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Anticancer effect of a single-chain variable fragment against pro-matrix metalloproteinase-7 in colon cancer
Shinhye Min1, Bohee Jang1, Ji-Hye Yun2
1Department of Life Sciences, Ewha Womans University, Seoul 03760, South Korea.
Abstract:
Disrupting the interaction between matrix metalloproteinase-7 (MMP-7) and syndecan-2 (SDC-2) can yield anticancer effects in colon cancer cells. Here, a single-chain variable fragment (scFv) targeting the pro-domain of MMP-7 was generated as a potential candidate anticancer agent. Among the generated scFvs, those designated 1B7 and 1C3 showed the strongest abilities to inhibit the ability of MMP-7 pro-domain to directly interact with SDC-2 in vitro and decrease the cancer activities of human HT29 colon adenocarcinoma cells. Consistently, 1B7 and 1C3 inhibited the cell-surface localization of pro-MMP-7, reduced the gelatinolytic activity of MMP-7, and suppressed the cancer activities of metastatic HCT116 human colon carcinoma cells. Notably, 1B7 inhibited the primary tumor growth and lung metastasis of CT26 mouse colon cancer cells in a mouse model. Compared to 1B7, the 1B7-Fc fusion antibody showed better anti-tumorigenic activity against HCT116 cells in culture and a syngeneic mouse model. Together, these data suggest that 1B7-Fc exerts anticancer effects by interfering with the interaction of MMP-7 and SDC-2 and could be a promising therapeutic antibody for colon cancer.
Insights
Targeting matrix metalloproteinase-7 (MMP-7) and syndecan-2 (SDC-2) interaction shows promise for colon cancer therapy. A novel antibody fragment (1B7-Fc) effectively inhibited tumor growth and metastasis in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Matrix metalloproteinase-7 (MMP-7) and syndecan-2 (SDC-2) interaction is implicated in colon cancer progression.
- Targeting this interaction presents a potential therapeutic strategy for colon cancer.
Purpose of the Study:
- To develop and evaluate a single-chain variable fragment (scFv) targeting the MMP-7 pro-domain.
- To assess the efficacy of scFvs in inhibiting MMP-7/SDC-2 interaction and colon cancer cell activities.
- To investigate the in vivo therapeutic potential of a derived antibody (1B7-Fc).
Main Methods:
- Generation and screening of scFvs against MMP-7 pro-domain.
- In vitro assays to measure MMP-7/SDC-2 binding inhibition and effects on colon cancer cell lines (HT29, HCT116).
- In vivo studies using mouse models (CT26) to evaluate tumor growth and metastasis inhibition by 1B7 and 1B7-Fc.
Main Results:
- scFvs 1B7 and 1C3 effectively inhibited MMP-7/SDC-2 interaction and colon cancer cell activities.
- 1B7 and 1C3 reduced cell-surface pro-MMP-7, MMP-7 gelatinolytic activity, and metastatic HCT116 cell activities.
- 1B7 demonstrated in vivo efficacy against primary tumor growth and lung metastasis in a mouse model.
- 1B7-Fc exhibited superior anti-tumorigenic activity compared to 1B7 in vitro and in vivo.
Conclusions:
- Disrupting the MMP-7/SDC-2 interaction via scFvs is a viable strategy for colon cancer treatment.
- The 1B7-Fc antibody demonstrates significant anti-tumorigenic effects and holds promise as a therapeutic agent for colon cancer.
