通过几何优化设计三特异性IL-2受体激动抗体，以增强Treg靶向性
Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting.
摘要(中文译文)
调节性T细胞（Tregs）是维持免疫耐受的核心，通过白细胞介素-2（IL-2）信号通路选择性激活Tregs为自身免疫性疾病和移植排斥提供了有前景的治疗策略。本研究开发了IL-2受体（IL-2R）激动剂，采用三特异性抗体同时结合全部三个IL-2R亚基。该设计优先激活并扩增Tregs，而非表达二聚体IL-2R（CD122和CD132）的常规T细胞和自然杀伤细胞。引入第二个靶向CD25的VHH结构域进一步增强了对CD25⁺ Tregs的特异性和效力。随后对抗体几何构型进行大量工程改造对于最大化Treg选择性至关重要，凸显了空间构型在受体结合中的重要性。本研究报道了靶向IL-2R的三特异性抗体的成功开发，并显著拓展了基于抗体的免疫调节的潜力。通过选择性激活Tregs上的高亲和力三聚体IL-2R，该多功能平台为自身免疫性疾病和移植排斥的治疗提供了一种差异化的、有前景的策略。
Abstract
Regulatory T cells (Tregs) are central to maintaining immune tolerance, and their selective activation via interleukin-2 (IL-2) signaling presents a promising therapeutic strategy for autoimmune diseases and transplant rejection. Here, we develop IL-2 receptor (IL-2R) agonists, employing trispecific antibodies that simultaneously engage all three IL-2R subunits. This design preferentially activates and expands Tregs over conventional T cells and natural killer cells that express the dimeric IL-2R (CD122 and CD132). Incorporation of a second CD25-targeting VHH domain confers further enhanced specificity and potency for CD25⁺ Tregs. Extensive engineering of antibody geometry was then critical to maximize Treg selectivity, highlighting the importance of spatial configuration in receptor engagement. This study reports the successful development of trispecific IL-2R-targeting antibodies and significantly expands the potential of antibody-based immunomodulation. By selectively activating the high-affinity trimeric IL-2R on Tregs, this versatile platform offers a differentiated and promising strategy for the treatment of autoimmune diseases and transplant rejection.
如何引用
AMA
Valentina Lykhopiy, Emilie Pollenus, Laurie Rangan, Michelle Stakenborg, Tugsan Tezil, Michiel Varheust, et al. Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting.. Nature communications. 2026; doi:10.1038/s41467-026-75024-6.
APA
Valentina Lykhopiy, Emilie Pollenus, Laurie Rangan, Michelle Stakenborg, Tugsan Tezil, Michiel Varheust, et al (2026). Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting.. Nature communications. https://doi.org/10.1038/s41467-026-75024-6
GB/T 7714
Valentina Lykhopiy, Emilie Pollenus, Laurie Rangan, Michelle Stakenborg, Tugsan Tezil, Michiel Varheust, et al. Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75024-6.
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