A novel immunotherapy targeting MMP-14 limits hypoxia, immune suppression and metastasis in triple-negative breast
Binbing Ling1, Kathleen Watt1, Sunandan Banerjee2
1Department of Biomedical and Molecular Sciences, Queen's University, Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, ON, Canada.
Abstract:
Matrix metalloproteinase-14 (MMP-14) is a clinically relevant target in metastatic cancers due to its role in tumor progression and metastasis. Since active MMP-14 is localized on the cell surface, it is amenable to antibody-mediated blockade in cancer, and here we describe our efforts to develop novel inhibitory anti-MMP-14 antibodies. A phage-displayed synthetic humanized Fab library was screened against the extracellular domain of MMP-14 and a panel of MMP14-specific Fabs were identified. A lead antibody that inhibits the catalytic domain of MMP-14 (Fab 3369) was identified and treatment of MDA-MB-231 breast cancer cells with Fab 3369 led to significant loss of extracellular matrix degradation and cell invasion abilities. In mammary orthotopic tumor xenograft assays, MMP-14 blockade by IgG 3369 limited tumor growth and metastasis. Analysis of tumor tissue sections revealed that MMP-14 blockade limited tumor neoangiogenesis and hypoxia. Similar effects of MMP-14 blockade in syngeneic 4T1 mammary tumors were observed, along with increased detection of cytotoxic immune cell markers. In conclusion, we show that immunotherapies targeting MMP-14 can limit immune suppression, tumor progression, and metastasis in triple-negative breast cancer.
Insights
Novel antibodies targeting matrix metalloproteinase-14 (MMP-14) effectively inhibit cancer progression. This immunotherapy approach reduces tumor growth, metastasis, and immune suppression in triple-negative breast cancer models.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Matrix metalloproteinase-14 (MMP-14) is crucial for tumor progression and metastasis in cancers.
- Its cell-surface localization makes MMP-14 an accessible target for antibody-based therapies.
Purpose of the Study:
- To develop novel inhibitory antibodies against MMP-14.
- To evaluate the therapeutic potential of MMP-14 blockade in preclinical cancer models.
Main Methods:
- Screening of a phage-displayed humanized Fab library against MMP-14.
- Characterization of lead antibody Fab 3369 for its inhibitory activity.
- In vitro assays using MDA-MB-231 breast cancer cells.
- In vivo studies using mammary orthotopic tumor xenograft and syngeneic 4T1 models.
Main Results:
- Identification of MMP-14 specific Fabs, with Fab 3369 inhibiting catalytic activity.
- Fab 3369 treatment reduced extracellular matrix degradation and invasion of breast cancer cells.
- MMP-14 blockade with IgG 3369 limited tumor growth, metastasis, neoangiogenesis, and hypoxia in vivo.
- MMP-14 blockade also enhanced cytotoxic immune cell markers in syngeneic models.
Conclusions:
- Antibodies targeting MMP-14 demonstrate significant anti-cancer effects.
- MMP-14 blockade can overcome immune suppression and inhibit tumor progression and metastasis.
- This highlights the potential of MMP-14-targeted immunotherapies for triple-negative breast cancer.
