Effects of pharmaceutical PEGylation on drug metabolism and its clinical concerns

Zhang, Qizhou; Wang, Huan; Ma, Zhiguo; Wu, Baojian

doi:10.1517/17425255.2014.967679

Cited by 89 publications

(57 citation statements)

References 71 publications

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“…The relatively short duration of our study could contribute to this finding, as it has been reported that more patients on LB03002 treatment developed anti-rhGH antibody during the second year of the study vs the first year (12). Additionally, pegylated proteins/drugs usually have low immunogenicity/antigenicity (25, 26). …”

Section: Discussionmentioning

confidence: 99%

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

Luo

Hou

et al. 2017

European Journal of Endocrinology

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ObjectiveWe assessed the efficacy and safety of a weekly pegylated human growth hormone (PEG-rhGH) (Jintrolong) vs daily rhGH for children with growth hormone deficiency (GHD).DesignPhase II and III, multicenter, open-label, randomized controlled trials.Methods108 and 343 children with treatment-naive GHD from 6 hospitals in China were enrolled in the phase II and III studies respectively. Patients in the phase II study were randomized 1:1:1 to weekly Jintrolong (0.1 mg/kg/week PEG-rhGH complex), weekly Jintrolong (0.2 mg/kg/week PEG-rhGH complex) or daily rhGH (0.25 mg/kg/week) for 25 weeks. Patients in the phase III study were randomized in a 2:1 ratio to weekly Jintrolong (0.2 mg/kg/week) or daily rhGH (0.25 mg/kg/week) for 25 weeks. The primary endpoint for both studies was height velocity (HV) increase at the end of treatment. Other growth-related parameters, safety and compliance were also monitored.ResultsThe phase II study established the preliminary efficacy, safety and recommended dose of Jintrolong PEG-rhGH. In the phase III study, we demonstrated significantly greater HV increases in patients receiving Jintrolong treatment (from 2.26 ± 0.87 cm/year to 13.41 ± 3.72 cm/year) vs daily rhGH (from 2.25 ± 0.82 cm/year to 12.55 ± 2.99 cm/year) at the end of treatment (P < 0.05). Additionally, significantly greater improvement in the height standard deviation scores was associated with Jintrolong throughout the treatment (P < 0.05). Adverse event rates and treatment compliance were comparable between the two groups.ConclusionJintrolong PEG-rhGH at a dose of 0.2 mg/kg/week for 25 weeks is effective and safe for GHD treatment and is non-inferior to daily rhGH.

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Section: Discussionmentioning

confidence: 99%

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

Luo

Hou

et al. 2017

European Journal of Endocrinology

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“…In principle, a sub-library of m macrocycles and sub-library of n squaraine scaffolds can be mixed in parallel combinatorial fashion to create a library of m x n fluorescent probes, each with incremental structural changes such as ligand copy number, linker distance, linker flexibility, and degree of PEGylation to control biodistribution. 30, 31 The macrocycle threading process that is the basis of the pre-assembly method is shown in Figure 2 and we call it Synthavidin (Synthetic Avidin) technology. 32 The macrocycle is a water-soluble tetralactam with anthracene sidewalls, and previous studies have shown that it can be threaded by a PEGylated squaraine dye to give a highly stable complex with nanomolar dissociation constant.…”

Section: Introductionmentioning

confidence: 99%

Pre-Assembly of Near-Infrared Fluorescent Multivalent Molecular Probes for Biological Imaging

et al. 2016

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A programmable pre-assembly method is described and shown to produce near-infrared fluorescent molecular probes with tunable multivalent binding properties. The modular assembly process threads one or two copies of a tetralactam macrocycle onto a fluorescent PEGylated squaraine scaffold containing a complementary number of docking stations. Appended to the macrocycle periphery are multiple copies of a ligand that is known to target a biomarker. The structure and high purity of each threaded complex was determined by independent spectrometric methods and also by gel electrophoresis. Especially helpful were diagnostic red-shift and energy transfer features in the absorption and fluorescence spectra. The threaded complexes were found to be effective multivalent molecular probes for fluorescence microscopy and in vivo fluorescence imaging of living subjects. Two multivalent probes were prepared and tested for targeting of bone in mice. A pre-assembled probe with twelve bone-targeting iminodiacetate ligands produced more bone accumulation than an analogous pre-assembled probe with six iminodiacetate ligands. Notably, there was no loss in probe fluorescence at the bone target site after 24 hours in the living animal, indicating that the pre-assembled fluorescent probe maintained very high mechanical and chemical stability on the skeletal surface. The study shows how this versatile pre-assembly method can be used in a parallel combinatorial manner to produce libraries of near-infrared fluorescent multivalent molecular probes for different types of imaging and diagnostic applications, with incremental structural changes in the number of targeting groups, linker lengths, linker flexibility, and degree of PEGylation.

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“…Since 2013, 15 GPCR-related drugs were approved as new chemical entities (NCEs) in 31 months, with exclusions as specified in Table 2. Among these NCEs, naloxegol 12 is a derivative of a known opioid receptor (OR) antagonist that is covalently linked to a short polyethylene glycol (PEG) chain to prevent its intestinal absorption; thus, it selectively blocks opiate receptors in the gut to prevent side effects of systemic opiates [5]. Several of these new drugs treat sleep conditions: suvorexant 10 blocks two subtypes of the orexin receptor, which is a first drug in that category [6].…”

Section: Introductionmentioning

confidence: 99%

New paradigms in GPCR drug discovery

Jacobson

2015

Biochemical Pharmacology

153

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G protein-coupled receptors (GPCRs) remain a major domain of pharmaceutical discovery. The discovery of GPCR lead compounds and their optimization are now structure-based, thanks to advances in X-ray crystallography, molecular modeling, protein engineering and biophysical techniques. In silico screening provides useful hit molecules. New pharmacological approaches to tuning the pleotropic action of GPCRs include: allosteric modulators, biased ligands, GPCR heterodimer-targeted compounds, manipulation of polypharmacology, receptor antibodies and tailoring of drug molecules to fit GPCR pharmacogenomics. Measurements of kinetics and drug efficacy are factors influencing clinical success. With the exception of inhibitors of GPCR kinases, targeting of intracellular GPCR signaling or receptor cycling for therapeutic purposes remains a futuristic concept. New assay approaches are more efficient and multidimensional: cell-based, label-free, fluorescence-based assays, and biosensors. Tailoring GPCR drugs to a patient’s genetic background is now being considered. Chemoinformatic tools can predict ADME-tox properties. New imaging technology visualizes drug action in vivo. Thus, there is reason to be optimistic that new technology for GPCR ligand discovery will help improve the current narrowing of the pharmaceutical pipeline.

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Effects of pharmaceutical PEGylation on drug metabolism and its clinical concerns

Cited by 89 publications

References 71 publications

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

Pre-Assembly of Near-Infrared Fluorescent Multivalent Molecular Probes for Biological Imaging

New paradigms in GPCR drug discovery

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