PDLI---Protein Design Labs: Engineered Antibodies Ready to Attack the Competition
by Margaret Medina
Bio Technology Stocks Jun 9 2000 2:05PM CST
Protein Design Labs {PDLI} uses genetic engineering to make improved forms of antibodies called humanized antibodies, which are protective proteins made by the immune system to protect against bacteria or viruses. Produced by white blood cells called B cells, the different kinds of antibodies number in the millions. All have different shapes that bind to and inactivate different foreign molecules called antigens. When antibodies attach to antigens, the immune system is alerted to attack the antigen.
In order to produce a sufficient supply of antibodies to treat human disease, scientists have traditionally used mice as antibody "factories". Genetically, mouse and human antibodies are similar. However, there are some limitations with a pure mouse antibody. The human immune system perceives the mouse antibody as a foreign entity in itself, so in order to get around the immune system response, scientists developed humanized antibodies - part human, part mouse molecules that isolate the disease-fighting, cell-binding region of the mouse (and a few key amino acids) combined within the framework of a human antibody.
More than 30 humanized antibodies developed by various companies are in current clinical trials. With the exception of vaccines, antibody drugs are the largest class of biotechnology drugs being researched today. Since its inception in March 1986, Protein Design Labs has become a leading developer of humanized antibodies with seven such antibodies currently in clinical trials. The biotech firm designed a technology called SMART technology that uses the company's computer modeling software to optimize the genetic structure of humanized antibodies. When mouse and human antibodies are combined, the mouse antibody binding region is sometimes distorted, impairing its ability to bind to antigens effectively. PDLI's SMART technology predicts the molecular structure of antibodies, helping researchers produce antibodies that retain the binding ability of the mouse antibody while minimizing the chance of autoimmune rejection.
Marketed and Pipeline Products
The biotech firm's sole commercialized product is Zenapax, which is used to prevent kidney transplant rejection. The drug works by blocking a receptor called interleukin-2 (IL-2) on immune system T cells. IL-2 is a substance released in an autoimmune response and often occurs after organ transplants. IL-2 activates T cell division, which is integral to an immune response. By blocking the binding of T cell receptors, Zenapax inhibits the proliferation of T cells and suppresses the immune response. Zenapax is also in Phase 3 trials to treat cardiac transplants, in Phase 1 and 2 trials to treat psoriasis, and in simultaneous Phase 1 and 2 trials to treat uveitis, an autoimmune eye disease characterized by inflammation.
The company has seven additional antibodies in clinical trials to treat autoimmune and inflammatory conditions, transplantation and cancer. They include:
SMART M195, an antibody developed to treat myeloid leukemia, a major type of adult leukemia. The antibody binds to cancer cells, and prevents further cell division. Researchers are also investigating its use against a precancerous condition called myelodysplastic syndrome in Phase 2 trials.
Smart Anti-CD3 antibody, named after the CD3 antigen it binds to, is designed treat autoimmune disease and kidney transplant rejection. The antibody is in Phase 1 and 2 trials for psoriasis and organ transplant anti-rejection applications. Johnson and Johnson markets a drug called OKT3 to treat acute kidney, heart and transplant rejection that is effective but extremely toxic. Smart Anti-CD3 differs in that is engineered to reduce certain immune system interactions that contribute to the toxicity of OKT3.
SMART Anti-L Selectin is under Phase 2 studies by privately held European biotech company Scil to study its effects on trauma. The drug acts on white blood cells' binding to the lining of blood vessels, and may be effective in preventing multiple organ failure after severe injury.
Phase 1 trials include testing of SMART 1D10 Antibody for non-Hodgkin's B-cell lymphoma. This product acts on a different B cell antigen from that acted upon by a currently marketed drug called Rituxan, and may provide an alternative treatment for the disease. Humanized anti-IL4 antibody is in Phase 1 trials for asthma patients. PDLI licensed the antibody to SmithKline Beecham which has rights to co-market the drug upon FDA approval. This antibody blocks the effects of Interleukin-4, a protein thought crucial to the development of asthma and allergies. PDLI began a Phase 1 trial to study Smart Interferon-Gamma Antibody effects of the antibody which targets a gamma interferon protein that stimulates several kinds of white blood cells involved in autoimmune diseases. PDLI is seeking a partner to further develop Anti-EP Selectin, which acts on the inside of blood vessels, and is suspected to play a role in inflammation. Phase 1 trials have shown the drug to be safe in a wide range of doses.
Leveraging Technological Expertise
Perhaps PDLI's greatest strength is its expertise in humanized antibodies. PDLI's Zenaplax was the first humanized monoclonal antibody to be approved by the FDA. It is likely to continue to benefit from the resurgence of interest in monoclonal antibodies, which are multiple copies of specific disease-fighting proteins. Monoclonal antibody research, fueled by hopes of cures for many diseases, surged in the late 80's and early 90's. Problems with mouse antibodies provoking human anti-mouse antibodies, however, led to disappointing clinical trial results. Consequently, many investors lost confidence in companies pursuing antibody research. Genetic engineering advances, however, have led to humanized antibodies - new versions containing just enough mouse antibody to effectively target antigens within a framework that is 90 to 95 percent human.
Protein Design Labs generates revenues from three sources - sales from marketed products, sale royalties from human antibodies and R&D contracts. Hoffman-LaRoche markets Zenapax in exchange for sales royalties while PDLI's patents covering humanized antibodies generate license fees. The company also receives annual maintenance payments and royalties on product sales from antibodies developed by other companies. Two currently marketed drugs licensed under PDLI's patents include breast-cancer drug Herceptin, developed by Genentech {GNE}, and respiratory virus drug Synagis, developed by MediImmune {MEDI}. It has also licensed nine other companies developing humanized antibodies, including Biogen {BGEN}, IDEC Pharmaceuticals {IDPH}, NeoRX Corp.{NERX} and Merck {MRK}. Thirdly, PDLI develops humanized antibodies for other companies in exchange for upfront fees, milestone payments and royalties on product sales.
Through its expertise, PDLI has developed a diverse and promising potential product pipeline, licensing agreements with a number of large pharmaceutical firms such as SmithKline Beecham and Eli Lilly {LLY}, and R&D contracts with companies such as Progenics Pharmaceuticals {PGNX}. One potential thorn in PDLI's side, however, is the March decision by the European Patent Office to revoke claims covering Zenapax under its humanization patents in Europe. The company is appealing the ruling, which suspends the decision of the EPO until the issue is resolved. PDLI expects that appeal could take several years.
The recent market correction brought PDLI down from a lofty $338, 52-week high in March, but the company will remain one of the more promising biotech companies given its expertise in monoclonal humanized antibodies. With a cash position of $291 million, and numerous collaborations and contracts with biotech and pharmaceutical firms both large and small, Protein Design Labs offers much potential as the company advances more pipeline products toward commercialization.
|
