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 ␣ (anti-TNF␣) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNF␣ 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-TNF␣ agents by analyzing their biologic activities on transmembrane TNF␣.Methods. Jurkat T cells stably expressing an uncleavable form of transmembrane TNF␣ were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNF␣, 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 TNF␣ estimated by apoptosis and cell cycle analysis using flow cytometry.Results. All of the anti-TNF␣ agents bound to transmembrane TNF␣. 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 TNF␣-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNF␣.Conclusion. Three different anti-TNF agents showed different biologic effects on transmembrane TNF␣. This finding suggests that CDC and outside-toinside signals by anti-TNF␣ antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.

Risk of tuberculosis is higher with anti–tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three‐year prospective french research axed on tolerance of biotherapies registry

“…In a murine model of chronic TB, neutralization of TNF by antibody but not the TNFR fusion molecule exacerbated chronic TB because of better penetration of antibodies into granulomas (19). In humans, higher avidity and better stability of membrane-bound TNF was demonstrated with anti-TNF mAb (20), which in some studies leads to more efficient apoptosis (21)(22)(23).…”

Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial

“…This may prevent or lessen the rate of apoptosis of immunocompetent cells [35,36]. A previous report showed that infliximab and adalimumab, but not ETN, induced apoptosis and cell-cycle arrest in T-cells transfected with transmembrane TNF-a [37]. These findings suggest that different anti-TNF-a therapies have different biologic effects on transmembrane TNF-a.…”

Dr. N. Jacob and Dr. C.O. Jacob reply

“…None of the 3 agents induced complement-dependent cytotoxicity when bound to activated human PBMC 3 . In contrast, induction of complement-dependent cytotoxicity in TNF-transfected cell lines has been reported for infliximab and adalimumab but not for etanercept [3][4][5] . Further, adalimumab or infliximab induced antibody-dependent cellular cytotoxicity (ADCC) much more potently than etanercept 6 .…”

“…Avidity of binding to soluble TNF was 10-to 20-fold greater for etanercept than for adalimumab or infliximab 3 . All the anti-TNF agents bound to membrane TNF-α on Jurkat cell lines 4 . On the other hand, binding of these agents to membrane TNF in human peripheral blood mononuclear cells (PBMC) under conditions that are more similar to those in patients showed that infliximab and etanercept had lower affinities/avidities for membrane TNF than adalimumab 3 .…”