Interferon-Based Biopharmaceuticals: Overview on the Production, Purification, and Formulation

Abstract

The advent of biopharmaceuticals in modern medicine brought enormous benefits to the treatment of numerous human diseases and improved the well-being of many people worldwide. First introduced in the market in the early 1980s, the number of approved biopharmaceutical products has been steadily increasing, with therapeutic proteins, antibodies, and their derivatives accounting for most of the generated revenues. The success of pharmaceutical biotechnology is closely linked with remarkable developments in DNA recombinant technology, which has enabled the production of proteins with high specificity. Among promising biopharmaceuticals are interferons, first described by Isaacs and Lindenmann in 1957 and approved for clinical use in humans nearly thirty years later. Interferons are secreted autocrine and paracrine proteins, which by regulating several biochemical pathways have a spectrum of clinical effectiveness against viral infections, malignant diseases, and multiple sclerosis. Given their relevance and sustained market share, this review provides an overview on the evolution of interferon manufacture, comprising their production, purification, and formulation stages. Remarkable developments achieved in the last decades are herein discussed in three main sections: (i) an upstream stage, including genetically engineered genes, vectors, and hosts, and optimization of culture conditions (culture media, induction temperature, type and concentration of inducer, induction regimens, and scale); (ii) a downstream stage, focusing on single- and multiple-step chromatography, and emerging alternatives (e.g., aqueous two-phase systems); and (iii) formulation and delivery, providing an overview of improved bioactivities and extended half-lives and targeted delivery to the site of action. This review ends with an outlook and foreseeable prospects for underdeveloped aspects of biopharma research involving human interferons.

Forms and Methods for Interferon's Encapsulation

“…The 163 clinical trials with currently active IFNs reinforce their importance as therapeutics for human health [144]. On the economic side, total market sales of IFNs reached $6.9 billion in 2019, and these figures are expected to grow in the future due to the increasing incidence of viral and chronic diseases, and the growing adoption of biosimilars for potential therapeutics or prophylaxis of future pandemics, among others [88].…”

“…IFNs are broad-spectrum antivirals that are effective against viruses of recent interest, such as MERS-CoV [145], SARS-CoV [146], and SARS-CoV-2 [147]. These proteins exert autocrine or paracrine action on surrounding cells [88]. In an uninfected cell, binding of IFN to its receptor and subsequent IFN signaling renders the cell refractory to viral infection.…”

“…Due to the lack of success of transport systems in bringing these compounds to a clinical stage, researchers have focused on using micro and nanoencapsulation to protect IFNs from degradation and extend their half-life. With this approach, small doses can be administered in a sustained manner with minimal side effects [88]. Microencapsulation and nanoencapsulation are a set of technologies that allow the trapping of active ingredients, also known as core materials, using a surrounding element (encapsulation or coating) [89].…”

“…Nanoparticles are nanoscale structures that, like microparticles, can be capsules or spheres depending on their internal constitution [135]. These systems make it possible to simplify the administration of IFNs, improve their therapeutic effects and reduce their dose-related side effects without reducing their biological activity or changing the protein structure [88].…”

Vaccine Formulation for Infectious Diseases and Adjuvant Mechanisms of Action

“…Four review articles in this issue highlight the production, purification, and formulation of interferon-based biopharmaceuticals (by Castro et al) [ 8 ], the efficacy of natural and synthetic saponins such as QS-21 as adjuvants (by P. Wang) [ 9 ], and the efficacy of cyclic dinucleotide (CDNs) second messengers with immunomodulatory functions such as cyclic di-adenosine monophosphate (cyclic di-AMP), cyclic di-guanosine monophosphate (cyclic di-GMP), and cyclic GMP–AMP (cGAMP) as adjuvants (by Gogoi et al) [ 10 ]. Finally, Fourie and Wilson highlighted how stress response proteins may have immunomodulation attributes making them potential adjuvants or immunotherapeutics [ 11 ].…”