title: Immunogenicity of therapeutics: a matter of efficacy and safety.
abstract: BACKGROUND
  The unwanted immunogenicity of therapeutic proteins is a major concern regarding patient safety. Furthermore, pharmacokinetic, pharmacodynamic and clinical efficacy can be seriously affected by the immunogenicity of therapeutic proteins. Authorities have fully recognized this issue and demand appropriate and well-characterized assays to detect anti-drug antibodies (ADAs).
  
  
  METHODS
  We provide an overview of the immunogenicity topic in general, the regulatory background and insight into underlying immunological mechanisms and the limited ability to predict clinical immunogenicity a priori. Furthermore, we comment on the analytical testing approach and the status-quo of appropriate method validation.
  
  
  RESULTS
  The review provides insight regarding the analytical approach that is expected by regulatory authorities overseeing immunogenicity testing requirements. Additionally, the factors influencing immunogenicity are summarized and key references regarding immunogenicity testing approaches and method validation are discussed.
  
  
  CONCLUSIONS
  The unwanted immunogenicity of protein therapeutics is of major concern because of its potential to affect patient safety and drug efficacy. Analytical testing is sophisticated and requires more than one assay. Because immunogenicity in humans is hardly predictable, assay development has to start in a timely fashion and for clinical studies immunogenicity assay validation is mandatory prior to analyzing patient serum samples. Regarding ADAs, the question remains as to when such antibodies are regarded of clinical relevance and what levels are, if at all, acceptable. In summary, the detection of ADAs should raise the awareness of the physician concerning patient safety and of the sponsor/manufacture concerning the immunogenic potential of the drug product.
authors: Vela pharmazeutische Entwicklung und Laboranalytik GmbH, Brunnerstrasse 59, 1230, Vienna, Austria. a.nechansky@vela-labs.at
authors: Andreas
authors: A
authors: Nechansky
authors: Ralf
authors: R
authors: Kircheis
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000276:immunology / Q000502:physiology*; D057134:Antibodies, Neutralizing / Q000276:immunology; D017951:Antigen Presentation / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007158:Immunologic Techniques; D007880:Legislation, Drug; D061214:Patient Safety; D004364:Pharmaceutical Preparations / Q000737:chemistry; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000906:Antibodies; D057134:Antibodies, Neutralizing; D004364:Pharmaceutical Preparations