CN1759123A - Il-23激动剂及拮抗剂的用途;相关试剂 - Google Patents
Il-23激动剂及拮抗剂的用途;相关试剂 Download PDFInfo
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- CN1759123A CN1759123A CNA2004800067148A CN200480006714A CN1759123A CN 1759123 A CN1759123 A CN 1759123A CN A2004800067148 A CNA2004800067148 A CN A2004800067148A CN 200480006714 A CN200480006714 A CN 200480006714A CN 1759123 A CN1759123 A CN 1759123A
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Abstract
本发明提供治疗肿瘤的方法。具体地,本发明提供用于调节细胞因子分子及其受体的活性的方法。
Description
发明领域
本发明涉及哺乳动物的细胞因子分子的用途及相关试剂。更具体地,本发明涉及可用于治疗增殖性病症的哺乳动物的细胞因子样蛋白质及其抑制剂的鉴定。
发明背景
癌症及肿瘤可由免疫系统来控制或消除。免疫系统包括几种类型的淋巴及骨髓细胞,例如单核细胞、巨噬细胞、树突细胞(DC)、嗜酸性细胞、T细胞、B细胞及中性粒细胞。这些淋巴及骨髓细胞产生分泌的信号传递蛋白质,这些蛋白质称为细胞因子。这些细胞因子包括:例如,白介素-10(IL-10)、干扰素-γ(IFN-γ)、IL-12及IL-23。免疫应答包括炎症,也即全身性或身体的特殊部位的免疫细胞的积聚。反应于感染剂或外来物质,免疫细胞会分泌细胞因子,而细胞因子又调节免疫细胞的增殖、发育、分化或迁移。免疫应答可产生病理后果,例如在涉及过度炎症时,其如同自身免疫病的情形,而受损的免疫应答会导致癌症。经免疫系统的抗肿瘤反应包括:先天免疫,例如经巨噬细胞、NK细胞及中性粒细胞介导的免疫;及获得性免疫,例如经抗原呈递细胞(APC)、T细胞及B细胞介导的免疫(例如,参见Abbas等人(eds.)(2000)Cellular and Molecular Immunology,W.B.SaundersCo.,Philadelphia,PA;Oppenheim及Feldmann(eds.)(2001)CytokineReference,Academic Press,San Diego,CA;von Andrian及Mackay(2000)New Engl.J.Med.343:1020-1034;Davidson及Diamond(2001)New Engl.J.Med.345:340-350)。
调节免疫应答的方法已用于治疗诸如黑素瘤的癌症。这些方法包括以细胞因子或抗细胞因子抗体,例如IL-2、IL-12、肿瘤坏死因子-α(TNF-α)、IFN-γ、粒细胞巨噬细胞集落刺激因子(GM-CSF)及转化生长因子(TGF)来进行治疗。当癌细胞可产生增强其自身生长或其自身存活的细胞因子时,抗细胞因子抗体可作为适当的治疗剂(例如,参见Ramirez-Montagut等人(2003)Oncogene 22:3180-3187;Braun等人(2000)J.Immunol.164:4025-4031;Shaw等人(1998)J.Immunol.161:2817-2824;Coussens及Werb(2002)Nature 420:860-867;Baxevanis等人(2000)J.Immunol.164:3902-3912;Shimizu等人(1999)J.Immunol.163:5211-5218;Belardelli及Ferrantini(2002)TRENDSImmunol.23:201-208;Seki等人(2002)J.Immunol.168:3484-3492;Casares等人(2003)J.Immunol.171:5931-5939;Oft等人(2002)NatureCell Biol.4:487-494)。
白介素-23(IL-23)是由两个亚基(也即p19及p40)组成的异二聚细胞因子。p19亚基在结构上与IL-6、粒细胞集落刺激因子(G-CSF)及IL-12的p35亚基相关。IL-23的p40亚基也为IL-12的部分,IL-12是包含p35及p40的异二聚细胞因子。IL-23通过结合至由IL-23R及IL-12β1所组成的异二聚受体来介导信号传递。IL-12β1亚基由IL-12受体共有,该IL-12受体由IL-12β1及IL-12β2组成。大量早期研究证实:p40的遗传缺陷的生理后果(p40剔除小鼠;p40KO小鼠;p40-/-小鼠)不同于p35KO小鼠中所发现的生理后果,例如比其更严重或更不严重。这些结果中有一些结果最终由IL-23的发现及p40KO防止IL-12与IL-23二者的表达的发现来解释(Oppmann等人(2000)Immunity 13:715-725;wiekowski等人(2001)J.Immunol.166:7563-7570;Parham等人(2002)J.Immunol 168,5699-708;Frucht(2002)SciSTKE 2002,E1-E3;Elkins等人(2002)Infection Immunity 70:1936-1948;Cua等人(2003)Nature 421:744-748)。
目前用于治疗癌症的方法并非完全有效,且诸如IL-12或IFN-γ的细胞因子会产生毒副作用(例如,参见Naylor及Hadden(2003)Int.Immunopharmacol.3:1205-1215;Fernandez等人(1999)J.Immunol.162:609-617)。本发明通过提供使用IL-23激动剂及拮抗剂的方法来解决这些问题。
发明概述
本发明是基于IL-23激动剂或拮抗剂可调节肿瘤生长的发现。
本发明提供一种调节肿瘤生长的方法,该方法包含使肿瘤细胞与有效量的IL-23激动剂或拮抗剂接触。本发明也提供其中IL-23拮抗剂抑制或防止肿瘤细胞生长的上述方法;及其中肿瘤细胞表达IL-23的上述方法。在另一方面中,本发明提供其中IL-23激动剂或拮抗剂包含特异性结合p19(SEQ ID NOs:1、2、3或4)或IL-23R(SEQ IDNOs:5或6)的多肽或核酸的结合组合物的上述方法;或其中结合组合物包含下列物质的上述方法:抗体的抗原结合位点,IL-23R(SEQ IDNOs:5或6)的细胞外区域,小分子,反义核酸或小干扰RNA(siRNA),或可检测标记;及其中结合组合物包含下列物质的上述方法:多克隆抗体,单克隆抗体,人源化抗体或其片段,Fab、Fv或F(ab′)2片段,或抗体的肽模拟物(peptide mimetic)。
而本发明的另一实施方案提供一种调节肿瘤生长的方法,该方法包括使肿瘤细胞与有效量的IL-23激动剂或拮抗剂接触;其中,肿瘤细胞为:结肠癌细胞,卵巢癌细胞,乳腺癌细胞或黑素瘤细胞。
在另一方面中,本发明提供一种治疗患有癌症或肿瘤的患者的方法,该方法包括给患者施用有效量的IL-23激动剂或拮抗剂;及其中IL-23拮抗剂抑制:癌症或肿瘤的生长,恶病质,厌食,或血管发生的上述方法。本发明也提供其中IL-23拮抗剂包含特异性结合p19(SEQ ID NOs:1、2、3或4)或IL-23R(SEQ ID NOs:5或6)的多肽或核酸的结合组合物的上述方法。而本发明的另一实施方案提供其中结合组合物包含下列物质的上述方法:抗体的抗原结合位点,IL-23R(SEQ ID NOs:5或6)的细胞外区域,反义核酸或小干扰RNA(siRNA),小分子,或可检测的标记;及其中结合组合物包含下列物质的上述方法:多克隆抗体,单克隆抗体,人源化抗体或其片段,Fab、Fv或F(ab′)2片段,或抗体的肽模拟物。
在另一实施方案中,本发明提供其中癌症或肿瘤是以下系统的癌症或肿瘤的上述方法:胃肠道,呼吸道,生殖系统或内分泌系统;以及其中癌症或肿瘤为以下癌症或肿瘤的上述方法:结肠癌,卵巢癌,黑素瘤,或乳腺癌。
本发明的另一方面提供以下两种方法:一种诊断癌症或肿瘤的方法,该方法包括使来自受试者的样品与上述方法的结合组合物接触;以及其中结合组合物包含特异性结合或杂交至SEQ ID Nos 1、2或5的多核苷酸的核酸探针或引物的上述诊断方法。
而本发明的另一实施方案提供一种用于诊断癌症或肿瘤的试剂盒,该试剂盒包含上述方法的结合组合物及腔室或者使用或处置说明。本发明也提供其中结合组合物包含特异性结合至p19(SEQ IDNOs:1、2、3或4)或IL-23R(SEQ ID NOs:5或6)的抗体的上述试剂盒。
发明详述
如本文,包括所附权利要求所使用,除非上下文明确另行指出,否则诸如”一个″,“一种”及″该″等词的单数形式包括其相应的复数形式。本文所引用的所有文献均以引用的方式并入本文,该引用的程度就如同已特定地及个别地将各个公开文件、专利申请或专利的公开内容以引用的方式并入一样。
I.定义
当″活化″、″刺激″及″治疗″应用于细胞或受体时,其可具有相同的含义,例如,除非上下文或明确另行指出,否则表示以配体来活化、刺激或治疗细胞或受体。″配体″涵盖天然及合成配体,例如细胞因子、细胞因子变体、类似物、突变蛋白质及源于抗体的结合组合物。″配体″也涵盖小分子,例如细胞因子的肽模拟物及抗体的肽模拟物。″活化″是指经内部机制调控及经外部或环境因子调控的细胞活化。″反应″,例如细胞、组织或器官的反应,涵盖生化或生理行为的变化,例如生物腔室内的浓度、密度、粘附或迁移的变化,基因表达的速率的变化,或分化状态的变化,其中变化与活化、刺激或治疗、或者诸如遗传程式化的内部机制相关。
分子的″活性″可描述或指代:将分子与配体或受体结合,或催化活性;刺激基因表达或细胞信号传递、分化或成熟的能力;抗原活性,对其它分子的活性的调节等。分子的″活性″也可指调节或维持细胞与细胞间的诸如粘附的相互作用的活性,或维持诸如细胞膜或细胞骨架的细胞结构的活性。″活性″也可意谓比活性,例如[催化活性]/[毫克蛋白质],或[免疫活性]/[毫克蛋白质],生物腔室中的浓度等。″增殖活性″涵盖:促进例如正常细胞分裂及癌症、肿瘤、发育异常、细胞转化、转移、血管发生的活性;或其所必需的活性;或与其特异性相关的活性。
当″施用″及″治疗″应用于动物、人类、实验对象、细胞、组织、器官或生物流体时,其是指使外源性药剂、治疗剂、诊断剂、化合物或组合物与动物、人类、受试者、细胞、组织、器官或生物流体接触。″施用″及″治疗″可指,例如,治疗方法、安慰剂方法、药代动力学方法、诊断方法、研究方法及实验方法。″细胞的治疗″涵盖使试剂与细胞接触及使试剂与流体接触,其中该流体与细胞接触。″施用″及″治疗″也意谓经试剂、诊断剂、结合组合物或经另一细胞来体外及离体治疗例如细胞。当″治疗″应用于人类、兽医或研究对象时,其是指对研究及诊断应用的治疗性处理、预防性或防止性措施。当″治疗″应用于人类、牲畜或研究对象、或者细胞、组织或器官时,其涵盖使IL-23激动剂或IL-23拮抗剂与人类或动物对象、细胞、组织、生理腔室或生理流体接触。″细胞的治疗″也涵盖如下两种情形:IL-23激动剂或IL-23拮抗剂接触IL-23受体(IL-23R及IL-12Rβ1的异二聚物),例如在流体相或胶体相中;及激动剂或拮抗剂接触流体,例如流体接触细胞或受体,但未证实激动剂或拮抗剂接触细胞或受体的情形。
″结合组合物″是指能够与目标结合的分子、小分子、大分子、抗体、其片段或类似物、或可溶性受体。″结合组合物″也可指能够与目标结合的下列物质:分子复合物,例如非共价复合物;离子化分子;及共价或非共价修饰的分子,例如经磷酸化、酰化、交联、环化或有限裂解来修饰的分子。″结合组合物″也可指与稳定剂、赋形剂、盐、缓冲剂、溶剂或添加剂组合的分子。″结合″可定义为结合组合物与目标的缔合,其中若结合组合物可溶解于或悬浮于溶液中,则该缔合会导致结合组合物的正常的布朗运动减少。
″恶病质″是涉及肌肉和脂肪损失(肌肉消耗)的消耗综合征,其由代谢的失调引起。恶病质发生于各种癌症、慢性阻塞性肺病(COPD)、晚期器官衰竭及AIDS中。″癌症恶病质″为伴随癌症并发的恶体质。癌症恶体质的特征在于:例如显著的体重减轻、厌食、衰弱及贫血。厌食是由于缺乏进食动力所引起的病症,例如厌恶食物(例如,参见MacDonald等人(2003)J.Am.Coll.Surg.197:143-161;Rubin(2003)Proc.Natl.Acad.Sci.USA 100:5384-5389;Tisdale(2002)NatureReviews Cancer 2:862:871;Argiles等人(2003)Drug Discovery Today8:838:844;Lelli等人(2003)J.Chemother.15:220-225;Argiles等人(2003)Curr.Opin.Clin.Nutr.Metab.Care 6:401-406)。
″保守修饰的变体″适用于氨基酸序列及核酸序列二者。就特殊核酸序列而言,保守修饰的变体是指:编码相同或基本相同的氨基酸序列的核酸;或当核酸并未编码氨基酸序列时,其是指基本相同的核酸序列。因为遗传密码的简并,所以大量功能相同的核酸可编码任意给定的蛋白质。
关于氨基酸序列,本领域技术人员将了解:取代保守氨基酸的编码序列中的氨基酸或小百分比氨基酸的对核酸、肽、多肽或蛋白质序列的各个取代为″保守修饰的变体″。提供功能相似的氨基酸的保守取代表在本领域是公知的。保守取代的一个实例为将下列各组的一组中的一种氨基酸交换成同组中的另一种氨基酸(授予Lee等人的美国专利第5,767,063号;Kyte及Doolittle(1982)J.Mol.Biol.157:105-132):
(1)疏水性:正亮氨酸、Ile、Val、Leu、Phe、Cys或Met;
(2)中性亲水性:Cys、Ser、Thr;
(3)酸性:Asp、Glu;
(4)碱性:Asn、Gln、His、Lys、Arg;
(5)影响链取向的残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe;
(7)小氨基酸:Gly、Ala、Ser。
″有效量″涵盖足以改善或防止医学状况的症状或体征的剂量。有效量也意谓足以允许或便于诊断的剂量。特殊患者或兽医对象的有效量可依各种因素而变化,例如正在治疗的状况、患者的总体健康状况、施用方法途径与剂量及副作用的严重程度(例如,参见授予Netti等人的美国专利第5,888,530号)。有效量可为避免显著副作用或毒性作用的最大剂量或定量给药方案。其效果将导致诊断量度或参数改进至少5%,通常至少10%,更通常至少20%,最通常至少30%,优选至少40%,更优选至少50%,最优选至少60%,理想地至少70%,更理想至少80%,且最理想至少90%,其中将100%界定为正常受试者所显示的诊断参数(例如,参见Maynard等人(1996)A Handbook of SOPsfor Good Clinical Practice,Interpharm Press,Boca Raton,FL;Dent(2001)Good Laboratory and Good Clinical Practice,Urch Publ.,London,UK)。
视上下文,″外源性″是指产生于生物体、细胞或人体外的物质。视上下文,″内源性″是指产生于细胞、生物体或人体内的物质。
″免疫状况″或″免疫病″涵盖,例如病理性炎症、炎症性病症及自身免疫病症或疾病。″免疫状况″也指感染、持续感染及增殖状况,例如癌症、肿瘤及血管发生,包括抵抗免疫系统根除的感染、肿瘤及癌症。″癌状况″包括例如癌症、癌细胞、肿瘤、血管发生及诸如发育异常的癌前状况。
″炎症性病症″意谓其中病理是完全或部分由例如免疫系统的细胞的数目改变、迁移速率改变或活化改变引起的病症或病理性状况。免疫系统的细胞包括例如T细胞、B细胞、单核细胞或巨噬细胞、抗原呈递细胞(APC)、树突细胞、小胶质细胞、NK细胞、NKT细胞、中性粒细胞、嗜酸性细胞、肥大细胞或其它与免疫学有特定关联的细胞,例如产生细胞因子的内皮细胞或上皮细胞。
″抑制剂″及″拮抗剂″或″活化剂″及″激动剂″分别指抑制分子或活化分子,例如,其活化例如配体、受体、辅因子、基因、细胞、组织或器官。例如基因、受体、配体或细胞的调节剂是改变基因、受体、配体或细胞的活性的分子,其中可活化、抑制或改变其调控性质中的活性。调节剂可单独作用,或可使用辅因子,例如蛋白质、金属离子或小分子。抑制剂是减少、阻断、防止、延迟活化、灭活、脱敏或下调例如基因、蛋白质、配体、受体或细胞的化合物。活化剂是增加、活化、促进、增强活化、敏化或上调例如基因、蛋白质、配体、受体或细胞的化合物。抑制剂也可定义为减少、阻断或灭活组成型活性的组合物。″激动剂″是与目标相互作用以引起或促进目标的活化增加的化合物。″拮抗剂″是与激动剂的作用相反的化合物。拮抗剂防止、减少、抑制或中和激动剂的活性。即使没有鉴定的激动剂,拮抗剂仍可防止、抑制或减少诸如目标受体的目标的组成型活性。
例如,为检查抑制的程度,以可能的活化剂或抑制剂来处理包含给定的例如蛋白质、基因、细胞或生物体的样品或测定,并将其与未用抑制剂处理的对照样品进行比较。对照样品,也即不以拮抗剂处理的样品,被赋予100%的相对活性值。当相对于对照值的活性值为以下值时则完成了抑制:约90%或更少,典型为85%或更少,更典型为80%或更少,最典型为75%或更少,一般为70%或更少,更一般为65%或更少,最一般为60%或更少,典型为55%或更少,通常为50%或更少,更通常为45%或更少,最通常为40%或更少,优选为35%或更少,更优选为30%或更少,再优选为25%或更少,最优选为低于25%。当相对于对照值的活性值为以下值时则完成了活化:约110%,一般至少为120%,更一般至少为140%,最一般至少为160%,经常至少为180%,更经常至少为2倍,最经常至少为2.5倍,通常至少为5倍,更通常至少为10倍,优选至少为20倍,更优选至少为40倍,且最优选超过40倍。
活化或抑制终点可监控如下。例如,对细胞、生理流体、组织、器官及动物或人类对象的治疗的活化、抑制及反应可由终点来监控。终点可包含预定量或百分比的例如炎症、肿瘤发生或细胞脱粒或分泌的指征,例如细胞因子、毒性氧或蛋白酶的释放。终点可包含:例如预定量的离子流或转运;细胞迁移;细胞粘附;细胞增殖;转移的可能;细胞分化;及表型改变,例如炎症、细胞凋亡、转化、细胞周期或转移相关的基因表达的改变(例如,参见Knight(2000)Ann.Clin.Lab.Sci.30:145-158;Hood及Cheresh(2002)Nature Rev.Cancer2:91-100;Timme等人(2003)Curr.Drug Targets 4:251-261;Robbins及Itzkowitz(2002)Med.Clin.North Am.86:1467-1495;Grady及Markowitz(2002)Annu.Rev.Genomics Hum.Genet.3:101-128;Bauer等人(2001)Glia 36:235-243;Stanimirovic及Satoh(2000)Brain Pathol.10:113-126)。
抑制终点一般为对照值的75%或更少,优选为对照值的50%或更少,更优选为对照值的25%或更少,且最优选为对照值的10%或更少。一般而言,活化终点为对照值的至少150%,优选为对照值的至少2倍,更优选为对照值的至少4倍,且最优选为对照值的至少10倍。
经光谱方法、光化学方法、生物化学方法、免疫化学方法、同位素方法或化学方法,可直接或间接检测″经标记″的组合物。例如,可用的标记包括32P、33P、35S、14C、3H、125I、稳定同位素、萤光染料、高电子试剂、底物、表位标记或酶,例如用于酶联免疫测定法中的那些,或fluorettes(例如,参见Rozinov及Nolan(1998)Chem.Biol.5:713-728)。
″配体″是指例如小分子、肽、多肽及膜相关分子或膜结合分子或者其复合物,其可充当受体的激动剂或拮抗剂。″配体″也涵盖一种试剂,它并非激动剂或拮抗剂,但其可与受体结合而不会显著影响其生物学性质,例如信号传递或粘附。此外,″配体″包括已通过例如化学或重组方法改变为可溶形式的膜结合配体的膜结合配体。按照惯例,当配体是结合于第一个细胞的膜上时,受体通常出现于另一个细胞上。第二个细胞可具有与第一细胞相同或不同的实体。配体或受体可完全在细胞内,即其可位于胞质溶胶、细胞核或某些其它细胞内腔室中。配体或受体可改变其位置,例如,从细胞内腔室改变至细胞质膜的外表面。配体与受体的复合物称为″配体受体复合物″。当配体及受体包含在信号传递途径内时,配体出现在信号传递途径的上游位置,而受体出现在信号传递途径的下游位置。
提供″小分子″以治疗肿瘤及癌症的生理学及病症。将″小分子″界定为分子量小于10kD、典型地是小于2kD,而优选者小于1kD的分子。小分子包括但不限于无机分子、有机分子、含有无机成分的有机分子、包含放射性原子的分子、合成分子、肽模拟物及抗体模拟物。作为治疗剂而言,小分子比大分子更易透过细胞、更不易降解,且更不易于引起免疫应答。业已描述了小分子,例如抗体及细胞因子的肽模拟物以及小分子毒素(例如,参见Casset等人(2003)Biochem.Biophys.Res.Commun.307:198-205;Muyldermans(2001)J.Biotechnol.74:277-302;Li(2000)Nat.Biotechnol.18:1251-1256;Apostolopoulos等人(2002)Curr.Med.Chem.9:411-420;Monfardini等人(2002)Curr.Pharm.Des.8:2185-2199;Domingues等人(1999)Nat.Struct.Biol.6:652-656;Sato及Sone(2003)Biochem.J.371:603-608;授予Stewart等人的美国专利第6,326,482号)。
当″特异性″或″选择性″结合是指配体/受体、抗体/抗原或其它结合对时,其表示对蛋白质与其它生物制剂的异质群体中的蛋白质的存在具有决定作用的结合反应。因此,在指定条件下,特定的配体与特殊受体结合,而不与该样品中存在的其它蛋白质大量结合。所涵盖的方法中,抗体或抗体的抗原结合位点衍生的结合组合物与其抗原或变体或突变蛋白质以一定的亲和力结合,相较于任何其它抗体或由其衍生的结合组合物的亲和力,该亲和力至少高2倍,优选为至少高10倍,更优选为至少高20倍,且最优选为至少高100倍。在优选实施方案中,例如经Scatchard分析所测定的抗体的亲和力将大于约109升/摩尔(Munsen等人(1980)Analyt.Biochem.107:220-239)。
II.总则
本发明提供使用IL-23异二聚物、p19亚基、p40亚基、IL-23受体异二聚物、IL-23R亚基或IL-12Rβ1亚基的多肽、核酸、变体、突变蛋白质及模拟物的方法。本发明也提供使用hyperkine(意即包含例如连接至p40亚基的p19亚基的融合蛋白质)及编码hyperkine的核酸(例如,参见SEQ ID NOs:10或11)的方法(Oppmann等人supra;Fischer等人(1997)Nature Biotechnol.15:142-145;Rakemann等人(1999)J.Biol.Chem.274:1257-1266;及Peters等人(1998)J.Immunol.161:3575-3581)。
白介素-23(IL-23,又名IL-B30)是由IL-12的p19亚基(SEQ IDNOs:2或4)及p40亚基(SEQ ID NOs:8或9)组成的异二聚细胞因子(Oppmann等人,同上)。如同p35,为了生物活性,p19要求p40的共同表达(wiekowski等人,同上)。IL-23受体包含结合p19的新受体亚基(IL-23R;SEQ ID NOs:6)及结合p40的IL-12Rβ1(SEQ IDNOs:7)(例如,参见Parham等人(2002)J.Immunol.168:5699-5708)。这些两种受体亚基形成功能性信号传递复合物,且其表达在CD4+CD45Rb10记忆T细胞及IFN-γ活化的骨髓巨噬细胞上(Parham等人,同上)。
抗体可产生为天然存在(全长)形式或其重组形式(例如,参见SEQID NOs:2、4、10或11)的各种细胞因子蛋白质,包括单独、多形态、等位、株或种变体及其片段。此外,抗体可产生为天然(或活性)形式或非活性形式(例如,变性形式)的受体蛋白质(例如,参见SEQ IDNOs:6)。也可使用抗独特型抗体。
施用IL-23激动剂(也即IL-23或IL-23hyperkine)可诱导例如记忆T细胞、PHA胚细胞、CD45RO T细胞、CD45RO T细胞的增殖;经PHA胚细胞或CD45RO T细胞增强干扰素-γ(IFN-γ)的产生。与IL-12相比,相对于人和小鼠中的幼稚T细胞群,IL-23优先刺激记忆T细胞。IL-23活化大量细胞内细胞信号传递分子,例如Jak2、Tyk2、Stat1、Stat2、Stat3及Stat4。IL-12活化同组分子,但Stat4对IL-23的反应相对较弱,而Stat4对IL-12的反应较强(Oppmann等人,supra;Parham等人(2002)J.Immunol.168:5699-5708)。
IL-12及IL-23涉及类似的信号传导机制。占据其受体复合物的IL-23活化Jak2、Tyk2及Stat-1、-3、-4及-5,IL-12也如此。然而,Stat-4的活化对IL-23的反应显著地弱于对IL-12的反应。同样地,与IL-12相比,由IL-23所诱导的最突出的Stat为Stat-3(例如,参见Parham等人supra)。
施用IL-23的p19亚基可导致:例如动物的矮化生长、不育及死亡,以及诸如胃肠道、肺部、皮肤及肝脏的炎症性浸润,及上皮细胞的过度增殖、小细胞贫血、中性粒细胞计数增加、血清TNFα增加;及肝脏中的急性期基因表达增加;(wiekowski等人supra)。增强的IL-23表达出现在永生性非转化的上皮细胞系中。因此,IL-23可提供体内潜在肿瘤的早期信号。
其它研究已证实IL-23调节对感染的免疫应答(例如,参见Pirhonen等人(2002)J.Immunol.169:5673-5678;Broberg等人(2002)J.Interferon Cytokine Res.22:641-651;Elkins等人(2002)InfectionImmunity 70:1936-1948;Cooper等人(2002)J.Immunol.168:1322-1327)。
关于癌症,来自个体的活检组织中的相对较高量的转录产物的存在表明了发生疾病的倾向,或可提供在出现实际临床症状的检测疾病的方法。基因表达资料是在疾病及病理状况的诊断及治疗中的有用工具(例如,参见Li及wong(2001)Genome Informatics 12:3-13;Lockhart等人(1996)Nature Biotechnol.14:1675-1680;Homey等人(2000)J.Immanol.164:3465-3470;Debets等人(2000)J.Immunol.165:4950-4956)。
III.激动剂、拮抗剂及结合组合物
本发明提供使用IL-23激动剂及拮抗剂的方法。IL-23激动剂涵盖:例如IL-23、IL-23变体、突变蛋白质、hyperkine、或肽模拟物、IL-23R的激动抗体,及编码这些激动剂的核酸。IL-23的拮抗剂包括:例如IL-23的抗体、IL-23R的阻断抗体,基于IL-23R的亚基的细胞外区域的可溶性受体、其肽模拟物,及编码这些拮抗剂的核酸。
本发明提供使用p19、p19与p40的复合物、IL-23R、及IL-23R与IL-12Rβ1的复合物的激动剂及拮抗剂的方法,包括使用特异性结合至p19、p19与p40的复合物、IL-23R、及IL-23R与IL-12Rβ1的复合物的蛋白质及蛋白质复合物的结合组合物的方法。
IL-23byperkine涵盖例如包含p19及p40的多肽序列的融合蛋白质,其中p19及p40出现在连续多肽链中。p19及p40的序列可为任何顺序。融合蛋白质可含有连接序列,该连接序列位于一连续多肽链中的p19与p40序列之间。
抗原性增加的区域可用于抗体产生。人p19的抗原性增加区域出现在:例如GenBank AAQ89442(gi:37183284)的氨基酸16-28;57-87、110-114、136-154及182-186处。人IL-23R的抗原性增加区域出现在例如GenBank AAM44229(gi:21239252)的氨基酸22-33、57-63、68-74、101-112、117-133、164-177、244-264、294-302、315-326、347-354、444-473、510-530及554-558处。经使用Vector NTISuite(Informax,Inc.,Bethesda,MD)的Parker作图来进行分析。本发明也提供IL-23拮抗剂,其为可溶性受体,意即包含IL-23R的细胞外区域,例如GenBankAAM44229的氨基酸1-353或其片段,其中细胞外区域或其片段特异性结合至IL-23。小鼠IL-23R是GenBank NP_653131(gi:21362353)。涵盖突变蛋白质及变体,例如聚乙二醇化或诱变以移除或取代脱酰胺的天冬酰胺残基。
可制备单克隆、多克隆及人源化抗体(例如,参见Sheperd及Dean(eds.)(2000)Monoclonal Antibodies,Oxford Univ.Press,New York,NY;Kontermann及Dubel(eds.)(2001)Antibody Engineering,Springer-Verlag,New York;Harlow及Lane(1988)Antibodies ALaboratory Manual,Cold Spring Harbor Laboratory Press,ColdSpring Harbor,NY,第139-243页;Carpenter等人(2000)J.Immunol.165:6205;He等人(1998)J.Immunol.160:1029;Tang等人(1999)J.Biol.Chem.274:27371-27378;Baca等人(1997)J.Biol.Chem.272:10678-10684;Chothia等人(1989)Nature 342:877-883;Foote及Winter(1992)J.Mol.Biol.224:487-499;授予Vasquez等人的美国专利第6,329,511号)。
对于抗体的产生而言,并非必须纯化抗原。可经DNA载体免疫来进行免疫,例如,参见Wang等人(1997)Virology 228:278-284。或者,以携带目的抗原的细胞来使动物免疫。于是,脾细胞可自免疫动物分离,且脾细胞可随骨髓瘤细胞系融合以产生杂交瘤(Meyaard等人(1997)Immunity 7:283-290;Wright等人(2000)Immunity13:233-242;Preston等人(1997)Eur.J.Immunol.27:1911-1918)。可经功能测定或生物测定,即不取决于是否具有纯化抗原的测定,来筛选所得杂交瘤以产生所需抗体。可证明:对于抗体的产生而言,经细胞的免疫优于经纯化抗原的免疫(Kaithamana等人(1999)J.Immunol.163:5157-5164)。
抗体对抗原及配体对受体的结合性质可经诸如表面等离子共振(Karlsson等人(1991)J.Immunol.Methods 145:229-240;Neri等人(1997)Nat.Biotechnol.15:1271-1275;Jonsson等人(1991)Biotechniques 11:620-627)或经竞争ELISA(Friguet等人(1985)J.Immunol.Methods 77:305-319;Hubble(1997)Immunol.Today18:305-306)来测量。抗体可用于亲和纯化以分离抗体的目标抗原及相关的结合蛋白,例如,参见wilchek等人(1984)Meth.Enzymol.104:3-55。
抗体通常以至少约10-3M,更通常至少10-6M,典型至少10-7M,更典型至少10-8M,优选至少约10-9M,且更优选至少约10-10M,且最优选至少10-11M的KD结合(例如,参见Presta等人(2001)Thromb.Haemost.85:379-389;Yang等人(2001)Crit.Rev.Oncol.Hematol.38:17-23;Carnahan等人(2003)Clin.Cancer Res.(Suppl.)9:3982s-3990s)。
提供包含IL-23或IL-12Rβ1受体多肽的细胞外域的可溶性受体。可溶性受体可根据标准方法来制备及使用(例如,参见Jones等人(2002)Biochim.Biophys.Acta 1592:251-263;Prudhomme等人(2001)ExpertOpinion Biol.Ther.1:359-373;Fernandez-Botran(1999)Crit.Rev.Clin.Lab Sci.36:165-224)。
IV.治疗组合物,方法
本发明提供IL-23及抗IL-23R,其用于例如治疗增殖性状况及病症,包括癌症、肿瘤、血管发生、恶病质、癌症恶病质、厌食及癌症前期病症,例如发育异常。也提供核酸以用于这些治疗用途,例如编码IL-23或IL-23R的核酸、或其抗原片段、相应反义核酸、及其杂交产物。本发明也提供用于siRNA干扰的组合物(例如,参见Arenz及Schepers(2003)Naturwissenschaften 90:345-359;Sazani及Kole(2003)J.Clin.Invest.112:481-486;Pirollo等人(2003)Pharmacol.Therapeutics 99:55-77;Wang等人(2003)Antisense Nucl.Acid DrugDevel.13:169-189)。
为制备包括IL-23激动剂或拮抗剂的药物组合物或无菌组合物,将细胞因子类似物或突变蛋白质、其抗体、或其核酸与药物可接受的载体或赋形剂混合,例如,参见Remington′s Pharmaceutical Sciencesand U.S.Pharmacopeia:National Formulary,Mack PublishingCompany,Easton,PA(1984)。治疗剂及诊断剂的制剂可经将其与生理学上可接受的诸如冻干粉末、浆料、水溶液或悬浮液形式的载体、赋形剂或稳定剂混合来制备(例如,参见Hardman等人(2001)Goodmanand Gilman′s The Pharmacological Basis of Therapeutics,McGraw-Hill,New York,NY;Gennaro(2000)Remington:The Science andPractice of Pharmacy,Lippincott,Williams,and Wilkins,New York,NY;Avis等人(eds.)(1993)Pharmaceutical Dosage Forms:ParenteralMedications,Marcel Dekker,NY;Lieberman等人(eds.)(1990)Pharmaceutical Dosage Forms:Tablets,Marcel Dekker,NY;Lieberman等人(eds.)(1990)Pharmaceutical Dosage Forms:DisperseSystems,Mareel Dekker,NY;Weiner及Kotkoskie(2000)ExcipientToxicity and Safety,Marcel Dekker,Inc.,New York,NY)。
施用途径是经例如局部或皮肤施用,皮下注射,经静脉内、腹膜内、脑内、肌肉内、眼内、动脉内、脑脊髓内、病变内或肺部途径的注射或输注,或经持续释放系统或植入物。对例如中枢神经系统的基因转移载体已有描述(例如,参见Cua等人(2001)J.Immunol.166:602-608;Sidman等人(1983)Biopolymers 22:547-556;Langer等人(1981)J.Biomed.Mater.Res.15:167-277;Langer(1982)Chem.Tech.12:98-105;Epstein等人(1985)Proc.Natl.Acad.Sci.USA 82:3688-3692;Hwang等人(1980)Proc.Natl.Acad.Sci.USA 77:4030-4034;美国专利第6,350,466号及第6,316,024号)。
治疗剂的施用方式的选择取决于若干因素,包括实体的血清或组织更新速度、症状程度、实体的免疫原性、生物基质中的目标细胞的可接近性。施用方案优选使送递给患者的符合可接受程度的副作用的治疗剂的量最大化。因此,所送递的生物生物制品的量部分取决于特定实体及正在治疗的状况的严重程度。可以获得选择抗体、细胞因子及小分子的适当剂量方面的指导(例如,参见wawrzynczak(1996)Antibody Therapy,Bios Scientific Pub.Ltd,Oxfordshire,UK;Kresina(ed.)(1991)Monoclonal Antibodies,Cytokines and Arthritis,MareelDekker,New York,NY;Bach(ed.)(1993)Monoclonal Antibodies andPeptide Therapy in Autoimmune Diseases,Marcel Dekker,NewYork,NY;Baert等人(2003)New Engl.J.Med.348:601-608;Milgrom等人(1999)New Engl.J.Med.341:1966-1973;Slamon等人(2001)NewEngl,J.Med.344:783-792;Beniaminovitz等人(2000)New Engl.J.Med.342:613-619;Ghosh等人(2003)New Engl J.Med.348:24-32;Lipsky等人(2000)New Engl.J.Med.343:1594-1602)。
抗体、抗体片段及细胞因子可经连续输注或经间隔剂量(例如,1天、1周或每周1-7次)来提供。可静脉内、皮下、局部、口服、经鼻、直肠、肌肉内、脑内、脊髓内或经吸入来提供剂量。优选的剂量方案为包括避免明显不良副作用的最大剂量或剂量频率的方案。每周总剂量一般为至少0.05μg/kg体重,更一般为至少0.2μg/kg,最一般为至少0.5μg/kg,典型为至少1μg/kg,更典型为至少10μg/kg,最典型为至少100μg/kg,优选为至少0.2mg/kg,更优选为至少1.0mg/kg,最优选为至少2.0mg/kg,较理想为至少10mg/kg,更理想为至少25mg/kg,且最理想为至少50mg/kg(例如,参见Yang等人(2003)NewEngl.J.Med.349:427-434;Herold等人(2002)New Engl.J.Med.346:1692-1698;Liu等人(1999)J.Neurol.Neurosurg.Psych.67:451-456;Portielii等人(2003)Cancer Immunol.Immunother.52:133-144)。诸如肽模拟物、天然产品或有机化学品的小分子治疗剂的所要剂量约与抗体或多肽相同,其以摩尔/千克为基础。
特定患者的有效量可视多个因素而变化,例如正在治疗的状况、患者的总体健康状况、施用方法途径与剂量及副作用的严重程度(例如,参见Maynard等人(1996)A Handbook of SOPs for Good ClinicalPractice,Interpharm Press,Boca Raton,FL;Dent(2001)GoodLaboratory and Good Clinical Practice,Urch Publ.,London,UK)。
典型兽医、实验或研究对象包括猴子、狗、猫、大鼠、小鼠、兔、豚鼠、马及人类。
适当剂量是经临床医师例如利用本领域已知或怀疑会影响治疗或预测会影响治疗的参数或因素来决定。一般而言,剂量以稍微少于最优剂量的量来开始,且其后增加小增量直至达到相对于任何不良副作用的所需或最优效果。重要的诊断量度包括例如炎症的症状的量度或所产生的炎性细胞因子的水平。使用的生物制品优选源于与治疗目标动物相同的物种,藉此最小化对试剂的体液应答。
用于与第二治疗剂,例如,细胞因子、类固醇、化学治疗剂、抗生素或辐射来共同施用或治疗的方法在本领域中是公知的(例如,参见Hardman等人(eds.)(2001)Goodman及Gilman′s ThePharmacological Basis of Therapeutics,第10版,McGraw-Hill,NewYork,NY;Poole及Peterson(eds.)(2001)Pharmacotherapeutics forAdvanced Practice:A Practical Approach,Lippincott,Williams &Wilkins,Phila.,PA;Chabner及Longo(eds.)(2001)CancerChemotherapy and Biotherapy,Lippincott,Williams & Wilkins,Phila.,PA)。治疗剂的有效量会使症状减轻:典型为至少10%,通常为至少20%,优选为至少30%,更优选为至少40%,且最优选为至少50%。
V.试剂盒及诊断试剂
本发明提供在诊断试剂盒中的IL-23蛋白质、其片段、核酸及其片段。本发明也提供用于检测IL-23与IL-23受体及其代谢物与分解产物的结合组合物,包括抗体或抗体片段。该试剂盒一般具有一腔室,该腔室含有p19多肽或其抗原片段、其结合组合物、或核酸,例如,核酸探针或引物。核酸探针或引物在严格条件下与编码p19或IL-23R的核酸特异性杂交。
该试剂盒可包含,例如试剂及腔室,试剂及使用说明,或具有腔室的试剂与使用说明。试剂可包含p19、p19与p40的复合物、IL-23R、IL-23R与IL-12Rβ1的复合物、或其抗原片段、结合组合物或核酸。用于测定测试化合物(例如,自生物样品或化学实验室取得)的结合的试剂盒可包含对照化合物、经标记的化合物及用于将无标记化合物与经结合的标记化合物分离的方法。
可与诸如活细胞、细胞提取物、细胞溶解物、固定的细胞、细胞培养物、体液或法医样品的生物基质一起使用诊断测定。可用于诊断或试剂盒目的的偶联抗体包括偶联至染料、同位素、酶及金属的抗体(例如,参见Le Doussal等人(1991)New Engl.J.Med.146:169-175;Gibellini等人(1998)J.Immunol.160:3891-3898;Hsing及Bishop(1999)New Engl.J.Med.162:2804-2811;Everts等人(2002)New Engl.J.Med.168:883-889)。存在各种测定形式,例如放射免疫测定(RIA)、ELISA及在芯片上的实验(美国专利第6,176,962号及第6,517,234号)。
本发明提供在诊断试剂盒中的IL-23及IL-23R的多肽及核酸、及其片段,例如用于增殖性状况、癌症、肿瘤及癌症前期病症(例如发育异常)的诊断。
本发明也提供用于检测p19、p19与p40的复合物、IL-23R、IL-23R与IL-23Rβ1的复合物、及其代谢物与分解产物的结合组合物,包括抗体或抗体片段。该试剂盒一般具有腔室,该腔室含有IL-23或IL-23R多肽、或其抗原片段、其结合组合物、或核酸,例如,核酸探针、引物,或分子信标(例如,参见Rajendran等人(2003)Nucleic AcidsRes.31:5700-5713;Cockerill(2003)Arch.Pathol.Lab.Med.127:1112-1120;Zammatteo等人(2002)Biotech.Annu.Rev.8:85-101;Klein(2002)Trends Mol.Med.8:257-260)。
诊断方法可包含使来自受试者,例如,测试受试者的样品与结合组合物接触,其中该结合组合物特异结合于p19、p19与p40的复合物、IL-23R、及IL-23R与IL-12Rβ1的复合物的多肽或核酸。该方法可进一步包含使来自对照受试者、正常受试者的样品或来自测试受试者的正常组织或流体与该结合组合物接触。此外,该方法可额外包含:将该组合物同测试受试者的特异性结合与该组合物同正常受试者、对照受试者或来自测试受试者的正常组织或流体的特异性结合进行比较。测试样品或测试受试者的表达或活性可与来自对照样品或对照受试者的表达或活性进行比较。对照样品可包含例如患有免疫病的患者的未受影响或无炎症组织的样品。所提供的来自对照受试者或对照样品的表达或活性可作为一预定值,例如自统计学上适当的组的对照受试者取得的值。
VI.用途
本发明提供使用IL-23激动剂及拮抗剂的方法,其用于通过调控免疫应答以治疗及诊断炎性病症及状况,其中炎性病症及状况为例如肿瘤性疾病、癌症、肿瘤、血管发生、诸如发育异常的癌前状况、厌食、恶病质及癌症恶病质。
本发明提供的方法是用以治疗或诊断增殖性状况或病症,例如子宫、子宫颈、乳腺、前列腺、睾丸、阴茎、胃肠道(例如,食道、口咽、胃、小肠或大肠、结肠或直肠)、肾、肾细胞、膀胱、骨、骨髓、皮肤、头或颈、皮肤、肝脏、胆囊、心脏、肺、胰腺、唾液腺、肾上腺、甲状腺、脑、神经节、中枢神经系统(CNS)及周围神经系统(PNS)、及免疫系统(例如,脾与胸腺)的癌症。本发明提供用于治疗以下疾病的方法:例如免疫原性肿瘤、非免疫原性肿瘤、休眠肿瘤、病毒诱导的癌症,例如上皮细胞癌、内皮细胞癌、鳞状细胞癌、乳头状瘤病毒、腺癌、淋巴瘤、癌、黑素瘤、白血病、骨髓瘤、肉瘤、畸胎瘤、化学诱导的癌症、转移及血管发生。本发明也期望例如经对调控T细胞(Treg)的活性的调节来降低肿瘤细胞或癌细胞抗原的耐受性(例如,参见Ramirez-Montagut等人(2003)Oncogene 22:3180-3187;Sawaya等人(2003)New Engl.J.Med.349:1501-1509;Farrar等人(1999)J.Immunol.162:2842-2849;Le等人(2001)J.Immunol 167:6765-6772;Cannistra及Niloff(1996)New Engl.J.Med.334:1030-1038;Osborne(1998)New Engl.J.Med.339:1609-1618;Lynch及Chapelle(2003)New Engl J.Med.348:919-932;Enzinger及Mayer(2003)New Engl J.Med.349:2241-2252;Forastiere等人(2001)New Engl.J.Med.345:1890-1900;Izbicki等人(1997)New Engl.J.Med.337:1188-1194;Holland等人(eds.)(1996)Cancer Medicine Encyclopedia of Cancer.第4版,Academic Press,San Diego,CA)。
本发明提供用于采用IL-23激动剂或拮抗剂及至少一种额外治疗剂或诊断剂来治疗增殖性状况、癌症、肿瘤或诸如发育异常的癌前状况的方法。该至少一种额外治疗剂或诊断剂可为例如细胞因子或细胞因子拮抗剂(例如,IL-12、干扰素-α或抗外皮生长因子受体)、阿霉素、表柔比星、抗叶酸物(例如氨甲喋呤或氟尿嘧啶、伊立替康、环磷酰胺、放射疗法、激素或抗激素治疗(例如雄激素、雌激素、抗雌激素、氟他米特或已烯雌酚)、外科手术、他莫西芬、异环磷酰胺、二溴卫矛醇、烷化剂(例如,美法兰或顺铂)、足叶乙甙、温诺平利宾、长春碱、长春酰胺、糖皮质激素、组胺受体拮抗剂、血管发生抑制剂、辐射、辐射敏化剂、蒽环霉素、长春花生物碱、紫杉烷(例如,紫杉醇(paclitaxel)及多西紫杉醇(docetaxel)),细胞周期抑制剂(例如,细胞周期蛋白依赖性激酶抑制剂)、单克隆抗体、单克隆抗体与毒素的复合物、T细胞佐剂、骨髓移植、或抗原呈递细胞(例如,树突细胞治疗)。可提供疫苗作为例如可溶性蛋白质或编码蛋白质的核酸(例如,参见Le等人supra;Greco及Zellefsky(eds.)(2000)Radiotherapy of ProstateCancer,Harwood Academic,Amsterdam;Sh apiro及Recht(2001)NewEngl.J.Med.344:1997-2008;Hortobagyi(1998)New Engl.J.Med.339:974-984;Catalona(1994)New Engl.J.Med.33l:996-1004;Naylor及Hadden(2003)Int.Immunopharmacol.3:1205-1215;The Int.Adjuvant Lung Cancer Trial Collaborative Group(2004)New Engl.J.Med.350:351-360;Slamoa等人(2001)New Engl.J.Med.344:783-792;Kudelka等人(1998)New Engl.J.Med.338:991-992;van Netten等人(1996)New Engl.J.Med.334:920-921)。
本发明提供用于治疗及诊断厌食及恶病质(包括癌症恶病质)的方法。恶病质是一种消耗性综合征,其发生在大量疾病中,包括癌症,例如肺癌及上胃肠道癌。所有癌症患者中约有一半出现恶病质。恶病质的诊断是根据大量体重减轻、胃口减少及深度虚弱(以上是针对晚期疾病而言)及肌肉消耗(瘦体重损耗)的病史。已将细胞因子,例如IL-6、IL-1、TNF-α及IFN-γ,与恶病质相联系(例如,参见MacDonald等人,supra;Rubin,supra;Tisdale,supra;Lelli等人,supra;Argiles等人,supra)。
本发明也提供治疗癌症的髓外造血(EMH)的方法。EMH已有描述(例如,参见Rao等人(2003)Leuk.Lymphoma 44:715-718;Lane等人(2002)J Cutan.Pathol.29:608-612)。
胃肠道包含例如嘴唇、口腔、食道、胃、小肠、阑尾、大肠、结肠、肛门及直肠。呼吸道包含例如气管、细支气管、支气管、肺、肺泡。生殖系统包括例如睾丸、阴茎、卵巢、子宫、输卵管。内分泌系统包括例如垂体、下丘脑、松果腺、甲状腺、甲状旁腺、内分泌胰腺、胰岛、性腺及肾上腺。
参考以下实施例可最好地理解本发明的广阔范围,这些实施例并无意将本发明限制为具体实施方案。
本文所有引证均以引用的方式并入本文,该引用的程度就如同以特定地及个别地将各个公开文献或专利申请的公开内容以引用的方式并入一般。
本发明的许多修改及变化可在未脱离其精髓及范畴的情况下作出,此对于本领域技术人员而言将显而易见。本文所描述的具体实施方案仅作为举例,且本发明受限于所附权利要求及赋予这些权利要求的等同方案的全部范畴;且本发明不限于本文中举例的具体实施方案。
实施例
I.一般方法
分子生物学的标准方法已有描述(Maniatis等人(1982)MolecularCloning,A Laboratory Manual,Cold Spring Harbor LaboratoryPress,Cold Spring Harbor,NY;Sambrook及Russell(2001)MolecularCloning,第三版,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,NY;Wu(1993)Recombinant DNA,Vol.217,AcademicPress,San Diego,CA)。标准方法也发表在Ausbel等人(2001)CurrentProtocols in Molecular Biology,Vols.1-4,John Wiley及Sons,Inc.NewYork,NY,其描述了细菌细胞中的克隆技术(cloning)及DNA诱变(Vol.1),哺乳动物细胞及酵母中的克隆技术(Vol.2),糖缀合物(glycoconjugate)及蛋白质表达(Vol.3),及生物信息学(Vol.4)。
蛋白质纯化方法已有描述,包括免疫沉淀、层析法、电泳法、离心法及结晶法(Coligan等人(2000)Current Protocols in ProteinScience,Vol.1,John Wiley and Sons,Inc.,New York)。化学分析、化学修饰、转移后修饰、融合蛋白质的产生、蛋白质的糖基化已有描述(例如,参见Coligan等人(2000)Current Protocols in ProteinScience,Vol.2,John Wiley and Sons,Inc.,New York;Ausubel等人(2001)Current Protocols in Molecular Biology,Vol.3,John Wileyand Sons,Inc.,NY,NY,pp.16.0.5-16.22.17;Sigma-Aldrich,Co.(2001)Products for Life Science Research,St.Louis,MO;pp.45-89;Amersham Pharmacia Biotech(2001)BioDirectory,Piscataway,N.J.,pp.384-391)。多克隆及单克隆抗体的产生、纯化及片段化已有描述(Coligan等人(2001)Current Protcols in Immunology,Vol.1,JohnWiley and Sons,Inc.,New York;Harlow及Lane(1999)UsingAntibodies,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,NY;Harlow及Lane,supra)。可以获得用于表征配体/受体相互作用的标准技术(例如,参见Coligan等人(2001)CurrentProtcols in Immunology,Vol.4,John Wiley,Inc.,New York)。
可以获得流式细胞术,包括萤光活化细胞分选(FACS)(例如,参见Owens等人(1994)FloW Cytometry Principles for ClinicalLaboratory Practice,John Wiley及Sons,Hoboken,NJ;Givan(2001)Flow Cytometry,第二版,wiley-Liss,Hoboken,NJ;Shapiro(2003)Practical Flow Cytometry,John Wiley and Sons,Hoboken,NJ)。可以获得适于修饰核酸(包括核酸引物及探针)、多肽及抗体的萤光试剂,以用作例如诊断试剂(Molecular Probes(2003)Catalogue,Molecular Probes,Inc.,Eugene,OR;Sigma-Aldrich(2003)Catalogue,St.Louis,MO)。
免疫系统组织学的标准方法已有描述(例如,参见Muller-Harmelink(ed.)(1986)Human Thymus:Histopathology及Pathology,Springer Verlag,New York,NY;Hiatt等人(2000)ColorAtlas of Histology,Lippincott,Williams,and Wilkins,Phila,PA;Louis等人(2002)Basic Histology:Text and Atlas,McGraw-Hill,NewYork,NY)。
用于治疗及诊断癌症的方法已有描述(例如,参见Alison(ed.)(2001)The Cancer Handbook,Grove′s Dictionaries,Inc.,St.Louis,MO;Oldham(ed.)(1998)Principles of Cancer Biotherapy,第三版,KluwerAcademic Publ.,Hingham,MA;Thompson等人(eds.)(2001)Textbookof Melanoma,Martin Dunitz,Ltd.,London,UK;Devita等人(eds.)(2001)Cancer:Principles and Practice of Oncology,第六版,Lippincott,Phila,PA;Holland等人(eds.)(2000)Holland-Frei CancerMedicine,BC Decker,Phila.,PA;Garrett及Sell(eds.)(1995)CellularCancer Markers,Humana Press,Totowa,NJ;MacKie(1996)SkinCancer,第二版,Mosby,St.Louis;Moertel(1994)New Engl.J.Med.330:1136-1142;Engleman(2003)Semin.Oncol.30(3 Suppl.8):23-29;Mohr等人(2003)Onkologie 26:227-233)。
可以获得用于测定例如抗原片段、前导序列、蛋白质折叠、功能域、糖基化位点及序列比对的软件包及数据库(例如,参见GenBank,Vector NTISuite(Informax,Inc,Bethesda,MD);GCG WisconsinPackage(Aceelrys,Inc.,San Diego,CA):DeCypher(TimeLogicCorp.,Crystal Bay,Nevada);Menne等人(2000)Bioinformatics16:741-742;Menne等人(2000)Bioinformatics Applications Note16:741-742;Wren等人(2002)Comput.Methods Programs Biomed.68:177-181;von Heijne(1983)Eur.J.Biochem.133:17-21;von Heijne(1986)Nucleic Acids Res.14:4683-4690)。
II.小鼠及肿瘤诱发
如上文Cua等人所述地产生IL-23 p19缺陷的小鼠。特定地缺乏IL-23的小鼠(p19KO小鼠,p19剔除小鼠,p19-/-小鼠)、p19+/-小鼠及p19+/+野生类对照小鼠具有B6/129 F2背景。
以化学方法诱发野生型小鼠(wt)或IL-23缺陷小鼠(p19KO小鼠)的皮肤肿瘤。使用50微克7,12二甲基苯并蒽(DMBA)引发肿瘤,随后进行由两次处理组成的促进步骤,其中每一处理各为每周30微克TPA(例如,参见Oft等人(2002)Nat.Cell.Biol.4:487-494)。
就对Ep2XlBl-nu/nu小鼠所作的肿瘤研究而言,肿瘤转移,同时并未出现恶病质。小鼠死于(例如)髓外造血(EMH))。就对Ep2XBl-Balb/c小鼠所作的肿瘤研究而言,未出现肿瘤转移,此显然是因为这些小鼠的完整的免疫系统。
III.p19及IL-23R亚基的表达
IL-23的p19亚基及IL-23受体的IL-23R亚基的表达在大量癌症、肿瘤及细胞系中提高,例如胃肠道癌、生殖道癌、皮肤癌及乳腺癌(表1)。
表1.经Taqman分析的19及IL-23R的亚基相对于遍在蛋白(1.0)的表达。所示值是来自患病组织及邻近正常组织。
人p19的表达 | |||
正常结肠,邻近的 | 4.8 | I期结肠腺癌 | 30.5 |
正常结肠,邻近的 | 2.0 | II期结肠腺癌 | 73.4 |
正常结肠,邻近的 | 0.8 | II期结肠腺癌 | 18.1 |
正常结肠,邻近的 | 0.21 | III期结肠腺癌 | 34.0 |
邻近的正常皮肤 | 2.2 | 人皮肤II期黑素瘤 | 21.8 |
邻近的正常皮肤 | 6.7 | 人皮肤II期结节状黑素瘤 | 16.4 |
邻近的正常皮肤 | 8.4 | 人皮肤II期结节状黑素瘤 | 26.8 |
邻近的正常皮肤 | 9.3 | 人皮肤II期浅表播散性黑素瘤 | 75.1 |
邻近的子宫 | 1.6 | 卵巢乳头状浆液性囊腺癌 | 55.0 |
邻近的卵巢 | 1.9 | 卵巢乳头状浆液性囊腺癌 | 17.7 |
邻近的乳腺 | 8.2 | IIB期乳腺癌,髓样 | 32.0 |
邻近的乳腺 | 0.6 | IIA期乳腺癌,浸润导管 | 3.1 |
邻近的乳腺 | 0.2 | IIA期乳腺癌,浸润导管 | 3.9 |
人IL-23R的表达 | |||
单核细胞/静息的PBMC | 10.0 | ||
淋巴细胞白血病SR细胞系 | 415.8 | ||
淋巴细胞白血病K562细胞系 | 396.7 | ||
淋巴细胞白血病MOLT-4细胞系 | 0.0 | ||
淋巴细胞白血病HL60 TB细胞系 | 374.1 |
使用Rneasy柱(Qiagen,Valencia)提取来自组织或细胞沉淀物的RNA,并以Dnase I(Promega,Madison,WI)对其进行处理。制备cDNA,且将其用作供定量实时PCR用的模板。使用GeneAmp5700序列检测系统(Applied Biosystems,Foster City,CA)来分析cDNA(25ng)的一定范围的基因的表达。将对来自正常及肿瘤结肠及卵巢组织的cDNA样品的分析标准化为管家基因遍在蛋白的表达。
IV.p19拮抗剂防止或减轻肿瘤
例如用抗p19抗体进行治疗或经p19亚基(p19KO)的基因切除,根除或减轻了以IL-23拮抗剂治疗的小鼠中由所注射的肿瘤细胞或由化学致癌作用所诱发的肿瘤。p19仅为IL-23的亚基,而p40是为IL-23及IL-12两者的亚基。相比之下,在某些情况下,以IL-12进行治疗会使肿瘤恶化,意即导致肿瘤体积相对于对照小鼠增加。
小鼠中的肿瘤导致癌症、癌症恶病质、髓外造血及死亡。以抗p19抗体治疗携带肿瘤的Balb/c小鼠会导致停止增加肿瘤体积,而以抗p40抗体进行治疗会激起动物体重增加(此可能是恶病质的逆转),但肿瘤体积增加(表2)。
表2.以Ep2(又名XTb细胞)癌细胞(ras转化小鼠乳腺细胞)接种的Balb/c小鼠的肿瘤生长
抗体治疗 | 肿瘤大小(mm3) | ||
第1天 | 第11天 | 第21天 | |
同种型抗体(8D5) | 0mm3 | 225mm3 | 500mm3 |
抗-p19抗体(29A2) | 0 | 200 | 250 |
抗-p40抗体(C17.8) | 0 | 250 | 1150 |
诱发小鼠中的癌症致死及癌症恶病质,其中用抗p40抗体来防止死亡及体重减轻。对小鼠注射1×106EpXT肿瘤细胞(s.c.)。携带肿瘤的裸鼠(Ep2XBl nu/nu)死于致命性肺部转移,其中死亡发生于注射后22-42天。携带肿瘤的Exp2XBl Balb/c小鼠死于注射后大约22-49天,这些死亡的BalbC/c小鼠并无肺部转移。恶病质由体重出现下降(死亡前)来指示。进行性体重减轻在约第16天开始发生。第1天的初始体重为22-23克,而死亡时的体重在16-18克范围内。
以C17.8大鼠抗p40抗体(1毫克/周)进行抗体治疗。经抗体治疗,Ep2XBl-Balb/C小鼠(免疫感受态小鼠)存活至约第64天,之后直至第85天才死亡。抗p40抗体治疗也导致一半的小鼠体重保持不变(大约17克),其余小鼠在实验期间内体重逐渐增加至22-23克的最大值。因此,根据存活时间及体重恢复,抗p40抗体会导致健康改善,但抗p40抗体也可导致健康下降,如肿瘤大小增加所示(表2)。
经每周以DMBA(50微克)及2×30微克十四烷酰佛波醇-13-乙酸酯(TPA)处理来化学诱发癌症(Gschwendt等人(1991)Trends BiochemSci.16:167-169)。将化学致癌处理施用于B6/129野生型小鼠及p19KO小鼠。野生型小鼠较易发生肿瘤,但p19KO小鼠并不会得肿瘤(表3)。
表3.p19KO小鼠抵抗化学致癌
用DMBA起始(50毫克);用TPA促进(2×30毫克/周,共13周) | 用DMBA起始(50毫克);用TPA促进(2×30毫克/周,共20周) | |||
第一次出现肿瘤(TPA后) | 每只小鼠的肿瘤数目 | 第一次出现肿瘤(TPA后) | 每只小鼠的肿瘤数目 | |
B2/129野生型小鼠 | 8周 | 11 | 8周 | 8 |
p19KO小鼠 | 在检验的时间段中未发现 | 0 | 在检验的时间段中未发现 | 0 |
独立研究证实:p19KO防止肿瘤形成,而p35KO加剧肿瘤形成(表4)。
表4.p19KO与p35KO对化学致癌的影响
每只小鼠的平均肿瘤数目 | |
C57/129野生型 | 10.0 |
p19KO(C57/129) | 0.0 |
C57B/6野生型 | 4.5 |
p35KO(C57/129) | 11.0 |
在致癌物处理后测定IL-23的亚基及IL-12的亚基的组织及细胞表达。单独的DMBA、单独的TPA、及DMBA与TPA诱导IL-23的p19亚基的表达,将这些化学物质施加至小鼠后背。举例而言,以DMBA处理2天后,导致p19表达自1.5(未处理)增加至6.3(第2天)。P40表达增加,但在该时间间隔内相对较低(未处理时为0.1,第2天为0.4)。以TPA处理5小时后,导致p19表达增加(对照值为2.5,以TPA处理值为15.5),但p40表达相对变化较小(对照值为2.0,以TPA处理值为3.5)。以DMBA加TPA处理5小时后,导致p19表达有较大增加(对照值为6.0,DMBA+TPA值为32.0),但p40表达仅有中等程度的增加(对照值为2.0,DMBA+TPA值为4.0)。
也测定人体角化细胞对例如DMBA、TPA及脂多糖(LPS)的反应(表5)。TPA特异性诱导p19,且极少或没有诱导p40(其为IL-23及IL-12的共同亚基)。LPS诱导p19,此表示先天反应中在IL-23中的作用。结合LPS的toll样受体出现在角化细胞上(例如,参见Song等人(2002)J.Invest.Dermatol.119:424-432)。足叶乙甙是抑制拓扑异构酶(topoisomerase)II及诱导细胞凋亡的抗癌剂(例如,参见Robertson等人(2000)J.BioL.Chem.275:32438-32443;Karpinich等人(2000)J.Biol.Chem.277:16547-16552)。
表5.人体角化细胞对各种添加剂的反应。N.D.意谓未检测。
添加物 | p19 | p40 | p35 | IL-27的EBI3亚基(p28+EBI3) |
对照 | 1.1 | N.D. | 0.4 | 0.01 |
DMBA | 1.0 | N.D. | N.D. | N.D. |
TPA | 1.9 | N.D. | 0.2 | 1.25 |
LPS | 4.45 | 0.05 | 0.35 | 0.25 |
足叶乙甙 | 2.5 | 0.4 | 1.75 | 0.6 |
测试抗p19抗体对4T1小鼠乳腺癌细胞模型的影响。以对照mIgGl(27F11)抗体或以抗p19抗体(29A2)处理小鼠。在第1、3、4、5、6、7、8、9、10及11天监控肿瘤生长。在第2、5、8及10天施用抗体(1毫克/剂)。在第4天,以对照抗体治疗的小鼠的肿瘤大小为约175mm3,而以抗p19抗体治疗的小鼠的肿瘤大小为约135mm3。因此,抗p19抗体可有效地治疗乳腺癌模型。4天后,两组肿瘤以大约相同的速率生长,此表示在以后的时期内抗体剂量不足以及时抵消肿瘤所表达的IL-23。
Ep2小鼠的乳腺癌模型的组织学证实了IL-23R与NK细胞的共定位,如经结合至IL-23R的p19染色及经CD49B(其为NK细胞的标记)染色所测定。该共定位发生在肿瘤的中心部位,意即在坏死区域。Ep2小鼠的乳腺癌组织学也证实了p19及T细胞的共定位。T细胞定位是经CD3染色来测定。该共定位发生在肿瘤的外周部位。
V.序列表标识
SEQ ID NOs:1是人IL-23 p19核酸序列;
SEQ ID NOs:2是人1L-23 p19氨基酸序列;
SEQ ID NOs:3是小鼠IL-23 p19核酸序列;
SEQ ID NOs:4是小鼠IL-23 p19氨基酸序列;
SEQ ID NOs:5是人IL-23受体核酸序列;
SEQ ID NOs:6是人IL-23受体氨基酸序列;
SEQ ID NOs:7是人IL-12Rβ1氨基酸序列;
SEQ ID NOs:8是人IL-12 p40氨基酸序列;
SEQ ID NOs:9是小鼠IL-12 p40氨基酸序列;
SEQ ID NOs:10是小鼠IL-23 hyperkine;
SEQ ID NOs:11是人体IL-23 hyperkine。
本文所有引证均以引用的方式并入本文,该引用的程度就如同以特定地及个别地将各个公开文献或专利申请的公开内容以引用的方式并入一般。
本发明的许多修改及变化可在未脱离其精髓及范畴的情况下作出,此对于本领域技术人员而言将显而易见。本文所描述的具体实施方案仅作为举例,且本发明受限于所附权利要求及赋予这些权利要求的等同方案的全部范畴;且本发明不限于本文中举例的具体实施方案。
序列表
<110>Schering Corporation
Oft,Martin
McClanahan,Terrill K
<120>IL-23激动剂及拮抗剂的用途;相关试剂
<130>DX06022WO01
<150>U.S.60/453,672
<151>2003-03-10
<160>11
<170>PatentIn version 3.1
<210>1
<211>570
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<222>(1)..(567)
<223>
<220>
<221>mat_肽
<222>(64)..(567)
<223>
<400>1
atg ctg ggg agc aga gct gta atg ctg ctg ttg ctg ctg ccc tgg aca 48
Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr
-20 -15 -10
gct cag ggc aga gct gtg cct ggg ggc agc agc cct gcc tgg act cag 96
Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln
-5 -1 1 5 10
tgc cag cag ctt tca cag aag ctc tgc aca ctg gcc tgg agt gca cat 144
Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His
15 20 25
cca cta gtg gga cac atg gat cta aga gaa gag gga gat gaa gag act 192
Pro Leu Val Gly His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr
30 35 40
aca aat gat gtt ccc cat atc cag tgt gga gat ggc tgt gac ccc caa 240
Thr Asn Asp Val Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln
45 50 55
gga ctc agg gac aac agt cag ttc tgc ttg caa agg atc cac cag ggt 288
Gly Leu Arg Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly
60 65 70 75
ctg att ttt tat gag aag ctg cta gga tcg gat att ttc aca ggg gag 336
Leu Ile Phe Tyr Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu
80 85 90
cct tct ctg ctc cct gat agc cct gtg gcg cag ctt cat gcc tcc cta 384
Pro Ser Leu Leu Pro Asp Ser Pro Val Ala Gln Leu His Ala Ser Leu
95 100 105
ctg ggc ctc agc caa ctc ctg cag cct gag ggt cac cac tgg gag act 432
Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr
110 115 120
cag cag att cca agc ctc agt ccc agc cag cca tgg cag cgt ctc ctt 480
Gln Gln Ile Pro Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu
125 130 135
ctc cgc ttc aaa atc ctt cgc agc ctc cag gcc ttt gtg gct gta gcc 528
Leu Arg Phe Lys Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala
140 145 150 155
gcc cgg gtc ttt gcc cat gga gca gca acc ctg agt ccc taa 570
Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Ser Pro
160 165
<210>2
<211>189
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<213>人
<400>2
Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr
-20 -15 -10
Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln
-5 -1 1 5 10
Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His
15 20 25
Pro Leu Val Gly His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr
30 35 40
Thr Asn Asp Val Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln
45 50 55
Gly Leu Arg Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly
60 65 70 75
Leu Ile Phe Tyr Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu
80 85 90
Pro Ser Leu Leu Pro Asp Ser Pro Val Ala Gln Leu His Ala Ser Leu
95 100 105
Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr
110 115 120
Gln Gln Ile Pro Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu
125 130 135
Leu Arg Phe Lys Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala
140 145 150 155
Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Ser Pro
160 165
<210>3
<211>1203
<212>DNA
<213>小鼠
<220>
<221>CDS
<222>(113)..(700)
<223>
<220>
<221>mat_肽
<222>(176)..(700)
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<400>3
cgcttagaag tcggactaca gagttagact cagaaccaaa ggaggtggat agggggtcca 60
caggcctggt gcagatcaca gagccagcca gatctgagaa gcagggaaca ag atg ctg 118
Met Leu
-20
gat tgc aga gca gta ata atg cta tgg ctg ttg ccc tgg gtc act cag 166
Asp Cys Arg Ala Val Ile Met Leu Trp Leu Leu Pro Trp Val Thr Gln
-15 -10 -5
ggc ctg gct gtg cct agg agt agc agt cct gac tgg gct cag tgc cag 214
Gly Leu Ala Val Pro Arg Ser Ser Ser Pro Asp Trp Ala Gln Cys Gln
-1 1 5 10
cag ctc tct cgg aat ctc tgc atg cta gcc tgg aac gca cat gca cca 262
Gln Leu Ser Arg Asn Leu Cys Met Leu Ala Trp Asn Ala His Ala Pro
15 20 25
gcg gga cat atg aat cta cta aga gaa gaa gag gat gaa gag act aaa 310
Ala Gly His Met Asn Leu Leu Arg Glu Glu Glu Asp Glu Glu Thr Lys
30 35 40 45
aat aat gtg ccc cgt atc cag tgt gaa gat ggt tgt gac cca caa gga 358
Asn Asn Val Pro Arg Ile Gln Cys Glu Asp Gly Cys Asp Pro Gln Gly
50 55 60
ctc aag gac aac agc cag ttc tgc ttg caa agg atc cgc caa ggt ctg 406
Leu Lys Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile Arg Gln Gly Leu
65 70 75
gct ttt tat aag cac ctg ctt gac tct gac atc ttc aaa ggg gag cct 454
Ala Phe Tyr Lys His Leu Leu Asp Ser Asp Ile Phe Lys Gly Glu Pro
80 85 90
gct cta ctc cct gat agc ccc atg gag caa ctt cac acc tcc cta cta 502
Ala Leu Leu Pro Asp Ser Pro Met Glu Gln Leu His Thr Ser Leu Leu
95 100 105
gga ctc agc caa ctc ctc cag cca gag gat cac ccc cgg gag acc caa 550
Gly Leu Ser Gln Leu Leu Gln Pro Glu Asp His Pro Arg Glu Thr Gln
110 115 120 125
cag atg ccc agc ctg agt tct agt cag cag tgg cag cgc ccc ctt ctc 598
Gln Met Pro Ser Leu Ser Ser Ser Gln Gln Trp Gln Arg Pro Leu Leu
130 135 140
cgt tcc aag atc ctt cga agc ctc cag gcc ttt ttg gcc ata gct gcc 646
Arg Ser Lys Ile Leu Arg Ser Leu Gln Ala Phe Leu Ala Ile Ala Ala
145 150 155
cgg gtc ttt gcc cac gga gca gca act ctg act gag ccc tta gtg cca 694
Arg Val Phe Ala His Gly Ala Ala Thr Leu Thr Glu Pro Leu Val Pro
160 165 170
aca gct taaggatgcc caggttccca tggctaccat gataagacta atctatcagc 750
Thr Ala
175
ccagacatct accagttaat taacccatta ggacttgtgc tgttcttgtt tcgtttgttt 810
tgcgtgaagg gcaaggacac cattattaaa gagaaaagaa acaaacccca gagcaggcag 870
ctggctagag aaaggagctg gagaagaaga ataaagtctc gagcccttgg ccttggaagc 930
gggcaagcag ctgcgtggcc tgaggggaag ggggcggtgg catcgagaaa ctgtgagaaa 990
acccagagca tcagaaaaag tgagcccagg ctttggccat tatctgtaag aaaaacaaga 1050
aaaggggaac attatacttt cctgggtggc tcagggaaat gtgcagatgc acagtactcc 1110
agacagcagc tctgtacctg cctgctctgt ccctcagttc taacagaatc tagtcactaa 1170
gaactaacag gactaccaat acgaactgac aaa 1203
<210>4
<211>196
<212>PRT
<213>小鼠
<400>4
Met Leu Asp Cys Arg Ala Val Ile Met Leu Trp Leu Leu Pro Trp Val
-20 -15 -10
Thr Gln Gly Leu Ala Val Pro Arg Ser Ser Ser Pro Asp Trp Ala Gln
-5 -1 1 5 10
Cys Gln Gln Leu Ser Arg Asn Leu Cys Met Leu Ala Trp Asn Ala His
15 20 25
Ala Pro Ala Gly His Met Asn Leu Leu Arg Glu Glu Glu Asp Glu Glu
30 35 40
Thr Lys Asn Asn Val Pro Arg Ile Gln Cys Glu Asp Gly Cys Asp Pro
45 50 55
Gln Gly Leu Lys Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile Arg Gln
60 65 70 75
Gly Leu Ala Phe Tyr Lys His Leu Leu Asp Ser Asp Ile Phe Lys Gly
80 85 90
Glu Pro Ala Leu Leu Pro Asp Ser Pro Met Glu Gln Leu His Thr Ser
95 100 105
Leu Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Asp His Pro Arg Glu
110 115 120
Thr Gln Gln Met Pro Ser Leu Ser Ser Ser Gln Gln Trp Gln Arg Pro
125 130 135
Leu Leu Arg Ser Lys Ile Leu Arg Ser Leu Gln Ala Phe Leu Ala Ile
140 145 150 155
Ala Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Thr Glu Pro Leu
160 165 170
Val Pro Thr Ala
175
<210>5
<211>2859
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<213>人
<220>
<221>CDS
<222>(119)..(2005)
<223>
<220>
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<222>(188)..(2005)
<223>
<400>5
gtggtacggg aattccattg tgttgggcag ccaacaaggg tggcagcctg gctctgaagt 60
ggaattatgt gcttcaaaca ggttgaaaga gggaaacagt cttttcctgc ttccagac 118
atg aat cak gtc act att caa tgg gat gca gta ata gcc ctt tac ata 166
Met Asn Xaa Val Thr Ile Gln Trp Asp Ala Val Ile Ala Leu Tyr Ile
-20 -15 -10
ctc ttc agc tgg tgt cat gga gga att aca aat ata aac tgc tct ggc 214
Leu Phe Ser Trp Cys His Gly Gly Ile Thr Asn Ile Asn Cys Ser Gly
-5 -1 1 5
cac atc tgg gta gaa cca gcc aca att ttt aag atg ggt atg aat atc 262
His Ile Trp Val Glu Pro Ala Thr Ile Phe Lys Met Gly Met Asn Ile
10 15 20 25
tct ata tat tgc caa gca gca att aag aac tgc caa cca agg aaa ctt 310
Ser Ile Tyr Cys Gln Ala Ala Ile Lys Asn Cys Gln Pro Arg Lys Leu
30 35 40
cat ttt tat aaa aat ggc atc aaa gaa aga ttt caa atc aca agg att 358
His Phe Tyr Lys Asn Gly Ile Lys Glu Arg Phe Gln Ile Thr Arg Ile
45 50 55
aat aaa aca aca gct cgg ctt tgg tat aaa aac ttt ctg gaa cca cat 406
Asn Lys Thr Thr Ala Arg Leu Trp Tyr Lys Asn Phe Leu Glu Pro His
60 65 70
gct tct atg tac tgc act gct gaa tgt ccc aaa cat ttt caa gag aca 454
Ala Ser Met Tyr Cys Thr Ala Glu Cys Pro Lys His Phe Gln Glu Thr
75 80 85
ctg ata tgt gga aaa gac att tct tct gga tat ccg cca gat att cct 502
Leu Ile Cys Gly Lys Asp Ile Ser Ser Gly Tyr Pro Pro Asp Ile Pro
90 95 100 105
gat gaa gta acc tgt gtc att tat gaa tat tca ggc aac atg act tgc 550
Asp Glu Val Thr Cys Val Ile Tyr Glu Tyr Ser Gly Asn Met Thr Cys
110 115 120
acc tgg aat gct rgg aag ctc acc tac ata gac aca aaa tac gtg gta 598
Thr Trp Asn Ala Xaa Lys Leu Thr Tyr Ile Asp Thr Lys Tyr Val Val
125 130 135
cat gtg aag agt tta gag aca gaa gaa gag caa cag tat ctc acc tca 646
His Val Lys Ser Leu Glu Thr Glu Glu Glu Gln Gln Tyr Leu Thr Ser
140 145 150
agc tat att aac atc tcc act gat tca tta caa ggt ggc aag aag tac 694
Ser Tyr Ile Asn Ile Ser Thr Asp Ser Leu Gln Gly Gly Lys Lys Tyr
155 160 165
ttg gtt tgg gtc caa gca gca aac gca cta ggc atg gaa gag tca aaa 742
Leu Val Trp Val Gln Ala Ala Asn Ala Leu Gly Met Glu Glu Ser Lys
170 175 180 185
caa ctg caa att cac ctg gat gat ata gtg ata cct tct gca gcc gtc 790
Gln Leu Gln Ile His Leu Asp Asp Ile Val Ile Pro Ser Ala Ala Val
190 195 200
att tcc agg gct gag act ata aat gct aca gtg ccc aag acc ata att 838
Ile Ser Arg Ala Glu Thr Ile Asn Ala Thr Val Pro Lys Thr Ile Ile
205 210 215
tat tgg gat agt caa aca aca att gaa aag gtt tcc tgt gaa atg aga 886
Tyr Trp Asp Ser Gln Thr Thr Ile Glu Lys Val Ser Cys Glu Met Arg
220 225 230
tac aag gct aca aca aac caa act tgg aat gtt aaa gaa ttt gac acc 934
Tyr Lys Ala Thr Thr Asn Gln Thr Trp Asn Val Lys Glu Phe Asp Thr
235 240 245
aat ttt aca tat gtg caa cag tca gaa ttc tac ttg gag cca aac att 982
Asn Phe Thr Tyr Val Gln Gln Ser Glu Phe Tyr Leu Glu Pro Asn Ile
250 255 260 265
aag tac gta ttt caa gtg aga tgt caa gaa aca ggc aaa agg tac tgg 1030
Lys Tyr Val Phe Gln Val Arg Cys Gln Glu Thr Gly Lys Arg Tyr Trp
270 275 280
cag cct tgg agt tca ccg ttt ttt cat aaa aca cct gaa aca gtt ccc 1078
Gln Pro Trp Ser Ser Pro Phe Phe His Lys Thr Pro Glu Thr Val Pro
285 290 295
cag gtc aca tca aaa gca ttc caa cat gac aca tgg aat tct ggg cta 1126
Gln Val Thr Ser Lys Ala Phe Gln His Asp Thr Trp Asn Ser Gly Leu
300 305 310
aca gtt gct tcc atc tct aca ggg cac ctt act tct gac aac aga gga 1174
Thr Val Ala Ser Ile Ser Thr Gly His Leu Thr Ser Asp Asn Arg Gly
315 320 325
gac att gga ctt tta ttg gga atg atc gtc ttt gct gtt atg ttg tca 1222
Asp Ile Gly Leu Leu Leu Gly Met Ile Val Phe Ala Val Met Leu Ser
330 335 340 345
att ctt tct ttg att ggg ata ttt aac aga tca ttc cga act ggg att 1270
Ile Leu Ser Leu Ile Gly Ile Phe Asn Arg Ser Phe Arg Thr Gly Ile
350 355 360
aaa aga agg atc tta ttg tta ata cca aag tgg ctt tat gaa gat att 1318
Lys Arg Arg Ile Leu Leu Leu Ile Pro Lys Trp Leu Tyr Glu Asp Ile
365 370 375
cct aat atg aaa aac agc aat gtt gtg aaa atg cta cag gaa aat agt 1366
Pro Asn Met Lys Asn Ser Asn Val Val Lys Met Leu Gln Glu Asn Ser
380 385 390
gaa ctt atg aat aat aat tcc agt gag cag gtc cta tat gtt gat ccc 1414
Glu Leu Met Asn Asn Asn Ser Ser Glu Gln Val Leu Tyr Val Asp Pro
395 400 405
atg att aca gag ata aaa gaa atc ttc atc cca gaa cac aag cct aca 1462
Met Ile Thr Glu Ile Lys Glu Ile Phe Ile Pro Glu His Lys Pro Thr
410 415 420 425
gac tac aag aag gag aat aca gga ccc ctg gag aca aga gac tac ccg 1510
Asp Tyr Lys Lys Glu Asn Thr Gly Pro Leu Glu Thr Arg Asp Tyr Pro
430 435 440
caa aac tcg cta ttc gac aat act aca gtt gta tat att cct gat ctc 1558
Gln Asn Ser Leu Phe Asp Asn Thr Thr Val Val Tyr Ile Pro Asp Leu
445 450 455
aac act gga tat aaa ccc caa att tca aat ttt ctg cct gag gga agc 1606
Asn Thr Gly Tyr Lys Pro Gln Ile Ser Asn Phe Leu Pro Glu Gly Ser
460 465 470
cat ctc agc aat aat aat gaa att act tcc tta aca ctt aaa cca cca 1654
His Leu Ser Asn Asn Asn Glu Ile Thr Ser Leu Thr Leu Lys Pro Pro
475 480 485
gtt gat tcc tta gac tca gga aat aat ccc agg tta caa aag cat cct 1702
Val Asp Ser Leu Asp Ser Gly Asn Asn Pro Arg Leu Gln Lys His Pro
490 495 500 505
aat ttt gct ttt tct gtt tca agt gtg aat tca cta agc aac aca ata 1750
Asn Phe Ala Phe Ser Val Ser Ser Val Asn Ser Leu Ser Asn Thr Ile
510 515 520
ttt ctt gga gaa tta agc ctc ata tta aat caa gga gaa tgc agt tct 1798
Phe Leu Gly Glu Leu Ser Leu Ile Leu Asn Gln Gly Glu Cys Ser Ser
525 530 535
cct gac ata caa aac tca gta gag gag gaa acc acc atg ctt ttg gaa 1846
Pro Asp Ile Gln Asn Ser Val Glu Glu Glu Thr Thr Met Leu Leu Glu
540 545 550
aat gat tca ccc agt gaa act att cca gaa cag acc ctg ctt cct gat 1894
Asn Asp Ser Pro Ser Glu Thr Ile Pro Glu Gln Thr Leu Leu Pro Asp
555 560 565
gaa ttt gtc tcc tgt ttg ggg atc gtg aat gag gag ttg cca tct att 1942
Glu Phe Val Ser Cys Leu Gly Ile Val Asn Glu Glu Leu Pro Ser Ile
570 575 580 585
aat act tat ttt cca caa aat att ttg gaa agc cac ttc aat agg att 1990
Asn Thr Tyr Phe Pro Gln Asn Ile Leu Glu Ser His Phe Asn Arg Ile
590 595 600
tca ctc ttg gaa aag tagagctgtg tggtcaaaat caatatgaga aagctgcctt 2045
Ser Leu Leu Glu Lys
605
gcaatctgaa cttgggtttt ccctgcaata gaaattgaat tctgcctctt tttgaaaaaa 2105
atgtattcac atacaaatct tcacatggac acatgttttc atttcccttg gataaatacc 2165
taggtagggg attgctgggc catatgataa gcatatgttt cagttctacc aatcttgttt 2225
ccagagtagt gacatttctg tgctcctacc atcaccatgt aagaattccc gggagctcca 2285
tgccttttta attttagcca ttcttctgcc tmatttctta aaattagaga attaaggtcc 2345
cgaaggtgga acatgcttca tggtcacaca tacaggcaca aaaacagcat tatgtggacg 2405
cctcatgtat tttttataga gtcaactatt tcctctttat tttccctcat tgaaagatgc 2465
aaaacagctc tctattgtgt acagaaaggg taaataatgc aaaatacctg gtagtaaaat 2525
aaatgctgaa aattttcctt taaaatagaa tcattaggcc aggcgtggtg gctcatgctt 2585
gtaatcccag cactttggta ggctgaggtr ggtggatcac ctgaggtcag gagttcgagt 2645
ccagcctggc caatatgctg aaaccctgtc tctactaaaa ttacaaaaat tagccggcca 2705
tggtggcagg tgcttgtaat cccagctact tgggaggctg aggcaggaga atcacttgaa 2765
ccaggaaggc agaggttgca ctgagctgag attgtgccac tgcactccag cctgggcaac 2825
aagagcaaaa ctctgtctgg aaaaaaaaaa aaaa 2859
<210>6
<211>629
<212>PRT
<213>人
<220>
<221>misc_feature
<222>(-21)..(-21)
<223>第-21位的’Xaa’代表Gln式His.
<220>
<221>misc_feature
<222>(126)..(126)
<223>第126位的’Xaa’代表Gly或Arg.
<400>6
Met Asn Xaa Val Thr Ile Gln Trp Asp Ala Val Ile Ala Leu Tyr Ile
-20 -15 -10
Leu Phe Ser Trp Cys His Gly Gly Ile Thr Asn Ile Asn Cys Ser Gly
-5 -1 1 5
His Ile Trp Val Glu Pro Ala Thr Ile Phe Lys Met Gly Met Asn Ile
10 15 20 25
Ser Ile Tyr Cys Gln Ala Ala Ile Lys Asn Cys Gln Pro Arg Lys Leu
30 35 40
His Phe Tyr Lys Asn Gly Ile Lys Glu Arg Phe Gln Ile Thr Arg Ile
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Asn Lys Thr Thr Ala Arg Leu Trp Tyr Lys Asn Phe Leu Glu Pro His
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Ala Ser Met Tyr Cys Thr Ala Glu Cys Pro Lys His Phe Gln Glu Thr
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Leu Ile Cys Gly Lys Asp Ile Ser Ser Gly Tyr Pro Pro Asp Ile Pro
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Asp Glu Val Thr Cys Val Ile Tyr Glu Tyr Ser Gly Asn Met Thr Cys
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Thr Trp Asn Ala Xaa Lys Leu Thr Tyr Ile Asp Thr Lys Tyr Val Val
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His Val Lys Ser Leu Glu Thr Glu Glu Glu Gln Gln Tyr Leu Thr Ser
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Ser Tyr Ile Asn Ile Ser Thr Asp Ser Leu Gln Gly Gly Lys Lys Tyr
155 160 165
Leu Val Trp Val Gln Ala Ala Asn Ala Leu Gly Met Glu Glu Ser Lys
170 175 180 185
Gln Leu Gln Ile His Leu Asp Asp Ile Val Ile Pro Ser Ala Ala Val
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Ile Ser Arg Ala Glu Thr Ile Asn Ala Thr Val Pro Lys Thr Ile Ile
205 210 215
Tyr Trp Asp Ser Gln Thr Thr Ile Glu Lys Val Ser Cys Glu Met Arg
220 225 230
Tyr Lys Ala Thr Thr Asn Gln Thr Trp Asn Val Lys Glu Phe Asp Thr
235 240 245
Asn Phe Thr Tyr Val Gln Gln Ser Glu Phe Tyr Leu Glu Pro Asn Ile
250 255 260 265
Lys Tyr Val Phe Gln Val Arg Cys Gln Glu Thr Gly Lys Arg Tyr Trp
270 275 280
Gln Pro Trp Ser Ser Pro Phe Phe His Lys Thr Pro Glu Thr Val Pro
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Gln Val Thr Ser Lys Ala Phe Gln His Asp Thr Trp Asn Ser Gly Leu
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Thr Val Ala Ser Ile Ser Thr Gly His Leu Thr Ser Asp Asn Arg Gly
315 320 325
Asp Ile Gly Leu Leu Leu Gly Met Ile Val Phe Ala Val Met Leu Ser
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Ile Leu Ser Leu Ile Gly Ile Phe Asn Arg Ser Phe Arg Thr Gly Ile
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Lys Arg Arg Ile Leu Leu Leu Ile Pro Lys Trp Leu Tyr Glu Asp Ile
365 370 375
Pro Asn Met Lys Asn Ser Asn Val Val Lys Met Leu Gln Glu Asn Ser
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Glu Leu Met Asn Asn Asn Ser Ser Glu Gln Val Leu Tyr Val Asp Pro
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Met Ile Thr Glu Ile Lys Glu Ile Phe Ile Pro Glu His Lys Pro Thr
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Asp Tyr Lys Lys Glu Asn Thr Gly Pro Leu Glu Thr Arg Asp Tyr Pro
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Gln Asn Ser Leu Phe Asp Asn Thr Thr Val Val Tyr Ile Pro Asp Leu
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Asn Thr Gly Tyr Lys Pro Gln Ile Ser Asn Phe Leu Pro Glu Gly Ser
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His Leu Ser Asn Asn Asn Glu Ile Thr Ser Leu Thr Leu Lys Pro Pro
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Val Asp Ser Leu Asp Ser Gly Asn Asn Pro Arg Leu Gln Lys His Pro
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Asn Phe Ala Phe Ser Val Ser Ser Val Asn Ser Leu Ser Asn Thr Ile
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Phe Leu Gly Glu Leu Ser Leu Ile Leu Asn Gln Gly Glu Cys Ser Ser
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Pro Asp Ile Gln Asn Ser Val Glu Glu Glu Thr Thr Met Leu Leu Glu
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Asn Asp Ser Pro Ser Glu Thr Ile Pro Glu Gln Thr Leu Leu Pro Asp
555 560 565
Glu Phe Val Ser Cys Leu Gly Ile Val Asn Glu Glu Leu Pro Ser Ile
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Asn Thr Tyr Phe Pro Gln Asn Ile Leu Glu Ser His Phe Asn Arg Ile
590 595 600
Ser Leu Leu Glu Lys
605
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Met Ala His Thr Phe Arg Gly Cys Ser Leu Ala Phe Met Phe Ile Ile
1 5 10 15
Thr Trp Leu Leu Ile Lys Ala Lys Ile Asp Ala Cys Lys Arg Gly Asp
20 25 30
Val Thr Val Lys Pro Ser His Val Ile Leu Leu Gly Ser Thr Val Asn
35 40 45
Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys Phe His Tyr Ser Arg
50 55 60
Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg Arg Ile Asn Phe His
65 70 75 80
His Gly His Ser Leu Asn Ser Gln Val Thr Gly Leu Pro Leu Gly Thr
85 90 95
Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn Ser Asp Glu Ile Gln
100 105 l10
Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala Pro Glu Gln Pro Gln
115 120 125
Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly Thr Val Ala Cys Thr
130 135 140
Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr Glu Tyr Thr Leu Gln
145 150 155 160
Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys Gln Cys Lys Asp Ile
165 170 175
Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu Thr Pro Glu Ser Pro
180 185 190
G1u Ser Asn Phe Thr Ala Lys Val Thr Ala Val Asn Ser Leu Gly Ser
195 200 205
Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu Asp Ile Val Arg Pro
210 215 220
Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe Gln Lys Ala Ser Val Ser
225 230 235 240
Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly Leu Val Leu Leu Asn Arg
245 250 255
Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu Trp Asn Met Val Asn Val
260 265 270
Thr Lys Ala Lys Gly Arg His Asp Leu Leu Asp Leu Lys Pro Phe Thr
275 280 285
Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu His Leu Tyr Lys Gly Ser
290 295 300
Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala Gln Thr Pro Glu Glu Glu
305 310 315 320
Pro Thr Gly Met Leu Asp Val Trp Tyr Met Lys Arg His Ile Asp Tyr
325 330 335
Ser Arg Gln Gln Ile Ser Leu Phe Trp Lys Asn Leu Ser Val Ser Glu
340 345 350
Ala Arg Gly Lys Ile Leu His Tyr Gln Val Thr Leu Gln Glu Leu Thr
355 360 365
Gly Gly Lys Ala Met Thr Gln Asn Ile Thr Gly His Thr Ser Trp Thr
370 375 380
Thr Val Ile Pro Arg Thr Gly Asn Trp Ala Val Ala Val Ser Ala Ala
385 390 395 400
Asn Ser Lys Gly Ser Ser Leu Pro Thr Arg Ile Asn Ile Met Asn Leu
405 410 415
Cys Glu Ala Gly Leu Leu Ala Pro Arg Gln Val Ser Ala Asn Ser Glu
420 425 430
Gly Met Asp Asn Ile Leu Val Thr Trp Gln Pro Pro Arg Lys Asp Pro
435 440 445
Ser Ala Val Gln Glu Tyr Val Val Glu Trp Arg Glu Leu His Pro Gly
450 455 460
Gly Asp Thr Gln Val Pro Leu Asn Trp Leu Arg Ser Arg Pro Tyr Asn
465 470 475 480
Val Ser Ala Leu Ile Ser Glu Asn Ile Lys Ser Tyr Ile Cys Tyr Glu
485 490 495
Ile Arg Val Tyr Ala Leu Ser Gly Asp Gln Gly Gly Cys Ser Ser Ile
500 505 510
Leu Gly Asn Ser Lys His Lys Ala Pro Leu Ser Gly Pro His Ile Asn
515 520 525
Ala Ile Thr Glu Glu Lys Gly Ser Ile Leu Ile Ser Trp Asn Ser Ile
530 535 540
Pro Val Gln Glu Gln Met Gly Cys Leu Leu His Tyr Arg Ile Tyr Trp
545 550 555 560
Lys Glu Arg Asp Ser Asn Ser Gln Pro Gln Leu Cys Glu Ile Pro Tyr
565 570 575
Arg Val Ser Gln Asn Ser His Pro Ile Asn Ser Leu Gln Pro Arg Val
580 585 590
Thr Tyr Val Leu Trp Met Thr Ala Leu Thr Ala Ala Gly Glu Ser Ser
595 600 605
His Gly Asn Glu Arg Glu Phe Cys Leu Gln Gly Lys Ala Asn Trp Met
610 615 620
Ala Phe Val Ala Pro Ser Ile Cys Ile Ala Ile Ile Met Val Gly Ile
625 630 635 640
Phe Ser Thr His Tyr Phe Gln Gln Lys Val Phe Val Leu Leu Ala Ala
645 650 655
Leu Arg Pro Gln Trp Cys Ser Arg Glu Ile Pro Asp Pro Ala Asn Ser
660 665 670
Thr Cys Ala Lys Lys Tyr Pro Ile Ala Glu Glu Lys Thr Gln Leu Pro
675 680 685
Leu Asp Arg Leu Leu Ile Asp Trp Pro Thr Pro Glu Asp Pro Glu Pro
690 695 700
Leu Val Ile Ser Glu Val Leu His Gln Val Thr Pro Val Phe Arg His
705 710 715 720
Pro Pro Cys Ser Asn Trp Pro Gln Arg Glu Lys Gly Ile Gln Gly His
725 730 735
Gln Ala Ser Glu Lys Asp Met Met His Ser Ala Ser Ser Pro Pro Pro
740 745 750
Pro Arg Ala Leu Gln Ala Glu Ser Arg Gln Leu Val Asp Leu Tyr Lys
755 760 765
Val Leu Glu Ser Arg Gly Ser Asp Pro Lys Pro Glu Asn Pro Ala Cys
770 775 780
Pro Trp Thr Val Leu Pro Ala Gly Asp Leu Pro Thr His Asp Gly Tyr
785 790 795 800
Leu Pro Ser Asn Ile Asp Asp Leu Pro Ser His Glu Ala Pro Leu Ala
805 810 815
Asp Ser Leu Glu Glu Leu Glu Pro Gln His Ile Ser Leu Ser Val Phe
820 825 830
Pro Ser Ser Ser Leu His Pro Leu Thr Phe Ser Cys Gly Asp Lys Leu
835 840 845
Thr Leu Asp Gln Leu Lys Met Arg Cys Asp Ser Leu Met Leu
850 855 860
<210>8
<211>328
<212>PRT
<213>人
<400>8
Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu
1 5 10 15
Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser
325
<210>9
<211>335
<212>PRT
<213>小鼠
<400>9
Met Cys Pro Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu
1 5 10 15
Val Ser Pro Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val
20 25 30
Val G1u Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln
50 55 60
Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys
65 70 75 80
Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr
85 90 95
Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp
100 105 110
Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys
115 120 125
Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln
130 135 140
Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro
145 150 155 160
Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys
165 170 175
Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln
180 185 190
Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu
195 200 205
Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser
210 215 220
Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln
225 230 235 240
Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro
245 250 255
Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val
260 265 270
Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys
275 280 285
Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln
290 295 300
Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn
305 310 315 320
Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser
325 330 335
<210>10
<211>531
<212>PRT
<213>小鼠
<400>10
Met Ser Ala Leu Leu Ile Leu Ala Leu Val Gly Ala Ala Val Ala Asp
1 5 10 15
Tyr Lys Asp Asp Asp Asp Lys Leu Met Trp Glu Leu Glu Lys Asp Val
20 25 30
Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val
35 40 45
Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser
50 55 60
Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr
65 70 75 80
Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly
85 90 95
Glu Thr Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly
100 105 110
Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu
115 120 125
Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu
130 135 140
Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser
145 150 155 160
Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala
165 170 175
Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser
180 185 190
Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile
195 200 205
Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser
210 215 220
Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu
245 250 255
Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe
260 265 270
Phe Val Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu
275 280 285
Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu
290 295 300
Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr
305 310 315 320
Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg
325 330 335
Ser Ser Arg Gly Gly Ser Gly Ser Gly Gly Ser Gly Gly Gly Gly Ser
340 345 350
Lys Leu Leu Ala Val Pro Arg Ser Ser Ser Pro Asp Trp Ala Gln Cys
355 360 365
Gln Gln Leu Ser Arg Asn Leu Cys Met Leu Ala Trp Asn Ala His Ala
370 375 380
Pro Ala Gly His Met Asn Leu Leu Arg Glu Glu Glu Asp Glu Glu Thr
385 390 395 400
Lys Asn Asn Val Pro Arg Ile Gln Cys Glu Asp Gly Cys Asp Pro Gln
405 410 415
Gly Leu Lys Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile Arg Gln Gly
420 425 430
Leu Val Phe Tyr Lys His Leu Leu Asp Ser Asp Ile Phe Lys Gly Glu
435 440 445
Pro Ala Leu Leu Pro Asp Ser Pro Met Glu Gln Leu His Thr Ser Leu
450 455 460
Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Asp His Pro Arg Glu Thr
465 470 475 480
Gln Gln Met Pro Ser Leu Ser Ser Ser Gln Gln Trp Gln Arg Pro Leu
485 490 495
Leu Arg Ser Lys Ile Leu Arg Ser Leu Gln Ala Phe Leu Ala Ile Ala
500 505 510
Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Thr Glu Pro Leu Val
515 520 525
Pro Thr Ala
530
<210>11
<211>521
<212>PRT
<213>人
<400>11
Met Ser Ala Leu Leu Ile Leu Ala Leu Val Gly Ala Ala Val Ala Asp
1 5 10 15
Tyr Lys Asp Asp Asp Asp Lys Leu Ile Trp Glu Leu Lys Lys Asp Val
20 25 30
Tyr Val Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val
35 40 45
Val Leu Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu
50 55 60
Asp Gln Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln
65 70 75 80
Val Lys Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly
85 90 95
Glu Val Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly
100 105 110
Ile Trp Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys
115 120 125
Thr Phe Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys
130 135 140
Trp Trp Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser
145 150 155 160
Ser Arg Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr
165 170 175
Leu Ser Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser
180 185 190
Val Glu Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu
195 200 205
Pro Ile Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn
210 215 220
Tyr Thr Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro
225 230 235 240
Asn Asn Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val
245 250 255
Ser Trp Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser
260 265 270
Leu Thr Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys
275 280 285
Asp Arg Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys
290 295 300
Asn Ala Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser
305 310 315 320
Trp Ser Glu Trp Ala Ser Val Pro Cys Ser Gly Ser Gly Ser Ser Arg
325 330 335
Gly Gly Ser Gly Ser Gly Gly Ser Gly Gly Gly Gly Ser Lys Leu Arg
340 345 350
Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln Cys Gln Gln Leu
355 360 365
Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His Pro Leu Val Gly
370 375 380
His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr Thr Asn Asp Val
385 390 395 400
Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln Gly Leu Arg Asp
405 410 415
Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly Leu Ile Phe Tyr
420 425 430
Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu Pro Ser Leu Leu
435 440 445
Pro Asp Ser Pro Val Ala Gln Leu His Ala Ser Leu Leu Gly Leu Ser
450 455 460
Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr Gln Gln Ile Pro
465 470 475 480
Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu Leu Arg Phe Lys
485 490 495
Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala Ala Arg Val Phe
500 505 510
Ala His Gly Ala Ala Thr Leu Ser Pro
515 520
Claims (18)
1.一种用于调节肿瘤生长的方法,包括使肿瘤细胞与有效量的IL-23激动剂或拮抗剂接触。
2.如权利要求1的方法,其中该IL-23拮抗剂抑制或防止肿瘤生长。
3.如权利要求的方法,其中该肿瘤细胞表达IL-23。
4.如权利要求1的方法,其中该IL-23激动剂或拮抗剂包含特异性结合下列多肽或核酸的结合组合物:
a)p19(SEQ ID NOs:1、2、3或4);或
b)IL-23R(SEQ ID NOs:5或6)。
5.如权利要求4的方法,其中该结合组合物包含:
a)抗体的抗原结合位点;
b)IL-23R(SEQ ID NOs:5或6)的胞外区域;
c)小分子;
d)反义核酸或小干扰RNA(siRNA);或
e)可检测标记。
6.如权利要求4的方法,其中该结合组合物包含:
a)多克隆抗体;
b)单克隆抗体;
c)人源化抗体,或其片段;
d)Fab、Fv或F(ab′)2片段;或
e)抗体的肽模拟物。
7.如权利要求1的方法,其中该肿瘤细胞为:
a)结肠癌细胞;
b)卵巢癌细胞;
c)乳腺癌细胞;或
d)黑素瘤细胞。
8.一种用于治疗患有癌症或肿瘤的患者的方法,包括给患者施用有效量的IL-23激动剂或拮抗剂。
9.如权利要求8的方法,其中该IL-23拮抗剂抑制:
a)该癌症或肿瘤的生长;
b)恶病质;
c)厌食;或
d)血管发生。
10.如权利要求8的方法,其中该IL-23拮抗剂包含特异性结合下列多肽或核酸的结合组合物:
a)p19(SEQ ID NOs:1、2、3或4);或
b)IL-23R(SEQ ID NOs:5或6)。
11.如权利要求10的方法,其中该结合组合物包含:
a)抗体的抗原结合位点;
b)IL-23R(SEQ ID NOs:5或6)的胞外区域;
c)反义核酸或小干扰RNA(siRNA);
d)小分子;或
e)可检测标记。
12.如权利要求10的方法,其中该结合组合物包含:
a)多克隆抗体;
b)单克隆抗体;
c)人源化抗体,或其片段;
d)Fab、Fv或F(ab′)2片段;或
e)抗体的肽模拟物。
13.如权利要求8的方法,其中该癌症或肿瘤是下列系统的癌症或肿瘤:
a)胃肠道;
b)呼吸道;
c)生殖系统;或
d)内分泌系统。
14.如权利要求8的方法,其中该癌症或肿瘤是:
a)结肠癌;
b)卵巢癌;
c)黑素瘤;或
d)乳腺癌。
15.一种用于诊断癌症或肿瘤的方法,包括使来自受试者的样品接触权利要求10的方法的结合组合物。
16.如权利要求15的方法,其中该结合组合物包含特异性结合或杂交于SEQ ID NOs1、2或5的多核苷酸的核酸探针或引物。
17.一种用于诊断癌症或肿瘤的试剂盒,其包含权利要求10的方法的结合组合物及:
a)一个腔室;或
b)使用说明或处置说明。
18.如权利要求17的试剂盒,其中该结合组合物包含一种抗体,该抗体特异性结合于:
a)p19(SEQ ID NOs:1、2、3或4);或
b)IL-23R(SEQ ID NOs:5或6)。
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US45367203P | 2003-03-10 | 2003-03-10 | |
US60/453,672 | 2003-03-10 | ||
PCT/US2004/007198 WO2004081190A2 (en) | 2003-03-10 | 2004-03-09 | Uses of il-23 agonists and antagonists; related reagents |
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CN1759123B CN1759123B (zh) | 2011-04-13 |
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US (4) | US7282204B2 (zh) |
EP (2) | EP1601694B1 (zh) |
JP (4) | JP4605798B2 (zh) |
CN (1) | CN1759123B (zh) |
AT (1) | ATE440864T1 (zh) |
AU (2) | AU2004219625B9 (zh) |
BR (1) | BRPI0408247A (zh) |
CA (1) | CA2518262C (zh) |
CL (1) | CL2004000467A1 (zh) |
CY (1) | CY1109468T1 (zh) |
DE (1) | DE602004022781D1 (zh) |
DK (1) | DK1601694T3 (zh) |
ES (1) | ES2330220T3 (zh) |
HK (1) | HK1076477A1 (zh) |
MX (1) | MXPA05009717A (zh) |
NO (1) | NO20054630L (zh) |
NZ (2) | NZ567860A (zh) |
PL (1) | PL1601694T3 (zh) |
PT (1) | PT1601694E (zh) |
SI (1) | SI1601694T1 (zh) |
TW (2) | TWI439285B (zh) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101668775B (zh) * | 2007-02-12 | 2014-05-07 | 默沙东公司 | Il-23拮抗剂治疗感染的用途 |
CN101668531B (zh) * | 2007-02-28 | 2014-05-07 | 默沙东公司 | 用于治疗免疫病症的联合治疗 |
Families Citing this family (51)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101668775B (zh) * | 2007-02-12 | 2014-05-07 | 默沙东公司 | Il-23拮抗剂治疗感染的用途 |
CN101668531B (zh) * | 2007-02-28 | 2014-05-07 | 默沙东公司 | 用于治疗免疫病症的联合治疗 |
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