Improved pharmacokinetics and stability properties of catalase by chemical glycosidation with end‐group activated dextran

Villalonga, Reynaldo; Valdivia, Aymara; Pérez, Y.; Chongo, Bertha

doi:10.1002/app.25019

Cited by 5 publications

(10 citation statements)

References 20 publications

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“…Although PEGylation remains the most widely applied strategy for formulation biologics for IV administration, alternative conjugation techniques to PEGylation have been explored to prolong the delivery of biotherapeutics given by the IV route. Villalonga and co-workers have reported the preparation of dextran-catalase conjugates by using a 5 kDa dextran coupled to glutamic and aspartic acid residues on the enzyme, and with dextran activated with an ε-aminocaproic acid spacer [ 176 ]. A 20-fold (from 0.8 to 16 h) and 7-fold prolongation of half-life (from 0.7 to 5.1 h) were observed, respectively, with corresponding decrease in clearance and increase in total drug exposure [ 176 , 177 ].…”

Section: Polypeptide Deliverymentioning

confidence: 99%

“…Villalonga and co-workers have reported the preparation of dextran-catalase conjugates by using a 5 kDa dextran coupled to glutamic and aspartic acid residues on the enzyme, and with dextran activated with an ε-aminocaproic acid spacer [ 176 ]. A 20-fold (from 0.8 to 16 h) and 7-fold prolongation of half-life (from 0.7 to 5.1 h) were observed, respectively, with corresponding decrease in clearance and increase in total drug exposure [ 176 , 177 ]. A HESylated analogue of anakinra, a recombinant human IL-1 receptor antagonist approved for the treatment of rheumatoid arthritis, has been reported [ 178 ].…”

Section: Polypeptide Deliverymentioning

confidence: 99%

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Injectables and Depots to Prolong Drug Action of Proteins and Peptides

et al. 2020

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Proteins and peptides have emerged in recent years to treat a wide range of multifaceted diseases such as cancer, diabetes and inflammation. The emergence of polypeptides has yielded advancements in the fields of biopharmaceutical production and formulation. Polypeptides often display poor pharmacokinetics, limited permeability across biological barriers, suboptimal biodistribution, and some proclivity for immunogenicity. Frequent administration of polypeptides is generally required to maintain adequate therapeutic levels, which can limit efficacy and compliance while increasing adverse reactions. Many strategies to increase the duration of action of therapeutic polypeptides have been described with many clinical products having been developed. This review describes approaches to optimise polypeptide delivery organised by the commonly used routes of administration. Future innovations in formulation may hold the key to the continued successful development of proteins and peptides with optimal clinical properties.

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Section: Polypeptide Deliverymentioning

confidence: 99%

Section: Polypeptide Deliverymentioning

confidence: 99%

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

et al. 2020

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“…Gel filtration studies of the fluorescein–dextran conjugates demonstrated a linear relationship between dextran size and column retention time, with larger dextrans displaying shorter retention times . In addition, conjugation of dextran has been shown to decrease in vitro enzymatic degradation of catalase and to reduce the immunogenicity of xenogeneic antibodies …”

Section: Carbohydrate Polymersmentioning

confidence: 99%

“…Dextran conjugation via a spacer has been extensively explored for small molecules, but has also been applied to peptides and enzymes . Introduction of spacers such as ϵ‐aminocaproic acid at the reducing end has enabled site‐specific conjugation of dextran to the N‐terminus of catalase subunits (Figure B) . Lastly, dextran conjugation to proteins has also been obtained by an enzymatic approach using microbial transglutaminase to attach dextran with hexylenediamine at the reducing end to surface Gln residues of catalase …”

Section: Carbohydrate Polymersmentioning

confidence: 99%

“…Although catalase activity was decreased by 23 %, this catalase–dextran variant displayed improved thermostability as well as decreased susceptibility to trypsin digestion (functional half‐life extension from 40 min to 2 h as compared with native catalase). Intravenous administration of the dextran–catalase conjugate to rats revealed a seven‐fold extension of half‐life relative to unmodified catalase (from 0.7 to 5.1 h) as well as a 104‐fold increase in exposure (from 1.9 to 197 U h mL −1 ), and a 100‐fold decrease in clearance (from 110 to 1.1 mL min −1 ) …”

Section: Carbohydrate Polymersmentioning

confidence: 99%

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Half‐Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation

2016

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Peptides and proteins constitute a vast pool of excellent drug candidates. Evolution has equipped these molecules with superior drug-like properties such as high specificity and potency. However, native peptides and proteins suffer from an inadequate pharmacokinetic profile, and their outstanding pharmacological potential can only be realized if this issue is addressed during drug development. To overcome this challenge, a variety of half-life extension techniques relying on covalent chemical modification have been developed. These methods include PEGylation, fusion to unstructured polypeptide-based PEG mimetics, conjugation of large polysaccharides, native-like glycosylation, lipidation, fusion to albumin or the Fc domain of IgG, and derivatization with bio-orthogonal moieties that direct self-assembly. This review provides an overview of available conjugation chemistries, biophysical properties, and safety data associated with these concepts. Moreover, the effects of these modifications on peptide and protein pharmacokinetics are demonstrated through key examples.

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TRAIL‐Inspired Multivalent Dextran Conjugates Efficiently Induce Apoptosis upon DR5 Receptor Clustering

et al. 2019

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Triggering apoptosis of tumor cells has been in focus of cancer‐inspired research since decades. As clustering of death receptor 5 (DR5), which is overexpressed on various cancer cells, leads to formation of the death‐inducing signaling cascade (DISC), DR5 has recently become a promising target for tumor treatment. Herein, we demonstrate that covalent multimerization of a death receptor targeting peptide (DR5TP) on a dextran scaffold generates potent apoptosis‐inducing conjugates (EC50=2–20 nm). A higher conformational flexibility compared to reported DR5TP multimerization approaches, introduced by the polysaccharide framework compensates the reported need for the defined ligand orientation that was considered as essential prerequisite for effective receptor clustering and apoptosis induction. Enzyme‐catalyzed ligation of a hydrophilic dextran conjugate bearing multiple DR5‐targeting sites to a human fragment crystallizable (Fc) receptor did not affect the potency (EC50=2–7 nm), providing an option for improved in vivo half‐life and prospective conjugation to an antibody of interest in view of bispecific tumor targeting.

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Improved pharmacokinetics and stability properties of catalase by chemical glycosidation with end‐group activated dextran

Cited by 5 publications

References 20 publications

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

Half‐Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation

TRAIL‐Inspired Multivalent Dextran Conjugates Efficiently Induce Apoptosis upon DR5 Receptor Clustering

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