Abstract
HM-3, an integrin antagonist, exhibits anti-tumor biological responses and therefore has potential as a therapeutic polypeptide. However, the clinical applications of HM-3 are limited by its short half-life. In this study, we genetically fused human serum albumin (HSA) to the N or C-terminus of HM-3 to improve HM-3 pharmacokinetics. HM-3/HSA proteins were successfully expressed in Pichia pastoris and displayed improved pharmacokinetic properties and stability. Among them, the half-life of HM-3-HSA was longer than HSA-HM-3. In vitro, the IC50 values of HSA-HM-3 and HM-3-HSA were 0.38 ± 0.14 μM and 0.25 ± 0.08 μM in B16F10 cells, respectively. In vivo, the inhibition rates of B16F10 tumor growth were 36% (HSA-HM-3) and 56% (HM-3-HSA), respectively, indicating antitumor activity of HM-3-HSA was higher than HSA-HM-3. In conclusion, these results suggested that the HM-3/HSA fusion protein might be potential candidate HM-3 agent for treatment of melanoma and when HSA was fused at the C-terminus of HM-3, the fusion protein had a higher stability and activity.
Highlights
HM-3 (IVRRADRAAVPGGGGRGD) is a polypeptide which displayed antitumor activity in multiple animal tumor models such as melanoma and hepatocellular carcinoma [1,2].HM-3 was constructed by the connection of RGD to the C-terminus of the ES-2 peptide with the GGGG linker
human serum albumin (HSA) was genetically fused to the N-terminus (Figure 1A) or C-terminus (Figure 1B)
HSA-HM-3 or HM-3-HSA was cloned into the pPinkα-HC vector (Figure 1C,D) and followed by the expression in Pichiapink strain
Summary
HM-3 (IVRRADRAAVPGGGGRGD) is a polypeptide which displayed antitumor activity in multiple animal tumor models such as melanoma and hepatocellular carcinoma [1,2]. HM-3 was constructed by the connection of RGD to the C-terminus of the ES-2 peptide with the GGGG linker. RGD is a tri-peptide sequence that has a high affinity to integrin αvβ. ES-2, corresponding to amino acids 60–70 of endostatin, inhibits tumor cells and endothelial cells migration and invasion by binding to integrin α5β1 and αvβ3 [1,3,4]. HM-3 has recently entered clinical trials in China to treat solid tumors (CTR20200847). The short circulating half-life of unmodified HM-3 makes frequent dosing over an extended period necessary, which place constraints on its therapeutic applicability
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