PO.IM01.15 · 免疫学
一种多模式IL-2——SLC-3010，将肿瘤免疫环境重编程为抗肿瘤应答
A multi-modal IL-2, SLC-3010, reprograms the tumor immune environment toward antitumor responses
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：CD122偏向性IL-2信号传导已被公认为一种精细化的免疫调节策略，用于强化抗肿瘤T细胞应答。然而，包括CD122偏向性变体在内的以CD122为核心的IL-2方法临床疗效有限，表明仅靶向CD122并不能充分利用内源性IL-2的复杂性。我们开发了SLC-3010，一种人IL-2与抗IL-2抗体TCB2的非共价偶联物，旨在强化CD122偏向性信号传导，并使TCB2、IL-2和IL-2受体之间实现动态相互作用。这种新型结构实现了三重作用——CD122偏向性IL-2递送、阻止Treg介导的负反馈，以及与内源性IL-2协同再刺激T细胞——同时维持对CD25+CD8 T细胞的激活。虽然SLC-3010的设计和主要活性此前已有表征，但通过体内解离产生的游离TCB2的生物学意义仍未完全阐明。在本研究中，我们旨在通过一系列在各种实验条件下评估其药代动力学特征和其他药物特性的研究来表征SLC-3010的多方面特性。
方法：通过ELISA在小鼠血清中评估SLC-3010与游离TCB2之间的动态相互作用。通过流式细胞术评估新鲜和活化PBMC中的STAT5磷酸化。在hIL-2 TG和野生型（wt）小鼠中分析游离TCB2的免疫学作用以及MP CD8 T细胞中的转录组学改变。随后在两种品系的荷MC38和EO771肿瘤小鼠中评估抗肿瘤疗效。
结果：游离TCB2在体内的持续时间长于SLC-3010，并结合内源性IL-2，产生额外的CD122偏向性但CD25许可性信号，这与CD25⁻CD8 T细胞中STAT5磷酸化增强相一致。游离TCB2与重新形成的SLC-3010之间的动态相互作用进一步增强了CD122偏向性IL-2信号传导，导致Treg扩增受到抑制，并使hIL-2 TG小鼠中肿瘤浸润CD8/Treg比值增加3.65倍。游离TCB2驱动的信号传导促进了MP CD8 T细胞中的增殖性转录程序。SLC-3010在hIL-2 TG小鼠中的抗肿瘤疗效在MC38和EO771肿瘤模型中均优于wt小鼠。
结论：SLC-3010通过一种统一的三重作用机制发挥功能，该机制结合了CD122偏向性但CD25可及的IL-2信号传导以激活抗肿瘤效应细胞，同时通过游离TCB2与内源性IL-2之间的体内复合来破坏Treg稳态并再度放大免疫刺激。
查看英文原文 English abstract
Purpose CD122-biased IL-2 signaling has gained recognition as a refined immunomodulatory strategy for strengthening antitumor T cell responses. However, the modest clinical efficacy of CD122-focused IL-2 approaches, including CD122-biased variants, suggests that targeting CD122 alone does not fully leverage the complexity of endogenous IL-2. We developed SLC-3010, a noncovalent conjugate of human IL-2 and the anti-IL-2 antibody TCB2, designed to reinforce CD122-biased signaling and enable a dynamic interplay among TCB2, IL-2, and IL-2 receptors. This novel structure enables a triple action - CD122-biased IL-2 delivery, prevention of Treg-mediated negative feedback, and restimulation of T cells in conjunction with endogenous IL-2 - while maintaining activation of CD25 + CD8 T cells. While the design and primary activity of SLC-3010 have been characterized before, the biological significance of free TCB2 generated through in vivo dissociation remains incompletely understood. In this study, we aimed to characterize the multifaceted features of SLC-3010 through a series of studies assessing its pharmacokinetic profile and other drug properties under various experimental settings.
Methods Dynamic interplay between SLC-3010 and free TCB2 was evaluated by ELISA in mouse serum. STAT5 phosphorylation in fresh and activated PBMCs was assessed by flow cytometry. The immunologic role of free TCB2 and transcriptomic alterations in MP CD8 T cells were analyzed in hIL-2 TG and wt mice. Antitumor efficacy was then evaluated in MC38- and EO771-bearing mice of both strains.
Results Free TCB2 persisted longer in vivo than SLC-3010 and bound endogenous IL-2, generating additional CD122-biased yet CD25-permissive signaling consistent with enhanced STAT5 phosphorylation in CD25⁺CD8 T cells. The dynamic interplay between free TCB2 and re-formed SLC-3010 further enhanced CD122-biased IL-2 signaling, leading to suppressed Treg expansion and a 3.65-fold increase in the tumor-infiltrating CD8/Treg ratio in hIL-2 TG mice. Free TCB2-driven signaling promoted a proliferative transcriptional program in MP CD8 T cells. SLC-3010 showed greater antitumor efficacy in hIL-2 TG mice than in wt mice in both MC38 and EO771 tumor models.
Conclusions SLC-3010 functions through a unified triple-action mechanism that combines CD122-biased yet CD25-accessible IL-2 signaling to activate antitumor effector cells, while concurrently disrupting Treg homeostasis and re-amplifying immune stimulation through in vivo complexing between free TCB2 and endogenous IL-2.
利益披露 Disclosure
J. Heo,
Selecxine Inc. Employment, Stock Option.
D. Kim,
Selecxine Inc. Employment, Stock Option.
G. Kim,
Selecxine Inc. Employment, Stock Option.
J. Lee,
Selecxine Inc. Employment, g., Board of Directors, non-salaried role), Stock, Stock Option.
S. Rha, None.