The First WHO International Standard for Harmonizing the Biological Activity of Bevacizumab.

Haiyan Jia,Peter Rigsby,Parvathy Harikumar,Eleanor Atkinson,Meenu Wadhwa

doi:10.3390/biom11111610

Abstract

Several Bevacizumab products are approved for clinical use, with many others in late-stage clinical development worldwide. To aid the harmonization of potency assessment across different Bevacizumab products, the first World Health Organization (WHO) International Standard (IS) for Bevacizumab has been developed. Two preparations of a Bevacizumab candidate and comparator were assessed for their ability to neutralize and bind vascular endothelial growth factor (VEGF) using different bioassays and binding assays in an international collaborative study. Relative potency estimates were similar across different assays for the comparator or the duplicate-coded candidate sample. Variability in relative potency estimates was reduced when the candidate standard was used for calculation compared with various in-house reference standards, enabling harmonization in bioactivity evaluations. The results demonstrated that the candidate standard is suitable to serve as an IS for Bevacizumab, with assigned unitages for VEGF neutralization and VEGF binding activity. This standard coded 18/210 was established by the WHO Expert Committee on Biological Standardization, which is intended to support the calibration of secondary standards for product development and lifecycle management. The availability of IS 18/210 will help facilitate the global harmonization of potency evaluation to ensure patient access to Bevacizumab products with consistent safety, quality and efficacy.

Highlights

Neovascular diseases, including cancers and intraocular diseases, are hallmarked by excess new blood vessels, which arise from pre-existing ones in the form of angiogenesis [1].This process is driven by local tissue hypoxia due to an increasing metabolic demand to microcirculation in the case of neoplasm growth and progression
The biological activity of the candidate material was compared with the drug material in cell proliferation inhibitory assays using primary human umbilical vein endothelial cells (HUVECs) and exhibited comparable potency for inhibition of VEGF165-dependent HUVEC proliferation
These study results—including stability assessment—support the conclusion that the Bevacizumab preparation is suitable to serve as the 1st International Standard (IS) for determining the in vitro bioactivity of Bevacizumab products

Summary

Introduction

Neovascular diseases, including cancers and intraocular diseases, are hallmarked by excess new blood vessels, which arise from pre-existing ones in the form of angiogenesis [1]. This process is driven by local tissue hypoxia due to an increasing metabolic demand to microcirculation in the case of neoplasm growth and progression. In eye disorders such as diabetic retinopathy and neovascular age-related macular degeneration, tissue hypoxia is mainly caused by either hyperglycemia or aging-induced capillary loss and ischemia. Tissue hypoxia in turn triggers overexpression of pro-angiogenic factors including vascular endothelial growth factor (VEGF) [2]. VEGF is dominantly upregulated and the expression level of VEGF correlates with neovascular density and metastatic spread in some cancer types, including colorectal, breast and cervical cancers

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