PEGylation extends circulation half-life while preserving in vitro and in vivo activity of tissue inhibitor of metalloproteinases-1 (TIMP-1).
PEGylation extends circulation half-life while preserving in vitro and in vivo activity of tissue inhibitor of metalloproteinases-1 (TIMP-1).
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DOI：
10.1371/journal.pone.0050028
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Radisky ES
中科院分区：
文献类型：
--
作者：
Batra J;Robinson J;Mehner C;Hockla A;Miller E;Radisky DC;Radisky ES
基质金属蛋白酶（MMPs）的过度蛋白水解活性有助于关节炎、心血管疾病和癌症进展的发展，暗示这些酶是治疗靶点。虽然已经开发了许多MMPs的小分子抑制剂，但临床用途受到限制，部分原因是毒性和脱靶效应。内源性金属蛋白酶组织抑制剂（TIMPs）作为重组生物药物的开发代表了另一种治疗方法;然而，重组TIMPs的短血浆半衰期限制了其在这一竞技场中的潜力。为了克服这一局限性，我们通过聚乙二醇化赖氨酸残基修饰重组人TIMP-1（rhTIMP-1）。我们分析了通过连接20 kDa mPEG链（PEG 20 K-TIMP-1）修饰的单聚乙二醇化和二聚乙二醇化rhTIMP-1物质的混合物，如SELDI-TOF质谱法所证实。该制剂保留了对MMP-3催化结构域的完全抑制活性和对全长MMP-9的部分抑制活性。药物动力学研究表明，PEG修饰后rhTIMP-1在小鼠体内的血浆半衰期由1.1 h延长至28 h。在生物测定中，PEG 20 K-TIMP-1抑制MMP依赖性癌细胞侵袭和肿瘤细胞相关明胶酶活性。总之，这些结果表明，聚乙二醇化TIMP-1表现出作为抗癌重组蛋白治疗剂的开发潜力，并且另外可以提供在治疗其他疾病中的临床应用的潜力。
Excess proteolytic activity of matrix metalloproteinases (MMPs) contributes to the development of arthritis, cardiovascular diseases and cancer progression, implicating these enzymes as therapeutic targets. While many small molecule inhibitors of MMPs have been developed, clinical uses have been limited, in part by toxicity and off-target effects. Development of the endogenous tissue inhibitors of metalloproteinases (TIMPs) as recombinant biopharmaceuticals represents an alternative therapeutic approach; however, the short plasma half-life of recombinant TIMPs has restricted their potential in this arena. To overcome this limitation, we have modified recombinant human TIMP-1 (rhTIMP-1) by PEGylation on lysine residues. We analyzed a mixture of mono- and di-PEGylated rhTIMP-1 species modified by attachment of 20 kDa mPEG chains (PEG20K-TIMP-1), as confirmed by SELDI-TOF mass spectrometry. This preparation retained complete inhibitory activity toward the MMP-3 catalytic domain and partial inhibitory activity toward full length MMP-9. Pharmacokinetic evaluation showed that PEGylation extended the plasma half-life of rhTIMP-1 in mice from 1.1 h to 28 h. In biological assays, PEG20K-TIMP-1 inhibited both MMP-dependent cancer cell invasion and tumor cell associated gelatinase activity. Overall these results suggest that PEGylated TIMP-1 exhibits improved potential for development as an anti-cancer recombinant protein therapeutic, and additionally may offer potential for clinical applications in the treatment of other diseases.
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影响因子：
8.8
作者：
Ito, A;Nakajima, S;Sasaguri, Y;Nagase, H;Mori, Y
通讯作者：
Mori, Y
DOI：
10.1016/s0378-4347(00)00612-5
发表时间：
2001-04-15
期刊：
JOURNAL OF CHROMATOGRAPHY B
影响因子：
--
作者：
Bateman, KP;Castonguay, G;Chan, CC
通讯作者：
Chan, CC
影响因子：
3.6
作者：
Brand, Karsten
通讯作者：
Brand, Karsten
影响因子：
10.3
作者：
ALVAREZ, OA;CARMICHAEL, DF;DECLERCK, YA
通讯作者：
DECLERCK, YA
影响因子：
64.8
作者：
GomisRuth, FX;Maskos, K;Bode, W
通讯作者：
Bode, W