Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and drug concentrations: the POETIC Study

Ungar, Bella; Engel, Tal; Yablecovitch, Doron; Lahat, Adi; Lang, Alon; Avidan, Benjamin; Har-Noy, Ofir; Carter, Dan; Levhar, Nina; Selinger, Limor; Neuman, Sandra; Natour, Ola Haj; Yavzori, Miri; Fudim, Ella; Picard, Orit; Kopylov, Uri; Chowers, Yehuda; Naftali, Timna; Broide, Efrat; Shachar, Eyal; Eliakim, Rami; Ben‐Horin, Shomron

doi:10.1038/s41395-018-0073-0

Cited by 71 publications

(54 citation statements)

References 33 publications

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“…For IFX, a TL cut-off >5 mg/ml is considered therapeutic during maintenance thrapy [19,20]. For ADL, steady-state serum levels >5 mg/ml are associated with mucosal healing [18][19][20][21]. Interestingly, it seems that optimal cut-off points for anti-TNF serum levels may depend on the desired treatment goal (i.e., clinical remission, mucosal or fistula healing, etc.).…”

Section: Discussionmentioning

confidence: 99%

“…For IFX, only trough levels (TLs) were used. For ADL, all serum drug measurements between two injections were eligible for inclusion, since all patients were on maintenance treatment and reached steady state [18]. Information about demographics, disease and treatment duration, fistula characteristics, dosing regimens, smoking status, immunogenicity and concomitant immunomodulator use was collected.…”

Section: Methodsmentioning

confidence: 99%

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Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn’s disease patients

Strik

Löwenberg

Buskens

et al. 2019

Scandinavian Journal of Gastroenterology

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Objectives: Anti-TNF agents are effective to treat perianal Crohn's disease (CD). Evidence suggests that Crohn's disease patients with perianal fistulas need higher infliximab (IFX) serum concentrations compared to patients without perianal CD to achieve complete disease control. Our aim was to compare anti-TNF serum concentrations between patients with actively draining and closed perianal fistulas. Methods: A retrospective survey was performed in CD patients with perianal disease treated with IFX or adalimumab (ADL). Fistula closure was defined as absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imaging. Results: We identified 66 CD patients with a history of perianal fistulas treated with IFX (n ¼ 47) and ADL (n ¼ 19). Median IFX serum trough concentrations ([interquartile range]) were higher in patients with closed fistulas (n ¼ 32) compared to patients with actively draining fistulas (n ¼ 15): 6.0 mg/ml [5.4-6.9] versus 2.3 mg/ml [1.1-4.0], respectively (p < .001)). A similar difference was seen in patients treated with ADL: median serum concentrations were 7.4 mg/ml [6.5-10.8] in 13 patients with closed fistulas versus 4.8 mg/ml [1.7-6.2] in 6 patients with producing fistulas (p ¼ .003). Serum concentrations of 5.0 mg/ml for IFX (area under the curve of 0.92; 95% CI: 0.82-1.00)) and 5.9 mg/ml for ADL (area under the curve of 0.89; 95% CI 0.71-1.00) were associated with fistula closure. Conclusion: Cut-off serum concentrations 5.0 mg/ml for IFX and 5.9 mg/ml for ADL were associated with perianal fistula closure. Hence, patients with producing perianal fistulas may benefit from anti-TNF dose intensification to achieve fistula closure.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn’s disease patients

Strik

Löwenberg

Buskens

et al. 2019

Scandinavian Journal of Gastroenterology

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“…Using a drug tolerant assay, this rate raised between 20% and 25% 1 without, however, having any idea about the function and significance of these antibodies. Under ADA or IFX, the development of anti‐drug antibodies during induction was associated significantly with primary non response to anti‐TNF 5,6 . Thirdly, the authors did not report any data about mucosal healing and histological remission.…”

mentioning

confidence: 94%

Editorial: therapeutic drug monitoring for golimumab – ready for prime time?

Roblin

Roy

Paul

2020

Aliment Pharmacol Ther

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“…The reported immunogenicity extent of these drugs is inconsistent. Whereas, pharmaceutical companies report 10-15 and 2.6-26% immunogenicity for IFX and ADL, respectively (14), clinical data suggest higher immunogenicity rates for these drugs (15). Patients treated with IFX and ADL can be stratified based on the characteristics of their response to treatment or lack thereof.…”

Section: Introductionmentioning

confidence: 99%

“…Patients treated with IFX and ADL can be stratified based on the characteristics of their response to treatment or lack thereof. Primary non-responders are patients whose disease does not respond to the drug at all, and a certain subset of these may be mediated via early formation of ADA (15,16). Secondary nonresponders are patients who initially respond to the drug but later fail treatment, often due to development of ADA (for IFX, this was reported to develop mostly within 12 months of treatment initiation) (16).…”

Section: Introductionmentioning

confidence: 99%

Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNFα Antagonists

et al. 2019

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Drugs formulated from monoclonal antibodies (mAbs) are clinically effective in various diseases. Repeated administration of mAbs, however, elicits an immune response in the form of anti-drug-antibodies (ADA), thereby reducing the drug's efficacy. Notwithstanding their importance, the molecular landscape of ADA and the mechanisms involved in their formation are not fully understood. Using a newly developed quantitative bio-immunoassay, we found that ADA concentrations specific to TNFα antagonists can exceed extreme concentrations of 1 mg/ml with a wide range of neutralization capacity. Our data further suggest a preferential use of the λ light chain in a subset of neutralizing ADA. Moreover, we show that administration of TNFα antagonists result in a vaccine-like response whereby ADA formation is governed by the extrafollicular T cell-independent immune response. Our bio-immunoassay coupled with insights on the nature of the immune response can be leveraged to improve mAb immunogenicity assessment and facilitate improvement in therapeutic intervention strategies.

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Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and drug concentrations: the POETIC Study

Cited by 71 publications

References 33 publications

Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn’s disease patients

Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn’s disease patients

Editorial: therapeutic drug monitoring for golimumab – ready for prime time?

Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNFα Antagonists

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