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

Abstract

Background 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 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. Results Herein, 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. Conclusions 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.

Tackling Immune Targets for Breast Cancer: Beyond PD-1/PD-L1 Axis

“…Treatment with maraviroc, CCR5 antagonist, significantly suppresses bone metastasis in a xenograft rat model implanted with breast cancer cells (MDA-MB-231) (131). Leronlimab (PRO 140) is another CCR5 antagonist under investigation in breast cancer clinical trials (129,132,133).…”

Pparγ1 Facilitates ErbB2-Mammary Adenocarcinoma in Mice

“…Transwell migration assay was performed in 24 well transwell inserts (Corning, Tewksbury, MA, USA) as previously described [ 103 , 104 ]. See the supplemental methods for the details.…”

An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

“…CCR5 is overexpressed breast [ 84 , 94 ], prostate [ 92 ], pancreatic, colorectal [ 95 , 96 ], head and neck [ 97 ], gastric [ 87 ], and esophageal [ 98 ] cancer as well as acute lymphocytic leukemia [ 99 ], melanoma, Hodgkin’s lymphoma, and other tumors [ 88 , 93 ]. In humans, CCR5 has the peculiar characteristic of being a developmentally nonessential gene, which participates in diverse pathological processes, including infection with HIV [ 100 , 101 , 102 , 103 ], progression of stroke [ 104 ], and cancer metastasis [ 84 , 93 , 105 ]. Although metastasis involves multiple distinct steps, CCR5 was shown essential to govern the homing step of breast cancer metastasis in mice, as demonstrated by the anti-metastatic activity of the CCR5 inhibitor maraviroc [ 84 , 93 , 105 ].…”

“…In humans, CCR5 has the peculiar characteristic of being a developmentally nonessential gene, which participates in diverse pathological processes, including infection with HIV [ 100 , 101 , 102 , 103 ], progression of stroke [ 104 ], and cancer metastasis [ 84 , 93 , 105 ]. Although metastasis involves multiple distinct steps, CCR5 was shown essential to govern the homing step of breast cancer metastasis in mice, as demonstrated by the anti-metastatic activity of the CCR5 inhibitor maraviroc [ 84 , 93 , 105 ]. Subsequent studies showed the importance of CCR5 in both the formation of new metastasis and the growth of previously formed breast [ 105 ] and gastric cancers [ 106 ].…”

“…Although metastasis involves multiple distinct steps, CCR5 was shown essential to govern the homing step of breast cancer metastasis in mice, as demonstrated by the anti-metastatic activity of the CCR5 inhibitor maraviroc [ 84 , 93 , 105 ]. Subsequent studies showed the importance of CCR5 in both the formation of new metastasis and the growth of previously formed breast [ 105 ] and gastric cancers [ 106 ].…”