Yadav Vijayshree, Bourdette Dennis N, Bowen James D, Lynch Sharon G, Mattson David, Preiningerova Jana, Bever Christopher T, Simon Jack, Goldstein Andrew, Burrows Gregory G, Offner Halina, Ferro Al J, Vandenbark Arthur A
Department of Neurology, Oregon Health & Science University, L226, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Autoimmune Dis. 2012;2012:954739. doi: 10.1155/2012/954739. Epub 2012 Apr 5.
Background. Recombinant T-cell receptor ligand 1000 (RTL1000) is a single-chain protein construct containing the outer two domains of HLA-DR2 linked to myelin-oligodendrocyte-glycoprotein- (MOG-) 35-55 peptide. Analogues of RTL1000 induce T-cell tolerance, reverse clinical and histological disease, and promote repair in experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic, C57BL/6, and SJL/J mice. Objective. Determining the maximum tolerated dose, safety, and tolerability of RTL1000 in multiple sclerosis (MS) subjects. Methods. This was a multicenter, Phase I dose-escalation study in HLA-DR2(+) MS subjects. Consecutive cohorts received RTL1000 doses of 2, 6, 20, 60, 200, and 100 mg, respectively. Subjects within each cohort randomly received a single intravenous infusion of RTL1000 or placebo at a 4 : 2 ratio. Safety monitoring included clinical, laboratory, and brain magnetic resonance imaging (MRI) evaluations. Results. Thirty-four subjects completed the protocol. All subjects tolerated the 2-60 mg doses of RTL1000. Doses ≥100 mg caused hypotension and diarrhea in 3 of 4 subjects, leading to discontinuation of further enrollment. Conclusions. The maximum tolerated dose of RTL1000 in MS subjects is 60 mg, comparable to effective RTL doses in EAE. RTL1000 is a novel approach for MS treatment that may induce immunoregulation without immunosuppression and promote neural repair.
背景。重组T细胞受体配体1000（RTL1000）是一种单链蛋白质构建体，包含与髓鞘少突胶质细胞糖蛋白（MOG）-35-55肽相连的HLA-DR2的外侧两个结构域。RTL1000的类似物可诱导T细胞耐受，逆转临床和组织学疾病，并促进DR2转基因小鼠、C57BL/6小鼠和SJL/J小鼠实验性自身免疫性脑脊髓炎（EAE）的修复。目的。确定RTL1000在多发性硬化症（MS）受试者中的最大耐受剂量、安全性和耐受性。方法。这是一项针对HLA-DR2（+）MS受试者的多中心I期剂量递增研究。连续队列分别接受2、6、20、60、200和100mg的RTL1000剂量。每个队列中的受试者以4∶2的比例随机接受单次静脉输注RTL1000或安慰剂。安全性监测包括临床、实验室和脑磁共振成像（MRI）评估。结果。34名受试者完成了方案。所有受试者都耐受2 - 60mg剂量的RTL1000。≥100mg的剂量导致4名受试者中的3名出现低血压和腹泻，导致停止进一步入组。结论。RTL1000在MS受试者中的最大耐受剂量为60mg，与EAE中的有效RTL剂量相当。RTL1000是一种治疗MS的新方法，可能在不进行免疫抑制的情况下诱导免疫调节并促进神经修复。
