title: Evaluation of pre-existing antibody presence as a risk factor for posttreatment anti-drug antibody induction: analysis of human clinical study data for multiple biotherapeutics.
abstract: Biotherapeutic-reactive antibodies in treatment-naïve subjects (i.e., pre-existing antibodies) have been commonly detected during clinical immunogenicity assessments; however information on pre-existing antibody prevalence, physiological effects, and impact on posttreatment anti-drug antibody (ADA) induction remains limited. In this analysis, pre-existing antibody prevalence and impact on posttreatment ADA induction were determined using ADA data from 12 biotherapeutics analyzed in 32 clinical studies. Approximately half (58%) of the biotherapeutics were associated with some level of pre-existing antibodies and 67% of those were associated with posttreatment ADA induction. Across all studies, 5.6% of study subjects demonstrated presence of pre-existing antibodies, among which, 17% of the individual subjects had posttreatment increases in their ADA titers while 16% had decreased titers and 67% had no change in titers. However, in studies conducted in the rheumatoid arthritis (RA) population, 14.8% of RA patients were associated with pre-existing antibodies and 30% of those had posttreatment titer increases. The results suggest that in most study subjects, pre-existing antibodies pose a low risk for posttreatment ADA induction. That said, the high risk of induction implicated for RA patients, primarily observed in treatments evaluating novel antibody-based constructs, indicates that further understanding of the contribution of product and disease-specific factors is needed. Cross-industry efforts to collect and analyze a larger data set would enhance understanding of the prevalence, nature, and physiological consequences of pre-existing antibodies, better inform the immunogenicity risk profiles of products associated with these antibodies and lead to better fit-for-purpose immunogenicity management and mitigation strategies.
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism (PDM-NBE), Immunogenicity Sciences, Pfizer Inc., Andover, MA, USA. li.xue@pfizer.com
authors.forename: Li
authors.initials: L
authors.lastname: Xue
authors.forename: Bonita
authors.initials: B
authors.lastname: Rup
mesh_terms: D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000097:blood*; D001685:Biological Factors / Q000097:blood* / Q000276:immunology; D001691:Biological Therapy / Q000379:methods; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D001685:Biological Factors