title: Mice expressing a humanized form of VEGF-A may provide insights into the safety and efficacy of anti-VEGF antibodies.
abstract: 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.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gerber
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.forename: Lanlan
authors.initials: L
authors.lastname: Yu
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Xiao Huan
authors.initials: XH
authors.lastname: Liang
authors.forename: Chingwei V
authors.initials: CV
authors.lastname: Lee
authors.forename: Germaine
authors.initials: G
authors.lastname: Fuh
authors.forename: Christine
authors.initials: C
authors.lastname: Olsson
authors.forename: Lisa
authors.initials: L
authors.lastname: Damico
authors.forename: David
authors.initials: D
authors.lastname: Xie
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Meng
authors.forename: Johnny
authors.initials: J
authors.lastname: Gutierrez
authors.forename: Racquel
authors.initials: R
authors.lastname: Corpuz
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Linda
authors.initials: L
authors.lastname: Hall
authors.forename: Linda
authors.initials: L
authors.lastname: Rangell
authors.forename: Ron
authors.initials: R
authors.lastname: Ferrando
authors.forename: Henry
authors.initials: H
authors.lastname: Lowman
authors.forename: Franklin
authors.initials: F
authors.lastname: Peale
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
mesh_terms: 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*
chemical_list: D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A