A novel humanized MUC1 antibody–drug conjugate for the treatment of trastuzumab-resistant breast cancer

Abstract

Mucin 1 (MUC1) has been regarded as an ideal target for cancer treatment, since it is overexpressed in a variety of different cancers including the majority of breast cancer. However, there are still no approved monoclonal antibody drugs targeting MUC1. In this study, we generated a humanized MUC1 (HzMUC1) antibody from our previously developed MUC1 mouse monoclonal antibody that only recognizes MUC1 on the surface of tumor cells. Furthermore, an antibody–drug conjugate (ADC) was generated by conjugating HzMUC1 with monomethyl auristatin (MMAE), and the efficacy of HzMUC1-MMAE on the MUC1-positive HER2+ breast cancer in vitro and in ‘Xenograft’ model was tested. Results from western blot analysis and immunoprecipitation revealed that the HzMUC1 antibody did not recognize cell-free MUC1-N in sera from breast cancer patients. Confocal microscopy analysis showed that HzMUC1 antibody bound to MUC1 on the surface of breast cancer cells. Results from mapping experiments suggested that HzMUC1 may recognize an epitope present in the interaction region between MUC1-N and MUC1-C. Results from colony formation assay and flow cytometry demonstrated that HzMUC1-MMAE significantly inhibited cell growth by inducing G2/M cell cycle arrest and apoptosis in trastuzumab-resistant HER2-positive breast cancer cells. Meanwhile, HzMUC1-MMAE significantly reduced the growth of HCC1954 xenograft tumors by inhibiting cell proliferation and enhancing cell death. In conclusion, our results indicate that HzMUC1-ADC is a novel therapeutic drug that can overcome trastuzumab resistance of breast cancer. HzMUC1-ADC should also be an effective therapeutic drug for the treatment of different MUC1-positive cancers in clinic.

Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression

“…MAb 3D1 was generated against the MUC1-C extracellular domain α-3 helix, which becomes exposed with MUC1-C activation [ 120 ] ( Figure 2 ). Other antibodies are under development that target the junction between MUC1-N and MUC1-C [ 121 , 122 ] and the MUC1-C extracellular domain, including the SKM1 series [ 123 ] and MIN-C2 (Minerva Biotechnologies, Waltham, MA, USA). However, to our knowledge, there are no reports of MAbs that react with the α-3 helix.…”

“…Accordingly, the cell-penetrating GO-203 inhibitor (D-amino acids: (R9-CQCRRKN)) was developed to block the CQC motif and MUC1-C activity ( Figure 3 ). In multiple studies, GO-203 exhibited dose-dependent activity against MUC1-expressing human tumor xenograft models [ 59 , 122 , 123 , 124 , 125 ]. In addition, GO-203 treatment phenocopies the effects of targeting MUC1-C genetically in cancer cells, supporting the use of this agent to inhibit MUC1-C function [ 58 , 108 , 109 , 128 , 129 , 130 , 131 , 132 , 133 ].…”

Implantable Devices for the Treatment of Breast Cancer

“…However, since some breast cancers are not considered to be highly immunogenic, this phenomenon may help in installing implantable devices in humans and therapy execution [87]. In addition, a humanized mouse model can also provide a detailed scenario of how implantable device-based immune therapy might work in some types of breast cancers [88][89][90][91]. Considering the invasive nature of breast cancer, any implantable devices need careful evaluation of possible causes of the human immune reaction due to those devices.…”

A prognosis marker MUC1 correlates with metabolism and drug resistance in bladder cancer: a bioinformatics research

“…MUC1 can not only mediate hypoxia-driven angiogenesis by regulating a variety of angiogenic factors; it can also stabilize and activate hypoxia inducible factor-1α (HIF-1α) to promote the metabolic reprogramming of cancer cells [ 11 , 12 ]. Recently, studies have developed antibody–drug conjugated (ADC) based on MUC1 employed in the treatment trastuzumab-resistant breast cancer patients [ 13 ]. Besides, a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine developed by Bilusic et al was recently introduced into phase I trials [ 14 ].…”