Utility of free and total target measurements as target engagement and efficacy biomarkers in biotherapeutic development--opportunities and challenges.

For biotherapeutics directed against soluble targets, most often monoclonal antibodies (mAbs), their therapeutic efficacy theoretically is driven by the magnitude and duration of free target suppression. However, for soluble targets of rapid turnover and low abundance, it can be technically challenging to directly measure the lowering of free target following treatment with biologics. The opportunities, challenges, and practical approaches to assess free and bound soluble targets and the utility of free and bound target measurements as biomarkers for target engagement and efficacy are covered in this review. In particular, case examples are presented to illustrate the interplay between drug and free/bound target, and how an integrated bioanalytical and pharmacokinetic/target engagement/pharmacodynamic (PK/TE/PD) modeling approach can be used to assess the target engagement for biologics directed against soluble targets with rapid turnover. Important caveats of the modeling approach in the absence of free target measurements are also discussed.