Derocq J M, Laurent G, Casellas P, Vidal H, Poncelet P, Fauser A, Demur C, Jansen F
Centre de Recherches Clin-Midy/Sanofi, Montpellier, France.
Transplantation. 1987 Dec;44(6):763-9. doi: 10.1097/00007890-198712000-00008.
A series of 25 different ricin A-chain immunotoxins (IT) were prepared with monoclonal antibodies reacting with several T cell antigens belonging to different clusters of differentiation (CD) to select the most appropriate immunotoxins (IT) for mature T cell depletion. Our screening procedure was performed in 2 steps. First, IT were evaluated using protein synthesis inhibition assay on clonogenic malignant cells in order to determine the most active IT for a given CD. Second, IT thus selected were evaluated for both mature T cell killing efficacy and tolerance on hematopoietic progenitor cells (HPC). This study showed that (1) different IT directed against the same CD antigen displayed a wide range of activity, suggesting the need for a large screening of IT to determine the most appropriate antibody for a given target antigen; (2) anti-CD3 and anti-CD5 ricin A-chain IT are the most active, displaying a cytoreduction of more than 2 logs on mature T cells; (3) the 3 different anti-CD2 ricin A-chain IT evaluated in this study induced poor mature T cell cytoreduction despite their relative efficacy on leukemic cells; (4) anti-CD8 ricin A-chain IT showed almost no efficacy on relevant target cells; (5) no toxicity on HPC was found for concentrations up to 10(-8) of A-chain whatever the IT used.
制备了一系列25种不同的蓖麻毒素A链免疫毒素（IT），这些免疫毒素与几种属于不同分化簇（CD）的T细胞抗原发生反应的单克隆抗体，以选择最适合用于清除成熟T细胞的免疫毒素（IT）。我们的筛选程序分两步进行。首先，使用蛋白质合成抑制试验对克隆形成性恶性细胞评估IT，以确定针对给定CD的最具活性的IT。其次，对如此选择的IT进行成熟T细胞杀伤效力和对造血祖细胞（HPC）耐受性的评估。本研究表明：（1）针对相同CD抗原的不同IT表现出广泛的活性范围，这表明需要对IT进行大量筛选以确定针对给定靶抗原的最合适抗体；（2）抗CD3和抗CD5蓖麻毒素A链IT活性最高，对成熟T细胞的细胞减少率超过2个对数；（3）本研究中评估的3种不同的抗CD2蓖麻毒素A链IT尽管对白血病细胞有相对疗效，但诱导的成熟T细胞细胞减少效果较差；（4）抗CD8蓖麻毒素A链IT对相关靶细胞几乎没有疗效；（5）无论使用何种IT，对于高达10^(-8) A链浓度的情况，未发现对HPC有毒性。
