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

Florian Heil , Galina Babitzki , Alice Julien-Laferriere , Chia Huey Ooi , Manuel M. Hidalgo , Christophe Massard (1) , Mariá J. Martinez-Garcia , Christophe Le Tourneau (2, 3) , Mark M. Kockx , Peter Gerber , Simona Rossomanno , Oliver Krieter , Angelika Lahr , Norbert Wild , Suzana Vega Harring , Katharina Lechner

1 DITEP - Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy]
2 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
3 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe

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.

Mots clés: Angiopoietin-2; Biomarkers; Micro vessel density; Mode of action; Phase I clinical trial; Vanucizumab

Domaines: Cancer; Pharmacologie

Florian Heil, Galina Babitzki, Alice Julien-Laferriere, Chia Huey Ooi, Manuel M. Hidalgo, et al.. Vanucizumab mode of action: Serial biomarkers in plasma, tumor, and skin-wound-healing biopsies. Translational Oncology, 2021, 14 (2), pp.100984. ⟨10.1016/j.tranon.2020.100984⟩. ⟨hal-03141470⟩