title: Recombinant T-Cell Receptor Ligand (RTL) for Treatment of Multiple Sclerosis: A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study.
abstract: 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.
authors.affiliation: Department of Neurology, Oregon Health & Science University, L226, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Vijayshree
authors.initials: V
authors.lastname: Yadav
authors.forename: Dennis N
authors.initials: DN
authors.lastname: Bourdette
authors.forename: James D
authors.initials: JD
authors.lastname: Bowen
authors.forename: Sharon G
authors.initials: SG
authors.lastname: Lynch
authors.forename: David
authors.initials: D
authors.lastname: Mattson
authors.forename: Jana
authors.initials: J
authors.lastname: Preiningerova
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Bever
authors.forename: Jack
authors.initials: J
authors.lastname: Simon
authors.forename: Andrew
authors.initials: A
authors.lastname: Goldstein
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Burrows
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
authors.forename: Al J
authors.initials: AJ
authors.lastname: Ferro
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark