Najjari Abbas, Shahbazmohammadi Hamid, Omidinia Eskandar, Movafagh Abolfazl M
Enzyme Technology Laboratory, Department of Biochemistry, Genetic and Metabolism Research Group,Pasteur Institute of Iran, Tehran, Iran.
Department Medical Genetic, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Asian Pac J Cancer Prev. 2021 Feb 1;22(2):627-632. doi: 10.31557/APJCP.2021.22.2.627.
Management of hyperuricemia is crucial to controlling tumor lysis syndrome (TLS) during cancer therapy. Urate oxidase (UOX) that catalyzes the enzymatic oxidation of uric acid into allantoin, is effective in lowering plasma uric acid levels and controlling hyperuricemia. Recently, we developed a new recombinant conjugate variant of UOX therapeutic drug using PASylation technology. This study was designed to evaluate the stability, plasma half-life and immunogencity of PASylated UOX.
A recombinant variant of PASylated UOX from the Aspergillus flavus was manufactured using bioinformatics and experimental techniques. Ex vivo evaluation of stability of PASylated UOX was done in 50% human serum. For half-life test, recombinant PASylated UOX and rasburicase were administered at 1.5 mg/kg to 10 rats in two different groups and samples were collected after injection Production of antibodies against PASylated drug was also assayed.
Residual activity of PASylated UOX in 50% human serum was higher than rasburicase and native UOX. Stability of PASylated UOX at 25°C and 37°C was also higher than rasburicase and native UOX. The PASylated half-life was ~32.1 hours, whereas half-life for rasburicase and native UOX was ~25.1 and ~22.8 hours, respectively. In immunogenicity examination, there is 33% and 36% decrease in the absorbance of native UOX and rasburicase, respectively when compared with that of PASylated UOX.
Our data confirmed the efficacy and stability of PASylated UOX in comparison to the rasburicase. In summary, the results indicated that PASylated UOX drug is effective at lowering plasma uric acid levels with prolonged plasma half-life and decreased cost.
.
高尿酸血症的管理对于癌症治疗期间控制肿瘤溶解综合征（TLS）至关重要。尿酸氧化酶（UOX）可催化尿酸酶促氧化生成尿囊素，对降低血浆尿酸水平和控制高尿酸血症有效。最近，我们利用聚唾液酸化技术开发了一种新型的UOX治疗药物重组缀合物变体。本研究旨在评估聚唾液酸化UOX的稳定性、血浆半衰期和免疫原性。
利用生物信息学和实验技术制备了来自黄曲霉的聚唾液酸化UOX重组变体。在50%人血清中对聚唾液酸化UOX进行体外稳定性评估。对于半衰期测试，将重组聚唾液酸化UOX和拉布立酶以1.5mg/kg的剂量分别给予两组共10只大鼠，并在注射后采集样本。同时还检测了针对聚唾液酸化药物的抗体产生情况。
聚唾液酸化UOX在50%人血清中的残留活性高于拉布立酶和天然UOX。聚唾液酸化UOX在25℃和37℃的稳定性也高于拉布立酶和天然UOX。聚唾液酸化UOX的半衰期约为32.1小时，而拉布立酶和天然UOX的半衰期分别约为25.1小时和22.8小时。在免疫原性检测中，与聚唾液酸化UOX相比，天然UOX和拉布立酶的吸光度分别降低了33%和36%。
我们的数据证实了聚唾液酸化UOX与拉布立酶相比的有效性和稳定性。总之，结果表明聚唾液酸化UOX药物在降低血浆尿酸水平方面有效，且血浆半衰期延长，成本降低。
