Kreitman R J, Margulies I, Stetler-Stevenson M, Wang Q C, FitzGerald D J, Pastan I
Laboratory of Molecular Biology, Division of Cancer Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2000 Apr;6(4):1476-87.
Chemical conjugates of anti-CD22 monoclonal antibodies and toxins have been used to treat CD22+ hematological malignancies. A new anti-CD22 recombinant immunotoxin RFB4(dsFv)-PE38, composed of the Fv portion of the monoclonal antibody RFB4 fused to a truncated form of Pseudomonas exotoxin A, is being developed to target CD22+ tumor cells. To explore the potential clinical utility of this recombinant toxin in treating patients with B-cell malignancies, the fresh cells of patients were incubated ex vivo with RFB4(dsFv)-PE38. Specific cytotoxicity was demonstrated in the malignant cells of 25 of 28 patients with a variety of B-cell malignancies, including acute and chronic lymphocytic leukemias and large cell, mantle cell, and follicular lymphomas. The IC50S, the concentrations necessary for 50% inhibition of protein synthesis, were 3-10 ng/ml in five patients and 10-50 ng/ml in seven patients. Cytotoxicity correlated with cell death upon direct examination of the malignant cells. Significant cytotoxicity was observed with cells containing as few as 350 CD22 sites/cell. A more active derivative of RFB4(dsFv)-PE38, RFB4(dsFv)-PE38KDEL, was produced and was slightly to more than 10-fold more cytotoxic toward patient cells and about twice as toxic to mice. Thus, RFB4(dsFv)-PE38 was specifically cytotoxic toward malignant cells from patients with B-cell leukemias. These data support the testing of RFB4(dsFv)-PE38 in patients with CD22+ leukemias and lymphomas, which is presently under way.
抗CD22单克隆抗体与毒素的化学偶联物已被用于治疗CD22+血液系统恶性肿瘤。一种新型抗CD22重组免疫毒素RFB4(dsFv)-PE38正在研发中，它由单克隆抗体RFB4的Fv部分与截短形式的铜绿假单胞菌外毒素A融合而成，用于靶向CD22+肿瘤细胞。为了探索这种重组毒素在治疗B细胞恶性肿瘤患者中的潜在临床应用价值，将患者的新鲜细胞与RFB4(dsFv)-PE38进行体外孵育。28例患有各种B细胞恶性肿瘤（包括急性和慢性淋巴细胞白血病以及大细胞、套细胞和滤泡性淋巴瘤）的患者中，有25例患者的恶性细胞表现出特异性细胞毒性。50%抑制蛋白质合成所需的浓度（IC50）在5例患者中为3 - 10 ng/ml，在7例患者中为10 - 50 ng/ml。直接检查恶性细胞时，细胞毒性与细胞死亡相关。在每个细胞含有低至350个CD22位点的细胞中观察到显著的细胞毒性。产生了一种活性更高的RFB4(dsFv)-PE38衍生物RFB4(dsFv)-PE38KDEL，它对患者细胞的细胞毒性比对小鼠的毒性高10倍以上，对患者细胞的毒性约为对小鼠毒性的两倍。因此，RFB4(dsFv)-PE38对B细胞白血病患者的恶性细胞具有特异性细胞毒性。这些数据支持在CD22+白血病和淋巴瘤患者中对RFB4(dsFv)-PE38进行测试，目前该测试正在进行中。
