Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio.
Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio.
Cancer Res. 2024 Nov 15;84(22):3848-3863. doi: 10.1158/0008-5472.CAN-23-4099.
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.
三阴性乳腺癌（TNBC）是一种高度侵袭性和异质性疾病，在接受标准放疗和细胞毒性化疗后常复发。联合治疗有可能治疗难治性转移性 TNBC。在这项研究中，我们旨在开发一种具有双重有效载荷的抗体药物偶联物（DualADC）作为 TNBC 的化疗免疫治疗。超过 60%的 TNBC 患者中存在免疫检查点跨膜 CD276（也称为 B7-H3）的过表达，与血管生成、转移和免疫耐受有关。开发一种能够靶向表面 CD276 细胞外结构域的 mAb 能够将有效载荷递送到肿瘤中，并建立了一个平台，用于同时将传统细胞毒性有效载荷和免疫调节 Toll 样受体 7/8 激动剂共轭到 CD276 mAb 上。DualADC 有效杀伤多种 TNBC 亚型，显著增强肿瘤微环境中的免疫功能，并在动物研究中使肿瘤负担减少 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。本研究表明，开发的 DualADC 可能代表一种有前途的 TNBC 靶向化疗免疫治疗。意义：一种与细胞毒性药物和免疫增强剂偶联的抗 CD276 单克隆抗体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。
