Site-specific targeting of antibody activity in vivo mediated by disease-associated proteases.
Site-specific targeting of antibody activity in vivo mediated by disease-associated proteases.
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DOI：
10.1016/j.jconrel.2012.05.035
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发表时间：
2012-08-10
期刊：
影响因子：
--
通讯作者：
Daugherty PS
中科院分区：
文献类型：
--
作者：
Erster O;Thomas JM;Hamzah J;Jabaiah AM;Getz JA;Schoep TD;Hall SS;Ruoslahti E;Daugherty PS
作为体内选择性靶向抗体活性的一般策略，设计分子结构以使结合活性依赖于疾病组织中的蛋白酶。以血管细胞粘附分子1（VCAM-1）为靶点，通过基质金属蛋白酶（MMP）敏感性连接子将结合位点掩蔽肽连接到抗体上，构建了蛋白酶激活抗体（前抗体）。MMP-1在体外激活前抗体，使结合亲和力增加200倍，并恢复了Apoe（-/-）小鼠离体组织切片中的抗VCAM-1结合。前抗体可被ApoE（−/−）主动脉组织提取物中的天然蛋白酶有效激活，但不能被正常小鼠激活，并在体内主动脉斑块中积累，与未修饰抗体相比，选择性增强。前抗体在主动脉斑块中的积累是MMP依赖性的，并且被广谱MMP抑制剂显著抑制。这些结果表明，疾病相关蛋白酶的活性可用于体内位点特异性靶向抗体活性。
As a general strategy to selectively target antibody activity in vivo, a molecular architecture was designed to render binding activity dependent upon proteases in disease tissues. A protease-activated antibody (pro-antibody) targeting vascular cell adhesion molecule 1 (VCAM-1), a marker of atherosclerotic plaques, was constructed by tethering a binding site-masking peptide to the antibody via a matrix metalloprotease (MMP) susceptible linker. Pro-antibody activation in vitro by MMP-1 yielded a 200-fold increase in binding affinity and restored anti-VCAM-1 binding in tissue sections from ApoE(−/−) mice ex vivo. The pro-antibody was efficiently activated by native proteases in aorta tissue extracts from ApoE(−/−), but not from normal mice, and accumulated in aortic plaques in vivo with enhanced selectivity when compared to the unmodified antibody. Pro-antibody accumulation in aortic plaques was MMP-dependant, and significantly inhibited by a broad-spectrum MMP inhibitor. These results demonstrate that the activity of disease-associated proteases can be exploited to site-specifically target antibody activity in vivo.
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