Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindings.

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-11-26 DOI:10.1080/19420862.2024.2432403
Maria Meira, Aurore Frey, Neila Chekkat, Magda Rybczynska, Zaki Sellam, Joon Seok Park, Francesca Smylie Gazzaniga, Alexia Parmentier, Marianne Le Gall, Gordon James Freeman, Dennis Lee Kasper, Arlene Helen Sharpe, Eric Rambeaux, Abdijapar Shamshiev
{"title":"Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindings.","authors":"Maria Meira, Aurore Frey, Neila Chekkat, Magda Rybczynska, Zaki Sellam, Joon Seok Park, Francesca Smylie Gazzaniga, Alexia Parmentier, Marianne Le Gall, Gordon James Freeman, Dennis Lee Kasper, Arlene Helen Sharpe, Eric Rambeaux, Abdijapar Shamshiev","doi":"10.1080/19420862.2024.2432403","DOIUrl":null,"url":null,"abstract":"<p><p>Therapeutic efficacy with durable responses has been demonstrated with several antibody drugs that block key immune checkpoint receptors, including PD-1, PD-L1, and CTLA-4. Despite the success of these drugs, a substantial proportion of patients do not benefit. Targeting multiple inhibitory pathways simultaneously to augment anti-tumor immunity has proven to be a promising approach. The emergence of Repulsive Guidance Molecule b (RGMb), a ligand for PD-L2, as a novel co-inhibitory pathway in T cells, together with its regulation by the gut microbiome, encouraged the discovery and development of fully human anti-RGMb antibodies. Here, we describe phage display-derived monoclonal antibodies (mAbs) 2C11 and 5C10 that bind human RGMb with high affinities of 1.4 nM and 0.72 nM, respectively. Both mAbs 2C11 and 5C10 potently inhibited RGMb interaction with PD-L2. MAb 2C11 effectively inhibited RGMb interaction with bone morphogenetic proteins 2 and 4 (BMP2-4), while leaving RGMb interaction with Neogenin 1 (Neo1) unaffected. Conversely, mAb 5C10 disrupted RGMb interaction with Neo1 while maintaining RGMb binding to BMP2-4. These findings map the 2C11 epitope at the membrane-distal N-terminal region of RGMb, which coincides with both PD-L2- and BMP2-4-binding sites. The PD-L2 binding interface is likely positioned between RGMb's N-terminal BMP-binding and C-terminal Neo1-binding regions. The in vivo activity of mAb 2C11 in combination with anti-PD-1 or anti-PD-L1 was tested in MC38 and B16-OVA cancer models and demonstrated synergistic effects by significantly enhancing anti-tumor responses. These properties make mAb 2C11 a promising candidate for therapeutic use to overcome immune checkpoint inhibitor resistances, warranting further exploration in clinical settings.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2432403"},"PeriodicalIF":5.6000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601088/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"mAbs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/19420862.2024.2432403","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Therapeutic efficacy with durable responses has been demonstrated with several antibody drugs that block key immune checkpoint receptors, including PD-1, PD-L1, and CTLA-4. Despite the success of these drugs, a substantial proportion of patients do not benefit. Targeting multiple inhibitory pathways simultaneously to augment anti-tumor immunity has proven to be a promising approach. The emergence of Repulsive Guidance Molecule b (RGMb), a ligand for PD-L2, as a novel co-inhibitory pathway in T cells, together with its regulation by the gut microbiome, encouraged the discovery and development of fully human anti-RGMb antibodies. Here, we describe phage display-derived monoclonal antibodies (mAbs) 2C11 and 5C10 that bind human RGMb with high affinities of 1.4 nM and 0.72 nM, respectively. Both mAbs 2C11 and 5C10 potently inhibited RGMb interaction with PD-L2. MAb 2C11 effectively inhibited RGMb interaction with bone morphogenetic proteins 2 and 4 (BMP2-4), while leaving RGMb interaction with Neogenin 1 (Neo1) unaffected. Conversely, mAb 5C10 disrupted RGMb interaction with Neo1 while maintaining RGMb binding to BMP2-4. These findings map the 2C11 epitope at the membrane-distal N-terminal region of RGMb, which coincides with both PD-L2- and BMP2-4-binding sites. The PD-L2 binding interface is likely positioned between RGMb's N-terminal BMP-binding and C-terminal Neo1-binding regions. The in vivo activity of mAb 2C11 in combination with anti-PD-1 or anti-PD-L1 was tested in MC38 and B16-OVA cancer models and demonstrated synergistic effects by significantly enhancing anti-tumor responses. These properties make mAb 2C11 a promising candidate for therapeutic use to overcome immune checkpoint inhibitor resistances, warranting further exploration in clinical settings.

针对 RGMb 的相互作用:发现阻断多种配体结合的强效抗 RGMb 抗体并对其进行临床前鉴定。
阻断包括 PD-1、PD-L1 和 CTLA-4 在内的关键免疫检查点受体的几种抗体药物已被证明具有持久疗效。尽管这些药物取得了成功,但仍有相当一部分患者未能从中获益。事实证明,同时靶向多种抑制途径以增强抗肿瘤免疫力是一种很有前景的方法。PD-L2 的配体--排斥性引导分子 b(RGMb)是 T 细胞中的一种新型协同抑制途径,它的出现以及肠道微生物组对它的调控促进了全人源抗 RGMb 抗体的发现和开发。在这里,我们描述了噬菌体展示衍生的单克隆抗体(mAbs)2C11 和 5C10,它们分别以 1.4 nM 和 0.72 nM 的高亲和力与人类 RGMb 结合。MAb 2C11 和 5C10 都能有效抑制 RGMb 与 PD-L2 的相互作用。MAb 2C11 能有效抑制 RGMb 与骨形态发生蛋白 2 和 4(BMP2-4)的相互作用,而不影响 RGMb 与 Neogenin 1(Neo1)的相互作用。相反,mAb 5C10 会破坏 RGMb 与 Neo1 的相互作用,同时保持 RGMb 与 BMP2-4 的结合。这些发现将 2C11 表位映射到了 RGMb 的膜远端 N 端区域,该区域与 PD-L2 结合位点和 BMP2-4 结合位点重合。PD-L2 结合界面可能位于 RGMb 的 N 端 BMP 结合区和 C 端 Neo1 结合区之间。在 MC38 和 B16-OVA 癌症模型中测试了 mAb 2C11 与抗-PD-1 或抗-PD-L1 联用的体内活性,结果表明它们具有协同作用,能显著增强抗肿瘤反应。这些特性使 mAb 2C11 有希望成为克服免疫检查点抑制剂抗药性的候选治疗药物,值得在临床环境中进一步探索。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
mAbs
mAbs 工程技术-仪器仪表
CiteScore
10.70
自引率
11.30%
发文量
77
审稿时长
6-12 weeks
期刊介绍: mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.
×
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