Effects of a monoclonal anti-αvβ3 integrin antibody on blood vessels—A pharmacodynamic study
Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, Madison, Wisconsin, United States Investigational New Drugs
(Impact Factor: 2.92).
03/2007; 25(1):49-55. DOI: 10.1007/s10637-006-9013-8
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.
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.
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.
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.
Available from: Xinjie Lu
- "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 phosphorylated focal adhesion kinase (pFAK) were reduced during MEDI-522 treatment, suggesting a modulating effect on this signaling molecule (Zhang et al. 2007; Gramoun et al. 2007). "
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ABSTRACT: Integrins have been reported to mediate cell survival, proliferation, differentiation, and migration programs. For this reason, the past few years have seen an increased interest in the implications of integrin receptors in cancer biology and tumor cell aggression. This review considers the potential role of integrins in cancer and also addresses why integrins are present attractive targets for drug design. It discusses of the several properties of the integrin-based chemotherapeutic agents currently under consideration clinically and provides an insight into cancer drug development using integrin as a target.
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