GALACTOSYLATED ANTIBODIES AND ANTIBODY-ENZYME CONJUGATES IN ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY
GALACTOSYLATED ANTIBODIES AND ANTIBODY-ENZYME CONJUGATES IN ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY
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DOI：
10.1002/1097-0142(19940201)73:3
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发表时间：
1994-02-01
期刊：
影响因子：
6.2
通讯作者：
SHERWOOD, RF
中科院分区：
文献类型：
--
作者：
SHARMA, SK;BAGSHAWE, KD;SHERWOOD, RF
抗体导向酶前药疗法(ADEPT)是一个两相和三相系统，利用肿瘤相关抗原的抗体将酶传递到肿瘤部位，在肿瘤部位将相对无毒的前药转化为细胞毒剂。在这样的系统中，有必要在前药注射前让酶活性从血液中清除，以避免前药在血浆中激活而引起的毒性。为了加速血浆中酶活性的清除，人们研究了两种方法。用抗癌胚抗原单抗片段A5B7-F(ab‘)(2)与细菌酶CpG2(CPG2)偶联，在LS174T异种移植小鼠中进行了研究。在第一种方法中，使用针对CPG2的单抗(SB43)，在体外和体内灭活CPG2。SB43被半乳糖化，使其有足够的时间与血浆CPG2形成复合体，导致该复合体失活并通过肝脏中的碳水化合物特异性受体从血浆中清除。在注射放射性标记的结合物19小时后注射SB43gal19小时后，在不影响肿瘤水平的情况下降低每克血液中注射剂量的百分比。第二种方法涉及结合物的半乳糖化，使其通过肝脏中的去唾液酸糖蛋白受体迅速从血液中清除。通过单次注射与受体竞争性结合的抑制剂(8毫克/只)阻断该受体约8小时，实现了放射性标记的结合物的定位。这允许肿瘤定位，随后当抑制剂被消耗时，半乳糖基化的结合物从血液中快速清除。瘤血比在注射后24小时达到45：1，注射后72小时增加到100：1。这些加速清除机制已在ADEPT的抗肿瘤研究中得到应用。癌症1994；73：1114-20。
Antibody directed enzyme prodrug therapy (ADEPT) has been studied as a two- and three-phase system in which an antibody to a tumor-associated antigen has been used to deliver an enzyme to tumor sites where it can convert a relatively nontoxic prodrug to a cytotoxic agent. In such a system, it is necessary to allow the enzyme activity to clear from the blood before prodrug injection to avoid toxicity caused by prodrug activation in plasma. To accelerate plasma clearance of enzyme activity, two approaches have been studied. The studies have been performed with a monoclonal anticarcinoembryonic-antigen antibody fragment A5B7-F(ab')(2) conjugated to a bacterial enzyme, carboxypeptidase G2 (CPG2), in LS174T xenografted mice. In the first approach, a monoclonal antibody (SB43), directed at CPG2, was used, which inactivates CPG2 in vitro and in vivo. SB43 was galactosylated so that it had sufficient time to form a complex with plasma CPG2, resulting in the inactivation and clearance of the complex from plasma via the carbohydrate-specific receptors in the liver. Injection of SB43gal 19 hours after administration of the radiolabeled conjugate reduced the percentage of injected dose per gram in blood without affecting levels in the tumor.The second approach involved galactosylation of the conjugate so that it cleared rapidly from blood via the asialoglycoprotein receptors in the liver. Localization of the radiolabeled conjugate was achieved by blocking this receptor for about 8 hours with a single injection (8 mg/ mouse) of an inhibitor that binds competitively to the receptor. This allowed tumor localization of the conjugate followed by a rapid clearance of the galactosylated conjugate from blood as the inhibitor was consumed. A tumor-to-blood ratio of 45:1 was obtained at 24 hours, which increased to 100:1 at 72 hours after the conjugate injection. These accelerated clearance mechanisms have been applied in antitumor studies in ADEPT. Cancer 1994; 73:1114-20.-