Characterization and Oral Delivery of Proinsulin-Transferrin Fusion Protein Expressed Using ExpressTec

Chen, Yu‐Sheng; Zaro, Jennica L.; Zhang, Deshui; Huang, Ning; Simon, A.; Shen, Wei‐Chiang

doi:10.3390/ijms19020378

Cited by 13 publications

(6 citation statements)

References 18 publications

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“…Such a non-exclusive cleavage is in agreement with our finding that removing the furin cleavage site reduced but did not completely prevent FGF21-transferrin degradation ( Figure 2 and Supplementary Figure 2 ). In this respect, other linkers could be tested in the future to increase FGF21-transferrin fusion protein stability, e.g., a rigid EA-linker ( Supplementary Table 7 ; Amet et al, 2009 ; Kim et al, 2010 ; Fu et al, 2011 ; Wang et al, 2011 , 2014 ; Chen et al, 2012 , 2018 ; Choi et al, 2014 ; Liu et al, 2020 ). However, a linker may not be necessary at all as we showed by using the liver-targeting PLUS peptide ( Lu et al, 2014 ; Ma et al, 2014 , 2017 ; Taverner et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Seed- and leaf-based expression of FGF21-transferrin fusion proteins for oral delivery and treatment of non-alcoholic steatohepatitis

Hou

Bishop²,

Huckauf³

et al. 2022

Front. Plant Sci.

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Non-alcoholic steatohepatitis (NASH) is a global disease with no effective medication. The fibroblast growth factor 21 (FGF21) can reverse this liver dysfunction, but requires targeted delivery to the liver, which can be achieved via oral administration. Therefore, we fused FGF21 to transferrin (Tf) via a furin cleavage site (F), to promote uptake from the intestine into the portal vein, yielding FGF21-F-Tf, and established its production in both seeds and leaves of commercial Nicotiana tabacum cultivars, compared their expression profile and tested the bioavailability and bioactivity in feeding studies. Since biopharmaceuticals need to be produced in a contained environment, e.g., greenhouses in case of plants, the seed production was increased in this setting from 239 to 380 g m–2 a–1 seed mass with costs of 1.64 € g–1 by side branch induction, whereas leaves yielded 8,193 g m–2 a–1 leave mass at 0.19 € g–1. FGF21-F-Tf expression in transgenic seeds and leaves yielded 6.7 and 5.6 mg kg–1 intact fusion protein, but also 4.5 and 2.3 mg kg–1 additional Tf degradation products. Removing the furin site and introducing the liver-targeting peptide PLUS doubled accumulation of intact FGF21-transferrin fusion protein when transiently expressed in Nicotiana benthamiana from 0.8 to 1.6 mg kg–1, whereas truncation of transferrin (nTf338) and reversing the order of FGF21 and nTf338 increased the accumulation to 2.1 mg kg–1 and decreased the degradation products to 7% for nTf338-FGF21-PLUS. Application of partially purified nTf338-FGF21-PLUS to FGF21–/– mice by oral gavage proved its transfer from the intestine into the blood circulation and acutely affected hepatic mRNA expression. Hence, the medication of NASH via oral delivery of nTf338-FGF21-PLUS containing plants seems possible.

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Section: Discussionmentioning

confidence: 99%

Seed- and leaf-based expression of FGF21-transferrin fusion proteins for oral delivery and treatment of non-alcoholic steatohepatitis

Hou

Bishop²,

Huckauf³

et al. 2022

Front. Plant Sci.

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“… Administered orally in medication. 55 , 197 HTF directs the absorption and transportation of drugs through the rich TFR in intestinal epithelial cells, 198 Additionally, HTF possesses robust anti-protease hydrolysis capabilities, rendering it an efficient carrier for oral proteins and peptide-based therapeutic agents intended for systemic treatment. It can effectively prolong the efficacy of GLP-1 by linking with GLP-1.…”

Section: Transferrin-like Fusion Protein-based Drugsmentioning

confidence: 99%

“…Utilizing the transgenic rice expression system, it is possible to produce ProINS-TF with high activity and oral administration at a low cost and a large scale, which provides a material guarantee for future research. 197 …”

Section: Transferrin-like Fusion Protein-based Drugsmentioning

confidence: 99%

Research Advances in Fusion Protein-Based Drugs for Diabetes Treatment

Deng,

Zhao,

Zou

et al. 2024

DMSO

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Diabetes mellitus (DM) is a chronic metabolic disease characterized by elevated blood glucose levels, resulting in multi-organ dysfunction and various complications. Fusion proteins can form multifunctional complexes by combining the target proteins with partner proteins. It has significant advantages in improving the performance of the target proteins, extending their biological half-life, and enhancing patient drug compliance. Fusion protein-based drugs have emerged as promising new drugs in diabetes therapeutics. However, there has not been a systematic review of fusion protein-based drugs for diabetes therapeutics. Hence, we conducted a comprehensive review of published literature on diabetic fusion protein-based drugs for diabetes, with a primary focus on immunoglobulin G (IgG) fragment crystallizable (Fc) region, albumin, and transferrin (TF). This review aims to provide a reference for the subsequent development and clinical application of fusion protein-based drugs in diabetes therapeutics.

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“…Moreover, they were still detected in the plasma 4 h after administration [ 271 ]. Tf has also been used as a carrier for human growth hormone [ 16 ], G-CSF [ 17 ], pro-insulin [ 272 ] and 100 nm model polystyrene NPs [ 273 ].…”

Section: Strategies To Improve the Oral Delivery Of Biologicsmentioning

confidence: 99%

Challenges and Opportunities in the Oral Delivery of Recombinant Biologics

Masloh,

Culot,

Gosselet

et al. 2023

Pharmaceutics

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Recombinant biological molecules are at the cutting-edge of biomedical research thanks to the significant progress made in biotechnology and a better understanding of subcellular processes implicated in several diseases. Given their ability to induce a potent response, these molecules are becoming the drugs of choice for multiple pathologies. However, unlike conventional drugs which are mostly ingested, the majority of biologics are currently administered parenterally. Therefore, to improve their limited bioavailability when delivered orally, the scientific community has devoted tremendous efforts to develop accurate cell- and tissue-based models that allow for the determination of their capacity to cross the intestinal mucosa. Furthermore, several promising approaches have been imagined to enhance the intestinal permeability and stability of recombinant biological molecules. This review summarizes the main physiological barriers to the oral delivery of biologics. Several preclinical in vitro and ex vivo models currently used to assess permeability are also presented. Finally, the multiple strategies explored to address the challenges of administering biotherapeutics orally are described.

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Characterization and Oral Delivery of Proinsulin-Transferrin Fusion Protein Expressed Using ExpressTec

Cited by 13 publications

References 18 publications

Seed- and leaf-based expression of FGF21-transferrin fusion proteins for oral delivery and treatment of non-alcoholic steatohepatitis

Seed- and leaf-based expression of FGF21-transferrin fusion proteins for oral delivery and treatment of non-alcoholic steatohepatitis

Research Advances in Fusion Protein-Based Drugs for Diabetes Treatment

Challenges and Opportunities in the Oral Delivery of Recombinant Biologics

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