CN111787946A - 抗-类egf结构域多重6(egfl6)抗体及其于癌症诊断及治疗中的应用 - Google Patents
抗-类egf结构域多重6(egfl6)抗体及其于癌症诊断及治疗中的应用 Download PDFInfo
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Abstract
本发明系关于抗‑类EGF结构域多重6抗体(抗‑EGFL6抗体)及使用该抗‑EGFL6抗体的癌症检测(或诊断)及治疗。本发明产生能够结合至EGFL6且抑制血管生成及癌细胞生长的抗‑EGFL6抗体,尤其系单链抗体片段(scFv)及人类化抗体。
Description
技术领域
本发明系关于癌症检测(或诊断)及治疗的领域。特定而言,本发明系关于抗-类EGF结构域多重6抗体(抗-EGFL6抗体)及使用该抗-EGFL6抗体的癌症检测(或诊断)及治疗。
背景技术
癌症系在身体任何部位中异常细胞的不受控生长。异常细胞称为癌细胞、恶性细胞或肿瘤细胞。癌症的早期诊断通常增加了成功治疗或治愈该疾病的可能性。
生物标记物系检测癌症的潜在工具。EGFL6系表皮生长因子(EGF)重复超家族蛋白的成员且由类EGF重复区及整联蛋白缔合基序(RGD)组成。EGFL6促进内皮细胞迁移及血管生成。George Yeung等人报导,EGFL6编码预期信号肽,从而表明其得以分泌,且其转录物表现于脑及肺肿瘤及胎儿组织中(George Yeung等人,Genomics 62,1999,pp.304-307)。实施研究以鉴别卵巢肿瘤血管系统的分子特征且展示肿瘤血管标记物可用作卵巢癌的潜在生物标记物及分子靶,其中EGFL6系该等标记物之一(Ronald J.Buckanovich等人,Journalof Clinical Oncology,2007,第25卷,第7期,pp.852-861)。然而,一文章报导,EGFL6 mRNA以高含量发现于卵巢癌中,其与良性脑膜瘤中相当,且与纤维母细胞脑膜瘤相比,EGFL6mRNA含量在所有其他所研究肿瘤中(包含神经胶质瘤、肺癌、肝细胞癌、胰脏癌、胃癌、乳癌、前列腺癌、结肠直肠癌及膀胱癌)显著降低(Xuanchun Wang等人,PLOS ONE;2012,第7卷,第12期,e52707)。
亦报导,EGFL6过度表现于W1TR细胞系中且系促进内皮细胞迁移及血管生成的分泌蛋白(Radoslaw Januchowski等人,Oncology Reports 32:1981-1990,2014)。另一文章报导,EGFL6系乳癌中的候选肿瘤血管系统配体(Benjimin M Larimer,J.Mol BiomarkDiagn.2014,5(3):doi:10.4172/2155-9929.1000178)。WO2009057849揭示用于结肠癌的诊断组合物,其包括量测一或多种选自KLK6、CKS2、IFITMl、SPPl、DPEPl、CSTl、CDH3、ANLN、CXCLl、MELK、CDCAl、CTHRCl、CEACAM6、MMPl、LCN2、HS6ST2、EGFL6及CA9的基因的mRNA或蛋白质含量的药剂。
然而,实际上并无单独EGFL6应用于临床癌症诊断。此外,亦需要研发用于癌症治疗的抗-EGFL6抗体。
发明内容
本发明提供经分离抗-EGFL6抗体或其抗原结合部分,其包括以下中的至少一者:由SEQ ID NO:1或2的胺基酸残基组成的轻链CDR1(L-CDR1),或具有与SEQ ID NO:1及2中的任一者具有至少80%一致性的胺基酸序列的变体;由SEQ ID NO:3或4的胺基酸残基组成的轻链CDR2(L-CDR2),或具有与SEQ ID NO:3及4中的任一者具有至少80%一致性的胺基酸序列的变体;及由SEQ ID NO:5或6的胺基酸残基组成的轻链CDR3(L-CDR3),或具有与SEQ IDNO:5及6中的任一者具有至少80%一致性的胺基酸序列的变体;及
以下中的至少一者:由SEQ ID NO:7或8的胺基酸残基组成的重链互补决定区1(H-CDR1),或具有与SEQ ID NO:7及8中的任一者具有至少80%一致性的胺基酸序列的变体;由SEQ ID NO:9或10的胺基酸残基组成的重链CDR2(H-CDR2),或具有与SEQ ID NO:9及10中的任一者具有至少80%一致性的胺基酸序列的变体;及由SEQ ID NO:11或12的胺基酸残基组成的重链CDR3(H-CDR3),或具有与SEQ ID NO:11及12中的任一者具有至少80%一致性的胺基酸序列的变体;从而该经分离抗体或其抗原结合部分结合至EGFL6。
本发明抗体的某些实施例包含单株抗体、嵌合抗体、人类化抗体及人类抗体。在一些实施例中,经分离抗-EGFL6抗体系单链Fv(scFv)、IgG、Fab、(Fab)2或(scFv')2。
本发明一实施例包含含有具有选自由SEQ ID NO:13或14组成的群的序列的胺基酸序列的轻链。
本发明一实施例包含含有具有选自由SEQ ID NO:15或16组成的群的序列的胺基酸序列的重链。
在另一实施例中,本发明包括含有具有如SEQ ID NO:13中所陈述胺基酸序列的轻链及具有如SEQ ID NO:15中所陈述胺基酸序列的重链的经分离抗体(EL6_S12)。在另一实施例中,本发明包括含有具有如SEQ ID NO:14中所陈述胺基酸序列的轻链及具有如SEQ IDNO:16中所陈述胺基酸序列的重链的经分离抗体(EL6_E5)。
本发明提供一种医药组合物,其包括本发明的抗-EGFL6抗体及医药上可接受的载剂或赋形剂。
本发明亦提供治疗或预防个体的血管生成病症的方法,其包括向个体投与本发明的抗-EGFL6抗体。
本发明亦提供抑制个体中的癌细胞生长或癌症转移的方法,其包括向个体投与本发明的抗-EGFL6抗体。
在一些实施例中,上文所鉴别组合物及治疗方法中的每一者可另外包含其他抗肿瘤药物及投与一或多种其他抗肿瘤药物。
本发明进一步提供检测或诊断个体中的癌症或升高的未来癌症发生风险或预测癌症的转移或预后的方法,其包括使来自个体的生物样本与本发明的抗-EGFL6抗体接触,量化样本中的EGFL6抗原与抗体的结合,及比较该结合与代表抗-EGFL6抗体与来自未患有癌症的对照个体的样本中所测定EGFL6抗原间的结合的参考值。
本发明进一步提供监测已经诊断患有癌症的个体中的癌症进展的方法。
本发明进一步提供用于检测或诊断个体中的癌症或升高的未来癌症发生风险或预测癌症的转移或预后或监测癌症进展的套组,其包括本发明的抗-EGFL6抗体。
附图说明
图1展示使用ELISA测得的抗-EGFL6抗体的结合活性。
图2A及2B展示在西方印渍(Western blotting)中藉由E5 scFv(A)及S12 scFv(B)鉴别的全长EGFL6蛋白及EGFL6-F396截短片段。
图3展示藉由西方印渍量测的EGFL6在各种癌细胞系中的蛋白质表现。
图4(A)及(B)展示,单链抗体Ab4、Ab5(E5)及Ab10可有效抑制癌细胞迁移(A),且抗-EGFL6单链抗体与经太平洋紫杉醇(Paclitaxel)治疗的对照组相比可有效地抑制肿瘤囊的形成(B)。
图5展示经抗-EGFL6单链抗体E5及S12治疗的裸小鼠的基质胶束中的血红蛋白含量。
图6(A)及(B)展示,人类化IgG抗体S12及/或E5能够抑制结肠直肠癌细胞HCT-116(A)及非小细胞肺癌A549(B)中的肿瘤生长。
图7(A)及(B)展示,人类化IgG抗体E5能够抑制三阴性乳癌细胞MDA-MB-231(A)及神经胶母细胞瘤癌细胞U87(B)中的肿瘤生长。
图8展示与太平洋紫杉醇组合的人类化IgG抗体E5在人类非小细胞肺癌A549异种移植物模型中的抗癌活性。
具体实施方式
使用本文术语来阐述本发明的具体实施例,但其使用并不界定本发明,除非在申请专利范围中概述。应理解,前述一般说明及下列详细说明两者皆仅系实例及解释性的且并不限制本申请案中所主张的目标物。
诸如「一个(a、an)」及「该(the)」等术语并不仅意欲系指单数实体,但包含一般种类,可使用特定实例来阐释该一般种类。
在本申请案中,除非另外陈述,否则所用的「或」意指「及/或」。另外,所用的术语「包含(including)」以及其他形式(例如「包含(includes)」及「包含(included)」)不具有限制意义。
定义
如本文中所使用,术语「肿瘤」、「癌症」及「癌瘤」可互换使用且系指所有赘瘤性细胞生长及增殖(不论恶性抑或良性)及所有癌前期及癌性细胞及组织。
如本文中所使用,术语「标记物」或「生物标记物」可在本文中互换使用,且在本发明的上下文中系指与自对照个体(例如具有阴性诊断者、正常或健康个体)获取的相当样本相比以不同方式表现于自患有癌症的个体所获取样本中的基因。
如本文中所使用,术语「生物样本」系指自患者获得的样本。举例而言,生物样本可自血液、组织(例如肿瘤)、血清、粪便、尿、痰液、脑脊髓液、乳头抽吸物及来自细胞溶解物的上清液获得。
如本文中所使用,术语「诊断」意指鉴别病理学病状的存在或性质且包含鉴别处于发生癌症的风险下的个体。诊断方法的不同的处在于其敏感性及特异性。诊断分析的「敏感性」系测试为阳性的患病个体的百分比(「真阳性」百分比)。藉由分析检测的患病个体系「假阴性」。未患病且在分析中测试为阴性的个体称为「真阴性」。诊断分析的「特异性」系由此正确鉴别的阴性的比例(例如未患病且正确鉴别为未患有病状的个体的百分比)的量度。
如本文中所使用,术语「检测(detection)」、「检测(detecting)」及诸如此类可用于检测生物标记物或检测癌症(例如在获得阳性分析结果时)的背景中。在后一背景中,「检测」与「诊断」视为同义。
标记物的「测试量」系指存在于所测试样本中的标记物的量。
标记物的「对照量」可为与标记物的测试量比较的任一量或量范围。
术语「在……的风险下」欲指与正常个体相比或与对照组相比处于增加的风险下。因此,「在发生癌症的风险下」之个体与正常群体相比处于增加的风险下,且「在癌症复发的风险下」的个体可视为与所有经治疗癌症患者中的复发风险相比处于增加的复发风险下。
如本文中所使用,术语「增加的风险」或「升高的风险」意指(例如)个体发生癌症或其复发的机率的任一统计学显著增加。
如本文中所使用术语「预后」系指预测可归因于癌症的死亡或进展(包含赘瘤性疾病(例如卵巢癌)的复发、转移性扩散及药物抗性)的可能性。术语「较差预后」意指,存活及疾病恢复的愿景系不可能的,即使使用标准护理(亦即手术、辐射、化学疗法)来治疗癌症(例如前列腺癌)。不良预后系存活小于中值存活的患者类别。
如本文中所使用,术语「转移」定义为癌症自身体的一个部分扩散至另一部分。由扩散细胞形成的肿瘤称为「转移性肿瘤」或「转移」。
如本文中所使用,术语「转移风险」系指基于统计学预测因子特定患者,尤其人类患者的癌症进展至转移性状态的预后适应症。未必实际上进展至转移性状态,且预计采用治疗方式来试图延迟或预防实现该风险。
如本文中所使用,表达「参考值」系指用作藉助自个体所获得样本获得的值/数据的参考的实验室值。
如本文中所使用,「测定含量(determination of a level、determining alevel)」或「量测含量」通常系指计算特定物质的量或浓度或量化来自代表特定物质的量或浓度的探针的信号的强度。
如本文中所使用,术语「抗体」系以最广泛意义使用且具体而言涵盖(例如)单一单株抗体(包含激动剂、拮抗剂及中和抗体)、具有多表位特异性的抗体组合物、多株抗体、单链抗抗体及抗体片段(参见下文),只要其特异性结合天然多肽及/或展现本发明的生物活性或免疫活性。根据一实施例,抗体结合至靶蛋白的寡聚形式(例如三聚形成)。词组抗体的「功能片段或类似物」系与所提及抗体具有公用定性生物活性的化合物。举例而言,本发明抗体的功能片段或类似物可为可特异性结合至EGFR者。在一实施例中,抗体可预防或实质上减小EGFR诱导细胞增殖的能力。
如本文中所使用,「经分离抗体」系已经鉴别并自其自然环境组分中分离及/或回收的抗体。其自然环境的污染组分系将干扰抗体的诊断或治疗用途的材料,且可包含酶、激素及其他蛋白质性溶质或非蛋白质性溶质。在较佳实施例中,将抗体纯化至以下程度:(1)大于95重量%的抗体,如藉由劳里法(Lowry method)所测定,及最佳地大于99重量%;(2)足以获得N-末端或内部胺基酸序列的至少15个残基的程度,如藉由使用旋杯式序列分析仪所测定;或(3)均质,如藉由SDS-PAGE在还原或非还原条件下使用考马斯蓝(Coomassieblue)或较佳地银染色所测定。经分离抗体包含重组细胞内的原位抗体,此乃因抗体天然环境的至少一种组分将不存在。然而,通常藉由至少一个纯化步骤来制备经分离抗体。
如本文中所使用,关于肽、多肽或抗体序列的「胺基酸序列一致性百分比(%)」系指在比对序列并引入空位(若需要)以达成最大序列一致性百分比之后,且不将任何保守取代视为序列一致性的一部分的情况下,候选序列中与特定肽或多肽序列中的胺基酸残基一致的胺基酸残基的百分比。出于确定胺基酸序列一致性百分比的目的,比对可以熟习此项技术者所熟知的各种方式来达成,例如使用可公开获得的计算机软件,例如BLAST、BLAST-2、ALIGN或MEGALIGN(DNASTAR)软件。熟习此项技术者可测定用于量测比对的适当参数,包含在所比较序列的全长范围内达成最大比对所需的业内已知的任何算法。
如本文中所使用,术语「Fab」指示包含可变结构域及第一恒定结构域的Ig(不论如何制备)的抗原结合片段。
如本文中所使用,「Fv」系含有完全抗原识别及结合位点的最小抗体片段。此片段由重链一个可变区结构域与一个轻链可变区结构域呈紧密非共价缔合形式的二聚体组成。该两个结构域的折迭会产生有助于胺基酸残基的抗原结合且赋予抗体抗原结合特异性的6个超变环(各来自H链及L链的3个环)。然而,即使单一可变结构域(或Fv的一半,其仅包括三个对抗原具有特异性的HVR)亦具有识别并结合抗原的能力,但其亲和力低于完整结合位点。
如本文中所使用,术语「单链Fv」(亦缩写为「sFv」或「scFv」)系包括连结成单一多肽链的VH及VL抗体结构域的抗体片段。较佳地,sFv多肽进一步包括VH结构域与VL结构域之间的多肽链接体,其使得sFv能够形成用于抗原结合的期望结构。关于sFv的综述,参见Pluckthun,The Pharmacology of Monoclonal Antibodies,第113卷,Rosenburg及Moore编辑,Springer-Verlag,New York,第269-315页(1994)。
如本文中所使用,术语「互补决定区」(CDR)系指出现在重链及轻链多肽的可变区内的非邻接抗原组合位点。CDR已由以下文献阐述:Kabat等人,J.Biol.Chem.252:6609-6616(1977);Kabat等人,U.S.Dept.of Health and Human Services,「Sequences ofproteins of immunological interest」(1991);Chothia等人,J.Mol.Biol.196:901-917(1987);及MacCallum等人,J.Mol.Biol.262:732-745(1996),其中该等定义包括在彼此比对时的胺基酸残基重迭或子组。
如本文中所使用,术语「人类化抗体」系指如下重组蛋白:其中来自一种物种的抗体(例如鼠类或鸡抗体)的CDR自该物种抗体的重可变链及轻可变链转移至人类重链及轻链可变结构域(框架区)中。抗体分子的恒定结构域系衍生自人类抗体的彼等结构域。在一些情形下,人类化抗体的框架区的特定残基(尤其指彼等接触或靠近CDR序列者)可加以修饰,例如经来自原始鼠类、啮齿类动物、近似人类的灵长类动物或其他动物抗体的相应残基置换。可藉由各种方法来达成人类化抗体,该等方法包括:(a)仅将非人类CDR接枝于人类框架区及恒定区上且保留或不保留关键框架残基;或(b)移植整个非人类可变结构域,但使用人类样区段藉由置换表面残基来将其「伪装」。可用于实践本发明的该等方法包括揭示于Padlan,Mol.Immunol.,31(3):169-217(1994)中者。
如本文中所使用,术语「嵌合抗体」系指含有抗体重链及轻链的可变结构域(包含衍生自一种物种的抗体、较佳地啮齿类动物抗体或鸡抗体、更佳地鼠类抗体的互补决定区(CDR))的重组蛋白,而抗体分子的恒定结构域系衍生自人类抗体的彼等结构域。
如本文中所使用,术语「治疗(treatment或treating)」疾病系获得有益或期望结果(包含临床结果)的方式。出于本发明目的,有益或期望临床结果包含(但不限于)下列结果中的一或多者:缓解一或多种源自疾病的症状,减弱疾病程度,稳定疾病(例如预防或延迟疾病恶化),预防或延迟疾病扩散(例如转移),预防或延迟疾病复发,延迟或减缓疾病进展,改善疾病状态,缓解(部分或完全)疾病,降低治疗疾病所需的一或多种其他药剂的剂量,延迟疾病进展,增加或改良生化质量,增加增重,及/或延长存活。「治疗」亦涵盖减小癌症的病理学结果(例如肿瘤体积)。本文所提供的方法涵盖该等治疗态样中的任一者或多者。
如本文中所使用,术语「投与(administer或administration)」系指将存在于身体外部的物质(例如本发明调配物)注射或另外以物理方式递送至患者的动作,例如黏膜、真皮内、静脉内、肌内递送及/或本文所阐述或业内已知的任一其他物理递送方法。在治疗疾病或其症状时,通常在疾病或其症状发作的后投与物质。在预防疾病或其症状时,通常在发作疾病或其症状之前投与物质。
如本文中可互换使用,术语「个体(individual)」、「个体(subject)」、「宿主」及「患者」系指哺乳动物,包含(但不限于)鼠类(大鼠、小鼠)、非人类灵长类动物、人类、犬类、猫、有蹄动物(例如马、牛、绵羊、猪、山羊)等。
如本文中所使用,术语「治疗有效量」或「有效量」系指标的抗-EGFL6抗体在投与哺乳动物或其他个体以用于治疗疾病时足以实现该疾病治疗的量。
抗-EGFL6抗体及其在癌症治疗中的应用
本发明产生能够结合至EGFL6且抑制血管生成及癌细胞生长的抗-EGFL6抗体,尤其系单链抗体片段(scFv)及人类化抗体。
在另一态样中,本发明提供经分离抗-EGFL6抗体或其抗原结合部分,其包括以下中的至少一者:由SEQ ID NO:1或2的胺基酸残基组成的轻链CDR1(L-CDR1),或具有与SEQID NO:1及2中的任一者具有至少80%一致性的胺基酸序列的变体;由SEQ ID NO:3或4的胺基酸残基组成的轻链CDR2(L-CDR2),或具有与SEQ ID NO:3及4中的任一者具有至少80%一致性的胺基酸序列的变体;及由SEQ ID NO:5或6的胺基酸残基组成的轻链CDR3(L-CDR3),或具有与SEQ ID NO:5及6中的任一者具有至少80%一致性的胺基酸序列的变体;及
以下中的至少一者:由SEQ ID NO:7或8的胺基酸残基组成的重链互补决定区1(H-CDR1),或具有与SEQ ID NO:7及8中的任一者具有至少80%一致性的胺基酸序列的变体;由SEQ ID NO:9或10的胺基酸残基组成的重链CDR2(H-CDR2),或具有与SEQ ID NO:9及10中的任一者具有至少80%一致性的胺基酸序列的变体;及由SEQ ID NO:11或12的胺基酸残基组成的重链CDR3(H-CDR3),或具有与SEQ ID NO:11及12中的任一者具有至少80%一致性的胺基酸序列的变体;从而该经分离抗体或其抗原结合部分结合至EGFL6。较佳地,如上文所提及的序列一致性为至少81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%。
轻链及重链中的互补决定区的胺基酸序列及列示于下文中。
轻链的CDR
L-CDR1 | L-CDR2 | L-CDR3 |
GNDKY(SEQ ID NO:1) | ETR(SEQ ID NO:3) | GGYDSSAGYAGM(SEQ ID NO:5) |
SGRYG(SEQ ID NO:2) | DND(SEQ ID NO:4) | GSYDRSGGVGT(SEQ ID NO:6) |
重链的CDR
在一些实施例中,经分离抗-EGFL6抗体系单株抗体、嵌合抗体、人类化抗体或人类抗体。在一些实施例中,经分离抗-EGFL6抗体系单链抗体(例如Fv(scFv)、IgG、Fab、(Fab)2或(scFv')2)。
根据本发明,本发明抗体的轻链及重链的胺基酸的实施例列示于下文中。
在一些实施例中,本发明提供包括具有选自由SEQ ID NO:13或14组成的群的序列的胺基酸序列的轻链。
在一些实施例中,轻链包括具有如SEQ ID NO:13所示序列的胺基酸序列,其中L-CDR1、L-CDR2及L-CDR3分别经SEQ ID NO:2、SEQ ID NO:4及SEQ ID NO:6置换。在另一实施例中,轻链包括具有如SEQ ID NO:14所示序列的胺基酸序列,其中L-CDR1、L-CDR2及L-CDR3分别经SEQ ID NO:1、SEQ ID NO:3及SEQ ID NO:5置换。
在一些实施例中,本发明提供包括具有选自由SEQ ID NO:15或16组成的群的序列的胺基酸序列的重链。
在一些实施例中,重链包括具有如SEQ ID NO:15所示序列的胺基酸序列,其中H-CDR1、H-CDR2及H-CDR3分别经SEQ ID NO:8、SEQ ID NO:10及SEQ ID NO:12置换。在另一实施例中,重链包括具有如SEQ ID NO:16所示序列的胺基酸序列,其中H-CDR1、H-CDR2及H-CDR3分别经SEQ ID NO:7、SEQ ID NO:9及SEQ ID NO:11置换。
在其他实施例中,本发明包括经分离抗体,该抗体包括:具有如选自由SEQ ID NO:13及14组成的群的序列所示胺基酸序列的轻链,或与SEQID NO:13及14中的任一者具有至少80%一致性的变体;及(ii)具有如选自由SEQ ID NO:15及16组成的群的序列所示胺基酸序列的重链;或与SEQ ID NO:15至16中的任一者具有至少80%一致性的变体。较佳地,如上文所提及的序列一致性为至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%。
在另一实施例中,本发明包括含有具有如SEQ ID NO:13中所陈述胺基酸序列的轻链及具有如SEQ ID NO:15中所陈述胺基酸序列的重链的经分离抗体(EL6_S12)。在另一实施例中,本发明包括含有具有如SEQ ID NO:14中所陈述胺基酸序列的轻链及具有如SEQ IDNO:16中所陈述胺基酸序列的重链的经分离抗体(EL6_E5)。在另一实施例中,本发明包括含有具有如SEQ ID NO:13中所陈述胺基酸序列的轻链及具有如SEQ ID NO:16中所陈述胺基酸序列的重链的经分离抗体。在另一实施例中,本发明包括含有具有如SEQ ID NO:14中所陈述胺基酸序列的轻链及具有如SEQ ID NO:15中所陈述胺基酸序列的重链的经分离抗体。
用于制备实际上针对任一靶抗原的单株抗体的技术在业内已众所周知。例如参见Kohler及Milstein,Nature 256:495(1975)及Coligan等人(编辑),CURRENT PROTOCOLS INIMMUNOLOGY,第1卷,第2.5.1-2.6.7页(John Wiley&Sons 1991)。简言之,可藉由以下方式来获得单株抗体:向小鼠或鸡注射包括抗原的组合物,取出脾以获得B-淋巴球,使B-淋巴球与骨髓瘤细胞融合以产生杂交瘤,选殖杂交瘤,选择产生针对抗原的抗体的阳性纯系,培养产生针对抗原的抗体的纯系,且自杂交瘤培养物分离抗体。
各种技术(例如产生嵌合或人类化抗体)可涉及抗体选殖及构筑的程序。可藉由各种分子选殖程序(例如RT-PCR、5'-RACE及cDNA库筛选)来获得所关注抗体的抗原结合可变轻链及可变重链序列。可藉由PCR扩增来选殖来自表现鼠类抗体的细胞的抗体的可变重链或轻链序列基因且测序。为证实其真实性,可使经选殖VL及VH基因作为嵌合抗体表现于细胞培养物中,如由Orlandi等人(Proc.Natl.Acad.Sci.,USA,86:3833(1989))所阐述。基于可变重链或轻链基因序列,然后可设计并构筑人类化抗体,如由Leung等人(Mol.Immunol.,32:1413(1995))所阐述。
嵌合抗体系重组蛋白,其中人类抗体的可变区已由(例如)小鼠抗体的可变区(包含小鼠抗体的互补决定区(CDR))置换。在投与个体时,嵌合抗体展现降低的免疫原性及增加的稳定性。构筑嵌合抗体的方法在业内已众所周知(例如Leung等人,1994,Hybridoma13:469)。
可藉由将来自小鼠免疫球蛋白的重可变链及轻可变链的小鼠CDR转移至人类抗体的相应可变结构域中来使嵌合单株抗体人类化。嵌合单株抗体中的小鼠框架区(FR)亦经人类FR序列置换。为保留人类化单株的稳定性及抗原特异性,可藉由小鼠对应体残基置换一或多个人类FR残基。人类化单株抗体可用于个体的治疗性治疗。产生人类化单株抗体的技术在业内已众所周知(例如参见Jones等人,1986,Nature,321:522;Riechmann等人,Nature,1988,332:323;Verhoeyen等人,1988,Science,239:1534;Carter等人,1992,Proc.Nat'l Acad.Sci.USA,89:4285;Sandhu,Crit.Rev.Biotech.,1992,12:437;Tempest等人,1991,Biotechnology 9:266;Singer等人,J.Immun.,1993,150:2844)。
可使用噬菌体显示技术自来自未免疫化供体的免疫球蛋白可变(V)结构域基因谱在活体外产生抗-EGFL6抗体及抗体片段。根据此技术,将抗体V结构域基因框架内选殖至丝状噬菌体(例如M13或fd)的主要或次要外壳蛋白基因中,并在噬菌体颗粒表面上显示为功能抗体片段。因丝状颗粒含有噬菌体基因体的单股DNA拷贝,故基于抗体功能性质的选择亦导致对编码展现彼等性质的抗体的基因的选择。因此,噬菌体模拟B细胞的一些性质。噬菌体显示可以各种形式实施,且综述于(例如)Johnson,Kevin S.及Chiswell,David J.,Curr.Opin Struct.Biol.3:564-571(1993)中。可使用若干V-基因区段来源进行噬菌体显示。Clackson等人,Nature,352:624-628(1991)自衍生自经免疫小鼠脾脏的V基因的小型随机组合库分离出抗-恶唑酮抗体的多样性数组。在其他实施例中,可使用核糖体显示技术在活体外产生抗-EGFL6抗体及抗体片段。
已研发各种技术来产生抗体片段。传统上,经由完整抗体的蛋白质水解性消解作用来衍生该等片段。然而,该等片段现可藉由重组宿主细胞,例如:使用编码本发明抗-EGFL6抗体的核酸,直接产生。Fab、Fv及scFv抗体片段可皆于大肠杆菌(E.coli)中表现且由其分泌,由此容许直接产生大量该等片段。亦可自如上文所论述的抗体噬菌体库来分离抗-EGFL6抗体片段。或者,可自大肠杆菌直接回收Fab'-SH片段且以化学方式偶合以形成F(ab')2片段。根据另一方式,可自重组宿主细胞培养物直接分离F(ab')2片段。具有延长的活体内半衰期的Fab及F(ab')2抗体片段的生产法阐述于US 5,869,046中。在其他实施例中,所选抗体系单链Fv片段(scFv)。
可对编码本文所阐述多肽的核酸进行修饰而不减弱其生物活性。可进行一些修饰以促进靶向分子在融合蛋白中的选殖、表现或纳入。该等修饰为熟习此项技术者所熟知且包含(例如)终止密码子、添加于胺基末端以提供起始位点的甲硫胺酸、置于任一末端以产生合宜定位的限制位点的其他胺基酸、或有助于纯化步骤的其他胺基酸(例如聚His)。除重组方法外,亦可完全或部分地部分使用业内熟知的标准肽合成来构筑本发明抗体。
双链抗体纯化方案的修改系由重链及轻链区分开溶解及还原,然后于再折迭溶液中组合。当这两种蛋白质混合时的莫耳比例可以使其中一种蛋白质超过另一种蛋白质的莫耳量不超过5倍时,获得实例性产率。在完成氧化还原-改组之后,可向再折迭溶液中添加过量已氧化的麸胱甘肽或其他氧化性低分子量化合物。
除重组方法外,亦可完全或部分地使用标准肽合成来构筑本文所揭示的抗体及其变体。可藉由将序列的C-末端胺基酸附接至不溶性载体、随后依序添加序列中的剩余胺基酸来达成多肽的固相合成。用于固相合成的技术阐述于以下文献中:Barany&Merrifield,The Peptides:Analysis,Synthesis,Biology.第2卷:Special Methods in PeptideSynthesis,部分A.pp.3-284;Merrifield等人,J.Am.Chem.Soc.85:2149-2156,1963;及Stewart等人,Solid Phase Peptide Synthesis,第2版,Pierce Chem.Co.,Rockford,Ill.,1984。可藉由缩合较短片段的胺基及羧基末端来合成较大长度的蛋白质。
包括抗EDFL6抗体的医药组合物及抗EDFL6抗体的治疗或预防应用
某些实施例系关于包括本发明的抗-EGFL6抗体及医药上可接受的载剂或赋形剂的医药组合物。术语「医药上可接受的载剂」意欲包含(但不限于)熟习此项技术者已知的任一类型的无毒固体、半固体或液体填充剂、稀释剂、囊封材料或调配助剂。可使用稀释剂(例如多元醇、聚乙二醇及右旋糖酐)来增加偶联物的生物半衰期。
可根据习用方法(例如Remington's Pharmaceutical Science,最新版,MarkPublishing Company,Easton,U.S.A.)来调配本发明的医药组合物,且该医药组合物亦可含有医药上可接受的载剂及添加剂。实例包含(但不限于)表面活性剂、赋形剂、着色剂、矫味剂、防腐剂、稳定剂、缓冲剂、悬浮剂、等渗剂、黏合剂、崩解剂、润滑剂、流动促进剂及矫正剂,且可适宜地使用其他常用载剂。载剂的具体实例包含光无水硅酸、乳糖、结晶纤维素、甘露醇、淀粉、羧甲基纤维素钙、羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯缩醛二乙基胺基乙酸酯、聚乙烯基吡咯啶酮、明胶、中链三甘油酯、聚氧乙烯硬化蓖麻油60、蔗糖、羧甲基纤维素、玉米淀粉、无机盐等等。
一实施例系关于治疗或预防个体的血管生成病症的方法,其包括向个体投与本发明的抗-EGFL6抗体。或者,一实施例系关于本发明的抗-EGFL6抗体的用途,其用以制造用于治疗或预防个体的血管生成病症的药剂。特征在于病理学血管生成的病症系指异常或反常血管生成(单独或与其他现象组合)有助于病症的引起、起源或症状的病症。此病症的实例包含各种癌症(例如血管化肿瘤)、眼部病症、发炎性病症及其他病症。
另一实施例系关于抑制个体中的癌细胞生长或癌症转移的方法,其包括向个体投与本发明的抗-EGFL6抗体。或者,另一实施例系关于本发明的抗-EGFL6抗体的用途,其用以制造用于抑制个体中的癌细胞生长或癌症转移的药剂。因血管生成涉及原发性癌症生长及转移,故由本发明提供的抗血管生成治疗能够抑制一级位点处的癌细胞生长以及预防二级位点处的肿瘤转移。实例性实体肿瘤包含(但不限于)皮肤癌、肾癌、前列腺癌、脂肪组织癌、肺癌、乳癌、骨癌、卵巢癌、胃癌、胰脏癌、喉癌、食道癌、睪丸癌、肝癌、腮腺癌、胆道癌、结肠癌、直肠癌、子宫颈癌、子宫癌、子宫内膜癌、肾癌、膀胱癌、前列腺癌、甲状腺癌、鳞状细胞癌、腺癌、小细胞癌、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、神经母细胞瘤、卡波西氏肉瘤(Kaposi's sarcoma)及肉瘤(例如胃肠道基质肿瘤)。在另一实施例中,癌症系结肠直肠癌、结肠癌或直肠癌。
本发明方法亦包括投与本发明的抗-EGFL6抗体(与其他标准疗法同时或之后),其中该标准疗法系选自由以下组成的群:放射疗法、手术及化学疗法。
在较佳实施例中,个体系哺乳动物。实例性哺乳动物包含人类、猪、绵羊、山羊、马、小鼠、狗、猫、牛等。可使用抗-EGFL6抗体或其医药组合物治疗的疾病包含癌症(例如肝癌、皮肤癌、头颈癌、肺癌、乳癌、前列腺癌、卵巢癌、子宫内膜癌、子宫颈癌、结肠癌、直肠癌、结肠及直肠癌、膀胱癌、脑癌、胃癌、胰脏癌或淋巴系统)。较佳地,癌症系结肠直肠癌。
可经静脉内、经腹膜腔内、经动脉内、经鞘内、经膀胱内或经肿瘤内来投与抗-EGFL6抗体或其医药组合物。熟习此项技术者应了解,可根据经验来测定抗-EGFL6抗体的有效量。应理解,在投与人类患者时,由主治医师在合理医学判断的范围内来决定抗-EGFL6抗体或组合物的总日用量。任一特定患者的具体治疗有效剂量值取决于以下多种因素:拟达成细胞反应的类型及程度;所采用具体抗-EGFL6抗体或化合物的活性;患者的年龄、体重、总体健康状况、性别及饮食;抗-EGFL6抗体的投与时间、投与途径及排泄速率;治疗持续时间;与抗-EGFL6抗体组合或同时使用的药物;及医学技术中已为人熟知的类似因素。
上文所鉴别组合物及治疗方法中的每一者可另外包含其他抗肿瘤药物及投与其他一或多种抗肿瘤药物。适用于本发明的抗肿瘤药物包含(但不限于)诱导细胞凋亡的药剂、抑制腺苷去胺酶功能的药剂、抑制嘧啶生物合成的药剂、抑制嘌呤环生物合成的药剂、抑制核苷酸互变的药剂、抑制核糖核苷酸还原酶的药剂、抑制单磷酸胸苷(TMP)合成的药剂、抑制二氢叶酸盐还原的药剂、抑制DNA合成的药剂、与DNA形成加合物的药剂、损害DNA的药剂、抑制DNA修复的药剂、插入DNA的药剂、去胺基天门冬酰胺的药剂、抑制RNA合成的药剂、抑制蛋白质合成或稳定性的药剂、抑制微管合成或功能的药剂及诸如此类。其他抗肿瘤药物的实例包含(但不限于)1)生物碱类,包含微管抑制剂(例如长春新碱(vincristine)、长春碱(vinblastine)及长春地辛(vindesine)等)、微管稳定剂(例如太平洋紫杉醇(TAXOL)及多西他赛(docetaxel)等)及染色质功能抑制剂(包含拓扑异构酶抑制剂,例如及表鬼臼毒素(epipodophyllotoxin)(例如依托泊苷(etoposide)(VP-16)及替尼泊苷(teniposide)(VM-26)等)及靶向拓扑异构酶I的药剂(例如喜树碱(camptothecin)及伊丝立替康(isirinotecan)(CPT-11)等));2)共价DNA结合剂(烷基化剂),包含氮芥(nitrogenmustard)(例如双氯乙基甲胺(mechlorethamine)、氮芥苯丁酸(chlorambucil)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosphamide)及白消安(busulfan)(MYLERAN)等)、亚硝基脲(例如卡莫司汀(carmustine)、洛莫司汀(lomustine)及司莫司汀(semustine)等)及其他烷基化剂(例如替莫唑胺(temozolomide)、达喀尔巴嗪(dacarbazine)、羟甲基三聚氰胺(hydroxymethylmelamine)、噻替派(thiotepa)及丝裂霉素(mitomycin)等);3)非共价DNA-结合剂(抗肿瘤抗生素),包含核酸抑制剂(例如更生霉素(dactinomycin)(放线菌素(actinomycin)D)等)、蒽环(例如柔红霉素(daunorubicin)(道诺霉素(daunomycin)及正定霉素(cerubidine))、多柔比星(doxorubicin)(阿霉素(adriamycin))及伊达比星(idarubicin)(去甲氧柔红霉素(idamycin))等)、蒽二酮(例如蒽环类似物,例如米托蒽醌(mitoxantrone)等)、博来霉素(bleomycin)(BLENOXANE)等及普利霉素(plicamycin)(光辉霉素(mithramycin))等;4)抗代谢物,包含抗叶酸剂(例如胺甲喋呤(methotrexate)、FOLEX及MEXATE等)、嘌呤抗代谢物(例如6-巯基嘌呤(6-MP、PURINETHOL)、6-硫基鸟嘌呤(6-TG)、硫唑嘌呤(azathioprine)、阿昔洛韦(acyclovir)、更昔洛韦(ganciclovir)、氯脱氧腺苷、2-氯脱氧腺苷(CdA)及2'-脱氧助间型霉素(2'-deoxycoformycin)(喷司他丁(pentostatin))等)、嘧啶拮抗剂(例如氟嘧啶(例如5-氟尿嘧啶(5-fluorouracil)(ADRUCIL)、5-氟脱氧尿苷(FdUrd)(氟尿苷(floxuridine)))等)及胞嘧啶阿拉伯糖苷(例如CYTOSAR(ara-C)及氟达拉滨(fludarabine)等);5)酶,包含L-天门冬酰胺酶及羟基脲(hydroxyurea)等;6)激素,包含糖皮质激素、抗雌激素(例如他莫昔芬(tamoxifen)等)、非类固醇抗雄激素(例如氟他胺(flutamide)等)及芳香酶抑制剂(例如阿那曲唑(anastrozole)(ARIMIDEX)等);7)铂化合物(例如顺铂(cisplatin)及卡铂(carboplatin)等);8)与抗癌药、毒素及/或放射性核素等偶联的单株抗体;9)生物反应修饰剂(例如干扰素(例如IFN-α等)及介白素(例如IL-2等)等);10)接受性免疫疗法;11)造血生长因子;12)诱导肿瘤细胞分化的药剂(例如全反视黄酸等);13)基因疗法技术;14)反义疗法技术;15)肿瘤疫苗;16)针对肿瘤转移的疗法(例如巴马司他(batimastat)等);17)血管生成抑制剂;18)蛋白体抑制剂(例如VELCADE);19)乙酰化及/或甲基化抑制剂(例如HDAC抑制剂);20)NFκB调节剂;21)细胞周期调控抑制剂(例如CDK抑制剂);及22)p53蛋白质功能调节剂。
使用抗-EGFL6抗体的癌症检测或诊断
本发明亦展示,EGFL6含量与癌症严重程度之间存在关联;因此,EGFL6或其片段在生物样本中的高表现程度(与EGFL6或其片段在对照样本中的参考表现程度相比)可指示预测的转移或较差预后。本发明出人意料地发现,本发明的抗-EGFL6抗体可用作诊断或预测个体中癌症的预后或升高的转移或未来发生风险的指示剂。因此,本发明提供检测或诊断个体中的癌症或升高的未来癌症发生风险或预测癌症的转移或预后的方法,其包括使来自个体的生物样本与本发明的抗-EGFL6抗体接触,量化样本中的EGFL6抗原与抗体的结合,及比较该结合与代表在来自未患有癌症的对照个体的样本中所测定抗-EGFL6抗体与EGFL6抗原间的结合的参考值。
在一实施例中,生物样本可为细胞、组织、器官、器官样本、组织生检、血液、血浆、血清、腹水液、淋巴球、尿、骨髓液、淋巴液、唾液、泪液、黏液、羊水或其组合。
适于偶联至抗体及其他结合试剂的可检测标记包含放射性同位素、荧光标记、酶受质标记、发色标记、化学发光标记及胶质金颗粒。
量测方法的实例包含(但不限于)荧光免疫分析(FIA)方法、酶免疫分析(EIA)方法、放射性免疫分析(RIA)方法、西方印渍方法、点印渍、免疫组织化学分析、荧光活化细胞分选仪(FACS)、活体内成像及放射性成像分析。
本发明进一步提供监测已经诊断患有癌症的个体中的癌症进展的方法。在一些实施例中,可使用监测来评估特定治疗是否成功。
在一些实施例中,监测癌症进展包括:藉由本发明的抗-EGFL6抗体测定自经诊断患有癌症的个体获得的第一生物样本中EGFL6或其片段的第一含量;及在预定时间段的后藉由本发明的抗-EGFL6抗体测定自个体获得的第二生物样本中EGFL6或其片段的第二含量;比较EGFL6或其片段的第一含量及第二含量;其中第二样本与第一样本相比的EGFL6或其片段的较高含量指示疾病进展及恶化。类似地,第二样本与第一样本相比的EGFL6或其片段的较低含量指示改良。
本发明的诊断方法可与已知癌症诊断方法进行组合。
本发明的另一态样涵盖一种套组,其用于检测或诊断个体的癌症或升高的未来癌症发生风险或预测癌症转移或预后或监测癌症进展。其通常呈含有所有要素(视情况包含说明书)的包装形式。包装可分开,从而各组分并混合直至期望时。个别组分可单独包装于套组内。套组可含有检测标记物基因的表现程度所需的试剂。套组系的任一制品(例如包装或容器),其包括至少一种用于特异性检测及/或量测标记物基因在样本中的表现程度的试剂(例如抗体试剂)。
本发明涵盖具有不同组分的各种套组。概言之,套组包含用于量化个体中的EGFL6或更多生物标记物的构件。在另一实施例中,套组包含用于收集生物样本的构件、用于量化生物样本中的EGFL6或更多生物标记物的构件及使用套组内容物的说明书。在某些态样中,套组包括用于量化生物标记物的量的构件。在其他态样中,用于量化生物标记物的量的构件包括检测生物标记物的量所需的试剂。
已阐述本发明的若干实施例。然而,将理解,可在不背离本发明的精神及范围的情况下作出各种修改。因此,下列实例意欲加以阐释,但并不限制申请专利范围中所阐述的发明范围。
实例
实例1抗-EGFL6单链抗体库的构筑及生物淘选
藉由肌内注射使用50ug于等体积弗罗因德氏完全佐剂(Freund’s completeadjuvant)中的重组EGF6对雌性白色来亨鸡(white leghorn)(家鸡(Gallus domesticus))实施免疫。以7天间隔使用不完全佐剂实施三个其他免疫化。在每一免疫化之后,收集蛋黄中的鸡IgY抗体并藉由酶联免疫吸附分析(ELISA)滴定以测定体液抗-EGFL6抗体免疫反应的存在。根据公开方案(Akita,E.M.及Nakai,S.(1993).Production and purification ofFab'fragments from chicken egg yolk immunoglobulin Y(IgY).J Immunol Methods162,155-164)使用10%硫酸右旋糖酐自氮白分离蛋黄以用于IgY纯化。
基于先前报告(Andris-Widhopf,J.,Rader,C.,Steinberger,P.,Fuller,R.及Barbas,C.F.3rd(2000).Methods for the generation of chicken monoclonalantibody fragments by phage display.J Immunol Methods 242,159-181.Barbas,C.F.,3rd,Kang,A.S.,Lerner,R.A.及Benkovic,S.J.(1991).Assembly of combinatorialantibody libraries on phage surfaces:the gene III site.Proc Natl Acad Sci U SA 88,7978-7982)来确立抗体库。简言之,收获鸡脾并立即置于特里佐尔(Trizol)中。将10ug总RNA逆转录至第一链cDNA中。在使用鸡特异性引子扩增之后,对具有短或长连接体的重链及轻链可变(VH及VL)区的PCR产物实施第二轮PCR,使用SfiI消解并选殖至pComb3X载体中。藉由电穿孔将重组DNA转变至大肠杆菌ER2738菌株中。藉由添加VCS-M13辅助噬菌体来产生重组噬菌体,使用4%聚乙二醇8000及3%NaCl(w/v)沈淀,再悬浮于含有1%牛血清白蛋白(BSA)的磷酸盐缓冲盐水(PBS)中。然后,将1011个斑块形成单位(pfu)的重组噬菌体添加至经EGFL6蛋白(0.5ug/孔)预涂覆的孔中,并在37℃下培育2h。使用0.1M HCl/甘胺酸(pH 2.2)/0.1%BSA洗脱所结合噬菌体,使用2M Tris碱缓冲液中和并用于感染ER2738菌株。如上文所阐述回收经扩增噬菌体以用于下一轮选择。重复淘选程序6次。纯化总DNA并转变至TOP 10F’大肠杆菌菌株中。随机选择20个纯系并自最终淘选过程生长。裂解细菌细胞并分析scFv抗体表现及EGFL6结合反应性。使用Ni2+-带电琼脂糖纯化ScFv抗体,如由制造商(Amersham Biosciences,UK)所阐述。图1展示使用ELISA测得的抗-EGFL6抗体的结合活性。使用在第6轮生物淘选之后14个随机选自每一ELISA-阳性噬菌体库的纯系的总细胞溶解物来检验其抗-EGFL6活性。可发现,大部分scFv抗体可特异性结合至EGFL6蛋白(参见图1)。
实例2抗-EGFL6单链抗体的结合分析
纯化大肠杆菌表现的scFv抗体并与固定于硝基纤维素膜上的EGFL6蛋白一起培育。随后藉由添加山羊抗鸡IgY轻链、随后添加HRP偶联的驴抗山羊Ig抗体来检测其结合。在三次洗涤之后,使用二胺基联苯胺(DAB)受质使膜显影直至达到期望强度为止。图2展示重组全长EGFL6蛋白(泳道EGFL6),且使用N-末端截短片段(泳道EGFL6-F37)及C-末端截短片段(泳道EGFL6-F396)在还原条件下进行SDS-PAGE分析。图2A及2B展示在西方印渍中藉由E5scFv(图2A)及S12 scFv(图2B)鉴别的全长EGFL6蛋白及EGFL6-F396截短片段。
实例3结肠直肠癌患者的血清中的EGFL6表现
在癌症患者的血清中评估表皮生长因子样蛋白6(EGFL6)的表现。
如图3中所展示,藉由西方印渍量测肺癌、结肠癌、卵巢癌、前列腺癌、脑癌、子宫癌及乳癌细胞系中的EGFL6的蛋白质表现。EGFL6未表现于正常细胞系中。该等结果表明,EGFL6可发现于癌症患者中且EGFL6可用作癌症标记物。
实例4在动物模型中藉由抗-EGFL6单链抗体S12及E5评估单链抗体对结肠直肠癌细胞系HCT116的细胞迁移抑制及癌症转移抑制
实施细胞渗透迁移分析以评估单链抗体抑制结肠直肠癌细胞系HCT116的细胞迁移的能力。如图4(A)中所展示,将抗-EGFL6单链抗体添加至结肠直肠癌细胞系HCT116中且在细胞培养条件下抑制癌细胞生长。结果表明,抗体Ab4、Ab5(E5)及Ab10有效抑制癌细胞迁移。
在CT26同种移植物小鼠模型中,在向小鼠投与抗-EGFL6单链抗体(S12及E5)及小分子药物太平洋紫杉醇之后,观察抑制结肠直肠癌细胞CT26向肺的转移的能力。以15mg/kg的剂量每三天一次来投与抗-EGFL6单链抗体S12及E5,而以20mg/kg的剂量每4天一次来投与太平洋紫杉醇。如图4(B)中所展示,与使用太平洋紫杉醇以20mg/kg的剂量每4天一次治疗的对照组相比,使用两种抗-EGFL6单链抗体以15mg/kg的剂量每三天一次治疗的组可有效地抑制肿瘤囊形成。
实例5藉由单链抗体E5及S12在活体内抑制血管生成
向5周龄裸小鼠经皮下注射500μl与EGF混合的基质胶以诱导血管生成。将裸小鼠分成以下4组:(1)仅使用基质胶,作为阴性对照组(基础);(2)使用与EGF(150ng/mL)混合的基质胶,作为阳性对照组(对照);(3)使用单链抗体E5以15mg/kg的剂量在EGF诱导条件下治疗的组;及(4)使用单链抗体S12以15mg/kg的剂量在EGF诱导条件下治疗的组。每一组具有3只裸小鼠且藉由尾部静脉注射在一周内每周三次投与单链抗体E5及S12。在第8天将裸小鼠处死。取出小鼠腹部中的基质胶束并藉由碾磨杆均质化,随后量测血红蛋白含量。
如图5中所展示,血管生成未展示于仅注射基质胶的阴性对照组(基础)中。与阴性对照组(基础)相比,在24小时之后,血管生成展示于注射与EGF混合的基质胶的阳性对照组(对照)中。如图5中所展示,显而易见,使用两种抗-EGFL6单链抗体E5及S12治疗的组展示抑制血管生成的效应。另外,将裸小鼠处死且取出小鼠腹部中的基质胶束,并量测血红蛋白含量。图5图解说明,使用抗-EGFL6单链抗体E5及S12治疗的裸小鼠的基质胶束中的血红蛋白含量展示与裸小鼠实体观察相关的较低值。另外,如图5中所展示,抗-EGFL6单链抗体E5及S12展现抑制血管生成的显著效应。使用抗-EGFL6单链抗体E5及S12治疗的组的血红蛋白含量几乎等效于阴性对照组(基础)的含量。该等结果证实,抗-EGFL6单链抗体E5及S12能够中和EGFL6,且由此达成抑制血管生成的效应。
实例6藉由抗-EGFL6人类化IgG抗体在活体内抑制动物模型中的肿瘤生长
藉助藉由先前研究中所应用的算法生成的分子模型来实施鸡scFv抗体的可变区的人类化(Tsurushita等人,2004;Zilber等人,1990)。简言之,基于序列同源性来选择用作抗-EGFL6 scFv抗体的CDR的受体的人类V区框架。使用鸡抗-EGFL6 scFv抗体的相应残基来取代自三维模型所预测对于适当形成CDR结构较为重要的人类化V区中的胺基酸残基。组合其他方法且用于进一步微调人类化抗-EGFL6抗体的结构(Ewert等人,2003;Sidhu等人,2004)。
评估两种抗-EGFL6人类化IgG抗体(S12及E5)抑制异种移植物小鼠中的结肠直肠癌细胞HCT116、非小细胞肺癌A549、三阴性乳癌细胞MDA-MB-231及神经胶母细胞瘤癌细胞U87的生长的能力。每周两次向小鼠投与指示剂量及静脉内注射。初始肿瘤大小约为200mm3。在实验结束时,计算肿瘤生长抑制比率(TGI%)并与对照组进行比较。如图6(A)中所展示,使用人类化IgG抗体S12及E5的两组皆能够抑制肿瘤生长(结肠直肠癌细胞HCT-116)。使用S12抗体的组的TGI%为7.5%,而使用E5抗体的组为36.2%。如图6(B)中所展示,人类化IgG抗体E5能够抑制非小细胞肺癌A549中的肿瘤生长。使用E5抗体(10mg/kg)的组的TGI%为14.3%,而使用E5抗体(20mg/kg)的组为80.8%。
如图7(A)中所展示,使用人类化IgG抗体E5的组能够抑制肿瘤生长(三阴性乳癌细胞MDA-MB-231)。使用E5抗体(20mg/kg)的组的TGI%为65.1%,而使用E5抗体(40mg/kg)的组为65.4%。如图7(B)中所展示,使用单链抗体E5的组能够抑制肿瘤生长(神经胶母细胞瘤癌细胞)。使用E5抗体(20mg/kg)的组的TGI%为36.5%。
另外,分析与太平洋紫杉醇组合的人类化IgG抗体E5在人类非小细胞肺癌A549异种移植物模型中的抗癌活性。将太平洋紫杉醇(5mg/kg)、E5 IgG(10mg/kg)及太平洋紫杉醇(5mg/kg)与E5 IgG(10mg/kg)的组合经静脉内注射至小鼠中。如图8中所展示,使用抗体E5IgG的组能够抑制肿瘤生长且太平洋紫杉醇与E5 IgG的组合具有抑制肿瘤的意外效能。使用E5抗体(10mg/kg)的组的TGI%为14.3%,而使用太平洋紫杉醇与E5 IgG的组合的组为61.8%。
序列表
<110> 台北医学大学
彰化基督教医疗财团法人彰化基督教医院
蔡耿彰
<120> 抗-类EGF结构域多重6(EGFL6)抗体及其于癌症诊断及治疗中的应用
<130> T54267/CN32599
<150> US 62/566,509
<151> 2017-10-01
<160> 16
<170> PatentIn version 3.5
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Claims (26)
1.一种经分离抗-EGFL6抗体或其抗原结合部分,其包括以下中的至少一者:由SEQ IDNO:1或2的胺基酸残基组成的轻链CDR1(L-CDR1);由SEQ ID NO:3或4的胺基酸残基组成的轻链CDR2(L-CDR2);及由SEQ ID NO:5或6的胺基酸残基组成的轻链CDR3(L-CDR3);及以下中的至少一者:包括SEQ ID NO:7或8的胺基酸残基的重链互补决定区1(H-CDR1);包括SEQID NO:9或10的胺基酸残基的重链CDR2(H-CDR2);及包括SEQ ID NO:11或12的胺基酸残基的重链CDR3(H-CDR3);从而由所述经分离抗体或其抗原结合部分与EGFL6结合。
2.根据权利要求1所述的抗-EGFL6抗体或其抗原结合部分,其系单株抗体、嵌合抗体、人类化抗体或人类抗体。
3.根据权利要求1所述的抗-EGFL6抗体或其抗原结合部分,其系单链Fv(scFv)、IgG、Fab、(Fab)2或(scFv')2。
4.一种轻链,其包括具有选自由SEQ ID NO:13或14组成的群的序列的胺基酸序列。
5.一种轻链,其包括具有如SEQ ID NO:13中所陈述序列的胺基酸序列,其中L-CDR1、L-CDR2及L-CDR3分别经SEQ ID NO:2、SEQ ID NO:4及SEQ ID NO:6置换。
6.一种轻链,其包括具有如SEQ ID NO:14中所陈述序列的胺基酸序列,其中L-CDR1、L-CDR2及L-CDR3分别经SEQ ID NO:1、SEQ ID NO:3及SEQ ID NO:5置换。
7.一种重链,其包括具有如SEQ ID NO:15或16所示序列的胺基酸序列。
8.一种重链,其包括具有如SEQ ID NO:15所示序列的胺基酸序列,其中H-CDR1、H-CDR2及H-CDR3分别经SEQ ID NO:8、SEQ ID NO:10及SEQ ID NO:12置换。
9.一种重链,其包括具有如SEQ ID NO:16所示序列的胺基酸序列,其中H-CDR1、H-CDR2及H-CDR3分别经SEQ ID NO:7、SEQ ID NO:9及SEQ ID NO:11置换。
10.一种经分离抗体,其包括具有如选自由SEQ ID NO:13及14组成的群的序列所示胺基酸序列的轻链;及(ii)具有如选自由SEQ ID NO:15及16组成的群的序列所示胺基酸序列的重链。
11.根据权利要求10所述的经分离抗体,其包括具有如SEQ ID NO:13所示胺基酸序列的轻链及具有如SEQ ID NO:15所示胺基酸序列的重链。
12.根据权利要求10所述的经分离抗体,其包括具有如SEQ ID NO:14所示胺基酸序列的轻链及具有如SEQ ID NO:16所示胺基酸序列的重链。
13.根据权利要求10所述的经分离抗体,其包括具有如SEQ ID NO:13所示胺基酸序列的轻链及具有如SEQ ID NO:16所示胺基酸序列的重链。
14.根据权利要求10所述的经分离抗体,其包括具有如SEQ ID NO:14所示胺基酸序列的轻链及具有如SEQ ID NO:15所示胺基酸序列的重链。
15.一种医药组合物,其包括根据权利要求1至14中任一者所述的抗-EGFL6抗体及医药上可接受的载剂或赋形剂。
16.根据权利要求15所述的医药组合物,其进一步包括其他一或多种抗肿瘤药物。
17.一种根据权利要求1至14中任一者所述的抗-EGFL6抗体的用途,其用以制造用于治疗或预防个体的血管生成病症的药剂。
18.根据权利要求17所述的用途,其中所述血管生成病症系癌症、眼部病症或发炎性病症。
19.一种根据权利要求1至14中任一者所述的抗-EGFL6抗体的用途,其用以制造用于抑制个体中的癌细胞生长或癌症转移的药剂。
20.根据权利要求19所述的用途,其中所述药剂进一步与其他一或多种抗肿瘤药物一起投与。
21.根据权利要求19所述的用途,其中所述癌症系皮肤癌、肾癌、前列腺癌、脂肪组织癌、肺癌、乳癌、骨癌、卵巢癌、胃癌、胰脏癌、喉癌、食道癌、睪丸癌、肝癌、腮腺癌、胆道癌、结肠癌、直肠癌、子宫颈癌、子宫癌、子宫内膜癌、肾癌、膀胱癌、前列腺癌、甲状腺癌、鳞状细胞癌、腺癌、小细胞癌、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、神经母细胞瘤、卡波西氏肉瘤(Kaposi's sarcoma)或肉瘤。
22.根据权利要求19所述的用途,其中所述癌症系结肠直肠癌。
23.一种检测或诊断个体中的癌症或升高的未来癌症发生风险或预测癌症的转移或预后的方法,其包括使来自个体的生物样本与根据权利要求1至14中任一者所述的抗-EGFL6抗体接触,定量所述样本中的EGFL6抗原与所述抗体的结合,及比较所述结合与代表在来自未患有癌症的对照个体的样本中所测定所述抗-EGFL6抗体与所述EGFL6抗原间的结合的参考值。
24.根据权利要求23所述的方法,其中所述生物样本系细胞、组织、器官、器官样本、组织生检、血液、血浆、血清、腹水液、淋巴球、尿、骨髓液、淋巴液、唾液、泪液、黏液、羊水或其组合。
25.一种监测已经诊断患有癌症的个体中的癌症进展的方法,其包括藉由根据权利要求1至14中任一者所述的抗-EGFL6抗体,在自经诊断患有癌症的个体获得的第一生物样本中测定EGFL6或其片段的第一含量;及在预定时间段之后,藉由根据权利要求1至14中任一者所述的抗-EGFL6抗体,在自所述个体获得的第二生物样本中测定EGFL6或其片段的第二含量;比较EGFL6或其片段的所述第一含量及所述第二含量;其中所述第二样本的EGFL6或其片段的含量高于所述第一样本时,即指示疾病进展及恶化。
26.一种用于检测或诊断个体中的癌症或升高的未来癌症发生风险、或预测癌症的转移或预后、或监测癌症进展的套组,其包括根据权利要求1至14中任一者所述的抗-EGFL6抗体。
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