双付抗体 - 药物缀合物的靶向CD276/B7-H3引起三阴性乳腺癌的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
影响因子:16.60000
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
摘要
三阴性乳腺癌（TNBC）是一种高度侵略性和异质性疾病，在使用标准放射性疗法和细胞毒性化学疗法治疗后通常会复发。联合疗法具有治疗难治性转移TNBC的潜力。在这项研究中，我们旨在开发具有双重有效载荷（DualADC）的抗体 - 药物结合物作为TNBC的化学免疫疗法。在60％以上的TNBC患者中，免疫检查点跨膜CD276（也称为B7-H3）的过表达与血管生成，转移和免疫耐受性有关。开发能够针对表面CD276的细胞外域的MAB的开发，可以将有效载荷传递到肿瘤，并建立了一个平台，以同时连接传统的细胞毒性有效载荷和免疫调节的TOLL TOLL样受体7/8 Agonist向CD276 MAB进行7/8 Agonist。 DualADC有效地杀死了多种TNBC亚型，在肿瘤微环境中显着增强了免疫功能，并使肿瘤负担减少了90％至100％。单细胞RNA测序，多重细胞因子分析和组织学阐明了治疗对肿瘤细胞和免疫景观的影响。这项研究表明，开发的DualADC可以代表有希望的TNBC靶向化学免疫疗法。意义：一种抗CD276单克隆抗体与细胞毒性药物和免疫促进试剂偶联，通过诱导肿瘤细胞死亡和刺激免疫细胞浸润，有效地靶向三阴性乳腺癌。
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.