High-yield production of biologically active mono-PEGylated salmon calcitonin by site-specific PEGylation

Youn, Yu Seok; Na, Dong Hee; Lee, Kang Choon

doi:10.1016/j.jconrel.2006.11.013

Cited by 33 publications

(23 citation statements)

References 28 publications

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“…Free sCT and the sCT conjugates induced similar hypocalcaemia and the reductions obtained were typical of the maximum achieved following i.v. administration [37]. The non-linear relationship between serum calcium reduction and [sCT] suggests a highly complex relationship [21,38], and there is obvious difficulty in rank-ordering formulations when the window of the calcium reduction is so narrow.…”

Section: Discussionmentioning

confidence: 99%

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Ryan

Frías²,

Wang

et al. 2011

Journal of Controlled Release

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Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped endfunctionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E max and an EC 50 of 3.7 nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 15-30 % over 240 min, the half life (T½) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40 kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T½ for sCT, the 40 kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.

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Section: Discussionmentioning

confidence: 99%

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Ryan

Frías²,

Wang

et al. 2011

Journal of Controlled Release

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“…A nasal spray formulation of salmon calcitonin is currently being marketed by Novartis, and research groups are trying to find methods of prolonging its half-life by PEGylation. PEGylation at Lys (18) has been reported to result in maximal biological activity (defined as in vitro cAMP-releasing activity and in vivo hypocalcemic efficacy), and a number of successful attempts have been made to achieve the selective PEGylation sCT and to identify alternative routes for administrating Lys(18)-PEG-sCT (per nasal or oral) to improve drug delivery [90][91][92][93]. 6.4.1 CDP791 (alacizumab Pegol) CDP791 is a PEGylated di-Fab′ against VEGF receptor-2 (VEGFR-2) and inhibits the angiogenesis pathway.…”

Section: Peg-salmon Calcitoninmentioning

confidence: 99%

Emerging PEGylated drugs

Kang

DeLuca

Lee

2009

Expert Opinion on Emerging Drugs

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230

194

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PEGylation is a pharmaceutical technology that involves the covalent attachment of polyethylene glycol (PEG) to a drug to improve its pharmacokinetic, pharmacodynamic, and immunological profiles, and thus, enhance its therapeutic effect. Currently, PEGylation is used to modify proteins, peptides, oligonucleotides, antibody fragments, and small organic molecules. Research groups are striving to improve the consistencies of PEGylated drugs and to PEGylate commercialized proteins and small organic molecules. Furthermore, the PEGylations of novel medications, like oligonucleotides and antibody fragments, are being pursued to improve their bioavailabilities. This active research in the PEGylation field and the continued growth of the biopharmaceutical market predicts that PEGylated drugs have a bright future.

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“…The quantitative conversion of GFP–C–N 3 also facilitated the purification of GFP–C–PEG with a high yield of >80%, which compares favorably with the 10–20% overall yield often seen in conventional PEGylation processes. [17] Gel permeation chromatography (GPC) curves showed monomodal and symmetric elution peaks for GFP–C–PEG that exhibited a clear shift to a larger size with increasing MW of DBCO–PEG (Figure 2e). A cyclooctyne terminated polycarbonate, polyphosphoester, and PMPC were separately conjugated to the C–terminus of GFP by using identical reaction procedures (Figure 2f and Table S1).…”

mentioning

confidence: 99%

A Modular Method for the High‐Yield Synthesis of Site‐Specific Protein–Polymer Therapeutics

Pang

Liu

et al. 2016

Angew Chem Int Ed

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A new and versatile method is described to engineer precisely defined protein/peptide–polymer therapeutics by a modular approach that consists of three steps: (1) fuse a protein/peptide of interest with an elastin–like–polypeptide that enables facile purification and high yield; followed by (2) installation of a clickable group at the C–terminus of the recombinant protein/peptide with close to complete conversion by enzyme–mediated ligation; and subsequently (3) attachment of a polymer by a click reaction with near quantitative conversion. We demonstrate that this modular approach is applicable to various protein/peptide drugs and used it to conjugate structurally diverse water-soluble polymers that prolong the plasma circulation duration of proteins. These protein/peptide–polymer conjugates exhibit significantly improved pharmacokinetics and improved therapeutic effects over the native protein/peptide after administration to mice. The studies reported here provide a facile methodology for synthesis of protein/peptide-polymer conjugates for therapeutic use and other applications.

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High-yield production of biologically active mono-PEGylated salmon calcitonin by site-specific PEGylation

Cited by 33 publications

References 28 publications

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Emerging PEGylated drugs

A Modular Method for the High‐Yield Synthesis of Site‐Specific Protein–Polymer Therapeutics

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