Greenaway S, Henniker A J, Walsh M, Bradstock K F
Haematology Department, I.C.P.M.R., Westmead Hospital, N.S.W., Australia.
Leuk Lymphoma. 1994 Apr;13(3-4):323-31. doi: 10.3109/10428199409056297.
The use of monoclonal antibodies (MABs) for the therapy of malignant diseases offers the potential advantage of greater target cell specificity, and therefore less toxicity. A major limitation of this therapeutic approach has been the inability of most MABs to kill the cell once bound to the target antigen. We have previously reported the development of two murine IgM MABs, WM63 (CD48) and WM66 (unclustered), that react with panleucocyte antigens widely expressed on cells from lymphoproliferative disorders, and are lytic with human complement. These antibodies have subsequently been administered intravenously to patients with chronic lymphocytic leukaemia (CLL) in a Phase One trial. Seven patients with progressive CLL received increasing daily doses of WM66 (Patients 1-3) or WM63 (Patients 4-7), with one patient also receiving a continuous infusion of WM63 over 20 hours. All patients demonstrated a significant but transient reduction in the number of circulating leucocytes, and no overall effect on disease progression was observed. Antibody coating of circulating lymphocytes was seen in patients receiving WM-63. Patients receiving large doses of WM63 (cases 5-7) demonstrated a decline in complement levels during treatment. There were no major adverse reactions to WM66, but two patients developed dose limiting side effects to WM63. No human anti-mouse antibody (HAMA) responses were documented. These findings indicate that in vitro cytotoxicity mediated by Mabs fixing human complement correlates poorly with clinical responses, and support earlier observations which indicate that cell-mediated cytotoxicity is necessary for effective antibody therapy.
使用单克隆抗体（MABs）治疗恶性疾病具有潜在优势，即具有更高的靶细胞特异性，因此毒性较小。这种治疗方法的一个主要局限性是，大多数单克隆抗体一旦与靶抗原结合就无法杀死细胞。我们之前报道过两种鼠源IgM单克隆抗体WM63（CD48）和WM66（未聚类）的研发情况，它们与广泛表达于淋巴增殖性疾病细胞上的全白细胞抗原发生反应，并可被人补体溶解。随后，这些抗体在一项一期试验中被静脉注射给慢性淋巴细胞白血病（CLL）患者。7例进行性CLL患者接受了递增剂量的WM66（患者1 - 3）或WM63（患者4 - 7），其中1例患者还接受了20小时的WM63持续输注。所有患者的循环白细胞数量均出现显著但短暂的减少，且未观察到对疾病进展有总体影响。接受WM - 63的患者出现了循环淋巴细胞的抗体包被现象。接受大剂量WM63（病例5 - 7）的患者在治疗期间补体水平下降。WM66未出现重大不良反应，但有2例患者出现了针对WM63的剂量限制性副作用。未记录到人类抗小鼠抗体（HAMA）反应。这些发现表明，由固定人补体的单克隆抗体介导的体外细胞毒性与临床反应相关性较差，并支持了早期的观察结果，即细胞介导的细胞毒性对于有效的抗体治疗是必要的。
