Biological anti-TNF drugs: immunogenicity underlying treatment failure and adverse events

ABSTRACT

Introduction: Genetically engineered monoclonal antibodies and fusion proteins directed against cytokines or their receptors represent a breakthrough in the treatment of various chronic immune-inflammatory diseases.

Areas covered: Studies show high remission rates in several diseases, but clinical practice shows a significant percentage of individuals who do not exhibit the desired response. Loss of therapeutic benefit after initial successful response is designated secondary failure. Immune-biological agents are not self-antigens and are therefore potentially immunogenic. Secondary failure is frequently caused by antibodies against immune-biologicals, known as anti-drug antibodies (ADA). ADA that neutralize circulating immune-biologicals and/or promote their clearance can reduce treatment efficacy. Furthermore, ADA can induce adverse events by diverse immunological mechanisms. This review provides a comprehensive overview of ADA in rheumatoid arthritis patients treated with anti-TNF immune-biologicals, and explores the concept of therapeutic drug monitoring (TDM) as an effective strategy to improve therapeutic management.

Expert opinion: Monitoring circulating ADA and therapeutic immune-biological drugs is helpful when evaluating patients with secondary failure. However, immunological tests for ADA vary considerably regarding their ability to detect different types of ADA. Several assays are not designed to determine ADA-induced drug neutralizing capacity, and they may report clinically non-relevant data, especially if drug is present in test samples.

KEYWORDS:

• Anti-drug antibodies
• anti-TNF
• immune-biological
• immunogenicity
• rheumatoid arthritis
• TNF

Article highlights

• Lack of awareness of anti-drug antibodies (ADA) challenges patient safety as immune-mediated adverse events are not anticipated.

• Concomitant use of immunosuppressive drugs, e.g. MTX and azathioprine, may diminish the frequency of ADA-positive patients. It is unknown if this is mediated by immunosuppression, i.e. an effect on ADA production, or the anti-inflammatory effect of these drugs.

• Therapeutic drug monitoring can improve patient management providing a rationale for evidence-based individualized therapies.

• Therapeutic drug monitoring may significantly reduce health-care costs of anti-TNF therapies as documented by prospective, randomized and controlled studies of patients with Crohn’s disease.

• The heterogeneity of assays for detection and quantification of ADA negatively impacts therapeutic decision-making. For example, most currently available assays fail to show the in vivo functionality of detected ADA, i.e. drug neutralization.

This box summarizes key points contained in the article.

Declaration of interest

K Bendtzen’s research received financial support from the Danish Biotechnology Program. Within the last 3 years the author has received speaker fees from Pfizer and Novartis, and he owns stocks in Novo-Nordisk and Eurodiagnostica. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.