The first World Health Organization International Standard for infliximab products: A step towards maintaining harmonized biological activity

Abstract

Due to the increase in the number of infliximab products, the need for global harmonization of the bioactivity of this monoclonal antibody was recognized by the World Health Organization (WHO). In response, the National Institute for Biological Standards and Control (NIBSC) developed the first international standard (IS) for infliximab, which targets tumour necrosis factor (TNF). Each ampoule is assigned values of 500 IU of TNF neutralizing activity and 500 IU of binding activity. Two preparations of infliximab were formulated and lyophilized at NIBSC prior to evaluation in a collaborative study for their suitability to serve as an IS for the in vitro biological activity of infliximab. The study involved participants using in vitro cell-based bioassays (TNF neutralization, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) and binding assays. The results of this study showed that the candidate preparation, coded 16/170, is suitable as an IS for infliximab bioactivity. This infliximab IS from NIBSC, is intended to support in vitro bioassay calibration and validation by defining international units of bioactivity. The proposed unitages, however, are not intended to revise product labelling or dosing requirements, as any decisions regarding this relies solely with the regulatory authorities. Furthermore, the infliximab IS is not intended for determining the specific activity of products, nor to serve any regulatory role in defining biosimilarity. We briefly discuss the future use of WHO international standards in supporting the global harmonisation of biosimilar infliximab products.

High prevalence of antibodies to infliximab and their relation to clinical outcomes in inflammatory bowel disease patients

“…A prospective study—using the same assay as our centre—showed median subtherapeutic IFX trough level of 0.9 ug/mL in 138 CD patients . Another study reported that 52% of their IBD cohort had subtherapeutic IFX levels, though using a lower threshold of <2 µg/mL Assays can vary in their detection of IFX levels but this disparity should improve with the recent introduction of an international standard …”

“…24 Another study reported that 52% of their IBD cohort had subtherapeutic IFX levels, 25 though using a lower threshold of <2 µg/mL Assays can vary in their detection of IFX levels 26 but this disparity should improve with the recent introduction of an international standard. 27 We have also described here the late development of ATI. The risk of antibody development seems to be present throughout treatment with IFX but is highest in the first 12 months of treatment with nearly 80% of patients developed ATI during this period.…”

In vitro Cell-Based Assays for Potency Testing of Anti-TNF-α Biological Drugs

“…Recently, the WHO has prepared two international standards for the two anti-TNF-α biologics, etanercept and infliximab. These have been tested by several laboratories within an international collaborative study using a number of different cell-based assays [12,13]. In this chapter, we have presented an overview of the most routinely used tests for potency testing of anti-TNF-α biologics, which measure in vitro responses of nonmanipulated or genetically engineered human and animal cell lines, with various readout systems.…”

“…Table 1 contains some basic information regarding the most frequently used routine TNF-α neutralization (A), ADCC (B), and CDC (C) tests. The majority of data on bioassays presented in Table 1 (see next page) were summarized from two publications describing the establishment of the first infliximab and etanercept World Health Organization (WHO) International Standards [12,13]. These were performed within international collaborative studies, confirming their high degree of relevance and analytical laboratory utility.…”

Characterizing Phage-Host Interactions in a Simplified Human Intestinal Barrier Model

“…This aberrant response may be as a result of a reduction in commensal bacteria and an increase in potentially pathogenic bacteria [ 3 ]. Most of the treatments developed for IBD use small molecules, vaccines, anti-TNF, or monoclonal antibodies to modulate the immune response in the gut [ 4 , 5 , 6 ]. Unfortunately, these therapies fail for a third of patients, most likely because of the complexity of the disease and the suggested imbalance of the gut microbiota [ 7 , 8 , 9 ].…”