A few of the basics
Achondroplasia is the most common form of disproportionate dwarfism. Its prevalence is of about 1/25000 births. It is caused by a simple mutation in a protein called fibroblast growth factor receptor 3 (FGFR3). FGFR3 is an enzyme that is produced in significant amounts by almost one type of cell in the growing body, the chondrocyte living in the growth plate of the long bones. Chondrocytes are the masters of bone growth. Through a very complex growth program they awake from a dorment state, undergo rapid multiplication and enlargement and expand the long bones by building a scaffold of cartilage that is later substituted by bone (1). The growth program is tightly regulated by dozens of agents, many of them "telling" the chondrocyte to grow (1). However, the growth program also includes some growth inhibitors or brakes and one of them is FGFR3. So, FGFR3 naturally works as a brake in the growth program. If there was no FGFR3 bones would grow excessively, also resulting in clinical complications (2).
In achondroplasia, due to the mutation, FGFR3 is working much more than normal, and this leads to significant bone growth impairment. Translating this effect to the real world, the mutation does not allow the body to grow proportionally and this results in a series of clinical complications, from neurological symptoms due to spinal cord compression, respiratory distress and repeated ear infections in childhood to several and potentially disabilitating orthopedic manifestations later in life (1).
You can learn more about achondroplasia visiting earlier pages of this blog. Just look at your preferred language index page on the top menu. This will help you to not feel lost with the technical information in the more recent pages, specially if you are coming for the first time.
Antibodies fight diseases
Antibodies are a standard strategy employed by our immune system to block foreign agents. Let's give an example. When our body is exposed to a virus, such as the Flu one, some of the white cells start producing a kind of protein called immunoglobulin (the antibody) that is specifically designed to block the virus. This is very efficient and helps other cells of the immune system to clear the virus from the body.
Science has been using antibodies to treat diseases for a long time now. Some of these antibodies have changed the history of several difficult diseases in the last ten years. For instance, trastuzumab, an antibody created to block an enzyme similar to FGFR3 has changed the fate of many women with breast cancer. Belimumab is an unique antibody designed to control an important molecule active in systemic lupus erythematosus, a complex autoimmune disease that causes a lot of severe complications in the affected individuals.
Many other syntetic antibodies have been generated in the last decade, targeting a high number of proteins in the body that have been associated with many human diseases. This is also true in the case of FGFR3
Blocking FGFR3 with antibodies
Bioclin, a small biotech from the Bay Area in California has announced it has just started the phase 2 study of B-701, a specific antibody targeting FGFR3, in advanced bladder cancer. It has posted in their website that this antibody is being also evaluated for achondroplasia, in pre-clinical settings.
As mentioned before, antibodies against FGFR3 are not a new development. The first one was described more than 10 years ago by the pioneer group of Dr. Avner Yayon (ProChon/ProCore). In 2003, his group published a compelling review of achondroplasia, where they discussed almost all therapy strategies to beat the overactive FGFR3 to restore normal, or near to normal growth in affected children, including the use of antibodies (3). They mentioned not only the advantages of using this strategy, such as the possibility to obtain high affinity for the mutated receptor and specificity but also the challenges as well, including their large size (classic antibodies are very large). Nevertheless, they developed a series of antibody fragments (named Fabs), which were described later in another study (4). A couple of years later their work resulted in the development of the antibody PRO-001, which was being tested for some types of cancer that use FGFR3 to progress.
You can stop here and consult one of the blog`s articles that review the bone growth plate, which will help you to understand why large molecules are not welcome there.
Well, there are already at least two other known good anti-FGFR3 candidate antibodies, MFGR1877S,
Genentech and IMC-D11,
ImClone, both developed for the combat of FGFR3-dependent cancers. We have already reviewed them in other articles. Neither of them has been explored for achondroplasia, or at least no information has been published about it.
The thing is that a classic antibody is too large to travel across the growth plate and reach FGFR3. It is difficult to say this new one would be capable of without knowing a bit more about it composition. Bioclin doesn't reveal the kind of antibody B-701 is. I also couldn't find any information about a patent related to B-701. It looks like we will need to wait for more information before assuming it will be efficient for achondroplasia.
News about vosoritide (BMN-111)
Biomarin has just updated the information about the phase 2 study with vosoritide (BMN-111) in ClinicalTrials.gov. Among other information it has included a description of the 4th and 5th cohorts and reviewed inclusion and exclusion criteria. Furthermore, in the last two public conferences, Biomarin confirmed the plan to start the phase 3 study in the first quarter of 2016. They also mentioned they are now in conversation with both FDA and EMA to align some pieces of the study, such as its duration, six months or one year. Possibly, they are also trying to define which will be the dose to be tested, the one identified during the phase 2 (15 mcg/kg) or one of those of the newest cohorts. The fourth cohort has just started. Perhaps they will wait to see its results before commencing the new study. It is relevant to note that the 4th cohort is active now, implying that the drug keeps not showing safety issues. To learn more about vosoritide, pay a visit to this recent article.
1. Narayana J and Horton WA. FGFR3 biology and skeletal disease. Connect Tissue Res 2015;19:1-7.
2. Makrythanasis P et
al. A novel homozygous mutation in FGFR3 causes tall stature, severe
lateral tibial deviation, scoliosis, hearing impairment, camptodactyly,
and arachnodactyly. Hum Mutat 2014;35(8):959-63.
3. Aviezer D et al. Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia-genetic short limbed dwarfism. Curr Drug Targets 2003;4(5):353-65.
4. Rauchenberger R et al. Human combinatorial Fab library yielding specific and functional antibodies against the human fibroblast growth factor receptor 3. J Biol Chem 2003; 278 (40):38194–205. Free access.