Engert A, Gottstein C, Winkler U, Amlot P, Pileri S, Diehl V, Thorpe P
Med. Universitätsklinik I, Köln, Germany.
Leuk Lymphoma. 1994 May;13(5-6):441-8. doi: 10.3109/10428199409049633.
In the present paper we describe the evaluation of ricin A-chain immunotoxins for clinical application in Hodgkin's disease. The immunotoxins were constructed by chemically linking deglycosylated ricin-A to monoclonal antibodies (MoAb) recognising lymphocyte activation markers CD25, CD30, or IRac, which are expressed by Hodgkin's and Reed-Sternberg (H-RS) cells. The cytotoxic effects of the immunotoxins were investigated in vitro against L540Cy Hodgkin cells and in vivo against Hodgkin's tumors in nude mice and disseminated Hodgkin's tumors in SCID mice. MoAbs were evaluated for crossreactivity with normal human tissues and staining of sections from Hodgkin's disease tissue. Of 32 MoAbs, eight showed little crossreactivity with vital human organs and produced highly active immunotoxins. The most effective immunotoxin, RFT5 gamma l.dgA (CD25), inhibits the growth of H-RS cells at concentrations of 7 x 10(-12) M. RFT5 gamma l.dgA destroys about 60% of solid Hodgkin's tumors of 0.5 cm diameter in nude mice and induces complete remissions in 95% of SCID mice with disseminated Hodgkin's tumors when administered one day after tumor challenge. This immunotoxin binds to all H-RS cells in more than 90% of patients with Hodgkin's disease. Patients with refractory Hodgkin's disease are currently being treated in a phase-I/II clinical trial.
在本论文中，我们描述了对用于霍奇金病临床应用的蓖麻毒素A链免疫毒素的评估。这些免疫毒素是通过将去糖基化的蓖麻毒素A与识别淋巴细胞活化标志物CD25、CD30或IRac的单克隆抗体（MoAb）化学连接而构建的，这些标志物由霍奇金和里德-施特恩贝格（H-RS）细胞表达。在体外研究了免疫毒素对L540Cy霍奇金细胞的细胞毒性作用，以及在体内对裸鼠霍奇金肿瘤和重症联合免疫缺陷（SCID）小鼠播散性霍奇金肿瘤的细胞毒性作用。评估了单克隆抗体与正常人体组织的交叉反应性以及霍奇金病组织切片的染色情况。在32种单克隆抗体中，有8种与人体重要器官的交叉反应性较小，并产生了高活性的免疫毒素。最有效的免疫毒素RFT5γ1.dgA（CD25）在浓度为7×10⁻¹² M时可抑制H-RS细胞的生长。RFT5γ1.dgA可破坏裸鼠中约60%直径为0.5 cm的实体霍奇金肿瘤，并在肿瘤接种后一天给药时，使95%患有播散性霍奇金肿瘤的SCID小鼠完全缓解。这种免疫毒素与90%以上霍奇金病患者的所有H-RS细胞结合。难治性霍奇金病患者目前正在进行I/II期临床试验。
