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 : 2024-12-02 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

Significance: This study reveals that Fc-enhanced anti-CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti-CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies.

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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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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.