As biomarker research and development gains traction, many companies seek to accomplish a couple goals: to distinguish oneself from competitors, and to refine the means of targeting diseases and their associated genes to maximize their R&D dollar.
Even the FDA is getting involved. On their website, www.fda.gov, they acknowledge that pharmacogenomics allows us to define sources of an individual's profile of drug response and predict the best possible treatment option for this individual.
The use of genomic information, accelerated by the sequencing of the human genome and the advent of new tools and technologies, has opened new possibilities in drug discovery and development. Consequently, regulatory science and regulations need to be set in place appropriately.
"With regards to the FDA guidelines, one of the most important points that was discussed [at IBC's Drug Discovery Technology meeting, held recently in Boston] is their emphasis on the need to fully validate any markers that may be used in diagnostics and clinical submissions," said Joseph Monforte, vp and CSO at Althea Technologies (San Diego).
"Validation is critical to providing consistent and verifiable genetic information. PCR methods, like TaqMan and multiplexed XP PCR, are useful for providing this kind of information."
Althea Technologies applies its resources, scientific expertise, and knowledge of regulatory affairs to facilitate the progression from drug discovery to clinical approval.
High Throughput Gene Expression Analysis
Althea's current services include high throughput gene expression analysis using its eXpress Profiling technology, custom real-time qPCR assay development services, cGMP protein and plasmid DNA production services, and aseptic vial and syringe filling of Phase I, II, and III clinical products.
"It's a common trend where microarray-based global gene expression surveys yield small sets of key genes, typically fewer than 100," said Monforte. "What we're offering is a way to move these genes from microarrays into low-cost multiplex PCR assays, enabling larger throughput, quantitative studies of these genes."
Althea's Discovery Services are driven by the application of eXpress Profiling (XP PCR) for high throughput gene expression analysis.
XP PCR is a patented, highly multiplexed, quantitative RT-PCR strategy that incorporates the use of gene-specific and universal primers to lock gene ratios during the amplification process.
This method, which yields data on 2035 genes per reaction, enables researchers to extend their gene expression studies to a large number of samples, increasing the statistical power of gene expression information."The technology is highly complementary to microarray analysis and enables researchers to further exploit their microarray discoveries," said Monforte.
Althea provides access to eXpress Profiling for a variety of research applications performed under GLP and non-GLP conditions.
These applications start with basic services such as microarray data validation and extend to comprehensive research programs, like Signature Discovery Services, that involve microarray experiments, detailed data mining and analysis, and high throughput application with XP PCR.
XP PCR has been licensed to Beckman Coulter and is being commercialized as the GeXP line of equipment and reagents.
"Through our partnership with Beckman we are making the process, now only performed in our lab, broadly available to the scientific community," Monforte noted. "The system lends itself not only to research but for diagnostic purposes as well. The only customization is what genes you're looking at. It makes it cost-efficient."
A&G Pharmaceutical (Columbia, MD) is a theranostic company creating and developing monoclonal antibodies to disease-specific targets as a basis for novel therapeutic and diagnostic products addressing a broad range of diseases.
The company is currently advancing a near-term opportunity to develop and commercialize a line of diagnostic test kits that will improve early detection, diagnosis, and treatment of breast cancer based on a patented and proprietary biomarker discovered by A&G researchers.
A&G is developing the same marker protein as a novel breast cancer therapeutic, and the firm's customized antibody service generates revenue to fund the drug development effort by accelerating the generation of novel, functional antibody therapeutics for pharmaceutical and biotechnology companies as well as federal laboratories.
Co-founder and CEO Ginette Serrero, Ph.D., discovered this protein as a biomarker for breast cancer with therapeutic and diagnostic capabilities termed PC Cell-Derived Growth Factor (PCDGF|GP88, or GP88).
GP88 is an 88 kDa glycoprotein autocrine growth factor that is produced by cancer cells and, in turn, binds back to the same cancer cells, fueling the growth of the breast cancer. GP88 thus plays a major role in promoting human metastatic breast cancer cell survival, growth, and invasiveness. A&G is developing both therapeutic and diagnostic products with this new theranostic target.
"The one thing we are doing differently is that we are using biomarkers for therapeutic as well as diagnostic targets," Dr. Serrero said. "And the beauty of what we're doing is that our kits can be used for both diagnostic purposes and, as we grow, we'll be looking to use them to monitor therapy as well. Our ultimate goal is to have a good therapy in place."
"Basically, what we are dealing with is a biological target overexpressed in invasive ductal carcinoma that induces tamoxifen resistance in ER-positive breast cancer cell lines, both in in vitro and in vivo mouse xenografts," Dr. Serrero explained. "Tamoxifen-resistant cell lines had a 10-fold higher instance with this biomarker than tamoxifen-sensitive counterparts."
"The biological target, or biomarker, we've identified can be used both for diagnostic and therapeutic purposes," Dr. Serrero said. "And we've developed an application that can do both.
Iconix Pharmaceuticals (Mountain View, CA) is pioneering the field of chemogenomics, or the integration of chemistry and genomics to profile drug candidates. Chemogenomics can be defined as the use of genomics to measure the broad effect of a compound on all the pathways in an intact biological system. It is the study of the genomic response of an intact biological system to chemical compounds.
The emphasis is on the intact biological system, not isolated components such as an individual protein target. As such, chemogenomics is related to pharmacology, which measures the in vivo physiological response to drug treatment, but uses genomic tools to measure biological responses.
"When I talk about biomarkers, I am referring to multigene biomarkers that can be viewed via a microarray," said Mark Fielden, principal scientist, chemogenomics and toxicology at Iconix Pharmaceuticals.
"Basically, what our technology does is provide preclinical drug screening and investigative toxicology services to biotech and pharma, and our DrugMatrix database allows us to discover biomarkers and validate them."
Iconix' chemogenomic capabilities enable pharmaceutical companies to increase the odds of advancing the right compounds to the clinic, reducing attrition rates, and the costs of drug discovery. "When customers have molecules in development, they need a screen to prioritize the list, and that's where our technology comes in," Fielden said.
Iconix provides reference systems and know-how to predict toxic liabilities and side effects of drug candidates and determine if they are on or off target. "This is the direction in which biomarkers are heading," Fielden said.
"Right now, the process is a little backward; up until now toxicology hasn't been addressed until late-stage drug development, which is a costly problem. Something can be in development for 7 to 10 years before you find that there's toxicity limiting clinical application of the treatment. Discovery always precedes toxicity assessment.
"There's a real push to screen out liabilities early on," he continued. "And the FDA is on boardthey just released guidelines on their website. They are using our database to assess compound toxicity."
Metabolon (Research Triangle Park, NC) utilizes metabolomics, the study of the repertoire of non-proteinaceous, endogenously synthesized small molecules present in an organism.
"We are initially focusing on drug development and treatment for ALS," said John Ryals, president and CEO of Metabolon. "In collaboration with Massachusetts General Hospital, our program has identified biomarkers for the disease and for the action of Rilutek, an Aventis drug for the treatment of ALS."
"Early on, Metabolon recognized the value of determining the collection of small molecules in a human cell," Ryals said. "Based on that realization, we have developed a unique research capability. By analyzing a sample using multiple mass spectrometry-based technologies, integrating the data and analyzing through proprietary software and algorithms, our scientists can develop an understanding of a disease state much faster and more accurately than previously possible."
Metabolon has the ability to determine the repertoire of biochemical changes inherent in a given disease, and then map these changes to known pathways, allowing researchers to build a biochemical hypothesis for a disease. Based on this hypothesis, the enzymes and proteins critical to the disease can be elucidated and druggable disease targets identified.
"Our technology provides a leap beyond current technologies such as genomics, transcript profiling, or proteomics. Using metabolomics, we know what the molecule is and how it fits into human metabolism. With this context, we are able to identify disease targets faster and more accurately," Ryals stated.
The first step in a modern drug discovery process is to identify a protein or enzyme that may be causally linked to the disease. This step is referred to as target identification. In the past, this linkage has been based on years of research using cellular or animal models.
More recently, with the advent of genomics, it has been much faster to identify targets for disease based on the use of genomics technologies, such as gene-expression profiling or DNA microarrays (also known as transcriptomics).
Metabolon's ability to determine the physiological status by examining biochemical changes and linking these changes to pathways greatly enhances target identification.
Biochemical changes associated with a disease state can be determined and mapped to known pathways, allowing researchers to build a biochemical hypothesis for a disease. Based on this hypothesis, enzymes or proteins that may be critical to the disease process become apparent.
"We are currently applying our technology to produce biomarker discoveries for diseases such as Huntingdon's disease and diabetes," Ryals added. "Based on our understanding of metabolic pathways involved in each area and our ability to detect the early onset of disease, we endeavor to set new standards for drug therapies."