(W1230-02-12) Translational PK/PD and First-in-Human Dose Selection of a Monoclonal Antibody Targeting a Membrane Protein

Purpose: Here we present a preclinical strategy to determine the first-in-human (FIH) dose for an antibody therapy utilizing the totality of preclinical research and modeling and simulation to inform a safe yet pharmacologically relevant starting dose in patients.

Methods: We characterized the pharmacokinetics (PK)/toxicokinetics (TK) of antibody (A) in mice, rats and cynomolgus monkeys following single- or repeat-dose intravenous (IV) administration across multiple studies at doses ranging from 1-150 mg/kg. A two-compartment Vmax/Km model along with allometric scaling (1) was used to predict human PK and tumor receptor (RO).

Results: Following administration of a single IV dose of 10 mg/kg to cynomolgus monkeys, antibody (A) showed biphasic PK behavior with a mean clearance (CL) of 2.17 mL/kg/day consistent with humanized IgG1 antibodies. The single IV dose-ranging PK study conducted in severe combined immunodeficient (SCID) mice showed antibody (A) binding to antigen (A) resulted in dose-dependent target-mediated changes in CL. The repeat-dose rat toxicity study showed linear, dose-proportional increases in Cmax and AUC following IV dose administration. The 25 mg/kg dose was defined as the NOAEL (no-observed-adverse-effect-level). Based on the totality of the preclinical data and modeling approach the recommended FIH of 60 mg was predicted to be safe and may have some pharmacological activity as supported by the RO and PD. In addition, modeling suggested a dosing regime of once every 3 weeks could achieve the desired RO.

Conclusion: Overall, this work provides a translational research strategy to collect relevant nonclinical data to guide selection of starting clinical dose and dosing regimens and informs clinical translatability of these findings and further clinical development.

References: 1. Deng, R., Iyer, S., Theil, F.-P., Mortensen, D.L., Fielder, P.J., and Prabhu, S. (2011). Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data. mAbs 3, 61–66. 10.4161/mabs.3.1.13799.