Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study.
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%).


CONCLUSIONS
These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.
Baslund
Bo
B
Rigshospitalet, Copenhagen, Denmark.
Tvede
Niels
N
Danneskiold-Samsoe
Bente
B
Larsson
Per
P
Panayi
Gabriel
G
Petersen
Joergen
J
Petersen
Lars J
LJ
Beurskens
Frank J M
FJ
Schuurman
Janine
J
van de Winkel
Jan G J
JG
Parren
Paul W H I
PW
Gracie
J Alastair
JA
Jongbloed
Sarah
S
Liew
Foo Y
FY
McInnes
Iain B
IB
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D006801:Humans; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D012720:Severity of Illness Index; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D019409:Interleukin-15; D007371:Interferon-gamma