Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by progressive cognitive decline. The two cardinal neuropathological hallmarks of AD include the buildup of cerebral β amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. The current disease-modifying treatments are still not effective enough to lower the rate of cognitive decline. There is an urgent need to identify early detection and disease progression biomarkers that can facilitate AD drug development. The current established readouts based on the expression levels of amyloid beta, tau, and phospho-tau have shown many discrepancies in patient samples when linked to disease progression. There is an urgent need to identify diagnostic and disease progression biomarkers from blood, cerebrospinal fluid (CSF), or other biofluids that can facilitate the early detection of the disease and provide pharmacodynamic readouts for new drugs being tested in clinical trials. Advances in proteomic approaches using state-of-the-art mass spectrometry are now being increasingly applied to study AD disease mechanisms and identify drug targets and novel disease biomarkers. In this report, we describe the application of quantitative proteomic approaches for understanding AD pathophysiology, summarize the current knowledge gained from proteomic investigations of AD, and discuss the development and validation of new predictive and diagnostic disease biomarkers.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by progressive cognitive decline. The two cardinal neuropathological hallmarks of AD include buildup of cerebral β amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. The current disease-modifying treatments are still not effective enough to lower the rate of cognitive decline. The paucity of early detection and disease progression biomarkers also seems to present a major obstacle to AD drug development. The current established readouts based on expression levels of amyloid beta, tau and phospho tau have shown many discrepancies in patient samples when linked to disease progression. There is an urgent need to identify diagnostic and disease progression biomarkers from blood, CSF or other biofluids that can facilitate early detection of the disease and provide pharmacodynamic readouts for new drugs being tested in clinical trials. Advances in proteomic approaches using state-of-the-art mass spectrometry, are now being increasingly applied to study AD disease mechanisms, identify drug targets and novel disease biomarkers. In this report, we describe applications of the quantitative proteomic approaches for understanding AD pathophysiology, summarize the current knowledge gained from proteomic investigations of AD and discuss development and validation of new predictive and diagnostic disease biomarkers.

Antibody–drug conjugates (ADCs) represent a rapidly evolving therapeutic modality, combining the selective targeting of monoclonal antibodies with highly potent small molecule payloads. Their inherent structural complexity demands a sophisticated and multi-faceted bioanalytical approach spanning preclinical discovery through late-stage clinical development. This white paper, developed by the ADC Working Group of the AAPS bioanalytical community, comprising over 100 members from industry, contract research organizations (CROs), and regulatory agencies, provides updated recommendations for ADC bioanalysis. Building upon the foundational 2013 AAPS position paper and recent publications governing regulatory frameworks on PK considerations, this work addresses advances in bioanalytical quantitation strategies for total antibody (tAb), conjugated ADC, free (unconjugated) payload, and drug-to antibody ratio (DAR); novel immunogenicity assessment considerations; soluble target interference; critical reagent lifecycle management; payload-specific stability requirements; cross-validation strategies; and regulatory considerations. The recommendations presented herein reflect over a decade of scientific progress and are designed to serve as a comprehensive, empirically validated, and industry aligned bioanalytical framework for contemporary ADC drug development.