Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, is effective against tumors poorly responsive to conventional immunotherapy.

IF 29.7 1区 医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2024-07-31 DOI:10.1158/2159-8290.CD-24-0190
Dhan Chand, David A Savitsky, Shanmugarajan Krishnan, Gabriel Mednick, Chloe Delepine, Pilar Garcia-Broncano, Kah Teong Soh, Wei Wu, Margaret K Wilkens, Olga Udartseva, Sylvia Vincent, Bishnu Joshi, Justin G Keith, Mariana Manrique, Marilyn Marques, Antoine Tanne, Daniel L Levey, Haiyong Han, Serina Ng, Jackson Ridpath, Olivia Huber, Benjamin Morin, Claire Galand, Sean Bourdelais, Randi B Gombos, Rebecca Ward, Yu Qin, Jeremy D Waight, Matthew R Costa, Alvaro Sebastian-Yague, Nils-Petter Rudqvist, Malgorzata Pupecka-Swider, Vignesh Venkatraman, Andrew Slee, Jaymin M Patel, Joseph E Grossman, Nicholas S Wilson, Daniel D Von Hoff, Justin Stebbing, Tyler J Curiel, Jennifer S Buell, Steven J O'Day, Robert B Stein
{"title":"Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, is effective against tumors poorly responsive to conventional immunotherapy.","authors":"Dhan Chand, David A Savitsky, Shanmugarajan Krishnan, Gabriel Mednick, Chloe Delepine, Pilar Garcia-Broncano, Kah Teong Soh, Wei Wu, Margaret K Wilkens, Olga Udartseva, Sylvia Vincent, Bishnu Joshi, Justin G Keith, Mariana Manrique, Marilyn Marques, Antoine Tanne, Daniel L Levey, Haiyong Han, Serina Ng, Jackson Ridpath, Olivia Huber, Benjamin Morin, Claire Galand, Sean Bourdelais, Randi B Gombos, Rebecca Ward, Yu Qin, Jeremy D Waight, Matthew R Costa, Alvaro Sebastian-Yague, Nils-Petter Rudqvist, Malgorzata Pupecka-Swider, Vignesh Venkatraman, Andrew Slee, Jaymin M Patel, Joseph E Grossman, Nicholas S Wilson, Daniel D Von Hoff, Justin Stebbing, Tyler J Curiel, Jennifer S Buell, Steven J O'Day, Robert B Stein","doi":"10.1158/2159-8290.CD-24-0190","DOIUrl":null,"url":null,"abstract":"<p><p>Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7000,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.CD-24-0190","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Botensilimab是一种Fc增强型抗CTLA-4抗体,对传统免疫疗法反应不佳的肿瘤有效。
以CTLA-4为靶点的传统免疫检查点抑制剂(ICI)可获得持久生存,但主要针对免疫炎症肿瘤患者。尽管人们对抗 CTLA-4 反应的机制仍不甚了解,但 FcγR IIIA 共同参与似乎对活性至关重要,这可能是已获批准的抗 CTLA-4 抗体临床疗效一般的原因。我们证明,为增强 FcγR 亲和力而设计的抗 CTLA-4 可利用 FcγR 依赖性机制来增强 T 细胞的反应性、减少瘤内 Tregs 并增强抗原提呈细胞的活化。与传统的抗CTLA-4相比,Fc增强型抗CTLA-4能促进小鼠模型的卓越疗效,并重塑先天和适应性免疫。这些研究结果扩展到了使用博腾西利单抗(一种Fc增强型抗CTLA-4抗体)治疗的患者身上,博腾西利单抗对多种免疫原性较差的癌症和ICI治疗难治性癌症具有临床活性。疗效与肿瘤新抗原负荷或FcγRIIIA基因型无关。然而,FcγRIIA和FcγRIIIA的表达成为潜在的反应生物标志物。这些数据凸显了Fc增强型抗CTLA-4抗体在对传统ICI疗法无反应的癌症中的治疗潜力。
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 去求助
来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
期刊最新文献
Clinical Validation of a Cell-Free DNA Fragmentome Assay for Augmentation of Lung Cancer Early Detection. The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma. Single-Cell View of Tumor Microenvironment Gradients in Pleural Mesothelioma. A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer. Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer.
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1