Non-response to infliximab may be due to innate neutralizing anti-tumour necrosis factor-α antibodies

Abstract

SummaryInfliximab is a chimeric anti-tumour necrosis factor (TNF)-a antibody that is therapeutic in many patients with inflammatory bowel disease. What causes certain patients not to respond is unknown. The question posed is whether innate anti-TNF-a antibodies play any role in the response to infliximab. Blood was drawn prior to the initial dose of infliximab. Serum anti-TNF-a antibodies were quantitated by enzyme-linked immunosorbent assay (ELISA). Affinity-purified anti-TNF-a antibodies were isolated from serum immunoglobulin G using TNF-a-coated beads. The ability of these antibodies to induce apoptosis of macrophages was measured by annexin and propidium iodide staining. Changes in TNF receptor type 2 (TNFR2) expression and release were determined by immunofluorescence and ELISA respectively. TNF-a-neutralization was assessed by the reversal of the lytic actions of TNF-a on WEHI cells. The amounts of innate anti-TNF-a antibodies in the serum from infliximab responders versus non-responders were the same. Apoptosis of monocytes increased with infliximab and by several of the purified anti-TNF-a antibodies, but these findings did not vary with the patients' responses to infliximab. Effects of the anti-TNF-a antibodies on the expression of TNFR2 on monocytes and their release of soluble TNFR2 did not vary with the patients' responses to infliximab. However, the neutralizing capacity of these antibodies differed, with responders having antibodies that reduced only 47 Ϯ 4% of the TNF-a activity while those from non-responders reduced 70 Ϯ 5% of the TNF-a activity (P < 0·01). Non-responders have innate anti-TNF-a antibodies with greater neutralizing activity than antibodies from responders. Any TNF-a-mediated disease process would be neutralized by intrinsic antibodies, so that the disease is likely to be driven by non-TNF-a-mediated events.

New strategies to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors: A systematic analysis

“…Among the 34 infliximab studies, 14 were in IBD and included 2016 patients, 14 were in RA and included 855 patients, 5 were in AS/PsA/psoriasis and included 184 patients and 1 was in a mixed population that included 23 patients with RA and 14 with spondyloarthropathies. However, 1 study in IBD [29] provided no patient numbers and another in the previously mentioned mixed population [47] also included 34 patients with vasculitis; the latter were excluded from the total number of patients provided. Among the 18 adalimumab studies, 3 were in IBD and included 222 patients, 12 were in RA and included 1829 patients and 3 were in AS/PsA/psoriasis and included 86 patients.…”

Immunogenicity of Anti-TNF-α Agents in Autoimmune Diseases

“…A study with RA patients showed a frequency of 0% of HACA in patients that received concomitantly infliximab and 7.5 mg/week of MTX versus 7% of these antibodies in patients that were treated only with infliximab [19]. On the other hand, other immunosuppressive drugs, like cyclosporine, azathioprine (AZA), and sulfasalazine, did not have any influence on the development of those antibodies in the RA [24]. In CD, on the other hand, 6-mercaptopurine, AZA, and MTX reduced importantly the incidence of anti-infliximab antibodies [8,[21][22][23]34], but no association was found between the use of mesalamine and the development HACAs [20,21].…”

“…Ebert et al [24] demonstrated the presence of innate anti-TNF-α immunoglobulin G (IgG) antibodies in patients with ulcerative colitis and CD with no influence on clinical response to infliximab. The role of these antibodies has not been clarified and just some of them have neutralizing activity.…”

Prevention of acute adverse events related to infliximab infusions in pediatric patients

“…There is some evidence that antibody formation to infliximab increases the probability of an acute infusion reaction, and reintroduction of the therapy after a long interval is potentially risky (11). To this end, it is evident that acute reactions are not IgE mediated, but generally the underlying mechanisms are poorly understood (12).…”