Delmonico F L, Cosimi A B
Transplantation Unit, Massachusetts General Hospital, Boston 02114, USA.
Clin Transplant. 1996 Oct;10(5):397-403.
Because they can be selected to target only cells which are crucial for rejection, monoclonal antibodies (mAbs) offer enormous potential for specific manipulation of the immune response. Interest in the clinical potential of anti-CD4 mAbs has been heightened by the demonstration, in experimental models, that such therapy can produce long-term donor-specific non-responsiveness. Early clinical trials using two murine anti-CD4 mAbs (BL4 and mT-151) were discouraging, with over 50% of recipients suffering early rejection episodes. Another murine preparation, OKT4A, was initially found to prolong allograft survival in non-human primates. Limited clinical trials revealed that this mAb was well tolerated, that most recipients produced an antimurine response, and that only 26% of patients suffered rejection episodes during the first 3 post-operative months. Another murine preparation, Max. 16H5, has been reported to reverse late onset acute rejection episodes as effectively as, but more safely than, conventional immunosuppression. More recent interest has focused upon humanized recombinants of these earlier murine anti-CD4 preparations. cMT-412, has been studied in recipients of heart or heart-lung allografts. These patients were observed to have less frequent and markedly delayed rejection episodes, fewer infectious complications, and better overall survival than that observed in an ATG-treated control group. Further studies are thus being undertaken. A CDR grafted IgG4 preparation of OKT4A has also been studied. This molecule (OKTcdr4a) contains only 8% of the parent murine sequence while retaining the binding affinity of OKT4A for the human CD4 antigen. In a pilot trial, biopsy-proven reversible rejection episodes were observed in 2/11 (18%) of renal allograft recipients. There were no allograft failures and no antibody response to the mAb. These and other trials emphasize the intense interest in immunosuppressive regimens incorporating anti-CD4 mAbs as well as the difficulties encountered in defining optimal protocols. Nevertheless, the impressive results observed in rodent and non-human primate models suggest that these agents are likely to play an important role in future immunosuppressive protocols, particularly those designed to induce tolerance.
由于单克隆抗体（mAb）可以被选择仅靶向对排斥反应至关重要的细胞，因此它们在特异性调控免疫反应方面具有巨大潜力。在实验模型中已证实抗CD4单克隆抗体疗法可产生长期的供体特异性无反应性，这使得人们对其临床潜力的兴趣日益浓厚。早期使用两种鼠源抗CD4单克隆抗体（BL4和mT - 151）的临床试验结果令人沮丧，超过50%的接受者出现早期排斥反应。另一种鼠源制剂OKT4A最初被发现可延长非人灵长类动物同种异体移植物的存活时间。有限的临床试验表明，这种单克隆抗体耐受性良好，大多数接受者产生了抗鼠反应，并且在术后的前三个月中只有26%的患者出现排斥反应。据报道，另一种鼠源制剂Max. 16H5在逆转迟发性急性排斥反应方面与传统免疫抑制方法效果相同，但更安全。最近的研究兴趣集中在这些早期鼠源抗CD4制剂的人源化重组体上。cMT - 412已在心脏或心肺同种异体移植接受者中进行了研究。观察发现，与接受抗胸腺细胞球蛋白（ATG）治疗的对照组相比，这些患者的排斥反应发作频率更低、明显延迟，感染并发症更少，总体存活率更高。因此正在进行进一步的研究。一种OKT4A的互补决定区（CDR）移植IgG4制剂也已被研究。该分子（OKTcdr4a）仅包含8%的亲本鼠源序列，同时保留了OKT4A对人CD4抗原的结合亲和力。在一项初步试验中，11例肾移植受者中有2例（18%）经活检证实出现可逆性排斥反应。没有同种异体移植物失败，也没有对该单克隆抗体的抗体反应。这些试验以及其他试验强调了人们对包含抗CD4单克隆抗体的免疫抑制方案的浓厚兴趣，以及在确定最佳方案时遇到的困难。然而，在啮齿动物和非人灵长类动物模型中观察到的令人印象深刻的结果表明，这些药物可能在未来的免疫抑制方案中发挥重要作用，特别是那些旨在诱导耐受性的方案。
