CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
ZP4：三阴性乳腺癌 CAR-T 细胞治疗的新靶点
英文原题：ZP4: A novel target for CAR-T cell therapy in triple negative breast cancer.
查看英文原题
ZP4: A novel target for CAR-T cell therapy in triple negative breast cancer.
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中文摘要
三阴性乳腺癌（TNBC）由于缺乏有效的靶向治疗，仍然是治疗难度最大的乳腺癌亚型之一。嵌合抗原受体（CAR）-T细胞具有应用前景，但其在实体瘤中的疗效往往受到靶向/脱靶毒性的限制。通过对公开RNA和蛋白质组学数据进行全面的生物信息学分析，我们确定了透明带糖蛋白4（ZP4）作为TNBC的一个新靶点。在一部分TNBC患者样本和患者来源异种移植（PDX）模型中检测到了ZP4 RNA和蛋白，除此之外其表达仅限于卵母细胞。我们制备了89种ZP4特异性新型单克隆抗体，并利用排名前三的候选抗体的单链可变片段（scFv）抗原结合结构域构建了CAR结构。ZP4 CAR-T 细胞在ZP4表达的TNBC细胞和PDX模型中显示出疗效。此外，我们发现scFv抗原结合结构域的变异会显著影响CAR-T 细胞的功能。
展开英文摘要原文
Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat due to a lack of effective targeted therapies. Chimeric antigen receptor (CAR)-T cells hold promise, but their efficacy in solid tumors is often limited by on-target/off-tumor toxicities.
Through comprehensive bioinformatic analysis of public RNA and proteomic data, we identified zona pellucida glycoprotein 4 (ZP4) as a novel target for TNBC. ZP4 RNA and protein were detected in a subset of TNBC patient samples and patient-derived xenograft (PDX) models, with expression otherwise restricted to oocytes.
We generated 89 ZP4-specific novel monoclonal antibodies and used the single-chain variable fragment (scFv) antigen binding domains from the top three candidates to engineer CAR constructs. ZP4 CAR-T cells demonstrated efficacy against ZP4-expressing TNBC cells and PDX models.
Additionally, we found that variations in the scFv antigen binding domain significantly influence CAR-T cell function.
论文信息
- 作者
- Somes LK、Lei JT、Yi X、Chamorro DF、Shafer P、Gad AZ、Dobrolecki LE、Madaras E
- 单位
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: lauren.somes@bcm.edu.United States
- 期刊
- Molecular therapy : the journal of the American Society of Gene Therapy2025 Apr 2
- 原文标识
- PubMed 39980195 · DOI 10.1016/j.ymthe.2025.02.029
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