AB0055 Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralization

Abstract

Background Worldwide millions of patients are treated with monoclonal antibodies. These biological therapeutics can be immunogenic, resulting in antibody formation which lead to loss of response. Fully human biologics such as the anti-TNFα antibody adalimumab are considered to be weakly immunogenic, but we found that the majority of Rheumatoid Arthritis patients develop anti-drug antibodies (ADA) within 28 weeks of treatment. Objectives Here we unraveled the mechanism by which ADA lead to loss of response by investigating the full specificity of the repertoire of anti-adalimumab antibodies. Methods The specificity of the repertoire of anti-adalimumab antibodies in a cohort of 50 ADA-positive RA patients was elucidated. In inhibition experiments using TNFa and patient derived anti-adalimumab monoclonal antibodies that were recombinantly generated after isolation of adalimumab-specific B cells. Results The antibody response against adalimumab is highly restricted: Fab fragments of a single, monoclonal antibody specific for the idiotype of adalimumab inhibited 98.65% (25th-75th percentiles: 98.25- 99.90) of the total anti-adalimumab reactivity in sera of 50 different ADA-positive RA patients. Furthermore, we found that the anti-adalimumab response is confined to the TNFα binding region of adalimumab, thereby neutralizing its therapeutic efficacy. In line with this restricted specificity, we observed small immune complexes in the circulation of ADA-forming patients. Conclusions The humoral immune response against adalimumab is highly restricted and limited to the idiotype of the therapeutic antibody. All antibodies result in functional neutralization of the drug, thereby providing a mechanism in which ADA formation leads to clinical non-response. Disclosure of Interest None Declared

Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis

“…Based on the findings of previous studies,9 10 14– –16 23––25 meta-analyses as well as recommendations18 32 44 46––48 and our results, we recommend an algorithm (figure 4) with an emphasis on therapeutic strategies based on drug trough levels and ADAb positivity for RA patients with different responses to anti-TNF-α therapy. Also, recent reports24 25 have proposed that determination of the drug trough level may serve as the front-line evaluation and help to predict therapeutic response.…”

“…Moreover, our results showed an inverse correlation between ADAb levels and improvement of disease activity (ΔDAS28). The mechanisms through which the emergence of ADAb hampers therapeutic response may include the formation of immune complexes leading to acceleration of drug clearance10 43 or functional neutralisation of the drug through blockage of its binding to the target 10…”

“…Although anti-TNF-α therapy can be effective and well tolerated for RA patients,4––6 not all patients respond to them from the start (primary failure) and the effectiveness diminishes in some patients over time (secondary failure) 7. The exact mechanism of the inadequate response to anti-TNF-α therapy has not been fully explored 8––10…”

Surface plasmon resonance-based methodology for anti-adalimumab antibody identification and kinetic characterization

“…These results are relevant in the context of the discussion on anti-ADA antibody neutralizing capacity [16]. In fact, a recent study reporting affinity and specificity of patientderived monoclonal anti-ADA antibodies hypothesized that although antibodies compete for binding to TNF, the response is clonally diverse and involves multiple epitopes on the drug ADA [36].…”

“…In any case, a general consensus associating the presence of anti-ADA antibodies to treatment failure or lower clinical remission was reached [15]. In fact, anti-ADA antibodies not only increase drug clearance but also appear to be directed mainly, if not exclusively, to the TNF binding site, thus efficiently neutralizing the drug [16,17].…”