VEGF is a key factor in tumor angiogenesis, and it has become a major target of anti-angiogenic cancer therapy (1
). A large body of evidence suggests that the free plasma VEGF concentration is elevated several fold in cancer patients compared to healthy subjects (2
). Therapies targeting VEGF have shown promising results in cancer. Bevacizumab (Avastin®, Genentech Inc., South San Francisco, CA), a recombinant humanized monoclonal antibody to VEGF, has demonstrated efficacy in colorectal cancer, non-small cell lung cancer, breast cancer, renal cell carcinoma and glioblastoma. The drug has been approved by the Food and Drug Administration for these indications under certain conditions in combination with chemotherapeutic agents and is being tested for other types of cancer and other conditions in numerous clinical trials.
Despite the growing clinical applications of bevacizumab, the mechanism of action of this anti-VEGF agent and that of other anti-VEGF large molecules is not sufficiently understood (3
). Specifically, two important questions remain: whether the drug acts by sequestering VEGF in the blood, tumor interstitium or both; and whether, as a result, the VEGF concentration in these compartments is reduced to ‘normal’ levels. Answering these questions would significantly contribute to understanding the mechanism of action not only at the molecular level, but also at the levels of tissue, organ and whole body and would help in the design of anti-VEGF agents. Gordon et al. reported that the intravenous injection of bevacizumab led to an increase in serum total VEGF in clinical trials while free VEGF concentration was reduced (4
). Since then, other groups have reported counterintuitive increases in the plasma VEGF level following bevacizumab administration (5
). In the ocular setting, Campa et al. reported that intravitreal bevacizumab injection increased the VEGF concentration in the aqueous humor (8
). Several hypotheses have been formulated to explain this phenomenon. Hsei et al. have suggested that the clearance of complexed VEGF is lower than that of free VEGF in rats and hypothesized that this lower clearance could explain the accumulation of total VEGF in serum (9
). Other groups have suggested alternate pathways activated by the injection of bevacizumab, such as: accumulation of hypoxia-inducible factor leading to an increase of VEGF in serum; or secondary macular edema for the eye (8
). Loupakis et al. immunodepleted plasma to remove bevacizumab and bevacizumab-VEGF complexes, and found that plasma free VEGF was significantly reduced after bevacizumab administration (12
); this methodology helps to circumvent the problem that the ELISA method used in a number of studies cannot distinguish between free and total (including bevacizumab-bound) VEGF. The results of the study corroborate an earlier proposal by Christofanilli et al. (13
) that free VEGF can serve as a surrogate marker.
Systems biology approaches, and specifically computational and mathematical modeling, are emerging as powerful tools in fundamental studies of cancer and design of therapeutics (14
). To better understand VEGF distribution in the body, we have built a three-compartment model composed of normal (healthy) tissue, blood and tumor (16
). In this study, we have extended our computational model by including an anti-VEGF agent delivered by the intravenous infusion (i.e., into the blood compartment). The model describes the effect of such administration on the VEGF distribution in the blood, normal and diseased tissues. Our goal is to understand how the distribution of VEGF, anti-VEGF agent and their products changes following the agent administration; in particular, we will investigate whether the plasma VEGF level increases or decreases following an intravenous injection of the anti-VEGF agent.
Even though the results are presented using the parameters for bevacizumab, the model can be applied to other anti-VEGF agents. One such agent is aflibercept or VEGF Trap (Regeneron Pharmaceuticals Inc., Tarrytown, NY), a soluble humanized VEGF receptor protein designed to bind all VEGF-A isoforms and placental growth factor (PlGF). This fusion protein serves as a soluble decoy receptor and is currently in clinical trials.
Our model includes two VEGF-A isoforms (VEGF121
), as well as VEGF receptors (VEGFR1 and VEGFR2) and the co-receptor neuropilin-1 (NRP1). In this study, we assume that VEGFR1, VEGFR2 and NRP1 are present only on the abluminal surface of the endothelial cells. The transcapillary microvascular permeability for the diffusible molecules (VEGF, anti-VEGF and the VEGF/anti-VEGF complex) is included, as well as lymphatic drainage from the interstitial space into the blood compartment. The model equations are presented in the Supplemental Information (Supplement 1)