Tumor penetration and epidermal growth factor receptor saturation by panitumumab correlate with antitumor activity in a preclinical model of human cancer

Daniel J Freeman,Selam Ogbagabriel,Kevin McDorman,Carl Kozlosky,Charlie Starnes,Sameer Doshi,Juan Jose Perez-Ruxio,William Fanslow,Bing-Bing Yang,Robert Radinsky

doi:10.1186/1476-4598-11-47

Daniel J Freeman, Selam Ogbagabriel + Show 8 more

Open Access

https://doi.org/10.1186/1476-4598-11-47

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Abstract

BackgroundSuccessful treatment of solid tumors relies on the ability of drugs to penetrate into the tumor tissue.MethodsWe examined the correlation of panitumumab (an anti-epidermal growth factor [EGFR] antibody) tumor penetration and EGFR saturation, a potential obstacle in large molecule drug delivery, using pharmacokinetics, pharmacodynamics, and tumor growth rate in an A431 epidermoid carcinoma xenograft model of human cancer. To determine receptor saturation, receptor occupancy, and levels of proliferation markers, immunohistochemical and flow cytometric methods were used. Pharmacokinetic data and modeling were used to calculate growth characteristics of panitumumab-treated tumors.ResultsTreatment with panitumumab in vivo inhibited pEGFR, Ki67 and pMAPK levels vs control. Tumor penetration and receptor saturation were dose- and time-dependent, reaching 100% and 78%, respectively. Significant tumor inhibition and eradication (p < 0.05) were observed; plasma concentration associated with tumor eradication was estimated to be 0.2 μg/ml. The tumor inhibition model was able to describe the mean tumor growth and death rates.ConclusionsThese data demonstrate that the antitumor activity of panitumumab correlates with its ability to penetrate into tumor tissue, occupy and inhibit activation of EGFR, and inhibit markers of proliferation and MAPK signaling.

Highlights

Solid tumors differ from the normal tissue from which they were derived with respect to their vasculature, interstitial fluid pressure, lymphatic drainage, cell density, and extracellular matrix components [1]
Panitumumab inhibits ligand-induced epidermal growth factor receptor (EGFR) phosphorylation in vitro and in vivo To determine if panitumumab inhibits EGFR activation in A431 cells in vitro, serum-starved subconfluent cells were pretreated with panitumumab at varying concentrations and stimulated with EGF for 15 minutes
Panitumumab treatment resulted in a dose-dependent inhibition of ligand-induced pEGFR (Figure 1A)

Summary

Introduction

Solid tumors differ from the normal tissue from which they were derived with respect to their vasculature, interstitial fluid pressure, lymphatic drainage, cell density, and extracellular matrix components [1] This complex physiologic barrier can be especially challenging for large molecule therapeutics, such as targeted monoclonal antibodies. The intrinsic properties of antibodies such as the size of the therapeutic and affinity for the target may further hinder penetration into the tumor tissue These properties must be balanced with the Understanding the relationship among pharmacokinetic, pharmacodynamic, and anti-tumor parameters is critical for the development of an oncology therapeutic. It allows for the proper selection of dose and schedule of the molecule and the potential development of a clinically applicable marker of target coverage. Successful treatment of solid tumors relies on the ability of drugs to penetrate into the tumor tissue

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