Demonstration of specific antibodies against infliximab induced during treatment of a patient with ankylosing spondylitis

Abstract

Therapeutic proteins, such as infliximab, have revolutionized the treatment of many diseases during the last decade and more than 80 therapeutic proteins are currently approved for clinical use. However, all exogenous proteins have the potential to cause antibody formation. In order to ensure patient safety and the efficacy of therapeutic proteins, careful monitoring of the immunogenicity of therapeutic proteins is therefore necessary not only during preclinical trials, but also during the treatment of patients. Here, we report a clear-cut demonstration of the induction of anti-infliximab antibodies during the treatment of a patient with ankylosing spondylitis (AS). Assessment of anti-infliximab antibodies in sera obtained at various time periods were performed using a highly specific double antigen assay system developed in our laboratory. Immunoreactivity was found to be solely specific for infliximab. Because all sera obtained from the patient were found to be negative for the presence of human anti-mouse antibody (HAMA) and anti-human antibodies. The loss of effect of infliximab, as judged by observing the relapse of signs and symptoms of disease in the patient, seemed to be related with the appearance of antibodies. This study clearly demonstrates that monitoring for the induction of specific antibodies during clinical trials is an important issue for therapeutic proteins.

Immunogenicity of Anti-TNF-α Agents in Autoimmune Diseases

“…The sensitivity of detection is of 0.0003 mg/l [25]. With the method previously used, requiring monoclonal human IgG, human anti-human antibody like the IgG rheumatoid factor, and anti-haplotype antibodies could interfere in the quantification of anti-infliximab antibodies in assays using the solid phase, overestimating its value [27]. However, the exact values of the anti-infliximab concentration are not determined precisely by ELISA because the presence of light kappa infliximab chains in the serum interferes in the gauging, increasing the proportion of false negatives.…”

Investigation of the functional characteristics of antibodies to therapeutic anti-human tumor necrosis factor alpha monoclonal antibody

“…The presence of antibodies to infliximab (ATI) was demonstrated by a highly specific double antigen ELISA as described before in detail [13]. The potential interfering factors, such as human anti-mouse antibodies (HAMA) and human anti-human antibodies, including rheumatoid factor and anti-allotype antibodies were analyzed and were found to be negative (data not shown).…”

“…We previously reported a clear-cut demonstration of the induction of anti-infliximab antibodies during treatment of a patient [13]. The development of the anti-idiotypic antibodies bearing the internal image of human TNF-␣ antigen in the serum of patients undergoing infliximab therapy has been postulated as one of the possible causes of the loss of response to infliximab and exacerbation of the signs and symptoms during therapy.…”

“…The development of the anti-idiotypic antibodies bearing the internal image of human TNF-␣ antigen in the serum of patients undergoing infliximab therapy has been postulated as one of the possible causes of the loss of response to infliximab and exacerbation of the signs and symptoms during therapy. Therefore, the availability of ATI positive sera [13] prompted us to investigate the possibility of developing anti-idiotypic antibodies and evaluate their biological properties.…”

Hukukta Duygularin Di̇ri̇li̇şi̇

“…Adaleti "herkese hakkını olanı vermektir veya ahlaki olarak doğru olan şeydir" 63 diye tanımlayınca, adalet kavramının geniş olarak tutulması ve hem usul olarak hem de esas bakımından taraflara hak ettiğini vermek şeklinde anlamak buradaki incelemenin amacına uygun olacaktır. Adalet sadece şekilsel kurallara uymaktan öte "en yüksek ahlâk ülküsü, en iyi ve en doğru çözümü gösteren bir temel fikir, bir erdemdir …" 64 . Hukukçu gözüyle bakınca adalet, herkese hak ettiği hakkı ve cezayı vermektir.…”