类别6的SEQ ID NO: 129的变体;所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 134、SEQ ID NO: 134的变体、SEQ ID NO: 134的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 134的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ IDNO: 137、SEQ ID NO: 137的变体、SEQ ID NO: 137的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 137的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 140、SEQID NO: 140的变体、SEQ ID NO: 140的保守修饰的变体或包含规范结构类别1的SEQ IDNO: 140的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 146、SEQ ID NO: 146的变体、SEQ ID NO: 146的保守修饰的变体和包含规范结构类别3A的SEQ ID NO: 146的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 151、SEQ ID NO: 151的变体、SEQID NO: 151的保守修饰的变体或包含规范结构类别15的SEQ ID NO: 151的变体。在这类的具体实施方案中,当所述抗体(或其抗原结合片段)结合犬白介素-4受体α(IL-4Rα)时,所述抗体结合SEQ ID NO: 125或SEQ ID NO: 126的氨基酸序列内或SEQ ID NO: 125和SEQ IDNO: 126二者内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个氨基酸残基或更多。
在哺乳动物抗体(包括犬化抗体)的其它实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 131、SEQ ID NO: 131的变体、SEQ ID NO: 131的保守修饰的变体或包含规范结构类别3的SEQ ID NO: 131的变体;所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 60、SEQ ID NO: 60的变体、SEQ ID NO: 60的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 60的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 138、SEQ ID NO: 138的变体、SEQ ID NO: 1385的保守修饰的变体或包含规范结构类别3的SEQID NO: 138的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 142、SEQ ID NO:142的变体、SEQ ID NO: 142的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 142的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 147、SEQ ID NO: 147的变体、SEQ ID NO: 147的保守修饰的变体和包含规范结构类别3A的SEQ ID NO: 147的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 152、SEQ ID NO: 152的变体、SEQ ID NO:152的保守修饰的变体或包含规范结构类别9的SEQ ID NO: 152的变体。在这类的具体实施方案中,当所述抗体(或其抗原结合片段)结合犬白介素-4受体α(IL-4Rα)时,所述抗体结合SEQ ID NO: 154或SEQ ID NO: 155或SEQ ID NO: 156或它们的任意组合的氨基酸序列内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个氨基酸残基或更多。
在哺乳动物抗体(包括犬化抗体)的其它的实施方案中,所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 129、SEQ ID NO: 129的变体、SEQ ID NO: 129的保守修饰的变体或包含规范结构类别6的SEQ ID NO: 129的变体;所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 132、SEQ ID NO: 132的变体、SEQ ID NO: 132的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 132的变体;所述CDRL3包含选自以下的氨基酸序列:SEQ IDNO: 139、SEQ ID NO: 139的变体、SEQ ID NO: 139的保守修饰的变体或包含规范结构类别1的SEQ ID NO: 139的变体;所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 143、SEQID NO: 143的变体、SEQ ID NO: 143的保守修饰的变体或包含规范结构类别1的SEQ IDNO: 143的变体;所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 148、SEQ ID NO: 148的变体、SEQ ID NO: 148的保守修饰的变体和包含规范结构类别3A的SEQ ID NO: 148的变体;所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 153、SEQ ID NO: 153的变体、SEQID NO: 153的保守修饰的变体或包含规范结构类别13的SEQ ID NO: 153的变体。在这类的具体实施方案中,当所述抗体(或其抗原结合片段)结合犬白介素-4受体α(IL-4Rα)时,所述抗体结合SEQ ID NO: 159或SEQ ID NO: 160或SEQ ID NO: 161或它们的任意组合的氨基酸序列内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个氨基酸残基或更多。
本发明包括特异性地结合犬白介素-4受体α(IL-4Rα)的抗体及其抗原结合片段。在这类的具体实施方案中,所述抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬IL-4和/或IL-13的结合。如上面指出的,所述分离的哺乳动物抗体或其抗原结合片段可以是犬化抗体或其犬化抗原结合片段。在其它实施方案中,所述分离的哺乳动物抗体或其抗原结合片段可以是鼠抗体或其鼠抗原结合片段。
本发明的犬化抗体或其犬化抗原结合片段可以包含铰链区。在这类的一个具体实施方案中,所述铰链区包含SEQ ID NO: 101的氨基酸序列。在另一个实施方案中,所述铰链区包含SEQ ID NO: 102的氨基酸序列。在另一个实施方案中,所述铰链区包含SEQ ID NO:103的氨基酸序列。在另一个实施方案中,所述铰链区包含SEQ ID NO: 104的氨基酸序列。
在某些实施方案中,所述犬化抗体或其抗原结合片段含有包含SEQ ID NO: 164的氨基酸序列的重链。在这类的具体实施方案中,所述重链由SEQ ID NO: 163的核苷酸序列编码。在其它实施方案中,所述犬化抗体或其抗原结合片段含有包含SEQ ID NO: 166的氨基酸序列的重链。在这类的具体实施方案中,所述重链由SEQ ID NO: 165的核苷酸序列编码。在其它实施方案中,所述犬化抗体或其抗原结合片段含有包含SEQ ID NO: 168的氨基酸序列的重链。在这类的具体实施方案中,所述重链由SEQ ID NO: 167的核苷酸序列编码。在这类的具体实施方案中,当所述犬化抗体(或其抗原结合片段)结合犬白介素-4受体α(IL-4Rα)时,所述抗体结合SEQ ID NO: 154或SEQ ID NO: 155或SEQ ID NO: 156或它们的任意组合的氨基酸序列内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个氨基酸残基或更多。
在有关的实施方案中,所述犬化抗体或其抗原结合片段含有包含SEQ ID NO: 170的氨基酸序列的轻链。在这类的具体实施方案中,所述轻链由SEQ ID NO: 169的核苷酸序列编码。在其它实施方案中,所述犬化抗体或其抗原结合片段含有包含SEQ ID NO: 172的氨基酸序列的轻链。在这类的具体实施方案中,所述轻链由SEQ ID NO: 171的核苷酸序列编码。在其它的实施方案中,所述犬化抗体或其抗原结合片段含有包含SEQ ID NO: 174的氨基酸序列的轻链。在这类的具体实施方案中,所述轻链由SEQ ID NO: 173的核苷酸序列编码。在这类的具体实施方案中,当所述犬化抗体(或其抗原结合片段)结合犬白介素-4受体α(IL-4Rα)时,所述抗体结合SEQ ID NO: 154或SEQ ID NO: 155或SEQ ID NO: 156或它们的任意组合的氨基酸序列内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个氨基酸残基或更多。
本发明还提供了包含这样的重链和轻链的组合的抗体。在具体实施方案中,所述重链包含SEQ ID NO: 164的氨基酸序列,且所述轻链包含SEQ ID NO: 170的氨基酸序列。在这类的更具体的实施方案中,所述重链由SEQ ID NO: 163的核苷酸序列编码,且所述轻链由SEQ ID NO: 169的核苷酸序列编码。在其它实施方案中,所述重链包含SEQ ID NO:166的氨基酸序列,且所述轻链包含SEQ ID NO: 172的氨基酸序列。在这类的更具体的实施方案中,所述重链由SEQ ID NO: 165的核苷酸序列编码,且所述轻链由SEQ ID NO: 171的核苷酸序列编码。在其它的实施方案中,所述重链包含SEQ ID NO: 168的氨基酸序列,且所述轻链包含SEQ ID NO: 174的氨基酸序列。在这类的更具体的实施方案中,所述重链由SEQID NO: 167的核苷酸序列编码,且所述轻链由SEQ ID NO: 173的核苷酸序列编码。
在有关的实施方案中,所述重链包含SEQ ID NO: 164的氨基酸序列,且所述轻链包含SEQ ID NO: 172的氨基酸序列。在其它实施方案中,所述重链包含SEQ ID NO: 164的氨基酸序列,且所述轻链包含SEQ ID NO: 174的氨基酸序列。在其它的实施方案中,所述重链包含SEQ ID NO: 166的氨基酸序列,且所述轻链包含SEQ ID NO: 170的氨基酸序列。在其它的实施方案中,所述重链包含SEQ ID NO: 166的氨基酸序列,且所述轻链包含SEQ IDNO: 174的氨基酸序列。在其它的实施方案中,所述重链包含SEQ ID NO: 168的氨基酸序列,且所述轻链包含SEQ ID NO: 170的氨基酸序列。在其它实施方案中,所述重链包含SEQID NO: 168的氨基酸序列,且所述轻链包含SEQ ID NO: 172的氨基酸序列。
在这类的具体实施方案中,当所述犬化抗体(或其抗原结合片段)结合犬白介素-4受体α(IL-4Rα)时,所述抗体结合SEQ ID NO: 154或SEQ ID NO: 155或SEQ ID NO: 156或它们的任意组合的氨基酸序列内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个或更多个氨基酸残基。
因此,本发明还提供了特异性地结合犬白介素-4受体α(IL-4Rα)的分离的哺乳动物抗体或其抗原结合片段(包括犬化抗体或其抗原结合片段),且当结合犬IL-4Rα时,所述抗体结合SEQ ID NO: 125或SEQ ID NO: 126或SEQ ID NO: 127或SEQ ID NO: 128或SEQID NO: 154或SEQ ID NO: 155或SEQ ID NO: 156或SEQ ID NO: 157或SEQ ID NO: 158或SEQ ID NO: 159或SEQ ID NO: 160或SEQ ID NO: 161或SEQ ID NO: 162或它们的任意组合的氨基酸序列内的至少一个氨基酸残基,优选地2-5个氨基酸残基,和/或更优选地3-8个氨基酸残基或更多。在具体实施方案中,所述抗体或其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
本发明还提供了以低于1 X 10-12 M (例如,1 X 10-13 M或更低)的解离常数(Kd)结合犬IL-4Rα的哺乳动物抗体或其抗原结合片段。在具体实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 10-5 M至1 X 10-12 M的解离常数结合犬IL-4Rα。在更具体的实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 10-7 M至1 X 10-11 M的解离常数结合犬IL-4Rα。在还更具体的实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 10-8 M至1 X10-11 M的解离常数结合犬IL-4Rα。在还更具体的实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 10-8 M至1 X 10-10 M的解离常数结合犬IL-4Rα。
本发明还提供了以大于1 X 107 M-1s-1的结合速率(kon)结合犬IL-4Rα的哺乳动物抗体或其抗原结合片段。在具体实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X102 M-1s-1至1 X 107 M-1s-1的结合速率结合犬IL-4Rα。在更具体的实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 103 M-1s-1至1 X 106M-1s-1的结合速率结合犬IL-4Rα。在还更具体的实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 103 M-1s-1至1 X 105M- 1s-1的结合速率结合犬IL-4Rα。在还更具体的实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 104 M-1s-1至1 X 105M-1s-1的结合速率结合犬IL-4Rα。
本发明还提供了以低于1 X 10-7 s-1的解离速率(koff)结合犬IL-4Rα的哺乳动物抗体或其抗原结合片段。在具体实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 10-3s-1至1 X 10-8 s-1的解离速率结合犬IL-4Rα。在更具体的实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 10-4 s-1至1 X 10-7 s-1的解离速率结合犬IL-4Rα。在还更具体的实施方案中,所述哺乳动物抗体或其抗原结合片段以1 X 10-5 s-1至1 X 10-7 s-1的解离速率结合犬IL-4Rα。
在具体实施方案中,本发明的哺乳动物抗体(包括嵌合抗体)阻断犬IL-4与IL-4Rα的结合。在更具体的实施方案中,所述抗体以1 X10-8 M至1 X10-9 M或甚至更低浓度的最小EC50阻断犬IL-4与IL-4Rα的结合。在更具体的实施方案中,所述EC50是5 X10-9 M至5 X10-13 M。在更具体的实施方案中,所述EC50是在5 X10-9 M至5 X10-11 M之间。
在有关的实施方案中,所述哺乳动物抗体或其抗原结合片段消极地减弱(例如,抑制)由与I型和/或II型IL-4受体结合的IL-4和/或IL-13介导的细胞信号传递途径。在具体实施方案中,所述哺乳动物抗体或其抗原结合片段改善动物受试者中有瘙痒的炎症性皮肤疾病,例如,特应性皮炎。在更具体的实施方案中,所述动物受试者是犬。在一个有关的实施方案中,所述动物受试者是猫。
因此,本发明的任意抗体可以表现出1、2、3、4种或所有这些性质,即,前述与犬IL-4Rα的解离常数,前述与犬IL-4Rα的结合的结合速率,前述从抗体-犬IL-4Rα结合复合物解离的解离速率,抑制由与I型和/或II型IL-4受体结合的IL-4和/或IL-13介导的细胞信号传递途径,或改善动物受试者中有瘙痒的炎症性皮肤疾病,例如,特应性皮炎。
如上面指出的,包括前述抗体(和其抗原结合片段)在内的本发明的抗体(和其抗原结合片段)可以是单克隆抗体(和其抗原结合片段)、哺乳动物抗体(和其抗原结合片段),例如,鼠(小鼠)抗体(和其抗原结合片段)、包括犬化鼠抗体(和其抗原结合片段)在内的犬化抗体(和其抗原结合片段),且在某些实施方案中,所述抗体(和其抗原结合片段)是分离的。
本发明还提供了核酸(包括分离的核酸),其编码本发明的犬化抗体的任一个轻链。类似地,本发明提供了分离的核酸,其编码本发明的犬化抗体的任一个重链。
本发明还提供了表达载体,其包含一个或多个本发明的核酸(包括分离的核酸)。本发明还提供了宿主细胞,其包含一个或多个本发明的表达载体。
在具体实施方案中,所述抗体是重组抗体或其抗原结合片段。在有关的实施方案中,所述可变重链结构域和可变轻链结构域通过柔性接头连接以形成单链抗体。
在具体实施方案中,所述抗体或抗原结合片段是Fab片段。
在其它实施方案中,所述抗体或抗原结合片段是Fab' 片段。在其它实施方案中,所述抗体或抗原结合片段是(Fab')2片段。在其它实施方案中,所述抗体或抗原结合片段是双体。在具体实施方案中,所述抗体或抗原结合片段是结构域抗体。在具体实施方案中,所述抗体或抗原结合片段是单结构域抗体。
在具体实施方案中,犬化鼠抗-犬IL-4Rα抗体或抗原结合片段消极地减弱正在治疗的动物受试者(例如,犬)中由与I型和/或II型IL-4受体结合的IL-4和/或IL-13介导的细胞信号传递途径。在更具体的实施方案中,本发明的犬化鼠抗-犬IL-4Rα抗体或抗原结合片段的施用用于改善正在治疗的动物受试者(例如,犬)中的特应性皮炎的一种或多种症状。
本发明还提供了分离的核酸,其编码犬化鼠抗-犬IL-4Rα抗体或其部分。在有关的实施方案中,这样的抗体或抗原结合片段可以用于制备药物以治疗犬受试者中的特应性皮炎。可选地,或者联合地,本发明提供了本发明的任何抗体或抗体片段用于诊断应用的用途。在其它实施方案中,提供了一种试剂盒,其包含本文中公开的任何犬化抗体或抗原结合片段。
在还其它实施方案中,提供了一种包含分离的核酸的表达载体,所述核酸编码本发明的任何犬化鼠抗-犬IL-4Rα抗体或抗原结合片段。本发明也涉及一种宿主细胞,其包含本文描述的任何表达载体。在具体实施方案中,本发明的这些核酸、表达载体或多肽可用在制备抗体的方法中。
本发明还提供了由80个或更少氨基酸残基组成的肽(包括分离的抗原肽),所述肽包含SEQ ID NO: 125或SEQ ID NO: 126或SEQ ID NO: 127或SEQ ID NO: 128或SEQ IDNO: 154或SEQ ID NO: 155或SEQ ID NO: 156或SEQ ID NO: 157或SEQ ID NO: 158或SEQID NO: 159或SEQ ID NO: 160或SEQ ID NO: 161或SEQ ID NO: 162的氨基酸序列。在有关的实施方案中,所述肽(包括分离的抗原肽)由60个或更少氨基酸残基组成,所述肽包含SEQID NO: 125或SEQ ID NO: 126或SEQ ID NO: 127或SEQ ID NO: 128或SEQ ID NO: 154或SEQ ID NO: 155或SEQ ID NO: 156或SEQ ID NO: 157或SEQ ID NO: 158或SEQ ID NO:159或SEQ ID NO: 160或SEQ ID NO: 161或SEQ ID NO: 162的氨基酸序列。在有关的实施方案中,所述肽(包括分离的抗原肽)由10-45个氨基酸残基组成,所述肽包含SEQ ID NO:125或SEQ ID NO: 126或SEQ ID NO: 127或SEQ ID NO: 128或SEQ ID NO: 154或SEQ IDNO: 155或SEQ ID NO: 156或SEQ ID NO: 157或SEQ ID NO: 158或SEQ ID NO: 159或SEQID NO: 160或SEQ ID NO: 161或SEQ ID NO: 162的氨基酸序列。在其它的实施方案中,所述肽(包括分离的抗原肽)由5-25个氨基酸残基组成,所述肽来自或包含SEQ ID NO: 125或SEQ ID NO: 126或SEQ ID NO: 127或SEQ ID NO: 128或SEQ ID NO: 154或SEQ ID NO:155或SEQ ID NO: 156或SEQ ID NO: 157或SEQ ID NO: 158或SEQ ID NO: 159或SEQ IDNO: 160或SEQ ID NO: 161或SEQ ID NO: 162的氨基酸序列。
本发明还提供了由80个或更少氨基酸残基组成的抗原肽(包括分离的肽),所述肽包含这样的氨基酸序列:其与SEQ ID NO: 125或SEQ ID NO: 126或SEQ ID NO: 127或SEQID NO: 128或SEQ ID NO: 154或SEQ ID NO: 155或SEQ ID NO: 156或SEQ ID NO: 157或SEQ ID NO: 158或SEQ ID NO: 159或SEQ ID NO: 160或SEQ ID NO: 161或SEQ ID NO:162的氨基酸序列具有80%、85%、90%、95%或100%同一性且结合本发明的分离的哺乳动物抗体或其抗原结合片段。在有关的实施方案中,所述抗原肽(包括分离的抗原肽)由60个或更少氨基酸残基组成,所述肽包含这样的氨基酸序列:其与SEQ ID NO: 125或SEQ ID NO:126或SEQ ID NO: 127或SEQ ID NO: 128或SEQ ID NO: 154或SEQ ID NO: 155或SEQ IDNO: 156或SEQ ID NO: 157或SEQ ID NO: 158或SEQ ID NO: 159或SEQ ID NO: 160或SEQID NO: 161或SEQ ID NO: 162的氨基酸序列具有80%、85%、90%、95%或100%同一性且结合分离的哺乳动物抗体或其抗原结合片段。在其它实施方案中,所述肽由5-25个氨基酸残基组成,所述肽来自或包含这样的氨基酸序列:其与SEQ ID NO: 125或SEQ ID NO: 126或SEQID NO: 127或SEQ ID NO: 128或SEQ ID NO: 154或SEQ ID NO: 155或SEQ ID NO: 156或SEQ ID NO: 157或SEQ ID NO: 158或SEQ ID NO: 159或SEQ ID NO: 160或SEQ ID NO:161或SEQ ID NO: 162的氨基酸序列具有80%、85%、90%、95%或100%同一性且结合分离的哺乳动物抗体或其抗原结合片段。在具体实施方案中,所述哺乳动物抗体包含4D8的CDR。在其它实施方案中,所述哺乳动物抗体包含11H2的CDR。在其它的实施方案中,所述哺乳动物抗体包含4H3的CDR。在其它的实施方案中,所述哺乳动物抗体包含11B6的CDR。在其它的实施方案中,所述哺乳动物抗体包含2E2的CDR。在其它的实施方案中,所述哺乳动物抗体包含6C12的CDR。
本发明还提供了包含任意前述肽的融合蛋白。在一个具体实施方案中,所述融合蛋白包含这样的抗原肽和非-犬哺乳动物IgG抗体的Fc区。在更具体的实施方案中,所述融合蛋白包含非-犬哺乳动物IgG抗体的Fc区。在某些实施方案中,所述非-犬哺乳动物IgG抗体是鼠IgG。在可选实施方案中,所述非-犬哺乳动物IgG抗体是人IgG。在其它实施方案中,所述非-犬哺乳动物IgG抗体是马IgG。在还其它的实施方案中,所述非-犬哺乳动物IgG抗体是猪IgG。在还其它的实施方案中,所述非-犬哺乳动物IgG抗体是牛IgG。
在具体实施方案中,所述非-犬哺乳动物IgG抗体是IgG1。在其它实施方案中,所述非-犬哺乳动物IgG抗体是IgG2a。在还其它的实施方案中,所述非-犬哺乳动物IgG抗体是IgG3。在还其它的实施方案中,所述非-犬哺乳动物IgG抗体是IgG4。在其它实施方案中,所述融合蛋白包含任意前述抗原肽和麦芽糖结合蛋白。在还其它实施方案中,所述融合蛋白包含任意前述抗原肽和β-半乳糖苷酶。在还其它的实施方案中,所述融合蛋白包含任意前述抗原肽和谷胱甘肽S-转移酶。在还其它实施方案中,所述融合蛋白包含任意前述抗原肽和硫氧还蛋白。在其它的实施方案中,所述融合蛋白包含任意前述抗原肽和Gro EL。在还其它的实施方案中,所述融合蛋白包含任意前述抗原肽和NusA。
本发明还提供了编码本发明的抗原肽和对应融合蛋白的核酸(包括分离的核酸)。本发明还提供了包含这些核酸的表达载体和包含本发明的一种或多种表达载体的宿主细胞。
另外,本发明包括药物组合物,其包含本发明的抗-犬IL-4Rα抗体或其抗原结合片段、来自犬IL-4Rα的抗原肽(包括分离的抗原肽)、包含本发明的来自犬IL-4Rα的抗原肽的融合蛋白、编码本发明的抗原片段和/或融合蛋白的核酸(包括分离的核酸)、包含这样的核酸的表达载体、或它们的任意组合和药学上可接受的载体或稀释剂。
另外,本发明提供了消极地减弱IL-4和/或IL-13的活性的方法,所述方法包括给有此需要的动物受试者施用治疗有效量的这样的药物组合物。在某些实施方案中,所述方法用于治疗犬的特应性皮炎。
具体地,本发明涉及以下技术方案:
1. 一种分离的哺乳动物抗体或其抗原结合片段,其特异性地结合犬白介素-4受体α(IL-4Rα),所述哺乳动物抗体或其抗原结合片段包含三个轻链互补决定区(CDR):CDR轻1 (CDRL1)、CDR轻2 (CDRL2)和CDR轻3 (CDRL3);和三个重链CDR:CDR重1 (CDRH1)、CDR重2(CDRH2)和CDR重3 (CDRH3);
(a) 其中所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 47、SEQ ID NO:54、SEQ ID NO: 48、SEQ ID NO: 52、SEQ ID NO: 55、SEQ ID NO: 49、SEQ ID NO: 50、SEQID NO: 51、SEQ ID NO: 53、SEQ ID NO: 129、SEQ ID NO: 130、SEQ ID NO: 131,SEQ IDNO: 47、SEQ ID NO: 54、SEQ ID NO: 48、SEQ ID NO: 52、SEQ ID NO: 55、SEQ ID NO: 49、SEQ ID NO: 50、SEQ ID NO: 51、SEQ ID NO: 53、SEQ ID NO: 129、SEQ ID NO: 130或SEQID NO: 131的保守修饰的变体,包含规范结构类别1的SEQ ID NO: 47或SEQ ID NO: 54的变体,包含规范结构类别2A的SEQ ID NO: 48、SEQ ID NO: 52或SEQ ID NO: 55的变体,包含规范结构类别4的SEQ ID NO: 49的变体,包含规范结构类别3的SEQ ID NO: 50、SEQ IDNO: 51或SEQ ID NO: 131的变体,和包含规范结构类别6的SEQ ID NO: 53、SEQ ID NO:129或SEQ ID NO: 130的变体;
(b) 其中所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 56、SEQ ID NO:57、SEQ ID NO: 58、SEQ ID NO: 59、SEQ ID NO: 60、SEQ ID NO: 61、SEQ ID NO: 62、SEQID NO: 63、SEQ ID NO: 64、SEQ ID NO: 132、SEQ ID NO: 133、SEQ ID NO: 134,SEQ IDNO: 56、SEQ ID NO: 57、SEQ ID NO: 58、SEQ ID NO: 59、SEQ ID NO: 60、SEQ ID NO: 61、SEQ ID NO: 62、SEQ ID NO: 63、SEQ ID NO: 64、SEQ ID NO: 132、SEQ ID NO: 133或SEQID NO: 134的保守修饰的变体,和SEQ ID NO: 56、SEQ ID NO: 57、SEQ ID NO: 58、SEQ IDNO: 59、SEQ ID NO: 60、SEQ ID NO: 61、SEQ ID NO: 62、SEQ ID NO: 63、SEQ ID NO: 64、SEQ ID NO: 132、SEQ ID NO: 133或SEQ ID NO: 134的变体,其中所述变体包含规范结构类别1;
(c) 其中所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 65、SEQ ID NO:66、SEQ ID NO: 67、SEQ ID NO: 68、SEQ ID NO: 69、SEQ ID NO: 70、SEQ ID NO: 71、SEQID NO: 72、SEQ ID NO: 73、SEQ ID NO: 135、SEQ ID NO: 136、SEQ ID NO: 137、SEQ IDNO: 138、SEQ ID NO: 139,SEQ ID NO: 65、SEQ ID NO: 66、SEQ ID NO: 67、SEQ ID NO:68、SEQ ID NO: 69、SEQ ID NO: 70、SEQ ID NO: 71、SEQ ID NO: 72、SEQ ID NO: 73、SEQID NO: 135、SEQ ID NO: 136、SEQ ID NO: 137、SEQ ID NO: 138或SEQ ID NO: 139的保守修饰的变体,包含规范结构类别1的SEQ ID NO: 65、SEQ ID NO: 66、SEQ ID NO: 67、SEQID NO: 68、SEQ ID NO: 69、SEQ ID NO: 70、SEQ ID NO: 71、SEQ ID NO: 72、SEQ ID NO:73、SEQ ID NO: 135、SEQ ID NO: 136、SEQ ID NO: 137或SEQ ID NO: 139的变体,和包含规范结构类别3的SEQ ID NO: 138的变体;
(d) 其中所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 74、SEQ ID NO:75、SEQ ID NO: 76、SEQ ID NO: 77、SEQ ID NO: 78、SEQ ID NO: 79、SEQ ID NO: 80、SEQID NO: 81、SEQ ID NO: 82、SEQ ID NO: 140、SEQ ID NO: 141、SEQ ID NO: 142、SEQ IDNO: 143,SEQ ID NO: 74、SEQ ID NO: 75、SEQ ID NO: 76、SEQ ID NO: 77、SEQ ID NO:78、SEQ ID NO: 79、SEQ ID NO: 80、SEQ ID NO: 81、SEQ ID NO: 82、SEQ ID NO: 140、SEQID NO: 141、SEQ ID NO: 142或SEQ ID NO: 143的保守修饰的变体,和SEQ ID NO: 74、SEQID NO: 75、SEQ ID NO: 76、SEQ ID NO: 77、SEQ ID NO: 78、SEQ ID NO: 79、SEQ ID NO:80、SEQ ID NO: 81、SEQ ID NO: 82、SEQ ID NO: 140、SEQ ID NO: 141、SEQ ID NO: 142或SEQ ID NO: 143的变体,其中所述变体包含规范结构类别1;
(e) 其中所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 83、SEQ ID NO:84、SEQ ID NO: 91、SEQ ID NO: 85、SEQ ID NO: 88、SEQ ID NO: 89、SEQ ID NO: 87、SEQID NO: 90、SEQ ID NO: 144、SEQ ID NO: 145、SEQ ID NO: 146、SEQ ID NO: 147、SEQ IDNO: 148,SEQ ID NO: 83、SEQ ID NO: 84、SEQ ID NO: 91、SEQ ID NO: 85、SEQ ID NO:88、SEQ ID NO: 89、SEQ ID NO: 87、SEQ ID NO: 90、SEQ ID NO: 144、SEQ ID NO: 145、SEQ ID NO: 146、SEQ ID NO: 147、SEQ ID NO: 148的保守修饰的变体,包含规范结构类别3A的SEQ ID NO: 83、SEQ ID NO: 144、SEQ ID NO: 146、SEQ ID NO: 147或SEQ ID NO:148的变体,包含规范结构类别2A的SEQ ID NO: 84、SEQ ID NO: 91或SEQ ID NO: 145的变体,包含规范结构类别2B的SEQ ID NO: 85、SEQ ID NO: 88或SEQ ID NO: 89的变体,和包含规范结构类别1的SEQ ID NO: 87或SEQ ID NO: 90的变体;
(f) 其中所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 92,SEQ ID NO: 92的保守修饰的变体,包含规范结构类别12的SEQ ID NO: 92的变体,SEQ ID NO: 93,SEQ IDNO: 93的保守修饰的变体,包含规范结构类别7的SEQ ID NO: 93的变体,SEQ ID NO: 94,SEQ ID NO: 96,SEQ ID NO: 149,SEQ ID NO: 151,SEQ ID NO: 94、SEQ ID NO: 96、SEQID NO: 149或SEQ ID NO: 151的保守修饰的变体,包含规范结构类别15的SEQ ID NO: 94、SEQ ID NO: 96、SEQ ID NO: 149或SEQ ID NO: 151的变体,SEQ ID NO: 95,SEQ ID NO:95的保守修饰的变体或包含规范结构类别11的SEQ ID NO: 95的变体,SEQ ID NO: 97,SEQID NO: 100,SEQ ID NO: 97或SEQ ID NO: 100的保守修饰的变体,包含规范结构类别6的SEQ ID NO: 97或SEQ ID NO: 100的变体,SEQ ID NO: 98,SEQ ID NO: 98的保守修饰的变体,包含规范结构类别4的SEQ ID NO: 98的变体,SEQ ID NO: 99,SEQ ID NO: 153,SEQ IDNO: 99或SEQ ID NO: 153的保守修饰的变体,包含规范结构类别13的SEQ ID NO: 99或SEQID NO: 153的变体,SEQ ID NO: 150,SEQ ID NO: 150的保守修饰的变体,包含规范结构类别10的SEQ ID NO: 150的变体,SEQ ID NO: 152,SEQ ID NO: 152的保守修饰的变体和包含规范结构类别9的SEQ ID NO: 152的变体;其中所述抗体及其抗原结合片段结合犬IL-4Rα。
2. 技术方案1所述的分离的哺乳动物抗体或抗原结合片段,
(a) 其中所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 54、SEQ ID NO:129、SEQ ID NO: 130、SEQ ID NO: 131,SEQ ID NO: 54、SEQ ID NO: 129、SEQ ID NO: 130或SEQ ID NO: 131的保守修饰的变体,包含规范结构类别1的SEQ ID NO: 54的变体,包含规范结构类别3的SEQ ID NO: 131的变体,和包含规范结构类别6的SEQ ID NO: 129或SEQID NO: 130的变体;
(b) 其中所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 60、SEQ ID NO:63、SEQ ID NO: 132、SEQ ID NO: 133、SEQ ID NO: 134,SEQ ID NO: 60、SEQ ID NO: 63、SEQ ID NO: 132、SEQ ID NO: 133或SEQ ID NO: 134的保守修饰的变体,和SEQ ID NO:60、SEQ ID NO: 63、SEQ ID NO: 132、SEQ ID NO: 133或SEQ ID NO: 134的变体,其中所述变体包含规范结构类别1;
(c) 其中所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 72、SEQ ID NO:135、SEQ ID NO: 136、SEQ ID NO: 137、SEQ ID NO: 138、SEQ ID NO: 139,SEQ ID NO:72、SEQ ID NO: 135、SEQ ID NO: 136、SEQ ID NO: 137、SEQ ID NO: 138或SEQ ID NO:139的保守修饰的变体,包含规范结构类别1的SEQ ID NO: 72、SEQ ID NO: 135、SEQ IDNO: 136、SEQ ID NO: 137或SEQ ID NO: 139的变体,和包含规范结构类别3的SEQ ID NO:138的变体;
(d) 其中所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 81、SEQ ID NO:140、SEQ ID NO: 141、SEQ ID NO: 142、SEQ ID NO: 143,SEQ ID NO: 81、SEQ ID NO:140、SEQ ID NO: 141、SEQ ID NO: 142或SEQ ID NO: 143的保守修饰的变体,和SEQ IDNO: 81、SEQ ID NO: 140、SEQ ID NO: 141、SEQ ID NO: 142或SEQ ID NO: 143的变体,其中所述变体包含规范结构类别1;
(e) 其中所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 90、SEQ ID NO:144、SEQ ID NO: 145、SEQ ID NO: 146、SEQ ID NO: 147、SEQ ID NO: 148,SEQ ID NO:90、SEQ ID NO: 144、SEQ ID NO: 145、SEQ ID NO: 146、SEQ ID NO: 147、SEQ ID NO: 148的保守修饰的变体,包含规范结构类别3A的SEQ ID NO: 144、SEQ ID NO: 146、SEQ ID NO:147或SEQ ID NO: 148的变体,包含规范结构类别2A的SEQ ID NO: 145的变体,和包含规范结构类别1的SEQ ID NO: 90的变体;
(f) 其中所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 149、SEQ ID NO:151,SEQ ID NO: 149或SEQ ID NO: 151的保守修饰的变体,包含规范结构类别15的SEQ IDNO: 149或SEQ ID NO: 151的变体,SEQ ID NO: 99,SEQ ID NO: 153,SEQ ID NO: 99或SEQID NO: 153的保守修饰的变体,包含规范结构类别13的SEQ ID NO: 99或SEQ ID NO: 153的变体,SEQ ID NO: 150,SEQ ID NO: 150的保守修饰的变体,包含规范结构类别10的SEQID NO: 150的变体,SEQ ID NO: 152,SEQ ID NO: 152的保守修饰的变体和包含规范结构类别9的SEQ ID NO: 152的变体;
其中所述抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
3. 技术方案2所述的分离的哺乳动物抗体或抗原结合片段,
(a) 其中所述CDRL1包含选自以下的氨基酸序列:SEQ ID NO: 129、SEQ ID NO:129的保守修饰的变体和包含规范结构类别6的SEQ ID NO: 129的变体;
(b) 其中所述CDRL2包含选自以下的氨基酸序列:SEQ ID NO: 132、SEQ ID NO:132的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 132的变体;
(c) 其中所述CDRL3包含选自以下的氨基酸序列:SEQ ID NO: 135、SEQ ID NO:135的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 135的变体;
(d) 其中所述CDRH1包含选自以下的氨基酸序列:SEQ ID NO: 140、SEQ ID NO:140的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 140的变体;
(e) 其中所述CDRH2包含选自以下的氨基酸序列:SEQ ID NO: 144、SEQ ID NO:144的保守修饰的变体和包含规范结构类别3A的SEQ ID NO: 144的变体;
(f) 其中所述CDRH3包含选自以下的氨基酸序列:SEQ ID NO: 149、SEQ ID NO:149的保守修饰的变体和包含规范结构类别15的SEQ ID NO: 149的变体;且
其中所述抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
4. 技术方案2所述的分离的哺乳动物抗体或抗原结合片段,
(a) 其中所述CDRL1选自以下的氨基酸序列:SEQ ID NO: 130、SEQ ID NO: 130的保守修饰的变体和包含规范结构类别6的SEQ ID NO: 130的变体;
(b) 其中所述CDRL2选自以下的氨基酸序列:SEQ ID NO: 133、SEQ ID NO: 133的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 133的变体;
(c) 其中所述CDRL3选自以下的氨基酸序列:SEQ ID NO: 136、SEQ ID NO: 136的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 136的变体;
(d) 其中所述CDRH1选自以下的氨基酸序列:SEQ ID NO: 141、SEQ ID NO: 141的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 141的变体;
(e) 其中所述CDRH2选自以下的氨基酸序列:SEQ ID NO: 145、SEQ ID NO: 145的保守修饰的变体和包含规范结构类别2A的SEQ ID NO: 145的变体;
(f) 其中所述CDRH3选自以下的氨基酸序列:SEQ ID NO: 150、SEQ ID NO: 150的保守修饰的变体和包含规范结构类别10的SEQ ID NO: 150的变体;且
其中所述抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
5. 技术方案2所述的分离的哺乳动物抗体或抗原结合片段,
(a) 其中所述CDRL1选自以下的氨基酸序列:SEQ ID NO: 129、SEQ ID NO: 129的保守修饰的变体和包含规范结构类别6的SEQ ID NO: 129的变体;
(b) 其中所述CDRL2选自以下的氨基酸序列:SEQ ID NO: 134、SEQ ID NO: 134的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 134的变体;
(c) 其中所述CDRL3选自以下的氨基酸序列:SEQ ID NO: 137、SEQ ID NO: 137的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 137的变体;
(d) 其中所述CDRH1选自以下的氨基酸序列:SEQ ID NO: 140、SEQ ID NO: 140的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 140的变体;
(e) 其中所述CDRH2选自以下的氨基酸序列:SEQ ID NO: 146、SEQ ID NO: 146的保守修饰的变体和包含规范结构类别3A的SEQ ID NO: 146的变体;
(f) 其中所述CDRH3选自以下的氨基酸序列:SEQ ID NO: 151、SEQ ID NO: 151的保守修饰的变体和包含规范结构类别15的SEQ ID NO: 151的变体;且
其中所述抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
6. 技术方案2所述的分离的哺乳动物抗体或抗原结合片段,
(a) 其中所述CDRL1选自以下的氨基酸序列:SEQ ID NO: 131、SEQ ID NO: 131的保守修饰的变体和包含规范结构类别3的SEQ ID NO: 131的变体;
(b) 其中所述CDRL2选自以下的氨基酸序列:SEQ ID NO: 60、SEQ ID NO: 60的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 60的变体;
(c) 其中所述CDRL3选自以下的氨基酸序列:SEQ ID NO: 138、SEQ ID NO: 138的保守修饰的变体和包含规范结构类别3的SEQ ID NO: 138的变体;
(d) 其中所述CDRH1选自以下的氨基酸序列:SEQ ID NO: 142、SEQ ID NO: 142的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 142的变体;
(e) 其中所述CDRH2选自以下的氨基酸序列:SEQ ID NO: 147、SEQ ID NO: 147的保守修饰的变体和包含规范结构类别3A的SEQ ID NO: 147的变体;
(f) 其中所述CDRH3选自以下的氨基酸序列:SEQ ID NO: 152、SEQ ID NO: 152的保守修饰的变体和包含规范结构类别9的SEQ ID NO: 152的变体;且
其中所述抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
7. 技术方案2所述的分离的哺乳动物抗体或抗原结合片段,
(a) 其中所述CDRL1选自以下的氨基酸序列:SEQ ID NO: 129、SEQ ID NO: 129的保守修饰的变体和包含规范结构类别6的SEQ ID NO: 129的变体;
(b) 其中所述CDRL2选自以下的氨基酸序列:SEQ ID NO: 132、SEQ ID NO: 132的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 132的变体;
(c) 其中所述CDRL3选自以下的氨基酸序列:SEQ ID NO: 139、SEQ ID NO: 139的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 139的变体;
(d) 其中所述CDRH1选自以下的氨基酸序列:SEQ ID NO: 143、SEQ ID NO: 143的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 143的变体;
(e) 其中所述CDRH2选自以下的氨基酸序列:SEQ ID NO: 148、SEQ ID NO: 148的保守修饰的变体和包含规范结构类别3A的SEQ ID NO: 148的变体;
(f) 其中所述CDRH3选自以下的氨基酸序列:SEQ ID NO: 153、SEQ ID NO: 153的保守修饰的变体和包含规范结构类别13的SEQ ID NO: 153的变体;且
其中所述抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
8. 技术方案2所述的分离的哺乳动物抗体或抗原结合片段,
(a) 其中所述CDRL1选自以下的氨基酸序列:SEQ ID NO: 54、SEQ ID NO: 54的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 54的变体;
(b) 其中所述CDRL2选自以下的氨基酸序列:SEQ ID NO: 63、SEQ ID NO: 63的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 63的变体;
(c) 其中所述CDRL3选自以下的氨基酸序列:SEQ ID NO: 72、SEQ ID NO: 72的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 72的变体;
(d) 其中所述CDRH1选自以下的氨基酸序列:SEQ ID NO: 81、SEQ ID NO: 81的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 81的变体;
(e) 其中所述CDRH2选自以下的氨基酸序列:SEQ ID NO: 90、SEQ ID NO: 90的保守修饰的变体和包含规范结构类别1的SEQ ID NO: 90的变体;
(f) 其中所述CDRH3选自以下的氨基酸序列:SEQ ID NO: 99、SEQ ID NO: 99的保守修饰的变体和包含规范结构类别13的SEQ ID NO: 99的变体;且
其中所述抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
9. 技术方案1、2、3、4、5、6、7或8所述的分离的哺乳动物抗体或其抗原结合片段,其中所述哺乳动物抗体是鼠抗体。
10. 技术方案1、2、3、4、5、6、7或8所述的分离的哺乳动物抗体或其抗原结合片段,它为犬化抗体或其犬化抗原结合片段。
11. 技术方案10所述的犬化抗体或其犬化抗原结合片段,它包含铰链区,所述铰链区包含选自SEQ ID NO: 101、SEQ ID NO: 102、SEQ ID NO: 103和SEQ ID NO: 104的氨基酸序列。
12. 技术方案6所述的分离的哺乳动物抗体或其抗原结合片段,它是犬化抗体或其犬化抗原结合片段。
13. 技术方案12所述的犬化抗体或其抗原结合片段,它包含含有选自SEQ ID NO:164、SEQ ID NO: 166和SEQ ID NO: 168的氨基酸序列的重链、含有选自SEQ ID NO: 170、SEQ ID NO: 172和SEQ ID NO: 174的氨基酸序列的轻链或所述重链与所述轻链的组合。
14. 技术方案13所述的犬化抗体或其抗原结合片段,它包含由选自SEQ ID NO:163、SEQ ID NO: 165和SEQ ID NO: 167的核苷酸序列编码的重链、由选自SEQ ID NO:169、SEQ ID NO: 171和SEQ ID NO: 173的核苷酸序列编码的轻链或所述重链与所述轻链的组合。
15. 分离的特异性地结合犬白介素-4受体α(IL-4Rα)的哺乳动物抗体或其抗原结合片段,其中当与犬IL-4Rα结合时,所述抗体结合SEQ ID NO: 125、SEQ ID NO: 126、SEQID NO: 127、SEQ ID NO: 128、SEQ ID NO: 154、SEQ ID NO: 155、SEQ ID NO: 156、SEQ IDNO: 157、SEQ ID NO: 158、SEQ ID NO: 159、SEQ ID NO: 160、SEQ ID NO: 161、SEQ IDNO: 162或它们的任意组合的氨基酸序列内的至少一个氨基酸残基;其中所述抗体或其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
16. 技术方案1、2、3、4、5、6、7或8所述的分离的哺乳动物抗体或其抗原结合片段、或技术方案10、11、12、13或14所述的犬化抗体或其抗原结合片段,其中当结合犬IL-4Rα时,所述哺乳动物抗体或其抗原结合片段或所述犬化抗体或其抗原结合片段结合SEQ ID NO:125、SEQ ID NO: 126、SEQ ID NO: 127、SEQ ID NO: 128、SEQ ID NO: 154、SEQ ID NO:155、SEQ ID NO: 156、SEQ ID NO: 157、SEQ ID NO: 158、SEQ ID NO: 159、SEQ ID NO:160、SEQ ID NO: 161、SEQ ID NO: 162或它们的任意组合的氨基酸序列内的至少一个氨基酸残基;其中所述抗体或其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
17. 技术方案6或7所述的分离的哺乳动物抗体或其抗原结合片段、或技术方案12、13或14所述的犬化抗体或其抗原结合片段,其中当结合犬IL-4Rα时,所述哺乳动物抗体或其抗原结合片段或所述犬化抗体或其抗原结合片段结合选自SEQ ID NO: 154、SEQ IDNO: 155、SEQ ID NO: 156、SEQ ID NO: 159、SEQ ID NO: 160、SEQ ID NO: 161和它们的任意组合的氨基酸序列内的至少一个氨基酸残基;且其中所述抗体或其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
18. 技术方案1、2、3、4、5、6、7、8、15、16或17所述的哺乳动物抗体或其抗原结合片段或技术方案10、11、12、13、14、16或17所述的犬化抗体或其抗原结合片段,其中所述哺乳动物抗体或其抗原结合片段或所述犬化抗体或其抗原结合片段表现出1、2、3、4、5、6种或所有下述性质:
(i)以1 X 10-5 M至1 X 10-12 M的解离常数(Kd)结合犬IL-4Rα;
(ii)以1 X 102 M-1s-1至1 X 107 M-1s-1的结合速率(kon)结合犬IL-4Rα;
(iii)以1 X 10-3 s-1至1 X 10-8 s-1的解离速率(koff)结合犬IL-4Rα;
(iv)阻断IL-4与I型IL-4受体的结合;
(v)阻断IL-13与I型IL-4受体的结合;
(vi)阻断IL-4与II型IL-4受体的结合;和
(vii)阻断IL-13与II型IL-4受体的结合。
19. 一种犬化单克隆抗体或其抗原结合片段,其与技术方案1、2、3、4、5、6、7、8、15、16、17或18所述的一种或多种哺乳动物抗体或其抗原结合片段、或技术方案10、11、12、13、14、16、17或18所述的犬化抗体或其抗原结合片段交叉竞争对犬IL-4Rα的结合;其中所述犬化单克隆抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬IL-4的结合。
20. 一种分离的核酸,其编码技术方案1、2、3、4、5、6、7、8、15、16、17或18所述的哺乳动物抗体的轻链或其抗原结合片段、技术方案9所述的鼠抗体或其抗原结合片段、或技术方案10、11、12、13、14、16、17、18或19所述的犬化抗体或其抗原结合片段。
21. 一种分离的核酸,它编码技术方案1、2、3、4、5、6、7、8、15、16、17或18所述的哺乳动物抗体的重链或其抗原结合片段、技术方案9所述的鼠抗体或其抗原结合片段、或技术方案10、11、12、13、14、16、17、18或19所述的犬化抗体或其抗原结合片段。
22. 技术方案20或21所述的分离的核酸,所述核酸编码选自SEQ ID NO: 47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、87、88、89、90、91、92、93、94、95、96、97、98、99、100、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、140、141、142、143、144、145、146、147、148、149、150、151、152和153的一个或多个氨基酸序列。
23. 一种表达载体,其包含技术方案20、21或22所述的分离的核酸。
24. 一种宿主细胞,其包含技术方案23所述的表达载体。
25. 一种分离的肽,其包含5-25个氨基酸残基,所述肽与选自SEQ ID NO: 125、SEQ ID NO: 126、SEQ ID NO: 127、SEQ ID NO: 128、SEQ ID NO: 154、SEQ ID NO: 155、SEQ ID NO: 156、SEQ ID NO: 157、SEQ ID NO: 158、SEQ ID NO: 159、SEQ ID NO: 160、SEQ ID NO: 161、SEQ ID NO: 162的氨基酸序列具有95%同一性且结合技术方案1、2、3、4、5、6、7、8、15、16、17或18所述的分离的哺乳动物抗体或其结合片段、或技术方案10、11、12、13、14、16、17、18或19所述的犬化抗体或其抗原结合片段。
26. 一种融合蛋白,其包含技术方案25所述的肽。
27. 技术方案26所述的融合蛋白,所述融合蛋白还包含非-犬哺乳动物IgG的Fc区。
28. 一种分离的核酸,其编码技术方案25所述的分离的肽、技术方案26所述的融合蛋白或技术方案27所述的融合蛋白。
29. 一种表达载体,其包含技术方案28所述的分离的核酸。
30. 一种宿主细胞,其包含技术方案29所述的表达载体。
31. 药物组合物,其包含技术方案10、11、12、13、14、16、17、18或19所述的犬化抗体、或技术方案20、21、22或28所述的核酸、技术方案23或29所述的表达载体、技术方案25所述的分离的肽、技术方案26或27所述的融合蛋白或它们的任意组合和药学上可接受的载体或稀释剂。
32. 一种降低免疫细胞的活性的方法,所述方法包括给有此需要的受试者施用治疗有效量的技术方案31所述的药物组合物。
33. 技术方案32所述的方法,其中所述方法用于:
(i) 治疗特应性皮炎;或
(ii) 治疗哮喘;或
(iii) 治疗特应性皮炎和治疗哮喘。
通过参考以下附图说明和详细描述会更好地理解本发明的这些和其它方面。
附图说明
图1显示了经纯化的小鼠抗-犬IL-4Rα单克隆抗体(mAb)对犬IL-4Rα的细胞外结构域的反应性。针对它们与犬IL-4Rα的细胞外结构域的结合,通过ELISA测试了多种小鼠mAb。测试的mAb被命名为:1A3(●)、1A9(■)、1B12 (▲)、10C12(▼)、10F2(◆)、10E10(●)、10G8(■)、11B6(▲)、11D3(▼)和对照抗体(◆)。横坐标描绘了加入的mAB (nM)的对数浓度,纵坐标描绘了通过ELISA得到的光密度。
图2A显示了使用基于细胞的CHO-cIL-4R α 结合测定,犬IL-4与在CHO细胞表面上表达的犬IL-4Rα的结合的剂量响应曲线。横坐标描绘了加入的IL-4的对数浓度,纵坐标描绘了采用FACS的平均荧光强度(MFI)。
图2B描绘了小鼠抗-犬IL-4Rα单克隆抗体(mAb)对CHO-cIL-4R α 的剂量响应曲线:11B6(●)、4D8(■)、4H3(▲)、2E2(▼)、11H2(◆)和6C12(о)。横坐标描绘了加入的mAb (nM)的对数浓度,纵坐标描绘了采用FACS的平均荧光强度(MFI)。在下面表2中提供了每种抗体的半数最大有效浓度(EC50)。
图3A和3B显示了接连地稀释的各种小鼠抗-犬IL-4Rα单克隆抗体(mAb)的添加对IL-4与基于细胞的CHO-cIL-4R α 的结合的影响结果。图3A描绘了单克隆抗体11B6(◆)、4D8(■)、4H3(▲)、2E2(▼)和11H2(◆)单独地阻断IL-4与基于细胞的CHO-cIL-4R α 的结合的浓度依赖性能力。图3B描绘了单克隆抗体11H2(◆)和6C12(■)单独地阻断IL-4与基于细胞的CHO-cIL-4R α 的结合的浓度依赖性能力。横坐标描绘了加入的mAb (nM)的对数浓度,纵坐标描绘了采用FACS的平均荧光强度(MFI)。
图4描绘了通过ELISA评价的嵌合的和犬化单克隆抗体与犬IL-4Rα的结合。犬化单克隆抗体对犬IL-4受体α链的剂量依赖性反应性如下:4H3 M-C (●);2G9 M-C (◇);c4H3H1-L1 (■);c4H3 H2-L2(▲);c4H3 H3-L3 (о)。
具体实施方式
现在许多临床试验中研究了多种用于治疗人AD的方案[综述在Malajian等人,New pathogenic and therapeutic paradigms in atopic dermatitis Cytokine, (2014)]。这些方案中的一些的目的在于干扰一个或多个信号传递分子/事件,所述信号传递分子/事件导致Th2细胞的发育和活化。在该领域中的一线研究包括用于阻断Th2途径的关键白介素驱动剂的作用的方案。基于以下观察结果:AD主要是Th2控制的疾病,并且积累的数据支持IL-4和IL-13的联合作用作为Th2细胞发育的关键驱动剂的关键作用,并且基于这样的数据:其指示IL-4受体α链是来自两种细胞因子的信号传递的必要受体,本发明描述了这样的单克隆抗体的制备和表征:其阻断犬IL-4和犬IL-13与I型和II型IL-4受体的结合,并随后抑制来自犬IL-4和IL-13的信号传递。这些抗体在如本文中公开的伴侣动物的特应性皮炎和其它疾病的治疗中具有效用。
缩写
贯穿本发明的详细描述和实例,将使用以下缩写:
ADCC 抗体依赖性细胞毒作用
CDC 依赖补体的细胞毒性
CDR 在免疫球蛋白可变区中的互补性决定区,使用Kabat编号系统定义
CHO 中国仓鼠卵巢
EC50 导致50%效力或结合的浓度
ELISA 酶联免疫吸附测定
FR 抗体框架区:不包括CDR区域的免疫球蛋白可变区。
HRP 辣根过氧化物酶
IFN 干扰素
IC50 导致50%抑制的浓度
IgG 免疫球蛋白G
Kabat 由Elvin A. Kabat [Sequences of Proteins of Immunological
Interest, 第5版Public Health Service, National Institutes
of Health, Bethesda, Md. (1991)]开辟的免疫球蛋白比对和编号系统
mAb 单克隆抗体(也表示为Mab或MAb)
MES 2-(N-吗啉代)乙磺酸
MOA 作用机理
NHS 正常人血清
PCR 聚合酶链式反应
PK 药代动力学
SEB 葡萄球菌属肠毒素B
TT 破伤风类毒素
V区域 在不同抗体之间在序列上可变的IgG链区段。它延伸至轻链中的Kabat
残基109和重链中的Kabat残基113。
VH 免疫球蛋白重链可变区
VL 免疫球蛋白轻链可变区
VK 免疫球蛋白κ轻链可变区。
定义
定义
为了可以更容易地理解本发明,下面特别地定义了某些技术和科学术语。除非在本文件别处特别地定义,本文中使用的所有其它技术和科学术语具有本发明所属领域的普通技术人员通常理解的含义。
如本文(包括所附技术方案书)中使用的,词语的单数形式诸如“一个/种”和“所述”包括它们的对应复数形式,除非上下文另外清楚地指明。
“活化”在应用于细胞或受体时表示用配体活化或处理细胞或受体,除非上下文另外指出或明确地指出。“配体”包括天然的和合成的配体,例如,细胞因子、细胞因子变体、类似物、突变蛋白和从抗体衍生出的结合化合物。“配体”也包括小分子,例如,细胞因子的肽模拟物和抗体的肽模拟物。“活化”可以表示被内部机制以及被外部或环境因子调节的细胞活化。
分子的“活性”可以描述或表示分子与配体或与受体的结合,表示催化活性;表示刺激基因表达或细胞信号传递、分化或成熟的能力;表示抗原活性,表示其它分子的活性的调节等。分子的“活性”还可以表示调节或维持细胞-与-细胞相互作用(例如,粘附)的活性,或维持细胞的结构(例如,细胞膜或细胞骨架)的活性。“活性”也可以是指比活性,例如,[催化活性]/[mg蛋白]或[免疫学活性]/[mg蛋白],在生物区室中的浓度,等。“活性”可以表示先天性或适应性免疫系统的组分的调节。
“施用”和“处理”当应用于动物(例如,犬实验受试者)、细胞、组织、器官或生物流体时表示外源药物、治疗剂、诊断剂或组合物与动物(例如,犬受试者、细胞、组织、器官或生物流体)的接触。细胞的处理包括试剂与细胞的接触,以及试剂与流体的接触,其中流体与细胞发生接触。“施用”和“处理”也指用试剂、诊断剂、结合化合物或用另一种细胞体外和先体内后体外处理(例如,细胞)。术语”受试者”包括任何生物体,优选动物,更优选哺乳动物(例如,犬、猫或人),且最优选犬。
本文中使用的“用另一个氨基酸残基置换抗体的氨基酸序列中的一个氨基酸残基”例如等同于“用另一个氨基酸残基替换一个氨基酸残基”,且表示在所述氨基酸序列的特定位置处的特定氨基酸残基已经被一个不同的氨基酸残基替换(或置换)。这样的置换可以特别地设计,即,通过例如重组DNA技术故意用丝氨酸替换氨基酸序列的特定位置处的丙氨酸。可选地,通过更多天然选择过程,例如,基于细胞产生的抗体结合该抗原上的给定区域(例如,含有表位或其部分的区域,和/或对于抗体而言,包含特定CDR,其保留与它正在替换的CDR相同的规范结构)的能力,可以用一个或多个氨基酸残基替换抗体的一个特定氨基酸残基或氨基酸残基串。这样的置换/替换可以产生“变体”CDR和/或变体抗体。
“治疗”或“处理”是指给犬受试者或患者在内部或在外部施用治疗剂,诸如含有本发明的任何抗体或抗原结合片段的组合物,所述犬受试者或患者具有一种或多种疾病症状或疑似具有疾病,所述药剂对所述疾病症状或疾病具有治疗活性。
通常地,所述药剂以有效地减轻和/或改善受治疗的受试者或群体中的一种或多种疾病症状的量施用,无论是通过诱导这样的症状的消退还是在任何临床上可测量的程度上抑制这样的症状的进展。有效地减轻任何具体疾病症状的治疗剂的量(也被称作“治疗有效量”)可以随因素诸如患者(例如,犬)的疾病状态、年龄和重量以及药物组合物在受试者中引起期望应答的能力而变化。疾病症状是否已经减轻或改善,可以通过兽医或其它熟练的健康护理提供者通常地使用的任何临床测量来评估,以评估该症状的严重程度或进展状态。尽管本发明的一个实施方案(例如,治疗方法或制成品)可能不会有效地减轻每个受试者中的靶疾病症状,但是它会减轻统计上显著数目的受试者中的靶疾病症状,如通过本领域已知的任何统计检验来确定的,诸如Student's t-检验、chi2-检验、根据Mann和Whitney的U-检验、Kruskal-Wallis检验(H-检验)、Jonckheere-Terpstra-检验和Wilcoxon-检验。
“治疗”当应用于人、兽医(例如,犬)或研究受试者时表示治疗性处理以及研究和诊断应用。“治疗”当应用于人、兽医(例如,犬)或研究受试者或细胞、组织或器官时包括本发明的抗体或抗原结合片段与犬或其它动物受试者、细胞、组织、生理学隔室或生理学流体的接触。
本文中使用的术语“犬”包括所有家养狗、家犬(Canis lupus familiaris 或Canis familiaris),除非另外指出。
本文中使用的术语“猫科动物”表示猫科的任何成员。该科的成员包括野生的、动物园的和家养的成员,诸如猫亚科的任何成员,例如,猫、狮子、老虎、美洲狮、美洲虎、豹、雪豹、黑豹、北美山狮、猎豹、猞猁、山猫、野猫或它们的任何杂交种。猫也包括家养猫、纯种的和/或杂种的伴侣猫、展示猫、实验室猫、克隆猫以及野生的或未驯服的猫。
本文中使用的术语“犬框架”表示除了高变区残基(在本文中被定义为CDR残基)以外的犬抗体重链和轻链的氨基酸序列。关于犬化抗体,在大多数实施方案中,在两条链中天然犬CDR的氨基酸序列被对应的外来CDR (例如,来自小鼠抗体的那些)替代。任选地,犬抗体的重链和/或轻链可以含有一些外来的非-CDR残基,例如,从而维持在犬抗体内的外来CDR的构象和/或改变Fc功能,如下面具体说明的。
已经发现犬IL-4Rα包含SEQ ID NO: 2的氨基酸序列[SEQ ID NO: 4,没有信号序列]。在一个具体实施方案中,犬IL-4Rα由包含SEQ ID NO: 1的核苷酸序列[SEQ ID NO: 3,没有信号序列]的核酸编码。犬IL-4Rα序列可能差别在于具有,例如,在非保守区中的保守变异,但是犬IL-4Rα具有与包含SEQ ID NO: 2的氨基酸序列[SEQ ID NO: 4,没有信号序列]的犬IL-4Rα基本上相同的生物学功能。
细胞因子IL-4和IL-13已经牵涉进人类和动物的多种变态反应性疾病(包括哮喘和特应性皮炎)的发病机制中。因为IL-4受体α链是来自这些细胞因子中的任一种的信号传递的必要受体,本发明描述了这样的单克隆抗体的制备和表征:其阻断犬IL-4和犬IL-13与IL-4Rα的结合,并由此抑制来自两种犬IL-4和IL-13的信号传递。这些抗体因此在本文中公开的伴侣动物的特应性皮炎和其它疾病的治疗中具有效用。另外,犬IL-4Rα的生物学功能可能是具有例如在本发明的公开内容的抗体所特异性地结合的细胞外结构域中的表位。
一种具体犬IL-4Rα氨基酸序列通常与包含SEQ ID NO: 4的氨基酸序列的犬IL-4Rα具有至少90%同一性。在某些情况下,犬IL-4Rα可以与包含SEQ ID NO: 4的氨基酸序列的犬IL-4Rα具有至少95%或甚至至少96%、97%、98%或99%同一性。在某些实施方案中,犬IL-4Rα氨基酸序列将表现出与包含SEQ ID NO: 4的氨基酸序列的犬IL-4Rα的不超过10个氨基酸差异。在某些实施方案中,所述犬IL-4Rα氨基酸序列将表现出与包含SEQ ID NO: 4的氨基酸序列的犬IL-4Rα的不超过5个或甚至不超过4、3、2或1个氨基酸差异。可以如下文所述确定同一性百分比。
术语“免疫应答”表示例如淋巴细胞、抗原呈递细胞、吞噬细胞、粒细胞和由以上细胞产生的可溶性大分子或肝(包括抗体、细胞因子和补体)的作用,所述作用导致对癌细胞、被病原体感染的细胞或组织、或侵入病原体的选择性损伤、破坏、或从哺乳动物身体(例如,犬身体)消除。
抗-犬IL-4Rα抗体
本发明提供了分离的结合犬IL-4Rα的抗体(特别是鼠抗-犬IL-4Rα抗体和其犬化抗体)或其抗原结合片段以及这样的抗体或其片段的用途。在具体实施方案中,提供了来自鼠抗-犬IL-4Rα抗体的鼠抗-犬IL-4RαCDR,其已经被证实会结合犬IL-4Rα和阻断犬IL-4Rα与它的配体犬IL-4或IL-13中的一种或多种的结合。这些CDR可以插入犬抗体的经修饰的犬框架中以产生犬化鼠抗-犬IL-4Rα抗体。
本文中使用的“抗-犬IL-4Rα抗体”表示这样的抗体:其针对犬IL-4Rα产生(例如,在哺乳动物诸如小鼠或兔中)且特异性地结合犬IL-4Rα。“特异性地结合犬IL-4Rα”和特别是犬IL-4Rα的抗体或“特异性地结合包含犬IL-4Rα的氨基酸序列的多肽”的抗体是这样的抗体:其表现出与其它抗原相比对犬IL-4Rα的优先结合,但是该特异性不需要绝对结合特异性。在以下情况下认为抗-犬IL-4Rα抗体是对犬IL-4Rα“特异性的”:如果它的结合是样品中犬IL-4Rα的存在的确定因素,或如果它能够改变犬IL-4Rα的活性而不会不适当地干扰犬样品中的其它分子的活性,例如不会产生不希望的结果诸如在诊断背景下的假阳性或在治疗背景下的副作用。抗-犬IL-4Rα抗体所需的特异性程度可能取决于抗体的预期用途,且至少由它就用于预期目的而言的适合性来限定。预见到的方法的抗体或从抗体的抗原结合位点衍生出的结合化合物与它的抗原或其变体或突变蛋白的结合亲和力是与任意其它抗原的亲和力的至少2倍,优选地至少10倍,更优选地至少20倍,且最优选地至少100倍。
如本文使用的,将视本文中使用的抗体特异性地结合包含给定抗原序列的多肽(在该情况下,犬IL-4Rα的氨基酸序列的一部分):如果它结合包含犬IL-4Rα的氨基酸序列的该部分的多肽,但是不结合缺少犬IL-4Rα的序列的该部分的其它犬蛋白。例如,特异性地结合包含犬IL-4Rα的多肽的抗体可以结合FLAG®-标记的犬IL-4Rα形式,但是不会结合其它FLAG®-标记的犬蛋白。在以下情况下,抗体或从抗体的抗原结合位点衍生出的结合化合物会“特异性地”结合它的犬抗原或其变体或突变蛋白:当它对犬抗原或其变体或突变蛋白的亲和力是它对测试的任意其它犬抗原的亲和力的至少10倍,更优选地至少20倍,且甚至更优选地至少100倍时。
本文中使用的术语“抗体”表示表现出期望的生物活性的任意形式的抗体。因而,它以最宽的含义使用,并具体地涵盖,但不限于,单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如,双特异性抗体)、犬化抗体、全犬抗体、嵌合抗体和骆驼源化的单结构域抗体。“亲本抗体”是在为了预期用途修饰抗体(诸如用作犬治疗性抗体的抗体的犬化)之前通过将免疫系统暴露于抗原而得到的抗体。
如本文中使用的,除非另有说明,否则“抗体片段”或“抗原结合片段”表示抗体的抗原结合片段,即保留特异性地结合被全长抗体结合的抗原的能力的抗体片段,例如保留一个或多个CDR区域的片段。抗原结合片段的例子包括、但不限于Fab、Fab'、F(ab')2和Fv片段;双体;直链抗体;单链抗体分子,例如,sc-Fv;纳米抗体(nanobodies)和由多个抗体片段形成的多特异性抗体。
“Fab片段”包含一个轻链以及一个重链的CH1和可变区。Fab分子的重链不可与另一个重链分子形成二硫键。“Fab片段”可以是抗体的木瓜蛋白酶切割的产物。
“片段可结晶”(“Fc”)区域含有两个包含抗体的CH3和CH2结构域的重链片段。所述两个重链片段通过两个或更多个二硫键和通过CH3结构域的疏水相互作用保持在一起。
“Fab' 片段”含有一个轻链以及含有VH结构域和C H1结构域且也含有在CH1和CH2结构域之间的区域的一个重链的部分或片段,使得链间二硫键可以在两个Fab' 片段的两个重链之间形成以形成F(ab') 2分子。
“F(ab')2片段”含有两个轻链和两个重链,所述重链含有在CH1和CH 2结构域之间的恒定区部分,使得链间二硫键在两个重链之间形成。F(ab')2片段因而由两个Fab' 片段组成,所述Fab' 片段通过两个重链之间的二硫键保持在一起。“F(ab')2片段”可以是抗体的木瓜蛋白酶切割的产物。
“Fv区域”包含来自重链和轻链的可变区,但是缺少恒定区。
术语“单链Fv”或“scFv”抗体表示包含抗体的VH和VL结构域的抗体片段,其中这些结构域存在于单个多肽链中。通常,Fv多肽还包含在VH和VL结构域之间的多肽接头,其使scFv能够形成期望的结构用于抗原结合[参见,Pluckthun, The Pharmacology ofMonoclonal Antibodies, 第113卷Rosenburg和Moore编, Springer-Verlag, New York,第269-315页(1994);WO 88/01649;和美国4,946,778和美国5,260,203]。
本文中使用的术语“规范结构”表示在它们所停留的框架内的抗体的重链和轻链的每个高变区可以采用的局部构象。对于每个高变区,存在小数目的规范结构(通常用简单整数诸如1或2等表示),它们可以以大准确度从对应高变区的氨基酸序列[特别是在它的框架的氨基酸序列的上下文内,如下面关于对应的抗-犬IL-4Rα可变结构域所提供的(参见,下面表3)]预测。这些规范结构可以关于给定CDR的氨基酸序列的修饰是否将导致结合它的抗原结合配偶体的能力的保留或丧失而起决定作用[参见,Chothia和Lesk, Canonical Structures for the hypervariable regions of immunoglobulins, J. Mol. Biol. 196:901-917(1987);Chothia等人,Conformation of immunoglobulin hypervaribale regions, Nature, 34:877-883(1989);和Al-Lazikani等人, Standard Conformations for the canonical structures of immunoglobulins, J. Mol. Biol.273:927-948(1997)]。
“结构域抗体”是仅含有重链的可变区或轻链的可变区的免疫学上有功能的免疫球蛋白片段。在某些情况下,两个或更多个VH区域用肽接头共价地连接以建立二价结构域抗体。二价结构域抗体的两个VH区域可以靶向相同的或不同的抗原。
“二价抗体”包含两个抗原结合位点。在某些情况下,所述两个结合位点具有相同的抗原特异性。但是,二价抗体可以是双特异性的(参见下面)。
在某些实施方案中,本文中的单克隆抗体也包括骆驼源化的单结构域抗体[参见, 例如,Muyldermans等人,Trends Biochem. Sci. 26:230 (2001); Reichmann等人,J. Immunol. Methods 231:25 (1999); WO 94/04678; WO 94/25591;美国6,005,079]。在一个实施方案中,本发明提供了包含两个VH结构域的单结构域抗体,所述VH结构域经过修饰从而形成单结构域抗体。
本文中使用的术语“双体”表示具有两个抗原结合位点的小抗体片段,所述片段包含在相同多肽链中与轻链可变结构域(VL)连接的重链可变结构域(VH) (VH-VL或VL-VH)。通过使用因为过短而不允许相同链上的两个结构域之间配对的接头,迫使所述结构域与另一个链的互补结构域配对并建立两个抗原结合位点[参见,EP 0 404 097 B1; WO 93/11161;和Holliger等人,Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993)]。关于经工程改造的抗体变体的综述[通常参见Holliger和Hudson Nat. Biotechnol. 23:1126-1136(2005)]。
通常地,当以摩尔基础表达该活性时,本发明的抗体或抗原结合片段保留它的犬IL-4Rα结合活性的至少10%(当与亲本抗体相比时)。优选地,本发明的抗体或抗原结合片段保留亲本抗体的犬IL-4Rα结合亲和力的至少20%、50%、70%、80%、90%、95%或100%或更多。还预见到,本发明的抗体或抗原结合片段可以包括不会实质上改变它的生物学活性的保守或非保守氨基酸置换(被称作抗体的“保守变体”或“功能保守变体”)。
“分离的抗体”表示纯化状态,且在这样的背景下是指所述分子基本上不含有其它生物分子诸如核酸、蛋白、脂质、碳水化合物或其它物质诸如细胞碎片和生长培养基。通常,术语“分离的”无意表示这样的物质完全不存在或表示水、缓冲剂或盐的缺失,除非它们以实质上干扰如本文中所述的结合化合物的实验或治疗用途的量存在。
本文中使用的“嵌合抗体”是具有来自第一抗体的可变结构域和来自第二抗体的恒定结构域的抗体,其中所述第一抗体和第二抗体来自不同的物种[美国4,816,567;和Morrison等人,Proc. Natl. Acad. Sci. USA 81: 6851-6855 (1984)]。通常地,所述可变结构域得自来自实验动物(诸如啮齿动物)的抗体(“亲本抗体”),且所述恒定结构域序列得自动物受试者(例如,人或犬)抗体,使得得到的嵌合抗体比亲本(例如,啮齿动物)抗体以更低可能性分别在犬或人受试者中引起不利的免疫应答。
本文中使用的术语“犬化抗体”表示含有来自犬和非-犬(例如,鼠)抗体的序列的抗体形式。一般而言,所述犬化抗体将包含基本上所有的或至少一个或多个(通常,两个)可变结构域,其中所有或基本上所有的高变环对应于非-犬免疫球蛋白(例如,包含6个如下面举例说明的鼠抗-犬IL-4RαCDR)的高变环,且所有或基本上所有的框架(FR)区(和通常所有或基本上所有的剩余框架)是犬免疫球蛋白序列的框架区。如本文中举例说明的,犬化抗体包含来自鼠抗-犬IL-4Rα抗体的三个重链CDR和三个轻链CDR以及犬框架或修饰的犬框架。修饰的犬框架包含一个或多个如本文中举例说明的氨基酸变化,其进一步优化犬化抗体的有效性,例如,增加它与犬IL-4Rα的结合和/或它的阻断犬IL-4和/或犬IL-13与I型和/或II型IL-4受体的结合的能力。
术语“全犬抗体”表示仅包含犬免疫球蛋白蛋白序列的抗体。如果在小鼠中、在小鼠细胞中或在从小鼠细胞衍生出的杂交瘤中生产,全犬抗体可以含有鼠碳水化合物链。类似地,“小鼠抗体”表示仅包含小鼠免疫球蛋白序列的抗体。可选地,如果在大鼠中、在大鼠细胞中或在从大鼠细胞衍生出的杂交瘤中生产,全犬抗体可以含有大鼠碳水化合物链。类似地,“大鼠抗体”表示仅包含大鼠免疫球蛋白序列的抗体。
狗IgG存在四种已知的IgG重链亚型,它们被称作IgG-A、IgG-B、IgG-C和IgG-D。两种已知的轻链亚型被称作λ和κ。
每个轻/重链对的可变区形成抗体结合位点。因而,一般而言,完整抗体具有两个结合位点。除了在双功能的或双特异性的抗体中以外,所述两个结合位点一般而言是相同的。
通常地,重链和轻链的可变结构域包含位于相对保守的框架区(FR)内的三个高变区,也称为互补性决定区(CDR)。所述CDR经常侧接框架区,能够结合至特定表位。一般而言,从N-端至C-端,轻链和重链可变结构域都包含FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。向每个结构域的氨基酸分配通常是根据以下文献的定义:Sequences of Proteins of Immunological Interest, Kabat, 等人.; National Institutes of Health,Bethesda, Md.;第5版; NIH Publ. No. 91-3242 (1991); Kabat, Adv. Prot. Chem.32:1-75 (1978); Kabat, 等人,J. Biol. Chem. 252:6609-6616 (1977); Chothia, 等 人,J. Mol. Biol. 196:901-917 (1987)或Chothia, 等人,Nature 342:878-883(1989)]。
本文中使用的术语“高变区”表示抗体的负责抗原结合的氨基酸残基。所述高变区包含来自“互补性决定区”或“CDR”(即在轻链可变结构域中的CDRL1、CDRL2和CDRL3和在重链可变结构域中的CDRH1、CDRH2和CDRH3)的氨基酸残基[参见Kabat等人.Sequences of Proteins of Immunological Interest, 第5版Public Health Service, NationalInstitutes of Health, Bethesda, Md. (1991),其用序列限定了抗体的CDR区域;也参见Chothia和Lesk, J. Mol. Biol. 196: 901-917 (1987),其用序列限定了抗体的CDR区域]。本文中使用的术语“框架”或“FR”残基表示除了高变区残基(在本文中被定义为CDR残基)以外的那些可变结构域残基。
除了犬免疫细胞的结合和活化以外,针对IL-4Rα的犬或犬化抗体最佳地具有两种属性:
1. 缺少效应子功能诸如抗体依赖性细胞毒作用(ADCC)和依赖补体的细胞毒性(CDC),和
2. 容易使用工业标准技术(诸如基于Protein A层析的技术)大规模纯化。
没有天然存在的犬IgG同种型满足两个标准。例如,IgG-B可以使用Protein A进行纯化,但是具有高水平的ADCC活性。另一方面,IgG-A微弱地结合Protein A,但是表现出不希望的ADCC活性。此外,IgG-C和IgG-D都不可以在Protein A柱上纯化,尽管IgG-D没有表现出ADCC活性。(IgG-C具有相当的ADCC活性)。本发明克服该困难的一条途径是,提供对IL-4Rα特异性的突变体犬IgG-B抗体;这样的抗体缺少效应子功能诸如ADCC,且可以使用工业标准Protein A层析容易地纯化。
“同源性”表示当将它们最佳地比对时两个多核苷酸序列之间或两个多肽序列之间的序列相似性。当在两个对比的序列中的位置被相同碱基或氨基酸单体亚基占据时,例如,如果两个DNA分子的每一个中的位置被腺嘌呤占据时,那么所述分子在该位置是同源的。同源性百分比是两个序列共有的同源位置的数目除以对比的位置的总数×100。例如,当将序列最佳地比对时,如果两个序列的10个位置中的6个是匹配的或同源的,那么所述两个序列是60%同源的。通常,当比对两个序列以给出最大同源性百分比时,做出所述对比。
“分离的核酸分子”是指基因组、mRNA、cDNA或合成起源或它们的某种组合的DNA或RNA,所述DNA或RNA与在自然界中在其中发现所述分离的多核苷酸的多核苷酸的全部或部分无关,或与在自然界中它没有与其连接的多核苷酸连接。为了本公开内容的目的,应当理解,包含特定核苷酸序列的“核酸分子”不包括完整的染色体。除了指定的序列以外,分离的“包含”指定的核酸序列的核酸分子还可以包括,多达10个或甚至多达20个或更多个其它蛋白或其部分或片段的编码序列,或可以包括可操作地连接的控制列举的核酸序列的编码区的表达的调节序列,和/或可以包括载体序列。
短语“控制序列”表示可操作地连接的编码序列在特定宿主生物体中的表达所必需的DNA序列。适合用于原核生物的控制序列例如包括启动子、任选的操纵子序列和核糖体结合位点。已知真核细胞使用启动子、多腺苷酸化信号和增强子。
当核酸与另一个核酸序列发生功能关联时,所述核酸是“可操作地连接的”。例如,前序列或分泌型前导序列的DNA与多肽的DNA可操作地连接,条件是其表达为参与所述多肽的分泌的前蛋白;启动子或增强子与编码序列可操作地连接,条件是其影响所述序列的转录;或核糖体结合位点与编码序列可操作地连接,条件是其被定位为促进翻译。通常,“可操作地连接的”是指,被连接的DNA序列是连续的,且在分泌型前导序列的情况下,是连续的且在阅读相中。然而,增强子不必须是连续的。连接通过在方便的限制性位点处的连接来实现。如果所述位点不存在,则合成的寡核苷酸适体或接头根据常规实践使用。
本文中使用的表述“细胞”、“细胞系”和“细胞培养物”可互换使用,且所有这些名称都包括子代。因此,词语“转化子”和“转化的细胞”包括原代受试细胞和由其衍生出的培养物,而不考虑转移的次数。还应当理解,由于故意的或非故意的突变,并非所有后代都具有精确地相同的DNA含量。包括具有相同功能或生物活性的突变体后代,如在最初转化的细胞中所筛选的。在意指不同名称时,它从上下文是清楚的。
本文中使用的“种系序列”表示未重新排列的免疫球蛋白DNA序列的序列。可以使用未重新排列的免疫球蛋白序列的任意合适的来源。人种系序列可以例如在美国国立卫生研究院的国家关节炎和肌肉骨骼疾病和皮肤疾病研究所(National Institute ofArthritis and Musculoskeletal and Skin Diseases of the United States NationalInstitutes of Health)的网站上从JOINSOLVER®种系数据库得到。可以得到小鼠种系序列,例如,如在Giudicelli等人[Nucleic Acids Res. 33:D256-D261 (2005)]中所述。
鼠抗-犬IL-4Rα和犬化鼠抗-犬IL-4Rα抗体的性质
本发明提供了分离的鼠抗-犬IL-4Rα抗体及其犬化抗体,在疾病的治疗(例如,犬中特应性皮炎的治疗)中使用所述抗体或其抗原结合片段的方法。在犬中,存在四种IgG重链,被称作A、B、C和D。这些重链代表狗IgG的四种不同亚类,它们被称作IgGA、IgGB、IgGC和IgGD。所述两个重链中的每一个由一个可变结构域(VH)和三个恒定结构域(被称作CH-1、CH-2和CH-3)组成。所述CH-1结构域通过被称作“铰链”或可选地被称作“铰链区”的氨基酸序列连接至CH-2结构域。
Tang等人[Vet. Immunol. Immunopathol. 80: 259-270 (2001)]首先鉴别了这4个重链的DNA和氨基酸序列。这些重链的氨基酸和DNA序列也可得自GenBank数据库。例如,IgGA重链的氨基酸序列具有登录号AAL35301.1,IgGB具有登录号AAL35302.1,IgGC具有登录号AAL35303.1,且IgGD具有登录号(AAL35304.1)。犬抗体也含有两类轻链κ和λ。这些轻链的DNA和氨基酸序列可以得自GenBank数据库。例如κ轻链氨基酸序列具有登录号ABY57289.1,且λ轻链具有登录号ABY 55569.1。
在本发明中,四种犬IgG Fc片段中的每一种的氨基酸序列是基于Tang等人(出处同上)确定的CH1和CH2结构域的鉴别边界。结合犬IL-4Rα的犬化鼠抗-犬IL-4Rα抗体包括、但不限于包含犬IgG-A、IgG-B和IgG-D重链和/或犬κ轻链以及鼠抗-犬IL-4RαCDR的抗体。因此,本发明提供了分离的鼠抗-犬IL-4Rα和/或犬化鼠抗-犬IL-4Rα抗体或其抗原结合片段,它们结合犬IL-4Rα并阻断犬IL-4和犬IL-13与I型或II型IL-4受体的结合。
本发明还提供了全长犬重链,其可以与对应的轻链匹配以制备犬化抗体。因此,本发明还提供了犬化鼠抗-犬抗原抗体(包括分离的犬化鼠抗-犬IL-4Rα抗体)和在疾病的治疗(例如,犬中特应性皮炎的治疗)中使用所述抗体或其抗原结合片段的方法。
本发明还提供了包含犬片段可结晶区域(cFc区)的犬化鼠抗-犬-IL-4Rα抗体,其中所述cFc已经被遗传修饰以增加、减小或消除一种或多种效应子功能。在本发明的一个方面,所述遗传修饰的cFc会减小或消除一种或多种效应子功能。在本发明的另一个方面,所述遗传修饰的cFc会增加一种或多种效应子功能。在某些实施方案中,所述遗传修饰的cFc区是遗传修饰的犬IgGB Fc区。在另一个这样的实施方案中,所述遗传修饰的cFc区是遗传修饰的犬IgGC Fc区。在一个具体实施方案中,所述效应子功能是被增加、减小或消除的抗体依赖性的细胞毒性(ADCC)。在另一个实施方案中,所述效应子功能是被增加、减小或消除的补体依赖性的细胞毒性(CDC)。在另一个实施方案中,所述cFc区已经被遗传修饰以增加、减小或消除ADCC和CDC。
为了制备缺乏效应子功能的犬IgG的变体,制备了许多突变体犬IgGB重链。这些变体可以在重链氨基酸序列的Fc部分中包括以下单个或组合置换中的一个或多个:P4A、D31A、N63A、G64P、T65A、A93G和P95A。将变体重链(即,含有这样的氨基酸置换)克隆进表达质粒中并与含有编码轻链的基因的质粒一起转染进HEK 293细胞中。针对与FcᵧRI和C1q的结合评价从HEK 293细胞表达并纯化的完整抗体,以评估它们的介导免疫效应子功能的潜力[参见,2014年7月30日提交的美国临时专利申请62/030,812和2014年12月16日提交的美国临时专利申请62/092,496,它们二者的内容特此通过引用整体并入]。
本发明还提供了经修饰的犬IgGD,它们在它的天然IgGD铰链区的地方包含来自以下的铰链区:
IgGA: fnecrctdtppcpvpep, SEQ ID NO: 101;
IgGB: pkrengrvprppdcpkcpapem, SEQ ID NO: 102;或
IgGC: akececkcncnncpcpgcgl, SEQ ID NO: 103。
可选地,通过用脯氨酸残基替换丝氨酸残基,可以遗传修饰IgGD铰链区,即,PKESTCKCIPPCPVPES, SEQ ID NO: 104 (其中带有下划线且以粗体显示的脯氨酸残基(P)替换天然存在的丝氨酸残基)。这样的修饰可以产生缺乏fab臂交换的犬IgGD。使用重组DNA技术的标准方法[例如,Maniatis等人,MolecularCloning, A Laboratory Manual(1982)],可以构建经修饰的犬IgGD。为了构建这些变体,可以修饰编码犬IgGD的氨基酸序列的核酸,使得它们编码经修饰的IgGD。然后将经修饰的核酸序列克隆进表达质粒中用于蛋白表达。
结合犬IL-4Rα的抗体或其抗原结合片段可以包含如本文中所述的鼠抗-犬抗体的1、2、3、4、5或6个互补性决定区(CDR)。1、2、3、4、5或6个CDR可以独立地选自在下面提供的那些的CDR序列。在另一个实施方案中,分离的结合犬IL-4Rα的抗体或其抗原结合片段包含含有鼠轻链CDR-1、CDR-2和/或CDR-3的犬抗体κ轻链和含有鼠重链CDR-1、CDR-2和/或CDR-3的犬抗体重链IgG。
在其它实施方案中,本发明提供了这样的抗体或其抗原结合片段:它们特异性地结合IL-4Rα且具有犬抗体κ轻链和犬抗体重链IgG,同时仍然表现出期望的结合和功能性质,所述犬抗体κ轻链包含1-6个与SEQ ID NO: 47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72和/或73的氨基酸序列具有至少80%、85%、90%、95%、98%或99%序列同一性的不同CDR,且所述犬抗体重链IgG包含1-6个与SEQ ID NO:74、75、76、77、78、79、80、81、82、83、84、85、87、88、89、90、91、92、93、94、95、96、97、98、99和/或100的氨基酸序列具有至少80%、85%、90%、95%、98%或99%序列同一性的不同CDR。在另一个实施方案中,本发明的抗体或抗原结合片段包含犬框架,同时仍然表现出期望的结合和功能性质,所述犬框架包含IgG重链序列与κ轻链的组合,所述κ轻链具有一个或多个上述CDR氨基酸序列,含有0、1、2、3、4或5个保守的或非保守氨基酸置换。
序列同一性表示,当最佳地比对两个序列时,两个多肽的氨基酸在相同位置相同的程度。如本文中使用的,当两个序列的氨基酸残基相同时,一个氨基酸序列与第二个氨基酸序列具有100%“同一性”。因此,当两个氨基酸序列的50%的氨基酸残基相同时,一个氨基酸序列与第二个氨基酸序列具有50%“同一性”。在给定蛋白所包含的连续氨基酸残基段中执行序列对比,例如,对比蛋白或多肽的部分。在一个具体实施方案中,考虑选择的缺失或插入,其否则会改变两个氨基酸序列之间的对应。
序列相似性包括相同的残基和不相同的生化上有关的氨基酸。讨论了共有类似的性质且可以互换的生化上有关的氨基酸。
“保守修饰变体”或“保守置换”表示用具有类似特征(例如电荷、侧链大小、疏水性/亲水性、主链构象和刚度等)的其它氨基酸置换蛋白中的氨基酸,使得所述变化可以经常做出,而不改变蛋白的生物活性。本领域技术人员意识到,一般而言,在多肽的非必需区域中的单个氨基酸置换不会实质上改变生物活性[参见,例如,Watson等人, Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., 第224页(第4版; 1987)]。另外,在结构上或在功能上类似的氨基酸的置换不太可能破坏生物活性。示例性的保守置换阐述在下面紧邻的表1中。
表1
示例性的保守氨基酸置换
。
本发明也预见到本发明的抗体的功能保守变体。本文中使用的“功能保守变体”表示这样的抗体或片段:其中一个或多个氨基酸残基已经被改变,而没有改变期望的性质,诸如抗原亲和力和/或特异性。这样的变体包括、但不限于用具有类似性质的氨基酸替换一个氨基酸,诸如上面表1的保守氨基酸置换。
核酸
本发明还包括核酸,其编码本文中公开的鼠抗-犬IL-4Rα和/或犬化鼠抗-犬IL-4Rα抗体和其抗原结合片段的免疫球蛋白链(参见下面的实施例)。
本发明还包括编码免疫球蛋白多肽的核酸,当通过BLAST算法(其中选择算法的参数以在各个参照序列的整个长度上给出各个序列之间的最大匹配)执行对比时,所述免疫球蛋白多肽的氨基酸序列与本文提供的CDR和抗体的氨基酸序列具有至少约70%同一性,优选地至少约80%同一性,更优选地至少约90%同一性和最优选地至少约95%同一性(例如,95%、96%、97%、98%、99%、100%)。本发明还提供了编码免疫球蛋白多肽的核酸,当用BLAST算法(其中选择算法的参数以在各个参照序列的整个长度上给出各个序列之间的最大匹配)执行对比时,所述免疫球蛋白多肽的氨基酸序列与任何参照氨基酸序列具有至少约70%相似性,优选地至少约80%相似性,更优选地至少约90%相似性和最优选地至少约95%相似性(例如,95%、96%、97%、98%、99%、100%),也被本发明包括。
如本文中使用的,使用C, MacVector (MacVector, Inc. Cary, NC 27519),Vector NTI (Informax, Inc. MD), Oxford Molecular Group PLC (1996)和Clustal W算法(具有比对默认参数和关于同一性的默认参数),可以确定核苷酸和氨基酸序列同一性百分比。这些商购可得的程序还可以用于使用相同的或类似的默认参数确定序列相似性。可选地,可以使用在默认过滤条件下的Advanced Blast检索,例如,使用GCG (GeneticsComputer Group, Program Manual for the GCG Package, 第7版, Madison,Wisconsin)累积程序(pileup program)使用默认参数。
以下参考文献涉及经常用于序列分析的BLAST算法:BLAST ALGORITHMS:Altschul, S.F., 等人,J. Mol. Biol. 215:403-410 (1990); Gish, W., 等人,Nature Genet. 3:266-272 (1993); Madden, T.L., 等人,Meth. Enzymol. 266:131-141(1996);Altschul, S.F., 等人,Nucleic Acids Res. 25:3389-3402 (1997); Zhang, J., 等人, Genome Res. 7:649-656 (1997); Wootton, J.C., 等人,Comput. Chem. 17:149-163(1993); Hancock, J.M. 等人,Comput. Appl. Biosci. 10:67-70 (1994); ALIGNMENTSCORING SYSTEMS: Dayhoff, M.O., 等人, “A model of evolutionary change inproteins.”in Atlas of Protein Sequence and Structure, 第5卷, 增刊3. M.O.Dayhoff (编), 第345-352页, (1978); Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M., 等人, “Matrices for detecting distant relationships.”in Atlasof Protein Sequence and Structure, 第5卷, 增刊3.”(1978), M.O. Dayhoff (编),第353-358页(1978), Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F.,J. Mol. Biol. 219:555-565 (1991); States, D.J., 等人,Methods 3:66-70(1991);Henikoff, S., 等人,Proc. Natl. Acad. Sci. USA 89:10915-10919 (1992);Altschul, S.F., 等人,J. Mol. Evol. 36:290-300 (1993); ALIGNMENT STATISTICS:Karlin, S., 等人,Proc. Natl. Acad. Sci. USA 87:2264-2268 (1990); Karlin, S.,等人,Proc. Natl. Acad. Sci. USA 90:5873-5877 (1993); Dembo, A., 等人,Ann. Prob. 22:2022-2039 (1994);和Altschul, S.F. “Evaluating the statisticalsignificance of multiple distinct local alignments.”in Theoretical and Computational Methods in Genome Research (S. Suhai, 编), 第1-14页, Plenum,New York (1997)。
本发明还提供了包含本发明的分离的核酸的表达载体,其中所述核酸可操作地连接至控制序列,当用所述载体转染宿主细胞时,所述控制序列被宿主细胞识别。还提供了包含本发明的表达载体的宿主细胞和用于生产本文中公开的抗体或其抗原结合片段的方法,所述方法包括:在培养基中培养携带编码抗体或抗原结合片段的表达载体的宿主细胞,和从宿主细胞或培养基分离所述抗原或其抗原结合片段。
表位结合和结合亲和力
本发明还提供了与本文中公开的鼠抗-犬IL-4Rα抗体结合相同犬IL-4Rα表位的氨基酸残基的抗体或其抗原结合片段。在具体实施方案中,所述鼠抗-犬IL-4Rα抗体或其抗原结合片段也能够抑制/阻断犬IL-4和犬IL-13与I型和/或II型IL-4受体的结合。
通过本领域中已知的方法,可以重组地生产犬化鼠抗-犬IL-4Rα抗体。可用作用于表达本文中公开的抗体或片段的宿主的哺乳动物细胞系是本领域众所周知的,且包括许多可从美国通常培养物保藏中心(ATCC)得到的永生化的细胞系。这些尤其包括中国仓鼠卵巢(CHO)细胞、NSO、SP2细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人肝细胞癌细胞(例如,Hep G2)、A549细胞、3T3细胞、HEK-293细胞和许多其它细胞系。哺乳动物宿主细胞包括人、小鼠、大鼠、狗、猴、猪、山羊、牛、马和仓鼠细胞。通过确定哪些细胞系具有高表达水平,选择特别优选的细胞系。可以使用的其它细胞系是昆虫细胞系,诸如Sf9细胞、两栖动物细胞、细菌细胞、植物细胞和真菌细胞。当将编码重链或其抗原结合部分或片段、轻链和/或其抗原结合片段的重组表达载体引入哺乳动物宿主细胞中时,如下生产抗体:将所述宿主细胞培养足以允许所述抗体在宿主细胞中的表达的时间段,或者更优选地,使所述抗体分泌进宿主细胞在其中生长的培养基中。
使用标准的蛋白纯化方法,可以从培养基回收抗体。此外,使用许多已知技术,可以增强本发明的抗体(或源自它的其它部分)从生产细胞系的表达。例如,谷氨酰胺合成酶基因表达系统(GS系统)是一种用于增强在特定条件下的表达的常见方案。与欧洲专利号0216 846、0 256 055和0 323 997和欧洲专利申请号89303964.4关联地完整地或部分地讨论了GS系统。
一般而言,在特别的细胞系或转基因动物中生产的糖蛋白将具有在所述细胞系或转基因动物中生产的糖蛋白所特有的糖基化模式。因此,抗体的特别的糖基化模式将取决于用于生产所述抗体的特别的细胞系或转基因动物。但是,由本文提供的核酸分子编码的、或者包含本文提供的氨基酸序列的所有抗体构成本发明,独立于所述抗体可以具有的糖基化模式。类似地,在特别的实施方案中,具有仅包含未岩藻糖基化的N-聚糖的糖基化模式的抗体可能是有利的,因为这些抗体已经被证实通常地在体外和在体内表现出比它们的岩藻糖基化的相应物更有效的效力[参见例如,Shinkawa等人,J. Biol. Chem. 278: 3466-3473 (2003);美国专利号6,946,292和7,214,775]。
本发明还包括本文中公开的鼠抗-犬IL-4Rα抗体的抗体片段。所述抗体片段包括F(ab)2片段,其可以通过例如胃蛋白酶对IgG的酶切割来生产。Fab片段可以通过例如用二硫苏糖醇或巯基乙胺还原F(ab)2来生产。Fab片段是通过二硫键附加至VH-CH1链的VL-CL链。F(ab)2片段是两个又通过两个二硫键附加的Fab片段。F(ab)2分子的Fab部分包括二硫键位于其中间的Fc区部分。FV片段是VL或VH区域。
在一个实施方案中,所述抗体或抗原结合片段包含重链恒定区,例如,犬恒定区,诸如IgG-A、IgG-B、IgG-C和IgG-D犬重链恒定区或其变体。在另一个实施方案中,所述抗体或抗原结合片段包含轻链恒定区,例如,犬轻链恒定区,诸如λ或κ犬轻链区域或其变体。作为例子,且非限制性地,所述犬重链恒定区可以来自IgG-D,且所述犬轻链恒定区可以来自κ。
抗体工程
本发明的犬化鼠抗-犬IL-4Rα抗体可以经过工程改造以包括对亲本(即,犬)单克隆抗体的可变结构域内的犬框架和/或犬框架残基的修饰,例如以改善抗体的性质。
实验和诊断用途
本发明的鼠抗-犬IL-4Rα和/或犬化鼠抗-犬IL-4Rα抗体或其抗原结合片段也可以用在犬IL-4Rα蛋白的诊断测定中,例如,检测它与特应性皮炎结合和/或相关的表达。
例如,这样的方法包括下述步骤:
(a)用鼠抗-犬IL-4Rα抗体或其抗原结合片段包被基质(例如,微孔滴定板孔的表面,例如,塑料板);
(b)向所述基质施加要测试犬IL-4Rα的存在的样品;
(c)洗涤所述板,使得所述样品中未结合的物质被除去;
(d)施加可检测地标记的抗体(例如,酶连接的抗体),所述抗体也对IL-4Rα抗原具有特异性;
(e)洗涤所述基质,使得未结合的、标记的抗体被除去;
(f)如果标记的抗体是酶连接的,施加被所述酶转化成荧光信号的化学物质;和
(g)检测所述标记的抗体的存在。
在另一个实施方案中,所述标记的抗体用过氧化物酶标记,所述过氧化物酶与ABTS [例如,2,2'-联氮基-双(3-乙基苯并噻唑啉-6-磺酸)]或3,3’,5,5’-四甲基联苯胺反应以产生可检测的颜色变化。可选地,所述标记的抗体用可检测的放射性同位素(例如,3H)标记,所述放射性同位素可以在有闪烁剂存在下用闪烁计数器检测。本发明的鼠抗-犬IL-4Rα抗体可以用在蛋白质印迹或免疫蛋白印迹程序中。
这样的程序形成本发明的组成部分,且包括例如:
(i)使要测试结合的犬IL-4Rα或其片段的存在的膜或其它固体基质与本发明的鼠抗-犬IL-4Rα抗体或其抗原结合片段接触。这样的膜可以呈基于硝酸纤维素或乙烯树脂[例 如,聚偏氟乙烯(PVDF)]的膜的形式,要在非变性PAGE (聚丙烯酰胺凝胶电泳)凝胶或SDS-PAGE (十二烷基硫酸钠聚丙烯酰胺凝胶电泳)凝胶中测试犬IL-4Rα的存在的蛋白已经转移至所述膜(例如,在凝胶中电泳分离以后)。在膜与鼠抗-犬IL-4Rα抗体或其抗原结合片段接触之前,任选地将所述膜用例如脱脂奶粉等封闭,从而结合所述膜上的非特异性的蛋白结合位点。
(ii)将所述膜洗涤一次或多次以除去未结合的鼠抗-犬IL-4Rα抗体或其抗原结合片段和其它未结合的物质;和
(iii)检测结合的鼠抗-犬IL-4Rα抗体或其抗原结合片段。
结合的抗体或抗原结合片段的检测可以是通过抗体或抗原结合片段与可检测地标记的第二抗体(抗-免疫球蛋白抗体)的结合,并然后检测所述第二抗体的存在。
本文中公开的鼠抗-犬IL-4Rα抗体和其抗原结合片段也可以用于免疫组织化学。这样的方法形成本发明的组成部分,且包括,例如,(1)使要测试犬IL-4Rα的存在的细胞与本发明的鼠抗-犬IL-4Rα抗体或其抗原结合片段接触;和(2)检测所述细胞的表面上或内部的抗体或片段。如果抗体或抗原结合片段本身被可检测地标记,可以直接地检测它。可选地,所述抗体或抗原结合片段可以被可检测地标记的第二抗体结合,检测所述第二抗体。
成像技术包括SPECT成像(单光子发射计算机断层摄影术)或PET成像(正电子发射断层摄影术)。标记包括例如,碘-123 (123I)和锝-99m (99mTc),例如,与SPECT成像结合,或11C、13N、15O或18F,例如,与PET成像结合,或铟-111 [参见例如,Gordon等人,International Rev. Neurobiol. 67:385-440 (2005)]。
交叉阻断抗体
此外,本发明的抗-犬IL-4Rα抗体或其抗原结合片段包括结合本文中讨论的抗体和片段所结合的犬IL-4Rα中的相同表位的任何抗体或其抗原结合片段以及交叉阻断(部分地或完全地)本文中讨论的抗体或片段的犬IL-4Rα结合或者被本文中讨论的抗体或片段交叉阻断(部分地或完全地)犬IL-4Rα结合的任何抗体或抗原结合片段;以及它们的任意变体。
基于它们在标准结合测定(例如,BIACore®、ELISA,如下面举例说明的,或流式细胞计量术)中与本文公开的抗体(基于如下面在实施例5中提供的CDR)(即,1A3、1A9、1B12、10C12、10F2、10E10、10G8和/或11D3;或更具体地,11B6和/或6C12;和甚至更具体地4D8、4H3、2E2和/或11H2)交叉竞争的能力,可以鉴别本文中讨论的交叉阻断抗体和其抗原结合片段。例如,可以使用标准ELISA测定,其中将重组犬IL-4Rα蛋白固定化在平板上,将抗体之一荧光地标记,并评价未标记抗体竞争掉标记的抗体的结合的能力。额外地或可选地,可以使用BIAcore®分析来评估所述抗体的交叉竞争的能力。测试抗体的抑制例如1A3、1A9、1B12、10C12、10F2、10E10、10G8和/或11D3或更具体地11B6和/或6C12和甚至更具体地4D8、4H3、2E2和/或11H2与犬IL-4Rα的结合的能力证实,所述测试抗体可以与1A3、1A9、1B12、10C12、10F2、10E10、10G8、11D3、11B6、6C12、4D8、4H3、2E2和/或11H2竞争对犬IL-4Rα的结合,且因而,在某些情况下,可以与1A3、1A9、1B12、10C12、10F2、10E10、10G8、11D3、11B6、6C12、4D8、4H3、2E2和/或11H2结合犬IL-4Rα上的相同表位。如上所述,结合与本发明的任何抗-犬IL-4Rα抗体或片段相同的表位的抗体和片段也形成本发明的组成部分。
药物组合物和施用
为了制备犬化鼠抗-犬IL-4Rα抗体或其抗原结合片段的药物或无菌组合物,可以将它与药学上可接受的载体或赋形剂混合[参见,例如,Remington'sPharmaceutical Sciences和U.S. Pharmacopeia: National Formulary, Mack Publishing Company,Easton, PA (1984)]。
通过与可接受的载体、赋形剂或稳定剂混合,可以制备治疗剂和诊断剂的制剂,所述制剂呈例如冻干粉剂、浆剂、水溶液或混悬液的形式[参见,例如,Hardman, 等人(2001)Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill,New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy,Lippincott, Williams, and Wilkins, New York, NY; Avis, 等人(编) (1993)Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY;Lieberman, 等人(编) (1990) Pharmaceutical Dosage Forms: Tablets, MarcelDekker, NY; Lieberman, 等人(编) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner和Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY]。在一个实施方案中,将本发明的抗-IL-4Rα抗体在乙酸钠溶液(pH 5-6)中稀释至适当浓度,并为了张度加入NaCl或蔗糖。可以加入另外的试剂(诸如聚山梨酯20或聚山梨酯80)以增强稳定性。
单独地或与另一种试剂联合地施用的抗体组合物的毒性和治疗效果可以通过标准药物操作在细胞培养物或实验动物中确定,例如,确定LD50 (对群体的50%致命的剂量)和ED50 (对群体中的50%治疗上有效的剂量)。有毒和治疗效果之间的剂量比是治疗指数(LD50/ED50)。在具体方面,表现出高治疗指数的抗体是期望的。从这些细胞培养测定和动物研究得到的数据可以用于阐明用在犬中的剂量的范围。这样的化合物的剂量优选地在包括ED50又几乎没有或没有毒性的循环浓度范围内。所述剂量可以在该范围内变化,取决于采用的剂型和施用途径。
施用模式可以变化。合适的施用途径包括口服、直肠、经粘膜、经肠、胃肠外;肌肉内、皮下、真皮内、骨髓内、鞘内、直接心室内、静脉内、腹膜内、鼻内、眼内、吸入、吹入法、局部、皮肤、透皮或动脉内。在具体实施方案中,可以通过侵袭性途径(诸如通过注射)来施用鼠抗-犬IL-4Rα抗体或其抗原结合片段。在本发明的其它实施方案中,静脉内地、皮下地、肌肉内地、动脉内地、或通过吸入、气雾剂递送,施用鼠抗-犬IL-4Rα抗体或其抗原结合片段或其药物组合物。通过非侵袭性途径(例如,口服地;例如,在丸剂、胶囊剂或片剂中)的施用也在本发明范围内。
可以用本领域已知的医疗装置施用组合物。例如,通过用皮下针(包括、例如,预装注射器或自动注射器)注射,可以施用本发明的药物组合物。还可以用无针皮下注射装置施用本文中公开的药物组合物;诸如在美国专利号6,620,135、6,096,002、5,399,163、5,383,851、5,312,335、5,064,413、4,941,880、4,790,824或4,596,556中公开的装置。
还可以通过输注来施用本文中公开的药物组合物。用于施用药物组合物的众所周知的植入物和模块形式的例子包括: 美国专利号4,487,603,其公开了一种用于以受控的速率分配药物的可植入的微量输液泵;美国专利号4,447,233,其公开了一种用于以精确的输注速率递送药物的药物输液泵;美国专利号4,447,224,其公开了一种用于连续药物递送的可变流可植入的输注设备;美国专利号4,439,196,其公开了一种具有多个腔隔室的渗透药物递送系统。许多其它这样的植入物、递送系统和模块是本领域技术人员众所周知的。
可选地,可以以局部方式而不是全身方式施用鼠抗-犬或犬化鼠抗-犬IL-4Rα抗体,例如,通过将抗体直接注射进特征在于免疫病理学的关节炎关节或病原体诱导的病灶中,经常为贮库或持续释放制剂。此外,可以在靶向药物递送系统中施用所述抗体,例如,在用组织特异性抗体包被的脂质体中,所述组织特异性抗体靶向例如特征在于免疫病理学的关节炎关节或病原体诱导的病灶。所述脂质体将选择性地靶向患病组织和被患病组织摄入。
施用方案取决于几个因素,包括治疗性抗体的血清或组织周转率、症状的水平、治疗性抗体的免疫原性和靶细胞在生物基质中的可达性。优选地,施用方案递送足够的治疗性抗体以实现靶疾病状态的改善,同时使不希望的副作用最小化。因此,递送的生物试剂的量部分地取决于特定治疗性抗体和要治疗的病症的严重程度。可得到选择治疗性抗体的适当剂量的指南[参见,例如,Wawrzynczak Antibody Therapy, Bios Scientific Pub.Ltd, Oxfordshire, UK (1996); Kresina (编) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY (1991); Bach (编) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, NewYork, NY (1993); Baert, 等人.New Engl. J. Med. 348:601-608 (2003); Milgrom等 人.New Engl. J. Med. 341:1966-1973 (1999); Slamon等人.New Engl. J. Med. 344:783-792 (2001); Beniaminovitz等人.New Engl. J. Med. 342:613-619 (2000); Ghosh等人.New Engl. J. Med. 348:24-32 (2003); Lipsky等人.New Engl. J. Med. 343:1594-1602 (2000)]。
适当剂量的确定由兽医做出,例如,使用本领域已知或疑似影响治疗的参数或因素。通常,所述剂量开始于稍微小于最适剂量的量,并且它在此后增加小增量,直到与任何负面副作用相比达到期望的或最适的效果。重要的诊断措施包括例如炎症的症状的诊断措施或产生的炎症性细胞因子的水平的诊断措施。
可以通过连续输注或通过例如每天1次、每周1-7次、每周1次、每2周1次、每月1次、每2月1次、每季度1次、每半年1次、每年1次等施用的剂量来提供本文中公开的抗体或其抗原结合片段。可以例如静脉内地、皮下地、局部地、口服地、鼻地、直肠地、肌肉内地、大脑内地、脊椎内地或通过吸入提供剂量。总每周剂量通常是至少0.05 μg/kg体重,更通常是至少0.2 μg/kg、0.5 μg/kg、1 μg/kg、10 μg/kg、100 μg/kg、0.25 mg/kg、1.0 mg/kg、2.0 mg/kg、5.0 mg/ml、10 mg/kg、25 mg/kg、50 mg/kg或更多[参见,例如,Yang, 等人.New Engl. J. Med. 349:427-434 (2003);Herold, 等人.New Engl. J. Med. 346:1692-1698(2002);Liu, 等人.J.Neurol. Neurosurg. Psych. 67:451-456 (1999);Portielji, 等 人.Cancer Immunol. Immunother. 52:133-144 (2003)]。还可以提供剂量以达到犬化鼠抗-犬IL-4Rα抗体在受试者的血清中的预定靶浓度,诸如0.1、0.3、1、3、10、30、100、300µg/ml或更多。在其它实施方案中,每周、每2周、“每4周”、每月、每2月或每季度以10、20、50、80、100、200、500、1000或2500 mg/受试者皮下地或静脉内地施用本发明的犬化鼠抗-犬IL-4Rα抗体。
被抗-犬IL-4RαmAb识别的抗原肽也可以用作疫苗以引起阻断犬IL-4和犬IL-13与I型和II型IL-4受体的结合的抗体。这样的疫苗可以用作疾病(诸如特应性皮炎)的治疗疫苗。为了使用这些抗原肽作为疫苗,可以用化学法或通过重组DNA技术的技术将这些肽中的一种或多种偶联至另一种载体蛋白以便增强这些肽的免疫原性和引起肽特异性抗体。用于将肽偶联至载体蛋白的技术是本领域技术人员已知的。肽疫苗可以用于通过肌肉内(IM)、皮下(S/C)、口服、喷雾或在卵内(in ovo)途径给动物接种疫苗。肽疫苗可以用作从细菌、病毒、酵母或杆状病毒系统表达的亚基蛋白。可选地,如通过本领域技术人员已知的方法可以实践的,在施用多种表达这样的肽疫苗的病毒或细菌载体以后可以递送这样的肽疫苗。肽疫苗可以以1-1000µg的剂量施用,且可以任选地含有佐剂和可接受的药用载体。
本文中使用的“抑制”或“治疗”或“处理”包括与病症有关的症状的发展的延迟和/或这样的病症的症状的严重性的减少。该术语还包括改善既有的失控的或不希望的症状,阻止另外的症状,和改善或阻止这样的症状的基础原因。因而,该术语表示,已经给脊椎动物受试者赋予有益的结果,所述脊椎动物受试者具有病症、疾病或症状或具有发展这样的病症、疾病或症状的潜力。
本文中使用的术语“治疗有效量”、“治疗有效剂量”和“有效量”表示这样的本发明的犬化鼠抗-犬IL-4Rα抗体或其抗原结合片段的量:当单独地或与另外的治疗剂组合地施用给细胞、组织或受试者时,所述量有效地造成疾病或病症的一种或多种症状或这样的疾病或病症的进展的可测量的改善。治疗有效剂量还表示,足以导致症状的至少部分改善的结合化合物的量,例如,有关的医学状况的治疗、治愈、预防或改善,或这样的状况的治疗、治愈、预防或改善的速率的增加。当应用于单独施用的单个活性成分时,治疗有效剂量表示单独的该成分。当应用于组合时,治疗有效剂量表示产生治疗效果的活性成分的组合量,无论是组合地、连续地还是同时地施用。有效量的治疗剂将导致诊断测量或参数改善至少10%;经常至少20%;优选地至少约30%;更优选地至少40%,和最优选地至少50%。在使用主观测量来评估疾病严重程度的情况下,有效量还可以导致主观测量的改善。
其它联合治疗
如前面描述的,本发明的犬化鼠抗-犬IL-4Rα抗体或其抗原结合片段和/或抗原肽可以与一种或多种其它治疗剂(诸如在下一段中讨论的抑制剂)和/或鼠(或犬化的鼠)抗-犬TSLP抗体[参见,美国8,791,242]一起共同施用。所述抗体可以连接至所述试剂(作为免疫复合物),和/或可以与所述试剂或其它抗体分开施用。在后一种情况(分开施用)下,所述抗体可以在所述试剂之前、之后或并行地施用,或可以与其它已知的疗法一起共同施用。
试剂盒
还提供了包含一种或多种组分的试剂盒,所述组分包括、但不限于与一种或多种另外组分组合的如本文所讨论的特异性地结合IL-4Rα的抗体或抗原结合片段(例如,犬化鼠抗-犬IL-4Rα抗体或其抗原结合片段),所述另外组分包括、但不限于药学上可接受的载体和/或抑制剂诸如Janus激酶(JAK)抑制剂,例如,奥拉替尼 [参见,WO 2013/040241],脾酪氨酸激酶(SYK)抑制剂[参见例如,美国8,759,366],或针对在TH2细胞上表达的化学引诱物受体同源分子的拮抗剂[参见例如,WO 2010/099039; WO 2010/031183;和美国8,546,422]。上面刚才描述的结合组合物和/或抑制剂可以配制为纯的组合物或在药物组合物中与药学上可接受的载体相组合。
在一个实施方案中,所述试剂盒包括在一个容器中(例如,在无菌的玻璃或塑料小瓶中)的本发明的结合组合物(例如,犬化鼠抗-犬IL-4Rα或其药物组合物)和在另一个容器中(例如,在无菌的玻璃或塑料小瓶中)的其药物组合物和/或上述抑制剂。
如果试剂盒包括用于胃肠外施用给受试者的药物组合物,所述试剂盒还可以包括用于执行这样的施用的装置。例如,所述试剂盒可以包括一个或多个皮下针头或如上面讨论的其它注射装置。所述试剂盒还可以包括包装说明书,其包括关于所述试剂盒内的药物组合物和剂型的信息。通常,这样的信息会帮助宠物主人和兽医有效地和安全地使用包封的药物组合物和剂型。例如,以下关于本发明的组合的信息可以提供在插页中:药代动力学、药效动力学、临床研究、效力参数、适应症和用法、禁忌证、警告、注意、不良反应、超量给药、适当剂量和施用、供应规格、适当贮存条件、参考文献、生产商/分销商信息和专利信息。
为了方便,可以将本文中公开的抗体或特异性结合剂与关于执行诊断或检测测定的说明书一起提供在试剂盒(即,预定量的试剂的包装组合)中。在用酶标记抗体的情况下,所述试剂盒将包括所述酶需要的底物和辅因子(例如,提供可检测的发色团或荧光团的底物前体)。另外,可能包括其它添加剂,诸如稳定剂、缓冲剂(例如,封闭缓冲液或裂解缓冲液)等。各种试剂的相对量可以宽泛地变化,以提供实质上优化测定的灵敏度的试剂溶液的浓度。具体地,所述试剂可以提供为干粉,经常是冻干的,其包括在溶解后会提供具有适当浓度的试剂溶液的赋形剂。
实施例
实施例1
犬IL-4受体α链受体的鉴别和克隆
通过检索Genbank数据库(登记号XM_547077.4;也参见, US 7,208,579 B2),鉴别出编码预测的全长犬IL-4受体α链的cDNA (SEQ ID NO: 1)。该预测的cDNA编码823个氨基酸(SEQ ID NO: 2)(包括25氨基酸前导序列),且被鉴别为登记号XP_547077.3。成熟的预测的犬IL-4受体α链蛋白(SEQ ID NO: 4)与人IL-4受体α链(登记号NP_000409.1)具有65%同一性且与猪IL-4受体α链(登记号NP_999505.1)具有70%同一性。成熟的预测的犬IL-4受体α链蛋白由被鉴别为SEQ ID NO: 3的核苷酸序列编码。预测的成熟的IL-4受体α链与人IL-4受体α链的已知序列的对比鉴别出成熟的犬IL-4受体α链蛋白的细胞外结构域(ECD),且被命名为SEQ ID NO: 6。编码成熟的犬IL-4受体α链的ECD的DNA序列被鉴别为SEQ ID NO: 5。
具有信号序列的犬IL-4受体α链全长DNA (SEQ ID NO:1):
具有以粗体显示的信号序列的犬IL-4受体α全长蛋白(SEQ ID NO: 2)
没有信号序列的犬IL-4受体成熟全长蛋白(SEQ ID NO: 4)
没有信号序列的犬IL-4受体成熟全长DNA (SEQ ID NO: 3)
没有信号序列的犬IL-4受体α链细胞外蛋白结构域(SEQ ID NO: 6):
没有信号序列的犬IL-4受体α链细胞外DNA结构域(SEQ ID NO: 5):
具有c-端8 HIS标签的犬IL-4受体α链细胞外结构域(SEQ ID NO: 8):
具有c-端8 HIS标签的犬IL-4受体α链细胞外DNA结构域(SEQ ID NO: 7):
犬IL-4受体α链细胞外结构域+人IgG1 Fc (SEQ ID NO: 10):
犬IL-4受体α链细胞外DNA结构域+人IgG1 Fc (SEQ ID NO: 9):
实施例2
鼠抗-犬IL-4受体α链抗体
抗-犬IL-4受体α链单克隆抗体的制备 :
将共三只Balb/c小鼠在17天时段内免疫多次(每次用10µg)。免疫抗原是犬IL-4 Rα链细胞外结构域(ECD)-人Fc融合蛋白。在免疫接种以后,从每只小鼠收集血清,并用犬IL-4受体α链ECD HIS标记的蛋白测试反应性。使具有最高血清抗-IL-4受体α链ECD滴度的小鼠的脾细胞与骨髓瘤P3X63Ag8.653细胞系融合。在融合以后大约2周,将得自假定杂交瘤细胞的上清液通过ELISA测试它们与IL-4受体α链ECD HIS标记的蛋白的反应性。将在ELISA中产生强阳性信号的杂交瘤通过有限稀释进行亚克隆,并针对与犬IL-4受体α链ECD HIS标记的蛋白的反应性再次测试。
与犬IL-4受体α链的单克隆抗体反应性的证实 :
通过ELISA证实了杂交瘤分泌的抗体与犬IL-4受体α链的ECD的反应性。将杂交瘤细胞使用CELLine生物反应器(Integra-biosciences)培养10-30天。将细胞最初维持在补充了4 mM L-谷氨酰胺和10%Ultra Low IgG胎牛血清(FBS)(来自Gibco)的DMEM中。将杂交瘤细胞在15 mL相同培养基(含有增加至20%的FBS浓度)中以大约2x106个细胞/mL的细胞密度接种在CELLine生物反应器细胞室中。给外室填充1 L营养培养基(含有4mM L-谷氨酰胺和2%标准FBS的DMEM)。经3-7天使细胞室中的杂交瘤细胞扩增至大约2.5x107个细胞/mL。然后,从细胞室收获10 mL细胞混悬液,并用新鲜培养基替换以允许细胞的再繁殖和随后的收获。在必要时重复该程序,以从每个杂交瘤克隆得到足够量的mAb。将收获的细胞混悬液离心,并将上清液穿过0.2微米过滤膜过滤。对于抗体纯化,使用Protein G Sepharose 4快速流5 mL柱(GE Healthcare)通过重力流动纯化每个克隆的上清液。在用Tris-EDTA (TE)缓冲液pH 8.0洗涤以后,将结合的抗体使用0.1 M甘氨酸缓冲液pH 2.7洗脱,随后使用1 MTris(pH 8.0)进行pH中和。将抗体浓缩,并使用Centriprep YM-10 kDa NMWL离心过滤器单元(Millipore)将缓冲液交换进磷酸盐缓冲盐水(PBS)中。使用分光光度法定量抗体浓度。将纯化的抗-犬IL-4受体α链mAb如下通过ELISA测试与犬IL-4受体α链的HIS标记的ECD结构域的反应性:将HIS-标记的犬IL-4受体α链蛋白在包被缓冲液(碳酸盐/碳酸氢盐pH 9.0)中稀释至10µg/mL,并以100µl/孔分配在96-孔平底ELISA平板(NUNC)中。将平板在4℃温育过夜。然后将平板用含有0.05%吐温-20的磷酸盐缓冲盐水(PBST)洗涤3次。接着,将200µl封闭缓冲液(在PBST中的5%脱脂乳)加入每个孔,并将平板在37℃温育60分钟。然后将平板用PBST洗涤3次。接着,将100µl在封闭缓冲液中稀释的测试mAb加入适当列的第一个孔中。然后将测试mAb 3倍稀释至适当的平板位置。将平板在37℃温育60分钟以后,将平板用PBST洗涤3次。接着,将100µl/孔的辣根过氧化物酶缀合的山羊抗-小鼠IgG (KPL)的1:2,000稀释液加入平板,然后将平板在37℃温育60分钟。然后,将平板用PBST洗涤3次,并将100µl/孔的3,3’,5,5’四甲基联苯胺、(TMB)底物(得自KPL)加入平板。允许颜色反应在37℃发展5-20分钟,然后在650nm测量吸光度。
针对它们的结合犬IL-4Rα的细胞外结构域的能力,通过ELISA测定多种小鼠抗-犬IL-4Rα单克隆抗体(mAb)。如在图1中所示,这些mAb中的大多数表现出阳性的剂量依赖性结合。
实施例3
抗-犬IL-4受体α链单克隆抗体的重链和轻链可变结构域的DNA和预测蛋白序列的
鉴别
使用标准分子生物学方法从每个杂交瘤分离mRNA以后,鉴别小鼠VH和VL链的DNA序列。下面列出了来自这些杂交瘤的VH和VL的DNA和预测氨基酸序列的SEQ ID NO.。编码信号序列的DNA和与预测的信号序列对应的氨基酸标有下划线,与CDR对应的氨基酸以粗体显示,FR既没有标下划线也没有以粗体显示(即, 信号序列-FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)。
mAb 1A3
重链: DNA序列(SEQ ID NO: 11):
重链: 氨基酸序列(SEQ ID NO: 12):
轻链: DNA序列(SEQ ID NO: 13):
轻链: 氨基酸序列(SEQ ID NO: 14):
mAb 1A9
重链: DNA序列(SEQ ID NO: 15):
重链: 氨基酸序列(SEQ ID NO: 16):
轻链: DNA序列(SEQ ID NO: 17):
轻链: 氨基酸序列(SEQ ID NO: 18):
mAb 1B12
重链: DNA序列(SEQ ID NO: 19):
重链: 氨基酸序列(SEQ ID NO: 20):
轻链: DNA序列(SEQ ID NO: 21):
轻链: 氨基酸序列(SEQ ID NO: 22):
mAb 10C12
重链: DNA序列(SEQ ID NO: 23):
重链: 氨基酸序列(SEQ ID NO: 24):
轻链: DNA序列(SEQ ID NO: 25):
轻链: 氨基酸序列(SEQ ID NO: 26):
mAb 10F2
重链: DNA序列(SEQ ID NO: 27):
重链: 氨基酸序列(SEQ ID NO: 28):
轻链: DNA序列(SEQ ID NO: 29):
轻链: 氨基酸序列(SEQ ID NO: 30):
mAb 10E10
重链: DNA序列(SEQ ID NO: 31):
重链: 氨基酸序列(SEQ ID NO: 32):
轻链: DNA序列(SEQ ID NO: 33):
轻链: 氨基酸序列(SEQ ID NO: 34):
mAb 10G8
重链: DNA序列(SEQ ID NO: 35):
重链: 氨基酸序列(SEQ ID NO: 36):
轻链: DNA序列(SEQ ID NO: 37):
轻链: 氨基酸序列(SEQ ID NO: 38):
mAb 11B6
重链: DNA序列(SEQ ID NO: 39):
重链: 氨基酸序列(SEQ ID NO: 40):
轻链: DNA序列(SEQ ID NO: 41):
轻链: 氨基酸序列(SEQ ID NO: 42):
mAb 11D3
重链: DNA序列(SEQ ID NO: 43):
重链: 氨基酸序列(SEQ ID NO: 44):
轻链: DNA序列(SEQ ID NO: 45):
轻链: 氨基酸序列(SEQ ID NO: 46):
mAb 11H2
重链: DNA序列(SEQ ID NO: 105)
重链: 氨基酸序列(SEQ ID NO: 106)
轻链: DNA序列(SEQ ID NO: 107)
轻链: 氨基酸序列(SEQ ID NO: 108)
mAb 6C12
重链: DNA序列(SEQ ID NO: 109)
重链: 氨基酸序列(SEQ ID NO: 110)
轻链: DNA序列(SEQ ID NO: 111)
轻链: 氨基酸序列(SEQ ID NO: 112)
mAb 4H3
重链: DNA序列(SEQ ID NO: 113)
重链: 氨基酸序列(SEQ ID NO: 114)
轻链: DNA序列(SEQ ID NO: 115)
轻链: 氨基酸序列(SEQ ID NO: 116)
mAb 4D8
重链: DNA序列(SEQ ID NO: 117)
重链: 氨基酸序列(SEQ ID NO: 118)
轻链: DNA序列(SEQ ID NO: 119)
轻链: 氨基酸序列(SEQ ID NO: 120)
mAb2E2
重链: DNA序列(SEQ ID NO: 121)
重链: 氨基酸序列(SEQ ID NO: 122)
轻链: DNA序列(SEQ ID NO: 123)
轻链: 氨基酸序列(SEQ ID NO: 124)
实施例4
表达犬IL-4受体α 链的CHO细胞系的构建和在配体阻断测定中的应用
将编码全长犬IL-4受体α链(cIL-4Rα; SEQ ID NO: 4)的基因合成并亚克隆进哺乳动物表达载体中。将得到的质粒转染进CHO DG44细胞中。在转染后48小时,将所述细胞稀释进96-孔平板中以产生单细胞克隆。4-周温育以后得到约130个克隆。使用抗-cIL-4Rα单克隆抗体6B2针对cIL-4Rα的表达通过FACS筛选所有克隆。选择3个克隆用于稳定性评价。通过FACS监测20个通道的稳定性。
为了评估对犬IL-4受体α特异性的单克隆抗体的阻断犬IL-4与在CHO细胞表面上表达的犬IL-4 Rα的结合的能力,如下设置配体阻断测定:
试剂和设备:
● 细胞生长培养基: CD OptiCHO培养基+ 8mM L-谷氨酰胺+ 0.018%F-68
● FACS缓冲液: BD Pharmingen Stain缓冲液(BD目录号: 554657)
● R-藻红蛋白缀合的抗生蛋白链菌素(Life Technologies: SB66)
● 犬IL-4 (R&D system, 目录号754-CL/CF)
● Lightning-Link生物素缀合试剂盒A型(Novus: 704-0010),按照生产商的推荐用于将犬IL-4生物素化
● 流式细胞计: BD Accuri-C6
程序:
1. 将CHO-DH44-canIL-4Rα细胞培养至2 - 4 x10 6个细胞/mL,具有超过96%生存力。
2. 将所述细胞离心,抛弃上清液,并将细胞悬浮于FACS缓冲液中至2 x 10 7个细胞/mL。
3. 将所述细胞分布进U-形96-孔板中,每个孔50µl。
4. 将在FACS缓冲液中的抗-犬IL-4RαmAb在96-孔板上从50µg/mL开始从顶孔向下至底孔稀释3倍。
5. 将50µl每种稀释的Ab转移进细胞板中,并然后在冰上温育30 min。
6. 将所述细胞用FACS缓冲液洗涤2次。
7. 将所述细胞重新悬浮进100µl的0.32µg/mL的生物素化的犬IL-4在FACS缓冲液中的溶液中,并在冰上温育30 min。
8. 将所述细胞用FACS缓冲液洗涤2次。
9. 将所述细胞重新悬浮进100µl的R-藻红蛋白缀合的抗生蛋白链菌素(1:1000稀释度)在FACS缓冲液中的溶液中,并在冰上温育30 min。
10. 将所述细胞用FACS缓冲液洗涤2次。
11. 将所述细胞在FACS缓冲液中调至300µl。
12. 通过BD Accuri-C6读出每个样品的10,000个细胞。
13. 通过FlowJo分析得到的读出以获得平均荧光强度(MFI)。
使用基于细胞的CHO-cIL-4R α 结合测定,得到关于犬IL-4与在CHO细胞表面上表达的犬IL-4Rα的结合的剂量响应曲线(参见,图2A)。从该曲线确定25 nM的半数最大有效浓度(EC50)。接着,得到关于以下小鼠抗-犬IL-4Rα单克隆抗体(mAb)与CHO-cIL-4R α 的结合的剂量响应曲线:11B6、4D8、4H3、2E2、11H2和6C12 (参见,图2B)。在下面表2中提供了每种抗体的半数最大有效浓度(EC50)。
表2
各种mAB的结合/阻断
mAB | EC50 (nM) | IC50 (nM) |
11B6 | 7.5 | 53.2 |
4D8 | 1.1 | 4.2 |
4H3 | 1.6 | 3.9 |
2E2 | 1.2 | 2.1 |
11H2 | 1.2 | 1.7/1.0* |
6C12 | 8.6 | 19.3 |
*来自两个单独研究的测定。
然后针对它们的阻断犬IL-4与基于细胞的CHO-cIL-4R α 的结合的能力,测定了小鼠抗-犬IL-4Rα单克隆抗体(mAb)。如在图3A中所示,5种mAb、11B6、4D8、4H3、2E2和11H2表现出显著的阻断能力。在补充研究中,测试了第六种mAb (6C12),并在图3A中与测试的5种mAb之一(11H2)进行对比。如从图3B和表2中可见,6C12 mAb具有比11H2 mAb显著更高的半数最大抑制浓度(IC50)。4种抗-cIL-4Rα单克隆抗体4D8、2E2、4D8和11H2表现出优越的阻断能力,如在图3A和3B中、以及在表2中所见。
实施例5
小鼠CDR的氨基酸序列
来自小鼠抗-犬IL-4受体α链单克隆抗体的CDR:
表3
规范结构
* 在CDR中的半胱氨酸
** 考虑到特定模式可以做出的最佳分配。
实施例6
鼠抗-犬IL-4受体α抗体的表位作图
抗体与它们的相应蛋白抗原的相互作用通过抗体的具体氨基酸(互补位)与靶抗原的具体氨基酸(表位)的结合来介导。表位是造成免疫球蛋白的特异性反应的抗原决定簇。表位由抗原表面上的一组氨基酸组成。目标蛋白可以含有几个被不同抗体识别的表位。被抗体识别的表位分类为线性或构象表位。线性表位由蛋白中的连续氨基酸序列段形成,而构象表位由基本氨基酸序列中的不连续(例如,分开较远)的氨基酸组成,但是在三维蛋白折叠后集合在一起。
表位作图表示鉴别被它们的靶抗原上的抗体识别的氨基酸序列(即,表位)的过程。被靶抗原上的单克隆抗体(mAb)识别的表位的鉴别具有重要的用途。例如,它可以辅助开发新的治疗剂、诊断剂和疫苗。表位作图还可以辅助选择经优化的治疗性mAb并帮助阐明它们的作用机制。在IL-4受体α上的表位信息还可以阐明独特表位和限定疫苗的保护或致病作用。表位鉴别也可以导致亚单位疫苗开发,其基于鉴别出的肽表位与载体蛋白或其它免疫刺激剂的化学或遗传偶联。
可以使用多克隆或单克隆抗体进行表位作图,并根据表位的疑似性质(即,线性表位相对于构象表位)采用几种方法用于表位鉴别。描绘线性表位的图谱是更简单的且相对更容易执行。为此目的,用于线性表位作图的商业服务经常采用肽扫描。在该情况下,将靶蛋白的短肽序列的重叠集合化学合成,并测试它们的结合目标抗体的能力。所述策略是快速的、高通量的且相对廉价地执行。另一方面,不连续表位的作图更有技术挑战性,且需要更专门的技术诸如单克隆抗体以及它的靶蛋白的x-射线共晶学、氢-氘(H/D)交换、与酶消化偶联的质谱法以及本领域技术人员已知的几种其它方法。
使用质谱法描绘犬IL-4受体α表位:
采用基于化学交联和质谱法检测的方法鉴别被抗-犬IL-4受体αmAb识别的表位[CovalX Instrument Incorporated]。该技术用于犬IL-4受体α链的表位作图的应用导致在表4中列出的mAb所识别的表位的鉴别。
用在表4中包括的6种抗体对犬IL-4受体α的表位作图的结果指示,所述mAb识别存在于犬IL-4受体α的细胞外结构域内的特定肽表位。值得注意的是,为测试的6种单克隆抗体(mAb)中的每一种鉴别出2-3个表位。令人感兴趣的是,发现为mAb 2E2鉴别出的表位之一具有与mAb 11B6的表位完全相同的氨基酸序列(即,SEQ ID NO: 158)。如在下面表4中所示,mAb: 4D8、11H2和11B6都识别用“1”标记的表位,所述表位是相同直链氨基酸序列的部分;mAb: 11H2、4H3和2E2都识别用“2”标记的表位,所述表位是另一个直链氨基酸序列的部分;和mAb 4H3和2H2识别用“3”标记的表位,所述表位是第三个直链氨基酸序列的部分。有关表位的鉴别中的该相对一致性指示,这6种单克隆抗体识别有限数目的犬IL-4受体α在它的细胞外结构域内的部分。
表4
抗-犬IL-4受体α单克隆抗体识别的IL-4受体α表位
1, 2, 3标识源自3个抗原部分的3个单独表位群。
与在实施例5中关于上面表4中列出的6种抗体提供的CDR一起,在每组CDR和表4中它们的对应表位之间限定一对一关联。该关联允许实施例5中的6种CDR的集合(针对表4中的6种抗体中的每一种)与它们所结合的对应表位之间的确定联系。因此,具有在实施例5中提供的6种CDR(其结合表4中的对应表位)的确定集合的抗体(例如,犬化抗体)也是本发明的部分。
实施例7
犬化抗-犬IL-4受体α单克隆抗体的构建
为了执行犬化的过程,确定编码犬IgG的重链和轻链的DNA序列。犬重链和轻链的DNA和蛋白序列是本领域已知的,且可以通过检索NCBI基因和蛋白数据库得到。如上面指出的,对于犬抗体,存在4种已知的IgG亚型:IgG-A、IgG-B、IgG-C和IgG-D,和2类轻链,即,κ和 λ。不受任何特定方案约束,生产犬化重链和轻链(其可以以不同组合混合以产生犬化抗-犬IL-4受体αmAb)的整个过程涉及以下方案:
i) 鉴别包含期望的抗-IL-4受体αmAb的CDR的VH和VL结构域的DNA序列
ii) 鉴别期望的抗-IL-4受体mAb的H和L链CDR
iii) 鉴别犬IgG的H和L链的合适序列
iv) 鉴别编码以上序列的犬IgG H和L链的内源性CDR的DNA序列。
v) 用编码期望的抗-IL-4受体αCDR的DNA序列替换编码内源性犬H和L链CDR的DNA序列。另外,任选地,用来自期望的抗-IL-4受体mAb框架区的选定残基替换一些犬框架残基。
vi) 合成来自步骤(v)的DNA,将它克隆进合适的表达质粒中,并将含有期望的犬化H和L链的质粒转染进HEK 293细胞中。
vii) 从HEK 293上清液纯化表达的犬化抗体。
viii) 针对与犬IL-4受体α链的结合测试纯化的犬化抗体。
上述步骤的应用产生一组犬化H和L链序列,在下面表5中列出了它们的SEQ IDNO.。
表5
犬化的全长重链和轻链序列
。
本发明提供了由上面表5中列出的各种犬化重链和轻链的组合形成的犬化抗体;这样的抗体具有与犬IL-4受体α的特别紧密的结合。在一个具体实施方案中,所述重链包含SEQ ID NO: 164的氨基酸序列,且所述轻链包含SEQ ID NO: 170的氨基酸序列。在这类的一个更具体的实施方案中,所述重链由SEQ ID NO: 163的核苷酸序列编码,且所述轻链由SEQ ID NO: 169的核苷酸序列编码。在另一个实施方案中,所述重链包含SEQ ID NO: 166的氨基酸序列,且所述轻链包含SEQ ID NO: 172的氨基酸序列。在这类的一个更具体的实施方案中,所述重链由SEQ ID NO: 165的核苷酸序列编码,且所述轻链由SEQ ID NO: 171的核苷酸序列编码。在另一个实施方案中,所述重链包含SEQ ID NO: 168的氨基酸序列,且所述轻链包含SEQ ID NO: 174的氨基酸序列。在这类的一个更具体的实施方案中,所述重链由SEQ ID NO: 167的核苷酸序列编码,且所述轻链由SEQ ID NO: 173的核苷酸序列编码。这些犬化抗体与IL-4受体α的结合研究描绘在图4中,如下面实施例8中所述。
如上面指出的,所述犬化抗体的Fc部分是基于经修饰的犬IgG-B的序列,以便除去ADCC和CDC效应子功能。这些抗体的Fc区可以用来自其它犬IgG同种型的经修饰的Fc替换,和/或可以与如以上所讨论的置换铰链区组合,并在以下文献中举例说明和公开:2014年7月30日提交的美国临时申请62/030,812;2014年9月30日提交的美国临时申请62/057,541;2014年12月16日提交的美国临时申请62/092,496;2015年6月8日提交的美国临时申请62/172,511;和WO2015/091910,它们全部的内容特此通过引用整体并入。
犬化的4H3 (vH1)
SEQ ID NO: 163
SEQ ID NO: 164
犬化的4H3 (vH2)
SEQ ID NO: 165
SEQ ID NO: 166
犬化的4H3 (vH3):
SEQ ID NO: 167
SEQ ID NO: 168
犬化的4H3 (vL1)
SEQ ID NO: 169
SEQ ID NO: 170
犬化的4H3 (vL2)
SEQ ID NO: 171
SEQ ID NO: 172
犬化的4H3 (vL3)
SEQ ID NO: 173
SEQ ID NO: 174
实施例8
犬化抗体对犬IL-4受体α的反应性
针对与犬IL-4受体α的反应性如下测试了犬化抗体:
1. 将200 ng/孔的IL-4受体α包被在免疫平板上,并将所述平板在4℃温育过夜。
2. 将所述平板用含有0.05%吐温20的磷酸盐缓冲盐水(PBS) (PBST)洗涤3次。
3. 将所述平板用0.5%牛血清白蛋白(BSA)在PBS中的溶液在室温封闭45 - 60min。
4. 将所述平板用PBST洗涤3次。
5. 从0.3µg/mL开始在稀释平板的每个列或行中3倍稀释犬化抗体。
6. 将经稀释的犬化抗体转移进免疫平板的每个列或行中,并将所述平板在室温温育45 - 60 min。
7. 将所述平板用PBST洗涤3次。
8. 将1:4000稀释的辣根过氧化物酶标记的抗-犬IgG Fc加入所述平板的每个孔中,然后将所述平板在室温温育45 - 60 min。
9. 将所述平板用PBST洗涤3次。
10. 将3,3’,5,5’-四甲基联苯胺(TMB)底物加入所述平板的每个孔中,并将所述平板在室温温育10-15 min以显色。
11. 将100µL 1.5 M磷酸加入每个孔中以停止反应。用540 nm参考波长在450 nm读出平板。
如在图4中所示,研究了五种(5)抗体与IL-4受体α的结合:4H3 M-C、c4H3 H1-L1、c4H3 H2-L2、c4H3 H3-L3和2G9 M-C。将2G9 M-C用作阴性对照抗体。4H3 M-C是由本文公开的4H3抗体的小鼠可变重链区与犬恒定区和来自小鼠4H3抗体的轻链一起组成的嵌合抗体。c4H3 H1-L1、c4H3 H2-L2、c4H3 H3-L3是小鼠4H3抗体的三种犬化变体,且包括在上面表5中描述的特定重链和轻链。2G9 M-C是由小鼠抗体(其针对与IL-4受体α完全无关的抗原)的小鼠可变重链区与犬恒定区和来自小鼠抗体(其针对该无关抗原)的轻链一起组成的嵌合抗体。一致地,2G9 M-C没有结合IL-4受体α,而研究的剩余四种抗体(即,4H3 M-C、c4H3 H1-L1、c4H3 H2-L2和c4H3 H3-L3)都相对紧密地结合(参见,图4)。
序列表
<110> 英特维特国际股份有限公司
Morsey, Mohamad
Zhang, Yuanzheng
<120> 针对犬白介素-4受体α的抗体
<130> 24065
<150> US 62/142,108
<151> 2015-04-02
<150> US 62/269,486
<151> 2015-12-18
<150> US 62/310,250
<151> 2016-03-18
<160> 174
<170> PatentIn 3.5版
<210> 1
<211> 2469
<212> DNA
<213> 家犬
<400> 1
atgggcagac tgtgcagcgg cctgaccttc cccgtgagct gcctggtgct ggtgtgggtg 60
gccagcagcg gcagcgtgaa ggtgctgcac gagcccagct gcttcagcga ctacatcagc 120
accagcgtgt gccagtggaa gatggaccac cccaccaact gcagcgccga gctgagactg 180
agctaccagc tggacttcat gggcagcgag aaccacacct gcgtgcccga gaacagagag 240
gacagcgtgt gcgtgtgcag catgcccatc gacgacgccg tggaggccga cgtgtaccag 300
ctggacctgt gggccggcca gcagctgctg tggagcggca gcttccagcc cagcaagcac 360
gtgaagccca gaacccccgg caacctgacc gtgcacccca acatcagcca cacctggctg 420
ctgatgtgga ccaaccccta ccccaccgag aaccacctgc acagcgagct gacctacatg 480
gtgaacgtga gcaacgacaa cgaccccgag gacttcaagg tgtacaacgt gacctacatg 540
ggccccaccc tgagactggc cgccagcacc ctgaagagcg gcgccagcta cagcgccaga 600
gtgagagcct gggcccagac ctacaacagc acctggagcg actggagccc cagcaccacc 660
tggctgaact actacgagcc ctgggagcag cacctgcccc tgggcgtgag catcagctgc 720
ctggtgatcc tggccatctg cctgagctgc tacttcagca tcatcaagat caagaagggc 780
tggtgggacc agatccccaa ccccgcccac agccccctgg tggccatcgt gatccaggac 840
agccaggtga gcctgtgggg caagagaagc agaggccagg agcccgccaa gtgcccccac 900
tggaagacct gcctgaccaa gctgctgccc tgcctgctgg agcacggcct gggcagagag 960
gaggagagcc ccaagaccgc caagaacggc cccctgcagg gccccggcaa gcccgcctgg 1020
tgccccgtgg aggtgagcaa gaccatcctg tggcccgaga gcatcagcgt ggtgcagtgc 1080
gtggagctga gcgaggcccc cgtggacaac gaggaggagg aggaggtgga ggaggacaag 1140
agaagcctgt gccccagcct ggagggcagc ggcggcagct tccaggaggg cagagagggc 1200
atcgtggcca gactgaccga gagcctgttc ctggacctgc tgggcggcga gaacggcggc 1260
ttctgccccc agggcctgga ggagagctgc ctgccccccc ccagcggcag cgtgggcgcc 1320
cagatgccct gggcccagtt ccccagagcc ggccccagag ccgcccccga gggccccgag 1380
cagcccagaa gacccgagag cgccctgcag gccagcccca cccagagcgc cggcagcagc 1440
gccttccccg agcccccccc cgtggtgacc gacaaccccg cctacagaag cttcggcagc 1500
ttcctgggcc agagcagcga ccccggcgac ggcgacagcg accccgagct ggccgacaga 1560
cccggcgagg ccgaccccgg catccccagc gccccccagc cccccgagcc ccccgccgcc 1620
ctgcagcccg agcccgagag ctgggagcag atcctgagac agagcgtgct gcagcacaga 1680
gccgcccccg cccccggccc cggccccggc agcggctaca gagagttcac ctgcgccgtg 1740
aagcagggca gcgcccccga cgccggcggc cccggcttcg gccccagcgg cgaggccggc 1800
tacaaggcct tctgcagcct gctgcccggc ggcgccacct gccccggcac cagcggcggc 1860
gaggccggca gcggcgaggg cggctacaag cccttccaga gcctgacccc cggctgcccc 1920
ggcgccccca cccccgtgcc cgtgcccctg ttcaccttcg gcctggacac cgagcccccc 1980
ggcagccccc aggacagcct gggcgccggc agcagccccg agcacctggg cgtggagccc 2040
gccggcaagg aggaggacag cagaaagacc ctgctggccc ccgagcaggc caccgacccc 2100
ctgagagacg acctggccag cagcatcgtg tacagcgccc tgacctgcca cctgtgcggc 2160
cacctgaagc agtggcacga ccaggaggag agaggcaagg cccacatcgt gcccagcccc 2220
tgctgcggct gctgctgcgg cgacagaagc agcctgctgc tgagccccct gagagccccc 2280
aacgtgctgc ccggcggcgt gctgctggag gccagcctga gccccgccag cctggtgccc 2340
agcggcgtga gcaaggaggg caagagcagc cccttcagcc agcccgccag cagcagcgcc 2400
cagagcagca gccagacccc caagaagctg gccgtgctga gcaccgagcc cacctgcatg 2460
agcgccagc 2469
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Met Gly Arg Leu Cys Ser Gly Leu Thr Phe Pro Val Ser Cys Leu Val
1 5 10 15
Leu Val Trp Val Ala Ser Ser Gly Ser Val Lys Val Leu His Glu Pro
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Ser Cys Phe Ser Asp Tyr Ile Ser Thr Ser Val Cys Gln Trp Lys Met
35 40 45
Asp His Pro Thr Asn Cys Ser Ala Glu Leu Arg Leu Ser Tyr Gln Leu
50 55 60
Asp Phe Met Gly Ser Glu Asn His Thr Cys Val Pro Glu Asn Arg Glu
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Asp Ser Val Cys Val Cys Ser Met Pro Ile Asp Asp Ala Val Glu Ala
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Asp Val Tyr Gln Leu Asp Leu Trp Ala Gly Gln Gln Leu Leu Trp Ser
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Gly Ser Phe Gln Pro Ser Lys His Val Lys Pro Arg Thr Pro Gly Asn
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Leu Thr Val His Pro Asn Ile Ser His Thr Trp Leu Leu Met Trp Thr
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Asn Pro Tyr Pro Thr Glu Asn His Leu His Ser Glu Leu Thr Tyr Met
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Val Asn Val Ser Asn Asp Asn Asp Pro Glu Asp Phe Lys Val Tyr Asn
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Val Thr Tyr Met Gly Pro Thr Leu Arg Leu Ala Ala Ser Thr Leu Lys
180 185 190
Ser Gly Ala Ser Tyr Ser Ala Arg Val Arg Ala Trp Ala Gln Thr Tyr
195 200 205
Asn Ser Thr Trp Ser Asp Trp Ser Pro Ser Thr Thr Trp Leu Asn Tyr
210 215 220
Tyr Glu Pro Trp Glu Gln His Leu Pro Leu Gly Val Ser Ile Ser Cys
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Leu Val Ile Leu Ala Ile Cys Leu Ser Cys Tyr Phe Ser Ile Ile Lys
245 250 255
Ile Lys Lys Gly Trp Trp Asp Gln Ile Pro Asn Pro Ala His Ser Pro
260 265 270
Leu Val Ala Ile Val Ile Gln Asp Ser Gln Val Ser Leu Trp Gly Lys
275 280 285
Arg Ser Arg Gly Gln Glu Pro Ala Lys Cys Pro His Trp Lys Thr Cys
290 295 300
Leu Thr Lys Leu Leu Pro Cys Leu Leu Glu His Gly Leu Gly Arg Glu
305 310 315 320
Glu Glu Ser Pro Lys Thr Ala Lys Asn Gly Pro Leu Gln Gly Pro Gly
325 330 335
Lys Pro Ala Trp Cys Pro Val Glu Val Ser Lys Thr Ile Leu Trp Pro
340 345 350
Glu Ser Ile Ser Val Val Gln Cys Val Glu Leu Ser Glu Ala Pro Val
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Asp Asn Glu Glu Glu Glu Glu Val Glu Glu Asp Lys Arg Ser Leu Cys
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Pro Ser Leu Glu Gly Ser Gly Gly Ser Phe Gln Glu Gly Arg Glu Gly
385 390 395 400
Ile Val Ala Arg Leu Thr Glu Ser Leu Phe Leu Asp Leu Leu Gly Gly
405 410 415
Glu Asn Gly Gly Phe Cys Pro Gln Gly Leu Glu Glu Ser Cys Leu Pro
420 425 430
Pro Pro Ser Gly Ser Val Gly Ala Gln Met Pro Trp Ala Gln Phe Pro
435 440 445
Arg Ala Gly Pro Arg Ala Ala Pro Glu Gly Pro Glu Gln Pro Arg Arg
450 455 460
Pro Glu Ser Ala Leu Gln Ala Ser Pro Thr Gln Ser Ala Gly Ser Ser
465 470 475 480
Ala Phe Pro Glu Pro Pro Pro Val Val Thr Asp Asn Pro Ala Tyr Arg
485 490 495
Ser Phe Gly Ser Phe Leu Gly Gln Ser Ser Asp Pro Gly Asp Gly Asp
500 505 510
Ser Asp Pro Glu Leu Ala Asp Arg Pro Gly Glu Ala Asp Pro Gly Ile
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Pro Ser Ala Pro Gln Pro Pro Glu Pro Pro Ala Ala Leu Gln Pro Glu
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Pro Glu Ser Trp Glu Gln Ile Leu Arg Gln Ser Val Leu Gln His Arg
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Ala Ala Pro Ala Pro Gly Pro Gly Pro Gly Ser Gly Tyr Arg Glu Phe
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Thr Cys Ala Val Lys Gln Gly Ser Ala Pro Asp Ala Gly Gly Pro Gly
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Phe Gly Pro Ser Gly Glu Ala Gly Tyr Lys Ala Phe Cys Ser Leu Leu
595 600 605
Pro Gly Gly Ala Thr Cys Pro Gly Thr Ser Gly Gly Glu Ala Gly Ser
610 615 620
Gly Glu Gly Gly Tyr Lys Pro Phe Gln Ser Leu Thr Pro Gly Cys Pro
625 630 635 640
Gly Ala Pro Thr Pro Val Pro Val Pro Leu Phe Thr Phe Gly Leu Asp
645 650 655
Thr Glu Pro Pro Gly Ser Pro Gln Asp Ser Leu Gly Ala Gly Ser Ser
660 665 670
Pro Glu His Leu Gly Val Glu Pro Ala Gly Lys Glu Glu Asp Ser Arg
675 680 685
Lys Thr Leu Leu Ala Pro Glu Gln Ala Thr Asp Pro Leu Arg Asp Asp
690 695 700
Leu Ala Ser Ser Ile Val Tyr Ser Ala Leu Thr Cys His Leu Cys Gly
705 710 715 720
His Leu Lys Gln Trp His Asp Gln Glu Glu Arg Gly Lys Ala His Ile
725 730 735
Val Pro Ser Pro Cys Cys Gly Cys Cys Cys Gly Asp Arg Ser Ser Leu
740 745 750
Leu Leu Ser Pro Leu Arg Ala Pro Asn Val Leu Pro Gly Gly Val Leu
755 760 765
Leu Glu Ala Ser Leu Ser Pro Ala Ser Leu Val Pro Ser Gly Val Ser
770 775 780
Lys Glu Gly Lys Ser Ser Pro Phe Ser Gln Pro Ala Ser Ser Ser Ala
785 790 795 800
Gln Ser Ser Ser Gln Thr Pro Lys Lys Leu Ala Val Leu Ser Thr Glu
805 810 815
Pro Thr Cys Met Ser Ala Ser
820
<210> 3
<211> 2394
<212> DNA
<213> 家犬
<400> 3
gtgaaggtgc tgcacgagcc cagctgcttc agcgactaca tcagcaccag cgtgtgccag 60
tggaagatgg accaccccac caactgcagc gccgagctga gactgagcta ccagctggac 120
ttcatgggca gcgagaacca cacctgcgtg cccgagaaca gagaggacag cgtgtgcgtg 180
tgcagcatgc ccatcgacga cgccgtggag gccgacgtgt accagctgga cctgtgggcc 240
ggccagcagc tgctgtggag cggcagcttc cagcccagca agcacgtgaa gcccagaacc 300
cccggcaacc tgaccgtgca ccccaacatc agccacacct ggctgctgat gtggaccaac 360
ccctacccca ccgagaacca cctgcacagc gagctgacct acatggtgaa cgtgagcaac 420
gacaacgacc ccgaggactt caaggtgtac aacgtgacct acatgggccc caccctgaga 480
ctggccgcca gcaccctgaa gagcggcgcc agctacagcg ccagagtgag agcctgggcc 540
cagacctaca acagcacctg gagcgactgg agccccagca ccacctggct gaactactac 600
gagccctggg agcagcacct gcccctgggc gtgagcatca gctgcctggt gatcctggcc 660
atctgcctga gctgctactt cagcatcatc aagatcaaga agggctggtg ggaccagatc 720
cccaaccccg cccacagccc cctggtggcc atcgtgatcc aggacagcca ggtgagcctg 780
tggggcaaga gaagcagagg ccaggagccc gccaagtgcc cccactggaa gacctgcctg 840
accaagctgc tgccctgcct gctggagcac ggcctgggca gagaggagga gagccccaag 900
accgccaaga acggccccct gcagggcccc ggcaagcccg cctggtgccc cgtggaggtg 960
agcaagacca tcctgtggcc cgagagcatc agcgtggtgc agtgcgtgga gctgagcgag 1020
gcccccgtgg acaacgagga ggaggaggag gtggaggagg acaagagaag cctgtgcccc 1080
agcctggagg gcagcggcgg cagcttccag gagggcagag agggcatcgt ggccagactg 1140
accgagagcc tgttcctgga cctgctgggc ggcgagaacg gcggcttctg cccccagggc 1200
ctggaggaga gctgcctgcc cccccccagc ggcagcgtgg gcgcccagat gccctgggcc 1260
cagttcccca gagccggccc cagagccgcc cccgagggcc ccgagcagcc cagaagaccc 1320
gagagcgccc tgcaggccag ccccacccag agcgccggca gcagcgcctt ccccgagccc 1380
ccccccgtgg tgaccgacaa ccccgcctac agaagcttcg gcagcttcct gggccagagc 1440
agcgaccccg gcgacggcga cagcgacccc gagctggccg acagacccgg cgaggccgac 1500
cccggcatcc ccagcgcccc ccagcccccc gagccccccg ccgccctgca gcccgagccc 1560
gagagctggg agcagatcct gagacagagc gtgctgcagc acagagccgc ccccgccccc 1620
ggccccggcc ccggcagcgg ctacagagag ttcacctgcg ccgtgaagca gggcagcgcc 1680
cccgacgccg gcggccccgg cttcggcccc agcggcgagg ccggctacaa ggccttctgc 1740
agcctgctgc ccggcggcgc cacctgcccc ggcaccagcg gcggcgaggc cggcagcggc 1800
gagggcggct acaagccctt ccagagcctg acccccggct gccccggcgc ccccaccccc 1860
gtgcccgtgc ccctgttcac cttcggcctg gacaccgagc cccccggcag cccccaggac 1920
agcctgggcg ccggcagcag ccccgagcac ctgggcgtgg agcccgccgg caaggaggag 1980
gacagcagaa agaccctgct ggcccccgag caggccaccg accccctgag agacgacctg 2040
gccagcagca tcgtgtacag cgccctgacc tgccacctgt gcggccacct gaagcagtgg 2100
cacgaccagg aggagagagg caaggcccac atcgtgccca gcccctgctg cggctgctgc 2160
tgcggcgaca gaagcagcct gctgctgagc cccctgagag cccccaacgt gctgcccggc 2220
ggcgtgctgc tggaggccag cctgagcccc gccagcctgg tgcccagcgg cgtgagcaag 2280
gagggcaaga gcagcccctt cagccagccc gccagcagca gcgcccagag cagcagccag 2340
acccccaaga agctggccgt gctgagcacc gagcccacct gcatgagcgc cagc 2394
<210> 4
<211> 798
<212> PRT
<213> 家犬
<400> 4
Val Lys Val Leu His Glu Pro Ser Cys Phe Ser Asp Tyr Ile Ser Thr
1 5 10 15
Ser Val Cys Gln Trp Lys Met Asp His Pro Thr Asn Cys Ser Ala Glu
20 25 30
Leu Arg Leu Ser Tyr Gln Leu Asp Phe Met Gly Ser Glu Asn His Thr
35 40 45
Cys Val Pro Glu Asn Arg Glu Asp Ser Val Cys Val Cys Ser Met Pro
50 55 60
Ile Asp Asp Ala Val Glu Ala Asp Val Tyr Gln Leu Asp Leu Trp Ala
65 70 75 80
Gly Gln Gln Leu Leu Trp Ser Gly Ser Phe Gln Pro Ser Lys His Val
85 90 95
Lys Pro Arg Thr Pro Gly Asn Leu Thr Val His Pro Asn Ile Ser His
100 105 110
Thr Trp Leu Leu Met Trp Thr Asn Pro Tyr Pro Thr Glu Asn His Leu
115 120 125
His Ser Glu Leu Thr Tyr Met Val Asn Val Ser Asn Asp Asn Asp Pro
130 135 140
Glu Asp Phe Lys Val Tyr Asn Val Thr Tyr Met Gly Pro Thr Leu Arg
145 150 155 160
Leu Ala Ala Ser Thr Leu Lys Ser Gly Ala Ser Tyr Ser Ala Arg Val
165 170 175
Arg Ala Trp Ala Gln Thr Tyr Asn Ser Thr Trp Ser Asp Trp Ser Pro
180 185 190
Ser Thr Thr Trp Leu Asn Tyr Tyr Glu Pro Trp Glu Gln His Leu Pro
195 200 205
Leu Gly Val Ser Ile Ser Cys Leu Val Ile Leu Ala Ile Cys Leu Ser
210 215 220
Cys Tyr Phe Ser Ile Ile Lys Ile Lys Lys Gly Trp Trp Asp Gln Ile
225 230 235 240
Pro Asn Pro Ala His Ser Pro Leu Val Ala Ile Val Ile Gln Asp Ser
245 250 255
Gln Val Ser Leu Trp Gly Lys Arg Ser Arg Gly Gln Glu Pro Ala Lys
260 265 270
Cys Pro His Trp Lys Thr Cys Leu Thr Lys Leu Leu Pro Cys Leu Leu
275 280 285
Glu His Gly Leu Gly Arg Glu Glu Glu Ser Pro Lys Thr Ala Lys Asn
290 295 300
Gly Pro Leu Gln Gly Pro Gly Lys Pro Ala Trp Cys Pro Val Glu Val
305 310 315 320
Ser Lys Thr Ile Leu Trp Pro Glu Ser Ile Ser Val Val Gln Cys Val
325 330 335
Glu Leu Ser Glu Ala Pro Val Asp Asn Glu Glu Glu Glu Glu Val Glu
340 345 350
Glu Asp Lys Arg Ser Leu Cys Pro Ser Leu Glu Gly Ser Gly Gly Ser
355 360 365
Phe Gln Glu Gly Arg Glu Gly Ile Val Ala Arg Leu Thr Glu Ser Leu
370 375 380
Phe Leu Asp Leu Leu Gly Gly Glu Asn Gly Gly Phe Cys Pro Gln Gly
385 390 395 400
Leu Glu Glu Ser Cys Leu Pro Pro Pro Ser Gly Ser Val Gly Ala Gln
405 410 415
Met Pro Trp Ala Gln Phe Pro Arg Ala Gly Pro Arg Ala Ala Pro Glu
420 425 430
Gly Pro Glu Gln Pro Arg Arg Pro Glu Ser Ala Leu Gln Ala Ser Pro
435 440 445
Thr Gln Ser Ala Gly Ser Ser Ala Phe Pro Glu Pro Pro Pro Val Val
450 455 460
Thr Asp Asn Pro Ala Tyr Arg Ser Phe Gly Ser Phe Leu Gly Gln Ser
465 470 475 480
Ser Asp Pro Gly Asp Gly Asp Ser Asp Pro Glu Leu Ala Asp Arg Pro
485 490 495
Gly Glu Ala Asp Pro Gly Ile Pro Ser Ala Pro Gln Pro Pro Glu Pro
500 505 510
Pro Ala Ala Leu Gln Pro Glu Pro Glu Ser Trp Glu Gln Ile Leu Arg
515 520 525
Gln Ser Val Leu Gln His Arg Ala Ala Pro Ala Pro Gly Pro Gly Pro
530 535 540
Gly Ser Gly Tyr Arg Glu Phe Thr Cys Ala Val Lys Gln Gly Ser Ala
545 550 555 560
Pro Asp Ala Gly Gly Pro Gly Phe Gly Pro Ser Gly Glu Ala Gly Tyr
565 570 575
Lys Ala Phe Cys Ser Leu Leu Pro Gly Gly Ala Thr Cys Pro Gly Thr
580 585 590
Ser Gly Gly Glu Ala Gly Ser Gly Glu Gly Gly Tyr Lys Pro Phe Gln
595 600 605
Ser Leu Thr Pro Gly Cys Pro Gly Ala Pro Thr Pro Val Pro Val Pro
610 615 620
Leu Phe Thr Phe Gly Leu Asp Thr Glu Pro Pro Gly Ser Pro Gln Asp
625 630 635 640
Ser Leu Gly Ala Gly Ser Ser Pro Glu His Leu Gly Val Glu Pro Ala
645 650 655
Gly Lys Glu Glu Asp Ser Arg Lys Thr Leu Leu Ala Pro Glu Gln Ala
660 665 670
Thr Asp Pro Leu Arg Asp Asp Leu Ala Ser Ser Ile Val Tyr Ser Ala
675 680 685
Leu Thr Cys His Leu Cys Gly His Leu Lys Gln Trp His Asp Gln Glu
690 695 700
Glu Arg Gly Lys Ala His Ile Val Pro Ser Pro Cys Cys Gly Cys Cys
705 710 715 720
Cys Gly Asp Arg Ser Ser Leu Leu Leu Ser Pro Leu Arg Ala Pro Asn
725 730 735
Val Leu Pro Gly Gly Val Leu Leu Glu Ala Ser Leu Ser Pro Ala Ser
740 745 750
Leu Val Pro Ser Gly Val Ser Lys Glu Gly Lys Ser Ser Pro Phe Ser
755 760 765
Gln Pro Ala Ser Ser Ser Ala Gln Ser Ser Ser Gln Thr Pro Lys Lys
770 775 780
Leu Ala Val Leu Ser Thr Glu Pro Thr Cys Met Ser Ala Ser
785 790 795
<210> 5
<211> 624
<212> DNA
<213> 家犬
<400> 5
gtgaaggtgc tgcacgagcc cagctgcttc agcgactaca tcagcaccag cgtgtgccag 60
tggaagatgg accaccccac caactgcagc gccgagctga gactgagcta ccagctggac 120
ttcatgggca gcgagaacca cacctgcgtg cccgagaaca gagaggacag cgtgtgcgtg 180
tgcagcatgc ccatcgacga cgccgtggag gccgacgtgt accagctgga cctgtgggcc 240
ggccagcagc tgctgtggag cggcagcttc cagcccagca agcacgtgaa gcccagaacc 300
cccggcaacc tgaccgtgca ccccaacatc agccacacct ggctgctgat gtggaccaac 360
ccctacccca ccgagaacca cctgcacagc gagctgacct acatggtgaa cgtgagcaac 420
gacaacgacc ccgaggactt caaggtgtac aacgtgacct acatgggccc caccctgaga 480
ctggccgcca gcaccctgaa gagcggcgcc agctacagcg ccagagtgag agcctgggcc 540
cagacctaca acagcacctg gagcgactgg agccccagca ccacctggct gaactactac 600
gagccctggg agcagcacct gccc 624
<210> 6
<211> 208
<212> PRT
<213> 家犬
<400> 6
Val Lys Val Leu His Glu Pro Ser Cys Phe Ser Asp Tyr Ile Ser Thr
1 5 10 15
Ser Val Cys Gln Trp Lys Met Asp His Pro Thr Asn Cys Ser Ala Glu
20 25 30
Leu Arg Leu Ser Tyr Gln Leu Asp Phe Met Gly Ser Glu Asn His Thr
35 40 45
Cys Val Pro Glu Asn Arg Glu Asp Ser Val Cys Val Cys Ser Met Pro
50 55 60
Ile Asp Asp Ala Val Glu Ala Asp Val Tyr Gln Leu Asp Leu Trp Ala
65 70 75 80
Gly Gln Gln Leu Leu Trp Ser Gly Ser Phe Gln Pro Ser Lys His Val
85 90 95
Lys Pro Arg Thr Pro Gly Asn Leu Thr Val His Pro Asn Ile Ser His
100 105 110
Thr Trp Leu Leu Met Trp Thr Asn Pro Tyr Pro Thr Glu Asn His Leu
115 120 125
His Ser Glu Leu Thr Tyr Met Val Asn Val Ser Asn Asp Asn Asp Pro
130 135 140
Glu Asp Phe Lys Val Tyr Asn Val Thr Tyr Met Gly Pro Thr Leu Arg
145 150 155 160
Leu Ala Ala Ser Thr Leu Lys Ser Gly Ala Ser Tyr Ser Ala Arg Val
165 170 175
Arg Ala Trp Ala Gln Thr Tyr Asn Ser Thr Trp Ser Asp Trp Ser Pro
180 185 190
Ser Thr Thr Trp Leu Asn Tyr Tyr Glu Pro Trp Glu Gln His Leu Pro
195 200 205
<210> 7
<211> 648
<212> DNA
<213> 人工序列
<220>
<223> 具有HIS标签的家犬
<400> 7
gtgaaggtgc tgcacgagcc cagctgcttc agcgactaca tcagcaccag cgtgtgccag 60
tggaagatgg accaccccac caactgcagc gccgagctga gactgagcta ccagctggac 120
ttcatgggca gcgagaacca cacctgcgtg cccgagaaca gagaggacag cgtgtgcgtg 180
tgcagcatgc ccatcgacga cgccgtggag gccgacgtgt accagctgga cctgtgggcc 240
ggccagcagc tgctgtggag cggcagcttc cagcccagca agcacgtgaa gcccagaacc 300
cccggcaacc tgaccgtgca ccccaacatc agccacacct ggctgctgat gtggaccaac 360
ccctacccca ccgagaacca cctgcacagc gagctgacct acatggtgaa cgtgagcaac 420
gacaacgacc ccgaggactt caaggtgtac aacgtgacct acatgggccc caccctgaga 480
ctggccgcca gcaccctgaa gagcggcgcc agctacagcg ccagagtgag agcctgggcc 540
cagacctaca acagcacctg gagcgactgg agccccagca ccacctggct gaactactac 600
gagccctggg agcagcacct gccccaccac caccaccacc accaccac 648
<210> 8
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 具有HIS标签的家犬
<400> 8
Val Lys Val Leu His Glu Pro Ser Cys Phe Ser Asp Tyr Ile Ser Thr
1 5 10 15
Ser Val Cys Gln Trp Lys Met Asp His Pro Thr Asn Cys Ser Ala Glu
20 25 30
Leu Arg Leu Ser Tyr Gln Leu Asp Phe Met Gly Ser Glu Asn His Thr
35 40 45
Cys Val Pro Glu Asn Arg Glu Asp Ser Val Cys Val Cys Ser Met Pro
50 55 60
Ile Asp Asp Ala Val Glu Ala Asp Val Tyr Gln Leu Asp Leu Trp Ala
65 70 75 80
Gly Gln Gln Leu Leu Trp Ser Gly Ser Phe Gln Pro Ser Lys His Val
85 90 95
Lys Pro Arg Thr Pro Gly Asn Leu Thr Val His Pro Asn Ile Ser His
100 105 110
Thr Trp Leu Leu Met Trp Thr Asn Pro Tyr Pro Thr Glu Asn His Leu
115 120 125
His Ser Glu Leu Thr Tyr Met Val Asn Val Ser Asn Asp Asn Asp Pro
130 135 140
Glu Asp Phe Lys Val Tyr Asn Val Thr Tyr Met Gly Pro Thr Leu Arg
145 150 155 160
Leu Ala Ala Ser Thr Leu Lys Ser Gly Ala Ser Tyr Ser Ala Arg Val
165 170 175
Arg Ala Trp Ala Gln Thr Tyr Asn Ser Thr Trp Ser Asp Trp Ser Pro
180 185 190
Ser Thr Thr Trp Leu Asn Tyr Tyr Glu Pro Trp Glu Gln His Leu Pro
195 200 205
His His His His His His His His
210 215
<210> 9
<211> 1317
<212> DNA
<213> 人工序列
<220>
<223> 家犬和人
<400> 9
gtgaaggtgc tgcacgagcc cagctgcttc agcgactaca tcagcaccag cgtgtgccag 60
tggaagatgg accaccccac caactgcagc gccgagctga gactgagcta ccagctggac 120
ttcatgggca gcgagaacca cacctgcgtg cccgagaaca gagaggacag cgtgtgcgtg 180
tgcagcatgc ccatcgacga cgccgtggag gccgacgtgt accagctgga cctgtgggcc 240
ggccagcagc tgctgtggag cggcagcttc cagcccagca agcacgtgaa gcccagaacc 300
cccggcaacc tgaccgtgca ccccaacatc agccacacct ggctgctgat gtggaccaac 360
ccctacccca ccgagaacca cctgcacagc gagctgacct acatggtgaa cgtgagcaac 420
gacaacgacc ccgaggactt caaggtgtac aacgtgacct acatgggccc caccctgaga 480
ctggccgcca gcaccctgaa gagcggcgcc agctacagcg ccagagtgag agcctgggcc 540
cagacctaca acagcacctg gagcgactgg agccccagca ccacctggct gaactactac 600
gagccctggg agcagcacct ggagcccaag agctgcgaca agacccacac ctgccccccc 660
tgccccgccc ccgagctgct gggcggcccc agcgtgttcc tgttcccccc caagcccaag 720
gacaccctga tgatcagcag aacccccgag gtgacctgcg tggtggtgga cgtgagccac 780
gaggaccccg aggtgaagtt caactggtac gtggacggcg tggaggtgca caacgccaag 840
accaagccca gagaggagca gtacaacagc acctacagag tggtgagcgt gctgaccgtg 900
ctgcaccagg actggctgaa cggcaaggag tacaagtgca aggtgagcaa caaggccctg 960
cccgccccca tcgagaagac catcagcaag gccaagggcc agcccagaga gccccaggtg 1020
tacaccctgc cccccagcag agacgagctg accaagaacc aggtgagcct gacctgcctg 1080
gtgaagggct tctaccccag cgacatcgcc gtggagtggg agagcaacgg ccagcccgag 1140
aacaactaca agaccacccc ccccgtgctg gacagcgacg gcagcttctt cctgtacagc 1200
aagctgaccg tggacaagag cagatggcag cagggcaacg tgttcagctg cagcgtgatg 1260
cacgaggccc tgcacaacca ctacacccag aagagcctga gcctgagccc cggcaag 1317
<210> 10
<211> 439
<212> PRT
<213> 人工序列
<220>
<223> 家犬和人
<400> 10
Val Lys Val Leu His Glu Pro Ser Cys Phe Ser Asp Tyr Ile Ser Thr
1 5 10 15
Ser Val Cys Gln Trp Lys Met Asp His Pro Thr Asn Cys Ser Ala Glu
20 25 30
Leu Arg Leu Ser Tyr Gln Leu Asp Phe Met Gly Ser Glu Asn His Thr
35 40 45
Cys Val Pro Glu Asn Arg Glu Asp Ser Val Cys Val Cys Ser Met Pro
50 55 60
Ile Asp Asp Ala Val Glu Ala Asp Val Tyr Gln Leu Asp Leu Trp Ala
65 70 75 80
Gly Gln Gln Leu Leu Trp Ser Gly Ser Phe Gln Pro Ser Lys His Val
85 90 95
Lys Pro Arg Thr Pro Gly Asn Leu Thr Val His Pro Asn Ile Ser His
100 105 110
Thr Trp Leu Leu Met Trp Thr Asn Pro Tyr Pro Thr Glu Asn His Leu
115 120 125
His Ser Glu Leu Thr Tyr Met Val Asn Val Ser Asn Asp Asn Asp Pro
130 135 140
Glu Asp Phe Lys Val Tyr Asn Val Thr Tyr Met Gly Pro Thr Leu Arg
145 150 155 160
Leu Ala Ala Ser Thr Leu Lys Ser Gly Ala Ser Tyr Ser Ala Arg Val
165 170 175
Arg Ala Trp Ala Gln Thr Tyr Asn Ser Thr Trp Ser Asp Trp Ser Pro
180 185 190
Ser Thr Thr Trp Leu Asn Tyr Tyr Glu Pro Trp Glu Gln His Leu Glu
195 200 205
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
210 215 220
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
225 230 235 240
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
245 250 255
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
260 265 270
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
275 280 285
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
290 295 300
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
305 310 315 320
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
325 330 335
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
340 345 350
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
355 360 365
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
370 375 380
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
385 390 395 400
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
405 410 415
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
420 425 430
Leu Ser Leu Ser Pro Gly Lys
435
<210> 11
<211> 420
<212> DNA
<213> 小家鼠
<400> 11
atggactcca ggctcaattt agttttcctt gtccttattt taaaaggtgt ccggtgtgag 60
gtgcagctgg tggagtctgg gggagactta gtgaagcctg gagggtccct gaaactctcc 120
tgtgcagcct ctggattcac tttcagtgac tttggaatgc actgggttcg tcaggctcca 180
gagaaggggc tggggtgggt tgcatacatt agtagtggca gtggtaccat ctactatgca 240
gacacagtga ggggccgatt caccatctcc agagacaatg tcaagaacac cctgttcctg 300
caaatgacca gtctgaggtc tgaggacacg gccatgtatt actgtgtaag gggggacctt 360
tactacggta gtagtttcga tgcttattgg ggccgaggga ctctggtcac tgtctctgca 420
<210> 12
<211> 140
<212> PRT
<213> 小家鼠
<400> 12
Met Asp Ser Arg Leu Asn Leu Val Phe Leu Val Leu Ile Leu Lys Gly
1 5 10 15
Val Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asp Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu
50 55 60
Gly Trp Val Ala Tyr Ile Ser Ser Gly Ser Gly Thr Ile Tyr Tyr Ala
65 70 75 80
Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn
85 90 95
Thr Leu Phe Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Val Arg Gly Asp Leu Tyr Tyr Gly Ser Ser Phe Asp Ala
115 120 125
Tyr Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ala
130 135 140
<210> 13
<211> 384
<212> DNA
<213> 小家鼠
<400> 13
atggattttc aagtgcagat tttcagcttc ctgctaatca gtgcttcagt cataatgtcc 60
agaggacaaa ttgttctctc ccagtctcca gcaatcctgt ctgcatctcc aggggagaag 120
gtcacaatga cttgcagggc cagctcaagt gtaagtttca tgttctggta ccagcagaag 180
ccaggatcct cccccaaacc ctggatttat gacacatcca acctggcttc tggagtccct 240
gctcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagagtggag 300
gctgaagatg ctgccactta ttactgccag cagtggagta gtaacccact cacgttcggt 360
gctgggacca agctggagct gaaa 384
<210> 14
<211> 128
<212> PRT
<213> 小家鼠
<400> 14
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Ser Phe Met Phe Trp Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Asp Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
115 120 125
<210> 15
<211> 405
<212> DNA
<213> 小家鼠
<400> 15
atggaatggc cttgtatctt tctcttcctc ctgtcagtaa ctgaaggtgt ccactcccag 60
gttccgctgc agcagtctgg acctgagctg gtgaagcctg gggcctcagt gaagatttcc 120
tgcaaggctt ctggctacgc attcagtagc tcctggatga actgggtgaa gcagaggcct 180
ggaaagggtc ttgagtggat tggacggatt tatcctggag atggagatac taagtacaat 240
gggaagttca agggcaaggc cacactgact gcagacaaat cctccagcac agcctacatg 300
caactcagca gcctgacatc ggaggactct gcggtttact tctgtgcaag agatgattac 360
gacgaggctt cctggggcca agggactctg gtcactgtct ctgca 405
<210> 16
<211> 135
<212> PRT
<213> 小家鼠
<400> 16
Met Glu Trp Pro Cys Ile Phe Leu Phe Leu Leu Ser Val Thr Glu Gly
1 5 10 15
Val His Ser Gln Val Pro Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe
35 40 45
Ser Ser Ser Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Lys Tyr Asn
65 70 75 80
Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Phe Cys Ala Arg Asp Asp Tyr Asp Glu Ala Ser Trp Gly Gln Gly
115 120 125
Thr Leu Val Thr Val Ser Ala
130 135
<210> 17
<211> 393
<212> DNA
<213> 小家鼠
<400> 17
atgggcatca agatggagtt tcagacccag gtctttgtat tcgtgttgct ctggttgtct 60
ggtgttgatg gagacattgt gatgacccag tctcaaaaat tcatgtccac atcagtagga 120
gacagggtca gcatcacctg caaggccagt cagaatgttc gttctgctgt agcctggtat 180
caacagaaac cagggcagtc tcctaaatca ctgatttact tggcatccaa ccggcacact 240
ggagtccctg atcgcttcac aggcagtgga tctgggacag atttcactct caccattagc 300
aatgtgcaat ctgaagacct ggcagattat ttctgtctgc aacattggaa ttatccattc 360
acgttcggct cggggacaaa gttggaaata aaa 393
<210> 18
<211> 131
<212> PRT
<213> 小家鼠
<400> 18
Met Gly Ile Lys Met Glu Phe Gln Thr Gln Val Phe Val Phe Val Leu
1 5 10 15
Leu Trp Leu Ser Gly Val Asp Gly Asp Ile Val Met Thr Gln Ser Gln
20 25 30
Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys
35 40 45
Ala Ser Gln Asn Val Arg Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Ser Leu Ile Tyr Leu Ala Ser Asn Arg His Thr
65 70 75 80
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr Phe Cys
100 105 110
Leu Gln His Trp Asn Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu
115 120 125
Glu Ile Lys
130
<210> 19
<211> 429
<212> DNA
<213> 小家鼠
<400> 19
atgggatgga gctggatctt tctctttctc ctgtcaggaa ctgcaggtgt cctctctgag 60
gtccagctgc aacaatctgg acctgagctg gtgaagcctg gggcttcagt gaagatatcc 120
tgtaaggctt ctggatacac gttcactgac tattacatga actgggtgaa gcagagccat 180
ggaaagagcc ttgagtggat tggagacatt attcctagca atggtggtac tagctacaac 240
cagaagttca agggcaaggc cacattgact gtagacaagt cctccagcgc agcctacatg 300
gagctccgca gcctgacatc tgaggactct gcagtctatt actgtgcaag agggatcagc 360
tactatggta accgatatta ctttactatg gactattggg gtcaaggaac ctcagtcacc 420
gtctcctca 429
<210> 20
<211> 143
<212> PRT
<213> 小家鼠
<400> 20
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu
50 55 60
Glu Trp Ile Gly Asp Ile Ile Pro Ser Asn Gly Gly Thr Ser Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Ala Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Ile Ser Tyr Tyr Gly Asn Arg Tyr Tyr Phe
115 120 125
Thr Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
130 135 140
<210> 21
<211> 396
<212> DNA
<213> 小家鼠
<400> 21
atgaggtgcc tagctgagtt cctggggctg cttgtgctct ggatccctgg agccattggg 60
gatattgtga tgactcaggc tgcaccctct gtacctgtca ctcctggaga gtcagtatcc 120
atctcctgca ggtctagtaa gagtctcctg catagtaatg gcaacactta cttgttttgg 180
ttcgtgcaga ggccaggcca gtctcctcag ctcctgatat atcggatgtc caaccttgcc 240
tcaggagtcc cagacaggtt cagtggcagt gggtcaggaa ctgctttcac actgagaatc 300
agtagagtgg aggctgagga tgtgggtgtt tattactgta tgcaacatct agaatatcca 360
ttcacgttcg gctcggggac aaagttggac ataaaa 396
<210> 22
<211> 132
<212> PRT
<213> 小家鼠
<400> 22
Met Arg Cys Leu Ala Glu Phe Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
Gly Ala Ile Gly Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro
20 25 30
Val Thr Pro Gly Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser
35 40 45
Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Phe Trp Phe Val Gln Arg
50 55 60
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe
85 90 95
Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
100 105 110
Cys Met Gln His Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys
115 120 125
Leu Asp Ile Lys
130
<210> 23
<211> 417
<212> DNA
<213> 小家鼠
<400> 23
atggaatgga gctggatctt tctcttcctc ctgtcagtaa ctgcaggtgt ccaatcccag 60
gttcaactgc agcagtctgg ggctgagctg gtgaggcctg gggcttcagt gaagctgtcc 120
tgcaaggctt cgggctacac atttactgac tatgaaatgc actgtgtgaa gcagacacct 180
gtgcacggcc tggaatggat tggagctatt gatcctgaaa cttgtggtac tgcctacaat 240
cagaagttca agggcaaggc cacactgact gcagacaaat cctccagcac agcctacatg 300
gagctccgca gcctgacatc tgaggactct gccgtctatt actgtacaag atcgaaactg 360
ggacgagggt ggtacttcga tgtctggggc acagggacca cggtcaccgt ctcctca 417
<210> 24
<211> 139
<212> PRT
<213> 小家鼠
<400> 24
Met Glu Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Val Thr Ala Gly
1 5 10 15
Val Gln Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Glu Met His Cys Val Lys Gln Thr Pro Val His Gly Leu
50 55 60
Glu Trp Ile Gly Ala Ile Asp Pro Glu Thr Cys Gly Thr Ala Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Thr Arg Ser Lys Leu Gly Arg Gly Trp Tyr Phe Asp Val
115 120 125
Trp Gly Thr Gly Thr Thr Val Thr Val Ser Ser
130 135
<210> 25
<211> 399
<212> DNA
<213> 小家鼠
<400> 25
atggaatcac agacccaggt cctcatgttt cttctgctct gggtatctgg tgcctgtgca 60
gacattgtga tgacacagtc tccatcctcc ctggctatgt cagtaggaca gaaggtcact 120
atgagctgca agtccagtca gagcctttta aatagtagca atcaaaagaa ctatttggcc 180
tggtaccagc agaaaccagg acagtctcct aaacttctgg tatactttgc atccactagg 240
gaatctgggg tccctgatcg cttcataggc agtggatctg ggacagattt cactcttacc 300
atcagcagtg tgcaggctga agacctggca gattacttct gtcagcaaca ttatagcact 360
ccgtacacgt tcggaggggg gaccaagctg gaaataaaa 399
<210> 26
<211> 133
<212> PRT
<213> 小家鼠
<400> 26
Met Glu Ser Gln Thr Gln Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
Gly Ala Cys Ala Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala
20 25 30
Met Ser Val Gly Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser
35 40 45
Leu Leu Asn Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg
65 70 75 80
Glu Ser Gly Val Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr
100 105 110
Phe Cys Gln Gln His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Leu Glu Ile Lys
130
<210> 27
<211> 426
<212> DNA
<213> 小家鼠
<400> 27
atggctgtcc tggcactgct cctctgcctg gtgacattcc caaactgtgt cctgtcccag 60
gtgcacctga aggagtcagg acctggcctg gtggcgccct cacagagcct gtccatcaca 120
tgcactgtct cagggttctc tttaaccagc tatggtgtaa gctgggttcg ccagcctcca 180
ggagagggtc tggagtggct gggagtaata tggggtgacg ggagcacata ttttcattca 240
gctctcatat ccagactgag catcagcaag gatgactcca agagccaagt tttcttaaaa 300
ttgaacagtc tacaaactga tgacacagcc acgtactact gtgccaaaca agggacgatc 360
tatgatggtt actacaacta tgctatggac tactggggtc aaggaacctc agtcaccgtc 420
tcctca 426
<210> 28
<211> 142
<212> PRT
<213> 小家鼠
<400> 28
Met Ala Val Leu Ala Leu Leu Leu Cys Leu Val Thr Phe Pro Asn Cys
1 5 10 15
Val Leu Ser Gln Val His Leu Lys Glu Ser Gly Pro Gly Leu Val Ala
20 25 30
Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Thr Ser Tyr Gly Val Ser Trp Val Arg Gln Pro Pro Gly Glu Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Gly Asp Gly Ser Thr Tyr Phe His Ser
65 70 75 80
Ala Leu Ile Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln
85 90 95
Val Phe Leu Lys Leu Asn Ser Leu Gln Thr Asp Asp Thr Ala Thr Tyr
100 105 110
Tyr Cys Ala Lys Gln Gly Thr Ile Tyr Asp Gly Tyr Tyr Asn Tyr Ala
115 120 125
Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
130 135 140
<210> 29
<211> 399
<212> DNA
<213> 小家鼠
<400> 29
atggattcac aggcccaggt tcttatgtta ctgctgctat gggtatctgg tacctgtggg 60
gacattgtga tgtcacagtc tccatcctcc ctaactgtgt cagttggaga gaaggttact 120
atgagctgca agtccagtca gaacctttta tatggtggca atcaaaagaa ctacttggcc 180
tggtaccagc agaaaccagg gcagtctcct aaactgctga tttactgggc atccactagg 240
gaatctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 300
atcagcagtg tgagggctga agacctggca gtttattact gtcagcaata ttatgactat 360
ccgtacacgt tcggaggggg gaccaagctg gaaataaaa 399
<210> 30
<211> 133
<212> PRT
<213> 小家鼠
<400> 30
Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Trp Val Ser
1 5 10 15
Gly Thr Cys Gly Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Thr
20 25 30
Val Ser Val Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Asn
35 40 45
Leu Leu Tyr Gly Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
65 70 75 80
Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Val Arg Ala Glu Asp Leu Ala Val Tyr
100 105 110
Tyr Cys Gln Gln Tyr Tyr Asp Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Leu Glu Ile Lys
130
<210> 31
<211> 402
<212> DNA
<213> 小家鼠
<400> 31
atgggatgga gctggatctt tctcttcctc ctgtcaggaa ctgcaggtgt ccactcccag 60
gttcagctgc agcagtctgg acctgagctg gtgaagcctg gggcttcagt gaagttgtcc 120
tgcaaggctt ctggctacac cttcacaacc tacgatatac actgggtgaa gcagaggcct 180
gggcagggcc ttgagtggat tggatggatt tatcctagag atggtcgtac tacttacaat 240
gagaagttca aggccaaggc cacattgact gtagacacat cctccaccac agcgtacatg 300
gagctccaca gcctgacatc tgaggactct gcggtctatt tctgtgcgag aagtagcccc 360
tttggctact ggggccaagg caccactctc acagtctcct ca 402
<210> 32
<211> 134
<212> PRT
<213> 小家鼠
<400> 32
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Thr Tyr Asp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Trp Ile Tyr Pro Arg Asp Gly Arg Thr Thr Tyr Asn
65 70 75 80
Glu Lys Phe Lys Ala Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Thr
85 90 95
Thr Ala Tyr Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Phe Cys Ala Arg Ser Ser Pro Phe Gly Tyr Trp Gly Gln Gly Thr
115 120 125
Thr Leu Thr Val Ser Ser
130
<210> 33
<211> 381
<212> DNA
<213> 小家鼠
<400> 33
atgaagtttc cttctcaact tctgctcttc ctgctgttca gaatcacagg cataatatgt 60
gacatccaga tgacacaatc ttcatcctac ttgtctgtat ctctaggagg cagagtcacc 120
attacttgca aggcaagtga ccacattaat aattggttag cctggtatca gcagaaacca 180
ggaaatgctc ctaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 240
agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 300
gaagatgctg ctacttatca ctgtcaccag tattggagta ttccgtacac gttcggaggg 360
gggaccaagg tggaaataaa a 381
<210> 34
<211> 127
<212> PRT
<213> 小家鼠
<400> 34
Met Lys Phe Pro Ser Gln Leu Leu Leu Phe Leu Leu Phe Arg Ile Thr
1 5 10 15
Gly Ile Ile Cys Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser
20 25 30
Val Ser Leu Gly Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His
35 40 45
Ile Asn Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro
50 55 60
Arg Leu Leu Ile Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr
85 90 95
Ser Leu Gln Thr Glu Asp Ala Ala Thr Tyr His Cys His Gln Tyr Trp
100 105 110
Ser Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
115 120 125
<210> 35
<211> 396
<212> DNA
<213> 小家鼠
<400> 35
atggaatgga gctgggtctt tctcttcctc ctgtcagtaa ttgcaggtgt ccaatcccag 60
gttcaactgc agcagtctgg ggctgagctg gtggggcctg gggcttcagt gacgctgtcc 120
tgcaaggctt cgggctacac atttactgac tatgaaatgc actgggtgaa gcagacacct 180
gtgcatggcc tggaatgcat tggagctatt gatcctgaaa ctggtggtac tgcctacaat 240
cagaagttca agggcaaggc catactgact gcagacaaat cctctagcac agcctacatg 300
gagctccgca gcctgacatc tgaggactct gccgtctatt actgtctaac tgggtttgac 360
tactggggcc aaggcaccac tctcacagtc tcctca 396
<210> 36
<211> 132
<212> PRT
<213> 小家鼠
<400> 36
Met Glu Trp Ser Trp Val Phe Leu Phe Leu Leu Ser Val Ile Ala Gly
1 5 10 15
Val Gln Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Gly
20 25 30
Pro Gly Ala Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Glu Met His Trp Val Lys Gln Thr Pro Val His Gly Leu
50 55 60
Glu Cys Ile Gly Ala Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Ile Leu Thr Ala Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Leu Thr Gly Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu
115 120 125
Thr Val Ser Ser
130
<210> 37
<211> 390
<212> DNA
<213> 小家鼠
<400> 37
atggattttc aggtgcagat tttcagcttc ctgctaatca gtgtctcagt cataatgtcc 60
agaggacaaa ttgttctcac ccagtctcca gcaatcatgt ctgcatctcc tggggagaag 120
gtcaccttga cctgcagtgc cagctcaagt gtgaattcca gctacttgta ctggtaccag 180
cagaagccag gatcctcccc caaactctgg atttatagca catccaacct ggcttctgga 240
gtccctgctc gcttcagtgg cagtgggtct gggacctctt actctctcac aatcagcagc 300
atggaggctg aagatgctgc ctcttatttc tgccatcagt ggagtagtta cccgtacacg 360
ttcggagggg ggaccaagct ggaaataaaa 390
<210> 38
<211> 130
<212> PRT
<213> 小家鼠
<400> 38
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
20 25 30
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Leu Thr Cys Ser Ala Ser
35 40 45
Ser Ser Val Asn Ser Ser Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly
50 55 60
Ser Ser Pro Lys Leu Trp Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly
65 70 75 80
Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu
85 90 95
Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Ser Tyr Phe Cys His
100 105 110
Gln Trp Ser Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
115 120 125
Ile Lys
130
<210> 39
<211> 417
<212> DNA
<213> 小家鼠
<400> 39
atgatggtgt taagtcttct gtacctgttg acagcccttc cgggtatcct gtcagaggtg 60
cagcttcagg agtcaggacc tggcctggca aaaccttctc agactctgtc cctcacctgt 120
tctgtcactg gctactccat caccagtgat tactggaact ggatccggaa attcccaggg 180
aataaacttg aatacatggg gtacataaac tacagtggta acacttacta caatccatct 240
ctcaaaagtc gaatctccat aactcgagac acatccaaga accagtatta cctgcaattg 300
aattctgtga ctactgagga cacagccacg tattactgtg caagatatgg gggattacga 360
cagggttcct ggcacttcga tgtctggggc ccagggacca cggtcaccgt ctcctca 417
<210> 40
<211> 139
<212> PRT
<213> 小家鼠
<400> 40
Met Met Val Leu Ser Leu Leu Tyr Leu Leu Thr Ala Leu Pro Gly Ile
1 5 10 15
Leu Ser Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Ala Lys Pro
20 25 30
Ser Gln Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Thr
35 40 45
Ser Asp Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu
50 55 60
Tyr Met Gly Tyr Ile Asn Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser
65 70 75 80
Leu Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr
85 90 95
Tyr Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr
100 105 110
Cys Ala Arg Tyr Gly Gly Leu Arg Gln Gly Ser Trp His Phe Asp Val
115 120 125
Trp Gly Pro Gly Thr Thr Val Thr Val Ser Ser
130 135
<210> 41
<211> 384
<212> DNA
<213> 小家鼠
<400> 41
atggattttc aggtgcagat tttcagcttc ctgctaatca gtgcctcagt cataatgtcc 60
agaggacaaa ttgttctcac ccagtctcca gcaatcatgt ctgcatctcc aggggagaag 120
gtcaccatat cctgcagtgc cagctcaagt gtaagttaca tgtactggta ccagcagaag 180
ccaggatcct cccccaaacc ctggatttat cgcacatcca acctggcttc tggagtccct 240
gcgcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagcatggag 300
gctgaagatg ctgccactta ttactgccag cagtatcata gttacccagc gacgttcggt 360
ggaggcacca agctggaaat caaa 384
<210> 42
<211> 128
<212> PRT
<213> 小家鼠
<400> 42
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
20 25 30
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Ile Ser Cys Ser Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr
100 105 110
His Ser Tyr Pro Ala Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
115 120 125
<210> 43
<211> 402
<212> DNA
<213> 小家鼠
<400> 43
atgggttggc tgtggaactt gctattcctg atggcagctg cccaaagtgc ccaagcacag 60
atccagttgg tacagtctgg acctgagctg aagaagcctg gagagacagt caagatctcc 120
tgcaaggctt ctgggtatat cttcacaacc tatggaatgt actgggtgaa acaggctcca 180
ggaaagggtt taaagtggat gggctggata aacacctact ctggagtgcc aacatatgtt 240
gatgacttca agggacggtt tgccttctct ttggaaacat ctgccagcac tgcctatttg 300
cagatcaaca acctcaaaaa tgaggacacg gctacatatt tctgtgtagt tgccgggtgg 360
tttgcttact ggggccaagg gactctggtc actgtctctg ca 402
<210> 44
<211> 134
<212> PRT
<213> 小家鼠
<400> 44
Met Gly Trp Leu Trp Asn Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ala Gln Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys
20 25 30
Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe
35 40 45
Thr Thr Tyr Gly Met Tyr Trp Val Lys Gln Ala Pro Gly Lys Gly Leu
50 55 60
Lys Trp Met Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Val
65 70 75 80
Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser
85 90 95
Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr
100 105 110
Tyr Phe Cys Val Val Ala Gly Trp Phe Ala Tyr Trp Gly Gln Gly Thr
115 120 125
Leu Val Thr Val Ser Ala
130
<210> 45
<211> 387
<212> DNA
<213> 小家鼠
<400> 45
atggacatga ggacccctgc tcagtttctt ggaatcttgt tgctctggtt tccaggtatc 60
aaatgtgaca tcaagatgac ccagtctcca tcttccatgt atgcatctct aggagagaga 120
gtcactatca cttgcaaggc gagtcaggac attaagagct atttaagctg gttccagcag 180
aaaccaggga aatctcctaa gaccctgatc tatcgtgcaa atatattgat agatggggtc 240
ccatcaaggt tcagtggcag tggatctggg caagattatt ctctcaccat cagcagcctg 300
gagtatgaag atatgggaat ttattattgt ctacaatatg atgagtttcc gtacacgttc 360
ggagggggga ccaagctgga aataaaa 387
<210> 46
<211> 129
<212> PRT
<213> 小家鼠
<400> 46
Met Asp Met Arg Thr Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ile Lys Cys Asp Ile Lys Met Thr Gln Ser Pro Ser Ser
20 25 30
Met Tyr Ala Ser Leu Gly Glu Arg Val Thr Ile Thr Cys Lys Ala Ser
35 40 45
Gln Asp Ile Lys Ser Tyr Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys
50 55 60
Ser Pro Lys Thr Leu Ile Tyr Arg Ala Asn Ile Leu Ile Asp Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr
85 90 95
Ile Ser Ser Leu Glu Tyr Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln
100 105 110
Tyr Asp Glu Phe Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
115 120 125
Lys
<210> 47
<211> 10
<212> PRT
<213> 小家鼠
<400> 47
Arg Ala Ser Ser Ser Val Ser Phe Met Phe
1 5 10
<210> 48
<211> 11
<212> PRT
<213> 小家鼠
<400> 48
Lys Ala Ser Gln Asn Val Arg Ser Ala Val Ala
1 5 10
<210> 49
<211> 16
<212> PRT
<213> 小家鼠
<400> 49
Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Phe
1 5 10 15
<210> 50
<211> 17
<212> PRT
<213> 小家鼠
<400> 50
Lys Ser Ser Gln Ser Leu Leu Asn Ser Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 51
<211> 17
<212> PRT
<213> 小家鼠
<400> 51
Lys Ser Ser Gln Asn Leu Leu Tyr Gly Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 52
<211> 11
<212> PRT
<213> 小家鼠
<400> 52
Lys Ala Ser Asp His Ile Asn Asn Trp Leu Ala
1 5 10
<210> 53
<211> 12
<212> PRT
<213> 小家鼠
<400> 53
Ser Ala Ser Ser Ser Val Asn Ser Ser Tyr Leu Tyr
1 5 10
<210> 54
<211> 10
<212> PRT
<213> 小家鼠
<400> 54
Ser Ala Ser Ser Ser Val Ser Tyr Met Tyr
1 5 10
<210> 55
<211> 11
<212> PRT
<213> 小家鼠
<400> 55
Lys Ala Ser Gln Asp Ile Lys Ser Tyr Leu Ser
1 5 10
<210> 56
<211> 7
<212> PRT
<213> 小家鼠
<400> 56
Asp Thr Ser Asn Leu Ala Ser
1 5
<210> 57
<211> 7
<212> PRT
<213> 小家鼠
<400> 57
Leu Ala Ser Asn Arg His Thr
1 5
<210> 58
<211> 7
<212> PRT
<213> 小家鼠
<400> 58
Arg Met Ser Asn Leu Ala Ser
1 5
<210> 59
<211> 7
<212> PRT
<213> 小家鼠
<400> 59
Phe Ala Ser Thr Arg Glu Ser
1 5
<210> 60
<211> 7
<212> PRT
<213> 小家鼠
<400> 60
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 61
<211> 7
<212> PRT
<213> 小家鼠
<400> 61
Gly Ala Thr Ser Leu Glu Thr
1 5
<210> 62
<211> 7
<212> PRT
<213> 小家鼠
<400> 62
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 63
<211> 7
<212> PRT
<213> 小家鼠
<400> 63
Arg Thr Ser Asn Leu Ala Ser
1 5
<210> 64
<211> 7
<212> PRT
<213> 小家鼠
<400> 64
Arg Ala Asn Ile Leu Ile Asp
1 5
<210> 65
<211> 9
<212> PRT
<213> 小家鼠
<400> 65
Gln Gln Trp Ser Ser Asn Pro Leu Thr
1 5
<210> 66
<211> 9
<212> PRT
<213> 小家鼠
<400> 66
Leu Gln His Trp Asn Tyr Pro Phe Thr
1 5
<210> 67
<211> 9
<212> PRT
<213> 小家鼠
<400> 67
Met Gln His Leu Glu Tyr Pro Phe Thr
1 5
<210> 68
<211> 9
<212> PRT
<213> 小家鼠
<400> 68
Gln Gln His Tyr Ser Thr Pro Tyr Thr
1 5
<210> 69
<211> 9
<212> PRT
<213> 小家鼠
<400> 69
Gln Gln Tyr Tyr Asp Tyr Pro Tyr Thr
1 5
<210> 70
<211> 9
<212> PRT
<213> 小家鼠
<400> 70
His Gln Tyr Trp Ser Ile Pro Tyr Thr
1 5
<210> 71
<211> 9
<212> PRT
<213> 小家鼠
<400> 71
His Gln Trp Ser Ser Tyr Pro Tyr Thr
1 5
<210> 72
<211> 9
<212> PRT
<213> 小家鼠
<400> 72
Gln Gln Tyr His Ser Tyr Pro Ala Thr
1 5
<210> 73
<211> 9
<212> PRT
<213> 小家鼠
<400> 73
Leu Gln Tyr Asp Glu Phe Pro Tyr Thr
1 5
<210> 74
<211> 5
<212> PRT
<213> 小家鼠
<400> 74
Asp Phe Gly Met His
1 5
<210> 75
<211> 5
<212> PRT
<213> 小家鼠
<400> 75
Ser Ser Trp Met Asn
1 5
<210> 76
<211> 5
<212> PRT
<213> 小家鼠
<400> 76
Asp Tyr Tyr Met Asn
1 5
<210> 77
<211> 5
<212> PRT
<213> 小家鼠
<400> 77
Asp Tyr Glu Met His
1 5
<210> 78
<211> 5
<212> PRT
<213> 小家鼠
<400> 78
Ser Tyr Gly Val Ser
1 5
<210> 79
<211> 5
<212> PRT
<213> 小家鼠
<400> 79
Thr Tyr Asp Ile His
1 5
<210> 80
<211> 5
<212> PRT
<213> 小家鼠
<400> 80
Asp Tyr Glu Met His
1 5
<210> 81
<211> 5
<212> PRT
<213> 小家鼠
<400> 81
Ser Asp Tyr Trp Asn
1 5
<210> 82
<211> 5
<212> PRT
<213> 小家鼠
<400> 82
Thr Tyr Gly Met Tyr
1 5
<210> 83
<211> 17
<212> PRT
<213> 小家鼠
<400> 83
Tyr Ile Ser Ser Gly Ser Gly Thr Ile Tyr Tyr Ala Asp Thr Val Arg
1 5 10 15
Gly
<210> 84
<211> 17
<212> PRT
<213> 小家鼠
<400> 84
Arg Ile Tyr Pro Gly Asp Gly Asp Thr Lys Tyr Asn Gly Lys Phe Lys
1 5 10 15
Gly
<210> 85
<211> 17
<212> PRT
<213> 小家鼠
<400> 85
Asp Ile Ile Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 86
<211> 17
<212> PRT
<213> 小家鼠
<400> 86
Ala Ile Asp Pro Glu Thr Cys Gly Thr Ala Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 87
<211> 16
<212> PRT
<213> 小家鼠
<400> 87
Val Ile Trp Gly Asp Gly Ser Thr Tyr Phe His Ser Ala Leu Ile Ser
1 5 10 15
<210> 88
<211> 17
<212> PRT
<213> 小家鼠
<400> 88
Trp Ile Tyr Pro Arg Asp Gly Arg Thr Thr Tyr Asn Glu Lys Phe Lys
1 5 10 15
Ala
<210> 89
<211> 17
<212> PRT
<213> 小家鼠
<400> 89
Ala Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 90
<211> 16
<212> PRT
<213> 小家鼠
<400> 90
Tyr Ile Asn Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 91
<211> 17
<212> PRT
<213> 小家鼠
<400> 91
Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Val Asp Asp Phe Lys
1 5 10 15
Gly
<210> 92
<211> 12
<212> PRT
<213> 小家鼠
<400> 92
Gly Asp Leu Tyr Tyr Gly Ser Ser Phe Asp Ala Tyr
1 5 10
<210> 93
<211> 7
<212> PRT
<213> 小家鼠
<400> 93
Asp Asp Tyr Asp Trp Ala Ser
1 5
<210> 94
<211> 15
<212> PRT
<213> 小家鼠
<400> 94
Gly Ile Ser Tyr Tyr Gly Asn Arg Tyr Tyr Phe Thr Met Asp Tyr
1 5 10 15
<210> 95
<211> 11
<212> PRT
<213> 小家鼠
<400> 95
Ser Lys Leu Gly Arg Gly Trp Tyr Phe Asp Val
1 5 10
<210> 96
<211> 15
<212> PRT
<213> 小家鼠
<400> 96
Gln Gly Thr Ile Tyr Asp Gly Tyr Tyr Asn Tyr Ala Met Asp Tyr
1 5 10 15
<210> 97
<211> 6
<212> PRT
<213> 小家鼠
<400> 97
Ser Ser Pro Phe Gly Tyr
1 5
<210> 98
<211> 4
<212> PRT
<213> 小家鼠
<400> 98
Gly Phe Asp Tyr
1
<210> 99
<211> 13
<212> PRT
<213> 小家鼠
<400> 99
Tyr Gly Gly Leu Arg Gln Gly Ser Trp His Phe Asp Val
1 5 10
<210> 100
<211> 6
<212> PRT
<213> 小家鼠
<400> 100
Ala Gly Trp Phe Ala Tyr
1 5
<210> 101
<211> 17
<212> PRT
<213> 家犬
<400> 101
Phe Asn Glu Cys Arg Cys Thr Asp Thr Pro Pro Cys Pro Val Pro Glu
1 5 10 15
Pro
<210> 102
<211> 22
<212> PRT
<213> 家犬
<400> 102
Pro Lys Arg Glu Asn Gly Arg Val Pro Arg Pro Pro Asp Cys Pro Lys
1 5 10 15
Cys Pro Ala Pro Glu Met
20
<210> 103
<211> 20
<212> PRT
<213> 家犬
<400> 103
Ala Lys Glu Cys Glu Cys Lys Cys Asn Cys Asn Asn Cys Pro Cys Pro
1 5 10 15
Gly Cys Gly Leu
20
<210> 104
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> modified 家犬
<400> 104
Pro Lys Glu Ser Thr Cys Lys Cys Ile Pro Pro Cys Pro Val Pro Glu
1 5 10 15
Ser
<210> 105
<211> 429
<212> DNA
<213> 小家鼠
<400> 105
atgaacttgg ggctcagctt gattttcctt gtccttgttt taaaaggtgt ccagtgtgac 60
gtgaagctgg tggagtctgg gggaggctta gtgcagcctg gagggtccct gaaactctcc 120
tgtgcagcct ctggattcac tttcagtgac tattacatgt attgggttcg ccagactcca 180
gagaagagac tggagtgggt cgcatatgtt agtagtggtg gtggtagtat ctattatcca 240
gacactgtaa agggccgatt caccatctcc agagacaatg ccaagaacac cctgtatttg 300
caaatgagcc gtctgaagtc tgaggacaca gccatgtatt actgtgcaag gcatgggtcc 360
cccttcggta gtagccgagg ggcctggttt gcttactggg gccaggggac tctggtcact 420
gtctctgca 429
<210> 106
<211> 143
<212> PRT
<213> 小家鼠
<400> 106
Met Asn Leu Gly Leu Ser Leu Ile Phe Leu Val Leu Val Leu Lys Gly
1 5 10 15
Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asp Tyr Tyr Met Tyr Trp Val Arg Gln Thr Pro Glu Lys Arg Leu
50 55 60
Glu Trp Val Ala Tyr Val Ser Ser Gly Gly Gly Ser Ile Tyr Tyr Pro
65 70 75 80
Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Ser Arg Leu Lys Ser Glu Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Ala Arg His Gly Ser Pro Phe Gly Ser Ser Arg Gly Ala
115 120 125
Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
130 135 140
<210> 107
<211> 381
<212> DNA
<213> 小家鼠
<400> 107
atgagtgtgc ccactcaggt cctggggttg ctgctgctgt ggcttacagg tgccagatgt 60
gacatccaga tgactcagtc tccagcctcc ctgtctgcat ctgtgggaga aactgtcacc 120
atcacatgtc gagcaagtga gaatatttac agttatttag catggtatca gcagaaacag 180
ggaaaatctc ctcagctcct ggtctataat gcaaaaacct tagcagaggg tgtgccatca 240
aggttcagtg gcagtggatc aggcacacag ttttctctga agatcaacag cctgcagcct 300
gaagattttg ggaattatta ctgtcaacat tatgatggtt ttccgttcac gttcggtggt 360
gggaccaagc tggagctgaa a 381
<210> 108
<211> 127
<212> PRT
<213> 小家鼠
<400> 108
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser
20 25 30
Ala Ser Val Gly Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn
35 40 45
Ile Tyr Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro
50 55 60
Gln Leu Leu Val Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn
85 90 95
Ser Leu Gln Pro Glu Asp Phe Gly Asn Tyr Tyr Cys Gln His Tyr Asp
100 105 110
Gly Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
115 120 125
<210> 109
<211> 414
<212> DNA
<213> 小家鼠
<400> 109
atgggttggc tgtggaactt gctattcctg atggcagctg cccaaagtgc ccaagcacag 60
atccagttga tacagtctgg acctgagctg aagaagcctg gagagacagt caagatctcc 120
tgcaaggctt ctgggtatac cttcacaacc tttggaatga gctgggtgaa acaggctcca 180
ggaaagggtt taaagtggat gggctggata agcacctact ctggagtgcc aacatatgct 240
gatgacttca agggacggtt tgccttctct ttggaaacct ctgccagcac tgcctatttg 300
cagatcaaca acctcaaaaa tgaggacacg gcttcatatt tctgtgcaag acacaccttc 360
caaagtcgcg ggttggctta ctggggccaa gggactctgg tcactgtctc tgca 414
<210> 110
<211> 138
<212> PRT
<213> 小家鼠
<400> 110
Met Gly Trp Leu Trp Asn Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ala Gln Ala Gln Ile Gln Leu Ile Gln Ser Gly Pro Glu Leu Lys Lys
20 25 30
Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Thr Phe Gly Met Ser Trp Val Lys Gln Ala Pro Gly Lys Gly Leu
50 55 60
Lys Trp Met Gly Trp Ile Ser Thr Tyr Ser Gly Val Pro Thr Tyr Ala
65 70 75 80
Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser
85 90 95
Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Ser
100 105 110
Tyr Phe Cys Ala Arg His Thr Phe Gln Ser Arg Gly Leu Ala Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ala
130 135
<210> 111
<211> 393
<212> DNA
<213> 小家鼠
<400> 111
atgggcatca aaatggagtc acagattcag gtctttgtat tcgtgtttct ctggttgtct 60
ggtgttgacg gagacattgt gatgacccag tctcacaaat tcatgtccac atcagtagga 120
gacagggtca gcatcacctg caaggccagt caggatgtga ttactactgt agcctggtat 180
caacagaaac caggacaatc tcctaaacta ctgatttact cggcatccta ccggtacact 240
ggagtccctg atcgcttcac tggcagtgga tctgggacgg atttcacttt caccatcacc 300
agtgtgcaga ctgaagacct ggcagtttat tactgtcagc aacattatag tactccgtgg 360
acgttcggtg gaggcaccaa gctggaaatc aaa 393
<210> 112
<211> 131
<212> PRT
<213> 小家鼠
<400> 112
Met Gly Ile Lys Met Glu Ser Gln Ile Gln Val Phe Val Phe Val Phe
1 5 10 15
Leu Trp Leu Ser Gly Val Asp Gly Asp Ile Val Met Thr Gln Ser His
20 25 30
Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys
35 40 45
Ala Ser Gln Asp Val Ile Thr Thr Val Ala Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr
65 70 75 80
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Phe Thr Ile Thr Ser Val Gln Thr Glu Asp Leu Ala Val Tyr Tyr Cys
100 105 110
Gln Gln His Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys
130
<210> 113
<211> 411
<212> DNA
<213> 小家鼠
<400> 113
atgggatgga gctgtatcat gctcttcttg gcagcaacag ctacaggtgt ccactcccag 60
gtccaactgc agcagcctgg ggctgagctt gtgaagcctg gggcttcagt gaagctgtcc 120
tgcaaggctt ctggctacac cttcaccaac tactggatac actggatgaa gcagaggcct 180
ggacgaggcc ttgagtggat tggaaggatt gatcctaata gtggtggtac taagtacaat 240
gagaagttca agagcaaggc cacactgact gtcgacaaac cctccatcac agcctacatg 300
cagctcagca gcctgacatc tgaggactct gcggtctatt attgtgcagc attcggtagt 360
acctacgggt ttgcttactg gggccaaggg actctggtca ctgtctctgc a 411
<210> 114
<211> 137
<212> PRT
<213> 小家鼠
<400> 114
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asn Tyr Trp Ile His Trp Met Lys Gln Arg Pro Gly Arg Gly Leu
50 55 60
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Gly Thr Lys Tyr Asn
65 70 75 80
Glu Lys Phe Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Pro Ser Ile
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Ala Phe Gly Ser Thr Tyr Gly Phe Ala Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ala
130 135
<210> 115
<211> 396
<212> DNA
<213> 小家鼠
<400> 115
atggattcac aggcccaggt tcttatattg ctgctgctat gggtatctgg tacctgtggg 60
gacattgtga tgtcacagtc tccatcctcc ctggctgtgt cagcaggaga gaaggtcact 120
atgagttgca aatccagtca gagtctgctc aacagtagaa cccgaaagaa ctacttggct 180
tggtaccagc agaaaccagg gcagtctcct aaactgctga tctactgggc atccactagg 240
gaatctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 300
atcagcagtg tgcaggctga agacctggca gtttattact gcaagcaatc ttataatctg 360
tacacgttcg gaggggggac caagctggaa ataaaa 396
<210> 116
<211> 132
<212> PRT
<213> 小家鼠
<400> 116
Met Asp Ser Gln Ala Gln Val Leu Ile Leu Leu Leu Leu Trp Val Ser
1 5 10 15
Gly Thr Cys Gly Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala
20 25 30
Val Ser Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser
35 40 45
Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
65 70 75 80
Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr
100 105 110
Tyr Cys Lys Gln Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys
115 120 125
Leu Glu Ile Lys
130
<210> 117
<211> 429
<212> DNA
<213> 小家鼠
<400> 117
atgaacttgg ggctcagctt gattttcctt gtccttgttt taaaaggtgt ccagtgtgaa 60
gtgacgctgg tggagtctgg gggaggctta gtgcagcctg gagggtccct gaaactctcc 120
tgtgcagcct ctggattcac tttcagtgac tattacatgt attgggttcg ccagactcca 180
gagaagaggc tggagtgggt cgcatacatt agtcctggtg gtggtagcac ctattatccg 240
gacactataa agggccgatt caccatctcc agagacaatg ccaagaacac cctgtacctg 300
caaatgagcc gtctgaagtc tgaggacaca gccatgtatt actgtacaag acatgggtcc 360
ccctacggta gtagtcgagg ggcctggttt gcttactggg gccaagggac tctggtcact 420
gtctctgca 429
<210> 118
<211> 143
<212> PRT
<213> 小家鼠
<400> 118
Met Asn Leu Gly Leu Ser Leu Ile Phe Leu Val Leu Val Leu Lys Gly
1 5 10 15
Val Gln Cys Glu Val Thr Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asp Tyr Tyr Met Tyr Trp Val Arg Gln Thr Pro Glu Lys Arg Leu
50 55 60
Glu Trp Val Ala Tyr Ile Ser Pro Gly Gly Gly Ser Thr Tyr Tyr Pro
65 70 75 80
Asp Thr Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Ser Arg Leu Lys Ser Glu Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Thr Arg His Gly Ser Pro Tyr Gly Ser Ser Arg Gly Ala
115 120 125
Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
130 135 140
<210> 119
<211> 381
<212> DNA
<213> 小家鼠
<400> 119
atgagtgtgc ccactcaggt cctggggttg ctgctgctgt ggcttacagg tgccagatgt 60
gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga aactgtcacc 120
atcacatgtc gagcaagtga gaatatttac agttatttag catggtatca gcagaaacag 180
ggaaaatctc ctcagctcct ggtctataat ggaaaaacct tagcagaagg tgtgccagca 240
aggttcagtg gcagtggatc aggcacacag ttttctctga agatcaacag cctacagcct 300
gaagattttg ggagttatta ctgtcaacat catgatggta ttccggtcac gttcggtgct 360
gggaccaagc tggagctgaa a 381
<210> 120
<211> 127
<212> PRT
<213> 小家鼠
<400> 120
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser
20 25 30
Ala Ser Val Gly Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn
35 40 45
Ile Tyr Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro
50 55 60
Gln Leu Leu Val Tyr Asn Gly Lys Thr Leu Ala Glu Gly Val Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn
85 90 95
Ser Leu Gln Pro Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Asp
100 105 110
Gly Ile Pro Val Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
115 120 125
<210> 121
<211> 423
<212> DNA
<213> 小家鼠
<400> 121
atgaacttgg ggctcagctt gattttcctt gtccttgttt taaaaggtgt ccagtgtgaa 60
gtgaagctgg tggagtcggg gggaggctta gtgcagcctg gagggtccct gaaactctcc 120
tgtgtagcct ctggattcac tttcagtgac tatcacatgc attgggttcg ccagactcca 180
gagaagaggc tggagtgggt cgcatacatt agtaaaggtg gtggtagcac ctattatcca 240
gacactgaaa agggccgatt caccatctcc agagacaatg ccaagaatac cctgtacctg 300
caaatgagcc gtctgaagtc tgaggacaca gccatgtatt actgtgcaag atcccccggc 360
cctagtagct tctactggta cttcgatgtc tggggcacag ggaccacggt caccgtctcc 420
tca 423
<210> 122
<211> 141
<212> PRT
<213> 小家鼠
<400> 122
Met Asn Leu Gly Leu Ser Leu Ile Phe Leu Val Leu Val Leu Lys Gly
1 5 10 15
Val Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asp Tyr His Met His Trp Val Arg Gln Thr Pro Glu Lys Arg Leu
50 55 60
Glu Trp Val Ala Tyr Ile Ser Lys Gly Gly Gly Ser Thr Tyr Tyr Pro
65 70 75 80
Asp Thr Glu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Ser Arg Leu Lys Ser Glu Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Ala Arg Ser Pro Gly Pro Ser Ser Phe Tyr Trp Tyr Phe
115 120 125
Asp Val Trp Gly Thr Gly Thr Thr Val Thr Val Ser Ser
130 135 140
<210> 123
<211> 381
<212> DNA
<213> 小家鼠
<400> 123
atgagtgtgc ccactcaggt cctggggttg ctgctgctgt ggcttacagg tgccagatgt 60
gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga aactgtcacc 120
atcacatgtc gagcaagtga gaatatttac agttatttag catggtatca gcagaaacag 180
ggaaaatctc ctcagctcct ggtctataat gcaaaaacct tagcagaagg tgtgccatca 240
aggttcagtg gcagtggatc aggcacacag ttttctctga agatcaacag cctgcagcct 300
gaagattttg ggagttatta ctgtcaacat cattatggta ttccggtcac ggtcggtgta 360
gggaccaagc tggagctgaa a 381
<210> 124
<211> 127
<212> PRT
<213> 小家鼠
<400> 124
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser
20 25 30
Ala Ser Val Gly Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn
35 40 45
Ile Tyr Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro
50 55 60
Gln Leu Leu Val Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn
85 90 95
Ser Leu Gln Pro Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr
100 105 110
Gly Ile Pro Val Thr Val Gly Val Gly Thr Lys Leu Glu Leu Lys
115 120 125
<210> 125
<211> 11
<212> PRT
<213> 家犬
<400> 125
Ser Ala Glu Leu Arg Leu Ser Tyr Gln Leu Asp
1 5 10
<210> 126
<211> 11
<212> PRT
<213> 家犬
<400> 126
Phe Gln Pro Ser Lys His Val Lys Pro Arg Thr
1 5 10
<210> 127
<211> 21
<212> PRT
<213> 家犬
<400> 127
Ala Gly Gln Gln Leu Leu Trp Ser Gly Ser Phe Gln Pro Ser Lys His
1 5 10 15
Val Lys Pro Arg Thr
20
<210> 128
<211> 9
<212> PRT
<213> 家犬
<400> 128
Thr Leu Lys Ser Gly Ala Ser Tyr Ser
1 5
<210> 129
<211> 11
<212> PRT
<213> 小家鼠
<400> 129
Arg Ala Ser Glu Asn Ile Tyr Ser Tyr Leu Ala
1 5 10
<210> 130
<211> 11
<212> PRT
<213> 小家鼠
<400> 130
Lys Ala Ser Gln Asp Val Ile Thr Thr Val Ala
1 5 10
<210> 131
<211> 17
<212> PRT
<213> 小家鼠
<400> 131
Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 132
<211> 7
<212> PRT
<213> 小家鼠
<400> 132
Asn Ala Lys Thr Leu Ala Glu
1 5
<210> 133
<211> 7
<212> PRT
<213> 小家鼠
<400> 133
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 134
<211> 7
<212> PRT
<213> 小家鼠
<400> 134
Asn Gly Lys Thr Leu Ala Glu
1 5
<210> 135
<211> 9
<212> PRT
<213> 小家鼠
<400> 135
Gln His Tyr Asp Gly Phe Pro Phe Thr
1 5
<210> 136
<211> 9
<212> PRT
<213> 小家鼠
<400> 136
Gln Gln His Tyr Ser Thr Pro Trp Thr
1 5
<210> 137
<211> 9
<212> PRT
<213> 小家鼠
<400> 137
Gln His His Asp Gly Ile Pro Val Thr
1 5
<210> 138
<211> 8
<212> PRT
<213> 小家鼠
<400> 138
Lys Gln Ser Tyr Asn Leu Tyr Thr
1 5
<210> 139
<211> 9
<212> PRT
<213> 小家鼠
<400> 139
Gln His His Tyr Gly Ile Pro Val Thr
1 5
<210> 140
<211> 5
<212> PRT
<213> 小家鼠
<400> 140
Asp Tyr Tyr Met Tyr
1 5
<210> 141
<211> 5
<212> PRT
<213> 小家鼠
<400> 141
Thr Phe Gly Met Ser
1 5
<210> 142
<211> 5
<212> PRT
<213> 小家鼠
<400> 142
Asn Tyr Trp Ile His
1 5
<210> 143
<211> 5
<212> PRT
<213> 小家鼠
<400> 143
Asp Tyr His Met His
1 5
<210> 144
<211> 17
<212> PRT
<213> 小家鼠
<400> 144
Tyr Val Ser Ser Gly Gly Gly Ser Ile Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 145
<211> 17
<212> PRT
<213> 小家鼠
<400> 145
Trp Ile Ser Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 146
<211> 17
<212> PRT
<213> 小家鼠
<400> 146
Tyr Ile Ser Pro Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Thr Ile Lys
1 5 10 15
Gly
<210> 147
<211> 17
<212> PRT
<213> 小家鼠
<400> 147
Arg Ile Asp Pro Asn Ser Gly Gly Thr Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Ser
<210> 148
<211> 17
<212> PRT
<213> 小家鼠
<400> 148
Tyr Ile Ser Lys Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Thr Glu Lys
1 5 10 15
Gly
<210> 149
<211> 15
<212> PRT
<213> 小家鼠
<400> 149
His Gly Ser Pro Phe Gly Ser Ser Arg Gly Ala Trp Phe Ala Tyr
1 5 10 15
<210> 150
<211> 10
<212> PRT
<213> 小家鼠
<400> 150
His Thr Phe Gln Ser Arg Gly Leu Ala Tyr
1 5 10
<210> 151
<211> 15
<212> PRT
<213> 小家鼠
<400> 151
His Gly Ser Pro Tyr Gly Ser Ser Arg Gly Ala Trp Phe Ala Tyr
1 5 10 15
<210> 152
<211> 9
<212> PRT
<213> 小家鼠
<400> 152
Phe Gly Ser Thr Tyr Gly Phe Ala Tyr
1 5
<210> 153
<211> 13
<212> PRT
<213> 小家鼠
<400> 153
Ser Pro Gly Pro Ser Ser Phe Tyr Trp Tyr Phe Asp Val
1 5 10
<210> 154
<211> 11
<212> PRT
<213> 家犬
<400> 154
Glu Asp Ser Val Cys Val Cys Ser Met Pro Ile
1 5 10
<210> 155
<211> 12
<212> PRT
<213> 家犬
<400> 155
Met Trp Thr Asn Pro Tyr Pro Thr Glu Asn His Leu
1 5 10
<210> 156
<211> 7
<212> PRT
<213> 家犬
<400> 156
Ala Ser Thr Leu Lys Ser Gly
1 5
<210> 157
<211> 14
<212> PRT
<213> 家犬
<400> 157
Trp Ser Gly Ser Phe Gln Pro Ser Lys His Val Lys Pro Arg
1 5 10
<210> 158
<211> 12
<212> PRT
<213> 家犬
<400> 158
Val Tyr Asn Val Thr Tyr Met Gly Pro Thr Leu Arg
1 5 10
<210> 159
<211> 18
<212> PRT
<213> 家犬
<400> 159
Val Leu His Glu Pro Ser Cys Phe Ser Asp Tyr Ile Ser Thr Ser Val
1 5 10 15
Cys Gln
<210> 160
<211> 14
<212> PRT
<213> 家犬
<400> 160
Glu Asn Arg Glu Asp Ser Val Cys Val Cys Ser Met Pro Ile
1 5 10
<210> 161
<211> 13
<212> PRT
<213> 家犬
<400> 161
Lys Ser Gly Ala Ser Tyr Ser Ala Arg Val Arg Ala Trp
1 5 10
<210> 162
<211> 10
<212> PRT
<213> 家犬
<400> 162
Tyr Tyr Glu Pro Trp Glu Gln His Leu Pro
1 5 10
<210> 163
<211> 1359
<212> DNA
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 163
gaggtgcagc tggtggagag cggaggcgac ctggtgaaac ccggaggcag cctgagactg 60
agctgtgtgg ccagcggcta caccttcacc aactactgga ttcattgggt gaggcaggct 120
cccggcaaag gactgcagtg ggtggccagg attgatccca acagcggcgg caccaagtac 180
aacgagaagt tcaagagcag gttcaccatc agcagggaca acgccaagaa caccctctac 240
ctgcagatga acagcctgag ggccgaggac accgccgtgt actactgcac caggttcggc 300
agcacctacg gcttcgccta ctggggccaa ggcaccctgg tgaccgtgag cagcgcttcc 360
acaaccgcgc catcagtctt tccgttggcc ccatcatgcg ggtcgacgag cggatcgact 420
gtggccctgg cgtgcttggt gtcgggatac tttcccgaac ccgtcacggt cagctggaac 480
tccggatcgc ttacgagcgg tgtgcatacg ttcccctcgg tcttgcaatc atcagggctc 540
tactcgctgt cgagcatggt aacggtgccc tcatcgaggt ggccctccga aacgttcaca 600
tgtaacgtag cacatccagc ctccaaaacc aaggtggata aacccgtgcc gaaaagagag 660
aatgggcggg tgcctcgacc ccctgattgc cccaagtgtc cggctccgga aatgctcggt 720
ggaccctcag tgtttatctt ccctccgaag cccaaggaca ctctgctgat cgcgcgcact 780
ccagaagtaa catgtgtagt ggtggcactt gatcccgagg accccgaagt ccagatctcc 840
tggtttgtag atgggaaaca gatgcagacc gcaaaaactc aacccagaga ggagcagttc 900
gcaggaacat accgagtggt atccgtcctt ccgattggcc accaggactg gttgaaaggg 960
aagcagttta cgtgtaaagt caacaataag gcgttgccta gccctattga gcggacgatt 1020
tcgaaagcta ggggacaggc ccaccagcca tcggtctatg tccttccgcc ttcccgcgag 1080
gagctctcga agaatacagt gagccttaca tgcctcatta aggatttctt cccgcctgat 1140
atcgacgtag agtggcaatc aaacggtcaa caggagccgg aatccaagta tagaaccact 1200
ccgccccagc ttgacgagga cggatcatac tttttgtatt caaaactgtc ggtggataag 1260
agccggtggc agagaggtga caccttcatc tgtgcggtga tgcacgaagc actccataat 1320
cactacaccc aagagagcct ctcgcattcc cccggaaag 1359
<210> 164
<211> 453
<212> PRT
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 164
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Val
35 40 45
Ala Arg Ile Asp Pro Asn Ser Gly Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ala 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
Thr Arg Phe Gly Ser Thr Tyr Gly Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Cys Gly Ser Thr Ser Gly Ser Thr Val Ala Leu Ala
130 135 140
Cys Leu Val Ser Gly Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ser Leu Thr Ser Gly Val His Thr Phe Pro Ser Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Ser Ser
180 185 190
Arg Trp Pro Ser Glu Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser
195 200 205
Lys Thr Lys Val Asp Lys Pro Val Pro Lys Arg Glu Asn Gly Arg Val
210 215 220
Pro Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Met Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu
245 250 255
Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Leu Asp Pro
260 265 270
Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met
275 280 285
Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Ala Gly Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly
305 310 315 320
Lys Gln Phe Thr Cys Lys Val Asn Asn Lys Ala Leu Pro Ser Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val
340 345 350
Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser
355 360 365
Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu
370 375 380
Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr
385 390 395 400
Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu
405 410 415
Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser
435 440 445
His Ser Pro Gly Lys
450
<210> 165
<211> 1359
<212> DNA
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 165
gaggtgcagc tggtggagag cggcggagat ctggtgaagc ccggcggaag cctgagactg 60
agctgtgtgg ccagcggcta caccttcacc aactactgga ttcattgggt gagacaggcc 120
cctggcaagg gcctgcagtg gatcggcagg atcgacccca acagcggcgg caccaagtac 180
aacgagaagt tcaagagcaa ggccaccctg agcgtggaca aggccaagaa caccctgtac 240
ctgcagatga actccctgag ggccgaggac accgccgtgt actactgcgc cgcctttggc 300
agcacctacg gcttcgccta ctggggccag ggaaccctgg tgaccgtgag cagcgcttcc 360
acaaccgcgc catcagtctt tccgttggcc ccatcatgcg ggtcgacgag cggatcgact 420
gtggccctgg cgtgcttggt gtcgggatac tttcccgaac ccgtcacggt cagctggaac 480
tccggatcgc ttacgagcgg tgtgcatacg ttcccctcgg tcttgcaatc atcagggctc 540
tactcgctgt cgagcatggt aacggtgccc tcatcgaggt ggccctccga aacgttcaca 600
tgtaacgtag cacatccagc ctccaaaacc aaggtggata aacccgtgcc gaaaagagag 660
aatgggcggg tgcctcgacc ccctgattgc cccaagtgtc cggctccgga aatgctcggt 720
ggaccctcag tgtttatctt ccctccgaag cccaaggaca ctctgctgat cgcgcgcact 780
ccagaagtaa catgtgtagt ggtggcactt gatcccgagg accccgaagt ccagatctcc 840
tggtttgtag atgggaaaca gatgcagacc gcaaaaactc aacccagaga ggagcagttc 900
gcaggaacat accgagtggt atccgtcctt ccgattggcc accaggactg gttgaaaggg 960
aagcagttta cgtgtaaagt caacaataag gcgttgccta gccctattga gcggacgatt 1020
tcgaaagcta ggggacaggc ccaccagcca tcggtctatg tccttccgcc ttcccgcgag 1080
gagctctcga agaatacagt gagccttaca tgcctcatta aggatttctt cccgcctgat 1140
atcgacgtag agtggcaatc aaacggtcaa caggagccgg aatccaagta tagaaccact 1200
ccgccccagc ttgacgagga cggatcatac tttttgtatt caaaactgtc ggtggataag 1260
agccggtggc agagaggtga caccttcatc tgtgcggtga tgcacgaagc actccataat 1320
cactacaccc aagagagcct ctcgcattcc cccggaaag 1359
<210> 166
<211> 453
<212> PRT
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 166
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Ile
35 40 45
Gly Arg Ile Asp Pro Asn Ser Gly Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Ser Val Asp Lys Ala 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 Ala Phe Gly Ser Thr Tyr Gly Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Cys Gly Ser Thr Ser Gly Ser Thr Val Ala Leu Ala
130 135 140
Cys Leu Val Ser Gly Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ser Leu Thr Ser Gly Val His Thr Phe Pro Ser Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Ser Ser
180 185 190
Arg Trp Pro Ser Glu Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser
195 200 205
Lys Thr Lys Val Asp Lys Pro Val Pro Lys Arg Glu Asn Gly Arg Val
210 215 220
Pro Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Met Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu
245 250 255
Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Leu Asp Pro
260 265 270
Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met
275 280 285
Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Ala Gly Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly
305 310 315 320
Lys Gln Phe Thr Cys Lys Val Asn Asn Lys Ala Leu Pro Ser Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val
340 345 350
Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser
355 360 365
Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu
370 375 380
Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr
385 390 395 400
Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu
405 410 415
Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser
435 440 445
His Ser Pro Gly Lys
450
<210> 167
<211> 1359
<212> DNA
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 167
gaggtgcagc tggtggagag cggcggcgat ctggtgaagc ctggcggaag cctgagactg 60
agctgcgtgg ccagcggcta caccttcacc aactactgga ttcattggat gaggcaggcc 120
cctggcaagg gactgcagtg gatcggcaga atcgacccca acagcggcgg caccaagtac 180
aacgagaagt tcaagagcaa ggccaccctg agcgtggaca aggccaagaa caccgcctac 240
atgcagctga acagcctgag ggccgaggac accgccgtgt actactgcgc cgcctttggc 300
agcacctacg gcttcgccta ttggggccag ggcaccctgg tgaccgtgag cagcgcttcc 360
acaaccgcgc catcagtctt tccgttggcc ccatcatgcg ggtcgacgag cggatcgact 420
gtggccctgg cgtgcttggt gtcgggatac tttcccgaac ccgtcacggt cagctggaac 480
tccggatcgc ttacgagcgg tgtgcatacg ttcccctcgg tcttgcaatc atcagggctc 540
tactcgctgt cgagcatggt aacggtgccc tcatcgaggt ggccctccga aacgttcaca 600
tgtaacgtag cacatccagc ctccaaaacc aaggtggata aacccgtgcc gaaaagagag 660
aatgggcggg tgcctcgacc ccctgattgc cccaagtgtc cggctccgga aatgctcggt 720
ggaccctcag tgtttatctt ccctccgaag cccaaggaca ctctgctgat cgcgcgcact 780
ccagaagtaa catgtgtagt ggtggcactt gatcccgagg accccgaagt ccagatctcc 840
tggtttgtag atgggaaaca gatgcagacc gcaaaaactc aacccagaga ggagcagttc 900
gcaggaacat accgagtggt atccgtcctt ccgattggcc accaggactg gttgaaaggg 960
aagcagttta cgtgtaaagt caacaataag gcgttgccta gccctattga gcggacgatt 1020
tcgaaagcta ggggacaggc ccaccagcca tcggtctatg tccttccgcc ttcccgcgag 1080
gagctctcga agaatacagt gagccttaca tgcctcatta aggatttctt cccgcctgat 1140
atcgacgtag agtggcaatc aaacggtcaa caggagccgg aatccaagta tagaaccact 1200
ccgccccagc ttgacgagga cggatcatac tttttgtatt caaaactgtc ggtggataag 1260
agccggtggc agagaggtga caccttcatc tgtgcggtga tgcacgaagc actccataat 1320
cactacaccc aagagagcct ctcgcattcc cccggaaag 1359
<210> 168
<211> 453
<212> PRT
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 168
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Met Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Ile
35 40 45
Gly Arg Ile Asp Pro Asn Ser Gly Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Ser Val Asp Lys Ala Lys Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Phe Gly Ser Thr Tyr Gly Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Cys Gly Ser Thr Ser Gly Ser Thr Val Ala Leu Ala
130 135 140
Cys Leu Val Ser Gly Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ser Leu Thr Ser Gly Val His Thr Phe Pro Ser Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Ser Ser
180 185 190
Arg Trp Pro Ser Glu Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser
195 200 205
Lys Thr Lys Val Asp Lys Pro Val Pro Lys Arg Glu Asn Gly Arg Val
210 215 220
Pro Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Met Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu
245 250 255
Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Leu Asp Pro
260 265 270
Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met
275 280 285
Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Ala Gly Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly
305 310 315 320
Lys Gln Phe Thr Cys Lys Val Asn Asn Lys Ala Leu Pro Ser Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val
340 345 350
Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser
355 360 365
Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu
370 375 380
Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr
385 390 395 400
Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu
405 410 415
Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser Leu Ser
435 440 445
His Ser Pro Gly Lys
450
<210> 169
<211> 669
<212> DNA
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 169
gacatcgtga tgacccagac ccctctgagc ctgtccgtga gccctggcga acctgccagc 60
atcagctgca agagcagcca gagcctgctg aacagcagga ccaggaagaa ctacctggcc 120
tggttcagac agaagcccgg ccagagcccc cagagactga tctactgggc cagcaccaga 180
gagagcggcg tgcctgacag atttagcggc agcggcagcg gcacagactt caccctgagg 240
atcagcagag tggaggccga cgatgccggc gtgtactact gcaagcagag ctacaacctg 300
tacaccttcg gccagggcac caaggtggag atcaagagga acgacgctca gccagccgtg 360
tacctcttcc agccttcgcc ggaccagctt catacggggt cagcgtcggt ggtgtgcctg 420
ttgaactcgt tttaccccaa ggacattaac gtgaagtgga aggtagacgg ggtaattcaa 480
gacactggca ttcaagagtc cgtcacggaa caagactcaa aagactcaac gtattcactg 540
tcgtcaacct tgacgatgtc aagcaccgag tatcttagcc atgagctgta ttcgtgcgag 600
atcacccaca agtccctccc ctccactctt atcaaatcct ttcagcggtc ggaatgtcag 660
cgggtcgat 669
<210> 170
<211> 223
<212> PRT
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 170
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Phe Arg Gln Lys Pro Gly Gln
35 40 45
Ser Pro Gln Arg Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg
65 70 75 80
Ile Ser Arg Val Glu Ala Asp Asp Ala Gly Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Asn Asp Ala Gln Pro Ala Val Tyr Leu Phe Gln Pro Ser Pro Asp
115 120 125
Gln Leu His Thr Gly Ser Ala Ser Val Val Cys Leu Leu Asn Ser Phe
130 135 140
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Val Asp Gly Val Ile Gln
145 150 155 160
Asp Thr Gly Ile Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Met Ser Ser Thr Glu Tyr Leu
180 185 190
Ser His Glu Leu Tyr Ser Cys Glu Ile Thr His Lys Ser Leu Pro Ser
195 200 205
Thr Leu Ile Lys Ser Phe Gln Arg Ser Glu Cys Gln Arg Val Asp
210 215 220
<210> 171
<211> 669
<212> DNA
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 171
gacatcgtga tgacccagac ccctctgagc ctgagcgtga gccctggaga gcctgccagc 60
atcagctgca agagcagcca gagcctgctg aacagcagga ccaggaagaa ctacctggcc 120
tggtacaggc agaagcctgg ccagagcccc cagctgctga tctactgggc cagcaccaga 180
gagagcggag tgcctgacag gttcagcgga agcggcagcg gcaccgactt caccctgagg 240
atcagcagag tggaggccga tgacgccggc gtgtactact gcaagcagag ctacaacctg 300
tacaccttcg gccagggcac caaggtggag atcaagagga acgacgctca gccagccgtg 360
tacctcttcc agccttcgcc ggaccagctt catacggggt cagcgtcggt ggtgtgcctg 420
ttgaactcgt tttaccccaa ggacattaac gtgaagtgga aggtagacgg ggtaattcaa 480
gacactggca ttcaagagtc cgtcacggaa caagactcaa aagactcaac gtattcactg 540
tcgtcaacct tgacgatgtc aagcaccgag tatcttagcc atgagctgta ttcgtgcgag 600
atcacccaca agtccctccc ctccactctt atcaaatcct ttcagcggtc ggaatgtcag 660
cgggtcgat 669
<210> 172
<211> 223
<212> PRT
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 172
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Arg Gln Lys Pro Gly Gln
35 40 45
Ser Pro Gln Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg
65 70 75 80
Ile Ser Arg Val Glu Ala Asp Asp Ala Gly Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Asn Asp Ala Gln Pro Ala Val Tyr Leu Phe Gln Pro Ser Pro Asp
115 120 125
Gln Leu His Thr Gly Ser Ala Ser Val Val Cys Leu Leu Asn Ser Phe
130 135 140
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Val Asp Gly Val Ile Gln
145 150 155 160
Asp Thr Gly Ile Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Met Ser Ser Thr Glu Tyr Leu
180 185 190
Ser His Glu Leu Tyr Ser Cys Glu Ile Thr His Lys Ser Leu Pro Ser
195 200 205
Thr Leu Ile Lys Ser Phe Gln Arg Ser Glu Cys Gln Arg Val Asp
210 215 220
<210> 173
<211> 669
<212> DNA
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 173
gacatcgtga tgacccagac ccctctgagc ctgagcgtga gccctggaga gcctgccagc 60
atcagctgca agagcagcca gagcctgctg aacagcagga ccaggaagaa ctacctggcc 120
tggtaccagc agaagcctgg ccagagcccc cagctgctga tctactgggc cagcaccaga 180
gagagcggag tgcctgacag gttcagcgga agcggcagcg gcaccgactt caccctgagg 240
atcagcagag tggaggccga tgacgccggc gtgtactact gcaagcagag ctacaacctg 300
tacaccttcg gccagggcac caaggtggag atcaagagga acgacgctca gccagccgtg 360
tacctcttcc agccttcgcc ggaccagctt catacggggt cagcgtcggt ggtgtgcctg 420
ttgaactcgt tttaccccaa ggacattaac gtgaagtgga aggtagacgg ggtaattcaa 480
gacactggca ttcaagagtc cgtcacggaa caagactcaa aagactcaac gtattcactg 540
tcgtcaacct tgacgatgtc aagcaccgag tatcttagcc atgagctgta ttcgtgcgag 600
atcacccaca agtccctccc ctccactctt atcaaatcct ttcagcggtc ggaatgtcag 660
cgggtcgat 669
<210> 174
<211> 223
<212> PRT
<213> 人工序列
<220>
<223> 嵌合的犬小鼠
<400> 174
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Gln Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg
65 70 75 80
Ile Ser Arg Val Glu Ala Asp Asp Ala Gly Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Asn Asp Ala Gln Pro Ala Val Tyr Leu Phe Gln Pro Ser Pro Asp
115 120 125
Gln Leu His Thr Gly Ser Ala Ser Val Val Cys Leu Leu Asn Ser Phe
130 135 140
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Val Asp Gly Val Ile Gln
145 150 155 160
Asp Thr Gly Ile Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Met Ser Ser Thr Glu Tyr Leu
180 185 190
Ser His Glu Leu Tyr Ser Cys Glu Ile Thr His Lys Ser Leu Pro Ser
195 200 205
Thr Leu Ile Lys Ser Phe Gln Arg Ser Glu Cys Gln Arg Val Asp
210 215 220
Claims (10)
1.一种分离的哺乳动物抗体或其抗原结合片段,其特异性地结合犬白介素-4受体α(IL-4Rα),所述哺乳动物抗体或其抗原结合片段包含三个轻链互补决定区(CDR):CDR轻1(CDRL1)、CDR轻2(CDRL2)和CDR轻3(CDRL3);和三个重链CDR:CDR重1(CDRH1)、CDR重2(CDRH2)和CDR重3(CDRH3);
(a)其中所述CDRL1由SEQ ID NO:129的氨基酸序列所示;
(b)其中所述CDRL2由SEQ ID NO:132的氨基酸序列所示;
(c)其中所述CDRL3由SEQ ID NO:135的氨基酸序列所示;
(d)其中所述CDRH1由SEQ ID NO:140的氨基酸序列所示;
(e)其中所述CDRH2由SEQ ID NO:144的氨基酸序列所示;并且
(f)其中所述CDRH3由SEQ ID NO:149的氨基酸序列所示;其中所述抗体及其抗原结合片段结合犬IL-4Rα。
2.权利要求1所述的分离的哺乳动物抗体或其抗原结合片段,其中所述抗体及其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
3.权利要求1或2所述的分离的哺乳动物抗体或其抗原结合片段,它是犬化抗体或其犬化抗原结合片段。
4.权利要求3所述的分离的哺乳动物抗体或其抗原结合片段,其中所述犬化抗体或其犬化抗原结合片段包含铰链区,所述铰链区由选自SEQ ID NO:101、SEQ ID NO:102、SEQ IDNO:103和SEQ ID NO:104的氨基酸序列所示。
5.权利要求1或2所述的分离的哺乳动物抗体或其抗原结合片段,其中当结合犬IL-4Rα时,所述哺乳动物抗体或其抗原结合片段结合SEQ ID NO:127、SEQ ID NO:128或这两者的氨基酸序列内的至少一个氨基酸残基;其中所述抗体或其抗原结合片段结合犬IL-4Rα并阻断犬IL-4Rα与犬白介素-4的结合。
6.一种分离的核酸,其编码权利要求1、2、3、4或5所述的哺乳动物抗体或其抗原结合片段的轻链和权利要求1、2、3、4或5所述的哺乳动物抗体或其抗原结合片段的重链。
7.一种表达载体,其包含权利要求6所述的分离的核酸。
8.一种宿主细胞,其包含权利要求7所述的表达载体。
9.一种药物组合物,其包含权利要求1、2、3、4或5所述的哺乳动物抗体或其抗原结合片段、权利要求6所述的核酸、权利要求7所述的表达载体或它们的任意组合和药学上可接受的载体或稀释剂。
10.权利要求9所述的药物组合物在制备药物中的用途,所述药物用于治疗选自犬哮喘和犬特应性皮炎的疾病。
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CN201680032086.3A CN107683291B (zh) | 2015-04-02 | 2016-04-01 | 针对犬白介素-4受体α的抗体 |
PCT/EP2016/057256 WO2016156588A1 (en) | 2015-04-02 | 2016-04-01 | Antibodies to canine interleukin-4 receptor alpha |
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2016
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CA3232537A1 (en) | 2016-10-06 |
CA2980087A1 (en) | 2016-10-06 |
CA3232651A1 (en) | 2016-10-06 |
JP6938383B2 (ja) | 2021-09-22 |
CN107683291B (zh) | 2021-11-19 |
HK1250514A1 (zh) | 2018-12-21 |
US20180346580A1 (en) | 2018-12-06 |
PT3277722T (pt) | 2021-10-06 |
WO2016156588A1 (en) | 2016-10-06 |
US10858437B2 (en) | 2020-12-08 |
RU2017134495A (ru) | 2019-04-04 |
CN113861294A (zh) | 2021-12-31 |
US20210040223A1 (en) | 2021-02-11 |
EP3954710A2 (en) | 2022-02-16 |
RU2017134495A3 (zh) | 2019-10-23 |
EP3277722A1 (en) | 2018-02-07 |
EP3277722B1 (en) | 2021-08-18 |
CN107683291A (zh) | 2018-02-09 |
JP7371070B2 (ja) | 2023-10-30 |
JP2018511322A (ja) | 2018-04-26 |
JP2021191779A (ja) | 2021-12-16 |
JP2024010002A (ja) | 2024-01-23 |
RU2736732C2 (ru) | 2020-11-19 |
ES2893148T3 (es) | 2022-02-08 |
AU2016239858A1 (en) | 2017-10-12 |
DK3277722T3 (da) | 2021-10-11 |
BR112017020915A2 (pt) | 2018-07-10 |
AU2016239858B2 (en) | 2021-07-01 |
EP3954710A3 (en) | 2022-07-20 |
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