From the Department of Rare Diseases Research, Institute of Medical Science (T.S., A.L.G.C.-R., N.Y., N.A., Y.Y.), Medical Informatics (E.I.), and the Departments of Pharmacology (N.M.) and Neurology (Y.H.), St. Marianna University School of Medicine, and the Department of Advanced Medical Innovation, St. Marianna University Graduate School of Medicine (T.W., Y.Y.), Kawasaki, the Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto (R.F., M.M.), the Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo (K.U.), and the Department of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto (M.M.) - all in Japan.
N Engl J Med. 2018 Feb 8;378(6):529-538. doi: 10.1056/NEJMoa1704827.
Human T-lymphotropic virus type 1 (HTLV-1) causes the debilitating neuroinflammatory disease HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP) as well as adult T-cell leukemia-lymphoma (ATLL). In patients with HAM-TSP, HTLV-1 infects mainly CCR4+ T cells and induces functional changes, ultimately causing chronic spinal cord inflammation. We evaluated mogamulizumab, a humanized anti-CCR4 monoclonal antibody that targets infected cells, in patients with HAM-TSP.
In this uncontrolled, phase 1-2a study, we assessed the safety, pharmacokinetics, and efficacy of mogamulizumab in patients with glucocorticoid-refractory HAM-TSP. In the phase 1 dose-escalation study, 21 patients received a single infusion of mogamulizumab (at doses of 0.003 mg per kilogram of body weight, 0.01 mg per kilogram, 0.03 mg per kilogram, 0.1 mg per kilogram, or 0.3 mg per kilogram) and were observed for 85 days. Of those patients, 19 continued on to the phase 2a study and received infusions, over a period of 24 weeks, of 0.003 mg per kilogram, 0.01 mg per kilogram, or 0.03 mg per kilogram at 8-week intervals or infusions of 0.1 mg per kilogram or 0.3 mg per kilogram at 12-week intervals.
The side effects of mogamulizumab did not limit administration up to the maximum dose (0.3 mg per kilogram). The most frequent side effects were grade 1 or 2 rash (in 48% of the patients) and lymphopenia and leukopenia (each in 33%). The dose-dependent reduction in the proviral load in peripheral-blood mononuclear cells (decrease by day 15 of 64.9%; 95% confidence interval [CI], 51.7 to 78.1) and inflammatory markers in cerebrospinal fluid (decrease by day 29 of 37.3% [95% CI, 24.8 to 49.8] in the CXCL10 level and of 21.0% [95% CI, 10.7 to 31.4] in the neopterin level) was maintained with additional infusions throughout the phase 2a study. A reduction in spasticity was noted in 79% of the patients and a decrease in motor disability in 32%.
Mogamulizumab decreased the number of HTLV-1-infected cells and the levels of inflammatory markers. Rash was the chief side effect. The effect of mogamulizumab on clinical HAM-TSP needs to be clarified in future studies. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare; UMIN trial number, UMIN000012655 .).
人类 T 淋巴细胞病毒 1 型（HTLV-1）会引起使人衰弱的神经炎症性疾病 HTLV-1 相关脊髓病-热带痉挛性截瘫（HAM-TSP）以及成人 T 细胞白血病-淋巴瘤（ATLL）。在 HAM-TSP 患者中，HTLV-1 主要感染 CCR4+T 细胞并诱导功能改变，最终导致慢性脊髓炎症。我们评估了 mogamulizumab，一种针对感染细胞的人源化抗 CCR4 单克隆抗体，用于 HAM-TSP 患者。
在这项非对照的 1-2a 期研究中，我们评估了 mogamulizumab 在糖皮质激素难治性 HAM-TSP 患者中的安全性、药代动力学和疗效。在 1 期剂量递增研究中，21 名患者接受了 mogamulizumab 的单次输注（剂量分别为 0.003mg/kg、0.01mg/kg、0.03mg/kg、0.1mg/kg 或 0.3mg/kg），并观察了 85 天。其中 19 名患者继续进入 2a 期研究，在 24 周内每隔 8 周接受 0.003mg/kg、0.01mg/kg 或 0.03mg/kg 的输注，或每隔 12 周接受 0.1mg/kg 或 0.3mg/kg 的输注。
mogamulizumab 的副作用并未限制剂量增至最大（0.3mg/kg）。最常见的副作用是 1 级或 2 级皮疹（占患者的 48%）和淋巴细胞减少症和白细胞减少症（各占 33%）。外周血单核细胞中病毒载量的剂量依赖性减少（第 15 天减少 64.9%[95%置信区间，51.7 至 78.1]）和脑脊液中炎症标志物的减少（第 29 天减少 37.3%[95%置信区间，24.8 至 49.8]的 CXCL10 水平和 21.0%[95%置信区间，10.7 至 31.4]的新蝶呤水平）在整个 2a 期研究中通过额外的输注得以维持。79%的患者痉挛程度减轻，32%的患者运动功能障碍减轻。
mogamulizumab 减少了 HTLV-1 感染细胞的数量和炎症标志物的水平。皮疹是主要的副作用。mogamulizumab 对临床 HAM-TSP 的影响需要在未来的研究中进一步阐明。（由日本医疗研究与发展机构和卫生、劳动和福利部资助；UMIN 试验编号：UMIN000012655）。
