Recombinant T-cell receptor ligand (RTL) for treatment of multiple sclerosis: A double-blind, placebo-controlled, phase 1, dose-escalation study

Vijayshree Yadav, Dennis N. Bourdette, James D. Bowen, Sharon G. Lynch, David Mattson, Jana Preiningerova, Christopher T. Bever, Jack Simon, Andrew Goldstein, Gregory G. Burrows, Halina Offner, Al J. Ferro, Arthur A. Vandenbark

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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 100mg, 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 2-60mg doses of RTL1000. Doses 100mg 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 60mg, 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.

Original languageEnglish (US)
Article number954739
JournalAutoimmune Diseases
Volume1
Issue number1
DOIs
StatePublished - 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Immunology and Microbiology (miscellaneous)

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