Therapeutics – just a different name for medicine. And protein therapeutics is just another type of medicine we use to save and prolong lives, just as for example antihypertensives or anticoagulants.
Admittingly, proteins used in medicine are not that known, as for example warfarin, perhaps the most popular anticoagulant.
With exception of insulin of course. So what are protein therapeutics and what makes them so different from "normal" medicine?
Proteins are almost a completely new world when it comes to production, storage or administration to patients. Only 25 years ago a first recombinant protein therapeutic – human insulin – was introduced, yet today protein therapy is one of the most developing fields in pharmacy (1) Despite the enormous efforts of scientists over more decades we are only just taking a peek into the full potential of this new class of medicine.
And we still have a lot to learn.
So, medicine. How do you produce it? What is it?
In pharmacy we obtain different chemical compounds with healing properties from various sources. Early in history of medicine the plants were the most common source of remedies – a term chemical synthesis was not so well defined back then. Of course people kept experimenting and gradually building up knowledge until reaching the level where we didn't have to rely solely on experience i.e. that plant killed the neighbour when he cooked it, but the one with yellow flowers healed the my cousin's cough.
It took a lot of time to figure out "what" was the thing that healed. One of the pioneers on that field was Paul Ehrlich which made the term "Magic Bullet" popular. In his opinion there must be a chemical compound that would selectively kill the bacteria yet not harm the human tissue. Inspired by colouring agents used to stain bacteria for microscopy he soon developed Salvarsan for treating Syphilis. It was one of the most widely prescribed drug after being put on market in 1910 and until production of penicillin in 1940.
To sum it up, medicine or API (active pharmaceutical ingredient), the compound is the one that does the "healing". It all comes down to chemistry. Even in remedies deriving from the plants, for example to cure malaria – it is a chemical "quinine" that kills the parasite plasmodium falciparum. (Bark from the cinchona tree was historically used as antimalarial agent, since it contained quinine).
Many API are nowadays chemically synthesized in labs, strict regulations, careful handling and constant testings allow us to always have a safe pill in the pharmacy whenever we feel sick… and at low cost. What more could we possibly want?
Figure 1: Exercise from Pharmaceutical Chemistry, a simple distillation, in one of the laboratories of Faculty of Pharmacy, Ljubljana. Courtesy of Rok Kelher.
How about proteins then?
It is slightly more complicated. The mechanism of action for previously described compounds can be really simple. Sometimes it is a matter of whether the compound can fit into a gap or hole in the enzyme. If it fits correctly it can slow down or accelerate it, and thus affecting the patient via changed metabolism or similar.
With proteins however, one needs to bear in mind that we are made of proteins. They are usually much, much bigger than the "traditional chemical compounds" and quite often extremely specific.
In order to treat patients we can either supply the patient with protein that he is unable to produce (for example insulin), develop immune protection of the patient (vaccination) or target "special targets" in the body. The following classification may shed some light on the whole matter: (1)
Group I: protein therapeutics with enzymatic or regulatory activity
• Ia: Replacing a protein that is deficient or abnormal.
• Ib: Augmenting an existing pathway.
• Ic: Providing a novel function or activity.
Group II : protein therapeutics with special targeting activity
• IIa: Interfering with a molecule or organism.
• IIb: Delivering other compounds or proteins.
Group III : protein vaccines
• IIIa: Protecting against a deleterious foreign agent.
• IIIb: Treating an autoimmune disease.
• IIIc: Treating cancer.
The following classification was taken from the article "Protein therapeutics: a summary and pharmacological classification" by Benjamin Leader, Quentin J. Baca and David E. Golan, published in Nature Reviews 2008. For further info see the references.
There is the sheer amount of different proteins that we could theoretically produce – current estimation is that there are 30,000 – 40,000 different genes in human genome (2), resulting in much higher number of possible proteins. However, there are few other characteristic that sets them apart from small molecule drugs. They are generally extremely difficult to produce, costly and unstable.
For example it often requires genetical engineering, usually bacteria or yeast. By changing their DNA we trick them into producing the proteins we want. Afterwards they need to be somehow isolated and purified so that no other hazardous remains of the previous hosts would inflict injuries to the patients. Purification is therefore a very important step in pharmaceutical industry.
It is quite obvious that running a bioreactor, growing bacteria, purifying the protein and handling it with extreme care in sterile conditions is somewhat more expensive then running a chemical reaction even if it consists of multiple steps.
Administration to the patient
Perhaps you are familiar with how the insulin is administered. There are no insulin pills because being a protein it would get digested in our stomach (although scientists are busy trying to change that, for example Novo Nordisk was working on "oral insulin" (3). The protein therapeutics still have to be injected, which causes discomfort to the patient. Injection is not where the problems stop however. Many factors such as distribution through the body, degradation and clearance play an important factor in making things more complicated.
An area of intensive research. Depending on the protein, they may prefer sticking together instead of remaining dissolved in the water. So called aggregation or fibrillation is a nightmare of every scientist working in protein production. Insoluble aggregates are simply useless for the patient, not to mention that smaller so called subvisible particles are often immunogenic. (4)
The proteins offer a lot, yet they are also demanding. They are probably never going to replace traditional, small molecule medicine synthesised in chemical laboratories because of huge difference in cost. Nevertheless they will continue to address number of illnesses that would otherwise be incurable as we discover more and more protein therapeutics. One of the most interesting and promising areas is definitely cancer research.
1. Benjamin Leader, Quentin J. et al. Protein therapeutics: a summary and pharmacological classification. Nature Reviews, vol 7, January 2008
2. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
3. Novo Nordisk article about the pursuit of oral insulin.
4. Subvisible Particle Content, Formulation, and Dose of an Erythropoietin Peptide Mimetic Product Are Associated With Severe Adverse Postmarketing Events., DOI: 10.1016/S0022-3549(15)00180-X