Mechanisms for cytotoxic effects of anti–tumor necrosis factor agents on transmembrane tumor necrosis factor α–expressing cells: Comparison among infliximab, etanercept, and adalimumab

Abstract Objective Three anti–tumor necrosis factor α (anti‐TNFα) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti‐TNFα monoclonal antibodies, while etanercept is engineered from human type II TNF receptors. In spite of all 3 agents' equal efficacy for RA, both infliximab and adalimumab are effective for other diseases such as Crohn's disease and Wegener's granulomatosis, while etanercept is not. We undertook this study to understand the different clinical effects of these anti‐TNFα agents by analyzing their biologic activities on transmembrane TNFα. Methods Jurkat T cells stably expressing an uncleavable form of transmembrane TNFα were used for the following studies: 1) flow cytometric analysis of binding activities of anti‐TNF agents to cell surface transmembrane TNFα, 2) complement‐dependent cytotoxicity (CDC), 3) antibody‐dependent cell‐mediated cytotoxicity (ADCC) by using peripheral blood mononuclear cells, and 4) outside‐to‐inside (reverse) signal transduction through transmembrane TNFα estimated by apoptosis and cell cycle analysis using flow cytometry. Results All of the anti‐TNFα agents bound to transmembrane TNFα. Infliximab and adalimumab exerted almost equal CDC activities, while etanercept showed considerably lower activity. ADCC activities were almost equal among these 3 agents. Adalimumab and infliximab induced apoptosis and cell cycle arrest in transmembrane TNFα–expressing Jurkat T cells, reflecting an outside‐to‐inside signal transduction through transmembrane TNFα. Conclusion Three different anti‐TNF agents showed different biologic effects on transmembrane TNFα. This finding suggests that CDC and outside‐to‐inside signals by anti‐TNFα antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.