CN112472710A - 烟酰胺腺嘌呤二核苷酸前体在制备免疫检查点抑制剂抗肿瘤增敏药物中的应用 - Google Patents

烟酰胺腺嘌呤二核苷酸前体在制备免疫检查点抑制剂抗肿瘤增敏药物中的应用 Download PDF

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CN112472710A
CN112472710A CN202011224948.7A CN202011224948A CN112472710A CN 112472710 A CN112472710 A CN 112472710A CN 202011224948 A CN202011224948 A CN 202011224948A CN 112472710 A CN112472710 A CN 112472710A
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王红阳
杨文�
吕洪伟
吕桂帅
陈赐安
宗倩妮
向威
杏福雪
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Abstract

本发明涉及医药技术领域，具体是烟酰胺腺嘌呤二核苷酸或其前体在制备免疫检查点抑制剂抗肿瘤增敏药物中的应用。本发明从体外细胞培养和体内动物实验两个方面研究发现补充NAD+前体物质能增强多种肿瘤对免疫检查点抑制剂的敏感性。通过体外实验发现，补充NAD+前体能促进干扰素γ诱导的预测免疫检查点抑制剂疗效的关键指标之一——PD‑L1的表达上调；进一步通过体内实验发现，补充NAD+前体显著增强抗PD‑L1抗体对原发和继发免疫治疗耐受性肿瘤的生长抑制作用。本发明为NAD+前体提供了一种新用途。本发明也为对肿瘤免疫治疗耐受的肿瘤的治疗提供了新的思路。

Description

烟酰胺腺嘌呤二核苷酸前体在制备免疫检查点抑制剂抗肿瘤 增敏药物中的应用
技术领域
本发明涉及医药技术领域，具体地说，是烟酰胺腺嘌呤二核苷酸(NAD+)或其前体在制备免疫检查点抑制剂的抗肿瘤增敏药物中的应用。
背景技术
近几年，免疫检查点抑制剂改善晚期肺癌、黑色素瘤、肾癌、霍奇金淋巴瘤等患者的生存方面取得了重大进展(文献：Ribas A,Wolchok JD.Cancer immunotherapy usingcheckpoint blockade.Science,2018,359:1350-1355.)。其中以程序性细胞死亡受体1(PD-1)或配体(PD-L1)为靶点的免疫检查点抑制剂因其显著临床疗效而备受关注，包括抗PD-1抗体：纳武单抗(Opdivo)和派姆单抗(Keytruda)、抗PD-L1抗体：阿替利珠单抗和度伐单抗等。虽然免疫检查点抑制剂在临床应用中取得了明显的治疗效果，但是在实体瘤中的有效率低是其非常突出的局限性。因此，寻找行之有效的疗效预测标志是提高肿瘤免疫治疗效果和推进肿瘤精准免疫治疗的重要方法(文献：Gibney GT,Weiner LM,AtkinsMB.Predictive biomarkers or checkpoint inhibitor-based immunotherapy.Lancetoncol.,2016,17:e542-e551)。越来越多的证据表明，PD-L1高表达的肿瘤癌患者能从抗PD-1/PD-L1抗体治疗中获得更好的疗效(文献：Reck M,Rodríguez-Abreu D,Robinson AG,HuiR,
Figure BDA0002763337690000011
T,
Figure BDA0002763337690000012
A,Gottfried M,Peled N,Tafreshi A,Cuffe S,O'Brien M,Rao S,Hotta K,Leiby MA,Lubiniecki GM,Shentu Y,Rangwala R,Brahmer JR；KEYNOTE-024Investigators.Pembrolizumab versus chemotherapy for PD-L1-positivenonsmall-cell lung cancer.N.Engl.J.Med.,2016,375:1823-1833.)。长时间持续性的单一使用免疫检查点抑制剂治疗肿瘤并不能收到预期的疗效，甚至容易引发免疫耐受，其中NAD+消耗酶CD38就是最近发现的调控继发性免疫检查点抑制剂耐受的关键分子，(文献：Chen,L.,Diao,L.,Yang,Y.,Yi,X.,Rodriguez,B.L.,Li,Y.,Villalobos,P.A.,Cascone,T.,Liu,X.,Tan,L.,et al.(2018).CD38-mediated immunosuppression as a mechanismof tumor cell escape from PD-1/PD-L1blockade.Cancer Discov.8,1156-1175.)因此联合治疗成为肿瘤免疫治疗的新思路(文献：Tang J,Shalabi A,Hubbard-LuceyVM.Comprehensive analysis of the clinical immuno-oncologylandscape.Ann.Oncol.,2018,29:84-91.)。
烟酰胺腺嘌呤二核苷酸(NAD+)是非常重要的代谢氧化还原辅酶，是500多种酶促反应所必需的(文献：Ryu,K.W.,Nandu,T.,Kim,J.,Challa,S.,DeBerardinis,R.J.,&Kraus,W.L.(2018).Metabolic regulation of transcription throughcompartmentalized NAD+biosynthesis.Science,360(6389),eaan5780.)。它在包括代谢，衰老，细胞死亡，DNA修复和基因表达在内的各种生物学过程中起着至关重要的作用(文献：Verdin,E.(2015).NAD(t)in aging,metabolism,and neurodegeneration.Science 350,1208-1213.)。因此，NAD+对于人类健康和长寿至关重要。NAD+前体物质包括β-烟酰胺单核苷酸(NMN)、烟酰胺(NAM)、烟酰胺核糖(NR)、烟酸(NA,也叫维生素B3)、色氨酸和NAD+本身等。在哺乳动物细胞中，主要通过NMN合成NAD+，以补充NAD+消耗酶参与包括DNA修复，代谢和细胞死亡在内的生理过程的消耗。相应地，NAD+代谢异常直接影响包括癌症在内的许多疾病的发生和发展。
发明内容
本发明的目的在于提供烟酰胺腺嘌呤二核苷酸(NAD+)前体用于增强免疫检查点抑制剂之抗肿瘤作用的新用途。
为了实现上述目的，本发明的第一方面，提供烟酰胺腺嘌呤二核苷酸(NAD+)或其前体在制备免疫检查点抑制剂抗肿瘤增敏药物中的应用。
本发明的第二方面，提供烟酰胺腺嘌呤二核苷酸(NAD+)或其前体和免疫检查点抑制剂联用在制备抗肿瘤药物中的应用。
本发明的第三方面，提供烟酰胺腺嘌呤二核苷酸(NAD+)或其前体在制备免疫检查点抑制剂的抗肿瘤增敏剂中的应用。
进一步的，所述的烟酰胺腺嘌呤二核苷酸(NAD+)前体为β-烟酰胺单核苷酸(NMN)、烟酰胺(NAM)、烟酰胺核糖(NR)、烟酸(NA，也叫维生素B3)、色氨酸等。
进一步的，所述的免疫检查点抑制剂为以程序性细胞死亡受体1(PD-1)或配体(PD-L1)为靶点的免疫检查点抑制剂；包括抗PD-1抗体：纳武单抗(Opdivo)和派姆单抗(Keytruda)、抗PD-L1抗体：阿替利珠单抗和度伐单抗等。
进一步的，所述的肿瘤为胰腺癌、肺癌、肝癌、黑色素瘤等。
更进一步的，所述的肿瘤为原发性免疫治疗耐受性胰腺癌、肺癌、肝癌、黑色素瘤。
更进一步的，所述的肿瘤为继发性免疫治疗耐受性胰腺癌、肺癌、肝癌、黑色素瘤。
本发明的第四方面，提供烟酰胺腺嘌呤二核苷酸(NAD+)或其前体在制备促进或上调肿瘤细胞的诱导型PD-L1表达药物中的应用。
本发明的第五方面，提供一种抗肿瘤药物，包括烟酰胺腺嘌呤二核苷酸(NAD+)或其前体，和免疫检查点抑制剂。
本发明从体外细胞培养和体内动物实验两个方面研究发现补充NAD+前体物质(β-烟酰胺单核苷酸(NMN)、烟酰胺(NAM)、烟酰胺核糖(NR)、烟酸(NA，也叫维生素B3)、色氨酸和NAD+本身等)能增强多种肿瘤对免疫检查点抑制剂的敏感性。通过体外实验发现，补充NAD+前体能促进干扰素γ诱导的预测免疫检查点抑制剂疗效的关键指标之一——PD-L1的表达上调；进一步通过体内实验发现，补充NAD+前体显著增强抗PD-L1抗体对原发和继发免疫治疗耐受性肿瘤的生长抑制作用。
本发明为NAD+前体提供了一种新用途。本发明也为对肿瘤免疫治疗耐受的肿瘤的治疗提供了新的思路。
附图说明
图1：实时荧光定量PCR检测小鼠胰腺癌细胞系Pan02(A)、小鼠肺癌细胞系LLC(B)、小鼠肝癌细胞系Hepa1-6(C)和人肝癌细胞系Huh7(D)先经NAD+前体NAM或NMN预处理后，干扰素γ诱导的PD-L1 mRNA表达水平。实验数据用平均值土标准差(mean±SD)表示。*表示p值<0.05，**表示p值<0.01，***表示p值<0.001。
图2：对照组、单用抗PD-L1抗体组、单用NMN组和NMN+抗PD-L1抗体组之间肿瘤体积的比较；其中A为免疫治疗耐受性胰腺癌，B为免疫治疗耐受性肺癌。实验数据用平均值土标准差(mean±SD)表示。**表示p值<0.01，***表示p值<0.001。
图3：继发免疫治疗耐受肝癌模型中对照组、单用抗PD-L1抗体组、单用NMN组和NMN+抗PD-L1抗体组之间肿瘤体积的比较。实验数据用平均值土标准差(mean±SD)表示。***表示p值<0.001。
具体实施方式
下面结合实施例对本发明提供的具体实施方式作详细说明。
实施例1：体外补充NAD+前体NAM或NMN升高肿瘤细胞的诱导型PD-L1表达。
实验方法：将处于对数生长期的小鼠胰腺癌细胞系Pan02、小鼠肺癌细胞系LLC、小鼠肝癌细胞系Hepa1-6和人肝癌细胞系Huh7接种于六孔细胞培养板中，待细胞密度长至约50％，分别添加0.5-1mM的NAM或NMN，对照组添加等量水溶剂，处理24小时后，再添加100ng/ml的干扰素γ或等量的对应溶剂作为对照，最后刺激24小时后，收集细胞RNA，检测PD-L1转录水平的变化。
结果：如图1A-D所示，添加100ng/ml的干扰素γ后，预先补充NAD+前体NAM或NMN的肿瘤细胞PD-L1 mRNA表达水平显著高于对照组，说明体外补充NAD+前体可上调人和小鼠肿瘤细胞的诱导型PD-L1表达。
实施例2：补充NAD+前体NMN在体内增强抗PD-L1抗体对免疫治疗耐受性胰腺癌和肺癌的生长抑制作用。
实验方法：1×106个小鼠胰腺癌细胞Pan02或小鼠肺癌细胞LLC接种在6-8周龄雄性C57BL/6小鼠的后肢皮下，一周后，将小鼠随机分为4组：对照组、单用抗PD-L1抗体组、单用NMN组和NMN+抗PD-L1抗体组，每组各5只，NMN：每天腹腔注射1次(300mg/kg)，抗PD-L1抗体：每周腹腔注射2次(100μg/只)，每3天测量肿瘤体积大小(肿瘤体积大小的计算公式为：体积＝1/2×肿瘤长径×短径2)。
结果：如图2A和B所示，分组治疗两周后，仅用抗PD-L1抗体组与对照组相比无明显差别，说明该肿瘤模型对抗PD-L1抗体治疗不敏感，而NMN与抗PD-L1抗体联用可以明显抑制肿瘤生长，导致肿瘤体积变小，说明NMN可以增强抗PD-L1抗体对原发性免疫治疗耐受性胰腺癌和肺癌的杀伤作用。
实施例3：补充NAD+前体NMN在体内增强抗PD-L1抗体对免疫治疗继发耐受性肝癌的生长抑制作用。
实验方法：1×106个过表达继发免疫治疗耐受调控分子CD38的小鼠肝癌细胞Hepa1-6接种在6-8周龄雄性C57BL/6小鼠的后肢皮下，一周后，将小鼠随机分为4组：对照组、单用抗PD-L1抗体组、单用NMN组和NMN+抗PD-L1抗体组，每组各5只，NMN：每天腹腔注射1次(300mg/kg)，抗PD-L1抗体：每周腹腔注射2次(100μg/只)，每3天测量肿瘤体积大小(肿瘤体积大小的计算公式为：体积＝1/2×肿瘤长径×短径2)。
结果：如图3所示，分组治疗两周后，仅用抗PD-L1抗体组与对照组相比无明显差别，说明该肿瘤模型对抗PD-L1抗体治疗不敏感，而NMN与抗PD-L1抗体联用可以明显抑制肿瘤生长，导致肿瘤体积变小，说明NMN可以增强抗PD-L1抗体对继发性免疫治疗耐受性肝癌的杀伤作用。
以上已对本发明创造的较佳实施例进行了具体说明，但本发明创造并不限于所述实施例，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可做出种种的等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。

Claims (10)

1.烟酰胺腺嘌呤二核苷酸或其前体在制备免疫检查点抑制剂抗肿瘤增敏药物中的应用。
2.烟酰胺腺嘌呤二核苷酸或其前体和免疫检查点抑制剂联用在制备抗肿瘤药物中的应用。
3.烟酰胺腺嘌呤二核苷酸或其前体在制备免疫检查点抑制剂的抗肿瘤增敏剂中的应用。
4.烟酰胺腺嘌呤二核苷酸或其前体在制备促进或上调肿瘤细胞的诱导型PD-L1表达药物中的应用。
5.根据权利要求1-4任一所述的应用，其特征在于，所述的烟酰胺腺嘌呤二核苷酸前体为β-烟酰胺单核苷酸、烟酰胺、烟酰胺核糖、烟酸、色氨酸。
6.根据权利要求1-4任一所述的应用，其特征在于，所述的免疫检查点抑制剂为以程序性细胞死亡受体1或配体为靶点的免疫检查点抑制剂。
7.根据权利要求1-4任一所述的应用，其特征在于，所述的肿瘤为胰腺癌、肺癌、肝癌、黑色素瘤。
8.根据权利要求1-4任一所述的应用，其特征在于，所述的肿瘤为原发性免疫治疗耐受性胰腺癌、肺癌、肝癌、黑色素瘤。
9.根据权利要求1-4任一所述的应用，其特征在于，所述的肿瘤为继发性免疫治疗耐受性胰腺癌、肺癌、肝癌、黑色素瘤。
10.一种抗肿瘤药物，其特征在于，包括烟酰胺腺嘌呤二核苷酸或其前体，和免疫检查点抑制剂。
CN202011224948.7A 2020-11-05 2020-11-05 烟酰胺腺嘌呤二核苷酸前体在制备免疫检查点抑制剂抗肿瘤增敏药物中的应用 Pending CN112472710A (zh)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114009399A (zh) * 2021-10-28 2022-02-08 复旦大学附属华山医院 肝癌免疫检查点抗体耐药小鼠及细胞株的制备与应用
CN114469978A (zh) * 2022-01-20 2022-05-13 山东大学 基于nad+代谢靶向的nk细胞在疾病治疗中应用
WO2024089418A1 (en) * 2022-10-24 2024-05-02 Cancer Research Technology Limited Tumour sensitisation to checkpoint inhibitors with redox status modifier

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108601840A (zh) * 2015-12-07 2018-09-28 国立大学法人京都大学 Pd-1信号抑制剂的并用疗法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108601840A (zh) * 2015-12-07 2018-09-28 国立大学法人京都大学 Pd-1信号抑制剂的并用疗法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HONGWEI LV等: "NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion", 《CELL METABOLISM》 *
MING LI等: "Local targeting of NAD+ salvage pathway alters the immune tumor microenvironment and enhances checkpoint immunotherapy in glioblastoma", 《CANCER RESEARCH》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114009399A (zh) * 2021-10-28 2022-02-08 复旦大学附属华山医院 肝癌免疫检查点抗体耐药小鼠及细胞株的制备与应用
CN114469978A (zh) * 2022-01-20 2022-05-13 山东大学 基于nad+代谢靶向的nk细胞在疾病治疗中应用
WO2024089418A1 (en) * 2022-10-24 2024-05-02 Cancer Research Technology Limited Tumour sensitisation to checkpoint inhibitors with redox status modifier

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