Infusion reactions during infliximab treatment are not associated with IgE anti-infliximab antibodies

Schie, Karin A van; Heer, Pleuni Ooijevaar-de; Kruithof, Simone; Plasencia, C.; Jurado, Teresa; Salcedo, Dora Pascual; Brandse, Johannan F.; D’Haens, Geert R.; Wolbink, Gertjan; Rispens, Theo

doi:10.1136/annrheumdis-2016-211035

Cited by 13 publications

(9 citation statements)

References 16 publications

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“…A panel of patient-derived recombinant monoclonal anti-infliximab antibodies was produced 23. All monoclonal antibodies competed with tumour necrosis factor (TNF) for binding infliximab, as determined with a TNF competition assay (online supplementary table S1).…”

Section: Resultsmentioning

confidence: 99%

Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies

et al. 2018

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ObjectivesTherapeutic antibodies can provoke an antidrug antibody (ADA) response, which can form soluble immune complexes with the drug in potentially high amounts. Nevertheless, ADA-associated adverse events are usually rare, although with notable exceptions including infliximab. The immune activating effects and the eventual fate of these ‘anti-idiotype’ complexes are poorly studied, hampering assessment of ADA-associated risk of adverse events. We investigated the in vitro formation and biological activities of ADA-drug anti-idiotype immune complexes using patient-derived monoclonal anti-infliximab antibodies.MethodsSize distribution and conformation of ADA-drug complexes were characterised by size-exclusion chromatography and electron microscopy. Internalisation of and immune activation by complexes of defined size was visualised with flow imaging, whole blood cell assay and C4b/c ELISA.ResultsSize and conformation of immune complexes depended on the concentrations and ratio of drug and ADA; large complexes (>6 IgGs) formed only with high ADA titres. Macrophages efficiently internalised tetrameric and bigger complexes in vitro, but not dimers. Corroborating these results, ex vivo analysis of patient sera demonstrated only dimeric complexes in circulation.No activation of immune cells by anti-idiotype complexes was observed, and only very large complexes activated complement. Unlike Fc-linked hexamers, anti-idiotype hexamers did not activate complement, demonstrating that besides size, conformation governs immune complex potential for triggering effector functions.ConclusionsAnti-idiotype ADA-drug complexes generally have restricted immune activation capacity. Large, irregularly shaped complexes only form at high concentrations of both drug and ADA, as may be achieved during intravenous infusion of infliximab, explaining the rarity of serious ADA-associated adverse events.

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Section: Resultsmentioning

confidence: 99%

Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies

et al. 2018

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“…The asparagine residues to which glycans can be attached are located in CDR1 (N L 37), CDR2 (N H 59), and FR3 (N H 77, N H 82, N H 84, N L 79, and N L 86). The human monoclonal patient-derived anti-adalimumab and anti-infliximab antibodies and mutants were obtained, designed, and produced as described previously ( 3 , 13 , 14 ). Briefly, single antigen-specific memory B cells were isolated from patients producing antibodies against adalimumab or infliximab and cultured and screened for specificity.…”

Section: Methodsmentioning

confidence: 99%

Variable Domain N-Linked Glycans Acquired During Antigen-Specific Immune Responses Can Contribute to Immunoglobulin G Antibody Stability

et al. 2018

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Immunoglobulin G (IgG) can contain N-linked glycans in the variable domains, the so-called Fab glycans, in addition to the Fc glycans in the CH2 domains. These Fab glycans are acquired following introduction of N-glycosylation sites during somatic hypermutation and contribute to antibody diversification. We investigated whether Fab glycans may—in addition to affecting antigen binding—contribute to antibody stability. By analyzing thermal unfolding profiles of antibodies with or without Fab glycans, we demonstrate that introduction of Fab glycans can improve antibody stability. Strikingly, removal of Fab glycans naturally acquired during antigen-specific immune responses can deteriorate antibody stability, suggesting in vivo selection of stable, glycosylated antibodies. Collectively, our data show that variable domain N-linked glycans acquired during somatic hypermutation can contribute to IgG antibody stability. These findings indicate that introducing Fab glycans may represent a mechanism to improve therapeutic/diagnostic antibody stability.

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“…A recombinant IgM antibody was generated by cloning the rearranged variable regions of a Vel‐specific single B‐cell clone into a vector containing the IgM constant regions. Using a similar approach, we previously generated anti‐D IgG, anti‐adalimumab, anti‐natalizumab, and anti‐infliximab . This demonstrates the usability of this protocol to manufacture recombinant MoAbs customized to any immunoglobulin class (IgG, IgM, etc.).…”

Section: Discussionmentioning

confidence: 81%

“…Using a similar approach, we previously generated anti-D IgG, anti-adalimumab, anti-natalizumab, and anti-infliximab. 9,10,[14][15][16] This demonstrates the usability of this protocol to manufacture recombinant MoAbs customized to any immunoglobulin class (IgG, IgM, etc.). Therefore, the generation of hybridoma cultures is not required.…”

Section: Discussionmentioning

confidence: 82%

Development of a recombinant anti‐Vel immunoglobulin M to identify Vel‐negative donors

Rijst

Lissenberg-Thunnissen

Ligthart

et al. 2019

Transfusion

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BACKGROUND Alloimmunization against the high‐frequency Vel blood group antigen may result in transfusion reactions or hemolytic disease of fetus and newborn. Patients with anti‐Vel alloantibodies require Vel‐negative blood but Vel‐negative individuals are rare (1:4000). Identification of Vel‐negative donors ensures availability of Vel‐negative blood; however, accurate Vel blood group typing is difficult due to variable Vel antigen expression and limited availability of anti‐Vel typing sera. We report the production of a recombinant anti‐Vel that also identifies weak Vel expression. STUDY DESIGN AND METHODS A recombinant anti‐Vel monoclonal antibody was produced by cloning the variable regions from an anti‐Vel–specific B cell isolated from an alloimmunized patient into a vector harboring the constant regions of immunoglobulin (Ig)G1‐kappa or IgM‐kappa. Antibody Vel specificity was tested by reactivity to SMIM1‐transfected HEK293T cells and by testing various red blood cells (RBCs) of donors with normal, weak, or no Vel expression. High‐throughput donor screening applicability was tested using an automated blood group analyzer. RESULTS A Vel‐specific IgM class antibody was produced. The antibody was able to distinguish between Vel‐negative and very weak Vel antigen–expressing RBCs by direct agglutination and in high‐throughput settings using a fully automated blood group analyzer and performed better than currently used human anti‐Vel sera. High‐throughput screening of 13,288 blood donations identified three new Vel‐negative donors. CONCLUSION We generated a directly agglutinating recombinant anti‐Vel IgM, M3F5S‐IgM, functional in manual, automated agglutination assays and flow cytometry settings. This IgM anti‐Vel will improve diagnostics by facilitating the identification of Vel‐negative blood donors.

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Infusion reactions during infliximab treatment are not associated with IgE anti-infliximab antibodies

Abstract: IgE-ADA is rarely detected in infliximab-treated patients. Moreover, the absence of IgE-ADA in the majority of IR+ patients suggests that IgE-ADA is not associated with infusion reactions.

Cited by 13 publications

References 16 publications

Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies

Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies

Variable Domain N-Linked Glycans Acquired During Antigen-Specific Immune Responses Can Contribute to Immunoglobulin G Antibody Stability

Development of a recombinant anti‐Vel immunoglobulin M to identify Vel‐negative donors

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