The disposition of antibody-based therapeutics is generally determined by both target-mediated and non-target processes, the latter being an often-overlooked aspect. Target-independent liabilities can significantly increase the elimination rate of a candidate protein, which could lead to reduced efficacy and attrition during drug development. However, the ability to identify at-risk proteins via in vitro techniques has remained challenging. This presentation will highlight key mechanisms causing pharmacokinetic shortfalls for antibody-based therapeutics. Additionally, it will demonstrate how cell-based assays can successfully predict target-independent problems to identify candidates with the most optimal pharmacokinetic properties.