Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, 100 East Lancaster Avenue, LIMR R234, Wynnewood, PA, 19096, USA.
Division of Perinatal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.
Breast Cancer Res. 2021 Jan 23;23(1):11. doi: 10.1186/s13058-021-01391-1.
Triple-negative breast cancer (BCa) (TNBC) is a deadly form of human BCa with limited treatment options and poor prognosis. In our prior analysis of over 2200 breast cancer samples, the G protein-coupled receptor CCR5 was expressed in > 95% of TNBC samples. A humanized monoclonal antibody to CCR5 (leronlimab), used in the treatment of HIV-infected patients, has shown minimal side effects in large patient populations.
A humanized monoclonal antibody to CCR5, leronlimab, was used for the first time in tissue culture and in mice to determine binding characteristics to human breast cancer cells, intracellular signaling, and impact on (i) metastasis prevention and (ii) impact on established metastasis.
Herein, leronlimab was shown to bind CCR5 in multiple breast cancer cell lines. Binding of leronlimab to CCR5 reduced ligand-induced Ca signaling, invasion of TNBC into Matrigel, and transwell migration. Leronlimab enhanced the BCa cell killing of the BCa chemotherapy reagent, doxorubicin. In xenografts conducted with Nu/Nu mice, leronlimab reduced lung metastasis of the TNBC cell line, MB-MDA-231, by > 98% at 6 weeks. Treatment with leronlimab reduced the metastatic tumor burden of established TNBC lung metastasis.
The safety profile of leronlimab, together with strong preclinical evidence to both prevent and reduce established breast cancer metastasis herein, suggests studies of clinical efficacy may be warranted.
三阴性乳腺癌（BCa）（TNBC）是一种致命形式的人 BCa，治疗选择有限，预后不良。在我们对超过 2200 个乳腺癌样本的先前分析中，G 蛋白偶联受体 CCR5 在>95%的 TNBC 样本中表达。一种用于治疗 HIV 感染患者的 CCR5 人源化单克隆抗体（leronlimab）在大量患者人群中显示出最小的副作用。
首次在组织培养和小鼠中使用针对 CCR5 的人源化单克隆抗体 leronlimab，以确定其与人类乳腺癌细胞的结合特性、细胞内信号传导以及对（i）预防转移和（ii）对已建立的转移的影响。
在此，leronlimab 被证明可与多种乳腺癌细胞系中的 CCR5 结合。leronlimab 与 CCR5 的结合减少了配体诱导的 Ca 信号转导、TNBC 侵入 Matrigel 和 Transwell 迁移。leronlimab 增强了 BCa 化疗试剂阿霉素对 BCa 细胞的杀伤作用。在 Nu/Nu 小鼠中进行的异种移植中，leronlimab 在 6 周时将 TNBC 细胞系 MB-MDA-231 的肺转移减少了>98%。用 leronlimab 治疗可减少已建立的 TNBC 肺转移的转移性肿瘤负担。
leronlimab 的安全性概况，以及本文中预防和减少已建立的乳腺癌转移的强烈临床前证据，表明可能需要进行临床疗效研究。
