Signal Peptide Optimization to Prevent N-terminal Truncation of Glucagon Like Peptide-1/IgG-Fc Fusion Protein

Dulaglutide (glucagon like peptide-1/IgG-Fc fusion protein, GLP-1-Fc) is a long lasting GLP-1 agonist, which consists of two arms of GLP-1 moieties fused to IgG Fc fragment. Dulaglutide is a safe and effective medication for type 2 diabetes. In an attempt to develop a biosimilar version of dulagluti...

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Published in:International journal of peptide research and therapeutics 2021-03, Vol.27 (1), p.579-586
Main Authors: Cao, Chunlai, Wei, Suzhen, Xu, Xukun, Song, Suqin, Lai, Yongjie, Li, Jing
Format: Article
Language:English
Subjects:
Animal Anatomy
Batch culture
Biochemistry
Biomedical and Life Sciences
Cell culture
Diabetes mellitus (non-insulin dependent)
Fc receptors
Fusion protein
GLP-1 receptor agonists
Glucagon
Histology
Immunoglobulin G
Life Sciences
Molecular Medicine
Morphology
N-Terminus
Peptides
Pharmaceutical Sciences/Technology
Pharmacology/Toxicology
Polymer Sciences
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container_end_page 586
container_issue 1
container_start_page 579
container_title International journal of peptide research and therapeutics
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creator Cao, Chunlai
Wei, Suzhen
Xu, Xukun
Song, Suqin
Lai, Yongjie
Li, Jing
description Dulaglutide (glucagon like peptide-1/IgG-Fc fusion protein, GLP-1-Fc) is a long lasting GLP-1 agonist, which consists of two arms of GLP-1 moieties fused to IgG Fc fragment. Dulaglutide is a safe and effective medication for type 2 diabetes. In an attempt to develop a biosimilar version of dulaglutide, we found that up to 75% of GLP-1-Fc displayed N -terminal truncations in one or both GLP-1 arms. We proposed that the N -terminal heterogeneity was caused by mis-cleavage of signal peptide and solved this problem through signal peptide optimization. Murine immunoglobulin kappa light chain signal peptide (KASP) significantly improves GLP-1-Fc N -terminal integrity and homogeneity. 92.8–95.7% of GLP-1-Fc molecules directed by KASP contain intact N -terminus. The productivity of GLP-1-Fc could reach 2.2 g/L in shaking flask fed batch culture. KASP is an optimal signal peptide for GLP-1-Fc expression in Chinese hamster ovary (CHO) cells.
doi_str_mv 10.1007/s10989-020-10112-9
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subjects Animal Anatomy
Batch culture
Biochemistry
Biomedical and Life Sciences
Cell culture
Diabetes mellitus (non-insulin dependent)
Fc receptors
Fusion protein
GLP-1 receptor agonists
Glucagon
Histology
Immunoglobulin G
Life Sciences
Molecular Medicine
Morphology
N-Terminus
Peptides
Pharmaceutical Sciences/Technology
Pharmacology/Toxicology
Polymer Sciences
title Signal Peptide Optimization to Prevent N-terminal Truncation of Glucagon Like Peptide-1/IgG-Fc Fusion Protein
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