Effects of a monoclonal anti-alphavbeta3 integrin antibody on blood vessels - a pharmacodynamic study.
OBJECTIVE
The integrin alphavbeta3 is an adhesion molecule expressed by proliferating endothelial cells and antibodies blocking this integrin inhibit angiogenesis in preclinical models. MEDI-522 is a second generation humanized anti-alphavbeta3 antibody designed for antiangiogenic therapy. The purpose of this study was to examine potential effects of this agent on blood vessels.


METHODS
In a phase I dose escalation study, MEDI-522 was administered by weekly infusions to 25 adult patients with advanced solid organ malignancies. As a surrogate angiogenesis assay, a wound was created by punch biopsy of the arm skin. This wound site was re-biopsied after a 7-day interval. Dual-label immunofluorescence experiments followed by computer-assisted image analysis were conducted to analyze the vasculature.


RESULTS
Sequential pretreatment and 4-week treatment skin biopsy pairs were available on 4 patients, who had received 6 or 10 mg/kg of MEDI-522. MEDI-522 was detected in the dermal blood vessels as well as the dermal interstitium both in intact and wounded skin sites following treatment. No statistically significant difference was found between pretreatment and treatment samples of skin for vascular area, endothelial cell proliferation and apoptosis, or beta3 integrin levels. Phosphorylated focal adhesion kinase (pFAK) was significantly diminished in skin wound vessels during MEDI-522 treatment compared to the pretreatment samples.


CONCLUSIONS
MEDI-522 was detectable both in quiescent and in angiogenically active skin blood vessels as well as in the dermal interstitial space. The levels of pFAK were reduced during MEDI-522 treatment, suggesting a modulating effect on this signaling molecule.
Zhang
Dahua
D
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53792, USA.
Pier
Thomas
T
McNeel
Douglas G
DG
Wilding
George
G
Friedl
Andreas
A
D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique / Q000379:methods; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007262:Infusions, Intravenous; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000276:immunology*; D008223:Lymphoma / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D039302:Integrin alphaVbeta3; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human