Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: Evaluation of an antidrug antibody ELISA using clinical adverse event-driven immunogenicity testing.

BACKGROUND: Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody directed against the interleukin-6 receptor. In Europe, TCZ is approved for use in combination with methotrexate in the treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have failed to respond to or were unable to tolerate previous therapy with one or more disease-modifying antirheumatic drugs or tumor necrosis factor (TNF) antagonists; in the United States, it is approved for the treatment of adult patients with moderate to severe active RA who have failed to respond to one or more TNF antagonists. As part of the Phase III clinical development program, the immunogenicity of TCZ was evaluated using a bridging ELISA; however, this assay is considered limited in detecting low-affinity or immunoglobulin G4 subisotype antidrug antibodies (ADAs).
OBJECTIVE: This study assessed the validity of the ELISA for detecting anti-TCZ ADAs by using complementary bioanalytic assays to test samples from a subgroup of patients with clinical adverse events (AEs) of a potentially immunogenic nature, who were considered highly likely to have ADAs. The goal was to determine whether use of these additional assays led to detection of ADAs not found on the ELISA, thus minimizing the risk of false-negative results.
METHODS: The Phase III program for TCZ consisted of 5 core studies in which adult patients with RA received either TCZ 4 or 8 mg/kg IV or control every 4 weeks, with or without concomitant antirheumatic therapy. Blood samples obtained at baseline and at regular intervals thereafter were tested using the ELISA for ADA screening and confirmation. Regardless of the results on ADA screening, samples from patients who developed clinical AEs of a potentially immunogenic nature (ie, falling within predefined system organ classes, occurring during or within 24 hours of TCZ infusion, considered related to TCZ therapy, or leading to study withdrawal) were subjected to additional testing with a surface plasmon resonance (SPR) assay for isotyping and epitope localization and a standard ImmunoCAP immunoglobulin E (IgE) assay made specific for TCZ.
RESULTS: The 5 core studies and their open-label, longterm extension studies enrolled a total of 4199 adult patients with RA (82.1% female; 74.0% white; mean age, 52.0 years [range, 18-89 years]; mean weight, 73.4 kg [range, 35-150 kg]); 2928 patients received TCZ and 1271 received control. Of the 2816 samples from TCZ-treated patients tested, 64 (2.3%) had samples that tested positive at least once on the ELISA screening and confirmation assay, 48 (75.0%) of them at baseline. A clinical AE of a potentially immunogenic nature occurred during TCZ treatment in 21 patients, 8 of whom had an anaphylactic reaction. Eleven of the samples from these 21 patients had tested negative for AD As on the screening ELISA. Only 1 of these 11 patients tested positive for ADAs on both additional assays; all others tested negative. The results of the ELISA, SPR, and IgE assays were consistent for 16 of 18 tested patients (88.9%) who provided data on at least 2 of the 3 assays.
CONCLUSIONS: Based on the findings of this analysis in a relevant patient population, the bridging-type screening and confirmation ELISA was a valid method of detecting anti-TCZ ADAs. Immunogenicity testing of samples from patients with clinical AEs of a potentially immunogenic nature using assays complementary to the ELISA added valuable information about the incidence and character of ADAs.