title: Antidrug Antibody Formation in Oncology: Clinical Relevance and Challenges.
abstract: : In oncology, an increasing number of targeted anticancer agents and immunotherapies are of biological origin. These biological drugs may trigger immune responses that lead to the formation of antidrug antibodies (ADAs). ADAs are directed against immunogenic parts of the drug and may affect efficacy and safety. In other medical fields, such as rheumatology and hematology, the relevance of ADA formation is well established. However, the relevance of ADAs in oncology is just starting to be recognized, and literature on this topic is scarce. In an attempt to fill this gap in the literature, we provide an up-to-date status of ADA formation in oncology. In this focused review, data on ADAs was extracted from 81 clinical trials with biological anticancer agents. We found that most biological anticancer drugs in these trials are immunogenic and induce ADAs (63%). However, it is difficult to establish the clinical relevance of these ADAs. In order to determine this relevance, the possible effects of ADAs on pharmacokinetics, efficacy, and safety parameters need to be investigated. Our data show that this was done in fewer than 50% of the trials. In addition, we describe the incidence and consequences of ADAs for registered agents. We highlight the challenges in ADA detection and argue for the importance of validating, standardizing, and describing well the used assays. Finally, we discuss prevention strategies such as immunosuppression and regimen adaptations. We encourage the launch of clinical trials that explore these strategies in oncology.
  
  
  
  Because of the increasing use of biologicals in oncology, many patients are at risk of developing antidrug antibodies (ADAs) during therapy. Although clinical consequences are uncertain, ADAs may affect pharmacokinetics, patient safety, and treatment efficacy. ADA detection and reporting is currently highly inconsistent, which makes it difficult to evaluate the clinical consequences. Standardized reporting of ADA investigations in the context of the aforementioned parameters is critical to understanding the relevance of ADA formation for each drug. Furthermore, the development of trials that specifically aim to investigate clinical prevention strategies in oncology is needed.
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Emilie M J
authors.initials: EM
authors.lastname: van Brummelen
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Willeke
authors.initials: W
authors.lastname: Ros
authors.affiliation: Immunopathology, Sanquin Research, Amsterdam, The Netherlands Reade Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands.
authors.forename: Gertjan
authors.initials: G
authors.lastname: Wolbink
authors.affiliation: Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands j.schellens@nki.nl.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000906:Antibodies / Q000032:analysis / Q000633:toxicity; D000911:Antibodies, Monoclonal / Q000276:immunology; D000917:Antibody Formation; D000970:Antineoplastic Agents / Q000276:immunology*; D001688:Biological Products / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007108:Immune Tolerance; D000074324:Ipilimumab
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001688:Biological Products; D000074324:Ipilimumab
keywords: Antidrug antibody; Cancer; Clinical relevance; Detection assays; Efficacy; Immunogenicity; Oncology; Pharmacokinetics; Toxicity