Anti-Tumor Activity and Pharmacokinetics of AP25-Fc Fusion Protein

Abstract

AP25 is an anti-tumor peptide with a high affinity for integrins. It exerts its anti-tumor activity by inhibiting angiogenesis and by directly inhibiting the growth of tumor cells. Its half-life time in vivo is only about 50 minutes, which limits its clinical application. In order to prolong the half-life time of AP25 while preserving its anti-tumor activity, several fusion proteins of AP25 and IgG4 Fc were designed and expressed; their anti-tumor activity and pharmacokinetics properties were evaluated. Firstly, four AP25-Fc fusion protein sequences were designed, and the corresponding proteins were expressed and purified. Based on the results of HUVEC migration inhibition assay, HUVEC and tumor cell proliferation inhibition assay and yields of expression by HEK293 cells, the fusion protein designated PSG4R was selected for further evaluation. The anti-tumor effect of PSG4R was then evaluated in vivo on HCT-116 nude mice xenograft model. And the pharmacokinetics properties of PSG4R were investigated in rats. The results showed that PSG4R could inhibit the growth of xenografts of human colon cancer cell line HCT-116 in nude mice by intravenous administration of 40 mg/kg once every two days. The half-life time of PSG4R was 56.270 ± 15.398 h. This study showed that the construction of AP25-Fc fusion protein could significantly prolong the half-life of AP25 while retaining its anti-tumor activity, which provides a new direction for new drug development of AP25.

Advances in screening, synthesis, modification, and biomedical applications of peptides and peptide aptamers

“…The computational modeling and validation using alphaFold2 combined with molecular dynamics simulations demonstrated improved pharmacokinetics and prolonged in vivo bioactivity of the EKP‐GCSF fusion protein produced in E. coli . Pei et al 165 designed and expressed 25 variants of AP25 fused with IgG4 Fc, creating the AP25‐Fc fusion protein. They evaluated its antitumor activity and pharmacokinetic properties, showing that the AP25‐Fc fusion protein extended the half‐life of AP25 while maintaining its antitumor activity, providing a direction for the development of AP25 peptide as a novel antitumor drug.…”