Epitope characterization of anti-drug antibodies-a tool for discovery and health: an overview of the necessity of early epitope characterization to avoid anti-drug antibodies and promote patient health.

Introduction: The market for monoclonal antibody (mAb) therapies is growing rapidly as the pharmaceutical industry expands its development across a broad spectrum of diseases. Unfortunately, as shown in the recent failure of bococizumab by Pfizer, these treatments often stimulate the formation of problematic anti-drug antibodies (ADAs). ADAs can cause side effects and limit efficacy for many patients. To increase efficacy and decrease safety concerns from ADAs, immunogenicity characterization is needed early in the drug development process. Here, we present emerging techniques that hold promise to improve ADA assays and their potential applications to pharmaceutical development and personalized medicine.Areas covered: This manuscript outlines the importance of epitope characterization to better understand immunogenicity and describes a strategy for using this information in treating patients taking mAb therapies.Expert opinion: We propose using high-information assays to characterize epitopes to help mAb therapy engineering and potentially improve individual patient outcomes. To understand this, we will discuss three different aspects of ADAs: (1) the problem of ADAs and what is currently being done about them, (2) the current state of epitope characterization and how it is being utilized, and (3) how early epitope characterization can advance drug discovery and improve outcomes for patients taking mAb therapies.

Long-Term Evaluation of Biotronik Linox and Linox(smart) Implantable Cardioverter Defibrillator Leads.

INTRODUCTION: Expert consensus holds that post-market, systematic surveillance of ICD leads is essential to ensure confirmation of adequate lead performance. GALAXY (NCT00836589) and CELESTIAL (NCT00810264) are ongoing multicenter, prospective, non-randomized registries conducted to confirm the long-term safety and reliability of Biotronik leads. METHODS AND RESULTS: ICD and CRT-D patients are followed for Linox and Linox(smart) ICD lead performance and safety for 5 years post-implant. All procedural and system-related adverse events (AEs) were assessed at each follow-up, along with lead electrical parameters. An independent CEC of EPs adjudicated AEs to determine AE category and lead relatedness. The analysis used categories of lead observations per ISO 5841-2 (Third edition). A total of 3,933 leads were implanted in 3,840 patients (73.0% male, mean age 67.0 ± 12.2 years) at 146 US centers. The estimated cumulative survival probability was 96.3% at 5 years after implant for Linox leads and 96.6% at 4 years after implant for Linox(smart) leads. A comparison of the Linox and Linox(smart) survival functions did not find evidence of a difference (P = 0.2155). The most common AEs were oversensing (23, 0.58%), conductor fracture (14, 0.36%), failure to capture (13, 0.33%), lead dislodgement (12, 0.31%), insulation breach (10, 0.25%), and abnormal pacing impedance (8, 0.20%). CONCLUSIONS: Linox and Linox(smart) ICD leads are safe, reliable and infrequently associated with lead-related AEs. Additionally, estimated cumulative survival probability is clinically acceptable and well within industry standards. Ongoing data collection will confirm the longer-term safety and performance of the Linox family of ICD leads.