Iida Shinsuke, Ishida Takashi, Ueda Ryuzo
Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences.
Yakugaku Zasshi. 2015;135(5):663-9. doi: 10.1248/yakushi.14-00230-3.
Mogamulizumab (Moga; KW-0761) is a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody engineered to exert potent antibody-dependent cellular cytotoxicity (ADCC). A collaborative investigation with industry in preclinical studies has demonstrated in vitro and in vivo efficacy via ADCC for adult T-cell leukemia/lymphoma (ATLL) and CCR4-positive peripheral T-cell lymphoma (PTCL). In a phase I study, once-weekly administration of mogamulizumab (0.01-1.0 mg/kg) for 4 weeks was well tolerated. In a phase II study of once-weekly mogamulizumab (1.0 mg/kg) for 8 weeks in relapsed/refractory ATLL patients, an overall response rate of 50% including 30% complete response rate with a median progression-free survival of 5.2 months was observed. The drug was subsequently approved by Pharmaceuticals and Medical Devices Agency(PMDA) in March 2012. Because CCR4 is abundantly expressed on the surface of effector regulatory T cells, a phase I study is being conducted to enhance antitumor immune response in patients with solid tumors. However, approximately 60% of patients receiving mogamulizumab experience skin eruption with 19% showing grade ≥ 3 rash. Postmarketing surveillance of mogamulizumab revealed a 3-4% incidence rate of skin-related serious adverse events (SAEs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Therefore we initiated a search for predictive genomic biomarkers in the blood of patients with ATLL or solid tumors prior to treatment with mogamulizumab for not only efficacy but also immune-related SAEs. We believe the results of this study may lead to safer and more efficient use of this agent in the near future.
莫加穆单抗（Moga；KW-0761）是一种去岩藻糖基化的人源化抗CC趋化因子受体4（CCR4）抗体，经工程改造可发挥强大的抗体依赖性细胞毒性（ADCC）作用。一项与行业合作开展的临床前研究表明，莫加穆单抗通过ADCC对成人T细胞白血病/淋巴瘤（ATLL）和CCR4阳性外周T细胞淋巴瘤（PTCL）具有体内外疗效。在一项I期研究中，莫加穆单抗（0.01-1.0mg/kg）每周给药一次，共4周，耐受性良好。在一项针对复发/难治性ATLL患者的II期研究中，莫加穆单抗（1.0mg/kg）每周给药一次，共8周，观察到总体缓解率为50%，其中完全缓解率为30%，无进展生存期的中位数为5.2个月。该药物随后于2012年3月获得日本药品和医疗器械管理局（PMDA）批准。由于CCR4在效应调节性T细胞表面大量表达，目前正在进行一项I期研究，以增强实体瘤患者的抗肿瘤免疫反应。然而，约60%接受莫加穆单抗治疗的患者会出现皮疹，其中19%的患者皮疹分级≥3级。莫加穆单抗的上市后监测显示，与皮肤相关的严重不良事件（SAE）如史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN）的发生率为3-4%。因此，我们在ATLL或实体瘤患者接受莫加穆单抗治疗前，对其血液中的预测性基因组生物标志物进行了研究，这不仅是为了评估疗效，也是为了评估与免疫相关的SAE。我们相信，这项研究的结果可能会在不久的将来使该药物的使用更加安全和有效。
