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.

中文翻译：

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Botensilimab 是一种 Fc 增强的抗 CTLA-4 抗体，可有效对抗对传统免疫疗法反应不佳的肿瘤


针对 CTLA-4 的传统免疫检查点抑制剂 (ICI) 可以实现持久生存，但主要是针对免疫炎症肿瘤患者。尽管对抗 CTLA-4 反应的机制仍知之甚少，但 Fc-γ 受体 (FcγR) IIIA 共同参与似乎对活性至关重要，这可能解释了已批准的抗 CTLA-4 抗体的适度临床益处。我们证明，为增强 FcγR 亲和力而设计的抗 CTLA-4 利用 FcγR 依赖性机制来增强 T 细胞反应性、减少瘤内 Tregs 并增强抗原呈递细胞活化。与传统的抗 CTLA-4 相比，Fc 增强的抗 CTLA-4 在小鼠模型中具有卓越的功效，并重塑了先天性和适应性免疫。这些发现扩展到接受 Botensilimab（一种 Fc 增强型抗 CTLA-4 抗体）治疗的患者，该抗体对多种免疫原性差和 ICI 治疗难治性癌症具有临床活性。功效与肿瘤新抗原负荷或 FcγRIIIA 基因型无关。然而，FcγRIIA 和 FcγRIIIA 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 治疗无反应的癌症中的治疗潜力。