Vanucizumab mode of action: Serial biomarkers in plasma, tumor, and skin-wound-healing biopsies

Highlights • Angiogenesis is critical to the development and survival of solid tumors. • Vanucizumab inhibits both vascular endothelial growth factor and angiopoietin-2. • Vanucizumab exhibits anti-tumor, anti-angiogenic and anti-metastatic effects. • It markedly reduced blood-vessel markers in tumor/skin samples in cancer patients. • Skin biopsies are a valuable surrogate for studying angiogenesis-related mechanisms.
Vanucizumab is a novel bispecific antibody inhibiting vascular endothelial growth factor (VEGF-A) and angiopoietin-2 (Ang-2) that demonstrated safety and anti-tumor activity in part I of a phase I study of 42 patients with advanced solid tumors. Part II evaluated the pharmacodynamic effects of vanucizumab 30 or 15 mg/kg every 2 weeks in 32 patients. Serial plasma samples, paired tumor, and skin-wound-healing biopsies were taken over 29 days to evaluate angiogenic markers. Vanucizumab was associated with marked post-infusion reductions in circulating unbound VEGF-A and Ang-2. By day 29, tumor samples revealed mean reductions in density of microvessels (−32.2%), proliferating vessels (−47.9%) and Ang-2 positive vessels (−62.5%). Skin biopsies showed a mean reduction in density of microvessels (−49.0%) and proliferating vessels (−25.7%). Gene expression profiling of tumor samples implied recruitment and potential activation of lymphocytes. Biopsies were safely conducted. Vanucizumab demonstrated a consistent biological effect on vascular-related biomarkers, confirming proof of concept. Skin-wound-healing biopsies were a valuable surrogate for studying angiogenesis-related mechanisms.