The diagnosis and treatment of human diseases and the development of new drugs increasingly rely on our ability to determine patient genotypes using accurate and sensitive pharmacogenomic tests. Many PCR and next-generation sequencing (NGS) based assay platforms are currently available.

However, the type of DNA sequence variants, the number of targets, and the sensitivity requirements are highly diverse in different studies. Here Dr. Peter Zhang describes the design, performance, and regulatory considerations of several assay platforms that are accurate, high throughput, cost-effective and customizable. These platforms provide high-quality pharmacogenomic data ideally suited to meet the needs of individual studies.

Accurate determination of the drug-to-antibody ratio (DAR) of interchain cysteine-linked antibody–drug conjugates (ADCs) is challenging. High-resolution mass spectrometry (HRMS) analysis of the ADCs at the intact or subunit level provides a feasible way to measure the DAR. However, the measured DAR is usually lower than the true DAR because of the variation in ionization efficiency between different DAR species. In this work, we developed a novel standard-free HRMS method involving isotope-labeled payload conjugation, protease digestion, and liquid chromatography–HRMS (LC-HRMS) analysis for accurate determination of the DAR of the interchain cysteine-linked ADCs with cleavable or non-cleavable linkers. Isotope-labeled payload conjugations eliminated the structural and chemical differences between different DAR species and ensured that the drugs or payload-containing peptides could be separated from each other in the mass spectrometer. A papain digestion strategy for ADCs with cleavable linkers showed a DAR of 3.79, with a relative standard deviation (RSD) of 0.48 (n = 3). Similarly, the trypsin and chymotrypsin digestion strategy that is applicable to ADCs with non-cleavable linkers showed a DAR of 3.77 and an RSD of 0.86 (n = 3). The DAR determined by this method was consistent with the DAR of the ADCs that was measured by the UV/Vis method. This method will be very useful to researchers working in the field of ADC discovery and development.

Drug-induced liver injury (DILI) accounts for >50% acute liver failures, and is the leading cause of drug development failure, boxed warning and market withdrawal of approved drugs. Inhibition of BSEP and MDR3 is one of the underlying mechanisms for DILI. BSEP and MDR3 are the primary hepatic transporters responsible for exporting bile salts and phosphatidylcholine, respectively. In humans, inhibition of BSEP and/or MDR3 can result in serious liver injury. This presentation will discuss our patented platforms BSEPcyte® and MDR3cyte® using primary hepatocytes in suspension for higher throughput assessment of DILI potentials. In addition, a brief review of the critical transporter studies to inform DDI potentials will also be discussed. This presentation will benefit scientists wanting to learn more about DILI and/or those needing guidance on crucial transporter studies for better assessment of DDI potentials that is aligned with regulatory guidance.