Preparation of four daunomycin‐monoclonal antibody 79IT/36 conjugates with anti‐tumour activity
Preparation of four daunomycin‐monoclonal antibody 79IT/36 conjugates with anti‐tumour activity
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四种具有抗肿瘤活性的道诺霉素单克隆抗体79IT/36缀合物的制备
DOI：
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发表时间：
1984
影响因子：
6.4
通讯作者：
R. W. Baldwin
中科院分区：
文献类型：
--
作者：
J. Gallego;M. Price;R. W. Baldwin
作为一种开发更特异的抗肿瘤治疗药物的方法，道诺霉素已与人类肿瘤定位的小鼠单克隆抗体79IT/36共价连接。研究了药物与抗体偶联的四种方法。通过与丁二酸酐或顺式乌头酸酐反应修饰道霉素的糖基，并将其与抗体结合，利用碳二亚胺试剂产生稳定的肽键。另外，14 -溴道诺霉素直接与含有游离巯基的抗体或通过异双功能试剂SPDP [N -琥珀酰酰- 3 （2 - py -吡啶二硫代）丙酸]引入的抗体相连，从而产生硫醚连锁。虽然琥珀酸酐衍生物的细胞毒性最小，但每一种药物-抗体比为3:1的偶联物都保留了一定比例的药物活性。另外三种偶联物特异性结合到表达79IT/36抗体定义抗原的肿瘤细胞上。在短期实验中，肿瘤细胞短暂暴露于偶联物，然后清洗以去除非结合的偶联物，结果表明，具有顺式乌头键的偶联物对与79IT/36抗体反应的肿瘤细胞表现出最大的选择性细胞毒性。这些研究说明了制备化学定义的药物-抗体偶联物的可行性，这些偶联物保留了对肿瘤细胞的细胞毒性和选择性作用。
As an approach to developing more specific anti‐tumour therapeutic agents, daunomycin has been covalently linked to the human tumour localizing, murine monoclonal antibody 79IT/36. Four procedures for coupling drug to antibody were investigated. The sugar amino group of daunomycin was modified by reaction with succinic anhydride or cis aconitic anhydride and these derivatives were linked to antibody, a carbodiimide reagent being used to produce stable peptide bonding. Alternatively, 14‐bromo daunomycin was linked directly to antibody or antibody containing free thiol groups introduced by means of the heterobifunctional reagent SPDP [N‐succinimidyl‐3 (2‐py‐ridyldithio) propionate] thus producing a thioether linkage. Each of the conjugates, with drug‐antibody ratios of 3 to 4:1, retained a proportion of drug activity although the succinic anhydride derivative was the least cytotoxic. The three other conjugates specifically bound to tumour cells expressing the 79IT/36 antibody defined antigen. In shorterm assays in which tumour cells were briefly exposed to conjugates and then washed to remove non‐bound conjugate, it was determined that the conjugate with the cis aconityl linkage displayed the greatest selective cytotoxicity against tumour cells reactive with the 79IT/36 antibody. These studies illustrate the feasibility of preparing chemically defined drug‐antibody conjugates retaining cytotoxicity and selectivity of action against tumour cells.
DOI：
10.1016/0006-291x(81)91644-2
发表时间：
1981-01-01
影响因子：
3.1
作者：
SHEN, WC;RYSER, HJP
通讯作者：
RYSER, HJP