Rowland A J, McKenzie I F, Pietersz G A
Austin Research Institute, Austin Hospital, Heidelberg, Vic., Australia.
J Drug Target. 1994;2(2):113-21. doi: 10.3109/10611869409015899.
The heterogeneity of tumour antigen expression, the differential sensitivity of individual cells to drugs and the use drug--antibody immunoconjugates with limited potency can limit the antitumour effects of immunoconjugate therapy. In this study we have used two different antibodies linked to two different drugs Melphalan (Mel) and Idarubicin (Ida), each with a different site action, to evaluate the potential of using cocktails of immunoconjugates. A series of drug combinations were screened for their synergistic activity in vitro using the inhibition of [3H]-thyrmidine uptake by E3 cells, and constructing isobolagrams: Mel plus Ida was the only combination found to be synergistic in vitro and this synergism extended to the drugs after conjugation to antibodies. In addition, in vivo studies in mice bearing E3 tumours showed that synergy between both free drugs and between Ida-anti-Ly-2.1 and N-AcMEL-anti-Ly-3.1 immunoconjugates was time dependent, requiring treatment with Ida or Ida-MoAb conjugates prior to the addition of the second melphalan containing immunoconjugate. The use of two different antibodies, anti-Ly-2.1 and anti-Ly-3.1 against E3 (Ly-2.1+ve, Ly-3.1+ve) gave greater synergy in vitro compared to using only one antibody. Again a cocktail of two antibody immunoconjugates provided significantly greater antitumour efficacy when given to tumour bearing mice, provided that the Ida-anti-Ly-2.1 was given 24 h before injection of N-AcMEL-anti-Ly-3.1. The enhanced antitumour effect was not observed when the immunoconjugates were given simultaneously, or if the same antibody was used in each conjugate. Of importance was the finding that although the anti-tumour effect was synergistic, there was no increase in toxicity noted. The increased therapeutic index observed by using a double cocktail (2 antibodies + 2 drugs) could have major implications for immunoconjugate therapy.
肿瘤抗原表达的异质性、单个细胞对药物的不同敏感性以及效力有限的药物 - 抗体免疫缀合物的使用，可能会限制免疫缀合物疗法的抗肿瘤效果。在本研究中，我们使用了与两种不同药物美法仑（Mel）和伊达比星（Ida）相连的两种不同抗体，每种药物具有不同的作用位点，以评估使用免疫缀合物鸡尾酒的潜力。使用E3细胞对[3H] - 胸腺嘧啶摄取的抑制作用，对一系列药物组合进行体外协同活性筛选，并构建等效线图：Mel加Ida是唯一在体外发现具有协同作用的组合，并且这种协同作用在与抗体缀合后也延伸至药物。此外，在携带E3肿瘤的小鼠体内研究表明，游离药物之间以及Ida - 抗Ly - 2.1和N - AcMEL - 抗Ly - 3.1免疫缀合物之间的协同作用是时间依赖性的，在添加第二种含美法仑的免疫缀合物之前，需要先用Ida或Ida - MoAb缀合物进行治疗。与仅使用一种抗体相比，针对E3（Ly - 2.1 +ve，Ly - 3.1 +ve）使用两种不同抗体抗Ly - 2.1和抗Ly - 3.1在体外产生了更大的协同作用。同样，当给荷瘤小鼠注射两种抗体免疫缀合物的鸡尾酒时，只要在注射N - AcMEL - 抗Ly - 3.1之前24小时给予Ida - 抗Ly - 2.1，就会提供显著更高的抗肿瘤功效。当同时给予免疫缀合物或在每个缀合物中使用相同抗体时，未观察到增强的抗肿瘤效果。重要的是发现，尽管抗肿瘤作用是协同的，但未发现毒性增加。使用双重鸡尾酒（2种抗体 + 2种药物）观察到的治疗指数增加可能对免疫缀合物疗法具有重要意义。
