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Designing the better mousetrap? Technologies that expand therapeutic options
Designing the better mousetrap? Technologies that expand therapeutic options Editorial overview Gary Woodnutt and Frank S Walsh Current Opinion in Biotechnology 2006, 17:628–630 Available online 7th November 2006 0958-1669/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.copbio.2006.10.011
Gary Woodnutt Gary Woodnutt 9381, Judicial Drive, Suite 200, San Diego, CA 92121, USA e-mail: [email protected]
Gary Woodnutt worked for over 20 years with GlaxoSmithKline within the anti-infective and supportive care areas. More recently he led groups working on protein evolution and natural product discovery and is currently Head of Biology at CovX Research in San Diego. His current interests are in the discovery and development of peptide/antibody fusions in a number of therapeutic areas. Frank S Walsh Discovery Research, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA e-mail: [email protected]
Frank S Walsh is Executive Vice President and Head of Discovery Research at Wyeth Research in Collegeville, Pennsylvania, USA. Prior to his current position, he was with GlaxoSmithKline and Smith-Kline Beecham. His group of 1500 scientists is responsible for the delivery of 15 drug candidates to the clinic each year. His own research is in the area of neuroregeneration and the role of inhibitory components of the myelin sheath.
The pharmaceutical industry continues to face challenges in filling pipelines that are sufficiently robust to weather the attrition associated with drug discovery, development and regulatory hurdles. The sequencing of the human genome was heralded as a great opportunity to exploit a seemingly endless supply of new and important targets; however, the initial excitement was tempered on realizing that this wealth was not immediately addressable. In this respect, the sequence information obtained was in advance of the technology required to fully validate its use, thus it is only recently that we have been able to fully utilize the available data. Huge changes in high-throughput screening capabilities have further enabled researchers to obtain molecules that interact with targets in a massively parallel fashion. However, the availability of targets and our ability to screen them highlights the next hurdle in the sequence of discovery, which is the availability of appropriate molecules that can be screened. Combinatorial chemistry and parallel synthesis efforts have provided the opportunity to expand small-molecule compound libraries, but available diversity is limited. The use of biological molecules, initially as replacement therapies but more recently as specific modulators of biological processes, has also become an increasingly important intervention strategy and has been particularly successful over the past decade. The development of new technologies to further expand the armamentarium that will complement and expand existing capabilities is a focus of many companies. Many of these technologies enhance current abilities, some are being used to resurrect older and, at least partially, ignored capabilities while many are ‘blue sky’ approaches that require further validation before being accepted for general usage. In this series of articles we have tried to give a sampling of some of these technologies and of their potential utility. In the first two articles the focus is on areas that have fallen out of favor over the years owing to the characteristics of the molecules discovered, which make them difficult to identify, isolate, derivitise and/or dose appropriately. Soil or other environmental samples have been, and continue to be, an important source of clinically relevant natural molecules but in general these molecules tend to be difficult to isolate and characterize. Moreover, even when a potential candidate is selected the structure has proven many times to be intractable for further derivitisation by standard organic chemistry. Significant improvements in analytical and preparative techniques have allowed the rapid identification and isolation of active components from the complex mixture present in extracts of environmental samples. Koehn provides examples of natural products in development that could indicate
Current Opinion in Biotechnology 2006, 17:628–630
www.sciencedirect.com
Editorial overview Woodnutt and Walsh 629
that there is a huge and increasing potential in these areas. In particular, he identifies approaches that can now allow manipulation of the structure to develop structure-activity relationships around the parent molecule that were previously very difficult. It is very likely that this will become a major growth area in the next decade. In the second article, Wood and colleagues discuss the merits of peptides, another series of molecules that have been down prioritized as potential therapeutic agents. Peptides hold therapeutic and commercial promise because they possess enormous structural diversity, are highly specific and potent, and generally have fewer safety issues relative to small molecules. These properties led to interest in naturally occurring peptides and a number of companies generated large synthetic libraries. Unfortunately, the synthetic libraries promised much, but delivered little and, in general, perturbation of protein–protein interactions has been extremely difficult to achieve in practice, although the tide seems now to be turning. New expression and display technologies have enabled screening of massive, synthetic peptide libraries which have been further expanded through the development of techniques to incorporate unnatural amino acids and to alter glycosylation and so on. These are now producing good quality leads. Unfortunately, the major down sides for peptide therapeutics are their short half-life (either from renal or protease clearance) and limitations on cellular access. Wood and colleagues describe how a series of technologies have been developed or are in development that should address these issues and we predict this will be another growth area in the future. As noted, the chemical diversity present in current libraries addresses a small part of the total chemical diversity and it is hard to envision this changing in the future. The concept of using fragment screening to enable smaller libraries to be screened with the potential that a combination of fragments would result in a more potent molecule could provide access to a more extensive range of diversity. Erlanson describes the state-of-the-art for this technology and demonstrates the capability with a number of examples. Although optimization of a single fragment has shown potential, in theory the coupling of two independent fragments should result in a significantly more effective end-product and the examples shown bear this out. Further optimization of the lead can then be carried out by standard medicinal chemistry techniques. However, it is evident that a crucial step in the evolution of this technology will center on the development of efficient linking strategies to enable maximal benefit (affinity, stability etc.). Insulin has been used therapeutically for over 75 years, thus the use of proteins to treat disease is well established. In comparison, the biotechnology industry is relatively young but has been highly successful — driven mostly by growth in the monoclonal antibody arena. Antibodies www.sciencedirect.com
demonstrate exquisite specificity combined with high affinity and they are, in general, very safe. Technologies developed over the past few years have also enabled these complex proteins to be engineered to generate more effective molecules with properties (e.g. stability, effector function etc.) designed to suit particular clinical indications. These methodologies have been reviewed extensively elsewhere. An alternative to altering the amino acid components of the antibody is to develop new scaffolds that retain many of the beneficial properties of antibodies (selectivity, potency). Gill and Damle provide an extensive review of novel protein scaffolds. A number of these scaffolds are significantly smaller than antibodies and thus may demonstrate better tissue distribution/tumor penetration. Benefits on cost are also evident as there are examples where bacterial production is feasible, removing reliance on costly mammalian cell expression. There may be increases in efficacy that allow differentiation from existing antibody reagents, owing to their smaller size and enhanced tissue penetration properties. Many of these strategies appear to have promise and have been progressed into very promising clinical trials. The results from these and future studies will define what the true benefits of these approaches will be. If successful these pioneers will, in all likelihood, generate increased interest in these alternate scaffold approaches. More investigational technologies examining macromolecules (RNA, DNA and proteins) as potential therapies are described by Briggs. These agents have been used extensively for target validation studies, but are now being looked at more extensively as therapeutics. Although specificity was originally thought to be an advantage for the RNA/DNA-based approaches, it has been evident that target specificity still needs to be examined closely to ensure reduced off-target effects. Earlier stage efforts include the regulation of transcription using zinc-finger proteins. As with the alternate scaffolds noted above, these should be easy to produce and have a potential advantage that they can be designed and tested rapidly. As with RNA/DNA approaches a major issue is one of delivery to the cell as, by definition, the use of transcriptional regulators needs penetration into the nucleus to produce an effect. The delivery methodologies described are still being developed, but most are feasible at least in vitro. Nevertheless, the methods bring their own issues as a result of their mode of action. The most advanced of these agents have already entered clinical trials or are marketed and it will be interesting to see how successful (high efficacy, low toxicity) any agents arising from the more speculative methodologies will be. As we have discussed, a lot of effort is being applied in many companies to expand our diversity pool and thereby to broaden therapeutic options. However, these molecules are of limited value unless we understand what is required Current Opinion in Biotechnology 2006, 17:628–630
630 Pharmaceutical biotechnology
to treat any pathology adequately. Much of this data comes relatively late in the R&D process and depends upon results from clinical trials that are time-consuming and costly. If there was potential to predict the effects of a molecule earlier in this process based upon an extensive outcomes-based simulation, this could be a significant advantage in choosing the correct molecule to move forward — thus reducing attrition rates in the more costly stages of development. In the last article of this series, Michelson, Sehgal and Friedrich describe some of the in silico tools that are being developed to provide this prediction. The key to improving the predictiveness of the model would center on ensuring that the disease process is adequately modeled. A virtual patient population can than be defined against which the initial properties of the candidate molecule can be simulated. The hope would
Current Opinion in Biotechnology 2006, 17:628–630
be that deficiencies in the starting molecule could then be addressed and more efficient clinical trials could be defined. Failure rates within the drug development process remain high and thus methodologies of this type can only be of benefit. The examples given indicate that simulations such as these are now being used more routinely for early stage clinical trial design, but their utility for discovery has still to be evaluated. These reviews describe a small subset of potential new technologies that are becoming available to expand the capabilities in the drug discovery and development process. It is unlikely that all of them will come to fruition and be fully validated. However, each will continue to drive the innovation that is necessary to ensure the discovery of the next drug candidates.
www.sciencedirect.com
Gary Woodnutt Gary Woodnutt 9381, Judicial Drive, Suite 200, San Diego, CA 92121, USA e-mail: [email protected]
Gary Woodnutt worked for over 20 years with GlaxoSmithKline within the anti-infective and supportive care areas. More recently he led groups working on protein evolution and natural product discovery and is currently Head of Biology at CovX Research in San Diego. His current interests are in the discovery and development of peptide/antibody fusions in a number of therapeutic areas. Frank S Walsh Discovery Research, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA e-mail: [email protected]
Frank S Walsh is Executive Vice President and Head of Discovery Research at Wyeth Research in Collegeville, Pennsylvania, USA. Prior to his current position, he was with GlaxoSmithKline and Smith-Kline Beecham. His group of 1500 scientists is responsible for the delivery of 15 drug candidates to the clinic each year. His own research is in the area of neuroregeneration and the role of inhibitory components of the myelin sheath.
The pharmaceutical industry continues to face challenges in filling pipelines that are sufficiently robust to weather the attrition associated with drug discovery, development and regulatory hurdles. The sequencing of the human genome was heralded as a great opportunity to exploit a seemingly endless supply of new and important targets; however, the initial excitement was tempered on realizing that this wealth was not immediately addressable. In this respect, the sequence information obtained was in advance of the technology required to fully validate its use, thus it is only recently that we have been able to fully utilize the available data. Huge changes in high-throughput screening capabilities have further enabled researchers to obtain molecules that interact with targets in a massively parallel fashion. However, the availability of targets and our ability to screen them highlights the next hurdle in the sequence of discovery, which is the availability of appropriate molecules that can be screened. Combinatorial chemistry and parallel synthesis efforts have provided the opportunity to expand small-molecule compound libraries, but available diversity is limited. The use of biological molecules, initially as replacement therapies but more recently as specific modulators of biological processes, has also become an increasingly important intervention strategy and has been particularly successful over the past decade. The development of new technologies to further expand the armamentarium that will complement and expand existing capabilities is a focus of many companies. Many of these technologies enhance current abilities, some are being used to resurrect older and, at least partially, ignored capabilities while many are ‘blue sky’ approaches that require further validation before being accepted for general usage. In this series of articles we have tried to give a sampling of some of these technologies and of their potential utility. In the first two articles the focus is on areas that have fallen out of favor over the years owing to the characteristics of the molecules discovered, which make them difficult to identify, isolate, derivitise and/or dose appropriately. Soil or other environmental samples have been, and continue to be, an important source of clinically relevant natural molecules but in general these molecules tend to be difficult to isolate and characterize. Moreover, even when a potential candidate is selected the structure has proven many times to be intractable for further derivitisation by standard organic chemistry. Significant improvements in analytical and preparative techniques have allowed the rapid identification and isolation of active components from the complex mixture present in extracts of environmental samples. Koehn provides examples of natural products in development that could indicate
Current Opinion in Biotechnology 2006, 17:628–630
www.sciencedirect.com
Editorial overview Woodnutt and Walsh 629
that there is a huge and increasing potential in these areas. In particular, he identifies approaches that can now allow manipulation of the structure to develop structure-activity relationships around the parent molecule that were previously very difficult. It is very likely that this will become a major growth area in the next decade. In the second article, Wood and colleagues discuss the merits of peptides, another series of molecules that have been down prioritized as potential therapeutic agents. Peptides hold therapeutic and commercial promise because they possess enormous structural diversity, are highly specific and potent, and generally have fewer safety issues relative to small molecules. These properties led to interest in naturally occurring peptides and a number of companies generated large synthetic libraries. Unfortunately, the synthetic libraries promised much, but delivered little and, in general, perturbation of protein–protein interactions has been extremely difficult to achieve in practice, although the tide seems now to be turning. New expression and display technologies have enabled screening of massive, synthetic peptide libraries which have been further expanded through the development of techniques to incorporate unnatural amino acids and to alter glycosylation and so on. These are now producing good quality leads. Unfortunately, the major down sides for peptide therapeutics are their short half-life (either from renal or protease clearance) and limitations on cellular access. Wood and colleagues describe how a series of technologies have been developed or are in development that should address these issues and we predict this will be another growth area in the future. As noted, the chemical diversity present in current libraries addresses a small part of the total chemical diversity and it is hard to envision this changing in the future. The concept of using fragment screening to enable smaller libraries to be screened with the potential that a combination of fragments would result in a more potent molecule could provide access to a more extensive range of diversity. Erlanson describes the state-of-the-art for this technology and demonstrates the capability with a number of examples. Although optimization of a single fragment has shown potential, in theory the coupling of two independent fragments should result in a significantly more effective end-product and the examples shown bear this out. Further optimization of the lead can then be carried out by standard medicinal chemistry techniques. However, it is evident that a crucial step in the evolution of this technology will center on the development of efficient linking strategies to enable maximal benefit (affinity, stability etc.). Insulin has been used therapeutically for over 75 years, thus the use of proteins to treat disease is well established. In comparison, the biotechnology industry is relatively young but has been highly successful — driven mostly by growth in the monoclonal antibody arena. Antibodies www.sciencedirect.com
demonstrate exquisite specificity combined with high affinity and they are, in general, very safe. Technologies developed over the past few years have also enabled these complex proteins to be engineered to generate more effective molecules with properties (e.g. stability, effector function etc.) designed to suit particular clinical indications. These methodologies have been reviewed extensively elsewhere. An alternative to altering the amino acid components of the antibody is to develop new scaffolds that retain many of the beneficial properties of antibodies (selectivity, potency). Gill and Damle provide an extensive review of novel protein scaffolds. A number of these scaffolds are significantly smaller than antibodies and thus may demonstrate better tissue distribution/tumor penetration. Benefits on cost are also evident as there are examples where bacterial production is feasible, removing reliance on costly mammalian cell expression. There may be increases in efficacy that allow differentiation from existing antibody reagents, owing to their smaller size and enhanced tissue penetration properties. Many of these strategies appear to have promise and have been progressed into very promising clinical trials. The results from these and future studies will define what the true benefits of these approaches will be. If successful these pioneers will, in all likelihood, generate increased interest in these alternate scaffold approaches. More investigational technologies examining macromolecules (RNA, DNA and proteins) as potential therapies are described by Briggs. These agents have been used extensively for target validation studies, but are now being looked at more extensively as therapeutics. Although specificity was originally thought to be an advantage for the RNA/DNA-based approaches, it has been evident that target specificity still needs to be examined closely to ensure reduced off-target effects. Earlier stage efforts include the regulation of transcription using zinc-finger proteins. As with the alternate scaffolds noted above, these should be easy to produce and have a potential advantage that they can be designed and tested rapidly. As with RNA/DNA approaches a major issue is one of delivery to the cell as, by definition, the use of transcriptional regulators needs penetration into the nucleus to produce an effect. The delivery methodologies described are still being developed, but most are feasible at least in vitro. Nevertheless, the methods bring their own issues as a result of their mode of action. The most advanced of these agents have already entered clinical trials or are marketed and it will be interesting to see how successful (high efficacy, low toxicity) any agents arising from the more speculative methodologies will be. As we have discussed, a lot of effort is being applied in many companies to expand our diversity pool and thereby to broaden therapeutic options. However, these molecules are of limited value unless we understand what is required Current Opinion in Biotechnology 2006, 17:628–630
630 Pharmaceutical biotechnology
to treat any pathology adequately. Much of this data comes relatively late in the R&D process and depends upon results from clinical trials that are time-consuming and costly. If there was potential to predict the effects of a molecule earlier in this process based upon an extensive outcomes-based simulation, this could be a significant advantage in choosing the correct molecule to move forward — thus reducing attrition rates in the more costly stages of development. In the last article of this series, Michelson, Sehgal and Friedrich describe some of the in silico tools that are being developed to provide this prediction. The key to improving the predictiveness of the model would center on ensuring that the disease process is adequately modeled. A virtual patient population can than be defined against which the initial properties of the candidate molecule can be simulated. The hope would
Current Opinion in Biotechnology 2006, 17:628–630
be that deficiencies in the starting molecule could then be addressed and more efficient clinical trials could be defined. Failure rates within the drug development process remain high and thus methodologies of this type can only be of benefit. The examples given indicate that simulations such as these are now being used more routinely for early stage clinical trial design, but their utility for discovery has still to be evaluated. These reviews describe a small subset of potential new technologies that are becoming available to expand the capabilities in the drug discovery and development process. It is unlikely that all of them will come to fruition and be fully validated. However, each will continue to drive the innovation that is necessary to ensure the discovery of the next drug candidates.
www.sciencedirect.com