VEGF-A is important in
tumor angiogenesis, and a humanized anti-
VEGF-A monoclonal antibody (
bevacizumab) has been approved by the FDA as a treatment for metastatic colorectal and nonsquamous,
non-small-cell lung cancer in combination with
chemotherapy. However, contributions of both
tumor- and stromal-cell derived
VEGF-A to vascularization of human
tumors grown in immunodeficient mice hindered direct comparison between the pharmacological effects of anti-
VEGF antibodies with different abilities to block host
VEGF. Therefore, by gene replacement technology, we engineered mice to express a humanized form of
VEGF-A (hum-X
VEGF) that is recognized by many anti-
VEGF antibodies and has biochemical and biological properties comparable with WT mouse and human
VEGF-A. The hum-X
VEGF mouse model was then used to compare the activity and safety of a panel of
VEGF Mabs with different affinities for
VEGF-A. Although in vitro studies clearly showed a correlation between binding affinity and potency at blocking endothelial cell proliferation stimulated by
VEGF, in vivo experiments failed to document any consistent correlation between antibody affinity and the ability to inhibit
tumor growth and angiogenesis in most animal models. However, higher-affinity
antibodies were more likely to result in glomerulosclerosis during long-term treatment.