How the immune system responds to therapeutic biological agents

Biological agents target disease mechanisms and have modified the natural history of several immune-mediated disorders. Biological agents are structurally immunogenic, and therefore usually elicit a minor, subclinical and transient phenomenon. Occasionally, however, these drugs induce complete cellular and humoral immune responses, with the main clinical consequences being hypersensitivity reactions or loss of treatment response. This article considers the relative pathogenic mechanisms influencing immunogenicity in biological agents and discusses mechanisms of tolerance and adaptive immune response, including adaptive T-regulatory cell induction and immune response induction. Methods of determining cellular and humoral immune response to biological agents are identified and examined. Assays to detect antidrug antibodies and their isotypes can assist in monitoring immunogenicity and in preventing adverse events. Such strategies also enable resource conservation and may provide regulatory authorities with new insights that can be useful during the process of approving new biological or biosimilar agents.

[1]  A. Liston,et al.  Humoral autoimmunity: a failure of regulatory T cells? , 2015, Autoimmunity reviews.

[2]  E. Havrdová,et al.  Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium , 2015, Clinical and experimental immunology.

[3]  D. Murray,et al.  Tumor necrosis factor inhibitors: clinical utility in autoimmune diseases. , 2015, Translational research : the journal of laboratory and clinical medicine.

[4]  Vibha Jawa,et al.  T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation. , 2013, Clinical immunology.

[5]  P. Rutgeerts,et al.  Antibody Response to Infliximab and its Impact on Pharmacokinetics can be Transient , 2013, The American Journal of Gastroenterology.

[6]  J. Hillert,et al.  Characterization of anti-natalizumab antibodies in multiple sclerosis patients , 2013, Multiple sclerosis.

[7]  L. Aarden,et al.  Long-term measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding test shows predictive value and transient antibody formation , 2013, Annals of the rheumatic diseases.

[8]  Theo Rispens,et al.  Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralization , 2012 .

[9]  A. Matucci,et al.  Drug-Specific Th2 Cells and IgE Antibodies in a Patient with Anaphylaxis to Rituximab , 2012, International Archives of Allergy and Immunology.

[10]  S. Danese,et al.  TNFα inhibitors restrict T cell activation and cycling via Notch-1 signalling in inflammatory bowel disease , 2011, Gut.

[11]  Bjoern Peters,et al.  Applications for T-cell epitope queries and tools in the Immune Epitope Database and Analysis Resource. , 2011, Journal of immunological methods.

[12]  M. Genovese,et al.  Subcutaneous Abatacept vErsus Intravenous Abatacept: A Phase IIIb Noninferiority Study in Patients With an Inadequate Response to Methotrexate , 2011, Arthritis and rheumatism.

[13]  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.

[14]  A. Compston,et al.  A Novel Strategy To Reduce the Immunogenicity of Biological Therapies , 2010, The Journal of Immunology.

[15]  A. Matucci,et al.  Anti‐infliximab IgE and non‐IgE antibodies and induction of infusion‐related severe anaphylactic reactions , 2010, Allergy.

[16]  A. Sette,et al.  Optimizing Use of Tumor Necrosis Factor Inhibitors in the Management of Immune-Mediated Inflammatory Diseases , 2010, The Journal of Rheumatology. Supplement.

[17]  E. Bonfá,et al.  Immunogenicity of Anti-TNF-α Agents in Autoimmune Diseases , 2010, Clinical reviews in allergy & immunology.

[18]  Takahiko Horiuchi,et al.  Transmembrane TNF-α: structure, function and interaction with anti-TNF agents , 2010, Rheumatology.

[19]  Huub Schellekens,et al.  Immunological mechanism underlying the immune response to recombinant human protein therapeutics. , 2010, Trends in pharmacological sciences.

[20]  D. Scott,et al.  Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". , 2008, Blood.

[21]  A. Cheifetz,et al.  The impact of infliximab infusion reactions on long‐term outcomes in patients with Crohn’s disease , 2008, Alimentary pharmacology & therapeutics.

[22]  A. Kavanaugh,et al.  Adverse reactions to biologic agents: focus on autoimmune disease therapies. , 2005, The Journal of allergy and clinical immunology.

[23]  J. Brandt,et al.  Effect of double antigen bridging immunoassay format on antigen coating concentration dependence and implications for designing immunogenicity assays for monoclonal antibodies. , 2005, Journal of pharmaceutical and biomedical analysis.

[24]  Huub Schellekens,et al.  Factors influencing the immunogenicity of therapeutic proteins. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[25]  P. Anderson.  Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. , 2005, Seminars in arthritis and rheumatism.

[26]  E. Keystone,et al.  Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number. , 2004, The Journal of rheumatology.

[27]  S. Hanauer,et al.  Infliximab in the treatment of Crohn's disease: a user's guide for clinicians , 2002, American Journal of Gastroenterology.

[28]  T. Schaible.  Long term safety of infliximab. , 2000, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[29]  A. Denman.  Cellular and Molecular Immunology , 1992 .

[30]  M. Siddiqui,et al.  Infliximab: a review of its use in Crohn's disease and rheumatoid arthritis. , 2005, Drugs.