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An engineered PD1-Fc fusion produced in N. benthamiana plants efficiently blocks PD1/PDL1 interaction
Shiva Izadi1, Rafaela Abrantes2,3,4, Simon Gumpelmair5
1Department of Biotechnology and Food Science Institute of Plant Biotechnology and Cell Biology, BOKU University, Muthgasse 18, 1190, Vienna, Austria.
Plant Cell Reports
|March 22, 2025
Summary
Plant-made PD1-Fc fusion proteins offer a cost-effective alternative to antibody-based immune checkpoint inhibitors. These engineered proteins efficiently block PD1/PDL1 interactions, potentially overcoming limitations of current cancer immunotherapies.
Area of Science:
- Biotechnology
- Immunology
- Plant Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 (PD1) pathway have transformed cancer immunotherapy.
- However, significant patient non-response, treatment resistance, and immune-related adverse events limit the efficacy of current antibody-based ICIs.
- Alternative strategies are needed to improve PD1 pathway-targeted therapies.
Purpose of the Study:
- To develop and characterize plant-made PD1-Fc fusion proteins as potential alternatives to antibody-based immune checkpoint inhibitors.
- To engineer these fusion proteins for optimized glycosylation and Fc-receptor engagement.
- To evaluate their efficacy in blocking PD1/PDL1 interactions and PD1 signaling.
Main Methods:
- Utilized a plant expression platform (Nicotiana benthamiana) to generate immunoglobulin fusion proteins with wild-type or affinity-enhanced PD1 ectodomains.
- Engineered variants with differing glycosylation profiles and Fc-receptor engagement capabilities.
- Assessed PDL1 binding using protein- and cell-based assays, and evaluated PD1 signaling blockade in a T cell reporter assay.
Main Results:
- Affinity-enhanced PD1-Fc fusion proteins demonstrated significantly augmented PDL1 engagement compared to wild-type versions.
- Plant-derived PD1-Fc fusion protein binding to PDL1 was independent of PDL1 glycosylation status.
- Demonstrated high efficiency in blocking inhibitory PD1 signaling in T cells.
Conclusions:
- Plant-made PD1-Fc fusions, engineered for optimized glycosylation and Fc-receptor engagement, are effective in blocking PD1/PDL1 interactions.
- These plant-derived biologics represent a promising and potentially cost-effective alternative to antibody-based immune checkpoint inhibitors.
- This approach highlights the utility of plant-based expression systems for generating therapeutic proteins with potential to reduce overstimulation while retaining ICI benefits.
