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.
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.