Standardization of the homogeneous mobility shift assay protocol for evaluation of anti-infliximab antibodies. Application of the method to Crohn’s disease patients treated with infliximab

Hernández-Breijo, Borja; Chaparro, María; Cano-Martínez, D.; Guerra, Iván; Iborra, Marisa; Cabriada, José Luis; Bujanda, Luís; Taxonera, Carlos; García–Sánchez, Valle; Marín-Jiménez, Ignacio; Acosta, Manuel Barreiro‐de; Vera, Isabel; Martín-Arranz, María Dolores; Mesonero, Francisco; Sempere, Laura; Gomollón, Fernando; Hinojosa, Joaquín; Gisbert, Javier P.; Guijarro, Luis

doi:10.1016/j.bcp.2016.09.019

Cited by 11 publications

(5 citation statements)

References 21 publications

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“…Several other techniques have been reported to evaluate serum ADA levels. These assays include radio-immunoassays ( 127 ), Biotin-drug Extraction with Acid Dissociation (BEAD) ( 128 ), Precipitation and Acid dissociation (PANDA) ( 129 ), Affinity Capture Elution ELISA (ACE) ( 130 ), and Homogenous Mobility Shift Assay (HMSA) ( 131 ); these assays have been reviewed in detail elsewhere ( 126 ). While these assays presumably detect all serum ADA, they primarily provide qualitative measures to assist healthcare providers deciding on appropriate patient interventions, and many (if not all) studies underestimate actual ADA levels.…”

Section: Assays For Immunogenicity Assessment and Tools For Immunogenmentioning

confidence: 99%

The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment With Monoclonal Antibodies

et al. 2020

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Monoclonal antibodies (mAbs) are a crucial asset for human health and modern medicine, however, the repeated administration of mAbs can be highly immunogenic. Drug immunogenicity manifests in the generation of anti-drug antibodies (ADAs), and some mAbs show immunogenicity in up to 70% of patients. ADAs can alter a drug’s pharmacokinetic and pharmacodynamic properties, reducing drug efficacy. In more severe cases, ADAs can neutralize the drug’s therapeutic effects or cause severe adverse events to the patient. While some contributing factors to ADA formation are known, the molecular mechanisms of how therapeutic mAbs elicit ADAs are not completely clear. Accurate ADA detection is necessary to provide clinicians with sufficient information for patient monitoring and clinical intervention. However, ADA assays present unique challenges because both the analyte and antigen are antibodies, so most assays are cumbersome, costly, time consuming, and lack standardization. This review will discuss aspects related to ADA formation following mAb drug administration. First, we will provide an overview of the prevalence of ADA formation and the available diagnostic tools for their detection. Next, we will review studies that support possible molecular mechanisms causing the formation of ADA. Finally, we will summarize recent approaches used to decrease the propensity of mAbs to induce ADAs.

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Section: Assays For Immunogenicity Assessment and Tools For Immunogenmentioning

confidence: 99%

The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment With Monoclonal Antibodies

et al. 2020

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“…Many methods were previously reported to evaluate serum ADA levels. These assays include radio-immunoassays (43), Biotin-drug Extraction with Acid Dissociation (BEAD) (44), Precipitation and acid dissociation (PANDA) (45), affinity capture elution ELISA (ACE) (46), and Homogenous Mobility Shift Assay (HMSA) (47). While these assays are not limited to the λ light chain detection like the AHLC assay, they provide mostly qualitative measures to assist physicians in deciding the most appropriate intervention when treating patients, and many (if not all) studies underestimated actual ADA levels (19).…”

Section: Discussionmentioning

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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“…16 Patients came from the Predicrohn study, which is a multicenter study aiming to optimize treatment with anti-TNF drugs. 17 The trial included 150 CD patients naïve to anti-TNF treatment; only patients with active disease, based on the Crohn’s Disease Activity Index (CDAI) at baseline, were eligible for the genetic approach. All patients were naïve to anti-TNF therapy and received 160/80 mg adalimumab at weeks 0 and 2, and 40 mg every other week thereafter, or infliximab 5 mg/kg at weeks 0, 2, 6, and 14, and every 8 weeks thereafter.…”

Section: Methodsmentioning

confidence: 99%

Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease

Chaparro

Aterido

Guerra

et al. 2019

Therap Adv Gastroenterol

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Background: The effect of low-frequency functional variation on anti-tumor necrosis factor alpha (TNF) response in Crohn’s disease (CD) patients remains unexplored. The objective of this study was to investigate the impact of functional rare variants in clinical response to anti-TNF therapy in CD. Methods: CD anti-TNF naïve patients starting anti-TNF treatment due to active disease [Crohn’s Disease Activity Index (CDAI > 150)] were included. The whole genome was sequenced using the Illumina Hiseq4000 platform. Clinical response was defined as a CDAI score <150 at week 14 of anti-TNF treatment. Low-frequency variants were annotated and classified according to their damaging potential. The whole genome of CD patients was screened to identify homozygous loss-of-function (LoF) variants. The TNF signaling pathway was tested for overabundance of damaging variants using the SKAT-O method. Functional implication of the associated rare variation was evaluated using cell-type epigenetic enrichment analyses. Results: A total of 41 consecutive CD patients were included; 3250 functional rare variants were identified (2682 damaging and 568 LoF variants). Two homozygous LoF mutations were found in HLA-B and HLA-DRB1 genes associated with lack of response and remission, respectively. Genome-wide LoF variants were enriched in epigenetic marks specific for the gastrointestinal tissue (colon, p = 4.11e–4; duodenum, p = 0.011). The burden of damaging variation in the TNF signaling pathway was associated with response to anti-TNF therapy ( p = 0.016); damaging variants were enriched in epigenetic marks from CD8+ ( p = 6.01e–4) and CD4+ ( p = 0.032) T cells. Conclusions: Functional rare variants are involved in the response to anti-TNF therapy in CD. Cell-type enrichment analysis suggests that the gut mucosa and CD8+ T cells are the main mediators of this response.

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Standardization of the homogeneous mobility shift assay protocol for evaluation of anti-infliximab antibodies. Application of the method to Crohn’s disease patients treated with infliximab

Cited by 11 publications

References 21 publications

The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment With Monoclonal Antibodies

The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment With Monoclonal Antibodies

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

Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease

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