CN1416432A - Cd25结合分子在治疗胃肠道炎性疾病中的用途 - Google Patents
Cd25结合分子在治疗胃肠道炎性疾病中的用途 Download PDFInfo
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Abstract
CD25结合分子在胃肠道炎性疾病治疗中的用途,其中CD25结合分子包含至少一个抗原结合位点,且该抗原结合位点包含至少一个结构域,该结构域依次包含高变区CDR1、CDR2和CDR3;所述的CDR1具有氨基酸序列Arg-Tyr-Trp-Met-His,所述的CDR2具有氨基酸序列Ala-Ile-Tyr-Pro-Gly-Asn-Ser-Asp-Thr-Ser-Tyr-Asn-Gln-Lys-Phe-Glu-Gly,且所述的CDR3具有氨基酸序列Asp-Tyr-Gly-Tyr-Tyr-Phe-Asp-Phe。
Description
本发明涉及CD25结合分子在治疗胃肠(GI)道炎性疾病中的用途。
更明确地,本发明首先提供了CD25结合分子及其直接等同物在治疗胃肠道疾病中的用途,其中所述CD25结合分子包含至少一个抗原结合位点,且该抗原结合位点至少包含依次含有3个高变区CDR1、CDR2和CDR3的一个结构域;所述的CDR1具有氨基酸序列Arg-Tyr-Trp-Met-His,所述的CDR2具有氨基酸序列Ala-Ile-Tyr-Pro-Gly-Asn-Ser-Asp-Thr-Ser-Tyr-Asn-Gln-Lys-Phe-Glu-Gly,所述的CDR3具有氨基酸序列Asp-Tyr-Gly-Tyr-Tyr-Phe-Asp-Phe。
胃肠道炎性疾病的治疗包括疾病和/或其后遗症,例如症状的控制或改善,以及病原成分的控制和改善。治疗也包括临床复发的抑制。
胃肠道炎性疾病包括慢性炎性肠疾病,例如过敏性肠综合征(IBS)、节段性回肠炎、溃疡性结肠炎和炎性肠疾病以及其它炎性胃肠道失调和胃肠道的炎性疾病。
“CD25结合分子”是指可单独或与其它分子一起同CD25抗原结合以形成高亲和力IL-2受体的任何分子。
优选地,使用包含至少一个抗原结合位点的CD25结合分子,其中抗原结合位点包含:
a)依次包含高变区CDR1、CDR2和CDR3的第一结构域;所述的CDR1具有氨基酸序列Arg-Tyr-Trp-Met-His,所述的CDR2具有氨基酸序列Ala-Ile-Tyr-Pro-Gly-Asn-Ser-Asp-Thr-Ser-Tyr-Asn-Gln-Lys-Phe-Glu-Gly,所述的CDR3具有氨基酸序列Asp-Tyr-Gly-Tyr-Tyr-Phe-Asp-Phe,以及
b)依次包含高变区CDR1’、CDR2’和CDR3’的第二结构域,所述的CDR1’具有氨基酸序列Ser-Ala-Ser-Ser-Ser-Ile-Ser-Tyr-Met-Gln,所述的CDR2’具有氨基酸序列Asp-Thr-Ser-Lys-Leu-Ala-Ser,所述的CDR3具有氨基酸序列His-Gln-Arg-Ser-Tyr-Thr;
或者它们的直接等同物。
除非另有说明,此处描述的任何多肽链为具有起始于N-末端并终止于C-末端的氨基酸序列。
当抗原结合位点包含第一结构域和第二结构域时,它们可位于同一多肽分子上,或者优选地,每一结构域可分别位于不同的多肽链上,第一结构域为免疫球蛋白重链或其片段的一部分,且第二结构域为免疫球蛋白轻链或其片段的一部分。
因此,本发明也提供了包含至少一个抗原结合位点的CD25结合分子在胃肠道炎性疾病治疗中的用途,所述抗原结合位点包含第一结构域或所述第一结构域和第二结构域,其中第一结构域的氨基酸序列与EP449,769中Seq.Id.No.1所示(起始于第1位氨基酸并终止于第117位氨基酸)相同或基本相同,该专利的内容在此引用作为参考,其中第二结构域的氨基酸序列与EP449,769中Seq.Id.No.2所示(起始于第1位氨基酸并终止于第104位氨基酸)相同或基本相同,该专利的内容在此引用作为参考。
用于本发明的更优选CD25结合分子选自抗CD25嵌合抗体,其包含至少:
a)一条免疫球蛋白重链或其片段,其中含有(i)一个依次包含高变区CDR1、CDR2和CDR3的可变结构域,和(ii)人重链的恒定部分或其片段;所述的CDR1具有氨基酸序列Arg-Tyr-Trp-Met-His,所述的CDR2具有氨基酸序列Ala-Ile-Tyr-Pro-Gly-Asn-Ser-Asp-Thr-Ser-Tyr-Asn-Gln-Lys-Phe-Glu-Gly,所述的CDR3具有氨基酸序列Asp-Tyr-Gly-Tyr-Tyr-Phe-Asp-Phe,以及
b)一条免疫球蛋白轻链或其片段,其中含有i)一个依次包含高变区CDR1’、CDR2’和CDR3’的可变结构域,和(ii)人轻链的恒定部分或其片段;所述的CDR1’具有氨基酸序列Ser-Ala-Ser-Ser-Ser-Ile-Ser-Tyr-Met-Gln,所述的CDR2’具有氨基酸序列Asp-Thr-Ser-Lys-Leu-Ala-Ser,所述的CDR3’具有氨基酸序列His-Gln-Arg-Ser-Tyr-Thr;
以及它们的直接等同物。
此外,用于本发明的CD25结合分子可选自包含抗原结合位点的单链结合分子,其中抗原结合位点包含:
a)依次包含高变区CDR1、CDR2和CDR3的第一结构域,所述的高变区具有EP449,769中Seq.Id.No.1所示的氨基酸序列,该专利的内容在此引用作为参考,
b)依次包含高变区CDR1’、CDR2’和CDR3’的第二结构域,所述的高变区具有EP449,769中Seq.Id.No.2所示的氨基酸序列,该专利的内容在此引用作为参考,以及
c)一个肽接头,它结合于第一结构域的N-末端和第二结构域的C-末端,或者结合于第一结构域的C-末端和第二结构域的N-末端;
以及它们的直接等同物。
如众所周知的那样,氨基酸序列的微小改变,例如一个、几个或者多个氨基酸的删除、添加或替换可产生具有与原始蛋白质性质(例如抗原结合活性)相同或基本相同的等位蛋白质。因此,术语“其直接等同物”意指下列任何单结构域的CD25结合分子(分子X):
(i)其中的高变区CDR1、CDR2和CDR3整体上讲与EP449,769中Seq.Id.No.1所示的高变区(该专利内容在此引用作为参考)具有至少80%的同源性,优选地具有至少90%的同源性,更优选地具有至少95%的同源性,且
(ii)它能抑制IL-2与其受体的结合,抑制程度基本上与参照分子相同,其中参照分子的构架区等同于分子X的构架区,但参照分子的高变区CDR1、CDR2和CDR3等同于EP449,769的Seq.Id.No.1中所示的那些高变区(该专利内容在此引用作为参考)。
术语“其直接等同物”或者是指每一结合位点具有至少两个结构域的任何下列CD25结合分子(分子X’):
(i)其中的高变区CDR1、CDR2、CDR3、CDR1’、CDR2’和CDR3’整体上讲与EP449,769中Seq.Id.No.1和Seq.Id.No.2所示氨基酸序列(该专利内容在此引用作为参考)具有至少80%的同源性,优选地具有至少90%的同源性,更优选地具有至少95%的同源性,且
(ii)它能抑制IL-2与其受体的结合,抑制程度基本上与参照分子相同,其中参照分子的构架区和恒定部分与分子X’相同,但参照分子的高变区CDR1、CDR2、CDR3、CDR1’、CDR2’和CDR3’等同于EP449,769的Seq.Id.No.1和Seq.Id.No.2中所示的那些高变区(该专利内容在此引用作为参考)。
可用EP449,769中所描述的多种方法方便地检测后一条标准,该专利内容在此引用作为参考。
用于本发明的最优选的CD25结合分子是为CD25嵌合抗体,特别是这样的CD25嵌合抗体,其包含至少:
a)一条重链,其包含具有氨基酸序列等同于或几乎等同于EP449,769中(该专利的内容在此引用作为参考)Seq.Id.No.1所示的、起始于第1位氨基酸并终止于第117位氨基酸的可变结构域和人重链的恒定部分,和
b)一条轻链,其包含具有氨基酸序列等同于或几乎等同于EP449,769中(该专利的内容在此引用作为参考)Seq.Id.No.2所示的、起始于第1位谷氨酸并终止于第104位谷氨酸的可变结构域和人轻链的恒定部分。
人重链的恒定部分可以是γ1、γ2、γ3、γ4、μ、α1、α2、δ或者ε型,优选的是γ型,更优选的是γ1型,而人轻链的恒定部分可以是κ或者λ型(其中包括λ1、λ2和λ3亚型),但优选的是κ型。这些恒定部分的氨基酸序列已在Kabat等人的文章[具有免疫学重要性的蛋白质序列(Sequences of Proteins of Immunological Interest),US Department ofHealth and Human Services,Public Health Services,NIH]中给出。
最优选的CD25结合分子是basiliximab,其在市场上可以购得,商品名为SIMULECT,由Novartis AG公司生产。
适用于本发明的CD25结合分子可以根据例如EP449,769,特别是其实施例1至5所公开的技术生产,该专利的内容在此引用作为参考。
如EP-B-449,769中所述,根据在例如混合淋巴细胞反应检测中所观察到的活性,已发现该CD25结合分子可用于预防或治疗移植排斥反应。
根据本发明,现在令人惊奇地发现该CD25结合分子在治疗胃肠道炎性疾病方面是有效的。
所以本发明也提供了:
(i)一种用于在需要此类治疗的患者中治疗胃肠道炎性疾病的方法,其包括施与患者有效剂量的上述CD25结合分子。
(ii)一种用于在需要此类治疗的受试者中治疗胃肠道炎性疾病的方法,其包括例如同时或依次施与该受试者有效剂量的a)上述的CD25结合分子和b)在治疗胃肠道炎性疾病方面有效的其它药用物质。
(iii)一种用于上述(i)和(ii)所描述的方法的药物组合物,其包含上述的CD25结合分子和可作药用的载体或稀释剂。
(iv)如上所述的CD25结合分子,其用于生产药物以用于如(i)或(ii)中所描述的方法。
(v)用于上述(i)和(ii)中所描述的任何一种方法的治疗性组合,例如成套药具盒或药具包,其中所述的组合不仅包括含有如上所述的CD25结合分子的药物组合物,还包括包含至少一种对治疗胃肠道炎性疾病有效的其它药用物质的药物组合物。
依照本发明的用途,最适使用剂量当然依据各种条件例如所采用的特定的CD25结合分子、宿主、给药方式、病情的严重程度和预期效果的不同而不同。通常可在剂量约0.1mg至约100mg之间取得满意的结果。当考虑到疾病在临床上是明显的或者为了预防性地阻止临床复发时,给药可以是单次或在一段时间内多次进行,例如给药剂量上可从约5mg直到约100mg,时间上可从1天直到5周,如每3~6天给药一次,一直到病情得到控制或改善为止。优选的给药剂量方案为在第0天给予20mg CD25结合分子如basiliximab,然后在第4天再给予另一个20mg。CD25结合分子可通过非肠道给药方式,如静脉注射的方式施用于肘前静脉或其它外周静脉。另外可选的示范给药剂量方案是每28天静脉注射40mg直到病情得到控制或改善。
本发明的药物组合物可用如EP449,769中所述的方法常规生产,该专利的内容在此引用作为参考。
CD25结合分子可以作为单独的活性成分给药,也可与其它免疫调节药物或者其它抗炎药一起给药。例如,依照本发明CD25结合分子可联合环孢菌素、雷帕霉素、子囊霉素类药物或它们的免疫抑制类似物如环孢菌素A、环孢菌素G、FK-506和雷帕霉素等;皮质类固醇类药物,例如强的松;环磷酰胺;硫唑嘌呤;氨甲蝶呤;金盐类、柳氮磺胺吡啶、抗疟药类、布利喹啉(brequinar);来氟米特;咪唑立宾;霉酚酸;霉酚酸莫非替尔;15-脱氧精胍菌素;其它免疫抑制性单克隆抗体,例如抗白细胞受体的单克隆抗体,如抗MHC、CD2、CD3、CD4、CD7、CD28、B7、CD40、CD45或CD58的单克隆抗体或者这些白细胞受体的配基;或者其它免疫调节化合物如CTLA4Ig等一起使用。
如果该CD25结合分子与其它药用物质一起使用,二者可分别包装置于同一容器内,内附指导混合或同时使用的说明书。成套药具盒例子包括如多针管的注射器或独立的单位剂量形式组成的姊妹包。
静脉注射剂可按照下述方法制备:将冷冻干燥抗体混合在一起,并分散于含有4.5%wt.人白蛋白的100ml无菌平衡盐溶液中。该盐水分散剂可采用静脉弹丸注射或于15分钟内静脉输注的方式施用于患者。
截止目前,研究表明给患者注射所采用剂量水平的CD25结合分子没有不可接受的副作用。尤其是优选的CD25结合分子basiliximab是安全的,已由美国联邦药品管理局(FDA)批准上市,在市场上可以购得。
CD25结合分子在胃肠道炎性疾病的治疗中的效用可通过如在下文中所述的多种动物模型系统以及临床试验来评定。因而,如CD25结合分子减轻结肠炎的能力可通过三硝基苯磺酸(TNBS)诱导的IBD模型来证明。
大鼠TNBS模型
TNBS模型是用于IBD研究的标准IBD模型之一,现已在啮齿类动物中得到广泛评价。例如,见C.O.Elson等人(1995),炎性肠疾病的实验模型,胃肠病学(Gastroenterology),109:1344-1367以及该文引用的参考文献。在这一模型中,一次TNBS灌肠诱导出长期的结肠炎性反应(高达几周),髓过氧物酶(“MPO”)活性的增强证明该炎性反应是跨壁的并伴随着氧化损伤。此外,炎性反应还具有不连续的急性坏死区、炎症和肌肉增厚的特征。在IBD患者身上具有抗炎效果的药剂在这一模型中体现了效能。尽管TNBS诱导炎性反应的机理仍不清楚,但据认为有免疫学基础。
结肠炎的诱导
雄性Sprague-Dawley大鼠(200-250g)饲养于标准鼠笼中(2只/笼),饲以鼠粮并以水龙头水随意饮用。在一夜的禁食后,将大鼠带到实验室并随机分到治疗组中。利用接有5cm聚乙烯导管的1ml注射器对大鼠直肠内施用0.5ml TNBS溶液(50mg/kg,溶于50%乙醇)以诱导结肠炎。对照组动物同时接受生理盐水(0.9%)或1%的甲基纤维素悬液。
组织分析
在施用TNBS3天后,杀死大鼠并切下结肠后纵向剖开。在结肠的5cm段上,依据下述标准确定总体形态学分级:
等级 | 表现 |
0 | 没有损伤 |
1 | 1个炎症区域(红色),没有溃疡 |
2 | 溃疡,没有炎症区域 |
3 | 溃疡,1个炎症区域 |
4 | 超过2处溃疡,在1个部位有炎症 |
5 | 超过2处溃疡,炎症>1cm |
记录每一5cm结肠段的重量以评价炎症导致的水肿。
剂量方案
在TNBS模型中,CD25结合分子以1mg/kg皮下注射(口服)剂量使用。每一受试化合物均在施用TNBS前1小时皮下注射。对照大鼠仅注射生理盐水。
与对照组相比,CD25结合分子一般可以减轻TNBS诱导的损伤。其它的动物模型系统也可用来评估CD25结合分子减轻TNBS诱导的损伤的能力,包括小鼠硫酸葡聚糖IBD模型和Elson等人描述的其它模型(出处同上)。
节段性回肠炎试验
CD25结合分子在治疗胃肠道炎性疾病中的效用在下述用basiliximab维持缓解节段性回肠炎的临床病例中得到展示。
60位节段性回肠炎患者参加了该试验。合格受试者的标准包括年龄至少年满18岁,通过典型的钡餐X射线检查、外科检查时总体外观、内窥镜检查或者病理学包括组织学检查确诊的与节段性回肠炎相一致的病史。
节段性回肠炎(包括组织学)
参加者是那些在最近4年里至少发作2次,最近18个月发作1次或最近做了切除术的患者。把节段性回肠炎活性指数(CDAI)(Best等人,胃肠病学,1976,70:439-444)得分<150,在基线附近且同时以前30天内没有症状定义为症状缓解。
排除标准包括以前做过全直肠结肠切除术;短肠综合征;在最近10年内有超过3次切除术的病史;可能干扰结果评估的慢性肛周疾病;溃疡性结肠炎的诊断;粪便病原菌(沙门氏菌属(Salmonella)、志贺氏菌属(Shigella)、耶尔森氏菌属(Yersinia)和弯曲杆菌属(Campylobacter))、寄生虫或艰难梭菌(Clostridium difficile)毒素阳性;有酗酒或药物滥用史;有临床上明显的肝脏、神经系统、内分泌、肾或其它主要的系统疾病而使执行治疗方案或解释结果困难的;有癌症史(不包括皮肤基底细胞或鳞状细胞癌)和不能出具正式知情同意书。在最近90天里使用过免疫抑制剂(咪唑硫嘌呤、6-巯基嘌呤和环孢菌素),最近30天里使用过皮质类固醇或者最近7天内服用过5-氨基水杨酸或灭滴灵的患者。
在研究期间下述药物必须明确排除:口服或直肠使用皮质类固醇类药物;5-氨基水杨酸制剂;阿司匹林或其它非类固醇类抗炎药物;免疫抑制类药物;除允许用来控制腹泻的可待因或洛派丁胺之外的麻醉药;长期(>4周)使用消胆胺;硫糖铝;H2-受体阻滞剂;奥美拉唑或抗酸剂和抗生素类使用时间>14天。
60位患者随机分到两组中的一组,其中一组接受basiliximab治疗,另一组给予安慰剂。
在试验开始前走访了每位受试者以取得正式的知情同意书并分发了用以计算CDAI的日记卡。对每位患者的节段性回肠炎的病史和总的人口统计数据进行了回顾;并留取了用以检测虫卵、寄生虫、培养敏感性和艰难梭菌的大便样本。CDAI<150的患者返回来再次进行基线评估,包括回顾最近7天的日记卡和计算CDAI。进行了体格检查;患者填写了一份生活质量问卷调查表,炎性肠道疾病问卷调查表(IBDQ)(Guyatt等人,胃肠病学,1989,96:804-810),并进行了多种检查,包括全血计数、红细胞沉降速率、血清生物化学检测(葡萄糖、尿素、氮、肌氨酸酐、电解质、钙、磷、胆红素、碱性磷酸酶、天冬氨酸转氨酶、乳酸脱氢酶、总蛋白、白蛋白、淀粉酶和脂肪酶)以及尿分析。
Basiliximab于第0天静脉注射60mg,第90天和180天各静脉注射40mg。患者分别在第4、12、24、36和48周进行药物安全性、有效性和疾病结果评价。每次评价均有内科医师检查,包括体格检查、生活质量评价、重复实验室检查和询问不良反应。每次回访均评价腹痛与否、腹部柔软还是存在硬块、功能容量和营养状况。每次均计算CDAI。
初步效果标准是复发时间和预期复发时间。当首次出现CDAI>150或者绝对数值高出基线至少60点以上时定义为治疗失败或者复发。
接受basiliximab治疗的患者与接受安慰剂治疗的患者相比,前者可明显维持节段性回肠炎的缓解。
溃疡性结肠炎试验
CD25结合分子在治疗溃疡性结肠炎中的效用通过与以上描述的节段性回肠炎的临床试验相似的临床试验得以显示。诊断患有溃疡性结肠炎的患者在该试验中作为受试者,Rachmillewitz指数用以判断病情严重程度。排除标准包括Rachmillewitz指数<6和其它在节段性回肠炎中所描述的标准。接受CD25结合分子如basiliximab治疗的患者与接受安慰剂治疗的患者相比,前者显示了症状的改善。
序列表
序列表<110>诺瓦提斯公司<120>CD25结合分子在治疗胃肠道炎性疾病中的用途<130>4-31368A<160>10<170>PatentIn version3.0<210>1<211>5<212>PRT<213>人工/未知<220><221>肽<222>(1)..(5)<223>高变区CRD1<400>1Arg Tyr Trp Met His1 5<210>2<211>17<212>PRT<213>人工/未知<220><221>肽<222>(1)..(17)<223>高变区CRD2<400>2Ala Ile Tyr Pro Gly Asn Ser Asp Thr Ser Tyr Asn Gln Lys Phe Glu1 5 10 15Gly<210>3<211>8<212>PRT<213>人工/未知<220><221>肽<222>(1)..(8)<223>高变区CRD3<400>3Asp Tyr Gly Tyr Tyr Phe Asp Phe1 5<210>4<211>10<212>PRT<213>人工/未知<220><221>肽<222>(1)..(10)<223>高变区CRD1’<400>4Ser Ala Ser Ser Ser Ile Ser Tyr Met Gln1 5 10<210>5<211>7<212>PRT<213>人工/未知<220><221>肽<222>(1)..(7)<223>高变区CRD2’<400>5Asp Thr Ser Lys Leu Ala Ser1 5<210>6<211>7<212>PRT<213>人工/未知<220><221>肽<222>(1)..(7)<223>高变区CRD3’<400>6His Gln Arg Ser Ser Tyr Thr1 5<210>7<211>492<212>DNA<213>人工/未知<220><221>CDS<222>(1)..(45)<223>免疫球蛋白重链可变结构域的前导序列<220><221>CDS<222>(130)..(492)<223>RFT5抗体的免疫球蛋白重链可变结构域<400>7atg gaa tgt aac tgg ata ctt cct ttt att ctg tcg gta att tca 45Met Glu Cys Asn Trp Ile Leu Pro Phe Ile Leu Ser Val Ile Ser1 5 10 15ggtaaggggc tcaccagttc catatctgaa agaggataca gggtctgaag tgacaatgac 105atctactctg ctgttctctc caca ggg gtc tac tca gag gtt cag ctc cag 156
Gly Val Tyr Ser Glu Val Gln Leu Gln
20cag tct ggg act gtg ctg gct agg cct ggg gct tcc gtg aag atg tcc 204Gln Ser Gly Thr Val Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser25 30 35 40tgc aag gct tct ggc tac agc ttt acc agg tac tgg atg cac tgg ata 252Cys Lys Ala Ser Gly Tyr Ser Phe Thr Arg Tyr Trp Met His Trp Ile
45 50 55aaa cag agg cct gga cag ggt cta gaa tgg att ggt gct att tat cct 300Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro
60 65 70gga aat agt gat act agt tac aac cag aag ttc gag ggc aag gcc aaa 348Gly Ash Ser Asp Thr Ser Tyr Asn Gln Lys Phe Glu Gly Lys Ala Lys
75 80 85ctg act gca gtc aca tcc gcc agc act gcc tac atg gag ctc agc agc 396Leu Thr Ala Val Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser
90 95 100ctg aca cat gag gac tct gcg gtc tat tac tgt tca aga gac tac ggc 444Leu Thr His Glu Asp Ser Ala Val Tyr Tyr Cys Ser Arg Asp Tyr Gly105 110 115 120tac tac ttt gac ttc tgg ggc caa ggc acc act ctc aca gtc tcc tca 492Tyr Tyr Phc Asp Phe Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
125 130 135<210>8<211>136<212>PRT<213>人工/未知<400>8Met Glu Cys Asn Trp Ile Leu Pro Phe Ile Leu Ser Val Ile Ser Gly1 5 10 15Val Tyr Ser Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Ala Arg
20 25 30Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe
35 40 45Thr Arg Tyr Trp Met His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Ser Tyr Asn65 70 75 80Gln Lys Phe Glu Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Ser
85 90 95Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr His Glu Asp Ser Ala Val
100 105 110Tyr Tyr Cys Ser Arg Asp Tyr Gly Tyr Tyr Phe Asp Phe Trp Gly Gln
115 120 125Gly Thr Thr Leu Thr Val Ser Ser
130 135<210>9<211>555<212>DNA<213>人工/未知<220><221>CDS<222>(1)..(48)<223>免疫球蛋白轻链可变结构域的前导序列<220><221>CDS<222>(226)..(555)<223>RFT5的免疫球蛋白轻链可变结构域<400>9atg gat ttt cag gtg cag att ttc agc ttc ctg cta atc agt gcc tca 48Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser1 5 10 15ggtaacagag ggcagggaat ttgagatcag aatccaacca aaattatttt ccctggggaa 108tttgagtcta aaatacagtt tttttttctt tttcttcatc tgaatgttgg gtggtataaa 168attatttttg tttctctatt tctactaatc cctttctctc tattttgctt ttttcta 225gtc ata ctg tcc aga gga caa att gtt ctc acc cag tct cca gca atc 273Val Ile Leu Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
20 25 30atg tct gca tct cca ggg gag aag gtc acc atg acc tgc agt gcc agc 321Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser
35 40 45tca agt ata agt tac atg cag tgg tac cag cag aag cca ggc acc tcc 369Ser Ser Ile Ser Tyr Met Gln Trp Tyr Gln Gln Lys Pro Gly Thr Ser
50 55 60ccc aaa aga tgg att tat gac aca tcc aaa ctg gct tct gga gtc cct 417Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro65 70 75 80gct cgc ttc agt ggc agt ggg tct ggg acc tct tat tct ctc aca atc 465Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
85 90 95agc agc atg gag gct gaa gat gct gcc act tat tac tgc cat cag cgg 513Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg
100 105 110agt agt tac acg ttc gga ggg ggg acc aaa ctg gaa ata aaa 555Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
115 120 125<210>10<211>126<212>PRT<213>人工/未知<400>10Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser1 5 10 15Val Ile Leu Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
20 25 30Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser
35 40 45Ser Ser Ile Ser Tyr Met Gln Trp Tyr Gln Gln Lys Pro Gly Thr Ser
50 55 60Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro65 70 75 80Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
85 90 95Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg
100 105 110Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
115 120 125
Claims (10)
1.用于治疗胃肠道炎性疾病的包含至少一个抗原结合位点的CD25结合分子或其直接等同物,其中抗原结合位点包含至少一个结构域,该结构域依次包含3个高变区CDR1、CDR2和CDR3的;所述的CDR1具有氨基酸序列Arg-Tyr-Trp-Met-His,所述的CDR2具有氨基酸序列Ala-Ile-Tyr-Pro-Gly-Asn-Ser-Asp-Thr-Ser-Tyr-Asn-Gln-Lys-Phe-Glu-Gly,所述的CDR3具有氨基酸序列Asp-Tyr-Gly-Tyr-Tyr-Phe-Asp-Phe。
2.如权利要求1所定义的CD25结合分子,其用于生产治疗胃肠道炎性疾病的药物。
3.用以治疗胃肠道炎性疾病的药物组合物,其包含如权利要求1所定义的CD25结合分子以及可作药用的载体或稀释剂。
4.一种治疗胃肠道炎性疾病的方法,其用于需要此类治疗的患者,该方法包括给患者使用有效剂量的如权利要求1所定义的CD25结合分子。
5.一种治疗胃肠道炎性疾病的方法,其用于需要此类治疗的受试者,该方法包括给所述的受试者施用有效量的a)如权利要求1所定义的CD25结合分子和b)其它在治疗胃肠道炎性疾病中有效的药用物质。
6.一种用于如权利要求5中所述的方法的治疗性组合,该组合包括含有如权利要求1中所定义的CD25结合分子的药物组合物外,且还包括至少一种含有其它在治疗胃肠道炎性疾病中有效的药用物质的药物组合物。
7.根据权利要求4和5中任意一项所述的方法,其中CD25结合分子是basiliximab。
8.根据权利要求1或2所述的CD25结合分子,其为basiliximab。
9.根据权利要求3或6所述的组合物或组合,其中CD25结合分子是basiliximab。
10.根据权利要求1或2所述的CD25结合分子,其用于治疗过敏性肠综合征(IBS)、节段性回肠炎、溃疡性结肠炎或炎性肠道疾病。
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GB0007911.1 | 2000-03-30 | ||
GBGB0007911.1A GB0007911D0 (en) | 2000-03-30 | 2000-03-30 | Organic compounds |
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CN1416432A true CN1416432A (zh) | 2003-05-07 |
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CN01806231A Pending CN1416432A (zh) | 2000-03-30 | 2001-03-28 | Cd25结合分子在治疗胃肠道炎性疾病中的用途 |
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US (2) | US20050226872A1 (zh) |
EP (1) | EP1268553A1 (zh) |
JP (1) | JP2003528890A (zh) |
KR (2) | KR20080079702A (zh) |
CN (1) | CN1416432A (zh) |
AU (2) | AU4651601A (zh) |
BR (1) | BR0109549A (zh) |
CA (1) | CA2401249A1 (zh) |
GB (1) | GB0007911D0 (zh) |
HU (1) | HUP0301846A3 (zh) |
IL (1) | IL151089A0 (zh) |
NO (1) | NO20024579L (zh) |
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PL (1) | PL357014A1 (zh) |
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SK (1) | SK13892002A3 (zh) |
WO (1) | WO2001072845A1 (zh) |
ZA (1) | ZA200207736B (zh) |
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IL158060A0 (en) * | 2001-04-06 | 2004-03-28 | Univ Bristol | Use of cd25 binding molecules in steroid-resistant patients |
US10416162B2 (en) * | 2007-12-20 | 2019-09-17 | Monogram Biosciences, Inc. | Her2 diagnostic methods |
EP2438442B1 (en) | 2008-12-01 | 2017-08-09 | Laboratory Corporation of America Holdings | Methods and assays for measuring p95 and/or p95 complexes in a sample and antibodies specific for p95 |
WO2010083470A1 (en) | 2009-01-15 | 2010-07-22 | Laboratory Corporation Of America Holdings | Methods of determining patient response by measurement of her-3 |
WO2010083463A1 (en) * | 2009-01-15 | 2010-07-22 | Laboratory Corporation Of America Holdings | Methods of determining patient response by measurement of her-2 expression |
RU2500427C2 (ru) * | 2010-07-15 | 2013-12-10 | Олег Ильич Эпштейн | Лекарственное средство для лечения функциональных нарушений желудочно-кишечного тракта и способ лечения функциональных нарушений желудочно-кишечного тракта |
CN107998388B (zh) * | 2011-05-02 | 2023-07-14 | 千禧制药公司 | 抗α4β7抗体的制剂 |
WO2018106959A1 (en) | 2016-12-07 | 2018-06-14 | Progenity Inc. | Gastrointestinal tract detection methods, devices and systems |
EP4108183A1 (en) | 2017-03-30 | 2022-12-28 | Biora Therapeutics, Inc. | Treatment of a disease of the gastrointestinal tract with an immune modulatory agent released using an ingestible device |
WO2019246317A1 (en) | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease or condition in a tissue originating from the endoderm |
WO2019246312A1 (en) | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an immunomodulator |
WO2020106757A1 (en) | 2018-11-19 | 2020-05-28 | Progenity, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
US11707610B2 (en) | 2019-12-13 | 2023-07-25 | Biora Therapeutics, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
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HUT60768A (en) * | 1990-03-16 | 1992-10-28 | Sandoz Ag | Process for producing cd25 fixing molecules |
JPH05244982A (ja) * | 1991-12-06 | 1993-09-24 | Sumitomo Chem Co Ltd | 擬人化b−b10 |
EP1100829B1 (en) * | 1998-07-27 | 2007-09-05 | Novartis AG | Use of basiliximab in the treatment of rheumatoid arthritis or skin diseases |
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- 2001-03-28 IL IL15108901A patent/IL151089A0/xx unknown
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Also Published As
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US20050226872A1 (en) | 2005-10-13 |
JP2003528890A (ja) | 2003-09-30 |
NZ520547A (en) | 2005-04-29 |
AU2001246516B2 (en) | 2005-06-30 |
CA2401249A1 (en) | 2001-10-04 |
RU2286797C2 (ru) | 2006-11-10 |
NO20024579D0 (no) | 2002-09-24 |
KR20020084107A (ko) | 2002-11-04 |
NO20024579L (no) | 2002-11-11 |
HUP0301846A3 (en) | 2010-07-28 |
ZA200207736B (en) | 2003-05-08 |
IL151089A0 (en) | 2003-04-10 |
BR0109549A (pt) | 2003-06-10 |
EP1268553A1 (en) | 2003-01-02 |
GB0007911D0 (en) | 2000-05-17 |
RU2002127800A (ru) | 2004-03-27 |
US20090041775A1 (en) | 2009-02-12 |
AU4651601A (en) | 2001-10-08 |
WO2001072845A1 (en) | 2001-10-04 |
PL357014A1 (en) | 2004-07-12 |
SK13892002A3 (sk) | 2003-05-02 |
HUP0301846A2 (hu) | 2003-09-29 |
KR20080079702A (ko) | 2008-09-01 |
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