The "Naked" Truth About Antibodies For Cancer Therapy

Antibodies are naturally occurring proteins that help our body fight bacteria, viruses and cancer. Upon its release into the blood stream, an antibody can identify and bind a specific pathogen, and by doing so, it can neutralize the pathogen or “flag” it for attack by the immune system. Our body is able to generate antibodies against a virtually infinite number of targets, thanks to brilliant biological mechanisms developed throughout the course of evolution. Once a pathogen enters our body, our immune system conducts a high-throughput screen of all the antibodies it can generate (around 10 billion different antibodies). After the appropriate antibodies are selected, special white blood cells called B-cell lymphocytes enter a mass production phase in which large amounts of the selected antibodies are secreted into the blood stream “in search” of their specific target. The combination of diversity on the one hand and specificity on the other hand, makes antibodies a crucial component of our defense mechanism. This combination also makes antibodies an extremely popular platform among drug companies.

Harnessing the incredible mechanism by which antibodies operate as a basis for drugs has always seemed very promising. Understanding and controlling the natural processes which design and produce antibodies may enable the creation of “artificial” antibodies which recognize and “flag” a chosen target. Such targets might be cancer cells, harmful proteins or inflammation molecules. After years of trials (and errors), scientists have managed to manipulate the biological processes which lead to the formation of antibodies and develop therapeutic antibodies. Although the first therapeutic antibody was approved more than 20 years ago, the majority of therapeutic antibodies have hit the market only during the past 10 years.

Therapeutic antibodies have proven effective at fighting cancer, especially in cases where conventional therapy fails: Out of the 21 marketed therapeutic antibodies, 9 are for the treatment of cancer. Even more encouraging is that antibodies for cancer generally operate in a distinct mechanism from traditional chemotherapy or radiotherapy, so they can often be combined with traditional therapies to generate a synergistic effect. Without a doubt, cancer antibodies are one of the biggest breakthroughs in cancer therapy’s history.

Examining any medium or large biotech company’s pipeline demonstrates how central antibodies’ place is in the pharma industry. It is hard finding a company without at least a hand-full of therapeutic antibodies in various stages of clinical development. Some companies preferred entering the antibody market by acquiring antibody-specialized companies (AstraZeneca’s acquisition of Cambridge Antibody Technology.)

Without underrating antibodies’ important position in the field of cancer therapy, there is still a lot of room for improvement. Cancer antibodies rarely cure the disease, especially in its more advanced stages, and the life expectancy benefit generally ranges from several months to several years. When it comes to solid tumors, which represent a tougher nut to crack (therapeutically speaking), the performance has been notably poor. Even though solid tumors consist the vast majority of cancer cases (lung cancer, breast cancer, colon cancer, etc.), out of 9 FDA-approved antibodies for cancer, only 3 target solid tumors (Herceptin®, Erbitux®, Vectibix®), with the rest aimed at non-solid targets.

As previously stated, antibodies are generally administered in combination with chemotherapy or radiotherapy in order to obtain optimal effects. When comparing the general characteristics of cancer antibodies like Herceptin® and Rituxan® with those of traditional therapies like Taxol®, Doxorubicin®, and radiotherapy, there are two obvious differences:

The first one is the very high specificity antibodies possess compared to that of chemotherapy agents and radiotherapy. Both chemotherapy and radiotherapy are non- targeted therapies. Chemotherapy substances are usually distributed throughout the patient’s body while radiotherapy exposes large portions of the patient’s body to radiation. Antibodies, on the other hand, bind cancer cells and affect them almost exclusively, sparing normal cells.

The second difference is potency. Chemotherapy agents are very strong and toxic compounds, some of which are actually derived from deadly natural poisons. With numerous mechanisms of action, such as interference with DNA replication and cell division, chemotherapy agents are very effective against cancer tissues but also, to a lesser extent, harmful to healthy tissues. Antibodies operate in a different manner. By binding to cancer cells they can induce an immune response towards those cells or block growth and proliferation signals, but they are much less potent.

It is therefore clear that the advantage of chemo/radio-therapy is the Achilles hill of antibodies and vice versa. This leads to the unbearable compromise doctors and caregivers have to make: On the one hand, they are limited in the amount of chemotherapy and radiation they administer, due to the severe side-effects. On the other hand, they can administer monoclonal antibodies which cause less side-effects, but cannot inflict enough damage on cancer cells.

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.

Disclosure: none

Comments

[genvec cures]

hammertime.. could you write an article on immunogen (imgn). IMGN has many partners as you know.
DNA and AVE being the most prevalent. DNA currently owns 3 other licenses to bring new tap conjugates into phase trials. Though DNA has not yet identified the targets, patents on file suggest prostate and ovarian cancers, along with NHL being the potential targets for drugs and possibly have trials begin sometime in calendar 2008.

IMGN also likely expects its partners BIIB, CNTO, Biotest, and SAN_AVE to bring conjugates into clinic with the next 18 months.

IMGN will likely have 4-6 new drugs in the clinic by yaer end 2009.

[skitahoe]

I believe IMGN's latest guidance is for 2 to 4 drugs by June 2008, the end of their fiscal year. Eight targets currently are licensed to IMGN's partners, and the CEO has guided that SNY will claim at least ten targets to license from IMGN's pipeline by the end of August, 2008. By the end of 2009 the potential of going substantially higher than 4 to 6 new drugs is great.

Something we have almost no knowledge of is just how much work has been done preclinically since the SNY partnership took place. We know SNY has a choice of up to 20 targets from IMGN's pipeline, and that the choice was from 40 or more targets in the pipeline. If over the five years of the partnership many of these 20 to 40 targets they've been looking at have advanced substantially preclinically, by the end of 2009 either IMGN or SNY may put one or more of these in the clinic. Today we know of at least one that SNY intends to bring to the clinic as it appears on SNY's website, even though the drug's not yet licensed with IMGN.

I hope everyone knows when I'm referring to a target it actually represents potentially many different drugs. PSMA was the target IMGN licensed with MLNM, who also had the rights to J591 an MAB developed by BZL which targets it. There are other MAB's that also target PSMA, IMGN won't license them as long as MLNM holds the target rights. While MLN2704 didn't go to Phase II, it was a conjugate of J591 with DM1 with one of IMGN's oldest linkers. Today IMGN could conjugate that MAB with different linkers as well as different effector molecules. It could also conjugate other MAB's targeted at PSMA, but only for MLNM, or if MLNM agreed to sell or abandon its license with IMGN. No one outside the partnered companies seem to know how long licenses are for, so it's also possible that in time they expire if drugs are not being actively pursued from the license.

I believe that Tras-DM1 could be the first approved TAP drug, though there are other possibilities. As I see it, ten or twenty years from now DNA could come back to IMGN and improve on the drug with a better linker, effector molecule, or both, as I don't believe the license would expire just because a drug was approved from it.

These are just my opinions, but I've been invested in the company almost from the beginning.

Gary

[Ohad Hammer]

Thank you for your great replies. IMGN is shaping up to be a true leader in the immunoconjugate field, but no one knows exactly when this market will kick into gear. I must admit, though, that their Trastuzumab-DM1 results have been far from being impressive imho. They haven't published a scientific article about this trial so perhaps it's too early to comment, but the results look as if it was just another naked antibody, instead of a highly toxic compound (cytotoxicity of maytansine is thought to be 200- to 1000-fold higher than that of other tubulin polymerization drugs like taxol, and its deriviatives, like DM1, are even more toxic). it doesn't imply their technology is inferior, it just means that they'll have to try agian and again until they make it. in drug development statisitics are alway against us, so many agents must be evaluated before finding a truly successful one.

I am planning to write an article about IMGN but for now I am working on several other articles, including a SGEN article which (hopefully) will be published next month.

Ohad