Biochemical and biopharmaceutical properties of PEGylated uricase

Freitas, Débora da Silva; Spencer, Patrick Jack; Vassão, Ruth Camargo; Abrahão-Neto, José

doi:10.1016/j.ijpharm.2009.11.034

Cited by 59 publications

(20 citation statements)

References 37 publications

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“…In result, PEGylation of UC-r with methoxypolyethilenoglycol- p -nitrophenyl-carbonate and methoxy PEG-4, 6-dichloro- s -triazine retained the enzyme activity (87 and 75%, respectively) and significantly reduced the immunogenicity of native UC-r in Balb/c mice. Also, PEGylation did not induce any detectable antibody response [18]. …”

Section: Chemical Modificationsmentioning

confidence: 99%

Recent Developments in Protein and Peptide Parenteral Delivery Approaches

2014

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Discovery of insulin in the early 1900s initiated the research and development to improve the means of therapeutic protein delivery in patients. In the past decade, great emphasis has been placed on bringing protein and peptide therapeutics to market. Despite tremendous efforts, parenteral delivery still remains the major mode of administration for protein and peptide therapeutics. Other routes such as oral, nasal, pulmonary and buccal are considered more opportunistic rather than routine application. Improving biological half-life, stability and therapeutic efficacy is central to protein and peptide delivery. Several approaches have been tried in the past to improve protein and peptide in vitro/in vivo stability and performance. Approaches may be broadly categorized as chemical modification and colloidal delivery systems. In this review we have discussed various chemical approaches such as PEGylation, hyperglycosylation, mannosylation, and colloidal carriers including microparticles, nanoparticles, liposomes, carbon nanotubes and micelles for improving protein and peptide delivery. Recent developments on in situ thermosensitive gel-based protein and peptide delivery have also been described. This review summarizes recent developments on some currently existing approaches to improve stability, bioavailability and bioactivity of peptide and protein therapeutics following parenteral administration.

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Section: Chemical Modificationsmentioning

confidence: 99%

Recent Developments in Protein and Peptide Parenteral Delivery Approaches

2014

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“…It suffers rapid clearance upon injection narrowing its applicability to short-term treatment of tumor lysis syndrome [37,38]. Although PEGylation of Uox through random coupling to lysine residues achieved a significant extension of serum half-life [39–42], non-specific and excessive modification raises concerns of heterogeneity, immune responses against PEGs [43], and reduced efficacy [44,45]. Therefore, in order to circumvent these concerns, developing alternative strategies to prolong in vivo activity of Uox is required.…”

Section: Introductionmentioning

confidence: 99%

Site-specific albumination of a therapeutic protein with multi-subunit to prolong activity in vivo

Lim

Hahn

Kwon

2015

Journal of Controlled Release

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Albumin fusion/conjugation (albumination) has been an effective method to prolong in vivo half-life of therapeutic proteins. However, its broader application to proteins with complex folding pathway or multi-subunit is restricted by incorrect folding, poor expression, heterogeneity, and loss of native activity of the proteins linked to albumin. We hypothesized that the site-specific conjugation of albumin to a permissive site of a target protein will expand the utilities of albumin as a therapeutic activity extender to proteins with a complex structure. We show here the genetic incorporation of a non-natural amino acid (NNAA) followed by chemoselective albumin conjugation to prolong therapeutic activity in vivo. Urate oxidase (Uox), a therapeutic enzyme for treatment of hyperuricemia, is a homotetramer with multiple surface lysines, limiting conventional approaches for albumination. Incorporation of p-azido-l-phenylalanine into two predetermined positions of Uox allowed site-specific linkage of dibenzocyclooctyne-derivatized human serum albumin (HSA) through strain-promoted azide-alkyne cycloaddition (SPAAC). The bio-orthogonality of SPAAC resulted in the production of a chemically well-defined conjugate, Uox-HSA, with a retained enzymatic activity. Uox-HSA had a half-life of 8.8 h in mice, while wild-type Uox had a half-life of 1.3 h. The AUC increased 5.5-fold (1657 vs. 303 mU/mL × h). These results clearly demonstrated that site-specific albumination led to the prolonged enzymatic activity of Uox in vivo. Site-specific albumination enabled by NNAA incorporation and orthogonal chemistry demonstrates its promise for the development of long-acting protein therapeutics with high potency and safety.

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“…Freitas da Silva et al [29] have obtained a recombinant uricase from Candida sp. pegylated with mPEG-pNP or mPEG-CN.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity of Polyethylene Glycol (PEG)

Garay¹,

Labaune²

2011

TOPROCJ

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Covalent attachment of polyethylene glycol (PEG) to active proteins (PEGylation technology) successfully generated several FDA-approved compounds, including four blockbusters, which are considered non immunogenic. However, PEG antibodies and intolerance to the infusion were reported in some patients with gout treated with pegloticase, a PEG-uricase recently approved by the FDA (Food and Drug Administration, USA). Therefore, we reviewed the literature concerning immunogenicity of PEG alone or covalently attached to proteins. We consulted databases (Scirus, Pub Med, Cochrane Library, and Science Direct) and the references of selected articles and main journals publishing articles on the subject. Animal studies clearly showed that PEG-uricases and some other PEGylated proteins might elicit antibody formation against PEG. This anti-PEG response can accelerate the clearance of PEGylated proteins. Of major importance is the recent finding of a 22%-25% occurrence of PEG antibodies in healthy blood donors. PEG antibodies may limit therapeutic efficacy and/or reduce tolerance of PEG-asparaginase (PEG-ASNase) in patients with acute lymphoblastic leukemia and of pegloticase in patients with chronic gout, but apparently do not impair hyposensitization of allergic patients with mPEG-modified ragweed extract and honey bee venom or the response to PEGinterferon in patients with hepatitis C. In conclusion, pre-existing or newly developed PEG antibodies may limit therapeutic efficacy and/or reduce tolerance of PEGylated proteins in some patients. The immunogenicity of PEGylated therapeutic agents in clinical use or development deserves to be re-examined by investigating PEG antibodies.

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Biochemical and biopharmaceutical properties of PEGylated uricase

Cited by 59 publications

References 37 publications

Recent Developments in Protein and Peptide Parenteral Delivery Approaches

Recent Developments in Protein and Peptide Parenteral Delivery Approaches

Site-specific albumination of a therapeutic protein with multi-subunit to prolong activity in vivo

Immunogenicity of Polyethylene Glycol (PEG)

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