摘要B009:靶向TRAIL激动剂受体的单克隆抗体的新进展

A. Dubuisson
{"title":"摘要B009:靶向TRAIL激动剂受体的单克隆抗体的新进展","authors":"A. Dubuisson","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B009","DOIUrl":null,"url":null,"abstract":"Restoring programmed-cell death of cancer cells is a real challenge in oncology. To date, several monoclonal antibodies targeting TRAIL agonist death receptors have been developed, but none has been found to display significant clinical effects, so far. Efforts should be continued to develop novel DR4 and DR5 antibodies with improved properties. In this regard, novel monoclonal antibodies targeting DR4 and DR5 have been generated here using DNA-immunization in order to produce antibodies that can recognise DR4 or DR5 in their native forms. This cost- and time-effective technique allows the production of proteins of interest directly into the mice. Plasmids encoding DR4 or DR5 sequences have been injected into the tail veins of mice. Immunizations elicited significant humoral anti-DR4 and anti-DR5 responses and fusions of the corresponding spleens resulted in numerous hybridomas that can specifically recognise DR4 or DR5 in their native forms. After an intensive screening, anti-DR4 and anti-DR5 clones were selected for production and 4 to 5 were assessed for selectivity and affinity towards their respective targets by flow cytometry (FACS) and bio-layer interferometry (BLI). All antibodies efficiently bind to their targets with a very high affinity (nanomolar range). They were then characterized and tested for their capacity to induce apoptosis in a wide range of cancer cell lines. Of the four anti-DR4 antibodies of interest, one antibody displayed agonistic properties alone, one was able to inhibit and two were found to potentiate TRAIL-induced apoptosis. Similarly, one out of the four anti-DR5 antibodies behaved as an agonist whereas another one was found to enhance TRAIL. The most potent antibody was assessed in vivo, and preliminary results indicate that the latter is also able to inhibit tumor growth in animal models. In summary, this study is the first demonstration that DNA-based immunization method can be used to generate efficient therapeutic monoclonal antibodies targeting receptors of the TNF superfamily. Citation Format: Agathe Dubuisson. New development of monoclonal antibodies targeting TRAIL agonist receptors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B009.","PeriodicalId":352838,"journal":{"name":"Convergence of Technology and Cancer Immunotherapy","volume":"70 1","pages":"0"},"PeriodicalIF":0.0000,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Abstract B009: New development of monoclonal antibodies targeting TRAIL agonist receptors\",\"authors\":\"A. Dubuisson\",\"doi\":\"10.1158/2326-6074.CRICIMTEATIAACR18-B009\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Restoring programmed-cell death of cancer cells is a real challenge in oncology. To date, several monoclonal antibodies targeting TRAIL agonist death receptors have been developed, but none has been found to display significant clinical effects, so far. Efforts should be continued to develop novel DR4 and DR5 antibodies with improved properties. In this regard, novel monoclonal antibodies targeting DR4 and DR5 have been generated here using DNA-immunization in order to produce antibodies that can recognise DR4 or DR5 in their native forms. This cost- and time-effective technique allows the production of proteins of interest directly into the mice. Plasmids encoding DR4 or DR5 sequences have been injected into the tail veins of mice. Immunizations elicited significant humoral anti-DR4 and anti-DR5 responses and fusions of the corresponding spleens resulted in numerous hybridomas that can specifically recognise DR4 or DR5 in their native forms. After an intensive screening, anti-DR4 and anti-DR5 clones were selected for production and 4 to 5 were assessed for selectivity and affinity towards their respective targets by flow cytometry (FACS) and bio-layer interferometry (BLI). All antibodies efficiently bind to their targets with a very high affinity (nanomolar range). They were then characterized and tested for their capacity to induce apoptosis in a wide range of cancer cell lines. Of the four anti-DR4 antibodies of interest, one antibody displayed agonistic properties alone, one was able to inhibit and two were found to potentiate TRAIL-induced apoptosis. Similarly, one out of the four anti-DR5 antibodies behaved as an agonist whereas another one was found to enhance TRAIL. The most potent antibody was assessed in vivo, and preliminary results indicate that the latter is also able to inhibit tumor growth in animal models. In summary, this study is the first demonstration that DNA-based immunization method can be used to generate efficient therapeutic monoclonal antibodies targeting receptors of the TNF superfamily. Citation Format: Agathe Dubuisson. New development of monoclonal antibodies targeting TRAIL agonist receptors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B009.\",\"PeriodicalId\":352838,\"journal\":{\"name\":\"Convergence of Technology and Cancer Immunotherapy\",\"volume\":\"70 1\",\"pages\":\"0\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2019-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Convergence of Technology and Cancer Immunotherapy\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B009\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Convergence of Technology and Cancer Immunotherapy","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B009","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

恢复癌细胞的程序性细胞死亡是肿瘤学的一个真正的挑战。迄今为止,已经开发了几种针对TRAIL激动剂死亡受体的单克隆抗体,但迄今为止尚未发现具有显着的临床效果。应继续努力开发性能更好的新型DR4和DR5抗体。在这方面,针对DR4和DR5的新型单克隆抗体已经在这里使用dna免疫产生,以便产生能够识别天然形式的DR4或DR5的抗体。这种成本和时间效益高的技术允许直接在小鼠体内生产感兴趣的蛋白质。编码DR4或DR5序列的质粒已被注射到小鼠尾静脉中。免疫引起显著的体液抗DR4和抗DR5反应,相应的脾脏融合导致许多杂交瘤能够特异性识别天然形式的DR4或DR5。经过密集筛选,选择抗dr4和抗dr5克隆进行生产,并通过流式细胞术(FACS)和生物层干涉术(BLI)评估4 ~ 5个抗dr4和抗dr5克隆对各自靶点的选择性和亲和力。所有抗体都能以非常高的亲和力(纳摩尔范围)有效地与它们的靶标结合。然后对它们进行了表征并测试了它们在多种癌细胞系中诱导细胞凋亡的能力。在四种抗dr4抗体中,一种抗体单独表现出激动特性,一种能够抑制,两种被发现能够增强trail诱导的细胞凋亡。同样,四种抗dr5抗体中的一种表现为激动剂,而另一种被发现增强TRAIL。在体内对最有效的抗体进行了评估,初步结果表明后者在动物模型中也能抑制肿瘤生长。综上所述,本研究首次证明基于dna的免疫方法可用于产生针对TNF超家族受体的高效治疗性单克隆抗体。引文格式:Agathe Dubuisson。靶向TRAIL激动剂受体的单克隆抗体新进展[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约,纽约。费城(PA): AACR;癌症免疫学杂志,2019;7(2增刊):摘要nr B009。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract B009: New development of monoclonal antibodies targeting TRAIL agonist receptors
Restoring programmed-cell death of cancer cells is a real challenge in oncology. To date, several monoclonal antibodies targeting TRAIL agonist death receptors have been developed, but none has been found to display significant clinical effects, so far. Efforts should be continued to develop novel DR4 and DR5 antibodies with improved properties. In this regard, novel monoclonal antibodies targeting DR4 and DR5 have been generated here using DNA-immunization in order to produce antibodies that can recognise DR4 or DR5 in their native forms. This cost- and time-effective technique allows the production of proteins of interest directly into the mice. Plasmids encoding DR4 or DR5 sequences have been injected into the tail veins of mice. Immunizations elicited significant humoral anti-DR4 and anti-DR5 responses and fusions of the corresponding spleens resulted in numerous hybridomas that can specifically recognise DR4 or DR5 in their native forms. After an intensive screening, anti-DR4 and anti-DR5 clones were selected for production and 4 to 5 were assessed for selectivity and affinity towards their respective targets by flow cytometry (FACS) and bio-layer interferometry (BLI). All antibodies efficiently bind to their targets with a very high affinity (nanomolar range). They were then characterized and tested for their capacity to induce apoptosis in a wide range of cancer cell lines. Of the four anti-DR4 antibodies of interest, one antibody displayed agonistic properties alone, one was able to inhibit and two were found to potentiate TRAIL-induced apoptosis. Similarly, one out of the four anti-DR5 antibodies behaved as an agonist whereas another one was found to enhance TRAIL. The most potent antibody was assessed in vivo, and preliminary results indicate that the latter is also able to inhibit tumor growth in animal models. In summary, this study is the first demonstration that DNA-based immunization method can be used to generate efficient therapeutic monoclonal antibodies targeting receptors of the TNF superfamily. Citation Format: Agathe Dubuisson. New development of monoclonal antibodies targeting TRAIL agonist receptors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B009.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信