title: A therapeutic anti-VEGF antibody with increased potency independent of pharmacokinetic half-life.
abstract: Bevacizumab [Avastin; anti-vascular endothelial growth factor (VEGF) antibody] is an antiangiogenic IgG approved for treating patients with certain types of colon, breast, and lung cancer. In these indications, bevacizumab is administered every 2 to 3 weeks, prompting us to study ways to reduce the frequency of administration. Increasing affinity to neonatal Fc receptor (FcRn) may extend the pharmacokinetic half-life of an antibody, but the quantitative effect of FcRn affinity on clearance has not been clearly elucidated. To gain further insight into this relationship, we engineered a series of anti-VEGF antibody variants with minimal amino acid substitutions and showed a range of half-life improvements in primates. These results suggest that, if proven clinically safe and effective, a modified version of bevacizumab could potentially provide clinical benefit to patients on long-term anti-VEGF therapy through less-frequent dosing and improved compliance with drug therapy. Moreover, despite having half-life similar to that of wild-type in mice due to the species-specific FcRn binding effects, the variant T307Q/N434A exhibited superior in vivo potency in slowing the growth of certain human tumor lines in mouse xenograft models. These results further suggest that FcRn variants may achieve increased potency through unidentified mechanisms in addition to increased systemic exposure.
authors.affiliation: Departments of Antibody Engineering, Genentech, Inc, South San Francisco, California, USA.
authors.forename: Yik Andy
authors.initials: YA
authors.lastname: Yeung
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Reyes
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vernes
authors.forename: Samantha
authors.initials: S
authors.lastname: Lien
authors.forename: John
authors.initials: J
authors.lastname: Lowe
authors.forename: Mauricio
authors.initials: M
authors.lastname: Maia
authors.forename: William F
authors.initials: WF
authors.lastname: Forrest
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Meng
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Damico
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Henry B
authors.initials: HB
authors.lastname: Lowman
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D008252:Macaca fascicularis; D051379:Mice; D009368:Neoplasm Transplantation; D015202:Protein Engineering / Q000379:methods; D011961:Receptors, Fc / Q000737:chemistry; D020349:Surface Plasmon Resonance; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology* / Q000493:pharmacokinetics
chemical_list: D020533:Angiogenesis Inhibitors; D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D011961:Receptors, Fc; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab