抗 FcRn 单克隆抗体罗扎尼单抗与 Fcγ 受体的相互作用以及对体外免疫细胞的功能影响。

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-01-19 DOI:10.1080/19420862.2023.2300155
Omar S Qureshi, Emma J Sutton, Rosemary F Bithell, Shauna M West, Rona M Cutler, Gillian McCluskey, Graham Craggs, Asher Maroof, Nicholas M Barnes, David P Humphreys, Stephen Rapecki, Bryan J Smith, Anthony Shock
{"title":"抗 FcRn 单克隆抗体罗扎尼单抗与 Fcγ 受体的相互作用以及对体外免疫细胞的功能影响。","authors":"Omar S Qureshi, Emma J Sutton, Rosemary F Bithell, Shauna M West, Rona M Cutler, Gillian McCluskey, Graham Craggs, Asher Maroof, Nicholas M Barnes, David P Humphreys, Stephen Rapecki, Bryan J Smith, Anthony Shock","doi":"10.1080/19420862.2023.2300155","DOIUrl":null,"url":null,"abstract":"<p><p>Rozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower affinity for Fc gamma receptors (FcγR) and lack of C1q engagement. However, with growing evidence suggesting that no Fc-containing agent is truly \"silent\" in this respect, we explored the engagement of FcγRs and potential functional consequences with rozanolixizumab. In the study presented here, rozanolixizumab was shown to bind to FcγRs in both protein-protein and cell-based assays, and the kinetic data were broadly as expected based on published data for an IgG4 mAb. Rozanolixizumab was also able to mediate antibody bipolar bridging (ABB), a phenomenon that led to a reduction of labeled FcγRI from the surface of human macrophages in an FcRn-dependent manner. However, the presence of exogenous human IgG, even at low concentrations, was able to prevent both binding and ABB events. Furthermore, data from <i>in vitro</i> experiments using relevant human cell types that express both FcRn and FcγRI indicated no evidence for functional sequelae in relation to cellular activation events (e.g., intracellular signaling, cytokine production) upon either FcRn or FcγR binding of rozanolixizumab. These data raise important questions about whether therapeutic antagonistic mAbs like rozanolixizumab would necessarily engage FcγRs at doses typically administered to patients in the clinic, and hence challenge the relevance and interpretation of <i>in vitro</i> assays performed in the absence of competing IgG.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2300155"},"PeriodicalIF":5.6000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10802195/pdf/","citationCount":"0","resultStr":"{\"title\":\"Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells <i>in vitro</i>.\",\"authors\":\"Omar S Qureshi, Emma J Sutton, Rosemary F Bithell, Shauna M West, Rona M Cutler, Gillian McCluskey, Graham Craggs, Asher Maroof, Nicholas M Barnes, David P Humphreys, Stephen Rapecki, Bryan J Smith, Anthony Shock\",\"doi\":\"10.1080/19420862.2023.2300155\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Rozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower affinity for Fc gamma receptors (FcγR) and lack of C1q engagement. However, with growing evidence suggesting that no Fc-containing agent is truly \\\"silent\\\" in this respect, we explored the engagement of FcγRs and potential functional consequences with rozanolixizumab. In the study presented here, rozanolixizumab was shown to bind to FcγRs in both protein-protein and cell-based assays, and the kinetic data were broadly as expected based on published data for an IgG4 mAb. Rozanolixizumab was also able to mediate antibody bipolar bridging (ABB), a phenomenon that led to a reduction of labeled FcγRI from the surface of human macrophages in an FcRn-dependent manner. However, the presence of exogenous human IgG, even at low concentrations, was able to prevent both binding and ABB events. Furthermore, data from <i>in vitro</i> experiments using relevant human cell types that express both FcRn and FcγRI indicated no evidence for functional sequelae in relation to cellular activation events (e.g., intracellular signaling, cytokine production) upon either FcRn or FcγR binding of rozanolixizumab. These data raise important questions about whether therapeutic antagonistic mAbs like rozanolixizumab would necessarily engage FcγRs at doses typically administered to patients in the clinic, and hence challenge the relevance and interpretation of <i>in vitro</i> assays performed in the absence of competing IgG.</p>\",\"PeriodicalId\":18206,\"journal\":{\"name\":\"mAbs\",\"volume\":\"16 1\",\"pages\":\"2300155\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10802195/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"mAbs\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/19420862.2023.2300155\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"mAbs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/19420862.2023.2300155","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

摘要

Rozanolixizumab是一种人源化的抗新生儿Fc受体(FcRn)单克隆抗体(mAb),属于免疫球蛋白G4(IgG4)亚类,目前正处于临床开发阶段,用于治疗IgG自身抗体驱动的疾病。这种形式的 mAb 通常用于治疗,因为它对 FcγR 受体(FcγR)的亲和力较低,而且缺乏 C1q 参与。然而,越来越多的证据表明,没有一种含 Fc 的药物在这方面是真正 "沉默 "的,因此我们探索了罗扎尼珠单抗与 FcγR 的啮合以及潜在的功能性后果。在本文介绍的研究中,罗扎尼珠单抗在蛋白-蛋白和基于细胞的实验中都与 FcγRs 结合,而且根据已发表的 IgG4 mAb 数据,其动力学数据与预期的大致相同。罗扎尼珠单抗还能介导抗体双极桥接(ABB),这种现象以 FcRn 依赖性方式导致人巨噬细胞表面标记的 FcγRI 减少。然而,外源性人类 IgG 的存在,即使浓度很低,也能阻止结合和 ABB 事件的发生。此外,使用同时表达 FcRn 和 FcγRI 的相关人类细胞类型进行的体外实验数据显示,没有证据表明罗扎尼珠单抗与 FcRn 或 FcγR 结合后会产生与细胞活化事件(如细胞内信号传导、细胞因子产生)相关的功能性后遗症。这些数据提出了一些重要问题,即罗扎尼珠单抗等治疗性拮抗 mAbs 是否一定会以临床上通常给患者使用的剂量与 FcγR 结合,从而对在没有竞争 IgG 的情况下进行的体外检测的相关性和解释提出了挑战。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitro.

Rozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower affinity for Fc gamma receptors (FcγR) and lack of C1q engagement. However, with growing evidence suggesting that no Fc-containing agent is truly "silent" in this respect, we explored the engagement of FcγRs and potential functional consequences with rozanolixizumab. In the study presented here, rozanolixizumab was shown to bind to FcγRs in both protein-protein and cell-based assays, and the kinetic data were broadly as expected based on published data for an IgG4 mAb. Rozanolixizumab was also able to mediate antibody bipolar bridging (ABB), a phenomenon that led to a reduction of labeled FcγRI from the surface of human macrophages in an FcRn-dependent manner. However, the presence of exogenous human IgG, even at low concentrations, was able to prevent both binding and ABB events. Furthermore, data from in vitro experiments using relevant human cell types that express both FcRn and FcγRI indicated no evidence for functional sequelae in relation to cellular activation events (e.g., intracellular signaling, cytokine production) upon either FcRn or FcγR binding of rozanolixizumab. These data raise important questions about whether therapeutic antagonistic mAbs like rozanolixizumab would necessarily engage FcγRs at doses typically administered to patients in the clinic, and hence challenge the relevance and interpretation of in vitro assays performed in the absence of competing IgG.

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
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