Parlevliet K J, ten Berge I J, Yong S L, Surachno J, Wilmink J M, Schellekens P T
Renal Transplant Unit, Academic Medical Center, University of Amsterdam, The Netherlands.
J Clin Invest. 1994 Jun;93(6):2519-25. doi: 10.1172/JCI117262.
Side effects after the first administration of OKT3, a murine anti-CD3 monoclonal antibody (mAb) of the IgG2a class, are largely attributed to the release of cytokines as a result of T cell activation caused by interaction with Fc receptors (FcR) on human monocytes. As human monocytes possess FcR for murine IgG2a but not for IgA, it is expected that an anti-CD3 mAb of the IgA class causes less side-effects than an IgG2a anti-CD3 mAb of the same idiotype. To test this hypothesis we treated 20 renal transplant patients prophylactically with either IgG2a or IgA anti-CD3 mAb in a prospective randomized double-blind study. The patients received 0.5 mg anti-CD3 mAb, either IgA (T3.A) or IgG2a (T3.G2a), twice daily during 10 d. Rejection incidence after T3.A and T3.G2a was not significantly different. Side effects score after the first administration of mAb was significantly less after T3.A than after T3.G2a (0.7 vs 2.7, P = 0.002). IL-6 and gamma IFN levels increased significantly at 3 h after T3.G2a, but not after T3.A. The TNF peak level occurring at 1 h after T3.A was much lower than after T3.G2a. In plasma, complement and neutrophil activation products only increased after T3.G2a and not after T3.A. Both T3.A and T3.G2a resulted in a complete depletion of CD3+ cells, but after T3.A, CD3 depletion was of shorter duration than after IgG2a. Finally, in contrast to T3.G2a, T3.A did not affect coagulation and fibrinolysis. In conclusion, an anti-CD3 mAb of the IgA class causes hardly any cytokine release and less side-effects as compared with its IgG2a switch variant. Provided T3.A is sufficiently immunosuppressive, it is superior to OKT3.
首次注射OKT3（一种IgG2a类鼠抗人CD3单克隆抗体）后的副作用，很大程度上归因于其与人类单核细胞上的Fc受体（FcR）相互作用导致T细胞激活，进而释放细胞因子。由于人类单核细胞拥有针对鼠IgG2a的FcR，但不拥有针对IgA的FcR，因此预计同型的IgA类抗CD3单克隆抗体比IgG2a类抗CD3单克隆抗体引起的副作用更少。为了验证这一假设，我们在一项前瞻性随机双盲研究中，对20例肾移植患者预防性使用IgG2a或IgA抗CD3单克隆抗体进行治疗。患者每天两次接受0.5mg抗CD3单克隆抗体，分别为IgA（T3.A）或IgG2a（T3.G2a），持续10天。T3.A和T3.G2a治疗后的排斥反应发生率无显著差异。首次注射单克隆抗体后的副作用评分，T3.A组显著低于T3.G2a组（0.7对2.7，P = 0.002）。T3.G2a注射后3小时，IL - 6和γ干扰素水平显著升高，但T3.A注射后未出现这种情况。T3.A注射后1小时出现的TNF峰值水平远低于T3.G2a注射后。在血浆中，补体和中性粒细胞激活产物仅在T3.G2a注射后增加，而T3.A注射后未增加。T3.A和T3.G2a均导致CD3⁺细胞完全耗竭，但T3.A注射后CD3耗竭的持续时间比IgG2a注射后短。最后，与T3.G2a不同，T3.A不影响凝血和纤维蛋白溶解。总之，与IgG2a转换变体相比，IgA类抗CD3单克隆抗体几乎不引起细胞因子释放，副作用更少。如果T3.A具有足够的免疫抑制作用，它优于OKT3。
