Targeting interleukin‐15 in patients with rheumatoid arthritis: A proof‐of‐concept study
Open Access
- 2 September 2005
- journal article
- clinical trial
- Published by Wiley in Arthritis & Rheumatism
- Vol. 52 (9), 2686-2692
- https://doi.org/10.1002/art.21249
Abstract
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.Keywords
This publication has 30 references indexed in Scilit:
- Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexateArthritis & Rheumatism, 2004
- Effector function of type II collagen–stimulated T cells from rheumatoid arthritis patients: Cross‐talk between T cells and synovial fibroblastsArthritis & Rheumatism, 2004
- IL-15Rα Recycles and Presents IL-15 In trans to Neighboring CellsImmunity, 2002
- Anti-Cytokine Therapy for Rheumatoid ArthritisAnnual Review of Medicine, 2000
- A proinflammatory role for IL-18 in rheumatoid arthritisJCI Insight, 1999
- THE MULTIFACETED REGULATION OF INTERLEUKIN-15 EXPRESSION AND THE ROLE OF THIS CYTOKINE IN NK CELL DIFFERENTIATION AND HOST RESPONSE TO INTRACELLULAR PATHOGENSAnnual Review of Immunology, 1999
- Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells In vitro and in the SCID mouse-human rheumatoid arthritis model In vivo.JCI Insight, 1998
- American college of rheumatology preliminary definition of improvement in rheumatoid arthritisArthritis & Rheumatism, 1995
- Cloning of a T Cell Growth Factor that Interacts with the β Chain of the Interleukin-2 ReceptorScience, 1994
- Measurement of patient outcome in arthritisArthritis & Rheumatism, 1980