An orally available PD-1/PD-L1 blocking peptide OPBP-1-loaded trimethyl chitosan hydrogel for cancer immunotherapy.

Abstract

Blockade of the immune checkpoint PD-1/PD-L1 with monoclonal antibodies demonstrated unprecedented clinical efficacies in many cancers. But the orally available low molecular weight inhibitors remain infancy. Compared to small molecules, peptide exhibits better selectivity and fewer side effects, but poor half-life and a big challenge to be orally administrated. Here, we developed a proteolysis-resistant D peptide OPBP-1 (Oral PD-L1 Binding Peptide 1) which could selectively bind PD-L1, significantly block PD-1/PD-L1 interaction and enhance IFN-γ (interferon γ) secretion from CD8+ T cells in human PBMCs (Peripheral blood mononuclear cells). OPBP-1 could significantly inhibit tumor growth in murine colorectal CT26 and melanoma B16-OVA models at a relatively low dose of 0.5 mg/kg, with enhancing the infiltration and function of CD8+ T cells. More interestingly, oral delivery of OPBP-1 loaded TMC (N, N, N-trimethyl chitosan) hydrogel (OPBP-1@TMC) showed promising OPBP-1 oral bioavailability (52.8%) and prolonged half-life (14.55 h) in rats, and also significantly inhibited tumor growth in CT26 model. In conclusion, we discovered and optimized a PD-1/PD-L1 blocking peptide OPBP-1, and subsequently loaded into a TMC based hydrogel oral delivery system, in order to maximally elevate the oral bioavailability of the peptide drug and effectively inhibit tumor growth. These results opened up a new prospect for oral drug development in cancer immunotherapy.

• Authors: Wanqiong Li, Xueqin Zhu, Xiuman Zhou, Xiaoxi Wang, Wenjie Zhai, Bingyu Li, Jiangfeng Du, Guodong Li, Xinghua Sui, Yahong Wu, Mingxia Zhai, Yuanming Qi, Guanyu Chen, Yanfeng Gao
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 334 Pg. 376-388 (06 10 2021) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 33940058 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• B7-H1 Antigen
• Hydrogels
• Peptides
• Programmed Cell Death 1 Receptor
• Chitosan

Topics

• Animals
• B7-H1 Antigen
• CD8-Positive T-Lymphocytes
• Chitosan
• Hydrogels
• Immunotherapy
• Leukocytes, Mononuclear
• Mice
• Neoplasms (drug therapy)
• Peptides
• Programmed Cell Death 1 Receptor
• Rats