Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular metastasis and enhances cell death induced by DNA damaging chemotherapy

Xuanmao Jiao,Richard G Pestell,Anthony W Ashton,Dong Ni,Zhao Zhang,David W Speicher,Hsin-Yao Tang,Min Wang,Zhiping Li

doi:10.1186/s13058-021-01391-1

Abstract

BackgroundTriple-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.MethodsA 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.ResultsHerein, leronlimab was shown to bind CCR5 in multiple breast cancer cell lines. Binding of leronlimab to CCR5 reduced ligand-induced Ca+ 2 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.ConclusionsThe 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.

Highlights

Breast cancer (BCa) remains the most common malignancy in women other than skin cancer, representing approximately one third of all malignancies diagnosed among women in the USA [1, 2]
The binding of leronlimab with CCR5 expressed in breast cancer cells In order to determine the binding of leronlimab to human CCR5 in breast cancer cells, we used an MDA-MB231 human breast cancer cell line transfected with a human CCR5 expression vector as a model system
MDA-MB-231-CCR5 cells were stained with leronlimab, and the concentration ranged from 1 to 140 μg/ml

Summary

Introduction

Breast cancer (BCa) remains the most common malignancy in women other than skin cancer, representing approximately one third of all malignancies diagnosed among women in the USA [1, 2]. > 95% of triple-negative breast cancer (TNBC) were CCR5+ [12]. Several characteristics of CCR5 suggest the receptor may be important in human breast cancer. CCR5 receptor levels correlate with poor prognosis in breast cancer [13,14,15]. CCR5 expression correlates well with increased tumor heterogeneity in breast cancer [16, 17]. CCR5+ breast cancer epithelial cells have both enhanced tumor-initiating capacity and form mammospheres with greater efficiency in mice [13], a feature of cancer stem cells. 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

Methods

Results

Conclusion