针对CD276/B7-H3的双药载抗体-药物偶联物在三阴性乳腺癌中诱导细胞毒性和免疫激活

A Dual-Payload Antibody-Drug Conjugate Targeting CD276/B7-H3 Elicits Cytotoxicity and Immune Activation in Triple-Negative Breast Cancer

CANCER RESEARCH

影响因子:16.6

分区:医学1区 Top / 肿瘤学1区

发表日期:2024 Nov 15

作者: Zhuoxin Zora Zhou, Yingnan Si, Jiashuai Zhang, Kai Chen, Ashley George, Seulhee Kim, Lufang Zhou, Xiaoguang Margaret Liu

DOI: 10.1158/0008-5472.CAN-23-4099

摘要

三阴性乳腺癌（TNBC）是一种高度侵袭性且异质性强的疾病，常在标准放疗和细胞毒性化疗后复发。联合疗法在治疗难治性转移性TNBC方面具有潜力。本研究旨在开发具有双药载的抗体-药物偶联物（DualADC）作为TNBC的化学免疫治疗。免疫检查点跨膜蛋白CD276（也称为B7-H3）在超过60%的TNBC患者中与血管生成、转移和免疫耐受有关。开发能靶向表面CD276的单克隆抗体（mAb），实现药物的靶向递送，并建立平台进行传统细胞毒药物和免疫调节性Toll样受体7/8激动剂的共偶联。DualADC有效杀死多种TNBC亚型，显著增强肿瘤微环境中的免疫功能，并在动物模型中将肿瘤负荷降低至90%至100%。单细胞RNA测序、多重细胞因子分析和组织学检测了治疗对肿瘤细胞及免疫环境的影响。研究表明，所开发的DualADC具有作为潜在靶向化学免疫治疗的前景。意义：一种同时结合细胞毒药物和免疫增强剂的抗CD276单抗偶联物，能有效靶向三阴性乳腺癌，通过诱导肿瘤细胞死亡和促进免疫细胞浸润，展现出良好的治疗潜力。

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous disease that often relapses following treatment with standard radiotherapies and cytotoxic chemotherapies. Combination therapies have potential for treating refractory metastatic TNBC. In this study, we aimed to develop an antibody-drug conjugate with dual payloads (DualADC) as a chemoimmunotherapy for TNBC. The overexpression of an immune checkpoint transmembrane CD276 (also known as B7-H3) was associated with angiogenesis, metastasis, and immune tolerance in more than 60% of patients with TNBC. Development of a mAb capable of targeting the extracellular domain of surface CD276 enabled delivery of payloads to tumors, and a platform was established for concurrent conjugation of a traditional cytotoxic payload and an immunoregulating Toll-like receptor 7/8 agonist to the CD276 mAb. The DualADC effectively killed multiple TNBC subtypes, significantly enhanced immune functions in the tumor microenvironment, and reduced tumor burden by up to 90% to 100% in animal studies. Single-cell RNA sequencing, multiplex cytokine analysis, and histology elucidated the impact of treatment on tumor cells and the immune landscape. This study suggests that the developed DualADC could represent a promising targeted chemoimmunotherapy for TNBC. Significance: An anti-CD276 monoclonal antibody conjugated with both a cytotoxic drug and an immune boosting reagent effectively targets triple-negative breast cancer by inducing tumor cell death and stimulating immune cell infiltration.