Keyword: FGFR3 = fibroblast growth factor receptor type 3.
During the last annual meeting of the American Society of Hematology, Genentech presented the results of a phase 1 clinical trial conducted with an exclusive anti-FGFR3 antibody, the MFGR1877S, in patients with Multiple Myeloma (MM). (Trudel et al, 2012)
In a very simplified definition, MM is a form of cancer that affects a specific type of cells of the blood. In an expressive number of cases of MM, these cancer cells have been showed to express (produce) increased quantities of FGFR3, sometimes bearing mutations similar to those found in bone dysplasias related to FGFR3 such as tanatophoric dysplasia.
Scientists think that the presence of increased production of FGFR3 in MM causes further increase in cancer cell proliferation and survival. You might remember we have reviewed this: with the exception of the chondrocytes, FGFR3 uses to stimulate cell multiplication. If FGFR3 is making cancer cells multiply, then developing a therapy directed against FGFR3 in MM seems to be reasonable. Without the proliferation trigger, maybe MM can be more efficiently treated.
What is an antibody? How does it work?
An antibody is a kind of protein created by the cells of the immune system (the body defense system) to attack a given target (another protein, complex molecules, a virus, etc.) Attack here means that this protein, designed to bind to a specific area of the target, will form a large complex with it, allowing the defense system to destroy it.
Antibodies are made by demand and tailored for a specific target. For instance, when you take a vaccine, let’s say a flu vaccine, you are being inoculated with inactivated parts of the virus which causes the flu. This will bring the attention of the immune system, which will understand the protein in the vaccine is not a friend and will start producing proteins (antibodies) specifically against that foreign protein. When the real flu virus invades the body, there will be already an extremely effective defense barrier and the virus will be quickly defeated. And the individual will not get the flu.
Scientists have long ago understood this mechanism and now we are also able to create antibodies that target proteins linked to specific diseases. One of the best current examples is one that I have described before in the blog (here): trastuzumab, an antibody that binds to the extracellular part of a cellular receptor similar to FGFR3, the epithelial growth factor receptor (EGFR). You can visit this link to see how it works.
Trastuzumab helped to change the history of a subtype of breast cancer where the cancer cells produce enormous quantities of EGFR. They do this because this receptor is linked to cell multiplication and survival, tasks similar to those of FGFR3 in MM. When trastuzumab binds to the extracellular part of EGFR, it prevents the binding of an EGF to its receptor, thus stopping the chemical reaction cascade that would be turned on if the receptor was activated (watch the animation!). With EGFR knocked down, the cancer cells lose the ability to multiply and die easier.
Today, similar strategies are being used for many other types of cancer, like in leukemia and lymphoma. They are also being tested in other chronic inflammatory diseases such as lupus and rheumatoid arthritis, where some of the proteins of the body, deemed to be responsible for the disease progression, are being targeted. So far, antibody therapy has been showing to be very effective to control these disorders.
Can an antibody specific against FGFR3 be used to treat achondroplasia?
The relevant news about the results of this study with MFGR1877S is that it seems that there is an active antibody against FGFR3, the protein which, when mutated, causes achondroplasia, already in clinical development. Second, it showed signs that it does block the receptor in humans.
Now, we must ask: could such an antibody be used to treat achondroplasia? The answer is also an interrogation. Theoretically, if you have an antibody against FGFR3, it should be able to bind to the receptor and “close” it (take a look in the animation of trastuzumab). Nevertheless, antibodies are large molecules. When the target is located in a tissue which has direct blood flow, it is likely the antibody will be successful. However, when the target has a natural barrier where the surrounding tissue is not bathed by blood, as in the case of the growth plate, things may turn difficult. The growth plate is a formidable natural barrier for big molecules, as the scientific evidence has been showing (see here).
Well, there are already at least three known good anti-FGFR3 candidate antibodies (PRO-001, Prochon; MFGR1877S, Genentech; IMC-D11, ImClone, all free access). How could we test them?
First, these antibodies have already reached the clinical stage of development, so no major safety issues have been found to date. Available results imply that they do find their target in patients. For achondroplasia, however, tests should start in a mouse model of achondroplasia, not because major concerns about safety, but because we would need to see if the candidate antibody would reach the growth plate in a living animal in therapeutic and safe doses. If one of these antibodies showed to prove its efficacy in such conditions, then I think the further research could go faster to the clinical development, again because they have already been tested in humans and has been showing, according to the available information, to be safe.
We must be realistic
It is said that PRO-001 was an antibody originally developed to tackle achondroplasia about 10 years ago. It has been probably tested (only a guess, I am not stating this) in the conditions I described above but we see no further research published. As there are no papers describing such tests, we can only guess that results of these presumed tests in animals were not positive. Publishing negative results has always been a matter of debate across the scientific community. In short, publishing “bad” results is not good for one’s CV.
An interested party would probably have to perform tests in an appropriate achondroplasia model to see if it would be advisable to further test the candidate antibody in children with achondroplasia. Again, mainly not because major concerns about safety in reasonable therapeutic doses, but because of the chance of it not having the desired efficacy.
A test in a mouse model of achondroplasia has its complexities, but it’s not too time consuming or excessively expensive. What we need now is to have a developer interested in pursuing responses for the natural question one is able to make: there is a mutated protein causing a condition that produces a lot of undesired clinical consequences, for which there is no treatment available. It has a mapped function and most of all, it works mainly in a single cell type (the chondrocyte), in a single tissue (the growth plate). I have an antibody to inhibit this protein. Why don’t test it, to see if would be useful to treat this condition?
You see, it is always a matter of will.
Trudel S et al. A Phase I Study of the Safety and Pharmacokinetics of Escalating Doses of MFGR1877S, a Fibroblast Growth Factor Receptor 3 (FGFR3) Antibody, in Patients with Relapsed or Refractory t(4;14)-Positive Multiple MyelomaBlood (ASH Annual Meeting Abstracts) 2012 120: Abstract 4029. (free access)