The Biological Properties,Assay,and Standardization of Interferon-Alpha: A Need for a WHO Collaborative Study

Abstract

Interferon-alpha (IFN-α) exists as a range of closely related, biologically active proteins and has been the subject of extensive research and clinical investigation. Standardization of IFN-α and the uniform reporting of IFN-α activity in International Units (IU) is critical to preclinical research and the clinical development of IFN-α products as therapeutic agents. Currently, several different IFN-α-containing reference preparations, established as World Health Organization (WHO) International Standards (IS) for particular IFN-α proteins (mixtures or single molecular species) are available for assay calibration. Nevertheless, the heterogeneous nature of IFN-α has raised standardization issues relating to the activity of individual IFN-α proteins, henceforth termed subtypes, in the various biologic assays used for determining IFN-α levels. These issues include the question of parallelism of dose-response curves among particular IFN-α subtypes and different, naturally produced IFN-α subtype mixtures, for example, leukocyte IFN-α, and the applicablity of IU of IFN-α activity defined by antiviral assays to alternative biologic assays, for example, antiproliferative assays. To address such issues, a WHO Consultative Group on Cytokine Standardization requested that the National Institute for Biological Standards and Control (NIBSC) and the Centre for Biologies Evaluation and Research (CBER) organize an international collaborative study to compare the activities and relative potencies of the several available IFN-α preparations, including those derived from human cells containing mixtures of IFN-α subtypes and those derived by rDNA methods containing single IFN-α subtypes, in different assays. To date, 111 participants in 32 countries have been recruited to the study and have agreed to assay a total of 17 different natural and recombinant IFN-α preparations or a defined subset thereof in specific in-house assays. The assay results generated will be statistically analyzed and evaluated to address the stated issues and to assess whether any individual IFN-α preparation is suitable to serve as an IS for all IFN-α preparations or whether more than one IS will be needed for this purpose.