Schuler Walter, Bigaud Marc, Brinkmann Volker, Di Padova Franco, Geisse Sabine, Gram Hermann, Hungerford Valerie, Kleuser Beate, Kristofic Colette, Menninger Klaus, Tees Reet, Wieczorek Grazyna, Wilt Corinne, Wioland Catherine, Zurini Mauro
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
Transplantation. 2004 Mar 15;77(5):717-26. doi: 10.1097/01.tp.0000116563.72763.83.
Anti-CD154 monoclonal antibodies (mAbs) cause long-term graft survival in preclinical allotransplantation experiments. This is the first report on the efficacy and safety of ABI793, a novel human anti-human CD154 mAb, in Cynomolgus renal transplant recipients.
ABI793 (human immunoglobulin-G1:kappa) was derived from a hybridoma generated after immunization of human immunoglobulin transgenic mice (HuMAb-Mouse, Medarex Inc., Annandale, NJ). Cynomolgus monkey recipients of major histocompatibility complex-mismatched, life-supporting renal allografts were treated repeatedly with intravenous ABI793 for a 3-month period posttransplantation. Graft function was monitored by serum creatinine, and rejection was confirmed histologically.
ABI793 binds to human, Cynomolgus and Rhesus monkey CD154; it inhibits dose dependently in vitro CD154:CD40 binding and human mixed lymphocyte reaction. ABI793 is comparable to the mouse anti-human CD154 mAbs 5c8 and 24-31 with respect to affinity, inhibitory capacity, and species specificity; however, ABI793 binds to a different CD154 epitope. With 20 mg/kg of ABI793, five of nine recipients showed substantially prolonged graft survival after cessation of treatment, whereas four of nine recipients were killed because of high serum creatinine while still receiving treatment. ABI793 treatment was associated with episodes of severe acute tubular necrosis (which was unrelated to rejection and responded to fluid and diuretic treatment) and a decrease in platelet numbers. Chronic and acute thromboembolic vascular lesions with hemorrhages were observed in the lung and brain of two allograft recipients. None of these side effects were observed in animals that underwent autotransplantation, thus excluding direct toxicity of ABI793.
ABI793 treatment effectively prevents graft rejection in Cynomolgus monkeys. Evidence for rare thromboembolic events, as also previously observed with different anti-human CD154 mAbs, suggests that thromboembolic complications may be a class effect of anti-CD154 mAbs, unrelated to their epitope specificity.
抗CD154单克隆抗体（mAb）在临床前同种异体移植实验中可使移植物长期存活。本文首次报道了新型人源抗人CD154单克隆抗体ABI793在食蟹猴肾移植受者中的疗效和安全性。
ABI793（人免疫球蛋白G1：κ）源自人免疫球蛋白转基因小鼠（HuMAb-Mouse，Medarex公司，新泽西州安嫩代尔）免疫后产生的杂交瘤。对主要组织相容性复合体不匹配、接受维持生命的同种异体肾移植的食蟹猴受者在移植后3个月内反复静脉注射ABI793进行治疗。通过血清肌酐监测移植物功能，并通过组织学确认排斥反应。
ABI793可与人、食蟹猴和恒河猴的CD154结合；它在体外剂量依赖性地抑制CD154：CD40结合和人混合淋巴细胞反应。在亲和力、抑制能力和物种特异性方面，ABI793与小鼠抗人CD154单克隆抗体5c8和24-31相当；然而，ABI793结合不同的CD154表位。使用20mg/kg的ABI793，9只受者中有5只在停止治疗后移植物存活时间显著延长，而9只受者中有4只因血清肌酐升高在仍接受治疗时死亡。ABI793治疗与严重急性肾小管坏死发作（与排斥反应无关，对补液和利尿治疗有反应）以及血小板数量减少有关。在2只同种异体移植受者的肺和脑中观察到伴有出血的慢性和急性血栓栓塞性血管病变。在接受自体移植的动物中未观察到这些副作用，因此排除了ABI793的直接毒性。
ABI793治疗可有效预防食蟹猴的移植物排斥反应。罕见血栓栓塞事件的证据，正如之前在不同抗人CD154单克隆抗体中所观察到的那样，表明血栓栓塞并发症可能是抗CD154单克隆抗体的类效应，与其表位特异性无关。
