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Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.

ABSTRACT: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti-vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials.Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab.Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P

SUBMITTER: O'Connor JP

PROVIDER: S-EPMC4688942 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.

O'Connor James P B JP Carano Richard A D RA Clamp Andrew R AR Ross Jed J Ho Calvin C K CC Jackson Alan A Parker Geoff J M GJ Rose Chris J CJ Peale Franklin V FV Friesenhahn Michel M Mitchell Claire L CL Watson Yvonne Y Roberts Caleb C Hope Lynn L Cheung Sue S Reslan Hani Bou HB Go Mary Ann T MA Pacheco Glenn J GJ Wu Xiumin X Cao Tim C TC Ross Sarajane S Buonaccorsi Giovanni A GA Davies Karen K Hasan Jurjees J Thornton Paula P del Puerto Olivia O Ferrara Napoleone N van Bruggen Nicholas N Jayson Gordon C GC

Clinical cancer research : an official journal of the American Association for Cancer Research 20091027 21

<h4>Purpose</h4>Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti-vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials.<h4>Experimental design</h4>Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imagin ...[more]

PMID: 19861458

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Project description:PURPOSE:To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN:Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS:Participants with available plasma samples (N = 436). METHODS:Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES:Changes in the natural log (ln) of plasma VEGF levels. RESULTS:Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS:These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

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Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.

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Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.

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