研究动态
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靶向 CD276/B7-H3 的双有效负载抗体药物缀合物在三阴性乳腺癌中引发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.

发表日期:2024 Aug 26
作者: Zhuoxin Zhou, Yingnan Si, Jiashuai Zhang, Kai Chen, Ashley George, Seulhee Kim, Lufang Zhou, XXiaoguang Liu
来源: CANCER RESEARCH

摘要:

三阴性乳腺癌(TNBC)是一种高度侵袭性和异质性的疾病,在标准放射疗法和细胞毒性化疗后经常复发。联合疗法具有治疗难治性转移性 TNBC 的潜力。在这里,我们的目标是开发一种具有双有效负载的抗体药物偶联物 (DualADC) 作为 TNBC 的化学免疫疗法。在超过 60% 的 TNBC 患者中,免疫检查点跨膜 CD276(也称为 B7-H3)的过度表达与血管生成、转移和免疫耐受相关。开发了一种能够靶向表面 CD276 胞外域的单克隆抗体 (mAb),能够将有效负载递送至肿瘤,并建立了一个平台,用于将传统的细胞毒性有效负载和免疫调节 Toll 样受体 7/8 激动剂同时缀合到肿瘤上。 CD276 单克隆抗体。 DualADC有效杀灭多种TNBC亚型,显着增强肿瘤微环境中的免疫功能,在动物研究中减少肿瘤负荷高达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环境的影响。这项研究表明,开发的 DualADC 可以代表一种有前途的 TNBC 靶向化学免疫疗法。
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.