Translational PK-PD modeling analysis of MCLA-128, a HER2/HER3 bispecific monoclonal antibody, to predict clinical efficacious exposure and dose.

Abstract

Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study. Methods A PK-PD model was developed based on PK data from cynomolgus monkeys and tumor growth data from a mouse JIMT-1 xenograft model. Allometric scaling was used to scale PK parameters between species. Simulations were performed to predict the safe and efficacious clinical dose, based on AUCs, receptor occupancies and PK-PD model simulations. Results MCLA-128 PK in cynomolgus monkeys was described by a two-compartment model with parallel linear and nonlinear clearance. The xenograft tumor growth model consisted of a tumor compartment with a zero-order growth rate and a first-order dying rate, both affected by MCLA-128. Human doses of 10 to 480 mg q3wk were predicted to show a safety margin of >10-fold compared to the cynomolgus monkey AUC at the no-observed-adverse-effect-level (NOAEL). Doses of ≥360 mg resulted in predicted receptor occupancies above 99% (Cmax and Cave). These doses showed anti-tumor efficacy in the PK-PD model. Conclusions This analysis predicts that a flat dose of 10 to 480 mg q3wk is suitable as starting dose for a First-in-Human study with MCLA-128. Flat doses ≥360 mg q3wk are expected to be efficacious in human, based on receptor occupancies and PK-PD model simulations.

• Authors: Aurelia H M de Vries Schultink, Robert P Doornbos, Alexander B H Bakker, Kees Bol, Mark Throsby, Cecile Geuijen, David Maussang, Jan H M Schellens, Jos H Beijnen, Alwin D R Huitema
• Journal: Investigational new drugs (Invest New Drugs) Vol. 36 Issue 6 Pg. 1006-1015 (12 2018) ISSN: 1573-0646 [Electronic] United States
• PMID: 29728897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• Antibodies, Monoclonal
• Immunoglobulin G
• zenocutuzumab

Topics

• Animals
• Antibodies, Bispecific (pharmacokinetics, pharmacology)
• Antibodies, Monoclonal (pharmacokinetics, pharmacology)
• Area Under Curve
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Computer Simulation
• Dose-Response Relationship, Immunologic
• Female
• Humans
• Immunoglobulin G (pharmacology)
• Macaca fascicularis
• Mice
• Mice, SCID
• Models, Biological
• Translational Research, Biomedical
• Treatment Outcome
• Tumor Burden
• Xenograft Model Antitumor Assays