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

Vijayshree Yadav, Dennis 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 Vandenbark

Research output: Contribution to journalArticle

23 Citations (Scopus)

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

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T-Cell Antigen Receptor
Multiple Sclerosis
Placebos
Ligands
HLA-DR2 Antigen
Therapeutics
Maximum Tolerated Dose
Autoimmune Experimental Encephalomyelitis
Safety
Intravenous Infusions
Hypotension
Immunosuppression
Diarrhea
Magnetic Resonance Imaging
T-Lymphocytes
Peptides
Brain

ASJC Scopus subject areas

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

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Recombinant T-cell receptor ligand (RTL) for treatment of multiple sclerosis : A double-blind, placebo-controlled, phase 1, dose-escalation study. / Yadav, Vijayshree; Bourdette, Dennis; 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.

In: Autoimmune Diseases, Vol. 1, No. 1, 954739, 2012.

Research output: Contribution to journalArticle

Yadav, Vijayshree ; Bourdette, Dennis ; 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. / Recombinant T-cell receptor ligand (RTL) for treatment of multiple sclerosis : A double-blind, placebo-controlled, phase 1, dose-escalation study. In: Autoimmune Diseases. 2012 ; Vol. 1, No. 1.
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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.",
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AU - Bourdette, Dennis

AU - Bowen, James D.

AU - Lynch, Sharon G.

AU - Mattson, David

AU - Preiningerova, Jana

AU - Bever, Christopher T.

AU - Simon, Jack

AU - Goldstein, Andrew

AU - Burrows, Gregory G.

AU - Offner, Halina

AU - Ferro, Al J.

AU - Vandenbark, Arthur

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N2 - 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.

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