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Researchers synthesize chimeric peptide that elicits antitumor activity for cancer immunotherapy

July 3, 2023
in Health
Researchers synthesize chimeric peptide that elicits antitumor activity for cancer immunotherapy
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Design of a novel chimeric peptide via dual blockade of CD47/SIRPα and PD-1/PD-L1 for cancer immunotherapy

The peptide Pal-DMPOP consists a peptide inhibitor of CD47/SIRPα, a D-peptide inhibitor of PD-1/PD-L1, and a palmitic acid tail conjugated at its N-terminal through a PEG4 linker. This design made this peptide resistant to serum proteolysis and accumulated in the tumor tissues. It can block CD47/SIRPα and PD-1/PD-L1 to enhance the phagocytosis of macrophage, and block PD-1/PD-L1 to restore the function of T cell. Credit: ©Science China Press

Professor Yanfeng Gao’s team from the School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University have designed and synthesized Pal-DMPOP, a chimeric peptide that can simultaneously block CD47/SIRPα and PD-1/PD-L1. This bispecific peptide elicits synergistic antitumor activity by enhancing macrophages phagocytosis and activating CD8+ T cells. The findings are published in the journal Science China Life Sciences.

Although immune checkpoint inhibition has been shown to effectively activate antitumor immunity in various tumor types, only a small subset of patients can benefit from PD-1/PD-L1 blockade. CD47 expressed on tumor cells protects them from phagocytosis through interaction with SIRPα on macrophages, while PD-L1 dampens T cell-mediated tumor killing.

Also, it was reported that macrophages can also express PD-1 to mediate a “don’t eat me” signal through interaction with PD-L1 on tumor cells. Compared with antibodies, peptides have better tumor penetration ability and easy to be synthesized. Therefore, design of peptides dual-targeting blockade of both PD-1/PD-L1 and CD47/SIRPα may improve the efficacy of cancer immunotherapy.

Design of a novel chimeric peptide via dual blockade of CD47/SIRPα and PD-1/PD-L1 for cancer immunotherapy

Pal-DMPOP (1 mg/kg, i.p., daily) significantly inhibits the tumor growth (A), has no impact on body weights (B), enhances CD8+ T cell infiltration (C) and its IFN-γ secretion in the tumor tissue (D). The infiltration of intratumoral macrophages (CD45+CD11b+F480+) (E) and the M1/M2 ratio (F) in the tumor tissue were elevated. Credit: ©Science China Press

In this article, the authors designed a chimeric peptide Pal-DMPOP. It consists of the smallest fragment of the D-peptide inhibitor of PD-1/PD-L1 (OPBP-1) and the optimized peptide inhibitor of CD47/SIRPα (Pep-20). Also, the palmitic acid tail was modified at its N-terminal to improve its anti-enzymatic ability and in vivo half-life.

The research team verified that Pal-DMPOP can improve the phagocytosis of macrophages on tumor cells, and can also restore the killing effect of CD8+T cells on tumor cells in vitro. The effect of tumor immunotherapy in vivo has been determined in MC38 and CT26 mouse models. The tumor volume in Pal-DMPOP administration group is significantly reduced compared with the control group, and Pal-DMPOP has no obvious toxic effect in the tumor-bearing mice.

More information:
Zheng Hu et al, Design of a novel chimeric peptide via dual blockade of CD47/SIRPα and PD-1/PD-L1 for cancer immunotherapy, Science China Life Sciences (2023). DOI: 10.1007/s11427-022-2285-6

Citation:
Researchers synthesize chimeric peptide that elicits antitumor activity for cancer immunotherapy (2023, June 30)
retrieved 3 July 2023
from https://medicalxpress.com/news/2023-06-chimeric-peptide-elicits-antitumor-cancer.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.

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Copyright for syndicated content belongs to the linked Source : Medical Xpress – https://medicalxpress.com/news/2023-06-chimeric-peptide-elicits-antitumor-cancer.html

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