TY - JOUR
T1 - Targeting interleukin-15 in patients with rheumatoid arthritis
T2 - a proof-of-concept study
AU - Baslund, Bo
AU - Tvede, Niels
AU - Danneskiold-Samsoe, Bente
AU - Larsson, Per
AU - Panayi, Gabriel
AU - Petersen, Joergen
AU - Petersen, Lars J
AU - Beurskens, Frank J M
AU - Schuurman, Janine
AU - van de Winkel, Jan G J
AU - Parren, Paul W H I
AU - Gracie, J Alastair
AU - Jongbloed, Sarah
AU - Liew, Foo Y
AU - McInnes, Iain B
PY - 2005/9
Y1 - 2005/9
N2 - OBJECTIVE: Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA.METHODS: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15. HuMax-IL15 was administered to 30 RA patients who received no other disease-modifying antirheumatic drugs in a 12-week, dose-ascending, placebo-controlled, double-blind, phase I-II proof-of-concept study.RESULTS: In vitro studies showed that HuMax-IL15 suppressed proliferation and induced apoptosis in an IL-15-dependent cell line, BDB2, and was capable of suppressing the release of interferon-gamma by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL-15. Furthermore, HuMax-IL15 F(ab')2 fragments suppressed exogenous IL-15-induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax-IL15 can specifically neutralize several biologic effects of IL-15 in synovial tissue in vitro. In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%).CONCLUSION: These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.
AB - OBJECTIVE: Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA.METHODS: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15. HuMax-IL15 was administered to 30 RA patients who received no other disease-modifying antirheumatic drugs in a 12-week, dose-ascending, placebo-controlled, double-blind, phase I-II proof-of-concept study.RESULTS: In vitro studies showed that HuMax-IL15 suppressed proliferation and induced apoptosis in an IL-15-dependent cell line, BDB2, and was capable of suppressing the release of interferon-gamma by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL-15. Furthermore, HuMax-IL15 F(ab')2 fragments suppressed exogenous IL-15-induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax-IL15 can specifically neutralize several biologic effects of IL-15 in synovial tissue in vitro. In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%).CONCLUSION: These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.
KW - Adult
KW - Aged
KW - Antibodies, Monoclonal
KW - Apoptosis
KW - Arthritis, Rheumatoid
KW - Cell Death
KW - Cell Proliferation
KW - Dose-Response Relationship, Drug
KW - Feasibility Studies
KW - Humans
KW - Injections, Subcutaneous
KW - Interferon-gamma
KW - Interleukin-15
KW - Killer Cells, Natural
KW - Leukocytes, Mononuclear
KW - Middle Aged
KW - Severity of Illness Index
KW - Synovial Fluid
KW - T-Lymphocyte Subsets
KW - Treatment Outcome
U2 - 10.1002/art.21249
DO - 10.1002/art.21249
M3 - Journal article
C2 - 16142748
SN - 0004-3591
VL - 52
SP - 2686
EP - 2692
JO - Arthritis & Rheumatism
JF - Arthritis & Rheumatism
IS - 9
ER -