CN112771159A - 精氨酸酶1多肽 - Google Patents
精氨酸酶1多肽 Download PDFInfo
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- CN112771159A CN112771159A CN201980062504.7A CN201980062504A CN112771159A CN 112771159 A CN112771159 A CN 112771159A CN 201980062504 A CN201980062504 A CN 201980062504A CN 112771159 A CN112771159 A CN 112771159A
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- arginase
- cells
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Abstract
本发明涉及衍生自精氨酸酶1的新型多肽。本发明还涉及编码所述多肽的多核苷酸。本发明还涉及包含所述多肽和多核苷酸的组合物。本发明还涉及所述多肽、多核苷酸和组合物的用途。
Description
技术领域
本发明涉及新的多肽,其衍生自精氨酸酶1。本发明还涉及编码多肽的多核苷酸。本发明还涉及包含多肽和多核苷酸的组合物。本发明还涉及多肽、多核苷酸和组合物的用途。
背景技术
精氨酸酶是催化将氨基酸L-精氨酸转化为L-鸟氨酸和脲的反应的酶。这消耗了精氨酸的微环境并导致对肿瘤特异性细胞毒性T细胞应答的抑制。已在乳腺癌、肺癌、结肠癌或前列腺癌患者的癌细胞中检测到精氨酸酶活性升高。已经在体外和体内证明用大鼠精氨酸酶基因转染的小鼠巨噬细胞促使共培养的肿瘤细胞的增殖。此外,已表明诱导巨噬细胞的精氨酸酶表达可通过聚胺合成而增加肿瘤血管形成。鼠肺癌模型的结果表明,存在成熟肿瘤相关骨髓细胞(myeloid cell)的亚群,其表达高水平的精氨酸酶。这些肿瘤相关骨髓细胞消耗了胞外L-精氨酸,这抑制肿瘤浸润淋巴细胞(TIL)的抗原特异性增殖。在小鼠中,注入精氨酸酶抑制剂阻断了肺癌的生长。这表明了在肿瘤细胞和肿瘤相关骨髓细胞中诱导精氨酸酶表达是如何通过抑制抗肿瘤免疫应答(通过对TIL的不利作用)来促使肿瘤生长。
MDSC(髓源性抑制细胞)抑制效应T细胞和天然杀伤细胞的活化、增殖和细胞毒性,以及诱导Treg分化和扩增。肿瘤细胞和MDSC都能通过经由酶一氧化氮合酶(NOS)和精氨酸酶操控L-精氨酸代谢来抑制T细胞。许多肿瘤表现出精氨酸酶和可诱导NOS(iNOS)的表达增加,导致肿瘤微环境中的精氨酸消耗。若干研究强调这种改变的肿瘤精氨酸代谢在抑制肿瘤特异性T细胞应答中的重要性,并且最近证明,急性髓细胞样白血病(AML)BLAST显示出精氨酸酶依赖性的抑制T细胞增殖和造血干细胞的能力。此外,精氨酸酶和iNOS抑制剂降低了AML的抑制活性。
发明内容
本发明的发明人之前已经鉴定了精氨酸酶1的50个氨基酸的区域,其为免疫原性的“热点”。该区域对应于全长人精氨酸酶1(SEQ ID NO:10)的第161-210位。在WO2018065563中记载了该区域和由其衍生的肽。(注意,术语“精氨酸酶1”、“Arg1”、“精氨酸酶1”在本文可互换使用)。
本发明的发明人现已鉴定衍生自该区域的多肽的特定子集(sub-set)在刺激免疫应答方面特别有效。因此,预期本发明的多肽在刺激针对精氨酸酶1和表达精氨酸酶1的细胞的有益免疫应答方面特别有效。癌症的新免疫疗法的开发需要充分理解发病机理中涉及的分子以及免疫系统识别的特定蛋白。在临床环境下,诱导精氨酸酶特异性免疫应答,除杀伤癌细胞以外,还能够通过抑制表达精氨酸酶的细胞(特别是MDSC和肿瘤相关巨噬细胞(TAM))的免疫抑制功能而在总体上支持抗癌免疫应答。因此,由于表达精氨酸酶的细胞拮抗其他免疫治疗方法的所需效果,所以靶向骨髓树突细胞(例如通过免疫接种本发明的多肽)将与其他抗癌免疫疗法高度协同。
本发明提供:
一种分离的多肽,其由以下氨基酸序列的任一个组成:
a.ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRL(SEQ ID NO:1);
b.ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKL(SEQ ID NO:2);
c.ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSM(SEQ ID NO:3);
d.ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSM(SEQ ID NO:4);
e.ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK(SEQ ID NO:5);
f.ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKLGIGK(SEQ ID NO:6)。
本发明进一步提供了编码本发明的多肽的多核苷酸,其任选地包含在载体中。
本发明还提供了一种组合物,其包含本发明的多肽或多核苷酸、至少一种可药用的稀释剂、载体或防腐剂,以及任选地佐剂。
本发明还提供了一种在受试者中治疗或预防疾病或病症的方法,所述方法包括将本发明的多肽、多核苷酸或组合物给予受试者。
附图说明
图1示出了对长Arg1衍生的肽的应答
对来自四个健康捐赠者(HD)的PBMC中的ArgLong、ArgLong2和ArgLong3肽的IFNγELISPOT应答。柱状图代表每个孔的平均斑点数+平均值的标准误差。对于每个捐赠者,还示出了添加和不添加肽的对应ELISPOT孔图像。实验以5x105PBMC/孔进行,重复三次。TNTC-数量众多而无法计数。*-根据无分布重采样(DFR)规则,p≤0.05。
图2示出了与20聚体(20-mer)肽相比,对ArgLong2的应答
在19名健康捐赠者(上图)和16名癌症患者(下图)中,对Arg171-190、Arg181-200、Arg191-210和ArgLong2的IFNγELISPOT应答。每个点代表单个患者/捐赠者的肽特异性斑点的平均数。通过从肽刺激的孔中的平均斑点计数中减去对照孔中的平均斑点计数来计算应答。对于健康捐赠者,实验以4.5-5x105PBMC/孔进行,重复三次或两次,且对于癌症患者,实验以2.2-5x105PBMC/孔进行,重复三次或两次。在6名健康捐献者和2名癌症患者中,对ArgLong2的应答数量众多而无法计数(TNTC),并将其设定为>500个斑点。
图3示出了CD4+和CD8+T细胞在体外(in vitro)和离体(ex vivo)对ArgLong2的应答
3A–在来自2名健康捐献者和1名乳腺癌患者的PBMC的胞内染色中,CD4+(左)和CD8+(右)T细胞中对ArgLong2的体外应答。在ELISPOT测定前,用ArgLong2和低剂量IL-2刺激PBMC 1周。
3B–未经预先刺激(BC-乳腺癌,MM-恶性黑色素瘤),来自2名癌症患者的PBMC的胞内染色中,CD4+(左)和CD8+(右)T细胞中对ArgLong2的离体应答。
图4示出了ArgLong2特异性CD4+和CD8+细胞是记忆T细胞
4A–在4名健康捐赠者(HD)和2名癌症患者(BC-乳腺癌,MM-恶性黑色素瘤)中对ArgLong2的离体应答。实验以1-5x105个细胞/孔进行,重复三次。
4B–来自4名健康捐赠者和2名癌症患者(乳腺癌和恶性黑色素瘤)的PBMC的分选的CD4+记忆T细胞(CD45RO+)的离体IFNγELISPOT。实验以1-3x105个细胞/孔进行,重复三次。
4C–来自2名健康捐赠者的PBMC的分选的CD8+记忆T细胞(CD45RO+)的离体IFNγELISPOT。实验以1-3x105个细胞/孔进行,重复两次或进行单次。柱状图代表肽刺激的孔和对照孔中的平均斑点计数+SEM。
图5示出了IL-4刺激激活ArgLong2特异性T细胞
A–由IL-4和/或IL-2刺激一周的黑色素瘤患者PBMC中的ArgLong2应答的IFNγELISPOT。未刺激的PBMC用作对照。重叠的柱状图示出了对照孔和肽刺激的孔的平均斑点数+SEM。实验以3x105个细胞/孔进行,重复三次。B–用IL-2(120U/ml)或IL-4(100U/ml)刺激一周后,来自6名健康捐赠者(HD)和2名癌症患者(BC–乳腺癌,MM–恶性黑色素瘤)的PBMC中的ArgLong2特异性应答。没有细胞因子刺激的细胞用作对照。应答以ELISPOT中肽刺激的孔与对照孔的平均斑点计数之差来计算。实验以3x105个细胞/孔进行,重复三次或两次。
图6示出了免疫接种后体内产生的ArgLong2特异性IFNγ免疫应答
4只小鼠用ArgLong2肽免疫接种,并在7天后通过IFNγELISPOT评估了针对该肽产生的免疫应答。将来自单个小鼠的脾和引流淋巴结的细胞进行ELISPOT测定。柱状图代表平均斑点数。在添加和不添加ArgLong2肽的情况下,进行ELISPOT,重复三次。“TNTC”表示数量众多而无法计数。**表示根据无分布重采样方法(DFR),p<0.01。
图7示出了ArgLong2免疫接种在MC38结肠腺癌肿瘤模型中诱导抗肿瘤效果
在第0天,将0.5×106个MC38肿瘤细胞经皮下接种于30只小鼠的右侧腹。在同一天开始免疫接种。治疗组中的15只小鼠用Montanide乳液中的100μg的ArgLong2处理,对照组中的15只小鼠用Montanide乳液中的H2O处理。根据混合效应分析,p=0.030。
图8示出了ArgLong2免疫接种在B16F10黑素瘤肿瘤模型中诱导抗肿瘤效果
在第0天,将0.5×106个B16F10肿瘤细胞经皮下接种于30只小鼠的右侧腹。在同一天开始免疫接种。治疗组中的15只小鼠用Montanide乳液中的100μg的ArgLong2处理,对照组中的15只小鼠用Montanide乳液中的H2O处理。三次免疫接种后,停止治疗。当肿瘤体积超过864mm3时,对小鼠实施安乐死。
图9示出了ArgLong2特异性T细胞克隆识别表达精氨酸酶1的THP-1细胞
A和B–当由Th2细胞因子诱导精氨酸酶1表达时,ArgLong2特异性CD4T细胞克隆可识别THP-1细胞,其通过细胞内细胞因子染色进行定量。C–qPCR数据示出了THP-1细胞的IL-13预刺激诱导精氨酸酶1表达。
图10示出了单独的体外细胞因子刺激足以增强T细胞对ArgLong2表位的应答
将PBMC用诱导精氨酸酶1的Th2细胞因子(IL-4/IL-13)或ArgLong2肽处理7天,然后通过IFNγELISPOT体外定量ArgLong2特异性T细胞。
序列简述
SEQ ID NO:1–9各自为多肽的氨基酸序列,其衍生自对应于全长人源精氨酸酶1或鼠精氨酸酶1的第161-210位的区域。
SEQ ID NO:10和11为全长人精氨酸酶1和鼠精氨酸酶1的氨基酸序列。
SEQ ID NO:12为对应于全长人精氨酸酶1的第161-210位的区域的氨基酸序列。
SEQ ID NO:13为对应于全长鼠精氨酸酶1的第161-210位的区域的氨基酸序列。
具体实施方式
应理解,所公开的产物和方法的不同应用可被改变以适应本领域的具体需求。还应理解,本文使用的术语的目的仅为描述本发明的具体实施方案,并且不意欲进行限制。
此外,如在本说明书和所附权利要求中所使用的,,除非内容中另外明确说明,单数形式“一”、“一个”和“所述”包括复数指代物。因此,例如,提及“一种多肽”包括“多种多肽”等。
本文使用的“多肽”最广义上指两个或更多个亚基氨基酸、氨基酸类似物或其他肽模拟物的化合物。因此,术语“多肽”包括短肽序列,还包括更长的多肽和蛋白。本文使用的术语“氨基酸”指天然和/或非天然或合成的氨基酸,包括D或L光学异构体,以及氨基酸类似物和肽模拟物。
术语“患者”和“受试者”可互换使用,并且通常指人。
本文引用的所有公开出版物、专利和专利申请,无论上文或下文,均以引用的方式全文纳入本文。
本发明的发明人之前已鉴定了人和鼠精氨酸酶1的50个氨基酸的区域,其为免疫原性的“热点”。该区域对应于全长人精氨酸酶1(SEQ ID NO:10)或全长鼠精氨酸酶1(SEQID NO:11)的第161-210位。该区域和从其衍生的肽片段记载在WO2018065563中。本发明的发明人现已发现相对于来自相同区域的其他氨基酸序列,由该区域的特定连续氨基酸序列组成的多肽出人意料地为免疫原性的。
本文中“免疫原性”意指多肽能够引发对精氨酸酶1蛋白的免疫应答,优选地当所述蛋白存在于表达精氨酸酶1蛋白的细胞中或之上时。换言之,所述多肽可描述为对精氨酸酶1具有免疫原性。或者所述多肽可描述为精氨酸酶1的免疫原性片段。免疫应答优选地为T细胞应答。在将所述多肽给予至少一个个体(或在从该个体获取的样品)后,可以在所述个体(或所述样品)中检测到免疫应答。
可使用任何适合的方法(包括体外方法)来将多肽鉴定为免疫原性的。例如,如果肽具有以下特征中至少一种,则其可被鉴定为免疫原性的:
(i)通过ELISPOT测定,其能够在健康受试者和/或癌症患者的PBL群中诱导产生IFN-γ的细胞,和/或
(ii)其能够在肿瘤组织样品中原位检测与精氨酸酶1反应的CTL;
和/或
(iii)其能够诱导特异性T细胞的体外生长。
以下实施例部分还描述了适于测定多肽是否具有免疫原活性的方法。
本发明的多肽可以包含:
-对应于全长人精氨酸酶1的第169-206位的氨基酸序列。该多肽在本文中可以称为ArgLong2。其序列提供为SEQ ID NO:1。
-对应于全长鼠精氨酸酶1的第169-206位的氨基酸序列。该多肽在本文中可以称为mArgLong2。其序列提供为SEQ ID NO:2。
-对应于全长人精氨酸酶1的第169-200位的氨基酸序列。该多肽在本文中可以称为ArgLong3。其序列提供为SEQ ID NO:3。
-对应于全长鼠精氨酸酶1的第169-200位的氨基酸序列。该多肽在本文中可以称为mArgLong3。其序列提供为SEQ ID NO:4。
-对应于全长人精氨酸酶1的第169-210位的氨基酸序列。该多肽在本文中可以称为ArgLong。其序列提供为SEQ ID NO:5。
-对应于全长鼠精氨酸酶1的第169-210位的氨基酸序列。该多肽在本文中可以称为mArgLong。其序列提供为SEQ ID NO:6。
多肽优选地由对应于全长人或鼠精氨酸酶1的第169-206位的氨基酸序列组成,即其由SEQ ID NO:1或2的氨基酸序列组成。即,所述多肽优选地为ArgLong2或mArgLong2。
多肽最优选地由对应于全长人精氨酸酶1的第169-206位的氨基酸序列组成,即其由SEQ ID NO:1的氨基酸序列组成。即,所述多肽优选地为ArgLong2。
在本文所述的任何多肽中,氨基酸序列可以通过1、2、3、4或5个(最高达5个)添加、删除或置换进行修饰,条件是与具有未修饰序列的多肽相比,具有修饰序列的多肽表现出相同或增加的对精氨酸酶1的免疫原性。“相同”应理解为与未修饰序列的多肽相比,修饰序列的多肽没有表现出显著降低的对精氨酸酶1的免疫原性。序列间免疫原性的任何比较均使用相同的测定法进行。除非另有说明,多肽序列的修饰优选地为保守性氨基酸置换。保守性置换用具有相似化学结构、相似化学性质或相似侧链体积的其他氨基酸替换氨基酸。引入的氨基酸可以具有与其替换的氨基酸相似的极性、亲水性、疏水性、碱性、酸性、中性或电荷。或者,保守性置换可以引入另一个芳族或脂肪族氨基酸来替换现有的芳族或脂肪族氨基酸。保守性氨基酸变化是本领域所公知的,并且可以根据下表A1中定义的20种主要氨基酸的性质选择。如果氨基酸具有相似的极性,这可以通过参考表A2中氨基酸侧链的亲水性级别(hydropathy)来确定。
表A1-氨基酸的化学性质
表A2-亲水性级别
在本文公开的任何多肽中,可以进行任何一种或多种以下修饰以改善其生理化学性质(例如稳定性),条件是与具有未修饰序列的多肽相比,所述多肽表现出相同或增加的对精氨酸酶1的免疫原性:
a)用相应的酰胺替换C末端氨基酸(可以增加对羧肽酶的抗性)
b)用相应的酰化氨基酸替换N末端氨基酸(可以增加对氨肽酶的抗性);
c)用相应的甲基化氨基酸替换一个或多个氨基酸(可以提高蛋白水解抗性);
d)用D-构型的对应氨基酸替换一种或多种氨基酸(可以提高蛋白水解抗性)。
对于(c)和(d)类的修饰,一个优选的实施例为对应于SEQ ID NO:1的第29位的位置上的Tyr残基的修饰(例如用N-甲基(Tyr)替换或用D构型Tyr替换)。这是因为Tyr就出现在第28位的Lys残基之后,因此位于胰蛋白酶样蛋白酶(其通常在Lys后裂解)的蛋白水解的潜在位点。
本文公开的任何多肽可以在N和/或C末端连接至少一个额外的部分以提高溶解度、稳定性和/或有助于制备/分离,条件是与缺少额外部分的多肽相比,所述多肽表现出相同或增加的对精氨酸酶1的免疫原性。适合的部分包括亲水性氨基酸。例如,氨基酸序列KK、KR或RR可以添加在N末端和/或C末端。其他适合的部分包括白蛋白或PEG(聚乙二醇)。
本文公开的多肽可以通过任何适合的方法制备。例如,可以使用本领域已知的标准技术直接合成多肽,例如Fmoc固相化学、Boc固相化学或通过溶液相肽合成。或者,可以通过用编码所述多肽的核酸分子或载体转化细胞(通常是细菌细胞)来制备多肽。本发明提供了编码本发明多肽的核酸分子和载体。本发明还提供了包含该核酸或载体的宿主细胞。
术语“核酸分子”和“多核苷酸”在本文中可互换使用,并且指任何长度的聚合形式的核苷酸(脱氧核糖核苷酸或核糖核苷酸,或其类似物)。多核苷酸的非限制性实例包括基因、基因片段、信使RNA(mRNA)、cDNA、重组多核苷酸、质粒、载体、任何序列的分离DNA、任何序列的分离、RNA、核酸探针和引物。本发明的多核苷酸可以以分离或基本上分离的形式提供。基本上分离意指可以从任何周围介质中基本上但非全部分离出多肽。可以将多核苷酸与不会干扰其预期用途的载体或稀释剂混合,并且其仍被认为是基本上分离的。“编码”所选多肽的核酸序列是一种核酸分子,当其置于适当的调控序列的控制下时,所述核酸分子在体内转录(在DNA的情况下)并翻译为多肽(在mRNA的情况下),例如在表达载体中。编码序列的边界由在5'(氨基)末端的起始密码子和在3'(羧基)末端的翻译终止密码子确定。对于本发明,这样的核酸序列可以包括但不限于来自病毒的cDNA、原核或真核mRNA、来自病毒或原核DNA或RNA的基因组序列,以及甚至合成的DNA序列。转录终止序列可以位于编码序列的3'。
可以根据本领域公知的方法合成多核苷酸,如例如在Sambrook et al(1989,Molecular Cloning-a laboratory manual;Cold Spring Harbor Press)中所记载的。本发明的核酸分子可以以表达盒(expression cassette)的形式提供,所述表达盒包括可操作地连接至插入序列的控制序列,因此允许在体内表达本发明的多肽。这些表达盒通常又在载体(例如质粒或重组病毒载体)内提供。这样的表达盒可以直接给予宿主受试者。或者,可以将包含本发明的多核苷酸的载体给予宿主受试者。优选地使用遗传载体制备和/或给予多核苷酸。适合的载体可以是能够携带足够量的遗传信息且允许本发明的多肽表达的任何载体。
因此,本发明包括含这样的多核苷酸序列的表达载体。这样的表达载体在分子生物学领域中以常规方法构建,且可以例如涉及使用质粒DNA和适当的起始密码子(initiator)、启动子、增强子以及其它元件(例如可能必要的多腺苷酸化信号),并且其以正确的方向放置,以允许本发明的肽表达。其他适合的载体对于本领域技术人员来说将是显而易见的。关于这方面的其他实例,本发明人参考Sambrook et al.。
本发明还包括已经被修饰以表达本发明的多肽的细胞。这样的细胞通常包括原核细胞,例如细菌细胞(例如大肠杆菌(E.coli))。可以使用常规方法培养这样的细胞以产生本发明的多肽。
本发明的多肽可以为基本上分离的形式。其可以与不会干扰预期用途的载体、防腐剂或稀释剂(下文讨论),和/或与佐剂(也在下文讨论)混合,并且仍被认为是基本分离的。其还可以为基本上纯化的形式,在这种情况下,通常将在制剂中包含至少90%(例如至少95%、98%或99%)的蛋白质。
包含多肽或多核苷酸的组合物
另一方面,本发明提供了包含本发明的多肽的组合物。本发明还提供了包含编码本发明的多肽的多核苷酸的组合物。例如,本发明提供了组合物,其包含一种或多种本发明的多肽,和至少一种可药用的载体、防腐剂或赋形剂。或者,本发明提供了组合物,其包含一种或多种编码本发明的多肽的多核苷酸,以及至少一种可药用的载体、防腐剂或赋形剂。载体、防腐剂和赋形剂在与所述组合物的其他成分相容的意义上必须是“可接受的”,并且对被给予该组合物的受试者无害。通常,所有组分和最终组合物为无菌且无热原的。所述组合物可以为药物组合物。所述组合物可优选地包含佐剂。
佐剂为任何这样的物质,即其混合到组合物中将增加或以其他方式改变所述组合物引起的免疫应答。广义定义的佐剂为促进免疫应答的物质。佐剂还可优选地具有储库效应,即它们还使活性剂从给药位置缓慢且持续的释放。佐剂的一般性讨论在Goding,Monoclonal Antibodies:Principles&Practice(第二版,1986)的第61-63页中提供。
佐剂可选自:AlK(SO4)2,AlNa(SO4)2,AlNH4(SO4),二氧化硅,明矾,Al(OH)3,Ca3(PO4)2,高岭土,碳,氢氧化铝,胞壁酰二肽,N-乙酰-胞壁酰-L-苏氨酰-D-异谷氨酰胺(thr-DMP),N-乙酰-去甲胞壁酰(nornuramyl)-L-丙氨酰-D-异谷氨酰胺(CGP 11687,还称为nor-MDP),N-乙酰胞壁酰-L-丙氨酰-D-异谷氨酰胺酰-L-丙氨酸-2-(1'2'-二棕榈酰-sn-丙三氧基-3-羟磷氧基)-乙胺(CGP 19835A,还称为MTP-PE),溶于2%鲨烯/吐温-80.RTM.乳液中的RIBI(MPL+TDM+CWS),脂多糖及其多种衍生物,包括脂质A、弗氏完全佐剂(FCA)、弗氏不完全佐剂、Merck佐剂65,多核苷酸(例如多IC和多AU酸),来自结核分枝杆菌(Mycobacteriumtuberculosis)的D蜡,存在于短小棒状杆菌(Corynebacterium parvum)、百日咳博德特氏菌(Bordetella pertussis)和布鲁氏菌属(Brucella)成员中的物质,Titermax,ISCOMS,Quil A,ALUN(参见US 58767和5,554,372),脂质A衍生物,霍乱毒素衍生物,HSP衍生物,LPS衍生物,合成肽基质或GMDP,白细胞介素1,白细胞介素2,Montanide ISA-51和QS-21。还已经建议多种皂素(saponin)提取物适用于作为免疫原性组合物中的佐剂。粒细胞-巨噬细胞集落刺激因子(GM-CSF)也可用作佐剂。
用于本发明的优选佐剂包括基于油/表面活性剂的佐剂,例如Montanide佐剂(可获自比利时Seppic),优选Montanide ISA-51。其他优选佐剂为基于细菌DNA的佐剂,例如包含CpG寡核苷酸序列的佐剂。其他优选佐剂为基于病毒dsRNA的佐剂,例如poly I:C。GM-CSF和Imidazochiniline也是优选佐剂的实例。
佐剂最优选地为Montanide ISA佐剂。Montanide ISA佐剂优选地为MontanideISA 51或Montanide ISA 720。
在Goding,Monoclonal Antibodies:Principles&Practice(第二版,1986)第61-63页中,还记载了,当目的抗原分子量小或免疫原性差时,推荐偶联至免疫原性载体。因此,本发明的多肽可偶联至载体。载体可独立于佐剂存在。载体的功能可以是,例如,增加多肽片段的分子量以增加活性或免疫原性,赋予稳定性,提高生物活性,或增加血清半衰期。此外,载体可帮助将多肽或其片段呈递到T细胞。因此,在组合物中,多肽可与载体(例如下文所述的那些)结合(associate)。
载体可以是本领域技术人员已知的任何适合的载体,例如蛋白或抗原呈递细胞,例如树突细胞(DC)。载体蛋白包括钥孔血蓝蛋白(keyhole limpet hemocyanin),血清蛋白如转铁蛋白、牛血清白蛋白、人血清白蛋白、甲状腺球蛋白或卵白蛋白,免疫球蛋白,或激素如胰岛素或棕榈酸。或者,载体蛋白可以是破伤风类毒素或白喉类毒素。或者,载体可以是葡聚糖如琼脂糖。载体必须是人生理上可接受的及安全的。
如果所述组合物包含赋形剂,其在与所述组合物的其他成分相容的意义上必须是“可药用的”并且对其接受者无害。辅助物质,例如润湿剂或乳化剂、pH缓冲物质等可存在于赋形剂中。这些赋形剂和辅助物质通常是制药试剂(pharmaceutical agent),其在接受组合物的个体中不引起免疫应答并且可被给药而不产生过度毒性。可药用的赋形剂包括但不限于液体,例如水、盐水、聚乙二醇、透明质酸、甘油和乙醇。其中还可包含可药用的盐,例如无机酸盐类,例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐等;有机酸盐类,例如乙酸盐、丙酸盐、丙二酸盐、苯甲酸盐等。可药用的赋形剂、载体(vehicle)和辅助物质的详细讨论参见Remington’s Pharmaceutical Sciences(Mack Pub.Co.,N.J.1991)。
适合的组合物的配制可以使用标准药物制剂化学和方法来进行,其全部对于本领域技术人员是容易获得的。可以以适于推注给药或适于连续给药的形式制备、包装或销售该组合物。可以以单位剂型(例如以安瓿瓶)或以任选地包含防腐剂的多剂量容器来制备、包装或销售可注射组合物。组合物包括但不限于悬浮剂、溶液剂、油性或水性载体中的乳剂、糊剂和可植入缓释或生物可降解制剂。在组合物的一个实施方案中,活性成分以干燥形式(例如粉末或颗粒)提供,以使用适合的溶剂(vehicle)(例如无菌无热原的水)来复原,之后给予经复原的组合物。可以以无菌可注射水性或油性悬浮液或溶液的形式来制备、包装或销售组合物。该悬浮液或溶液可以根据已知的现有技术来配制,除活性成分以外可包含其他成分,例如本文所述的佐剂、赋形剂和辅助物质。可以使用无毒、肠外可接受的稀释剂或溶剂(例如水或1,3-丁二醇)来制备这类无菌可注射制剂。其他可接受的稀释剂和溶剂包括但不限于Ringer's溶液、等渗氯化钠溶液和不易挥发的油类(例如合成的甘油单酯或甘油二酯)。其他可使用的组合物包括这样的组合物,其包含微晶形式、在脂质体制品中、或作为生物可降解聚合物系统的组分的活性成分。用于缓释或植入的组合物可包括可药用的聚合材料或疏水材料,例如乳液、离子交换树脂、微溶性聚合物或微溶性盐。或者,组合物的活性成分可被包入胶囊(encapsulate)、吸收至微粒载体或与微粒载体结合(associate)。适合的微粒载体包括衍生自聚甲基丙烯酸甲酯聚合物,以及衍生自聚(丙交酯)和聚(丙交酯-共-乙交酯)的PLG微粒。参见,例如Jeffery et al.(1993)Pharm.Res.10:362-368。还可使用其他微粒系统和聚合物,例如,聚合物如聚赖氨酸、聚精氨酸、聚鸟氨酸、精胺、亚精胺,以及这些分子的缀合物。
使用方法
本发明的多肽、多核苷酸或组合物可以用于在受试者中治疗或预防疾病或病症的方法。本发明的多肽、多核苷酸或组合物可以用于制备用于治疗或预防受试者的疾病或病症的方法的药物。所述方法包括向所述受试者给予所述多肽、所述多核苷酸或所述组合物。可以将治疗或预防上有效量的所述多肽、所述多核苷酸或所述组合物给予至有需要的受试者。
所述疾病或病症的特征可以至少部分在精氨酸酶1的不适当或过度的免疫抑制功能。所述疾病或病症可以为癌症,优选表达精氨酸酶1和/或与精氨酸酶1的不适当或过度的免疫抑制功能相关的癌症。癌症可以为乳腺癌、肺癌、结肠癌或前列腺癌,或者可以为白血病,优选急性髓细胞样白血病(AML),或者可以为黑色素瘤。
所述方法可以包括同时或依序给予额外的癌症疗法。额外的癌症疗法可以选自细胞因子疗法、T细胞疗法、NK疗法、免疫系统检查点抑制剂、化学疗法、放射疗法、免疫刺激物质、基因疗法或抗体。
抗体可以为阿巴伏单抗(Abagovomab)、阿昔单抗(Abciximab)、阿卡单抗(Actoxumab)、阿达木单抗(Adalimumab)、阿达卡莫单抗(Adecatumumab)、阿非莫单抗(Afelimomab)、阿芙土珠单抗(Afutuzumab)、培阿赛珠单抗(Alacizumab pegol)、ALD518、阿仑珠单抗(Alemtuzumab)、阿妥莫单抗(Alirocumab)、喷替酸阿妥莫单抗(Altumomabpentetate)、阿马昔单抗(Amatuximab)、马安莫单抗(Anatumomab mafenatox)、安鲁单抗(Anrukinzumab)、阿泊珠单抗(Apolizumab)、阿西莫单抗(Arcitumomab)、阿塞珠单抗(Aselizumab)、安妥明单抗(Atinumab)、阿特利单抗(Atlizumab)(=托珠单抗(tocilizumab))、Atorolimumab、巴匹珠单抗(Bapineuzumab)、巴利昔单抗(Basiliximab)、巴维昔单抗(Bavituximab)、贝妥莫单抗(Bectumomab)、贝利木单抗(Belimumab)、贝拉珠单抗(Benralizumab)、柏替木单抗(Bertilimumab)、贝索单抗(Besilesomab)、贝伐单抗(Bevacizumab)、贝佐洛单抗(Bezlotoxumab)、比西单抗(Biciromab)、双马单抗(Bimagrumab)、莫比伐单抗(Bivatuzumab mertansine)、博纳吐单抗(Blinatumomab)、Blosozumab、利妥昔单抗(Brentuximab vedotin)、布里亚明单抗(Briakinumab)、溴达拉单抗(Brodalumab)、卡那奴单抗(Canakinumab)、莫坎妥珠单抗(Cantuzumab mertansine)、坎妥单抗瑞伐坦(Cantuzumab ravtansine)、卡普利单抗(Caplacizumab)、卡罗单抗喷地肽偶联物(Capromab pendetide)、卡路单抗(Carlumab)、卡妥索单抗(Catumaxomab)、CC49、西利珠单抗(Cedelizumab)、培化舍珠单抗(Certolizumab pegol)、西妥昔单抗(Cetuximab)、Ch.14.18、伯格西他土珠单抗(Citatuzumab bogatox)、西妥木单抗(Cixutumumab)、克拉扎珠单抗(Clazakizumab)、克立昔单抗(Clenoliximab)、替坦司可利妥珠单抗(Clivatuzumabtetraxetan)、康妥单抗(Conatumumab)、康昔单抗(Concizumab)、克伦单抗(Crenezumab)、CR6261、达塞珠单抗(Dacetuzumab)、达利珠单抗(Daclizumab)、达妥珠单抗(Dalotuzumab)、达雷木单抗(Daratumumab)、地昔单抗(Demcizumab)、地舒单抗(Denosumab)、地莫单抗(Detumomab)、阿托度单抗(Dorlimomab aritox)、Drozitumab、杜利妥单抗(Duligotumab)、度匹鲁单抗(Dupilumab)、杜昔单抗(Dusigitumab)、依美昔单抗(Ecromeximab)、依库珠单抗(Eculizumab)、埃巴单抗(Edobacomab)、依屈洛单抗(Edrecolomab)、依法珠单抗(Efalizumab)、依芬古单抗(Efungumab)、埃罗妥珠单抗(Elotuzumab)、艾西莫单抗(Elsilimomab)、恩伐珠单抗(Enavatuzumab)、培戈赖莫单抗(Enlimomab pegol)、依诺珠单抗(Enokizumab)、依诺替单抗(Enoticumab)、恩师妥昔单抗(Ensituximab)、西依匹莫单抗(Epitumomab cituxetan)、依帕珠单抗(Epratuzumab)、厄利珠单抗(Erlizumab)、厄马索单抗(Ertumaxomab)、依他珠单抗(Etaracizumab)、依曲利珠单抗(Etrolizumab)、依洛尤单抗(Evolocumab)、艾韦单抗(Exbivirumab)、法索单抗(Fanolesomab)、法拉莫单抗(Faralimomab)、法鲁珠单抗(Farletuzumab)、法辛单抗(Fasinumab)、FBTA05、泛维珠单抗(Felvizumab)、费扎尼单抗(Fezakinumab)、非卡妥珠单抗(Ficlatuzumab)、菲妥木单抗(Figitumumab)、法兰妥单抗(Flanvotumab)、芬特妥珠单抗(Fontolizumab)、福拉木单抗(Foralumab)、福韦单抗(Foravirumab)、非苏木单抗(Fresolimumab)、富拉单抗(Fulranumab)、伏妥昔单抗(Futuximab)、加利昔单抗(Galiximab)、加尼妥单抗(Ganitumab)、冈特莫单抗(Gantenerumab)、加维莫单抗(Gavilimomab)、吉妥珠单抗奥唑米星(Gemtuzumab ozogamicin)、格伐克单抗(Gevokizumab)、吉妥昔单抗(Girentuximab)、维格列巴单抗(Glembatumumab vedotin)、戈利木单抗(Golimumab)、高密昔单抗(Gomiliximab)、GS6624、伊巴珠单抗(Ibalizumab)、替伊莫单抗替西坦偶联物(Ibritumomab tiuxetan)、伊鲁库单抗(Icrucumab)、伊戈伏单抗(Igovomab)、英西单抗(Imciromab)、英加妥珠单抗(Imgatuzumab)、依克拉单抗(Inclacumab)、吲妥昔单抗瑞伐坦(Indatuximab ravtansine)、英夫利昔单抗(Infliximab)、英特单抗(Intetumumab)、伊诺莫单抗(Inolimomab)、伊珠单抗奥唑米星(Inotuzumab ozogamicin)、伊匹木单抗(Ipilimumab)、伊拉单抗(Iratumumab)、伊托珠单抗(Itolizumab)、衣克珠单抗(Ixekizumab)、克利昔单抗(Keliximab)、拉托唑单抗(Labetuzumab)、兰帕利单抗(Lampalizumab)、来瑞珠单抗(Lebrikizumab)、来马索单抗(Lemalesomab)、乐德木单抗(Lerdelimumab)、来沙木单抗(Lexatumumab)、利韦单抗(Libivirumab)、Ligelizumab、林妥珠单抗(Lintuzumab)、Lirilumab、络德昔单抗(Lodelcizumab)、莫洛伐妥单抗(Lorvotuzumab mertansine)、鲁卡木单抗(Lucatumumab)、Lumiliximab、马帕木单抗(Mapatumumab)、马司莫单抗(Maslimomab)、马维里单抗(Mavrilimumab)、马妥单抗(Matuzumab)、美泊利单抗(Mepolizumab)、美替木单抗(Metelimumab)、米拉组单抗(Milatuzumab)、明瑞莫单抗(Minretumomab)、米妥莫单抗(Mitumomab)、Mogamulizumab、莫罗木单抗(Morolimumab)、莫维珠单抗(Motavizumab)、莫妥昔单抗假单抗(Moxetumomab pasudotox)、莫罗单抗-CD3(Muromonab-CD3)、他那可单抗(Nacolomab tafenatox)、奈米布单抗(Namilumab)、萘妥莫单抗-衣塔芬毒素偶联物(Naptumomab estafenatox)、纳妥单抗(Narnatumab)、那他珠单抗(Natalizumab)、奈巴库单抗(Nebacumab)、奈妥木单抗(Necitumumab)、奈瑞莫单抗(Nerelimomab)、奈西伐单抗(Nesvacumab)、尼妥珠单抗(Nimotuzumab)、尼沃单抗(Nivolumab)、巯诺莫单抗-美培坦偶联物(Nofetumomab merpentan)、阿托珠单抗(Obinutuzumab)、奥卡鲁单抗(Ocaratuzumab)、奥克里昔单抗(Ocrelizumab)、奥杜莫单抗(Odulimomab)、奥法木单抗(Ofatumumab)、奥拉单抗(Olaratumab)、Olokizumab、奥马佐单抗(Omalizumab)、阿那妥单抗(Onartuzumab)、阿曲单抗-莫那毒素偶联物(Oportuzumab monatox)、奥戈伏单抗(Oregovomab)、奥替单抗(Orticumab)、奥立昔单抗(Otelixizumab)、奥索单抗(Oxelumab)、奥扎尼单抗(Ozanezumab)、奥索利单抗(Ozoralizumab)、帕吉巴昔单抗(Pagibaximab)、帕利珠单抗(Palivizumab)、帕木单抗(Panitumumab)、帕巴库单抗(Panobacumab)、帕撒单抗(Parsatuzumab)、帕考珠单抗(Pascolizumab)、帕替利单抗(Pateclizumab)、帕特利单抗(Patritumab)、帕尼单抗(Pemtumomab)、哌拉单抗(Perakizumab)、帕妥珠单抗(Pertuzumab)、培昔单抗(Pexelizumab)、匹利珠单抗(Pidilizumab)、维匹那妥单抗(Pinatuzumab vedotin)、品妥莫单抗(Pintumomab)、普鲁单抗(Placulumab)、泊洛妥珠单抗(Polatuzumab vedotin)、庞尼泽单抗(Ponezumab)、普利昔单抗(Priliximab)、普罗昔单抗(Pritoxaximab)、普鲁米单抗(Pritumumab)、PRO 140、奎珠单抗(Quilizumab)、拉托单抗(Racotumomab)、拉德鲁单抗(Radretumab)、拉维夫单抗(Rafivirumab)、拉莫鲁单抗(Ramucirumab)、雷珠单抗(Ranibizumab)、雷昔库单抗(Raxibacumab)、瑞加韦单抗抗(Regavirumab)、瑞利珠单抗(Reslizumab)、利妥珠单抗(Rilotumumab)、利妥昔单抗(Rituximab)、罗巴单抗(Robatumumab)、罗乐单抗(Roledumab)、罗莫索单抗(Romosozumab)、罗他珠单抗(Rontalizumab)、罗维珠单抗(Rovelizumab)、鲁普单抗(Ruplizumab)、沙马利单抗(Samalizumab)、Sarilumab、沙妥单抗-喷地肽偶联物(Satumomab pendetide)、塞库单抗(Secukinumab)、塞巴坦单抗(Seribantumab)、塞妥昔单抗(Setoxaximab)、司韦单抗(Sevirumab)、西罗珠单抗(Sibrotuzumab)、西法木单抗(Sifalimumab)、塞妥昔单抗(Siltuximab)、西妥珠单抗(Simtuzumab)、西普利单抗(Siplizumab)、西鲁库单抗(Sirukumab)、索冷珠单抗(Solanezumab)、索利单抗(Solitomab)、索普昔单抗(Sonepcizumab)、索妥单抗(Sontuzumab)、丝塔单抗(Stamulumab)、舒乐单抗(Sulesomab)、苏维珠单抗(Suvizumab)、他巴单抗(Tabalumab)、替珠单抗(Tacatuzumab tetraxetan)、塔多珠单抗(Tadocizumab)、塔利单抗(Talizumab)、坦纳单抗(Tanezumab)、帕他莫单抗(Taplitumomab paptox)、替非珠单抗(Tefibazumab)、阿替莫单抗(Telimomab aritox)、替纳单抗(Tenatumomab)、替尼昔单抗(Teneliximab)、替利珠单抗(Teplizumab)、四丙珠单抗(Teprotumumab)、TGN1412、替昔单抗(Ticilimumab)(=tremelimumab(曲美木单抗))、替拉珠单抗(Tildrakizumab)、替加妥单抗(Tigatuzumab)、TNX-650、托珠单抗(Tocilizumab)(=atlizumab(阿特利单抗))、托拉珠单抗(Toralizumab)、托西莫单抗(Tositumomab)、曲洛单抗(Tralokinumab)、曲妥珠单抗(Trastuzumab)、TRBS07、曲利单抗(Tregalizumab)、曲美木单抗(Tremelimumab)、图卡珠单抗-西莫白介素偶联物(Tucotuzumab celmoleukin)、妥韦单抗(Tuvirumab)、乌布妥昔单抗(Ublituximab)、乌洛单抗(Urelumab)、乌索单抗(Urtoxazumab)、乌司奴单抗(Ustekinumab)、伐利昔单抗(Vapaliximab)、伐他珠单抗(Vatelizumab)、维多珠单抗(Vedolizumab)、维妥珠单抗(Veltuzumab)、维帕莫单抗(Vepalimomab)、维森单抗(Vesencumab)、维西珠单抗(Visilizumab)、伏洛昔单抗(Volociximab)、沃塞妥单抗-马伏毒素偶联物(Vorsetuzumab mafodotin)、伏妥木单抗(Votumumab)、扎芦木单抗(Zalutumumab)、扎木单抗(Zanolimumab)、Zatuximab、齐拉木单抗(Ziralimumab)或阿佐莫单抗(Zolimomab aritox)。
优选的抗体包括那他珠单抗、维多珠单抗、贝利木单抗、阿塞西普(Atacicept)、阿列法西(Alefacept)、奥立昔单抗、替利珠单抗、利妥昔单抗、奥法木单抗、奥克里昔单抗、依帕珠单抗、阿仑珠单抗、阿巴西普(Abatacept)、依库珠单抗、奥马佐单抗、卡那奴单抗、美泊利单抗(Meplizumab)、瑞利珠单抗、托珠单抗、乌司奴单抗、布里亚明单抗、依那西普(Etanercept)、Inlfliximab、阿达木单抗、培化舍珠单抗、戈利木单抗、曲妥珠单抗、吉妥珠单抗、奥唑米星、替伊莫单抗、替西坦、Tostitumomab、西妥昔单抗、贝伐单抗、帕木单抗、地舒单抗、伊匹木单抗、利妥昔单抗和维多汀。
可以用于本发明的方法的特别优选的抗体包括:达雷木单抗、尼沃单抗、帕博利珠单抗(pembrolizumab)、阿维单抗(avelumab)、利妥昔单抗、曲妥珠单抗、帕妥珠单抗、阿仑珠单抗、西妥昔单抗、帕木单抗、托西莫单抗和奥法木单抗。尤其优选达雷木单抗。
其他癌症疗法选自:B12(Actimide)、阿扎胞苷(Azacitidine)、硫唑嘌呤(Azathioprine)、博来霉素(Bleomycin)、卡铂(Carboplatin)、卡培他滨(Capecitabine)、顺铂(Cisplatin)、苯丁酸氮芥(Chlorambucil)、环磷酰胺(Cyclophosphamide)、阿糖胞苷(Cytarabine)、柔红霉素(Dauno-rubicin)、多西他赛(Docetaxel)、去氧氟尿苷(Doxifluridine)、多柔比星(Doxorubicin)、表柔比星(Epirubicin)、依托泊苷(Etoposide)、氟达拉滨(Fludarabine)、氟尿嘧啶(Fluor-ouracil)、吉西他滨(Gemcitabine)、羟基脲(Hydroxyurea)、伊达比星(Idarubicin)、伊立替康(Irinotecan)、来那度胺(Lenalidomide)、甲酰四氢叶酸(Leucovorin)、氮芥(Mechlorethamine)、美法仑(Melphalan)、巯基嘌吟(Mercaptopurine)、甲氨蝶呤(Methotrexate)、米托蒽醌(Mitoxantrone)、奥沙利铂(Oxaliplatin)、紫杉醇(Paclitaxel)、培美曲塞(Pemetrexed)、瑞复美(Revlimid)、替莫唑胺(Temozolomide)、替尼泊苷(Teniposide)、硫鸟嘌呤(Thioguanine)、戊柔比星(Valrubicin)、长春碱(Vinblastine)、长春新碱(Vincristine)、长春地辛(Vindesine)和长春瑞滨(Vinorelbine)。
本发明的多肽或组合物还可以用于刺激精氨酸酶1特异性T细胞(如CD4T细胞和CD8T细胞)的方法,其包括使细胞与所述多肽或组合物接触。所述方法可以离体进行。所述细胞可以存在于从健康受试者或癌症患者获得的样品中,例如在肿瘤样品中。
本发明进一步通过以下实施例来举例说明,然而,所述实施例不应当理解为限制本发明的范围。上文描述和以下实施例中公开的特征可单独地或以其任意组合作为以其多种形式实现本发明的材料。
实施例1
材料和方法
患者材料
使用密度梯度分离法(LymphoprepTM(STEMCELL Technologies))分离健康捐赠者的PBMC,并在-150℃下冷冻保存于补充有10%DMSO的FBS中。终止任何抗癌治疗后至少四周,从血液样品中分离癌症患者的PBMC。该方案经丹麦首都地区科学伦理委员会批准,并根据《赫尔辛基宣言》的规定进行。在进入研究之前,已获得患者的书面知情同意。
肽
通过标准方法合成肽,并以溶解在DMSO中以获得10mM的储备浓度的形式来提供。在这些实验中使用的肽的序列在彼此比对中在下文完整示出,并且还列在标题为“序列”的部分中。通过SEQ ID NO、通过名称、或通过提及在精氨酸酶1的全长序列内各肽序列的起始和终止位置来描述肽。每种描述可互换使用。例如,SEQ ID NO:1的肽或者可通过名称ArgLong2来提及,或者可称为Arg 169-206(给出起始位置169和终止位置206)。基于上下文,每种情况下的预期的提及是清楚的。
较长的肽序列:
20聚体肽:
ELISPOT测定
对于体外ELISPOT,将来自癌症患者和健康捐赠者的PBMC在24孔板中用20mM精氨酸酶1衍生的肽和120U/ml IL-2脉冲处理(pulse)7天,然后用于ELISPOT测定。将细胞放置在预先包被了IFNγ捕获抗体(Mabtech)的96孔硝酸纤维素ELISPOT板中(MultiScreenMAIP N45;Millipore)。加入精氨酸酶肽至终浓度为5μM,并将板在37℃下孵育14-16小时。孵育后,洗去细胞并在室温下添加第二生物素化Ab(Mabtech,目录号3420-6-1000),持续2小时。洗去未结合的第二抗体,并在室温下添加链霉亲和素缀合的碱性磷酸酶(AP)(Mabtech,目录号3310-10),持续1小时。洗去未结合的缀合酶,并通过添加BCIP/NBT底物(Mabtech,目录3650-10)使测定显色。使用Immunospot软件v5.1,在CTL ImmunoSpotS6Ultimate-V分析仪上分析经显色的ELISPOT板。将应答报告为用精氨酸酶1刺激的孔中和没有添加肽的孔中斑点平均数之间的差异。
为了检查IL-4诱导的Arg1应答,将PBMC用IL-4(100或50U/ml)和/或IL-2(120或60U/ml)刺激一周,之后用于上述ELISPOT测定。
胞内染色
在BD GolgiPlugTM存在下(在肽刺激的第一小时后添加),用精氨酸酶衍生的肽刺激PBMC 5小时后,进行细胞培养物的胞内染色。用荧光标记的用于表面标记(CD3、CD4、CD8)的抗体染色刺激的细胞,之后使用固定/透化和透化缓冲液(eBioscience,目录号00-5123-43),根据制造商的说明进行透化。然后用针对IFNγ和TNFα的荧光染料标记的抗体对透化的细胞进行染色。在FACSCantoTMII(BD Biosciences)上进行流式细胞仪分析。根据制造商的说明,所用的抗体:IFNγ-APC(目录号341117)、TNFα-455BV421(目录号562783)、CD4-FITC(目录号347413)、CD8-PerCP(目录号345774),CD3-APC-H7(目录号560275)(全部来自BD Biosciences),死亡细胞染料-FVS510(564406,BD Biosciences)。
记忆T细胞分选
使用磁珠分选试剂盒,从新鲜解冻的健康捐赠者或癌症患者的PBMC样品中分选出CD4+和CD8+记忆T细胞:记忆CD4+T细胞分离试剂盒,人(目录号130-091-893,MiltenyiBiotec)和CD8+记忆T细胞分离试剂盒,人(目录号130-094-412,Miltenyi Biotec)。通过对CD4-FITC、CD8-PerCP、CD45RO-PE(全部来自BD Biosciences)染色来评估分离细胞的纯度,使用LIVE/DEADTM可固定近红外死亡细胞染色试剂盒(InvitrogenTM,ThermoFisherScientific)对死亡的细胞进行染色。
结果
精氨酸酶1肽长度决定T细胞刺激的效率
基于之前鉴定的在精氨酸酶1的第161-210位的50个氨基酸长的Arg1热点区域,选择了覆盖该区域主要部分的三种不同的肽,其还排除了精氨酸酶1的第168位的半胱氨酸(预期会改善可制备性、溶解度和稳定性)。这三种肽是:42聚体ArgLong(第169-210位)、38聚体ArgLong2(第169-206位)和32聚体ArgLong3(第169-200位)。
为了测试这些肽是否可用于鉴定精氨酸酶1应答,筛选了来自6名健康捐赠者的PBMC在IFNγELISPOT中的应答。用ArgLong2肽和低剂量IL-2刺激PBMC 1周,之后进行ELISPOT。尽管序列相似,但在刺激IFNγELISPOT中的T细胞应答上,ArgLong2肽似乎更优。如图1所示,在6名捐赠者中的4名中观察到对ArgLong2肽的高应答,而对ArgLong肽和ArgLong3肽存在低应答或无应答。
ArgLong2比ArgLong仅短4个氨基酸,且比ArgLong3长6个氨基酸。这表明肽长和序列可能在确保精氨酸酶肽的最佳处理和呈递中起关键作用。因此,它可以影响该肽激活Arg1特异性T细胞的能力。
为了确定ArgLong2肽是否与之前所述的覆盖相同序列的单个20聚体肽相当(参见WO2018065563实施例1、2和3),筛选来自19名健康捐赠者和16名癌症患者(8名黑色素瘤、6名多发性骨髓瘤、1名乳腺癌和1名肾细胞癌)的PBMC针对三种20聚体肽和38聚体ArgLong2的应答。在癌症患者和健康捐赠者中,与全部三种20聚体肽相比,ArgLong2产生的应答最多(参见图2)。在19名健康捐献者中的14名中和16名癌症患者中的8名中观察到针对ArgLong2的强应答。还观察到针对20聚体肽的应答,尽管这些应答更少且更低。总结:Arg171-190在3名健康捐赠者和3名癌症患者中显示应答,Arg181-200在4名健康捐献者和6名癌症患者中显示应答,Arg191-210在7名健康捐献者和3名癌症患者中显示应答。
对精氨酸酶1的CD4+和CD8+应答
之前所述针对20聚体Arg1肽的T细胞应答已在癌症患者和健康捐赠者中主要显示出CD4+T细胞应答(参见WO2018065563实施例2)。由于ArgLong2肽似乎被更有效地处理并随后被T细胞识别,因此通过胞内染色研究对ArgLong2的T细胞应答的类型。
在体外用ArgLong2和低剂量IL-2刺激一周后,通过胞内染色测试来自之前在ELISPOT中显示出对ArgLong2强应答的两名健康捐赠者(HD384、HD400)和一名乳腺癌患者(BD30)的PBMC。值得注意地,在癌症患者和健康捐献者中鉴定了针对ArgLong2肽的CD4+和CD8+T细胞应答。在一名健康捐赠者和乳腺癌患者PBMC中检测到了CD4+应答(图3A的左图)和CD8+应答(图3A的右图)。其他健康捐赠者仅显示CD8+T细胞应答。
值得注意的是,在没有预先肽刺激的情况下,在PBMC的胞内染色中也观察到针对ArgLong2的可检测的CD4+和CD8+应答。解冻来自2名癌症患者(1名恶性黑色素瘤(MM27)和1名乳腺癌(BC30))的PBMC,并在离体胞内染色中直接测试针对ArgLong2肽的应答。本发明人能够检测出来自2名癌症患者的PBMC中的离体CD4+应答(图3B,左)和乳腺癌患者PBMC中的离体CD8+应答(图3B,右)。
记忆对精氨酸酶1的CD4+和CD8+应答
针对ArgLong2的强应答表明,在没有任何预先肽刺激的情况下,在PBMC中可更通常检测到Arg1特异性T细胞的频率。在离体IFNγELISPOT中直接测试来自4名健康捐赠者和2名癌症患者(1名乳腺癌和1名恶性黑色素瘤)的PBMC(其在体外ELISPOT中显示出强应答)对ArgLong2肽的应答。本发明人在全部6名捐赠者中发现了显著的自发应答(参见图4A)。
在健康捐赠者和癌症患者的PBMC中存在针对ArgLong2肽的强的自发离体应答,表明精氨酸酶1特异性细胞是免疫系统的一个天然部分。为测试CD4+和CD8+记忆T细胞是从显示出强的自发离体免疫应答的癌症患者和健康捐赠者的PBMC中分选出来的。使用磁珠分选法从4名健康捐赠者和2名癌症患者的PBMC中分选出CD4+或CD8+记忆T细胞,并用于离体IFNγELISPOT。通过用于CD4+CD45RO+和CD8+CD45RO+T细胞的流式细胞技术分析证实了记忆T细胞分离的纯度,并确定其为>95%。本发明人在2名癌症患者和3名健康捐赠者中发现针对ArgLong2肽的CD4+记忆应答(参见图4B)。在2名健康捐赠者中可以检测到清晰的CD8+记忆应答(参见图4C)。
IL-4上调的精氨酸酶1表达增加针对ArgLong2的T细胞应答
由于Arg1特异性CD4+和CD8+记忆T细胞存在于癌症患者和健康捐赠者中,因此测试了这些T细胞是否可以参与响应于Arg1表达上调的免疫调节。之前已描述,响应于IL-4,Arg1在骨髓细胞中被上调。
首先,测试了来自1名黑色素瘤患者的PBMC,其之前已显示对ArgLong2肽具有强的自发离体应答。将PBMC解冻并用IL-4(50U/ml或100U/ml)、IL-2(120U/ml)或IL-4和IL-2的组合(分别为50U/ml和60U/ml)刺激一周,之后在IFNγELISPOT中测试其对ArgLong2的应答。未刺激的细胞用作对照。在全部IL-4刺激组中均观察到了强的显著应答:与未刺激或单独使用IL-2的刺激相比,观察到对IL-4刺激组的最高的应答,这表明Arg1特异性T细胞响应上调的Arg1表达而被激活。参见图5A。
然后,将之前已对ArgLong2显示出强的自发离体应答的来自2名癌症患者(BC30(乳腺癌)、MM27(恶性黑色素瘤))和6名健康捐赠者的PBMC用低剂量IL-2(120U/ml)或IL-4(100U/ml)刺激7天。未刺激的细胞用作对照。培养7天后,在IFNγELISPOT中测试PBMC针对ArgLong2的反应。与未刺激和IL-2刺激的对照相比,在IL-4刺激的培养物中,8个培养物中的6个显示出对ArgLong2的应答增加,进一步证实了体内Arg1特异性T细胞激活的可能的一般机制。参见图5B。
讨论
之前已经描述了Arg1特异性T细胞的存在。由于其在靶向免疫调节蛋白中的作用,这样的T细胞可以称为“抗Tregs”。还描述了针对其他免疫调节蛋白(例如PD-L1和IDO)的抗Treg应答。以上实验表明精氨酸酶1特异性抗Treg不仅自发存在于癌症患者和健康捐赠者中,而且作为记忆T细胞库的一部分存在,因为在分离的CD4+和CD8+记忆T细胞群体中观察到针对ArgLong2肽的应答。
为了保持免疫平衡,调节免疫细胞(例如Treg)、不同的树突细胞亚型、髓源性抑制细胞和M2巨噬细胞抑制或终止免疫反应。该调节臂(arm)确保无应答或耐受自身抗原。调节免疫细胞通过许多不同的细胞和胞外因子抑制免疫。相比之下,识别由胞内降解抗原产生的HLA限制的衍生表位的特异性抗Tregs能够直接消除调节免疫细胞。另外,抗Tregs可以通过分泌效应细胞因子来促进局部免疫激活。
TH2驱动的肺部炎症提高了骨髓细胞中精氨酸酶1的表达。特别地,IL-4——巨噬细胞M2表型的典型诱导物——诱导精氨酸酶1上调。本文已经表明精氨酸酶1特异性T细胞响应于TH2细胞因子IL-4而被激活。因此,这表明精氨酸酶1特异的TH1细胞浸润IL-4增加的环境并驱使免疫应答回到TH1通路,这可能是精氨酸酶1特异性抗Treg在控制免疫抑制和促进炎症中的重要作用。但是,表达精氨酸酶1的调节免疫细胞的抑制作用阻碍了精氨酸酶1特异性抗Treg本身。因此,在免疫调节网络中,精氨酸酶1特异性抗Treg抑制精氨酸酶1+调节免疫细胞的功能,反之亦然。因此,在正常生理条件下,免疫激活和免疫抑制之间的平衡对维持免疫稳态而言可能是必要的。
在健康个体中发现对精氨酸酶1特异的记忆T细胞(其响应于IL-4而扩增),与之前关于IDO和PD-L1特异性抗Treg的发现相符。循环IDO-或PD-L1特异性抗-Tregs已被鉴定存在于健康捐赠者中,尽管其检测不如在癌症患者中的检测频繁。另外,已经发现已知诱导IDO和PD-L1的促炎性细胞因子IL-2和IFN-γ在人PBMC中扩增IDO-或PD-L1特异性T细胞群而无额外的刺激。
免疫抑制骨髓细胞在肿瘤微环境中表达精氨酸酶1可通过L-精氨酸消耗抑制抗肿瘤T细胞应答。在精氨酸酶1阳性环境中,T细胞无法增殖,因此,有前景的治疗策略为通过激活促炎性精氨酸酶1特异性T细胞重建适应性免疫应答。通过肽免疫接种激活精氨酸酶1特异性抗Tregs提供了一种靶向癌症中特异性免疫抑制机制的新方法。
当靶向常规抑制机制时,在癌症治疗中开发新的免疫治疗方法可能是最有效和最通用的。如这些实验所示。精氨酸酶1特异性抗Treg作为免疫系统的一个天然部分存在,且可容易地用于使平衡远离癌症中的免疫抑制。
与不同长度的类似肽相比,覆盖之前描述的精氨酸酶1热点区域的主要部分的肽ArgLong2,已经证明在刺激精氨酸酶特异性CD4+和CD8+T细胞应答方面特别有效。因此,考虑到其刺激精氨酸酶1特异性抗Treg(其在肿瘤微环境中发挥效应功能和辅助功能)的潜力,ArgLong2在免疫接种环境下具有特别高的成功可能性。
实施例2-额外的肽的设计
为了设计适用于小鼠免疫接种实验并还可以在人中起作用的肽,将鼠精氨酸酶1的序列(SEQ ID NO:11)与人精氨酸酶1序列SEQ ID NO:10比较。在对应于SEQ ID NO:1的第161-210位的人精氨酸酶1的热点区中,相似性水平特别高。该区域与鼠精氨酸酶1中的对应区域的比对也如以下所示:
hArgl:
GFSWVTPCISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK(SEQ ID NO:12)
mArgl:
GFSWVTPCISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKLGIGK(SEQ ID NO:13)
50个残基中仅有2个残基不同,以粗体和下划线表示。人序列中的亮氨酸在小鼠中被替换为高度相似的脂肪族氨基酸异亮氨酸,人序列中的精氨酸在小鼠中被替换为相似的碱性赖氨酸。这两种变化都是保守的。因此,在人和小鼠之间热点区是高度保守的。因此,本发明的多肽包括由热点区的特定人序列组成的多肽,但其中进行了针对对应小鼠序列的置换。例如,SEQ ID NO:2对应于SEQ ID NO:1,但均具有上面提及的亮氨酸-异亮氨酸和精氨酸-赖氨酸置换。由SEQ ID NO:2组成的多肽在本文中可以称为mArgLong2。类似地,SEQ IDNO:4对应于SEQ ID NO:3,但具有上面提及的亮氨酸-异亮氨酸置换。由SEQ ID NO:2组成的多肽在本文中可称为mArgLong3。类似地,SEQ ID NO:6对应于SEQ ID NO:5,但具有上述亮氨酸-异亮氨酸和精氨酸-赖氨酸置换。由SEQ ID NO:6组成的多肽在本文中可称为mArgLong。鼠肽预期具有与其人的对应物相似的作为疫苗的潜力。
实施例3-在小鼠肿瘤模型中用人ArgEong2肽进行的体内实验
为了证明使用ArgLong2肽进行的免疫接种的治疗潜力,开发了小鼠模型。由于小鼠中对应的ArgLong2序列仅两个氨基酸不同,因此在后续实验中采用人ArgLong2序列。人和小鼠的ArgLong2序列的比较如以下所示:
人ArgLong2(SEQ ID NO:1)
-ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRL
小鼠ArgLong2(SEQ ID NO:2)
-ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKL
材料和方法
C57BL/6小鼠的肽免疫接种
动物皮下接种溶于DMSO/H2O中的100μg肽,其为含不完全Montanide ISA 51 VG的1:1乳液。Montanide ISA 51VG+DMSO/H2O用作对照疫苗。为了随后分析针对ArgLong2肽的免疫应答,在第7天将小鼠处死并采集脾和引流淋巴结(dLN)用于ELISPOT。
肽特异性应答的ELISPOT分析
对鼠免疫细胞进行ELISPOT分析。通过流经细胞滤器,从脾或dLN中制备单细胞悬浮液。裂解血细胞之后,将0.6-0.8×106细胞/孔接种到包被了抗IFNγ抗体的ELISPOT板。将目的肽添加到指定孔中并将细胞与肽过夜孵育。第二天,除去细胞,清洗板并与生物素化的监测抗体一起孵育。最后,添加链霉亲和素-ALP和底物之后,出现可见斑点。每个斑点对应于单个的产IFNγ的细胞。在Immunospot分析仪中分析板并作图。
15-16/17-20周龄的雌性C57BL/6小鼠的肿瘤免疫接种,每组15只小鼠
每只动物经皮下接种100μl培养基中的0.5×106同基因肿瘤细胞到右侧腹。使用同基因B16F10黑色素瘤细胞系和同基因MC38结肠腺癌细胞系。第0天开始免疫接种,并每周重复一次(第7天和第14天)。肽和对照接种如上所述进行。
监测肿瘤生长并约每隔一天测量肿瘤。肿瘤体积以V[mm3]=L×W2/2(其中L为最长直径且W垂直于L)计算。对小鼠实施安乐死前,最大肿瘤尺寸为864mm3(L=12mm、W=12mm)。
结果
发现ArgLong2在C57BL/6小鼠中具有强免疫原性,其显示出仅在一次免疫接种后检测到的高频率的疫苗特异性T细胞应答(图6)。
在肿瘤研究中,与对照免疫接种相比,用ArgLong2免疫接种显著延迟了肿瘤生长。在结肠腺癌的MC38模型(图7)和黑素瘤的B16模型(图8)中均观察到肿瘤生长的延迟。
实施例4ArgLong2特异性T细胞克隆识别表达精氨酸酶1的THP-1细胞
材料和方法
ArgLong2特异性T细胞克隆的产生
遵循标准的快速扩增方案(REP),富含ArgLong2特异性细胞的T细胞培养物产生ArgLong2克隆培养物:ArgLong2特异性细胞是通过磁珠分选产生TNFα的T细胞进行分离,并以~1个细胞/孔于96孔板中用于有限稀释克隆。每个孔中含有200μl的REP混合物(来自3个不同血沉棕黄层(buffy coat)的辐照饲养细胞、αCD3抗体和6000U/ml IL-2)以促进ArgLong2特异性T细胞的生长。
通过qPCR定量THP-1细胞中的精氨酸酶1mRNA
用20ng/ml IL-13(TriChem)刺激THP-1细胞48小时。收获细胞,在PBS中洗涤,并通过以300g离心5分钟沉淀。将沉淀在冰上保存,重悬于350μl RLT Plus-Buffer(Qiagen)中。根据制造商的说明,使用RNAeasy试剂盒(Qiagen)纯化RNA,最后用30μl的无RNA水洗脱。在NanoDrop 2000分光光度计(Thermo Scientific)上测量RNA浓度。RNA储存在-80℃。
使用High Capacity cDNA逆转录试剂盒(Applied Biosystems)逆转录总RNA。对于每个反应,将1000ng RNA逆转录。对于RT-qPCR,将cDNA以1:5稀释,并使用TaqMan基因表达测定于Roche Lightcycler 480仪器上进行RT-qPCR分析。进行RT-qPCR,平行重复四次,并使用ddCT方法分析数据,将其标准化为看家基因RPLPO和对照样品的表达水平。对于未扩增的低浓度样品,将Ct设置为40。无逆转录酶对照(无逆转录酶的cDNA反应设置)用作特异性扩增的对照。Arg1人引物购买自Thermo fisher(未公开序列,产品编号Hs00163660_m1)。
测定ArgLong2特异性T细胞对THP-1细胞的识别
洗涤未处理的和经IL-4/IL-13处理的THP-1细胞,并将其分为两组:将HLA-DR/DQ/DP阻断抗体(克隆Tü39)以10μg/ml的浓度添加至第一组,在37℃下持续20min。第二组的THP-1细胞未经处理。20min后,洗涤HLA-II阻断的THP-1细胞。然后将用IL-4/IL-13处理的THP-1细胞(有或没有HLA-II阻断)与ArgLong2肽特异性T细胞以2:1的效靶比混合,然后根据标准胞内细胞因子染色方案进行处理。
结果
为了进一步评估ArgLong2特异性T细胞的功能,从之前鉴定为强ArgLong2应答的健康捐赠者产生T细胞克隆,并且检验了其特异性识别表达精氨酸酶1的靶标的能力。
已知Th2细胞因子(例如IL-4或IL-3)上调骨髓细胞中ARG1的表达。为了测试ArgLong2特异性T细胞是否会特异性识别Th2细胞因子处理的骨髓细胞,测试了ArgLong2T细胞克隆识别HLA匹配的单核THP-1细胞系的能力,所述细胞系用IL-4(100U/ml)或IL-13(20U/ml)预先刺激48小时。
Th2-细胞因子处理的THP-1显示出增加的精氨酸酶1的表达。在这点上,图9C显示,当用IL-13预处理时,在THP-1细胞中诱导了精氨酸酶1表达,从而增加了精氨酸酶1衍生的肽表位在这些细胞的表面上的呈递。
证明了ArgLong2特异性CD4T细胞克隆识别IL-4和IL-13处理的THP-1细胞,如与未处理的THP-1相比,针对这些细胞的TNFα和IFNγ的产生增加所表明的(图9A)。HLA II类分子的阻断消除了对IL-4或IL-13处理的THP-1细胞的增加的识别,其表明对IL-4和IL-13处理的THP-1细胞的增加的识别取决于ARG1肽的HLA II类呈递。图9B以点图形式举例说明图9A的代表性数据,其示出了在有或没有HLA II类阻断的情况下,响应于IL-4和IL-13处理的THP-1细胞的IFNγ和TNFα的产生。
在一个单独实验中,将来自健康捐赠者(HD22,已知其对ArgLong2具有预先存在的离体应答)的PBMC用IL-4(100U/ml)或IL-13(20U/ml)处理7天以增加PBMC培养物中精氨酸酶1衍生肽的呈递,从而刺激在PBMC中存在的固有的ArgLong2特异性T细胞。用IL-4或IL-13刺激7天后,在IFNγELISPOT测定中分析PBMC,以检查ArgLong2特异性T细胞的频率变化。
与未处理对照相比,在IL-4和IL-13处理的PBMC培养物中观察到增加的ArgLong2应答。IL-13刺激的ArgLong2应答的强度与体外ArgLong2肽刺激后观察到的应答相当,这表明在Th2细胞因子条件下,精氨酸酶1特异性细胞的强激活。
序列
*表示来自鼠精氨酸酶1的序列,其相对于人精氨酸酶1的对应区域,包含至少一个差异。与对应的人序列不相同的残基为粗体并加下划线。鼠和人精氨酸酶1的长度相同,因此起始和终止位置相同。
全长人精氨酸酶1(NP_000036.2)(SEQ ID NO:10)
MSAKSRTIGI IGAPFSKGQP RGGVEEGPTV LRKAGLLEKL KEQECDVKDY GDLPFADIPNDSPFQIVKNP RSVGKASEQL AGKVAEVKKN GRISLVLGGD HSLAIGSISG HARVHPDLGV IWVDAHTDINTPLTTTSGNL HGQPVSFLLK ELKGKIPDVP GFSWVTPCIS AKDIVYIGLR DVDPGEHYIL KTLGIKYFSM TEVDRLGIGK VMEETLSYLL GRKKRPIHLS FDVDGLDPSF TPATGTPVVG GLTYREGLYI TEEIYKTGLLSGLDIMEVNP SLGKTPEEVT RTVNTAVAIT LACFGLAREG NHKPIDYLNP PK
被鉴定为免疫原性热点的区域以粗体和下划线表示
全长鼠精氨酸酶1(NP_031508.1)(SEQ ID NO:11)
MSSKPKSLEI IGAPFSKGQP RGGVEKGPAA LRKAGLLEKL KETEYDVRDH GDLAFVDVPNDSSFQIVKNP RSVGKANEEL AGVVAEVQKN GRVSVVLGGD HSLAVGSISG HARVHPDLCV IWVDAHTDINTPLTTSSGNL HGQPVSFLLK ELKGKFPDVP GFSWVTPCIS AKDIVYIGLR DVDPGEHYII KTLGIKYFSM TEVDKLGIGK VMEETFSYLL GRKKRPIHLS FDVDGLDPAF TPATGTPVLG GLSYREGLYI TEEIYKTGLLSGLDIMEVNP TLGKTAEEVK STVNTAVALT LACFGTQREG NHKPGTDYLK PPK
被鉴定为免疫原性热点的区域以粗体和下划线表示
人精氨酸酶1中的热点-SEQ ID NO:10的第161-210位
GFSWVTPCISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK(SEQ ID NO:12)
鼠精氨酸酶1中的热点-SEQ ID NO:11的第161-210位
GFSWVTPCISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKLGIGK(SEQ ID NO:13)
与对应的人序列不相同的残基为粗体并加下划线。
序列表
<110> IO Biotech ApS
<120> 精氨酸酶1多肽
<130> N414498WO
<150> GB1815549.9
<151> 2018-09-24
<160> 13
<170> PatentIn version 3.5
<210> 1
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> 人精氨酸酶1的肽片段(ArgLong2)
<400> 1
Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro
1 5 10 15
Gly Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met
20 25 30
Thr Glu Val Asp Arg Leu
35
<210> 2
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> 鼠精氨酸酶1的肽片段(mArgLong2)
<400> 2
Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro
1 5 10 15
Gly Glu His Tyr Ile Ile Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met
20 25 30
Thr Glu Val Asp Lys Leu
35
<210> 3
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 人精氨酸酶1的肽片段(ArgLong3)
<400> 3
Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro
1 5 10 15
Gly Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met
20 25 30
<210> 4
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 鼠精氨酸酶1的肽片段 (mArgLong3)
<400> 4
Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro
1 5 10 15
Gly Glu His Tyr Ile Ile Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met
20 25 30
<210> 5
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 人精氨酸酶1的肽片段(ArgLong)
<400> 5
Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro
1 5 10 15
Gly Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met
20 25 30
Thr Glu Val Asp Arg Leu Gly Ile Gly Lys
35 40
<210> 6
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 鼠精氨酸酶1的肽片段 (mArgLong)
<400> 6
Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro
1 5 10 15
Gly Glu His Tyr Ile Ile Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met
20 25 30
Thr Glu Val Asp Lys Leu Gly Ile Gly Lys
35 40
<210> 7
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人精氨酸酶1的肽片段(Arg1-18)
<400> 7
Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro Gly Glu
1 5 10 15
His Tyr Ile Leu
20
<210> 8
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人精氨酸酶1的肽片段(Arg1-19)
<400> 8
Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys
1 5 10 15
Tyr Phe Ser Met
20
<210> 9
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人精氨酸酶1的肽片段(Arg1-20)
<400> 9
Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu
1 5 10 15
Gly Ile Gly Lys
20
<210> 10
<211> 322
<212> PRT
<213> 智人(Homo sapiens)
<400> 10
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 11
<211> 323
<212> PRT
<213> 小鼠(Mus musculus)
<400> 11
Met Ser Ser Lys Pro Lys Ser Leu Glu Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Lys Gly Pro Ala Ala Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Thr Glu Tyr Asp Val Arg
35 40 45
Asp His Gly Asp Leu Ala Phe Val Asp Val Pro Asn Asp Ser Ser Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Asn Glu Glu Leu
65 70 75 80
Ala Gly Val Val Ala Glu Val Gln Lys Asn Gly Arg Val Ser Val Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Val Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Cys Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Ser Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Phe Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Ile Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Lys Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Phe Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ala Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Leu Gly Gly Leu Ser Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Thr Leu Gly Lys Thr Ala Glu Glu
275 280 285
Val Lys Ser Thr Val Asn Thr Ala Val Ala Leu Thr Leu Ala Cys Phe
290 295 300
Gly Thr Gln Arg Glu Gly Asn His Lys Pro Gly Thr Asp Tyr Leu Lys
305 310 315 320
Pro Pro Lys
<210> 12
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人精氨酸酶1的肽片段
<400> 12
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
1 5 10 15
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
20 25 30
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
35 40 45
Gly Lys
50
<210> 13
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 鼠精氨酸酶1的肽片段
<400> 13
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
1 5 10 15
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Ile Lys Thr
20 25 30
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Lys Leu Gly Ile
35 40 45
Gly Lys
50
Claims (12)
1.一种多肽,其由以下氨基酸序列中的任一个组成:
a.ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRL(SEQ ID NO:1);
b.ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKL(SEQ ID NO:2);
c.ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSM(SEQ ID NO:3);
d.ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSM(SEQ ID NO:4);
e.ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK(SEQ ID NO:5);
f.ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKLGIGK(SEQ ID NO:6);
g.根据a.–f.中任一项的序列,其中最高达三个氨基酸被保守性置换所替换,条件是与由不进行置换的对应序列组成的多肽相比,所述多肽没有表现出显著降低的对精氨酸酶1的免疫原性;或
h.编码a.–g.中任一项的多肽的多核苷酸,任选地包含在载体内。
2.权利要求1的多肽,其由SEQ ID NO:1的氨基酸序列组成。
3.权利要求1或2的多肽,其中所述C末端氨基酸被对应的酰胺替换。
4.一种组合物,其包含权利要求1至3中任一项的多肽或多核苷酸以及佐剂。
5.根据权利要求4的组合物,其包含至少一种可药用的稀释剂、载体或防腐剂。
6.根据权利要求4或5的组合物,其中所述佐剂选自:基于细菌DNA的佐剂、基于油/表面活性剂的佐剂、基于病毒dsRNA的佐剂、imidazochiniline和Montanide ISA佐剂。
7.一种治疗或预防受试者中的疾病或病症的方法,所述方法包括将权利要求1至3中任一项的多肽或多核苷酸或权利要求4至6的组合物给予所述受试者。
8.权利要求7的方法,其中所述疾病或病症的特征至少部分在于精氨酸酶的不适当或过度的免疫抑制功能,和/或其中所述疾病或病症是癌症。
9.权利要求7或8的方法,其中所述疾病或病症是癌症,且任选地其中所述方法还包括同时或依序给予额外的癌症疗法,优选抗体。
10.权利要求7至9中任一项的方法,其中所述癌症是乳腺癌、肺癌、结肠癌或前列腺癌,或是黑色素瘤,或是白血病,优选急性髓细胞样白血病(AML)。
11.一种刺激精氨酸酶1特异性T细胞的方法,所述方法包括将所述细胞与权利要求1至3中任一项的多肽或权利要求4至6的组合物接触。
12.权利要求11的方法,其中所述细胞存在于取自健康受试者或取自癌症患者的样品中,任选地为肿瘤样品。
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GBGB1815549.9A GB201815549D0 (en) | 2018-09-24 | 2018-09-24 | Arginase1 polypeptides |
PCT/EP2019/075731 WO2020064744A1 (en) | 2018-09-24 | 2019-09-24 | Arginase1 polypeptides |
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CA (1) | CA3113004A1 (zh) |
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CN101781369A (zh) * | 2009-01-20 | 2010-07-21 | 江苏先声药物研究有限公司 | 一种重组人精氨酸酶融合蛋白及其应用 |
US20160367648A1 (en) * | 2014-04-29 | 2016-12-22 | Bio-Cancer Treatment International Limited | Methods and compositions for modulating the immune system with arginase i |
WO2018065563A1 (en) * | 2016-10-07 | 2018-04-12 | Herlev Hospital | Immunogenic arginase peptides |
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US58767A (en) | 1866-10-16 | John brougjbton | ||
US5554372A (en) | 1986-09-22 | 1996-09-10 | Emory University | Methods and vaccines comprising surface-active copolymers |
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CN101781369A (zh) * | 2009-01-20 | 2010-07-21 | 江苏先声药物研究有限公司 | 一种重组人精氨酸酶融合蛋白及其应用 |
US20160367648A1 (en) * | 2014-04-29 | 2016-12-22 | Bio-Cancer Treatment International Limited | Methods and compositions for modulating the immune system with arginase i |
WO2018065563A1 (en) * | 2016-10-07 | 2018-04-12 | Herlev Hospital | Immunogenic arginase peptides |
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JØRGENSEN M A等: "Spontaneous T-cell responses against Arginase-1 in the chronic myeloproliferative neoplasms relative to disease stage and type of driver mutation", ONCOIMMUNOLOGY, vol. 7, no. 9, pages 1468957 * |
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AU2019350356A8 (en) | 2021-05-27 |
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IL281762A (en) | 2021-05-31 |
US20220031818A1 (en) | 2022-02-03 |
GB201815549D0 (en) | 2018-11-07 |
CA3113004A1 (en) | 2020-04-02 |
EP3856899A1 (en) | 2021-08-04 |
AU2019350356A1 (en) | 2021-04-15 |
SG11202102378WA (en) | 2021-04-29 |
WO2020064744A1 (en) | 2020-04-02 |
KR20210091696A (ko) | 2021-07-22 |
JP2022501046A (ja) | 2022-01-06 |
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