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.
Highlights
Breast cancer afflicts one in eight women in North America, and is a leading cause of cancer-related death in women [1]
To develop improved tools for the blockade of Matrix metalloproteinase-14 (MMP-14) activity, we produced a construct expressing the extracellular domain (ECD) of matrix metalloproteinase (MMP)-14 fused to the human IgG1 Fc domain (Figure 1A)
MMP-14 is highly expressed in metastatic cancers, is associated with poor prognosis, and a proven clinical target
Summary
Breast cancer afflicts one in eight women in North America, and is a leading cause of cancer-related death in women [1]. Metastasis is the leading cause of cancer-related deaths [7], and this process involves cancer cells gaining the ability to degrade basement membranes and spread to other tissues via blood or lymphatic vessels [8]. Targeting early steps in metastasis, such as extracellular matrix (ECM) degradation and invasion in cancer cells, could improve outcomes in TNBC [9]. Over the last two decades, several broad spectrum, small molecule MMP inhibitors have been developed and tested in cancer clinical trials. These inhibitors have failed due to adverse side effects due to lack of selectivity for these small molecules targeting the catalytic domains of MMPs that are highly conserved [12]. It may be possible to develop highly selective inhibitory antibodies to individual www.impactjournals.com/oncotarget
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