Novel fully human Anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys
Novel fully human Anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys
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DOI：
10.1097/01.tp.0000286058.79448.c7
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发表时间：
2007-10-27
期刊：
影响因子：
6.2
通讯作者：
Todo, Satoru
中科院分区：
文献类型：
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作者：
Imai, Atsushi;Suzuki, Tomomi;Todo, Satoru
背景。抗cd154单克隆抗体阻断CD40-CD154通路可显著延长非人灵长类动物同种异体移植物的存活时间。然而，血栓栓塞并发症阻碍了临床应用。因此，用一种新的全人抗cd40单抗4D11来阻断对抗分子是一种有吸引力的替代方法。方法：在杂种食猴之间进行肾脏移植（混合淋巴细胞反应刺激指数>.3）。动物被分为五组：非治疗对照组（第1组，n= 3）， 10周给予10 mg/kg（第2组，n= 3）、20 mg/kg（第3组，n= 3）或40 mg/kg（第4组，n= 1）治疗，以及4周给予10 mg/kg、20 mg/kg或40 mg/kg治疗（第5组，各n= 1），然后每月给药。结果：组1（5、6、7）、组2（150、108、108）、组3（84、108、379）、组4（147）、组5（147、102、112）的生存期(d)。3组2只移植物功能正常的动物因肾积水和脑梗死而死亡。移植后4周，所有动物的B淋巴细胞均降至术前的1 / 3。大多数动物在停止药物治疗后或死亡时产生抗供体抗体。除1只动物外，其余动物均未形成抗4d11抗体。4D11似乎是一种很有前景的抗排斥治疗药物在临床器官移植。单克隆抗体（mAb）、可溶性蛋白或腺病毒介导的基因治疗阻断CD40-CD154通路，可在啮齿类动物的实验性器官移植中诱导供体特异性免疫抑制和/或耐受（1-6）。在非人灵长类动物的肾移植模型中，人源化的抗cd154单克隆抗体，如hu5C8、IDEC-131和ABI793，已被证明能显著延长同种异体移植肾的存活时间（7-10）。然而，在早期的一系列临床前试验中，这些药物与血栓栓塞有关，可能是由于抗体本身的性质和/或通过激活血小板（11-14）。尽管酮洛芬已被证明可以预防血栓栓塞并发症（15），但这种副作用的存在最终阻碍了抗cd154单克隆抗体的进一步临床开发（16,17）。因此，阻断伴侣分子CD40被认为是一种替代方法。嵌合单克隆抗体ch5D12和chi220在非人灵长类动物肾脏（18,19）和胰岛（20）移植后也能有效抑制抗cd40免疫。然而，当单独使用时，这些药物在免疫抑制方面不如抗cd154单克隆抗体有效。此外，这些单克隆抗体会耗尽B细胞并引起巨细胞病毒（CMV）感染，但无法阻止抗药物和抗供体抗体的产生（18,19）。
Background.CD40-CD154 pathway blockade by anti-CD154 monoclonal antibodies (mAbs) significantly prolongs allograft survival in nonhuman primates. However, thromboembolic complications have prevented clinical application. Thus, blockade of the counter molecule by a novel fully human anti-CD40 mAb, 4D11, is an attractive alternative.Methods.Kidney transplantations were performed between outbred cynomolgus monkeys (stimulation index> 3 in a mixed lymphocyte reaction). The animals were divided into five groups: nontreatment control (Group 1, n= 3), 10-week treatment with either 10 mg/kg (Group 2, n= 3), 20 mg/kg (Group 3, n= 3), or 40 mg/kg (Group 4, n= 1), and 4-week treatment (Group 5, n= 1 each) with 10 mg/kg, 20 mg/kg, or 40 mg/kg followed by monthly administration. Graft survival, biochemistry, complete blood counts, lymphocyte phenotypes, blood drug levels, antidonor and antidrug antibodies, and renal histology were examined.Results.Survival (days) was as follows: Group 1 (5, 6, 7), Group 2 (150, 108, 108), Group 3 (84, 108, 379), Group 4 (147), and Group 5 (147, 102, 112). Two animals in Group 3 with normal graft function were killed upon development of hydronephrosis and cerebral infarction. B lymphocytes fell to one-third of the preoperative value at 4 weeks after transplantation in all animals. Antidonor antibodies developed in most of the animals after stopping drug treatment or at the time of death. No animals except for one formed anti-4D11 antibody.Conclusion.4D11 appears to be a promising agent for antirejection treatment in clinical organ transplantation.Blockade of the CD40-CD154 pathway by monoclonal antibody (mAb), soluble proteins, or adenovirus-mediated gene therapy induces donor-specific immunosuppression and/or tolerance in experimental organ transplantation in rodents (1–6). Using a kidney transplantation model in nonhuman primates, the humanized anti-CD154 mAbs, such as hu5C8, IDEC-131, and ABI793, have been shown to markedly prolong renal allograft survival (7–10). During the early series of preclinical trials, however, these agents were associated with thromboembolism, presumably due to the nature of antibody itself and/or by activating platelets (11–14). Although administration of ketoprofen has been shown to prevent thromboembolic complications (15), existence of this side-effect has finally prevented further clinical development of the anti-CD154 mAbs (16, 17). Thus, blockade of the partner molecule, CD40 has been considered as an alternative approach. Chimeric mAbs, ch5D12 and chi220, are developed and found also effective for anti-CD40 immunosuppression after kidney (18, 19) and islet (20) transplantation in nonhuman primates. However, these agents are less potent than anti-CD154 mAbs in terms of immunosuppression when used alone. Further, these mAbs depleted B cells and caused cytomegalovirus (CMV) infection, but were incapable of preventing both antidrug and antidonor antibody production (18, 19).