Immunotherapy: Targeting Cancer
Raquel Welch . . . the name immediately brings to mind the picture of a sultry, sexy woman who stared in numerous movies wearing very little clothing. However, it is one of her more heavily clad roles, in the science fiction production Fantastic Voyage, that I want to focus on.
In this movie, Raquel was part of a team of research scientists whose mission is to seek out and destroy a blood clot in the brain of a politically important scientist. The only way to accomplish this is to have the entire team, including Raquel, and a submarine-type vessel miniaturized to microscopic proportions and injected into the bloodstream of the patient. During one scene, Raquel ventures out of the ship and into the bloodstream to check on something. As soon as she exposes herself to the patient’s flowing blood, she is immediately attacked by toxic, male (only kidding) antibodies produced in response to her physically invading presence. Of course Raquel survived, completed the mission, and saved the patient. But lets talk about what was happening with the antibodies in this scene.
Antibodies are the vigilant soldiers of the body’s immune system, defending against any foreign intrusions–an invading virus, a bacteria, a cancer cell, or even Raquel Welch. With today’s rapidly advancing technology, antibody development and the body’s own immune system are playing an increasingly important role in the development of new cancer treatments. Companies are now genetically developing drugs that mimic the stealth-like accuracy of human antibodies against intruders faster then ever before. Several companies are on the verge of uncovering normal human compounds that supercharge these antibodies and the body’s own immune system to attack and kill.
Antibodies and the treatment of cancer
Antibodies, as I mentioned, are crucial protein components of the body’s immune system. Our bodies are constantly producing antibodies unique to every invader. They target and bind to that invader like a glove and either destroy it outright or recruit other antibody gang members to finish the job. The attack is quick, effective, and surgically carried out to avoid damage to normal surrounding cells.
Antibodies are the terminators of the immune system–perfect killing machines. Companies have realized this for years and have tried to take advantage of this characteristic when developing new cancer treatments. A cancer cell, like a virus, is viewed as an unwanted intruder in the body by the immune system. Many scientists adhere to the “surveillance theory,” the concept that cancer cells are frequently forming in our body. The immune system acts as a surveillance system by destroying these cells with specific antibodies before they form a tumor mass that can be felt or seen on x-rays. When something disrupts this system, our bodies cannot destroy these cancer cells and thus they go on to form a mass or spread to other organs.
The current landscape of cancer chemotherapy is littered with problems. Many treatments are not specific and effective enough for whatever cancer they are aimed at. Chemotherapy, for example, can be very toxic to normal cells and lead to many unwanted side effects and complications. Antibodies, or antibody-like drugs, are the perfect answer to these problems. They are highly specific to the nuances of the cancer cell surface architecture and avoid the scorched earth approach to conventional chemotherapy.
Companies are currently producing highly specific protein-like drugs called monoclonal antibodies aimed many cancers. The monoclonal antibodies produced today are more effective and carry none of the problems seen in their early development. Their production is now more efficient and genetically engineered. Some of these same companies are also discovering new genes which are vital to antibody production, information that could translate into potential blockbuster treatments.
The immune system—a broader vision
In addition to producing pure human antibodies or antibody-like drugs to fight disease, scientists are also finding ways to supercharge the immune system in its battle against cancer cells. It is interesting to note that many human cancers are very “immune sensitive.” Somehow, someway, our own immune system plays a major role in treating these cancers. Melanoma, bladder cancer, neuroblastoma (a childhood neural tumor), and even colon cancer are sensitive to immune stimulation when treated.
Scientists are also discovering proteins (called cytokines) in the bloodstream that act to bulk up the immune system in a way never seen before. Cytokines are naturally occurring proteins that activate the body’s own immune system toward invaders.
The potential to turn some of these proteins into drugs to treat cancer is growing at a rapid pace. Researchers at the University of Pennsylvania recently used the gene for Interleukin-12, or IL-12 (a class of cytokines called the interleukins), to treat several patients with advanced melanoma. They introduced the gene that produces the protein IL-12 into melanoma cells from patients placed in lab dishes. After injecting the tumors of these patients with these IL-12 juiced cells, within minutes several tumor deposits just disappeared before their very eyes. The response was immediate. Research is ongoing to further investigate the anti-tumor activity of several more interleukins; companies able to convert these proteins into useable drugs will make a big impact on the cancer treatment market.
The companies
Oxigene Inc. [OXGN>OXGN]: Oxigene is a Boston-based biotechnology firm developing ways to enhance the effectiveness of radiation, chemotherapy, and immunotherapy in cancer patients. The company currently is working on a drug called CA4P, which, in animals, alters the cells that line the inside of blood vessels entering and leaving tumors. By this mechanism, CA4P may be able to strongly enhance the effect of antibody-based drugs in their ability to kill tumor cells. If the blood flow to and from tumors is altered, antibodies or antibody-based drugs will be able to sit inside tumor cells longer and have a longer-lasting toxic effect. This drug is currently in Phase I clinical trials and could benefit many types of cancer treatments if proven beneficial in humans. The company also is developing drug products to treat a variety of inflammatory diseases by using certain immune system boosting agents, all of which are in early phases of development. A recently announced collaboration with Active Biotech was made to further this technology.
Oxigene recently announced their second quarter earnings for 1999: The company lost $2.4M or $0.24/share versus $2.8M or $0.28/share for 1998. It has a decent cash reserve hopes to be profitable within the next several years. The stock is currently trading in the $8-$9 range and has been as high as $13.
Coulter Pharmaceutical Inc. [CLTR>CLTR]: This San Francisco-based company is also in the business of developing monoclonal antibody based technology for cancer. They are currently maturing a treatment for lymphoma in conjunction with SmithKline Beecham called Bexxar, a radiation-charged antibody that attaches to a specific site on cancer cells. Once attached, it wakes up the body’s own immune system to attack the cancer cells and also delivers a greater concentration of radiation to them. This technology is highly specific and minimizes the side effects to normal surrounding cells. The FDA recently granted priority status to Bexxar, meaning it will review its application and potentially approve it within six months. The market for the treatment of Non-Hodgkin’s lymphoma is expanding and Bexxar could be a valuable revenue-generating product for Coulter.
Coulter is currently unprofitable, but that may change if Bexxar is approved by the end of the year. Its second quarter 1999 loss was $13M or $0.08/share versus $8M or $0.62/share for 1998. The increased loss was primarily due to increased marketing costs in anticipation of Bexxar getting FDA approval by the end of the year. Coulter will receive a $5M milestone payment from SmithKline Beecham when Bexxar gets approved. I believe Bexxar will get FDA approval by the end of the year and Coulter stock may see a gradual climb in anticipation. Coulter is currently trading in the $24-$25 range, with a 52-week high of $30.
Human Genome Sciences [HGSI>HGSI]: This biotechnology company has been gaining in popularity since I first talked about it in February of this year. The stock price has doubled since then (from 30 to a close of 60 on August 6) on several new developments. It is in the business of identifying genes and producing medicinal products from those genes, including antibody-related products, to treat a variety of illnesses. One recent positive development was the identification of a protein called B Lymphocyte Stimulator (BLys). This protein charges B-cells in the body’s immune system to produce antibodies against a variety of foreign invaders (viruses, bacteria, cancer cells). This is a major breakthrough in understanding how to use B-cells and antibodies in fighting off disease. Scientists have been searching for this antibody signal charger for years and BLys seems to be it. The implications could be enormous in regard to using this protein as a drug or making products like it to treat all types of diseases.
On another front, Human Genome Sciences just recently identified two compounds from their genetic database that block blood vessel formation to tumors. These anti-angiogenesis compounds (see last article) appear to be stronger than anything described to this point.
Financially, Human Genome Sciences has yet to bring a product to market and does not turn a profit. However, the company is poised to become a leader in the field of pharmacogenetics. For the long term, this company is one to hold on to.
Abgenix [ABGX>ABGX]: This is the company of the antibody future. Abgenix is a fascinating biotech firm that has positioned itself to reap the best of both worlds. Not only is it developing antibody-based drugs to treat cancer, cardiovascular disease, transplant-related diseases and auto-immune disorders, it has perfected the technology to produce pure, highly specific, human monoclonal antibodies.
Why is this important? Currently there are eight antibody-based drugs on the market, with Genentech’s popular Herceptin leading the way. Herceptin is used to treat about 35% of all advanced breast cancers and it, like the other seven, are “hybrid antibodies.” They are part mouse and part human. Theoretically, the mouse component of these drugs can itself cause the body to view it as a foreign invader and make antibodies attacking it, diminishing its long-term effectiveness.
The ideal scenario would be to have a pure, human monoclonal antibody. This would be the perfect killing machine and Abgenix has created it. This company has genetically engineered mice to produce only pure human antibodies by replacing their antibody producing genes with human ones. They have created the better mouse, not the better mouse trap. This “xenomouse” technology has vast implications both for the company and the future of antibody based drug development. Abgenix is already seeing the benefits of many larger companies wanting to use this technology. It has multiple collaborations with several of the larger drug companies, including Pfizer, Schering-Plough, Novartis AG, and Amgen. It expects several more within the next year. Although it is two years away from having its own drug products come to market, there are several products in Phase I and II clinical trials.
Abgenix recently announced its second quarter 1999 numbers and it lost $3.6M versus $3.7M for the second quarter of 1998. It has $61M in cash and 22% of the company is owned by Cell Genesys (NASDAQ: CEGE). The stock hovered around $15/share for most of this year, until breaking out in June. It currently trades at $26-$27/share. I believe this company’s stock has a strong upside potential and much further to advance.
Medarex Inc. [MEDX>MEDX]: Medarex is a New Jersey based company involved in the development of antibody-based drugs to treat a variety of diseases, including cancer, AIDS, and rheumatoid arthritis. Like Abgenix, Medarex is in the business of producing pure human monoclonal antibodies by a unique technology. Their “HuMab-Mouse” system involves producing genetically altered mice that have the capability to produce highly specific human monoclonal antibodies. These antibodies have the capability of not only initiating the toxic hit on cancer cells, but can also recruit the body’s own immune system to come in and finish the job.
At a recent cancer research meeting in May, Medarex released positive results of Phase I/II clinical trials with its lead product MDX-447. This compound showed good results in stimulating the body’s own immune system against many different types of cancers. It is being developed in association with Merck KGaA and currently is in late stage clinical trials for the treatment of advanced head and neck cancers.
The company currently has no products on the market, but does have seven at various stages of clinical development. It has multiple associations with several large pharmaceutical companies, such as Bristol-Myers Squibb, Centocor, and Immunex. Its stock has been trading in the $4-$5 range and I suspect this will double in the next 12 months. It is direct competition with Abgenix, however, I believe the market is large enough for both to succeed.
Idec Pharmaceuticals [IDPH>IDPH]: Idec is one of the few biotechnology companies that turns a profit each year. Its technology focuses on producing radio-labeled monoclonal antibodies against cancer and other diseases. By piggybacking a radioactive particle onto a specific antibody, a lethal dose of toxic radiation is surgically directed against a cancer cell once it attaches. Normal cells are spared from the damaging effects of radiation while the cancer cell is destroyed.
Idec already has Rituxan (developed with Genentech) on the market for the treatment of non-Hodgkin’s Lymphoma. It generated $163M in sales in 1998 and is expected to approach $22M in 1999. Rituxan is a monoclonal antibody designed to attack only cancerous cells. It is growing in popularity among oncologists, particularly as non-Hodgkin’s Lymphoma is seen more in the elderly.
A new drug called Zevalin is currently being developed for the treatment of advanced non-Hodgkin’s Lymphoma. It is a monoclonal antibody with a radioactive particle attached and is should be approved by the middle of next year. Schering AG has signed an agreement with Idec to market the drug overseas that calls for Schering to make payments of up to $48M once the drug is approved. Zevalin will be in direct competition with Coulter Pharmaceuticals’ Bexxar.
As I mentioned, Idec is profitable with the sales of Rituxan growing. Its recent second quarter net income was $19.9M or $0.80/share (up from $10.1M for the same quarter 1998). Idec has several other compounds in development and is beginning to generate a pipeline. The stock, which had been trading in the $50 range, broke out in June and recently closed just above $100/share. I do not see Idec’s revenue stream slowing down anytime soon. It will continue to generate revenue from collaborations and its own products. This company is a good long-term investment and will continue to grow.
The Final Word
Monoclonal antibody based therapy was the darling of the biotech industry several years ago. However, because the technology was still in its infancy it did not catch on. That has all changed. This form of treatment, especially for cancer, is here to stay. The technology now is incredibly sophisticated and as more genes are discovered that control our immune system, more potential drugs will be developed. Companies like Abgenix and Medarix will be in high demand because of their technology as physicians look for better ways to treat the aging population.
Next Article: Vaccines and Cancer. Companies on the forefront of creating ways to prevent this disease.