Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase.
Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase.
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DOI：
10.1186/ar1861
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发表时间：
2006
影响因子：
4.9
通讯作者：
Hershfield MS
中科院分区：
文献类型：
--
作者：
Ganson NJ;Kelly SJ;Scarlett E;Sundy JS;Hershfield MS
聚乙二醇化的重组哺乳动物尿酸氧化酶(聚乙二醇尿酸酶)正在被开发用于治疗不能控制高尿酸血症或对现有治疗方法无效的慢性痛风患者。在一项开放标签的I期试验中，13名受试者(11名痛风患者)单次皮下注射聚乙二醇尿酸酶(4-24 mg)，其血尿酸浓度(PUAC)为11.3±2.1 mg/dl(平均值±SD)。注射聚乙二醇尿酸酶后第7天，PUAc平均下降7.9 mg/dl，11例恢复正常，平均PUAc降至2.8±2.2 mg/dl。在8、12和24 mg剂量下，注射后第21天的平均PUAC仍不超过6 mg/dl。在8名受试者中，在注射后21天(半衰期10.5天至19.9天)仍可检测到血浆尿酸酶活性。在其他5名受试者中，在注射后10天后无法检测到血浆尿酸酶活性；这与出现相对较低滴度的抗聚乙二醇尿酸酶IgM和IgG抗体有关。出乎意料的是，这些抗体针对的是聚乙二醇本身，而不是尿酸酶蛋白。3例聚乙二醇单抗阳性受试者在注射后第8~9天出现注射部位反应。6名受试者的痛风发作是唯一的其他显著不良反应，而聚乙二醇尿酸酶在其他方面耐受性良好。显著高尿酸血症患者延长的循环寿命和使血浆尿酸正常化的能力表明，在慢性或痛风患者中，聚乙二醇尿酸酶可能有效地消耗扩大的组织尿酸储存。抗聚乙二醇单抗的发展可能会限制某些患者的疗效，这与聚乙二醇非免疫原性的普遍假设相反。聚乙二醇酯的免疫原性值得进一步研究，因为它对其他聚乙二醇化治疗药物的临床应用具有潜在的意义。
PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial, single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout), whose plasma uric acid concentration (pUAc) was 11.3 ± 2.1 mg/dl (mean ± SD). By day seven after injection of PEG-uricase, pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 ± 2.2 mg/dl. At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects, plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for other PEGylated therapeutic agents in clinical use.
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影响因子：
30.5
作者：
Ackerman, AL;Kyritsis, C;Cresswell, P
通讯作者：
Cresswell, P
DOI：
10.1159/000233309
发表时间：
1983-01-01
期刊：
INTERNATIONAL ARCHIVES OF ALLERGY AND APPLIED IMMUNOLOGY
影响因子：
--
作者：
RICHTER, AW;AKERBLOM, E
通讯作者：
AKERBLOM, E
影响因子：
158.5
作者：
HERSHFIELD, MS;BUCKLEY, RH;ABUCHOWSKI, A
通讯作者：
ABUCHOWSKI, A
DOI：
10.1073/pnas.88.16.7185
发表时间：
1991-08-01
影响因子：
11.1
作者：
HERSHFIELD, MS;CHAFFEE, S;SHORT, SA
通讯作者：
SHORT, SA
影响因子：
2.9
作者：
GREENBERG, ML;HERSHFIELD, MS
通讯作者：
HERSHFIELD, MS