Effect of pegylation on pharmaceuticals

Harris, J. Milton; Chess, Robert B.

doi:10.1038/nrd1033

Cited by 2,981 publications

(2,346 citation statements)

References 56 publications

Supporting

Mentioning

2,289

Contrasting

Unclassified

Order By: Relevance

“…33,34 In other instances, antibodies against PEGylated antigens have been detected. 35 Both of these scenarios could have deleterious effects in patient populations in the context of inducing tolerance to natural adenoviral infection or prevention of successful readministration of the PEGylated virus over time, making additional studies to characterize the immunological properties of PEGylated HD-Ad vectors warranted.…”

Section: Discussionmentioning

confidence: 99%

PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile

et al. 2005

View full text Add to dashboard Cite

Transgene expression from helper-dependent adenoviral (HD-Ad) vectors is effective and long lasting, but not permanent. Their use is also limited by the host response against capsid proteins that precludes successful gene expression upon readministration. In this report, we test the hypothesis that PEGylation of HD-Ad reduces its toxicity and promotes transgene expression upon readministration. PEGylation did not compromise transduction efficiency in vitro and in vivo and reduced peak serum IL-6 levels two-fold. IL-12 and TNF-a levels were reduced three-and sevenfold, respectively. Thrombocytopenia was not detected in mice treated with the PEGylated vector. Serum transaminases were not significantly elevated in mice treated with either vector. Mice immunized with 1 Â 10 11 particles of unmodified HD-Ad expressing human alpha-1 antitrypsin (hA1AT) were rechallenged 28 days later with 8 Â 10 10 particles of unmodified or PEG-conjugated vector expressing beta-galactosidase. Trace levels of beta-galactosidase (52.23719.2 pg/mg protein) were detected in liver homogenates of mice that received two doses of unmodified HDAd. Mice rechallenged with PEGylated HD-Ad produced significant levels of beta-galactosidase (5.170.4 Â 10 5 pg/mg protein, P ¼ 0.0001). This suggests that PEGylation of HD-Ad vectors may be appropriate for their safe and efficient use in the clinic. Gene Therapy (2005) 12, 579-587.

show abstract

Section: Discussionmentioning

confidence: 99%

PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile

et al. 2005

View full text Add to dashboard Cite

show abstract

“…This is because PEG is conjugated at many different nucleophilic amine residues in the protein [4][5][6] . The relative proportion of each of these positional PEG-protein isomers depends on (i) terminal chemical functionality, (ii) molecular weight (MWt), (iii) morphology of PEG and (iv) the specific reaction conditions used for conjugation 7 .…”

Section: Existing Pegylation Technologiesmentioning

confidence: 99%

“…For example, the combination of PEGylated a-2 interferon and ribavirin eradicates hepatitis C virus in more than 50% of treated patients. This has led to several PEG-protein conjugates being approved for therapeutic use by the regulatory authorities 4 .…”

Section: Introductionmentioning

confidence: 99%

PEGylation of native disulfide bonds in proteins

et al. 2006

View full text Add to dashboard Cite

PEGylation has turned proteins into important new biopharmaceuticals. The fundamental problems with the existing approaches to PEGylation are inefficient conjugation and the formation of heterogeneous mixtures. This is because poly(ethylene glycol) (PEG) is usually conjugated to nucleophilic amine residues. Our PEGylation protocol solves these problems by exploiting the chemical reactivity of both of the sulfur atoms in the disulfide bond of many biologically relevant proteins. An accessible disulfide bond is mildly reduced to liberate the two cysteine sulfur atoms without disturbing the protein's tertiary structure. Site-specific PEGylation is achieved with a bis-thiol alkylating PEG reagent that sequentially undergoes conjugation to form a three-carbon bridge. The two sulfur atoms are re-linked with PEG selectively conjugated to the bridge. PEGylation of a protein can be completed in 24 h and purification of the PEG-protein conjugate in another 3 h. We have successfully applied this approach to PEGylation of cytokines, enzymes, antibody fragments and peptides, without destroying their tertiary structure or abolishing their biological activity

show abstract

“…An example of this is polyethylene glycol (PEG) (for review, see ref. 6), which, when conjugated to a drug, can increase its solubility and circulating half-life as well as reducing its immunogenicity. Examples of such drugs currently available are PEGylated forms of interferon-␣ and doxorubicin for the treatment of hepatitis C and breast cancer, respectively (5).…”

Section: Nonspecific Targeting Strategiesmentioning

confidence: 99%

“…Examples of such drugs currently available are PEGylated forms of interferon-␣ and doxorubicin for the treatment of hepatitis C and breast cancer, respectively (5). In addition, PEGylated soluble tumor necrosis factor (TNF) receptor and an anti-TNF antibody have both shown encouraging results in the treatment of RA (6).…”

Section: Nonspecific Targeting Strategiesmentioning

confidence: 99%