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The dual effects of a novel peptibody on angiogenesis inhibition and M2 macrophage polarization on sarcoma
Xiaoqing Zhu1, Jiali Yang1, Yanfeng Gao1
1School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
Abstract:
Inhibition of the VEGF/VEGF receptor (VEGFR) and angiopoietin-2 (Ang-2)/TEK receptor tyrosine kinase (Tie-2) pathway is a potential target for tumor angiogenesis. We previously showed that a peptide AS16 which dually inhibits VEGFR/Ang-2 could reduce the tumor growth and decrease the number of microvessels in tumor. However, its short circulating half-life in the serum limits its clinical applications. In this study, as an effort to prolong the short in vivo half-life of AS16, we designed a fusion protein containing peptide AS16 and an IgG Fc fragment. Pharmacokinetic study also revealed that AS16-Fc has a prolonged circulating half-life of about 231 min in rats. We examined the effects of treatment on the tumor vasculature and immune cell populations, tumor growth, in both the MCA-205 and S180 tumor models. We found that AS16-Fc dramatically reduced tumor volume, vascular density and tumor-associated macrophages. Macrophages were identified as potential novel targets following anti-angiogenic therapy, our findings imply a novel role for anti-angiogenic peptide AS16-Fc. These findings indicate that AS16-Fc could be more effective on inhibiting tumor growth angiogenesis and tumor immune microenvironment than that of peptide AS16.
Insights
A novel fusion protein, AS16-Fc, effectively inhibits tumor growth and angiogenesis by targeting VEGF/VEGFR and Ang-2/Tie-2 pathways. This engineered peptide demonstrates improved pharmacokinetics and impacts tumor-associated macrophages, offering enhanced therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Targeting tumor angiogenesis via VEGF/VEGFR and Ang-2/Tie-2 pathways is a key strategy.
- A dual inhibitor peptide, AS16, showed efficacy but suffered from a short half-life.
- Improving the pharmacokinetic profile of AS16 is crucial for clinical application.
Purpose of the Study:
- To engineer a fusion protein (AS16-Fc) by combining AS16 with an IgG Fc fragment.
- To evaluate the pharmacokinetic properties and anti-tumor efficacy of AS16-Fc.
- To investigate the effects of AS16-Fc on tumor vasculature and immune microenvironment.
Main Methods:
- AS16 was fused with an IgG Fc fragment to create AS16-Fc.
- Pharmacokinetic studies were conducted in rats to determine the circulating half-life.
- AS16-Fc efficacy was assessed in MCA-205 and S180 tumor models, analyzing tumor volume, vascular density, and immune cell populations.
Main Results:
- AS16-Fc exhibited a significantly prolonged circulating half-life (approx. 231 minutes in rats).
- Treatment with AS16-Fc markedly reduced tumor volume and vascular density in both tumor models.
- AS16-Fc decreased tumor-associated macrophages, suggesting an impact on the tumor immune microenvironment.
Conclusions:
- AS16-Fc demonstrates improved pharmacokinetics compared to AS16, enhancing its therapeutic potential.
- AS16-Fc effectively inhibits tumor growth and angiogenesis, outperforming the original peptide.
- The fusion protein AS16-Fc represents a promising strategy for cancer therapy by targeting both angiogenesis and the tumor immune microenvironment.
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