title: Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies.
abstract: A major obstacle compromising the successful application of many of the new targeted anticancer drugs, including angiogenesis inhibitors, is the empiricism associated with determining an effective biological/therapeutic dose because many of these drugs express optimum therapeutic activity below the maximum tolerated dose, if such a dose can be defined. Hence, surrogate markers are needed to help determine optimal dosing. Here we describe such a molecular marker, increased plasma levels of vascular endothelial growth factor (VEGF), in normal or tumor-bearing mice that received injections of an anti-VEGF receptor (VEGFR)-2 monoclonal antibody, such as DC101. Rapid increases of mouse VEGF (e.g., within 24 hours) up to 1 order of magnitude were observed after single injections of DC101 in non-tumor-bearing severe combined immunodeficient or nude mice; similar increases in human plasma VEGF were detected in human tumor-bearing mice. RAFL-1, another anti-VEGFR-2 antibody, also caused a significant increase in plasma VEGF. In contrast, increases in mouse VEGF levels were not seen when small molecule VEGFR-2 inhibitors were tested in normal mice. Most importantly, the increases in plasma VEGF were induced in a dose-dependent manner, with the maximum values peaking when doses previously determined to be optimally therapeutic were used. Plasma VEGF should be considered as a possible surrogate pharmacodynamic marker for determining the optimal biological dose of antibody drugs that block VEGFR-2 (KDR) activity in a clinical setting.
authors.affiliation: Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.forename: Shane K
authors.initials: SK
authors.lastname: Green
authors.forename: Giulio
authors.initials: G
authors.lastname: Francia
authors.forename: John M L
authors.initials: JM
authors.lastname: Ebos
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: du Manoir
authors.forename: Adina
authors.initials: A
authors.lastname: Weinerman
authors.forename: Urban
authors.initials: U
authors.lastname: Emmenegger
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Philip
authors.initials: P
authors.lastname: Thorpe
authors.forename: Andrew
authors.initials: A
authors.lastname: Davidoff
authors.forename: James
authors.initials: J
authors.lastname: Huber
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000098:blood supply / Q000628:therapy; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood; D001792:Blood Platelets / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000097:blood* / Q000098:blood supply / Q000628:therapy*; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000097:blood / Q000628:therapy; D011471:Prostatic Neoplasms / Q000097:blood* / Q000098:blood supply / Q000628:therapy*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology*
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2