Studies on antigenicity of the polyethylene glycol (PEG)-modified uricase

Tsuji, Jun; Hirose, Katsumi; Kasahara, Etsuko; Naitoh, Maki; Yamamoto, Itary

doi:10.1016/0192-0561(85)90158-4

Cited by 39 publications

(3 citation statements)

References 11 publications

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“…PAcM, PEG, and PEG2 were found to reduce remarkably the uricase antigenicity. The reduction of uricase antigenicity obtained with both poly(ethylene glycol) derivatives confirms the known efficiency of these polymers in enhancing the antigenic character of this protein (29). PAcM also was found to reduce the protein antigenicity although at a lower extent with respect to the poly(ethylene glycol)s.…”

Section: Resultssupporting

confidence: 72%

Immunological Properties of Uricase Conjugated to Neutral Soluble Polymers

2001

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For a comparative study of immunological properties of protein-polymer conjugates, uricase was modified with (a) poly(N-vinylpyrrolidone) 6000 Da, (b) poly(N-acriloylmorpholine) 6000 Da, (c) branched monomethoxypoly(ethylene glycol) 10000 Da, and (d) linear monomethoxypoly(ethylene glycol) 5000 Da. Spectroscopic studies performed by UV, fluorescence, and circular dichroism did not show any relevant difference in protein conformation among the native and the conjugates. Immunological studies showed that both uricase antigenicity and immunogenicity were altered by polymer conjugation to an extent that depended upon the polymer composition; in particular, monomethoxypoly(ethylene glycol) 10000 Da remarkably reduced the protein antigenicity, while unexpectedly, the poly(N-vinylpyrrolidone) derivative presented higher antigenicity than the native protein. In Balb/c mice, the native protein elicited a rapid and intense immunoresponse whereas all the conjugates induced a lower production of anti-native uricase antibodies. The rank order of immunogenicity was native uricase > uricase-poly(N-vinylpyrrolidone) > or = uricase-poly(N-acriloylmorpholine) > uricase-monomethoxypoly(ethylene glycol) 5000 Da > uricase-monomethoxypoly(ethylene glycol) 10000 Da. The four conjugates also induced anti polymer immunoresponse. Anti poly(N-vinylpyrrolidone) and anti poly(N-acriloylmorpholine) antibodies were generated from the first immunization while low levels of anti polymer antibodies were found with both poly(ethylene glycol) conjugates only after the second immunization.

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Section: Resultssupporting

confidence: 72%

Immunological Properties of Uricase Conjugated to Neutral Soluble Polymers

2001

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“…So PEGylation is a good choice, which is used to widen the therapeutic and biotechnological uses of proteins and to enable a more convenient dosing regimen because of its high solubility, low toxicity, and low immunogenicity. [46][47][48][49][50] In the initial phase 1 trial, PEG-UOX was administered by subcutaneous injection to human subjects with refractory gout, however, in several subjects the circulating life and efficacy of PEG-UOX was foreshortened by the induction of anti-PEG, 51) which was specific against the PEG residue rather than against the uricase itself. 52) In 2010, the U.S. Food and Drug Administration (FDA) approved pegloticase (trade name Krystexxa), a PEGylated recombinant porcine-like uricase, for the treatment of chronic gout in adult patients refractory to conventional therapy.…”

Section: The Likely Impact Of Immunological Responsementioning

confidence: 99%

“…[46][47][48][49][50] In the initial phase 1 trial, PEG-UOX was administered by subcutaneous injection to human subjects with refractory gout, however, in several subjects the circulating life and efficacy of PEG-UOX was foreshortened by the induction of anti-PEG, 51) which was specific against the PEG residue rather than against the uricase itself. 52) In 2010, the U.S. Food and Drug Administration (FDA) approved pegloticase (trade name Krystexxa), a PEGylated recombinant porcine-like uricase, for the treatment of chronic gout in adult patients refractory to conventional therapy. In the current situation, pegloticase is probably the most powerful drug to treat the disease, but its use is hampered by occurrence of anti-PEG, leading to increased drug clearance and may bring about risk of subsequent infusion reaction.…”

Section: The Likely Impact Of Immunological Responsementioning

confidence: 99%

Discussion about Several Potential Drawbacks of PEGylated Therapeutic Proteins

Zhang

Murong

Wan

2014

Biological & Pharmaceutical Bulletin

116

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PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug, while it also causes some disadvantages of which cannot be neglected. The available data manifests that polyethylene glycol (PEG) itself shows potential risk, such as immunogenicity of the PEG and PEG-containing vacuoles in cells observed with PEGylated biologicals. Decreased activity and heterogeneity are also the negative aspects of PEGylation. The unfavorable impacts which are brought by the PEGylation are described here with examples of modified therapeutic proteins on the market and used in the clinical trials.

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Biodegradable Polymers for Protein and Peptide Therapeutics: Next Generation Delivery Systems

Dyawanapelly

Jain

et al. 2017

Handbook of Composites From Renewable Materials

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Studies on antigenicity of the polyethylene glycol (PEG)-modified uricase

Cited by 39 publications

References 11 publications

Immunological Properties of Uricase Conjugated to Neutral Soluble Polymers

Immunological Properties of Uricase Conjugated to Neutral Soluble Polymers

Discussion about Several Potential Drawbacks of PEGylated Therapeutic Proteins

Biodegradable Polymers for Protein and Peptide Therapeutics: Next Generation Delivery Systems

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