Investing in the Future
   

Jamin Chi, Scientist I,
Wyeth-Ayerst Research
Biotechnology opens a new world of pharmaceutical discovery and development

AHP is committed to remaining at the forefront of pharmaceutical research in the new millennium and is making significant investments in biotechnology. We are applying these technologies throughout the drug development process to speed up the discovery of proprietary targets, improve target validation, screen potential treatments more quickly, and design safer and more efficacious products in all three of our primary discovery platforms: small molecules, proteins and vaccines. We also have established strategic alliances with leading genomics and biotechnology companies around the world to supplement our internal resources, such as the agreements we signed in 2000 with Celera Genomics Group and Incyte Genomics, Inc. to access their extensive genetic databases, including the entire human genome sequence.

The benefits of these investments clearly are demonstrated by the innovative products we have introduced in recent years and by our strong R&D pipeline. In the articles that follow, three AHP research scientists describe in their own words the impact of biotechnology on key research projects. Their stories are representative of the efforts made by thousands of AHP's scientists and technicians who are using new biotechnology tools to develop novel therapies for challenging medical conditions that will benefit people throughout the world.
"rhBMP-2 could fundamentally change the clinical approach to bone regeneration and repair." John Wozney, Ph.D., Assistant Vice President, Bone Biology, Wyeth-Ayerst Research

 "Our research addresses the clinical problem of bone regeneration in cases where bone either is lost or does not heal properly due to trauma. Currently, surgeons attempt to regenerate and heal bone through the use of medical devices, bone grafts or bone graft materials -all of which have shortcomings. We wanted to find a biological solution that would stimulate the body's own ability to form bone.

We knew that bone growth is triggered by cellular activity during embryonic development or following a bone injury. However, it was only through the recent availability of advanced biotechnology tools that we were able to explore this process at a molecular level and begin to uncover the proteins that were involved. The successful application of this approach led to the discovery of the bone morphogenetic proteins, or BMPs - a family of proteins that helps to control the development of many tissue types, including bone.

One of these proteins, BMP-2, appeared to be a very promising therapeutic candidate to induce bone formation. Biotechnology allowed us to derive the gene sequence of this protein, isolate and clone the sequence, and insert the BMP-2 gene into a production cell to create a recombinant form of the protein - rhBMP-2 - for clinical testing. In clinical trials, we found that rhBMP-2 does indeed induce bone formation in patients when applied locally. In February 2001, our Pre-marketing Authorization Application was accepted by the U.S. Food and Drug Administration for the use of rhBMP-2 in the treatment of long-bone fractures that require open surgical management. The introduction of rhBMP-2 could fundamentally change the clinical approach to bone regeneration and repair.

In addition to bone growth, the BMP family of proteins holds tremendous potential for therapies involving many other types of tissues, including cartilage regeneration in osteoarthritis, tendon and ligament repair, and even the regeneration of lost function in the kidney or the brain. In fact, the discovery of BMPs has created a whole new area of basic research in tissue repair and regeneration. And biotechnology made it all possible."
"Biotechnology gives us the tools to unravel the secrets of proteins."
Gray Shaw, Senior Scientist and Laboratory Head, Wyeth-Ayerst Research

"Biotechnology has dramatically altered the process of drug discovery in the 20 years since I entered the field as a molecular biologist. Today, pharmaceutical development largely is centered on the study of proteins and genes. Virtually every drug on the market either is a small molecule that binds to a protein target, such as an enzyme, or is itself a protein. Biotechnology gives us the tools to unravel the secrets of proteins to find potential targets for therapies and provides the ability to reproduce these protein targets for faster and more efficient testing of drugs to change their function.

Our discovery of the PSGL-1 gene is a good example of how the ability to isolate and characterize a gene can lead to multiple therapeutic opportunities. The gene encodes the human PSGL-1 glycoprotein, which extends from the surface of white blood cells, or leukocytes, and helps the cells bind to the blood vessel wall in a process known as cell adhesion. Thus, PSGL-1 plays a critical role in the migration of these cells from the bloodstream to the site of tissue damage.

While this process is essential in helping the body heal itself after an injury, it also can be harmful. Immediately following a heart attack, for example, the leukocytes that attach to the damaged blood vessels create inflammation, which actually causes additional tissue damage, called reperfusion injury. Biotechnology allowed us to understand the molecular details of this process and then create a genetically engineered protein that links the adhesive part of PSGL-1 to the tail portion of a human antibody. This new therapeutic, called rPSGL-Ig, protects the site of tissue damage by preventing leukocytes and platelets from adhering and causing inappropriate inflammation.

Currently, rPSGL-Ig is in Phase II clinical trials evaluating its ability to help accelerate clot destruction and prevent reperfusion injury following a heart attack.

While the creation of a potentially beneficial new drug is extremely rewarding, we are equally gratified that our research has revealed many other therapeutic opportunities. With our detailed knowledge of this cell adhesion pathway, we are exploring additional therapies - both small molecule and protein - that could block this process in other inflammatory and autoimmune conditions, such as strokes and organ transplant rejection. Ultimately, the integration of biotechnology into our discovery process makes this an exciting time to be doing pharmaceutical research."

"Biotechnology helped us develop a potential life-saving treatment more quickly."
Kurt Steiner, Ph.D., Senior Director, Biological Research, Wyeth-Ayerst Research
"Biotechnology played a key role in the development of PTP-112, a novel treatment for type II diabetes. In type II patients - who constitute the vast majority of diabetics - the pancreas continues to produce insulin, but the tissues in the body that normally react to insulin don't respond properly or efficiently. As a result of this 'insulin resistance,' blood sugar levels rise, and vital processes in the body that usually are triggered by insulin don't respond appropriately, creating serious health problems such as kidney failure, nerve damage and blindness.

Until the 1990s, the standard treatments for type II diabetes stimulated release of insulin to compensate for resistance - an approach that often did not work effectively or led to secondary failure later as patients became less responsive over time. More recent treatments have targeted insulin resistance but have met with limited success.

We wanted to get at the root of the problem and find a way to overcome insulin resistance. Our search for potential therapeutic targets focused on the PTPase family of enzymes because they are directly involved in the process of 'turning off' insulin receptors. With the help of biotechnology, we validated one specific target enzyme, PTP-1B. We then created a humanized, recombinant version of the protein to use with a high-throughput screen, rapidly testing tens of thousands of compounds to find one that would inhibit the action of this enzyme. Upon finding a promising candidate, we refined it using technologies such as x-ray crystallography and molecular modeling along with creative medicinal chemistry to enhance the structure of the compound for greater efficacy. The result of that work was PTP-112, a small molecule with a novel therapeutic action that keeps the insulin receptor 'turned on' and prolongs the body's responses to insulin. PTP-112 is scheduled to begin Phase II clinical trials during 2001.

Biotechnology helped us develop a potential life-saving treatment more quickly and efficiently than we could have in the past. It enhanced our ability to find a likely therapeutic target and allowed us to create a recombinant version for validation and testing - something that is possible only with these advanced capabilities. Perhaps most important, biotechnology provided us with the data we needed to move this product forward into clinical testing with greater confidence."