A therapeutic anti-VEGF antibody with increased potency independent of pharmacokinetic half-life.
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.
Yeung
Yik Andy
YA
Departments of Antibody Engineering, Genentech, Inc, South San Francisco, California, USA.
Wu
Xiumin
X
Reyes
Arthur E
AE
Vernes
Jean-Michel
JM
Lien
Samantha
S
Lowe
John
J
Maia
Mauricio
M
Forrest
William F
WF
Meng
Y Gloria
YG
Damico
Lisa A
LA
Ferrara
Napoleone
N
Lowman
Henry B
HB
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
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