Translational pharmacokinetics of a novel bispecific antibody against Ebola virus (MBS77E) from animal to human by PBPK modeling & simulation

[Display omitted] •MBS77E is a humanized bispecific antibody with potential against Ebola virus.•FcRn plays important role in mAbs’ in vivo disposition process.•Developed and validated a PBPK model based on pre-clinical PK and in vitro studies.•Utilized a PBPK model of MBS77E for translational predictions of human PK. The goal of this study was to construct a PBPK model to accelerate the translation of MBS77E, a humanized bispecific antibody against the Ebola virus. In-depth nonclinical pharmacokinetic studies in rats, monkeys, wild-type mice and transgenic mice were conducted. The pH-dependent affinities (KD) of MBS77E to recombinant FcRn of different species were determined by surface plasmon resonance analysis. A mechanistic whole-body PBPK model of MBS77E was developed and validated in the assessment of PK profiles and tissue distributions in preclinical models. This PBPK model was finally used to predict human PK behaviors of MBS77E. Simulations from the PBPK model with measured and fitted parameters were able to yield good predictions of the serum and tissue pharmacokinetic parameters of MBS77E within 2-fold errors. The predicted serum concentration in humans was able to maintain a sufficiently high level for more than 14 days after 50 mg/kg i.v. administrating. This achievement unlocks that PBPK modeling is a powerful tool to gain insights into the properties of antibody drugs. It guided experimental efforts to obtain necessary information before entry into humans.