Physiologically Based Modeling of the Pharmacokinetics of “Catch-and-Release” Anti-Carcinoembryonic Antigen Monoclonal Antibodies in Colorectal Cancer Xenograft Mouse Models

• Published in: Journal of pharmaceutical sciences 2019-01, Vol.108 (1), p.674-691
• Main Authors: Polli, Joseph Ryan, Engler, Frank A., Balthasar, Joseph P.
• Format: Article
• Language: English
• Subjects: Animals; antibodies; Antibodies, Monoclonal - pharmacokinetics; Area Under Curve; carcinoembryonic antigen; Carcinoembryonic Antigen - metabolism; catch-and-release; Cell Line, Tumor; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Disease Models, Animal; Heterografts - metabolism; Humans; Mice; Mice, Inbred C57BL; pH sensitive; pharmacokinetics; physiologically based pharmacokinetics; Tissue Distribution - physiology
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2018.09.037

Engineered monoclonal antibodies (mAbs) with pH-sensitive target release, or “catch-and-release” (CAR) binding, have shown promise in decreasing the extent of target-mediated mAb elimination, increasing mAb exposure, and increasing dose potency. This study developed a mechanistic physiologically based pharmacokinetic (PBPK) model to evaluate the effects of pH-sensitive CAR target binding on the disposition of anti-carcinoembryonic antigen (CEA) mAbs in mouse models of colorectal cancer. The PBPK model was qualified by comparing model-predicted plasma concentration-time data with data observed in tumor-bearing mice following the administration of T84.66, a “standard” anti-CEA mAb that demonstrates strong binding at pH 7.4 and 5.5. Further simulations evaluated the effects CAR pH-dependent binding, with decreasing CEA affinity with decreasing pH, on anti-CEA mAb plasma pharmacokinetics. Simulated data were compared with data observed for a novel CAR mAb, 10H6. The PBPK model provided precise parameter estimates, and excellent data characterization (median prediction error 18.4%) following fitting to T84.66 data. Simulations well predicted 10H6 data (median prediction error 21.4%). Sensitivity analyses demonstrated that key determinants of the disposition of CAR mAbs include the following: antigen binding affinity, the rate constant of mAb-CEA dissociation in acidified endosomes, antigen concentration, and the tumor vasculature reflection coefficient.