Krönke M, Depper J M, Leonard W J, Vitetta E S, Waldmann T A, Greene W C
Blood. 1985 Jun;65(6):1416-21.
Adult T cell leukemia (ATL) is an almost uniformly fatal malignancy of mature T cells associated with human T cell leukemia/lymphoma virus type 1 (HTLV-1) infection. Cells from this leukemia are characterized by the expression of large numbers of receptors for interleukin 2 (IL-2). In an attempt to prepare an immunotoxin with selective cytotoxicity for ATL cells, we conjugated anti-Tac, a monoclonal anti-IL-2 receptor antibody, to purified ricin A chains. Although unmodified anti-Tac had no effect on the protein synthesis of these cells, anti-Tac-ricin A chain conjugates produced half-maximal inhibition of protein synthesis in HTLV-1-infected leukemic T cell lines at concentrations of 2 to 6 X 10(-10) mol/L (ID50). An essentially identical ID50 was obtained with leukemic peripheral blood T lymphocytes isolated from two patients with ATL. In contrast, half-maximal inhibition of protein synthesis in HTLV-uninfected, IL-2 receptor-negative T and B cell lines required 200- to 1,000-fold higher concentrations of anti-Tac-ricin A chain conjugates. Both unconjugated anti-Tac and immunoaffinity-purified IL-2 completely inhibited the toxic effects of anti-Tac-ricin A, confirming the specificity of the conjugate-IL-2 receptor interaction. Clonogenic assays demonstrated that anti-Tac-ricin A chain was able to eliminate greater than 99.9% of an HTLV-1-infected T cell population at concentrations only marginally affecting IL-2 receptor-negative cells. The data presented demonstrate that anti-Tac-ricin A is selectively cytotoxic for HTLV-1-infected leukemic T cells in vitro and raises the future possibility of specific therapeutic intervention with immunotoxins in this disease.
成人T细胞白血病（ATL）是一种几乎一致致命的成熟T细胞恶性肿瘤，与人T细胞白血病/淋巴瘤病毒1型（HTLV-1）感染相关。这种白血病的细胞特征是表达大量白细胞介素2（IL-2）受体。为了制备对ATL细胞具有选择性细胞毒性的免疫毒素，我们将抗Tac（一种抗IL-2受体单克隆抗体）与纯化的蓖麻毒素A链偶联。虽然未修饰的抗Tac对这些细胞的蛋白质合成没有影响，但抗Tac-蓖麻毒素A链偶联物在浓度为2至6×10⁻¹⁰ mol/L（半数抑制浓度ID50）时，对HTLV-1感染的白血病T细胞系的蛋白质合成产生半数最大抑制作用。从两名ATL患者分离的白血病外周血T淋巴细胞也获得了基本相同的ID50。相比之下，在未感染HTLV-1、IL-2受体阴性的T和B细胞系中，蛋白质合成的半数最大抑制需要抗Tac-蓖麻毒素A链偶联物的浓度高出200至1000倍。未偶联的抗Tac和免疫亲和纯化的IL-2都完全抑制了抗Tac-蓖麻毒素A的毒性作用，证实了偶联物与IL-2受体相互作用的特异性。克隆形成试验表明，抗Tac-蓖麻毒素A链能够在仅略微影响IL-2受体阴性细胞的浓度下消除超过99.9%的HTLV-1感染T细胞群体。所呈现的数据表明，抗Tac-蓖麻毒素A在体外对HTLV-1感染的白血病T细胞具有选择性细胞毒性，并增加了在这种疾病中使用免疫毒素进行特异性治疗干预的未来可能性。
