Chapter 8: Biologicals versus small molecules
Size and complexity
In 1860, acetylsalicylic acid (ASA, aspirin) is developed. This is a small molecule consisting of 21
atoms. In 1950 the human growth hormone (hGH) is developed and it consist of 3000 atoms, so
much bigger than aspirin. In 1990 the immunoglobulin G (IgG) antibody is developed, this consists of
25000 atoms. This is a murine antibody for human use. The biologicals are bigger then 5 kDa,
however, they are more than big chemicals.
Biologicals are not just “big chemicals”
Small molecule drugs Biologicals
Structure (Relatively) simple and well-defined Complex (heterogeneous)
Characterization Easy to characterize Complete characterization is not possible
Manufacturing Defined chemical synthesis Produced in living cells
Identical copy can be made Control of process is challenging
Identical copy is not possible
Stability Relatively stable Sensitive to external conditions (heat,
light, agitation, …)
Biologicals – What’s in a name
There are different definitions known for biologicals, because there is not one straight forward
definition for biologicals.
A diverse category of products, generally large, complex molecules. These products may be
produced through biotechnology in a living system, such as a microorganism, plant cell, or
animal cell, and are often more difficult to characterize than small molecule drugs (FDA)
A medicine whose active substance is made by a living organism (EMA)
Products derived from characterized cells through the use of a variety of expression systems
including bacteria, yeast, insect, plant, and mammalian cells. The active substances include
proteins and peptides, their derivatives and products of which they are components; they
could be derived from cell cultures or produced using recombinant DNA technology including
production by transgenic plants and animals (ICH guideline)
A protein is a specific regulatory or enzymatic function, for example human insulin. They cannot be
produced by small molecules. The proteins are expensive, so peptides are used in between small
molecules and biologicals. A vaccine is prophylactic (in COVID) or therapeutic (cancer vaccine, it
thrives epic genetic changes in the cancer cells which can treat resistant tumors). In addition, RNAi is
also a biological: it is based on the biological mechanisms where RNA interferes in case of external
invasion.
So, it is not black and white whether a drug is a biological or not. The vaccines can be DNA and RNA
based: they use fragments of the DNA of the virus and inject these in our body. Now we have
multiple copies of the spike protein and this gives us protection the next time when we are infected
with the virus. The adenovirus carries the spike protein of the COVID-19 is an example of a virus
vector. The adenovirus infects our cells which gives a strong immune response. This gives more
protection when the real COVID-19 virus enters the body. mRNA uses nucleosides as building blocks
and they are synthesized chemically. mRNA is degraded by the external environment, this is more
about the biologicals. But, there is a grey zone if mRNA vaccines are biologicals or not. So, in a
straight-line which things are a biological and which are not. The antiviral agents are small
molecules. The antibodies are for example directed against the spike protein of COVID-19. This
prevents the virus of adhering to our cells, and our cells cannot be infected anymore.
Antibodies – Immunoglobulins (Igs)
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