TY - JOUR
T1 - Recombinant T-cell receptor ligand (RTL) for treatment of multiple sclerosis
T2 - A double-blind, placebo-controlled, phase 1, dose-escalation study
AU - Yadav, Vijayshree
AU - Bourdette, Dennis N.
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 A.
PY - 2012
Y1 - 2012
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.
AB - 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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U2 - 10.1155/2012/954739
DO - 10.1155/2012/954739
M3 - Article
C2 - 22548151
AN - SCOPUS:84873711673
SN - 2090-0422
VL - 1
JO - Autoimmune Diseases
JF - Autoimmune Diseases
IS - 1
M1 - 954739
ER -