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

Abstract

VEGF is the best characterized mediator of tumor angiogenesis. Anti-VEGF agents have recently demonstrated impressive efficacy in human cancer trials, but the optimal dosing of such agents must still be determined empirically, because biomarkers to guide dosing have yet to be established. The widely accepted (but unverified) assumption that VEGF production is quite low in normal adults led to the notion that increased systemic VEGF levels might quantitatively reflect tumor mass and angiogenic activity. We describe an approach to determine host and tumor production of VEGF, using a high-affinity and long-lived VEGF antagonist now in clinical trials, the VEGF Trap. Unlike antibody complexes that are usually rapidly cleared, the VEGF Trap forms inert complexes with tissue- and tumor-derived VEGF that remain stably in the systemic circulation, where they are readily assayable, providing unprecedented capability to accurately measure VEGF production. We report that VEGF production is surprisingly high in non-tumor-bearing rodents and humans, challenging the notion that systemic VEGF levels can serve as a sensitive surrogate for tumor load; tumor VEGF contribution becomes significant only with very large tumor loads. These findings have the important corollary that anti-VEGF therapies must be sufficiently dosed to avoid diversion by host-derived VEGF. We further show that our assay can indicate when VEGF is optimally blocked; such biomarkers to guide dosing do not exist for other anti-VEGF agents. Based on this assay, VEGF Trap doses currently being assessed in clinical trials are in the efficacious range.

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

“…Data on binding affinities demonstrated that aflibercept binds VEGF-A with an approximately 100-fold higher binding affinity than that of ranibizumab or bevacizumab and it thereby neutralises VEGF-A with greater potency. Accordingly, it was found that far lower levels of aflibercept are required for similar anti-VEGF efficacy in neovascularisation models (Holash et al 2002;Rudge et al 2007). …”

Pharmacokinetics of Anti‐VEGF Agent Aflibercept in Cancer Predicted by Data‐Driven, Molecular‐Detailed Model

“…Therapeutic agents that inhibit VEGF act to bind VEGF directly, bind to its cell‐surface receptors, or inhibit intracellular signaling. Aflibercept (VEGF Trap; Regeneron, Tarrytown, NY) is a soluble decoy receptor consisting of a fusion of the second immunoglobulin domain of human vascular endothelial growth factor receptor‐1 (VEGFR‐1) to the third immunoglobulin domain of human VEGFR‐2 with the constant region (Fc) of human immunoglobulin G1 1. Aflibercept is approved for the treatment of metastatic colorectal cancer and is being investigated for its efficacy in treating other cancer types, including glioma, ovarian, and prostate cancers.…”

Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors

“…Assuming the level of VEGF-bound aflibercept can be used as a marker of VEGF blockade [41], this simulation allowed us to confirm the choice of the recommended dose of 4 mg/kg every 2 weeks which is sufficient to saturate circulating VEGF in most patients. The developed model can be used to simulate and predict the concentration-time profiles of free and bound aflibercept in a patient population of interest, for example obese patients and patients with low albumin, with new dosing regimens.…”