A Novel Pharmacodynamic Biomarker and Mechanistic Modeling Facilitate the Development of Tovetumab, a Monoclonal Antibody Directed Against Platelet-Derived Growth Factor Receptor Alpha, for Cancer Therapy.

Abstract

Tovetumab (MEDI-575) is a fully human IgG2κ monoclonal antibody that specifically binds to human platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor signal transduction by PDGF ligands. The affinity of tovetumab determined using surface plasmon resonance technology and flow cytometry demonstrated comparable binding affinity for human and monkey PDGFRα. In single and repeat-dose monkey pharmacokinetic-pharmacodynamic (PK-PD) studies, tovetumab administration resulted in dose-dependent elevation of circulating levels of PDGF-AA, a member of the PDGF ligand family, due to displacement of PDGF-AA from PDGFRα by tovetumab and subsequent blockade of PDGFRα-mediated PDGF-AA degradation. As such, PDGF-AA accumulation is an indirect measurement of receptor occupancy and is a novel PD biomarker for tovetumab. The nonlinear PK of tovetumab and dose-dependent increase in circulating PDGF-AA profiles were well described by a novel mechanistic model, in which tovetumab and PDGF-AA compete for the binding to PDGFRα. To facilitate translational simulation, the internalization half-lives of PDGF-AA and tovetumab upon binding to PDGFRα were determined using confocal imaging to be 14 ± 4min and 30 ± 8min, respectively. By incorporating PDGFRα internalization kinetics, the model not only predicted the target receptor occupancy by tovetumab, but also the biologically active agonistic ligand-receptor complex. This work described a novel PD biomarker approach applicable for anti-receptor therapeutics and the first mechanistic model to delineate the in vivo tri-molecular system of a drug, its target receptor, and a competing endogenous ligand, which collectively have been used for optimal dose recommendation supporting clinical development of tovetumab.