CN113710321A - 用于治疗癌症的方法和组合物 - Google Patents
用于治疗癌症的方法和组合物 Download PDFInfo
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Abstract
本发明涉及用于在有此需要的受试者中治疗癌症的组合物和方法。本发明更具体地涉及通过在有此需要的受试者中抑制PLA2GIB来治疗癌症的方法。
Description
技术领域
本发明涉及用于在有此需要的受试者中治疗癌症的组合物和方法。本发明更具体地涉及通过在有此需要的受试者中抑制PLA2GIB来治疗癌症的方法。
背景技术
IB组胰腺分泌型磷脂酶A2(PLA2-GIB)是一种低分子量(14kD)、高度稳定(7个二硫键)的分泌蛋白,其催化磷脂的sn-2脂肪酰基键的水解,以释放游离脂肪酸和溶血磷脂质(Lambeau&Gelb 2008)。发明人将PLA2-GIB鉴定为参与HIV感染患者中CD4 T失活(WO2015/097140)。
通过继续研究,发明人已经发现癌症患者中存在PLA2-GIB辅因子。发明人已经示出,此类辅因子与PLA2-GIB一起诱导癌症患者中免疫细胞的失活,从而允许肿瘤逃避免疫应答。发明人已经进一步示出,抑制PLA2-GIB可以恢复有效的免疫应答,并且因此有效地有助于癌症治疗。
发明内容
本发明的目的涉及一种用于在受试者中治疗癌症的方法,其包含将该受试者暴露于抑制PLA2-GIB的化合物。
本发明的进一步目的涉及一种抑制PLA2-GIB的化合物,其用于在受试者中治疗癌症的用途。
本发明的进一步目的涉及抑制PLA2-GIB的化合物用于制造药物的用途,该药物用于在受试者中治疗癌症。
抑制PLA2-GIB的化合物可以单独使用,或者与一种或多种其它治疗(如进一步的抗癌剂、手术、疫苗、放射疗法、超声疗法或PLA2-GIB辅因子的抑制剂)组合使用。
本发明可以用于治疗任何肿瘤或癌症,如特别是胰腺癌(pancreatic cancer)、黑色素瘤(melanoma)、肺癌、食管癌或咽喉癌、视网膜母细胞瘤、肝癌、乳腺癌、卵巢癌、肾癌、胃癌、十二指肠癌、子宫癌、宫颈癌、甲状腺癌、膀胱癌、前列腺癌、骨癌、脑癌或结直肠癌。本发明可以用于任何哺乳动物,特别是人类受试者。
附图说明
图1:与对照队列(cohort)相比,来自PDAC队列的血浆中PLA2-GIB浓度(前、活性和总计)的确定。
图2:PDAC血浆对来自健康供体的CD4 T细胞的IL-7应答的体外影响(A)。PLA2-GIB抑制剂的影响(B)。
图3:PDAC血浆对来自健康供体的CD4 T细胞的IL-2应答的体外影响(A)。PLA2-GIB抑制剂的影响(B)。
具体实施方式
本发明涉及用于在有此需要的受试者中治疗癌症和瘤形成(neoplasia)的组合物和方法。
定义
如本文所用,“治疗”或“处理”是指试图改变接受治疗的个体的自然病程的临床干预,并且可以出于预防或治愈目的而进行。癌症治疗的期望效果包括但不限于预防癌症的发生或复发、减轻症状、预防和治疗转移、降低或减缓癌症进展(的速度)、改善或缓和癌症状态、导致或允许癌症缓解、或者导致或诱导癌细胞破坏、或者为其它抗癌疗法提供协同效应。治疗还涵盖癌症发展中的任何延缓。
“受试者”是指哺乳动物。哺乳动物的实例包括人和非人动物,如但不限于家畜(例如牛、棉羊、猫、狗和马)、非人灵长类动物(如猴)、兔和啮齿动物(例如,小鼠和大鼠)。本发明特别适合于治疗人。
如本文所用,术语“分离的”是指从其自然环境的组分中取出、分离或分开,并且至少60%不含、优选75%不含、并且最优选90%不含自然与它们相关联的其它组分的分子(例如,核酸或氨基酸)。“分离的”多肽(或蛋白质)是例如从其自然环境的组分中分离出来的、并且优选地纯化至大于90%或95%纯度的多肽,该纯度是如通过例如电泳(例如,SDS-PAGE、等电聚焦(IEF)、毛细管电泳)或色谱(例如离子交换或反相HPLC)迁移所确定的。“分离的”核酸是指从其自然环境的组分中分离出来的和/或组装在不同构建体(例如,载体、表达盒、重组宿主等)中的核酸分子。
如应用于核酸或蛋白质序列的术语“序列同一性”是指使用标准化算法(如Smith-Waterman比对(Smith and Waterman(1981)J Mol Biol 147:195-197),CLUSTALW(Thompson等人,(1994)Nucleic Acids Res 22:4673-4680))、或BLAST2(Altschul等人,(1997)Nucleic Acids Res 25:3389-3402)比对的至少两个序列之间的核苷酸或氨基酸残基匹配的量化(通常为百分比)。BLAST2可以以标准化和可重现的方式用于在序列之一中插入缺口,以便优化比对并在它们之间实现更有意义的比较。
PLA2-GIB
如本文所用,“PLA2-GIB”(或“PLA2GIB”或“GIBsPLA2”)表示IB组胰腺磷脂酶A2。PLA2-GIB已从各种哺乳动物物种中鉴定并克隆出来。人PLA2-GIB蛋白公开在例如Lambeau和Gelb(2008)中。其序列可在Genbank No.NP_000919上获得。示例性人PLA2-GIB的氨基酸序列在下文以SEQ ID NO:1显示。
SEQ ID NO:1的氨基酸1至15(下划线)是信号序列,并且SEQ ID NO:1的氨基酸16至22(粗体)是前肽序列。PLA2-GIB的成熟形式通常通过蛋白水解切割来产生,因此没有信号序列和前肽序列。因此,PLA2-GIB的成熟形式的典型实例包含SEQ ID NO:1的氨基酸残基23-148(或基本上由其组成),如下文SEQ ID NO:2中所代表的。
在本发明的背景下,术语“PLA2-GIB”优选地表示以其任何形式(前形式或成熟形式)的人PLA2-GIB、以及其变体,如因多态性或剪接而导致的任何自然变体。
在特定的实施方案中,术语“PLA2-GIB”表示包含SEQ ID NO:1或2的人PLA2-GIB以及因多态性或剪接而导致的自然变体。
参考蛋白质的天然存在的变体与所述参考蛋白质相比包括具有一个或若干(通常为1、2或3个)氨基酸残基的一个或多个氨基酸取代、添加和/或缺失的任何蛋白质。优选地,与参考蛋白质相比,变体包括一个或若干(通常为1、2或3个)氨基酸残基的不超过10个不同的氨基酸取代、添加和/或缺失。典型的天然存在的变体保留了参考蛋白质的生物活性。在这方面,在一些实施方案中,PLA2-GIB具有至少一种活性,其选自:在来自健康受试者的CD4T细胞中诱导膜微结构域(membrane microdomain,MD)的形成,或致使健康受试者的CD4 T细胞对白细胞介素信号传导不起反应,如对IL-2信号传导不起反应或对IL-7信号传导不起反应。
在特定的实施方案中,术语PLA2-GIB表示人蛋白质(特别是包含SEQ ID NO:1或2或者由该序列组成的蛋白质)、或其天然存在的变体。
癌症的治疗
本发明涉及用于在受试者中治疗癌症的方法,其包含将抑制PLA2-GIB的化合物施用于该受试者。发明人已经示出,PLA2-GIB辅因子存在于癌症患者中,该辅因子与PLA2-GIB一起诱导免疫细胞的失活。发明人已经进一步示出,抑制PLA2-GIB可以在所述患者的血浆中恢复有效的免疫应答,并且因此有效地有助于癌症治疗。
在特定的实施方案中,本发明涉及用于在有此需要的受试者中治疗癌症或瘤形成的方法,其包含将抑制PLA2-GIB的化合物施用于该受试者。
本发明还涉及一种抑制PLA2-GIB的化合物,其用于在有此需要的受试者中治疗癌症或瘤形成的用途。
在特定的实施方案中,本发明的方法用于在有此需要的受试者(如处于瘤形成或癌症风险中的受试者)中预防癌症或降低癌症发生率。在这方面,本发明可以用于治疗癌症的风险因素,从而避免或降低癌症的风险/发生率。此类风险因素包括但不限于口腔、胃和/或肠道炎症和感染,如胰腺炎。
本发明还涉及一种抑制PLA2-GIB的化合物,其用于在有此需要的受试者中预防癌症或降低癌症发生率的用途。
在另一个特定的实施方案中,本发明的方法用于在患有癌症的受试者中降低癌症进展率。
在另一个特定的实施方案中,本发明涉及一种抑制PLA2-GIB的化合物,其用于在患有癌症的受试者中降低癌症进展率的用途。
在另一个特定的实施方案中,本发明的方法用于在患有癌症的受试者中降低或预防或治疗癌症转移,或者用于杀死癌细胞。
在另一个特定的实施方案中,本发明涉及一种抑制PLA2-GIB的化合物,其用于在患有癌症的受试者中降低或预防或治疗癌症转移的用途,或者用于在患有癌症的受试者中杀死癌细胞的用途。
发明人已经分析了患有实体瘤(如胰腺癌)的患者的若干队列。已经发现,与来自健康供体的血浆相比,来自所述患者的血浆中PLA2-GIB水平在统计学上没有差异。然而,令人惊讶地,他们发现了来自所述患者的血浆可以致使免疫细胞对由生理浓度的PLA2-GIB引起的失活敏感。更具体地,通过将T细胞暴露于来自所述癌症患者的血浆以及PLA2-GIB,所述免疫细胞变得无活性并且无法启动免疫应答。因此,所述患者的血浆含有一种或多种辅因子,其致使免疫细胞对PLA2-GIB失活敏感。发明人已经进一步示出,通过抑制PLA2-GIB,所述免疫细胞得以恢复并且不发生此类失活。
因此,本发明展示了人类癌症患者的血浆中存在PLA2-GIB辅因子。
本发明进一步展示了PLA2-GIB抑制可以用于治疗此类癌症。
在这方面,本发明可以用于治疗任何癌症。
在特定的实施方案中,癌症是实体癌。
在特定的实施方案中,该方法用于治疗患有癌症并表达PLA2-GIB辅因子的受试者。在优选的实施方案中,该方法用于在受试者中治疗癌症,其中PLA2-GIB辅因子或者表达PLA2-GIB辅因子的原核或真核细胞或病毒存在于所述受试者中。
在另一个特定的实施方案中,该方法用于治疗患有癌症的受试者,其中PLA2-GIB或PLA2-GIB辅因子存在于癌症微环境或血液中。
本发明还特别适合于在具有PLA2GIB相关CD4 T细胞缺陷的受试者中治疗癌症或瘤形成。
本发明可以用于治疗处于任何发展阶段的癌症。在这方面,大多数实体癌经由四个阶段形成:
.阶段I.该阶段通常是小的癌症或肿瘤,其尚未生长得深入至附近的组织中。其也尚未扩散至淋巴结或身体的其它部位。其通常称为早期癌症。
.阶段II和阶段III.一般而言,这2个阶段指示较大的癌症或肿瘤,其已经生长得更深入至附近的组织中。其也可能已经扩散至淋巴结,但尚未扩散至身体的其它部位。
.阶段IV.该阶段意味着癌症已经扩散至身体的其它器官或部位。其也可以称为晚期或转移性癌症。
一些癌症还具有阶段0。阶段0癌症仍然位于它们开始的地方,并且尚未扩散至附近的组织。该阶段的癌症通常是高度可治愈的,通常是通过手术去除整个肿瘤。
本发明可以用于治疗处于阶段0、I、II、III或IV的肿瘤或癌症。
本发明可以用于预防或减少或治疗处于阶段0、I、II或III的癌症的转移。
本发明可以用于降低处于阶段0、I、II或III的癌症的进展速率。
本发明可以特别用于治疗实体癌,其选自胰腺癌、黑色素瘤、肺癌、食管癌或咽喉癌、视网膜母细胞瘤、肝癌、乳腺癌、卵巢癌、肾癌、胃癌、十二指肠癌、子宫癌、宫颈癌、甲状腺癌、膀胱癌、前列腺癌、骨癌、脑癌或结直肠癌。
在具体的实施方案中,本发明的方法用于治疗胰腺癌。胰腺癌是根据胰腺的哪个部分受到影响来进行分类的:使消化物质导致外分泌癌的部分,使胰岛素和其它激素导致内分泌癌的部分。尽管有若干不同类型的胰腺癌,但是95%的病例归因于外分泌癌(胰腺导管腺癌(PDAC))。
PDAC在癌症导致的主要死因中排名第四。研究人员预测,到2030年,PDAC将成为美国癌症相关死亡的第二大最主要原因。30年来,发病率已经翻了一倍多,目前每年增加5%。5年相对存活率为大约5%,并且外科手术是治疗PDAC的最有效的选项。诊断方法的利用度有限,以及手术作为唯一现有的治愈选项仅具有10%诊断患者的存活可能性,这都增加了该疾病的可怕性。该疾病的不良预后可以通过缺乏用于筛选和早期检测的有效生物标志物以及侵袭性行为和对目前可用化学疗法的抗性来解释。
本发明示出了PLA2-GIB抑制可以用于治疗胰腺癌。本发明代表一种防止胰腺癌进展和转移的新策略。本发明可以用于任何类型/阶段的胰腺癌,如胰腺腺癌、神经内分泌肿瘤、导管内乳头状粘液性新生物、粘液性囊性新生物和严重囊性新生物。本发明特别适合于治疗处于任何阶段的胰腺腺癌。
本发明还特别适合于治疗结直肠癌、肺癌以及快速生长的癌症。结直肠癌是所有性别中最常见的癌症之一。在所有阶段,5年存活概率为约55%。(Bossard N,2007)。事实上,在法国、日本、美国、德国、意大利、西班牙和英国,2010年确诊的直肠癌新病例超过180,000例。结直肠癌分为四个阶段:阶段I,其为进行性最小的,并且主要通过手术来治疗;阶段II和III,在这两个阶段,患者接受组合放射化学疗法(RCT);以及阶段IV,其为非常晚期和转移阶段。当患者诊断出患有局部晚期(阶段II或III)结直肠癌时,患者通常在手术切除前接受RCT治疗。本发明适合于治疗阶段I、II、III和IV结直肠癌。本发明特别适合于治疗处于阶段II、III或IV的结直肠癌。
本发明还适合于治疗诱发胃肠道病状和代谢病状的癌症。
为了用于本发明,可以通过任何合适的途径来施用PLA2-GIB抑制剂。优选地,通过注射施用,如全身性或胃肠外注射或灌注,例如,肌内、静脉内、动脉内、皮下、肿瘤内等。施用通常是重复的或连续的。在特定的实施方案中,在治疗过程期间测量肿瘤或体液中PLA2-GIB或PLA2-GIB辅因子的水平,以指导治疗方案。
PLA2-GIB抑制剂可以单独使用,或者与进一步的癌症治疗组合使用。
在特定的实施方案中,本发明涉及一种用于在受试者中治疗癌症的方法,其包含将抑制PLA2-GIB的化合物与化学疗法或激素疗法组合施用于患有癌症的受试者。
在另一个特定的实施方案中,本发明涉及一种用于在受试者中治疗癌症的方法,其包含将抑制PLA2-GIB的化合物与放射化学疗法、超声疗法或纳米颗粒疗法组合施用于患有癌症的受试者。
在另一个特定的实施方案中,本发明涉及一种用于在受试者中治疗癌症的方法,其包含将抑制PLA2-GIB的化合物与检查点抑制剂、免疫疗法或抗癌疫苗组合施用于患有癌症的受试者。
在另一个特定的实施方案中,本发明涉及一种用于在受试者中治疗癌症的方法,其包含将抑制PLA2-GIB的化合物与PLA2-GIB辅因子的抑制剂组合施用于患有癌症的受试者。PLA2-GIB辅因子的抑制剂可以是所述辅因子的拮抗剂,或者是针对所述PLA2-GIB辅因子或针对表达所述PLA2-GIB辅因子的原核或真核细胞或病毒的细胞抑制剂或细胞毒性剂或疫苗。在这方面,在辅因子是细菌的情况下,抑制剂可以是针对所述细菌的抗生素。
在“组合”疗法中,多种活性剂可以同时或序贯、一起或交替使用。可以根据具体的时间表来使用每种活性剂。在其它例子中,所有活性剂可以一起配制和/或施用,如在灌注中。
在进一步的实施方案中,化合物在手术(肿瘤切除或去除)之前、期间或之后施用。
用于本发明的化合物可以配制成药物组合物,其包含一种或多种药物上可接受的载体。
“药物组合物”是指本发明的化合物(活性成分)与本领域普遍接受的介质的配制剂,该介质用于将生物活性化合物递送至有此需要的受试者。此种载体包括所有药物上可接受的载体、稀释剂、介质或其支持物。可以采用常规的药物实践来向受试者提供合适的配制剂或组合物,例如以单位剂型。
根据本发明的化合物或组合物可以配制成以下形式:软膏剂、凝胶、糊剂、液体溶液、悬浮液、片剂、明胶胶囊剂、胶囊剂、栓剂、粉剂、滴鼻剂或气雾剂,优选地配制成注射溶液或悬浮液的形式。例如,对于注射剂,化合物通常包装成液体悬浮液的形式,其可以通过注射器或灌注来注入。在这方面,通常将化合物溶解在与药物用途相容且本领域技术人员已知的盐水、生理、等渗或缓冲的溶液中。因此,组合物可以含有一种或多种试剂或赋形剂,其选自分散剂、增溶剂、稳定剂、防腐剂等。可以用于液体和/或注射用配制剂的试剂或赋形剂尤其是甲基纤维素、羟甲基纤维素、羧甲基纤维素、聚山梨醇酯80、甘露醇、明胶、乳糖、植物油、阿拉伯胶等。载体还可以选自例如甲基-β-环糊精、丙烯酸的聚合物(如卡波姆(carbopol))、聚乙二醇和聚丙二醇的混合物、单乙醇胺和羟甲基纤维素。
组合物通常包含约1μg至1000mg的PLA2-GIB抑制剂,如0.001-0.01、0.01-0.1、0.05-100、0.05-10、0.05-5、0.05-1、0.1-100、0.1-1.0、0.1-5、1.0-10、5-10、10-20、20-50和50-100mg,例如在0.05至100mg之间,优选在0.05至5mg之间,例如0.05、0.1,0.2、0.3、0.4、0.5、1、2、3、4或5mg。熟练技术人员可以根据调节剂和疾病来调整剂量。
组合物可以配制成任何合适的形式或配制在任何合适的容器(注射器、安瓿、烧瓶、瓶、小袋等)中。
在优选的实施方案中,治疗包含一次或若干次注射含有PLA2-GIB抑制剂的液体配制剂,任选地与一种或多种抗癌剂或治疗组合。注射优选地是全身性的,如静脉内、动脉内、肌内、癌内、皮内等。
从业人员可以调整施用的剂量和频率。
PLA2-GIB的抑制剂
适用于本发明的PLA2-GIB抑制剂可以是抑制或中和PLA2-GIB的表达或活性的任何化合物,如表达抑制剂、拮抗剂或隔离剂(sequestrator)。抑制剂的优选类型包括PLA2-GIB配体(共价或非共价)、抗PLA2-GIB抗体(及其片段和衍生物)、编码抗PLA2-GIB抗体(或其片段和衍生物)的核酸、抑制性核酸、肽或小药物、可溶性受体或其组合。替代地或另外,PLA2-GIB抑制剂可以是PLA2-GIB抗原,其在施用于受试者后诱导抗PLA2GIB抗体的产生。
抑制PLA2-GIB通常表示将PLA2-GIB水平或活性降低10%、20%、30%、40%、50%、60%、70%、80%或更多,以及完全阻断或抑制PLA2-GIB水平或活性。根据情况,抑制可以是短暂的、持续的或永久性的。
针对PLA2-GIB的抗体
PLA2-GIB抑制剂的具体实例是抗PLA2-GIB抗体,例如,结合至PLA2-GIB和/或通过用PLA2-GIB抗原免疫哺乳动物生成的抗体。
抗体可以是合成的、单克隆的或多克隆的,并且可以通过本领域众所周知的技术来制备。此类抗体通过抗体的抗原结合位点特异性结合(与非特异性结合相反)。PLA2-GIB多肽、片段、变体、融合蛋白等可以用作产生与其免疫反应的抗体的免疫原。更具体地,多肽、片段、变体、融合蛋白等含有引发抗体形成的抗原决定簇或表位。
术语“抗体”旨在包括多克隆抗体、单克隆抗体、其片段(如F(ab')2和Fab片段、单链可变片段(scFv)、单结构域抗体片段(VHH或纳米抗体)、二价抗体片段(双抗体)),以及任何重组和合成产生的结合配偶体、人抗体或人源化抗体。
优选地,如果抗体以大于或等于约107M-1的Ka结合至PLA2-GIB,则抗体定义为特异性结合。使用常规技术可以容易地确定抗体的亲和力,例如使用由Scatchard等人,Ann.N.Y.Acad.Sci.,51:660(1949)描述的那些技术。
使用本领域众所周知的程序,可以容易地从多种来源(例如,马、牛、驴、山羊、绵羊、狗、鸡、兔、小鼠或大鼠)中生成多克隆抗体。一般而言,通常通过胃肠外注射,将纯化的PLA2-GIB或适当缀合的基于PLA2-GIB氨基酸序列的肽施用于宿主动物。可以通过使用佐剂(例如,弗氏完全佐剂或不完全佐剂)来增强PLA2-GIB的免疫原性。在加强免疫之后,收集少量血清样品并测试对PLA2-GIB多肽的反应性。可用于此类确定的各种测定的实例包括Antibodies:A Laboratory Manual,Harlow and Lane(编),Cold Spring HarborLaboratory Press,1988中所描述的那些;以及程序,如逆流免疫电泳(CIEP)、放射免疫测定、放射免疫沉淀、酶联免疫吸附测定(ELISA)、斑点印迹测定和夹心测定。参见美国专利号4,376,110和4,486,530。
使用众所周知的程序可以容易地制备单克隆抗体。参见,例如,美国专利号RE 32,011、4,902,614、4,543,439和4,411,993;Monoclonal Antibodies,Hybridomas:A NewDimension in Biological Analyses,Plenum Press,Kennett,McKeam,and Bechtol(编),1980中所描述的程序。
例如,可以任选地在佐剂的存在下,以约3周的间隔,用分离的和纯化的野生型或突变型PLA2-GIB蛋白或者缀合的PLA2-GIB肽腹膜内地注射宿主动物(如小鼠)至少一次且优选至少两次。然后通过常规的斑点印迹技术或抗体捕获(ABC)来测定小鼠血清,以确定哪种动物最适合融合。大约两至三周后,对小鼠给予蛋白质或肽的静脉内加强。随后按照既定方案,处死小鼠,并且将脾细胞与市售骨髓瘤细胞(如Ag8.653(ATCC))融合。简而言之,将骨髓瘤细胞在培养基中洗涤若干次并将其以约三个脾细胞对一个骨髓瘤细胞的比例融合至小鼠脾细胞。融合剂可以是本领域中所使用的任何合适的试剂,例如聚乙二醇(PEG)。将融合物铺板在含有允许所融合的细胞选择性生长的培养基的平板中。然后可以允许所融合的细胞生长大约八天。收集来自所得杂交瘤的上清液并将其添加至首先涂覆有山羊抗小鼠Ig的平板中。洗涤后,将标记物(如标记的PLA2-GIB多肽)添加至每孔中,然后进行孵育。随后可以检测到阳性孔。阳性克隆可以以大量培养(bulk culture)的方式生长,随后将上清液在蛋白A柱(Pharmacia)上进行纯化。
可以使用替代技术来产生本公开的单克隆抗体,如使用由Alting-Mees等人,“Monoclonal Antibody Expression Libraries:A Rapid Alternative to Hybridomas”,Strategies in Molecular Biology 3:1-9(1990)描述的那些技术,其通过引用并入本文。类似地,可以使用重组DNA技术来构建结合配偶体,以掺入编码特异性结合抗体的基因的可变区。此种技术描述在Larrick等人,Biotechnology,7:394(1989)中。
可以通过常规技术产生的此类抗体的抗原结合片段也涵盖在本发明中。此类片段的实例包括但不限于Fab和F(ab')2片段。还提供了通过遗传工程技术产生的抗体片段和衍生物。
单克隆抗体包括嵌合抗体,例如,鼠单克隆抗体的人源化版本。此类人源化抗体可以通过已知技术制备,并且在将抗体施用于人时提供降低免疫原性的优点。在一个实施方案中,人源化单克隆抗体包含鼠抗体的可变区(或仅其抗原结合位点)和衍生自人抗体的恒定区。替代地,人源化抗体片段可以包含鼠单克隆抗体的抗原结合位点和衍生自人抗体的可变区片段(缺乏抗原结合位点)。用于产生嵌合抗体和进一步经工程化改造的单克隆抗体的程序包括描述在以下中的那些程序:Riechmann等人,(Nature 332:323,1988);Liu等人,(PNAS 84:3439,1987);Larrick等人,(Bio/Technology 7:934,1989);以及Winter andHarris(TIPS 14:139,May,1993)。用于转基因生成抗体的程序可以见于GB 2,272,440、美国专利号5,569,825和5,545,806。
可以使用通过遗传工程方法产生的包含人和非人部分二者的抗体如嵌合和人源化单克隆抗体,其可以使用标准重组DNA技术来制造。可以使用本领域已知的标准DNA技术,通过遗传工程来产生此类嵌合和人源化单克隆抗体,例如使用描述在以下中的方法:Robinson等人,国际公开号WO 87/02671;Akira等人,欧洲专利申请0184187;Taniguchi,M.,欧洲专利申请0171496;Morrison等人,欧洲专利申请0173494;Neuberger等人,PCT国际公开号WO 86/01533;Cabilly等人,美国专利号4,816,567;Cabilly等人,欧洲专利申请0125023;Better等人,Science 240:1041 1043,1988;Liu等人,PNAS 84:3439 3443,1987;Liu等人,J.Immunol.139:3521 3526,1987;Sun等人,PNAS 84:214 218,1987;Nishimura等人,Canc.Res.47:999 1005,1987;Wood等人,Nature 314:446 449,1985;以及Shaw等人,J.Natl.Cancer Inst.80:1553 1559,1988);Morrison,S.L.,Science 229:1202 1207,1985;Oi等人,BioTechniques 4:214,1986;Winter美国专利号5,225,539;Jones等人,Nature 321:552 525,1986;Verhoeyan等人,Science 239:1534,1988;以及Beidler等人,J.Immunol.141:4053 4060,1988。
关于合成和半合成抗体,此类术语旨在覆盖但不限于抗体片段、同种型转换抗体、人源化抗体(例如,小鼠-人、人-小鼠)、杂合物、具有多种特异性的抗体、以及全合成抗体样分子。
可以通过对含有人免疫球蛋白基因的转基因动物进行免疫来生成具有人恒定区和可变区的人单克隆抗体。参见Jakobovits等人,Ann NY Acad Sci 764:525-535(1995)。还可以使用从衍生自受试者淋巴细胞的mRNA制备的免疫球蛋白轻链和重链cDNA,通过构建组合免疫球蛋白文库(如Fab噬菌体展示文库或scFv噬菌体展示文库)来制备针对PLA2-GIB多肽的人单克隆抗体。参见,例如,McCafferty等人,PCT公开文本WO 92/01047;Marks等人,(1991)J.Mol.Biol.222:581 597;以及Griffths等人,(1993)EMBO J 12:725734。另外,可以通过对已知的人抗体进行突变来产生抗体可变区的组合文库。例如,可以通过例如使用随机改变的诱变寡核苷酸来突变已知结合PLA2-GIB的人抗体的可变区,以生成突变可变区的文库,然后可以筛选该文库以结合至PLA2-GIB。在免疫球蛋白重链和/或轻链的CDR区内诱导随机诱变的方法、将随机化重链和轻链进行杂交以形成配对的方法、以及筛选方法可以见于例如Barbas等人,PCT公开文本WO 96/07754;Barbas等人,(1992)Proc.Nat'lAcad.Sci.USA 89:4457 4461。
免疫球蛋白文库可以由展示包装(优选地衍生自丝状噬菌体)群来表达,以形成抗体展示文库。特别适合用于生成抗体展示文库的方法和试剂的实例可以见于例如Ladner等人,美国专利号5,223,409;Kang等人,PCT公开文本WO 92/18619;Dower等人,PCT公开文本WO 91/17271;Winter等人,PCT公开文本WO 92/20791;Markland等人,PCT公开文本WO 92/15679;Breitling等人,PCT公开文本WO 93/01288;McCafferty等人,PCT公开文本WO 92/01047;Garrard等人,PCT公开文本WO 92/09690;Ladner等人,PCT公开文本WO 90/02809;Fuchs等人,(1991)Bio/Technology 9:1370 1372;Hay等人,(1992)Hum AntibodHybridomas 3:81 85;Huse等人,(1989)Science 246:1275 1281;Griffths等人,(1993)见上文;Hawkins等人,(1992)J Mol Biol 226:889 896;Clackson等人,(1991)Nature 352:624 628;Gram等人,(1992)PNAS 89:3576 3580;Garrad等人,(1991)Bio/Technology 9:1373 1377;Hoogenboom等人,(1991)Nuc Acid Res 19:4133 4137;以及Barbas等人,(1991)PNAS 88:7978 7982。一旦展示在展示包装(例如,丝状噬菌体)的表面上,就筛选抗体文库以鉴定和分离表达结合PLA2-GIB多肽的抗体的包装。在优选的实施方案中,文库的初步筛选涉及用固定化PLA2-GIB多肽进行淘选,并且选择表达结合固定化PLA2-GIB多肽的抗体的展示包装。
用于本发明的优选抗体针对PLA2-GIB表位和/或已经通过用包含PLA2-GIB表位的多肽免疫来生成,该多肽选自:成熟PLA2-GIB蛋白、包含SEQ ID NO:1或2的至少8个连续氨基酸残基(或SEQ ID NO:1或2的自然变体的相应残基)的PLA2-GIB片段,所述片段优选地包含至少氨基酸70、氨基酸121、氨基酸50、氨基酸52、氨基酸54、氨基酸71或其组合(参照SEQID No:2进行编号)。
用于本发明的特定抗PLA2-GIB抗体结合成熟人PLA2-GIB,甚至更优选结合包含在PLA2-GIB的结构域中的表位,其包含选自下组的氨基酸残基:氨基酸70、氨基酸121、氨基酸50、氨基酸52、氨基酸54、氨基酸71或它们的组合(参照SEQ ID No:2进行编号)。用于本发明的特定抗体结合包含在成熟人PLA2-GIB的氨基酸残基50-71(参照SEQ ID NO:2)或SEQ IDNo:2的自然变体的相应残基之间的表位。适用于本发明的抗PLA2-GIB抗体的实例已经公开在WO2015/097140中。
用于本发明的进一步的特定抗-PLA2-GIB抗体结合包含至少一个选自人成熟PLA2-GIB的W3、R6、K7、K10、C77、Y75、G79和S80(参照SEQ ID NO:2进行编号)的氨基酸残基的表位,更优选地结合包含至少2个或至少3个选自人成熟PLA2-GIB的W3、R6、K7、K10、C77、Y75、G79和S80的氨基酸残基的表位,更进一步优选地结合包含至少4、至少5、至少6或至少7个选自人成熟PLA2-GIB的W3、R6、K7、K10、C77、Y75、G79和S80的氨基酸残基的表位。用于本发明的特定抗体结合包含在成熟人PLA2-GIB的氨基酸残基1-10或75-80(参照SEQ ID NO:2)或者SEQ ID No:2的自然变体的相应残基之间包含的氨基酸残基的表位。此类抗体表现出强有力的中和活性,并且代表用于本发明的有价值的治疗剂。适用于本发明的抗PLA2-GIB抗体的实例已经公开在目前尚未公布的EP18305229中。
在特定的实施方案中,用于本发明的抗体或衍生物是单克隆抗体14G9或抗PLA2-GIB抗体,其竞争性地抑制单克隆抗体14G9与人PLA2-GIB的结合,所述单克隆抗体14G9包含轻链可变区和重链可变区,该轻链可变区包含SEQ ID No:3,并且该重链可变区包含SEQ IDNO:4。抗体可以是人的或人源化的。
在另一个特定的实施方案中,用于本发明的抗体或衍生物是单克隆抗体#2B或抗PLA2-GIB抗体,其竞争性地抑制单克隆抗体#2B与人sPLA2-GIB的结合,所述单克隆抗体#2B包含轻链和重链,该轻链包含SEQ ID No:5或由其组成,并且该重链包含SEQ ID NO:6或由其组成。
在另一个特定的实施方案中,用于本发明的抗体或衍生物是单克隆抗体#2B1或抗PLA2-GIB抗体,其竞争性地抑制单克隆抗体#2B1与人sPLA2-GIB的结合,所述单克隆抗体#2B1包含轻链和重链,该轻链包含SEQ ID No:5或由其组成,并且该重链包含SEQ ID NO:7或由其组成。
在另一个特定的实施方案中,用于本发明的抗体或衍生物是单克隆抗体#2B2或抗PLA2-GIB抗体,其竞争性地抑制单克隆抗体#2B2与人sPLA2-GIB的结合,所述单克隆抗体#2B2包含轻链和重链,该轻链包含SEQ ID No:5或由其组成,并且该重链包含SEQ ID NO:8或由其组成。
术语“竞争性地抑制”指示抗体可以减少或抑制或置换参考抗体与sPLA2-GIB的结合。可以使用标准技术(如例如,竞争性ELISA或其它结合测定)来进行竞争测定。通常,竞争性结合测定涉及通常结合至固体基底或细胞的纯化靶抗原、未标记的测试抗体和标记的参考抗体。通过确定在测试抗体的存在下所结合的标记抗体的量来测量竞争性抑制。通常测试抗体过量存在,如参考抗体量的约5至500倍。通常,对于ELISA,测试抗体过量100X,并且对于酶法,测试抗体过量10X。当过量存在的测试抗体抑制或置换参考抗体与抗原的结合的至少70%时,其被认为是竞争性地抑制所述参考抗体。在具体的实施方案中,在ELISA中,当以100X过量存在的测试抗体抑制或置换参考抗体与抗原的结合的至少70%、更优选至少80%时,其被认为是竞争性地抑制所述参考抗体。优选的竞争抗体结合共享共同氨基酸残基的表位。
在特定的实施方案中,抑制剂是单克隆抗体,其包含:
(i)轻链可变区,其包含CDR-L1、CDR-L2、CDR-L3和FR-L,其中该CDR-L1、CDR-L2和/或CDR-L3分别由或基本上分别由SEQ ID NO:3或5的轻链可变区的CDR-L1、CDR-L2和CDR-L3组成,并且其中FR-L是人免疫球蛋白序列的;以及
(ii)重链可变区,其包含CDR-H1、CDR-H2、CDR-H3和FR-H,其中该CDR-H1、CDR-H2和/或CDR-H3分别由或基本上分别由SEQ ID NO:4、6、7或8的重链可变区的CDR-H1、CDR-H2和CDR-H3组成,并且其中FR-H是人免疫球蛋白序列的。
抗体的“可变区”是指重链或轻链(“VH”或“VL”)的氨基端结构域,其含有抗原结合位点。轻链或重链可变区(VL或VH)通常由以三个称为“互补决定区”或“CDR”的高变区中断的框架区(“FR”)组成。已经例如在Kabat中(参见“Sequences of Proteins ofImmunological Interest,”E.Kabat等人,U.S.Department of Health and HumanServices,(1983))、以及在Chothia中对框架区和CDR的程度进行了精确的定义。
参考SEQ ID NO:3,三个CDR区对应于以下氨基酸残基:
.CDR-L1:氨基酸残基QDVSTA(SEQ ID NO:3的残基27-31),
.CDR-L2:氨基酸残基WAS(SEQ ID NO:3的残基50-52),
.CDR-L3:氨基酸残基QQDYSTPPT(SEQ ID NO:3的残基89-97),
参考SEQ ID NO:4,三个CDR区对应于以下氨基酸残基:
.CDR-H1:氨基酸残基GYTFTNYW(SEQ ID NO:4的残基26-33),
.CDR-H2:氨基酸残基IDPSDTRT(SEQ ID NO:4的残基51-58),
.CDR-H3:氨基酸残基ARQTLYYEALDY(SEQ ID NO:4的残基97-108)。
在特定的实施方案中,本发明涉及单克隆抗体,其选自:
.单克隆抗体(14G9),其包含轻链和重链,该轻链包含SEQ ID NO:3、基本上由其组成或由其组成,并且该重链包含SEQ ID NO:4、基本上由其组成或由其组成;
.单克隆抗体(#2B),其包含轻链和重链,该轻链包含SEQ ID NO:5、基本上由其组成或由其组成,并且该重链包含SEQ ID NO:6、基本上由其组成或由其组成;
.单克隆抗体(#2B1),其包含轻链和重链,该轻链包含SEQ ID NO:5、基本上由其组成或由其组成,并且该重链包含SEQ ID NO:7、基本上由其组成或由其组成;
.单克隆抗体(克隆#2B2),其包含轻链和重链,该轻链包含SEQ ID NO:5、基本上由其组成或由其组成,并且该重链包含SEQ ID NO:8、基本上由其组成或由其组成;以及
.其衍生物。
如本文所用,术语“抗体衍生物”是指保留了参考抗体的抗原特异性但其中一个或多个氨基酸残基进行(化学或生物学)修饰以改善其特性的抗体。
此类化学修饰的例子包括例如通过烷基化、聚乙二醇化、酰化、酯或酰胺形成等。特别地,衍生物是一种如本文公开的抗体,其经修饰以含有一个或多个额外的非蛋白质部分,如水溶性聚合物。水溶性聚合物的实例包括但不限于PEG、乙二醇/丙二醇的共聚物、羧甲基纤维素、葡聚糖和聚乙烯醇。
还可以生成衍生物以增加或降低抗体糖基化的程度。可以通过改变氨基酸序列,使得创建或去除一个或多个糖基化位点来方便地实现对抗体添加或删除糖基化位点。在抗体包含Fc区的情况下,可以改变与其附接的碳水化合物。由哺乳动物细胞产生的天然抗体通常包含支化双触角寡糖,其通常通过N连接附接于Fc区的CH2结构域的Asn297(参见例如Wright等人,TIBTECH,1997,15:26-32)。寡糖可以包括各种碳水化合物,例如,甘露糖、N-乙酰葡糖胺(GlcNAc)、半乳糖和唾液酸、以及双触角寡糖结构的“茎”中附接至GlcNAc的岩藻糖。在一些实施方案中,可以对本发明的抗体中的寡糖进行修饰,以创建具有某些改进特性的抗体变体。
在一个实施方案中,提供了具有碳水化合物结构的抗体变体,该碳水化合物结构缺少附接(直接地或间接地)至Fc区的岩藻糖。例如,此类抗体中岩藻糖的量可以为1%至80%、1%至65%、5%至65%或20%至40%)。如通过MALDI-TOF质谱法所测量的,相对于附接至Asn297的所有糖结构(例如,复杂、杂合和高甘露糖结构)的总和,通过计算Asn 297处的糖链内岩藻糖的平均量来确定岩藻糖的量。Asn297是指位于Fc区中大致位置297处的天冬酰胺残基(Fc区残基的Eu编号);然而,由于抗体中轻微的序列变异,Asn297也可能位于位置297上游或下游的约±3个氨基酸处,即位置294与300之间。与“去岩藻糖基化”或“岩藻糖缺乏”抗体变体相关的出版物的实例包括但不限于Okazaki等人,J.Mol.Biol.336:1239-1249(2004)以及Yamane-Ohnuki N,Satoh M.mAbs.2009;1:230-236。能够产生去岩藻糖基化抗体的细胞系的实例包括缺乏蛋白质岩藻糖基化的Led 3CHO细胞(Ripka等人,Arch.Biochem.Biophys.249:533-545(1986))以及敲除细胞系,如α-1,6-岩藻糖基转移酶基因、FUT8、敲除CHO细胞(参见例如Yamane-Ohnuki等人,Biotech.Bioeng.87:614(2004);Kanda,Y.等人,Biotechnol.Bioeng.,94(4):680-688(2006))。
在某些实施方案中,可能期望创建半胱氨酸工程化抗体(例如,“thioMAb”),其中抗体的一个或多个残基被半胱氨酸残基取代。在特定的实施方案中,取代的残基存在于抗体的可接近位点处。通过用半胱氨酸取代那些残基,反应性硫醇基团由此定位在抗体的可接近位点处,并且可以用于将抗体缀合至其它部分(如药物部分或接头-药物部分),以创建免疫缀合物,如本文进一步所描述的。在某些实施方案中,以下残基中的任何一个或多个可以被半胱氨酸取代:轻链的V205(Kabat编号);重链的A118(EU编号);以及重链Fc区的S400(EU编号)。可以生成半胱氨酸工程化抗体,如例如美国专利号7,521,541中所描述的。
术语衍生物还包括免疫缀合物,其包含缀合至一个或多个异源性分子;或固体支持物,如琼脂糖珠或类似物的如上文所定义的抗sPLA2-GIB抗体,所述异源性分子包括但不限于细胞毒性剂、可检测部分(如荧光部分)、诊断放射性同位素或显像剂。细胞毒性剂的实例包括但不限于化学治疗剂或药物、生长抑制剂、毒素(例如,蛋白质毒素;细菌、真菌、植物或动物来源的酶活性毒素;或其片段)或放射性同位素。可以使用熟练技术人员众所周知的多种双功能蛋白质偶联剂来制备抗体与细胞毒性剂的缀合物。接头可以是“可切割的接头”,其促进细胞毒性药物在细胞中的释放。例如,可以使用酸不稳定性接头、肽酶敏感性接头、光不稳定性接头、二甲基接头或含二硫化物的接头(Chari等人,Cancer Res.52:127-131(1992))。
用于本发明的抗体通常是“分离的”,例如,已经从其自然环境的至少一个组分中分离出来。具体地,可以将抗体纯化至较高(例如,至少95%、至少96%;至少97%、至少98%或至少99%)纯度,如通过例如电泳(例如,SDS-PAGE、等电聚焦(IEF)、毛细管电泳)或色谱(例如,离子交换或反相HPLC)技术所确定的。关于用于评估抗体纯度的方法的综述,参见,例如,Flatman等人,J.Chromatogr.B 848:79-87(2007)。
本发明的优选抗体基本上是中和抗体,即,它们能够至少部分地抑制PLA2-GIB的活性。
sPLA2 GIB催化磷脂的sn-2脂肪酰基键的水解,以释放游离脂肪酸和溶血磷脂质。本发明的特定抗体抑制sPLA2-GIB的酶活性,如磷脂的sn-2脂肪酰基键的水解。用于测试此种特性的方法详细地公开在实验部分中。用于本发明的特定抗体抑制sPLA2-GIB与其底物的结合。用于本发明的进一步的特定抗体抑制sPLA2-GIB介导的对CD4 T细胞中IL-7诱导的磷酸STAT5核移位的抑制。用于测试此种特性的方法详细地公开在实验部分中。
可以使用例如结合或生物测定(如实验部分所描述的测试)在体外或体内确定抗体或衍生物的中和活性。抑制/中和可以是完全的或部分的。具体地,抗体可以抑制10%或更多的所测试活性,优选20%或更多、30%或更多、40%或更多、50%或更多。
在优选的实施方案中,抗体是IgG,例如,gG1、IgG2、IgG3或IgG4。
可以使用常规方法和介质来分离和保存抗体或衍生物。它们可以是冻干的。它们也可以是冷冻的。
编码重组抗体的核酸、载体和宿主细胞
在另一方面,PLA2-GIB抑制剂为以下各项或包含以下各项或由以下各项组成:编码抗PLA2-GIB抗体、或其轻链或重链、或其可变结构域的核酸分子;或与所述编码序列互补的核酸。
核酸可以是DNA(cDNA或gDNA)、RNA或其混合物。它可以是单链形式或双链体形式或两者的混合形式。它可以包含经修饰的核苷酸,其包含例如经修饰的键、经修饰的嘌呤或嘧啶碱基、或经修饰的糖。它可以通过本领域技术人员已知的任何方法来制备,这些方法包括化学合成、重组和诱变。可以从根据本发明的抗体的序列中推断出根据本发明的核酸,并且可以根据应当转录核酸的宿主细胞来调整密码子选择。可以根据本领域技术人员众所周知的方法来进行这些步骤,并且其中一些方法描述在参考手册Sambrook等人,(SambrookJ,Russell D(2001)Molecular cloning:a laboratory manual,第三版Cold SpringHarbor)中。
核酸可以编码包含轻链的氨基酸序列和/或包含抗体重链的氨基酸序列,或者可以与此类编码序列互补。
此类核酸序列的具体实例包括以SEQ ID NO:9-12提供的序列。
本发明进一步提供了包含本发明的核酸的载体。任选地,载体可以包含本发明的若干核酸。具体地,载体可以包含可操作地连接至调控区(即,包含一个或多个控制序列的区域)的本发明核酸。任选地,载体可以包含可操作地连接至若干调控区的本发明的若干核酸。
术语“控制序列”意指表达编码区所必需的核酸序列。控制序列可以是内源性的或异源性的。本领域熟练技术人员众所周知的且目前使用的控制序列会是优选的。此类控制序列包括但不限于启动子、信号肽序列和转录终止子。
术语“可操作地连接”意指如下的构造,其中以使得控制序列指导编码区表达的方式将控制序列放置在相对于编码序列的适当位置处。
本发明还涉及根据本发明的核酸或载体转化、转染或转导宿主细胞的用途。
本发明还提供了包含一种或若干本发明核酸和/或一种或若干本发明载体的宿主细胞。
术语“宿主细胞”还涵盖亲本宿主细胞的任何后代,其由于复制期间发生的突变而与亲本宿主细胞不相同。
用于克隆或表达编码抗体的载体的合适宿主细胞包括原核或真核细胞,如细菌、酵母、昆虫细胞、哺乳动物细胞等。
抑制性核酸
在另一个实施方案中,PLA2-GIB抑制剂是抑制性核酸,即,抑制PLA2-GIB基因或蛋白质表达的任何核酸分子。优选的抑制性核酸包括反义核酸、短干扰RNA(siRNA)、小发夹RNA(shRNA)、微小RNA、适体或核酶。在特定的实施方案中,抑制性核酸是阻止PLA2-GIBmRNA的翻译的小干扰RNA。在另一个特定的实施方案中,抑制性核酸是阻止PLA2-GIB mRNA的翻译的反义寡核苷酸。在另一个特定的实施方案中,抑制性核酸是阻止PLA2-GIB mRNA的翻译的小发夹RNA。
siRNA包含感兴趣的多核苷酸的有义核酸序列和反义核酸序列。将siRNA构建成使得单一转录物(双链RNA)具有来自靶基因的有义和互补反义序列二者。可以使用可从例如万维网上的Ambion网站获得的siRNA设计计算机程序来设计siRNA的核苷酸序列。
在一些实施方案中,反义寡核苷酸或siRNA的长度小于或等于10个核苷酸。在一些实施方案中,反义寡核苷酸和siRNA的长度与天然存在的转录物一样长。在一些实施方案中,反义寡核苷酸和siRNA具有18-30个核苷酸。在一些实施方案中,反义寡核苷酸和siRNA的长度小于25个核苷酸。
优选的抑制性核酸分子包含具有与PLA2-GIB基因或RNA的区域完全互补的核苷酸序列的结构域。此种结构域通常含有4至20个核苷酸,允许特异性杂交以及对基因转录或RNA翻译的最佳抑制。抑制性核酸的序列可以直接衍生自编码PLA2-GIB的基因的序列,如SEQ ID NO:2。替代地或另外,抑制性核酸可以杂交至PLA2-GIB基因或RNA中的调控元件(如启动子、剪接位点等),并且阻止其有效调控。
本发明的抑制性核酸分子的具体实例包括分离的单链核酸分子,其由编码SEQ IDNO:1的序列的10至50个连续核苷酸组成。本发明的抑制性核酸分子的具体实例是反义核酸,其由以下核苷酸序列或其完全互补链组成:
肽和小药物
在另一个替代实施方案中,PLA2-GIB抑制剂是抑制PLA2-GIB的活性的肽或小药物。肽或小药物通常是选择性结合PLA2-GIB、或PLA2-GIB的底物、或PLA2-GIB的辅因子、或PLA2-GIB路径的降解产物或代谢物的分子。
优选地,肽包含3至20个氨基酸残基,并且它们的序列可以与PLA2-GIB(诱饵肽)的结构域或与PLA2-GIB底物、辅因子、降解产物或代谢物的结构域相同。本发明的优选肽含有SEQ ID NO:1或2的(或SEQ ID NO:1或2的自然变体的相应序列的)4至30个连续氨基酸残基。本发明的最优选的肽包含SEQ ID NO:2的(或SEQ ID NO:2的自然变体的相应序列的)5至25个连续氨基酸残基,并且进一步包含SEQ ID NO:2的(或SEQ ID NO:2的自然变体的相应序列的)以下氨基酸残基中的至少一个:氨基酸3、氨基酸6、氨基酸7、氨基酸10、氨基酸70、氨基酸121、氨基酸50、氨基酸52、氨基酸54、氨基酸71、氨基酸75、氨基酸77、氨基酸79、氨基酸80或其组合。本发明的肽的具体实例是少于25个氨基酸的肽,其包含以下序列中的任何一个:
用于本发明的其它肽包括如WO2017/060405(其通过引用并入本文)中所公开的五肽。在具体的实施方案中,化合物是选自FLSYK(SEQ ID NO:32)、FLSYR(SEQ ID NO:33)和(2NapA)LS(2NapA)R(SEQ ID NO:34)的环肽。
本发明的肽可以包含肽键、非肽键和/或经修饰的肽键。在具体的实施方案中,肽包含至少一个拟肽键(peptidomimetic bond),其选自亚甲基(-CH2-)或磷酸根(-PO2-)基团、仲胺(-NH-)或氧(-O-)、α-氮杂肽、α-烷基肽、N-烷基肽、氨基磷酸酯、缩酚肽、羟基亚甲基、羟基亚乙基、二羟基亚乙基、羟乙胺、逆反肽(retro-inverso peptide)、亚甲基氧基、cetomethylene、酯、次膦酸酯(phosphinates)、phosphinics或膦酰胺(phosphonamides)。肽也可以包含受保护的N末端和/或C末端功能,例如通过酰化、和/或酰胺化和/或酯化获得。
本发明的肽可以通过本领域本身已知的技术(如化学、生物和/或基因合成)来产生。
分离形式的这些肽中的每种都代表本发明的特定目的。
优选的小药物是选择性结合PLA2-GIB的烃化合物。
小药物的实例包括吲哚化合物,如公开在WO2017/037041(其通过引用并入本文)中的那些。在特定的实施方案中,化合物是3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基)氧基)乙酸或其药物上可接受的盐、水合物或前药,如其钠盐(Varespladib)。
优选地,小药物和肽可通过包含以下各项的方法获得:(i)使测试化合物与PLA2-GIB或其片段接触,(ii)选择结合PLA2-GIB或所述其片段的测试化合物,以及(iii)选择抑制PLA2-GI的活性的(ii)的化合物。此种方法代表本发明的特定目的。
小药物和肽还可通过包含以下各项的方法获得:(i)使测试化合物与PLA2-GIB底物、辅因子、或降解产物、或其片段接触,(ii)选择结合所述PLA2-GIB底物、辅因子、或降解产物、或其片段的测试化合物,以及(iii)选择抑制PLA2-GIB的活性的(ii)的化合物。此种方法代表本发明的特定目的。
疫苗接种
在替代(或累积)实施方案中,PLA2-GIB抑制剂是PLA2-GIB抗原。由于用所述抗原对受试者进行疫苗接种或免疫,受试者产生抑制PLA2-GIB的抗体(或细胞)。具体地,注射PLA2-GIB抗原(例如,基本上没有生物活性的免疫原性PLA2-GIB)可以在接受治疗的受试者中生成抗体。这些抗体将防止PLA2-GIB表达过量,并且可以一起用作免疫疗法或疫苗预防。
因此,本发明的目的在于一种在患有实体癌的受试者中治疗实体癌的方法,其包含将PLA2-GIB抗原施用于该受试者。
本发明的进一步目的涉及一种用于在有此需要的受试者中治疗实体癌的PLA2-GIB抗原。
在具体实施方案中,PLA2-GIB抗原是失活的免疫原性分子,其在受试者中诱导针对PLA2-GIB的免疫应答。例如,可以通过化学地或物理地改变PLA2-GIB或通过突变或截短蛋白质,或通过二者来获得失活;并且免疫原性可以作为失活的结果和/或通过将蛋白质进一步缀合至合适的载体或半抗原(如KLH、HSA、聚赖氨酸、病毒去毒毒素等)和/或通过聚合等来获得。因此,可以对抗原进行化学或物理修饰,例如以提高其免疫原性。
在优选的实施方案中,PLA2-GIB抗原包含PLA2-GIB或其含有表位的片段或模拟表位。
在特定的实施方案中,PLA2-GIB抗原包含全长PLA2-GIB蛋白。在进一步的特定实施方案中,PLA2-GIB抗原包括包含SEQ ID No:2的蛋白质或与SEQ ID No:2具有至少90%同一性的序列。
在替代实施方案中,PLA2-GIB抗原包含PLA2-GIB蛋白的片段,其包含至少6个连续氨基酸残基并含有免疫原性表位或其模拟表位。在优选的实施方案中,PLA2-GIB抗原包含至少6至20个氨基酸残基。本发明的优选肽含有SEQ ID NO:2的(或SEQ ID NO:2的自然变体的相应序列的)4至30个连续氨基酸残基。本发明的最优选的肽包含SEQ ID NO:2的(或SEQID NO:2的自然变体的相应序列的)5至25个连续氨基酸残基,并且进一步包含SEQ ID NO:2的(或SEQ ID NO:2的自然变体的相应序列的)以下氨基酸残基中的至少一个:氨基酸3、6、7、10、70、121、50、52、54、71、75、77、79、80或其组合。本发明的肽的具体实例是少于50个氨基酸的肽,其包含以下序列中的任何一个:
PLA2-GIB抗原可以是各种形式,如游离形式、聚合的、化学或物理修饰的和/或偶联(即,连接)至载体分子。偶联至载体可以增加免疫原性并(进一步)抑制PLA2-GIB多肽的生物活性。在这方面,载体分子可以是免疫学中常规使用的任何载体分子或蛋白质,如例如KLH(匙孔戚血蓝蛋白)、卵清蛋白、牛血清白蛋白(BSA)、病毒或细菌去毒毒素(如类毒素tetanos、类毒素白喉B霍乱毒素、其突变体(如白喉毒素CRM 197))、外膜囊泡蛋白、聚赖氨酸分子或病毒样颗粒(VLP)。在优选的实施方案中,载体是KLH或CRM197或VLP。
可以使用连接化学基团或反应(如例如戊二醛、生物素等),通过共价化学来进行PLA2-GIB与载体的偶联。优选地,将缀合物或PLA2-GIB蛋白质或片段或模拟表位经受甲醛处理,以便完成PLA2-GIB的失活。
在特定的实施方案中,PLA2-GIB抗原包含全长PLA2-GIB蛋白,任选地偶联至载体蛋白。在优选的实施方案中,PLA2-GIB抗原包括偶联至载体蛋白的包含SEQ ID No:2的蛋白质或与SEQ ID No:2具有至少90%同一性的序列。
在另一个特定的实施方案中,PLA2-GIB抗原包含PLA2-GIB的免疫原性肽或模拟表位,任选地偶联至载体蛋白。在更优选的实施方案中,PLA2-GIB抗原包含至少10个氨基酸长的多肽,其包含SEQ ID NO:2的(或SEQ ID NO:2的自然变体的相应序列的)以下氨基酸残基中的至少一个:氨基酸70、氨基酸121、氨基酸50、氨基酸52、氨基酸54、氨基酸71或其组合,所述多肽任选地偶联至载体分子。
可以通过各种方法对PLA2-GIB抗原的免疫原性进行测试,如通过对移植有人免疫细胞的非人动物进行免疫,然后验证抗体的存在;或者通过使用人抗体或人源化抗体的夹心ELISA进行。可以通过本申请中所描述的任何活性测试来验证生物活性的缺乏。在优选的实施方案中,在(i)诱导CD4 T细胞中膜微结构域(MMD)的形成或(ii)致使CD4 T细胞对IL-2信号传导对不起反应或对IL-7信号传导不起反应的体外方法中,PLA2-GIB抗原具有野生型PLA2-GIB蛋白活性的小于20%、更优选小于15%、10%、5%或甚至1%。
此类分子和缀合物和疫苗代表强有力的试剂,其用于使受试者免疫,从而引起持续的PLA2-GIB抑制。重复后,此类方法可以用于引起永久性PLA2-GIB抑制。
本发明的进一步方面和优点公开在以下实验部分中,应认为该实验部分是说明性的。
实施例
A.材料和方法
A1.PLA2GIB夹心ELISA
使用先前生成的单抗来进行对前PLA2-GIB、PLA2GIB或二者形式特异性的夹心ELISA。对于前PLA2GIB的检测,#8G11 mAb用作捕获抗体,并且#1C11 mAb用作揭示mAb(revelation mAb)。对于PLA2GIB的检测,#14G9 mAb用作捕获抗体,并且#1C11 mAb用作揭示mAb。对于这两种形式的检测,#7A10 mAb用作捕获抗体,并且#1C11 mAb用作揭示mAb。典型的测定条件如下:将#8G11或#14G9涂覆的微板与重组人前PLA2GIB或PLA2GIB标准品(测定缓冲液中不同浓度的蛋白质)一起孵育1小时,以生成校准曲线。将EDTA血浆样品在稀释缓冲液中稀释(5至50倍)至其各自的孔中,并且将ELISA板在室温下孵育1小时。抽吸后,将孔用含有Tween 20 0.05%的PBS洗涤3次,并且在室温下将生物素化的#1C11缀合物添加至孔中,持续30分钟。在用含有0.05%Tween 20的PBS洗涤之后,通过在室温下用链霉亲合素-HRP缀合物处理15分钟来检测mAb的结合。添加TMB,停止反应,并且在酶标仪上确定450nm处的吸光度。使用PrismTM软件(Graph Pad),通过4参数拟合分析来对信号进行分析。
A2.IL7诱导的磷酸STAT5核移位
使用RosetteSep分离试剂盒(Stemcell Technologies,#15062)对人CD4进行纯化。将CD4 T细胞以106个细胞/ml重悬浮在RPMI 1640培养基(Lonza,Verviers,Belgium)(完全培养基)中,并且在37℃下在5%CO2加湿气氛中平衡至少2小时,该培养基补充有5%胎牛血清(FBS)、50mM HEPES pH 7.4、谷氨酰胺、青霉素、链霉素和两性霉素B(fungizone)。
使用共聚焦显微术跟踪pSTAT5核移位。平衡后,在血浆(最终浓度1%或3%)的存在下,将固定化细胞铺板在聚赖氨酸涂覆的载玻片上,然后用2nM IL-7活化15分钟。
对于PLA2GIB中和实验,首先在室温下将10μg(最终浓度)的#14G9 mAb与血浆(PBS中1或3%稀释v/v)一起孵育25分钟,然后在37℃下孵育5分钟。然后在37℃下在30分钟内将平衡混合物添加至从健康供体分离的CD4 T细胞中。然后用2nM IL-7活化细胞15分钟。
在37℃下将细胞固定在4%PFA中15分钟,然后在室温(RT)下固定15分钟,并且在-20℃下在90%甲醇/水溶液中进行透化。然后通过用驴抗兔AlexaFluor 555(LifeTechnologies,#A31572)标记的兔抗pSTAT5(CST,#9359)进行染色来揭示pSTAT5。对于人CD4 T淋巴细胞,用山羊抗小鼠AlexaFluor 488(Life Technologies,#A11029)标记的小鼠抗人CD4(eBioscience,#14-0042-82)对细胞进行染色。对于小鼠CD4 T淋巴细胞,用鸡抗大鼠AlexaFluor 488(Life Technologies,#A21470)标记的大鼠抗小鼠CD4(eBioscience,#14-0042-85)对细胞进行染色。在倒置激光扫描共焦显微镜(LSM700,Zeiss)上,用水浸复消色差40x/1.2NA物镜(Zeiss)或油浸平面复消色差63x/1.4NA物镜(Zeiss)来获取衍射极限以上的图像。使用ZEN软件(Zeiss)获取图像并进行分析。
A3.IL2诱导的磷酸化STAT5核移位
除使用2nM IL-2代替IL-7之外,使用与A2中相同的方案。
B.结果
B1.通过ELISA在来自PDAC患者的血浆中检测前PLAGIB、PLA2GIB或二者形式
ELISA夹心法用于检查来自患有胰腺导管腺癌(“PDAC”)患者的血浆中前LA2GIB和PLA2GIB分布。结果呈现在图1中。
在对照群体(n=99名健康供血者)中,平均(SD)前PLA2GIB水平为7.8(2.8)ng/mL,并且中位数为7.5ng/mL。平均(SD)PLA2GIB为287(243)pg/mL,并且中位数为170pg/mL。总PLA2GIB的平均(SD)值为9.3(3.2)ng/mL,并且中位数为9.1ng/mL。
在PDAC群体(n=19)中,平均(SD)前PLA2GIB水平为10.1(10.4)ng/mL,并且中位数为8.9ng/mL;平均(SD)PLA2GIB水平为310(345)pg/mL,并且中位数为194pg/mL;平均(SD)总PLA2GIB水平为11.7(10.5)ng/mL,并且中位数为10.4ng/mL。
在该实验中,对照队列与PDAC队列之间的血浆中PLA2GIB水平没有统计学上的显著差异。
B2.PDAC血浆对人CD4 T细胞的活性的体外影响。
我们通过测量磷酸STAT5核移位(pSTAT5 Nt),对来自PDAC患者的血浆调节CD4 T细胞的IL-7应答的能力进行了测试。
如图2A所示,我们观察了PDAC血浆在1%和3%稀释下对CD4 T细胞IL-7应答的抑制性影响。该结果展示,在癌症患者中,肿瘤微环境或血浆提供免疫调节,例如抑制。
B3.PLA2-GIB抑制剂对PDAC血浆诱导的人CD4 T细胞失活的影响。
通过将来自PDAC患者的血浆样品与#14G9 mAb一起孵育,对中和抗PLA2GIB mAb(克隆14G9)抵消从PDAC患者分离的血浆对CD4 T细胞中IL-7诱导的磷酸STAT5核移位的抑制性影响的能力进行了测试。
如图2B所描绘,在暴露于来自PDAC患者的血浆样品的健康供体的人CD4 T细胞中,#14G9 mAb恢复了有效的IL-7诱导的磷酸STAT5核移位。因此,PLA2-GIB抑制剂能够改善癌症受试者。该发现指示,癌症含有PLA2-GIB辅因子,其致使T细胞对由PLA2-GIB引起的失活敏感。
B4.PDAC血浆对人CD4 T细胞中IL2诱导的磷酸STAT5核移位的体外影响。
我们通过测量磷酸STAT5核移位(pSTAT5 Nt),对来自PDAC患者的血浆调节CD4 T细胞的IL-2应答的能力进行了测试。
如图3A所示,观察了PDAC血浆在1%和3%稀释下对CD4 T细胞IL-2应答的抑制性影响。该结果展示,在癌症患者中,肿瘤微环境或血浆提供免疫抑制。
B5.PLA2-GIB抑制剂对PDAC血浆诱导的人CD4 T细胞失活的影响。
通过将来自PDAC患者的血浆样品与#14G9 mAb一起孵育,对中和抗PLA2GIB mAb(克隆14G9)抵消从PDAC患者分离的血浆对CD4 T细胞中IL2诱导的磷酸STAT5核移位的抑制性影响的能力进行了测试。
如图3B所描绘,在暴露于来自PDAC患者的血浆样品的健康供体的人CD4 T细胞中,#14G9 mAb恢复了有效的IL2诱导的磷酸STAT5核移位。因此,PLA2-GIB抑制剂能够改善癌症受试者。该发现指示,癌症含有PLA2-GIB辅因子,其致使T细胞对由PLA2-GIB引起的失活敏感。
B6.来自癌症患者的血浆对人CD4 T细胞的体外影响。
测试了来自患有肺癌和十二指肠癌的患者的血浆对人T细胞的影响,如上文B2中所公开的。更具体地,制备所述血浆的稀释液(1%),并且使此种样品与来自健康供体的CD4T细胞接触。通过在IL7的存在下测量磷酸STAT5核移位(pSTAT5 Nt)来对此类样品调节CD4T细胞的活性的能力进行分析。
所述血浆样品的抑制性影响可以示出,在肺癌患者中,肿瘤微环境或血浆提供免疫抑制,其可以根据本发明恢复。
序列表
<110> 迪亚库雷特公司
<120> 用于治疗癌症的方法和组合物
<130> B2952
<160> 34
<170> PatentIn版本3.5
<210> 1
<211> 148
<212> PRT
<213> 智人
<400> 1
Met Lys Leu Leu Val Leu Ala Val Leu Leu Thr Val Ala Ala Ala Asp
1 5 10 15
Ser Gly Ile Ser Pro Arg Ala Val Trp Gln Phe Arg Lys Met Ile Lys
20 25 30
Cys Val Ile Pro Gly Ser Asp Pro Phe Leu Glu Tyr Asn Asn Tyr Gly
35 40 45
Cys Tyr Cys Gly Leu Gly Gly Ser Gly Thr Pro Val Asp Glu Leu Asp
50 55 60
Lys Cys Cys Gln Thr His Asp Asn Cys Tyr Asp Gln Ala Lys Lys Leu
65 70 75 80
Asp Ser Cys Lys Phe Leu Leu Asp Asn Pro Tyr Thr His Thr Tyr Ser
85 90 95
Tyr Ser Cys Ser Gly Ser Ala Ile Thr Cys Ser Ser Lys Asn Lys Glu
100 105 110
Cys Glu Ala Phe Ile Cys Asn Cys Asp Arg Asn Ala Ala Ile Cys Phe
115 120 125
Ser Lys Ala Pro Tyr Asn Lys Ala His Lys Asn Leu Asp Thr Lys Lys
130 135 140
Tyr Cys Gln Ser
145
<210> 2
<211> 126
<212> PRT
<213> 智人
<400> 2
Ala Val Trp Gln Phe Arg Lys Met Ile Lys Cys Val Ile Pro Gly Ser
1 5 10 15
Asp Pro Phe Leu Glu Tyr Asn Asn Tyr Gly Cys Tyr Cys Gly Leu Gly
20 25 30
Gly Ser Gly Thr Pro Val Asp Glu Leu Asp Lys Cys Cys Gln Thr His
35 40 45
Asp Asn Cys Tyr Asp Gln Ala Lys Lys Leu Asp Ser Cys Lys Phe Leu
50 55 60
Leu Asp Asn Pro Tyr Thr His Thr Tyr Ser Tyr Ser Cys Ser Gly Ser
65 70 75 80
Ala Ile Thr Cys Ser Ser Lys Asn Lys Glu Cys Glu Ala Phe Ile Cys
85 90 95
Asn Cys Asp Arg Asn Ala Ala Ile Cys Phe Ser Lys Ala Pro Tyr Asn
100 105 110
Lys Ala His Lys Asn Leu Asp Thr Lys Lys Tyr Cys Gln Ser
115 120 125
<210> 3
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 14G9 VL
<400> 3
Asp Ile Val Met Thr Gln Ser His Lys Leu Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Glu Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asn Arg Phe Thr Gly
50 55 60
Ser Arg Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln Asp Tyr Ser Thr Pro Pro
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile
115
<210> 4
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 14G9 VH
<400> 4
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Lys Arg Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asp Pro Ser Asp Thr Arg Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Ala Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Phe Tyr Cys
85 90 95
Ala Arg Gln Thr Leu Tyr Tyr Glu Ala Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr
115 120 125
Pro Leu
130
<210> 5
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 2B L
<400> 5
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Asp Tyr Ser Thr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 6
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 2B H
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asp Pro Ser Asp Thr Arg Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Thr Leu Tyr Tyr Glu Ala Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 7
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 2B1 H
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asp Pro Ser Asp Thr Arg Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Thr Leu Tyr Tyr Glu Ala Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Glu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 8
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 2B2 H
<400> 8
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asp Pro Ser Asp Thr Arg Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Thr Leu Tyr Tyr Glu Ala Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Glu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 9
<211> 726
<212> DNA
<213> 人工序列
<220>
<223> 2B L
<400> 9
gcggccgcca tgaattttgg actgaggctg attttcctgg tgctgaccct gaaaggcgtc 60
cagtgtgaga tcgtgatgac gcagtcgccg gcgacgctga gcgtgagtcc gggggagcgg 120
gcgacgctga gctgcaaggc gtcgcaggac gtgagcacgg ccgtcgcgtg gtatcaacag 180
aagccggggc aagcgccgcg gctgctgatc tactgggcga gcacgcggca cacgggcatc 240
ccggcgcgat tctcggggag ccggagcggg acggagtaca cgctgacgat ctcgtcgctg 300
caaagcgagg acttcgccgt ctactactgc cagcaggact actcgacgcc gccgacgttc 360
ggggggggta ccaaggtcga gatcaaacgt acggtcgcgg cgccttctgt gttcattttc 420
cccccatctg atgaacagct gaaatctggc actgcttctg tggtctgtct gctgaacaac 480
ttctacccta gagaggccaa agtccagtgg aaagtggaca atgctctgca gagtgggaat 540
tcccaggaat ctgtcactga gcaggactct aaggatagca catactccct gtcctctact 600
ctgacactga gcaaggctga ttacgagaaa cacaaagtgt acgcctgtga agtcacacat 660
caggggctgt ctagtcctgt gaccaaatcc ttcaataggg gagagtgctg atagtaaaag 720
ctttga 726
<210> 10
<211> 1431
<212> DNA
<213> 人工序列
<220>
<223> 2B H
<400> 10
gcggccgcca tgaattttgg actgaggctg attttcctgg tgctgaccct gaaaggcgtc 60
cagtgtcaag tccagctcgt ccagagcggg gcggaagtca agaagccggg ggcgagcgtg 120
aaagtctcgt gcaaggcgag cggatatacg ttcacgaact actggattca ctgggtccgg 180
caagcgccgg ggcaggggct ggagtggatc gggaacatcg acccgtcgga cacgcggacg 240
cactacaacc agaagttcaa ggaccgggcg acgctgaccg tcgacaagag cacgagcacg 300
gcgtacatgg agctgtcgag cctgcggagc gaggacacgg ccgtctacta ctgcgcgcgg 360
cagacgctgt actacgaggc gctggactac tgggggcagg ggacgctcgt cacggtctcg 420
agcgctagca caaagggccc tagtgtgttt cctctggctc cctcttccaa atccacttct 480
ggtggcactg ctgctctggg atgcctggtg aaggattact ttcctgaacc tgtgactgtc 540
tcatggaact ctggtgctct gacttctggt gtccacactt tccctgctgt gctgcagtct 600
agtggactgt actctctgtc atctgtggtc actgtgccct cttcatctct gggaacccag 660
acctacattt gtaatgtgaa ccacaaacca tccaacacta aagtggacaa aagagtggaa 720
cccaaatcct gtgacaaaac ccacacctgc ccaccttgtc ctgcccctga actgctggga 780
ggaccttctg tgtttctgtt cccccccaaa ccaaaggata ccctgatgat ctctagaacc 840
cctgaggtga catgtgtggt ggtggatgtg tctcatgagg accctgaggt caaattcaac 900
tggtacgtgg atggagtgga agtccacaat gccaaaacca agcctagaga ggaacagtac 960
aattcaacct acagagtggt cagtgtgctg actgtgctgc atcaggattg gctgaatggc 1020
aaggaataca agtgtaaagt ctcaaacaag gccctgcctg ctccaattga gaaaacaatc 1080
tcaaaggcca agggacagcc tagggaaccc caggtctaca ccctgccacc ttcaagagag 1140
gaaatgacca aaaaccaggt gtccctgaca tgcctggtca aaggcttcta cccttctgac 1200
attgctgtgg agtgggagtc aaatggacag cctgagaaca actacaaaac aaccccccct 1260
gtgctggatt ctgatggctc tttctttctg tactccaaac tgactgtgga caagtctaga 1320
tggcagcagg ggaatgtctt ttcttgctct gtcatgcatg aggctctgca taaccactac 1380
actcagaaat ccctgtctct gtctcccggg aaatgatagt aaaagctttg a 1431
<210> 11
<211> 1426
<212> DNA
<213> 人工序列
<220>
<223> 2B1 H
<400> 11
gcggccgcca tgaattttgg actgaggctg attttcctgg tgctgaccct gaaaggcgtc 60
cagtgtcaag tccagctcgt ccagagcggg gcggaagtca agaagccggg ggcgagcgtg 120
aaagtctcgt gcaaggcgag cggatatacg ttcacgaact actggattca ctgggtccgg 180
caagcgccgg ggcaggggct ggagtggatc gggaacatcg acccgtcgga cacgcggacg 240
cactacaacc agaagttcaa ggaccgggcg acgctgaccg tcgacaagag cacgagcacg 300
gcgtacatgg agctgtcgag cctgcggagc gaggacacgg ccgtctacta ctgcgcgcgg 360
cagacgctgt actacgaggc gctggactac tgggggcagg ggacgctcgt cacggtctcg 420
agcgctagca caaagggccc tagtgtgttt cctctggctc cctcttccaa atccacttct 480
ggtggcactg ctgctctggg atgcctggtg aaggattact ttcctgaacc tgtgactgtc 540
tcatggaact ctggtgctct gacttctggt gtccacactt tccctgctgt gctgcagtct 600
agtggactgt actctctgtc atctgtggtc actgtgccct cttcatctct gggaacccag 660
acctacattt gtaatgtgaa ccacaaacca tccaacacta aagtggacaa aagagtggaa 720
cccaaatcct gtgacaaaac ccacacctgc ccaccttgtc cggcgcctga agcggaagga 780
ggaccttctg tgtttctgtt cccccccaaa ccaaaggata ccctgatgat ctcgcgaacc 840
cctgaggtga catgtgtggt ggtggatgtg tctcatgagg accccgaagt caaatttaat 900
tggtatgtcg acggcgtcga ggtgcataat gccaaaacca agcctagaga ggaacagtac 960
aattcaacct acagagtcgt cagtgtgctg actgtgctgc atcaggattg gctgaatggc 1020
aaggaataca agtgtaaagt ctcaaacaag gccctgcctg ctccaattga gaaaacaatc 1080
tcaaaggcca agggacagcc tagggaaccc caggtctaca ccctgccacc ttcaagagag 1140
gaaatgacca aaaaccaggt gtccctgaca tgcctggtca aaggcttcta cccttctgac 1200
attgctgtgg agtgggagtc aaatggacag cctgagaaca actacaaaac aaccccccct 1260
gtgctggatt ctgatggctc tttctttctg tactccaaac tgactgtgga caagtctaga 1320
tggcagcagg ggaatgtctt ttcttgctct gtcatgcatg aggctctgca taaccactac 1380
actcagaaat ccctgtctct gtctcccggg aaatgataag ctttga 1426
<210> 12
<211> 1503
<212> DNA
<213> 人工序列
<220>
<223> 2B2 H
<400> 12
gcggccgcca tgaattttgg actgaggctg attttcctgg tgctgaccct gaaaggcgtc 60
cagtgtcaag tccagctcgt ccagagcggg gcggaagtca agaagccggg ggcgagcgtg 120
aaagtctcgt gcaaggcgag cggatatacg ttcacgaact actggattca ctgggtccgg 180
caagcgccgg ggcaggggct ggagtggatc gggaacatcg acccgtcgga cacgcggacg 240
cactacaacc agaagttcaa ggaccgggcg acgctgaccg tcgacaagag cacgagcacg 300
gcgtacatgg agctgtcgag cctgcggagc gaggacacgg ccgtctacta ctgcgcgcgg 360
cagacgctgt actacgaggc gctggactac tgggggcagg ggacgctcgt cacggtctcg 420
agcgctagca caaagggccc tagtgtgttt cctctggctc cctcttccaa atccacttct 480
ggtggcactg ctgctctggg atgcctggtg aaggattact ttcctgaacc tgtgactgtc 540
tcatggaact ctggtgctct gacttctggt gtccacactt tccctgctgt gctgcagtct 600
agtggactgt actctctgtc atctgtggtc actgtgccct cttcatctct gggaacccag 660
acctacattt gtaatgtgaa ccacaaacca tccaacacta aagtggacaa aagagtggaa 720
cccaaatcct gtgacaaaac ccacacctgc ccaccttgtc cggcgcctga agcggaagga 780
ggaccttctg tgtttctgtt cccccccaaa ccaaaggata ccctgatgat ctcgcgaacc 840
cctgaggtga catgtgtggt ggtggatgtg tctcatgagg accccgaagt caaatttaat 900
tggtatgtcg acggcgtcga ggtgcataat gccaaaacca agcctagaga ggaacagtac 960
aattcaacct acagagtcgt cagtgtgctg actgtgctgc atcaggattg gctgaatggc 1020
aaggaataca agtgtaaagt ctcaaacaag gccctgcctg cttcaattga gaaaacaatc 1080
tcaaaggcca agggacagcc tagggaaccc caggtctaca ccctgccacc ttcaagagag 1140
gaaatgacca aaaaccaggt gtccctgaca tgcctggtca aaggcttcta cccttctgac 1200
attgctgtgg agtgggagtc aaatggacag cctgagaaca actacaaaac aaccccccct 1260
gtgctggatt ctgatggctc tttctttctg tactccaaac tgactgtgga caagtctaga 1320
tggcagcagg ggaatgtctt ttcttgctct gtcatgcatg aggctctgca taaccactac 1380
actcagaaat ccctgtctct gtctcccggg aaatgataag ctttgatgtc atgcatgagg 1440
ctctgcataa ccactacact cagaaatccc tgtctctgtc tcccgggaaa tgataagctt 1500
tga 1503
<210> 13
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 13
atgaaactcc ttgtgctag 19
<210> 14
<211> 14
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 14
acagcggcat cagc 14
<210> 15
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 15
ttccgcaaaa tgatcaa 17
<210> 16
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 16
cccggggagt gacccc 16
<210> 17
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 17
tacggctgct actgtggctt 20
<210> 18
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 18
gacacatgac aactgctacg acc 23
<210> 19
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 19
acccacacct attcatactc gt 22
<210> 20
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 20
atcacctgta gcagca 16
<210> 21
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 21
agctccatat aacaaggca 19
<210> 22
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 抑制性核酸
<400> 22
caagaagtat tgtcagag 18
<210> 23
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 23
Asn Asn Tyr Gly Cys Tyr
1 5
<210> 24
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 24
Cys Tyr Cys Gly Leu Gly
1 5
<210> 25
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 25
Tyr Asn Asn Tyr Gly Cys Tyr Cys Gly Leu Gly Gly Ser Gly
1 5 10
<210> 26
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 26
Phe Leu Glu Tyr Asn Asn Tyr Gly Cys Tyr Cys Gly Leu Gly Gly Ser
1 5 10 15
Gly Thr Pro Val
20
<210> 27
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 27
Gln Thr His Asp Asn
1 5
<210> 28
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 28
Cys Gln Thr His Asp Asn Cys
1 5
<210> 29
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 29
Glu Cys Glu Ala Phe Ile Cys Asn Cys
1 5
<210> 30
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 30
Asp Arg Asn Ala Ala Ile
1 5
<210> 31
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 31
Asp Arg Asn Ala Ala Ile Cys Phe Ser Lys Ala Pro Tyr Asn Lys Ala
1 5 10 15
His Lys Asn Leu
20
<210> 32
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 32
Phe Leu Ser Tyr Lys
1 5
<210> 33
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<400> 33
Phe Leu Ser Tyr Arg
1 5
<210> 34
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抑制性肽
<220>
<221> MISC特征
<222> (1)..(1)
<223> X是2-萘基丙氨酸
<220>
<221> MISC特征
<222> (4)..(4)
<223> X是2-萘基丙氨酸
<400> 34
Xaa Leu Ser Xaa Arg
1 5
Claims (30)
1.一种抑制PLA2-GIB的化合物,其用于在有此需要的受试者中治疗癌症或瘤形成的用途。
2.根据权利要求1使用的化合物,其中所述化合物是结合PLA2-GIB的抗体或其片段或衍生物。
3.根据权利要求2使用的化合物,其中所述化合物是单克隆抗体。
4.根据权利要求3使用的化合物,其中所述单克隆抗体是人的或人源化的。
5.根据权利要求1使用的化合物,其中所述化合物是3-(2-氨基-1,2-二氧代乙基)-2-乙基-1-(苯基甲基)-1H-吲哚-4-基)氧基)乙酸或其药物上可接受的盐、水合物或前药,如其钠盐。
6.根据权利要求1使用的化合物,其中所述化合物是针对PLA2-GIB的疫苗。
7.根据权利要求1使用的化合物,其中所述化合物是选自FLSYK、FLSYR和(2NapA)LS(2NapA)R的环肽。
8.根据权利要求1至7中任一项使用的化合物,其中所述化合物与进一步的抗癌剂、疫苗或治疗组合施用。
9.根据权利要求8使用的化合物,其中所述化合物与化学疗法或激素疗法组合施用。
10.根据权利要求8使用的化合物,其中所述化合物与放射疗法、超声疗法或纳米颗粒疗法组合施用。
11.根据权利要求8使用的化合物,其中所述化合物与检查点抑制剂、免疫疗法或抗癌疫苗组合施用。
12.根据权利要求8使用的化合物,其中所述化合物与PLA2-GIB辅因子的抑制剂组合施用。
13.根据权利要求12使用的化合物,其中所述抑制剂是PLA2-GIB辅因子的拮抗剂,或者是针对PLA2-GIB辅因子或针对表达PLA2-GIB辅因子的原核或真核细胞或病毒的细胞抑制剂或细胞毒性剂或疫苗。
14.根据权利要求1至13中任一项使用的化合物,其中所述化合物在手术之前、期间或之后施用。
15.根据权利要求1至14中任一项使用的化合物,其中所述化合物重复地施用。
16.根据前述权利要求中任一项使用的化合物,其中所述癌症是实体癌。
17.根据权利要求1至16中任一项使用的化合物,其中PLA2-GIB辅因子或者表达PLA2-GIB辅因子的原核或真核细胞或病毒存在于所述受试者中。
18.根据权利要求1至17中任一项使用的化合物,其中PLA2-GIB或PLA2-GIB辅因子存在于所述癌症微环境或血液中。
19.根据权利要求1至18中任一项使用的化合物,其中所述受试者具有PLA2GIB相关CD4T细胞缺陷。
20.根据权利要求16使用的化合物,其中所述癌症选自胰腺癌、黑色素瘤、肺癌、食管癌或咽喉癌、视网膜母细胞瘤、肝癌、乳腺癌、卵巢癌、肾癌、胃癌、十二指肠癌、子宫癌、宫颈癌、甲状腺癌、膀胱癌、前列腺癌、骨癌、脑癌或结直肠癌。
21.根据权利要求20使用的化合物,其中所述癌症是胰腺癌。
22.根据权利要求21使用的化合物,其中所述癌症选自胰腺腺癌、神经内分泌肿瘤、导管内乳头状粘液性新生物、粘液性囊性新生物和严重囊性新生物。
23.根据权利要求1使用的化合物,其中所述癌症诱发胃肠道病状和代谢病状。
24.根据权利要求1至23中任一项使用的化合物,其用于预防癌症或降低癌症发生率。
25.根据权利要求1至23中任一项使用的化合物,其用于降低癌症进展率。
26.根据权利要求1至23中任一项使用的化合物,其用于降低或预防或治疗癌症转移。
27.根据权利要求1至23中任一项使用的化合物,其用于杀死癌细胞。
28.根据权利要求1至23中任一项使用的化合物,其用于治疗癌症的风险因素,特别是口腔-胃-肠道炎症或感染,如胰腺炎。
29.根据权利要求1至28中任一项使用的化合物,其中所述受试者是人。
30.根据权利要求1至29中任一项使用的化合物,其中测量所述肿瘤或体液中PLA2-GIB或PLA2-GIB辅因子的水平以指导治疗方案。
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EP19305140.6 | 2019-02-06 | ||
EP19305140.6A EP3693063A1 (en) | 2019-02-06 | 2019-02-06 | Methods and compositions for treating cancer |
PCT/EP2020/052818 WO2020161165A1 (en) | 2019-02-06 | 2020-02-05 | Methods and compositions for treating cancer |
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CN202080013080.8A Pending CN113710321A (zh) | 2019-02-06 | 2020-02-05 | 用于治疗癌症的方法和组合物 |
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US (1) | US20220127377A1 (zh) |
EP (2) | EP3693063A1 (zh) |
JP (1) | JP2022519716A (zh) |
KR (1) | KR20220143552A (zh) |
CN (1) | CN113710321A (zh) |
CA (1) | CA3128857A1 (zh) |
IL (1) | IL285036A (zh) |
MX (1) | MX2021009195A (zh) |
WO (1) | WO2020161165A1 (zh) |
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IL285036A (en) | 2021-09-30 |
EP3921036A1 (en) | 2021-12-15 |
JP2022519716A (ja) | 2022-03-24 |
MX2021009195A (es) | 2021-09-08 |
KR20220143552A (ko) | 2022-10-25 |
US20220127377A1 (en) | 2022-04-28 |
CA3128857A1 (en) | 2020-08-13 |
EP3693063A1 (en) | 2020-08-12 |
WO2020161165A1 (en) | 2020-08-13 |
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Application publication date: 20211126 |