ANTIBODY-ENHANCED THROMBOLYSIS - TARGETING OF TISSUE PLASMINOGEN-ACTIVATOR INVIVO
ANTIBODY-ENHANCED THROMBOLYSIS - TARGETING OF TISSUE PLASMINOGEN-ACTIVATOR INVIVO
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DOI：
10.1073/pnas.84.21.7659
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发表时间：
1987-11-01
影响因子：
11.1
通讯作者：
HABER, E
中科院分区：
文献类型：
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作者：
RUNGE, MS;BODE, C;HABER, E
组织纤溶酶原激活剂（tPA）的改性由单向交联剂N-琥珀酰亚胺3-（2-吡啶二硫代）丙酸酯和偶联亚氨基硫烷改性的抗纤维蛋白抗体59 D8通过在中性pH值下形成二硫键。通过两个亲和层析步骤纯化产生的tPA-抗纤维蛋白抗体结合物（tPA-59 D8）具有tPA和抗纤维蛋白抗体的活动。在定量兔血栓溶解模型中，将纯化的缀合物的活性与单独的tPA和tPA与地高辛特异性单克隆抗体之间的缀合物的活性进行比较。校正自发溶解后（10.9 ±. 2.5%），tPA-59 D8显示比单独的tPA更有效2.8-9.6倍。未结合的tPA和tPA-地高辛是等效的。在相等的血栓溶解浓度下，tPA-59 D8比单独的tPA降解更少的纤维蛋白原和消耗更少的α 2-抗纤溶酶。这表明，tPA可以通过与抗纤维蛋白单克隆抗体偶联而有效地导向血栓部位，从而导致更有效和更选择性的血栓溶解。
Tissue plasminogen activator (tPA) was modified by the unidirectional crosslinking reagent N-succinimidyl 3-(2-pyridyldithio)propionate and coupled to iminothiolane-modified anti-fibrin antibody 59D8 by the formation of disulfide bonds at neutral pH. Purification by two affinity-chromatography steps yielded tPA-antifibrin antibody conjugate (tPA-59D8) possessing both tPA and anti-fibrin antibody activities. In a quantitative rabbit thrombolysis model, the activity of the purified conjugate was compared with that of tPA alone and that of a conjugate between tPA and a digoxin-specific monoclonal antibody. After correction for spontaneous lysis (10.9 .+-. 2.5%), tPA-59D8 was shown to be 2.8-9.6 times more potent than tPA alone. Unconjugated tPA and tPA-digoxin were equipotent. At equivalent thrombolytic concentrations, tPA-59D8 degraded less fibrinogen and consumed less .alpha.2-anti-plasmin than did tPA alone. This suggests that tPA can be efficiently directed to the site of a thrombus by conjugation to an anti-fibrin monoclonal antibody, resulting in both more potent and more selective thrombolysis.