title: VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade.
abstract: VEGF is the best characterized mediator of tumor angiogenesis. Anti-VEGF agents have recently demonstrated impressive efficacy in human cancer trials, but the optimal dosing of such agents must still be determined empirically, because biomarkers to guide dosing have yet to be established. The widely accepted (but unverified) assumption that VEGF production is quite low in normal adults led to the notion that increased systemic VEGF levels might quantitatively reflect tumor mass and angiogenic activity. We describe an approach to determine host and tumor production of VEGF, using a high-affinity and long-lived VEGF antagonist now in clinical trials, the VEGF Trap. Unlike antibody complexes that are usually rapidly cleared, the VEGF Trap forms inert complexes with tissue- and tumor-derived VEGF that remain stably in the systemic circulation, where they are readily assayable, providing unprecedented capability to accurately measure VEGF production. We report that VEGF production is surprisingly high in non-tumor-bearing rodents and humans, challenging the notion that systemic VEGF levels can serve as a sensitive surrogate for tumor load; tumor VEGF contribution becomes significant only with very large tumor loads. These findings have the important corollary that anti-VEGF therapies must be sufficiently dosed to avoid diversion by host-derived VEGF. We further show that our assay can indicate when VEGF is optimally blocked; such biomarkers to guide dosing do not exist for other anti-VEGF agents. Based on this assay, VEGF Trap doses currently being assessed in clinical trials are in the efficacious range.
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. john.rudge@regeneron.com
authors.forename: John S
authors.initials: JS
authors.lastname: Rudge
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Holash
authors.forename: Donna
authors.initials: D
authors.lastname: Hylton
authors.forename: Michelle
authors.initials: M
authors.lastname: Russell
authors.forename: Shelly
authors.initials: S
authors.lastname: Jiang
authors.forename: Raymond
authors.initials: R
authors.lastname: Leidich
authors.forename: Nicholas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Erica A
authors.initials: EA
authors.lastname: Pyles
authors.forename: Al
authors.initials: A
authors.lastname: Torri
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Wiegand
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: Neil
authors.initials: N
authors.lastname: Stahl
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
mesh_terms: D000375:Aging / Q000502:physiology; D020533:Angiogenesis Inhibitors / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015415:Biomarkers; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011485:Protein Binding; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D023041:Xenograft Model Antitumor Assays; D002578:Uterine Cervical Dysplasia / Q000378:metabolism / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D000906:Antibodies; D015415:Biomarkers; D042442:Vascular Endothelial Growth Factors