Immunogenicity of biologicals
Increasing numbers of proteins are used as therapeutic agents. In particular, therapeutic monoclonal antibodies are used increasingly to treat a variety of disorders such as rheumatoid arthritis. Therapeutic proteins can induce an unwanted antibody response that diminishes treatment efficacy. Even fully human therapeutic antibodies can induce an antibody response. We study the responses to various therapeutic antibodies (anti-idiotype, neutralizing/non-neutralizing), the biology of immune complexes, and the regulation of B cell responses to therapeutic antibodies. This project is also firmly linked to Sanquin Diagnostic Services. Assay development is an integral part of this project resulting in new tests for immunogenicity testing.
Even where the therapeutic mAb is fully human, anti-idiotypic responses are elicited in a considerable number of the patients. This leads to reduced efficacy due to blocking of the therapeutic drug by anti-drug antibodies. Patients may also develop treatment-related side effects due to the formation of immune complexes (IC). We studied antibody formation in rheumatoid arthritis patients treated at 2-weekly intervals with the fully human anti-TNFα antibody adalimumab and found that within 6 months of treatment 70% of the patients produced anti-adalimumab antibodies, mostly of the IgG1 and IgG4 subclass. Small circulating IC could be detected in most patients even two weeks after the administration of adalimumab. In other words, these patients are permanently exposed to high concentrations of small IC.
- Van Schouwenburg PA, van de Stadt LA, de Jong RN, van Buren EE, Kruithof S, de Groot E, Hart M, van Ham SM, Rispens T, Aarden L, Wolbink GJ, Wouters D. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann Rheum Dis 2013; 72(1):104-9.
- Hart MH, de Vrieze H, Wouters D, Wolbink GJ, Killestein J, de Groot ER, Aarden LA, Rispens T. Differential effect of drug interference in immunogenicity assays. J Immunol Methods 2011; 372:196-203.
- Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, Dijkmans BA, Aarden L, Wolbink GJ. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 2011; 305:1460-8.
- Jamnitski A, Bartelds GM, Nurmohamed MT, van Schouwenburg PA, van Schaardenburg D, Stapel SO, Dijkmans BA, Aarden L, Wolbink GJ. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis 2011; 70:284-8.