THU0205 The effect of certolizumab drug concentration and anti-drug antibodies on tnf neutralisation

Abstract

BackgroundAlthough tumour necrosis factor- (TNF) inhibitors have proven to be a successful treatment option for patients with rheumatoid arthritis (RA), TNF-inhibitors, including certolizumab, elicit an immunogenic response leading to the formation of anti-drug antibodies (ADAs) (reported range ~5%–39% of the patients).ObjectivesWe sought to investigate the relationship between certolizumab concentrations, ADAs, and the effective TNF neutralising capacity in sera of RA patients. TNF neutralising capacity of certolizumab was compared to the neutralising capacity of adalimumab.MethodsBlood was collected of 35 consecutive certolizumab-treated RA patients at baseline and 4, 16, 28 and 52 weeks after treatment initiation. Certolizumab and ADA levels were quantified using a certolizumab bridging enzyme-linked immunosorbent assay (ELISA) and a drug-tolerant radioimmunoassay (RIA), respectively. TNF neutralisation of certolizumab and adalimumab in patient sera, in presence or absence of ADAs, was analysed using the TNF-sensitive WEHI bioassay.ResultsDespite a high incidence of ADAs during one year of follow-up (69%; 24/35 patients), certolizumab levels of ~>10 µg/mL were measured in most patients (Spearman’s r=−0.7155, p<0.0001 (n=118); figure 1A). Furthermore, TNF neutralisation, expressed by EC50 values, was highly correlated with certolizumab serum concentration, while there was no association with ADAs (Pearson r=0.9087, p<0.0001 (n=12) and Pearson r=−0.4712, p=0.1220 (n=12); figure 1B and C, respectively. Grey lines indicate log-log linear fit, weight by 1/Y^2). Similar results were obtained for adalimumab, although TNF neutralisation by adalimumab was less potent; the relative in vitroneutralising potency was 43 times higher for certolizumab compared to the neutralising potency of adalimumab.ConclusionsOur study shows that certolizumab is highly immunogenic. In most cases where ADAs are detected, certolizumab is also present in high amounts, and can still potently neutralise TNF. Furthermore, TNF neutralisation is highly correlated with certolizumab concentrations. Therefore, measurement of certolizumab concentrations is the relevant parameter to assess clinically relevant immunogenicity.Disclosure of InterestL. Berkhout: None declared, E. Vogelzang: None declared, M. Hart: None declared, N. Derksen: None declared, R. Wieringa: None declared, W. van Leeuwen: None declared, C. Krieckaert Speakers bureau: Pfizer, A. de Vries: None declared, M. Nurmohamed Consultant for: Abbott, Roche, Pfizer, MSD, UCB, SOBI, BMS, Speakers bureau: Abbott, Roche, Pfizer, G. Wolbink Grant/research support from: Pfizer, Speakers bureau: Pfizer, UCB, AbbVie, Biogen, BMS, T. Rispens Grant/research support from: Genmab, Speakers bureau: Pfizer, AbbVie, Regeneron

Impact of immunogenicity on clinical efficacy and toxicity profile of biologic agents used for treatment of inflammatory arthritis in children compared to adults

“…There is evidence that ADAs were still detected at higher certolizumab concentrations of >10 mg/l. 59 The majority of patients with ADA had detectable titres from week 16 onwards, and 65% remained ADA positive after 1 year of follow up. 59 There are no studies in paediatric populations.…”

Psoriasis: Recent progress in molecular‐targeted therapies

“…Additionally, the response ratios of groups treated with 200 and 400 mg eow of CZP are were 63.8% and 56.3% (placebo 23.5%) in ACR20, 44.2% and 40.0% (placebo 12.5%) in ACR50, and 28.3 and 23.7% (placebo 4.4%) in ACR70, respectively 65 . As observed in other TNF inhibitors, ADA can frequently be detected in CZP‐treated cases, but the existence of ADA is usually not associated with the trough level of CZP 66,67 …”

“…and 400 mg eow of CZP are were 63.8% and 56.3% (placebo 23.5%) in ACR20, 44.2% and 40.0% (placebo 12.5%) in ACR50, and 28.3 and 23.7% (placebo 4.4%) in ACR70, respectively 65. As observed in other TNF inhibitors, ADA can frequently be detected in CZP-treated cases, but the existence of ADA is usually not associated with the trough level of CZP 66,67. Functional IL-17 is composed of homodimers of each subtype or a heterodimer of IL-17A and IL-17F; the IL-17-signaling is transmitted via ligand-specific IL-17 receptors (IL-17R) (Figure2a), whereas IL-17A signaling can be transmitted via IL-17RA, IL-17RC, and IL-17RD [68][69][70][71].…”

Biologic Drugs for Rheumatoid Arthritis in the Context of Biosimilars, Genetics, Epigenetics and COVID-19 Treatment

“…Efficacy of CTZ seems to be comparable to other TNFi in RA treatment, although in the majority of patients neutralizing antibodies were found [ 63 ]. Yet, high concentrations of CTZ in sera (>10 mg/L) were able to sustain a sufficient clinical response in RA treatment [ 64 ]. Therefore, the presence of neutralizing antibodies could result from high concentrations of CTZ administration.…”