Book review: Therapeutic Proteins: Strategies to Modulate Their Plasma Half-lives
Article first published online: 29 NOV 2012
Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Special Issue: Nanobio vs. Bionano
Volume 8, Issue 2, pages 163–164, February 2013
How to Cite
Dingermann, T. (2013), Book review: Therapeutic Proteins: Strategies to Modulate Their Plasma Half-lives. Biotechnology Journal, 8: 163–164. doi: 10.1002/biot.201200295
- Issue published online: 5 FEB 2013
- Article first published online: 29 NOV 2012
Therapeutic Proteins: Strategies to Modulate Their Plasma Half-lives by Roland Kontermann, Wiley, 2012, 372 pages. ISBN: 978-3-527-32849-9
Theo Dingermann Dingermann@em.uni-frankfurt.de*, * Institut für Pharmazeutische Biologie – Biozentrum, Frankfurt, Germany
Since the mid 80s, recombinant drugs have been adding significant value to the repertoire of intervention options for the treatment of serious diseases. By definition, all of these drugs are proteins. From a pharmaceutical standpoint of view, this causes some problems as protein-medicines exhibit some serious shortcomings. They are chemically labile and therefore susceptible to degradation as it passes through the stomach/gut-passage. Additionally proteins are also physically labile and therefore require careful handling with respect to temperature exposure and agitation. Finally most of these drug substances exhibit a relatively short half-life in the range of minutes to hours, once injected into the body via intravenous, intramuscular of subcutaneous routes.
For two reasons, Therapeutic Proteins: Strategies to Modulate Their Plasma Half-live, edited by Roland Kontermann deserves ample attention: (i) it provides comprehensive data on plasma half-lives of therapeutic proteins, and (ii) it gives significant insight into strategies on how to improve the half-lives of these drugs. Some of these approaches optimize the pharmacological potential of recombinant drugs and are valuable options for life cycle management.
...recombinant drugs have been adding significant value to the repertoire of intervention options for the treatment of serious diseases.
This book is organized in four parts:
The first part (Part one) provides general information in two articles: an introduction to half-life modulating strategies, an overview of the pharmacokinetics, and the half-life of protein therapeutics. This is a fairly neglected aspect when discussing protein therapeutics, although it is well recognized that the efficacy of all drugs is strongly determined by pharmacokinetic properties. Eventually the plasma half-life of a protein provides the basis for tissue distribution and excretion. Although protein therapeutics are considered as high molecular weight drug substances, many of these molecules are rapidly cleared from circulation. Thus they have to be administered as infusion or repeatedly in order to maintain a therapeutic effective dose over a prolonged period of time.
The introductory chapter gives an overview of approved protein therapeutic and provides data on their terminal half-lives. Additionally strategies are summarized, which aim to modulate the half-life of protein therapeutics, either by increasing the molecular weight and consequently the hydrodynamic volume or by implementing functions, which allow reutilization through the neonatal Fc-receptor (FcRn).
Although protein therapeutics as well as small molecular weight chemically synthesized compounds exhibit well-defined pharmacokinetic properties that form the basis of dosing regimes as well as drug delivery strategies, potential differences, caveats and pitfalls may arise for these special molecules. All of these in addition to general pharmacokinetic principles are discussed in the second article in the first part of the book.
The second part (Part two) focuses on half-life extension through chemical and posttranslational modifications. Five articles discuss such strategies in detail.
Simona Jevsevar and Menci Kunstelj describe options of half-life extension through PEGylation (see also their review article in Biotechnology Journal ). This has been proven extremely successful not only for half-life extension but also for increasing protein solubility of decreasing immunogenicity of protein drugs.
One alternative to PEGylation is the use of recombinant PEG mimetics. This innovative concept was introduced and discussed by Uli Binder and Arne Skerra. One charming advantage of this strategy lies in the fact that PEG mimetics are itself peptides. They can therefore be conveniently fused to the coding part of the active therapeutic protein using recombinant DNA technologies.
In the next article, Fuad Fares discusses half-life extension through O-glyosylation. Proteins modified by this approach are mainly C-terminal fusion proteins. They carry the so-called carboxy-terminal extension peptide (CTP) sequence of human chorionic gonadotropin-β (hcGβ), which contains four recognition sites of O-linked oligosaccharides. Mainly protein hormones such as follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), erythropoietin (EPO), and growth hormone (GH) have been successfully modified using this approach.
Modulating antibody pharmacokinetics by polysialic acid and polysialylation is the topic of the next article authored by Constantinou et al. Polysialic acid (PSA) is a biodegradable biopolymer, this might be a solution to solve the problems that some foresee with PEGylation, as chronic use of PEGylated peptides could accumulate in tissues and cause unforeseen toxic effects.
The last article of the second part describes an approach of half-life extension through conjugation of hydroxyethyl starch (HESylation®). Hey et al. give a comprehensive overview of this attractive protein modification option.
Part three deals with half-life modulation involving recycling by the FcRn. This part starts with an introduction by Jonghan Kim into the biology of the FcRn. Jalal A. Jazayeri and Graeme J Carroll go into the details of half-life extension by fusion to the Fc region. They provide an impressive set of examples of clinical applications of Fc and Fab antibody fragments and of examples of Fc-fused cytokines/proteins. They further discuss the various Fc receptors and provide many more interesting facts about “peptibodies”, i.e. Fc-peptide fusion proteins. Dumont et al. concentrate on creating long lasting clotting factors by monomeric Fc fusions, Sally Ward and Raimund J. Ober discuss the diverse roles of the FcRn and the implications for antibody engineering.
The second half of part three concentrates on the principles and options of half-life extension by fusion to albumin, Metzner et al. introduce the topic. Christopher Herring and Oliver Schon describe the AlbudAb (TM) technology platform as versatile albumin-binding domains for the development of therapeutics with tunable half-lives.
“Therapeutic Proteins: Strategies to Modulate Their Plasma Half-lives” should be on hand for all those who work on protein therapeutics.
The article by Fredrik Frejd is titled “Half-life extension by binding to albumin through an albumin-bind-ing domain”. Sabrina Trussel, Joerg Scheuermann and Dario Neri extend this theme to another interesting approach with their chapter “Half-life extension by binding to albumin through small molecules”.
Part four of the book contains a few but important aspects of half-life extension with pharmaceutical formulations. Astrid Hartung and Gerd Bendas describe half-life extension through liposome formulations, and Katharina Landfester introduces nanoparticles as a formulation option for half-life extension.
Approaches described in this excellent book become more and more relevant. The majority of future protein therapeutics will be modified in one way or another using techniques and concepts described in this monograph. Therefore it can be safely stated that this is an extremely relevant contribution, which should be on hand for all those who think about or work on protein therapeutics.
Institut für Pharmazeutische Biologie – Biozentrum, Frankfurt, Germany
About the author
Prof. Roland Kontermann obtained his PhD in Molecular Biology from the University of Heidelberg in Germany. After working as a postdoc in the laboratory of Sir Gregory Winter at the MRC Centre for Protein Engineering, Cambridge, UK, he was a group leader at the Institute of Molecular Biology and Tumor Biology of the University of Marburg, Germany and subsequently Head of Research at Vectron Therapeutics AG. Since 2004 he is Professor of Biomedical Engineering at the Institute of Cell Biology and Immunology of the University of Stuttgart, Germany. Prof. Kontermann's current research focuses on the development of recombinant bispecific and bifunctional antibody molecules, including half-life extension strategies, and targeted nanoparticulate carrier systems for tumor therapy. He has over 60 scientific publications and co-editor (together with Stefan Dübel) of the Antibody Engineering Lab Manual.