A novel bispecific antibody targeting CD3 and prolactin receptor (PRLR) against PRLR-expression breast cancer
A novel bispecific antibody targeting CD3 and prolactin receptor (PRLR) against PRLR-expression breast cancer
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一种针对 CD3 和催乳素受体 (PRLR) 的新型双特异性抗体，针对 PRLR 表达乳腺癌
DOI：
10.1186/s13046-020-01564-4
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发表时间：
2020-05-12
影响因子：
11.3
通讯作者：
Zhu, Jianwei
中科院分区：
文献类型：
--
作者：
Zhou, Yuexian;Zong, Huifang;Zhu, Jianwei
背景催乳素受体（Prolactin receptor，PRLR）在乳腺癌和前列腺癌中高度表达，是肿瘤治疗的潜在靶点。在临床试验中，PRLR的阻断被证明是安全的，但疗效不佳。因此，迫切需要开发针对PRLR靶点的新疗法。双特异性抗体（Bispecific antibodies，BsAbs）是一种能够引导免疫细胞向肿瘤细胞方向移动的抗体，在某些肿瘤中具有显著的治疗效果。Biacore法和流式细胞仪法检测其结合活性，LDH释放法检测其靶向依赖性T细胞介导的细胞毒作用。ELISA法检测免疫细胞分泌细胞因子的情况。结果PRLR-DbsAb在体外可募集和激活T细胞，促进Th 1细胞因子IFN-γ和TNF-α的释放，从而杀伤表达PRLR的乳腺癌细胞。在乳腺癌T47 D细胞移植瘤模型中，腹腔注射PRLR-DbsAb的NOD/SCID小鼠的肿瘤生长明显受到抑制，且生存期较PRLR单克隆抗体（PRLR mAb）延长。免疫治疗可能是一种有前途的针对肿瘤靶点PRLR的治疗方法。
BackgroundProlactin receptor (PRLR) is highly expressed in a subset of human breast cancer and prostate cancer, which makes it a potential target for cancer treatment. In clinical trials, the blockade of PRLR was shown to be safe but with poor efficacy. It is therefore urgent to develop new therapies against PRLR target. Bispecific antibodies (BsAbs) could guide immune cells toward tumor cells, and produced remarkable effects in some cancers.MethodsIn this study, a bispecific antibody targeting both tumor antigen PRLR and T cell surface CD3 antigen (PRLR-DbsAb) was constructed by split intein mediated protein transsplicing (BAPTS) system for the first time. Its binding activity was determined by Biacore and Flow cytometry, and target-dependent T cell mediated cytotoxicity was detected using LDH release assay. ELISA was utilized to study the secretion of cytokines by immune cells. Subcutaneous tumor mouse models were used to analyze the in vivo anti-tumor effects of PRLR-DbsAb.ResultsPRLR-DbsAb in vitro could recruit and activate T cells to promote the release of Th1 cytokines IFN-γand TNF-α, which could kill PRLR expressed breast cancer cells. In xenograft models with breast cancer cell line T47D, NOD/SCID mice intraperitoneally injected with PRLR-DbsAb exhibited significant inhibition of tumor growth and a longer survival compared to mice treated with PRLR monoclonal antibody (PRLR mAb).ConclusionsBoth in vitro and in vivo experiments showed PRLR-DbsAb had a potential therapy of cancer treatment potential therapy for cancer. Immunotherapy may be a promising treatment against the tumor target of PRLR.