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stephen-guilfoy
Team TFS
Team TFS
Antibody analysisQuick question: what is a monoclonal antibody? What does it really do? If you already work in biotherapeutics, or if your high-school biology is within memory then you may know. But for the rest of us, do we really know? I’m a physicist by training so my view of an antibody is very naïve; that they are blobby killer monsters, much like the way that white blood cells are portrayed in the 1987 film, Inner Space.

Clearly my understanding is flawed, so I decided to do some investigating into what these important molecules really are, and how proteins are characterized, and also what the future looks like for them. According to Wikipedia, antibodies (link to article) are… “large Y-shape protein produced by plasma cells, used by the immune system to identify and neutralize pathogens”. So does that make them little monsters or benign helpers? As it happens, a bit of both!

 

How do Biotherapeutic Antibodies Work?


In order to understand a little more about the effect I spoke to my contacts in the industry, specifically Christian Luber from Novo Nordisk, and my contacts at The National Institute for Bioprocessing Research & Training. Apparently the key to understanding the way that these biotherapeutic antibodies work is to understand what their application is. Firstly, and probably the most widely known, are those that are used simply to mark certain cells for the destruction of the body’s own defenses. Christian likened it to planting a flag in the cell and saying, “OK guys, come and get it!” in the same way that you would use carrion to attract a shark. Obviously the big difference here being that instead of attracting sharks, we are attracting those bodily defenses, which have glorious names, such as Killer T-cells. Some of the better-known cancer therapies use this system, including Trastuzumab (trade name Herceptin, first developed by Genentech), a common treatment for certain types of breast cancer. There’s a good application note about monoclonal antibody characterization (link to PDF) that specifically talks about the difficulties and solutions when characterizing this product.

 

Antibodies & Autoimmune Diseases


The other common usage for monoclonal antibodies is in the treatment of autoimmune diseases, by which I mean those diseases caused by an overreaction from your own bodily defences. Rheumatoid arthritis is a well known example, and would you believe that the best selling drug in the world (link to article) by dollar value is a treatment for this condition? Yep, Humira is worth a stunning $10.7 billion dollars a year to Abbvie. So those nasty antibodies are actually pretty good money makers! For ailments of this kind, the monoclonal antibody acts to “block” the activity of the source of inflammation, which in the case of arthritis are called inflammatory cytokines. The antibody binds to the inflammatory cytokine and prevents it causing further inflammation. Still not sounding so bad are they?

But not so fast… It turns out that our monoclonal antibodies do have a nastier side. Meet antibody drug conjugates (ADCs). These are from a world where old-school pharma (the small molecules) meets biopharma (the big stuff like our antibodies). They consist of our old friend the monoclonal antibody, but with an active pharmaceutical attached. The modus operandi of these drugs is quite different. The antibody still acts as the locator for the target cell, but it doesn’t stop there. Once the antibody has located the cell it can then deliver the active drug, known sometimes in the industry as the payload. The payload is typically extremely concentrated and very powerful, and usually has the role of causing the death of the cell (more politely known as aptosis). These particular antibodies are potentially even harder than usual to characterize, but luckily we have HPLC columns that are great at ADC chromatographic separation (Thermo Scientific MAbPac HIC-Butyl HPLC column).

Now you can see the less friendly side of the monoclonal antibody! I’ll make these little warriors the subject of a later blog, as I think they are worthy of more discussion and the market predictions for them are very promising. There are lots of interesting reports about their future (unfortunately, the reports are rarely free) but there are good online guides and a great place to start for information is the Journal of Antibody Drug Conjugates (link to website).

 

Challenges of Regulating Biosimilars


My final subject is the issue of biosimilars, by which I mean biotherapeutic drugs that are copies of a biological drug that is no longer protected by patent. Here it gets a little murky, as it seems that even the regulators are not entirely sure about. If you take a look at the European Medicine Agency’s guidelines: Scientific Guidelines on Biosimilar Medicines (link to article), it’s clear that the issue is still hazy. It gets worse at the U.S. Food and Drug Administration, when talking about the structure of such proteins, including Post Translational Modifications (PTMs) and aggregates, the article, titled, Potential Need for Measurement Standards, (link to online article), states that “FDA has identified three properties of therapeutic proteins that cannot be sufficiently measured at this time but that are very important for understanding the behavior of protein drugs”.

So… that leaves us where exactly? I think that all of this just goes to show that we really are in the early stages of the biotherapeutic revolution, and once the really successful monoclonal antibodies start coming off patent then the regulators will have to be more descriptive with the guidelines. But these biotherapeutics will keep on coming, the rewards are great, both clinically and financially. Monsters or not, monoclonal antibodies are here to stay.

 

Do you have any insight into monoclonal antibodies, especially ADCs or biosimilars? If so, please let us know.