Mechanistic quantitative pharmacology strategies for the early clinical development of bispecific antibodies in oncology

Bispecific antibodies (bsAbs) have become an integral component of the therapeutic research strategy to treat cancer. In addition to clinically validated immune cell re‐targeting, bsAbs are being designed for tumor targeting and as dual immune modulators. Explorative preclinical and emerging clinical data indicate potential for enhanced efficacy and reduced systemic toxicity. However, bsAbs are a complex modality with challenges to overcome in early clinical trials including selection of relevant starting doses using a minimal anticipated biological effect level (MABEL) approach and predicting efficacious dose despite non‐intuitive dose response relationships. Multiple factors can contribute to variability in the clinic including differences in functional affinity due to avidity, receptor expression, effector to target cell ratio and presence of soluble target. Mechanistic modeling approaches are a powerful integrative tool to understand the complexities and aid in clinical translation, trial design and prediction of regimens and strategies to reduce dose limiting toxicities of bsAbs. In this tutorial the use of mechanistic modeling to impact decision making for bsAbs is presented and illustrated using case study examples…

Author(s): Alison Betts, Piet H. van der Graaf

Year: June 24, 2020