CN114949171A - 血管生成性疾病的免疫疗法 - Google Patents
血管生成性疾病的免疫疗法 Download PDFInfo
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Abstract
本发明提供用于治疗和预防血管生成性疾病的药物组合物,所述药物组合物包含癌抗原肽。
Description
本申请是原案申请日为2015年12月10日、申请号为201580075795.5 (国际申请号为PCT/JP2015/084709)、发明名称为“血管生成性疾病的免疫疗法”的专利申请的分案申请。
技术领域
本发明涉及血管生成性疾病的免疫疗法。
背景技术
对于血管生成性疾病,例如各种类型的癌症、多发性骨髓瘤、关节风湿病、牛皮癣、眼内血管生成性疾病如湿型年龄相关性黄斑变性、动脉粥样硬化斑块、血管畸形、血管凝集、卵巢肥大综合征、多囊卵巢、肉芽肿、血管瘤、肥厚性瘢痕、瘢痕疙瘩、硬皮病、疣,使用下述进行治疗:鱼精蛋白,类固醇和肝素的组合,类固醇和己糖醛基己糖胺聚糖硫酸盐的组合,米托蒽醌,内皮抑制素,纤连蛋白的肝素结合片段,前列腺素合成酶抑制剂,γ-干扰素,金化合物,淋巴毒素,D-青霉胺,类固醇和β-环糊精十四硫酸盐的组合,蛋白酶抑制剂,甲氨蝶呤,干扰素α-2a,抗VEGF药物等。
血管生成性疾病的典型类型包括眼内血管生成性疾病,例如湿型年龄相关性黄斑变性。眼内血管生成性疾病的常见治疗方法使用抗VEGF药物作为眼内注射剂。然而,使用抗VEGF药物的治疗方法花费大量金钱,需要定期重复注射,对于将注射针插入眼睛的患者提供了大量心理上的恐惧。此外,存在严重并发症的风险很大,例如治疗上极其困难的眼内感染、由注射刺激引起的眼内炎等,以及诱发视网膜脱离。此外,有报道说,在大多数情况下,通过使用抗VEGF药物的治疗,视力在一段时间内得到改善,然而即使持续治疗,视力也会再次长期恶化。也就是说,虽然在目前治疗中使用的抗VEGF药物成本很高,但是它具有危险,因此鉴于其效果不一定能够实现足够的治疗满意度。其它治疗包括手术方法,例如光动力治疗、激光光凝固和新生血管摘除,但这些方法在成本和治疗满意度方面也有问题,具有很高的侵袭性,并且有时需要住院治疗。因此,还没有用于眼内血管生成性疾病的常规治疗方法是令人满意的,并且因此认为在目前治疗中许多问题待克服。
近来据报道,作为癌抗原蛋白质的WT1蛋白也在癌组织的血管中出现(非专利文献1:N.Wagner等,Oncogene(2008)27,3662-3672)。
已经有许多关于使用癌抗原肽作为癌症疫苗的实验的报道,然而,没有关于使用癌抗原肽作为疫苗来治疗和预防血管生成性疾病的报道。
在上述情况下,需要一种用于血管生成性疾病的新的彻底治愈性疗法。
引用文献列表
非专利文献
非专利文献1:N. Wagner等,Oncogene (2008) 27, 3662-3672。
发明内容
要解决的问题
本发明的目的是提供治疗和预防血管生成性疾病的新制剂。此外,本发明的另一个目的是提供一种低侵袭性制剂,其可以以相对低的成本由患者自行给予。
解决问题的手段
为了解决上述问题进行了深入的研究后,本发明人发现通过使用癌抗原肽作为疫苗可以治疗或预防血管生成性疾病。此外,本发明人还发现血管生成性疾病可以通过全身给予WT1肽来治疗。本发明人基于这些发现完成了本发明。
因此,本发明提供以下内容。
(1)含有癌抗原肽的药物组合物,用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者。
(2)含有用癌抗原肽诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞的药物组合物,其用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者。
(3)根据(1)或(2)所述的药物组合物,其中所述癌抗原肽为WT1肽或变体WT1肽。
(4)根据(3)所述的药物组合物,其中所述WT1肽或变体WT1肽对HLA分子具有结合能力。
(5)根据(3)或(4)所述的药物组合物,其中所述WT1肽或变体WT1肽活化杀伤T细胞或辅助T细胞。
(6)根据(3)〜(5)中任一项所述的药物组合物,其中所述WT1肽的长度为7〜30个氨基酸。
(7)根据(3)〜(6)中任一项所述的药物组合物,其中所述WT1肽包含以下氨基酸序列:
(a)由SEQ ID NO: 1至SEQ ID NO: 39表示的任何氨基酸序列,或
(b)氨基酸序列,其中在根据上述(a)的氨基酸序列中一个或数个氨基酸被置换、缺失或添加。
(8)根据(3)〜(7)中任一项所述的药物组合物,其中所述WT1肽包含以下氨基酸序列:
(a)Arg Met Phe Pro Asn Ala Pro Tyr Leu(SEQ ID NO: 1),
(b)Cys Tyr Thr Trp Asn Gln Met Asn Leu(SEQ ID NO: 19),
(c)Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly SerLeu Gly(SEQ ID NO: 27),
(d)Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His(SEQ ID NO: 32),或
(e)氨基酸序列,其中在根据(a)至(d)的任何氨基酸序列中一个或数个氨基酸被置换、缺失或添加。
(9)根据(1)〜(8)中任一项所述的药物组合物,其中所述血管生成性疾病是眼内血管生成性疾病。
(10)根据(9)所述的药物组合物,其中眼内血管生成性疾病选自湿型年龄相关性黄斑变性、近视性黄斑变性、血管样条纹、中心性浆液性脉络膜视网膜病变、各种类型的视网膜色素上皮病、脉络膜萎缩、无脉络膜、脉络膜骨瘤、糖尿病性视网膜病变、早产儿视网膜病变、虹膜红变性青光眼和角膜新生血管形成。
(11)根据(1)〜(10)中任一项所述的药物组合物,其通过皮内给药、经皮给药或经粘膜给药而给予。
(12)根据(1)〜(11)所述的药物组合物,其与用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者的药物联合使用。
发明效果
本发明提供含有癌抗原肽的药物组合物,其用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者。此外,本发明提供含有用癌抗原肽诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞的药物组合物,其用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者。根据本发明的药物组合物是低侵袭性的,因为可利用全身给药如皮内给药、皮下给药、经皮给药和经粘膜给药,以及局部给药。此外,根据本发明的药物组合物可以由患者自行给予。此外,根据本发明的药物组合物具有高的治疗效果和高的患者治疗满意度。此外,当用根据本发明的药物组合物治疗眼内血管生成性疾病时,也可以预期对另一只眼睛的治疗或预防效果。
附图说明
图1是表示动物实验中的观察、测量、检查项目等的概要的方案。
图2是典型的荧光素荧光眼底图像,显示WT1肽疫苗的眼底抗血管生成作用。左侧的两张照片显示了PBS皮内给药(对照)的结果,右侧的两张照片显示了用WT1肽(WT1126:Arg Met Phe Pro Asn Ala Pro Tyr Leu (SEQ ID NO: 1))进行皮内给药的结果。
图3是显示以皮内给予1μg/个体、10μg/个体和100μg/个体的WT1肽(WT1126: ArgMet Phe Pro Asn Ala Pro Tyr Leu (SEQ ID NO: 1)),通过时间过程分析获得的脉络膜新生血管区域变化的图。
图4是显示以皮内给予1μg/个体、10μg/个体和100μg/个体的WT1肽(WT135: AlaPro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly Ser Leu Gly (SEQ IDNO: 27)),通过时间过程分析获得的脉络膜新生血管区域变化的图。
图5是显示以皮内给予200μg/个体的WT1肽(WT1235m: Cys Tyr Thr Trp Asn GlnMet Asn Leu (SEQ ID NO: 19)和WT1332: Lys Arg Tyr Phe Lys Leu Ser His Leu GlnMet His Ser Arg Lys His (SEQ ID NO: 32)),通过时间过程分析获得的脉络膜新生血管区域变化的图。
图6是显示当联合使用WT1肽(WT1126、WT1235m和WT1332)和阿普西柏(aflibercept)时,通过时间过程分析获得的脉络膜新生血管区域变化的图。
具体实施方式
一方面,本发明涉及含有癌抗原肽的药物组合物,其用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者。癌抗原肽是癌抗原蛋白的一部分。包括WT1在内的各种癌抗原蛋白是已知的。用于本发明的药物组合物中的癌抗原肽可以是一种,或者可以是两种或更多种。癌抗原WT1肽是否在受试者中对血管生成性疾病发挥治疗效果取决于癌抗原肽是否对应于受试者的HLA类型。目前,关于许多癌抗原肽,已知什么样的癌抗原肽与某种HLA类型相容,因此可以根据受试者的HLA类型选择本发明中使用的癌抗原肽。因此,两种或更多种癌抗原肽可用于本发明的药物组合物中以适应较广范围的受试者。各种血管生成性疾病也是已知的。血管生成性疾病的实例包括但不限于各种类型的癌症、多发性骨髓瘤、关节风湿病、牛皮癣、眼内血管生成性疾病如湿型年龄相关性黄斑变性、动脉粥样硬化斑块、血管畸形、血管凝集、卵巢肥大综合征、多囊卵巢、肉芽肿、血管瘤、肥厚性瘢痕、瘢痕疙瘩、硬皮病和疣。
可以将癌抗原肽给予受试者,或者加入样品如来自受试者的血液,以获得呈递所述癌抗原肽的抗原呈递细胞。呈递癌抗原的抗原呈递细胞刺激淋巴细胞诱导或活化杀伤T细胞或辅助T细胞。癌抗原肽的作用来源于如上所述诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞。因此,另一方面,本发明涉及含有用癌抗原肽诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞的药物组合物,其用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者。用于上述药物组合物中的抗原呈递细胞、杀伤T细胞或辅助T细胞可用任何癌抗原肽诱导或活化,例如用WT1肽诱导或活化。
血管生成性疾病的典型类型包括眼内血管生成性疾病。此外,广泛使用的癌抗原肽种类包括WT1肽。因此,在另一方面,本发明涉及含有WT1肽或变体WT1肽的药物组合物,其用于治疗眼内血管生成性疾病。
如本文所用,WT1肽是指由WT1基因(威尔姆斯瘤基因1)编码的癌抗原蛋白WT1的部分肽。癌抗原蛋白WT1的氨基酸序列由SEQ ID NO: 40表示。因此,WT1肽是由癌抗原蛋白WT1中包含的连续氨基酸序列组成的肽。WT1肽是本领域技术人员所熟知的,并且有许多具体涉及癌症免疫疗法的报道。可以通过公知的方法例如遗传工程方法或化学合成法来制备WT1肽。除非另有说明,本文所用的WT1肽是指源自人癌抗原蛋白WT1的肽。
用于本发明的WT1肽可以是由氨基酸组成的变体WT1肽,其中在WT1肽的氨基酸序列中一个或数个氨基酸被置换、缺失或添加。变体WT1肽可以是:具有人工修饰的氨基酸序列的WT1肽(也称为修饰的WT1肽),通过天然突变获得的WT1肽,或由于WT1肽来源的动物物种导致在氨基酸序列上有差异的WT1肽。如本文所用,变体WT1肽具有与天然型WT1肽相似的对眼内血管生成性疾病的治疗效果。本领域技术人员已知的氨基酸序列的置换、缺失或添加方法包括遗传工程程序和化学方法,因此本领域技术人员可以容易地获得所需的氨基酸序列。术语一个或数个是指例如1、2、3、4、5、6、7、8、9或10个,优选1、2、3、4或5个,更优选1、2或3个。更优选地,术语一个或数个是指1或2个。
变体WT1肽包括在WT1肽中具有氨基酸残基修饰的肽。肽中氨基酸残基的修饰类型和修饰方法是本领域技术人员已知的。作为修饰的具体实例,可以将各种物质如氨基酸、肽或其类似物结合到WT1肽的N末端和/或C末端。上述各种物质可以是用于控制本发明的WT1肽的溶解性,提高其稳定性(例如抗蛋白酶活性),将本发明的WT1肽特异性地递送到预定的组织/器官,或增强抗原呈递细胞的摄取效率的物质。另一方面,可以制备上述各种物质,使得可以在体内消除各种物质以提供WT1肽。
如本文所用,除非另有说明,术语WT1肽包括变体WT1肽。
本发明中使用的WT1肽的长度没有特别限定,然而优选由约7〜约30个氨基酸组成的WT1肽。优选的WT1肽具有与HLA分子结合并呈递的抗原肽的序列(基序)的规则性,并且具有与HLA分子的结合能力。可以通过本领域已知的方法分析对HLA分子的结合能力。这样的方法包括例如基于计算机的方法,例如Rankpep、BIMAS和SYFPEITHI,以及与具有HLA分子结合能力的已知WT1肽的竞争性结合测定。此外,优选的WT1肽活化杀伤T细胞或辅助T细胞。
活化杀伤T细胞的许多WT1肽(这里称为杀伤性WT1肽)是公知的。通常,优选的杀伤性WT1肽具有由7至12个氨基酸组成的氨基酸序列。更优选的杀伤性WT1肽具有由9个氨基酸组成的氨基酸序列。可用于本发明的杀伤性WT1肽的实例包括但不限于包含以下氨基酸序列或由以下氨基酸序列组成的肽:Arg Met Phe Pro Asn Ala Pro Tyr Leu (SEQ ID NO:1)、Arg Tyr Pro Ser Cys Gln Lys Lys Phe (SEQ ID NO: 2)、Arg Tyr Phe Pro Asn AlaPro Tyr Leu (SEQ ID NO: 3)、Ala Tyr Leu Pro Ala Val Pro Ser Leu (SEQ ID NO:4)、Asn Tyr Met Asn Leu Gly Ala Thr Leu (SEQ ID NO: 5)、Asp Gln Leu Lys Arg HisGln Arg Arg (SEQ ID NO: 6)、Val Thr Phe Asp Gly Thr Pro Ser Tyr (SEQ ID NO:7)、Gln Gly Ser Leu Gly Glu Gln Gln Tyr (SEQ ID NO: 8)、Cys Met Thr Trp Asn GlnMet Asn Leu (SEQ ID NO: 9)、Leu Ser His Leu Gln Met His Ser Arg (SEQ ID NO:10)、Phe Ser Arg Ser Asp Gln Leu Lys Arg (SEQ ID NO: 11)、Ser Asp Gln Leu LysArg His Gln Arg (SEQ ID NO: 12)、Thr Ser Glu Lys Pro Phe Ser Cys Arg (SEQ IDNO: 13)、Pro Ile Leu Cys Gly Ala Gln Tyr Arg (SEQ ID NO: 14)、Ser Ala Ser GluThr Ser Glu Lys Arg (SEQ ID NO: 15)、Ser His Leu Gln Met His Ser Arg Lys (SEQID NO: 16)、Thr Gly Val Lys Pro Phe Gln Cys Lys (SEQ ID NO: 17)、Ser Leu GlyGlu Gln Gln Tyr Ser Val (SEQ ID NO: 18)、Cys Tyr Thr Trp Asn Gln Met Asn Leu(SEQ ID NO: 19)、Phe Leu Gly Glu Gln Gln Tyr Ser Val (SEQ ID NO: 20)、Ser MetGly Glu Gln Gln Tyr Ser Val (SEQ ID NO: 21)、Ser Leu Met Glu Gln Gln Tyr SerVal (SEQ ID NO: 22)、Phe Met Phe Pro Asn Ala Pro Tyr Leu (SEQ ID NO: 23)、ArgLeu Phe Pro Asn Ala Pro Tyr Leu (SEQ ID NO: 24)、Arg Met Met Pro Asn Ala ProTyr Leu (SEQ ID NO: 25)或Arg Met Phe Pro Asn Ala Pro Tyr Val (SEQ ID NO: 26),和上述肽的变体WT1肽。杀伤性WT1肽的其它实例包括但不限于国际公开号WO 2000/018795(其通过引用整体并入本文)中公开的那些。
活化辅助T细胞的许多WT1肽(这里称为辅助性WT1肽)是公知的。通常,优选的辅助性WT1肽具有由10至25个氨基酸组成的氨基酸序列。更优选的辅助性WT1肽具有由13至20个氨基酸组成的氨基酸序列。可用于本发明的辅助性WT1肽的实例包括但不限于包含以下氨基酸序列或由以下氨基酸序列组成的肽:Ala Pro Val Leu Asp Phe Ala Pro Pro GlyAla Ser Ala Tyr Gly Ser Leu Gly (SEQ ID NO: 27)、Glu Gln Cys Leu Ser Ala PheThr Val His Phe Ser Gly Gln Phe Thr Gly (SEQ ID NO: 28)、Pro Asn His Ser PheLys His Glu Asp Pro Met Gly Gln Gln Gly (SEQ ID NO: 29)、Asn Leu Tyr Gln MetThr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln Met Asn Leu (SEQ ID NO: 30)、PheArg Gly Ile Gln Asp Val Arg Arg Val Pro Gly Val Ala Pro Thr Leu Val Arg (SEQID NO: 31)或Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His(SEQ ID NO: 32),和上述肽的变体WT1肽。
本发明的药物组合物中使用的WT1肽可以是一种,或两种或更多种。此外,本发明的药物组合物中使用的WT1肽可以是杀伤性WT1肽或辅助性WT1肽,或者杀伤性WT1肽和辅助性WT1肽可以混合用于药物组合物。
在本发明中,可以使用WT1肽的二聚体。可以通过在具有半胱氨酸残基的两个WT1肽之间形成二硫键来获得WT1肽的二聚体。
用于本发明的药物组合物中的WT1肽可以是一种,或者可以是两种或更多种。WT1肽是否在受试者中对眼内血管生成性疾病发挥治疗效果取决于WT1肽是否对应于受试者的HLA类型。目前,关于许多WT1肽,已知什么样的WT1肽与某种HLA类型相容,因此本发明中使用的WT1肽可以根据受试者的HLA类型来选择。此外,本发明的药物组合物中可以使用两种或更多种WT1肽,以适应较广范围的受试者。
例如,当受试者是HLA-A*0201-阳性时,在本发明的药物组合物中使用的优选WT1肽的实例包括但不限于包含以下氨基酸序列或由以下氨基酸序列组成的肽:Asp Leu AsnAla Leu Leu Pro Ala Val (SEQ ID NO: 33)、Arg Met Phe Pro Asn Ala Pro Tyr Leu(SEQ ID NO: 1)或Ser Leu Gly Glu Gln Gln Tyr Ser Val (SEQ ID NO: 18),以及包含氨基酸序列或由氨基酸序列组成的肽,其中在上述氨基酸序列中一个或数个氨基酸被置换、缺失或添加。
例如,当受试者是HLA-A*2601-阳性时,实例包括但不限于包含以下氨基酸序列或由以下氨基酸序列组成的肽:Val Thr Phe Asp Gly Thr Pro Ser Tyr (SEQ ID NO: 7)、Gln Gly Ser Leu Gly Glu Gln Gln Tyr (SEQ ID NO: 8)或Asp Gln Leu Lys Arg HisGln Arg Arg (SEQ ID NO: 34),以及包含氨基酸序列或由氨基酸序列组成的肽,其中在上述氨基酸序列中一个或数个氨基酸被置换、缺失或添加。
例如,当受试者是HLA-A*3303-阳性时,实例包括但不限于包含以下氨基酸序列或由以下氨基酸序列组成的肽:Leu Ser His Leu Gln Met His Ser Arg (SEQ ID NO: 10)、Phe Ser Arg Ser Asp Gln Leu Lys Arg (SEQ ID NO: 11)、Ser Asp Gln Leu Lys ArgHis Gln Arg (SEQ ID NO: 12)或Thr Ser Glu Lys Pro Phe Ser Cys Arg (SEQ ID NO:13),以及包含氨基酸序列或由氨基酸序列组成的肽,其中在上述氨基酸序列中一个或数个氨基酸被置换、缺失或添加。
例如,当受试者是HLA-A*1101-阳性时,实例包括但不限于包含以下氨基酸序列或由以下氨基酸序列组成的肽:Ala Ala Gly Ser Ser Ser Ser Val Lys (SEQ ID NO: 35)、Pro Ile Leu Cys Gly Ala Gln Tyr Arg (SEQ ID NO: 14)、Arg Ser Ala Ser Glu ThrSer Glu Lys (SEQ ID NO: 36)、Ser Ala Ser Glu Thr Ser Glu Lys Arg (SEQ ID NO:15)、Ser His Leu Gln Met His Ser Arg Lys (SEQ ID NO: 16)、Thr Gly Val Lys ProPhe Gln Cys Lys (SEQ ID NO: 17)、Lys Thr Cys Gln Arg Lys Phe Ser Arg (SEQ IDNO: 37)、Ser Cys Arg Trp Pro Ser Cys Gln Lys (SEQ ID NO: 38)或Asn Met His GlnArg Asn Met Thr Lys (SEQ ID NO: 39),以及包含氨基酸序列或由氨基酸序列组成的肽,其中在上述氨基酸序列中一个或数个氨基酸被置换、缺失或添加。
例如,当受试者是HLA-A*2402-阳性时,实例包括但不限于包含以下氨基酸序列或由以下氨基酸序列组成的肽:Cys Met Thr Trp Asn Gln Met Asn Leu (SEQ ID NO: 9)或Cys Tyr Thr Trp Asn Gln Met Asn Leu (SEQ ID NO: 19),包含SEQ ID NO: 9的氨基酸序列或由SEQ ID NO: 9的氨基酸序列组成的肽的二聚体,包含SEQ ID NO: 9的氨基酸序列或由SEQ ID NO: 9的氨基酸序列组成的肽的胱氨酸形式,以及包含氨基酸序列或由氨基酸序列组成的肽,其中在上述氨基酸序列中一个或数个氨基酸被置换、缺失或添加。
例如,当受试者是HLA-DRB1-阳性、HLA-DRB3-阳性、HLA-DRB4-阳性、HLA-DRB5-阳性、HLA-DPB1-阳性或HLA-DQB1-阳性时,实例包括但不限于包含以下氨基酸序列或由以下氨基酸序列组成的肽:Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala TyrGly Ser Leu Gly (SEQ ID NO: 27)、Glu Gln Cys Leu Ser Ala Phe Thr Val His PheSer Gly Gln Phe Thr Gly (SEQ ID NO: 28)、Pro Asn His Ser Phe Lys His Glu AspPro Met Gly Gln Gln Gly (SEQ ID NO: 29)、Asn Leu Tyr Gln Met Thr Ser Gln LeuGlu Cys Met Thr Trp Asn Gln Met Asn Leu (SEQ ID NO: 30)、Phe Arg Gly Ile GlnAsp Val Arg Arg Val Pro Gly Val Ala Pro Thr Leu Val Arg (SEQ ID NO: 31)或LysArg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His (SEQ ID NO: 32),以及包含氨基酸序列或由氨基酸序列组成的肽,其中在上述氨基酸序列中一个或数个氨基酸被置换、缺失或添加。
作为本发明的药物组合物中的活性成分,可以使用编码WT1肽的多核苷酸。可以基于WT1肽的氨基酸序列确定多核苷酸的碱基序列。该多核苷酸可以通过例如公知的DNA合成法或RNA合成法,例如化学合成法、PCR法等制备。
可以联合使用本发明的药物组合物和用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者的药物。用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者的药物的实例包括但不限于贝伐单抗、西妥昔单抗、帕尼单抗等。用于眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者的药物的实例包括但不限于血管内皮细胞生长因子抑制剂,例如阿普西柏、哌加他尼钠(pegaptanib sodium)、雷珠单抗等。
可以用本发明的药物组合物治疗的眼内血管生成性疾病包括但不限于湿型年龄相关性黄斑变性、近视性黄斑变性、血管样条纹、中心性浆液性脉络膜视网膜病变、各种类型的视网膜色素上皮病、脉络膜萎缩、无脉络膜、脉络膜骨瘤、糖尿病性视网膜病变、早产儿视网膜病变、虹膜红变性青光眼和角膜新生血管形成。
对于本发明的药物组合物的给药途径没有特别限定,然而优选的给药途径的实例包括皮内给药、皮下给药、经皮给药和经粘膜给药,例如滴眼剂、鼻喷雾剂和舌下剂。
本发明的药物组合物的剂型没有特别限定,剂型的实例包括注射液药剂、滴眼液药剂、鼻喷雾液药剂、洗剂、霜剂、贴剂、舌下片剂和锭剂。这些剂型可以通过本领域技术人员熟知的方法制备和给予。
当使用本发明的药物组合物时,WT1肽的剂量可以根据WT1肽的类型、给药途径、剂型、疾病类型、疾病严重程度、患者的健康状态等考虑而合适地变化。通常,成人的WT1肽的剂量为每日0.1μg/ kg至1mg / kg。此外,可以适当地改变WT1肽的类型、给药途径和剂型。除药学上可接受的载体和稀释剂之外,本发明的药物组合物可以包括合适的佐剂如氢氧化铝。另一方面,本发明的药物组合物可以含有包封在脂质体中的WT1肽。
另一方面,本发明涉及WT1肽在眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者中的用途。在另一方面,本发明涉及WT1肽在制备用于眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者的药物中的用途。在又一方面,本发明涉及用于眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者的方法,其特征在于向需要眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者的受试者给予WT1肽。以上描述也适用于这些方面。
在另一方面,本发明涉及含有用WT1肽诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞的药物组合物,其用于眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者。此外,本发明涉及用WT1肽诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞在眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者中的用途。此外,本发明涉及用WT1肽诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞在制备用于眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者的药物中的用途。在又一方面,本发明涉及用于眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者的方法,其特征在于向需要眼内血管生成性疾病的治疗和预防的任一者或治疗和预防两者的受试者给予用WT1肽诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞。以上描述也适用于这些方面。
用于诱导或活化抗原呈递细胞、杀伤T细胞或辅助T细胞的方法是本领域技术人员已知的。在体内,WT1肽可以给予受试者以诱导或活化杀伤T细胞和辅助T细胞。在体外,例如,含有来源于受试者的淋巴细胞的样品可以与WT1肽-HLA分子复合物反应以获得杀伤T细胞。此外,例如,可以在WT1肽的存在下培养来自受试者的外周血单核细胞,以从所述外周血单核细胞诱导WT1特异性CTL。此外,例如,可以在WT1肽的存在下培养来自受试者的未成熟抗原呈递细胞,以诱导通过HLA分子呈递WT1肽的抗原呈递细胞。未成熟抗原呈递细胞是指可以成熟为抗原呈递细胞的细胞,未成熟抗原呈递细胞的实例包括未成熟的树突细胞。此外,例如,可以将WT1肽加入到抗原呈递细胞中以活化辅助T细胞。可用任何WT1肽诱导或活化本发明药物组合物中使用的抗原呈递细胞、杀伤T细胞或辅助T细胞。因此,诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞可以给予受试者,优选给予自其获得这些细胞的受试者,以进行眼内血管生成性疾病的治疗和预防。
上述治疗和/或预防的描述主要是关于眼内血管生成性疾病,然而,上述描述也适用于其它血管生成性疾病。
下面具体和更详细地参考实施例来描述本发明,但是这些实施例不应被解释为以任何方式限制本发明。
实施例
实施例1
使用激光诱导的脉络层血管生成的小鼠模型证明WT1肽疫苗的治疗效果
实验方法
1-1.测试物质
两种WT1肽:WT1126 (Arg Met Phe Pro Asn Ala Pro Tyr Leu (SEQ ID NO: 1))和WT135 (Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly Ser LeuGly (SEQ ID NO: 27)),用作测试物质。
1-2.用于实验的动物
使用雄性C57BL/6J小鼠(由CLEA Japan,Inc.提供)。在实验开始时,小鼠为8周龄(体重:约20〜25g)。小鼠用实验室食物(由Oriental Yeast Co.,Ltd.制备)和自来水自由喂食。每个给药组使用6只小鼠。
1-3.剂量和给药方法
将作为WT1肽的WT1126或WT135溶解于无菌PBS中,使溶液浓度为22.7 mg/mL。用无菌PBS将所得物稀释至0.227或2.27 mg/mL。将得到的WT1溶液和Montanide ISA51 VG混合,使体积比为1:1.27,制成0.1 μl/μL、1 μl/μL和10 μl/μL的乳液。每种乳液以10 μL/个体,皮内给药。给药剂量为1 μg/个体、10 μg/个体和100 μg/个体。给药时间为在光凝固后15、22、29和36天。
具体而言,对于给予测试物质(WT1肽)的给药组(1〜4组)的小鼠,通过以下程序进行给药。
(1)在光凝固后14天,根据荧光渗漏面积进行分组。
(2)在光凝固后15、22、29和36天进行体重测量和一般症状观察。
(3)用发剪刮腹部,然后使用30G注射针进行皮内给药。
实验组的构成(6只动物/组)总结在表1中。
表1
1-4.光凝固和眼底成像
使用的程序如下。
(1)进行体重测量和一般症状观察。
(2)用Mydrin-P(由Santen Pharmaceutical Co.,Ltd.制备)进行瞳孔扩张,然后通过肌内给药以1 mL/kg的Ketalar注射液和Celactal注射液(7:1)的混合物进行全身麻醉。
(3)使用多色激光光凝固剂(红色)(由NIDEK CO.,LTD.制备)在以下凝固条件下进行光凝固:光点尺寸为50 μm,输出为60 mW,凝固时间为0.1秒。
(4)使用组织观察用盖玻片作为接触镜,然后进行4次光凝固,条件是排除后眼底的散发性大视网膜血管。
(5)光凝固后立即用Micron III(Phoenix Research Labs制造)进行眼底成像。
(6)将Hyalein眼用溶液的滴眼剂施用于双眼。
1-5.荧光眼底血管造影
使用的程序如下。
(1)在光凝固后14、21、28、35和42天进行体重测量和一般症状观察。
(2)用Mydrin-P进行瞳孔扩张,然后通过肌内注射,以1 mL/kg的Ketalar注射液(由DAIICHI SANKYO COMPANY,LIMITED制备)和Celactal注射液(由Bayer制备)(7:1)的混合物,进行全身麻醉。
(3)通过尾静脉以0.1 mL/kg注射Fluorescite(由Alcon,Inc.制备),然后使用Micron III进行荧光眼底血管造影。
(4)使用图像分析软件计算荧光渗漏的面积。
1-6.观察、测量、检查项目等的概述
图1总结了上述描述。
1-7.数据分析
使用Microsoft EXCEL进行数据分析,获得的结果显示为平均值+/-标准偏差。使用EXSUS 8.0.0版(SAS ver.9.3,CAC EXICARE Corporation)进行统计学分析,选择Dunnett型多组比较(组1对比组2、3和4)进行多重比较检验。所有测试均使用<5%的显著性水平。
2. 实验结果
光凝固后2周和6周,荧光眼底血管造影的血管生成测量结果如图2所示。与PBS给药组中的小鼠相比,在光凝固后6周给予WT1肽(WT1126)的小鼠眼底的血管生成显著受到抑制。
在光凝固后2周、3周、4周和6周进行荧光眼底血管造影,以分析脉络膜新生血管区域的时间依赖性变化。图3显示了WT1126给药的小鼠的数据,图4显示了WT135给药的小鼠的数据。在给予任一WT1肽的小鼠中观察到给予WT1肽的脉络膜新生血管区域的减少。
与PBS给药组相比,在WT1126给药组中,以1 μg/个体、10 μg/个体和100 μg/个体的任何施用剂量,脉络膜新生血管区域都减少。具体来说,在给予100 μg/个体的WT1126的组中,减少效果是显著的,即,在光凝固后6周的脉络膜新生血管区域减少到在光凝固后2周的脉络膜新生血管区域的约50%。另一方面,在PBS给药组中,在光凝固后6周的脉络膜新生血管区域增加至在光凝固后2周的脉络膜新生血管区域的约230%。
同样在WT135给药组中,也观察到以1 μg/个体、10 μg/个体和100 μg/个体的任何施用剂量,脉络膜新生血管区域的下降趋势。在光凝固后6周的脉络膜新生血管区域减少到在光凝固后2周的脉络膜新生血管区域的约50%。
实施例2
两种WT1肽:WT1235m (Cys Tyr Thr Trp Asn Gln Met Asn Leu (SEQ ID NO:19))和WT1332 (Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His(SEQ ID NO: 32))用作测试物质,并提供以下给药组设定,以与实施例1相同的方法和程序进行实验。WT1235m是其中WT1235(SEQ ID NO: 9)的2位的甲硫氨酸被酪氨酸置换的肽。
表2
在光凝固后2周、3周、4周、5周和6周进行荧光眼底血管造影,以分析脉络膜新生血管区域的时间依赖性变化。结果如图5所示。与PBS给药组相比,在给予WT1235m或WT1332的任一WT1肽的小鼠中观察到给予WT1肽的脉络膜新生血管区域的减少。在WT1332给药组中,在光凝固后6周的脉络膜新生血管区域减少至在光凝固后2周的脉络膜新生血管区域的约70%。在WT1235m给药组中,脉络膜新生血管区域的增加被抑制,即光凝固后6周的脉络膜新生血管区域与光凝固后2周相同。
实施例3
当联合使用WT1肽(WT1126、WT1235m和WT1332)和阿普西柏时,分析脉络膜新生血管区域的时间依赖性变化。给药组的设定提供如下(联合使用组:组3、4和5)。在激光应用的同一天进行阿普西柏对右眼的玻璃体内给药。
表3
结果如图6所示。当联合使用WT1肽和阿普西柏时,观察到脉络膜新生血管区域减少或对脉络膜新生血管区域增加的抑制,从而证实了联合效果。
根据上述实验结果,证实作为癌抗原肽的WT1肽在血管生成性疾病的治疗中是有效的。
工业适用性
本发明提供了含有癌抗原肽的药物组合物,其用于血管生成性疾病的治疗和预防的任一者或治疗和预防两者,因此可以尤其用于药物领域。
<110> 株式会社癌免疫研究所
<120> 血管生成性疾病的免疫疗法
<130> 672588
<150> JP 2014-251208
<151> 2014-12-11
<160> 40
<170> PatentIn version 3.2
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<210> 21
<211> 9
<212> PRT
<213> 智人
<400> 21
Ser Met Gly Glu Gln Gln Tyr Ser Val
1 5
<210> 22
<211> 9
<212> PRT
<213> 智人
<400> 22
Ser Leu Met Glu Gln Gln Tyr Ser Val
1 5
<210> 23
<211> 9
<212> PRT
<213> 智人
<400> 23
Phe Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210> 24
<211> 9
<212> PRT
<213> 智人
<400> 24
Arg Leu Phe Pro Asn Ala Pro Tyr Leu
1 5
<210> 25
<211> 9
<212> PRT
<213> 智人
<400> 25
Arg Met Met Pro Asn Ala Pro Tyr Leu
1 5
<210> 26
<211> 9
<212> PRT
<213> 智人
<400> 26
Arg Met Phe Pro Asn Ala Pro Tyr Val
1 5
<210> 27
<211> 18
<212> PRT
<213> 智人
<400> 27
Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly Ser
1 5 10 15
Leu Gly
<210> 28
<211> 17
<212> PRT
<213> 智人
<400> 28
Glu Gln Cys Leu Ser Ala Phe Thr Val His Phe Ser Gly Gln Phe Thr
1 5 10 15
Gly
<210> 29
<211> 15
<212> PRT
<213> 智人
<400> 29
Pro Asn His Ser Phe Lys His Glu Asp Pro Met Gly Gln Gln Gly
1 5 10 15
<210> 30
<211> 19
<212> PRT
<213> 智人
<400> 30
Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln
1 5 10 15
Met Asn Leu
<210> 31
<211> 19
<212> PRT
<213> 智人
<400> 31
Phe Arg Gly Ile Gln Asp Val Arg Arg Val Pro Gly Val Ala Pro Thr
1 5 10 15
Leu Val Arg
<210> 32
<211> 16
<212> PRT
<213> 智人
<400> 32
Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His
1 5 10 15
<210> 33
<211> 9
<212> PRT
<213> 智人
<400> 33
Asp Leu Asn Ala Leu Leu Pro Ala Val
1 5
<210> 34
<211> 9
<212> PRT
<213> 智人
<400> 34
Asp Gln Leu Lys Arg His Gln Arg Arg
1 5
<210> 35
<211> 9
<212> PRT
<213> 智人
<400> 35
Ala Ala Gly Ser Ser Ser Ser Val Lys
1 5
<210> 36
<211> 9
<212> PRT
<213> 智人
<400> 36
Arg Ser Ala Ser Glu Thr Ser Glu Lys
1 5
<210> 37
<211> 9
<212> PRT
<213> 智人
<400> 37
Lys Thr Cys Gln Arg Lys Phe Ser Arg
1 5
<210> 38
<211> 9
<212> PRT
<213> 智人
<400> 38
Ser Cys Arg Trp Pro Ser Cys Gln Lys
1 5
<210> 39
<211> 9
<212> PRT
<213> 智人
<400> 39
Asn Met His Gln Arg Asn Met Thr Lys
1 5
<210> 40
<211> 449
<212> PRT
<213> 智人
<400> 40
Met Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu Pro Ala Val Pro
1 5 10 15
Ser Leu Gly Gly Gly Gly Gly Cys Ala Leu Pro Val Ser Gly Ala Ala
20 25 30
Gln Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr
35 40 45
Gly Ser Leu Gly Gly Pro Ala Pro Pro Pro Ala Pro Pro Pro Pro Pro
50 55 60
Pro Pro Pro Pro His Ser Phe Ile Lys Gln Glu Pro Ser Trp Gly Gly
65 70 75 80
Ala Glu Pro His Glu Glu Gln Cys Leu Ser Ala Phe Thr Val His Phe
85 90 95
Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg Tyr Gly Pro Phe
100 105 110
Gly Pro Pro Pro Pro Ser Gln Ala Ser Ser Gly Gln Ala Arg Met Phe
115 120 125
Pro Asn Ala Pro Tyr Leu Pro Ser Cys Leu Glu Ser Gln Pro Ala Ile
130 135 140
Arg Asn Gln Gly Tyr Ser Thr Val Thr Phe Asp Gly Thr Pro Ser Tyr
145 150 155 160
Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro Asn His Ser Phe
165 170 175
Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu Gly Glu Gln Gln
180 185 190
Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr Asp Ser
195 200 205
Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro Tyr Ser Ser Asp
210 215 220
Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln
225 230 235 240
Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala Ala Gly Ser Ser Ser
245 250 255
Ser Val Lys Trp Thr Glu Gly Gln Ser Asn His Ser Thr Gly Tyr Glu
260 265 270
Ser Asp Asn His Thr Thr Pro Ile Leu Cys Gly Ala Gln Tyr Arg Ile
275 280 285
His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg Arg Val Pro
290 295 300
Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr Ser Glu Lys
305 310 315 320
Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg Tyr Phe Lys
325 330 335
Leu Ser His Leu Gln Met His Ser Arg Lys His Thr Gly Glu Lys Pro
340 345 350
Tyr Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser Arg Ser Asp
355 360 365
Gln Leu Lys Arg His Gln Arg Arg His Thr Gly Val Lys Pro Phe Gln
370 375 380
Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His Leu Lys Thr
385 390 395 400
His Thr Arg Thr His Thr Gly Lys Thr Ser Glu Lys Pro Phe Ser Cys
405 410 415
Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu Val
420 425 430
Arg His His Asn Met His Gln Arg Asn Met Thr Lys Leu Gln Leu Ala
435 440 445
Leu
Claims (6)
1.WT1肽在制备用于眼内血管生成性疾病的治疗的药物中的用途,
其中所述WT1肽由以下氨基酸序列组成:
(a)Arg Met Phe Pro Asn Ala Pro Tyr Leu(SEQ ID NO: 1),其中一个或两个氨基酸被置换、缺失或添加,
(b)Cys Tyr Thr Trp Asn Gln Met Asn Leu(SEQ ID NO: 19),其中一个或两个氨基酸被置换、缺失或添加,
(c)Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly Ser LeuGly(SEQ ID NO: 27),其中一个或两个氨基酸被置换、缺失或添加,或
(d)Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His(SEQ IDNO: 32),其中一个或两个氨基酸被置换、缺失或添加,
其中所述眼内血管生成性疾病选自湿型年龄相关性黄斑变性、近视性黄斑变性、血管样条纹、中心性浆液性脉络膜视网膜病变、各种类型的视网膜色素上皮病、脉络膜萎缩、无脉络膜、脉络膜骨瘤、糖尿病性视网膜病变、早产儿视网膜病变、虹膜红变性青光眼和角膜新生血管形成。
2.用WT1肽诱导或活化的抗原呈递细胞、杀伤T细胞或辅助T细胞在制备用于眼内血管生成性疾病的治疗的药物中的用途,
其中所述WT1肽由以下氨基酸序列组成:
(a)Arg Met Phe Pro Asn Ala Pro Tyr Leu(SEQ ID NO: 1),其中一个或两个氨基酸被置换、缺失或添加,
(b)Cys Tyr Thr Trp Asn Gln Met Asn Leu(SEQ ID NO: 19),其中一个或两个氨基酸被置换、缺失或添加,
(c)Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly Ser LeuGly(SEQ ID NO: 27),其中一个或两个氨基酸被置换、缺失或添加,或
(d)Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His(SEQ IDNO: 32),其中一个或两个氨基酸被置换、缺失或添加,
其中所述眼内血管生成性疾病选自湿型年龄相关性黄斑变性、近视性黄斑变性、血管样条纹、中心性浆液性脉络膜视网膜病变、各种类型的视网膜色素上皮病、脉络膜萎缩、无脉络膜、脉络膜骨瘤、糖尿病性视网膜病变、早产儿视网膜病变、虹膜红变性青光眼和角膜新生血管形成。
3.根据权利要求1或2所述的用途,其中所述WT1肽对HLA分子具有结合能力。
4.根据权利要求1或2所述的用途,其中所述WT1肽活化杀伤T细胞或辅助T细胞。
5.根据权利要求1或2所述的用途,其中所述药物通过皮内给药、经皮给药或经粘膜给药而给予。
6.WT1肽以及药物在制备用于眼内血管生成性疾病的治疗的联合药物中的用途,其中所述药物用于血管生成性疾病的治疗,
其中所述WT1肽由以下氨基酸序列组成:
(a)Arg Met Phe Pro Asn Ala Pro Tyr Leu(SEQ ID NO: 1),其中一个或两个氨基酸被置换、缺失或添加,
(b)Cys Tyr Thr Trp Asn Gln Met Asn Leu(SEQ ID NO: 19),其中一个或两个氨基酸被置换、缺失或添加,
(c)Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly Ser LeuGly(SEQ ID NO: 27),其中一个或两个氨基酸被置换、缺失或添加,或
(d)Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His(SEQ IDNO: 32),其中一个或两个氨基酸被置换、缺失或添加,
其中所述眼内血管生成性疾病选自湿型年龄相关性黄斑变性、近视性黄斑变性、血管样条纹、中心性浆液性脉络膜视网膜病变、各种类型的视网膜色素上皮病、脉络膜萎缩、无脉络膜、脉络膜骨瘤、糖尿病性视网膜病变、早产儿视网膜病变、虹膜红变性青光眼和角膜新生血管形成。
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ES2531142T3 (es) | 2005-10-17 | 2015-03-11 | Sloan Kettering Inst Cancer | Péptidos WT1 de unión a HLA de clase II, y composiciones y métodos que los comprenden |
CA2645766A1 (en) | 2006-04-10 | 2007-10-25 | Sloan Kettering Institute For Cancer Research | Immunogenic wt-1 peptides and methods of use thereof |
AR076349A1 (es) | 2009-04-23 | 2011-06-01 | Int Inst Cancer Immunology Inc | Peptido auxiliar del antigeno del cancer |
EP2802347B1 (en) | 2012-01-13 | 2019-01-09 | Memorial Sloan Kettering Cancer Center | Immunogenic wt-1 peptides and methods of use thereof |
US10815273B2 (en) | 2013-01-15 | 2020-10-27 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
US9919037B2 (en) | 2013-01-15 | 2018-03-20 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
WO2020071551A1 (ja) | 2018-10-05 | 2020-04-09 | 株式会社癌免疫研究所 | 良性腫瘍の予防または治療薬 |
JP2023525822A (ja) * | 2020-05-12 | 2023-06-19 | エルジー・ケム・リミテッド | 多量体t細胞調節性ポリペプチド及びその使用方法 |
CN112759634B (zh) * | 2021-01-21 | 2022-04-08 | 浙江辉肽生命健康科技有限公司 | 具有氨基酸结构feyieenky的生物活性肽及其制备方法和应用 |
EP4385519A1 (en) | 2021-08-12 | 2024-06-19 | International Institute of Cancer Immunology, Inc. | Pharmaceutical composition and method for treatment or prevention of cancer |
CN114652826B (zh) * | 2022-01-24 | 2022-10-14 | 景泽生物医药(合肥)有限公司 | 抗egfr抗体的用途 |
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ES2310052T3 (es) | 1998-09-30 | 2008-12-16 | Corixa Corporation | Composiciones y metodos para la inmunoterapia especifica de wt1. |
US7063854B1 (en) | 1998-09-30 | 2006-06-20 | Corixa Corporation | Composition and methods for WTI specific immunotherapy |
US7312243B1 (en) | 2003-08-29 | 2007-12-25 | Jay Pravda | Materials and methods for treatment of gastrointestinal disorders |
CN101580538B (zh) | 2003-11-05 | 2013-06-19 | 株式会社国际癌症免疫研究所 | Wt1衍生的hla-dr-结合抗原肽 |
DK1988163T3 (da) | 2006-02-22 | 2012-08-20 | Int Inst Cancer Immunology Inc | Hla-a*3303-begrænset wt1 peptid og farmaceutisk sammensætning omfattende det samme |
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EP3384926A1 (en) * | 2007-12-05 | 2018-10-10 | International Institute of Cancer Immunology, Inc. | Cancer vaccine composition |
AR076349A1 (es) * | 2009-04-23 | 2011-06-01 | Int Inst Cancer Immunology Inc | Peptido auxiliar del antigeno del cancer |
TWI646970B (zh) | 2012-12-17 | 2019-01-11 | 大塚製藥股份有限公司 | 活化輔助t細胞的方法 |
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CA2840988A1 (en) * | 2013-02-05 | 2014-08-05 | Nitto Denko Corporation | Wt1 peptide cancer vaccine composition for mucosal administration |
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EP3231438A1 (en) | 2017-10-18 |
US11413322B2 (en) | 2022-08-16 |
JP6266811B2 (ja) | 2018-01-24 |
US20200023029A1 (en) | 2020-01-23 |
KR20170092660A (ko) | 2017-08-11 |
MX2017007595A (es) | 2018-03-01 |
KR20230141904A (ko) | 2023-10-10 |
BR112017012381A2 (pt) | 2018-06-19 |
AU2015362379A1 (en) | 2017-07-13 |
CN108064163B (zh) | 2022-06-10 |
AU2015362379B2 (en) | 2020-05-14 |
CN108064163A (zh) | 2018-05-22 |
ES2805094T3 (es) | 2021-02-10 |
JPWO2016093326A1 (ja) | 2017-09-14 |
EP3231438A4 (en) | 2018-06-20 |
US20200078436A1 (en) | 2020-03-12 |
US20220313770A1 (en) | 2022-10-06 |
EP3231438B1 (en) | 2020-06-17 |
US20170368131A1 (en) | 2017-12-28 |
US10525096B2 (en) | 2020-01-07 |
HK1251184A1 (zh) | 2019-01-25 |
US11369656B2 (en) | 2022-06-28 |
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