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CD25-T 耗竭抗体保留效应 T 细胞上的 IL-2 信号转导，增强效应激活和抗肿瘤免疫。

CD25-T-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity.

机构信息

Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland.

出版信息

Nat Cancer. 2020 Dec;1(12):1153-1166. doi: 10.1038/s43018-020-00133-0. Epub 2020 Nov 9.

DOI:10.1038/s43018-020-00133-0
PMID:33644766
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7116816/
Abstract

Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies.

摘要

肿瘤内调节性 T 细胞（Treg）的丰度与人类癌症中抗肿瘤免疫的减弱和预后不良相关。最近的研究表明，IL-2 的高亲和力受体亚基 CD25 是小鼠和人类恶性肿瘤中 Treg 耗竭的选择性靶点；然而，由于抗人 CD25 抗体在效应 T 细胞上阻断了旁观者 IL-2 受体信号，从而限制了其抗肿瘤活性，因此未能在实体瘤中产生临床反应。在这里，我们证明了经过优化以耗竭 Treg 同时保留效应 T 细胞上的 IL-2-STAT5 信号的抗 CD25 抗体具有强大的单药活性，并在体内证明了与免疫检查点阻断的协同作用。具有等效特征的抗人 CD25（RG6292）抗体的临床前评估表明，在非人类灵长类动物和人源化小鼠模型中，均能有效耗竭 Treg，而无明显的免疫相关毒性。我们的数据支持 RG6292 的临床开发，并支持在临床研究中评估包含非 IL-2 阻断性抗 CD25 抗体的新型联合治疗。

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