Meyer D L, Jungheim L N, Law K L, Mikolajczyk S D, Shepherd T A, Mackensen D G, Briggs S L, Starling J J
Hybritech Incorporated, San Diego, California 92196-9006.
Cancer Res. 1993 Sep 1;53(17):3956-63.
Antibody-directed catalysis (ADC) is a two-step method for the delivery of chemotherapeutic agents in which enzyme-antibody conjugate, prelocalized to antigen-bearing tumor cells, catalyzes the site-specific conversion of prodrug to drug. An ADC system consisting of F(ab')-beta-lactamase conjugates and a cephalosporin derivative of the oncolytic agent 4-desacetylvinblastine-3-carboxhydrazide was investigated. The ability of the system to mediate antitumor activity was compared with that of free drug given alone and with covalent drug-antibody conjugates in LS174T and T380 colon carcinoma xenografts in nude mice. Efficacy increased from moderate tumor growth inhibition by using free 4-desacetylvinblastine-3-carboxhydrazide to tumor regression and long-term stabilization with the ADC system. Labile covalent drug-antibody conjugates prepared from the same antibodies were less effective than ADC and required much higher antibody doses. The antigens KS1/4, carcinoembryonic antigen, and tumor-associated glycoprotein-72, TAG-72, present on the model cell lines, were chosen to investigate the effect of differences in subcellular location and expression heterogeneity on the efficacy of ADC delivery. Response was equivalent with the three tumor antigens. Hence, heterogeneous expression and membrane shedding of carcinoembryonic antigen and TAG-72, did not diminish the suitability of these antigens as targets for ADC therapy. In contrast, drug-antibody conjugate efficacy was more sensitive to subcellular location and heterogeneity. Thus, ADC is a highly effective form of immunochemotherapy in preclinical models, with applicability toward a variety of antigen targets.
抗体导向催化（ADC）是一种用于递送化疗药物的两步法，其中预先定位于携带抗原的肿瘤细胞的酶-抗体偶联物催化前药向药物的位点特异性转化。研究了一种由F(ab')-β-内酰胺酶偶联物和溶瘤剂4-去乙酰长春碱-3-羧酰肼的头孢菌素衍生物组成的ADC系统。在裸鼠的LS174T和T380结肠癌异种移植模型中，将该系统介导抗肿瘤活性的能力与单独给予的游离药物以及共价药物-抗体偶联物的能力进行了比较。疗效从使用游离4-去乙酰长春碱-3-羧酰肼时的中度肿瘤生长抑制提高到使用ADC系统时的肿瘤消退和长期稳定。由相同抗体制备的不稳定共价药物-抗体偶联物比ADC效果差，并且需要更高的抗体剂量。选择模型细胞系上存在的抗原KS1/4、癌胚抗原和肿瘤相关糖蛋白-72（TAG-72）来研究亚细胞定位和表达异质性的差异对ADC递送疗效的影响。对这三种肿瘤抗原的反应是等效的。因此，癌胚抗原和TAG-72的异质性表达和膜脱落并没有降低这些抗原作为ADC治疗靶点的适用性。相比之下，药物-抗体偶联物的疗效对亚细胞定位和异质性更敏感。因此，在临床前模型中，ADC是一种高效的免疫化疗形式，适用于多种抗原靶点。
