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An orally available PD-1/PD-L1 blocking peptide OPBP-1-loaded trimethyl chitosan hydrogel for cancer immunotherapy
Wanqiong Li1, Xueqin Zhu2, Xiuman Zhou2
1School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China; School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
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.
Insights
Researchers developed a novel peptide, OPBP-1, to block PD-1/PD-L1 interactions for cancer immunotherapy. Oral delivery via a hydrogel improved bioavailability and effectively inhibited tumor growth, offering a new oral drug development prospect.
Area of Science:
- Immunology
- Oncology
- Drug Delivery
Background:
- Monoclonal antibodies targeting PD-1/PD-L1 have shown efficacy in cancer immunotherapy.
- Oral low-molecular-weight inhibitors are still in early development.
- Peptides offer selectivity but face challenges with stability and oral administration.
Purpose of the Study:
- To develop a proteolysis-resistant peptide inhibitor of PD-L1 for cancer immunotherapy.
- To enhance the oral bioavailability and therapeutic efficacy of the peptide drug.
Main Methods:
- Development of a proteolysis-resistant D-peptide, OPBP-1, targeting PD-L1.
- In vitro assessment of PD-1/PD-L1 interaction blockade and interferon-gamma secretion.
- In vivo evaluation of OPBP-1 efficacy in murine tumor models (CT26 and B16-OVA).
- Formulation of OPBP-1 into a N,N,N-trimethyl chitosan (TMC) hydrogel for oral delivery.
Main Results:
- OPBP-1 selectively bound PD-L1, blocked PD-1/PD-L1 interaction, and enhanced CD8+ T cell function.
- OPBP-1 significantly inhibited tumor growth in vivo at low doses and promoted CD8+ T cell infiltration.
- Oral delivery of OPBP-1@TMC hydrogel achieved 52.8% bioavailability and a 14.55-hour half-life in rats, with significant tumor inhibition.
Conclusions:
- OPBP-1 is an effective peptide inhibitor of PD-L1 with therapeutic potential in cancer.
- The TMC hydrogel system successfully improved oral bioavailability and half-life of OPBP-1.
- This study presents a promising strategy for developing orally available peptide drugs for cancer immunotherapy.
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