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.

  title={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.},
  author={Meina L. Liang and Bing Wang and Amy K. Schneider and Inna Vainshtein and Lorin K. Roskos},
  journal={The AAPS journal},
  volume={23 1},
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… 
Recent Advances in Translational Pharmacokinetics and Pharmacodynamics Prediction of Therapeutic Antibodies Using Modeling and Simulation
This review summarizes the recent advances and future direction of M&S-based approaches to the quantitative prediction of human PKPD for mAbs and discusses more complex mechanistic models, such as the quantitative systemics pharmacology model.


Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume.
  • G. Jayson, G. Parker, A. Jackson
  • Biology, Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2005
The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.
Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas
The concurrent expression of PDGFA and PDGFRA in different subtypes of glioma, reinforce the recognised significance of this signalling pathway in gliomas.
Antagonism of Platelet-Derived Growth Factor Receptor in Non–Small Cell Lung Cancer: Rationale and Investigations
Preclinical data suggest that dual targeting of pericytes and endothelial cells is a more effective antiangiogenic strategy than antiendothelial monotherapy and encouraging preclinical data can be translated into clinical benefit in non–small cell lung cancer.
A phase I dose-escalation study of MEDI-575, a PDGFRα monoclonal antibody, in adults with advanced solid tumors
Administration of MEDI-575 QW or Q3W resulted in a favorable safety profile, including a lack of DLTs, but without evidence of antitumor activity in patients with refractory solid tumors.
Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia
The various kinases inhibited by imatinib, nilotinib and dasatinib are reviewed, and the potential impact of kinase inhibition on the efficacy and safety of each agent is described.
Overexpression of platelet-derived growth factor receptor alpha promotes tumor progression and indicates poor prognosis in hepatocellular carcinoma
The study provided the evidence that PDGFRα may serve as a candidate prognostic marker and a novel therapeutic target for HCC and exhibited remarkably tumorigenic potential in tumor size and weight in vivo.
The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRα-positive hypereosinophilic syndrome. Results of a multicenter prospective study
All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRα rearrangement, and chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses.
The characterization of PDGFR-alpha and PDGFR-beta expression in malignant non-Hodgkin lymphoma.
Evaluating the PDGF receptor expression in follicular and diffuse forms of non-Hodgkin malignant lymphoma found it to represent an important therapeutic target in patients who do not respond to conventional therapy, but further research is needed for a careful evaluation of benefits and side effects of PDGFR inhibitors.
High levels of serum platelet-derived growth factor-AA and human epidermal growth factor receptor-2 are predictors of colorectal cancer liver metastasis
PDGFAA in tumor drainage and HER2 in PV blood may be useful predictive factors for synchronous liver metastasis of colorectal cancer.