- Email: [email protected]
Protein pharmaceuticals
Drug Discovery Today: Technologies
Vol. 5, No. 2–3 2008
Editors-in-Chief Kelvin Lam – Pfizer, Inc., USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Protein therapeutics
EDITORIAL
Protein pharmaceuticals Marco van de Weert, Eva Horn Moeller Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark. Email: [email protected], [email protected]
In the last two decades the pharmaceutical industry has paid increasing attention to the development of medicinal products containing (peptides and) proteins as the active compound. Two of the 20 largest pharmaceutical companies, Amgen and Genentech (recently merged with Roche), mainly market protein pharmaceuticals. Most other companies in this top 20 are rapidly increasing the number of protein pharmaceuticals in their portfolio. The drug discovery and development process of protein pharmaceuticals requires a markedly different approach to that of most conventional low molecular weight drugs. For example, most proteins are ‘discovered’ as potential drugs by their known physiological action, rather than the large-scale screening of conventional drugs towards a desired target. Moreover, proteins are almost invariably produced in cell-based production systems and administered through injection or infusion. Combined with the often complex and limited physicochemical stability, this makes the production of a protein pharmaceutical very challenging. In this theme issue of Drug Discovery Today: Technologies, the reviews deal with various challenges during design, production, formulation, and delivery of protein pharmaceuticals. A major problem for most protein pharmaceuticals are the production costs, and one method to decrease such costs is by optimising the yield of the production cells. Matasci et al. discuss approaches to (further) increase the production yields of mammalian cells, and argue that significant improvements (by several factors) is feasible through various methodologies. Another bottleneck is the limited number of possible protein molecules. Although one may expect that most proteins as ‘designed’ by Nature are optimised for their physiological function, their properties may actually be sub-optimal for use as a pharmaceutical entity. Hwang and 1740-6749/$ ß 2009 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddtec.2009.11.001
Marco van de Weert is Associate Professor in the Biomacromolecular Drug Delivery group at the Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark. His research focuses on pharmaceutical protein formulation and delivery, with an emphasis on the analytical and biophysical aspects. Of special interest to him are novel additives, amyloid fibril formation, and drying technologies. Marco holds a MSc (1996) and PhD (2001) from Utrecht University, the Netherlands. After a short stay (6 months) as junior Assistant Professor at Utrecht University he joined his current group as an Alfred Benzon Research fellow, and became an Assistant Professor in 2004, and Associate Professor in 2006. Marco has authored about 35 peer-reviewed papers, several book chapters, and edited a book on the immunogenicity of biopharmaceuticals. He is also a member of the Committee on Training and Education of the European Federation of Pharmaceutical Scientists. Eva Horn Moeller is an Assistant Professor in the Biomacromolecular Drug Delivery Group at the Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark. Her field of research focuses on the design of advanced protein delivery systems, with special interest in chemical modification of proteins and the biophysics of proteins in pharmaceutical formulations. Eva holds an MSc and a PhD from the University of Copenhagen and has a dual background in Medicinal Chemistry and Pharmaceutics. She is an author of 17 papers and book chapters.
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Drug Discovery Today: Technologies | Protein therapeutics
Park explain how modulation of various protein properties, such as stability and binding affinity, can be guided by computational methods. This increases the design space of protein pharmaceuticals and thus creates further options for improving the ‘drugability’. Computational analysis of protein structure is also of importance to predict potential immune responses to the protein pharmaceutical, as discussed by Roggen. Any possible antigenic sites may then be designed out of the protein, as long as this does not adversely affect other properties of the protein. Related to modulation of protein properties is the review by Veronese and Pasut, who discuss several chemical modification methods primarily aimed at increasing the circulation time of proteins. This reduces the number of required injections, while the sustained concentrations may also improve the pharmacological effect. However, as discussed by Mahmood, the optimal pharmacological profile may well be significantly different from the most practical profile. Moreover, Mahmood shows that determining protein pharmacokinetics is far from trivial, because many protein pharmaceuticals are very similar to endogenous compounds. The remaining reviews focus on the formulation and delivery of protein pharmaceuticals. As mentioned earlier, pro-
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www.drugdiscoverytoday.com
Vol. 5, No. 2–3 2008
teins are physicochemically labile. Capelle and Arvinte discuss high-throughput methods for formulation screening, with the main focus on physical stability of the protein, while Maltesen and van de Weert discuss current and developing drying techniques for obtaining a stable product. Horn Moeller and Jorgensen describe the current efforts in developing alternative administration strategies for proteins. With decreasing costs for the API, these alternative routes have become more feasible and may overcome the poor compliance related to injections. Finally, Torchilin discusses advanced delivery approaches for bringing proteins into cells, opening up the possibility to treat diseases that have an intracellular origin. The guest editors hope this theme issue serves as a condensed update of current events in the field of protein pharmaceuticals development. Moreover, we believe that this issue also points out the most important bottlenecks within this area, with various possible solutions, promising an exciting time ahead. With best wishes, Marco van de Weert Eva Horn Moeller
Vol. 5, No. 2–3 2008
Editors-in-Chief Kelvin Lam – Pfizer, Inc., USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Protein therapeutics
EDITORIAL
Protein pharmaceuticals Marco van de Weert, Eva Horn Moeller Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark. Email: [email protected], [email protected]
In the last two decades the pharmaceutical industry has paid increasing attention to the development of medicinal products containing (peptides and) proteins as the active compound. Two of the 20 largest pharmaceutical companies, Amgen and Genentech (recently merged with Roche), mainly market protein pharmaceuticals. Most other companies in this top 20 are rapidly increasing the number of protein pharmaceuticals in their portfolio. The drug discovery and development process of protein pharmaceuticals requires a markedly different approach to that of most conventional low molecular weight drugs. For example, most proteins are ‘discovered’ as potential drugs by their known physiological action, rather than the large-scale screening of conventional drugs towards a desired target. Moreover, proteins are almost invariably produced in cell-based production systems and administered through injection or infusion. Combined with the often complex and limited physicochemical stability, this makes the production of a protein pharmaceutical very challenging. In this theme issue of Drug Discovery Today: Technologies, the reviews deal with various challenges during design, production, formulation, and delivery of protein pharmaceuticals. A major problem for most protein pharmaceuticals are the production costs, and one method to decrease such costs is by optimising the yield of the production cells. Matasci et al. discuss approaches to (further) increase the production yields of mammalian cells, and argue that significant improvements (by several factors) is feasible through various methodologies. Another bottleneck is the limited number of possible protein molecules. Although one may expect that most proteins as ‘designed’ by Nature are optimised for their physiological function, their properties may actually be sub-optimal for use as a pharmaceutical entity. Hwang and 1740-6749/$ ß 2009 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddtec.2009.11.001
Marco van de Weert is Associate Professor in the Biomacromolecular Drug Delivery group at the Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark. His research focuses on pharmaceutical protein formulation and delivery, with an emphasis on the analytical and biophysical aspects. Of special interest to him are novel additives, amyloid fibril formation, and drying technologies. Marco holds a MSc (1996) and PhD (2001) from Utrecht University, the Netherlands. After a short stay (6 months) as junior Assistant Professor at Utrecht University he joined his current group as an Alfred Benzon Research fellow, and became an Assistant Professor in 2004, and Associate Professor in 2006. Marco has authored about 35 peer-reviewed papers, several book chapters, and edited a book on the immunogenicity of biopharmaceuticals. He is also a member of the Committee on Training and Education of the European Federation of Pharmaceutical Scientists. Eva Horn Moeller is an Assistant Professor in the Biomacromolecular Drug Delivery Group at the Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark. Her field of research focuses on the design of advanced protein delivery systems, with special interest in chemical modification of proteins and the biophysics of proteins in pharmaceutical formulations. Eva holds an MSc and a PhD from the University of Copenhagen and has a dual background in Medicinal Chemistry and Pharmaceutics. She is an author of 17 papers and book chapters.
e35
Drug Discovery Today: Technologies | Protein therapeutics
Park explain how modulation of various protein properties, such as stability and binding affinity, can be guided by computational methods. This increases the design space of protein pharmaceuticals and thus creates further options for improving the ‘drugability’. Computational analysis of protein structure is also of importance to predict potential immune responses to the protein pharmaceutical, as discussed by Roggen. Any possible antigenic sites may then be designed out of the protein, as long as this does not adversely affect other properties of the protein. Related to modulation of protein properties is the review by Veronese and Pasut, who discuss several chemical modification methods primarily aimed at increasing the circulation time of proteins. This reduces the number of required injections, while the sustained concentrations may also improve the pharmacological effect. However, as discussed by Mahmood, the optimal pharmacological profile may well be significantly different from the most practical profile. Moreover, Mahmood shows that determining protein pharmacokinetics is far from trivial, because many protein pharmaceuticals are very similar to endogenous compounds. The remaining reviews focus on the formulation and delivery of protein pharmaceuticals. As mentioned earlier, pro-
e36
www.drugdiscoverytoday.com
Vol. 5, No. 2–3 2008
teins are physicochemically labile. Capelle and Arvinte discuss high-throughput methods for formulation screening, with the main focus on physical stability of the protein, while Maltesen and van de Weert discuss current and developing drying techniques for obtaining a stable product. Horn Moeller and Jorgensen describe the current efforts in developing alternative administration strategies for proteins. With decreasing costs for the API, these alternative routes have become more feasible and may overcome the poor compliance related to injections. Finally, Torchilin discusses advanced delivery approaches for bringing proteins into cells, opening up the possibility to treat diseases that have an intracellular origin. The guest editors hope this theme issue serves as a condensed update of current events in the field of protein pharmaceuticals development. Moreover, we believe that this issue also points out the most important bottlenecks within this area, with various possible solutions, promising an exciting time ahead. With best wishes, Marco van de Weert Eva Horn Moeller