Anasetti C, Martin P J, Storb R, Appelbaum F R, Beatty P G, Davis J, Doney K, Hill H F, Stewart P, Sullivan K M
Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
Transplantation. 1992 Nov;54(5):844-51. doi: 10.1097/00007890-199211000-00015.
Treatment with the monoclonal antibody OKT3 specific for the CD3 complex associated with the T cell antigen receptor can reverse acute rejection of human renal allografts. However, efficacy of anti-CD3 antibodies for treatment of patients with acute graft-versus-host disease after marrow transplantation has not been established. The dose-limiting side effects resulting from T cell activation induced by some anti-CD3 antibodies in vivo have discouraged their use for this application. We now report a phase I-II study of GVHD treatment with the anti-CD3 antibody BC3, a monoclonal murine IgG2b that, unlike OKT3, does not activate T cells. Fourteen patients were treated with BC3 after progression of acute GVHD despite treatment with cyclosporine and corticosteroids, and three patients received BC3 as primary treatment for GVHD. BC3 was administered at a dose of 0.1 or 0.2 mg/kg/day for seven or eight days. Five patients achieved complete resolution of GVHD, eight patients had partial improvement, two patients had no change, and two patients had progression of GVHD on therapy. Responses were sustained in 8 of 13 patients. Mild chills, fever, hypertension, and chest discomfort occurred in various combinations following 6 of 17 (35%) initial infusions of BC3 and following 4 of 99 (4%) subsequent infusions. In each instance it was possible to continue BC3 therapy without adjusting the dose or treatment schedule. In each patient treated, the absolute count of peripheral blood lymphocytes decreased transiently but returned to baseline within 22 hr after the first infusion. Circulating T cells had surface CD3 molecules saturated by the infused antibody in all but one patient. Four patients survived longer than one year after treatment with antibody BC3, and 13 patients died of infection or organ failure. Administration of the nonmitogenic anti-CD3 antibody BC3 was associated with improvement in the clinical manifestations of GVHD with minimal acute toxicity. Efficacy of antibody treatment did not depend on depletion of circulating T cells. Therefore, antibody BC3 may be achieving therapeutic immunosuppression by modulating T cell function. Controlled studies in patients treated earlier in the course of GVHD should determine whether antibody BC3 can improve survival.
用针对与T细胞抗原受体相关的CD3复合物的单克隆抗体OKT3进行治疗，可以逆转人肾移植的急性排斥反应。然而，抗CD3抗体治疗骨髓移植后急性移植物抗宿主病患者的疗效尚未确定。一些抗CD3抗体在体内诱导T细胞活化所产生的剂量限制性副作用，阻碍了它们在该应用中的使用。我们现在报告一项用抗CD3抗体BC3治疗移植物抗宿主病的I-II期研究，BC3是一种鼠源单克隆IgG2b抗体，与OKT3不同，它不会激活T细胞。尽管使用了环孢素和皮质类固醇进行治疗，但14例急性移植物抗宿主病进展后的患者接受了BC3治疗，3例患者接受BC3作为移植物抗宿主病的初始治疗。BC3以0.1或0.2mg/kg/天的剂量给药，持续7或8天。5例患者的移植物抗宿主病完全缓解，8例患者部分改善，2例患者无变化，2例患者在治疗过程中移植物抗宿主病进展。13例患者中有8例的反应持续存在。在17次（35%）初始输注BC3后的6次以及99次（4%）后续输注后的4次中，出现了轻度寒战、发热、高血压和胸部不适等不同组合的症状。在每种情况下，都可以在不调整剂量或治疗方案的情况下继续BC3治疗。在接受治疗的每例患者中，外周血淋巴细胞绝对计数短暂下降，但在首次输注后22小时内恢复至基线水平。除1例患者外，所有患者循环T细胞表面的CD3分子都被注入的抗体饱和。4例患者在接受抗体BC3治疗后存活超过1年，13例患者死于感染或器官衰竭。给予非促有丝分裂的抗CD3抗体BC3与移植物抗宿主病临床表现的改善相关，且急性毒性最小。抗体治疗的疗效不依赖于循环T细胞的耗竭。因此，抗体BC3可能是通过调节T细胞功能来实现治疗性免疫抑制的。在移植物抗宿主病病程早期接受治疗的患者中进行对照研究，应能确定抗体BC3是否可以提高生存率。
