Recombinant T-Cell Receptor Ligand (RTL)‎ for Treatment of Multiple Sclerosis : A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study

Abstract EN

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.