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. Here, we aimed to develop an antibody-drug conjugate with dual payloads (DualADC) as a chemo-immunotherapy for TNBC. The overexpression of an immune checkpoint transmembrane CD276 (also known as B7-H3) was associated with angiogenesis, metastasis, and immune tolerance, in over 60% of TNBC patients. Development of a monoclonal antibody (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 90-100% 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 chemo-immunotherapy for TNBC.

中文翻译：

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靶向 CD276/B7-H3 的双有效载荷抗体-药物偶联物在三阴性乳腺癌中引发细胞毒性和免疫激活


三阴性乳腺癌 （TNBC） 是一种高度侵袭性和异质性的疾病，通常在标准放疗和细胞毒性化疗后复发。联合疗法有可能治疗难治性转移性 TNBC。在这里，我们旨在开发一种具有双有效载荷的抗体-药物偶联物 （DualADC） 作为 TNBC 的化学免疫疗法。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，在超过 60% 的 TNBC 患者中。能够靶向表面 CD276 细胞外结构域的单克隆抗体 （mAb） 的开发能够将有效载荷递送至肿瘤，并建立了一个平台，用于将传统细胞毒性有效载荷和免疫调节 toll 样受体 7/8 激动剂与 CD276 mAb 同时偶联。在动物研究中，DualADC 有效杀死了多种 TNBC 亚型，显著增强了肿瘤微环境中的免疫功能，并将肿瘤负荷降低了高达 90-100%。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 可能代表一种很有前途的 TNBC 靶向化学免疫疗法。