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‐γ 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.