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Key message <p><b>Plant-made PD1–Fc fusions engineered for optimized glycosylation and Fc-receptor engagement are highly efficient in blocking PD1/PDL1 interactions and can be cost-effective alternatives to antibody-based immune checkpoint inhibitors.</b></p> Abstract <p>Immune checkpoint inhibitors (ICIs) are antibodies to receptors that have pivotal roles during T-cell activation processes. The programmed cell death 1 (PD1) can be regarded as the primary immune checkpoint and antibodies targeting PD1 or its ligand PDL1 have revolutionized immunotherapy of cancer. However, the majority of patients fail to respond, and treatment resistance as well as immune-related adverse events are commonly associated with this therapy. Alternatives to antibody-based ICIs targeting the PD1 pathway may bear the potential to overcome some of these shortcomings. Here, we have used a plant expression platform based on the tobacco relative <i>Nicotiana benthamiana</i> to generate immunoglobulin fusion proteins harboring the wild type or an affinity-enhanced PD1 ectodomain. We have exploited the versatility of our system to generate variants that differed regarding their glycosylation profile as well as their capability to engage Fc-receptors. Unlike its wild-type counterpart, the affinity-enhanced versions showed strongly augmented capabilities to engage PDL1 in both protein- and cell-based assays. Moreover, in contrast with clinical antibodies, their binding is not affected by the glycosylation status of PDL1. Importantly, we could demonstrate that the plant-made PD1 fusion proteins are highly efficient in blocking inhibitory PD1 signaling in a T cell reporter assay. Taken together, our study highlights the utility of our plant-based protein expression platform to generate biologics with therapeutic potential. Targeting PDL1 with plant derived affinity-enhanced PD1 immunoglobulin fusion proteins may reduce overstimulation associated with antibody-based therapies while retaining favorable features of ICIs such as long serum half-life.</p>

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An engineered PD1-Fc fusion produced in N. benthamiana plants efficiently blocks PD1/PDL1 interaction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月22日

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  • Shiva Izadi,
  • Rafaela Abrantes,
  • Simon Gumpelmair,
  • Vinny Kunnummel,
  • Henrique O. Duarte,
  • Peter Steinberger,
  • Celso A. Reis,
  • Alexandra Castilho

摘要

Key message

Plant-made PD1–Fc fusions engineered for optimized glycosylation and Fc-receptor engagement are highly efficient in blocking PD1/PDL1 interactions and can be cost-effective alternatives to antibody-based immune checkpoint inhibitors.

Abstract

Immune checkpoint inhibitors (ICIs) are antibodies to receptors that have pivotal roles during T-cell activation processes. The programmed cell death 1 (PD1) can be regarded as the primary immune checkpoint and antibodies targeting PD1 or its ligand PDL1 have revolutionized immunotherapy of cancer. However, the majority of patients fail to respond, and treatment resistance as well as immune-related adverse events are commonly associated with this therapy. Alternatives to antibody-based ICIs targeting the PD1 pathway may bear the potential to overcome some of these shortcomings. Here, we have used a plant expression platform based on the tobacco relative Nicotiana benthamiana to generate immunoglobulin fusion proteins harboring the wild type or an affinity-enhanced PD1 ectodomain. We have exploited the versatility of our system to generate variants that differed regarding their glycosylation profile as well as their capability to engage Fc-receptors. Unlike its wild-type counterpart, the affinity-enhanced versions showed strongly augmented capabilities to engage PDL1 in both protein- and cell-based assays. Moreover, in contrast with clinical antibodies, their binding is not affected by the glycosylation status of PDL1. Importantly, we could demonstrate that the plant-made PD1 fusion proteins are highly efficient in blocking inhibitory PD1 signaling in a T cell reporter assay. Taken together, our study highlights the utility of our plant-based protein expression platform to generate biologics with therapeutic potential. Targeting PDL1 with plant derived affinity-enhanced PD1 immunoglobulin fusion proteins may reduce overstimulation associated with antibody-based therapies while retaining favorable features of ICIs such as long serum half-life.