Metaphorically, antibodies can be described as unarmed guided missiles, which have extraordinary precision and targeting abilities, but once they hit the target, they inflict minimal damage. Chemotherapy and radiotherapy can be described as artillery, very powerful, but unguided. In order to optimally use the two, the most logical step is arming those unarmed missiles with a variety of explosives. Using the same reasoning, there is a true need to develop anti-cancer therapies which have an antibody-like specificity as well as chemo/radio-therapy-like potency. Doing so enables us to take advantage of the selectivity of antibodies and the potent toxic activity of chemo/radio-therapy, thus creating superior cancer treatments. The antibody binds the target on the tumor, delivers its payload and kills the cell. Arming antibodies with effector molecules like chemotherapy agents and radio-isotopes results in a hybrid agent referred to as an Immunoconjugate. An antibody which is not conjugated to an effector is referred to as “naked” antibody.
The concept of immunoconjugates sounds very simple and promising, however, things are not as simple and trivial as they seem. In biology, brilliant concepts either take decades to materialize, or remain hypothetical forever. Just to get an idea about how frustrating drug development is, during the last 3 decades, more than 200 cancer antibodies entered commercially sponsored clinical trials. Out of these, only 9 antibodies have been approved by the FDA for the treatment of cancer to date, most of which in the last decade. Of the nine FDA approved cancer antibodies, there are only three immunoconjugates ( Bexxar®, Zevalin®, Mylotarg®) compared to six “naked” antibodies. Furthermore, these three immunoconjugates are aimed at treating less common conditions and as such they have not achieved sales in the scale of “naked” antibodies like Herceptin® and Rituxan®.
The development and approval of the nine therapeutic antibodies for cancer was possible through great advances in basic science combined with continuous efforts by the scientific community and drug companies. The same pattern can be found in other emerging technologies that have come a long way from inception to implementation. This will probably be the case with immunoconjugates as well, as there will be many more failures than success stories.
There is still room for cautious optimism, as the failures in the last 30 years have provided us with a great deal of insight into fighting cancer with “naked” antibodies and immunoconjugates. Even after all the progress that has been made, creating clinically effective immunoconjugates is still a formidable challenge. The art of developing immunoconjugates combines numerous disciplines such as chemistry, immunology, toxicology and radiology, so it necessitates interdisciplinary skills and know-how. The list of obstacles to be dealt with is very long. One is matching the right antibody to the right effector, as some combinations are more effective than others. Another challenging task is linking the antibody and the drug without damaging either of them. Then comes the challenge of finding the optimal amount of drug payload per antibody and designing the linker between them to be stable in the blood stream but cleavable, once inside the target cells.
The trend as in regard to immunoconjugates over the past decades is somewhat discouraging. According to an article published on May in Nature Reviews Drug Discoveries, out of the total antibodies in clinical trials the percentage of immunoconjugates decreased from 56% to 49% to 31% in the 1980s, 1990s and 2000-2005, respectively. These numbers imply that although the advantages inherent to immunoconjugates have always been clear, the technological foundations were not yet in place. For anybody who is familiar with the scientific side of the antibodies field, it is easy to understand why the early efforts in developing immunoconjugates resulted in failures. There were enough issues and challenges involving the development of “naked” antibodies alone, that trying to link those antibodies with drugs was simply “mission impossible” with the then available knowledge and techniques. Scientists simply aimed too high. Realizing that, the drug industry decided to focus more on “naked” antibodies in an effort that led them to some impressive successes. Of the cancer antibodies which are currently in clinical trials, only one third are immunoconjugates.
In addition to the obvious therapeutic advantages, there are also several more practical advantages that immunoconjugates have compared to”naked” antibodies.
First, since immunoconjugates are expected to be very potent and specific, there should be a decrease in the average administered dose, which might lead to lower treatment costs.
Second, it might enable drug companies to produce the antibody part of the immunoconjugate in bacteria or plant cells, rather than producing it by using mammalian cell cultures, which is a very expensive technique. Producing active cancer antibodies in plants and bacteria might be a cheaper and easier alternative, but is problematic when it comes to “naked” antibodies.
Third, the use of immunoconjugates opens the door for a reintroduction of a large number of antibodies that are ineffective by themselves. All those hundreds of antibodies that were scrapped throughout the years by drug companies might make a come-back as immunoconjugates. It might also let researchers use toxic compounds or compounds which cannot be used on a stand-alone basis because they are either too toxic or too ineffective. Fourth, there is virtually unlimited number of combinations for building immunoconjugates. If a company has 10 antibodies that target a specific target on a cancer cell and 10 toxic compounds, it can theoretically build 100 immunoconjugates and see which ones have the best effect.
In conclusion, the advantages represented by immunoconjugates over “naked” antibodies makes them the inevitable development in cancer therapy. There are indications that the shift from “naked” antibodies to immunoconjugates is already happening, at least conceptually. A good example might be Genentech’s attempt to arm their blockbuster breast cancer antibody, Herceptin®, with a toxic compound. Genentech is collaborating with a small company called Immunogen (IMGN), which specializes in conjugating drugs to antibodies. In the not so distant past, Genentech itself was a small niche player who managed to grow into a pharmaceutical giant because their niche, therapeutic antibodies, got very big and accretive. The company managed to grow through partnering with established drug companies which saw the potential in Genentech’s niche. This time, it is Genentech which is trying to penetrate into the immunoconjugate niche by partnering with a small company specializing in that field.
The fact that Genentech, a huge company with virtually unlimited resources chose to partner with a much smaller company, pay it a hefty sum in advance, and share future profits, only demonstrates how challenging the task is. It also demonstrates how small companies which specialize in the field of immunoconjugates will become valuable assets as enablers of the shift from “naked” antibodies to immunoconjugates.
So how should investors play the trend? The prudent option investors have is to invest in companies which dominate the cancer-antibody market. These companies include Genentech (DNA), Amgen (AMGN), Medarex (MEDX) and Imclone (IMCL), which have a decent arsenal of antibodies that can be used as a basis for constructing immunoconjugates. They can develop immunoconjugates by themselves or do what Genentech has done – forming partnerships with specialized players, or even acquire them. The risk-prone investors could invest in such small biotech companies specialized in the field of immunoconjugates. Companies like Seattle Genetics (SGEN), ImmunoGen (IMGN) and Immunomedics (IMMU) are involved in development of immunoconjugates as well as “naked” antibodies. The “naked” antibodies in their pipeline represent a “safer”, more mature opportunity whereas the immunoconjugate portion represents the riskier, more disruptive opportunity. Each company is currently engaged, either independently or in cooperation with larger companies, in multiple clinical trials. If and when arming antibodies becomes the central school of thought in cancer antibody therapy, niche companies like these will see an increased demand for their knowledge and expertise.