Increased Plasma Vascular Endothelial Growth Factor (VEGF) as a Surrogate Marker for Optimal Therapeutic Dosing of VEGF Receptor-2 Monoclonal Antibodies

Abstract

A major obstacle compromising the successful application of many of the new targeted anticancer drugs, including angiogenesis inhibitors, is the empiricism associated with determining an effective biological/therapeutic dose because many of these drugs express optimum therapeutic activity below the maximum tolerated dose, if such a dose can be defined. Hence, surrogate markers are needed to help determine optimal dosing. Here we describe such a molecular marker, increased plasma levels of vascular endothelial growth factor (VEGF), in normal or tumor-bearing mice that received injections of an anti-VEGF receptor (VEGFR)-2 monoclonal antibody, such as DC101. Rapid increases of mouse VEGF (e.g., within 24 hours) up to 1 order of magnitude were observed after single injections of DC101 in non-tumorbearing severe combined immunodeficient or nude mice; similar increases in human plasma VEGF were detected in human tumor-bearing mice. RAFL-1, another anti-VEGFR-2 antibody, also caused a significant increase in plasma VEGF. In contrast, increases in mouse VEGF levels were not seen when small molecule VEGFR-2 inhibitors were tested in normal mice. Most importantly, the increases in plasma VEGF were induced in a dose-dependent manner, with the maximum values peaking when doses previously determined to be optimally therapeutic were used. Plasma VEGF should be considered as a possible surrogate pharmacodynamic marker for determining the optimal biological dose of antibody drugs that block VEGFR-2 (KDR) activity in a clinical setting.

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

“…Our observations are consistent with recent studies by Bocci et al (27), which reported that plasma VEGF levels are normally very low or undetectable, but are rapidly increased upon treatment with blocking VEGFR2 antibodies. In these experiments, the observed acute increase in circulating VEGF was not associated with increased VEGF expression in normal tissues, or the tumors, but reflected displacement of VEGF from VEGF receptors.…”

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

“…In our study, the individual plasma VEGF concentrations of patients initially increased when compared to the baseline values in the first 3 weeks and then at lower doses constantly decreased. Despite the presence of a high variability, VEGF plasma levels may reflect both the initial elevated hypoxia of tumour tissue caused by the antiangiogenic therapy, as previously shown (Bocci et al, 2004;Motzer et al, 2006), and the low rate of VEGF secretion by tumour or tumourassociated stromal cells due to the long-term therapy (Colleoni et al, 2002). This PK/PD study underlines the importance to conduct further comparative studies with BSC or bevacizumab to establish the feasibility of metronomic irinotecan approach.…”

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

“…Plasma levels of VEGF and placental-derived growth factor (PlGF, a VEGF family member that specifically binds to VEGF receptor 1) are significantly increased in rectal cancer patients receiving bevacizumab [46]. In apparent contrast to some preclinical findings [56], other groups have reported similar observations in cancer patients treated with various anti-VEGF receptor TKIs (e.g. vatalanib and sunitinib), and have also found a decrease in soluble VEGF receptor 2 levels in the plasma [57][58][59].…”