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
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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.

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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。
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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.
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