Immunogenicity: Its Impact on ADME of Therapeutic Biologics

Abstract The immunogenicity of therapeutic biologics is an intensively studied feature shared by almost all biologics that have been developed. This chapter addresses essentially three aspects: which factors are key in initiating and orchestrating an anti‐drug antibody (ADA) response; the impact of ADA (both neutralizing and nonneutralizing) on the absorption, distribution, and clearance of biologics, such as monoclonal antibodies (mAbs) and other protein drugs; and how to deal with ADA responses in nonclinical and clinical studies in the establishment of a pharmacokinetic/pharmacodynamic (PK/PD) relationship. The impact of ADA on absorption, distribution, and clearance are discussed mainly based on nonclinical data. To establish a causal relationship between unexpected PK/ PD profiles and unwanted immune responses, PK/PD sampling needs to be accompanied by sampling for immunogenicity/ ADA testing and vice versa‐in both nonclinical and clinical studies.