Immunogenicity of biological therapeutics: from assay to patient

Purpose of reviewTo give an overview of the current knowledge on assay techniques and clinical implications of immunogenicity of biological therapeutics. Recent findingsAssay techniques for the measurement of immunogenicity have improved, expanding the understanding of the immune response against biological therapeutics. Knowledge on the clinical effect of immunogenicity enables the treatment of patients in a targeted fashion, as a step towards personalized medicine. SummaryBiological medications are able to induce an antidrug immune response. Immunogenicity impairs clinical response and is associated with adverse events. Several confounding factors influence the measurement of immunogenicity, including drug interference and background problems. Concomitant administration of methotrexate lowers the frequency and amount of antibodies formed, whereby the efficacy of biologicals is improved. Algorithms for therapeutic drug monitoring could aid in adapting treatment strategies in a controlled setting.

[1]  B. Dijkmans,et al.  The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept , 2010, Annals of the rheumatic diseases.

[2]  W. Lems,et al.  The effect of immunomodulators on the immunogenicity of TNF-blocking therapeutic monoclonal antibodies: a review , 2010, Arthritis Research & Therapy.

[3]  B. Dijkmans,et al.  Anti-adalimumab antibodies in rheumatoid arthritis patients are associated with interleukin-10 gene polymorphisms. , 2009, Arthritis and rheumatism.

[4]  E. Martı́n-Mola,et al.  Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. , 2011, Rheumatology.

[5]  P. V. van Riel,et al.  Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusioncycle: an open-label pharmacokinetic cohort study , 2011, BMC musculoskeletal disorders.

[6]  Hervé Watier,et al.  Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases , 2011, Arthritis research & therapy.

[7]  K. Bendtzen.  Is there a need for immunopharmacologic guidance of anti-tumor necrosis factor therapies? , 2011, Arthritis and rheumatism.

[8]  B. Dijkmans,et al.  Patients non-responding to etanercept obtain lower etanercept concentrations compared to responding patients , 2013 .

[9]  P. Rutgeerts,et al.  Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease , 2007, Gut.

[10]  B. Dijkmans,et al.  Surprising negative association between IgG1 allotype disparity and anti-adalimumab formation: a cohort study , 2010, Arthritis research & therapy.

[11]  T. Rispens,et al.  Human IgG4 Binds to IgG4 and Conformationally Altered IgG1 via Fc-Fc Interactions , 2009, The Journal of Immunology.

[12]  B. Dijkmans,et al.  Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. , 2011, JAMA.

[13]  B. Dijkmans,et al.  Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study , 2009, Annals of the rheumatic diseases.

[14]  S. Hanauer,et al.  Assessing Response and Loss of Response to Biological Therapies in IBD , 2011, The American Journal of Gastroenterology.

[15]  H. H. Kuper,et al.  Frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in daily clinical practice , 2010, Arthritis care & research.

[16]  G. Van Assche,et al.  Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease , 2012, Inflammatory bowel diseases.

[17]  W. Sandborn,et al.  Clinical Utility of Measuring Infliximab and Human Anti-Chimeric Antibody Concentrations in Patients With Inflammatory Bowel Disease , 2010, The American Journal of Gastroenterology.

[18]  P. Parren,et al.  Anti-galactose-α-1,3-galactose IgE from allergic patients does not bind α-galactosylated glycans on intact therapeutic antibody Fc domains , 2011, Nature Biotechnology.

[19]  K. Bendtzen,et al.  Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. , 2006, Arthritis and rheumatism.

[20]  B. Dijkmans,et al.  Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study. , 2011, Arthritis and rheumatism.

[21]  L. Aarden,et al.  Differential effect of drug interference in immunogenicity assays. , 2011, Journal of immunological methods.

[22]  L. Aarden,et al.  Dealing with immunogenicity of biologicals: assessment and clinical relevance , 2009, Current opinion in rheumatology.

[23]  M. Wadhwa,et al.  Unwanted immunogenicity: lessons learned and future challenges. , 2010, Bioanalysis.

[24]  L. Aarden,et al.  A novel method for the detection of antibodies to adalimumab in the presence of drug reveals "hidden" immunogenicity in rheumatoid arthritis patients. , 2010, Journal of immunological methods.

[25]  An Carbonez,et al.  Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. , 2003, The New England journal of medicine.

[26]  Quynh-Thu Le,et al.  Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. , 2008, The New England journal of medicine.

[27]  S. Misbah,et al.  Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. , 2008, The New England journal of medicine.

[28]  Steven J Swanson,et al.  Rheumatoid factor interference in immunogenicity assays for human monoclonal antibody therapeutics. , 2010, Journal of immunological methods.

[29]  L. Aarden,et al.  Antibodies to constant domains of therapeutic monoclonal antibodies: anti-hinge antibodies in immunogenicity testing. , 2012, Journal of immunological methods.

[30]  L. Aarden,et al.  Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis , 2006, Annals of the rheumatic diseases.

[31]  A. L. Wong,et al.  Localization of an Fc-binding reactivity to the constant region of human IgG4. Implications for the pathogenesis of rheumatoid arthritis. , 1995, Journal of immunology.

[32]  S. Swanson,et al.  Detection of neutralizing anti-therapeutic protein antibodies in serum or plasma samples containing high levels of the therapeutic protein. , 2006, Journal of immunological methods.

[33]  Allen R Nissenson,et al.  Pure red-cell aplasia and epoetin therapy. , 2004, The New England journal of medicine.

[34]  L. Aarden,et al.  Measurement of serum levels of natalizumab, an immunoglobulin G4 therapeutic monoclonal antibody. , 2011, Analytical biochemistry.