A Novel Bispecific Antibody against Human CD3 and Ephrin Receptor A10 for Breast Cancer Therapy.
A Novel Bispecific Antibody against Human CD3 and Ephrin Receptor A10 for Breast Cancer Therapy.
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DOI：
10.1371/journal.pone.0144712
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Tsunoda S
中科院分区：
文献类型：
--
作者：
Taki S;Kamada H;Inoue M;Nagano K;Mukai Y;Higashisaka K;Yoshioka Y;Tsutsumi Y;Tsunoda S
Ephrin受体A10（EphA 10）是一种与Ephrin结合的跨膜受体，是一种新发现的乳腺癌标志物蛋白，也已在HER 2阴性组织中检测到。在这项研究中，我们报告了一种新的双特异性抗体（BsAb）的创建结合EphA 10和CD 3，从而形成肿瘤和免疫细胞上表达的抗原之间的桥梁，并促进免疫细胞识别肿瘤细胞和细胞毒性T细胞（CTL）的重定向。该BsAb（EphA 10/CD 3）在BsAb基因转染的细胞的上清液中作为单体和二聚体分子表达。在体外将单体和二聚体BsAb添加到EphA 10过表达肿瘤细胞中时，观察到重定向的T细胞裂解。此外，二聚体BsAb（EphA 10/CD 3）比单体BsAb更具细胞毒性，通过较低浓度（≤10 - 1 μg/mL）和较低的效应细胞与靶细胞（E/T）比（E/T = 2.5）引起有效的肿瘤细胞裂解。二聚体BsAb（EphA 10/CD 3）在人异种移植小鼠模型中也显示出显著的抗肿瘤作用。总之，这些结果揭示了使用BsAb（EphA 10/CD 3）将CTL活性重定向到表达EphA 10的肿瘤细胞的机会，这可以在未来的临床试验中作为乳腺癌肿瘤的新型有效治疗剂进行测试。
Ephrin receptor A10 (EphA10), a transmembrane receptor that binds to ephrin, is a newly identified breast cancer marker protein that has also been detected in HER2-negative tissue. In this study, we report creation of a novel bispecific antibody (BsAb) binding both EphA10 and CD3, thereby forming a bridge between antigens expressed on both tumor and immune cells and promoting recognition of tumor cells by immune cells and redirection of cytotoxic T cells (CTL). This BsAb (EphA10/CD3) was expressed in supernatants of BsAb gene-transfected cells as monomeric and dimeric molecules. Redirected T-cell lysis was observed when monomeric and dimeric BsAb were added to EphA10-overexpressing tumor cells in vitro. Furthermore, dimeric BsAb (EphA10/CD3) was more cytotoxic than monomeric BsAb, with efficient tumor cell lysis elicited by lower concentrations (≤10−1 μg/mL) and a lower effector to target (E/T) cell ratio (E/T = 2.5). Dimeric BsAb (EphA10/CD3) also showed significant anti-tumor effects in human xenograft mouse models. Together, these results revealed opportunities to redirect the activity of CTL towards tumor cells that express EphA10 using the BsAb (EphA10/CD3), which could be tested in future clinical trials as a novel and potent therapeutic for breast cancer tumors.