Albumin-binding domain extends half-life of glucagon-like peptide-1

Tan, Huanbo; Su, Wencheng; Zhang, Wenyu; Zhang, Jie; Sattler, Michael; Zou, Pengfei

doi:10.1016/j.ejphar.2020.173650

Cited by 20 publications

(14 citation statements)

References 45 publications

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“…As an example of the power of this approach, an albumin binding domain with high affinity for human serum albumin was used to circumvent the short half-life of Glucagon-like peptide-1 (GLP-1), a promising peptide for the treatment of type 2 diabetes mellitus. Three different ABD-fusion GLP-1 proteins bound HSA with high affinity, extended its half-life, and improved the glucose-lowering effect of GLP-1 ( 318 ). Studies like this have important implications for altering in vivo pharmacokinetics of peptides and proteins to improve pharmacodynamic and pharmacokinetic properties.…”

Section: Albumin As a Therapeutic Half-life-extending Agentmentioning

confidence: 99%

Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

Molitoris

Sandoval

Yadav

et al. 2022

Physiological Reviews

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For nearly fifty years the proximal tubule has been known to reabsorb, process, and either catabolize or transcytose albumin from the glomerular filtrate. Innovative techniques and approaches have provided insights into these processes, and several genetic diseases, nonselective proximal tubule cell (PTC) defects, chronic kidney disease and acute PTC injury lead to significant albuminuria, reaching nephrotic range. Albumin is also known to stimulate PTC injury cascades. Thus, the mechanisms of albumin reabsorption, catabolism and transcytosis are being reexamined utilizing techniques that allow for novel molecular and cellular discoveries. Megalin, a scavenger receptor, cubilin, amnionless, and Dab2 form a nonselective multi-receptor complex that mediates albumin binding, uptake and directs proteins for lysosomal degradation following endocytosis. The neonatal Fc receptor mediates albumin transcytosis by its pH-dependent binding affinity in endosomal compartments. This transcytotic, reclamation, pathway minimizes urinary losses and cellular catabolism of albumin thus prolonging its serum half-life. It also serves as a PTC molecular sorting mechanism to preserve and reclaim physiologic albumin while allowing "altered" albumin that does not bind to FcRn to enter the lysosomal pathway. The clinical importance of PTC albumin metabolism has also increased as albumin is now being used to bind therapeutic agents to extend their half-life and minimize filtration and kidney injury. The purpose of this review is to update and integrate evolving information regarding the reabsorption and processing of albumin by proximal tubule cells including discussing genetic disorders and therapeutic considerations.

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Section: Albumin As a Therapeutic Half-life-extending Agentmentioning

confidence: 99%

Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

Molitoris

Sandoval

Yadav

et al. 2022

Physiological Reviews

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“…Recently, HSA fusion technology has also been utilized for extending the half-life of therapeutic proteins because of the special kinetic properties of HSA 65 , 66 . The mechanism of HSA fusion in prolonging half-life is the same as Fc fusion 67 , 68 .…”

Section: Existing Strategies To Manipulate the Drug In Vivo Clearancementioning

confidence: 99%

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

Shi

Wang

et al. 2021

Acta Pharmaceutica Sinica B

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The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of in vivo clearance and manipulation of drug release from delivery systems, respectively. And the current challenges and prospects of each strategy are discussed. In addition, we also briefly discuss the design principles of LAPFs and provide future perspectives of the rational design of more effective LAPFs for their further clinical translation.

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“…For instance, when researchers discovered the benefits of GLP-1 in diabetes and developed a therapeutic analog, they found that the native human GLP-1 (7-37) half-life was too short to have the desired therapeutic effect (Deacon et al, 1995). Lipidation of the peptide provided an extended half-life and thus brought liraglutide to clinical utility (Knudsen et al, 2000;Tan et al, 2021;Victoza, 2022). Modification of the naturally occurring alanine in position 8 of hGLP-1 (7-37) to the UAA aminoisobutyric acid (Aib) prevented degradation by dipeptidyl peptidase IV (DPP-IV) and further increased the half-life (Deacon et al, 1995), bringing semaglutide to the market (Ozempic, 2022;Rybelsus, 2022).…”

Section: Immunogenic Risk Assessment For Unnatural Amino Acid-contain...mentioning

confidence: 99%

“…First, the lysine in position 26 has been modified with a C18 diacid connected to the lysine side chain via a mini PEG spacer and γ-glutamic acid (OEG-OEG-γGlu-C18 diacid). The fatty acid chain reversibly binds human serum albumin in vivo while the mini PEG spacer provides flexibility to allow for improved binding to the receptor (Tan et al, 2021). Additionally, a modification from lysine to arginine in position 34 was introduced to ensure direct fatty acid conjugation to the lysine in position 26 (Knudsen et al, 2000).…”

Section: Example 2 Semaglutide Active Pharmaceutical Ingredientmentioning

confidence: 99%

In silico immunogenicity assessment for sequences containing unnatural amino acids: A method using existing in silico algorithm infrastructure and a vision for future enhancements

Mattei

Gutiérrez

Martin

et al. 2022

Front. Drug. Discov.

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The in silico prediction of T cell epitopes within any peptide or biologic drug candidate serves as an important first step for assessing immunogenicity. T cell epitopes bind human leukocyte antigen (HLA) by a well-characterized interaction of amino acid side chains and pockets in the HLA molecule binding groove. Immunoinformatics tools, such as the EpiMatrix algorithm, have been developed to screen natural amino acid sequences for peptides that will bind HLA. In addition to commonly occurring in synthetic peptide impurities, unnatural amino acids (UAA) are also often incorporated into novel peptide therapeutics to improve properties of the drug product. To date, the HLA binding properties of peptides containing UAA are not accurately estimated by most algorithms. Both scenarios warrant the need for enhanced predictive tools. The authors developed an in silico method for modeling the impact of a given UAA on a peptide’s likelihood of binding to HLA and, by extension, its immunogenic potential. In silico assessment of immunogenic potential allows for risk-based selection of best candidate peptides in further confirmatory in vitro, ex vivo, and in vivo assays, thereby reducing the overall cost of immunogenicity evaluation. Examples demonstrating in silico immunogenicity prediction for product impurities that are commonly found in formulations of the generic peptides teriparatide and semaglutide are provided. Next, this article discusses how HLA binding studies can be used to estimate the binding potentials of commonly encountered UAA and “correct” in silico estimates of binding based on their naturally occurring counterparts. As demonstrated here, these in vitro binding studies are usually performed with known ligands which have been modified to contain UAA in HLA anchor positions. An example using D-amino acids in relative binding position 1 (P1) of the PADRE peptide is presented. As more HLA binding data become available, new predictive models allowing for the direct estimation of HLA binding for peptides containing UAA can be established.

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Albumin-binding domain extends half-life of glucagon-like peptide-1

Cited by 20 publications

References 45 publications

Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

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

In silico immunogenicity assessment for sequences containing unnatural amino acids: A method using existing in silico algorithm infrastructure and a vision for future enhancements

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