PO.ET04.01 · 实验与分子治疗
由肺靶向脂质纳米颗粒递送的编码EpCAM-CD3双特异性抗体的mRNA可抑制原位肺肿瘤生长
EpCAM-CD3 bispecific antibody-encoding mRNA delivered by lung targeted lipid nanoparticles suppresses orthotopic lung tumor growth
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
双特异性T细胞衔接(BiTE)抗体的治疗应用在治疗恶性肿瘤方面显示出巨大潜力。然而,双特异性抗体(BsAb)潜力的充分发挥受到生产挑战和血清半衰期短的阻碍。相比之下,mRNA疗法已成为治疗多种疾病的强有力方法。其应用日益与靶向递送技术的进步相关联,而mRNA编码抗体的生产比传统方法更灵活且更具成本效益。在本研究中,我们开发了一种肺选择性器官靶向脂质纳米颗粒(SORT LNP)配制的RNA(RNA-LNP),其编码一种T细胞衔接双特异性抗体,该抗体结合T细胞标志物CD3并双价结合上皮细胞粘附分子(EpCAM)——一种在多种实体瘤上表达的上皮抗原。我们首先进行了体外流式细胞术分析,结果显示mRNA脂质纳米颗粒(LNP)有效介导了EpCAM阳性肿瘤细胞的杀伤并激活了人T细胞。随后我们在PBMC人源化小鼠中建立了NCI-H441肺原位肿瘤模型。我们在该肿瘤模型中观察到mRNA LNP强劲的抗肿瘤疗效。为评估mRNA分布,我们使用qPCR定量了其在各器官中的含量。结果证实了LNP的肺靶向特异性。此外,我们分析了mRNA LNP治疗后肿瘤浸润T细胞的激活情况。最后,我们对各器官进行了组织病理学检查,未发现LNP配制的mRNA给药产生不良反应的迹象。在这项全面的临床前评估中,我们证明了mRNA编码的双特异性抗体促进了人T细胞的激活和细胞毒性,在体内表现出对原位肺肿瘤生长的显著抑制。这些发现凸显了mRNA编码的CD3-EpCAM T细胞衔接器在治疗实体瘤方面的潜在研究价值,标志着基于蛋白质的T细胞衔接器在临床应用上的潜在转变。
查看英文原文 English abstract
The therapeutic use of bispecific T-cell engaging (BiTE) antibodies has shown great potential for treating malignancies. However, full exploitation of the potential of BsAbs is hindered by manufacturing challenges and short serum half-lives. In contrast, mRNA therapeutics have emerged as a powerful approach for treating a wide range of diseases. Their applications are increasingly linked to advancements in targeted delivery technologies and the production of mRNA encoded antibody is more flexible and cost-effective than the traditional method. In this work, We developed a lung selective organ targeting lipid nanoparticles (SORT LNPs)-formulated RNA (RNA-LNP) encoding a T cell-engaging bispecific antibody that binds the T cell marker CD3 and bivalently binds epithelial cell adhesion molecule (EpCAM), an epithelial antigen that is expressed on various solid tumors. We first performed In vitro flow cytometry analysis, which revealed that mRNA lipid nanoparticles (LNP) effectively mediated the killing of EpCAM positive tumor cells and activated human T cells. Then we established NCI-H441 lung orthotopic tumor model in PBMC humanized mice. We observed robust antitumor efficacy of mRNA LNP in this tumor model. To assess mRNA distribution, we quantified its content in various organs using qPCR. Results confirmed the lung targeting specificity of LNP. Moreover, we analyzed the activation of tumor-infiltrating T cells post mRNA LNP treatment. Finally, we conducted histopathological examination of various organs and we didn't find signs of adverse effects from LNP formulated mRNA administration. In this comprehensive preclinical evaluation, we demonstrated that mRNA-encoded bispecific antibody promoted the activation and cytotoxicity of human T cells, exhibiting significant inhibition of orthotopic lung tumor growth in vivo . These findings underscore the potential research value of mRNA-encoded CD3-EpCAM T cell engager in treating solid tumors, marking a potential shift in the clinical application of protein-based T-cell engagers.
利益披露 Disclosure
D. Wang, None..
G. Liu, None..
Y. Han, None..
M. Fu, None..
T. Li, None..
X. Qiang, None..
S. Zhang, None..
Z. Zhang, None..
L. Kuai, None.