Dataset Information

In vivo study of newly developed albumin-conjugated urate oxidase for gout treatment.

ABSTRACT:

Background

Exogenously providing engineered Uox with enhanced half-life is one of the important urate-lowering treatments for gout. The potential of PAT101, a recombinant human albumin (rHA)-conjugated variant, was evaluated and compared as a novel gout treatment through various in vivo studies with PAT101 and competing drugs.

Methods

PAT101 was produced by site-specific conjugation of rHA and Aspergillus flavus Uox (AfUox-rHA) through clickable non-natural amino acid (frTet) and Inverse electron demand Diels-Alder (IEDDA) reaction. In vivo pharmacokinetics, efficacy tests and in vitro immunogenetic assay were performed after single or multiple doses of PAT101 and its competitors in BALB/c mice, transgenic (TG) mice, Sprague-Dawley (SD) rats, and non-human primate (NHP).

Results

The half-life of PAT101 in single-dose treated TG mice was more than doubled compared to pegloticase. In SD rats with 4 weeks of repeated administration of rasburicase, only 24% of Uox activity remained, whereas in PAT101, it was maintained by 86%. In the Uox KO model, the survival rate of PAT101 was comparable to that of pegloticase. In addition, human PBMC-based CD4⁺/CD8⁺ T-cell activation analysis demonstrated that PAT101 has a lower immune response compared to the original drug, rasburicase.

Conclusion

All results suggest that this rHA-conjugated AfUox, PAT101, can be provided as a reliable source of Uox for gout treatment.

SUBMITTER: Cho J

PROVIDER: S-EPMC10726570 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

In vivo study of newly developed albumin-conjugated urate oxidase for gout treatment.

Cho Jeonghaeng J Yang Byungseop B Lee Jae Hun JH Kim Hyunwoo H Kim Hyeongseok H Go Eun Byeol EB Bak Dong-Ho DH Park Su Jin SJ Kwon Inchan I Choi Jong-Il JI Lee Kyunghee K

Arthritis research & therapy 20231218 1

<h4>Background</h4>Exogenously providing engineered Uox with enhanced half-life is one of the important urate-lowering treatments for gout. The potential of PAT101, a recombinant human albumin (rHA)-conjugated variant, was evaluated and compared as a novel gout treatment through various in vivo studies with PAT101 and competing drugs.<h4>Methods</h4>PAT101 was produced by site-specific conjugation of rHA and Aspergillus flavus Uox (AfUox-rHA) through clickable non-natural amino acid (frTet) and ...[more]

PMID: 38111075

Similar Datasets

Project description:ImportanceApproximately 12 million adults in the US have a history of gout, but whether serum urate levels can help predict recurrence is unclear.ObjectiveTo assess associations of a single serum urate measurement with subsequent risk of acute gout flares and subsequent risk of hospitalizations for gout among patients in the UK with a history of gout.Design, setting, and participantsThis retrospective study included patients with a history of gout identified from the UK between 2006 and 2010 who were followed up through Primary Care Linked Data medical record linkage until 2017 and through the Hospital Episode Statistics database until 2020.ExposuresSerum urate levels at enrollment.Main outcome and measureRate of recurrent acute gout, ascertained by hospitalization, outpatient, and prescription/procedure records, and adjusted rate ratios using negative binomial regressions.ResultsAmong 3613 patients with gout (mean age, 60 years; 3104 [86%] men), 1773 gout flares occurred over a mean follow-up of 8.3 years. Of these, 1679 acute gout flares (95%) occurred in people with baseline serum urate greater than or equal to 6 mg/dL and 1731 (98%) occurred in people with baseline serum urate greater than or equal to 5 mg/dL. Rates of acute gout flares per 1000 person-years were 10.6 for participants with baseline urate levels less than 6 mg/dL, 40.1 for levels of 6.0 to 6.9 mg/dL, 82.0 for levels of 7.0 to 7.9 mg/dL, 101.3 for levels of 8.0 to 8.9 mg/dL, 125.3 for urate levels of 9.0 to 9.9 mg/dL, and 132.8 for levels greater than or equal to 10 mg/dL. Rate ratio of flares were 1.0, 3.37, 6.93, 8.67, 10.81, and 11.42, respectively, over 10 years (1.61 [1.54-1.68] per mg/dL). Rates of hospitalization per 1000 person-years during follow-up were 0.18 for those with baseline serum urate less than 6 mg/dL, 0.97 for serum urate of 6.0 to 6.9 mg/dL, 1.8 for serum urate of 7.0 to 7.9 mg/dL, 2.2 for serum urate of 8.0 to 8.9 mg/dL, 6.7 for serum urate of 9.0 to 9.9 mg/dL, and 9.7 for serum urate greater than or equal to 10 mg/dL. Rate ratios of hospitalization for gout, adjusting for age, sex, and race were 1.0, 4.70, 8.94, 10.37, 33.92, and 45.29, respectively (1.87 [1.57-2.23] per mg/dL).Conclusions and relevanceIn this retrospective study of patients with a history of gout, serum urate levels at baseline were associated with the risk of subsequent gout flares and rates of hospitalization for recurrent gout. These findings support using a baseline serum urate level to assess risk of recurrent gout over nearly 10 years of follow-up.

Dataset Information

In vivo study of newly developed albumin-conjugated urate oxidase for gout treatment.

Background

Methods

Results

Conclusion

Publications

In vivo study of newly developed albumin-conjugated urate oxidase for gout treatment.

Similar Datasets

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