Vascular endothelial growth factor (
VEGF) and its receptors (VEGFR) have been implicated in promoting solid
tumor growth and
metastasis via stimulating
tumor-associated angiogenesis. We recently showed that certain 'liquid'
tumors such as
leukemia not only produce
VEGF, but also express functional VEGFR, resulting in an autocrine loop for
tumor growth and propagation. A chimeric anti-VEGFR2 (or
kinase insert domain-containing receptor, KDR) antibody,
IMC-1C11, was shown to be able to inhibit
VEGF-induced proliferation of human
leukemia cells in vitro, and to prolong survival of nonobese diabetic-severe combined immune deficient (NOD-SCID) mice inoculated with human
leukemia cells. Here we produced two fully human anti-KDR
antibodies (
IgG1), IMC-2C6 and IMC-1121, from
Fab fragments originally isolated from a large antibody phage display library. These
antibodies bind specifically to KDR with high affinities: 50 and 200 pM for IMC-1121 and IMC-2C6, respectively, as compared to 270 pM for
IMC-1C11. Like
IMC-1C11, both human
antibodies block
VEGF/KDR interaction with an IC(50) of approximately 1 nM, but IMC-1121 is a more potent inhibitor to
VEGF-stimulated proliferation of human endothelial cells. These anti-KDR
antibodies strongly inhibited
VEGF-induced migration of human
leukemia cells in vitro, and when administered in vivo, significantly prolonged survival of NOD-SCID mice inoculated with human
leukemia cells. It is noteworthy that the mice treated with antibody of the highest affinity, IMC-1121, survived the longest period of time, followed by mice treated with IMC-2C6 and
IMC-1C11. Taken together, our data suggest that anti-KDR
antibodies may have broad applications in the treatment of both solid
tumors and
leukemia. It further underscores the efforts to identify
antibodies of high affinity for enhanced antiangiogenic and antitumor activities.