Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results

Abstract

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNβ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNβ-1a subcutaneous (s.c.) and IFNβ-1b s.c. in favor of the least immunogenic preparation IFNβ-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNβ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNβ ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

“…Tocilizumab and rituximab also resulted in a higher ADA incidence in the ABIRISK prospective study than in previous reports, likely because of the sensitivity and drug tolerance of the MSD assay, which has not been used before for detecting ADAs against these BPs in RA [ 54 – 57 ]. Concerning the other biologicals analyzed in this study, the broad immunogenicity level was comparable to what has been previously reported [ 58 , 59 ].…”

A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients

“…The therapeutic use of monoclonal antibodies and other biopharmaceutical products can result in an immune response to the drug that, in some cases, affects its efficacy due to the production of neutralizing ADAs 5 . Several clinical studies have measured ADA levels in sera of selected cohorts of patients and concluded that not all antibody responses lead to drug neutralization [6][7][8][9][10][11] . However, an explanation for these heterogeneous responses and an integrated characterization of the B and T cell responses to the drug are still missing.…”

Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue

“…Development of ADAs can affect safety or efficacy 11,[28][29][30] may not be recognized until the commencement of large expensive phase 3 clinical studies 5 or even after approval. [31][32][33][34][35] This latestage failure of drugs adds considerable economic risk for the biotechnology industry. More important, the potential consequences of immunogenicity for a subject in a clinical study range from loss in quality of life 36 to a life-threatening situation.…”