TableIsummarizes major considerations that should be taken into account in the assessment of ADA responses, while TableIIhighlights some of the major gaps in our current understanding of immunogenicity. and neutralization capacity. This manuscript reviews the requirements necessary for understanding the nature of an ADA response in order to discern the impact of immunogenicity on pharmacokinetics/pharmacodynamics and efficacy. KEY WORDS:antibody, immunogenicity, pharmacodynamics, pharmacokinetics, protein therapeutics == INTRODUCTION AND BACKGROUND == The clinical development of protein therapeutics has made significant advances as evidenced by the increasing number of approvals. Protein therapeutics have complex structures which result in unique pharmacokinetic and pharmacodynamic (PK/PD) properties, including an oftentimes high degree of nonlinearity in the doseexposureresponse relationship due to high-affinity interactions with pharmacologic target structures and other endogenous proteins (1,2). Accurate measurement and modeling of PK/PD characteristics of therapeutic proteins are required to make decisions on adequate exposure in preclinical toxicology studies, select first-in-human starting doses for single and multiple dosing regimens, determine the efficacious dose for phase III trials, and assess drugdrug interactions (3). Administration of protein therapeutics can induce anti-drug antibodies (ADA), which can have an impact on their PK/PD characteristics. When produced in high1 amounts, these high-affinity mature ADA have an increased likelihood of modulating and even neutralizing the drug’s therapeutic effects. The characterization of these ADA responses presents bioanalytical challenges. Recent publications and regulatory guidance documents have provided significant insights and direction to meet the regulatory requirements of characterizing and quantifying Rabbit Polyclonal to POLE1 immune responses Tos-PEG4-NH-Boc to protein therapeutics (46). The ADA formation may impact either the pharmacokinetics of the protein therapeutic,i.e., the relationship between dose and the obtained concentrations in plasma or other organs and tissues, or the pharmacodynamics, which describes the relationship between systemic concentrations (exposure) and therapeutic effects, or both. Thus, ADA may ultimately affect the efficacy and/or toxicity profile of therapeutic proteins (7,8). In Tos-PEG4-NH-Boc order to delineate the impact of the immunogenicity on modulating PK and PD, drug development scientists are challenged with simultaneously considering the interplay of multiple influential factors that are major determinants in the occurrence, frequency, severity, quantifiability, and clinical impact of immune reactions to a protein therapeutic. Several factors influence the immunogenicity of therapeutic proteins. The European Medicine Agency guidance document and other reviews (4,6,9) have classified them into disease-, patient-, or product-related factors. Briefly, disease- and patient-related factors have the potential to predispose an individual to an immune response. Examples for disease-related factors include dysregulation of immune responses in autoimmune conditions, inflammatory responses due to an infectious agent, or an existing immune response in a patient due to a disease condition (4). A patient-related factor is for example the major histocompatibility complex background of subjects that has been demonstrated to influence the immunogenicity of protein therapeutics (10). Product-related factors that can influence immune response to a therapeutic protein have also been reported (11,12), such as the induction of an unanticipated inflammatory response in healthy subjects after administration of an immunomodulatory biologic (e.g., anti-CD28 mAb) (13). In summary, there is a multitude of interacting factors responsible for ADA formation against protein therapeutics that comprises product-specific critical quality attributes (14) including (1) amino acid sequence differences between therapeutic protein and endogenous proteins; (2) post-translational modification-associated changes; (3) structural alterations such as aggregation, oxidation, deamidation, degradation, and conformational changes; (4) changes due to storage conditions; (5) production/purification-associated modifications; and (6) formulation-associated changes, as well as other factors such as (7) route, frequency, and dose of administration; (8) immune status of the clinical subject/animal; and (9) genetic background of the subject. This review highlights some of the challenges in understanding the impact of immunogenicity on PK/PD through a series of questions and partial answers with examples. Listings of the current gaps and suggestions for further analyses are provided in TablesIandII. == Table I. == Considerations for Analyzing the Impact of Immunogenicity on PK/PD == Table II. == Gaps in Our Current Knowledge around the Impact of Immunogenicity on PK/PD Ordered by Priority for the Need to Be Addressed == WHAT ARE THE CHALLENGES IN THE METHODS FOR BIOANALYTICAL QUANTIFICATION OF ADA AND THERAPEUTIC PROTEINS? == The primary objective of accurate bioanalytical measurements of therapeutic proteins is to ensure the presence of drug concentrations in the target organ or tissue that are sufficient for inhibition or activation of Tos-PEG4-NH-Boc its molecular target. Several factors affect the accurate measurement of circulating protein therapeutics; these include interference of soluble target, bound ADA, and serum components (15,16). Advances in.
