PO.IM01.14 · 免疫学
通过双特异性抗体组合实现4-1BB受体的肿瘤选择性激活
Tumor-selective activation of 4-1BB receptor via bispecific antibody combinations
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：
4-1BB（CD137）是一种诱导型共刺激分子，在免疫激活中发挥关键作用。配体结合后，4-1BB形成三聚体信号复合体，触发受体激活。然而，靶向4-1BB的治疗性单克隆抗体常因系统性受体激活引起的外周毒性而面临挑战。为解决这一问题，已开发出双特异性抗体（bsAb）以肿瘤相关抗原（TAA）依赖的方式选择性激活4-1BB。本报告研究了配对4-1BB和TAA靶向臂的bsAb组合是否能进一步增强肿瘤微环境中4-1BB的聚集和激活。
方法：
生成了一组靶向4-1BB和HER2不同结构域的Fc静默bsAb，并进行组合测试以获得最佳4-1BB信号传导。为此，将4-1BB报告细胞与表达HER2的肿瘤细胞共培养。使用从外周血单个核细胞中分离的原代人T细胞进行体外功能实验，以评估细胞因子产生及其杀肿瘤活性。在接种JIMT-1（一种表达HER2的肿瘤细胞系）的PBMC移植NOG小鼠中评估体内疗效。
结果：
两种bsAb同时结合4-1BB上的同一表位，同时靶向HER2上不同的表位，相比单个bsAb显著增强4-1BB信号传导。由bsAb触发的4-1BB信号传导由HER2表达驱动，仅在HER2阳性细胞存在下观察到强烈的IL-2释放。在JIMT-1异种移植模型中，bsAb对与T细胞接合器（TCE）联合使用，相比单个bsAb加TCE或单独TCE，产生了更优越的抗肿瘤活性，并增强了肿瘤微环境内CD4+和CD8+ T细胞浸润。
结论：本研究提出了一种新型bsAb组合策略，可放大TAA驱动的4-1BB+ T细胞激活，并可能为OX40和CD40等其他TNFR超家族靶点开启类似机会。
查看英文原文 English abstract
INTRODUCTION:
4-1BB (CD137) is an inducible co-stimulatory molecule that plays crucial roles in immune activation. Upon ligand binding, 4-1BB forms trimeric signaling complexes triggering receptor activation. However, therapeutic monoclonal antibodies targeting 4-1BB often face challenges due to peripheral toxicities arising from systemic receptor activation. To address this, bispecific antibodies (bsAbs) have been developed to selectively activate 4-1BB in a tumor-associated antigen (TAA)-dependent manner. This report investigates whether a combination of bsAbs, pairing 4-1BB and TAA targeting arms, can further enhance 4-1BB clustering and activation in the tumor microenvironment.
METHODS:
A panel of Fc-silent bsAbs targeting different domains on 4-1BB and HER2 were generated and tested in combination for optimal 4-1BB signaling. For that purpose, 4-1BB reporter cells were co-cultured with HER2-expressing tumor cells. Functional in vitro assays were conducted using primary human T cells isolated from peripheral blood mononuclear cells to assess cytokine production and their tumoricidal activity. In vivo efficacy was evaluated in PBMC-engrafted NOG mice inoculated with JIMT-1, a HER2-expressing tumor cell line.
RESULTS:
The simultaneous binding of two bsAbs to the same epitope on 4-1BB, while targeting distinct epitopes on HER2, markedly enhances 4-1BB signaling, compared to the single bsAbs. 4-1BB signaling triggered by the bsAbs is driven by HER2 expression, with strong IL-2 release observed only in the presence of HER2-positive cells. In JIMT-1 xenograft models, combination of the bsAb pair with a T cell engager (TCE) resulted in superior antitumor activity and enhanced CD4⁺ and CD8⁺ T-cell infiltration within the tumor microenvironment, compared to either single bsAb plus TCE or the TCE alone.
CONCLUSIONS: This study introduces a novel bsAb combination strategy that amplifies TAA-driven activation of 4-1BB⁺ T cells and may unlock similar opportunities to other TNFR superfamily targets such as OX40 and CD40.
利益披露 Disclosure
L. Diby, None..
P. Malinge, None..
V. Moine, None..
L. Nouveau, None..
L. Chatel, None..
K. Masternak, None..
L. Shang, None..
W. Ferlin, None..
N. Fischer, None..
J. Saro, None..
M. Pittet, None..
V. Buatois, None..
E. Hatterer, None.