Mice expressing a humanized form of VEGF-A may provide insights into the safety and efficacy of anti-VEGF antibodies.
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.
Gerber
Hans-Peter
HP
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Wu
Xiumin
X
Yu
Lanlan
L
Wiesmann
Christian
C
Liang
Xiao Huan
XH
Lee
Chingwei V
CV
Fuh
Germaine
G
Olsson
Christine
C
Damico
Lisa
L
Xie
David
D
Meng
Y Gloria
YG
Gutierrez
Johnny
J
Corpuz
Racquel
R
Li
Bing
B
Hall
Linda
L
Rangell
Linda
L
Ferrando
Ron
R
Lowman
Henry
H
Peale
Franklin
F
Ferrara
Napoleone
N
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000915:Antibody Affinity / Q000235:genetics*; D002277:Carcinoma / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism*; D013045:Species Specificity; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A