CDR‐GRAFTED OKT4A MONOCLONAL ANTIBODY IN CYNOMOLGUS RENAL ALLOGRAFT RECIPIENTS1,2
CDR‐GRAFTED OKT4A MONOCLONAL ANTIBODY IN CYNOMOLGUS RENAL ALLOGRAFT RECIPIENTS1,2
复制标题
食蟹猴肾同种异体移植受者中 CDR 移植的 OKT4A 单克隆抗体1,2
作者：
J. Powelson;R. Knowles;F. Delmonico;T. Kawai;G. Mourad;F. Preffer;R. Colvin;A. Cosimi
为了提高治疗效果和限制对IgG2a单抗OKT4A的抗尿反应，从小鼠分子中制备了人源化互补决定区(CDR)嫁接的OKT4A单抗(IgG1和IgG4亚型)。对12例食蟹猴肾移植受者(IgG1期7例，IgG4期5例)进行临床前评估。对照组动物不接受任何治疗(n=2)或OKT3(n=2)。在移植当天单次给药10 mg/kg或多次给药1 mg/kg。对照组移植肾平均存活时间为9±0.7d，对照组为45.2±6.0d，P=0.002(单剂，n=5)，多次给药组为39±5.0d，P=0.053，多次给药组为35.3d±7.2d，P=0.034，多次给药组，P=.251。而用IgG4处理的动物外周血中的CD4+T细胞被包裹，而在用IgG1处理的动物中观察到显著的CD4+T细胞耗尽。这些结果证实了人源化OKT4A抗体的保留免疫抑制效果。与鼠类单抗相比，使用这些试剂不会排除针对不同表位的单抗进行连续治疗的可能性。尽管外周血中的CD4+细胞耗尽，但仍会发生排斥反应，这一事实表明，对灵长类动物的同种异体移植排斥反应进行无限期控制可能需要比在啮齿动物模型中证明有效的更密集的治疗。
In an attempt to improve therapeutic efficacy and limit antimurine responses to the IgG2a monoclonal antibody OKT4A, humanized complementarity determining region (CDR)-grafted OKT4A mAbs (IgG1 and IgG4 isotypes) were developed from the murine molecule. Preclinical evaluation was undertaken in 12 cynomolgus renal allograft recipients (IgG1, n=7; IgG4, n=5). Control animals received either no therapy (n=2) or OKT3 (n=2). The mAbs were given as a single 10-mg/kg bolus on the day of transplantation or as multiple 1-mg/kg doses. Mean allograft survival (±SEM) was 9±0.7 days in control animals; 45.2±6.0 days, P=0.002 (single dose, n=5), and 39±5.0 days, P=0.053, (multiple doses, n=2) in IgG1-treated animals; and 35.3±7.2 days, P=0.034, (single dose, n=3) and 15.5±6.5 days, P=.251 (multiple doses, n=2) in IgG4-treated animals. Whereas IgG4-treated animals showed coating of peripheral blood CD4+ T cells, significant CD4+ T cell depletion was observed in IgG1-treated animals. These results confirm the retained immunosuppressive efficacy of humanized OKT4A antibodies. In contrast to murine mAbs, the use of these agents would not preclude sequential treatment with mAbs directed against different epitopes. The fact that rejection can occur despite peripheral blood CD4+ cell depletion suggests that indefinite control of allograft rejection in primates may require more intensive therapy than has proved effective in rodent models.