Novel AGLP-1 albumin fusion protein as a long-lasting agent for type 2 diabetes

Abstract

Glucagon like peptide-1 (GLP-1) regulates glucose mediated-insulin secretion, nutrient accumulation, and β-cell growth. Despite the potential therapeutic usage for type 2 diabetes (T2D), GLP-1 has a short half-life in vivo (t1/2 ＜2 min). In an attempt to prolong half-life, GLP-1 fusion proteins were genetically engineered: GLP-1 human serum albumin fusion (GLP-1/HSA), AGLP-1/HSA which has an additional alanine at the N-terminus of GLP-1, and AGLP-1-L/HSA, in which a peptide linker is inserted between AGLP-1 and HSA. Recombinant fusion proteins secreted from the Chinese Hamster Ovary-K1 (CHO-K1) cell line were purified with high purity (＞96%). AGLP-1 fusion protein was resistant against the dipeptidyl peptidase-IV (DPP-IV). The fusion proteins activated cAMP-mediated signaling in rat insulinoma INS-1 cells. Furthermore, a C57BL/6N mice pharmacodynamics study exhibited that AGLP-1-L/HSA effectively reduced blood glucose level compared to AGLP-1/HSA. [BMB Reports 2013; 46(12): 606-610]

In vivo degradation forms, anti-degradation strategies, and clinical applications of therapeutic peptides in non-infectious chronic diseases

“…Current methods and emerging tactics to protect small peptides and elongate their half-lives. Modifications may introduce a decrease in binding affinity (John et al, 2008;Kim et al, 2013) Replacing L-AA(s) with D-AA(s) Conjugation with a macromolecule may cause unexpected changes in the pharmacokinetics of the peptide. (Bronden et al, 2017;Poole and Nowlan, 2014) Drug delivery vehicle Leuprolide (leuprorelin or Lupron®) with drug delivery vehicle DUROS® Allows administration of the peptide over a long period; protects the peptide from physical and chemical degradation; decreases the frequency of administration.…”

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

“…Meanwhile, HSA has the features of low immunogenicity and high biocompatibility 69 . Tanzeum® (albigutide), a GLP-1-HSA fusion protein approved in 2014, is the first product based on HSA fusion for the treatment of type 2 diabetes 70 . The half-life of native GLP-1 is 1–2 min, and the half-life of albigutide is 4–7 days, which can greatly reduce the frequency of administration in clinic.…”

Production of “biobetter” glucarpidase variants to improve drug detoxification and antibody directed enzyme prodrug therapy for cancer treatment

“…Human serum albumin, which has a circulation half-life of nineteen days 18 , has also been used to extend the half-life of biopharmaceuticals and to maintain their bioactivity 19,20 . Protein therapeutics that have been improved using this strategy include vascular endothelial growth factor 21 , interferon 22,23 , and interleukin-2 24 .…”