Frontiers in Clinical Drug Research - Anti Infectives: Volume 4

Atta-ur-Rahman

• Publisher: Bentham Science Publishers
• Year: 2017
• ISBN:
  9781681084879
• Topic: Physical Sciences
• Subtopic: Clinical Chemistry

Frontiers in Clinical Drug Research – Anti infectives is an eBook series that brings updated reviews to readers interested in learning about advances in the development of pharmaceutical agents for the treatment of infectious diseases. The scope of the eBook series covers a range of topics including the chemistry, pharmacology, molecular biology and biochemistry of natural and synthetic drugs employed in the treatment of infectious diseases. Reviews in this series also include research on multi drug resistance and pre-clinical / clinical findings on novel antibiotics, vaccines, antifungal agents and antitubercular agents. Frontiers in Clinical Drug Research – Anti infectives is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information for developing clinical trials and devising research plans in the field of anti infective drug discovery and epidemiology.
The fourth volume of this series features reviews that cover a variety of topics including:
-Strategies to prolong antibiotic life
-Catalytic antibodies for targeting rabies and influenza viruses
-Antiviral therapies for arenaviruses
-The role of steroids in viral infections
-Monoclonal antibody manufacturing processes
-Prevention and eradication of biofilms in medical devices

Monoclonal Antibodies – Addressing the Challenges on the Manufacturing Processing of an Advanced Class of Therapeutic Agents

Emanuel V. Capela^{1, 2}, Maria Raquel Aires-Barros², Mara G. Freire^{1, *}, Ana M. Azevedo^{2, *}

¹ CICECO – Aveiro Institute of Materials, Chemistry Department, University of Aveiro, 3810-193, Aveiro, Portugal

² iBB – Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal

Abstract

Monoclonal antibodies (mAbs) were firstly described by Köhler and Milstein in 1975, and their potential as powerful therapeutic agents recognized in the following years. Currently, the US Food and Drug Administration (FDA) has already approved 56 monoclonal antibodies for the treatment of several diseases, including cancer (e.g. breast cancer, leukemia and prostate cancer), auto-immune disorders (rheumatoid arthritis and Crohn’s disease), asthma, and cardiovascular and infectious diseases. Despite their advantages and therapeutic potential, the cost of manufacturing these biopharmaceuticals with high quality and purity level is still extremely high due to the absence of current cost-effective extraction/purification methods, and which has also impaired their widespread application as recurrent therapeutic agents. The upstream processing of mAbs has gone through several improvements in recent years, by using alternative expression systems or by optimizing the medium formulations and feeding strategies. On the contrary, the downstream processing is considered the bottleneck in the manufacturing of mAbs for therapeutic purposes at reliable costs, representing up to 80% of their total production costs – which is a frontier in clinical drug research. In the past years, several chromatographic and non-chromatographic alternatives have been explored for this purpose, resulting in the development of efficient platforms for the purification of mAbs, that are overviewed and discussed in this chapter. In summary, this chapter provides a vision on the current state of the art of the biopharmaceuticals market, on the production and use of mAbs as valuable therapeutic agents, including their use for the treatment of infectious diseases, while summarizing the mAbs-based products already approved by regulatory agencies. New insights concerning the development of new and alternative platforms or the extractionand purification of mAbs are also discussed, while envisaging the adoption of the most relevant techniques by the pharmaceutical industry to allow the widespread use of biopharmaceuticals in the near future.

Keywords: Affinity precipitation, Aqueous two-phase systems, Biopharma- ceuticals, Biopharmaceutical market, Cancer, Chromatographic methods, Downstream processing, High performance tangential flow filtration, Infectious diseases, Ionic exchange chromatography, IVIG, Magnetic separation, Monoclonal antibodies, Multimodal chromatography, Non-chromatographic methods, Passive immunity, Pharmaceutical industry, Preparative electrophoresis, Purification, Therapeutic agents, Upstream processing.

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^* Corresponding authors Mara G. Freire: CICECO – Aveiro Institute of Materials, Chemistry Department, University of Aveiro, 3810-193, Aveiro, Portugal; Tel: [phone]; Fax: [phone]; E-mail: [email protected]
Ana M. Azevedo: iBB – Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal; E-mail: [email protected]

Introduction

In recent years, human society has been facing several issues concerning the exponential emergence of drug-resistant microorganisms, diseases that are unresponsive to common drug therapies and the appearance of individuals with impaired immune systems who are unable to respond to conventional vaccines. These events fomented the search on effective alternative therapeutics, that is a crucial goal to be achieved within the next few years [1]. In this context, biopharmaceuticals have greatly improved the treatment of many diseases and sometimes are the only approved therapies available for a particular disease [2]. By definition, biopharmaceuticals are biological-based products, with high-molecular weight and complex molecular composition, obtained from heterogeneous mixtures from living beings, cells, animals or plants [3, 4]. Recombinant proteins, antibodies and nucleic-acid-based products are examples of biopharmaceuticals with application in several medicinal areas, such as in vaccination/immunization, oncology, cardiology, neurology and infectious diseases [2]. In what concerns antibodies, although being in many cases the only available therapy, the production cost of antibodies with high quality/purity for therapeutic applications still remains very high due to the absence of a cost-effective purification method, which has conditioned its application on a large scale and as a recurrent therapy [5].

Monoclonal antibodies (mAbs) are the most prevalent class of therapeutic recombinant proteins, used in the treatment of several diseases, including cancer (e.g. breast cancer, non-Hodgkin’s lymphoma, leukemia, colorectal and prostate cancer), auto-immune disorders (rheumatoid arthritis and Crohn’s disease), transplant rejection, asthma, and cardiovascular and infectious diseases [6]. Regarding the production of therapeutic mAbs, one of the most challenging aspects within the biopharmaceutical market is related with the need of quite high therapeutic doses, resulting in a crucial need of obtaining high amounts of pure mAbs [7]. These antibodies are biological products that can be produced by cell lines and extracted from their extracellular supernatant, thus exhibiting a high content of impurities. The current production process of therapeutic mAbs typically comprises two main steps: (i) the upstream processing, that relies on the production of antibodies by cell lines derived from mammalian cells; and (ii) the downstream processing, which consists on the recovery, purification and isolation of mAbs from cells and cell debris, processing medium and other impurities [15]. In the past few years, the upstream processing of mAbs has greatly improved; however, the downstream processing has not evolved at the same pace and is considered the bottleneck in the production of therapeutic mAbs – represe...